U.S. patent application number 13/606906 was filed with the patent office on 2013-03-14 for techniques for selecting signal delivery sites and other parameters for treating depression and other neurological disorders, and associated systems and methods.
The applicant listed for this patent is Bradford E. Gliner, Justin Hulvershorn, Brian Kopell. Invention is credited to Bradford E. Gliner, Justin Hulvershorn, Brian Kopell.
Application Number | 20130066391 13/606906 |
Document ID | / |
Family ID | 41653651 |
Filed Date | 2013-03-14 |
United States Patent
Application |
20130066391 |
Kind Code |
A1 |
Hulvershorn; Justin ; et
al. |
March 14, 2013 |
TECHNIQUES FOR SELECTING SIGNAL DELIVERY SITES AND OTHER PARAMETERS
FOR TREATING DEPRESSION AND OTHER NEUROLOGICAL DISORDERS, AND
ASSOCIATED SYSTEMS AND METHODS
Abstract
The present disclosure is directed generally to techniques for
selecting signal delivery sites and other signal delivery
parameters for treating depression and other neurological
disorders. A method in accordance with a particular embodiment
includes obtaining first imaging information corresponding to a
first region of a patient's brain, the first imaging information
being based at least in part on functional characteristics of the
first region. The method includes obtaining second imaging
information corresponding to a second region of the patient's
brain, the second region being a subset of the first region, the
second imaging information being based at least in part on
functional or structural characteristics of the second region. A
target neural population is selected based in part on the second
imaging information. The method still further includes applying an
electromagnetic signal to the target neural population to improve a
patient function.
Inventors: |
Hulvershorn; Justin;
(Seattle, WA) ; Gliner; Bradford E.; (Sammamish,
WA) ; Kopell; Brian; (Milwaukee, WI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hulvershorn; Justin
Gliner; Bradford E.
Kopell; Brian |
Seattle
Sammamish
Milwaukee |
WA
WA
WI |
US
US
US |
|
|
Family ID: |
41653651 |
Appl. No.: |
13/606906 |
Filed: |
September 7, 2012 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12395257 |
Feb 27, 2009 |
8262714 |
|
|
13606906 |
|
|
|
|
Current U.S.
Class: |
607/45 |
Current CPC
Class: |
A61B 5/055 20130101;
A61N 1/0531 20130101; A61N 2/004 20130101; A61N 1/36082 20130101;
A61B 6/501 20130101; A61B 5/4064 20130101 |
Class at
Publication: |
607/45 |
International
Class: |
A61N 1/36 20060101
A61N001/36 |
Claims
1-25. (canceled)
26. A method for treating a patient, comprising: identifying a
patient as having depression; identifying a baseline level of the
patient's motor cortex excitability; for multiple areas of the
patient's DLPFC: applying stimulation to the patient's DLPFC using
rTMS techniques; after applying stimulation to the patient's DLPFC,
identifying a change in the patient's motor cortex excitability
using paired-pulse TMS stimulation; based at least in part on
identified changes in the patient's motor cortex excitability for
the multiple areas of the patient's DLPFC, selecting a signal
delivery site; implanting at least one electrode proximate to the
signal delivery site, within a cranial cavity of the patient's
skull and outside a cortical surface of the patient's brain; and
reducing or eliminating patient depression by preferentially
directing electrical signals from the at least one electrode to the
signal delivery site.
27. The method of claim 26 wherein selecting a signal delivery site
includes selecting the signal delivery site to be at an area of the
DLPFC that has a greater effect on motor cortex excitability than
other areas of the DLPFC.
28. The method of claim 26, wherein applying stimulation to the
patient's DLPFC includes applying stimulation for a period of about
20 minutes.
29. The method of claim 26, further comprising repeating the
process of identifying a change in the patient's motor cortex
excitability and the process of selecting a signal delivery site
during the course of the patient's therapy to account for patient
adaptation to the electrical signals.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 12/395,257, filed Feb. 27, 2009, now U.S. Pat. No. 8,262,714,
which claims the benefit of U.S. Provisional Application No.
60/086,199, filed Aug. 5, 2008, the disclosures of which are fully
incorporated herein by reference for all purposes.
TECHNICAL BACKGROUND
[0002] Aspects of the present disclosure are directed generally
toward techniques for selecting signal delivery sites and other
signal delivery parameters for treating depression and other
neurological disorders, and associated systems and methods.
BACKGROUND
[0003] A wide variety of mental and physical processes are
controlled or influenced by neural activity in particular regions
of the brain. For example, the neural functions in some areas of
the brain (i.e., the sensory and motor cortices) are organized
according to physical or cognitive functions. Several areas of the
brain appear to have distinct functions in most individuals. In the
majority of people, for example, the areas of the occipital lobes
relate to vision, the regions of the left inferior frontal lobes
relate to language, and particular regions of the cerebral cortex
appear to be consistently involved with conscious awareness,
memory, and intellect.
[0004] Many problems or abnormalities can be caused by damage,
disease and/or disorders in the brain. Disorders include
neuropsychiatric and/or neuropsychological disorders, such as major
depression. A person's neuropsychiatric responses may be controlled
by a looped signal path between cortical structures, e.g.,
superficial structures at the prefrontal cortex of the brain, and
deeper neural populations.
[0005] Neurological problems or abnormalities are often related to
electrical and/or chemical activity in the brain. Neural activity
is governed by electrical impulses or "action potentials" generated
in neurons and propagated along synaptically connected neurons.
When a neuron is in a quiescent state, it is polarized negatively
and exhibits a resting membrane potential typically between -70 and
-60 mV. Through chemical connections known as synapses, any given
neuron receives excitatory and inhibitory input signals or stimuli
from other neurons. A neuron integrates the excitatory and
inhibitory input signals it receives, and generates or fires an
action potential when the integration exceeds a threshold
potential. A neural firing threshold, for example, may be
approximately -55 mV.
[0006] When electrical activity levels at either the superficial
cortical structure or the deep brain structure are irregular,
action potentials may not be generated in the normal manner. For
example, action potentials may be generated too frequently, or not
frequently enough. Such irregularities can result in a
neuropsychiatric disorder. It follows, then, that neural activity
in the brain can be influenced by electrical energy supplied from
an external source, such as a waveform generator. Various neural
functions can be promoted or disrupted by applying an electrical
current to the cortex or other region of the brain. As a result,
researchers have attempted to treat physical damage, disease and
disorders in the brain using electrical or magnetic stimulation
signals to control or affect brain functions.
[0007] Transcranial electrical stimulation (TES) is one such
approach that involves placing an electrode on the exterior of the
scalp and delivering an electrical current to the brain through the
scalp and skull. Another treatment approach, transcranial magnetic
stimulation (TMS), involves producing a magnetic field adjacent to
the exterior of the scalp over an area of the cortex. Yet another
treatment approach involves direct electrical stimulation of neural
tissue using implanted deep brain stimulation electrodes (DBS).
However, the foregoing techniques may not consistently produce the
desired effect with the desired low impact on the patient. For
example, TES may require high currents to be effective, which may
cause unwanted patient sensations and/or pain. TMS may not be
precise enough to target only specific areas of the brain. Deep
brain stimulation is a relatively invasive procedure, and it can be
relatively difficult to implant DBS electrodes in tissue located
well below the cortex. Accordingly, there exists a need for
providing more effective, less invasive treatments for
neuropsychiatric and neuropsychological disorders.
BRIEF SUMMARY
[0008] FIG. 1 is a flow diagram illustrating a method for treating
a patient in accordance with a particular embodiment of the
disclosure.
[0009] FIG. 2 is a schematic illustration of cortical and
sub-cortical brain structures, along with regions selected in
accordance with embodiments of the disclosure.
[0010] FIG. 3 is a flow diagram illustrating a method for treating
a patient's depression in accordance with an embodiment of the
disclosure.
[0011] FIG. 4 is a partially schematic illustration of brain and
peripheral structures that may be associated with the method shown
in FIG. 3.
[0012] FIG. 5 illustrates an electrode device operatively coupled
to an external controller in accordance with an embodiment of the
disclosure.
[0013] FIG. 6 is a schematic illustration of a pulse system
configured in accordance with several embodiments of the
disclosure.
[0014] FIG. 7 is an isometric illustration of an electrode device
that carries multiple electrodes in accordance with an embodiment
of the disclosure.
[0015] FIGS. 8A-8C are partially schematic illustrations of
electrode devices implanted at locations selected in accordance
with embodiments of the disclosure.
DETAILED DESCRIPTION
Introduction
[0016] The present disclosure is directed to methods for treating
neurologic dysfunction, which may include neuropsychiatric,
neuropsychological, neurodevelopmental and/or other disorders, and
associated systems for carrying out such methods. As used herein,
the phrase "neurologic dysfunction" is used to encompass a variety
of conditions or disorders, including neuropsychiatric disorders
and neuropsychological disorders. As a further shorthand, the term
"neuropsychiatric disorders" is used to include both
neuropsychiatric disorders and neuropsychological disorders.
Representative types of disorders falling within this definition
include major depression, mania and other mood disorders, bipolar
disorder, obsessive-compulsive disorder (OCD), Tourette's syndrome,
schizophrenia, dissociative disorders, anxiety disorders, phobic
disorders, post-traumatic stress disorder (PTSD), borderline
personality disorder, as well as others such as Attention
Deficit/Hyperactivity Disorder (ADHD) and/or craving or reward
driven behaviors (e.g., associated with an addiction to legal or
illegal drugs, gambling, sex, or another condition such as
obesity).
[0017] In general, various aspects of the methods and systems
disclosed herein are directed to treating neurological conditions
or states with electromagnetic stimulation, typically electrical
stimulation applied to particular cortical structures of the
patient's brain, e.g., from an epidural or subdural location. As
used herein, "stimulation" refers generally to extrinsic signals
directed to the patient to achieve a beneficial result. The signals
may have an inhibitory or excitatory effect on particular neural
populations. One representative technique includes using at least
two sets of imaging information to more particularly identify the
neural population to which therapeutic electromagnetic signals are
delivered. Another particular method, directed to depressed
patients, can include applying electromagnetic signals to one or
more patient brain regions expected to correspond to the
dorsolateral prefrontal cortex (DLPFC) and identifying a change in
a region of the brain other than the DLPFC. Based at least in part
upon this information, a practitioner can determine whether or not
the patient is a candidate for cortical signal delivery to address
depression, and/or the practitioner can select a target neural
population to receive cortical signals, and/or the practitioner can
update cortical signal delivery parameters. Further particular
embodiments are described in greater detail below with reference to
FIGS. 1-8C.
Systems and Methods for Patient Selection, Target Neural Population
Selection, and Signal Delivery Selection
[0018] FIG. 1 is a flow diagram illustrating a process 100 for
treating a patient in accordance with a particular embodiment of
the disclosure. The process 100 includes obtaining first imaging
information corresponding to a first region of a patient's brain,
with the first imaging information being based at least in part on
functional characteristics of the first region (process portion
101). For example, the first imaging information can be obtained
using functional magnetic resonance imaging (fMRI) techniques.
Process portion 102 can include obtaining second imaging
information corresponding to a second region of the patient's
brain, with the second region being a subset of the first region.
The second imaging information can be based at least in part on
functional or structural characteristics of the second region, and
can have a resolution greater than that of the first imaging
information. Accordingly, the second information can be used to
more precisely identify a target neural population that will
receive therapeutic electromagnetic signals. For example, a typical
fMRI-based process for locating a target neural population has a
resolution of about 1-3 centimeters. By adding the second
information, (e.g., using diffusion tensor imaging processes
described later) the practitioner can achieve a resolution of 3
millimeters or less. In addition to increased resolution, the
foregoing technique can be conducted without a surgical procedure
and is therefore less invasive than other techniques. Still
further, this technique can be readily used to identify target
neural populations of "silent" neurons, e.g., cognitive, emotive
and/or other neurons that typically do not produce an immediate
motor or sensory response.
[0019] The practitioner can use the first and/or second information
to identify particular areas of interest, and/or to eliminate from
further consideration areas that are not of interest. In any of
these cases, process portion 103 includes selecting a target neural
population based at least in part on the second imaging
information, and process portion 104 includes applying an
electromagnetic signal to the target neural population to improve a
patient function. For example, this technique can be used to
improve the functioning of a patient suffering from depression. A
representative example is described in further detail below with
reference to FIG. 2.
[0020] FIG. 2 is a schematic illustration of a patient's brain 220
illustrating cortical structures 221 (e.g., superficial or outer
structures) located at the cortex 223, and sub-cortical structures
222 (e.g., deeper, non-superficial structures) located below or
within the cortex 223. The cortical structures 221 can include the
dorsolateral prefrontal cortex (DLPFC) 224 which has neuronal
tracts (illustrated schematically by doubled-headed arrows in FIG.
2) extending to the sub-cortical structures 222. The DLPFC has
connections with many sub-cortical structures 222 but for purposes
of illustration, Brodmann area 10 and Brodmann area 25 are
specifically shown in FIG. 2. In a particular embodiment, the
practitioner can preferentially focus imaging tasks on one or brain
locations expected to form a portion of or correspond to the DLPFC
and then preferentially direct electromagnetic signals to portions
of the DLPFC. In other embodiments, the practitioner can focus
imaging tasks (and electromagnetic signals) on particular
neuroanatomical structures, portions of which may be included in
the DLPFC, e.g., portions of the patient's middle frontal gyrus,
and/or superior frontal gyrus. In still further embodiments, the
practitioner can focus imaging tasks (and/or electromagnetic
signals) on still other structures, e.g., the patient's inferior
frontal gyrus, orbitofrontal cortex, and/or ventrolateral
prefrontal cortex. Additional details of techniques for targeting
and applying therapy to these structures are included in pending
U.S. application Ser. No. 12/330,437, filed Dec. 8, 2008 and
incorporated herein by reference.
[0021] The DLPFC 224 can include subareas, for example, a cognitive
area 225 associated with the patient's cognitive functioning, and
an emotive area 226 associated with the patient's emotional
functioning, both shown schematically in FIG. 2. The locations of
these areas may in at least some cases vary from patient to
patient. In addition, individual patients may have a depression
condition that results from dysfunctions in the cognitive area 225
or the emotive area 226 or both the cognitive area 225 and the
emotive area 226. Using functional imaging techniques (e.g., fMRI),
a practitioner can identify which of the two areas is a likely
candidate for cortical stimulation. For example, the patient can be
exposed to a stimulus (described in further detail later) that
triggers an acute depression response, while the patient's brain is
imaged. In some cases, only one of the areas 225, 226 may be a
suitable candidate, and in other embodiments, both areas may be
suitable candidates. In any of these cases, the cognitive area 225
and/or the emotive area 226 can correspond to the first region of
the patient's brain described above with reference to FIG. 1. In
still another embodiment, neither the cognitive area 225 nor the
emotive area 226 may particularly stand out when the first imaging
information is obtained, and accordingly, the entire DLPFC 224 or
some other region of the DLPFC may correspond to the first region
described above with reference to FIG. 1.
[0022] As shown in FIG. 2, the cognitive area 225 and the emotive
area 226 may each have many tracts that descend to a variety of
sub-cortical structures 222. In certain embodiments, the
practitioner may be particularly interested in applying electrical
signals to those areas of the DLPFC 224 that have a significant
number of neuronal fibers or tracts that descend to Brodmann area
10 and/or Brodmann area 25. Accordingly, the practitioner can
obtain the second imaging information described above with
reference to FIG. 1 to identify a second, more precisely defined
region of the patient's brain suitable for receiving cortical
stimulation. For example, if the cognitive area 225 is of
particular interest, the second imaging information can be used to
identify a second region 227a that includes tracts (or a greater
number of tracts or density of tracts) extending to Brodmann area
25 and/or Brodmann area 10. If the emotive area 226 is of
particular interest, the practitioner can identify a second region
227b that has tracts (or a greater number of tracts or density of
tracts) descending to Brodmann area 25 and/or Brodmann area 10.
Accordingly, the first imaging information described above with
reference to FIG. 1 can identify a general region for cortical
stimulation with a first level of resolution, and the second
imaging information can identify one or more second regions with a
higher level of resolution to more precisely identify one or more
target neural populations. Further details of suitable techniques
for obtaining the first imaging information and the second imaging
information are described below.
[0023] In at least some embodiments, the first imaging information
is based at least in part on functional characteristics of the
first region. For example, the first information can be obtained
using correlates that are associated with or indicative of neural
functioning levels. Such correlates include blood flow, metabolism,
perfusion, glucose levels, water levels, magnetic characteristics,
and/or electrical characteristics. Suitable techniques for
identifying and/or measuring such correlates can include fMRI,
spectroscopy based on MRI, positron emission tomography (PET),
single photon emission computed tomography (SPECT), and/or computed
tomography (CT). In any of these embodiments, the image or
information used to produce the image is correlated with a
particular activity related to the patient's depression. For
example, in some cases, the patient's working memory is affected by
depression and accordingly, the patient can undertake working
memory tasks while the first imaging information is collected. In
other embodiments, the patient can be exposed to emotion-triggering
stimuli (e.g., visual, auditory, tactile and/or olfactory stimuli)
so as to identify regions of the brain that are active in response
to such stimuli and are correlated with the patient's depression.
Further details associated with assessing patient functioning are
included in co-pending U.S. Patent Publication No. US 2008/0103548,
incorporated herein by reference.
[0024] The second imaging information can be structural or
functional in nature and is generally obtained for a smaller region
of the brain (e.g., a subset of the first region) than is the first
imaging information. In a particular embodiment, diffusion tensor
imaging (DTI) techniques are used to identify neuronal tracts or
fibers descending to sub-cortical areas that are known or expected
to play a role in the patient's depression. More specifically, the
practitioner can identify a "seed point" at the DLPFC using the
first information. On the basis of the seed point, the practitioner
can perform a fiber tracking analysis to identify fibers that
connect the DLPFC to specific sub-cortical structures. This
technique can be performed for multiple seed points at the DLPFC,
and one or more target neural populations can be selected to
include the areas of the DLPFC having the highest density of
(intact) fiber tracts that descend to the specific sub-cortical
area(s) of interest. Accordingly, the foregoing tractography
analysis can apply to white matter in the brain, in contrast to
techniques that may apply only to gray matter.
[0025] The foregoing approach is expected to produce better (e.g.,
more efficacious) results than identifying and stimulating a deep
brain structure because many deep brain structures have a high
density of tracts that extend to many different superficial
locations, some of which may be associated with the patient's
depression, and many of which are not. As a result, methods that
focus on stimulating deep brain areas may be inefficient and/or may
create unintended cortical effects because it may be difficult to
accurately target the deep brain area(s) of particular interest.
Accordingly, in particular embodiments of the present techniques,
no deep brain stimulation is applied. In a further particular
aspect of this embodiment, simulation is applied only to areas
identified based on the second imaging information. Further
information relating to the use of DTI for site identification is
included in U.S. Patent Publication No. US 2008/0039895,
incorporated herein by reference.
[0026] In general terms, DTI techniques identify neuronal tracts by
identifying adjacent tissue volumes (voxels) having diffusion
tensors aligned in the same direction. In addition to or in lieu of
using diffusion characteristics to identify tracts, the
practitioner can use diffusion information to identify the level of
anisotropy of the brain tissue, typically referred to as fractional
anisotropy (FA). In general terms, FA refers to the magnitude of
the diffusion tensor, as opposed to its direction. It is expected
that in at least some embodiments, the level of anisotropy can be
indicative of regions affected by depression. For example, if the
FA level for a particular region of the DLPFC is relatively low
(e.g., lower than a standard or average value across a general
patient population), this can indicate an area associated with the
patient's depression. If the FA level is low, yet still above a
threshold value, this may indicate an area suitable for cortical
stimulation. Accordingly, the FA level can be used to identify
patients who are suitable candidates for cortical stimulation
therapy, and/or target neural populations in patients who are
suitable candidates. Suitable threshold FA values are expected to
be different for different brain areas and/or different
neuropsychiatric/neuropsychological conditions. FA values may also
be used to identify changes (e.g., improvements) in patient
condition over time, as a result of the therapeutic treatments
described herein. For example, it is expected that the patient's FA
values may increase as a result of structural changes, including
but not limited to dendritic sprouting and/or the formation of new
axons.
[0027] In other embodiments, functional characteristics of the
brain may be used to identify the second region described above
with reference to FIG. 1. For example, spectroscopy may be used. In
a particular aspect of this embodiment, the practitioner can
analyze fMRI results on a real-time or nearly real-time basis, and
conduct a magnetic resonance spectroscopy (MRS) diagnosis on a
subset region of the brain in a single patient visit. When the
practitioner uses spectroscopy to obtain the second information,
the practitioner can focus the analysis on a smaller area than may
be used to obtain the first information, resulting in a higher
sensitivity analysis and an expected increase in the precision of
the results.
[0028] Techniques other than spectroscopy may also be used to
identify the second brain region, based on structural
characteristics of the brain. For example, the thickness of the
gray matter within the first region can be used to identify the
second region. In a particular embodiment, the gray matter
thickness is assessed using MRI techniques. In general, the greater
the gray matter thickness, the greater the functionality of the
tissue. The practitioner can select highly functional tissue as the
target neural population in cases for which it is expected that
this will be beneficial, e.g., when it is expected that stimulation
will encourage the functional tissue to take on additional
functionality. The practitioner can select less functional tissue
in cases for which it is expected that stimulation can raise the
functionality to normal or approximately normal levels. These
techniques can be used separately or in combination.
[0029] As described above with reference to FIG. 1, once a suitable
second region has been selected, the practitioner can apply an
electromagnetic signal to the target neural population to improve a
patient function. In a particular embodiment, the practitioner uses
a cortical electrode (e.g., an electrode positioned epidurally or
subdurally within the cranial cavity of the patient's skull,
proximate to the target neural population, and outside a cortical
surface of the patient's brain) to apply electrical signals to the
target neural population. Depending upon the patient's condition,
the electromagnetic signals may be applied in a manner that
inhibits the target neural population, or excites or facilitates
the target neural population. The frequency and/or polarity (anodal
or cathodal) of the signal may be selected to achieve the desired
result. The stimulation may be delivered so as to have a direct
effect on the target neural population, for example, an effect that
lasts as long as or slightly longer than the stimulation itself. In
other embodiments, the stimulation may be applied to neural
populations that are expected to retain long-lasting changes (e.g.,
neuroplastic changes) that can last for days, weeks, months or
years after the stimulation has ceased. In such cases, the
treatment regimen can include an adjunctive therapy in combination
with the electrical stimulation. Representative adjunctive
therapies include working memory tasks, exposure to emotional
triggers, psychological counseling and others.
[0030] In other embodiments, techniques generally similar to the
foregoing techniques can be used to perform functions other than
identifying suitable target neural populations. For example, such
techniques can be used to screen treatment candidates. In a
particular embodiment, if the patient's FA level is low, the
patient may be a suitable candidate for cortical stimulation
treatment. However, if the FA level is too low, the patient may not
respond adequately to cortical stimulation and may accordingly be
screened out or selected for an alternative treatment.
[0031] In another embodiment, one or more of the foregoing
techniques can be used to select a particular treatment modality.
For example, if the patient's FA value is within a particular
range, the patient may be selected to undergo cortical stimulation.
If the FA value is within a different range, the patient may be
expected to respond better to transcranial magnetic stimulation
(TMS) techniques, or deep brain stimulation (DBS) techniques.
Accordingly, the particular technique or modality used to treat the
patient can depend upon the patient's FA value.
[0032] In still further embodiments, the FA value may change over
the course of time and/or during the course of treatment.
Accordingly, the foregoing techniques may be applied at additional
points during the patient's treatment regimen to update the signal
delivery location and/or the treatment modality used to affect
neurons at the target location. Any of the foregoing techniques may
also be used to select or update signal delivery parameters other
than the target neural population. Such parameters can include the
signal frequency, amplitude (voltage and/or current), polarity
(anodal or cathodal) and/or delivery mode (e.g., unipolar or
bipolar).
[0033] Other techniques may be used in addition to the foregoing
techniques to not only identify the target neural population, but
identify one or more electrode locations that are expected to
deliver signals to the target location in a particular (e.g.,
efficient) manner. For example, a practitioner can use numerical
simulation techniques in combination with structural MRI data to
estimate the conductivity of the region around the target neural
population. Such techniques typically use the different electrical
characteristics of different substances and structures in the brain
(e.g., cerebral spinal fluid, neurons, connective tissue, vascular
structures and others) to estimate the conductivity of different
electrical paths. The practitioner can then select the position of
a cortical electrode to be one that results in the shortest and/or
lowest conductivity path to the target neural population. It is
expected that such an arrangement can reduce the power required to
deliver signals to the target neural population, and can
accordingly provide stimulation for a greater period of time before
it becomes necessary to replace or recharge the power supply that
powers the electrodes. This approach can also reduce or eliminate
the possibility of misdirected current creating unintended effects
at populations other than the target neural population. Similar
techniques may also be used to aid the practitioner in aligning the
electric field lines generated by one or more electrodes with
anatomical features. For example, these techniques can be used to
align field lines with the axons of neurons at the target neural
population.
[0034] FIG. 3 is a flow diagram illustrating a process 300 in
accordance with another embodiment of the disclosure. The process
300 can make use of naturally occurring connections between the
patient's DLPFC and other areas of the patient's brain to provide
information that is then used to screen the patient, identify a
target neural population, and/or update signal delivery parameters.
In a representative example, once a patient is identified as having
depression or another neuropsychological/neuropsychiatric disorder
(process portion 301), the practitioner can identify a baseline
level of excitability for a first area of the patient's brain that
does not include the patient's DLPFC. For example, the first area
of the patient's brain can include the patient's motor cortex or
sensory cortex. Process portion 303 includes performing several
functions for at least one second area of the patient's brain,
located at the patient's DLPFC. These functions can include
applying stimulation to the patient's DLPFC (process portion 305)
and, after applying stimulation to the patient's DLPFC, identifying
a change in the patient's excitability level at the first area of
the brain (process portion 306). Based at least in part on the
identified change in the patient's excitability level at the first
area, process portion 307 can include performing any of the
following functions: identifying the patient as a candidate for
cortical signal delivery (process portion 309), selecting a target
neural population to receive cortical signals (process portion
310), and/or updating cortical signal delivery parameters (process
portion 311). A representative example implementing an embodiment
of the process 300 shown in FIG. 3 is described below with
reference to FIG. 4.
[0035] FIG. 4 is a partially schematic illustration of a portion of
the patient's brain 220, identifying the DLPFC 224 and cortical,
non-DLPFC brain areas with which the DLPFC 224 communicates. These
areas can include the motor cortex 230 and the sensory cortex 231,
among others. The motor cortex 230 communicates with one or more of
the patient's muscles 233 (e.g., at the patient's arm or hand) via
the spinal cord 232. The sensory cortex 231 communicates with one
or more of the patient's sensory receptors 234 (e.g., the patient's
olfactory nerve). In some cases, e.g. for tactile sensory receptors
at the patients trunk or extremities, this communication also
occurs via the spinal cord 232. In a representative procedure, the
practitioner identifies a baseline level of excitability of the
patient's motor cortex, for example, by assessing the patient's
response to motor stimuli. The practitioner can then apply
excitatory or inhibitory stimuli to the DLPFC 224. For example, the
practitioner can apply rTMS signals to the patient for a period of
about 20 minutes. After stimulating the DLPFC 224, the practitioner
can again assess the patient's level of motor excitability, for
example, by applying single-pulse and/or paired-pulse signals
(e.g., TMS signals) to the patient's brain and assessing the
response level. Single pulse TMS signals may be used to assess a
direct effect of the DLPFC on the patient's level of motor
excitability, and paired-pulse TMS signals may be used to isolate
the effect of inhibitory and/or excitatory interneurons on the
patient's level of motor excitability. In any of these embodiments,
the foregoing procedure can be repeated for multiple sites at the
DLPFC 224, and one or more of these sites can be selected as a
target neural population, based upon the effect that stimulation at
the site has on the patient's level of motor excitability.
[0036] In particular embodiments, it is expected that locations of
the DLPFC 224 that have a greater effect on motor excitability than
others may be suitable candidates for cortical stimulation. Similar
techniques can be used to optimize and/or update the signal
delivery parameters used to provide therapy to the patient, after a
cortical stimulation device has been implanted in the patient. For
example, the effect of the stimulation on the patient's motor
excitability at a variety of parameter settings (e.g., stimulation
amplitude, polarity, and/or frequency) can be determined and, based
upon this determination, particular parameters can be selected or
eliminated. The same or a similar technique can be used during the
course of the patient's therapy to update signal delivery
parameters, for example, as the patient's body adapts to the
applied therapy, and/or as the functional level of the target
neural population changes as a result of therapy.
[0037] Many aspects of the foregoing process can be automated in
certain instances. For example, once the patient has received a
cortical implant, the patient can also receive one or more
implanted sensors located at the motor cortex or sensory cortex, or
at the patient's spine (e.g., at a cervical location), or at a
peripheral location (e.g., at the patient's muscle or sensory
receptor). The sensor(s) can identify changes in the level of
excitability at any of these locations and can be coupled to a
controller which is in turn coupled to electrodes implanted at the
DLPFC. Accordingly, the controller can automatically adjust the
signal delivery parameters applied to the electrodes at the DLPFC
as the patient's responses to therapeutic signals (or test signals)
provided by the electrodes change. This closed-loop arrangement can
operate in a semi-automated or fully automated manner to reduce or
eliminate the need for the patient or the practitioner to
continuously monitor patient performance and/or response to the
therapy.
[0038] In many instances, it is desirable to compare the state of a
patient when the patient is acutely depressed, to a baseline state
of the patient. This technique can be used to identify areas of the
brain that are active or inactive when a patient is depressed. For
example, the practitioner can obtain an image of the patient's
brain when the patient is acutely depressed, and compare that image
with one obtained when the patient is in a stable or baseline
condition. This technique can be used to identify the first region
of the brain described above with reference to FIG. 1, or, in
particular embodiments (assuming a high degree of resolution), this
technique can be used to identify the second region. In any of
these cases, the practitioner will obtain an image of the patient's
brain or the relevant portion of the patient's brain when the
patient is in the baseline or first state, then acutely affect the
patient's emotional or cognitive functioning, obtain a second image
while the patient is in the second state, and compare the
images.
[0039] A variety of techniques are expected to be suitable for
creating such an effect. For example, rapid tryptophan depletion,
which is presently used to identify depression patients suitable
for SSRI treatments, can be used to trigger an acute depression
condition. Sleep deprivation is another technique that can acutely
modulate depression (e.g., it can cause acute remission of
depression symptoms), as is hypnosis. In other cases, a patient can
be shown sad pictures to induce sadness, depression, or another
emotion. In still further cases, multiple sessions of rTMS can
acutely modulate the patient's depression response. For example,
rTMS can cause a reduction in depression symptoms, or a remission
of depression. A variety of imaging/visualization techniques can be
used to identify brain areas associated with the acute response.
These areas may be hypoactive or hyperactive. Such techniques can
include PET scans based on FDG or water analysis, perfusion MRI,
connectivity fMRI, and/or task-related fMRI (e.g., in which a
patient performs a cognitive or memory task).
[0040] In particular cases, the DLPFC or portions of the DLPFC are
expected to be hypoperfused and/or hypometabolic when the patient
is depressed, and thus a suitable target neural population can be
identified using measures of perfusion/blood flow and/or glucose
consumption. In other cases, patients with depression or major
depressive disorder (MDD) may have reduced glutamate, and/or
reduced glutamate/glutamine peaks, and/or reduced choline levels at
the frontal cortex, the DLPFC, and/or other cortical regions or
subregions. Magnetic resonance spectroscopy (MRS) is expected to be
suitable for identifying such areas as target neural populations
and/or identifying indications of recovery after therapeutic
treatments in accordance with the present disclosure.
[0041] In still another embodiment, EEG measurements may be used to
identify areas with increased and/or otherwise perturbed activity.
For example, EEG measurements may be used to detect increased gamma
and/or theta wave activity, which is expected to correlate with
depression. In particular cases, EEG measurements can detect
changes in brain activity induced by rTMS stimulation.
Representative Stimulation System Embodiments
[0042] Many aspects of various techniques or procedures described
above can be performed by suitable systems configured to deliver
cortical stimulation and, in certain cases, stimulation in
accordance with other modalities. FIG. 5 schematically illustrates
a representative cortical signal delivery system 250. The system
250 can include a pulse system 260 that is positioned external to
the patient's skull. For example, as shown in FIG. 5, the pulse
system 260 can be placed on the external surface of the patient's
skull 235, beneath the scalp. In another arrangement, the pulse
system 260 can be implanted at a subclavicular location. The pulse
system 260 can be controlled internally via pre-programmed
instructions that allow the pulse system 260 to operate
autonomously after implantation. In other embodiments, the pulse
system 260 can be implanted at other locations, and at least some
features of the pulse system 260 can be controlled externally. For
example, FIG. 5 illustrates an external controller 265 that
controls the pulse system 260.
[0043] FIG. 6 schematically illustrates details of an embodiment of
the pulse system 260 described above. The pulse system 260
generally includes a housing 261 carrying a power supply 262, an
integrated controller 263, a pulse generator 266, and a pulse
transmitter 267. In certain embodiments, a portion of the housing
261 may include a signal return electrode. The power supply 262 can
include a primary battery, such as a rechargeable battery, or other
suitable device for storing electrical energy (e.g., a capacitor or
supercapacitor). In other embodiments, the power supply 262 can
include an RF transducer or a magnetic transducer that receives
broadcast energy emitted from an external power source and that
converts the broadcast energy into power for the electrical
components of the pulse system 260.
[0044] In one embodiment, the integrated controller 263 can include
a processor, a memory, and/or a programmable computer medium. The
integrated controller 263, for example, can be a microcomputer, and
the programmable computer medium can include software loaded into
the memory of the computer, and/or hardware that performs the
requisite control functions. In another embodiment identified by
dashed lines in FIG. 6, the integrated controller 263 can include
an integrated RF or magnetic controller 264 that communicates with
the external controller 265 via an RF or magnetic link. In such an
embodiment, many of the functions performed by the integrated
controller 263 may be resident on the external controller 265 and
the integrated portion 264 of the integrated controller 263 may
include a wireless communication system.
[0045] The integrated controller 263 is operatively coupled to, and
provides control signals to, the pulse generator 266, which may
include a plurality of channels that send appropriate electrical
pulses to the pulse transmitter 267. The pulse transmitter 267 is
coupled to a signal delivery device 240, e.g., an electrode device
241 that carries electrodes 242. In one embodiment, each of these
electrodes 242 is configured to be physically connected to a
separate lead, allowing each electrode 242 to communicate with the
pulse generator 266 via a dedicated channel. Accordingly, the pulse
generator 266 may have multiple channels, with at least one channel
associated with each of the electrodes 242 described above.
Suitable components for the power supply 262, the integrated
controller 263, the external controller 265, the pulse generator
266, and the pulse transmitter 267 are known to persons skilled in
the art of implantable medical devices.
[0046] The pulse system 260 can be programmed and operated to
adjust a wide variety of stimulation parameters, for example, which
electrodes 242 are active and inactive, whether electrical
stimulation is provided in a unipolar or bipolar manner, signal
polarity, and/or how stimulation signals are varied. In particular
embodiments, the pulse system 260 can be used to control the
polarity, frequency, duty cycle, amplitude, and/or spatial and/or
topographical qualities of the stimulation. Representative signal
parameter ranges include a frequency range of from about 0.5 Hz to
about 125 Hz, a current range of from about 0.5 mA to about 15 mA,
a voltage range of from about 0.25 volts to about 20 volts (e.g.,
approximately 10 volts), and a first pulse width range of from
about 10 psec to about 500 psec The stimulation can be varied to
match, approximate, or simulate naturally occurring burst patterns
(e.g., theta-burst and/or other types of burst stimulation), and/or
the stimulation can be varied in a predetermined, pseudorandom,
and/or other aperiodic manner at one or more times and/or
locations.
[0047] In particular embodiments, the pulse system 260 can receive
information from selected sources, with the information being
provided to influence the time and/or manner by which the signal
delivery parameters are varied. For example, the pulse system 260
can communicate with a database 270 that includes information
corresponding to reference or target parameter values. Sensors can
be coupled to the patient to provide measured or actual values
corresponding to one or more parameters. The measured values of the
parameter can be compared with the target value of the same
parameter. Accordingly, this arrangement can be used in a
closed-loop fashion to control when stimulation is provided and
when stimulation may cease. In one embodiment, some electrodes 242
may deliver electromagnetic signals to the patient while others are
used to sense the activity level of a neural population. In other
embodiments, the same electrodes 242 can alternate between sensing
activity levels and delivering electrical signals. In either
embodiment, information received from the signal delivery device
240 can be used to determine the effectiveness of a given set of
signal parameters and, based upon this information, can be used to
update the signal delivery parameters and/or halt the delivery of
the signals.
[0048] In other embodiments, other techniques can be used to
provide patient-specific feedback. For example, a detection system
or device 280 such as a magnetic resonance chamber can provide
information corresponding to the locations at which a particular
type of brain activity is occurring and/or the level of functioning
at these locations, and can be used to identify additional
locations and/or additional parameters in accordance with which
electrical signals can be provided to the patient to further
increase functionality. Accordingly, the system can include a
direction component configured to direct a change in an
electromagnetic signal applied to the patient's brain based at
least in part on an indication received from one or more sources.
These sources can include a detection component (e.g., the signal
delivery device and/or the magnetic resonance chamber 280).
[0049] FIG. 7 is a top, partially hidden isometric view of an
embodiment of a signal delivery device 740, configured to carry
multiple cortical electrodes 742. The electrodes 742 can be carried
by a flexible support member 744 to place each electrode 742 in
contact with a stimulation site of the patient when the support
member 744 is implanted. Electrical signals can be transmitted to
the electrodes 742 via leads carried in a communication link 745.
The communication link 745 can include a cable 746 that is
connected to the pulse system 260 (FIG. 6) via a connector 747, and
is protected with a protective sleeve 748. Coupling apertures or
holes 749 can facilitate temporary attachment of the signal
delivery device 740 to the dura mater at, or at least proximate to,
a stimulation site. The electrodes 742 can be biased cathodally
and/or anodally. In an embodiment shown in FIG. 7, the signal
delivery device 740 can include six electrodes 742 arranged in a
2.times.3 electrode array (i.e., two rows of three electrodes
each), and in other embodiments, the signal delivery device 740 can
include more or fewer electrodes 742 arranged in symmetrical or
asymmetrical arrays. The particular arrangement of the electrodes
742 can be selected based on the region of the patient's brain that
is to be stimulated, and/or the patient's condition.
[0050] FIG. 8A is a schematic illustration of a first electrode
device 841a implanted above or upon a patient's middle frontal
gyrus 236 in accordance with an embodiment of the disclosure. The
first electrode device 841a includes a first electrode 842a and a
second electrode 842b that are carried by a substrate or support
member 844. The first and second electrodes 841a, 841b are coupled
to a pulse generator (not shown) in a manner understood by one of
ordinary skill in the art. In this embodiment, each electrode 842a,
842b is generally circular. Depending upon embodiment details, such
electrodes 842a, 842b can be approximately 0.5-4.5 mm (e.g., 3.75
mm) in diameter, and can have a center-to-center spacing of
approximately 10-40 mm (e.g., 15 mm, 18 mm, or another separation
distance). The centers of the first electrode 842a and the second
electrode 842b can be positioned to approximately intersect or
reside along or proximate to a line or an arc 243a that generally
bisects at least a portion of the middle frontal gyrus 236 into
superior and inferior portions. The particular position along line
243a can be determined by any of the foregoing techniques directed
to identifying target neural populations and associated stimulation
sites (e.g., electrode placement sites). Such techniques can also
be used to place the electrodes at other cortical locations,
including, but not limited to, those described below with reference
to FIGS. 8B-8C.
[0051] FIG. 8B is a schematic illustration of a second electrode
device 841b implanted above or upon a patient's middle frontal
gyrus 236 in accordance with another embodiment of the previously
described surgical implantation protocol. The second electrode
device 841b includes a support member 844 that carries a first, a
second, and a third electrode 842a, 842b, 842c and possibly an nth
electrode 842d, where n is greater than or equal to 4. In several
embodiments, the second electrode device 841b can be positioned
such that as many electrodes 842a-842d as possible reside above,
along, or proximate to a line or an arc 243b that generally bisects
at least a portion of the middle frontal gyrus 236 as the line or
arc 243b extends between the middle frontal gyrus 236 and the
central sulcus 237 in an anterior-posterior direction.
[0052] FIG. 8C is a schematic illustration of a third electrode
device 841c implanted above or upon a patient's middle frontal
gyrus 236 in accordance with yet another embodiment of the
aforementioned surgical implantation protocol. The third electrode
assembly 841c includes a support member 844 that carries a first
and a second row of electrodes 851, 852, where each electrode row
851, 852 includes at least a first electrode 842a and possibly up
to an n.sup.th electrode 842d. The third electrode device 841c can
be positioned such that each electrode row 851, 852 is
approximately equidistant from a line or arc 243c that extends
anteriorly from the central sulcus 237 and which approximately
bisects a portion of the middle frontal gyrus 236; or such that a
superior and an inferior electrode row 851, 852 are approximately
equidistant from the superior frontal sulcus 238 and the inferior
frontal sulcus 239, respectively.
[0053] In some embodiments, the electrode device 841c can include
electrodes 842a-842d that are arranged, organized, or positioned in
a curvilinear or arcuate manner rather than in a linear manner. An
arc along which electrodes 842a-842d are positioned can be
predefined such that the electrodes carried by an as-manufactured
electrode device will conform or approximate conform to the
curvature of a particular portion or section of a neuroanatomical
structure, such as the crown of the middle frontal gyrus spanning
Brodmann areas 9, 46, and/or 9/46.
[0054] A stimulation procedure directed toward the application of
extrinsic stimulation signals to treat neuropsychiatric dysfunction
can include one or more time periods in which each electrode of a
given electrode assembly is electrically active. Additionally or
alternatively, a stimulation procedure can include one or more time
periods in which particular electrode subsets carried by a given
electrode assembly are electrically active. The activation of each
electrode and/or one or more electrode subsets can depend upon the
type of neurologic dysfunction under consideration and/or the
patient's clinical response, imaging response, and/or
electrophysiologically measured (e.g., ECoG) response to the
applied stimulation signals.
[0055] In a representative example, the electrode device 841b shown
in FIG. 8B can have an initially active electrode subset that
includes the first, second, and third electrodes 841a-841c.
Depending upon the nature and/or extent of a patient's response to
the extrinsic stimulation signals (for instance, the presence or
absence of a noticeable or favorable acute response, and/or the
presence or absence of a beneficial or adverse response that arises
over the course of a number of weeks (e.g., 2-12 weeks)),
additional, one or more anterior electrodes 841d can be activated
at one or more times. Moreover, one or more most-posterior
electrodes 841a, 841b can be deactivated at one or more times,
and/or stimulation signals applied to such more-posterior
electrodes 841a, 841b at a reduced intensity or level in the event
that clinical, imaging, and/or electrophysiologic data indicates
that such electrodes 841a, 841b provide relatively less or little
contribution to therapeutic efficacy.
[0056] In a representative embodiment, the third electrode device
841c shown in FIG. 8C can include any given electrode subset that
is active at one or more times, with active electrodes located in
one or both electrode rows 851, 852. In certain situations, an
initial set or subset of electrodes carried by an electrode device
can be used to initially apply stimulation signals. Depending upon
embodiment details, the initial set of electrodes can include some
or all of the electrodes carried by the electrode device. After a
first time period during which the patient experiences a favorable
therapeutic response, particular electrodes (e.g., one or more
most-posterior electrodes) within the initial set of electrodes can
be activated at a reduced signal intensity, level, or duration, or
deactivated during a second time period, and the patient monitored
to determine whether a sufficiently high or adequate level of
therapeutic benefit is present. Such a stimulation procedure can
successively, over time, determine a minimum number of active
electrodes that are useful for achieving or maintaining therapeutic
efficacy. In the event that therapeutic efficacy changes or
degrades over time following a generally stable period of
therapeutic benefit, the foregoing stimulation procedure can be
repeated, or additional electrodes can be successively
(re)activated, until a sufficient or desired level of therapeutic
benefit occurs. For example, the patient's neuropsychological
stability may be adversely affected after several months, such as 6
or 12 months, possibly due to an event in the patient's life.
[0057] In several embodiments, a threshold signal intensity or
level corresponding to a given electrode subset can be determined
by applying stimulation signals to this electrode subset, and
measuring or estimating a minimum or near-minimum stimulation
signal level that gives rise to a predetermined or minimum degree
of change in neurocognitive task performance. A treatment signal
intensity or level that is applied to the patient during a therapy
period can be based upon a threshold signal level corresponding to
one or more electrode subsets. For instance, a treatment signal
level can be a given percentage of (e.g., approximately 20-95%, or
approximately 50%, 80%, or 90% of) the activation threshold signal
level corresponding to the particular electrode subset that gave
rise to the lowest threshold signal level relative to each
electrode subset considered. The threshold level can correspond to
a level (e.g., current level or voltage level) that causes action
potentials in a large enough portion of the target neural
population to produce the patient function associated with the
target neural population. During a therapy period, a treatment
signal can be applied to the particular electrode subset that gave
rise to this lowest threshold level, and/or one or more other
electrode subsets. In addition or as an alternative to the
foregoing, a treatment signal intensity can be a mathematical
function such as an average or a weighted average of a plurality of
threshold signal intensities, where in some embodiments a weighting
function can prioritize a threshold signal intensity associated
with neurons in particular neural locations (e.g., more anterior
neurons) more heavily than a threshold signal intensity associated
with neurons within other (e.g., more posterior) neural locations.
In yet other embodiments, a treatment signal can be or include a
set of pulses that are delivered approximately at or even slightly
above a threshold or expected threshold level.
[0058] Many of the foregoing embodiments include techniques for
identifying a target neural population, a target stimulation site,
stimulation parameters, stimulation modalities, and/or suitable
patients using functional techniques, alone or in combination with
techniques based on the structure of the patient's brain. An
expected advantage of these techniques is that they can more
accurately identify characteristics associated with a stimulation
therapy than can techniques that rely on brain structure alone. In
some cases, these techniques can eventually be correlated with
brain structures that are common from one patient to the next and,
in such cases, a practitioner can revert back to site
identification and/or other parameter selection on the basis of one
or more structures that are defined with a new level of precision.
In other cases, the foregoing techniques can continue to be used on
a patient-by-patient basis to more accurately identify the
stimulation characteristics.
[0059] From the foregoing, it will be appreciated that specific
embodiments of the disclosure have been described herein for
purposes of illustration, but that various modifications may be
made in other embodiments. For example, the practitioner may use
structurally based and/or functionally based techniques that differ
from those specifically described above. The practitioner may use
more than two levels of information to identify target neural
populations in at least some cases. In some cases, the practitioner
may produce an actual image upon which to base a parameter
selection, and in other cases, at least some aspects of the
parameter selection may be automated and/or may rely on the
underlying data used to produce the image without actually
producing the image itself. For example, fractional anisotropy
levels may be determined without the need for an actual image, and
regions of high tract density may be correlated with a location in
space (referenced to a fiducial or anatomic feature) again, without
the need for an actual image. The signals applied in any of the
foregoing methods can have a direct effect on the target neural
population that lasts for as long as the signal is active, or a
long-term effect that can enhance, enable, augment and/or otherwise
facilitate the patient's natural neuroplastic responses. Such long
term effects can last for days, weeks, months or years after the
stimulation has ceased.
[0060] Several examples were described above in the context of
depression, but the same or generally similar methodologies can be
used to address other neuropsychiatric/neuropsychological
conditions, including post-traumatic stress disorder (PTSD), eating
disorders and others identified previously. In still further
embodiments, the foregoing methods can be applied to patients
without disorders, e.g. to improve the cognitive functioning of a
normal or above-normal patient. Many of the foregoing techniques
may be applied on a case-by-case basis that is specific to
individual patients. However, as discussed above, after a
sufficient database (e.g., group atlas) has been established as a
result of collecting individual data, practitioners may in some
cases be able to circumvent certain steps over the course of time.
For example, practitioners may find that for certain conditions
(e.g., certain types of depression), the same area of the DLPFC,
(as identified by anatomical landmarks), is always or nearly always
a suitable target neural population.
[0061] Several examples were provided above with reference to
specific brain areas (e.g., Brodmann areas 10 and 25) and/or
specific loops (e.g., thalamocortical loops). In other embodiments,
similar techniques can be applied to other areas. For example, when
treating depression, the anterior cingulate cortex (ACC) may be
identified as a non-superficial component of the thalamocortical
loop that also includes the DLPFC. Accordingly, target cortical
neural populations may be selected on the basis of tract density
descending to the ACC.
[0062] Certain aspects of the invention described in the context of
particular embodiments may be combined or eliminated in other
embodiments. For example, aspects of the technique described in the
context of FIG. 1 may be combined with aspects of the technique
described in FIG. 3. Further, while advantages associated with
certain embodiments have been described in the context of those
embodiments, other embodiments may also exhibit such advantages and
not all embodiments need necessarily exhibit such advantages to
fall within the scope of the present disclosure.
* * * * *