U.S. patent application number 10/952536 was filed with the patent office on 2005-07-21 for stimulation for treating and diagnosing conditions.
This patent application is currently assigned to BRAINSGATE LTD.. Invention is credited to Shalev, Alon.
Application Number | 20050159790 10/952536 |
Document ID | / |
Family ID | 32312162 |
Filed Date | 2005-07-21 |
United States Patent
Application |
20050159790 |
Kind Code |
A1 |
Shalev, Alon |
July 21, 2005 |
Stimulation for treating and diagnosing conditions
Abstract
A method is provided for facilitating a diagnosis of a condition
of a subject, including applying a current to a site of the subject
selected from the list consisting of: a sphenopalatine ganglion
(SPG) of the subject, and a neural tract originating in or leading
to the SPG, and configuring the current to increase conductance of
molecules from brain tissue of the subject through a blood brain
barrier (BBB) of the subject into a systemic blood circulation of
the subject. The method also includes sensing a quantity of the
molecules from a site outside of the brain of the subject,
following initiation of application of the current.
Inventors: |
Shalev, Alon; (Ra'anana,
IL) |
Correspondence
Address: |
DARBY & DARBY P.C.
P. O. BOX 5257
NEW YORK
NY
10150-5257
US
|
Assignee: |
BRAINSGATE LTD.
Ra'anana
IL
|
Family ID: |
32312162 |
Appl. No.: |
10/952536 |
Filed: |
September 27, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10952536 |
Sep 27, 2004 |
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PCT/IL03/00508 |
Jun 13, 2003 |
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10952536 |
Sep 27, 2004 |
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10294310 |
Nov 14, 2002 |
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10952536 |
Sep 27, 2004 |
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10783113 |
Feb 20, 2004 |
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10952536 |
Sep 27, 2004 |
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10258714 |
Jan 22, 2003 |
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10258714 |
Jan 22, 2003 |
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PCT/IL01/00402 |
May 7, 2001 |
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10952536 |
Sep 27, 2004 |
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PCT/IL03/00338 |
Apr 25, 2003 |
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60388931 |
Jun 14, 2002 |
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60400167 |
Jul 31, 2002 |
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60364451 |
Mar 15, 2002 |
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60506165 |
Sep 26, 2003 |
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60203172 |
May 8, 2000 |
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60376048 |
Apr 25, 2002 |
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60461232 |
Apr 8, 2003 |
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60506165 |
Sep 26, 2003 |
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Current U.S.
Class: |
607/45 |
Current CPC
Class: |
A61M 5/14276 20130101;
A61N 1/36046 20130101; A61N 1/0526 20130101; A61M 5/1723 20130101;
A61M 2210/0693 20130101; A61M 2205/3303 20130101; A61M 2210/0618
20130101; A61N 1/0546 20130101; A61N 1/0548 20130101 |
Class at
Publication: |
607/045 |
International
Class: |
A61N 001/18 |
Claims
1. A method for facilitating a diagnosis of a condition of a
subject, comprising: applying a current to a site of the subject
selected from the list consisting of: a sphenopalatine ganglion
(SPG) of the subject, and a neural tract originating in or leading
to the SPG; configuring the current to increase conductance of
molecules from brain tissue of the subject through a blood brain
barrier (BBB) of the subject into a systemic blood circulation of
the subject; and sensing a quantity of the molecules from a site
outside of the brain of the subject, following initiation of
application of the current.
2. The method according to claim 1, wherein sensing the quantity of
the molecules comprises sampling a fluid of the subject selected
from the list consisting of: blood, plasma, serum, ascites fluid,
and urine.
3. The method according to claim 1, comprising determining a
diagnostically-relevant parameter responsive to sensing the
quantity of the molecules.
4. The method according to claim 1, comprising administering a
hyperosmolarity-inducing agent to the subject at a dosage
sufficient to augment an increase in conductance of the molecules
caused by the application of the current.
5. The method according to claim 1, comprising inducing a state of
dehydration of the subject, of an extent sufficient to augment an
increase in conductance of the molecules caused by the application
of the current.
6. The method according to claim 1, comprising administering an
agent to the subject that modulates synthesis or metabolism of
nitric-oxide (NO) in blood vessels of the brain, at a dosage
sufficient to augment an increase in conductance of the molecules
caused by the application of the current.
7. The method according to claim 1, wherein applying the current
comprises implanting an electrode at the site, designated to remain
in the subject for a period greater than about one month.
8. The method according to claim 1, wherein applying the current
comprises implanting an electrode at the site, designated to remain
in the subject for a period less than about one week.
9. The method according to claim 1, wherein applying the current
comprises implanting a control unit in a nasal cavity of the
subject.
10. The method according to claim 1, wherein applying the current
comprises implanting a control unit at a lower side of a bony
palate of the subject.
11. The method according to claim 1, wherein applying the current
comprises implanting one or more electrodes in a nasal cavity of
the subject.
12. The method according to claim 11, wherein implanting comprises
inserting a flexible electrode through a nostril of the
subject.
13. A method for facilitating a diagnosis of a condition of a
central nervous system (CNS) of a subject, comprising: stimulating
sphenopalatine ganglion (SPG)-related tissue of the subject by
applying an electrical signal to the SPG-related tissue, the
SPG-related tissue selected from: an SPG of the subject and nerve
fibers of the subject which are directly anatomically connected to
the SPG; and configuring the stimulation so as to cause an increase
in molecular passage between the CNS and another body compartment
of the subject, so as to facilitate the diagnosis of the CNS
condition.
14. The method according to claim 13, comprising measuring a
constituent of the other body compartment.
15. The method according to claim 14, wherein stimulating the
SPG-related tissue comprises directly stimulating the SPG.
16. The method according claim 14, wherein the other body
compartment includes a systemic blood circulation of the subject,
and wherein configuring the stimulation comprises configuring the
stimulation so as to cause the increase in molecular passage
between the CNS and the systemic blood circulation.
17. The method according to claim 14, wherein the other body
compartment includes plasma of the subject, and wherein configuring
the stimulation comprises configuring the stimulation so as to
cause the increase in molecular passage between the CNS and the
plasma.
18. The method according to claim 14, wherein the other body
compartment includes serum of the subject, and wherein configuring
the stimulation comprises configuring the stimulation so as to
cause the increase in molecular passage between the CNS and the
serum.
19. The method according to claim 14, wherein the other body
compartment is ascites of the subject, and wherein configuring the
stimulation comprises configuring the stimulation so as to cause
the increase in molecular passage between the CNS and the
ascites.
20. The method according to claim 14, wherein the CNS condition
includes Parkinson's disease, and wherein configuring the
stimulation comprises configuring the stimulation so as to
facilitate the diagnosis of the Parkinson's disease.
21. The method according to claim 14, wherein the CNS condition
includes epilepsy, and wherein configuring the stimulation
comprises configuring the stimulation so as to facilitate the
diagnosis of the epilepsy.
22. The method according to claim 14, wherein the CNS condition
includes amyotrophic lateral sclerosis (ALS), and wherein
configuring the stimulation comprises configuring the stimulation
so as to facilitate the diagnosis of the ALS.
23. The method according to claim 14, wherein the CNS condition
includes multiple sclerosis (MS), and wherein configuring the
stimulation comprises configuring the stimulation so as to
facilitate the diagnosis of the MS.
24. The method according to claim 14, wherein stimulating the
SPG-related tissue comprises implanting an electrode at the site,
designated to remain in the subject for a period greater than about
one month.
25. The method according to claim 14, wherein stimulating the
SPG-related tissue comprises implanting an electrode at the site,
designated to remain in the subject for a period less than about
one week.
26. The method according to claim 14, wherein stimulating the
SPG-related tissue comprises implanting a control unit in a nasal
cavity of the subject.
27. The method according to claim 14, wherein stimulating the
SPG-related tissue comprises implanting a control unit at a lower
side of a bony palate of the subject.
28. The method according to claim 14, comprising correlating an
abnormal concentration of the constituent to a pathology of the CNS
condition.
29. The method according to claim 14, wherein the constituent is
selected from the group consisting of: a protein, a honnone, an
antibody, an electrolyte, a neuropeptide, and an enzyme, and
wherein measuring the constituent comprises measuring the selected
constituent.
30. A method for facilitating a diagnosis of a condition of a
central nervous system (CNS) of a subject, comprising: stimulating
sphenopalatine ganglion (SPG)-related tissue of the subject by
applying an electrical signal to the SPG-related tissue, the
SPG-related tissue selected from: an SPG of the subject and nerve
fibers of the subject which are directly anatomically connected to
the SPG; and configuring the stimulation so as to cause an increase
in molecular passage between cerebrospinal fluid (CSF) of the
subject and another body fluid of the subject, so as to facilitate
the diagnosis of the CNS condition.
31. The method according to claim 30, comprising measuring a
constituent of the other body fluid.
32. The method according to claim 31, wherein stimulating the
SPG-related tissue comprises directly stimulating the SPG.
33. The method according to claim 31, comprising correlating an
abnormal concentration of the constituent to a pathology of the CNS
condition.
34. The method according to claim 31, wherein the constituent is
selected from the group consisting of: a protein, a hormone, an
antibody, an electrolyte, a neuropeptide, and an enzyme, and
wherein measuring the constituent comprises measuring the selected
constituent.
35. The method according to claim 31, wherein the other body fluid
is selected from the list consisting of: whole blood, plasma,
serum, and ascites, and wherein measuring the constituent comprises
sampling the selected fluid.
36. The method according to claim 31, wherein measuring the
constituent comprises extracting the other body fluid from tissue
of the subject.
37. The method according to claim 31, wherein applying the current
comprises implanting an electrode at the site, designated to remain
in the subject for a period greater than about one month.
38. The method according to claim 31, wherein applying the current
comprises implanting an electrode at the site, designated to remain
in the subject for a period less than about one week.
39. The method according to claim 31, wherein applying the current
comprises implanting a control unit in a nasal cavity of the
subject.
40. The method according to claim 31, wherein applying the current
comprises implanting a control unit at a lower side of a bony
palate of the subject.
41. The method according to claim 31, wherein measuring the
constituent comprises measuring a plurality of constituents.
42. The method according to claim 41, comprising determining a
diagnostic result according to the interrelation between
concentrations of the constituents.
43. A method for facilitating a diagnosis of a condition of a
central nervous system (CNS) of a subject, comprising: stimulating
sphenopalatine ganglion (SPG)-related tissue of the subject by
applying an electrical signal to the SPG-related tissue, the
SPG-related tissue selected from: an SPG of the subject and nerve
fibers of the subject which are directly anatomically connected to
the SPG; and configuring the stimulation so as to cause an increase
in molecular passage between cerebrospinal fluid (CSF) of the
subject and a tissue of the subject, so as to facilitate a
diagnosis of the CNS condition.
44. The method according claim 43, comprising measuring a
constituent of the tissue.
45. The method according to claim 44, wherein stimulating the
SPG-related tissue comprises directly stimulating the SPG.
46. The method according to claim 44, comprising correlating an
abnormal concentration of the constituent to a pathology of the CNS
condition.
47. The method according to claim 44, wherein the constituent is
selected from the group consisting of: a protein, a hormone, an
antibody, an electrolyte, a neuropeptide, and an enzyme, and
wherein measuring the constituent comprises measuring the selected
constituent.
48. The method according to claim 44, wherein measuring the
constituent comprises measuring a plurality of constituents of the
tissue.
49. The method according to claim 48, comprising determining a
diagnostic result according to the interrelation between
concentrations of the constituents of the tissue.
50. A method for facilitating a diagnosis of a condition of a
central nervous system (CNS) of a subject, comprising: applying an
electrical signal to at least one site of the subject, the site
selected from the list consisting of: a sphenopalatine ganglion
(SPG) of the subject, an anterior ethmoidal nerve of the subject, a
posterior ethmoidal nerve of the subject, a communicating branch
between an anterior ethmoidal nerve and a retro-orbital branch of
an SPG of the subject, a communicating branch between a posterior
ethmoidal nerve and a retro-orbital branch of an SPG of the
subject, a greater palatine nerve of the subject, a lesser palatine
nerve of the subject, a sphenopalatine nerve of the subject, a
communicating branch between a maxillary nerve and an SPG of the
subject, a nasopalatine nerve of the subject, a posterior nasal
nerve of the subject, an infraorbital nerve of the subject, an otic
ganglion of the subject, an afferent fiber going into the otic
ganglion of the subject, an efferent fiber going out of the otic
ganglion of the subject, a vidian nerve of the subject, a greater
superficial petrosal nerve of the subject, and a lesser deep
petrosal nerve of the subject; and configuring the signal so as to
cause an increase in molecular passage between the CNS and another
body compartment of the subject, so as to facilitate a diagnosis of
the CNS condition.
51. The method according claim 50, comprising measuring a
constituent of the other body compartment.
52. A method for facilitating a diagnosis of a condition of a
central nervous system (CNS) of a subject, comprising: applying an
electrical signal to at least one site of the subject, the site
selected from the list consisting of: a sphenopalatine ganglion
(SPG) of the subject, an anterior ethmoidal nerve of the subject, a
posterior ethmoidal nerve of the subject, a communicating branch
between an anterior ethmoidal nerve and a retro-orbital branch of
an SPG of the subject, a communicating branch between a posterior
ethmoidal nerve and a retro-orbital branch of an SPG of the
subject, a greater palatine nerve of the subject, a lesser palatine
nerve of the subject, a sphenopalatine nerve of the subject, a
communicating branch between a maxillary nerve and an SPG of the
subject, a nasopalatine nerve of the subject, a posterior nasal
nerve of the subject, an infraorbital nerve of the subject, an otic
ganglion of the subject, an afferent fiber going into the otic
ganglion of the subject, an efferent fiber going out of the otic
ganglion of the subject, a vidian nerve of the subject, a greater
superficial petrosal nerve of the subject, and a lesser deep
petrosal nerve of the subject; and configuring the signal so as to
cause an increase in molecular passage between cerebrospinal fluid
(CSF) of the subject and another body fluid of the subject, so as
to facilitate a diagnosis of the CNS condition.
53. The method according claim 52, comprising measuring a
constituent of the other body fluid.
54. A method for facilitating a diagnosis of a condition of a
central nervous system (CNS) of a subject, comprising: applying an
electrical signal to at least one site of the subject, the site
selected from the list consisting of: a sphenopalatine ganglion
(SPG) of the subject, an anterior ethmoidal nerve of the subject, a
posterior ethmoidal nerve of the subject, a communicating branch
between an anterior ethmoidal nerve and a retro-orbital branch of
an SPG of the subject, a communicating branch between a posterior
ethmoidal nerve and a retro-orbital branch of an SPG of the
subject, a greater palatine nerve of the subject, a lesser palatine
nerve of the subject, a sphenopalatine nerve of the subject, a
communicating branch between a maxillary nerve and an SPG of the
subject, a nasopalatine nerve of the subject, a posterior nasal
nerve of the subject, an infraorbital nerve of the subject, an otic
ganglion of the subject, an afferent fiber going into the otic
ganglion of the subject, an efferent fiber going out of the otic
ganglion of the subject, a vidian nerve of the subject, a greater
superficial petrosal nerve of the subject, and a lesser deep
petrosal nerve of the subject; and configuring the signal so as to
cause an increase in molecular passage between cerebrospinal fluid
(CSF) of the subject and a tissue of the subject, so as to
facilitate a diagnosis of the CNS condition.
55. The method according claim 54, comprising measuring a
constituent of the tissue.
56. A method for facilitating a diagnosis of a condition of a
central nervous system (CNS) of a subject, the method comprising:
stimulating at least one site of the subject by applying an
electrical current to the site, the site selected from the list
consisting of: a sphenopalatine ganglion (SPG) of the subject, an
anterior ethmoidal nerve of the subject, a posterior ethmoidal
nerve of the subject, a communicating branch between the anterior
ethmoidal nerve and the SPG, a communicating branch between the
posterior ethmoidal nerve and the SPG, a nerve of the pterygoid
canal of the subject, a greater palatine nerve of the subject, a
lesser palatine nerve of the subject, a sphenopalatine nerve of the
subject, a communicating branch between a maxillary nerve of the
subject and the SPG, a nasopalatine nerve of the subject, a
posterior nasal nerve of the subject, an infraorbital nerve of the
subject, an otic ganglion of the subject, an afferent fiber going
into the otic ganglion, and an efferent fiber going out of the otic
ganglion; configuring the stimulation so as to cause an increase in
molecular passage between the CNS and another body compartment of
the subject; taking a sample from the body compartment; and
determining a level of a constituent of the sample, so as to
facilitate the diagnosis of the CNS condition.
57. The method according to claim 56, wherein the CNS condition
includes a neurodegenerative condition, and wherein determining the
level of the constituent comprises determining the level of the
constituent so as to facilitate the diagnosis of the
neurodegenerative condition.
58. The method according to claim 56, wherein the CNS condition
includes a neoplastic process, and wherein determining the level of
the constituent comprises determining the level of the constituent
so as to facilitate the diagnosis of the neoplastic process.
59. The method according to claim 56, wherein the CNS condition is
selected from the list consisting of: an immune-related disorder
and an autoimmune-related disorder, and wherein determining the
level of the constituent comprises determining the level of the
constituent so as to facilitate the diagnosis of the selected
condition.
60. The method according to claim 56, wherein the CNS condition
includes a CNS inflammatory process, and wherein determining the
level of the constituent comprises determining the level of the
constituent so as to facilitate the diagnosis of the CNS
inflammatory process.
61. The method according to claim 56, comprising interpreting a low
value of the level as indicative of an increased likelihood that
the subject suffers from the CNS condition.
62. The method according to claim 61, comprising interpreting a
high value of the level as indicative of a decreased likelihood
that the subject suffers from the CNS condition.
63. The method according to claim 61, wherein the body compartment
includes a systemic blood circulation of the subject, and wherein
configuring the stimulation comprises configuring the stimulation
so as to cause the increase in molecular passage between the CNS
and the systemic blood circulation.
64. The method according to claim 61, wherein the body compartment
includes plasma of the subject, and wherein configuring the
stimulation comprises configuring the stimulation so as to cause
the increase in molecular passage between the CNS and the
plasma.
65. The method according to claim 61, wherein the body compartment
includes serum of the subject, and wherein configuring the
stimulation comprises configuring the stimulation so as to cause
the increase in molecular passage between the CNS and the
serum.
66. The method according to claim 61, wherein the body compartment
is ascites of the subject, and wherein configuring the stimulation
comprises configuring the stimulation so as to cause the increase
in molecular passage between the CNS and the ascites.
67. The method according to claim 61, wherein the site includes the
SPG, and wherein stimulating the site comprises stimulating the
SPG.
68. The method according to claim 61 wherein the CNS condition
includes Alzheimer's disease, and wherein interpreting the low
value comprises interpreting the low value as indicative of the
increased likelihood that the subject suffers from Alzheimer's
disease.
69. The method according to claim 68, wherein the constituent
includes amyloid-beta peptide, and wherein determining the level of
the constituent comprises determining the level of the amyloid-beta
peptide.
70. The method according to claim 68, wherein the constituent
includes presenilin-1, and wherein determining the level of the
constituent comprises determining the level of the
presenilin-1.
71. A method for facilitating a diagnosis of a condition of a
central nervous system (CNS) of a subject, the method comprising:
stimulating at least one site of the subject selected from the list
consisting of: a sphenopalatine ganglion (SPG) of the subject, an
anterior ethmoidal nerve of the subject, a posterior ethmoidal
nerve of the subject, a communicating branch between the anterior
ethmoidal nerve and the SPG, a communicating branch between the
posterior ethmoidal nerve and the SPG, a nerve of the pterygoid
canal of the subject, a greater palatine nerve of the subject, a
lesser palatine nerve of the subject, a sphenopalatine nerve of the
subject, a communicating branch between a maxillary nerve of the
subject and the SPG, a nasopalatine nerve of the subject, a
posterior nasal nerve of the subject, an infraorbital nerve of the
subject, an otic ganglion of the subject, an afferent fiber going
into the otic ganglion, and an efferent fiber going out of the otic
ganglion; configuring the stimulation so as to cause an increase in
molecular passage between the CNS and another body compartment of
the subject; taking a sample from the body compartment; and
determining a level of a constituent of the sample, so as to
facilitate the diagnosis of the CNS condition.
72. The method according to claim 71, wherein the CNS condition
includes a neurodegenerative condition, and wherein determining the
level of the constituent comprises determining the level of the
constituent so as to facilitate the diagnosis of the
neurodegenerative condition.
73. The method according to claim 71, wherein the CNS condition
includes a neoplastic process, and wherein determining the level of
the constituent comprises determining the level of the constituent
so as to facilitate the diagnosis of the neoplastic process.
74. The method according to claim 71, wherein the CNS condition is
selected from the list consisting of: an immune-related disorder
and an autoimmune-related disorder, and wherein determining the
level of the constituent comprises determining the level of the
constituent so as to facilitate the diagnosis of the selected
condition.
75. The method according to claim 71, wherein the CNS condition
includes a CNS inflammatory process, and wherein determining the
level of the constituent comprises determining the level of the
constituent so as to facilitate the diagnosis of the CNS
inflammatory process.
76. The method according to claim 71, comprising interpreting a low
value of the level as indicative of an increased likelihood that
the subject suffers from the CNS condition.
77. The method according to claim 76, comprising interpreting a
high value of the level as indicative of a decreased likelihood
that the subject suffers from the CNS condition.
78. The method according to claim 76, wherein stimulating comprises
applying magnetic stimulation to the site.
79. The method according to claim 76, wherein stimulating comprises
applying electromagnetic stimulation to the site.
80. The method according to claim 76, wherein stimulating comprises
applying chemical stimulation to the site.
81. The method according to claim 76, wherein stimulating comprises
applying mechanical stimulation to the site.
82. The method according to claim 76, wherein the body compartment
includes a systemic blood circulation of the subject, and wherein
configuring the stimulation comprises configuring the stimulation
so as to cause the increase in molecular passage between the CNS
and the systemic blood circulation.
83. The method according to claim 76, wherein the body compartment
includes plasma of the subject, and wherein configuring the
stimulation comprises configuring the stimulation so as to cause
the increase in molecular passage between the CNS and the
plasma.
84. The method according to claim 76, wherein the body compartment
includes serum of the subject, and wherein configuring the
stimulation comprises configuring the stimulation so as to cause
the increase in molecular passage between the CNS and the
serum.
85. The method according to claim 76, wherein the body compartment
is ascites of the subject, and wherein configuring the stimulation
comprises configuring the stimulation so as to cause the increase
in molecular passage between the CNS and the ascites.
86. The method according to claim 76, wherein the site includes the
SPG, and wherein stimulating the site comprises stimulating the
SPG.
87. The method according to claim 76, wherein the CNS condition
includes Alzheimer's disease, and wherein interpreting the low
value comprises interpreting the low value as indicative of the
increased likelihood that the subject suffers from Alzheimer's
disease.
88. The method according to claim 87, wherein the constituent
includes amyloid-beta peptide, and wherein determining the level of
the constituent comprises determining the level of the amyloid-beta
peptide.
89. The method according to claim 87, wherein the constituent
includes presenilin-1, and wherein determining the level of the
constituent comprises determining the level of the
presenilin-1.
90. A method for treating a condition of a central nervous system
(CNS) of a subject, comprising: applying a current to a site of the
subject selected from the list consisting of: a sphenopalatine
ganglion (SPG) of the subject, and a neural tract originating in or
leading to the SPG; configuring the current to increase clearance
of molecules from brain tissue of the subject through a blood brain
barrier (BBB) of the subject into a systemic blood circulation of
the subject, so as to treat the CNS condition.
91. The method according to claim 90, wherein the molecules include
a toxin, and wherein configuring the current comprises configuring
the current to increase the clearance of the toxin from the brain
tissue, so as to treat the CNS condition.
92. The method according to claim 90, wherein applying the current
comprises implanting an electrode at the site, designated to remain
in the subject for a period greater than about one month.
93. The method according to claim 90, wherein applying the current
comprises implanting an electrode at the site, designated to remain
in the subject for a period less than about one week.
94. The method according to claim 90, wherein applying the current
comprises implanting a control unit in a nasal cavity of the
subject.
95. The method according to claim 90, wherein applying the current
comprises implanting a control unit at a lower side of a bony
palate of the subject.
96. A method for treating a condition of a central nervous system
(CNS) of a subject, comprising: stimulating sphenopalatine ganglion
(SPG)-related tissue of the subject by applying an electrical
signal to the SPG-related tissue, the SPG-related tissue selected
from: an SPG of the subject and nerve fibers of the subject which
are directly anatomically connected to the SPG; and configuring the
stimulation so as to cause an increase in clearance of a neurotoxic
compound from a brain of the subject through a blood brain barrier
(BBB) of the subject to a systemic blood circulation of the
subject, so as to treat the CNS condition.
97. The method according to claim 96, wherein stimulating the
SPG-related tissue comprises directly stimulating the SPG.
98. A method for treating a condition of a central nervous system
(CNS) of a subject, comprising: stimulating sphenopalatine ganglion
(SPG)-related tissue of the subject by presenting an odorant to an
air passage of the subject, the SPG-related tissue selected from:
an SPG of the subject and nerve fibers of the subject which are
directly anatomically connected to the SPG; and configuring the
stimulation so as to cause an increase in clearance of a neurotoxic
compound from a brain of the subject through a blood brain barrier
(BBB) of the subject to a systemic blood circulation of the
subject, so as to treat the CNS condition.
99. A method for treating a condition of a central nervous system
(CNS) of a subject, comprising: stimulating sphenopalatine ganglion
(SPG)-related tissue of the subject by applying an electrical
signal to the SPG-related tissue, the SPG-related tissue selected
from: an SPG of the subject and nerve fibers of the subject which
are directly anatomically connected to the SPG; and configuring the
stimulation so as to cause an increase in clearance of a neurotoxic
compound from cerebrospinal fluid (CSF) of the subject through a
blood brain barrier (BBB) of the subject to a systemic blood
circulation of the subject, so as to treat the CNS condition.
100. The method according to claim 99, wherein stimulating the
SPG-related tissue comprises directly stimulating the SPG.
101. A method for treating a condition of a central nervous system
(CNS) of a subject, comprising: stimulating sphenopalatine ganglion
(SPG)-related tissue of the subject by presenting an odorant to an
air passage of the subject, the SPG-related tissue selected from:
an SPG of the subject and nerve fibers of the subject which are
directly anatomically connected to the SPG; and configuring the
stimulation so as to cause an increase in clearance of a neurotoxic
compound from cerebrospinal fluid (CSF) of the subject through a
blood brain barrier (BBB) of the subject to a systemic blood
circulation of the subject, so as to treat the CNS condition.
102. Apparatus for facilitating a diagnosis of a condition of a
subject, comprising a stimulator adapted to: apply a current to a
site of the subject selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, and a neural tract
originating in or leading to the SPG, and configure the current to
increase conductance of molecules from brain tissue of the subject
through a blood brain barrier (BBB) of the subject into a systemic
blood circulation of the subject, so as to facilitate the diagnosis
of the condition.
103. The apparatus according to claim 102, wherein the stimulator
is adapted to directly stimulate the SPG.
104. The apparatus according to claim 102, wherein the apparatus is
adapted to measure a constituent of the other body compartment.
105. Apparatus for facilitating a diagnosis of a condition of a
central nervous system (CNS) of a subject, comprising a stimulator
adapted to: stimulate sphenopalatine ganglion (SPG)-related tissue
of the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG, and configure the stimulation so as to cause
an increase in molecular passage between the CNS and another body
compartment of the subject, so as to facilitate the diagnosis of
the CNS condition.
106. The apparatus according to claim 105, wherein the stimulator
is adapted to directly stimulate the SPG.
107. The apparatus according to claim 105, wherein the apparatus is
adapted to measure a constituent of the other body compartment.
108. The apparatus according to claim 107, wherein the other body
compartment includes a systemic blood circulation of the subject,
and wherein the apparatus is adapted to measure the constituent of
the systemic blood circulation.
109. The apparatus according to claim 107, wherein the other body
compartment includes plasma of the subject, and wherein the
apparatus is adapted to measure the constituent of the plasma.
110. The apparatus according to claim 107, wherein the other body
compartment includes serum of the subject, and wherein the
apparatus is adapted to measure the constituent of the serum.
111. The apparatus according to claim 107, wherein the other body
compartment is ascites of the subject, and wherein the apparatus is
adapted to measure the constituent of the ascites.
112. Apparatus for facilitating a diagnosis of a condition of a
central nervous system (CNS) of a subject, comprising a stimulator
adapted to: stimulate sphenopalatine ganglion (SPG)-related tissue
of the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG, and configure the stimulation so as to cause
an increase in molecular passage between cerebrospinal fluid (CSF)
of the subject and another body fluid of the subject, so as to
facilitate the diagnosis of the CNS condition.
113. The apparatus according to claim 112, wherein the stimulator
is adapted to directly stimulate the SPG.
114. The apparatus according to claim 112, wherein the apparatus is
adapted to measure a constituent of the other body fluid.
115. Apparatus for facilitating a diagnosis of a condition of a
central nervous system (CNS) of a subject, comprising a stimulator
adapted to: stimulate sphenopalatine ganglion (SPG)-related tissue
of the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG, and configure the stimulation so as to cause
an increase in molecular passage between cerebrospinal fluid (CSF)
of the subject and a tissue of the subject, so as to facilitate the
diagnosis of the CNS condition.
116. The apparatus according to claim 115, wherein the apparatus is
adapted to directly stimulate the SPG.
117. The apparatus according to claim 115, wherein the apparatus is
adapted to measure a constituent of the tissue.
118. Apparatus for facilitating a diagnosis of a condition of a
central nervous system (CNS) of a subject, comprising a stimulator
adapted to: apply an electrical signal to at least one site of the
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject, and
configure the signal so as to cause an increase in molecular
passage between the CNS and another body compartment of the
subject, so as to facilitate the diagnosis of the CNS
condition.
119. The apparatus according to claim 118, wherein the apparatus is
adapted to measure a constituent of the other body compartment.
120. Apparatus for facilitating a diagnosis of a condition of a
central nervous system (CNS) of a subject, comprising a stimulator
adapted to: apply an electrical signal to at least one site of the
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject, and
configure the signal so as to cause an increase in molecular
passage between cerebrospinal fluid (CSF) of the subject and
another body fluid of the subject, so as to facilitate the
diagnosis of the CNS condition.
121. The apparatus according to claim 120, wherein the apparatus is
adapted to measure a constituent of the other body fluid.
122. Apparatus for facilitating a diagnosis of a condition of a
central nervous system (CNS) of a subject, comprising a stimulator
adapted to: apply an electrical signal to at least one site of the
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject, and
configure the signal so as to cause an increase in molecular
passage between cerebrospinal fluid (CSF) of the subject and a
tissue of the subject, so as to facilitate the diagnosis of the CNS
condition.
123. The apparatus according to claim 122, wherein the apparatus is
adapted to measure a constituent of the tissue.
124. Apparatus for treating a condition of a central nervous system
(CNS) of a subject, comprising a stimulator adapted to: stimulate
sphenopalatine ganglion (SPG)-related tissue of the subject by
applying an electrical signal to the SPG-related tissue, the
SPG-related tissue selected from: an SPG of the subject and nerve
fibers of the subject which are directly anatomically connected to
the SPG, and configure the stimulation so as to cause an increase
in clearance of a neurotoxic compound from a brain of the subject
through a blood brain barrier (BBB) of the subject to a systemic
blood circulation of the subject, so as to treat the CNS
condition.
125. The apparatus according to claim 124, wherein the stimulator
is adapted to directly stimulate the SPG.
126. Apparatus for treating a condition of a central nervous system
(CNS) of a subject, comprising a stimulator adapted to: stimulate
sphenopalatine ganglion (SPG)-related tissue of the subject by
presenting an odorant to an air passage of the subject, the
SPG-related tissue selected from: an SPG of the subject and nerve
fibers of the subject which are directly anatomically connected to
the SPG, and configure the stimulation so as to cause an increase
in clearance of a neurotoxic compound from a brain of the subject
through a blood brain barrier (BBB) of the subject to a systemic
blood circulation of the subject, so as to treat the CNS
condition.
127. Apparatus for treating a condition of a central nervous system
(CNS) of a subject, comprising a stimulator adapted to: stimulate
sphenopalatine ganglion (SPG)-related tissue of the subject by
applying an electrical signal to the SPG-related tissue, the
SPG-related tissue selected from: an SPG of the subject and nerve
fibers of the subject which are directly anatomically connected to
the SPG, and configure the stimulation so as to cause an increase
in clearance of a neurotoxic compound from cerebrospinal fluid
(CSF) of the subject through a blood brain barrier (BBB) of the
subject to a systemic blood circulation of the subject, so as to
treat the CNS condition.
128. The apparatus according to claim 127, wherein the stimulator
is adapted to directly stimulate the SPG.
129. Apparatus for treating a condition of a central nervous system
(CNS) of a subject, comprising a stimulator adapted to: stimulate
sphenopalatine ganglion (SPG)-related tissue of the subject by
presenting an odorant to an air passage of the subject, the
SPG-related tissue selected from: an SPG of the subject and nerve
fibers of the subject which are directly anatomically connected to
the SPG, and configure the stimulation so as to cause an increase
in clearance of a neurotoxic compound from cerebrospinal fluid
(CSF) of the subject through a blood brain barrier (BBB) of the
subject to a systemic blood circulation of the subject, so as to
treat the CNS condition.
Description
CROSS-REFERENCES TO RELATED AND APPLICATIONS
[0001] The present application:
[0002] (a) is a continuation-in-part of (i) International Patent
Application PCT/IL03/00338, filed Apr. 25, 2003, (ii) International
Patent Application PCT/IL03/00508, filed Jun. 13, 2003, and (iii)
U.S. patent application Ser. No. 10/783,113, filed Feb. 20, 2004,
and
[0003] (b) claims priority from U.S. Provisional Patent Application
60/506,165 to Shalev, filed Sep. 26, 2003.
[0004] The '338 application claims priority from (a) U.S.
Provisional Patent Application 60/376,048 to Shalev, filed Apr. 25,
2002, and (b) U.S. Provisional Patent Application 60/461,232 to
Gross et al., filed Apr. 8, 2003.
[0005] The '508 application claims priority from (a) U.S.
Provisional Patent Application 60/388,931, filed Jun. 14, 2002, and
(b) U.S. patent application Ser. No. 10/294,310 to Gross et al.,
filed Nov. 14, 2002, which claims priority from: (i) U.S.
Provisional Patent Application 60/400,167, filed Jul. 31, 2002, and
(ii) U.S. Provisional Patent Application 60/364,451, filed Mar. 15,
2002.
[0006] The '113 application (a) claims priority from U.S.
Provisional Patent Application 60/506,165, filed Sep. 26, 2003, and
(b) is a continuation-in-part of U.S. patent application Ser. No.
10/258,714, filed Jan. 22, 2003, which is a US national phase
application of International Patent Application PCT/IL01/00402,
filed May 7, 2001, which claims priority from U.S. Provisional
Patent Application 60/203,172, filed May 8, 2000.
[0007] All of the above-mentioned applications are assigned to the
assignee of the present application and are incorporated herein by
reference.
FIELD OF THE INVENTION
[0008] The present invention relates generally to medical
procedures and electronic devices. More specifically, the invention
relates to the use of electrical devices for implantation in the
head, for example, in the nasal cavity. The invention also relates
to methods for using odorants to induce or to inhibit neural
activity for the treatment and/or diagnosis of a clinical
condition. The invention also relates to apparatus and methods for
administering drugs, for treating stroke and headaches such as
migraine and cluster headaches, and for improving cerebral blood
flow.
BACKGROUND OF THE INVENTION
[0009] The blood-brain barrier (BBB) is a unique feature of the
central nervous system (CNS) which isolates the brain from the
systemic blood circulation. To maintain the homeostasis of the CNS,
the BBB prevents access to the brain of many substances circulating
in the blood.
[0010] The BBB is formed by a complex cellular system of
endothelial cells, astroglia, pericytes, perivascular macrophages,
and a basal lamina. Compared to other tissues, brain endothelia
have the most intimate cell-to-cell connections: endothelial cells
adhere strongly to each other, forming structures specific to the
CNS called "tight junctions" or zonula occludens. They involve two
opposing plasma membranes which form a membrane fusion with
cytoplasmic densities on either side. These tight junctions prevent
cell migration or cell movement between endothelial cells. A
continuous uniform basement membrane surrounds the brain
capillaries. This basal lamina encloses contractile cells called
pericytes, which form an intermittent layer and probably play some
role in phagocytosis activity and defense if the BBB is breached.
Astrocytic end feet, which cover the brain capillaries, build a
continuous sleeve and maintain the integrity of the BBB by the
synthesis and secretion of soluble growth factors (e.g.,
gamma-glutamyl transpeptidase) essential for the endothelial cells
to develop their BBB characteristics.
[0011] Because of the BBB, certain non-surgical treatments of the
brain based upon systemic introduction of compounds through the
bloodstream have been ineffective or less effective. For example,
chemotherapy has been relatively ineffective in the treatment of
CNS metastases of systemic cancers (e.g., breast cancer, small cell
lung cancer, lymphoma, and germ cell tumors), despite clinical
regression and even complete remission of these tumors in non-CNS
systemic locations. The most important factors determining drug
delivery from blood into the CNS are lipid solubility, molecular
mass, and electrical charge. A good correlation exists between the
lipid solubility of a drug, expressed as the octanol/water
partition coefficient, and the drug's ability to penetrate or
diffuse across the BBB. This is particularly relevant for drugs
with molecular weights smaller than 600 dalton (Da). The normal BBB
prevents the passage of ionized water soluble drugs with a
molecular weight greater than 180 Da. Most currently-available
effective chemotherapeutic agents, however, have a molecular weight
between 200 and 1200 Da. Therefore, based both on their lipid
solubilities and molecular masses, the passage of many agents is
impeded by the BBB.
[0012] In addition to transcellular diffusion of lipophilic agents,
there are several specific transport mechanisms to carry certain
molecules across the brain's endothelial cells. Specific transport
proteins exist for required molecules, such as glucose and amino
acids. Additionally, absorptive endocytosis and transcytosis occur
for cationized plasma proteins. Specific receptors for certain
proteins, such as transferrin and insulin, mediate endocytosis and
transport across the cell.
[0013] Non-surgical treatment of neurological disorders is
generally limited to systemic introduction of compounds such as
neuropharmaceuticals and other neurologically-active agents that
might remedy or modify neurologically-related activities and
disorders. Such treatment is limited, however, by the relatively
small number of known compounds that pass through the BBB. Even
those that do cross the BBB often produce adverse reactions in
other parts of the body or in non-targeted regions of the
brain.
[0014] There have been a number of different studies regarding
efforts to cross the BBB--specifically, with regard to overcoming
the limited access of drugs to the brain. Such efforts have
included, for example, chemical modification, development of more
hydrophobic analogs, or linking an active compound to a specific
carrier. Transient opening of the BBB in humans has been achieved
by intracarotid infusion of hypertonic mannitol solutions or
bradykinin analogs. Also, modulation of the P-glycoprotein, whose
substrates are actively pumped out of brain cells into capillary
lumens, has been found to facilitate the delivery of drugs to the
brain. However, due to the inherent limitations of each of the
aforementioned procedures, there is still a need for more generic,
effective, and predictable ways to cross the BBB.
[0015] It would also be desirable to develop controllable means for
modulating cerebral blood flow. Many pathological conditions, such
as stroke, migraine, and Alzheimer's disease, are significantly
affected or exacerbated by abnormal cerebral blood flow.
[0016] Alzheimer's disease (AD) is the most common form of both
senile and presenile dementia in the world and is recognized
clinically as relentlessly progressive loss of memory and
intellectual function and disturbances in speech (Merritt, 1979, A
Textbook of Neurology, 6th edition, pp. 484-489, Lea & Febiger,
Philadelphia, which is incorporated herein by reference).
Alzheimer's disease begins with mildly inappropriate behavior,
uncritical statements, irritability, a tendency towards
grandiosity, euphoria, and deteriorating performance at work; it
progresses through deterioration in operational judgment, loss of
insight, depression, and loss of recent memory; and it ends in
severe disorientation and confusion, apraxia of gait, generalized
rigidity, and incontinence (Gilroy & Meyer, 1979, Medical
Neurology, pp. 175-179, MacMillan Publishing Co., which is
incorporated herein by reference,). Alzheimer's disease is found in
about 10% of the population over the age of 65 and 47% of the
population over the age of 85 (Evans et al., 1989, JAMA, 262:
2551-2556, which is incorporated herein by reference).
[0017] Alzheimer's Disease is characterized by the accumulation of
insoluble, 10 nm filaments containing .beta.-amyloid (A.beta.)
peptides, localized in the extracellular space of the cerebral
cortex and vascular walls. These 40 or 42 amino acid long A.beta.
peptides are derived from the larger .beta.-amyloid precursor
protein (.beta.APP) through the endopeptidase action of .beta. and
.gamma. secretases. In addition, the post-translational action of
putative aminopeptidases results in a heterogeneous shortening of
the 40 or 42 amino acid long A.beta. peptides that either terminate
at residue 40 or 42 and, therefore, are designated as ApN-40 and
A.beta.N-42. In familial forms of AD, the pathological appearance
of the A.beta. peptides in the brain is driven by the presence of
mutations in the .beta.APP gene or in the genes coding for the
proteins presenilin 1 and 2.
[0018] Sporadic AD accounts for more than 95% of the known AD
cases. Its etiology, however, remains obscure. An accepted view is
that sporadic AD results from the interplay between an individual's
genetic factors and the environment, leading to the deposition of
A.beta., neurodegeneration, and dementia. Despite this emerging
perspective, insufficient effort has been made in identifying
factors responsible for A.beta. accumulation in the brain.
[0019] The etiology of Alzheimer's disease is unknown. Evidence for
a genetic contribution comes from several important observations
such as the familial incidence, pedigree analysis, monozygotic and
dizygotic twin studies, and the association of the disease with
Down's syndrome (for review see Baraitser, 1990, The Genetics of
Neurological Disorders, 2nd edition, pp. 85-88, which is
incorporated herein by reference). Nevertheless, this evidence is
far from definitive, and it is clear that other factors are
involved.
[0020] Alzheimer's Disease is a neurodegenerative disease
characterized by a progressive decline of cognitive functions,
including loss of declarative and procedural memory, decreased
learning ability, reduced attention span, and severe impairment in
thinking ability, judgment, and decision making. Mood disorders and
depression are also often observed in AD patients. It is estimated
that AD affects about 4 million people in the USA and 20 million
people worldwide. Because AD is an age-related disorder (with an
average onset at 65 years), the incidence of the disease in
industrialized countries is expected to rise dramatically as the
population of these countries ages.
[0021] AD is characterized by the following neuropathological
features:
[0022] massive loss of neurons and synapses in the brain regions
involved in higher cognitive functions (association cortex,
hippocampus, amygdala). Cholinergic neurons are particularly
affected.
[0023] neuritic (senile) plaques that are composed of a core of
amyloid material surrounded by a halo of dystrophic neurites,
reactive type I astrocytes, and numerous microglial cells (Selkoe,
D. J., Annu Rev Neurosci 17: 489-517, 1994; Selkoe, D. J., J
Neuropathol Exp Neurol 53: 438-447, 1994; Dickson, D. W., J
Neuropathol Exp Neurol 56: 321-339, 1997; Hardy, J. et al., Science
282: 1075-1079, 1998; Selkoe, D. J., Cold Spring Harb Symp Quant
Biol 61: 587-596, 1996, all of which are incorporated herein by
reference. The major component of the core is a peptide of 39 to 42
amino acids called the amyloid P protein, or A.beta.. Although the
A.beta. protein is produced by the intracellular processing of its
precursor, APP, the amyloid deposits forming the core of the
plaques are extracellular. Studies have shown that the longer form
of A.beta. (A.beta.42) is much more amyloidogenic than the shorter
forms (A.beta.40 or A.beta.39).
[0024] neurofibrillary tangles that are composed of paired-helical
filaments (PHF) (Ray et al., Mol Med Today 4: 151-157, 1998; Brion,
Acta Neurol Belg 98: 165-174, 1998, both of which are incorporated
herein by reference). Biochemical analyses revealed that the main
component of PHF is a hyper-phosphorylated form of the
microtubule-associated protein .tau.. These tangles are
intracellular structures, found in the cell body of dying neurons,
as well as some dystrophic neurites in the halo surrounding
neuritic plaques. Both plaques and tangles are found in the same
brain regions affected by neuronal and synaptic loss.
[0025] Although the neuronal and synaptic loss is universally
recognized as the primary cause of the decline of cognitive
functions, the cellular, biochemical, and molecular events
responsible for this neuronal and synaptic loss are subject to
fierce controversy. The number of tangles shows a better
correlation than the amyloid load with the cognitive decline
(Albert, Proc Natl Acad Sci USA 93: 13547-13551, 1996, which is
incorporated herein by reference). On the other hand, a number of
studies showed that amyloid can be directly toxic to neurons,
resulting in behavioral impairment (Ma et al., Neurobiol Aging 17:
773-780, 1996, which is incorporated herein by reference). It has
also been shown that the toxicity of some compounds (amyloid or
tangles) could be aggravated by activation of the complement
cascade, suggesting the possible involvement of inflammatory
process in the neuronal death.
[0026] Genetic and molecular studies of some familial forms of AD
(FAD) have recently provided evidence that boosted the amyloid
hypothesis (Ii, Drugs Aging 7: 97-109, 1995; Price et al., Curr
Opin Neurol 8: 268-274, 1995; Hardy, Trends Neurosci 20: 154-159,
1997; Selkoe, J Biol Chem 271: 18295-18298, 1996, all of which are
incorporated herein by reference). The assumption is that since the
deposition of A.beta. in the core of senile plaques is observed in
all Alzheimer cases, if A.beta. is the primary cause of AD, then
mutations that are linked to FAD should induce changes that, in one
way or another, foster A.beta. deposition. There are 3 FAD genes
known so far (Hardy et al., Science 282: 1075-1079, 1998; Ray et
al., Mol Med Today 4: 151-157, 1998, both of which are incorporated
herein by reference), and the activity of all of them results in
increased A.beta. deposition, a very compelling argument in favor
of the amyloid hypothesis.
[0027] The first of the 3 FAD genes codes for the A.beta.
precursor, APP (Selkoe, J Biol Chem 271: 18295-18298, 1996, which
is incorporated herein by reference). Mutations in the APP gene are
very rare, but all of them cause AD with 100% penetrance and result
in elevated production of either total A.beta. or A.beta.42, both
in vitro (transfected cells) and in vivo (transgenic animals). The
other two FAD genes code for presenilin 1 and 2 (PS1, PS2) (Hardy,
Trends Neurosci 20: 154-159, 1997, which is incorporated herein by
reference). The presenilins contain 8 transmembrane domains and
several lines of evidence suggest that they are involved in
intracellular protein trafficking, although their exact function is
still unknown. Mutations in the presenilin genes are more common
than in the APP genes, and all of them also cause FAD with 100%
penetrance. In addition, in vitro and in vivo studies have
demonstrated that PS1 and PS2 mutations shift APP metabolism,
resulting in elevated A.beta.42 production. For a recent review on
the genetics of AD, see Lippa, J Mol Med 4: 529-536, 1999, which is
incorporated herein by reference.
[0028] In spite of these compelling genetic data, it is still
unclear whether A.beta. generation and amyloid deposition are the
primary cause of neuronal death and synaptic loss observed in AD.
Moreover, the biochemical events leading to A.beta. production, the
relationship between APP and the presenilins, and between amyloid
and neurofibrillary tangles are poorly understood. Thus, the
picture of interactions between the major Alzheimer proteins is
very incomplete, and it is clear that a large number of novel
proteins are yet to be discovered.
[0029] The diagnosis of Alzheimer's disease at autopsy is
definitive. Gross pathological changes are found in the brain,
including low weight and generalized atrophy of both the gray and
white matter of the cerebral cortex, particularly in the temporal
and frontal lobes (Adams & Victor, 1977, Principles of
Neurology, pp. 401-407 and Merritt, 1979, A Textbook of Neurology,
6th edition, Lea & Febiger, Philadelphia, pp. 484-489, both of
which are incorporated herein by reference). The histological
changes include neurofibrillary tangle (Kidd, Nature 197: 192-193,
1963; Kidd, Brain 87: 307-320, 1964, both of which are incorporated
herein by reference), which consists of a tangled mass of paired
helical and straight filaments in the cytoplasm of affected neurons
(Oyanagei, Adv. Neurol. Sci. 18: 77-88, 1979 and Grundke-Iqbal et
al., Acta Neuropathol. 66: 52-61, 1985, both of which are
incorporated herein by reference).
[0030] The diagnosis of Alzheimer's disease during life is more
difficult than at autopsy since the diagnosis depends upon inexact
clinical observations. In the early and middle stages of the
disease, the diagnosis is based on clinical judgment of the
attending physician. In the late stages, where the symptoms are
more recognizable, clinical diagnosis is more straightforward. But,
in any case, before an unequivocal diagnosis can be made, other
diseases, with partially overlapping symptoms, must be ruled out.
Usually a patient must be evaluated on a number of occasions to
document the deterioration in intellectual ability and other signs
and symptoms. The necessity for repeated evaluation is costly,
generates anxiety, and can be frustrating to patients and their
families. Furthermore, the development of an appropriate
therapeutic strategy is hampered by the difficulties of rapid
diagnosis, particularly in the early stages where early
intervention could leave the patient with significant intellectual
capacity and a reasonable quality of life. In brief, no unequivocal
laboratory test specific for Alzheimer's disease has been
reported.
[0031] Alzheimer's disease is associated with degeneration of
cholinergic neurons, in the basal forebrain, which play a
fundamental role in cognitive functions, including memory (Becker
et al., Drug Development Research 12: 163-195, 1988, which is
incorporated herein by reference). Progressive, inexorable decline
in cholinergic function and cholinergic markers in the brain of
Alzheimer's disease patients has been observed in numerous studies,
and includes, for example, a marked reduction in acetylcholine
synthesis, choline acetyltransferase activity, acetylcholinesterase
activity, and choline uptake (Davis, Brain Res. 171: 319-327, 1979
and Hardy et al., Neurochem. Int. 7: 545-563, 1985, which are
incorporated herein by reference). Even more, decreased cholinergic
function may be an underlying cause of cognitive decline seen in
Alzheimer's-disease patients (Kish et al., J. Neurol., Neurosurg.,
and Psych. 51: 544-548, 1988, which is incorporated herein by
reference). Choline acetyltransferase and acetylcholinesterase
activities decrease significantly as plaque count rises, and, in
demented subjects, the reduction in choline acetyl transferase
activity was found to correlate with intellectual impairment
(Perry, et al., Brit. Med. J. 25, November 1978, p. 1457, which is
incorporated herein by reference).
[0032] Nerve cells produce nerve growth factors, proteins that
regulate cell maturation during prenatal development and also play
an important role in cell survival, repair, and regeneration during
adult life. Because of their significance in cell maintenance and
repair, these factors have attracted attention as potential
treatments in Alzheimer's disease, stroke, spinal cord injury, and
other neurodegenerative conditions. However, nerve growth factors
are usually too large to cross the blood-brain barrier (BBB), a
protective shield that restricts passage of molecules to the
brain.
[0033] The BBB is functionally situated at the brain capillaries
endothelium layer and covers a surface area of 12 m2/g of brain
parenchyma. The total length of this capillary network is 650 km.
The cerebral capillary endothelial cell displays some peculiar
morphologic characteristics that form the anatomic basis of the
blood-brain barrier. It differs from the peripheral capillary
endothelial cell (referring to all non-CNS sites) in a number of
ways:
[0034] First, the CNS endothelial cell layer is not fenestrated.
Cells are joined by tight junctions composed of 6 to 8 pentalaminar
structures. They actively block protein movements, hydrophilic
transfer and even ionic diffusion. Thus, there is very little
movement of compounds between endothelial cells from the blood to
the CNS.
[0035] Second, and in contrast to the peripheral capillary
endothelial cell, transcellular movement of molecules through the
non-specific mechanism of fluid-phase endocytosis is generally
absent. The cerebral vascular endothelial cell possesses a
transcellular lipophilic pathway, allowing diffusion of small
lipophilic compounds. In addition to this route, specific
receptor-mediated transport systems are present for given
molecules, like insulin, transferrin, glucose, purines and amino
acids. These transport systems are highly selective and
asymmetric.
[0036] Third, the CNS endothelial cell displays a net negative
charge at its endoluminal side and at the basement membrane. This
provides an additional selective mechanism by impeding anionic
molecules to cross the membrane.
[0037] Fourth, the cerebral endothelial cell has very few pinocytic
vesicles, and these vesicles are not involved in any transport
function.
[0038] Fifth, astrocyte foot processes surround the microvascular
endothelium and cover more than 95 percent of its surface,
therefore interposing between capillaries and cerebral
neuropil.
[0039] By virtue of this selective barrier, the CNS can
preferentially regulate the extracellular concentration of certain
solutes, growth factors and neurotransmitters, keep certain
molecules in the CNS and isolate itself from some others, and
further isolate itself from sudden systemic homeostatic changes. It
is therefore an integral component of the mechanisms involved in
the tight regulation of the extra-cellular homeostasis necessary to
the normal CNS function. This relatively impermeable barrier has
some drawbacks, however, when considering the therapeutic delivery
of a molecule to the CNS.
[0040] The delivery of therapeutic molecules across the BBB has
proven to be a major obstacle in treating various brain disorders.
The normal blood-brain barrier prevents passage of ionized
water-soluble compounds with a molecular weight greater than 180
Daltons. Therefore, the BBB is a major impediment to the treatment
of CNS diseases as many drugs are unable to reach this organ at
therapeutic concentrations. More than 98% of the CNS-targeted drugs
do not cross the BBB. Example of such disorders are: primary brain
tumors, metastatic brain tumors, AD, addiction, ALS, head injury,
Huntington's disease, multiple sclerosis (MS), depression, Cerebral
Palsy, schizophrenia, epilepsy, stress and anxiety. Many new
neurotherapeutic agents are being discovered, but because of a lack
of suitable strategies for drug delivery across the BBB, these
agents are ineffective. Such drugs will only become effective if
strategies for brain delivery are developed in parallel.
[0041] Apart from molecular parameters, the permeability of the BBB
and active transport mechanisms, a major determinant of molecular
transport across the BBB is their concentration gradient--between
the CNS and the cerebral circulation.
[0042] Additionally, the functioning BBB inhibits clearance of
neurotoxic compounds, such as .beta.-Amyloid, tau, PS1, and PS2,
from the CNS into the systemic circulation. These neurotoxic
compounds are therefore not metabolized and removed from the body
to the extent desired, and therefore continue to have undesired
effects in the CNS.
[0043] PCT Publication WO 01/85094 and U.S. Patent Application
Publication 2004/0015068 to Shalev and Gross, which are assigned to
the assignee of the present patent application and are incorporated
herein by reference, describe apparatus for modifying a property of
a brain of a patient, including electrodes applied to a
sphenopalatine ganglion (SPG) or a neural tract originating in or
leading to the SPG. A control unit drives the electrodes to apply a
current capable of inducing (a) an increase in permeability of a
blood-brain barrier (BBB) of the patient, (b) a change in cerebral
blood flow of the patient, and/or (c) an inhibition of
parasympathetic activity of the SPG.
[0044] PCT Publication WO 04/010923 to Gross et al., which is
assigned to the assignee of the present application and is
incorporated herein by reference, describes a chemical agent
delivery system including a chemical agent supplied to a body of a
subject for delivery to a site in a central nervous system of said
subject via blood of said subject; and a stimulator for stimulating
parasympathetic fibers associated with the sphenopalatine ganglion,
thereby to render a blood brain barrier (BBB) of said subject
permeable to said chemical agent during at least a portion of the
time that said chemical agent is present in said blood.
[0045] PCT Publication WO 04/043218 to Gross et al., which is
assigned to the assignee of the present application and is
incorporated herein by reference, describes treatment apparatus
comprising (a) a stimulation device, adapted to be implanted in a
vicinity of a site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject and a neural tract
originating in or leading to the SPG; and (b) a connecting element,
coupled to the stimulation device, and adapted to be passed through
at least a portion of a greater palatine canal of the subject. Also
described is a method for implanting a treatment stimulation device
in a vicinity of a site of a subject, the method comprising passing
the device through a greater palatine foramen of the subject, and
bringing the device into contact with the vicinity of the site, the
site selected from the list consisting of: a sphenopalatine
ganglion (SPG) of the subject and a neural tract originating in or
leading to the SPG.
[0046] PCT Publication WO 04/044947 to Gross et al., which is
assigned to the assignee of the present application and is
incorporated herein by reference, describes apparatus for use with
an implanted medical device having two conductive elements in
contact with tissue of a subject. The apparatus comprises a shunt,
electrically coupled between the conductive elements, the shunt
adapted to be in a first state when the subject is exposed to a
source of radiofrequency (RF) energy, and adapted to be in a second
state when the subject is not exposed to the RF energy, the shunt
being characterized such that in the first state the shunt has a
first impedance, and in the second state the shunt has a second
impedance at least two times greater than the first impedance.
[0047] U.S. Patent Application Publication 2003/0176898 and PCT
Publication WO 04/043217 to Gross et al., which are assigned to the
assignee of the present application and are incorporated herein by
reference, describe apparatus for treating a condition of an eye of
a subject, comprising a stimulator adapted to stimulate at least
one site of the subject, so as to treat the eye condition, the site
selected from the list consisting of: a sphenopalatine ganglion
(SPG) of the subject, an anterior ethmoidal nerve of the subject, a
posterior ethmoidal nerve of the subject, a communicating branch
between an anterior ethmoidal nerve and a retro-orbital branch of
an SPG of the subject, a communicating branch between a posterior
ethmoidal nerve and a retro-orbital branch of an SPG of the
subject, a greater palatine nerve of the subject, a lesser palatine
nerve of the subject, a sphenopalatine nerve of the subject, a
communicating branch between a maxillary nerve and an SPG of the
subject, a nasopalatine nerve of the subject, a posterior nasal
nerve of the subject, an infraorbital nerve of the subject, an otic
ganglion of the subject, an afferent fiber going into the otic
ganglion of the subject, an efferent fiber going out of the otic
ganglion of the subject, a vidian nerve of the subject, a greater
superficial petrosal nerve of the subject, and a lesser deep
petrosal nerve of the subject.
[0048] U.S. Patent Application Publication 2003/0176892 and PCT
Publication WO 04/043334 to Shalev, which are assigned to the
assignee of the present application and are incorporated herein by
reference, describe apparatus for delivering a Non Steroidal
Anti-Inflammatory Drug (NSAID) supplied to a body of a subject for
delivery to at least a portion of a central nervous system (CNS) of
the subject via a systemic blood circulation of the subject,
including a stimulator adapted to stimulate at least one site of
the subject, so as to cause an increase in passage of the NSAID
from the systemic blood circulation across a blood brain barrier
(BBB) of the subject to the portion of the CNS, during at least a
portion of the time that the NSAID is present in the blood, the
site selected from the list consisting of: a sphenopalatine
ganglion (SPG) of the subject, an anterior ethmoidal nerve of the
subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject.
[0049] PCT Publication WO 04/045242 to Shalev et al., which is
assigned to the assignee of the present application and is
incorporated herein by reference, describes apparatus for treating
a condition of an ear of a subject, comprising a stimulator adapted
to stimulate at least one site of the subject at a level sufficient
to treat the ear condition, the site selected from the list
consisting of: an otic ganglion of the subject, an afferent fiber
going into the otic ganglion of the subject, an efferent fiber
going out of the otic ganglion of the subject, a sphenopalatine
ganglion (SPG) of the subject, an anterior ethmoidal nerve of the
subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, a vidian nerve of the subject, a greater
superficial petrosal nerve of the subject, and a lesser deep
petrosal nerve of the subject.
[0050] U.S. Pat. No. 5,756,071 to Mattem et al., which is
incorporated herein by reference, describes a method for nasally
administering aerosols of therapeutic agents to enhance penetration
of the blood brain barrier. The patent describes a metering spray
designed for pemasal application, the spray containing at least one
sex hormone or at least one metabolic precursor of a sex hormone or
at least one derivative of a sex hormone or combinations of these,
excepting the precursors of testosterone, or at least one biogenic
amine, with the exception of catecholamines.
[0051] U.S. Pat. No. 5,752,515 to Jolesz et al., which is
incorporated herein by reference, describes apparatus for
image-guided ultrasound delivery of compounds through the
blood-brain barrier. Ultrasound is applied to a site in the brain
to effect in the tissues and/or fluids at that location a change
detectable by imaging. At least a portion of the brain in the
vicinity of the selected location is imaged, e.g., via magnetic
resonance imaging, to confirm the location of that change. A
compound, e.g., a neuropharmaceutical, in the patients bloodstream
is delivered to the confirmed location by applying ultrasound to
effect opening of the blood-brain barrier at that location and,
thereby, to induce uptake of the compound there.
[0052] PCT Publication WO 01/97905 to Ansarinia, which is
incorporated herein by reference, describes a method for the
suppression or prevention of various medical conditions, including
pain, movement disorders, autonomic disorders, and neuropsychiatric
disorders. The method includes positioning an electrode on or
proximate to at least one of the patient's SPG, sphenopalatine
nerves, or vidian nerves, and activating the electrode to apply an
electrical signal to such nerve. In a further embodiment for
treating the same conditions, the electrode used is activated to
dispense a medication solution or analgesic to such nerve. The '905
publication also describes surgical techniques for implanting the
electrode.
[0053] U.S. Pat. No. 6,405,079 to Ansarinia, which is incorporated
herein by reference, describes a method for the suppression or
prevention of various medical conditions, including pain, movement
disorders, autonomic disorders, and neuropsychiatric disorders. The
method includes positioning an electrode adjacent to or around a
sinus, the dura adjacent a sinus, or falx cerebri, and activating
the electrode to apply an electrical signal to the site. In a
further embodiment for treating the same conditions, the electrode
dispenses a medication solution or analgesic to the site. The '079
patent also describes surgical techniques for implanting the
electrode.
[0054] U.S. Patent Application Publication 2002/0052311 to Solomon
et al., which is incorporated herein by reference, describes
methods for treating and/or diagnosing neurological conditions of
the CNS. Some embodiments include displaying a therapeutic molecule
capable of treating the condition on a viral display vehicle and
introducing the vehicle into a subject in need thereof by applying
the viral display vehicle to an olfactory system of the
subject.
[0055] PCT Publication WO 02/094191 to Wisniewski et al., which is
incorporated herein by reference, describes techniques for
diagnosing Alzheimer's disease in vivo using magnetic resonance
imaging. A labeled A-beta peptide or its derivative is injected
into the patient to be diagnosed, after which the patient is
subjected to magnetic resonance imaging.
[0056] U.S. Pat. No. 5,059,415 to Neuwelt, which is incorporated
herein by reference, describes a method for diagnosing and
characterizing brain lesions by first chemically modifying the
blood-brain barrier (BBB) in order to increase BBB permeability.
Thereafter, a chemical agent (e.g., mAb or pAb) is introduced which
binds to brain lesions.
[0057] U.S. Pat. No. 4,866,042 to Neuwelt, which is incorporated
herein by reference, describes a method for treating genetic and
acquired brain disorders by introducing genetic material into the
blood stream for delivery to the brain. Prior to delivery, the
interendothelial structure of the BBB is chemically altered to
permit passage of the genetic material therethrough.
[0058] U.S. Pat. No. 6,117,454 to Kreuter et al., which is
incorporated herein by reference, describes a method for delivering
drugs and diagnostics across the BBB or blood-nerve barrier by
incorporating these agents into nanoparticles which have been
fabricated in conventional ways and then coated with an additional
surfactant.
[0059] PCT Publication WO 00/73343 to Soreq et al., which is
incorporated herein by reference, describes techniques for
diagnosing CNS stress, elevated glucocorticoid level, disruption of
the blood-brain barrier or Alzheimer's disease, by testing a blood
sample using antibodies recognizing acetylcholinesterase or a
C-terminal peptide derived from acetylcholinesterase.
[0060] U.S. Pat. No. 5,268,164 to Kozarich et al., which is
incorporated herein by reference, describes techniques for using
polypeptides called receptor mediated permeabilizers to increase
the permeability of the blood-brain barrier to molecules such as
therapeutic agents or diagnostic agents.
[0061] U.S. Pat. No. 6,005,004 to Katz et al., which is
incorporated herein by reference, describes site-specific
biomolecular complexes comprising a therapeutic, prophylactic and
diagnostic agent, and an omega-3 fatty acid and derivatives
thereof, which complexes are covalently bonded with cationic
carriers and permeabilizer peptides for delivery across the BBB and
with targeting moieties for uptake by target brain cells.
[0062] U.S. Pat. No. 5,833,988 to Friden, which is incorporated
herein by reference, describes a method for delivering a
neuropharmaceutical or diagnostic agent across the BBB to the
brain. The method comprises administering to the host a
therapeutically effective amount of an antibody-neuropharmaceutical
or diagnostic agent conjugate wherein the antibody is reactive with
a transferrin receptor.
[0063] The following references, which are incorporated herein by
reference, may be useful:
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induced in the rat dura mater by stimulation of the parasympathetic
sphenopalatine ganglion," Experimental Neurology, 147, 389-400
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"Parasympathetic cerebrovascular innervation: An anterograde
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[0066] Jolliet-Riant P, Tillement JP, "Drug transfer across the
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Edvinsson L, "Effects of stimulation of the sphenopalatine ganglion
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[0072] Suzuki N, Hardebo JE, Kahrstrom J, Owman CH, "Effect on
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[0073] Major A, Silver W, "Odorants presented to the rat nasal
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OBJECTS OF THE INVENTION
[0087] It is an object of some aspects of the present invention to
provide improved methods and apparatus for delivery of compounds to
the brain, particularly through the BBB.
[0088] It is also an object of some aspects of the present
invention to provide such methods and apparatus as can be employed
to deliver such compounds through the BBB with a minimally invasive
approach.
[0089] It is a further object of some aspects of the present
invention to provide such methods and apparatus as can facilitate
delivery of large molecular weight compounds through the BBB.
[0090] It is yet a further object of some aspects of the present
invention to provide cost-effective methods and apparatus for
delivery of compounds through the blood-brain-barrier.
[0091] It is still a further object of some aspects of the present
invention to provide improved methods and apparatus for remedying
or modifying neurological activities and disorders via delivery of
compounds through the blood-brain-barrier.
[0092] It is also a further object of some aspects of the present
invention to modulate cerebral blood flow.
[0093] It is an additional object of some aspects of the present
invention to provide improved methods and apparatus for treating
stroke.
[0094] It is yet an additional object of some aspects of the
present invention to provide improved methods and apparatus for
treating migraine, cluster and other types of headaches.
[0095] It is still an additional object of some aspects of the
present invention to provide improved methods and apparatus for
treating and/or preventing neurological diseases (for example,
Alzheimer's disease), whose prognosis and evolution of pathological
symptoms are influenced by cerebral blood flow.
[0096] It is also an object of some aspects of the present
invention to provide implantable apparatus which affects a property
of the brain, without actually being implanted in the brain.
[0097] It is a further object of some aspects of the present
invention to provide methods which affect a property of the brain
without the use of implantable apparatus.
[0098] It is still an additional object of some aspects of the
present invention to provide improved methods and apparatus for
treating and/or preventing Alzheimer's disease.
[0099] It is also an object of some aspects of the present
invention to provide improved methods and apparatus for diagnosing
neurological diseases.
[0100] It is a further object of some aspects of the present
invention to provide improved methods and apparatus for diagnosing
Alzheimer's disease.
[0101] It is yet a further object of some aspects of the present
invention to affect a property of the brain by using the
neuroexcitatory and/or neuroinhibitory effects of odorants on
nerves in the head.
[0102] These and other objects of the invention will become more
apparent from the description of preferred embodiments thereof
provided hereinbelow.
SUMMARY OF THE INVENTION
[0103] In preferred embodiments of the present invention, an
electrical stimulator drives current into the sphenopalatine
ganglion (SPG) or into related neuroanatomical structures,
including neural tracts originating or reaching the SPG, including
outgoing and incoming parasympathetic and sympathetic tracts and
other parasympathetic centers. Typically, the stimulator drives the
current in order to control and/or modify SPG-related behavior,
e.g., in order to induce changes in cerebral blood flow and/or to
modulate permeability of the blood-brain barrier (BBB). These
embodiments may be used in many medical applications, such as, by
way of illustration and not limitation, (a) the treatment of
cerebrovascular disorders such as stroke, (b) the treatment of
migraine, cluster and other types of headaches, or (c) the
facilitation of drug transport across the BBB.
[0104] In the specification of the present patent application,
unless indication to the contrary is stated, stimulation of the SPG
is to be understood to alternatively or additionally include
stimulation of one or more of the following nerves or
ganglions:
[0105] an anterior ethmoidal nerve;
[0106] a posterior ethmoidal nerve;
[0107] a communicating branch between the anterior ethmoidal nerve
and the SPG (retro orbital branch);
[0108] a communicating branch between the posterior ethmoidal nerve
and the SPG (retro orbital branch)
[0109] a nerve of the pterygoid canal (also called a vidian nerve),
such as a greater superficial
[0110] a petrosal nerve (a preganglionic parasympathetic nerve) or
a lesser deep petrosal nerve (a postganglionic sympathetic
nerve);
[0111] a greater palatine nerve;
[0112] a lesser palatine nerve;
[0113] a sphenopalatine nerve;
[0114] a communicating branch between the maxillary nerve and the
sphenopalatine ganglion;
[0115] a nasopalatine nerve;
[0116] a posterior nasal nerve;
[0117] an infraorbital nerve;
[0118] an otic ganglion;
[0119] an afferent fiber going into the otic ganglion; and/or
[0120] an efferent fiber going out of the otic ganglion.
[0121] The SPG is a neuronal center located in the brain behind the
nose. It consists of parasympathetic neurons innervating the middle
cerebral and anterior cerebral lumens, the facial skin blood
vessels, and the lacrimal glands. Activation of this ganglion is
believed to cause vasodilation of these vessels. A second effect of
such stimulation is the opening of pores in the vessel walls,
causing plasma protein extravasation (PPE). This effect allows
better transport of molecules from within these blood vessels to
surrounding tissue.
[0122] The middle and anterior cerebral arteries provide the
majority of the blood supply to the cerebral hemispheres, including
the frontal and parietal lobes in their entirety, the insula and
the limbic system, and significant portions of the following
structures: the temporal lobes, internal capsule, basal ganglia and
thalamus. These structures are involved in many of the neurological
and psychiatric diseases of the brain, and preferred embodiments of
the present invention are directed towards providing improved blood
supply and drug delivery to these structures.
[0123] There is also some animal evidence for the presence of
SPG-originated parasympathetic innervation in the posterior
cerebral and basilar arteries. Consistent with the assumption that
this is also the case in humans, many regions of the human brain
are within the reach of treatments provided by preferred
embodiments of the present invention, as described hereinbelow.
[0124] Currently the SPG is a target of manipulation in clinical
medicine, mostly in attempted treatments of severe headaches such
as cluster headaches. The ganglion is blocked either on a
short-term basis, by applying lidocaine, or permanently, by
ablation with a radio frequency probe. In both cases the approach
is through the nostrils. In some preferred embodiments of the
present invention, similar methods for approaching the SPG are
utilized, to enable the electrical stimulation or electrical
blocking thereof.
[0125] According to a preferred embodiment of the instant
invention, a method and apparatus are provided to enhance delivery
of therapeutic molecules across the BBB by stimulation of the SPG
and/or its outgoing parasympathetic tracts and/or another
parasympathetic center. The apparatus typically stimulates the
parasympathetic nerve fibers of the SPG, thereby inducing the
middle and anterior cerebral arteries to dilate, and also causing
the walls of these cerebral arteries to become more permeable to
large molecules. In this manner, the movement of large
pharmaceutical molecules from within blood vessels to the cerebral
tissue is substantially increased. Preferably, therefore, this
method can serve as a neurological drug delivery facilitator,
without the sacrifices in molecular weight required by techniques
of the prior art. In general, it is believed that substantially all
pharmacological treatments aimed at cerebral cells for neurological
and psychiatric disorders are amenable for use with these
embodiments of the present invention. In particular, these
embodiments may be adapted for use in the treatment of disorders
such as brain tumors, epilepsy, Parkinson's disease, Alzheimer's
disease, multiple sclerosis, schizophrenia, depression, stress,
obesity, pain, anxiety, and any other CNS disorders that are
directly or indirectly affected by changes in cerebral blood flow
or by BBB permeability changes.
[0126] Advantageously (and even in the absence of BBB permeability
changes), patients with these and other disorders are generally
helped by the vasodilation secondary to stimulation of the SPG, and
the resultant improvement in oxygen supply to neurons and other
tissue. For some applications, this treatment is given on a
long-term basis, e.g., in the chronic treatment of Alzheimer's
patients. For other applications, the treatment is performed on a
short-term basis, e.g., to minimize the damage following an acute
stroke event and initiate neuronal and therefore functional
rehabilitation.
[0127] Blocking of nerve transmission in the SPG or in related
neural tracts is used in accordance with some preferred embodiments
of the present invention to treat or prevent migraine
headaches.
[0128] Alternatively or additionally, the changes induced by
electrical stimulation as described hereinabove are achieved by
presenting odorants to an air passage of a patient, such as a nasal
cavity or the throat. There is animal evidence that some odorants,
such as propionic acid, cyclohexanone, and amyl acetate,
significantly increase cortical blood flow when presented to the
nasal cavity. This has been interpreted by some researchers as
evidence that these odorants (e.g., environmental pollutants) may
be involved in the formation of various headaches by increasing
cerebral blood flow. The temporal profile and other quantitative
characteristics of such odorant stimulation are believed by the
present inventors to have a mechanism of action that has a
neuroanatomical basis overlapping with that of the electrical
stimulation of the SPG. Furthermore, experimental animal evidence
collected by the inventors and described in U.S. Provisional Patent
Application 60/368,657 to Shalev and Gross entitled, "SPG
stimulation," filed Mar. 28, 2002, which is assigned to the
assignee of the present invention and is incorporated herein by
reference, suggest a correlation between the mechanisms of
increasing cerebral blood flow and increased cerebrovascular
permeability. It is hypothesized that such increased cerebral blood
flow caused by odorants is a result of stimulation of
parasympathetic and/or trigeminal fibers. These fibers may mediate
cerebral blood flow changes directly, by communicating with the
SPG, or by some other mechanism. It is also hypothesized that these
odorants stimulate via reflex arcs the SPG or other autonomic
neural structures that innervate the cerebrovascular system.
Therefore, the inventors hypothesize, odorant "stimulation" may
increase cerebral blood flow in general, and cortical blood flow in
particular, by some or all of the same mechanisms as electrical
stimulation, as described hereinabove. Alternatively, odorants may
cause increased cortical blood flow by other mechanisms, such as by
entering the blood stream and reaching the affected blood vessels
in the brain or by parasympathetic stimulation via the olfactory
nerve. In addition to the effect on cerebral blood flow, the
introduction of odorants into an air passage is also expected to
induce an increase in the permeability of the anterior two thirds
of the cerebrovascular system to circulating agents of various
sizes, i.e., to increase the permeability of the BBB. Similarly,
presenting certain other odorants to an air passage decreases
cerebral blood flow and decreases the permeability of the BBB.
[0129] Odorants that may increase or decrease cerebral blood flow
and/or the permeability of the BBB include, but are not limited to,
propionic acid, cyclohexanone, amyl acetate, acetic acid, citric
acid, carbon dioxide, sodium chloride, ammonia, menthol, alcohol,
nicotine, piperine, gingerol, zingerone, allyl isothiocyanate,
cinnamaldehyde, cuminaldehyde, 2-propenyl/2-phenylethyl
isothiocyanate, thymol, and eucalyptol.
[0130] For some applications, delivery across the BBB of a
pharmacological agent is enhanced by presenting an odorant to an
air passage of a patient, such as a nasal cavity or the throat. Ln
the context of the present patent application and in the claims, a
pharmacological agent is an agent, for administration to a patient,
that is made using pharmacological procedures. Pharmacological
agents may thus include, by way of illustration and not limitation,
therapeutic agents and agents for facilitating diagnostic
procedures.
[0131] According to a preferred embodiment of the instant
invention, a method is provided to enhance delivery of therapeutic
molecules across the BBB by presenting an odorant to an air passage
of a patient, such as a nasal cavity or the throat. In a preferred
application, this method serves as a neurological drug delivery
facilitator. The odorant is preferably presented using apparatus
known in the art, such as aqueous spray nasal inhalers; metered
dose nasal inhalers; or air-dilution olfactometers. Alternatively
or additionally, the odorant is presented by means of an
orally-dissolvable capsule that releases the active odorants upon
contact with salivary liquids. The odorants reach the appropriate
neural structures and induce vasodilatation, vasoconstriction
and/or cerebrovascular permeability changes. Delivery of a drug can
be achieved by mixing the drug with the odorant; by intravenously,
intraperitoneally, or intramuscularly administering the drug, or by
other delivery methods known in the art. For some applications, it
is desirable to combine a local analgesic with the odorant in order
to diminish any possible sensation of pain or discomfort that may
directly or indirectly (e.g., via a reflex arc) accompany the
odorant action upon nerves in the head. For example, preventing
neural transmission in the neighboring pain fibers may be performed
as a "pre-odorant" treatment, by topical administration of
capsaicin together with a local analgesic for several days prior to
the use of odorant stimulation. In this manner, the odorants
typically induce the SPG-related response with a reduced or
eliminated sensation of pain or discomfort.
[0132] In general, it is believed that substantially all
pharmacological treatments aimed at cerebral cells for neurological
and psychiatric disorders are amenable for use with these
embodiments of the present invention. In particular, this
embodiment may be adapted for use in the treatment of disorders
such as brain tumors, epilepsy, Parkinson's disease, Alzheimer's
disease, multiple sclerosis, schizophrenia, depression, stress,
anxiety, obesity, pain, disorders requiring the administration of
various growth factors, and other CNS disorders that are directly
or indirectly affected by changes in cerebral blood flow or by BBB
permeability changes.
[0133] Alternatively or additionally, a method is provided for
increasing or reducing cortical blood flow and/or inducing or
inhibiting vasodilation (even in the absence of BBB permeability
changes) by presenting an odorant to an air passage of a patient,
such as a nasal cavity or the throat, for treatment of a condition.
Patients with the aforementioned disorders and other disorders are
generally helped by vasodilation and the resultant improvement in
oxygen supply to neurons and other tissue. For some applications,
this treatment is given on a long-term basis, e.g., in the chronic
treatment of Alzheimer's patients. For other applications, the
treatment is performed on a short-term basis, e.g., to minimize the
damage following an acute stroke event and initiate neuronal and
therefore functional rehabilitation. Alternatively or additionally,
the method provided above can be used for diagnostic purposes or in
conjunction with other diagnostic methods and/or apparatus known in
the art, in order to enhance diagnostic results, reduce procedure
risk, reduce procedure time, or otherwise improve such diagnostic
procedures and/or diagnostic results. For example, methods and
apparatus described herein may be used to increase the uptake into
the brain of a radio-opaque material, in order to facilitate a CT
scan.
[0134] Decreasing cerebral blood flow by presenting certain
odorants to an air passage is used in accordance with some
preferred embodiments of the present invention to treat or prevent
various types of headaches, especially with an autonomic nervous
system (ANS) etiology, such as migraine and cluster headaches.
[0135] Typically, for any of the odorant presentation applications
described herein, a suitable dosage of the odorant is determined
for a desired application (e.g., increasing or decreasing BBB
permeability, or increasing or decreasing cerebral blood flow). The
procedure for determine the suitable dosage is typically performed
in accordance with standard drug dosage determination procedures
known in the art, e.g., testing a range of very small doses for
safety and efficacy, and subsequently increasing the magnitude of
the doses as safety remains acceptable and efficacy continues to
increase.
[0136] In embodiments of the present invention, at least one
"modulation target site" (MTS), as defined hereinbelow, is
stimulated in order to facilitate a diagnosis of a condition of a
central nervous system (CNS) of a subject. The MTS is typically
stimulated by applying electrical, chemical, mechanical and/or
odorant stimulation to the site. Such stimulation is configured to
increase the permeability of the blood-brain barrier (BBB) in order
to increase the transport of (a) a diagnostic agent from the
systemic blood circulation of the subject into the CNS, and/or (b)
a constituent of the CNS, such as a biochemical agent, from the CNS
into the systemic circulation. The electrical, chemical, mechanical
and odorant stimulation techniques described herein may facilitate
the diagnosis of a number of CNS conditions, including, but not
limited to, neurodegenerative conditions (e.g., Alzheimer's
disease, Parkinson's Disease, and ALS), neoplastic processes
(either primary or metastatic), immune- and autoimmune-related
disorders (e.g., HIV and multiple sclerosis), and CNS inflammatory
processes.
[0137] In the present patent application, a "modulation target
site" (MTS) consists of:
[0138] a sphenopalatine ganglion (SPG) (also called a
pterygopalatine ganglion);
[0139] an anterior ethmoidal nerve;
[0140] a posterior ethmoidal nerve;
[0141] a communicating branch between the anterior ethmoidal nerve
and the SPG (retro-orbital branch);
[0142] a communicating branch between the posterior ethmoidal nerve
and the SPG (retro-orbital branch);
[0143] a nerve of the pterygoid canal (also called a vidian nerve),
such as a greater superficial petrosal nerve (a preganglionic
parasympathetic nerve) or a lesser deep petrosal nerve (a
postganglionic sympathetic nerve);
[0144] a greater palatine nerve;
[0145] a lesser palatine nerve;
[0146] a sphenopalatine nerve;
[0147] a communicating branch between the maxillary nerve and the
sphenopalatine ganglion;
[0148] a nasopalatine nerve;
[0149] a posterior nasal nerve;
[0150] an infraorbital nerve;
[0151] an otic ganglion;
[0152] an afferent fiber going into the otic ganglion; and/or
[0153] an efferent fiber going out of the otic ganglion.
[0154] The stimulation techniques described herein typically
enhance delivery of diagnostic and biochemical molecules across the
BBB by stimulating the nerve fibers of the MTS, thereby inducing
the middle and anterior cerebral arteries to dilate, for example,
and also causing the walls of these cerebral arteries to become
more permeable to large molecules. In this manner, the movement of
large molecules from within blood vessels to the cerebral tissue,
and from the cerebral issue to blood vessels, is substantially
increased. Without the use of the techniques described herein or
functional equivalents thereof, the intact BBB generally blocks or
substantially reduces the passage of such molecules.
[0155] In some embodiments of the present invention, stimulation of
an MTS is configured to increase the transport of a diagnostic
agent across the BBB from the systemic blood circulation into the
CNS. Prior to, during, or after such stimulation, the diagnostic
agent is administered to a non-CNS tissue of the subject, typically
the systemic blood circulation, such as intravenously, and a
diagnostic procedure, typically an imaging modality, is then
performed directly on the CNS. The diagnostic agent is typically a
contrast agent or enhancer, or a tracer, such as a radioisotope.
For example, an imaging procedure may be performed by intravenously
administering labeled (e.g., radiolabeled) beta-Amyloid monoclonal
antibody (mAb) or polyclonal antibody (pAb), stimulating an MTS to
transport the tracer across the BBB, and mapping the distribution
of the tracer in the brain using Positron Emission Tomography (PET)
or Single Photon Emission Computed Tomography (SPECT) imaging.
[0156] These techniques for facilitating the transport of
diagnostic agents into the CNS generally increase the accuracy of
CNS diagnostic procedures. Such increased accuracy is obtained in
part because a greater amount of the agent enters the CNS as a
result of the MTS stimulation. Additionally, MTS stimulation allows
diagnostic agents having greater molecular weights to cross the
BBB, which enables the effective use of a broader range of agents
having greater specificity, such as labeled antibodies and
cytokines. The greater diagnostic sensitivity of these techniques
also may allow the performance of a non-invasive imaging procedure
instead of a more invasive procedure, such as sampling of CNS
tissue or fluid (e.g., cerebrospinal fluid (CSF) lumbar puncture,
brain biopsy).
[0157] In other embodiments of the present invention, stimulation
of an MTS is configured to increase the transport of a biochemical
agent across the BBB from the CNS to a non-CNS tissue of the
subject, such as the systemic blood circulation. Such biochemical
agents are typically disease-specific biochemical markers. Prior to
stimulation of an MTS to increase BBB permeability, the
concentration of such a biochemical agent is typically greater in
the CNS than in the systemic circulation, i.e., there is a
concentration gradient across the endothelium. Therefore,
increasing the permeability of the BBB generally releases the agent
into the systemic circulation. Once in the systemic circulation,
diagnosis is typically performed by sampling a body fluid,
typically blood, and analyzing the whole blood, plasma, or
serum.
[0158] These techniques for facilitating the transport of
biochemical agents from the CNS into the systemic circulation
generally increase the rate of transfer and, consequently, the
amount of the agent in the systemic circulation. The diagnostic
signal, i.e., the statistical sample size, of the agent in the
circulation is thereby increased, generally resulting in increased
accuracy of the diagnostic procedure. Additionally, for some CNS
conditions, use of these techniques may allow the performance of a
minimally-invasive procedure instead of a more invasive procedure,
such as sampling of CNS tissue or fluid (e.g., CSF lumbar puncture,
brain biopsy).
[0159] In some embodiments of the present invention, stimulation of
at least one MTS is achieved by presenting odorants to an air
passage of a patient, such as a nasal cavity or the throat, as
described herein, so as to facilitate a diagnosis of a CNS
condition.
[0160] In some embodiments of the present invention, stimulation of
at least one MTS is achieved by applying a neuroexcitatory agent to
the MTS. Suitable neuroexcitatory agents include, but are not
limited to, acetylcholine and urocholine. For some applications,
the MTS is stimulated by applying a neuroinhibitory agent, such as
atropine, hexamethonium, or a local anesthetic (e.g.,
lidocaine).
[0161] In some embodiments of the present invention, stimulation of
the MTS is achieved by applying mechanical stimulation to the MTS,
e.g., vibration.
[0162] It is to be appreciated that references herein to specific
modulation target sites are to be understood as including other
modulation target sites, as appropriate.
[0163] It is to be appreciated that, whereas preferred embodiments
of the present invention are described with respect to driving
current into the SPG or into neural structures directly related
thereto, the scope of the present invention includes driving
current into other sites in the brain which upon stimulation
modulate cerebral blood flow or modulate permeability properties of
the BBB, as appropriate for a given application.
[0164] It is also to be appreciated that electrical "stimulation,"
as provided by preferred embodiments of the present invention, is
meant to include substantially any form of current application to
designated tissue, even when the current is configured to block or
inhibit the activity of nerves.
[0165] It is further to be appreciated that implantation and
stimulation sites, methods of implantation, and parameters of
stimulation are described herein by way of illustration and not
limitation, and that the scope of the present invention includes
other possibilities which would be obvious to someone of ordinary
skill in the art who has read the present patent application.
[0166] It is yet further to be appreciated that while preferred
embodiments of the invention are generally described herein with
respect to electrical transmission of power and electrical
stimulation of tissue, other modes of energy transport may be used
as well. Such energy includes, but is not limited to, direct or
induced electromagnetic energy, radiofrequency (RF) transmission,
mechanical vibration, ultrasonic transmission, optical power, and
low power laser energy (via, for example, a fiber optic cable).
[0167] It is additionally to be appreciated that whereas preferred
embodiments of the present invention are described with respect to
application of electrical currents to tissue, this is to be
understood in the context of the present patent application and in
the claims as being substantially equivalent to applying an
electrical field, e.g., by creating a voltage drop between two
electrodes.
[0168] As used in the present patent application, including the
claims, the central nervous system (CNS) is to be understood as
consisting of CSF, the brain, and the spinal cord.
[0169] There is therefore provided, in accordance with a preferred
embodiment of the present invention, apparatus for modifying a
property of a brain of a patient, including:
[0170] one or more electrodes, adapted to be applied to a site
selected from a group of sites consisting of: a sphenopalatine
ganglion (SPG) of the patient and a neural tract originating in or
leading to the SPG; and
[0171] a control unit, adapted to drive the one or more electrodes
to apply a current to the site capable of inducing an increase in
permeability of a blood-brain barrier (BBB) of the patient.
[0172] There is also provided, in accordance with a preferred
embodiment of the present invention, apparatus for modifying a
property of a brain of a patient, including:
[0173] one or more electrodes, adapted to be applied to a site
selected from a group of sites consisting of: a sphenopalatine
ganglion (SPG) of the patient and a neural tract originating in or
leading to the SPG; and
[0174] a control unit, adapted to drive the one or more electrodes
to apply a current to the site capable of inducing an increase in
cerebral blood flow of the patient.
[0175] There is further provided, in accordance with a preferred
embodiment of the present invention, apparatus for modifying a
property of a brain of a patient, including:
[0176] one or more electrodes, adapted to be applied to a site
selected from a group of sites consisting of: a sphenopalatine
ganglion (SPG) of the patient and a neural tract originating in or
leading to the SPG; and
[0177] a control unit, adapted to drive the one or more electrodes
to apply a current to the site capable of inducing a decrease in
cerebral blood flow of the patient.
[0178] There is still further provided, in accordance with a
preferred embodiment of the present invention, apparatus for
modifying a property of a brain of a patient, including:
[0179] one or more electrodes, adapted to be applied to a site
selected from a group of sites consisting of: a sphenopalatine
ganglion (SPG) of the patient and a neural tract originating in or
leading to the SPG; and
[0180] a control unit, adapted to drive the one or more electrodes
to apply a current to the site capable of inhibiting
parasympathetic activity of the SPG.
[0181] Preferably, the one or more electrodes are adapted for a
period of implantation in the patient greater than about one
month.
[0182] In a preferred embodiment, the apparatus includes a wire,
adapted to connect the control unit to the one or more electrodes,
wherein the control unit is adapted to drive the one or more
electrodes from a position external to the patient.
[0183] Alternatively or additionally, the control unit is adapted
to drive the one or more electrodes by wireless communication from
a position external to the patient. In a preferred embodiment, the
apparatus includes an electromagnetic coupling, adapted to couple
the control unit and the one or more electrodes. Alternatively or
additionally, the control unit is adapted to be in electro-optical
communication with the one or more electrodes. Further
alternatively or additionally, the control unit is adapted to be in
electro-acoustic communication with the one or more electrodes.
Still further alternatively or additionally, the control unit is
adapted to be implanted in a nasal cavity of the patient.
[0184] Preferably, the one or more electrodes are adapted to be
implanted in a nasal cavity of the patient. For some applications,
at least one of the one or more electrodes includes a flexible
electrode, adapted for insertion through a nostril of the patient
and to extend therefrom to the site.
[0185] The apparatus preferably includes at least one biosensor,
adapted to measure a physiological parameter of the patient and to
generate a signal responsive thereto. The control unit, in turn, is
preferably adapted to modify a parameter of the applied current
responsive to the signal. As appropriate, the biosensor may include
one or more of the following:
[0186] a blood flow sensor.
[0187] a temperature sensor.
[0188] a chemical sensor.
[0189] an ultrasound sensor.
[0190] transcranial Doppler (TCD) apparatus.
[0191] laser-Doppler apparatus.
[0192] a systemic blood pressure sensor.
[0193] an intracranial blood pressure sensor.
[0194] a detecting element adapted to be fixed to a cerebral blood
vessel, and wherein the control unit is adapted to analyze the
signal to detect an indication of a change in blood pressure
indicative of a clot.
[0195] a kinetics sensor (in this case, the control unit is
typically adapted to analyze the signal to detect an indication of
a change in body disposition of the patient).
[0196] an electroencephalographic (EEG) sensor.
[0197] a blood vessel clot detector.
[0198] In a preferred embodiment, the control unit is adapted to
configure the current so as to facilitate uptake of a drug through
the BBB when the permeability of the BBB is increased.
[0199] Alternatively or additionally, the control unit is adapted
to configure the current so as to increase a diameter of a blood
vessel and allow an embolus that is located at a site in the blood
vessel to move from the site in the blood vessel.
[0200] Further alternatively or additionally, the control unit is
adapted to drive the one or more electrodes to apply the current
responsive to an indication of stroke.
[0201] Still further alternatively or additionally, the control
unit is adapted to drive the one or more electrodes to apply the
current responsive to an indication of migraine of the patient.
[0202] There is also provided, in accordance with a preferred
embodiment of the present invention, a method for modifying a
property of a brain of a patient, including:
[0203] selecting a site from a group of sites consisting of: a
sphenopalatine ganglion (SPG) of the patient and a neural tract
originating in or leading to the SPG; and
[0204] applying a current to the site capable of inducing an
increase in permeability of a blood-brain barrier (BBB) of the
patient.
[0205] There is additionally provided, in accordance with a
preferred embodiment of the present invention, a method for
modifying a property of a brain of a patient, including:
[0206] selecting a site from a group of sites consisting of: a
sphenopalatine ganglion (SPG) of the patient and a neural tract
originating in or leading to the SPG; and
[0207] applying a current to the site capable of inducing an
increase in cerebral blood flow of the patient.
[0208] There is yet additionally provided, in accordance with a
preferred embodiment of the present invention, a method for
modifying a property of a brain of a patient, including:
[0209] selecting a site from a group of sites consisting of: a
sphenopalatine ganglion (SPG) of the patient and a neural tract
originating in or leading to the SPG; and
[0210] applying a current to the site capable of inducing a
decrease in cerebral blood flow of the patient.
[0211] There is still additionally provided, in accordance with a
preferred embodiment of the present invention, a method for
modifying a property of a brain of a patient, including:
[0212] selecting a site from a group of sites consisting of: a
sphenopalatine ganglion (SPG) of the patient and a neural tract
originating in or leading to the SPG; and
[0213] applying a current to the site capable of inhibiting
parasympathetic activity of the SPG.
[0214] For some applications, the one or more electrodes are
adapted for a period of implantation in the patient less than about
one week.
[0215] There is further provided, in accordance with a preferred
embodiment of the present invention, vascular apparatus,
including:
[0216] a detecting element, adapted to be fixed to a blood vessel
of a patient and to generate a signal responsive to energy coming
from the blood vessel; and
[0217] a control unit, adapted to analyze the signal so as to
determine an indication of an embolus in the blood vessel.
[0218] Preferably, the detecting element includes an energy
transmitter and an energy receiver. For example, the energy
transmitter may include an ultrasound transmitter or a transmitter
of electromagnetic energy.
[0219] There is yet further provided, in accordance with a
preferred embodiment of the present invention, a method for
detecting, including:
[0220] fixing a detecting element to a blood vessel of a
patient;
[0221] generate a signal responsive to energy coming from the blood
vessel; and
[0222] analyzing the signal so as to determine an indication of an
embolus in the blood vessel.
[0223] There is still further provided, in accordance with a
preferred embodiment of the present invention, a method for
modifying a property of a brain of a patient, including presenting
an odorant to an air passage of the patient, the odorant having
been selected for presentation to the air passage because it is
such as to increase conductance of molecules between a systemic
blood circulation of the patient and brain tissue of the patient,
by way of a blood brain barrier (BBB) of the brain.
[0224] For some applications, the method includes sensing a
parameter of the patient and presenting the odorant responsive
thereto. The parameter may include an indication of a behavior of
the patient, in which case sensing the parameter includes sensing
the indication of the behavior of the patient. Alternatively, the
parameter may be selected from the list consisting of: a
biochemical value of the patient and a physiological value of the
patient, in which case sensing the parameter includes sensing the
parameter selected from the list. For some applications, sensing
the parameter selected from the list includes sensing the parameter
using a modality selected from the list consisting of: CT, MRI,
PET, SPECT, angiography, ophthalmoscopy, fluoroscopy, light
microscopy, and oximetry. Alternatively or additionally, sensing
the parameter selected from the list includes measuring a level of
the molecules in the patient. For some applications, measuring the
level of the molecules includes sampling a body fluid of the
patient selected from the list consisting of: blood, plasma, serum,
ascites fluid, and urine.
[0225] In an embodiment of the present invention, presenting the
odorant to the air passage of the patient includes presenting the
odorant, the odorant having been selected for presentation to the
air passage because it is such as to increase conductance of the
molecules from the systemic blood circulation of the patient
through the blood brain barrier (BBB) into brain tissue of the
patient, the molecules being selected from the group consisting of:
an endogenous agent, a pharmacological agent, a therapeutic agent,
and an agent for facilitating a diagnostic procedure.
[0226] In an embodiment, presenting the odorant includes presenting
the odorant in a dosage determined to increase the conductance of
the molecules. In an embodiment, the method includes administering
the molecules for inhalation by the patient.
[0227] In an embodiment, the method includes administering the
molecules to the patient in a bolus. In an embodiment, the method
includes administering the molecules to the patient in a generally
continuous manner.
[0228] In an embodiment, the method includes administering an agent
capable of blocking a P-glycoprotein transporter from transporting
the molecules from a target site in the brain tissue.
[0229] In an embodiment, the method includes administering the
molecules to the systemic blood circulation. For some applications,
administering the molecules includes administering the molecules
mixed with the odorant. Alternatively or additionally,
administering the molecules includes administering the molecules to
the systemic blood circulation using a technique selected from the
list consisting of: per-oral administration intravenous
administration, intra-arterial administration, intraperitoneal
administration, subcutaneous administration, and intramuscular
administration.
[0230] In an embodiment, the molecules include the agent for
facilitating a diagnostic procedure, and presenting the odorant
includes presenting the odorant, the odorant being such as to
increase the conductance of the agent for facilitating the
diagnostic procedure. For some applications, the agent for
facilitating a diagnostic procedure includes an imaging contrast
agent, and presenting the odorant includes presenting the odorant,
the odorant being such as to increase the conductance of the
imaging contrast agent. Alternatively or additionally, the agent
for facilitating a diagnostic procedure includes a radio-opaque
material, and presenting the odorant includes presenting the
odorant, the odorant being such as to increase the conductance of
the radio-opaque material. Further alternatively or additionally,
the agent for facilitating a diagnostic procedure includes an
antibody, and presenting the odorant includes presenting the
odorant, the odorant being such as to increase the conductance of
the antibody.
[0231] In an embodiment, presenting the odorant includes selecting
the molecules, the molecules being appropriate for treating a
disorder of the central nervous system (CNS) of the patient. In an
embodiment, the CNS disorder is selected from the list consisting
of: a brain tumor, epilepsy, Parkinson's disease, Alzheimer's
disease, multiple sclerosis, schizophrenia, depression, stress,
obesity, pain, and anxiety, and selecting the molecules includes
selecting the molecules, the molecules being appropriate for
treating the selected CNS disorder.
[0232] In an embodiment, the method includes regulating a parameter
of the odorant presentation. For some applications, regulating the
parameter includes regulating a parameter selected from the list
consisting of: relative concentrations of two or more ingredients
of the odorant, a quantity of the odorant presented, a rate of
presentation of the odorant, a pressure of the odorant at
presentation, and a temperature of at least a portion of the
odorant. In an embodiment, the method includes administering the
molecules to the patient during a treatment session that is
subsequent to regulating the parameter of the odorant presentation.
In an embodiment, the method includes administering the molecules
to the patient during a treatment session, and regulating the
parameter of the odorant presentation during the same treatment
session. For some applications, regulating the parameter of the
odorant presentation includes selecting the parameter from a
predefined set of parameters for the odorant presentation.
[0233] For some applications, the method includes sensing a
parameter of the patient and regulating the parameter of the
odorant presentation responsive thereto. The parameter of the
patient may include an indication of a behavior of the patient, in
which case sensing the parameter of the patient includes sensing
the indication of the behavior of the patient Alternatively, the
parameter of the patient may be selected from the list consisting
of: a biochemical value of the patient and a physiological value of
the patient, in which case sensing the parameter of the patient
includes sensing the parameter of the patient selected from the
list.
[0234] In an embodiment, the molecules include the therapeutic
agent, and presenting the odorant includes presenting the odorant,
the odorant being such as to increase the conductance of the
therapeutic agent. For some applications, the therapeutic agent
includes a neurological drug, and presenting the odorant includes
presenting the odorant, the odorant being such as to increase the
conductance of the neurological drug. For some applications, the
therapeutic agent includes a protein, and presenting the odorant
includes presenting the odorant, the odorant being such as to
increase the conductance of the protein. For some applications, the
therapeutic agent includes a polymer, and presenting the odorant
includes presenting the odorant, the odorant being such as to
increase the conductance of the polymer. For some applications, the
therapeutic agent includes a viral vector, and presenting the
odorant includes presenting the odorant, the odorant being such as
to increase the conductance of the viral vector.
[0235] For some applications, the therapeutic agent includes an
anti-cancer drug, and presenting the odorant includes presenting
the odorant, the odorant being such as to increase the conductance
of the anti-cancer drug. For some applications, the therapeutic
agent includes an agent from the list consisting of: glatiramer
acetate and interferon beta-1b, and presenting the odorant includes
presenting the odorant, the odorant being such as to increase the
conductance of the agent selected from the list. For some
applications, the therapeutic agent includes an agent from the list
consisting of: an agent for DNA therapy and an agent for RNA
therapy, and presenting the odorant includes presenting the
odorant, the odorant being such as to increase the conductance of
the agent selected from the list. For some applications, the
therapeutic agent includes an agent from the list consisting
of:
[0236] (a) an antisense molecule against type-1 insulin-like growth
factor receptor, and (b) ADV-HSV-tk, and presenting the odorant
includes presenting the odorant, the odorant being such as to
increase the conductance of the agent selected from the list
consisting of the antisense molecule and the ADV-HSV-tk.
[0237] In an embodiment, the method includes administering the
molecules in conjunction with presenting the odorant. In an
embodiment, administering the molecules in conjunction with
presenting the odorant includes administering the molecules at a
time determined with respect to a time of presenting the odorant.
For some applications, administering the molecules includes
administering the molecules at least a predetermined time prior to
presenting the odorant. Alternatively, administering the molecules
includes administering the molecules at generally the same time as
presenting the odorant. Further alternatively, administering the
molecules includes administering the molecules at least a
predetermined time subsequent to presenting the odorant.
[0238] In an embodiment, the molecules include the pharmacological
agent, and presenting the odorant includes presenting the odorant,
the odorant being such as to increase the conductance of the
pharmacological agent. For some applications, the pharmacological
agent includes a viral vector, and presenting the odorant includes
presenting the odorant, the odorant being such as to increase the
conductance of the viral vector. For some applications, the
pharmacological agent includes an antibody, and presenting the
odorant includes presenting the odorant, the odorant being such as
to increase the conductance of the antibody. For some applications,
the antibody is selected from the list consisting of: a
toxin-antibody complex, a radiolabeled antibody, and anti-HER2 mAb,
and presenting the odorant includes presenting the odorant, the
odorant being such as to increase the conductance of the selected
antibody. Alternatively, the antibody is selected from the list
consisting of: anti-b-amyloid antibody and
anti-amyloid-precursor-protein antibody, and presenting the odorant
includes presenting the odorant, the odorant being such as to
increase the conductance of the selected antibody.
[0239] In an embodiment, the molecules include the endogenous
agent, and presenting the odorant includes presenting the odorant,
the odorant being such as to increase the conductance of the
endogenous agent. For some applications, the endogenous agent
includes an endogenous agent substantially unmodified by artificial
means, and presenting the odorant includes presenting the odorant,
the odorant being such as to increase the conductance of the
endogenous agent that is substantially unmodified by artificial
means. Alternatively, the endogenous agent includes an endogenous
agent an aspect of which is modified by artificial means, and
presenting the odorant includes presenting the odorant, the odorant
being such as to increase the conductance of the endogenous agent
the aspect of which is modified by artificial means. Further
alternatively, the endogenous agent includes an enzyme, and
presenting the odorant includes presenting the odorant, the odorant
being such as to increase the conductance of the enzyme. For some
applications, the enzyme includes hexosamimidase, and presenting
the odorant includes presenting the odorant, the odorant being such
as to increase the conductance of the hexosaminidase.
[0240] In an embodiment, the method includes administering the
molecules to a mucous membrane of the patient. For some
applications, administering the molecules includes administering
the molecules to oral mucosa of the patient. Alternatively,
administering the molecules includes administering the molecules to
nasal mucosa of the patient.
[0241] For some applications, administering the molecules includes
administering the molecules in combination with the odorant.
Alternatively, administering the molecules includes administering
the molecules separately from the odorant.
[0242] In an embodiment of the present invention, presenting the
odorant to the air passage of the patient includes presenting the
odorant, the odorant having been selected for presentation to the
air passage because it is such as to increase conductance of
molecules from the brain tissue of the patient through the blood
brain barrier (BBB) into the systemic blood circulation.
[0243] In an embodiment, the method includes sensing a quantity of
the molecules from a site outside of the brain of the patient,
following initiation of presentation of the odorant. For some
applications, sensing the quantity of the molecules includes
sensing using a modality selected from the list consisting of: CT,
MRI, PET, SPECT, angiography, ophthalmoscopy, fluoroscopy, light
microscopy, and oximetry. For some applications, sensing the
quantity of the molecules includes sampling a fluid of the patient
selected from the list consisting of: blood, plasma, serum, ascites
fluid, and urine.
[0244] In an embodiment, the method includes determining a
diagnostically-relevant parameter responsive to sensing the
quantity of the molecules.
[0245] In an embodiment, the method includes selecting a dosage of
the odorant responsive to a disorder of the patient. For some
applications, selecting the dosage of the odorant includes
determining a dosage of the odorant that increases conductance of
the molecules, responsive to presentation of the odorant, to an
extent sufficient to treat the disorder at least in part. For some
applications, selecting the dosage includes selecting the dosage
responsive to the disorder of the patient, the disorder being
selected from the list consisting of: a brain tumor, epilepsy,
Parkinson's disease, Alzheimer's disease, multiple sclerosis,
schizophrenia, depression, stress, obesity, pain, and anxiety.
[0246] In an embodiment, the method includes administering a
hyperosmolarity-inducing agent to the patient at a dosage
sufficient to augment an increase in conductance of the molecules
caused by presentation of the odorant.
[0247] In an embodiment, the method includes inducing a state of
dehydration of the patient, of an extent sufficient to augment an
increase in conductance of the molecules caused by presentation of
the odorant.
[0248] In an embodiment, the method includes administering an agent
to the patient that modulates synthesis or metabolism of
nitric-oxide (NO) in blood vessels of the brain, at a dosage
sufficient to augment an increase in conductance of the molecules
caused by presentation of the odorant.
[0249] There is additionally provided, in accordance with a
preferred embodiment of the present invention, a method for
modifying a property of a brain of a patient during or following a
stroke event, including presenting an odorant to an air passage of
the patient, the odorant having been selected for presentation to
the air passage because it is capable of inducing an increase in
cerebral blood flow of the patient, so as to reduce a pathology
associated with the stroke event.
[0250] In an embodiment, presenting the odorant includes presenting
the odorant in a dosage determined to increase the cerebral blood
flow.
[0251] There is also provided, in accordance with a preferred
embodiment of the present invention, a method for modifying a
property of a brain of a patient who suffers from headache attacks,
including presenting an odorant to an air passage of the patient,
the odorant having been selected for presentation to the air
passage because it is capable of modifying cerebral blood flow of
the patient, so as to reduce a severity of a headache attack of the
patient.
[0252] In an embodiment, presenting the odorant includes presenting
the odorant in a dosage determined to modify the cerebral blood
flow.
[0253] In an embodiment, presenting the odorant includes selecting
the odorant, the odorant being capable of decreasing the cerebral
blood flow, so as to reduce the severity of the headache
attack.
[0254] In an embodiment, the headache attack includes a migraine
headache attack of the patient, and presenting the odorant includes
presenting to the air passage an odorant that is capable of
reducing the cerebral blood flow, so as to reduce the severity of
the migraine headache attack. In an embodiment, the headache attack
includes a cluster headache attack of the patient, and presenting
the odorant includes presenting to the air passage an odorant that
is capable of reducing the cerebral blood flow, so as to reduce the
severity of the cluster headache attack.
[0255] There is further provided, in accordance with a preferred
embodiment of the present invention, a method for modifying a
property of a brain of a patient who suffers from a disorder of the
central nervous system (CNS), including presenting an odorant to an
air passage of the patient, the odorant having been selected for
presentation to the air passage because it is capable of modifying
cerebral blood flow of the patient, so as to treat the CNS
disorder.
[0256] In an embodiment, presenting the odorant includes presenting
the odorant in a dosage determined to modify the cerebral blood
flow.
[0257] In an embodiment, the CNS disorder is selected from the list
consisting of: a brain tumor, epilepsy, Parkinson's disease,
Alzheimer's disease, multiple sclerosis, schizophrenia, depression,
stress, obesity, pain, and anxiety, and presenting the odorant
includes presenting the odorant that is capable of modifying the
cerebral blood flow, so as to treat the selected CNS disorder.
[0258] In an embodiment, presenting the odorant includes selecting
the odorant, the odorant being capable of decreasing the cerebral
blood flow. In an embodiment, presenting the odorant includes
selecting the odorant, the odorant being capable of increasing
cerebral blood flow of the patient. In an embodiment, presenting
the odorant includes selecting the odorant, the odorant being
capable of increasing cortical blood flow of the patient.
[0259] There is still further provided, in accordance with a
preferred embodiment of the present invention, a method for
modifying a property of a brain of a patient, including presenting
an odorant to an air passage of the patient, the odorant having
been selected for presentation to the air passage because it is
such as to decrease conductance of molecules from a systemic blood
circulation of the patient through a blood brain barrier (BBB) of
the brain into brain tissue of the patient.
[0260] In an embodiment, presenting the odorant includes presenting
the odorant in a dosage determined to decrease the conductance of
the molecules.
[0261] In an embodiment, the method includes presenting in
association with the odorant an analgesic in a dosage configured to
reduce a sensation associated with the presenting of the odorant.
In an embodiment, presenting the analgesic includes topically
presenting the analgesic at a site selected from the list
consisting of: a vicinity of one or more nerves in a nasal cavity
of the patient, a vicinity of one or more nerves in an oral cavity
of the patient, and a vicinity of one or more nerves innervating a
face of the patient. In an embodiment, presenting the analgesic
includes topically presenting the analgesic in a vicinity of a
sphenopalatine ganglion (SPG) of the patient. In an embodiment,
presenting the analgesic includes administering the analgesic for
inhalation at generally the same time as the presenting of the
odorant.
[0262] In an embodiment, the air passage includes a nasal cavity of
the patient, and presenting the odorant includes presenting the
odorant to the nasal cavity.
[0263] In an embodiment, the air passage includes a throat of the
patient, and presenting the odorant includes presenting the odorant
to the throat.
[0264] In an embodiment, the odorant is selected from the list
consisting of: propionic acid, cyclohexanone, and amyl acetate, and
presenting the odorant includes presenting the selected odorant.
Alternatively, the odorant is selected from the list consisting of:
acetic acid, citric acid, carbon dioxide, sodium chloride, and
ammonia, and presenting the odorant includes presenting the
selected odorant. Further alternatively, the odorant is selected
from the list consisting of: menthol, alcohol, nicotine, piperine,
gingerol, zingerone, allyl isothiocyanate, cinnamaldehyde,
cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate, thymol, and
eucalyptol, and presenting the odorant includes presenting the
selected odorant.
[0265] In an embodiment, presenting the odorant includes presenting
a capsule for placement within a mouth of the patient, the capsule
being configured to dissolve upon contact with salivary liquids of
the patient, whereupon the odorant is presented to the air
passage.
[0266] In an embodiment, the method includes regulating a parameter
of the odorant presentation. For some applications, regulating the
parameter includes regulating a parameter selected from the list
consisting of: relative concentrations of two or more ingredients
of the odorant, a quantity of the odorant presented, a rate of
presentation of the odorant, a pressure of the odorant at
presentation, and a temperature of at least a portion of the
odorant. Alternatively or additionally, regulating the parameter of
the odorant presentation includes selecting the parameter from a
predefined set of parameters for the odorant presentation.
[0267] In an embodiment, the method includes sensing a parameter of
the patient and regulating the parameter of the odorant
presentation responsive thereto. For some applications, the
parameter of the patient includes an indication of a behavior of
the patient, and sensing the parameter of the patient includes
sensing the indication of the behavior of the patient.
[0268] In an embodiment, the parameter of the patient is selected
from the list consisting of: a biochemical value of the patient and
a physiological value of the patient, and sensing the parameter of
the patient includes sensing the parameter of the patient selected
from the list.
[0269] In an embodiment, the method includes sensing a parameter of
the patient and presenting the odorant responsive thereto. For some
applications, the parameter includes an indication of a behavior of
the patient, and sensing the parameter includes sensing the
indication of the behavior of the patient. Alternatively, the
parameter is selected from the list consisting of: a biochemical
value of the patient and a physiological value of the patient, and
sensing the parameter includes sensing the parameter selected from
the list. For some applications, sensing the parameter selected
from the list includes sensing the parameter using a modality
selected from the list consisting of: CT, MRI, PET, SPECT,
angiography, ophthalmoscopy, fluoroscopy, light microscopy, and
oximetry. Alternatively, sensing the parameter selected from the
list includes sampling a body fluid of the patient selected from
the list consisting of: blood, plasma, serum, ascites fluid, and
urine.
[0270] There is additionally provided, in accordance with a
preferred embodiment of the present invention, apparatus for
modifying a property of a brain of a patient, including:
[0271] an odorant-storage vessel;
[0272] an odorant for storage within the odorant-storage vessel,
the odorant being capable of increasing conductance of molecules
from a systemic blood circulation of the patient through a blood
brain barrier (BBB) of the brain into brain tissue of the patient,
the molecules being selected from the group consisting of: a
pharmacological agent, a therapeutic agent, and an agent for
facilitating a diagnostic procedure; and
[0273] an odorant-delivery element, adapted to present the odorant
to an air passage of the patient.
[0274] In an embodiment, the odorant-storage vessel is adapted to
store the odorant mixed with the molecules.
[0275] In an embodiment, the molecules include the therapeutic
agent, and the odorant is such as to increase the conductance of
the therapeutic agent.
[0276] In an embodiment, the therapeutic agent includes a
neurological drug, and the odorant is such as to increase the
conductance of the neurological drug.
[0277] In an embodiment, the molecules include the agent for
facilitating a diagnostic procedure, and the odorant is such as to
increase the conductance of the agent for facilitating the
diagnostic procedure. For some applications, the agent for
facilitating a diagnostic procedure includes a radio-opaque
material, and the odorant is such as to increase the conductance of
the radio-opaque material.
[0278] In an embodiment, the odorant includes an agent for
facilitating treatment of a disorder of the central nervous system
(CNS) of the patient. For some applications, the CNS disorder is
selected from the list consisting of: a brain tumor, epilepsy,
Parkinson's disease, Alzheimer's disease, multiple sclerosis,
schizophrenia, depression, stress, obesity, pain, and anxiety, and
the odorant includes an agent for facilitating treatment of the
selected CNS disorder.
[0279] There is yet additionally provided, in accordance with a
preferred embodiment of the present invention, apparatus for
modifying a property of a brain of a patient during or following a
stroke event, including:
[0280] an odorant-storage vessel;
[0281] an odorant, for storage within the odorant-storage vessel,
the odorant being capable of inducing an increase in cerebral blood
flow of the patient; and
[0282] an odorant-delivery element, adapted to present the odorant
to an air passage of the patient, so as to reduce a pathology
associated with the stroke event.
[0283] There is further provided, in accordance with a preferred
embodiment of the present invention, apparatus for modifying a
property of a brain of a patient who suffers from headache attacks,
including:
[0284] an odorant-storage vessel;
[0285] an odorant, for storage within the odorant-storage vessel,
the odorant being capable of modifying cerebral blood flow of the
patient; and
[0286] an odorant-delivery element, configured to present the
odorant to an air passage of the patient, so as to reduce a
severity of a headache attack of the patient.
[0287] In an embodiment, the odorant is capable of decreasing the
cerebral blood flow.
[0288] In an embodiment, the headache attack includes a migraine
headache attack of the patient, and the odorant is capable of
reducing the severity of the migraine headache attack. In an
embodiment, the headache attack includes a cluster headache attack
of the patient, and the odorant is capable of reducing the severity
of the cluster headache attack.
[0289] There is still additionally provided, in accordance with a
preferred embodiment of the present invention, apparatus for
modifying a property of a brain of a patient who suffers from a
disorder of the central nervous system (CNS), including:
[0290] an odorant-storage vessel;
[0291] an odorant for storage within the odorant-storage vessel,
the odorant being capable of modifying cerebral blood flow of the
patient; and
[0292] an odorant-delivery element, configured to present the
odorant to an air passage of the patient, so as to treat the CNS
disorder.
[0293] In an embodiment, the CNS disorder is selected from the list
consisting of: a brain tumor, epilepsy, Parkinson's disease,
Alzheimer's disease, multiple sclerosis, schizophrenia, depression,
stress, obesity, pain, and anxiety, and the odorant includes an
agent for facilitating treatment of the selected CNS disorder.
[0294] In an embodiment, the odorant is capable of decreasing the
cerebral blood flow. Alternatively, the odorant is capable of
increasing the cerebral blood flow. For some applications, the
odorant is capable of increasing cortical blood flow of the
patient.
[0295] There is further provided, in accordance with a preferred
embodiment of the present invention, apparatus for modifying a
property of a brain of a patient, including:
[0296] an odorant-storage vessel;
[0297] an odorant, for storage within the odorant-storage vessel,
the odorant being capable of decreasing conductance of molecules
from a systemic blood circulation of the patient through a blood
brain barrier (BBB) of the brain into brain tissue of the patient;
and
[0298] an odorant-delivery element, adapted to present the odorant
to an air passage of the patient.
[0299] In an embodiment, the apparatus includes an analgesic for
storage within the odorant-storage vessel in a dosage configured to
reduce a sensation associated with the presenting of the odorant,
and the odorant-delivery element is adapted to present the
analgesic to the air passage in association with the odorant.
[0300] In an embodiment, the odorant-storage vessel in combination
with the odorant-delivery element includes an aqueous spray nasal
inhaler. Alternatively, the odorant-storage vessel in combination
with the odorant-delivery element includes a metered dose nasal
inhaler. Further alternatively, the odorant-storage vessel in
combination with the odorant-delivery element includes an
air-dilution olfactometer.
[0301] In an embodiment, the air passage includes a nasal cavity of
the patient, and the odorant-delivery element is adapted to present
the odorant to the nasal cavity.
[0302] In an embodiment, the air passage includes a throat of the
patient, and the odorant-delivery element is adapted to present the
odorant to the throat.
[0303] In an embodiment, the odorant includes an agent selected
from the list consisting of: propionic acid, cyclohexanone, and
amyl acetate. Alternatively, the odorant includes an agent selected
from the list consisting of: acetic acid, citric acid, carbon
dioxide, sodium chloride, and ammonia. Further alternatively, the
odorant includes an agent selected from the list consisting of:
menthol, alcohol, nicotine, piperine, gingerol, zingerone, allyl
isothiocyanate, cinnamaldehyde, cuminaldehyde,
2-propenyl/2-phenylethyl isothiocyanate, thymol, and
eucalyptol.
[0304] In an embodiment, the odorant-storage vessel includes a
capsule for placement in a mouth of the patient, and the
odorant-delivery element includes a portion of the capsule adapted
to dissolve upon contact with salivary liquids of the patient,
whereupon the odorant is presented to the air passage of the
patient.
[0305] There is also provided, in accordance with a preferred
embodiment of the present invention, a method for treating
Alzheimer's disease (AD), including stimulating a sphenopalatine
ganglion (SPG) of a subject so that the concentration of a
substance in a brain of the subject changes.
[0306] In a preferred embodiment, the stimulation causes increased
clearance of the substance from the brain. As appropriate, the
substance may be one or more of the following:
[0307] amyloid;
[0308] tau protein;
[0309] PS1;
[0310] PS2;
[0311] RNA fragments;
[0312] cytokine;
[0313] a marker of neuronal death;
[0314] a marker of neuronal degeneration;
[0315] a marker of an inflammatory process; and
[0316] a neurotoxic substance.
[0317] Alternatively or additionally, the substance may include
DNA.
[0318] In another preferred embodiment, the stimulation causes
increased clearance of the substance from cerebrospinal fluid
(CSF). As appropriate, the substance may be one or more of the
following:
[0319] amyloid;
[0320] tau protein;
[0321] PS1;
[0322] PS2;
[0323] RNA fragments;
[0324] cytokine;
[0325] a marker of neuronal death;
[0326] a marker of neuronal degeneration;
[0327] a marker of an inflammatory process; and
[0328] a neurotoxic substance.
[0329] Alternatively or additionally, the substance may include
DNA.
[0330] There is additionally provided, in accordance with a
preferred embodiment of the present invention, a method for
treating Alzheimer's disease (AD), including:
[0331] supplying a pharmaceutical agent to blood of a subject;
and
[0332] stimulating a sphenopalatine ganglion (SPG) of the subject
so that the concentration of the pharmaceutical agent in a brain of
the subject increases.
[0333] As appropriate, the pharmaceutical agent may be one or more
of the following:
[0334] a glutamate receptor antagonist;
[0335] a .beta.-amyloid inhibitor;
[0336] an NMDA-receptor blocker;
[0337] a combination of an AD vaccine and an anti-inflammatory
drug;
[0338] a microglial activation modulator;
[0339] a cholinesterase inhibitor;
[0340] a stimulant of nerve regeneration;
[0341] a nerve growth factor;
[0342] a compound that stimulates production of nerve growth
factor;
[0343] an antioxidant;
[0344] a hormone;
[0345] an inhibitor of protein tyrosine phosphatases;
[0346] medium chain triglycerides;
[0347] an endogenous protein;
[0348] a gene therapy agent;
[0349] an anti-inflammatory drug;
[0350] a non-steroidal anti-inflammatory drug; and
[0351] an AD vaccine. More specifically, the AD vaccine may contain
antibodies against a specific protein that is characteristic of AD.
Still more specifically, the AD vaccine may contain antibodies
against P-amyloid and/or antibodies against tau protein.
[0352] Alternatively, the pharmaceutical agent is adapted to have
an inhibitory effect on the derivation of .beta.-amyloid from
amyloid precursor protein.
[0353] There is yet additionally provided, in accordance with a
preferred embodiment of the present invention, a method for
diagnosing Alzheimer's disease (AD), including stimulating a
sphenopalatine ganglion (SPG) of a subject so that molecular
passage increases between a central nervous system (CNS) of the
subject and another body compartment of the subject.
[0354] Preferably, the method includes measuring a constituent of
the other body compartment. As appropriate, the other body
compartment may be one of the following:
[0355] blood of the subject;
[0356] plasma of the subject;
[0357] serum of the subject; and
[0358] ascites of the subject.
[0359] There is still additionally provided, in accordance with a
preferred embodiment of the present invention, a method for
diagnosing Alzheimer's disease (AD), including stimulating a
sphenopalatine ganglion (SPG) of a subject so that molecular
passage increases between cerebrospinal fluid (CSF) of the subject
and another body fluid of the subject.
[0360] Preferably, the method includes measuring a constituent of
the other body fluid. More preferably, the method includes
correlating an abnormal concentration of the constituent to a
pathology of AD. As appropriate, the constituent may be selected
from the group consisting of the following: a protein, a hormone,
an antibody, an electrolyte, a neuropeptide, and an enzyme.
[0361] Alternatively or additionally, the measurement is performed
by sampling a fluid selected from the group consisting of the
following: whole blood, plasma, serum, and ascites. Further
alternatively or additionally, the measurement is performed by
extracting the fluid from tissue of the subject.
[0362] Optionally, the measurement may be performed by measuring
more than one constituent. In this case, a diagnostic result may be
determined according to the interrelation between concentrations of
the constituents.
[0363] There is also provided, in accordance with a preferred
embodiment of the present invention, a method for diagnosing
Alzheimer's disease (AD), including stimulating a sphenopalatine
ganglion (SPG) of a subject so that molecular passage increases
between cerebrospinal fluid (CSF) of the subject and a tissue of
the subject.
[0364] Preferably, the method includes measuring a constituent of
the tissue. More preferably, the method includes correlating an
abnormal concentration of the constituent to a pathology of AD. As
appropriate, the constituent may be selected from the group
consisting of the following: a protein, a hormone, an antibody, an
electrolyte, a neuropeptide, and an enzyme.
[0365] Optionally, the measurement may be performed by measuring
more than one constituent. In this case, a diagnostic result may be
determined according to the interrelation between concentrations of
the constituents.
[0366] There is further provided, in accordance with a preferred
embodiment of the present invention, a system for treating
Alzheimer's disease (AD), including a stimulator for stimulating
the sphenopalatine ganglion (SPG) of a subject, so that the
concentration of a substance in a brain of the subject changes.
[0367] There is yet further provided, in accordance with a
preferred embodiment of the present invention, a pharmaceutical
agent delivery system for treating Alzheimer's disease (AD),
including:
[0368] a pharmaceutical agent supplied to a body of a subject for
delivery to a brain of the subject via blood of said subject;
and
[0369] a stimulator for stimulating a sphenopalatine ganglion (SPG)
of the subject, so that the concentration of the pharmaceutical
agent in the brain increases.
[0370] There is still further provided, in accordance with a
preferred embodiment of the present invention, a system for
diagnosing Alzheimer's disease (AD), including a stimulator for
stimulating a sphenopalatine ganglion (SPG) of a subject, so that
molecular passage increases between a CNS of the subject and
another body compartment of the subject.
[0371] There is additionally provided, in accordance with a
preferred embodiment of the present invention, a system for
diagnosing Alzheimer's disease (AD), including a stimulator for
stimulating a sphenopalatine ganglion (SPG) of a subject, so that
molecular passage increases between cerebrospinal fluid (CSF) of
the subject and another body fluid of the subject.
[0372] There is yet additionally provided, in accordance with a
preferred embodiment of the present invention, a system for
diagnosing Alzheimer's disease (AD), including a stimulator for
stimulating a sphenopalatine ganglion (SPG) of a subject, so that
molecular passage increases between cerebrospinal fluid (CSF) of
the subject and a tissue of the subject.
[0373] There is therefore provided, in accordance with an
embodiment of the present invention, a method for treating
Alzheimer's disease (AD), including:
[0374] stimulating sphenopalatine ganglion (SPG)-related tissue of
a subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG; and
[0375] configuring the stimulation so as to cause an increase in
clearance of an AD-related constituent of a central nervous system
(CNS) of the subject, from a brain of the subject to a systemic
blood circulation of the subject, so as to treat the AD.
[0376] There is further provided, in accordance with an embodiment
of the present invention, a method for treating Alzheimer's disease
(AD), including:
[0377] stimulating sphenopalatine ganglion (SPG)-related tissue of
a subject by presenting an odorant to an air passage of the
subject, the SPG-related tissue selected from: an SPG of the
subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
[0378] configuring the stimulation so as to cause an increase in
clearance of an AD-related constituent of a central nervous system
(CNS) of the subject, from a brain of the subject to a systemic
blood circulation of the subject, so as to treat the AD.
[0379] There is still further provided, in accordance with an
embodiment of the present invention, a method for treating
Alzheimer's disease (AD), including:
[0380] stimulating sphenopalatine ganglion (SPG)-related tissue of
a subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG; and
[0381] configuring the stimulation so as to cause an increase in
clearance of an AD-related constituent of a central nervous system
(CNS) of the subject, from cerebrospinal fluid (CSF) of the subject
to a systemic blood circulation of the subject, so as to treat the
AD.
[0382] There is yet further provided, in accordance with an
embodiment of the present invention, a method for treating
Alzheimer's disease (AD), including:
[0383] stimulating sphenopalatine ganglion (SPG)-related tissue of
a subject by presenting an odorant to an air passage of the
subject, the SPG-related tissue selected from: an SPG of the
subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
[0384] configuring the stimulation so as to cause an increase in
clearance of an AD-related constituent of a central nervous system
(CNS) of the subject, from cerebrospinal fluid (CSF) of the subject
to a systemic blood circulation of the subject, so as to treat the
AD.
[0385] In an embodiment, stimulating the SPG-related tissue
includes directly stimulating the SPG.
[0386] For some applications, the AD-related constituent includes
an inflammatory-related constituent, tau protein, PS1, PS2, a DNA
fragment, an RNA fragment, a cytokine, a marker of neuronal death
or degeneration, a marker of an inflammatory process, a neurotoxic
substance, amyloid protein, an amyloid protein selected from the
list consisting of: wild amyloid protein and mutated amyloid
protein, and/or an amyloid protein selected from the list
consisting of: fragmented amyloid protein and whole amyloid
protein, and configuring the stimulation includes configuring the
stimulation so as to cause the increase in the clearance of the
inflammatory-related constituent, tau protein, PS1, PS2, DNA
fragment, RNA fragment, cytokine, marker of neuronal death or
degeneration, marker of an inflammatory process, neurotoxic
substance, amyloid protein, amyloid protein selected from the list
consisting of: wild amyloid protein and mutated amyloid protein,
and/or amyloid protein selected from the list consisting of:
fragmented amyloid protein and whole amyloid protein.
[0387] There is also provided, in accordance with an embodiment of
the present invention, a method for treating Alzheimer's disease
(AD), including:
[0388] supplying a pharmaceutical agent to a systemic blood
circulation of a subject;
[0389] stimulating sphenopalatine ganglion (SPG)-related tissue of
the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG; and
[0390] configuring the stimulation so as to cause an increase in
passage of the pharmaceutical agent from the systemic blood
circulation into a central nervous system (CNS) of the subject, so
as to treat the AD.
[0391] There is additionally provided, in accordance with an
embodiment of the present invention, a method for treating
Alzheimer's disease (AD), including:
[0392] supplying a pharmaceutical agent to a systemic blood
circulation of a subject;
[0393] stimulating sphenopalatine ganglion (SPG)-related tissue of
the subject by presenting an odorant to an air passage of the
subject, the SPG-related tissue selected from: an SPG of the
subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
[0394] configuring the stimulation so as to cause an increase in
passage of the pharmaceutical agent from the systemic blood
circulation into a central nervous system (CNS) of the subject, so
as to treat the AD.
[0395] In an embodiment, supplying the pharmaceutical agent
includes administering the pharmaceutical agent to the systemic
blood circulation using a technique selected from the list
consisting of: per-oral administration, intravenous administration,
intra-arterial administration, intraperitoneal administration,
subcutaneous administration, and intramuscular administration.
[0396] For some applications, the pharmaceutical agent includes a
glutamate receptor antagonist, an NMDA receptor blocker, an agent
having an inhibitory effect on derivation of .beta.-amyloid from
amyloid precursor protein, a cholinesterase inhibitor, a stimulant
of nerve regeneration, a nerve growth factor, a compound that
stimulates production of nerve growth factor, a microglial
activation modulator, an antioxidant, a hormone, an inhibitor of
protein tyrosine phosphatases, a medium chain triglyceride, a gene
therapy agent, a .beta.-amyloid inhibitor, an endogenous protein,
an anti-inflammatory agent, a non-steroidal anti-inflammatory drug
(NSAID), or a pharmaceutical agent selected from the list
consisting of: an AD vaccine, a component of an AD vaccine, and a
derivative of an AD vaccine (for example, the selected
pharmaceutical agent including (a) an anti-inflammatory drug, (b)
antibodies against a specific protein that is characteristic of AD,
(c) antibodies against .beta.-amyloid, or (d) antibodies against
tau protein), and configuring the stimulation includes configuring
the stimulation so as to cause the increase in the passage of the
pharmaceutical agent.
[0397] In an embodiment, supplying the pharmaceutical agent
includes administering the pharmaceutical agent for inhalation by
the subject. For example, administering the pharmaceutical agent
for inhalation by the subject may include administering the
pharmaceutical agent mixed with the odorant.
[0398] There is still additionally provided, in accordance with an
embodiment of the present invention, a method for treating
Alzheimer's disease (AD), including:
[0399] stimulating sphenopalatine ganglion (SPG)-related tissue of
the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG; and
[0400] configuring the stimulation so as to cause an increase in
cerebral blood flow (CBF) of the subject, so as to treat the
AD.
[0401] There is yet additionally provided, in accordance with an
embodiment of the present invention, a method for treating
Alzheimer's disease (AD), including:
[0402] stimulating sphenopalatine ganglion (SPG)-related tissue of
the subject by presenting an odorant to an air passage of the
subject, the SPG-related tissue selected from: an SPG of the
subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
[0403] configuring the stimulation so as to cause an increase in
cerebral blood flow (CBF) of the subject, so as to treat the
AD.
[0404] In an embodiment, configuring the stimulation includes
configuring the stimulation so as to cause an improvement in a
metabolic state of a central nervous system (CNS) of the
subject.
[0405] There is also provided, in accordance with an embodiment of
the present invention, a method for diagnosing Alzheimer's disease
(AD), including:
[0406] stimulating sphenopalatine ganglion (SPG)-related tissue of
a subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG; and
[0407] configuring the stimulation so as to cause an increase in
molecular passage between a central nervous system (CNS) of the
subject and another body compartment of the subject, so as to
facilitate a diagnosis of the AD.
[0408] There is additionally provided, in accordance with an
embodiment of the present invention, a method for diagnosing
Alzheimer's disease (AD), including:
[0409] stimulating sphenopalatine ganglion (SPG)-related tissue of
a subject by presenting an odorant to an air passage of the
subject, the SPG-related tissue selected from: an SPG of the
subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
[0410] configuring the stimulation so as to cause an increase in
molecular passage between a central nervous system (CNS) of the
subject and another body compartment of the subject, so as to
facilitate a diagnosis of the AD.
[0411] In an embodiment, the method includes measuring a
constituent of the other body compartment.
[0412] For some applications, the other body compartment includes a
systemic blood circulation of the subject, and configuring the
stimulation includes configuring the stimulation so as to cause the
increase in molecular passage between the CNS and the systemic
blood circulation. Alternatively or additionally, the other body
compartment includes plasma of the subject, and configuring the
stimulation includes configuring the stimulation so as to cause the
increase in molecular passage between the CNS and the plasma.
Further alternatively or additionally, the other body compartment
includes serum of the subject, and configuring the stimulation
includes configuring the stimulation so as to cause the increase in
molecular passage between the CNS and the serum. Still further
alternatively or additionally, the other body compartment is
ascites of the subject, and configuring the stimulation includes
configuring the stimulation so as to cause the increase in
molecular passage between the CNS and the ascites.
[0413] There is yet additionally provided, in accordance with an
embodiment of the present invention, a method for diagnosing
Alzheimer's disease (AD), including:
[0414] stimulating sphenopalatine ganglion (SPG)-related tissue of
a subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG; and
[0415] configuring the stimulation so as to cause an increase in
molecular passage between cerebrospinal fluid (CSF) of the subject
and another body fluid of the subject, so as to facilitate a
diagnosis of the AD.
[0416] There is still additionally provided, in accordance with an
embodiment of the present invention, a method for diagnosing
Alzheimer's disease (AD), including:
[0417] stimulating sphenopalatine ganglion (SPG)-related tissue of
a subject by presenting an odorant to an air passage of the
subject, the SPG-related tissue selected from: an SPG of the
subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
[0418] configuring the stimulation so as to cause an increase in
molecular passage between cerebrospinal fluid (CSF) of the subject
and another body fluid of the subject, so as to facilitate a
diagnosis of the AD.
[0419] In an embodiment, the method includes measuring a
constituent of the other body fluid.
[0420] In an embodiment, the method includes correlating an
abnormal concentration of the constituent to a pathology of AD.
[0421] For some applications, the constituent is selected from the
group consisting of: a protein, a hormone, an antibody, an
electrolyte, a neuropeptide, and an enzyme, and measuring the
constituent includes measuring the selected constituent.
Alternatively or additionally, the other body fluid is selected
from the list consisting of: whole blood, plasma, serum, and
ascites, and measuring the constituent includes sampling the
selected fluid.
[0422] Measuring the constituent typically includes extracting the
other body fluid from tissue of the subject, and, for some
applications, measuring a plurality of constituents. In an
embodiment, the method includes determining a diagnostic result
according to the interrelation between concentrations of the
constituents.
[0423] There is also provided, in accordance with an embodiment of
the present invention, a method for diagnosing Alzheimer's disease
(AD), including:
[0424] stimulating sphenopalatine ganglion (SPG)-related tissue of
a subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG; and
[0425] configuring the stimulation so as to cause an increase in
molecular passage between cerebrospinal fluid (CSF) of the subject
and a tissue of the subject, so as to facilitate a diagnosis of the
AD.
[0426] There is further provided, in accordance with an embodiment
of the present invention, a method for diagnosing Alzheimer's
disease (AD), including:
[0427] stimulating sphenopalatine ganglion (SPG)-related tissue of
a subject by presenting an odorant to an air passage of the
subject, the SPG-related tissue selected from: an SPG of the
subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
[0428] configuring the stimulation so as to cause an increase in
molecular passage between cerebrospinal fluid (CSF) of the subject
and a tissue of the subject, so as to facilitate a diagnosis of the
AD.
[0429] For some applications, the method includes measuring a
constituent of the tissue and/or correlating an abnormal
concentration of the constituent to a pathology of AD.
[0430] In accordance with an embodiment of the present invention,
the constituent is selected from the group consisting of: a
protein, a hormone, an antibody, an electrolyte, a neuropeptide,
and an enzyme, and measuring the constituent includes measuring the
selected constituent.
[0431] In an embodiment, measuring the constituent includes
measuring a plurality of constituents of the tissue. In this case,
for some applications, the method includes determining a diagnostic
result according to the interrelation between concentrations of the
constituents of the tissue.
[0432] There is still further provided, in accordance with an
embodiment of the present invention, a method for treating
Alzheimer's disease (AD), including:
[0433] applying an electrical signal to at least one site of a
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject; and
[0434] configuring the signal so as to cause an increase in
clearance of an AD-related constituent of a central nervous system
(CNS) of the subject, from a brain of the subject to a systemic
blood circulation of the subject, so as to treat the AD.
[0435] There is yet further provided, in accordance with an
embodiment of the present invention, a method for treating
Alzheimer's disease (AD), including presenting an odorant to an air
passage of a subject, the odorant having been selected for
presentation to the air passage because it is such as to cause an
increase in clearance of an AD-related constituent of a central
nervous system (CNS) of the subject from cerebrospinal fluid (CSF)
of the subject to a systemic blood circulation of the subject, so
as to treat the AD.
[0436] There is also provided, in accordance with an embodiment of
the present invention, a method for treating Alzheimer's disease
(AD), including:
[0437] supplying a pharmaceutical agent to a systemic blood
circulation of a subject;
[0438] applying an electrical signal to at least one site of a
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject; and
[0439] configuring the signal so as to cause an increase in passage
of the pharmaceutical agent from the systemic blood circulation
into a central nervous system (CNS) of the subject, so as to treat
the AD.
[0440] There is additionally provided, in accordance with an
embodiment of the present invention, a method for treating
Alzheimer's disease (AD), including:
[0441] supplying a pharmaceutical agent to a systemic blood
circulation of a subject; and
[0442] presenting an odorant to an air passage of the subject, the
odorant having been selected for presentation to the air passage
because it is such as to cause an increase in passage of the
pharmaceutical agent from the systemic blood circulation into a
central nervous system (CNS) of the subject, so as to treat the
AD.
[0443] There is still additionally provided, in accordance with an
embodiment of the present invention, a method for treating
Alzheimer's disease (AD), including:
[0444] applying an electrical signal to at least one site of a
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject; and
[0445] configuring the signal so as to cause an increase in
cerebral blood flow (CBF) of the subject, so as to treat the
AD.
[0446] There is yet additionally provided, in accordance with an
embodiment of the present invention, a method for treating
Alzheimer's disease (AD), including presenting an odorant to an air
passage of the subject, the odorant having been selected for
presentation to the air passage because it is such as to cause an
increase in cerebral blood flow (CBF) of the subject, so as to
treat the AD.
[0447] There is also provided, in accordance with an embodiment of
the present invention, a method for diagnosing Alzheimer's disease
(AD), including:
[0448] applying an electrical signal to at least one site of a
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject; and
[0449] configuring the signal so as to cause an increase in
molecular passage between a central nervous system (CNS) of the
subject and another body compartment of the subject, so as to
facilitate a diagnosis of the AD.
[0450] There is further provided, in accordance with an embodiment
of the present invention, a method for diagnosing Alzheimer's
disease (AD), including presenting an odorant to an air passage of
the subject, the odorant having been selected for presentation to
the air passage because it is such as to cause an increase in
molecular passage between a central nervous system (CNS) of the
subject and another body compartment of the subject, so as to
facilitate a diagnosis of the AD.
[0451] There is still further provided, in accordance with an
embodiment of the present invention, a method for diagnosing
Alzheimer's disease (AD), including:
[0452] applying an electrical signal to at least one site of a
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject; and
[0453] configuring the signal so as to cause an increase in
molecular passage between cerebrospinal fluid (CSF) of the subject
and another body fluid of the subject, so as to facilitate a
diagnosis of the AD.
[0454] There is yet further provided, in accordance with an
embodiment of the present invention, a method for diagnosing
Alzheimer's disease (AD), including presenting an odorant to an air
passage of the subject, the odorant having been selected for
presentation to the air passage because it is such as to cause an
increase in molecular passage between cerebrospinal fluid (CSF) of
the subject and another body fluid of the subject, so as to
facilitate a diagnosis of the AD.
[0455] There is also provided, in accordance with an embodiment of
the present invention, a method for diagnosing Alzheimer's disease
(AD), including:
[0456] applying an electrical signal to at least one site of a
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject; and
[0457] configuring the signal so as to cause an increase in
molecular passage between cerebrospinal fluid (CSF) of the subject
and a tissue of the subject, so as to facilitate a diagnosis of the
AD.
[0458] There is additionally provided, in accordance with an
embodiment of the present invention, a method for diagnosing
Alzheimer's disease (AD), including presenting an odorant to an air
passage of the subject, the odorant having been selected for
presentation to the air passage because it is such as to cause an
increase in molecular passage between cerebrospinal fluid (CSF) of
the subject and a tissue of the subject, so as to facilitate a
diagnosis of the AD.
[0459] In an embodiment, the method includes presenting in
association with the odorant an analgesic in a dosage configured to
reduce a sensation associated with the presenting of the odorant.
For some applications, the air passage includes a nasal cavity or a
throat of the patient, and presenting the odorant includes
presenting the odorant to the nasal cavity or the throat.
[0460] For some applications, the odorant is selected from the list
consisting of: propionic acid, cyclohexanone, and amyl acetate, and
presenting the odorant includes presenting the selected
odorant.
[0461] Alternatively or additionally, the odorant is selected from
the list consisting of: acetic acid, citric acid, carbon dioxide,
sodium chloride, and ammonia, and presenting the odorant includes
presenting the selected odorant.
[0462] Further alternatively or additionally, the odorant is
selected from the list consisting of: menthol, alcohol, nicotine,
piperine, gingerol, zingerone, allyl isothiocyanate,
cinnamaldehyde, cuminaldehyde, 2-propenyl/2-phenylethyl
isothiocyanate, thymol, and eucalyptol, and presenting the odorant
includes presenting the selected odorant.
[0463] In an embodiment, presenting the odorant includes presenting
a capsule for placement within a mouth of the patient, the capsule
being configured to dissolve upon contact with salivary liquids of
the patient, whereupon the odorant is presented to the air
passage.
[0464] There is yet additionally provided, in accordance with an
embodiment of the present invention, apparatus for treating
Alzheimer's disease (AD), including a stimulator adapted to:
[0465] stimulate sphenopalatine ganglion (SPG)-related tissue of a
subject by applying an electrical signal to the SPG-related tissue,
the SPG-related tissue selected from: an SPG of the subject and
nerve fibers of the subject which are directly anatomically
connected to the SPG, and
[0466] configure the stimulation so as to cause an increase in
clearance of an AD-related constituent of a central nervous system
(CNS) of the subject, from a brain of the subject to a systemic
blood circulation of the subject, so as to treat the AD.
[0467] There is still additionally provided, in accordance with an
embodiment of the present invention, apparatus for treating
Alzheimer's disease (AD), including a stimulator adapted to:
[0468] stimulate sphenopalatine ganglion (SPG)-related tissue of a
subject by presenting an odorant to an air passage of the subject,
the SPG-related tissue selected from: an SPG of the subject and
nerve fibers of the subject which are directly anatomically
connected to the SPG, and
[0469] configure the stimulation so as to cause an increase in
clearance of an AD-related constituent of a central nervous system
(CNS) of the subject, from a brain of the subject to a systemic
blood circulation of the subject, so as to treat the AD.
[0470] There is also provided, in accordance with an embodiment of
the present invention, apparatus for treating Alzheimer's disease
(AD), including a stimulator adapted to:
[0471] stimulate sphenopalatine ganglion (SPG)-related tissue of a
subject by applying an electrical signal to the SPG-related tissue,
the SPG-related tissue selected from: an SPG of the subject and
nerve fibers of the subject which are directly anatomically
connected to the SPG, and
[0472] configure the stimulation so as to cause an increase in
clearance of an AD-related constituent of a central nervous system
(CNS) of the subject, from cerebrospinal fluid (CSF) of the subject
to a systemic blood circulation of the subject, so as to treat the
AD.
[0473] There is further provided, in accordance with an embodiment
of the present invention, apparatus for treating Alzheimer's
disease (AD), including a stimulator adapted to:
[0474] stimulate sphenopalatine ganglion (SPG)-related tissue of a
subject by presenting an odorant to an air passage of the subject,
the SPG-related tissue selected from: an SPG of the subject and
nerve fibers of the subject which are directly anatomically
connected to the SPG, and
[0475] configure the stimulation so as to cause an increase in
clearance of an AD-related constituent of a central nervous system
(CNS) of the subject, from cerebrospinal fluid (CSF) of the subject
to a systemic blood circulation of the subject, so as to treat the
AD.
[0476] In an embodiment, the stimulator is adapted to directly
stimulate the SPG.
[0477] There is still further provided, in accordance with an
embodiment of the present invention, apparatus for treating
Alzheimer's disease (AD), including a stimulator adapted to:
[0478] stimulate sphenopalatine ganglion (SPG)-related tissue of
the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG, and
[0479] configure the stimulation so as to cause an increase in
passage from a systemic blood circulation of the subject into a
central nervous system (CNS) of the subject, of a pharmaceutical
agent supplied to the systemic blood circulation, so as to treat
the AD.
[0480] There is yet further provided, in accordance with an
embodiment of the present invention, apparatus for treating
Alzheimer's disease (AD), including a stimulator adapted to:
[0481] stimulate sphenopalatine ganglion (SPG)-related tissue of
the subject by presenting an odorant to an air passage of the
subject, the SPG-related tissue selected from: an SPG of the
subject and nerve fibers of the subject which are directly
anatomically connected to the SPG, and
[0482] configure the stimulation so as to cause an increase in
passage from a systemic blood circulation of the subject into a
central nervous system (CNS) of the subject, of a pharmaceutical
agent supplied to the systemic blood circulation, so as to treat
the AD.
[0483] There is also provided, in accordance with an embodiment of
the present invention, apparatus for treating Alzheimer's disease
(AD), including a stimulator adapted to:
[0484] stimulate sphenopalatine ganglion (SPG)-related tissue of
the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG, and configure the stimulation so as to cause
an increase in cerebral blood flow (CBF) of the subject, so as to
treat the AD.
[0485] There is additionally provided, in accordance with an
embodiment of the present invention, apparatus for treating
Alzheimer's disease (AD), including a stimulator adapted to:
[0486] stimulate sphenopalatine ganglion (SPG)-related tissue of
the subject by presenting an odorant to an air passage of the
subject, the SPG-related tissue selected from: an SPG of the
subject and nerve fibers of the subject which are directly
anatomically connected to the SPG, and
[0487] configure the stimulation so as to cause an increase in
cerebral blood flow (CBF) of the subject, so as to treat the
AD.
[0488] There is still additionally provided, in accordance with an
embodiment of the present invention, apparatus for diagnosing
Alzheimer's disease (AD), including a stimulator adapted to:
[0489] stimulate sphenopalatine ganglion (SPG)-related tissue of a
subject by applying an electrical signal to the SPG-related tissue,
the SPG-related tissue selected from: an SPG of the subject and
nerve fibers of the subject which are directly anatomically
connected to the SPG, and
[0490] configure the stimulation so as to cause an increase in
molecular passage between a central nervous system (CNS) of the
subject and another body compartment of the subject, so as to
facilitate a diagnosis of the AD.
[0491] There is yet additionally provided, in accordance with an
embodiment of the present invention, apparatus for diagnosing
Alzheimer's disease (AD), including a stimulator adapted to:
[0492] stimulate sphenopalatine ganglion (SPG)-related tissue of a
subject by presenting an odorant to an air passage of the subject,
the SPG-related tissue selected from: an SPG of the subject and
nerve fibers of the subject which are directly anatomically
connected to the SPG, and
[0493] configure the stimulation so as to cause an increase in
molecular passage between a central nervous system (CNS) of the
subject and another body compartment of the subject, so as to
facilitate a diagnosis of the AD.
[0494] There is also provided, in accordance with an embodiment of
the present invention, apparatus for diagnosing Alzheimer's disease
(AD), including a stimulator adapted to:
[0495] stimulate sphenopalatine ganglion (SPG)-related tissue of a
subject by applying an electrical signal to the SPG-related tissue,
the SPG-related tissue selected from: an SPG of the subject and
nerve fibers of the subject which are directly anatomically
connected to the SPG, and
[0496] configure the stimulation so as to cause an increase in
molecular passage between cerebrospinal fluid (CSF) of the subject
and another body fluid of the subject, so as to facilitate a
diagnosis of the AD.
[0497] There is further provided, in accordance with an embodiment
of the present invention, apparatus for diagnosing Alzheimer's
disease (AD), including a stimulator adapted to:
[0498] stimulate sphenopalatine ganglion (SPG)-related tissue of a
subject by presenting an odorant to an air passage of the subject,
the SPG-related tissue selected from: an SPG of the subject and
nerve fibers of the subject which are directly anatomically
connected to the SPG, and
[0499] configure the stimulation so as to cause an increase in
molecular passage between cerebrospinal fluid (CSF) of the subject
and another body fluid of the subject, so as to facilitate a
diagnosis of the AD.
[0500] There is still further provided, in accordance with an
embodiment of the present invention, apparatus for diagnosing
Alzheimer's disease (AD), including a stimulator adapted to:
[0501] stimulate sphenopalatine ganglion (SPG)-related tissue of a
subject by applying an electrical signal to the SPG-related tissue,
the SPG-related tissue selected from: an SPG of the subject and
nerve fibers of the subject which are directly anatomically
connected to the SPG, and
[0502] configure the stimulation so as to cause an increase in
molecular passage between cerebrospinal fluid (CSF) of the subject
and a tissue of the subject, so as to facilitate a diagnosis of the
AD.
[0503] There is yet further provided, in accordance with an
embodiment of the present invention, apparatus for diagnosing
Alzheimer's disease (AD), including a stimulator adapted to:
[0504] stimulate sphenopalatine ganglion (SPG)-related tissue of a
subject by presenting an odorant to an air passage of the subject,
the SPG-related tissue selected from: an SPG of the subject and
nerve fibers of the subject which are directly anatomically
connected to the SPG, and
[0505] configure the stimulation so as to cause an increase in
molecular passage between cerebrospinal fluid (CSF) of the subject
and a tissue of the subject, so as to facilitate a diagnosis of the
AD.
[0506] There is also provided, in accordance with an embodiment of
the present invention, apparatus for treating Alzheimer's disease
(AD), including a stimulator adapted to:
[0507] apply an electrical signal to at least one site of a
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject, and
[0508] configure the signal so as to cause an increase in clearance
of an AD-related constituent of a central nervous system (CNS) of
the subject, from a brain of the subject to a systemic blood
circulation of the subject, so as to treat the AD.
[0509] There is also provided, in accordance with an embodiment of
the present invention, apparatus for treating Alzheimer's disease
(AD), including a stimulator adapted to present an odorant to an
air passage of a subject, the odorant having been selected for
presentation to the air passage because it is such as to cause an
increase in clearance of an AD-related constituent of a central
nervous system (CNS) of the subject from cerebrospinal fluid (CSF)
of the subject to a systemic blood circulation of the subject, so
as to treat the AD.
[0510] There is additionally provided, in accordance with an
embodiment of the present invention, apparatus for treating
Alzheimer's disease (AD), including a stimulator adapted to apply
an electrical signal to at least one site of a subject, the site
selected from the list consisting of: a sphenopalatine ganglion
(SPG) of the subject, an anterior ethmoidal nerve of the subject, a
posterior ethmoidal nerve of the subject, a communicating branch
between an anterior ethmoidal nerve and a retro-orbital branch of
an SPG of the subject, a communicating branch between a posterior
ethmoidal nerve and a retro-orbital branch of an SPG of the
subject, a greater palatine nerve of the subject, a lesser palatine
nerve of the subject, a sphenopalatine nerve of the subject, a
communicating branch between a maxillary nerve and an SPG of the
subject, a nasopalatine nerve of the subject, a posterior nasal
nerve of the subject, an infraorbital nerve of the subject, an otic
ganglion of the subject, an afferent fiber going into the otic
ganglion of the subject, an efferent fiber going out of the otic
ganglion of the subject, a vidian nerve of the subject, a greater
superficial petrosal nerve of the subject, and a lesser deep
petrosal nerve of the subject, and
[0511] configure the signal so as to cause an increase in passage
from a systemic blood circulation of the subject into a central
nervous system (CNS) of the subject, of a pharmaceutical agent
supplied to the systemic blood circulation, so as to treat the
AD.
[0512] There is still additionally provided, in accordance with an
embodiment of the present invention, apparatus for treating
Alzheimer's disease (AD), including a stimulator adapted to present
an odorant to an air passage of the subject, the odorant having
been selected for presentation to the air passage because it is
such as to cause an increase in passage from a systemic blood
circulation of the subject into a central nervous system (CNS) of
the subject, of a pharmaceutical agent supplied to the systemic
blood circulation, so astotreatthe AD.
[0513] There is yet additionally provided, in accordance with an
embodiment of the present invention, apparatus for treating
Alzheimer's disease (AD), including a stimulator adapted to:
[0514] apply an electrical signal to at least one site of a
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject, and
[0515] configure the signal so as to cause an increase in cerebral
blood flow (CBF) of the subject, so as to treat the AD.
[0516] There is also provided, in accordance with an embodiment of
the present invention, apparatus for treating Alzheimer's disease
(AD), including a stimulator adapted to present an odorant to an
air passage of the subject, the odorant having been selected for
presentation to the air passage because it is such as to cause an
increase in cerebral blood flow (CBF) of the subject, so as to
treat the AD.
[0517] There is further provided, in accordance with an embodiment
of the present invention, apparatus for diagnosing Alzheimer's
disease (AD), including a stimulator adapted to:
[0518] apply an electrical signal to at least one site of a
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject, and
[0519] configure the signal so as to cause an increase in molecular
passage between a central nervous system (CNS) of the subject and
another body compartment of the subject, so as to facilitate a
diagnosis of the AD.
[0520] There is still further provided, in accordance with an
embodiment of the present invention, apparatus for diagnosing
Alzheimer's disease (AD), including a stimulator adapted to present
an odorant to an air passage of the subject, the odorant having
been selected for presentation to the air passage because it is
such as to cause an increase in molecular passage between a central
nervous system (CNS) of the subject and another body compartment of
the subject, so as to facilitate a diagnosis of the AD.
[0521] There is yet further provided, in accordance with an
embodiment of the present invention, apparatus for diagnosing
Alzheimer's disease (AD), including a stimulator adapted to:
[0522] apply an electrical signal to at least one site of a
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject, and
[0523] configure the signal so as to cause an increase in molecular
passage between cerebrospinal fluid (CSF) of the subject and
another body fluid of the subject, so as to facilitate a diagnosis
of the AD.
[0524] There is also provided, in accordance with an embodiment of
the present invention, apparatus for diagnosing Alzheimer's disease
(AD), including a stimulator adapted to present an odorant to an
air passage of the subject, the odorant having been selected for
presentation to the air passage because it is such as to cause an
increase in molecular passage between cerebrospinal fluid (CSF) of
the subject and another body fluid of the subject, so as to
facilitate a diagnosis of the AD.
[0525] There is additionally provided, in accordance with an
embodiment of the present invention, apparatus for diagnosing
Alzheimer's disease (AD), including a stimulator adapted to:
[0526] apply an electrical signal to at least one site of a
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject, and
[0527] configure the signal so as to cause an increase in molecular
passage between cerebrospinal fluid (CSF) of the subject and a
tissue of the subject, so as to facilitate a diagnosis of the
AD.
[0528] There is still additionally provided, in accordance with an
embodiment of the present invention, apparatus for diagnosing
Alzheimer's disease (AD), including a stimulator adapted to present
an odorant to an air passage of the subject, the odorant having
been selected for presentation to the air passage because it is
such as to cause an increase in molecular passage between
cerebrospinal fluid (CSF) of the subject and a tissue of the
subject, so as to facilitate a diagnosis of the AD.
[0529] There is yet additionally provided, in accordance with an
embodiment of the present invention, apparatus for treating
Alzheimer's disease (AD), including:
[0530] an odorant-storage vessel;
[0531] an odorant for storage within the odorant-storage vessel,
the odorant being capable of increasing clearance of an AD-related
constituent of a central nervous system (CNS) of the subject from
cerebrospinal fluid (CSF) of the subject to a systemic blood
circulation of the subject; and
[0532] an odorant-delivery element, adapted to present the odorant
to an air passage of the patient, so as to treat the AD.
[0533] There is also provided, in accordance with an embodiment of
the present invention, apparatus for treating Alzheimer's disease
(AD), including:
[0534] an odorant-storage vessel;
[0535] an odorant for storage within the odorant-storage vessel,
the odorant being capable of increasing passage, from a systemic
blood circulation of a subject into a central nervous system (CNS)
of the subject, of a pharmaceutical agent supplied to the systemic
blood circulation; and
[0536] an odorant-delivery element, adapted to present the odorant
to an air passage of the patient, so as to treat the AD.
[0537] There is further provided, in accordance with an embodiment
of the present invention, apparatus for treating Alzheimer's
disease (AD), including:
[0538] an odorant-storage vessel;
[0539] an odorant for storage within the odorant-storage vessel,
the odorant being capable of increasing cerebral blood flow (CBF)
of the subject; and
[0540] an odorant-delivery element, adapted to present the odorant
to an air passage of the patient, so as to treat the AD.
[0541] There is still further provided, in accordance with an
embodiment of the present invention, apparatus for diagnosing
Alzheimer's disease (AD), including:
[0542] an odorant-storage vessel;
[0543] an odorant for storage within the odorant-storage vessel,
the odorant being capable of increasing molecular passage between a
central nervous system (CNS) of the subject and another body
compartment of the subject; and
[0544] an odorant-delivery element, adapted to present the odorant
to an air passage of the patient, so as to facilitate a diagnosis
of the AD.
[0545] There is yet further provided, in accordance with an
embodiment of the present invention, apparatus for diagnosing
Alzheimer's disease (AD), including:
[0546] an odorant-storage vessel;
[0547] an odorant for storage within the odorant-storage vessel,
the odorant being capable of increasing molecular passage between
cerebrospinal fluid (CSF) of the subject and another body fluid of
the subject; and
[0548] an odorant-delivery element, adapted to present the odorant
to an air passage of the patient, so as to facilitate a diagnosis
of the AD.
[0549] There is also provided, in accordance with an embodiment of
the present invention, apparatus for diagnosing Alzheimer's disease
(AD), including:
[0550] an odorant-storage vessel;
[0551] an odorant for storage within the odorant-storage vessel,
the odorant being capable of increasing molecular passage between
cerebrospinal fluid (CSF) of the subject and a tissue of the
subject; and
[0552] an odorant-delivery element, adapted to present the odorant
to an air passage of the patient, so as to facilitate a diagnosis
of the AD.
[0553] In an embodiment, the odorant-storage vessel in combination
with the odorant-delivery element includes an aqueous spray nasal
inhaler.
[0554] In an embodiment, the odorant-storage vessel in combination
with the odorant-delivery element includes a metered dose nasal
inhaler.
[0555] In an embodiment, the odorant-storage vessel in combination
with the odorant-delivery element includes an air-dilution
olfactometer.
[0556] There is also provided, in accordance with an embodiment of
the present invention, a method for facilitating a diagnosis of a
condition of a patient, including:
[0557] stimulating a modulation target site of the patient at a
level sufficient to increase permeability of a blood-brain barrier
(BBB) of the patient; and
[0558] administering a diagnostic agent capable of passing through
the BBB and into a central nervous system (CNS) of the patient
while the permeability of the BBB is increased.
[0559] There is further provided, in accordance with an embodiment
of the present invention, a method for facilitating a diagnosis of
a condition of a patient, including:
[0560] stimulating a modulation target site of the patient at a
level sufficient to increase permeability of a blood-brain barrier
(BBB) of the patient; and
[0561] receiving a constituent of a central nervous system (CNS) of
the patient that passes from the CNS and through the BBB while the
permeability of the BBB is increased.
[0562] There is still further provided, in accordance with an
embodiment of the present invention, a method for facilitating a
diagnosis of a condition of a subject, including:
[0563] applying a current to a site of the subject selected from
the list consisting of: a sphenopalatine ganglion (SPG) of the
subject, and a neural tract originating in or leading to the
SPG;
[0564] configuring the current to increase conductance of molecules
from brain tissue of the subject through a blood brain barrier
(BBB) of the subject into a systemic blood circulation of the
subject; and
[0565] sensing a quantity of the molecules from a site outside of
the brain of the subject, following initiation of application of
the current.
[0566] For some applications, sensing the quantity of the molecules
includes sampling a fluid of the subject selected from the list
consisting of: blood, plasma, serum, ascites fluid, and urine.
[0567] For some applications, the method includes determining a
diagnostically-relevant parameter responsive to sensing the
quantity of the molecules.
[0568] For some applications, the method includes administering a
hyperosmolarity-inducing agent to the subject at a dosage
sufficient to augment an increase in conductance of the molecules
caused by the application of the current. Alternatively or
additionally, the method includes inducing a state of dehydration
of the subject, of an extent sufficient to augment an increase in
conductance of the molecules caused by the application of the
current.
[0569] For some applications, the method includes administering an
agent to the subject that modulates synthesis or metabolism of
nitric-oxide (NO) in blood vessels of the brain, at a dosage
sufficient to augment an increase in conductance of the molecules
caused by the application of the current.
[0570] For some applications, applying the current includes
implanting an electrode at the site, designated to remain in the
subject for a period greater than about one month. Alternatively,
for some applications, applying the current includes implanting an
electrode at the site, designated to remain in the subject for a
period less than about one week.
[0571] For some applications, applying the current includes
implanting a control unit in a nasal cavity of the subject. For
some applications, applying the current includes implanting a
control unit at a lower side of a bony palate of the subject. For
some applications, applying the current includes implanting one or
more electrodes in a nasal cavity of the subject. For some
applications, implanting includes inserting a flexible electrode
through a nostril of the subject.
[0572] There is also provided, in accordance with an embodiment of
the present invention, a method for facilitating a diagnosis of a
condition of a central nervous system (CNS) of a subject,
including:
[0573] stimulating sphenopalatine ganglion (SPG)-related tissue of
the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG; and
[0574] configuring the stimulation so as to cause an increase in
molecular passage between the CNS and another body compartment of
the subject, so as to facilitate the diagnosis of the CNS
condition.
[0575] In an embodiment, the method includes measuring a
constituent of the other body compartment.
[0576] For some applications, stimulating the SPG-related tissue
includes directly stimulating the SPG.
[0577] For some applications, the other body compartment includes a
systemic blood circulation of the subject, and configuring the
stimulation includes configuring the stimulation so as to cause the
increase in molecular passage between the CNS and the systemic
blood circulation. Alternatively or additionally, the other body
compartment includes plasma of the subject, and configuring the
stimulation includes configuring the stimulation so as to cause the
increase in molecular passage between the CNS and the plasma.
Further alternatively or additionally, the other body compartment
includes serum of the subject, and configuring the stimulation
includes configuring the stimulation so as to cause the increase in
molecular passage between the CNS and the serum. Still further
alternatively or additionally, the other body compartment is
ascites of the subject, and configuring the stimulation includes
configuring the stimulation so as to cause the increase in
molecular passage between the CNS and the ascites.
[0578] For some applications, the CNS condition includes
Parkinson's disease, and configuring the stimulation includes
configuring the stimulation so as to facilitate the diagnosis of
the Parkinson's disease. For some applications, the CNS condition
includes epilepsy, and configuring the stimulation includes
configuring the stimulation so as to facilitate the diagnosis of
the epilepsy. For some applications, the CNS condition includes
amyotrophic lateral sclerosis (ALS), and configuring the
stimulation includes configuring the stimulation so as to
facilitate the diagnosis of the ALS. For some applications, the CNS
condition includes multiple sclerosis (MS), and configuring the
stimulation includes configuring the stimulation so as to
facilitate the diagnosis of the MS.
[0579] For some applications, stimulating the SPG-related tissue
includes implanting an electrode at the site, designated to remain
in the subject for a period greater than about one month.
Alternatively, for some applications, stimulating the SPG-related
tissue includes implanting an electrode at the site, designated to
remain in the subject for a period less than about one week.
[0580] For some applications, stimulating the SPG-related tissue
includes implanting a control unit in a nasal cavity of the
subject. For some applications, stimulating the SPG-related tissue
includes implanting a control unit at a lower side of a bony palate
of the subject.
[0581] For some applications, the method includes correlating an
abnormal concentration of the constituent to a pathology of the CNS
condition.
[0582] For some applications, the constituent is selected from the
group consisting of: a protein, a hormone, an antibody, an
electrolyte, a neuropeptide, and an enzyme, and measuring the
constituent includes measuring the selected constituent.
[0583] There is additionally provided, in accordance with an
embodiment of the present invention, a method for facilitating a
diagnosis of a condition of a central nervous system (CNS) of a
subject, including:
[0584] stimulating sphenopalatine ganglion (SPG)-related tissue of
the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG; and
[0585] configuring the stimulation so as to cause an increase in
molecular passage between cerebrospinal fluid (CSF) of the subject
and another body fluid of the subject, so as to facilitate the
diagnosis of the CNS condition.
[0586] In an embodiment, the method includes measuring a
constituent of the other body fluid.
[0587] For some applications, stimulating the SPG-related tissue
includes directly stimulating the SPG.
[0588] For some applications, the method includes correlating an
abnormal concentration of the constituent to a pathology of the CNS
condition.
[0589] For some applications, the constituent is selected from the
group consisting of: a protein, a hormone, an antibody, an
electrolyte, a neuropeptide, and an enzyme, and measuring the
constituent includes measuring the selected constituent.
[0590] For some applications, the other body fluid is selected from
the list consisting of: whole blood, plasma, serum, and ascites,
and measuring the constituent includes sampling the selected
fluid.
[0591] For some applications, measuring the constituent includes
extracting the other body fluid from tissue of the subject.
[0592] For some applications, applying the current includes
implanting an electrode at the site, designated to remain in the
subject for a period greater than about one month. Alternatively,
for some applications, applying the current includes implanting an
electrode at the site, designated to remain in the subject for a
period less than about one week.
[0593] For some applications, applying the current includes
implanting a control unit in a nasal cavity of the subject. For
some applications, applying the current includes implanting a
control unit at a lower side of a bony palate of the subject.
[0594] For some applications, measuring the constituent includes
measuring a plurality of constituents. For some applications, the
method includes determining a diagnostic result according to the
interrelation between concentrations of the constituents.
[0595] There is yet additionally provided, in accordance with an
embodiment of the present invention, a method for facilitating a
diagnosis of a condition of a central nervous system (CNS) of a
subject, including:
[0596] stimulating sphenopalatine ganglion (SPG)-related tissue of
the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG; and
[0597] configuring the stimulation so as to cause an increase in
molecular passage between cerebrospinal fluid (CSF) of the subject
and a tissue of the subject, so as to facilitate a diagnosis of the
CNS condition.
[0598] In an embodiment, the method includes measuring a
constituent of the tissue.
[0599] For some applications, stimulating the SPG-related tissue
includes directly stimulating the SPG.
[0600] For some applications, the method includes correlating an
abnormal concentration of the constituent to a pathology of the CNS
condition.
[0601] For some applications, the constituent is selected from the
group consisting of: a protein, a hormone, an antibody, an
electrolyte, a neuropeptide, and an enzyme, and measuring the
constituent includes measuring the selected constituent.
[0602] For some applications, measuring the constituent includes
measuring a plurality of constituents of the tissue. For some
applications, the method includes determining a diagnostic result
according to the interrelation between concentrations of the
constituents of the tissue.
[0603] There is still additionally provided, in accordance with an
embodiment of the present invention, a method for facilitating a
diagnosis of a condition of a central nervous system (CNS) of a
subject, including:
[0604] applying an electrical signal to at least one site of the
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject; and
[0605] configuring the signal so as to cause an increase in
molecular passage between the CNS and another body compartment of
the subject, so as to facilitate a diagnosis of the CNS
condition.
[0606] In an embodiment, the method includes measuring a
constituent of the other body compartment.
[0607] There is further provided, in accordance with an embodiment
of the present invention, a method for facilitating a diagnosis of
a condition of a central nervous system (CNS) of a subject,
including:
[0608] applying an electrical signal to at least one site of the
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject; and
[0609] configuring the signal so as to cause an increase in
molecular passage between cerebrospinal fluid (CSF) of the subject
and another body fluid of the subject, so as to facilitate a
diagnosis of the CNS condition.
[0610] In an embodiment, the method includes measuring a
constituent of the other body fluid.
[0611] There is yet further provided, in accordance with an
embodiment of the present invention, a method for facilitating a
diagnosis of a condition of a central nervous system (CNS) of a
subject, including:
[0612] applying an electrical signal to at least one site of the
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject; and
[0613] configuring the signal so as to cause an increase in
molecular passage between cerebrospinal fluid (CSF) of the subject
and a tissue of the subject, so as to facilitate a diagnosis of the
CNS condition.
[0614] In an embodiment, the method includes measuring a
constituent of the tissue.
[0615] There is still further provided, in accordance with an
embodiment of the present invention, a method for facilitating a
diagnosis of a condition of a central nervous system (CNS) of a
subject, the method including:
[0616] stimulating at least one site of the subject by applying an
electrical current to the site, the site selected from the list
consisting of: a sphenopalatine ganglion (SPG) of the subject, an
anterior ethmoidal nerve of the subject, a posterior ethmoidal
nerve of the subject, a communicating branch between the anterior
ethmoidal nerve and the SPG, a communicating branch between the
posterior ethmoidal nerve and the SPG, a nerve of the pterygoid
canal of the subject, a greater palatine nerve of the subject, a
lesser palatine nerve of the subject, a sphenopalatine nerve of the
subject, a communicating branch between a maxillary nerve of the
subject and the SPG, a nasopalatine nerve of the subject, a
posterior nasal nerve of the subject, an infraorbital nerve of the
subject, an otic ganglion of the subject, an afferent fiber going
into the otic ganglion, and an efferent fiber going out of the otic
ganglion;
[0617] configuring the stimulation so as to cause an increase in
molecular passage between the CNS and another body compartment of
the subject;
[0618] taking a sample from the body compartment; and
[0619] determining a level of a constituent of the sample, so as to
facilitate the diagnosis of the CNS condition.
[0620] For some applications, the CNS condition includes a
neurodegenerative condition, and determining the level of the
constituent includes determining the level of the constituent so as
to facilitate the diagnosis of the neurodegenerative condition. For
some applications, the CNS condition includes a neoplastic process,
and determining the level of the constituent includes determining
the level of the constituent so as to facilitate the diagnosis of
the neoplastic process. For some applications, the CNS condition is
selected from the list consisting of: an immune-related disorder
and an autoimmune-related disorder, and determining the level of
the constituent includes determining the level of the constituent
so as to facilitate the diagnosis of the selected condition. For
some applications, the CNS condition includes a CNS inflammatory
process, and determining the level of the constituent includes
determining the level of the constituent so as to facilitate the
diagnosis of the CNS inflammatory process.
[0621] In an embodiment, the method includes interpreting a low
value of the level as indicative of an increased likelihood that
the subject suffers from the CNS condition. For some applications,
the method includes interpreting a high value of the level as
indicative of a decreased likelihood that the subject suffers from
the CNS condition. For some applications, the body compartment
includes a systemic blood circulation of the subject, and
configuring the stimulation includes configuring the stimulation so
as to cause the increase in molecular passage between the CNS and
the systemic blood circulation. Alternatively or additionally, the
body compartment includes plasma of the subject, and configuring
the stimulation includes configuring the stimulation so as to cause
the increase in molecular passage between the CNS and the plasma.
Further alternatively or additionally, the body compartment
includes serum of the subject, and configuring the stimulation
includes configuring the stimulation so as to cause the increase in
molecular passage between the CNS and the serum. Still further
alternatively or additionally, the body compartment is ascites of
the subject, and configuring the stimulation includes configuring
the stimulation so as to cause the increase in molecular passage
between the CNS and the ascites. For some applications, the site
includes the SPG, and stimulating the site includes stimulating the
SPG.
[0622] For some applications, the CNS condition includes
Alzheimer's disease, and interpreting the low value includes
interpreting the low value as indicative of the increased
likelihood that the subject suffers from Alzheimer's disease. For
some applications, the constituent includes amyloid-beta peptide,
and determining the level of the constituent includes determining
the level of the amyloid-beta peptide. Alternatively or
additionally, the constituent includes presenilin-1, and
determining the level of the constituent includes determining the
level of the presenilin-1.
[0623] There is additionally provided, in accordance with an
embodiment of the present invention, a method for facilitating a
diagnosis of a condition of a central nervous system (CNS) of a
subject, the method including:
[0624] stimulating at least one site of the subject selected from
the list consisting of: a sphenopalatine ganglion (SPG) of the
subject, an anterior ethmoidal nerve of the subject, a posterior
ethmoidal nerve of the subject, a communicating branch between the
anterior ethmoidal nerve and the SPG, a communicating branch
between the posterior ethmoidal nerve and the SPG, a nerve of the
pterygoid canal of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve of the subject and the SPG, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion, and an efferent fiber going out
of the otic ganglion;
[0625] configuring the stimulation so as to cause an increase in
molecular passage between the CNS and another body compartment of
the subject;
[0626] taking a sample from the body compartment; and
[0627] determining a level of a constituent of the sample, so as to
facilitate the diagnosis of the CNS condition.
[0628] For some applications, the CNS condition includes a
neurodegenerative condition, and determining the level of the
constituent includes determining the level of the constituent so as
to facilitate the diagnosis of the neurodegenerative condition. For
some applications, the CNS condition includes a neoplastic process,
and determining the level of the constituent includes determining
the level of the constituent so as to facilitate the diagnosis of
the neoplastic process. For some applications, the CNS condition is
selected from the list consisting of: an immune-related disorder
and an autoimmune-related disorder, and determining the level of
the constituent includes determining the level of the constituent
so as to facilitate the diagnosis of the selected condition. For
some applications, the CNS condition includes a CNS inflammatory
process, and determining the level of the constituent includes
determining the level of the constituent so as to facilitate the
diagnosis of the CNS inflammatory process.
[0629] In an embodiment, the method includes interpreting a low
value of the level as indicative of an increased likelihood that
the subject suffers from the CNS condition. For some applications,
the method includes interpreting a high value of the level as
indicative of a decreased likelihood that the subject suffers from
the CNS condition.
[0630] In an embodiment, stimulating includes applying magnetic
stimulation to the site. In an embodiment, stimulating includes
applying electromagnetic stimulation to the site. In an embodiment,
stimulating includes applying chemical stimulation to the site. In
an embodiment, stimulating includes applying mechanical stimulation
to the site.
[0631] For some applications, the body compartment includes a
systemic blood circulation of the subject, and configuring the
stimulation includes configuring the stimulation so as to cause the
increase in molecular passage between the CNS and the systemic
blood circulation.
[0632] Alternatively or additionally, the body compartment includes
plasma of the subject, and configuring the stimulation includes
configuring the stimulation so as to cause the increase in
molecular passage between the CNS and the plasma. Further
alternatively or additionally, the body compartment includes serum
of the subject, and configuring the stimulation includes
configuring the stimulation so as to cause the increase in
molecular passage between the CNS and the serum. Still further
alternatively or additionally, the body compartment is ascites of
the subject, and configuring the stimulation includes configuring
the stimulation so as to cause the increase in molecular passage
between the CNS and the ascites.
[0633] For some applications, the site includes the SPG, and
stimulating the site includes stimulating the SPG.
[0634] For some applications, the CNS condition includes
Alzheimer's disease, and interpreting the low value includes
interpreting the low value as indicative of the increased
likelihood that the subject suffers from Alzheimer's disease. For
some applications, the constituent includes amyloid-beta peptide,
and determining the level of the constituent includes determining
the level of the amyloid-beta peptide. Alternatively or
additionally, the constituent includes presenilin-1, and
determining the level of the constituent includes determining the
level of the presenilin-1.
[0635] There is also provided, in accordance with an embodiment of
the present invention, a method for treating a condition of a
central nervous system (CNS) of a subject, including:
[0636] applying a current to a site of the subject selected from
the list consisting of: a sphenopalatine ganglion (SPG) of the
subject, and a neural tract originating in or leading to the
SPG;
[0637] configuring the current to increase clearance of molecules
from brain tissue of the subject through a blood brain barrier
(BBB) of the subject into a systemic blood circulation of the
subject, so as to treat the CNS condition.
[0638] For some applications, the molecules include a toxin, and
configuring the current includes configuring the current to
increase the clearance of the toxin from the brain tissue, so as to
treat the CNS condition.
[0639] For some applications, applying the current includes
implanting an electrode at the site, designated to remain in the
subject for a period greater than about one month. Alternatively,
for some applications, applying the current includes implanting an
electrode at the site, designated to remain in the subject for a
period less than about one week.
[0640] For some applications, applying the current includes
implanting a control unit in a nasal cavity of the subject. For
some applications, applying the current includes implanting a
control unit at a lower side of a bony palate of the subject.
[0641] There is further provided, in accordance with an embodiment
of the present invention, a method for treating a condition of a
central nervous system (CNS) of a subject, including:
[0642] stimulating sphenopalatine ganglion (SPG)-related tissue of
the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG; and
[0643] configuring the stimulation so as to cause an increase in
clearance of a neurotoxic compound from a brain of the subject
through a blood brain barrier (BBB) of the subject to a systemic
blood circulation of the subject, so as to treat the CNS
condition.
[0644] For some applications, stimulating the SPG-related tissue
includes directly stimulating the SPG.
[0645] There is still further provided, in accordance with an
embodiment of the present invention, a method for treating a
condition of a central nervous system (CNS) of a subject,
including:
[0646] stimulating sphenopalatine ganglion (SPG)-related tissue of
the subject by presenting an odorant to an air passage of the
subject, the SPG-related tissue selected from: an SPG of the
subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
[0647] configuring the stimulation so as to cause an increase in
clearance of a neurotoxic compound from a brain of the subject
through a blood brain barrier (BBB) of the subject to a systemic
blood circulation of the subject, so as to treat the CNS
condition.
[0648] There is additionally provided, in accordance with an
embodiment of the present invention, a method for treating a
condition of a central nervous system (CNS) of a subject,
including:
[0649] stimulating sphenopalatine ganglion (SPG)-related tissue of
the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG; and
[0650] configuring the stimulation so as to cause an increase in
clearance of a neurotoxic compound from cerebrospinal fluid (CSF)
of the subject through a blood brain barrier (BBB) of the subject
to a systemic blood circulation of the subject, so as to treat the
CNS condition.
[0651] For some applications, stimulating the SPG-related tissue
includes directly stimulating the SPG.
[0652] There is yet additionally provided, in accordance with an
embodiment of the present invention, a method for treating a
condition of a central nervous system (CNS) of a subject,
including:
[0653] stimulating sphenopalatine ganglion (SPG)-related tissue of
the subject by presenting an odorant to an air passage of the
subject, the SPG-related tissue selected from: an SPG of the
subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
[0654] configuring the stimulation so as to cause an increase in
clearance of a neurotoxic compound from cerebrospinal fluid (CSF)
of the subject through a blood brain barrier (BBB) of the subject
to a systemic blood circulation of the subject, so as to treat the
CNS condition.
[0655] There is further provided, in accordance with an embodiment
of the present invention, apparatus for facilitating a diagnosis of
a condition of a subject, including a stimulator adapted to:
[0656] apply a current to a site of the subject selected from the
list consisting of: a sphenopalatine ganglion (SPG) of the subject,
and a neural tract originating in or leading to the SPG, and
[0657] configure the current to increase conductance of molecules
from brain tissue of the subject through a blood brain barrier
(BBB) of the subject into a systemic blood circulation of the
subject, so as to facilitate the diagnosis of the condition.
[0658] For some applications, the stimulator is adapted to directly
stimulate the SPG.
[0659] In an embodiment, the apparatus is adapted to measure a
constituent of the other body compartment.
[0660] There is still additionally provided, in accordance with an
embodiment of the present invention, apparatus for facilitating a
diagnosis of a condition of a central nervous system (CNS) of a
subject, including a stimulator adapted to:
[0661] stimulate sphenopalatine ganglion (SPG)-related tissue of
the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG, and
[0662] configure the stimulation so as to cause an increase in
molecular passage between the CNS and another body compartment of
the subject, so as to facilitate the diagnosis of the CNS
condition.
[0663] In an embodiment, the apparatus is adapted to measure a
constituent of the other body compartment.
[0664] There is further provided, in accordance with an embodiment
of the present invention, apparatus for facilitating a diagnosis of
a condition of a central nervous system (CNS) of a subject,
including a stimulator adapted to:
[0665] stimulate sphenopalatine ganglion (SPG)-related tissue of
the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG, and
[0666] configure the stimulation so as to cause an increase in
molecular passage between cerebrospinal fluid (CSF) of the subject
and another body fluid of the subject, so as to facilitate the
diagnosis of the CNS condition.
[0667] In an embodiment, the apparatus is adapted to measure a
constituent of the other body fluid.
[0668] There is also provided, in accordance with an embodiment of
the present invention, apparatus for facilitating a diagnosis of a
condition of a central nervous system (CNS) of a subject, including
a stimulator adapted to:
[0669] stimulate sphenopalatine ganglion (SPG)-related tissue of
the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG, and
[0670] configure the stimulation so as to cause an increase in
molecular passage between cerebrospinal fluid (CSF) of the subject
and a tissue of the subject, so as to facilitate the diagnosis of
the CNS condition.
[0671] In an embodiment, the apparatus is adapted to measure a
constituent of the tissue.
[0672] There is additionally provided, in accordance with an
embodiment of the present invention, apparatus for facilitating a
diagnosis of a condition of a central nervous system (CNS) of a
subject, including a stimulator adapted to:
[0673] apply an electrical signal to at least one site of the
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject, and
[0674] configure the signal so as to cause an increase in molecular
passage between the CNS and another body compartment of the
subject, so as to facilitate the diagnosis of the CNS
condition.
[0675] In an embodiment, the apparatus is adapted to measure a
constituent of the other body compartment.
[0676] There is yet additionally provided, in accordance with an
embodiment of the present invention, apparatus for facilitating a
diagnosis of a condition of a central nervous system (CNS) of a
subject, including a stimulator adapted to:
[0677] apply an electrical signal to at least one site of the
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject, and
[0678] configure the signal so as to cause an increase in molecular
passage between cerebrospinal fluid (CSF) of the subject and
another body fluid of the subject, so as to facilitate the
diagnosis of the CNS condition.
[0679] In an embodiment, the apparatus is adapted to measure a
constituent of the other body fluid.
[0680] There is still additionally provided, in accordance with an
embodiment of the present invention, apparatus for facilitating a
diagnosis of a condition of a central nervous system (CNS) of a
subject, including a stimulator adapted to:
[0681] apply an electrical signal to at least one site of the
subject, the site selected from the list consisting of: a
sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a
retro-orbital branch of an SPG of the subject, a communicating
branch between a posterior ethmoidal nerve and a retro-orbital
branch of an SPG of the subject, a greater palatine nerve of the
subject, a lesser palatine nerve of the subject, a sphenopalatine
nerve of the subject, a communicating branch between a maxillary
nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior nasal nerve of the subject, an infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent
fiber going into the otic ganglion of the subject, an efferent
fiber going out of the otic ganglion of the subject, a vidian nerve
of the subject, a greater superficial petrosal nerve of the
subject, and a lesser deep petrosal nerve of the subject, and
[0682] configure the signal so as to cause an increase in molecular
passage between cerebrospinal fluid (CSF) of the subject and a
tissue of the subject, so as to facilitate the diagnosis of the CNS
condition.
[0683] In an embodiment, the apparatus is adapted to measure a
constituent of the tissue.
[0684] There is also provided, in accordance with an embodiment of
the present invention, apparatus for treating a condition of a
central nervous system (CNS) of a subject, including a stimulator
adapted to:
[0685] stimulate sphenopalatine ganglion (SPG)-related tissue of
the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG, and
[0686] configure the stimulation so as to cause an increase in
clearance of a neurotoxic compound from a brain of the subject
through a blood brain barrier (BBB) of the subject to a systemic
blood circulation of the subject, so as to treat the CNS
condition.
[0687] There is further provided, in accordance with an embodiment
of the present invention, apparatus for treating a condition of a
central nervous system (CNS) of a subject, including a stimulator
adapted to:
[0688] stimulate sphenopalatine ganglion (SPG)-related tissue of
the subject by presenting an odorant to an air passage of the
subject, the SPG-related tissue selected from: an SPG of the
subject and nerve fibers of the subject which are directly
anatomically connected to the SPG, and
[0689] configure the stimulation so as to cause an increase in
clearance of a neurotoxic compound from a brain of the subject
through a blood brain barrier (BBB) of the subject to a systemic
blood circulation of the subject, so as to treat the CNS
condition.
[0690] There is yet further provided, in accordance with an
embodiment of the present invention, apparatus for treating a
condition of a central nervous system (CNS) of a subject, including
a stimulator adapted to:
[0691] stimulate sphenopalatine ganglion (SPG)-related tissue of
the subject by applying an electrical signal to the SPG-related
tissue, the SPG-related tissue selected from: an SPG of the subject
and nerve fibers of the subject which are directly anatomically
connected to the SPG, and
[0692] configure the stimulation so as to cause an increase in
clearance of a neurotoxic compound from cerebrospinal fluid (CSF)
of the subject through a blood brain barrier (BBB) of the subject
to a systemic blood circulation of the subject, so as to treat the
CNS condition.
[0693] There is still further provided, in accordance with an
embodiment of the present invention, apparatus for treating a
condition of a central nervous system (CNS) of a subject, including
a stimulator adapted to:
[0694] stimulate sphenopalatine ganglion (SPG)-related tissue of
the subject by presenting an odorant to an air passage of the
subject, the SPG-related tissue selected from: an SPG of the
subject and nerve fibers of the subject which are directly
anatomically connected to the SPG, and
[0695] configure the stimulation so as to cause an increase in
clearance of a neurotoxic compound from cerebrospinal fluid (CSF)
of the subject through a blood brain barrier (BBB) of the subject
to a systemic blood circulation of the subject, so as to treat the
CNS condition.
[0696] The present invention will be more fully understood from the
following detailed description of the preferred embodiments
thereof, taken together with the drawings, in which:
BRIEF DESCRIPTION OF THE DRAWINGS
[0697] FIGS. 1A and 1B are schematic pictorial views of a fully
implantable stimulator for stimulation of the SPG, in accordance
with preferred embodiments of the present invention;
[0698] FIG. 2 is a schematic pictorial view of another stimulator
for stimulation of the SPG, in accordance with a preferred
embodiment of the present invention;
[0699] FIG. 3 is a schematic block diagram illustrating circuitry
for use with the stimulator shown in FIGS. 1A and 1B, in accordance
with a preferred embodiment of the present invention;
[0700] FIG. 4 is a schematic block diagram illustrating circuitry
for use with the stimulator shown in FIG. 2, in accordance with a
preferred embodiment of the present invention;
[0701] FIGS. 5A and 5B are schematic illustrations depicting
different modes of operation of stimulators such as those shown in
FIGS. 1A, 1B, and 2, in accordance with preferred embodiments of
the present invention;
[0702] FIG. 6 is a schematic illustration of a mode of operation of
the stimulators shown in FIGS. 1A, 1B, and 2, synchronized with a
drug delivery system, in accordance with a preferred embodiment of
the present invention;
[0703] FIG. 7 is a schematic block diagram illustrating circuitry
for use with the stimulator shown in FIGS. 1A and 1B, where the
stimulator is driven by an external controller and energy source
using a modulator and a demodulator, in accordance with a preferred
embodiment of the present invention;
[0704] FIG. 8 depicts sample modulator and demodulator functions
for use with the circuitry of FIG. 7, in accordance with a
preferred embodiment of the present invention;
[0705] FIGS. 9, 10A, and 10B are schematic diagrams illustrating
further circuitry for use with implantable stimulators, in
accordance with respective preferred embodiments of the present
invention;
[0706] FIGS. 11 and 12 are bar graphs showing experimental data
collected in accordance with a preferred embodiment of the present
invention;
[0707] FIG. 13 is a schematic illustration of a sensor for
application to a blood vessel, in accordance with a preferred
embodiment of the present invention;
[0708] FIG. 14 is a schematic sectional illustration of a nasal
inhaler, for use in presenting an odorant to a subject, in
accordance with a preferred embodiment of the present
invention;
[0709] FIGS. 15-17 are graphs showing the results from SPG
stimulation experiments carried out in accordance with embodiments
of the present invention; and
[0710] FIG. 18 is a schematic illustration of an implantable
stimulator for stimulation of an MTS, in accordance with an
embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0711] FIGS. 1A and 1B are schematic pictorial views of a
fully-implantable stimulator 4, for stimulation of the
sphenopalatine ganglion (SPG) 6, a "modulation target site" (MTS),
or other parasympathetic site of a patient, in accordance with
preferred embodiments of the present invention. In FIGS. 1A and 1B,
a human nasal cavity 2 is shown. In FIG. 1A, stimulator 4 is
implanted adjacent to SPG 6. In FIG. 1B, stimulator 4 is implanted
between the hard palate and the mucoperiosteum (not shown) of the
roof of the mouth. Branches of parasympathetic neurons coming from
SPG 6 extend to the middle cerebral and anterior cerebral arteries
(not shown). Preferably, one or more relatively short electrodes 7
extend from stimulator 4 to contact or to be in a vicinity of SPG 6
or of nerves innervating SPG 6 (e.g., postganglionic
parasympathetic trunks thereof).
[0712] In the present patent application, a "modulation target
site" consists of:
[0713] a sphenopalatine ganglion (SPG) (also called a
pterygopalatine ganglion);
[0714] an anterior ethmoidal nerve;
[0715] a posterior ethmoidal nerve;
[0716] a communicating branch between the anterior ethmoidal nerve
and the SPG (retro-orbital branch);
[0717] a communicating branch between the posterior ethmoidal nerve
and the SPG (retro-orbital branch);
[0718] a nerve of the pterygoid canal (also called a vidian nerve),
such as a greater superficial petrosal nerve (a preganglionic
parasympathetic nerve) or a lesser deep petrosal nerve (a
postganglionic sympathetic nerve);
[0719] a greater palatine nerve;
[0720] a lesser palatine nerve;
[0721] a sphenopalatine nerve;
[0722] a communicating branch between the maxillary nerve and the
sphenopalatine ganglion;
[0723] a nasopalatine nerve;
[0724] a posterior nasal nerve;
[0725] an infraorbital nerve;
[0726] an otic ganglion;
[0727] an afferent fiber going into the otic ganglion; and/or
[0728] an efferent fiber going out of the otic ganglion.
[0729] For some applications, stimulator 4 is implanted on top of
the bony palate, in the bottom of the nasal cavity. Alternatively
or additionally, the stimulator is implanted at the lower side of
the bony palate, at the top of the oral cavity. In this instance,
one or more flexible electrodes 7 originating in the stimulator are
passed through the palatine bone or posterior to the soft palate,
so as to be in a position to stimulate the SPG or its
parasympathetic tracts, or another MTS. Further alternatively or
additionally, the stimulator may be directly attached to the SPG
and/or to its postganglionic parasympathetic trunk(s) and/or to
another MTS.
[0730] For some applications, stimulator 4 is delivered to a
desired point within nasal cavity 2 by removably attaching
stimulator 4 to the distal end of a rigid or slightly flexible
introducer rod (not shown) and inserting the rod into one of the
patient's nasal passages until the stimulator is properly
positioned. As appropriate, the placement process may be
facilitated by fluoroscopy, x-ray guidance, fine endoscopic surgery
(FES) techniques or by any other effective guidance method known in
the art, or by combinations of the aforementioned. Preferably, the
ambient temperature and/or cerebral blood flow is measured
concurrently with insertion. The cerebral blood flow may be
measured with, for example, a laser Doppler unit positioned at the
patient's forehead or transcranial Doppler measurements.
Verification of proper implantation of the electrodes onto the
appropriate neural structure may be performed by activating the
device, and generally simultaneously monitoring cerebral blood
flow.
[0731] The placement process may be performed using techniques
described in U.S. Provisional Patent Application 60/426,180 filed
Nov. 14, 2002, entitled, "Surgical tools and techniques for
stimulation," or in PCT Publication WO 04/043218 to Gross et al.,
which are assigned to the assignee of the present patent
application and is incorporated herein by reference.
[0732] The passage of certain molecules from cerebral blood vessels
into the brain is hindered by the BBB. The endothelium of the
capillaries, the plasma membrane of the blood vessels, and the foot
processes of the astrocytes all impede uptake by the brain of the
molecules. The BBB generally allows only small molecules (e.g.,
hydrophilic molecules of molecular weight less than about 200 Da,
and lipophilic molecules of less than about 500 Da) to pass from
the circulation into the brain.
[0733] In accordance with a preferred embodiment of the present
invention, parasympathetic activation induced by current from
stimulator 4 overcomes the resistance to trans-BBB molecular
movement generated by the endothelium of the cerebral capillaries
and the plasma membrane. For some applications, therefore,
stimulator 4 may be used to transiently remove a substantial
obstacle to the passage of drugs from the blood to the brain, of
diagnostic agents from the systemic blood circulation to the CNS,
and/or of biochemical agents from the CNS to the systemic blood
circulation. For example, the stimulator may cyclically apply
current for about two minutes, and subsequently have a rest period
of between about 1 and 20 minutes.
[0734] It is hypothesized that two neurotransmitters play an
important role in this change in properties of the BBB--vasoactive
intestinal polypeptide (VIP) and nitric oxide (NO). (Acetylcholine
may also be involved.) VIP is a short peptide, and NO is a gaseous
molecule. VIP is believed to be a major factor in facilitating
plasma protein extravasation (PPE), while NO is responsible for
vasodilation. For some applications, stimulator 4 is adapted to
vary parameters of the current applied to the SPG, as appropriate,
in order to selectively influence the activity of one or both of
these neurotransmitters. For example, stimulation of the
parasympathetic nerve at different frequencies can induce
differential secretion--low frequencies cause secretion of NO,
while high frequencies (e.g., above about 10 Hz) cause secretion of
peptides (VIP).
[0735] For other applications, a constant level DC signal, or a
slowly varying voltage ramp is applied, in order to block
parasympathetic neural activity in affected tissue. Alternatively,
similar results can be obtained by stimulating at a rate higher
than about 10 Hz, because this tends to exhaust neurotransmitters.
Thus, stimulator 4 may be configured to induce parasympathetic
electrical block, in order to cause vasoconstriction by mimicking
the overall effect of chemical block on the SPG. This
vasoconstrictive effect may be used, for example, to controllably
prevent or reverse the formation of migraine headaches. This
technique of electrical treatment of migraines stands in contrast
to methods of the prior art, in which pharmacological agents such
as lidocaine are applied so as to induce SPG block.
[0736] FIG. 2 is a schematic illustration of a stimulator control
unit 8 positioned external to a patient's body, in accordance with
a preferred embodiment of the present invention. At least one
flexible electrode 10 preferably extends from control unit 8,
through a nostril 12 of the patient, and to a position within the
nasal cavity 14 that is adjacent to SPG 6.
[0737] It is to be understood that electrodes 7 (FIGS. 1A and 1B)
and 10 may each comprise one or more electrodes, e.g., two
electrodes, or an array of microelectrodes. For applications in
which stimulator 4 comprises a metal housing that can function as
an electrode, then typically one electrode 7 is used, operating in
a monopolar mode. Regardless of the total number of electrodes in
use, typically only a single or a double electrode extends to SPG
6. Other electrodes 7 or 10 or a metal housing of stimulator 4 are
preferably temporarily or permanently implanted in contact with
other parts of nasal cavity 2.
[0738] Each of electrodes 7 and/or 10 preferably comprises a
suitable conductive material, for example, a
physiologically-acceptable material such as silver, iridium,
platinum, a platinum iridium alloy, titanium, nitinol, or a
nickel-chrome alloy. For some applications, one or more of the
electrodes have lengths ranging from about 1 to 5 mm, and diameters
ranging from about 50 to 100 microns. Each electrode is preferably
insulated with a physiologically-acceptable material such as
polyethylene, polyurethane, or a co-polymer of either of these. The
electrodes are preferably spiral in shape, for better contact, and
may have a hook shaped distal end for hooking into or near the SPG.
Alternatively or additionally, the electrodes may comprise simple
wire electrodes, spring-loaded "crocodile" electrodes, or adhesive
probes, as appropriate.
[0739] In a preferred embodiment of the invention, each one of
electrodes 7 and/or 10 comprises a substantially smooth surface,
except that the distal end of each such electrode is configured or
treated to have a large surface area. For example, the distal tip
may be porous platinized. Alternatively or additionally, at least
the tip of electrode 7 or 10, and/or a metal housing of stimulator
4 includes a coating comprising an anti-inflammatory drug, such as
beclomethasone sodium phosphate or beclomethasone phosphate.
Alternatively, such an anti-inflammatory drug is injected or
otherwise applied.
[0740] Typically, a determination regarding whether to use a
configuration such as that shown in FIG. 1B or that shown in FIG. 2
is made responsive to a frequency or total number of diagnostic
procedures anticipated. When this frequency or total number is
high, the preference is for a configuration such as that shown in
FIG. 1B, while one-time or infrequent diagnostic procedures
indicates for a configuration such as that shown in FIG. 2.
[0741] FIG. 3 is a schematic block diagram illustrating circuitry
comprising an implanted unit 20 and an external unit 30, for use
with stimulator 4, in accordance with a preferred embodiment of the
present invention. Implanted unit 20 preferably comprises a
feedback block 22 and one or more sensing or signal application
electrodes 24. Implanted unit 20 typically also comprises an
electromagnetic coupler 26, which receives power and/or sends or
receives data signals to or from an electromagnetic coupler 28 in
external unit 30.
[0742] External unit 30 preferably comprises a microprocessor 32
which receives an external control signal 34 (e.g., from a
physician or from the patient), and a feedback signal 36 from
feedback block 22. Control signal 34 may include, for example,
operational parameters such as a schedule of operation, patient
parameters such as the patient's weight, or signal parameters, such
as desired frequencies or amplitudes of a signal to be applied to
the SPG or another MTS. If appropriate, control signal 34 can
comprise an emergency override signal, entered by the patient or a
healthcare provider to terminate stimulation or to modify it in
accordance with a predetermined program. Microprocessor 32, in
turn, preferably processes control signal 34 and feedback signal 36
so as to determine one or more parameters of the electric current
to be applied through electrodes 24. Responsive to this
determination, microprocessor 32 typically generates an
electromagnetic control signal 42 that is conveyed by
electromagnetic coupler 28 to electromagnetic coupler 26. Control
signal 42 preferably corresponds to a desired current or voltage to
be applied by electrodes 24 to SPG 6 or another MTS, and, in a
preferred embodiment, inductively drives the electrodes. The
configuration of couplers 26 and 28 and/or other circuitry in units
20 or 30 may determine the intensity, frequency, shape, monophasic
or biphasic mode, or DC offset of the signal (e.g., a series of
pulses) applied to designated tissue.
[0743] Power for microprocessor 32 is typically supplied by a
battery 44 or, optionally, another DC power supply. Grounding is
provided by battery 44 or a separate ground 46. If appropriate,
microprocessor 32 generates a display signal 38 that drives a
display block 40 of external unit 30. Typically, but not
necessarily, the display is activated to show feedback data
generated by feedback block 22, or to provide a user interface for
the external unit.
[0744] Implanted unit 20 is preferably packaged in a case made of
titanium, platinum or an epoxy or other suitable biocompatible
material. Should the case be made of metal, then the case may serve
as a ground electrode and, therefore, stimulation typically is
performed in a monopolar mode. Alternatively, should the case be
made of biocompatible plastic material, two electrodes 24 are
typically driven to apply current to the SPG or another MTS.
[0745] For some applications, the waveform applied by one or more
of electrodes 24 to designated tissue, such as designated tissue of
an MTS (e.g., the SPG) comprises a waveform with an exponential
decay, a ramp up or down, a square wave, a sinusoid, a saw tooth, a
DC component, or any other shape known in the art to be suitable
for application to tissue. Alternatively or additionally, the
waveform comprises one or more bursts of short shaped or square
pulses--each pulse preferably less than about 1 ms in duration.
Generally, appropriate waveforms and parameters thereof are
determined during an initial test period of external unit 30 and
implanted unit 20. For some applications, the waveform is
dynamically updated according to measured physiological parameters,
measured during a period in which unit 20 is stimulating the SPG or
another MTS, and/or during a non-activation (i.e., standby)
period.
[0746] In the case of migraine treatment, the waveform may take the
form of a slowly varying shape, such as a slow saw tooth, or a
constant DC level, intended to block outgoing parasympathetic
messaging.
[0747] FIG. 4 is a schematic block diagram of circuitry for use,
for example, in conjunction with control unit 8 (FIG. 2), in
accordance with a preferred embodiment of the present invention. An
external unit 50 comprises a microprocessor 52 supplied by a
battery 54 or another DC power source. Grounding may be provided by
battery 54 or by a separate ground 56. Microprocessor 52 preferably
receives control and feedback signals 58 and 68 (analogous to
signal 34 and 36 described hereinabove), and generates responsive
thereto a stimulation signal 64 conveyed by one or more electrodes
66 to the SPG, another MTS, or other tissue. Typically, but not
necessarily, feedback signal 68 comprises electrical feedback
measured by one or more of electrodes 66 and/or feedback from other
sensors on or in the patients brain or elsewhere coupled to the
patient's body. If appropriate, microprocessor 52 generates a
display signal 60 which drives a display block 62 to output
relevant data to the patient or the patient's physician. Typically,
some or all of electrodes 66 are temporarily implanted in the
patient (e.g., following a stroke), and are directly driven by
wires connecting the external unit to the implanted unit.
[0748] FIG. 5A is a graph schematically illustrating a mode of
operation of one or more of the devices shown in FIGS. 1-4, in
accordance with a preferred embodiment of the present invention.
Preferably, the effect of the applied stimulation is monitored by
means of a temperature transducer at the SPG, at another MTS, or
elsewhere in the head, e.g., in the nasal cavity. As shown in FIG.
5A for a step (ON/OFF) mode of stimulation, stimulation of the SPG
or related tissue, or of another MTS, is initiated at a time T1,
and this is reflected by a measurable rise in temperature (due to
increased blood flow). Once the temperature rises to a
predetermined or dynamically-varying threshold (e.g., 37.degree.
C.), stimulation is terminated (time T2), responsive to which the
temperature falls. As appropriate, when the temperature drops to a
designated or dynamically-determined point, the stimulation is
reinitiated (time T3). Preferably, suitable temperatures or other
physiological parameters are determined for each patient so as to
provide the optimal treatment. If appropriate, control instructions
may also be received from the patient, e.g., to initiate
stimulation upon the onset of a migraine headache.
[0749] FIG. 5B is a graph schematically illustrating a mode of
operation of one or more of the devices shown in FIGS. 1-4, in
accordance with another preferred embodiment of the present
invention. In this embodiment, the amplitude of the waveform
applied to the SPG or another MTS is varied among a continuous set
of values (S1), or a discrete set of values (S2), responsive to the
measured temperature, in order to achieve the desired performance.
It will be appreciated that other feedback parameters measured in
the head (e.g., intracranial pressure and/or cerebral blood flow),
as well as measured systemic parameters (e.g., heart rate) and
subjective patient inputs (e.g., migraine pain=3/5) may be used in
conjunction with or separately from temperature measurements, in
order to achieve generally optimal performance of the implanted
apparatus.
[0750] FIG. 6 is a graph schematically illustrating a mode of
operation of one or more of the devices shown in FIGS. 1-4, in
accordance with a preferred embodiment of the present invention. In
this embodiment, a drug is administered to the patient at a
constant rate, e.g., intravenously, prior to the initiation of
stimulation of the SPG or another MTS at time T1. Advantageously,
this prior generation of heightened concentrations of the drug in
the blood tends to provide relatively rapid transfer of the drug
across the BBB and into the brain, without unnecessarily prolonging
the enhanced permeability of the BBB while waiting for the blood
concentration of the drug to reach an appropriate level.
Alternatively, for some applications it is desirable to give a
single injection of a bolus of the drug shortly before or after
initiation of stimulation of the SPG or another MTS. Typically,
combined administration and stimulation schedules are determined by
the patient's physician based on the biochemical properties of each
drug targeted at the brain.
[0751] As used in the specification and in the claims, stimulation
of an MTS to facilitate transport of a diagnostic agent from the
systemic blood circulation to the CNS, is to be understood as
including stimulation prior to, during, and/or after administration
of the agent to the systemic circulation. For subjects in whom an
MTS stimulator previously was implanted for therapeutic purposes,
such implanted stimulator may be used for performing stimulation to
facilitate a diagnosis, as described herein.
[0752] FIG. 7 is a schematic block diagram showing circuitry for
parasympathetic stimulation, which is particularly useful in
combination with the embodiments shown in FIGS. 1A and 1B, in
accordance with a preferred embodiment of the present invention. An
external unit 80 preferably comprises a microprocessor 82 that is
powered by a battery 84 and/or an AC power source. Microprocessor
82 is grounded through battery 84 or through an optional ground
86.
[0753] In a typical mode of operation, an external control signal
88 is input to microprocessor 82, along with a feedback signal 108
from one or more biosensors 106, which are typically disposed in a
vicinity of an implanted unit 100 or elsewhere on or in the
patient's body. Responsive to signals 88 and 108, microprocessor 82
preferably generates a display signal 89 which drives a display 90,
as described hereinabove. In addition, microprocessor 82 preferably
processes external control signal 88 and feedback signal 108, to
determine parameters of an output signal 92, which is modulated by
a modulator 94. The output therefrom preferably drives a current
through an electromagnetic coupler 96, which inductively drives an
electromagnetic coupler 98 of implanted unit 100. A demodulator
102, coupled to electromagnetic coupler 98, in turn, generates a
signal 103 which drives at least one electrode 104 to apply current
to the SPG or to other tissue, as appropriate.
[0754] Preferably, biosensor 106 comprises implantable or external
medical apparatus including, for example, one or more of the
following:
[0755] a blood flow sensor,
[0756] a temperature sensor,
[0757] a chemical sensor,
[0758] an ultrasound sensor,
[0759] transcranial Doppler (TCD) apparatus, laser-Doppler
apparatus,
[0760] a systemic or intracranial blood pressure sensor (e.g.,
comprising a piezoelectric crystal fixed to a major cerebral blood
vessel, capable of detecting a sudden blood pressure increase
indicative of a clot),
[0761] a kinetics sensor, comprising, for example, an acceleration,
velocity, or level sensor (e.g., a mercury switch), for indicating
body dispositions such as a sudden change in body attitude (as in
collapsing),
[0762] an electroencephalographic (EEG) sensor comprising EEG
electrodes attached to, or implanted in, the patients head, for
indicating changes in neurological patterns, such as symptoms of
stroke or migraine,
[0763] a blood vessel clot detector (e.g., as described hereinbelow
with reference to FIG. 13), or
[0764] other monitors of physiological quantities suitable for
carrying out the objects of this or other embodiments of the
present invention.
[0765] FIG. 8 is a schematic illustration showing operational modes
of modulator 94 and/or demodulator 102, in accordance with a
preferred embodiment of the present invention. The amplitude and
frequency of signal 92 in FIG. 7 can have certain values, as
represented in the left graph; however, the amplitude and frequency
are modulated so that signal 103 has different characteristics (not
necessarily those shown).
[0766] FIG. 9 is a schematic illustration of further apparatus for
stimulation of the SPG or another MTS, in accordance with a
preferred embodiment of the present invention. In this embodiment,
substantially all of the processing and signal generation is
performed by circuitry in an implanted unit 110 in the patient,
and, preferably, communication with a controller 122 in an external
unit 111 is performed only intermittently. The implanted unit 110
preferably comprises a microprocessor 112 coupled to a battery 114.
Microprocessor 112 generates a signal 116 that travels along at
least one electrode 118 to stimulate the SPG or another MTS. A
feedback signal 120 from a biosensor (not shown) and/or from
electrode 118 is received by microprocessor 112, which is adapted
to modify stimulation parameters responsive thereto. Preferably,
microprocessor 112 and controller 122 are operative to communicate
via electromagnetic couplers 126 and 124, in order to exchange data
or to change parameters. Further preferably, battery 114 is
inductively rechargeable by electromagnetic coupling.
[0767] FIG. 10A is a schematic illustration of a stimulator 150, in
accordance with a preferred embodiment of the present invention.
Preferably, substantially all of the electronic components
(including an electronic circuit 158 having a rechargeable energy
source) are encapsulated in a biocompatible metal case 154. An
inductive coil 156 and at least one electrode 162 are preferably
coupled to circuit 158 by means of a feed-through coupling 160. The
inductive coil is preferably isolated by an epoxy coating 152,
which allows for higher efficiency of the electromagnetic
coupling.
[0768] FIG. 10B is a schematic illustration of another
configuration of an implantable stimulator, in accordance with a
preferred embodiment of the present invention. Preferably,
substantially all of the electronic components (including an
inductive coil 176 and an electronic circuit 178 having a
rechargeable energy source) are encapsulated in a biocompatible
metal case 174. One or more feed-throughs are preferably provided
to enable coupling between at least one electrode 182 and the
electronic circuit, as well as between inductive coil 176 and
another inductive coil (not shown) in communication therewith.
[0769] With reference to FIGS. 10A and 10B, the energy source for
electronic circuits 158 and 178 may comprise, for example, a
primary battery, a rechargeable battery, or a super capacitor. For
applications in which a rechargeable battery or a super capacitor
is used, any kind of energizing means may be used to charge the
energy source, such as (but not limited to) standard means for
inductive charging or a miniature electromechanical energy
converter that converts the kinetics of the patient movement into
electrical charge. Alternatively, an external light source (e.g., a
simple LED, a laser diode, or any other light source) may be
directed at a photovoltaic cell in the electronic circuit. Further
alternatively, ultrasound energy is directed onto the implanted
unit, and transduced to drive battery charging means.
[0770] FIGS. 11 and 12 are bar graphs showing experimental results
obtained during rat experiments performed in accordance with a
preferred embodiment of the present invention. A common technique
in monitoring bio-distribution of materials in a system includes
monitoring the presence and level of radio-labeled tracers. These
tracers are unstable isotopes of common elements (e.g., Tc, In, Cr,
Ga, and Gd), conjugated to target materials. The chemical
properties of the tracer are used as a predictor for the behavior
of other materials with similar physiochemical properties, and are
selected based on the particular biological mechanisms that are
being evaluated. Typically, a patient or experimental animal is
placed on a Gamma camera, or target tissue samples can be harvested
and placed separately into a well counter. For the purpose of the
present set of experiments which were performed, the well counter
method was chosen due to its higher sensitivity and spatial
resolution. A series of experiments using 99Tc-DTPA (DTPA molecule
conjugated to a 99-Technetium isotope) were performed. The
molecular weight of 99Tc-DTPA is 458 Da, its lipophilicity is
negative, and its electric charge is +1. These parameters are quite
similar with pharmacological agents used in standard chemotherapy,
such as tamoxifen, etoposide and irinotecan.
[0771] FIGS. 11 and 12 show results obtained using 99Tc-DTPA
penetration assays using ordinary brain sampling techniques (FIG.
11) and peeled brain techniques (FIG. 12). The x-axis of each graph
represents different experimental runs, and the y-axis of each
graph is defined as: [(hemisphere radioactivity)/(hemisphere
weight)]/[(total injected radioactivity)/(total animal weight)].
The results obtained demonstrate an average 2.5-fold increase in
the penetration of 99Tc-DTPA to the rat brain. It is noted that
these results were obtained by unilateral stimulation of the SPG.
The inventors believe that bilateral SPG stimulation will
approximately double drug penetration, relative to unilateral SPG
stimulation.
[0772] In both FIG. 11 and FIG. 12, some animals were designated as
control animals, and other animals were designated as test animals.
In each group, the left and right hemispheres were tested
separately, and the height of each bar represents, for a given
animal and a given hemisphere, the normalized level of
radioactivity as defined above. Thus, FIG. 11 shows results from a
total of four test hemispheres and four control hemispheres. FIG.
12 shows results from six test hemispheres and fourteen control
hemispheres. The juxtaposition of control and test bars in the bar
graphs is not meant to imply pairing of control and test
hemispheres.
[0773] FIG. 13 is a schematic illustration of acoustic or optical
clot detection apparatus 202, for use, for example, in providing
feedback to any of the microprocessors or other circuitry described
hereinabove, in accordance with a preferred embodiment of the
present invention. The detection is preferably performed by
coupling to a major blood vessel 200 (e.g., the internal carotid
artery or aorta) a detecting element comprising an acoustic or
optical transmitter/receiver 206, and an optional reflecting
surface 204. Natural physiological liquids may serve as a mediating
fluid between the device and the vessel. Preferably, the
transmitter/receiver generates an ultrasound signal or
electromagnetic signal which is reflected and returned, and a
processor evaluates changes in the returned signal to detect
indications of a newly-present clot. Alternatively, a transmitter
is placed on side of the vessel and a receiver is placed on the
other side of the vessel. In either case, for some applications,
more than one such apparatus 202 are placed on the vessel, in order
to improve the probability of successful clot detection for
possible estimation of the clot's direction of motion within the
vessel, and to lower the false alarm (i.e. false detection)
rate.
[0774] FIG. 14 is a schematic sectional illustration of a nasal
inhaler 300, for use in presenting an odorant to a subject, in
accordance with a preferred embodiment of the present invention.
Nasal inhaler 300 preferably comprises apparatus known in the art,
such as an aqueous spray nasal inhaler, a metered dose nasal
inhaler, or an air-dilution olfactometer. The odorant is stored in
an odorant-storage vessel 302, and is delivered to a nasal passage
using an odorant-delivery element 304, such as a nasal piece.
Alternatively or additionally, the odorant is presented by means of
an orally-dissolvable capsule that releases the active odorants
upon contact with salivary liquids. The odorants reach the
appropriate neural structures and induce vasodilatation,
vasoconstriction and/or cerebrovascular permeability changes.
[0775] FIG. 15 is a graph showing the results of an efflux study,
performed in accordance with an embodiment of the present
invention. Techniques described in the following two articles,
which are incorporated herein by reference, were applied for use
with this embodiment:
[0776] Asaba et al., "Blood brain barrier is involved in the efflux
transport of a neuroactive steroid, dehydroepiandrosterone sulfate,
via organic anion transporting polypeptide 2." J. Neurochem. 75,
pp. 1907-1916, (2000).
[0777] Isakovic et al., "The efflux of purine nucleobases and
nucleosides from the rat brain." Neuroscience Letters 318, pp.
65-68, (2002).
[0778] Male Wistar rats (280-300 g; Harlan) were used. Six rats
were in an experimental group, and six rats were in a control
group. A BEI (brain efflux index) study was performed according to
the method described in an article by Kakee et al., "Brain efflux
index as a novel method of analyzing efflux transport at the blood
brain barrier." J. Pharmacol. Exp. Ther. 277, 1550-1559. (1996),
which is incorporated herein by reference. Rats were anesthetized
by intraperitoneal administration of Pentobarbital, and then
mounted on a stereotaxic frame. A burr hole was made 5.5 mm lateral
and 0.2 mm anterior to the bregma, and a fine injection needle was
advanced to a depth of 4.5 mm. Then, 0.50 ml of [3H]PNA (150,000
disintegrations per minute (dpm), 0.5'-CCGCTCCG-3', MW. 2122)
dissolved in extracellular fluid (ECF) buffer (122 mM NaCl, 25 mM
NaHCO3, 10 mM D-glucose, 3 mM KCl, 1.4 mM CaCl2, 1.2 mM MgSO4, 0.4
mM K2HPO4, 10 mM HEPES, pH 7.4) was administered over 1 min using a
5.0-ml microsyringe (Hamilton, Reno, Nebr., U.S.A.) fitted with a
fine needle at a depth of 4.5 mm from the surface of the scalp
(that is, in the parietal cortex area 2 (Par2) region). At the end
of the experiment (60 min), an aliquot of CSF was collected from
the cisterna magna, using techniques described in Kakee et al.,
1996. The whole brain was subsequently isolated, and the left
cerebrum, right cerebrum, and cerebellum were isolated. After
weighing, tissue samples were dissolved in 1 ml of 2 M NaOH at
50.degree. C. for 3 h and then were mixed with 4 ml of
scintillation cocktail. The associated radioactivity was measured
in a liquid scintillation counter equipped with an appropriate
crossover correction of 3H (LS-6500; Beckman, Fullerton, Calif.,
U.S.A.).
[0779] The SPG stimulation protocol included cycling between
on-periods, lasting 90 seconds, and off-periods, lasting for 60
seconds. During each on-period, a 5 volt, 10 Hz signal was applied
to the SPG, each pulse having a pulse width of 1 ms. The signal was
applied using a concentric bipolar electrode, both poles of the
electrode being inserted slightly into the SPG.
[0780] FIG. 15 clearly shows the increased clearance of the
injected tracer from the animals that received electrical SPG
stimulation, compared to the clearance in the non-stimulated (i.e.,
control) animals. The error bars represent one standard deviation.
No electrodes were inserted into the SPG of the control
animals.
[0781] FIG. 16 is a graph showing the results of an experiment
performed in accordance with an embodiment of the present
invention. Four beagles were in a control (non-stimulated) group,
and four beagles were in a stimulated group. No electrodes were
applied to the SPG of the animals of the control group. At time
zero, a solution of 10 kDa FITC-dextran tracer was administered
intravenously, and, at the same time, SPG stimulation was
initiated. Administration of the dextran was performed continuously
over a 20 minute period, and SPG stimulation continued for 30
minutes (i.e., for 10 minutes after termination of the dextran
administration). The SPG stimulation protocol included cycling
between on-periods, lasting 90 seconds, and off-periods, lasting
for 60 seconds. During each on-period, a 6 volt, 10 Hz signal was
applied to the SPG, each pulse having a pulse width of 1 ms. The
signal was applied using a concentric bipolar electrode, both poles
of the electrode being inserted slightly into the SPG.
[0782] After termination of the SPG stimulation (or equivalent time
period in the control group), each animal was sacrificed.
Concentrations of dextran in various parts of each beagle's brain
were measured. In the control group, concentrations in the left
half and the right half were measured separately, such that the
control results shown in FIG. 16 represent n=8, from four animals.
In the experimental group, four animals were used. For each
experimental animal, only one sample was taken from each brain
region, ipsilateral to the stimulation (thus n=4).
[0783] FIG. 16 shows results from six brain regions known to be
regulated to some extent by the SPG (the frontal cortex, the
temporal cortex, frontal white matter, the olfactory bulb, the
striatum, and the hippocampus). FIG. 16 also shows dextran
concentrations measured in the pons, a portion of the brain
regulated by the otic ganglion (and substantially not by the SPG).
Notably, the results of this experiment show that dextran
concentrations in each of the six regions regulated by the SPG were
significantly higher in the SPG-stimulated group than in the
control group. The high concentration of the dextran tracer (a
large molecule), indicates that BBB permeability was substantially
increased as a result of the SPG stimulation, in the brain regions
regulated by the SPG. Also notable is the almost exact equivalence
between the dextran levels in the pons of the SPG-stimulated
animals and in the pons of the control animals. The contrast
between:
[0784] (a) the equivalence of the experimental and control groups,
in a non-SPG-regulated brain tissue, and
[0785] (b) the significant differences between the experimental and
control groups in the SPG-regulated brain tissues, is a strong
indication that the displayed significant effect of the
experimental protocol shown in FIG. 16 is a result of modulating
the functioning of the SPG and its control over BBB permeability in
certain portions of the brain.
[0786] In addition to the results shown in FIG. 16 and described
hereinabove, the inventor additionally assessed the concentration
of the dextran tracer in temporal muscle of the animals in the
SPG-stimulated group and in the control group. It is noted that
temporal muscle, being outside of the brain, has no protection from
the BBB. The results show that the dextran concentrations rose to
high and essentially equivalent values in the temporal muscle of
the animals in both the SPG-stimulated group and the control group.
This, in combination with the pons data, shows that SPG stimulation
as provided herein only produced a measured effect on brain tissue
that is regulated by the SPG.
[0787] FIG. 17 shows results from an experiment which included one
hour of continuous SPG stimulation in five rats, in accordance with
an embodiment of the present invention. Prior to the initiation of
SPG stimulation, cerebral blood flow (CBF) was measured, and this
measurement provided a baseline for subsequent CBF measurements.
CBF was continuously recorded throughout the hour of SPG
stimulation, and continued to be recorded for 30 minutes after the
stimulation ceased. SPG stimulation protocols were identical to
those described hereinabove with reference to FIG. 15.
[0788] Three bars are shown in FIG. 17. The left bar represents the
average blood flow change 20 minutes after SPG stimulation was
initiated. The middle bar shows average blood flow change 40
minutes after stimulation was initiated, and the right bar shows
average blood flow change 20 minutes after the termination of SPG
stimulation. From this figure, it is evident that during SPG
stimulation, a CBF increase of around 50% (i.e. 150% of original
blood flow level) is measured. This increase in cerebral blood flow
is believed to be associated with improved metabolic state of brain
tissue supplied by the CBF, as supported by other data collected by
the inventor (not shown).
[0789] FIG. 18 is a schematic illustration of an implantable
stimulator 400 for stimulation of an MTS, in accordance with an
embodiment of the present invention. Stimulator 400 is preferably
implanted adjacent to orbital cavity 408 of a subject. At least one
electrode 402 extends from the stimulator to at least one of: an
anterior ethmoidal nerve 404 and a posterior ethmoidal nerve 406,
which are modulation target sites. Stimulator 400 is preferably
implanted through an incision made in the upper edge of the eyelid
(not shown).
[0790] In an embodiment of the present invention, an odorant is
presented to an air passage of a patient, such as a nasal cavity or
the throat, so as to increase transport of a diagnostic agent
across the BBB from the systemic blood circulation to the CNS, in
order to facilitate a diagnosis of a CNS condition. Alternatively
or additionally, an odorant is similarly presented in order to
enhance transport of a biochemical agent from the CNS to a non-CNS
tissue, such as the systemic blood circulation, in order to
facilitate a diagnosis of a CNS condition.
[0791] In an embodiment of the present invention, stimulation of
the MTS is achieved by applying a neuroexcitatory agent to the MTS.
Suitable neuroexcitatory agents include, but are not limited to
acetylcholine and urocholine. For some applications, the MTS is
stimulated by applying a neuroinhibitory agent, such as atropine,
hexamethonium, or a local anesthetic (e.g., lidocaine).
[0792] In an embodiment of the present invention, stimulation of
the MTS is achieved by applying mechanical stimulation to the MTS,
e.g., vibration.
[0793] Embodiments of the present invention have many medical
applications. For example, chemotherapeutic drugs need to pass into
cerebral tissue in order to treat brain tumors. Most of the
chemotherapeutic drugs have molecular weights of 200-1200 Da, and
thus their transport through the blood-brain barrier (BBB) is
highly restricted. To overcome the impedance of the BBB, an
intracarotid infusion of high osmotic load has been used in the
prior art in order to open the tight junctions of the BBB for a
very short period (e.g., 25 minutes), during which the medications
are given. This procedure is not simple--it is invasive, requires
general anesthesia, requires subsequent intensive care, and is in
any case relatively expensive. For these reasons, such intracarotid
infusions are used only in very few healthcare facilities, even
though some reports claim a substantial improvement in life
expectancy in patients receiving chemotherapy in this manner.
[0794] Preferably, embodiments of the present invention which
facilitate increased trans-BBB drug delivery, and therefore more
efficient chemotherapy, also enable a reduction or elimination of
the need for radiotherapy. It is noted that such irradiation of the
brain is indicated in the literature to be a significant cause of
long-term cognitive and other deficits.
[0795] The better delivery of drugs, as provided in accordance with
a preferred embodiment of the present invention, is also a factor
in the treatment of other disorders, such as Parkinson's disease,
Alzheimer's disease, and other neurological diseases. For some
applications, the trans-BBB delivery of various growth factors is
facilitated using the techniques described herein. Growth factors
are typically large molecules that stimulate the growth of neurons,
and may be used to treat degenerative disorders, such as
Parkinson's disease, Alzheimer's disease, and Motor Neuron Diseases
(e.g., Lou Gehrig's disease).
[0796] Another preferred application of the present invention
includes facilitating drug delivery across the BBB in order to
treat inflammation in the brain, e.g., for cases of infectious
diseases of the brain in immunocompromised patients. Similarly,
medications to treat AIDS may be more effectively administered to
sites in the brain through the BBB, when appropriate, through the
use of methods and apparatus described herein. A further
application of some embodiments of the present invention includes
the delivery through the BBB of viruses that are agents of gene
therapy (e.g., for treating Parkinson's disease). Similarly,
methods and apparatus described herein may be used for metabolic
disorders of the brain, such as GM2 gangliosidosis.
[0797] Another aspect of some preferred embodiments of the
invention relates to the modulation of cerebral blood flow. Roughly
750,000 Americans suffer strokes each year. Stroke is the United
States' third leading cause of death, killing about 160,000
Americans every year. More than 3 million people in the United
States have survived strokes, of whom more than 2 million suffer
crippling paralysis, speech loss and lapses of memory. About 85% of
strokes are ischemic, i.e., a blood vessel is occluded and its
territory is deprived of oxygen supply. A cerebral region that is
totally deprived of blood supply is surrounded by a second region
of partial lack of supply, whose vitality is at risk. This second
region is one of the main targets of some embodiments of the
invention--stimulation of the SPG will dilate its vessels and
significantly improve that region's likelihood of survival. If the
intervention is given early enough in the event (e.g., a few hours
post-stroke), it might help also the core region of the stroke, as
the thrombus is not yet organized, and dilation of the vessels may
reintroduce blood supply to the tissue. Alternatively, SPG
stimulation may allow the clot to move from a big vessel to a small
vessel, and thus deprive blood supply only from a much smaller
volume of the brain (which would, in any case, have probably been
deprived of blood supply had the clot remained in place).
[0798] Population-based studies have shown that about 5% of men and
16% of women suffer migraine attacks. Over 80% of these people
suffer some degree of headache-related disability. Parasympathetic
block (in contrast to stimulation) is known to cause
vasoconstriction. An embodiment of the present invention uses
electrical means to induce the vasoconstrictive effect and treat
migraine. For example, it may use techniques to block nerve
messaging, such as applying a slowly-varying voltage, or in some
cases, a constant level DC voltage.
[0799] Alzheimer's disease is becoming a major source of disability
and financial load with the increase in life expectancy. In recent
years, vascular factors have been considered prominent in the
pathophysiology of the disease. Current therapy is generally
concentrated along one line--cholinomimetic medications, which can,
at most, slow down the deterioration of cognitive function in
patients. SPG stimulation, as provided in accordance with a
preferred embodiment of the present invention, is believed to
increase blood flow and oxygen supply to the brain, and therefore
help these patients. For this use, permanent stimulators may be
implanted in the nasal cavity, for long-term intermittent
stimulation.
[0800] In general, it is believed that substantially all
pharmacological treatments aimed at cerebral cells for neurological
and psychiatric disorders are amenable for use with these
embodiments of the present invention. In particular, this
embodiment may be adapted for use in the treatment of disorders
such as brain tumors, epilepsy, Parkinson's disease, Alzheimer's
disease, multiple sclerosis, schizophrenia, depression, stress,
anxiety, disorders requiring the administration of various growth
factors, and other CNS disorders that are directly or indirectly
affected by changes in cerebral blood flow or by BBB permeability
changes.
[0801] Alternatively or additionally, a method is provided for
increasing or reducing cortical blood flow and/or inducing or
inhibiting vasodilation (even in the absence of BBB permeability
changes) by presenting an odorant to an air passage of a patient,
such as a nasal cavity or the throat, for treatment of a condition.
Patients with the aforementioned disorders and other disorders are
generally helped by vasodilation and the resultant improvement in
oxygen supply to neurons and other tissue. For some applications,
this treatment is given on a long-term basis, e.g., in the chronic
treatment of Alzheimer's patients. For other applications, the
treatment is performed on a short-term basis, e.g., to minimize the
damage following an acute stroke event and initiate neuronal and
therefore functional rehabilitation. Alternatively or additionally,
the method provided above can be used for diagnostic purposes or in
conjunction with other diagnostic methods and/or apparatus known in
the art, in order to enhance diagnostic results, reduce procedure
risk, reduce procedure time, or otherwise improve such diagnostic
procedures and/or diagnostic results. For example, methods and
apparatus described herein may be used to increase the uptake into
the brain of a radio-opaque material, in order to facilitate a CT
scan.
[0802] In a preferred embodiment of the present invention,
stimulation of the SPG may be performed using direct galvanic
contact, indirect electromagnetic induction, photonic excitation,
chemical excitation, mechanical excitation and other methods or
combinations thereof, which are known in the art of neural
stimulation. Stimulation of the SPG may be performed directly on
the SPG, or the nerves connected directly or indirectly with the
SPG, e.g., via reflex arc.
[0803] In a preferred embodiment of the present invention,
techniques described herein are applied in combination with methods
and apparatus described in PCT Application IL 01/00402, filed May
7, 2001, entitled, "Method and apparatus for stimulating the
sphenopalatine ganglion to modify properties of the BBB and
cerebral blood flow," U.S. Provisional Patent Application
60/364,451, filed Mar. 15, 2002, entitled, "Applications of
stimulating the sphenopalatine ganglion (SPG)," U.S. Provisional
Patent Application 60/368,657, filed Mar. 28, 2002, entitled, "SPG
stimulation," and/or U.S. Provisional Patent Application
60/376,048, filed Apr. 25, 2002, entitled, "Methods and apparatus
for modifying properties of the BBB and cerebral circulation by
using the neuroexcitatory and/or neuroinhibitory effects of
odorants on nerves in the head," all of which are assigned to the
assignee of the present invention and are incorporated herein by
reference.
[0804] The better delivery of drugs, as provided in accordance with
preferred embodiments of the present invention, is an important
factor in the treatment of various disorders, such as Parkinson's
disease, Alzheimer's disease, and other neurological diseases. For
some applications, the trans-BBB delivery of various growth factors
is facilitated using the techniques described herein. Growth
factors are typically large molecules that stimulate the growth of
neurons, and, in accordance with a preferred embodiment of the
present invention, are used to treat degenerative disorders, such
as Parkinson's disease, Alzheimer's disease, and Motor Neuron
Diseases (e.g., Lou Gehrig's disease).
[0805] Alzheimer's disease is becoming a major source of disability
and financial load with the increase in life expectancy. In recent
years, vascular factors have been considered prominent in the
pathophysiology of the disease. Current therapy is generally
concentrated along one line--cholinomimetic medications, which
typically, at most, slow down the deterioration of cognitive
function in patients. SPG stimulation, as provided in accordance
with preferred embodiments of the present invention, typically
increases blood flow and oxygen supply to the brain, and therefore
help these patients. For this use, permanent stimulators may be
implanted in the nasal cavity, for long-term intermittent
stimulation. In a preferred embodiment, the delivery of
cholinomimetic medications is facilitated by SPG stimulation.
[0806] Apart from molecular parameters, the permeability of the BBB
and active transport mechanisms, a major determinant of molecular
transport across the BBB is their concentration gradient--between
the CNS and the cerebral circulation. In cases where a compound has
a higher concentration in the brain than in the cerebral
circulation, opening of the BBB, preferably, but not necessarily,
using techniques described herein leads to an increased net
transport of that compound from the CNS into the circulation. In a
preferred embodiment, this technique is used to facilitate a
diagnosis, e.g., by enhancing permeability of the BBB, taking a
blood sample, and testing the blood sample for increased levels of
the compound.
[0807] In a preferred embodiment of the present invention,
parasympathetic fibers associated with the SPG are stimulated,
preferably by using electrical stimulation and/or odorant
presentation techniques described herein, thereby rendering the BBB
permeable to certain compounds in the CNS. One or more of such
compounds are then analyzed by analyzing the blood of the patient.
By testing such compounds that are indicative of the presence of
AD, AD is diagnosed. Advantageously, such a testing procedure is
minimally invasive. Alternatively or additionally, molecular
passage is increased to another body compartment and/or fluid, such
as plasma, serum, ascites, or cerebrospinal fluid.
[0808] Moreover, in accordance with a preferred embodiment of the
present invention, a controlled, reversible suppression of the
impedance of the BBB is useful as a stand-alone treatment, when
said suppression facilitates clearance of neurotoxic compounds,
such as .beta.-Amyloid, tau, PS1, and PS2, from the CNS into the
systemic circulation. Once in the systemic circulation, these
neurotoxic compounds may be metabolized and removed from the body
with greater ease and with fewer side effects, compared to effects
that accompany their presence in the CNS.
[0809] The following examples demonstrate selected therapeutic and
diagnostic applications of SPG stimulation in the management of
Alzheimer's disease. It should be appreciated by those of skill in
the art, that the following examples are set forth for
demonstrative purposes. However, those of skill in the art should,
in light of the present disclosure, appreciate that many changes
can be made in the specific embodiments disclosed and still obtain
a like or similar result without departing from the spirit and
scope of the invention. The following description relates to
specific embodiments for stimulation of the SPG and related neural
structures, possible system configurations for the stimulator
device, variations or combinations of the therapeutic and
diagnostic modalities that accompany SPG stimulation and
complementary explanation for the various mechanisms of actions of
such a system for AD management. Furthermore, the methods described
herein may be either directly, or indirectly applicable for the
management of other CNS disorders, such as Parkinson's disease,
epilepsy, ALS, MS and more. All references cited herein, including
articles, patents, and published patent applications, are
incorporated herein by reference.
EXAMPLE 1
Therapeutics (Glutamate Inhibitors)
[0810] Excitotoxicity is related to excessive activation of
glutamate receptors which results in neuronal cell death. The
physiological function of glutamate receptors is the mediation of
ligand-gated cation channels with the concomitant influx of
calcium, sodium and potassium through this receptor-gated channel.
The influx of these cations is essential for maintaining membrane
potentials and the plasticity of neurons which in itself plays a
pivotal role in cognitive function of the central nervous system
(Li, H. B. et al., Behav. Brain Res. 83: 225-228, 1997; Roesler, R.
et al., Neurology 50: 1195, 1998; Wheal, H. V. et al., Prog.
Neurobiol. 55: 611-640, 1998; Wangen, K et al., Brain Res. 99:
126-130, 1997). Excitotoxicity plays an important role in neuronal
cell death following acute insults such as hypoxia, ischemia,
stroke and trauma, and it also plays a significant role in neuronal
loss in AIDS dementia, epilepsy, focal ischemia (Coyle, J. T. et
al., Science 262: 689-695, 1993). Neurodegenerative disorders, such
as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's
disease (PD) and amyotrophic lateral sclerosis (ALS), are
characterized by the progressive loss of a specific population of
neurons in the central nervous system. Growing evidence suggests
that glutamate-mediated excitotoxicity may be a common pathway
which contributes to neuronal cell death in a wide range of
neurological disorders (Coyle, J. T. et al., Science 262: 689-695,
1993). The molecular mechanisms of excitotoxicity-mediated neuronal
cell death remains obscure. Over-production of free radicals that
lead to impairment of mitochondrial function is the most widely
held hypothesis (Beal, M. F. et al., Ann. Neurol. 38: 357-366,
1995; Coyle, J. T. et al., Science 262: 689-695, 1993). However, it
is unclear in the literature whether the increase of free radicals
is the precursor that initiates neuronal degeneration or, rather, a
subsequent consequence of neuronal degeneration. Interestingly,
administration of antioxidants is reported as having little
neuroprotective effect in patients suffering from various
neurodegenerative diseases (Shults, C. W. et al., Neurology 50:
793-795, 1998). Thus, some other mechanism(s) must exist for
excitotoxicity-induced neuronal cell death.
[0811] A potential treatment modality for AD is the systemic
administration of a JNK (c-Jun amino-terminal kinase) or MLK (Mixed
lineage kinase) apoptosis inhibitor as a means for preventing
AD-related apoptosis of brain cells. However, without the use of
the techniques described herein, achieving a therapeutic
concentration of such an inhibitor in the CNS may be accompanied by
undesired dose-related side effects. Advantageously, the use of
techniques described herein for enhancing drug delivery to the CNS
typically enables the achievement of therapeutic results at lower
dosages, which, in turn, lowers the risk of dose-related side
effects.
[0812] In a preferred embodiment of the present invention, the
therapeutic or prophylactic administration of such inhibitors is
enhanced by stimulation of the SPG and/or its related
neuroanatomical structures, by using electrical stimulation,
odorant presentation, and/or other means for stimulating the SPG or
for modulating permeability of the BBB.
EXAMPLE 2
Therapeutics .beta./.gamma. Secretase Inhibitors
[0813] In a preferred embodiment of the present invention, methods
for treatment of Alzheimer's disease target the formation of
.beta.-amyloid through the enzymes involved in the proteolytic
processing of .beta.-amyloid precursor protein. Compounds that
inhibit .beta. or .gamma. secretase activity, either directly or
indirectly, are used, in accordance with this embodiment, to
control the production of .beta.-amyloid. Advantageously, compounds
that specifically target .gamma. secretases, could control the
production of .beta.-amyloid. Typically, such inhibition of .beta.
or .gamma. secretases reduces production of A.beta., which, in
turn, reduces or prevents the neurological disorders associated
with A.beta. protein.
[0814] Compelling evidence accumulated during the last decade
revealed that A.beta. is an internal polypeptide derived from a
type I integral membrane protein, termed b amyloid precursor
protein (APP). P APP is normally produced by many cells both in
vivo and in cultured cells, derived from various animals and
humans. A.beta. is derived from cleavage of .beta. APP by as yet
unknown enzyme (protease) system(s), collectively termed
secretases.
[0815] The existence of at least four proteolytic activities has
been postulated. They include .beta. secretase(s), generating the
N-terminus of A.beta., a secretase(s) cleaving around the 16/17
peptide bond in A.beta., and .gamma. secretases, generating
C-terminal A.beta. fragments ending at position 38, 39, 40, 42, and
43 or generating C-terminal extended precursors which are
subsequently truncated to the above polypeptides.
[0816] Several lines of evidence suggest that abnormal accumulation
of A.beta. plays a key role in the pathogenesis of AD. First,
A.beta. is the major protein found in amyloid plaques. Second,
A.beta. is neurotoxic and may be causally related to neuronal death
observed in AD patients. Third, missense DNA mutations at position
717 in the 770 isoform of P APP can be found in affected members
but not unaffected members of several families with a genetically
determined (familiar) form of AD. In addition, several other .beta.
APP mutations have been described in familiar forms of AD. Fourth,
similar neuropathological changes have been observed in transgenic
animals overexpressing mutant forms of human .beta. APP. Fifth,
individuals with Down's syndrome have an increased gene dosage of
.beta. APP and develop early-onset AD. Taken together, these
observations strongly suggest that A.beta. depositions may be
causally related to the AD.
[0817] It is hypothesized by the inventors that inhibiting the
production of A.beta. inhibits neurological degeneration by
controlling the formation of amyloid plaques, reducing
neurotoxicity and, generally, mediating the pathology associated
with A.beta. production. One method of treatment preferred by the
inventors is based on drugs that inhibit the formation of A.beta.
in vivo, administered in combination with techniques for SPG
stimulation described herein.
[0818] Methods of treatment preferably target the formation of
A.beta. through the enzymes involved in the proteolytic processing
of P amyloid precursor protein. Compounds that inhibit .beta. or
.gamma. secretase activity, either directly or indirectly, could
control the production of A.beta.. Advantageously, compounds that
specifically target .gamma. secretases could control the production
of A.beta.. Such inhibition of p or .gamma. secretases could
thereby reduce production of A.beta., which, in turn, could reduce
or prevent the neurological disorders associated with A.beta.
protein.
[0819] U.S. Patent Application Publication 2002/0055501 to Olson et
al. describes pharmaceutical compositions and methods of use of
such compounds, which inhibit the processing of amyloid precursor
protein and, more specifically, inhibit the production of
A.beta.-peptide, thereby acting to prevent the formation of
neurological deposits of amyloid protein.
[0820] The efficacy of administration of pharmaceutical agents that
inhibit the processing of amyloid precursor protein into P-amyloid
is typically substantially increased when used in conjunction with
the techniques of SPG stimulation described herein.
[0821] In a preferred embodiment of the present invention, the
therapeutic or prophylactic administration of such compounds
targeting production of A.beta. is enhanced by stimulation of the
SPG and/or its related neuroanatomical structures, by using
electrical stimulation, odorant presentation, and/or other means
for stimulating the SPG or for modulating permeability of the
BBB.
EXAMPLE 3
Therapeutics (NMDA-Receptor Blocker)
[0822] U.S. Patent Application Publication 2002/0035145 to Tsai et
al., describes a method to treat various neuropsychiatric
disorders, including Alzheimer's disease. Their description relates
that neuropsychiatric disorders characterized by a deficit in
neurotransmission via the NMDA receptor can be alleviated by a
compound that acts as an agonist of the glycine site on the NMDA
receptor or an inhibitor of glycine uptake. The compound is either
a partial agonist such as D-cycloserine, which can be used at a
dosage of 105-500 mg, or a full agonist (e.g., D-serine or
D-alanine) that is selective for the NMDA receptor (compared to the
inhibitory glycine receptor and other receptors), or a glycine
uptake inhibitor (e.g., N-methylglycine). They describe methods for
treating neuropsychiatric disorders in patients (i.e., humans).
Examples of disorders that can be treated by the methods they
describe include schizophrenia, Alzheimer's disease, autism,
depression, benign forgetfulness, childhood learning disorders,
closed head injury, and attention deficit disorder. The methods
entail administering to a patient diagnosed as suffering from such
a neuropsychiatric disorder a pharmaceutical composition that
contains a therapeutically-effective amount of an agonist of the
glycine site of the NMDA receptor or a glycine uptake inhibitor,
which agonist is relatively selective for (a) the glycine site of
the NMDA receptor, compared with (b) the inhibitory glycine
receptor and other receptors. The pharmaceutical composition may
include, for example, (i) a therapeutically effective amount of
D-alanine (wherein the pharmaceutical composition is substantially
free of D-cycloserine) and/or (ii) a therapeutically effective
amount of D-serine, and/or (iii) D-cycloserine in an amount of
105-500 mg, and/or (iv) a therapeutically effective amount of
N-methylglycine.
[0823] U.S. Patent Application Publication 2001/0051633 to Bigge et
al., describes a subtype-selective NMDA receptor ligands and the
use thereof for treating or preventing neuronal loss associated
with neurodegenerative diseases including Alzheimer's disease by
treating or preventing the adverse consequences of the
overstimulation of the excitatory amino acids.
[0824] U.S. Patent Application Publication 2001/0047014 to Alanine
et al., describes a compound of the formula 1 its R,R-,
S,S-enantiomers and racemic mixtures, also suitable for the
treatment of Alzheimer's disease.
[0825] In a preferred embodiment of the present invention, the
therapeutic or prophylactic administration of such compounds
described in this example (Example 3), and/or the diagnostic use
thereof, is enhanced by stimulation of the SPG and/or its related
neuroanatomical structures, by using electrical stimulation,
odorant presentation, and/or other means for stimulating the SPG or
for modulating permeability of the BBB.
EXAMPLE 4
Therapeutics (Cholinesterase Inhibitors)
[0826] U.S. Patent Application Publication 2002/0028834 to
Villalobos et al., describes the use of cholinesterase inhibitors
for enhancing memory in patients suffering from dementia and
Alzheimer's disease. It is known that acetylcholinesterase
inhibitors are effective in enhancing cholinergic activity and
useful in improving the memory of Alzheimer's patients. By
inhibiting acetylcholinesterase enzyme, these compounds increase
the level of the neurotransmitter acetylcholine in the brain and
thus enhance memory. Becker et al., cited hereinabove, report that
behavioral changes following cholinesterase inhibition appear to
coincide with predicted peak levels of acetylcholine in the brain.
They also discuss the efficacy of three known acetylcholinesterase
inhibitors, physostigmine, metrifonate, and
tetrahydroaminoacridine.
[0827] In a preferred embodiment of the present invention, the
therapeutic or prophylactic administration of such cholinesterase
inhibitors is enhanced by stimulation of the SPG and/or its related
neuroanatomical structures, by using electrical stimulation,
odorant presentation, and/or other means for stimulating the SPG or
for modulating permeability of the BBB.
EXAMPLE 5
Therapeutics (Direct Stimulation of Neural Regeneration)
[0828] There are continuous efforts to use a Nerve Growth Factor
(NGF) as a stimulant of neural regeneration, thus potentially
slowing degenerative processes, or even reversing neural damage.
(NGF belongs to a large family of neural growth factors, including
BDNF, IGF, GDNF and other active stimulants of neural regeneration.
However, for the purpose of the present patent application, the
term NGF shall be used to represent any such compound, or
combinations thereof). Therefore, growth factor therapy for AD is
considered a potentially curative approach of disease management.
However, such an approach still has to overcome the challenge of
administering growth factor in adequate amounts, preferably over a
continuous period of time, into the CNS. In the prior art, the BBB
is generally considered impermeable to high molecular weight
compounds, and thus systemic administration of growth factor,
without using the techniques described herein, is not generally
considered a treatment option for a patient with a functional
BBB.
[0829] Because the BBB is generally considered in the prior art to
be impermeable to high molecular weight compounds, invasive methods
have been developed to enable NGF to reach a patient's brain. For
example, a possible method for AD therapy, currently being tested
in clinical trials, uses gene therapy techniques for the in-situ
production of growth factors. This method involves brain surgery,
where a patient's own cells are genetically modified to produce the
NGF. The patient's cells, called "fibroblasts," are obtained from
skin biopsies. The fibroblasts are genetically modified in vitro
and are then implanted into either 5 or 10 locations in the
patient's brain. The eventual goal of this research effort is to
determine whether NGF produced by the cells implanted into the
brain can prevent the death of some nerve cells that are affected
in Alzheimer's disease, and enhance the function of some remaining
brain cells.
[0830] In animal studies, fibroblasts genetically modified to
produce NGF have been shown to prevent the death of certain nerve
cells in the brain. This effectiveness has been shown in both the
rat brain and the monkey brain. The genetically-modified cells
prevent cell death after injury, and prevent cell atrophy that is a
natural consequence of aging in primates.
[0831] A straightforward approach to circumventing the BBB would be
to pierce the meninges and directly administer growth factors into
the CNS. This technique, however, has several drawbacks. First, it
puts the patient in a continuous risk of inflammatory brain
processes. Second, direct infusion into the brain is usually very
localized, and therefore its effectiveness is limited to the close
vicinity of the administration tip, especially where the active
molecule is of high molecular weight, making it less mobile. It is
therefore clear that a relatively safe method of transiently
opening the BBB to large molecular weight molecules, such as that
described herein, could make nerve growth factors a compound of
choice for the treatment of AD.
[0832] In a preferred embodiment of the present invention, the
therapeutic or prophylactic administration of nerve growth factor
is enhanced by stimulation of the SPG and/or its related
neuroanatomical structures, by using electrical stimulation,
odorant presentation, and/or other means for stimulating the SPG or
for modulating permeability of the BBB.
[0833] U.S. Patent Application Publication 2002/0040052 to Ito et
al., describes a method for extending neurites of neurocytes
without any side effects, and a method for preventing and/or
treating neurodegeneration diseases using compositions having
neurite extending effect. This invention is described as being
necessary because the more direct method of administering NGF
directly suffers from several limitations: "However, an NGF is a
protein having a molecular weight of 13000 in the form of monomer
and 26000 in the form of dimer, so that it cannot pass through the
blood-brain barrier. Therefore, in order to treat disorders of
central function, NGFs are required to be administrated
intraventricularly. Moreover, it is difficult to prepare NGFs in
large quantities. In these respects, there are many problems about
the use of NGF itself. As a result, it is very difficult to use NGF
itself clinically."
EXAMPLE 6
Therapeutics (Indirect Stimulation of Neural Regeneration)
[0834] One of the characteristics of Alzheimer's disease (AD) is
loss of presynaptic markers such as synaptophysin. Synaptophysin
decreases in neurodegenerative disorders along with a decline in
neurotransmission. Synaptophysin: (i) is a synaptic
vesicle-associated integral membrane protein (molecular weight
about 38 kDa), (ii) acts as a specific marker for the presynaptic
terminal, and (iii) is involved in neuronal transmission (Scheller,
R. H., "Membrane Trafficking in the Presynaptic Nerve Terminal,"
Neuron 14: 893-897, 1995). A combination of neurotrophic factors is
most effective in providing optimal trophic support for compromised
neuron functions, including neurotransmission (Rathbone M. P. et
al., "AIT-082 as a potential neuroprotective and regenerative agent
in stroke and central nervous system injury," Exp. Opin. Invest.
Drugs. 8: 1255-12652, 1999). Multiple neurotrophic factors may
synergistically regulate synaptophysin levels in a manner that can
lead to increased neurotransmission and improved neuronal
function.
[0835] Pharmaceutical agents that increase synaptophysin synthesis
and/or secretion, decrease its metabolism, increase its release or
improve its effectiveness may also be of benefit in reversing the
course of neurological diseases including neurodegenerative
diseases, such as Alzheimer's disease, and improve function in
neurodevelopmental disorders, such as Down's syndrome. U.S. Patent
Application Publication 2002/0040032 to Glasky et al. describes a
method of increasing the synthesis and/or secretion of
synaptophysin, comprising administering to a patient with a
neurological disease or a patient at risk of developing a
neurological disease an effective quantity of a purine derivative
or analogue, a tetrahydroindolone derivative or analogue, or a
pyrimidine derivative or analogue. If the compound is a purine
derivative, the purine moiety can be guanine or hypoxanthine.
[0836] Therefore, there exists a need for methods that can
stimulate the synthesis and/or secretion of synaptophysin in
patients with neurological diseases, including neurodegenerative
diseases such as AD and neurodevelopmental disorders such as Down's
syndrome, in order to preserve, restore or improve neuronal
transmission capability in such patients. Preferably, these methods
are combined with methods that enable active compounds to cross the
BBB, making combined therapy more efficient. These methods are
suitable for use with compounds or pharmaceutical compositions that
can stimulate nerve growth or regeneration in patients with
neurological diseases, including neurodegenerative diseases such as
AD and neurodevelopmental disorders such as Down's syndrome, thus
reversing the course of the disease.
[0837] In a preferred embodiment of the present invention, the
therapeutic or prophylactic administration of compounds affecting
synaptophysin, and/or the diagnostic use thereof, is enhanced by
stimulation of the SPG and/or its related neuroanatomical
structures, by using electrical stimulation, odorant presentation,
and/or other means for stimulating the SPG or for modulating
permeability of the BBB.
[0838] U.S. Patent Application Publication 2002/0019519 to Bingham
et al. describes the use of KIAA0551 polypeptides and
polynucleotides in the design of protocols for the treatment of
various neurological disorders, among which is AD.
[0839] In a preferred embodiment of the present invention, the
therapeutic or prophylactic administration of KIAA0551 polypeptides
and polynucleotides, and/or the diagnostic use thereof, is enhanced
by stimulation of the SPG its related neuroanatomical structures,
by using electrical stimulation, odorant presentation, and/or other
means for stimulating the SPG or for modulating permeability of the
BBB.
EXAMPLE 7
Therapeutics (Antioxidants)
[0840] A number of diseases and disorders are thought to be caused
by or to be associated with alterations in mitochondrial metabolism
and/or inappropriate induction or suppression of
mitochondria-related functions leading to apoptosis. These include,
by way of example and not limitation, chronic neurodegenerative
disorders such as Alzheimer's disease (AD) and Parkinson's disease
(PD); auto-immune diseases; diabetes mellitus, including Type I and
Type II; mitochondria associated diseases, including but not
limited to congenital muscular dystrophy with mitochondrial
structural abnormalities, fatal infantile myopathy with severe
mtDNA depletion and benign "later-onset" myopathy with moderate
reduction in mtDNA, MELAS (mitochondrial encephalopathy, lactic
acidosis, and stroke) and MIDD (mitochondrial diabetes and
deafness); MERFF (myoclonic epilepsy ragged red fiber syndrome);
arthritis; NARP (Neuropathy; Ataxia; Retinitis Pigmentosa); MNGIE
(Myopathy and external ophthalmoplegia; Neuropathy;
Gastro-Intestinal; Encephalopathy), LHON (Leber's; Hereditary;
Optic; Neuropathy), Kearns-Sayre disease; Pearson's Syndrome; PEO
(Progressive External Ophthalmoplegia); Wolfram syndrome DIDMOAD
(Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness);
Leigh's Syndrome; dystonia; schizophrenia; and hyperproliferative
disorders, such as cancer, tumors and psoriasis.
[0841] According to generally accepted theories of mitochondrial
function, proper ETC respiratory activity requires maintenance of
an electrochemical potential (ATm) in the inner mitochondrial
membrane by a coupled chemiosmotic mechanism. Conditions that
dissipate or collapse this membrane potential, including but not
limited to failure at any step of the ETC, may thus prevent ATP
biosynthesis and hinder or halt the production of a vital
biochemical energy source. Altered or defective mitochondrial
activity may also result in a catastrophic mitochondrial collapse
that has been termed "mitochondrial permeability transition" (MPT).
In addition, mitochondrial proteins such as cytochrome c and
"apoptosis inducing factor" may dissociate or be released from
mitochondria due to MPT (or the action of mitochondrial proteins
such as Bax), and may induce proteases known as caspases and/or
stimulate other events in apoptosis (Murphy, Drug Dev. Res. 46:
18-25, 1999).
[0842] Defective mitochondrial activity may alternatively or
additionally result in the generation of highly-reactive free
radicals that have the potential of damaging cells and tissues.
These free radicals may include reactive oxygen species (ROS) such
as superoxide, peroxynitrite and hydroxyl radicals, and potentially
other reactive species that may be toxic to cells. For example,
oxygen free radical induced lipid peroxidation is a well
established pathogenetic mechanism in central nervous system (CNS)
injury such as that found in a number of degenerative diseases, and
in ischemia (i.e., stroke). (Mitochondrial participation in the
apoptotic cascade is believed to also be a key event in the
pathogenesis of neuronal death.)
[0843] There are, moreover, at least two deleterious consequences
of exposure to reactive free radicals arising from mitochondrial
dysfunction that adversely impact the mitochondria themselves.
First, free radical mediated damage may inactivate one or more of
the myriad proteins of the ETC. Second, free radical mediated
damage may result in catastrophic mitochondrial collapse that has
been termed "transition permeability." According to generally
accepted theories of mitochondrial function, proper ETC respiratory
activity requires maintenance of an electrochemical potential in
the inner mitochondrial membrane by a coupled chemiosmotic
mechanism. Free radical oxidative activity may dissipate this
membrane potential, thereby preventing ATP biosynthesis and/or
triggering mitochondrial events in the apoptotic cascade.
[0844] There is evidence that defects in oxidative phosphorylation
within the mitochondria are at least a partial cause of sporadic
AD. The enzyme cytochrome c oxidase (COX), which makes up part of
the mitochondrial electron transport chain (ETC), is present in
normal amounts in AD patients; however, the catalytic activity of
this enzyme in AD patients and in the brains of AD patients at
autopsy has been found to be abnormally low. This suggests that the
COX in AD patients is defective, leading to decreased catalytic
activity that in some fashion causes or contributes to the symptoms
that are characteristic of AD.
[0845] One hallmark pathology of AD is the death of selected
neuronal populations in discrete regions of the brain. Cell death
in AD is presumed to be apoptotic because signs of programmed cell
death (PCD) are seen and indicators of active gliosis and necrosis
are not found (Smale et al., Exp. Neurolog. 133: 225-230, 1995;
Cotman et al., Molec. Neurobiol. 10: 19-45, 1995). The consequences
of cell death in AD, neuronal and synaptic loss, are closely
associated with the clinical diagnosis of AD and are highly
correlated with the degree of dementia in AD (DeKosky et al., Ann.
Neurology 2757-464, 1990).
[0846] Mitochondrial dysfunction is thought to be critical in the
cascade of events leading to apoptosis in various cell types
(Kroemer et al., FASEB J 9: 1277-1287, 1995), and may be a cause of
apoptotic cell death in neurons of the AD brain. Altered
mitochondrial physiology may be among the earliest events in PCD
(Zamzami et al., J. Exp. Med. 182: 367-77, 1995; Zamzami et al., J.
Exp. Med. 181: 1661-72, 1995) and elevated reactive oxygen species
(ROS) levels that result from such altered mitochondrial function
may initiate the apoptotic cascade (Ausserer et al., Mol. Cell.
Biol. 14: 5032-42, 1994). In several cell types, including neurons,
reduction in the mitochondrial membrane potential (.delta..psi.m)
precedes the nuclear DNA degradation that accompanies apoptosis. In
cell-free systems, mitochondrial, but not nuclear, enriched
fractions are capable of inducing nuclear apoptosis (Newmeyer et
al., Cell 70: 353-64, 1994). Perturbation of mitochondrial
respiratory activity leading to altered cellular metabolic states,
such as elevated intracellular ROS, may occur in mitochondria
associated diseases and may further induce pathogenetic events via
apoptotic mechanisms.
[0847] Oxidatively-stressed mitochondria may release a pre-formed
soluble factor that can induce chromosomal condensation, an event
preceding apoptosis (Marchetti et al., Cancer Res. 56: 2033-38,
1996). In addition, members of the Bcl-2 family of anti-apoptosis
gene products are located within the outer mitochondrial membrane
(Monaghan et al., J. Histochem. Cytochem. 40: 1819-25, 1992) and
these proteins appear to protect membranes from oxidative stress
(Korsmeyer et al, Biochim. Biophys. Act. 1271: 63, 1995).
Localization of Bcl-2 to this membrane appears to be indispensable
for modulation of apoptosis (Nguyen et al., J. Biol. Chem. 269:
16521-24, 1994). Thus, changes in mitochondrial physiology may be
important mediators of apoptosis. To the extent that apoptotic cell
death is a prominent feature of neuronal loss in AD, mitochondrial
dysfunction may be critical to the progression of this disease and
may also be a contributing factor in other mitochondria associated
diseases.
[0848] Focal defects in energy metabolism in the mitochondria, with
accompanying increases in oxidative stress, may be associated with
AD. It is well-established that energy metabolism is impaired in AD
brain (Palmer et al., Brain Res. 645: 338-42, 1994; Pappolla et
al., Am. J. Pathol. 140: 621-28, 1992; Jeandel et al., Gerontol.
35: 275, 1989; Balazs et al., Neurochem. Res. 19: 1131-37, 1994;
Mecocci et al., Ann. Neurol. 36: 747-751, 1994; Gsell et al., J.
Neurochem. 64: 1216-23, 1995). For example, regionally specific
deficits in energy metabolism in AD brains have been reported in a
number of positron emission tomography studies (Kuhl, et al., J.
Cereb. Blood Flow Metab. 7: S406, 1987; Grady, et al., J. Clin.
Exp. Neuropsychol. 10: 576-96, 1988; Haxby et al., Arch. Neurol. 4:
753-60, 1990; Azari et al., J. Cereb. Blood Flow Metab. 13: 438-47,
1993). Metabolic defects in the temporoparietal neocortex of AD
patients apparently presage cognitive decline by several years.
Skin fibroblasts from AD patients display decreased glucose
utilization and increased oxidation of glucose, leading to the
formation of glycosylation end products (Yan et al., Proc. Nat.
Acad. Sci. U.S.A. 91: 7787-91, 1994). Cortical tissue from
postmortem AD brain shows decreased activity of the mitochondrial
enzymes pyruvate dehydrogenase (Sheu et al., Ann. Neurol. 17:
444-49, 1985) and .alpha.-ketoglutarate dehydrogenase
(Mastrogiacomo et al., J. Neurochem. 6: 2007-2014, 1994), which are
both key enzymes in energy metabolism. Functional magnetic
resonance spectroscopy studies have shown increased levels of
inorganic phosphate relative to phosphocreatine in AD brain,
suggesting an accumulation of precursors that arises from decreased
ATP production by mitochondria (Pettegrew et al., Neurobiol. of
Aging 15: 117-32, 1994; Pettigrew et al., Neurobiol. of Aging 16:
973-75, 1995). In addition, the levels of pyruvate, but not of
glucose or lactate, are reported to be increased in the
cerebrospinal fluid of AD patients, consistent with defects in
cerebral mitochondrial electron transport chain (ETC) activity
(Pametti et al., Neurosci. Lett 199: 231-33, 1995).
[0849] Signs of oxidative injury are prominent features of AD
pathology and, as noted above, reactive oxygen species (ROS) are
critical mediators of neuronal degeneration. Indeed, studies at
autopsy show that markers of protein, DNA and lipid peroxidation
are increased in AD brain (Palmer et al., Brain Res. 645: 338-42,
1994; Pappolla et al., Am. J. Pathol. 140: 621-28, 1992; Jeandel et
al., Gerontol. 35: 275-82, 1989; Balazs et al., Arch. Neurol. 4:
864, 1994; Mecocci et al., Ann. Neurol. 36: 747-751, 1994; Smith et
al., Proc. Nat. Acad. Sci. U.S.A. 88: 10540-10543, 1991). In
hippocampal tissue from AD but not from controls, carbonyl
formation indicative of protein oxidation is increased in neuronal
cytoplasm, and nuclei of neurons and glia (Smith et al., Nature
382: 120-21, 1996). Neurofibrillary tangles also appear to be
prominent sites of protein oxidation (Schweers et al., Proc. Nat.
Acad. Sci. U.S.A. 92: 8463, 1995; Blass et al., Arch. Veurol. 4:
864, 1990). Under stressed and non-stressed conditions incubation
of cortical tissue from AD brains taken at autopsy demonstrate
increased free radical production relative to non-AD controls. In
addition, the activities of critical antioxidant enzymes,
particularly catalase, are reduced in AD (Gsell et al., J.
Neurochem. 64: 1216-23, 1995), suggesting that the AD brain is
vulnerable to increased ROS production. Thus, oxidative stress may
contribute significantly to the pathology of mitochondria
associated diseases such as AD, where mitochondrial dysfunction
and/or elevated ROS may be present.
[0850] Increasing evidence points to the fundamental role of
mitochondrial dysfunction in chronic neurodegenerative diseases
(Beal, Biochim. Biophys. Acta 1366: 211-223, 1998), and recent
studies implicate mitochondria for regulating the events that lead
to necrotic and apoptotic cell death (Susin et al., Biochim.
Biophys. Acta 1366: 151-168, 1998). Stressed (by, e.g., free
radicals, high intracellular calcium, loss of ATP, among others)
mitochondria may release pre-formed soluble factors that can
initiate apoptosis through an interaction with apoptosomes
(Marchetti et al., Cancer Res. 56: 2033-38, 1996; Li et al., Cell
91: 479-89, 1997). Release of preformed soluble factors by stressed
mitochondria, like cytochrome c, may occur as a consequence of a
number of events. In any event, it is thought that the magnitude of
stress (ROS, intracellular calcium levels, etc.) influences the
changes in mitochondrial physiology that ultimately determine
whether cell death occurs via a necrotic or apoptotic pathway. To
the extent that apoptotic cell death is a prominent feature of
degenerative diseases, mitochondrial dysfunction may be a critical
factor in disease progression.
[0851] In a preferred embodiment of the present invention, the
therapeutic or prophylactic administration of antioxidant
compounds, and/or the diagnostic use thereof, is enhanced by
stimulation of the SPG and/or its related neuroanatomical
structures, by using electrical stimulation, odorant presentation,
and/or other means for stimulating the SPG or for modulating
permeability of the BBB.
EXAMPLE 8
Therapeutics (.beta.-Amyloid Inhibitors)
[0852] U.S. Patent Application Publication 2002/0042420 to Briem
et. al., describes a method to prepare compounds which may be
capable of interfering (preferably in an inhibitory capacity) in
the process of the formation of A.beta. or its release from cells,
or of reducing the activity of A.beta. by inhibiting it. Their
description has the further objective of preparing compounds which
can be used effectively for the prevention or treatment of
Alzheimer's disease.
[0853] U.S. Patent Application Publication 2002/0025955 to Han et
al., describes the potential use of lactams that inhibit the
processing of amyloid precursor protein and, more specifically,
inhibit the production of A.beta.-peptide, thereby potentially
acting to prevent the formation of neurological deposits of amyloid
protein.
[0854] U.S. Patent Application Publication 2002/0022621 to
Chaturvedula et al., describes a series of arylacetamidoalanyl
derivatives of benzodiazepinones, which are inhibitors of
.beta.-amyloid peptide production and may be useful in the
treatment of Alzheimer's disease and other conditions characterized
by aberrant extract cellular deposition of amyloid.
[0855] U.S. Patent Application Publication 2001/0020097 to Audia et
al., describes compounds which inhibit .beta.-amyloid peptide
release and/or its synthesis, and, accordingly, may have utility in
treating Alzheimer's disease both prophylactically and
therapeutically. Introduction of the compounds into the brain, for
therapeutic purposes, or out of the brain, for diagnostic purposes,
may require crossing the BBB.
[0856] U.S. Pat. No. 6,211,235 to Wu et al., describes compounds
which inhibit p-amyloid peptide release and/or its synthesis, and,
accordingly, may have utility in treating Alzheimer's disease. It
also describes pharmaceutical compositions comprising a compound
which may inhibit .beta.-amyloid peptide release and/or its
synthesis when introduced either directly or indirectly into the
brain. Direct techniques usually involve placement of a drug
delivery catheter into the host's ventricular system to bypass the
blood-brain barrier. One such implantable delivery system used for
the transport of biological factors to specific anatomical regions
of the body is described in U.S. Pat. No. 5,011,472 to Aebischer et
al. Indirect techniques, which are generally preferred, usually
involve formulating the compositions to provide for drug
latentiation by the conversion of hydrophilic drugs into
lipid-soluble drugs. Latentiation is generally achieved through
blocking of the hydroxy, carbonyl, sulfate, and primary amine
groups present on the drug to render the drug more lipid soluble
and amenable to transportation across the BBB. Alternatively, the
delivery of hydrophilic drugs may be enhanced by intra-arterial
infusion of hypertonic solutions which may transiently open the BBB
to some extent.
[0857] However, without using the techniques described herein, no
general method is known to controllably open the BBB for the
efficient delivery of large-molecular weight pharmaceutical
compounds, or compounds with high plasma protein binding.
[0858] In a preferred embodiment of the present invention, the
therapeutic or prophylactic administration of the compounds
described in this example (Example 8), and/or the diagnostic use
thereof, is enhanced by stimulation of the SPG and/or its related
neuroanatomical structures, by using electrical stimulation,
odorant presentation, and/or other means for stimulating the SPG or
for modulating permeability of the BBB.
EXAMPLE 9
Therapeutics (.beta.-Amyloidpolymerization Inhibitors)
[0859] Bernd Bohrmann et al. reported (J Biol Chem, Vol. 274, Issue
23, 15990-15995, Jun. 4, 1999) that certain plasma proteins, at
physiological concentrations, are potent inhibitors of
.beta.-amyloid peptide polymerization. These proteins are also
present in cerebrospinal fluid, but at low concentrations having
little or no effect on P-amyloid. Thirteen proteins representing
more than 90% of the protein content in plasma and cerebrospinal
fluid were studied. Quantitatively, albumin was the most important
protein, representing 60% of the total amyloid inhibitory activity,
followed by .alpha.-1-antitrypsin and immunoglobulins A and G.
Albumin suppressed amyloid formation by binding to the oligomeric
or polymeric beta-amyloid, blocking a further addition of
peptide.
[0860] The results of Bohrmann et al. suggest that several
endogenous proteins are negative regulators of amyloid formation.
Plasma contains at least 300 times more amyloid inhibitory activity
than cerebrospinal fluid. These findings may provide one
explanation as to why .beta.-amyloid deposits are not found in
peripheral tissues but are only found in the central nervous
system. Moreover, the data suggest that some drugs that display an
affinity for albumin may enhance P-amyloid formation and promote
the development of AD.
[0861] Increased penetration of plasma proteins into the CNS may,
on the other hand, have an inhibitory effect on P-amyloid
polymerization, consequently slowing, or reversing, AD
progression.
[0862] In a preferred embodiment of the present invention, the
permeability of the BBB is enhanced by stimulation of the SPG
and/or its related neuroanatomical structures, by using electrical
stimulation, odorant presentation, and/or other means for
stimulating the SPG or for modulating permeability of the BBB, in
order to permit P-amyloid polymerization inhibitors naturally
occurring in the blood, particularly albumin, to pass from the
blood into the CNS.
EXAMPLE 10
Therapeutics (Microglial Activation Modulators)
[0863] Acute and chronic brain injuries can activate resident
microglia (resident macrophage-like cells found in the central
nervous system) as well as recruit peripheral immune cells to
injured brain regions that can exacerbate neuronal damage.
Inflammatory processes can induce cell death by (a) the release of
proteases and free radicals that induce lipid peroxidation, (b)
direct cytotoxic effects or (c) the phagocytosis of
sublethally-injured neurons. The attenuation of microglia and
peripheral immune cell activation has been correlated with
significant neuronal protection in pre-clinical studies of
ischemia, traumatic brain injury, spinal cord injury and
Alzheimer's disease. U.S. Patent Application Publication
20020022650 to Posmantur et al. describes methods of modulating or
inhibiting microglia activation comprising the administration of a
compound capable of inhibiting 5-LOX, FLA.beta., attenuating
degradation of I.kappa.Ba or inhibiting nuclear translocation of
the NF-KB active complex for the treatment of various disorders
associated with excessive production of inflammatory mediators in
the brain, among which is Alzheimer's disease.
[0864] In a preferred embodiment of the present invention, the
therapeutic or prophylactic administration of the compounds
described in this example (Example 10), and/or the diagnostic use
thereof, is enhanced by stimulation of the SPG and/or its related
neuroanatomical structures, by using electrical stimulation,
odorant presentation, and/or other means for stimulating the SPG or
for modulating permeability of the BBB.
EXAMPLE 11
Therapeutics (NSAID)
[0865] Studies support an inverse relationship between
anti-inflammatory medications used for treating patients with
rheumatoid arthritis and an associated low prevalence of
Alzheimer's disease (Rich, J. B. et al., Neurology 45: 51-55,
1995). Controlled studies of twin pairs having Alzheimer's disease
onset greater than 3 years apart provide additional support that
prior treatment with anti-inflammatory medications serves a
protective role in Alzheimer's disease (Breitner, J. C. S. et al.,
Neurology 44: 227-232, 1994). Specifically, controlled
double-blinded studies have found that the anti-inflammatory agent
"indomethacin" administered orally has a therapeutic benefit for
mild to moderately cognitively-impaired Alzheimer's disease
patients, and treatment with indomethacin during early stages of
the disease has a retarding effect on disease progression compared
to the placebo treated control group. (Rogers, J. et al., Neurology
43: 1609-1612, 1993). Alzheimer's patients with moderate cognitive
impairment treated with indomethacin also exhibit a reduction in
cognitive decline. However, patients treated with oral indomethacin
developed drug related adverse effects that required their
treatment to be discontinued and their removal from the study.
[0866] U.S. Patent Application Publication 2001/0027309 to Elsberry
describes a method for treating Alzheimer's disease, comprising
delivering indomethacin or nonsteroidal anti-inflammatory drugs
(NSAIDs) having cyclooxygenase inhibitor action directly to the
hippocampus or the lateral ventricle through an implanted
catheter.
[0867] It may also be advantageous to allow NSAID and other
anti-inflammatory drugs into the CNS in combination with
immunological (vaccine) treatment of AD. A vaccine, made by Elan
Corporation (Dublin, Ireland) and known by its code name AN-1792,
was tested in a clinical trial. In the trial, twelve volunteers
were reported to have fallen seriously ill with brain inflammation,
forcing the vaccine's manufacturer to halt the trial and raising
doubts about the product's clinical potential. The AN-1792 vaccine
had generated unusually intense enthusiasm among scientists and
patient advocates during the past two years, as experiments in mice
suggested it could halt the progression of Alzheimer's and perhaps
even cure the deadly disease.
[0868] In general, NSAIDs are known to be very extensively protein
bound (>99%). This characteristic makes the penetration of NSAID
into the CNS very scarce, since they are usually bound to plasma
proteins having molecular weights of around 70 kDa.
[0869] Therefore, allowing macromolecules into the CNS is expected
to allow the introduction of anti-inflammatory drugs. These, on
their own, or in conjunction with immunological or other
therapeutic approaches, can serve as an effective treatment for
AD.
[0870] In a preferred embodiment of the present invention, the
therapeutic or prophylactic administration of NSAIDs and other
anti-inflammatory agents, and/or the diagnostic use thereof, is
enhanced by stimulation of the SPG and/or its related
neuroanatomical structures, by using electrical stimulation,
odorant presentation, and/or other means for stimulating the SPG or
for modulating permeability of the BBB.
[0871] In another preferred embodiment of the present invention,
the administration of a vaccine is enhanced by stimulation of the
SPG and/or its related neuroanatomical structures, by using
electrical stimulation, odorant presentation, and/or other means
for stimulating the SPG or for modulating permeability of the
BBB.
EXAMPLE 12
Therapeutics (Vaccine)
[0872] U.S. Patent Application Publication 2002/0009445 to Du et
al., discusses the use of an anti-A.beta. antibody for diagnosing
and/or treating amyloid associated diseases, especially Alzheimer's
disease. They indicate that naturally-occurring A.beta. antibodies
exist in biologically relevant fluids, i.e., CSF and plasma, and
that levels of these antibodies differ between normal age-matched
healthy controls and AD patients. Based on these findings it was
concluded and then supported by experiments that these antibodies
can be used for diagnosis and treatment of amyloid associated
diseases and especially of Alzheimer's disease. In the context of
this application, the terms "anti-A.beta. antibodies" and "A.beta.
antibodies" are used interchangeably to designate the antibody of
their invention. An embodiment of their diagnostic method uses
lumbar CSF samples, on which A.beta. antibody levels were
determined utilizing an ELISA assay in which the A.beta. peptide
was used as the capture ligand.
[0873] In a preferred embodiment of the present invention, the
therapeutic or prophylactic administration of anti-A.beta.
antibodies, and/or the diagnostic use thereof, is enhanced by
stimulation of the SPG and/or its related neuroanatomical
structures, by using electrical stimulation, odorant presentation,
and/or other means for stimulating the SPG or for modulating
permeability of the BBB.
EXAMPLE 13
Therapeutics (Other Approaches)
[0874] U.S. Patent Application Publication 2002/0022593 to Yue
describes a method of treating neurodegenerative dysfunctions and
aging symptoms by administering a therapeutically-effective amount
of relaxin (a polypeptide hormone, whose molecular weight is
between 5,700 to 6,500 Da) to a patient. Neurodegenerative
dysfunctions potentially amenable to treatment with relaxin include
Alzheimer's, attention deficit disorder, Parkinson's, and others.
The aforementioned method is based on the recognition that some of
the symptoms associated with aging and/or neurodegenerative
dysfunctions can be alleviated by relaxin, and may in fact be
caused by a decrease of relaxin in the bloodstream. This lack of
relaxin in the blood stream may be congenital or the result of
another mechanism which suppresses the normal production or action
of relaxin.
[0875] In a preferred embodiment of the present invention, the
therapeutic or prophylactic administration of relaxin, and/or the
diagnostic use thereof, is enhanced by stimulation of the SPG
and/or its related neuroanatomical structures, by using electrical
stimulation, odorant presentation, and/or other means for
stimulating the SPG or for modulating permeability of the BBB.
[0876] U.S. Patent Application Publication 2002/0019412 to Andersen
et al., describes novel inhibitors of Protein Tyrosine Phosphatases
(PTPase's) such as PTPIB, CD45, SHP-1, SHP-2, PTPa, LAR and HePTP
or the like, for treatment of various systemic and CNS-related
disorders, including Alzheimer's disease.
[0877] In a preferred embodiment of the present invention, the
therapeutic or prophylactic administration of PTPase's, and/or the
diagnostic use thereof, is enhanced by stimulation of the SPG
and/or its related neuroanatomical structures, by using electrical
stimulation, odorant presentation, and/or other means for
stimulating the SPG or for modulating permeability of the BBB.
[0878] U.S. Patent Application Publication 2002/0006959 to
Henderson describes a method of potentially treating or preventing
dementia of Alzheimer's type, or other loss of cognitive function
caused by reduced neuronal metabolism, comprising administering an
effective amount of medium chain triglycerides to a patient in need
thereof.
[0879] In a preferred embodiment of the present invention, the
therapeutic or prophylactic administration of medium chain
triglycerides, and/or the diagnostic use thereof, is enhanced by
stimulation of the SPG and/or its related neuroanatomical
structures, by using electrical stimulation, odorant presentation,
and/or other means for stimulating the SPG or for modulating
permeability of the BBB.
EXAMPLE 14
Diagnostics
[0880] Accurate diagnosis of AD during life is highly desirable.
However, clinical evaluation is at best only about 80% accurate.
Therefore, there exists a need to identify specific biochemical
markers of AD. So far, analysis of blood or cerebrospinal fluid
(CSF) has not yielded a biochemical marker of sufficient diagnostic
value (Blass et al., 1998), although detectable differences are
reported in the levels of certain proteins (Motter et al., Ann.
Neurol. 38, 643-648, 1995).
[0881] Although recent reports of using positron-emission
tomography (PET) (Reiman, E. M., et al., New Eng. J. Med., 334:
752-758, 1996), determining the genotype of an individual's ApoE,
or measuring the levels of .beta.-amyloid protein in cerebral
spinal fluid may be promising, diagnosis of AD is currently
confirmed only upon autopsy to determine the presence of P-amyloid
senile plaques.
[0882] Moreover, recent studies have shown that damage to CNS
neurons due to Alzheimer's disease begins years before clinical
symptoms are evident (Reiman, E. M. et al., New Eng. J. Med., 334:
752-758, 1996), suggesting that therapy could begin in the
pre-symptomatic phase of the disease if a sensitive diagnostic test
and targeted therapies were available. There exists a great need to
determine the physiological mechanisms involved with the disease
and for an accurate and easy to perform assay to evaluate the risk
of developing Alzheimer's disease.
[0883] U.S. Patent Application Publication 2002/0042121 to Riesner
et al., describes a method for the diagnostic detection of diseases
associated with protein depositions (pathological protein
depositions) by measuring an association of substructures of the
pathological protein depositions, structures forming pathological
protein depositions, structures corresponding to pathological
protein depositions and/or pathological protein depositions as a
probe or a target.
[0884] U.S. Patent Application Publication 2002/0028462 to Tanzi et
al., describes a diagnostic method for AD based on genotyping the
Alpha-2-Macroglobulin locus. A statistically-significant
correlation was found between inheritance of particular alleles of
the Alpha-2-Macroglobulin gene and the occurrence of AD. The
diagnostic method involves the isolation of nucleic acid from an
individual and subsequent genotyping by means such as sequencing or
restriction fragment length polymorphism analysis. The invention
also describes a means for genotype analysis through protein
isotyping Alpha-2-Macroglobulin variant proteins. Finally, kits for
nucleic acid analysis or protein analysis are described.
[0885] U.S. Patent Application Publication 2002/0022242 to Small et
al., describes a method for the diagnosis of AD in a patient by
detecting the presence of BuChE with an altered glycosylation
pattern in an appropriate body fluid sample. It has been
established that on average approximately 93.6% of the BuChE in the
CSF of AD patients binds to Concanavalin (Con A). All embodiments
of this method are described as using either CSF or brain tissue as
the sample, thereby adding a risk factor to the diagnostic
procedure.
[0886] U.S. Patent Application Publication 2002/0019519 to Bingham
et al., describes the use of KIAA0551 polypeptides and
polynucleotides in the design of protocols for the treatment of and
also for diagnostics assays of AD.
[0887] U.S. Patent Application Publication 2001/0044126 to Holtzman
et al., describes a diagnostic method for identifying individuals
at risk for developing Alzheimer's disease, which relies on
elevated levels of the ratio of A.beta..sub.40/A.beta..sub.42
associated with lipoproteins in the cerebrospinal fluid of
individuals at risk as compared to this ratio in the overall
population. It is based on the assessment that the lipoprotein
fraction of CSF in such individuals has such increased ratios.
[0888] U.S. Patent Application Publication 2002/0019016 to
Vanmechelen et al., describes a method for the differential
diagnosis of an individual suffering from AD versus an individual
suffering from another neurological disease (dementia with Lewy
bodies, Parkinson's disease without dementia, multi-system atrophy
and/or progressive supranuclear palsy), where phospho-tau is used
as a neurological marker, the level of which is measured in a CSF
sample.
[0889] U.S. Patent Application Publication 2002/0009445 to Du et
al., cited and summarized hereinabove, describes the use of an
anti-A.beta. antibody for diagnosing and/or treating amyloid
associated diseases, especially Alzheimer's disease.
[0890] U.S. Patent Application Publication 2002/0006627 to Reitz et
al., describes a method for diagnosing Alzheimer's disease
involving analysis of a test sample in such a way that
.beta.-amyloid.sub.1-42 or A.beta.3pE is completely or nearly
completely (i.e., thoroughly) dissociated from binding proteins
prior to the analysis of the levels of .beta.-amyloid.sub.1-42 or
A.beta.3pE.
[0891] U.S. Patent Application Publication 2002/0002270 to
Zinkowski et al., describes a preparation comprising Alzheimer's
disease antigen (A68), as well as methods of obtaining this
purified antigen (Ag), and methods using the purified Ag, for
instance, for diagnosing Alzheimer's Disease, and also describes
treatments of these Ags that enhance their reactivity with
autoantibodies directed against A68. These treatments include
treatment with hypericin, free fatty acids, and/or hydroxynonenal
or other advanced glycation end products.
[0892] U.S. Patent Application Publication 2001/0026916 to Ginsberg
et al., describes a method of identifying senile plaques,
neurofibrillary tangles and neuropil threads in brain tissue which
comprises contacting brain tissue with a fluorescent dye capable of
intercalating selectively into nucleic acids and detecting any
fluorescence in the brain tissue indicative of senile plaques,
neurofibrillary tangles and neuropil threads in the brain
tissue.
[0893] U.S. Pat. No. 6,238,892 to Mercken et al., describes the use
of a monoclonal antibody which forms an immunological complex with
a phosphorylated epitope of an antigen belonging to human
abnormally phosphorylated tau protein. The tau protein can be
obtained from a brain homogenate, itself isolated from the cerebral
cortex of a patient having Alzheimer's disease. Methods for in-vivo
diagnosis of AD using the latter mAb, should preferably employ
techniques that leaves the meninges intact. Such methods are
described in this patent as being yet undeveloped.
[0894] The '892 patent provides an overview of tau (complete
references have been provided):
[0895] Tau is a microtubule-associated protein which is synthesized
in the neurons (Kosik, K. S. et al., Ann. Neurol. 26, 352-361,
1989) of several species, including humans, and which is abundantly
present in the axonal compartment of these neurons (Binder, L. I.
et al., J Cell Biol., 101: 1371-1378, 1985). Functionally the tau
protein is involved in the polymerization of tubulin (Weingarten,
M. D. et al., Proc. Natl. Acad. Sci. U.S.A. 72, 1868-1862, 1975)
and presumably in reducing microtubule instability (Bre, M. H. et
al., Cell Motil. Cytoskeleton 15, 88-98, 1990).
[0896] Tau protein is also the major constituent of paired helical
filaments (PHF), characteristic structures found as neurofibrillary
tangles in tissue sections of the brain of Alzheimer patients
(Greenberg, S. et al., Proc. Natl. Acad. Sci. U.S.A., 87,
5827-5831, 1990; Lee, V. M.-Y. et al., Science, 251, 675-678,
1991). The protein exists as a family of different isoforms of
which 4 to 6 isoforms are found in normal adult brain but only 1
isoform is detected in fetal brain (Goedert, M. et al., Neuron 3,
519-526, 1989). The diversity of the isoforms is generated from a
single gene by alternative mRNA splicing (Himmler, A., Mol. Cell.
Biol., 9, 1389-1396, 1989). The most striking feature of tau
protein as predicted from molecular cloning is a stretch of 31 or
32 amino acids occurring in the carboxy-terminal part of the
molecule that is repeated 3 or 4 times. Additional diversity is
generated through 29 or 58 amino acid long insertions in the
NH2-terminal part of the molecules (Goedert, M. et al., Neuron 3,
519-526, 1989).
[0897] Tau variants of 64 and 69 kDa, which are abnormally
phosphorylated as revealed by the decrease in their molecular mass
observed after alkaline phosphatase treatment, have been detected
exclusively in brain areas showing neurofibrillary tangles and
senile plaques (Flament, S. et al., A., J. Neurol. Sci. 92,
133-141, 1989; Flament, S. et al., Brain Res. 516, 15-19, 1990; and
Flament, S. et al., Nature 346, 6279, 1990). The sites of
phosphorylation by 4 different kinases have been mapped in the
C-terminal microtubule-binding half of tau and it could be shown
that the action of a calcium calmodulin-dependent kinase on
bacterially expressed tau resulted in a phosphorylation of Ser(405)
which induced a lower electrophoretical mobility (Steiner, B. et
al., The EMBO Journal 9, 3539-3544, 1990).
[0898] Several antibodies are reported that show reactivity to
human tau either because they are directed to nonspecific
phosphorylated epitopes present on neurofilament and subsequently
shown to cross-react with normal and abnormally phosphorylated tau
(Nukina, N. et al., Proc. Natl. Acad. Sci. U.S.A. 84, 3415-3419,
1987; Ksiezak-Reding et al., Proc. Natl. Acad. Sci. U.S.A., 84,
3410-3414, 1987) or because they recognized specific epitopes on
normal and abnormally phosphorylated tau.
[0899] The Alz50 monoclonal antibody (Wolozin, B. L. et al.,
Science 232, 648-650, 1986; Nukina et al., Neurosci. Lett 87,
240-246, 1988) recognizing a phosphate-independent epitope present
on tau variants of bovine origin and of normal and abnormally
phosphorylated tau from human origin (Ksiezak-Reding, H. et al., J.
Biol. Chem., 263, 7943-7947, 1988, Flament, S. et al., Brain Res.
516, 15-19, 1990; and Flament, S. et al., Nature 346, 6279, 1990)
belongs to the latter class of antibodies. The epitope recognized
by this monoclonal is specifically expressed in the somatodendritic
domain of degenerating cortical neurons during Alzheimer disease
(Delacourte, A. et al., Acta Neuropathol. 80, 111-117, 1990).
[0900] The Alz50 epitope has recently been mapped to the
NH2-terminal part of the tau molecule (Ksiezak-Reding, H. et al.,
J. Neurosci. Res., 25, 412-419, 1990; Goedert, M. et al., Neurosci.
Lett., 126, 149-154, 1991). Due to its cross-reactivity with normal
tau, this antibody is only able to discriminate normal from
abnormally phosphorylated tau by the use of Western blotting
detection of brain homogenates or by ammonium sulfate-concentrated
CSF, or also by using a sandwich immunoassay on brain homogenates
(Ghanbari et al., J. Clin. Laboratory Anal. 4, 189-192, 1990;
Wolozin, B. et al, Ann. Neurol. 22, 521-526, 1987; European Patent
Application Publication EP 0 444 856 to Ghanbari et al.). A
CSF-based assay using antibodies directed against PHF was first
described by Mehta et al., The Lancet, Jul. 35, 1985, but shows
considerable overlap between Alzheimer CSF and CSF from controls.
The epitope recognized by this antibody was identified as part of
ubiquitin (Perry et al., J. Neurochem. 52, 1523-1528, 1989).
[0901] Other monoclonal antibodies have been developed to recognize
tau protein. For instance, monoclonal antibody 5E2 was raised by
immunization with human fetal heat-stable microtubule-associated
proteins and recognizes an epitope spanning amino acids 156-175
which is present in normal and abnormally phosphorylated tau
(Kosik, K. S. et al., Neuron., 1, 817-825, 1988).
[0902] Other antibodies such as tau 1 and several others were
raised by immunization with bovine tau, bovine heat-stable
microtubule-associated protein, or rat brain extracts (Binder, L.
I. et al., J. Cell Biol. 101, 1371-1378, 1985; Kosik, K. S. et al.,
Neuron., 1, 817-825, 1988), and most of the antibodies recognize
the normal and the abnormally phosphorylated tau (Ksiezak-Reding,
H. et al., J. Neurosci. Res., 25, 412-419, 1990).
[0903] An antibody named "423", raised against the core of PHF,
reacted specifically with a 9.5 and 12-kDa fragment of the tau
protein, localized in the repetitive elements of tau, but
recognized neither normal human tau nor the abnormally
phosphorylated tau in Alzheimer's brain (Wischik, C. H. et al.,
Proc. Natl. Acad. Sci. U.S.A., 85, 4884-4888, 1988). This antibody
has been used to discriminate Alzheimer PHF pathology from normal
controls in brain homogenates (Harrington, C. R. et al., J.
Immunol. Methods 134, 261-271, 1990; PCT Publication WO89/03993 to
Wischik et al.).
[0904] Thus far, none of all the antibodies described heretofore
has had an absolute specificity for the abnormally phosphorylated
tau either by immunohistology, Western blotting, or ELISA.
Quantitative measurements of normal and abnormally phosphorylated
tau have until now only been able to detect tau in brain
homogenates, in brain extracts containing PHF, or in concentrated
CSF samples after Western blotting (Ghanbari H. A. et al., J. Clin.
Laboratory Anal. 4, 189-192, 1990; Harrington C. R. et al., J.
Immunol. Methods 134, 261-271, 1990, Wisniewski, H. M. et al.,
Biological Markers of Alzheimer's Disease, Boller, Katzman, Rascol,
Signoret & Christian eds., 23-29, 1989; Wolozin, B. et al.,
Ann. Neurol. 22, 521-526, 1987).
[0905] U.S. Patent Application Publication 2001/0018191 to Mercken
et al., describes monoclonal antibodies which are described as
specifically able to detect only abnormally-phosphorylated tau
present in brain tissue sections, in brain extracts, or in body
fluids such as cerebrospinal fluid. It is required that a method
for bypassing the BBB be employed in order to introduce the
monoclonal antibodies into the CNS.
[0906] U.S. Patent Application Publication 2001/0014670 to Balin et
al., describes a method of treating Alzheimer's disease in a mammal
comprising administering to the mammal an anti-microbial agent
having anti-Chlamydia pneumoniae activity. The description also
relates to a method of diagnosing Alzheimer's disease in a mammal
comprising measuring the serum anti-Chlamydia pneumoniae antibody
titer in a patient suspected of having Alzheimer's disease. It is
required that a method for bypassing the BBB be employed in order
to communicate the therapeutic compounds, antibodies, into the CNS,
or to be able to evaluate presence of diagnostic agents (e.g. C.
Pneumoniae) in a minimally invasive method.
[0907] U.S. Pat. No. 6,287,793 to Schenk et al., describes methods
for the identification of key diagnostic antibodies, antigens,
diagnostic kits and methods for diagnosis for AD, where the
diagnostic procedure uses a biological fluid from a subject--most
preferred are plasma and CSF sample.
[0908] Inducing changes in BBB permeability, as provided by
preferred embodiments of the present invention, is useful for
detecting acetylcholinesterase in human patients. Loss of
acetylcholinesterase in humans is associated with brain disorders,
such as dementia and epilepsy, muscle disorders, and disorders of
the digestive system. The methods of some embodiments of the
present invention are particularly useful for detecting
acetylcholinesterase in the brain of a patient suspected of
suffering from a dementia, such as Alzheimer's disease, thereby
allowing the diagnosis, estimating the severity of, and monitoring
the progression of the dementia. Certain brain disorders and
dementia, including Alzheimer's disease, are known to be
accompanied by a decrease in acetylcholinesterase concentration in
the brain. Thus, monitoring the concentration of
acetylcholinesterase in the brain of a patient suspected of
suffering from a brain disorder or dementia typically allows
diagnosis of the disorder or dementia, monitoring its progression,
and/or estimating its severity. Advantageously, this diagnosis and
monitoring is simply performed, for example, by stimulating the SPG
using techniques described herein, and, simultaneously or shortly
thereafter, extracting a blood sample using standard lab
techniques. Since the increase in BBB permeability allows the
acetylcholinesterase to pass therethrough, it is quickly in the
systemic bloodstream and detectable in the blood sample. It is to
be understood that other compounds of diagnostic value can be
extracted using essentially the same technique.
[0909] The methods of some embodiments of the present invention can
be used to provide a brain image that shows the distribution and
relative concentrations of acetylcholinesterase (or other compounds
of diagnostic value) in a patient's brain, thereby allowing
diagnosis, estimating the severity of, and analysis of the
progression of a disorder or dementia in a patient. The methods of
some embodiments of the invention can therefore be used to
diagnosis, estimate the severity, and monitor the progression of
any dementia, known or to be discovered, that is accompanied by a
detectable change in concentration of acetylcholinesterase or other
compounds of diagnostic value in the brain. In a preferred
embodiment, a molecule such as an antibody which is attracted to
acetylcholinesterase is injected, swallowed, or otherwise
introduced systemically, and its passage into the CNS is
facilitated by techniques described herein for increasing
permeability of the BBB. Imaging techniques which are able to
detect the introduced molecule are then utilized to determine the
locations or quantities of acetylcholinesterase or other diagnostic
compounds to which the molecule is attached.
[0910] Some of the diagnostic techniques mentioned above indicate
to the inventors that there is a need for performing diagnostic
tests on certain bio-chemical characteristics of the CSF by using a
simple blood test. Other diagnostic techniques mentioned above
indicate to the inventors that there is a need for increasing the
permeability of the BBB using techniques described herein in order
to facilitate the passage of diagnostic molecules into the CNS,
where the molecules can be detected, such as by imaging. Diagnostic
procedures, which are on one hand highly accurate and on the other
minimally invasive, typically substantially improve the management
of AD, when applied in accordance with a preferred embodiment of
the present invention. In a preferred embodiment of the present
invention, the diagnostic techniques described in this example
(Example 14) are enhanced and/or enabled by stimulation of the SPG
and/or its related neuroanatomical structures, by using electrical
stimulation, odorant presentation, and/or other means for
stimulating the SPG or for modulating permeability of the BBB.
[0911] The stimulation techniques described herein may facilitate
the diagnosis of a number of CNS conditions, including, but not
limited to, the following conditions:
[0912] neurodegenerative conditions, such as Alzheimer's disease,
Parkinson's Disease, ALS, age-associated cognitive decline,
progressive supranuclear palsy, vascular (i.e., multi-infarct)
dementia, Lewy body dementia, Huntington's Disease, Down's
syndrome, normal pressure hydrocephalus, corticobasal ganglionic
degeneration, multisystem atrophy, head trauma, Creutzfeld-Jacob
disease, viral encephalitis and hypothyroidism, a degenerative
disorder associated with learning, memory or cognitive dysfunction,
cerebral senility, multi-infarct dementia and senile dementia, and
electric shock induced amnesia or amnesia;
[0913] neoplastic processes (either primary or metastatic), such as
neuroectodermal tumors, malignant astrocytomas, and
glioblastomas;
[0914] immune- and autoimmune-related disorders, such as HIV and
multiple sclerosis; and
[0915] CNS inflammatory processes.
[0916] The stimulation techniques described herein may facilitate
the imaging of various aspects of the CNS, including biochemical
aspects (e.g., GGM in late onset Tay-Sachs disease, dopamine in
Parkinson's Disease), morphological aspects (e.g., ventricular
dimensions in hydrocephalus), and functional aspects (e.g., glucose
utilization in brain tumors).
[0917] In an embodiment of the present invention, stimulation of an
MTS is configured to increase the transport of a diagnostic agent
across the BBB from a non-CNS tissue, such as the systemic blood
circulation, into the CNS. The diagnostic agent is typically
administered to the systemic blood circulation, such as
intravenously, and a diagnostic procedure, typically an imaging
modality, is then performed directly on the CNS. For some
applications, the diagnostic agent comprises a tracer agent, such
as an imaging contrast agent, for example, a Magnetic Resonance
Imaging (MRI) contrast agent, a Single Photon Emission Computed
Tomography (SPECT) radioisotope, a Positron Emission Tomography
(PET) radioisotope, an ultrasound contrast enhancer, or an X-ray
contrast agent (e.g., for a Computerized Tomography (CT) or
angiography imaging sequence).
[0918] In an embodiment, the tracer is configured to be
disease-specific, typically by conjugation to a biochemical agent
for enhancing certain properties or constituents of the CNS (or
another physiological compartment). The conjugation is performed
either before administration of the agent to the patient, or the
conjugation occurs within the systemic circulation, the CNS, or
another physiological compartment. Examples of such constituents
include selected proteins, cells, biotoxins, pathological tissue,
or other biochemical entities that may aid in diagnosis of a CNS
condition, such as, for example, the HER2 protein that is
overexpressed on the outer membrane of malignant tumors, or certain
interleukins, the receptors of which are abundant on the surface
membranes of certain types of cancerous cells. In these
applications, the tracer may comprise a disease-specific
(endogenous or exogenous) biochemical entity, or may comprise a
biochemical entity that relates to a broad group of pathological
states (e.g., a probe for inflammatory markers).
[0919] For some applications, such diagnostic agents are conjugated
to the following types of biochemical agents:
[0920] Antibodies to proteins which are indicative of neoplastic
processes, such as beta-Amyloid monoclonal antibody (mAb) or
polyclonal antibody (pAb), and anti-HER2 mAb; and/or
[0921] Interleukins (cytokines whose amino acid structure is
known), such as IL-1-IL18, TNF, IL-1 beta, IL-1ra, and TNF beta.
This groups of macromolecules consists of both pro-inflammatory
(e.g., IL-6, IL-8) and anti-inflammatory (e.g., IL-4, IL-10)
proteins that affect the growth, proliferation, differentiation,
regeneration, and secretion of various immuno-active cells (e.g.,
B, T, CD4+ cells) and also the processes of hematopoiesis and
lymphopoiesis. Some of these macromolecules are also produced by
immune cells, such as B cells, T cells, macrophages, and
acute-phase response proteins. Some of these cytokines are
overexpressed by malignant cell lines, as well as in cases of
inflammation (e.g., adult T cell leukemia cell lines and
Epstein-Barr virus transformed B cells). Such cytokines therefore
generally represent diagnostic targets for neoplastic
processes.
[0922] In an embodiment of the present invention, stimulation of an
MTS is configured to increase the transport of a biochemical agent
across the BBB from the CNS to a non-CNS tissue, such as the
systemic blood circulation. Such biochemical agents are typically
disease-specific biochemical markers. Prior to stimulation of an
MTS to increase BBB permeability, the concentration of such a
biochemical agent is typically greater in the CNS than in the
systemic circulation, i.e., there is a concentration gradient
across the endothelium. Therefore, increasing the permeability of
the BBB, typically acutely, generally releases the agent into the
systemic circulation. Once in the systemic circulation, diagnosis
is typically performed by sampling a body tissue or fluid,
typically blood, and analyzing the whole blood, plasma, or serum.
Analysis is typically performed using a biochemical assay or
another analytical procedure, such as imaging, in order to
qualitatively or quantitatively probe the presence of the
biochemical agent of interest, a metabolite thereof, or a chemical
or biological derivative thereof.
[0923] Diagnostic assay modalities typically applicable to the
techniques described herein include, but are not limited to, High
Purity Liquid Chromatography (HPLC), SMAC, Enzyme Linked
Immuno-Sorbent Assay (ELISA), electrophoresis, gel filtration, UV
spectrophotometry, HPLC/fluorescence, Fluorescence Polarization
Immunoassay (FPIA), HPLC/UV, Gas Chromatography/GC/EC, capillary
electrophoresis, mobility shift combination assay, bioluminescent
assay, flow immunoassay, Polymerase Chain Reaction (PCR) ELISA,
gamma counter, beta counter, chemiluminescence immunoassay (e.g.,
chemiluminescent ELISA), Dissociated Enhanced Lanthanide
Fluorescence Immunoassay (DELFIA), Enzyme Immunoassay (EIA),
Fluorescence Immunoassay (FIA), Immunoradiometric Assay (IRMA),
Radioimmunoassay (RIA), and Scintillation Proximity Assay
(SPA).
[0924] Imaging modalities typically applicable to the techniques
described herein include, but are not limited to, PET, SPECT, CT,
MRI, magnetic resonance spectroscopy (MRS), Functional Magnetic
Resonance Imaging (fMRI), Proton MRSI, Single-voxel proton MRS,
Multi-nuclear MRS, gamma camera, and beta camera.
[0925] For some applications, techniques for transporting
diagnostic agents from the systemic circulation to the CNS are used
to transport one or more of the following radioisotopes for
facilitating nuclear imaging modalities, such as PET, SPECT, and
gamma cameras: 7Be, 22Na, 46Sc, 48V, 51Cr, 54Mn, 56Co, 65Zn, 75Se,
83Rb, 85Sr, 88Zr, 95 mTc, 103Ru, and 99Rh. These techniques may
also be used for transporting one or more of the following
diagnostic agents for facilitating PET: 18F-FDG, 18F-FUdR, 11C-MET,
11C-TYR, 15C-O2, 15C-O, H215O, 82Rb, 11C-5-HTP, 11C-L-DOPA,
11C-L-DEP, U-5-HIAA, 99 mTc, 201T1, 111In-Oncoscint, and 1502.
These techniques may also be used for transporting one or more of
the following diagnostic agents for facilitating SPECT: I-123
ligands (e.g., I-123-IMP, Iodine-123-QNB, Iodine-123-Iodine labeled
ligands IBZM and IBZP), Tc-99m ligands (e.g., Tc-99m-hexamethyl
propylamine oxime, Tc-Technetium-99m-bicisate), and Xenon-133
ligands.
[0926] The techniques described herein may also be used to
transport the diagnostic agents and types of diagnostic agents
shown in the following table. Although the agents are categorized
by typical diagnostic aims for which they are generally
appropriate, the techniques described herein are not limited to
facilitating transport for these diagnostic aims.
1 Cell proliferation .sup.11C-TdR, .sup.18F-3'FLT, .sup.124I-IUdR,
.sup.76Br- FbrAU Angiogenesis Blood flow .sup.15O-water,
.sup.99mTc-sestamibi, .sup.201Tl- thallium, .sup.133Xe-saline Blood
volume .sup.15O-- or .sup.11C-carbon monoxide-labeled Capillary
permeability erythrocytes (RBCs), .sup.99mTc-RBCs .sup.82Rb,
.sup.68Ga-DTPA, .sup.68Ga-transferrin, .sup.18F--, .sup.123I--,
.sup.131I--, .sup.124I-- or .sup.99mTc-labeled albumin Oxygen
metabolism .sup.15O (oxygen) Hypoxia .sup.18F-fluoromisonidazole,
.sup.61Cu-- or .sup.64Cu- ATSM, .sup.18F-EF1, .sup.18F-EF5
Transporter up-regulation Amino acid transporters
.sup.11C-methionine, .sup.18F-FET, .sup.18F-FACBC Nucleoside
transporters .sup.11C-FMAU Choline transporter
.sup.18F-fluorocholine Glucose transporter .sup.11C-3OMG,
.sup.18F-FDG Cell surface receptors/ antigens (endothelial cells
and tumor cells) Transferrin receptors .sup.67Ga-transferrin,
.sup.111In-DTPA transferrin EGF receptor (radiolabeled chelate
antibody or peptide) Benzodiazepine receptor iodinated-PK11195
Other cell surface receptors/ antigens (e.g., Flt1 and Flk1/ KDR
receptors for VEGF) Cell matrix antigens Integrins (RGD- and other
radiolabeled peptides)
[0927] For some applications, techniques for transporting
diagnostic agents from the systemic circulation to the CNS are used
to transport one or more of the following contrast agents for
facilitating MRI: gadolinium chelates (e.g., Gd-DTPA,
Gd-DOTA.beta., Gd-EOB-DTPA), manganese chelates, paramagnetic iron
oxide particles (e.g., polydisperse iron oxide particles, with a
partial dextran coat, or ultrasmall superparamagnetic iron
oxide-USPIO), and hyperpolarized gases (e.g.,
.sup.3He.sup.129Xe).
[0928] For some applications, techniques for transporting
diagnostic agents from the systemic circulation to the CNS are used
to transport one or more of the following contrast agents for
facilitating ultrasound imaging: polymer microbubbles, microscopic
bubbles (e.g., Imavist.TM.), investigational agent PB127-filled
(polylactide/albumin) or nitrogen-filled microspheres, and iron
oxide particles called ferumoxtran.
[0929] For some applications, techniques for transporting
diagnostic agents from the systemic circulation to the CNS are used
to transport one or more of the following contrast agents for
facilitating CT: radiopaque tracers (e.g., dysprosium-, iodine- and
gadolinium-based contrast agents) and stable xenon gas.
[0930] For some applications, techniques for transporting
diagnostic agents from the systemic circulation to the CNS are used
to transport diagnostic agents for facilitating optical intrinsic
signal (OIS) imaging.
[0931] For some applications, the stimulation techniques described
herein are used to facilitate diagnosis of Alzheimer's disease or
other conditions of the CNS in conjunction with techniques
described in the following patents. It should be appreciated by
those of skill in the art that the following techniques are set
forth for demonstrative purposes. However, those of skill in the
art should, in light of the present disclosure, appreciate that
many changes can be made in the specific embodiments disclosed and
still obtain a like or similar result without departing from the
spirit and scope of the invention.
[0932] U.S. Pat. No. 4,666,829 to Glenner et al., which is
incorporated herein by reference, describes a polypeptide and
fragments thereof that may be used to produce antibodies useful in
a diagnostic test for Alzheimer's disease. Nucleotide probes
corresponding to portions of the polypeptide are also described as
useful for diagnostic purposes. In an embodiment of the present
invention, stimulation techniques described herein for facilitating
transport of diagnostic agents from the systemic blood circulation
to the CNS are used in conjunction with techniques described in the
'829 patent.
[0933] U.S. Pat. No. 4,874,694 to Gandy et al., which is
incorporated herein by reference, describes a diagnostic method for
neurological and psychiatric disorders, utilizing the cerebrospinal
fluid incubated in the presence of 32-P labeled ATP and an
appropriate protein kinase. After termination of the reaction, a
sample is applied to gels for electrophoresis. Subsequent
autoradiography results in a disease-specific protein pattern that
can be used for diagnosis of disorders such as Alzheimer disease,
Huntington disease, Parkinson disease, dystonia ataxia,
schizophrenia, epilepsy brain tumors, brain irradiation, head
trauma, and acute and chronic encephalitic and vascular disease. In
an embodiment of the present invention, stimulation techniques
described herein for facilitating transport of biochemical agents
from the CNS to the systemic blood circulation are used in
conjunction with techniques described in the '694 patent.
[0934] U.S. Pat. No. 6,358,681 to Ginsberg et al., which is
incorporated herein by reference, describes methods for detecting
RNA in brain tissue in order to diagnose Alzheimer's disease. In an
embodiment of the present invention, stimulation techniques
described herein for facilitating transport of biochemical agents
from the CNS to the systemic blood circulation are used in
conjunction with techniques described in the '681 patent.
[0935] U.S. Pat. No. 6,329,531 to Turner et al., which is
incorporated herein by reference, describes the use of optical
diagnostic agents in in vivo and in vitro diagnosis of
neurodegenerative diseases such as Alzheimer's disease by means of
near infra-red radiation (NIR radiation) as a contrasting agent in
fluoresecence and transillumination diagnosis in the NIR range.
Diagnostic agents containing such components are also described. In
an embodiment of the present invention, stimulation techniques
described herein for facilitating transport of diagnostic agents
from the systemic blood circulation to the CNS are used in
conjunction with techniques described in the '531 patent.
[0936] U.S. Pat. No. 6,287,793 to Schenk et al., which is
incorporated herein by reference, describes methods for identifying
key diagnostic antibodies and antigens characteristic of a disease
state of interest, such as Alzheimer's disease.
[0937] U.S. Pat. No. 6,210,895 to Schipper et al., which is
incorporated herein by reference, describes a method for predicting
the onset of, diagnosing, and/or prognosticating dementing
diseases. The method comprises determining the concentration of
heme oxygenase-1 (HO-1) and/or a nucleotide sequence encoding HO-1
in tissue obtained from a patient, and comparing said concentration
with the corresponding concentration of HO-1 and/or an HO-1
encoding nucleotide sequence in corresponding tissue obtained from
at least one control person. The tissue is typically plasma,
lymphocytes, cerebrospinal fluid or fibroblasts. The method is
described as being useful where the dementing disease is any of
Alzheimer's disease, Age-Associated Cognitive Decline, Progressive
Supranuclear Palsy, Vascular (i.e., multi-infarct) Dementia, Lewy
Body Dementia, Huntington's Disease, Down's syndrome, normal
pressure hydrocephalus, corticobasal ganglionic degeneration,
multisystem atrophy, head trauma, Creutzfeldt-Jacob disease, viral
encephalitis and hypothyroidism. In an embodiment of the present
invention, stimulation techniques described herein for facilitating
transport of biochemical agents from the CNS to the systemic blood
circulation are used in conjunction with techniques described in
the '895 patent.
[0938] U.S. Pat. No. 6,200,768 to Mandelkow et al., which is
incorporated herein by reference, describes (a) epitopes of the
protein which are specifically occurring in a phosphorylated state
in tau protein from Alzheimer paired helical filaments, (b) protein
kinases which are responsible for the phosphorylation of the amino
acids of the tau protein giving rise to said epitopes, and (c)
antibodies specific for said epitopes. The patent also describes
pharmaceutical compositions for the treatment or prevention of
Alzheimer's disease, diagnostic compositions and methods for the
detection of Alzheimer's disease, and the use of said epitopes for
the generation of antibodies specifically detecting Alzheimer tau
protein. In an embodiment of the present invention, stimulation
techniques described herein for facilitating transport of
biochemical agents from the CNS to the systemic blood circulation
are used in conjunction with techniques described in the '768
patent. For some applications, these techniques facilitate
increased release of said epitopes of the phosphorylated tau into
the systemic circulation, after which a body fluid is analyzed for
the presence of the epitopes or chemical/biological derivatives
thereof.
[0939] U.S. Pat. No. 6,132,977 to Thompson et al., which is
incorporated herein by reference, describes methods for the
immunological identification and quantitation of SNA.beta.-25 in a
biological fluid, especially cerebrospinal fluid and amniotic
fluid. The quantitated levels of SNA.beta.-25 serve as a diagnostic
marker for some mental illnesses such as major depression,
Alzheimer's disease and schizophrenia. In an embodiment of the
present invention, stimulation techniques described herein for
facilitating transport of biochemical agents from the CNS to the
systemic blood circulation are used in conjunction with techniques
described in the '977 patent, in order to release the SNA.beta.-25
into the systemic circulation and thereafter analyze body fluid for
epitopes and/or chemical/biological derivatives thereof.
[0940] U.S. Pat. No. 6,114,175 to Klunk et al., which is
incorporated herein by reference, describes methods using amyloid
binding compounds which are non-azo derivatives of Chrysamine G, to
identify Alzheimer's brain in vivo and to diagnose other
pathological conditions characterized by amyloidosis, such as
Down's Syndrome. In an embodiment of the present invention,
stimulation techniques described herein for facilitating transport
of biochemical agents from the CNS to the systemic blood
circulation are used in conjunction with techniques described in
the '175 patent.
[0941] Other patents describe methods for aiding in the diagnosis
of Alzheimer's disease by measuring amyloid-beta peptide levels in
a CSF sample of the patient. In an embodiment of the present
invention, stimulation techniques described herein for facilitating
transport of diagnostic agents from the systemic blood circulation
to the CNS are used in conjunction with these methods, in order to
increase the permeability of the BBB to transport labeled (e.g.,
radiolabeled) amyloid-beta mAb or pAb into the CNS and thereafter
perform imaging to assess the amount of amyloid-beta peptide. In an
embodiment of the present invention, stimulation techniques
described herein for facilitating transport of biochemical agents
from the CNS to the systemic blood circulation are used in
conjunction with these methods. After transport across the BBB has
been facilitated, high levels of amyloid-beta peptide in body fluid
are considered inconsistent with a diagnosis of Alzheimer's
disease, while low levels may indicate a rationale for further
inquiries, and may also indicate an increased probability of
Alzheimer's disease.
[0942] U.S. Pat. No. 6,130,048 to Nixon, which is incorporated
herein by reference, describes a method for diagnosing Alzheimer's
disease by measuring the level of a lysosomal hydrolase or
lysosomal protease inhibitor in a patient's cerebrospinal fluid.
Also described are methods for measuring the progression of the
disease and for screening therapeutic compositions for treating the
disease. In an embodiment of the present invention, stimulation
techniques described herein for facilitating transport of
biochemical agents from the CNS to the systemic blood circulation
are used in conjunction with techniques described in the '048
patent.
[0943] U.S. Pat. No. 6,087,118 to Aronson et al., which is
incorporated herein by reference, describes a method for diagnosing
Alzheimer's disease using human blood platelets, wherein the
presence or absence of functioning calcium-dependent potassium
channels in blood platelets are determined by employing potassium
channel blockers such as apamin or charybdotoxin, the absence of
functioning calcium-dependent potassium channels indicating a
positive diagnosis for Alzheimer's disease. In an embodiment of the
present invention, stimulation techniques described herein for
facilitating transport of biochemical agents from the CNS to the
systemic blood circulation are used in conjunction with techniques
described in the '118 patent. It is hypothesized by the inventor of
the present invention that increasing the permeability of the BBB
increases the interaction between the intra-cephalic environment
and the systemic circulation, thereby increasing the efficacy and
statistical accuracy of the method described in the '118
patent.
[0944] U.S. Pat. No. 6,071,705 to Wands et al., which is
incorporated herein by reference, describes a method for detecting
and diagnosing neurological disease or dysfunction, such as
Alzheimer's disease and Down's Syndrome, using antibodies against a
neurological form of Pancreatic Thread Protein (nPTP), such
antibodies including monoclonal antibodies, a combination of those
monoclonal antibodies, or nucleic acid probes. In an embodiment of
the present invention, stimulation techniques described herein for
facilitating transport of diagnostic agents from the systemic blood
circulation to the CNS are used in conjunction with techniques
described in the '705 patent, in order to increase the permeability
of the BBB to transport labeled (e.g., radiolabeled) antibodies of
nPTP into the CNS and thereafter perform imaging to assess the
amount of nPTP bound to the labeled antibodies. Alternatively or
additionally, stimulation techniques described herein for
facilitating transport of biochemical agents from the CNS to the
systemic blood circulation are used in conjunction with techniques
described in the '705 patent, in order to increase the release of
nPTP into the systemic circulation and thereafter sample a body
fluid and analyze it for the presence of nPTP.
[0945] U.S. Pat. No. 6,001,331 to Caprathe et al., which is
incorporated herein by reference, describes a method of imaging
amyloid deposits, and radiolabeled compounds useful in imaging
amyloid deposits. In an embodiment of the present invention,
stimulation techniques described herein for facilitating transport
of diagnostic agents from the systemic blood circulation to the CNS
are used in conjunction with techniques described in the '331
patent, in order to increase the delivery of the radiolabeled
compounds into the CNS, thereby enhancing the contrast of the
plaque.
[0946] U.S. Pat. No. 5,985,581 to Nixon et al., which is
incorporated herein by reference, describes a method of diagnosing
Alzheimer's disease utilizing presenilin-1, whose level is found to
be substantially decreased in Alzheimer's patients. A CSF sample
(ventricular or lumbar) is taken, and the level of presenilin-1 is
measured using an immunoassay that uses antibodies to presenilin-1,
to a fragment thereof, or to a specific amino acid sequence. In an
embodiment of the present invention, the antibodies, antibody
fragments, or specific amino acid sequence described in the '581
patent are labeled (e.g., radiolabeled) to facilitate a subsequent
imaging procedure for assessing the amount of bound presenilin-1.
The stimulation techniques described herein for facilitating
transport of diagnostic agents from the systemic blood circulation
to the CNS are used to deliver the labeled compounds to the CNS. In
an embodiment of the present invention, stimulation techniques
described herein for facilitating transport of biochemical agents
from the CNS to the systemic blood circulation are used in
conjunction with techniques described in the '581 patent, in order
to increase the penetration of the abovementioned proteins from the
CNS into the systemic circulation and thereafter analyze a body
fluid using the methods and/or diagnostic kits described in the
'581 patent. Levels of the protein that are higher than a threshold
value may indicate the absence of Alzheimer's disease.
[0947] U.S. Pat. No. 5,981,194 to Jefferies et al., which is
incorporated herein by reference, describes methods for using p97
and iron-binding proteins as diagnostic and therapeutic agents,
including for the diagnosis of Alzheimer's disease. The methods are
based on evidence that Alzheimer's patients have elevated levels of
elevated levels of p97 in their serum and cerebrospinal fluid and
that p97 levels increase with duration of the disease. The levels
of p97 in patient samples may thus be used to diagnose and to
monitor the progression of the disease and the efficacy of
therapeutic treatments for Alzheimer's disease. Evidence is also
presented that microglial cells associated with senile plaques in
Alzheimer's disease express p97 and transferrin receptor.
Therefore, p97 and transferrin receptor can be used in the
diagnosis of Alzheimer's Disease. The finding that microglial cells
which deposit the amyloid protein have a high level of proteins
which operate in procurement of iron also suggests methods of
treatment of Alzheimer's disease based on depletion of iron from
these cells using substances such as p97, transferrin, and iron
chelators, for example, lactoferrin, ferritin, and ovotransferrin.
In an embodiment of the present invention, stimulation techniques
described herein for facilitating transport of biochemical agents
from the CNS to the systemic blood circulation are used in
conjunction with techniques described in the '194 patent. The use
of these techniques in combination typically enhances the accuracy
of diagnosis of Alzheimer's disease.
[0948] U.S. Pat. No. 5,849,600 to Nixon et al., which is
incorporated herein by reference, describes a method for diagnosing
Alzheimer's disease in a human patient by measuring the amount of
p33 present in a biological sample, such as a ventricular or lumbar
CSF sample, or brain tissue homogenate. In an embodiment of the
present invention, the stimulation techniques described herein are
used to facilitate transport of a labeled (e.g., radiolabeled)
anti-p33 mAb or pAb from the systemic circulation to the CNS. An
imaging procedure is subsequently performed to evaluate the amount
of p33 protein in the CNS. In an embodiment of the present
invention, stimulation techniques described herein for facilitating
transport of biochemical agents from the CNS to the systemic blood
circulation are used in conjunction with techniques described in
the '600 patent, in order to increase the penetration of the
abovementioned protein from the CNS into the systemic circulation.
Thereafter a body fluid is analyzed using the methods and/or
diagnostic kits described in the '600 patent. Levels of the protein
that are higher than a threshold value may indicate the presence of
Alzheimer's disease.
[0949] U.S. Pat. No. 5,833,988 to Friden, which is incorporated
herein by reference, describes a method for delivering a
neuropharmaceutical or diagnostic agent across the BBB to the
brain. The method comprises administering to the host a
therapeutically effective amount of an antibody-neuropharmaceutical
or diagnostic agent conjugate wherein the antibody is reactive with
a transferrin receptor. In an embodiment of the present invention,
the stimulation techniques described herein are used to facilitate
transport of an agent described in the '988 patent from the
systemic circulation to the CNS. An imaging procedure is
subsequently performed to evaluate the amount of a ligand of the
agent in the CNS.
[0950] U.S. Pat. No. 5,830,670 to de la Monte et al., which is
incorporated herein by reference, describes a method for diagnosing
Alzheimer's disease, neuroectodermal tumors, malignant
astrocytomas, and glioblastomas, by identifying recombinant hosts
and vectors which contain the genes coding for neuronal thread
proteins (NTPs) associated with these conditions. Specific targeted
NTPs have molecular weights of about 8 kDa, about 14 kDa, about 17
kDa, about 21 kDa, about 26 kDa or about 42 kDa. In an embodiment
of the present invention, the stimulation techniques described
herein are used to facilitate transport of a labeled (e.g.,
radiolabeled) antibody against an NTP from the systemic circulation
to the CNS. An imaging procedure is subsequently performed to
evaluate the amount of the NTP in the CNS. In an embodiment of the
present invention, stimulation techniques described herein for
facilitating transport of biochemical agents from the CNS to the
systemic blood circulation are used in conjunction with techniques
described in the '670 patent, in order to increase the penetration
of the abovementioned protein from the CNS into the systemic
circulation. Thereafter in vivo or in vitro analysis of body fluid
is performed, typically using a diagnostic kit. Levels of the
protein that are higher than a threshold value may indicate the
presence of Alzheimer's disease or other conditions described in
the '670 patent.
[0951] In an embodiment of the present invention, stimulation
techniques described herein are used to facilitate a diagnosis of
brain tumors (primary and secondary (metastatic) neoplasms in the
brain). Such stimulation typically facilitates the transfer from
the systemic circulation to the CNS of a labeled (e.g.,
radiolabeled) diagnostic agent, which may be specific for the
neoplasm to be diagnosed, for a group of neoplasms, or generally
for a pathologic state in the CNS.
[0952] For example, these stimulation techniques may be used to
diagnosis gliomas. Gliomas often overexpress a receptor for
interleukin 13 (IL-13). Because interleukins have large molecular
sizes (typically, ten of kilodaltons), they generally penetrate the
CNS poorly under a wide range of physiological conditions. In
conjunction with administration of labeled IL-13 into the systemic
circulation, an MTS is stimulated, allowing the IL-13 to pass into
the CNS, where the IL-13 typically concentrates in tumor locations.
Such concentration is detected using an imaging procedure. This
approach typically represents a relatively low-risk and highly
disease-specific approach to diagnosing such tumors.
[0953] Another example is the use of labeled (e.g., radiolabeled)
anti-HER2 mAb or pAb for imaging of breast cancer metastases in the
brain. HER2 is a protein over-expressed on the malignant cell outer
membrane in a significant percentage of patients with breast
cancer. The permeability of the BBB is increased using the
stimulation techniques described herein, in conjunction with
administration of labeled anti-HER2 mAb or mAb and performance of
an imaging procedure. This approach typically represents a
relatively low-risk and highly disease-specific approach to
diagnosing such metastases.
[0954] In an embodiment, methods are used for aiding the diagnosis
of brain tumors or screening for brain tumors. Typically, these
methods include using labeled interleukins, anti-cancer-cells
mAb/pAb or other possible markers of neoplasms in conjunction with
an imaging procedures. In an embodiment of the present invention,
stimulation techniques described herein for facilitating transport
of diagnostic agents from the systemic blood circulation to the CNS
are used to transport labeled (e.g., radiolabeled) amyloid-beta mAb
or pAb into the CNS, and a subsequent imaging procedure is
performed.
[0955] In an embodiment of the present invention, the stimulation
techniques described herein are used to facilitate increased
release of disease-related agents (e.g., proteins, DNA fragments,
etc.) from the CNS into the systemic circulation and body tissues.
To diagnose brain tumors, these techniques are used to facilitate
the transport of markers of the central malignant process (e.g.
glioma) from the CNS to the systemic circulation, where they are
detected using a suitable bioassay.
[0956] For some applications, the diagnostic techniques described
herein are used at more than one point in time in order to indicate
the possible progression of the CNS condition being diagnosed.
[0957] Some existing and proposed diagnostic techniques use a
sample of CSF for biochemical analysis. In an embodiment of the
present invention, stimulation techniques described herein are used
to increase transport of biochemical markers from the CSF to the
systemic circulation as an alternative to direct sampling of the
CSF.
[0958] "Diagnosis," as used in the present patent application,
including the claims, is to be understood as comprising the art or
act of recognizing the presence of disease from its signs or
symptoms, deciding as to the character (e.g., stage) of a disease,
screening for disease, and/or predicting the onset of disease.
Diagnosis may be performed in vivo or in vitro, as appropriate.
Diagnosis may comprise a combination of diagnostic procedures. For
example, the permeability of the BBB may be increased in
combination with taking a blood sample and analyzing it for the
presence of a biochemical marker of a CNS neoplastic process, and
performing PET imaging for a mAb or pAb to a protein that is
indicative of a neoplastic process.
[0959] Whereas some embodiments of the present invention are
described herein with respect to enhancing permeability of the BBB
so as to facilitate passage of molecules from the systemic
circulation to brain tissue of a patient, this is by way of
illustration and not limitation. In other embodiments, analogous
techniques are utilized so as to facilitate enhanced clearance of
molecules from brain tissue to the systemic circulation. For some
applications, this enhanced clearance is utilized to facilitate a
diagnostic procedure, for example by means of an imaging modality
or a blood sample taken during or subsequent to increased BBB
permeability. For other applications, the enhanced clearance of
molecules is a goal in and of itself, for example in order to
facilitate clearance of toxins from the brain.
[0960] Techniques described in this application may be practiced in
combination with methods and apparatus described in one or more of
the following patent applications, which are assigned to the
assignee of the present patent application and are incorporated
herein by reference:
[0961] PCT Publication WO 01/85094, filed May 7, 2001, entitled,
"Method and apparatus for stimulating the sphenopalatine ganglion
to modify properties of the BBB and cerebral blood flow," and U.S.
Patent Application Publication 2004/0015068 to Shalev and Gross
[0962] U.S. Provisional Patent Application 60/364,451, filed Mar.
15, 2002, entitled, "Applications of stimulating the sphenopalatine
ganglion (SPG)"
[0963] U.S. Provisional Patent Application 60/368,657, filed Mar.
28, 2002, entitled, "SPG Stimulation"
[0964] U.S. Provisional Patent Application 60/376,048, filed Apr.
25, 2002, entitled, "Methods and apparatus for modifying properties
of the BBB and cerebral circulation by using the neuroexcitatory
and/or neuroinhibitory effects of odorants on nerves in the
head"
[0965] U.S. Provisional Patent Application 60/388,931, filed Jun.
14, 2002, entitled "Methods and systems for management of
Alzheimer's disease"
[0966] U.S. Provisional Patent Application 60/400,167, filed Jul.
31, 2002, entitled, "Delivering compounds to the brain by modifying
properties of the BBB and cerebral circulation," and PCT
Publication WO 04/010923 to Gross et al.
[0967] U.S. Provisional Patent Application 60/426,180, filed Nov.
14, 2002, entitled, "Surgical tools and techniques for
sphenopalatine ganglion stimulation," and PCT Publication WO
04/043218 to Gross et al.
[0968] U.S. Provisional Patent Application 60/426,182, filed Nov.
14, 2002, entitled, "Stimulation circuitry and control of
electronic medical device," and PCT Publication WO 04/044947 to
Gross et al.
[0969] U.S. patent application Ser. No. 10/294,310, filed Nov. 14,
2002, entitled, "SPG stimulation for treating eye pathologies," and
PCT Publication WO 04/043217 to Gross et al.
[0970] U.S. patent application Ser. No. 10/294,343, filed Nov. 14,
2002, entitled, "Administration of anti-inflammatory drugs into the
CNS," and PCT Publication WO 04/043334 to Shalev
[0971] U.S. Provisional Patent Application 60/426,181, filed Nov.
14, 2002, entitled, "Stimulation for treating ear pathologies," and
PCT Publication WO 04/045242 to Shalev et al.
[0972] U.S. Provisional Patent Application 60/448,807, filed Feb.
20, 2003, entitled, "Stimulation for treating autoimmune-related
disorders of the CNS"
[0973] U.S. Provisional Patent Application 60/461,232 to Gross et
al., filed Apr. 8, 2003, entitled, "Treating abnormal conditions of
the mind and body by modifying properties of the blood-brain
barrier and cephalic blood flow".
[0974] In particular, techniques of electrical signal application
described in the above list of patent applications may be used
together with or instead of odorant presentation. Thus,
applications described herein which utilize odorant presentation
may instead use electrical signal application to achieve generally
similar results to those achieved through odorant presentation.
[0975] It is to be understood that the term "blood brain barrier
(BBB)," as used in the context of the present patent application
and in the claims, applies to the barrier between the systemic
circulation and the brain, as well as to the barrier between the
systemic circulation and a tumor in the brain (sometimes referred
to as the "blood tumor barrier").
[0976] It will be appreciated by persons skilled in the art that
the present invention is not limited to what has been particularly
shown and described hereinabove. Rather, the scope of the present
invention includes both combinations and subcombinations of the
various features described hereinabove, as well as variations and
modifications thereof that are not in the prior art, which would
occur to persons skilled in the art upon reading the foregoing
description. For example, elements which are shown in a figure to
be housed within one integral unit may, for some applications, be
disposed in a plurality of distinct units. Similarly, apparatus for
communication and power transmission which are shown to be coupled
in a wireless fashion may be, alternatively, coupled in a wired
fashion, and apparatus for communication and power transmission
which are shown to be coupled in a wired fashion may be,
alternatively, coupled in a wireless fashion. In addition, it is to
be understood that the scope of the present invention includes
apparatus for carrying out methods described and/or claimed herein,
and also includes methods corresponding to apparatus described
and/or claimed herein.
* * * * *