U.S. patent application number 15/651600 was filed with the patent office on 2017-11-02 for apparatus for modulation of effector organs.
This patent application is currently assigned to The Research Foundation of the City University of New York. The applicant listed for this patent is The Research Foundation of the City University of New York. Invention is credited to Zaghloul Ahmed.
Application Number | 20170312505 15/651600 |
Document ID | / |
Family ID | 57324092 |
Filed Date | 2017-11-02 |
United States Patent
Application |
20170312505 |
Kind Code |
A1 |
Ahmed; Zaghloul |
November 2, 2017 |
APPARATUS FOR MODULATION OF EFFECTOR ORGANS
Abstract
Modulation of target effector organs in vertebrate beings using
direct current stimulation for stimulation of spinal cord at
regions of autonomic innervation, using direct current for
peripheral nerve stimulation, by modulating central autonomic
outflow and combinations thereof.
Inventors: |
Ahmed; Zaghloul; (Staten
Island, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The Research Foundation of the City University of New York |
New York |
NY |
US |
|
|
Assignee: |
The Research Foundation of the City
University of New York
New York
NY
|
Family ID: |
57324092 |
Appl. No.: |
15/651600 |
Filed: |
July 17, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15190080 |
Jun 22, 2016 |
9707390 |
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15651600 |
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15046797 |
Feb 18, 2016 |
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15190080 |
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14579829 |
Dec 22, 2014 |
9283391 |
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15046797 |
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62092214 |
Dec 15, 2014 |
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61925423 |
Jan 9, 2014 |
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61919806 |
Dec 22, 2013 |
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62183045 |
Jun 22, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F 7/10 20130101; A61F
7/08 20130101; A61N 1/205 20130101; A61N 2/006 20130101; A61N
1/36007 20130101; A61N 2/002 20130101; A61N 1/20 20130101; A61N
1/3616 20130101; A61N 1/0456 20130101; A61N 1/0551 20130101; A61N
1/0514 20130101; A61N 1/36003 20130101 |
International
Class: |
A61N 1/20 20060101
A61N001/20; A61N 2/00 20060101 A61N002/00; A61N 1/36 20060101
A61N001/36; A61N 1/36 20060101 A61N001/36; A61N 1/20 20060101
A61N001/20; A61F 7/08 20060101 A61F007/08; A61N 1/05 20060101
A61N001/05; A61N 1/05 20060101 A61N001/05; A61N 1/04 20060101
A61N001/04; A61F 7/10 20060101 A61F007/10; A61N 2/00 20060101
A61N002/00; A61N 1/36 20060101 A61N001/36 |
Claims
1. A system for modulating activity of an autonomically-innervated
effector organ in a vertebrate being, the system comprising: a
first housing including a first DC power source that provides
direct current between power terminals of opposite polarity; a
first stimulation component including a spinal stimulation circuit
coupled to the power terminals and having an identified spinal
signal output connection and an identified spinal reference
connection, both on said housing, and configured to provide a
constant direct current spinal stimulation signal between a first
active electrode located at a spinal location associated with
efferent neural outflow to the autonomically-innervated effector
organ and a second return electrode for spinal direct current
stimulation associated with modulation of the activity of the
autonomically-innervated effector organ; a second housing including
a second DC power source that provides direct current between power
terminals of opposite polarity; and a second stimulation component
including a neural stimulation circuit coupled to the power
terminals of the second DC power source and having an identified
neural signal output connection and an identified neural reference
connection, both connections on said housing, that provides a
constant direct current neural stimulation signal between third
electrode and a fourth electrode configured to be attached across a
section of a nerve associated with the autonomically-innervated
effector organ.
2. The system of claim 1, wherein said autonomically-innervated
effector organ is the bladder.
3. The system of claim 2, wherein said spinal location is at spinal
level S2-S4 or at spinal level T11-L2.
4. The system of claim 1, wherein said second electrode is
positioned at an exterior abdominal location or iliac crest.
5. The system of claim 1, wherein at least one of the first
electrode and the second electrode is implanted.
6. The system of claim 1, wherein said second electrode is
positioned within the bladder trans-urethrally.
7. The system of claim 1, wherein said system is implanted.
8. The system of claim 1, further comprising an implanted feedback
device.
9. The system of claim 1, wherein said autonomically-innervated
effector organ is the bladder and said implanted feedback device is
a bladder pressure sensor.
10. The system of claim 1, wherein said signal-providing component
is transcranial direct current stimulation.
11. The system of claim 1, wherein said signal-providing component
is transcutaneous vagal nerve stimulation.
12. The system of claim 1, wherein said signal-providing component
is transcranial magnetic stimulation.
13. The system of claim 1, wherein said signal-providing component
is temperature stimulation.
14. The system of claim 1, wherein said signal-providing component
is a pharmacological agent.
15. The system of claim 1, wherein said first DC power source
communicates wirelessly with said second DC power source.
16. A method for modulating activity of an autonomically-innervated
effector organ in vertebrate beings, the method comprising:
applying a source of direct current to a spinal location associated
with efferent neural outflow to the autonomically-innervated
effector organ.
17. The method of claim 16, further comprising: applying a source
of pulsed direct current to a nerve providing neural control of
muscles of the autonomically-innervated effector organ.
18. The method of claim 17, further comprising: modulating central
autonomic outflow.
19. The method of claim 16, further comprising: modulating central
autonomic outflow.
20. The method of claim 16, wherein the activity of an
autonomically-innervated effector organ is bladder function.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of co-pending U.S.
application Ser. No. 15/190,080, filed Jun. 22, 2016, entitled
APPARATUS FOR MODULATION OF EFFECTOR ORGANS, which in turn is a
continuation-in part of co-pending U.S. application Ser. No.
15/046,797, filed Feb. 18, 2016, which is a continuation of U.S.
application Ser. No. 14/579,829, filed Dec. 22, 2014, now U.S. Pat.
No. 9,283,391, which claims priority of U.S. Provisional
Application Ser. No. 62/092,214, filed Dec. 15, 2014, U.S.
Provisional Application Ser. No. 61/925,423, filed Jan. 9, 2014,
and U.S. Provisional Application Ser. No. 61/919,806, filed Dec.
22, 2013. U.S. application Ser. No. 15/190,080 also claims priority
to U.S. Provisional Application Ser. No. 62/183,045, filed Jun. 22,
2015. All of the foregoing are incorporated herein by reference in
their entirety for all purposes.
FIELD
[0002] The present invention relates to method and apparatus for
modulating and regulating autonomically-innervated effector organs,
such as modulation and regulation of bladder function.
BACKGROUND
[0003] The nervous system includes the Central Nervous System (CNS)
and the Peripheral Nervous System (PNS), the latter including the
Somatic Nervous System (SNS) and Autonomic Nervous System (ANS).
The CNS includes the brain and the spinal cord. The spinal cord is
the main communication route for signals between the body and the
brain. The SNS and ANS overlap the CNS and PNS. There are 31 pairs
of spinal nerves arising from cervical (8), thoracic (12), lumbar
(5), sacral (5) and coccygeal (1) segments. The spinal nerves
contain both sensory and motor fibers. Efferent nerves (as opposed
to afferent nerves) are the nerves leading from the central nervous
system to an effector organ, and efferent neural signals refer to
neural signals from the brain that are transmitted via spinal cord
pathways to effector organs. Afferent nerves are the nerves leading
to the central nervous system, and afferent neural signals refer to
neural signals being transmitted to the brain.
[0004] The ANS consists of two divisions, the sympathetic nervous
system and the parasympathetic nervous system, FIG. 1, and is
responsible for regulating bodily functions including heart rate,
respiration, digestion, bladder tone, sexual response and other
functions. Activation of the sympathetic nervous system results in
preparation of the body for stressful or emergency situations,
while activation of the parasympathetic nervous system results in
conservation and restoration and controls body processes during
normal situations. For specific organs that are innervated by the
autonomic nervous system, it is well known which spinal levels are
involved. FIG. 2 shows segmental sympathetic and parasympathetic
innervation of various organs. Parasympathetic innervation is
either through the vagus nerve (cranial nerve X) or at the sacral
levels (S2-S4). Sympathetic preganglionic neurons either synapse in
the sympathetic chain ganglia or project through the sympathetic
chain ganglia and synapse at various ganglia such as superior
mesenteric ganglia or inferior mesenteric ganglia. The
post-ganglionic neuron then projects to the end organ that it
innervates. Parasympathetic pre-ganglionic neurons (from cranial
nerve X and below) synapse very close to the organ they innervate
and usually in a nerve plexus attached to the organ, and synapse
with a post-ganglionic neuron that sends projections to the organ.
The autonomic nervous system includes both sensory and motor
neurons.
[0005] The ability to activate or inhibit either the sympathetic or
parasympathetic nervous system would enable the regulation of
numerous bodily functions and enable the treatment of specific
disorders related to dysfunction of either the sympathetic or
parasympathetic system. Normal functions that are potentially
regulated by modulation of sympathetic or parasympathetic activity
include modulating bronchodilation in the airways, modulating
vasoconstriction in the skin and organs, stimulating
gluconeogenesis and glucose release from the liver, stimulating
secretion of epinephrine and norepinephrine by the adrenal gland,
modulation of sweating, slowing or increasing heartrate and pumping
efficiency, modulating tidal volume and rate of respiration,
slowing or increasing intestinal processes involved with digestion,
modulating urine production, modulating bladder contraction,
modulating sphincter control, stimulating erection and sexual
arousal, and numerous others. Beyond modulating normal functions,
there are numerous disorders of the ANS that have been described
and are referred to as dysautonomias, and is due to failure or
disruption of either the sympathetic or parasympathetic divisions
of the ANS. Specific such disorders include autoimmune autonomic
ganglionopathy, congenital central hypoventilation syndrome,
familiar dysautonomia, Holmes-Adie syndrome, multiple system
atrophy, Shy-Drager syndrome, neurally mediated syncope,
orthostatic hypotension, postural tachycardia syndrome,
striatonigral degeneration and vasovagal syncope. Elevated
sympathetic tone has been linked to disorders such as heart
failure, hypertension, obesity, obstructive sleep apnea, diabetes,
migraine, parkinsonian symptoms, septic shock, primary
hyperhidrosis, complex regional pain syndrome and numerous
others.
[0006] As there are many disorders and dysfunctions associated with
abnormal regulation of autonomically-innervated effector organs,
the ability to regulate the autonomic nervous system would enable
important new therapeutic strategies. We have developed novel
approaches to modulating the autonomic nervous system using various
implementations of trans-spinal direct current stimulation
(tsDCS).
[0007] The bladder is one example of an autonomically controlled
organ. The bladder functions as a reservoir and is responsible for
storing urine that has been formed by the kidneys in the process of
eliminating metabolites and excess water from the blood. The stored
urine is released via the urethra in the process of
micturition.
[0008] The pathways mediating neural control of bladder function
are well established and include sympathetic, parasympathetic and
somatic pathways. Referring to FIG. 3, sympathetic control of the
bladder is from sympathetic efferents from T11-L2 that run via the
sympathetic trunk and the splanchnic nerves to the inferior
mesenteric ganglion. Post-ganglionic fibers contribute to the
hypogastric plexus and reach the bladder where they synapse on the
detrusor muscle, and also synapse on the sphincter vesicae at the
bladder neck. Parasympathetic control is from parasympathetic
fibers that arise from S2-S4 and travel via the pelvic splanchnic
nerves to synapse on post-ganglionic neurons located in a dense
plexus among the detrusor smooth muscle cells in the wall of the
bladder. Post-ganglionic parasympathetic fibers cause contraction
of the bladder detrusor muscle and relaxation of the sphincter
vesicae. The external urethral sphincter (EUS) consists of striated
muscle and is under voluntary control via alpha motor neurons in
Onuf's nucleus in the ventral horns of S2-S4. Afferent responses
from bladder stretch receptors enter the spinal cord at T11-L2 and
also S2-S4 where they travel up to brainstem areas. Sensory fibers
in the urethral wall respond to urinary flow by causing firing of
their cell bodies located in dorsal root ganglia, which synapse on
neurons in the spinal cord dorsal horn. These sensory fibers travel
to the spinal cord via the pudendal nerve, and transection of this
sensory nerve reduces bladder contraction strength and voiding
efficiency.
[0009] Urinary retention is an inability to empty the bladder
completely and can be acute or chronic. Retention can be due to
numerous issues, including constipation, prostatic enlargement,
urethral strictures, urinary tract stones, tumors, and nerve
conduction problems. Such nerve conduction problems are seen in
brain and spinal cord injuries, diabetes, multiple sclerosis,
stroke, pelvic surgery, heavy metal poisoning, aging and
idiopathically. These result in either weak bladder contraction
and/or excess sphincter activation. As such, modulation strategies
that enable improved emptying of the bladder are of therapeutic
interest.
[0010] Urinary incontinence is loss of bladder control leading to
mild leaking all the way up to uncontrollable wetting. It results
from weak sphincter muscles, overactive bladder muscles, damage to
nerves that control the bladder from diseases such as multiple
sclerosis and Parkinson's disease, and can occur after prostate
surgery. As such, modulation strategies that treat urinary
incontinence are of therapeutic interest.
[0011] Neurogenic bladder refers to bladder malfunction due to any
type of neurological disorder, which can include stroke, multiple
sclerosis, spinal cord injury, peripheral nerve lesions and
numerous other conditions. Following a stroke, the brain often
enters a cerebral shock phase, and the urinary bladder will be in
retention (or detrusor areflexia). Around 25% of stroke patients
develop acute urinary retention. Following the cerebral shock
phase, the bladder often shows detrusor hyperreflexia, and the
patient will have urinary frequency, urgency and urge incontinence.
In multiple sclerosis, the most common urological dysfunction is
detrusor hyperreflexia, occurring in as many as 50-90% of patients
with MS. Detrusor areflexia is seen in 20-30% of patients, so
treatment must be individualized based on urodynamic findings. In
spinal cord injuries occurring from motor vehicle or diving
accidents, an initial response of spinal shock is seen in which
patients experience flaccid paralysis below the level of injury,
and experiences urinary retention consistent with detrusor
areflexia. Spinal shock phase lasts usually 6-12 weeks but may be
prolonged. During this period, the urinary bladder often must be
drained with either intermittent catheterization or an indwelling
catheter. Following the spinal shock phase, bladder function
returns, however with an increase in excitability, and results in
detrusor hyperreflexia. Peripheral nerve lesions can be due to
diabetes mellitus, herpes zoster, neurosyphilis, herniated lumbar
disk disease, pelvic surgery and other conditions, and can result
in detrusor areflexia. There is a continuing and unmet need for
improved ability to impose beneficial control over behavior of end
effectors. Embodiments of the present invention are variously
directed to meeting such need.
SUMMARY OF THE INVENTION
[0012] As there are many disorders and dysfunctions related to the
nervous system, such as those associated with abnormal regulation
of autonomically-innervated effector organs, the ability to
regulate related parts of the nervous system, such as the autonomic
nervous system, enables new therapeutic strategies and
interventions. We disclose novel systems, devices, apparatuses and
methods for modulating parts of the nervous systems using various
implementations of trans-spinal direct current stimulation (tsDCS)
and we provide new therapeutic strategies and interventions for
modulation of bladder and other organs using trans-spinal direct
current stimulation.
[0013] Therefore the present invention relates to methods and
systems utilizing trans-spinal direct current stimulation for
modulation of target effector organs. Illustrative embodiments of
this disclosure are directed to application of tsDCS to modulation
of effector constituents of the autonomic nervous system (ANS), and
illustrative embodiments include method and apparatus for treatment
of bladder dysfunctions. Such disclosure is by way of illustration
and not by way of limitation of the scope of the present invention
to other organs.
[0014] We apply tsDCS in various configurations. In some
embodiments, we use tsDCS by itself. In other embodiments, we use
coordinated multi-site neurostimulation that incorporates tsDCS
together with stimulation at other site(s) along the neural
axis.
[0015] In a double-stimulation configuration, we provide
simultaneous spinal tsDCS stimulation together with a second
stimulation. In one embodiment we provide tsDCS spinal stimulation
combined with direct current peripheral stimulation of a nerve
leading to a targeted effector organ. In an alternative
double-stimulation configuration, we provide simultaneous spinal
stimulation together with a second stimulation that modulates
central autonomic outflow.
[0016] In a triple-stimulation configuration, we provide
simultaneous stimulation of cerebral, spinal and peripheral sites
serving target effector organs, e.g., organs such as the bladder or
external urethral sphincter (EUS). Through such coordinated
multi-site neurostimulation, the descending cortical signals are
amplified by spinal-level tsDCS to drive stronger responses at the
target effector organ. This approach effectively stimulates neural
pathways and enables delivery of stronger cortical signals to drive
stronger effector responses.
[0017] In one embodiment, method and system for modulating function
of the autonomic nervous system in a vertebrate being is provided,
including a primary stimulation component which initiates central
autonomic outflow, and a second stimulation component which
modulates descending autonomic pathways at the level of the spinal
cord. A further embodiment includes a primary stimulation component
that includes either transcranial direct current stimulation,
transcutaneous vagal nerve stimulation, transcranial magnetic
stimulation, cold/hot pressors, oral or transdermal pharmaceutical
agents, visual stimuli, auditory stimuli, olfactory stimuli or
other forms of stimulation. In some embodiments, the secondary
stimulation component comprises trans-spinal direct current
stimulation and the autonomic outflow is either sympathetic outflow
or parasympathetic outflow.
[0018] A further method and system for modulating function of the
autonomic nervous system in a vertebrate being is provided,
including a primary stimulation component which initiates central
autonomic outflow, a second stimulation component which modulates
descending autonomic pathways at the level of the spinal cord, and
a third peripheral stimulation component which stimulates a nerve
leading to a target effector organ.
[0019] In embodiments of the invention we incorporate a wearable
tsDCS controller that modulates descending autonomic signals
traversing the spinal cord. In some embodiments, this is combined
with an implanted electrode that directly stimulates the nerve to a
targeted effector organ. The implanted electrode is in wireless
communication with the wearable tsDCS controller. This stimulation
is selected as either excitatory or inhibitory in practices of the
invention.
[0020] This approach is sufficient for certain applications. In
other applications, it is beneficial to directly modulate central
autonomic outflow before spinal level modulation via tsDCS. In
several practices of the invention, we increase or decrease
sympathetic outflow, or increase or decrease parasympathetic
outflow. Furthermore, in particular embodiments we provide
non-invasive and non-pharmacological modulation of autonomic
outflow for control and treatment of autonomically-related
functions and disorders. In other embodiments, we provide
pharmacological modulation of autonomic outflow for control and
treatment of autonomically-related functions and disorders.
[0021] We apply tsDCS in various configurations. In embodiments of
the invention, the stimulation applied to the spine is a continuous
constant current direct current signal. For practical reasons, this
constant tsDCS signal is ramped at the beginning and end of
application to reduce local induced stimulation artifacts. In some
embodiments this is a pulsed signal which delivers an equivalent
continuous constant-current signal to the stimulation site.
[0022] In various embodiments, the tsDCS spinal stimulation is
applied with an active electrode at the spine being driven as
either anode or cathode and cooperating with its complimentary
return electrode to define the spinal circuit. The distal neural
stimulation, sometimes referred to as peripheral direct current
stimulation (pDCS) is applied with the distal active electrode at a
nerve to the target effector organ being driven as either anode or
cathode at the opposite polarity of the active spinal electrode,
and also cooperating with the distal complementary return electrode
to define the distal peripheral circuit between these electrodes.
These spinal and peripheral stimulation circuits are energized and
during such energized state create a resulting circuit between the
active spinal electrode and the active neural electrode. This forms
an active resulting anode-cathode pair, with the resulting current
flow between this energized pair during the stimulation period
favorably polarizing the connecting neural pathway down to the
nerve at target effector organ. The result of applying such
stimulation is to modulate neural transmission from spinal cord to
the target effector organ, resulting in modulation of function at
the target effector organ.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] The above illustrative and further embodiments are described
below in conjunction with the following drawings, where
specifically numbered components are described and will be
appreciated to be thus described in all figures of the
disclosure:
[0024] FIG. 1 shows the two divisions of the Autonomic Nervous
System: the sympathetic nervous system and the parasympathetic
nervous system;
[0025] FIG. 2: shows segmental sympathetic and parasympathetic
innervation of various organs;
[0026] FIG. 3: shows well-known pathways mediating neural control
of bladder function;
[0027] FIG. 4A: shows illustrative stimulator devices in practice
of embodiments of the invention;
[0028] FIG. 4B: shows common TMS magnetic stimulator with
figure-eight probe in practice of embodiments of the invention;
[0029] FIGS. 5A-C: show illustrative wearable and implantable
components and configurations, including a closed-loop system, in
practice of embodiments of the invention;
[0030] FIG. 6A-B: shows surgical placement of cysostomy tube into
the bladder to enable measurement of bladder pressures and urine
output, in practice of embodiments of the invention;
[0031] FIG. 7A: shows bladder pressures and the frequency of
voiding and non-voiding contractions measured at baseline prior to
stimulation with cathodal tsDCS, in practice of embodiments of the
invention;
[0032] FIG. 7B: shows spinal to bladder tsDCS stimulation that
initiated bladder retention and voiding reflex in a vertebrate
being with severe chronic spinal cord injury, in practice of
embodiments of the invention;
[0033] FIG. 7C: shows bladder reflexes in subjects with acute
complete spinal cord injury and the effects of tsDCS, in practice
of embodiments of the invention;
[0034] FIG. 8: shows treatment of patient with a condition of
urinary incontinence involving detrusor hyperreflexia treated by
application of tsDCS in a configuration that decreases
parasympathetic tone, in practice of embodiments of the
invention;
[0035] FIG. 9: shows return electrode is positioned within the
bladder trans-urethrally, in practice of embodiments of the
invention;
[0036] FIGS. 10 and 11: show a subject with a condition of urinary
incontinence treated by application of tsDCS in a configuration
that increases sympathetic tone with an anodal return electrode
abdominally positioned anteriorly (FIG. 10) and at an and with the
return electrode positioned within the bladder trans-urethrally
(FIG. 11), in practice of embodiments of the invention;
[0037] FIG. 12 shows spinal stimulations which increase
parasympathetic outflow to the bladder combined with electrical
stimulation of the parasympathetic preganglionic fibers in pelvic
nerve, with cathodal tsDCS applied at S2-S4, in practice of
embodiments of the invention;
[0038] FIG. 13: shows spinal stimulations which increase
parasympathetic outflow to the bladder combined with electrical
inhibition of the pudendal nerve that innervates the EUS using
implanted electrodes, with cathodal tsDCS applied at S2-S4, in
practice of embodiments of the invention;
[0039] FIG. 14: shows spinal stimulations which increase
parasympathetic outflow to the bladder combined with electrical
stimulation of the pudendal nerve using implanted electrodes, with
cathodal tsDCS applied at S2-S4, in practice of embodiments of the
invention;
[0040] FIG. 15: shows cathodal spinal stimulations increase
sympathetic outflow to the bladder combined with implanted
microstimulator electrodes which stimulate the pudendal nerve, with
cathodal spinal stimulations at T11-L2, in practice of embodiments
of the invention;
[0041] FIG. 16: shows cathodal spinal stimulations which increase
sympathetic outflow to the bladder combined with implanted
electrodes which are applied to inhibit the parasympathetic
preganglionic fibers of the pelvic splanchnic nerves, with cathodal
spinal stimulations at T11-L2, in practice of embodiments of the
invention;
[0042] FIG. 17: shows non-invasive tDCS coupled with tsDCS at the
relevant spinal level to modulate autonomic outflow, with
sympathetic outflow from the brain increased by anodal tDCS over
the primary motor cortex and further increased at the spinal level
of the targeted effector organ by cathodal tsDCS at the high
thoracic level, in practice of embodiments of the invention;
[0043] FIG. 18A-B: shows transcutaneous vagal nerve stimulation
(tVNS) and an embodiment where auricular stimulation is combined
with a wearable tsDCS controller, in practice of embodiments of the
invention;
[0044] FIG. 19: shows pharmacological autonomic modulators, in
practice of embodiments of the invention; and
[0045] FIG. 20: shows a triple-stimulation approach in practice of
embodiments of these teachings, in practice of embodiments of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0046] The description is not to be taken in a limiting sense, but
is made merely for the purpose of illustrating the general
principles of these teachings, since the scope of these teachings
is best defined by the appended claims.
[0047] As used herein, the singular forms "a," "an," and "the"
include the plural reference unless the context clearly dictates
otherwise.
[0048] The following definitions pertain to the present disclosure,
with the understanding that such may be modified by context of use.
For purposes of the teaching of the present teachings:
[0049] The term "nerves" may be referred to herein as including
nerves, neurons, motor neurons and interneurons and the like, and
are generally referred to herein as "nerves" or "neurons";
[0050] The terms or concepts of nerve stimulation and neural
stimulation are used liberally and interchangeably to describe
applications of the stimulation of the teachings;
[0051] The terms neuromodulation, modulation, stimulation and
regulation are used interchangeably as equivalents for purposes of
this disclosure and indicate an effect imposed upon a target in
practice of present teachings;
[0052] The terms dysfunction, disorder, defect and abnormality are
used interchangeably as equivalents for purposes of this disclosure
and indicate the concept of medically recognized conditions
suitable for medical intervention:
[0053] The term effector organ refers to a neurally-innervated
organ that produces an effect in response to nerve stimulation.
Muscles are included within such definition for purposes of this
disclosure. The effects of stimulation of the present teachings
upon an effector organ or muscle may be discussed interchangeably
for purposes of inclusive discussion of the present teachings.
[0054] The term "stimulation," as used herein, refers to either
excitation or inhibition of nerve fibers, also referred to as up
regulation or down regulation.
[0055] The term "electrical stimulation," as used herein refers to
the production or introduction of current into spinal nerve,
neuron, circuit or pathway, whether by applying a voltage or
magnetically inducing a current.
[0056] Improved method and apparatus for neuromodulation and
regulation of effector organs are disclosed herein below.
[0057] In practice of embodiments of the invention, we provide
benchtop, wearable or implantable systems for modulating the
components of the nervous system, including effector organs.
Strategies that provide spinal stimulation via tsDCS
(mono-stimulation), spinal stimulation via tsDCS combined with
either peripheral stimulation or stimulation of central autonomic
outflow (double-stimulation), and spinal stimulation via tsDCS
combined with peripheral stimulation and stimulation of cortex
(e.g., motor cortex) or central autonomic outflow
(triple-stimulation), are disclosed. In illustrative embodiments
herein, we disclose methods and apparatus that apply these
strategies to modulate the autonomic nervous system and to regulate
autonomically-innervated effector organs such as the bladder. These
strategies treat nervous system conditions, including bladder
incontinence and bladder retention.
[0058] In practice of embodiments of the invention, we provide
benchtop, wearable or implantable systems for modulating the
components of the nervous system, including effector organs.
Strategies provide spinal stimulation by applying tsDCS on its own
(mono-stimulation), or tsDCS spinal stimulation combined with
peripheral stimulation (double-stimulation), or tsDCS spinal
stimulation combined with cerebral stimulation
(double-stimulation), or tsDCS spinal stimulation combined with two
other stimulations, which may include peripheral stimulation and
cerebral stimulation (triple-stimulation), are disclosed. In
illustrative embodiments herein, we disclose methods and apparatus
that apply these strategies to modulate the autonomic nervous
system and to regulate autonomically-innervated effector organs
such as, but not limited to, the bladder. These strategies treat
nervous system conditions, including bladder incontinence and
bladder retention.
[0059] FIG. 4A shows illustrative stimulator devices 10, 12, 14
which may be utilized in various practices of the invention. These
devices include a tsDCS stimulation device 10 which may be used on
its own to deliver a tsDCS mono-stimulation treatment or in
combination with additional stimulation devices 12 and/or 14 to
provide various double and triple stimulation treatments, in
several embodiments of the invention.
[0060] tsDCS stimulator device 10 delivers trans-spinal direct
current stimulation to a spinal location neurally associated with a
distal effector organ of interest, and more particularly associated
with function of a target effector organ, such as the bladder. In
various embodiments the stimulation supplied by stimulator device
10 provides monopolar, and an essentially or effectively
continuous, constant, non-varying direct current stimulation of a
selected polarity, in a range of 0.5 to 5 or 6 mA, typically 1-4.5
mA. Stimulator device 10 illustrates a tsDCS component in
embodiments of the invention. In this illustration, device 10
includes a computing and synchronizing unit 16, for provision of a
system control function, and including a signal polarity and
function controller 18, and having a system memory 19. The second
stimulator device 12 provides a known transcranial direct current
(tDCS) stimulation source of pulsed or constant direct current
stimulation to the cortex area C, having a circuit 20 for signal
computing and synchronizing, and for control of signal polarity and
function, integrated with resident memory 19. In an alternative
embodiment, repetitive pulsed magnetic stimulation (rTMS) is
provided to the cortical area C by a TMS magnetic stimulator 12A
using a figure-eight probe 22, as shown in FIG. 4B, as will be
understood by a person skilled in the art.
[0061] In an illustrative embodiment, pulsed electrical stimulation
of the motor cortex in an adult ranges at 100-400 mA, typically
around 200 mA, pulse width of 100-300 microseconds, typically
around 200 ms, 0.5 to 3 Hz repetition rate, operating voltage
400-800. For a child, 70-100 milliamps at 100 microseconds is a
target. Magnetic stimulation is alternatively applied, and in an
illustrative pulsed TMS embodiment, magnetic stimulation is
delivered at a rate of 0.5 to 3 Hz, 200 microsecond pulse width,
reaching stimulation current levels equivalent to the electrical
stimulation, as will be understood by a person skilled in the art.
In one TMS practice of the invention, rTMS is applied with a
magnetic flux density of 1.0 to 1.5 Tesla.
[0062] The third stimulator device 14 is a source of direct current
stimulation to stimulate a peripheral location of interest,
typically for stimulation of a nerve leading to a target effector
organ of interest, such as the bladder, and which may include
non-varying or pulsed direct current stimulation. This stimulator
device 14 includes a circuit 23 for signal computing and
synchronizing and for control of signal polarity and function, with
resident memory. An illustrative peripheral constant direct current
stimulation is applied at levels of 1-5 mA for double stimulation
and with pulsed peripheral intensity typically ranges is from 5 to
40 mA for triple stimulation. In a bladder treatment of the
invention, continuous tsDCS is applied to the Onuf's nucleus in the
sacral region of the spinal cord, with typical intensity in the
range from 1-4.5 mA.
[0063] All three of devices 10, 14, 12, are shown having an I/O
component for external signal connection, such as with electrodes,
24, 26, 30, 32, and 34, 36, respectively, providing +/- terminals
for electrode connection. Each unit is also provided with a
communication component 40, which enables data links 42 for wired
or wireless communication between the devices or with other
external devices. In this illustration, all three devices 10, 12,
14 have a user interface with microprocessor unit 44 and a power
supply P, such as rechargeable batteries.
[0064] The tsDCS stimulator device 10 is engaged on its own when
tsDCS mono-stimulation is provided. For double stimulation, the
tsDCS stimulator device 10 is engaged along with another
stimulation source, such as provided by the cortical stimulator
device 12 in one practice or by the peripheral stimulator device 14
in another practice of the invention. In one practice
double-stimulation is provided by two independent or isolated
circuits with the same or paired stimulation devices.
[0065] As will be appreciated by a person skilled in the art, in
several embodiments, where constant current stimulation is to be
delivered to the patient, the two cooperating stimulation sources,
such as devices 10 and 14 share a common ground in order to enable
an efficient control function as the circuits attempt to maintain
assigned signal levels over time in the presence of changing
resistance of the current path(s) within the patient.
[0066] In some embodiments, the tsDCS stimulator device 10 is
engaged to provide tsDCS in a triple-stimulation embodiment, in
cooperation with other two stimulation sources, such as with the
cortical stimulator device 12 and the peripheral stimulator device
14. In an illustrative embodiment, the tsDCS triple-stimulation
includes pulsed stimulation at the cortex, constant stimulation at
the spine and pulsed stimulation at the peripheral location.
[0067] Referring to FIG. 4A, a person to be treated is shown from
the back. Three sets of electrode connections are shown as would be
used during an illustrative triple stimulation practice of the
invention. Electrodes will be applied in locations discussed
below.
[0068] As an illustration only, in a tsDCS triple stimulation
embodiment, the cortical stimulator 12 provides transcortical
direct current (tDCS) stimulation as a source of direct current to
the local cortical area C via active cortical electrode 34 and
return (also called "reference") electrode 36. The stimulation path
34-36 is defined between the two electrodes to stimulate the local
cortex area C which is associated with the intended stimulation of
a target effector organ of interest, such as bladder 21 (indicated
by dotted symbol). In an alternative embodiment, repetitive pulsed
magnetic stimulation (rTMS) is supplied to cortical area C by a
probe 22 of a TMS magnetic stimulator 12A shown in FIG. 4B, for
application of known pulsed cortical stimulation, as will be
understood by a person skilled in the art.
[0069] The tsDCS stimulator 10 delivers trans-spinal direct current
mono-stimulation to a spinal location 15 associated with neural
outflow associated with a target effector organ, such as at the
bladder. The spinal active electrode 24 is applied at spinal
location 15 and a return electrode 26 is located distal to the
spinal area, such as at an anterior aspect of the body. In this
embodiment, a spinal stimulation circuit 17 is defined between
these two electrodes with the stimulation current traversing the
spinal processes at that location as a stimulation path of
interest.
[0070] The third stimulator 14 provides peripheral direct current
stimulation to stimulate a nerve leading to a target effector organ
or a nerve of the target effector organ, such as the bladder 21. In
one embodiment, the stimulation signal is monopolar and pulsed. In
another embodiment the stimulation signal is monopolar and
constant.
[0071] An illustrative embodiment of the invention includes method
and system having a single tsDCS stimulation circuit, for
mono-stimulation of the spinal cord, and defined by placing an
electrode at the spinal location of interest and a return electrode
on the anterior aspect of the body, thus defining a pathway of
interest between these electrodes. In various practices of the
invention, these electrodes are assigned as either anode or cathode
and a tsDCS stimulation circuit is thus created for applying
current between the electrodes and for modulating spinal cord
excitability. The applied current is delivered having a desired
signal character and level. In further embodiments of the
invention, we apply these teachings in wearable and implantable
embodiments.
[0072] In a further embodiment of the invention, a wearable
mono-stimulation device is provided. In this practice, there are
two electrodes which are skin surface type, serving as the active
spinal electrode and the spinal circuit return electrode. In one
embodiment, a surface of the wearable device provides the spinal
electrode and the device also connects to a return electrode, on
the opposite side of the spinal cord, which is placed on the skin
surface such as on the abdomen or iliac crest. In another
embodiment, the reference electrode is placed internal to the
bladder, such as by urethral catheter insertion, surgically, or the
like. The spinal location of interest is selected based on spinal
outflow to the target effector organ. In another implantable
mono-stimulation device of the invention, there are two electrodes
which are implantable electrodes, serving as the active spinal
electrode and the return electrode. In one embodiment, the
mono-stimulation device is fully implantable, with electrode leads
from the device to dorsal spinal location and ventral location
tunneled subcutaneously. The spinal location of interest is
selected based on spinal outflow to the target effector organ.
[0073] In a fully implantable subcutaneous double-stimulation
embodiment of the invention, two circuits are supplied by four
leads emanating from controller device. This embodiment delivers
two simultaneous stimulations, a spinal stimulation and a
peripheral stimulation applied to a nerve of the target effector
organ. There are two separate stimulation current paths with these
two circuits. But these circuits also interact to form a resulting
stimulation current path between the active electrode at the spine
of the spinal circuit and the electrode of opposite polarity
positioned at the nerve of the target effector organ. This provides
a polarization flow down along the neural path between the two
described electrodes. In this double stimulation embodiment, the
first current path is a tsDCS spinal circuit defined by placing an
active spinal electrode at the spinal location of interest and a
return electrode at a non-spinal location, with the applied current
running between these electrodes. The second current path is a
peripheral circuit defined by placing active and return electrodes
on or in proximity to a nerve of the target effector organ.
[0074] In a further embodiment, a two-part semi-implantable
stimulation device is provided. A first component is a wearable
mono-stimulation device which includes an active spinal electrode
applied by skin attachment and a return electrode. The second
component is an implanted peripheral stimulator or microstimulator
with two leads that has its own power supply. Both leads of the
second component are in contact with or in close proximity to a
nerve of a target effector organ. The wearable component can
communicate wirelessly with the implanted component. When the
wearable component turns on and issues its stimulation signal, the
implanted stimulator responds and issues a stimulation signal to
the target effector organ, which can be either excitatory or
inhibitory.
[0075] In a further embodiment of a wearable double-stimulation
device, two circuits are supplied by four leads emanating from
controller device. This embodiment delivers two simultaneous
stimulations. The first stimulation is a spinal stimulation
delivered via active spinal electrode applied by skin attachment
and a return electrode. The second stimulation modulates central
autonomic outflow, and can be either trans-cranial direct current
stimulation (tDCS) or trans-cutaneous vagal nerve stimulation
(tVNS). There are two separate stimulation current paths with these
two circuits but they are electrically isolated from each
other.
[0076] In a further embodiment, a two-part semi-implantable
stimulation device is provided. A first component is a wearable
double-stimulation device that provides a first stimulation that is
spinal stimulation, and a second stimulation that modulates central
autonomic outflow. The second component is an implanted peripheral
stimulator or microstimulator with two leads that has its own power
supply. Both leads of the second component are in contact with or
in close proximity to a nerve of a target effector organ. The
wearable component can communicate wirelessly with the implanted
component. When the wearable component turns on and issues its
stimulation signal, the implanted stimulator responds and issues a
stimulation signal to the target effector organ, which can be
either excitatory or inhibitory.
[0077] Illustrative embodiments of the invention is set forth in
FIG. 5A-C featuring wearable and implantable components.
[0078] In FIG. 5A, a disk-shaped wearable system 100 is disclosed.
As illustrated in FIG. 5A-B, system 100 includes a
wearable/implantable tsDCS controller 102, shown affixed to the
patient at its skin-side 104 optionally presenting an electrode
surface 111. External interaction with controller 102 is by buttons
or touch screen or by wireless interaction with a portable device
or cell phone 103 for user intervention. Controller 102 directs
action of implanted control unit 106.
[0079] Controller 102 incorporates a cognate circuit of device 10,
FIG. 4A, including a miniaturized version of computing and
synchronizing unit 16, with memory 19, for provision of system
control, and further including a signal polarity and function
controller 18, with appropriate instruction loaded set in memory 19
for instruction of implanted control unit 106. Control unit 106
includes a rechargeable power supply (not shown), and according to
instructions from controller 102, applies electrical stimulation to
a local peripheral nerve 108 that innervates a target effector
organ, such as the bladder. The stimulation can be adjusted as
needed, and is provided as constant continuous non-varying direct
current stimulation, or can be pulsed direct current stimulation,
in various practices of the invention.
[0080] In one embodiment, the implanted control unit 106 provides
electrical leads 109 to deliver the stimulation signal to suitable
electrode, shown as a cuff electrode 110, which is affixed at nerve
108. In one embodiment, controller 102 presents an electrode
surface 111 on the skin side of the device for affixation of the
device to the patient. This electrode surface 111 may include
electrically conductive adhesive to assist attachment to the
patient, and permits application of tsDCS stimulation at that
location. In further embodiments of the invention, system 100
further includes and cooperates with the implanted control unit
106, which in turn drives single or multiple implanted electrodes,
such as a cuff electrode 110 via leads 109. Cuff electrode 110 is
placed around a peripheral or autonomic nerve of interest 108 and
stimulates the nerve fibers to achieve either excitation or
inhibition of the effector organ, e.g., bladder. The cuff electrode
110 is made of soft, flexible materials such as silicone that
render an electrode flexible and less prone to injure the
peripheral nerve than common electrodes. Alternatively, two
electrode leads representing the anode and cathode are positioned
in contact with or in close proximity to the nerve 108.
[0081] In another embodiment of the present teachings, a wearable
tsDCS unit that wirelessly controls an implanted stimulator is
combined with a sensor that detects a relevant physiological state
to form a closed-loop system. The wearable tsDCS unit wirelessly
communicates with the sensor, which could be either implanted or
wearable, and activates tsDCS spinal stimulation and stimulation of
an effector organ via the implanted stimulator, when it detects a
relevant state. The sensor can be configured to detect blood
pressure, heart rate, body temperature, respiration rate, skin
turgor, skin conductivity, oxygenation state, bladder pressure,
urine osmolarity, hemodynamic parameters, specific cardiac rhythms
by EKG, urethral pressure, anal sphincter pressure, muscle
contraction state by EMG, specific brain waves by EEG,
electrolytes, specific proteins and signaling molecules in specific
tissue compartments, blood glucose concentration, gastric pH,
gastrointestinal motility sounds, environmental cues such as
specific sights, sounds and signals, and other parameters depending
on intended application. The neuromodulation system is thus
activated upon sensing a specific state, and inactivated when that
state no longer holds. In one embodiment of the present teachings,
the system also includes a sensor configured to detect a
predetermined parameter, such as those listed herein above, and
configured to provide a sensed value of the predetermined parameter
to the controller component. The controller component is further
configured to initiate stimulation, initiation of stimulation
determined by whether the sensed value is less than or exceeds a
predetermined value denoting the specific state.
[0082] A closed loop system 200 of the invention is shown in FIG.
5C and is configured to operate autonomously in the background with
reduced user interaction. As will be appreciated by a person
skilled in the art, the system 200 takes advantage of modern
wireless communications, as shown, which is available to implanted
medical systems. System 200 includes tsDCS controller 102 and
implanted control unit 106 with implanted electrode 110 at nerve
108, and including an implanted feedback device 112. The feedback
device 112 is in wireless communication with controller 102, which
then responsively instructs control unit 106 to adjust or initiate
or cease the stimulation function as needed. The implanted
stimulator, control unit 106, stimulates nerve 108 via leads 109
and electrode 110, consistent with instructions from controller
102.
[0083] In a bladder management embodiment, the implanted feedback
device 112 is a bladder pressure sensor 112A. Bladder data from
sensor 112A is wirelessly provided to controller 102 which
wirelessly instructs implanted control unit 106, or directly
instructs control unit 106, to control stimulation of bladder nerve
108 via electrode 110, to reduce incontinence or to reduce urinary
retention, for example.
[0084] Controller unit 102 has human interface, common instruction
memory store, and logic circuits, and or a microprocessor, for
executing its control instructions to control unit 106. In turn,
the control unit has a power supply which supplies the electrode
accordingly. Preferably the power supply is wirelessly
rechargeable.
[0085] The implanted sensor 112A closes the loop with the device
controller circuit 102 in system 200 such that the system
automatically adjusts without user intervention, according to
stored profiles. In one embodiment of bladder modulation, the
implanted sensor 112A is a bladder function sensor such as a
bladder pressure sensor which detects bladder pressure exerted by
urine volume in the bladder and enables and wirelessly informs the
needed neural stimulation instruction to be issued from controller
102 to control unit 106 to initiate stimulation and to obtain a
desired outcome, such as controlled voiding. In one embodiment, the
data from bladder sensor 112A is directly acted upon by control
unit 106.
[0086] In a further application of the closed-loop system 200 of
FIG. 5C, we combine stimulation that modulates central autonomic
outflow, in which a primary stimulation modulates either the
sympathetic or parasympathetic branch of the autonomic nervous
system, with the closed-loop system 200. Thus, cerebral and spinal
stimulations are combined with an implanted stimulator that is
under the control of the wearable tsDCS controller.
[0087] It will be appreciated that embodiments of the present
teachings feature tsDCS spinal stimulation. In many embodiments,
this tsDCS stimulation is augmented with stimulation of a
peripheral nerve leading to a target effector organ. In practices
of these teachings, peripheral direct current stimulation (pDCS) is
continuous, non-varying, steady-state direct current stimulation,
while in other embodiments, stimulation of a peripheral nerve or
autonomic nerve fiber associated with an effector organ may include
pulsed electrical stimulation, continuous DCS, pulsed DCS, or other
alternating signals. The present teachings also may be practiced
with wireless microstimulators as known in the art.
[0088] In practice of the invention, we apply tsDCS in various
configurations. A tsDCS stimulation system provides tsDCS
stimulation, which in various embodiments is applied by itself to
favorably polarize a target neural pathway of interest. In other
embodiments, we use coordinated multi-site neurostimulation that
incorporates the tsDCS polarizing stimulation together with
stimulation at other site(s) along the neural axis. We provide this
multi-site stimulation by combination of tsDCS stimulation with at
least one other stimulation, which includes cerebral stimulation
and/or peripheral stimulation.
[0089] In one embodiment of the present teachings, peripheral
stimulation is continuous steady-state and non-varying. In another
embodiment of the invention, excitation or inhibition of a
stimulated autonomic nerve fiber depends on the frequency of the
applied electrical stimulation. In one illustrative but
non-limiting practice of the invention, inhibition of
parasympathetic fibers is achieved with high-frequency monopolar
electrical stimulation (greater than about 50-100 Hz), while
excitation of parasympathetic fibers is achieved with low-frequency
monopolar electrical stimulation (less than about 50-100 Hz).
Similarly, inhibition of sympathetic fibers is achieved with
high-frequency electrical stimulation (greater than about 50-100
Hz), while excitation of sympathetic fibers is achieved with
low-frequency electrical stimulation (less than about 50-100 Hz).
In various embodiments we apply stimulation via skin surface
electrodes in a range up to about 1-6 mA or more often at 1-4.5
mA.
[0090] In embodiments of the present teachings, the tsDCS device is
fully implantable, with electrode leads from the device to dorsal
spinal location and ventral location tunneled subcutaneously.
Electrode leads from the tsDCS device which function for peripheral
stimulation are also tunneled subcutaneously with electrodes
implanted on the appropriate nerves of the effector organ being
modulated. In another embodiment, the tsDCS device remains external
to the body and wearable, but has electrode leads for peripheral
stimulation that are either surface mounted or implanted.
[0091] Illustrative Mono-Stimulation Embodiments
[0092] It will be appreciated that the mono-stimulation process
involves applying a single source of constant current stimulation
and is typically delivered by the tsDCS stimulator alone. In
practice of the present invention, we employ tsDCS to induce either
an area of increased or decreased neural activation within the
spinal cord.
[0093] The present invention teaches methods and systems utilizing
trans-spinal direct current stimulation for modulation of body
functions, such as at effector organs. Illustrative embodiments of
this disclosure are directed to application of such tsDCS to
modulation of effector constituents of the autonomic nervous system
(ANS). Illustrative embodiments include method and apparatus for
treatment of bladder dysfunctions. This disclosure is by way of
illustration and not by way of limitation of the scope of the
present invention.
[0094] It will now be appreciated that in various practices of the
invention, tsDCS stimulation is applied at the spinal location. At
peripheral sites (or cerebral sites in the case of transcutaneous
vagus nerve stimulation), stimulation can be of a broader variety
within the scope of the invention. In several practices of the
present invention, monopolar direct current stimulation is applied
at specific points along the neural axis. Monopolar direct current
electrical stimulation is applied and characterized as anodal or
cathodal. In an embodiment of the invention, this characterization
is indicative of the polarity of the current source as applied
between a spinal location of interest and a return location.
Depending upon the desired outcome, the circuit may be applied as
anodal, positive, at the location of interest, and cathodal,
negative, at the return location, or vice versa.
[0095] Single and/or multiple monopolar direct current stimulation
circuits are engaged in various embodiments. These monopolar
stimulations are, characterized as being anodal or cathodal, have a
polarizing effect over the stimulated pathways. This polarization
has significant favorable modulatory effect upon the transmission
efficiency of neural signals flowing over a neural pathway of
interest. Monopolar stimulation applied to a neural pathway has
potential polarizing and modulatory affects. In various practices
of the invention, we engage and harness these effects
accordingly.
[0096] In an illustrative embodiment of the invention in awake
healthy mice, a two-electrode mono-stimulation configuration of
tsDCS was utilized, employing a stimulator, with an active cathode
electrode on the lumbosacral spine (L6-S3), and a return anode
electrode on the abdomen. To enable measurements of bladder
function, we surgically placed a cysostomy tube (PE50 tubing) into
the bladder to enable measurement of bladder pressures and urine
output (FIG. 6). Bladder pressures, and the frequency of voiding
and non-voiding contractions were measured at baseline prior to
stimulation with cathodal tsDCS (FIG. 7A). In such embodiments with
cathodal tsDCS providing stimulation, there is a decrease in the
basal pressure, increase in the amplitude of bladder contractions,
increase in inter-voiding contraction interval, and increase the
number and amplitude of non-voiding contractions. In a series of
experiments, after 20 minutes of cathodal tsDCS, these effects were
still apparent. With such stimulation, the bladder can contract
more fully.
[0097] The same stimulation paradigm was also evaluated in awake
mice with chronic spinal cord injury, with spinal cord lesioning at
T10 level 30 days prior to stimulation studies. In these subjects,
there is excessive bladder activity and non-voiding contractions,
with higher bladder pressures as compared to healthy subjects, a
condition of detrusor hyperreflexia. Baseline measurements were
done in these subjects, followed by measurements during cathodal
tsDCS, and 2 hours after 20 minutes of cathodal tsDCS. In awake
subjects with chronic spinal cord injury, there is a decrease in
the basal pressure, larger non-voiding contractions, and a
decreased frequency of voiding contractions. Similar to awake
healthy subjects, cathodal tsDCS enables the bladder of subjects
with chronic spinal cord injury to contract more fully.
[0098] In another embodiment relating to treatment of chronic
spinal cord injury in mice, a two-electrode configuration of tsDCS
was utilized, with an anodal electrode on the lumbosacral spine
(L6-S3), and with, in one embodiment, the return electrode on the
front of the subject's abdomen, and in another embodiment, with the
return electrode at the bladder wall via transurethral insertion.
FIG. 7B shows spinal to bladder tsDCS stimulation that initiated
bladder retention and voiding reflex in a vertebrate being with
severe chronic spinal cord injury. The subject had demonstrated
skin irritation caused by excessive urination due to inability to
retain urine. The top provides cystometry traces showing
intravesicle pressure before, during, and after stimulation with
anode on the spine and cathode inside the bladder. Note that there
were no reflexes before or after stimulation. Traces on the right
are with expanded time scale to show the structure of the reflexes.
The bottom trace shows cystometry traces from the same subject
showing before, during stimulation 1 (anode inside the bladder),
stimulation 2 (cathode inside the bladder), and after. An improved
ability to retain urine is seen even after stimulation is switched
off.
[0099] In further studies of mice with acute spinal cord injury,
the same two-electrode configuration of tsDCS was utilized. In
acute spinal cord injury, there is spinal shock and detrusor
areflexia, during which period the bladder fills to high and
potentially dangerous pressures, with voiding pressures
significantly higher than normal subjects or in subjects with
chronic spinal cord injury. This represents a significant health
issue because it can cause stretch injuries to the bladder and
upper urinary tract complications.
[0100] FIG. 7C shows bladder reflexes in subjects with acute
complete spinal cord injury and the effects of tsDCS. Baseline
reflexes show very high voiding pressures that were further
increased by spinal anode/cathode in bladder arrangement. This
effect was maintained for at least 10 min after the current was
turned off. When the polarity was switched, with spinal cathode and
anode in bladder, this configuration immediately decreased the
voiding pressure and decreased inter-voiding contraction interval,
demonstrating that this configuration has therapeutically useful
effects in subjects with detrusor areflexia following acute spinal
cord injury.
[0101] These results are consistent with both normal and spinal
cord injured mammals. Excitability of small or moderate sized
spinal neurons is increased by cathodal tsDCS and depressed by
anodal tsDCS. Since autonomic preganglionic neurons are smaller in
size, they follow this principle. We have found that cathodal tsDCS
on the lumbosacral region increases the excitability of spinal
parasympathetic preganglionic neurons hence decreasing urine
storage reflexes and increasing voiding reflexes. Reverse polarity
induces opposite modulation, i.e., increasing urine storage
reflexes and decreasing voiding reflexes. In such practices, we
have found that placing the return electrode inside or around the
bladder enhances modulatory effects.
[0102] The described anodal spinal/cathodal bladder configuration
is effective in delaying the bladder voiding reflex to allow for
longer filling time. Moreover, the same arrangement produces
efficient voiding that is evident in lowering the basal pressure
after each voiding cycle. In an illustrative embodiment of the
invention, this anodal spinal/cathodal bladder configuration has an
inhibitory effect on the parasympathetic input to the bladder.
Inhibiting the parasympathetic inputs causes relaxation of the
bladder detrusor and contraction of the sphincter vesicae. This
allows for longer inter-voiding contraction interval. In addition,
this configuration enables increased sympathetic influence over
parasympathetic. This treatment is valuable in for achieving
conditions of low pressure storage and efficient bladder voiding.
In further practices of the invention, we treat conditions of
detrusor areflexia by switching the polarities of the electrodes
applied to spinal and bladder locations.
[0103] In practice of the present invention, a patient with a
condition of urinary incontinence involving detrusor hyperreflexia
is treated by application of tsDCS in a configuration that
decreases parasympathetic tone, FIG. 8. Such a decrease in
parasympathetic tone results in relaxation of the detrusor
contraction and increased contraction of the sphincter vesicae. In
one embodiment this is non-invasively achieved by anodal tsDCS at
the level of S2-S4 with a return cathodal electrode positioned
anteriorly at an abdominal location, such as the skin superior to
the iliac bone. In another embodiment, the return electrode is
positioned within the bladder trans-urethrally, FIG. 9. In further
practice of the invention these polarities (i.e., the anodal and
cathodal assignments,) are reversed for treatment of conditions of
urinary retention. In this embodiment, the configuration results in
an increase in parasympathetic tone.
[0104] In further embodiments of the present invention, a subject
with a condition of urinary incontinence is treated by application
of tsDCS in a configuration that increases sympathetic tone, FIG.
10. Such an increase in sympathetic tone results in relaxation and
expansion of the detrusor muscle, constriction of the sphincter
vesicae, and inhibition of parasympathetic nerves that trigger
bladder contraction. This is non-invasively achieved by cathodal
tsDCS at the T11-L2 spinal level with an anodal return electrode
positioned anteriorly at an abdominal location. In variant of the
embodiment, FIG. 11, the return electrode is positioned within the
bladder trans-urethrally. In further practice of the invention
these polarities (i.e., the anodal and cathodal assignments,) are
reversed for treatment of conditions of urinary retention, which
achieves a decrease of sympathetic tone.
[0105] An embodiment of the invention includes method and system
having a single tsDCS stimulation circuit, for mono-stimulation of
the spinal cord, and defined by placing an electrode at the spinal
location of interest and a return electrode on the anterior aspect
of the body, thus defining a pathway of interest between these
electrodes. In various practices of the invention, these electrodes
are assigned as either anode or cathode and a tsDCS stimulation
circuit is thus created for applying current between the electrodes
and for modulating spinal cord excitability. The applied current is
delivered having a desired signal character and level.
[0106] In a wearable mono-stimulation device embodiment of the
invention, there are two electrodes which are skin surface type,
serving as the active spinal electrode and the return electrode. In
one embodiment, the surface of the wearable device provides the
spinal electrode and the device also connects to a return electrode
on the opposite side of the spinal cord, which is placed on the
skin surface such as on the abdomen or iliac crest. In another
embodiment, the reference electrode is placed internal to the
bladder, such as by urethral catheter insertion, surgically, or the
like. The spinal location of interest is selected based on spinal
outflow to the target effector organ.
[0107] In an implantable mono-stimulation device of the invention,
there are two electrodes which are implantable electrodes, serving
as the active spinal electrode and the return electrode. In one
embodiment, the mono-stimulation device is fully implantable, with
electrode leads from the device to dorsal spinal location and
ventral location tunneled subcutaneously. The spinal location of
interest is selected based on spinal outflow to the target effector
organ.
[0108] Illustrative Double-Stimulation Embodiments
[0109] Beyond strategies that utilize spinal stimulation via tsDCS
on its own, we also disclose strategies that combine spinal
stimulation via tsDCS with additional stimulation.
[0110] We teach double-stimulation in various embodiments.
Illustrative embodiments include two stimulators electrically tied
together in as system for polarizing a critical neural pathway; a
wearable mono-stimulation device communicating wirelessly with an
implanted microstimulator; and two separate stimulators that are
electrically isolated, as when there is a cortical stimulation
using tDCS combined with spinal stimulation using tsDCS. Still
other configurations will occur consistent with this disclosure
that are also within the scope of the invention.
[0111] In one double-stimulation embodiment of the invention, we
provide simultaneous tsDCS spinal stimulation together with pulsed
peripheral direct current stimulation (pDCS) of a nerve leading to
a targeted effector organ. In one particular embodiment, a
resulting polarizing circuit is defined between an active spinal
tsDCS stimulation circuit and an active pulsed pDCS peripheral
stimulation circuit.
[0112] In one embodiment of the present invention, the described
spinal stimulations which increase parasympathetic outflow to the
bladder are combined with electrical stimulation of the
parasympathetic preganglionic fibers in pelvic nerve, FIG. 12, with
cathodal tsDCS applied at S2-S4. Stimulation of the pelvic
splanchnic nerve results in contraction of the bladder detrusor,
and relaxation of the sphincter vesicae, thereby further treating a
condition of urinary retention. In further practice of the
invention, these polarities (i.e., the anodal and cathodal
assignments,) are reversed for treatment of conditions of urinary
incontinence resulting in a decrease in parasympathetic tone.
[0113] Excessive activity in the somatic efferents innervating the
striated muscle of the external urethral sphincter (EUS) results in
contraction of the sphincter. In another embodiment of the present
invention, the described spinal stimulations which increase
parasympathetic outflow to the bladder are combined with electrical
inhibition of the pudendal nerve that innervates the EUS using
implanted electrodes, FIG. 13, with cathodal tsDCS applied at
S2-S4. This combination results in contraction of the bladder
detrusor, relaxation of the sphincter vesicae, and relaxation of
the EUS, thereby further treating a condition of urinary retention.
In further practice of the invention, these polarities (i.e., the
anodal and cathodal assignments,) are reversed for treatment of
conditions of urinary incontinence and the pudendal nerve
innervating the EUS is electrically stimulated using implanted
electrodes.
[0114] Stimulation of the sensory afferents that fire in response
to urine flow through urethra results in increased strength of
bladder contraction and voiding efficiency. In another embodiment
of the present invention, the described spinal stimulations which
increase parasympathetic outflow to the bladder are combined with
electrical stimulation of the pudendal nerve using implanted
electrodes, FIG. 14, with cathodal tsDCS applied at S2-S4.
[0115] In a further embodiment, cathodal spinal stimulations
increase sympathetic outflow to the bladder as combined with
implanted microstimulator electrodes which stimulate the pudendal
nerve, FIG. 15, with cathodal spinal stimulations at T11-L2.
Increased sympathetic tone results in relaxation of the bladder
detrusor and contraction of the sphincter vesicae, while
stimulation of the pudendal nerve results in contraction of the
external urethral sphincter, thereby further treating a condition
of urinary incontinence. In further practice of the invention,
these polarities (i.e., the anodal and cathodal assignments,) are
reversed for treatment of conditions of urinary retention and the
pudendal nerve innervating the EUS is electrically inhibited using
implanted electrodes. In such embodiments, the implanted
microstimulator communicates with and is controlled by a tsDCS
controller that provides spinal stimulations, that can be either a
wearable device, or an implanted subcutaneous device.
[0116] In a further embodiment, the cathodal spinal stimulations
which increase sympathetic outflow to the bladder are combined with
implanted electrodes which are applied to inhibit the
parasympathetic preganglionic fibers of the pelvic splanchnic
nerves, FIG. 16, with cathodal spinal stimulations at T11-L2.
Increased sympathetic tone results in relaxation of the bladder
detrusor and contraction of the sphincter vesicae, while inhibition
of the pelvic splanchnic nerves results in further relaxation of
the bladder detrusor, thereby further treating a condition of
urinary incontinence. In further practice of the invention, these
polarities (i.e., the anodal and cathodal assignments,) are
reversed for treatment of conditions of urinary retention.
[0117] In a fully implantable subcutaneous double-stimulation
embodiment of the invention, two circuits are supplied by four
leads emanating from controller device. This embodiment delivers
two simultaneous stimulations, a spinal stimulation and a
peripheral stimulation applied to a nerve of the target effector
organ. There are two separate stimulation current paths with these
two circuits. But these circuits also interact to form a resulting
stimulation current path between the anode of one circuit (i.e.,
active electrode at the spine of the spinal circuit) and the active
cathode at the nerve of the neural circuit. This provides a
polarization flow down along the neural path between the two active
electrodes. In this double stimulation embodiment, the first
current path is a tsDCS spinal circuit defined by placing an active
spinal electrode at the spinal location of interest and a return
electrode at a non-spinal location, with the applied current
running across the tissues between these electrodes. The second
current path is a peripheral circuit defined by placing active
cathode and anode electrodes on or in proximity to a nerve of the
target effector organ.
[0118] In a further embodiment, a two-part semi-implantable
stimulation device is provided. A first component is a wearable
mono-stimulation device which includes an active spinal electrode
applied by skin attachment and a return electrode. The second
component is an implanted peripheral stimulator or microstimulator
with two leads that has its own power supply. Both leads of the
second component are in contact with or in close proximity to a
nerve of a target effector organ. The wearable component can
communicate wirelessly with the implanted component. When the
wearable component turns on and issues its stimulation signal, the
implanted stimulator responds and issues a stimulation signal to
the target effector organ, which can be either excitatory or
inhibitory.
[0119] In a further embodiment of a wearable double-stimulation
device, two circuits are supplied by four leads emanating from
controller device. This embodiment delivers two simultaneous
stimulations. The first stimulation is a spinal stimulation
delivered via active spinal electrode applied by skin attachment
and a return electrode. The second stimulation modulates central
autonomic outflow, and can be either trans-cranial direct current
stimulation (tDCS) or trans-cutaneous vagal nerve stimulation
(tVNS). There are two separate stimulation current paths with these
two circuits that are electrically isolated from each other.
[0120] Triple-Stimulation Embodiments
[0121] We also herein describe strategies that combine spinal
stimulation, peripheral stimulation, and stimulation of central
autonomic outflow to modulate autonomic function. The previously
disclosed strategies based on mono-stimulation and
double-stimulation might be sufficient for certain applications. In
other applications, it will be necessary or beneficial to directly
modulate central autonomic outflow before spinal level modulation
via tsDCS and potential peripheral stimulation. Non-invasive
methods for modulating central autonomic outflow are combined with
other sites of stimulation using a variety of approaches:
[0122] Transcranial direct current stimulation (tDCS)--A number of
different tDCS montages have been utilized to modulate the
autonomic nervous system. Anodal tDCS over the primary motor
cortex, with cathode return electrode over the contralateral
supraorbital area has been reported to increase sympathetic
activity (Clancy et al., Brain Stim., 2014, 7:97-104). Anodal
stimulation of the left dorsolateral prefrontal cortex (DLPFC) has
been reported to increase parasympathetic activity, while anodal
stimulation of the right DLPFC has been reported to increase
sympathetic activity (Brunoni et al., Psychoneuroendocrinology,
2012). Other work has reported that anodal tDCS over the temporal
lobe results in increased parasympathetic activity. As such,
non-invasive tDCS can be coupled with tsDCS at the relevant spinal
level to modulate autonomic outflow. In one embodiment, sympathetic
outflow from the brain is increased by anodal tDCS over the primary
motor cortex and further increased at the spinal level of the
targeted effector organ by cathodal tsDCS at the high thoracic
level. This embodiment is shown in FIG. 17, where cortical
electrodes are shown combined with a wearable tsDCS controller. In
another embodiment, sympathetic outflow from the brain is increased
by anodal tDCS of the right DLPFC and further increased at the
spinal level of the targeted effector organ by cathodal tsDCS. In
yet another embodiment, parasympathetic outflow from the brain is
increased by anodal tDCS over the temporal lobe and further
increased at either the S2-S4 spinal level of the targeted effector
organ or the brainstem level of DMV by cathodal tsDCS.
[0123] Transcutaneous vagal nerve stimulation (tVNS)--The auricular
branch of the vagus nerve supplies sensation to the posterior parts
of the ear pinna, external auditory canal and tympanic membrane,
FIG. 18A. Nerve cell bodies are located in the superior (jugular)
ganglion of the vagus, and they project to the nucleus of the
tractus solitarius (NTS) in the brainstem. Electrical stimulation
of the ear concha (tVNS) produces activation of NTS and its known
projections (parabrachial nucleus, nucleus accumbens, hypothalamus,
amygdala). The dorsal motor nucleus of the vagus (DMV) in the
brainstem contains the cell bodies of the parasympathetic neurons
that project down the vagus nerve as preganglionic efferent fibers.
Direct connections between the NTS and DMV have been described, and
it is established that NTS sends projections to DMV. Stimulation of
the external ear tragus using electrical stimulation (10-50 mA, 30
Hz pulse frequency, 200 microsecond pulse width) results in
decreased sympathetic discharge (Clancy et al., Brain Stim., 2014,
7:817-877. In a practice of the present invention, we utilize this
non-invasive methodology for decreasing sympathetic tone and
coupling it with anodal tsDCS at the spinal level. Sympathetic
outflow from the brain is reduced by tVNS and further reduced at
the spinal level of the targeted effector organ by applied anodal
tsDCS. This embodiment is shown in FIG. 18B, where auricular
stimulation is combined with a wearable tsDCS controller.
[0124] Transcranial magnetic stimulation (TMS)--TMS, both
repetitive and single pulse, has been utilized in studies that
modulate the autonomic nervous system. Targeted sites include left
temporo-parietal cortex (Lai et al., 2010) and primary motor cortex
M1 (Vernieri et al., 2009 and Yozbatiran et al., 2009). TMS was
found to exert changes on autonomic control in these, and other
studies. Accordingly, in a further embodiment we combine TMS with
tsDCS at the spinal level. While FIG. 17 is illustrated showing
cortical stimulation via tDCS, it will be appreciated that TMS is
an alternative source of cortical stimulation in practices of the
present invention.
[0125] Cold/hot pressors--It is known that immersion of a subject's
hand in a bucket of ice water results in increased heart rate and
pulse pressure, thought to be due to increased sympathetic tone
activated by sensory afferents. As such, in practices of the
invention, we utilize this approach as a methodology to initiate
modulation of autonomic outflow. As a bucket of ice water is
impractical, we utilize alternative methodologies to achieve this
effect. More specifically, in one embodiment, this effect is
delivered as a cooling/heating pad that is affixed to a
thermosensitive area of skin such as the upper back, or in another
embodiment is presented as a vest or glove with cooling/heating
elements. This device is switched to either "cold stimulation" or
"hot stimulation" to provide that sensation to the skin. To
increase sympathetic tone to a specific effector organ, we combine
activation of "cold stimulation" to the subject's skin with
cathodal tsDCS at the relevant spinal level. To increase
parasympathetic tone to a specific effector organ, we combine
activation of "hot stimulation" to the subject's skin with cathodal
tsDCS at the S2-S4 level (or DMV brainstem level). In this way,
efferent outflow through either the sympathetic or parasympathetic
system is activated depending on which temperature "setting" is
used, and cathodal tsDCS amplifies the signals that are going to
autonomic neurons in the spinal cord.
[0126] Pharmacological autonomic modulators--Certain
pharmacological agents have modulatory effects on the autonomic
nervous system. Sympathomimetics increase sympathetic tone, and
include amphetamines and phenylephrine. Sympatholytics decrease
sympathetic tone, and include prazosin and yohimbine.
Parasympathomimetics increase parasympathetic tone, and include
muscarine, pilocarpine and choline esters. Parasympatholytics
decrease sympathetic tone, and include scopalamine and atropine.
Sympathomimetics can be given in combination with
parasympatholytics, and parasympathomimetics can be given in
combination with sympatholytics. Depending on specific molecular
characteristics, these pharmacological agents can be given orally,
subcutaneously, intramuscularly, transdermally, intravenously or as
depot injections. Pharmacological autonomic modulators are shown in
FIG. 19.
[0127] As will be understood by a person skilled in the art, in
practices of the present invention, we modulate autonomic outflow
and use various strategies to monitor effect. For example, in
various embodiments, we monitor readouts including heart rate,
heart rate variability, microneurography recording muscle
sympathetic nerve activity, blood pressure, pulse pressure,
pupillary size, skin conductance, sympathetic skin response,
respiratory rate, cerebral vasomotor reactivity, and body
temperature, the utility of which will be understood by a person
skilled in the art.
[0128] In another embodiment, various of the above described
approaches of modulating central autonomic outflow, is combined
with spinal stimulation and is further combined with a third
peripheral stimulation, delivered at the level of the nerve leading
to the target effector organ, to render a useful therapeutic
effect. This triple-stimulation approach is shown in FIG. 20.
[0129] In a further embodiment, a two-part semi-implantable
stimulation device is provided. A first component is a wearable
double-stimulation device that provides a first stimulation that is
spinal stimulation, and a second stimulation that modulates central
autonomic outflow. The second component is an implanted peripheral
stimulator or microstimulator with two leads that has its own power
supply. Both leads of the second component are in contact with or
in close proximity to a nerve of a target effector organ. The
wearable component can communicate wirelessly with the implanted
component. When the wearable component turns on and issues its
stimulation signal, the implanted stimulator responds and issues a
stimulation signal to the target effector organ, which can be
either excitatory or inhibitory.
[0130] In various embodiments, effector organ stimulation via the
nerve leading to the effector organ is achieved using energetic
modalities, including electrical stimulation, magnetic stimulation,
acoustic stimulation and others. In some instances, it is desirable
to directly stimulate such nerve using electrical stimulation. In
several embodiments of the invention, the electrical stimulation is
applied at the nerve leading to smooth muscle, skeletal muscle or
is at a ganglion or plexus associated with the targeted effector
organ. In some embodiments applied to the autonomic system,
stimulation is applied directly at the sympathetic trunk or
ganglia, celiac ganglion, superior mesenteric ganglion, inferior
mesenteric ganglion, or is stimulated at the post-ganglionic nerve.
The parasympathetic nervous system has ganglia in close proximity
to or located in the organs being innervated, and in some
embodiments electrodes are placed in proximity to these
parasympathetic ganglia to achieve the desired simulative effect at
the target effector organ.
[0131] Peripheral pulse intensity typically ranges is from 5 to 40
mA. In one triple stimulation bladder embodiment, continuous tsDCS
is applied to the Onuf's nucleus in the sacral region of the spinal
cord. The tsDCS is applied with typical intensity in the range from
2 to 5 mA.
[0132] Peripheral pulse intensity typically ranges is from 5 to 40
mA. In one triple stimulation bladder embodiment, continuous tsDCS
is applied to the Onuf's nucleus in the sacral region of the spinal
cord. The tsDCS is applied with typical intensity in the range from
2 to 5 mA.
[0133] In treating bladder dysfunction, the desired subthreshold
spinal tsDCS and subthreshold pDCS are established in view of the
level at which the effector organ responds to electrical
stimulation, which serves as the threshold indicator and value of
merit. In an embodiment, this level is in a range of 2-5 mA. In an
illustrative embodiment, 3-4.5 mA stimulation at the spine and 2-3
mA via the cathetered active peripheral electrode or 2.5-3.5 mA
when applied via abdominal surface electrode, delivers the desired
subthreshold peripheral stimulation, assuming the return electrode
is placed at a bony location. If the peripheral return electrode is
located closely associated with the bladder, such as by placement
near the bladder or into the bladder, then the threshold is
detected and adjusted accordingly, typically in the same range.
[0134] The embodiments described herein provide the basis to treat
neurogenic bladder conditions that result in either detrusor
hyperreflexia or detrusor areflexia with external devices, wearable
devices, or implanted devices that deliver the described
stimulations. It will be appreciated by a person skilled in the art
that the findings described herein and reduced to practice for
bladder modulation using a tsDCS-based approach are directly
applicable to controlling kidney, lung, heart, pancreas,
gastrointestinal system, stomach, anal sphincter and other
autonomically controlled effector organs and may be practiced
accordingly under the principals disclosed herein. It will now be
appreciated that we have illustrated single, double, and triple
stimulation configurations and methods in practice of embodiments
of the invention.
[0135] Some of the above described approaches combine a primary
stimulation that modulates either the sympathetic or
parasympathetic branch of the autonomic nervous system, with spinal
stimulation that amplifies the evoked response. A single constant
tsDCS stimulation impacting the target effector organ is useful and
successful in certain situations. In other situations, a
double-stimulation approach is useful in situations where
amplifying autonomic outflow at the spinal level is sufficient for
a therapeutic effect. In other situations, primary stimulation and
spinal stimulation is combined with a third stimulation, which is
delivered at the level of the nerve leading to the targeted
effector organ, to render a useful therapeutic effect. Effector
organ stimulation via the nerve leading to the effector organ is
achieved using selected energetic modalities, including electrical
stimulation, magnetic stimulation, acoustic stimulation and others.
In some instances, it is desirable to directly stimulate a nerve
using electrical stimulation. The electrical stimulation is
directed to the nerve leading to smooth muscle, skeletal muscle or
is at a ganglion or plexus associated with the ANS. This is
directly at the sympathetic trunk or ganglia, celiac ganglion,
superior mesenteric ganglion, inferior mesenteric ganglion, or is
stimulated at the post-ganglionic nerve. The parasympathetic
nervous system has ganglia in close proximity to or located in the
organs being innervated, and in some instances electrodes might be
placed in proximity to these parasympathetic ganglia.
[0136] In another embodiment, stimulation of the motor cortex using
TMS or tDCS is combined with spinal stimulation using tsDCS and
peripheral stimulation of a nerve leading to a striated muscle
under voluntary control. As it relates to bladder dysfunction, this
approach can be utilized to strengthen the external urinary
sphincter (EUS), which is a striated muscle under voluntary
control. In a preferred embodiment, TMS is applied to the motor
cortex area associated with the EUS, cathodal tsDCS is applied at
the spinal level corresponding to EUS, and peripheral stimulation
is applied to the pudendal nerve leading to the EUS using an
implanted electrode. In one practice of this embodiment, wherein
neural dysfunction of a distal effector organ (e.g., a urinary
sphincter) is to be treated, the tsDCS spinal stimulation is
applied for the duration of treatment (a "session") to the spine at
the spinal location and affecting a neural pathway associated with
neural control of that effector organ, and peripheral and cortical
stimulations are applied to locations associated with that effector
organ to improve neural communication to that target effector
organ. In another embodiment, this approach is applied to the
external anal sphincter.
[0137] In an illustrative triple stimulation embodiment of the
invention, pulsed stimulation and cortical stimulation are applied
in the presence of tsDCS at the spinal location (neural spinal
junction) of interest (i.e., a neural spinal junction associated
with cortical control of a target peripheral organ of interest,
such as the bladder). The cortical, spinal and peripheral
stimulation sites are connected by a common neural pathway. As
applied to the neural pathway, applied peripheral stimulation
pulses from a peripheral stimulator device (e.g., device 14) are
synchronized with applied cortical stimulation pulses from a
cortical stimulator 12 or 12A, such that the peripheral pulses
precede the cortical pulse in timing, in any one cycle. In a
typical stimulation cycle, at least one peripheral pulse and
preferably two, applied to the peripheral location of interest,
e.g., a nerve associated with bladder sphincter control, precede a
following cortical pulse, wherein such cortical electrical or
magnetic stimulation pulse is applied at a cortical location of
interest, such as at a cortical site associated with control of the
target organ, e.g., control of bladder sphincter. Latencies of
induced peripheral and cortical pulses are synchronized to give
maximal evoked response (MEP), wherein latencies typically range
from 20 to 45 ms, and as will be appreciated by a person skilled in
the art, the timing of the applied pulses is thus adjusted in view
of these latencies in order to induce the cortical and pulsed
neural signals on the neural pathway of interest as will flow to
the spinal junction and overlap at the spinal junction together in
the applied presence of the tsDCS stimulation, to achieve the
desired triple stimulation. Peripheral pulse intensity typically
ranges from 5 to 40 mA. In one triple stimulation bladder
embodiment, the tsDCS is applied to the Onuf's nucleus in the
sacral region of the spinal cord. tsDCS with typical intensity in
the range from 2 to 5 mA.
[0138] It will be appreciated that in practice of an embodiment of
the invention, we limit maximum current output for
double-stimulation with two simultaneous skin-surface DC
stimulations at or about 5 mA for both spinal and peripheral
stimulation locations. In one embodiment, an illustrative sponge
rubber electrode has a skin contact area of 9 cm2 resulting in a
maximum current density of 0.56 mA/cm2. As will be appreciated by a
persons skilled in the art, this is well below the reported safe
upper limit for current density of 14.29 ma/cm2 as cited in:
Nitsche M A, Liebetanz D, Lang N, Tergau F, Paulus W., in Safety
Criteria For Transcranial Direct Current Stimulation (TDCS) In
Humans. Clin Neurophysiol 2003; 114(11):2220e2."
[0139] It will be appreciated that the stimulation routines of the
invention utilizing cortical stimulation, either direct electrical
direct current stimulation or magnetic, as in TMS, follow the
triple stimulation teachings of our co-pending U.S. application
Ser. No. 14/665,220, filed Mar. 23, 2015, entitled: Method and
System for Treatment of Neuromotor Dysfunction, which is a
continuation of now issued U.S. Pat. No. 9,011,310, all having a
common inventor and assigned to a common owner, and all
incorporated herein by reference for all purposes whatsoever.
[0140] It will be appreciated that the stimulation teachings of the
invention utilizing double stimulation are an adaptation of the
teachings of our co-pending U.S. application Ser. No. 15/046,797,
filed Feb. 18, 2016, entitled: Trans-Spinal Direct Current
Modulation Systems, which is a continuation of now issued U.S. Pat.
No. 9,283,391, all having a common inventor and assigned to a
common owner, and all incorporated herein by reference for all
purposes whatsoever. In a further alternative illustrative
embodiment of the invention, pulsed implanted stimulation is
provided, as is known in the art for other pulsed peripheral
applications. Such stimulation can be set to an output of up to
10.5V for pulses up 240 microseconds at 14 Hz, 0.3% duty cycle,
providing a set voltage amplitude and adjusting the current to
maintain the set amplitude, with pulsed current up to 10 mA.
Voltage settings are set according to what the patient can
tolerate, as will be appreciated by a person skilled in the art.
The current is dependent on the electrode resistance, the electrode
tissue interface (likely appreciable) and the impedance of the
tissue itself, is illustratively at around 1 kohm.
[0141] In further embodiments of the invention we incorporate a
wearable tsDCS controller that modulates descending autonomic
signals traversing the spinal cord. In some embodiments, this is
combined with an implanted electrode that directly stimulates the
nerve to a targeted effector organ. This stimulation is selected as
either excitatory or inhibitory, and is further embodiments depends
on stimulation frequency as well as pulse amplitude and duration.
The implanted electrode is in wireless communication with the
wearable tsDCS controller.
[0142] This approach is sufficient for certain applications. In
other applications, it is beneficial to directly modulate central
autonomic outflow before spinal level modulation via tsDCS. In
practice of the invention, we increase or decrease sympathetic
outflow, or increase or decrease parasympathetic outflow, as a
person skilled in the art would appreciate. Furthermore in
particular embodiments we provide non-invasive and
non-pharmacological modulating of autonomic outflow for control and
treatment of autonomically-related functions and disorders.
[0143] Computer
[0144] This disclosure includes description by way of example of a
device configured to execute functions (hereinafter referred to as
computing device) which may be used with the presently disclosed
subject matter. The description of the various components of a
computing device is not intended to represent any particular
architecture or manner of interconnecting the components. Other
systems that have fewer or more components may also be used with
the disclosed subject matter. A communication device may constitute
a form of a computing device and may at least include a computing
device. The computing device may include an inter-connect (e.g.,
bus and system core logic), which can interconnect such components
of a computing device to a data processing device, such as a
processor(s) or microprocessor(s), or other form of partly or
completely programmable or pre-programmed device, e.g., hard wired
and or application specific integrated circuit ("ASIC") customized
logic circuitry, such as a controller or microcontroller, a digital
signal processor, or any other form of device that can fetch
instructions, operate on pre-loaded/pre-programmed instructions,
and/or followed instructions found in hardwired or customized
circuitry to carry out logic operations that, together, perform
steps of and whole processes and functionalities as described in
the present disclosure.
[0145] In this description, various functions, functionalities
and/or operations may be described as being performed by or caused
by software program code to simplify description. However, those
skilled in the art will recognize what is meant by such expressions
is that the functions result from execution of the program
code/instructions by a computing device as described above, e.g.,
including a processor, such as a microprocessor, microcontroller,
logic circuit or the like. Alternatively, or in combination, the
functions and operations can be implemented using special purpose
circuitry, with or without software instructions, such as using
Application-Specific Integrated Circuit (ASIC) or
Field-Programmable Gate Array (FPGA), which may be programmable,
partly programmable or hard wired. The application specific
integrated circuit ("ASIC") logic may be such as gate arrays or
standard cells, or the like, implementing customized logic by
metalization(s) interconnects of the base gate array ASIC
architecture or selecting and providing metalization(s)
interconnects between standard cell functional blocks included in a
manufacturer's library of functional blocks, etc. Embodiments can
thus be implemented using hardwired circuitry without program
software code/instructions, or in combination with circuitry using
programmed software code/instructions.
[0146] Thus, the techniques are limited neither to any specific
combination of hardware circuitry and software, nor to any
particular tangible source for the instructions executed by the
data processor(s) within the computing device. While some
embodiments can be implemented in fully functioning computers and
computer systems, various embodiments are capable of being
distributed as a computing device including, e.g., a variety of
forms and capable of being applied regardless of the particular
type of machine or tangible computer-readable media used to
actually effect the performance of the functions and operations
and/or the distribution of the performance of the functions,
functionalities and/or operations.
[0147] The interconnect may connect the data processing device to
define logic circuitry including memory. The interconnect may be
internal to the data processing device, such as coupling a
microprocessor to on-board cache memory or external (to the
microprocessor) memory such as main memory, or a disk drive or
external to the computing device, such as a remote memory, a disc
farm or other mass storage device, etc. Commercially available
microprocessors, one or more of which could be a computing device
or part of a computing device, include a PA-RISC series
microprocessor from Hewlett-Packard Company, an 80.times.86 or
Pentium series microprocessor from Intel Corporation, a PowerPC
microprocessor from IBM, a Sparc microprocessor from Sun
Microsystems, Inc, or a 68xxx series microprocessor from Motorola
Corporation as examples.
[0148] The inter-connect in addition to interconnecting such as
microprocessor(s) and memory may also interconnect such elements to
a display controller and display device, and/or to other peripheral
devices such as input/output (I/O) devices, e.g., through an
input/output controller(s). Typical I/O devices can include a
mouse, a keyboard(s), a modem(s), a network interface(s), printers,
scanners, video cameras and other devices which are well known in
the art. The inter-connect may include one or more buses connected
to one another through various bridges, controllers and/or
adapters. In one embodiment the I/O controller includes a USB
(Universal Serial Bus) adapter for controlling USB peripherals,
and/or an IEEE-1394 bus adapter for controlling IEEE-1394
peripherals.
[0149] The memory may include any tangible computer-readable media,
which may include but are not limited to recordable and
non-recordable type media such as volatile and non-volatile memory
devices, such as volatile RAM (Random Access Memory), typically
implemented as dynamic RAM (DRAM) which requires power continually
in order to refresh or maintain the data in the memory, and
non-volatile RAM (Read Only Memory), and other types of
non-volatile memory, such as a hard drive, flash memory, detachable
memory stick, etc. Non-volatile memory typically may include a
magnetic hard drive, a magnetic optical drive, or an optical drive
(e.g., a DVD RAM, a CD RAM, a DVD or a CD), or `other type of
memory system which maintains data even after power is removed from
the system.
[0150] For the purposes of describing and defining the present
teachings, it is noted that the term "substantially" is utilized
herein to represent the inherent degree of uncertainty that may be
attributed to any quantitative comparison, value, measurement, or
other representation. The term "substantially" is also utilized
herein to represent the degree by which a quantitative
representation may vary from a stated reference without resulting
in a change in the basic function of the subject matter at
issue.
[0151] While these teachings have been described in terms of
specific embodiments, it is evident in view of the foregoing
description that numerous alternatives, modifications and
variations will be apparent to those skilled in the art.
Accordingly, these teachings are intended to encompass all such
alternatives, modifications and variations which fall within the
scope and spirit of the present teachings and the following claims.
The foregoing description is illustrative validation of the present
invention. It will now be appreciated that tsDCS stimulation
according to embodiments of the invention can be practiced
non-invasively or invasively using direct current stimulation to
modulate spinal cord neurons. While these teachings have been
described in terms of specific embodiments, it is evident in view
of the foregoing description that numerous alternatives,
modifications and variations will be apparent to those skilled in
the art. Accordingly, these teachings are intended to encompass all
such alternatives, modifications and variations which fall within
the scope and spirit of the present teachings and the following
claims.
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