U.S. patent application number 10/047236 was filed with the patent office on 2002-07-25 for methods of treating persistent impairment of consciousness by vagus nerve stimulation.
This patent application is currently assigned to Board of Trustees of Southern Illinois University. Invention is credited to Browning, Ronald A., Clark, Kevin B., Jensen, Robert A., Naritoku, Dean K., Smith, Douglas C., Terry, Reese S. JR..
Application Number | 20020099417 10/047236 |
Document ID | / |
Family ID | 21789899 |
Filed Date | 2002-07-25 |
United States Patent
Application |
20020099417 |
Kind Code |
A1 |
Naritoku, Dean K. ; et
al. |
July 25, 2002 |
Methods of treating persistent impairment of consciousness by vagus
nerve stimulation
Abstract
Methods of treating persistent impairment of consciousness in
humans and animals by vagus nerve stimulation are provided. These
methods comprise selecting an appropriate human or animal subject
and applying to the subject's vagus nerve an electrical stimulation
signal having parameter values effective in modulating the
electrical activity of the vagus nerve in a manner so as to
modulate the activity of preselected portions of the brain.
Inventors: |
Naritoku, Dean K.;
(Springfield, IL) ; Jensen, Robert A.;
(Carbondale, IL) ; Browning, Ronald A.;
(Carbondale, IL) ; Clark, Kevin B.; (Murphysboro,
IL) ; Smith, Douglas C.; (Carbondale, IL) ;
Terry, Reese S. JR.; (Houston, TX) |
Correspondence
Address: |
SENNIGER POWERS LEAVITT AND ROEDEL
ONE METROPOLITAN SQUARE
16TH FLOOR
ST LOUIS
MO
63102
US
|
Assignee: |
Board of Trustees of Southern
Illinois University
|
Family ID: |
21789899 |
Appl. No.: |
10/047236 |
Filed: |
January 14, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10047236 |
Jan 14, 2002 |
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09613368 |
Jul 10, 2000 |
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09613368 |
Jul 10, 2000 |
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08866800 |
May 30, 1997 |
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60018813 |
May 31, 1996 |
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Current U.S.
Class: |
607/45 |
Current CPC
Class: |
A61N 1/36082 20130101;
A61N 1/36064 20130101; A61N 1/36157 20130101; A61N 1/36053
20130101; A61N 1/36167 20130101 |
Class at
Publication: |
607/45 |
International
Class: |
A61N 001/34 |
Claims
What is claimed is:
1. A method of treating a human or animal subject suffering from
persistent impairment of consciousness, the method comprising: (a)
selecting a human or animal subject suffering from persistent
impairment of consciousness; (b) applying to the vagus nerve of
said human or animal subject a stimulating electrical signal, said
electrical signal being effective to alleviate said persistent
impairment of consciousness; (c) monitoring said human or animal
subject to determine if said persistent impairment of consciousness
has been alleviated, or if further stimulation of said vagus nerve
is required to alleviate said persistent impairment of
consciousness; and (d) if required, further stimulating said vagus
nerve and monitoring said human or animal subject as in preceding
steps (b) and (c), respectively, until said persistent impairment
of consciousness has been alleviated.
2. A method as set forth in claim 1 further comprising producing
said stimulating electrical signal with a stimulus generator
implanted within said human or animal subject's body.
3. A method as set forth in claim 1 wherein the electrical signal
supplies a current to the vagus nerve in the range of from about
0.1 mA to about 10 mA.
4. A method as set forth in claim 1 wherein the electrical signal
supplies a current to the vagus nerve in the range of from about
0.1 mA to about 4 mA.
5. A method as set forth in claim 1 wherein the electrical signal
comprises a train of pulses, each pulse having a pulse width
ranging from about 50 .mu.sec. to about 1,500 .mu.sec.
6. A method as set forth in claim 1 wherein the electrical signal
comprises a train of pulses, each pulse having a pulse width
ranging from about 400 .mu.sec. to about 750 .mu.sec.
7. A method as set forth in claim 1 wherein the electrical signal
comprises a train of pulses having a frequency ranging from about 1
Hz to about 75 Hz.
8. A method as set forth in claim 1 wherein the electrical signal
comprises a train of pulses having a frequency ranging from about
10 Hz to about 40 Hz.
9. A method as set forth in claim 1 wherein the electrical signal
is monophasic, biphasic, or a combination thereof.
10. A method as set forth in claim 1 wherein the electrical signal
comprises a train of pulses having a train duration ranging from
about 1 second to about 4 hours.
11. A method as set forth in claim 1 wherein the electrical signal
comprises a train of pulses having a train duration ranging from
about 5 seconds to about 1 hour.
12. A method as set forth in claim 1 wherein the electrical signal
comprises trains of pulses having an interval between trains
ranging from about 1 second to about 1 week.
13. A method of as set forth in claim 1 wherein the electrical
signal comprises trains of pulses having an interval between trains
ranging from about 5 seconds to about 4 hours.
14. A method as set forth in claim 10 wherein trains are supplied
on demand.
15. A method as set forth in claim 1, wherein said monitoring of
step (c) is performed via a member selected from the group
consisting of clinical outcome, a clinical test, a laboratory test,
and combinations thereof.
16. A method as set forth in claim 15, wherein said laboratory test
is selected from the group consisting of a brain scan, a PET scan,
a SPECT scan, an EEG, an evoked potential, monitoring the level of
a neurotransmitter in the brain, and monitoring the level of a
neurotransmitter in spinal fluid.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of pending U.S. patent
application Ser. No. 09/613,368, filed Jul. 10, 2000, which is a
divisional of U.S. patent application Ser. No. 08/866,800 (now U.S.
Pat. No. 6,104,956), filed May 30,1997, which claims priority from
U.S. Provisional Patent Application Serial No. 60/018,813, filed
May 31, 1996. The texts of U.S. patent application Ser. No.
09/613,368; U.S. patent application Ser. No. 08/866,800 and U.S.
Provisional Patent Application Serial No. 60/018,813 are hereby
incorportated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to methods and apparatus for
modulating neural plasticity in the nervous system. Neural
plasticity includes phenomena such as memory and learning
consolidation processes, as well as recovery of function following
traumatic brain injury. The methods of the present invention are
directed to modulating neural plasticity, improving memory and
learning consolidation processes, cognitive processing, and motor
and perceptual skills in both normal subjects and subjects
suffering from chronic memory impairment, alleviating symptoms and
improving outcome in subjects suffering from traumatic brain
injury, preventing the development of epilepsy in subjects prone to
developing this condition, and treating persistent impairment of
consciousness. These methods employ electrical stimulation of the
vagus nerve in human or animal subjects via application of
modulating electrical signals to the vagus nerve by use of a
neurostimulating device.
BACKGROUND OF THE INVENTION
[0003] Vagal Afferents and their Influence on Physiology and
Behavior
[0004] The vagus nerve comprises both somatic and visceral
afferents (inward conducting nerve fibers that convey impulses
toward a nerve center such as the brain or spinal cord) and
efferents (outward conducting nerve fibers that convey impulses to
an effector to stimulate the same and produce activity). The vast
majority of vagal nerve fibers are C fibers, and a majority are
visceral afferents having cell bodies lying in masses or ganglia in
the neck. For the most part, the central projections terminate in
the nucleus of the solitary tract, which sends fibers to various
regions of the brain such as the hypothalamus, thalamus, and
amygdala. Other projections continue to the medial reticular
formation of the medulla, the cerebellum, the nucleus cuneatus, and
other regions. The solitary nucleus has important pathways to brain
regulatory networks, including the serotonergic nuclei and the
noradrenergic nuclei. These neurotransmitter systems are crucial
for memory, learning, cognitive and sensory/perceptual processing,
and motor skills. These neurotransmitters also prevent the
development of epilepsy, i.e., they are antiepileptogenic, and are
important for the processes that subserve brain recovery following
traumatic injury.
[0005] The majority of vagus nerve fibers are viscerosensory
afferents originating from receptors located in the lungs, aorta,
heart, and gastrointestinal tract, and convey, among other things,
cardiopulmonary and nocicepive information to various forebrain and
brainstem structures (Cechetto, D. F. (1987) Federation Proceedings
46:17-23). Three populations of vasal afferents are known to exist:
the vastly abundant unmyelinated C fibers involved in pain
mediation, and small myelinated B fibers and large A fibers which
subserve autonomic reflexes and probably more complex
visceroendocrine responses, such as glucose metabolism and fluid
homeostasis (Barraco, I. R. A. (1994) Nucleus of the Solitary
Tract, CRC Press, Boca Raton). Nearly all vagal afferents terminate
in the nucleus of the solitary tract (NTS), where the information
they carry is first integrated before being divergently projected
to each rostral level of the neuroaxis. Because NTS neurons impinge
on a number of CNS structures and regions, including the
hypothalamus, hippocampus, amygdaloid complex, dorsal raphe
nucleus, and mesencephalic reticular formation (Rutecki, P. (1990).
Epilepsia 31 (Suppl. 2):51-56), an equally large number of
cognitive, somatic, and visceral operations can be initiated or
coordinated with autonomic information. Thus, as one might expect,
neural signals sent via vagal afferents have a profound impact on
CNS function that, in turn, influence general behaviors and
arousal. For instance, electrical stimulation of the cervical vagus
can modify the electrophysiological profile of neocortical,
thalamic, and cerebellar neurons. These and other changes in
supramedullary circuits are thought to precipitate overt changes
in, for example, sleep, feeding behavior, responsiveness to noxious
stimuli, and monosynaptic muscular reflexes (Rutecki, supra).
[0006] Vagus Nerve Stimulation and the Brain
[0007] Vagus nerve stimulation has been shown to cause activation
of several parts of the brain that are specifically involved in
cognitive processing, memory, learning, sensory and motor
processing, and affects regions of the brain that are prone to
developing epilepsy or which regulate the development of epilepsy
(Naritoku et al. (1995) In Ashley et al., Eds., Traumatic Brain
Injury Rehabilitation, CRC Press, Boca Raton, pp. 43-65). These
studies demonstrate that vagus nerve stimulation activates the
amygdala and cingulate cortex, which are involved in learning and
cognitive processing. Such stimulation also activates several
thalamic nuclei which serve relay functions. In addition, it
activates several sensory nuclei, including the auditory, visual,
and somatic sensory systems. Finally, vagus nerve stimulation
activates monoaminergic nuclei, especially the locus ceruleus and
A5 groups, which provide norepinephrine to the brain. Monoamines
are crucial for both learning and memory, and for preventing the
development of epilepsy (Jobe et al. (1981) Biochem. Pharmacol.
30:3137-3144).
[0008] Modulation of Memory by Arousal
[0009] Both anecdotal and scientific reports have long suggested
that some memories are remembered far more distinctly than others
when those memories were stored at the time of a significant
emotional or stressful life event. This appears to be an important
memory mechanism by which the brain selectively enhances the
storage and retrievability of more important memories, while
minimizing interference from those that are comparatively
inconsequential. The research to date indicates that the storage of
permanent memories is susceptible to enhancing or disrupting
influences shortly after an initial exposure to salient information
(McGaugh, J. L. (1989) Annual Review of Neuroscience 12:255-287;
McGaugh, J. L. (1990) Psychological Science 1:15-25; Squire, L. R.
(1987) Memory and Brain, Oxford University Press, New York). In
clinical and animal studies, improved retention can be produced by
a wide variety of treatments, including the peripheral
administration of certain hormones, neuromodulators, and stimulant
drugs, such as amphetamine. One factor which seems to be common to
those agents that enhance memory is that most are related in some
way to arousal.
[0010] Arousal is associated with the release of adrenal
catecholamines and numerous other substances such as the pituitary
hormones ACTH and vasopressin. Peripheral administration of these
substances has consistently been shown to modulate memory in a
dose- and time-dependent fashion (McGaugh et al. (1989) "Hormonal
Modulation of Memory" In Brush et al., Eds., Psychoendocrinology,
Academic Press, New York). For instance, when moderate doses of
epinephrine or its agonists are given shortly after training on a
memory task, there is enhancement of retention performance measured
some time later (Gold et al. (1977) Behavioral Biology 20:197-207).
Importantly, many substances that modulate memory when either
endogenously released or delivered systemically do not freely cross
the blood-brain barrier, and are therefore unlikely to influence
memory by direct pharmacological action on the brain. Instead, they
appear to activate peripheral receptors that in turn send neural
messages to those central nervous system (CNS) structures involved
in memory consolidation.
[0011] Role of the Vagus Nerve in Mediating Arousal-induced Memory
Modulation
[0012] The vagus nerve appears to be at least partially responsible
for the observed memory-modulating effects of peripherally-acting
agents. Williams et al. ((1991) "Vagal afferents: A possible
mechanism for the modulation of memory by peripherally acting
agents" In: Frederickson et al., Eds., Neuronal control of bodily
function, basic and clinical aspects: Vol. 6., Peripheral signaling
of the brain: Role in neuralimmune interactions, learning and
memory, Hogrefe and Huber, Toronto, pp. 467-472) and Williams et
al. ((1993) Physiology and Behavior 54:659-663) demonstrated that
severing the vagus nerve below the level of the diaphragm
attenuated the memory-enhancing effects of 4-OH amphetamine, an
amphetamine derivative that does not freely enter the CNS, as well
as the memory-impairing effects of peripherally-administered
Leu-enkephalin. Similar attenuation has also been demonstrated with
respect to the memory-modulating capacity of cholecystokinin (Flood
et al. (1987) Science 234:832-834).
[0013] Clinical Measurements of Memory Modulation Induced by
Arousal
[0014] Arousal has also been demonstrated to affect memory
performance in humans. Nielson et al. ((1996) Neurobiology of
Learning and Memory 66:133-142) studied the effects of
muscle-tension-induced arousal on memory storage and later
retention performance. In that study, a moderate level of
muscle-tension-induced arousal was produced by having subjects,
young college students, squeeze a hand dynamometer at various times
during or following presentation of one practice and four 20-item
word lists presented as slides (one every 5 sec.). Thus, each
subject participated in four arousal conditions: no muscle tension;
muscle tension (100 sec.) during learning of the list (encoding);
muscle tension during the 100-sec. memory consolidation interval
(storage); and muscle tension (100 sec.) during the immediate
recall of the words (retrieval). List order remained the same for
all subjects, but the order of arousal conditions was
counterbalanced. A final recognition test was given 5 min. after
completion of all lists. The results demonstrated that
muscle-tension-induced arousal during the memory consolidation
interval significantly enhanced final recognition performance.
[0015] In another phase of this investigation, subjects were given
a series of two practice and twelve 200-word paragraphs to read.
Half of the test paragraphs contained highlighted words.
Immediately following completion of each paragraph, two questions
(one factual and one logical-inferential) were asked about the
content of that paragraph. In addition, for the paragraphs
containing highlighted words, subjects were asked to recall as many
of the highlighted words as they could. For the muscle-tension
arousal paragraphs, immediately after the paragraph was completed,
the subject was handed the hand dynamometer and asked to squeeze it
during the answering of the questions and the recalling of
highlighted words. Following completion of the final paragraph and
all questions, a final recognition test of all highlighted words
was given. The results indicated significant enhancement of
retention performance for the muscle-tension arousal paragraphs
compared to the no-tension paragraphs, indicating that arousal can
enhance memory storage in a working-memory task.
[0016] This experiment was replicated using elderly subjects
(Nielson et al. (1994) Behavioral and Neural Biology 62:190-200).
In this experiment, there were 22 normotensive elderly subjects, 21
elderly subjects taking either calcium-channel blockers or
angiotensin-converting enzyme inhibitors to control hypertension,
and 21 elderly subjects taking beta-blocker antihypertensive
medications. The normotensive elderly subjects and those taking
non-beta-blocker medications all showed enhanced long-term memory
performance as a result of muscle-tension-induced arousal. However,
those subjects chronically taking beta-receptor-antagonist
medications showed no enhancement of retention performance. These
findings suggest that when arousal occurs, there is an enhanced
release of adrenal catecholamines (epinephrine and norepinephrine),
and that these substances activate peripheral receptors that send
neural messages to the brain to modulate memory storage processes.
When these receptors are antagonized by beta-blocker-type
antihypertensive medications, the normal processes of memory
modulation are impaired. Since epinephrine and norepinephrine do
not freely cross the blood-brain barrier, their release by arousal
likely modulates memory by causing the transmission of neural
messages to the brain, possibly via the vagus nerve pathway.
Therefore, antagonizing peripheral beta receptors by
beta-blocker-type antihypertensive medications prevented the
initiation of these messages by the receptors, thus effectively
attenuating the normally occurring modulation of memory storage
processes by arousal.
[0017] Possible Role of Specific Central Serotonergic and
Noradrenergic Pathways in the Modulation of Memory by Vagus Nerve
Stimulation
[0018] The dorsal raphe nucleus is one of two monoaminergic
brainstem nuclei, the other being the locus coeruleus, that
receives indirect input from vagal afferents. Both nuclei then
project that information to various other brain structures
implicated in learning and memory processes, such as the amygdaloid
complex, hippocampus, and mesencephalic reticular formation (Vertes
et al. (1994) Journal of Comparative Neurology 340:11-26). Thus,
the dorsal raphe nucleus and locus coeruleus are well suited to
regulate the memory-modulating effects of autonomic arousal. In
addition, the dorsal raphe nucleus interacts with the amygdaloid
complex to produce conditioned fear responses to inescapable shock
and in learned-helplessness paradigms (Maier et al. (1993)
Behavioral Neuroscience 107:377-788). Elevations in the release of
serotonin by the dorsal raphe nucleus also reportedly increase
anxiety (Iversen (1984) Neuropharmacology 23:1553-1560). It is
therefore possible that changes in autonomic activity and arousal
are reflected in alterations of dorsal raphe nucleus activity and
the subsequent release of serotonin onto neurons found in the
amygdaloid complex. It is therefore possible that changes in
autonomic activity and arousal are transmitted to the brain via the
vagus nerve and are reflected in alterations in the activity of
neurons in the dorsal raphe nucleus and the subsequent release of
serotonin onto neurons of the amygdaloid complex, a brain structure
well-known to be involved in the modulation of learning and
memory.
[0019] Noradrenergic systems are also known to modulate memory
consolidation and amygdaloid complex activity (cf. McGaugh (1989)
Annual Review of Neuroscience 12:255-287); however, Holdefer et al.
((1987) Brain Research 417:108-117) demonstrated that locus
coeruleus-maintained discharge does not correlate with the memory
modulation produced by peripherally-injected 4-OH amphetamine,
D-amphetamine, or epinephrine. Although the locus coeruleus
receives indirect vagal input, it also receives serotonergic
projections from the dorsal raphe nucleus. Consequently, dorsal
raphe nucleus activity might suppress the responsiveness of locus
coeruleus neurons to autonomic stimulation, thereby increasing
serotonergic control over the amygdaloid complex and other brain
areas during the memory consolidation period. This hypothesis is
supported directly by studies of Naritoku et al.((1995) In Ashley
et al., Eds., Traumatic Brain Injury Rehabilitation, CRC Press,
Boca Raton, pp. 43-65), which demonstrated activation of the locus
ceruleus and A5 nuclei, which are noradrenergic neurons.
Preliminary evidence of Krahl et al. ((1994) Society for
Neuroscience Abstracts 20:1453) also indicates that cells found in
the dorsal locus coeruleus respond differentially to those found in
either the ventral locus coeruleus or subcoeruleus following vagus
nerve stimulation.
[0020] Modulation of Memory by Peripherally-acting Substances
[0021] Previous research has suggested that the vagus nerve plays a
role in the modulation of learning and memory brought about by
peripherally-acting substances such as catecholamines, peptides,
etc. (Williams et al. (1991) In Frederickson et al., Eds., Neuronal
Control of Bodily Function, Basic and Clinical Aspects: Volume 6,
Peripheral Signaling of the Brain: Role in Neural-Immune
Interactions, Learning and Memory, Hogrefe & Huber, Toronto,
pp. 467-472; Williams et al. (1993) Physiology and Behavior
54:659-663; Flood et al. (1987) Science 234:832-834). This work
suggests that the vagus nerve may represent a neural pathway
through which such substances alter retention performance. However,
the effects of direct electrical activation of the vagus nerve on
learning and memory in humans have not been previously studied.
[0022] Chemical vs. Direct Electrical Stimulation of the Vagus
Nerve
[0023] 1. Chemical Stimulation
[0024] Hormonal or chemical (drug) agents function by interacting
with specific receptor proteins on neurons. When activated by a
neurotransmitter, hormone, or drug, these receptor proteins then
either: 1) cause a chemical change in the cell, which indirectly
causes ion channels embedded in the membrane to either open or
close, thus causing a change in the electrical potential of the
cell, or 2) directly cause the opening of ion channels, which
causes a change in the electrical potential of the cell. This
change in electrical potential then triggers electrical events that
are conducted to the brain by the axons of sensory nerves such as
those contained in the vagus.
[0025] Neural activity is constantly being controlled by the
endogenous release of hormones, neurotransmitters, and
neuromodulators. However, for therapeutic or experimental purposes,
changes in neural activity can also be produced by the
administration of chemical or hormonal agents (drugs). When
administered exogenously, these agents interact with specific
proteins either inside neurons or on the surface of the cell
membrane to alter cell function. Chemical agents can stimulate the
release of a neurotransmitter or family of neurotransmitters, block
the release of neurotransmitters, block enzymatic breakdown of
neurotransmitters, block reuptake of neurotransmitters, or produce
any of a wide variety of other effects that alter nervous system
functioning. A chemical agent can act directly to alter central
nervous system functioning or it can act indirectly so that the
effects of the drug are carried by neural messages to the brain. A
number of chemical/hormonal agents such as epinephrine,
amphetamine, ACTH, vasopressin, pentylene tetrazol, and hormone
analogs all have been shown to modulate memory. Some act by
directly stimulating brain structures. Others stimulate specific
peripheral receptors.
[0026] 2. Electrical Stimulation
[0027] In contrast, electrical stimulation of a nerve involves the
direct depolarization of axons. When electrical current passes
through an electrode placed in close proximity to a nerve, the
axons are depolarized, and electrical signals travel along the
nerve fibers. The intensity of stimulation will determine what
portion of the axons are activated. A low-intensity stimulation
will activate those axons that are most sensitive, i.e., those
having the lowest threshold for the generation of action
potentials. A more intense stimulus will activate a greater
percentage of the axons.
[0028] Electrical stimulation of neural tissue involves the
placement of electrodes inside or near nerve pathways or central
nervous system structures. Functional nerve stimulation is a term
often used to describe the application of electrical stimulation to
nerve pathways in the peripheral nervous system. The term neural
prostheses describes applications of nerve stimulation in which the
electrical stimulation is used to replace or augment neural
functions which have been damaged in some way. One of the earliest
and most successful applications of electrical stimulation was the
development of the cardiac pacemaker. More recent applications
include the electrical stimulation of the auditory nerve to produce
synthetic hearing in deaf patients, and the enhancement of
breathing in patients with high-level spinal cord injury by
stimulation of the phrenic nerve to produce contractions of
diaphragm muscles. Recently, electrical stimulation of the vagus
nerve is being used to attenuate epileptic seizures.
[0029] The basis of the effects of electrical stimulation of neural
tissue comes from the observation that action potentials can be
propagated by applying a rapidly changing electric field near
excitable tissue such as nerve or muscle tissue. In this case, the
electrical stimulation, when passed through an electrode placed in
close proximity to a nerve, artificially depolarizes the cell
membrane which contains ion channels capable of producing action
potentials. Normally, such action potentials are initiated by the
depolarization of a postsynaptic membrane. However, in the case of
electrical stimulation, the action potentials are propagated from
the point of stimulation along the axon to the intended target
cells (orthodromic conduction). However, action potentials also
travel from the point of nerve stimulation in the opposite
direction as well (antidromic conduction).
[0030] Gold and his co-workers have demonstrated that
administration of glucose to rats or humans following a learning
experience enhances later retention performance (Gold, P. E. (1986)
Behavioral and Neural Biology 45:342-349; Manning et al. (1993)
Neurobiology of Aging 14:523-528). Gold has suggested that vagus
nerve stimulation may activate descending efferent vagus pathways
which directly and indirectly stimulate the liver to release
glucose into the systemic circulation. This increased plasma
glucose has been postulated to serve as a second messenger to
modulate the storage of memories. However, the present
investigators recently demonstrated in rats that blocking
descending vagus nerve pathways by a topical application of the
local anesthetic lidocaine to the nerve did not attenuate memory
enhancement produced by vagus nerve stimulation (Clark, K. B.,
Smith, D. C., Hassert, D. L., Browning, R. B., Naritoku, D. K., and
Jensen, R. A. (submitted for publication)). Posttraining electrical
stimulation of vagal afferents with concomitant efferent
inactivation enhances memory storage processes in the rat (Society
for Neuroscience Abstracts, 22). These results clearly indicate
that the ascending neural messages resulting from vagus nerve
stimulation are the active agent mediating the observed enhancement
in memory storage processes.
[0031] Few experiments in contemporary neuroscience research employ
direct nerve tract stimulation to alter global aspects of behavior
such as the storage of memories. Most researchers attempt to alter
memory and/or behavior by either administering a drug that
activates specific neural systems or by electrically stimulating
specific groups of neurons in the central nervous system. Thus, the
present inventors' discovery of vagus nerve stimulated enhancement
of particular neural processes as disclosed herein is novel. In
this case, stimulation of the vagus nerve results in the activation
of a variety of processes in the brain that result in changes in
brain function. It is likely that only some of these processes are
related to the modulation of memory storage and that this
stimulation also modulates other changes or plastic processes in
the brain as well. That direct vagus nerve stimulation influences
plastic processes related to brain development or the recovery of
function from brain injury is a very good possibility given the
already demonstrated effect on one major form of neural plasticity,
i.e., memory storage.
[0032] Modulation of Memory in Rats by Electrical Stimulation of
the Vagus Nerve
[0033] Jensen and co-workers (Clark, K. B., Krahl, S. E., Smith, D.
C., and Jensen, R. A. (1994) Society for Neuroscience Abstracts 20:
802; Clark, K. B., Krahl, S. E., Smith, D. C., and Jensen, R. A.
Neurobiology of Learning and Memory 63:213-216) demonstrated that
direct electrical stimulation of the vagus nerve at a particular
intensity (0.4 mA) and frequency (20 Hz) administered shortly after
a learning experience resulted in a pattern of effects on retention
performance similar to that reported following the administration
of some drugs that do not freely cross the blood-brain barrier
(chemical stimulation of peripheral receptors). In this experiment,
vagus nerve stimulation (0.4 mA) given during the memory
consolidation interval modulated later retention performance such
that stimulated rats showed better memory. Stimulation at either a
lower (0.2 mA) or higher (0.8 mA) intensity had no effect on
retention.
[0034] Whether one could reasonably predict that this effect
observed in rats might extrapolate to human beings is doubtful in
view of the substantial differences in neuroanatomy and complexity
of memory processes between laboratory rodents and humans. The
experiments performed in rats were based on a single-trial training
task of great simplicity, i.e., an inhibitory avoidance task. In
this task, the animals were placed in a runway, one end of which
was brightly illuminated, while the other end was darkened. As rats
are nocturnal, burrowing animals, they typically move quickly from
the lighted end into the darkened end when the door separating the
two ends of the runway is opened. A mild electrical footshock was
delivered in the darkened end. Immediately thereafter, each animal
was removed from the runway and returned to its home cage, where it
received either no stimulation or vagal stimulation through
chronically implanted cuff electrodes on the left cervical vagus
nerve. Retention was tested 24 hours later. Latency to step through
into the darkened end was taken as the measure of retention.
[0035] In the case of human memory, especially verbal memory, the
neural systems involved are much more complex than those involved
in the learning of a simple avoidance training task by the rat.
Learning of concepts, vocabulary, and procedures by humans is
qualitatively and quantitatively different from a rat's learning to
avoid the end of a runway where punishment, i.e., a footshock, has
occurred. Many human brain structures, such as those that mediate
language, for example, do not even exist in the laboratory rat. It
is therefore possible that the foregoing phenomenon observed in
rats is limited to infrahumans, and it is therefore not reasonably
predictable that vagal nerve stimulation modulation of memory in
the laboratory rat would generalize to human subjects. The
applicability of vagal nerve-stimulated modulation of learning of
tasks such as complex verbal tasks has for the first time been
demonstrated by the present inventors as disclosed herein.
[0036] Uniqueness of Vagus Nerve Stimulation in Modulating
Memory
[0037] Vagus nerve stimulation is completely unlike other
experimental manipulations known to modulate memory. Drugs,
hormones, and electrical brain stimulation are all known to alter
memory storage processes. For example, administration of adrenal
hormones (such as epinephrine) or pituitary hormones (such as ACTH)
after a learning experience results in the enhancement of memory in
a dose-dependent manner. Very low doses are without effect;
intermediate doses tend to improve retention performance; very high
doses tend to cause amnesia. These hormonal substances and
pharmacological agents are thought to act on memory processes by
activating specific receptors in the periphery which, in turn, send
neural messages to the brain to either enhance or impair the
storage of memories.
[0038] In contrast, vagus nerve stimulation directly activates one
principal nerve pathway connecting the central nervous system with
peripheral structures located in the viscera. In this case, the
step of chemically activating receptors in the periphery is
avoided. Rather, action potential messages in the nerve are
directly triggered by the electrical stimulation. These messages
pass along the vagus nerve and activate those brain structures in
which the nerve fibers terminate. The result is release of
neurotransmitters and activation of still other brain structures.
Following this, there are alterations in brain function such as the
well-established reduction in epileptic seizures and the recently
demonstrated enhancement in CNS plasticity, specifically,
facilitation of memory storage processes.
[0039] Brain Neural Plasticity
[0040] The term "neural plasticity" can be viewed as encompassing
those structural alterations in the brain that lead to changes in
neural function. Such changes in neural function then lead to
changes in behavior or in the capacity for behavior. Learning and
memory can be thought of as one common form of neural plasticity.
The storage of memories following a learning experience is the
result of structural and functional changes that occur in specific
groups of neurons. Every time something is learned, there is a
change in that organism's nervous system which encodes that new
information. Such a change does not necessarily result in an
immediate change in behavior; rather, it results in an alteration
in behavior potential.
[0041] During development of the nervous system both before and
after birth, there are profound plastic changes taking place which
shape the structure and function of the brain. Before birth, groups
of nerve cells form, migrate to their assigned location in the
brain, and then make connections with other cells. Following birth,
neurons continue to sprout new projections, and these branches
expand dramatically in complexity, sometimes extending great
distances, and making connections with other cells of the nervous
system. This process, another form of neural plasticity, continues
at a decreasing rate from the time of birth until adolescence.
[0042] Neural plasticity is thought to be moderated by a wide
variety of cellular and molecular events, including transcription
and translation of DNA, which produces cellular proteins that cause
long-term changes in neuronal function. One such signal is thought
to be the protein fos, which is produced by neurons under
conditions of high activity. This protein signals the transcription
of other proteins, and is thought to mediate long-term neuronal
changes. It may be induced by several neurotransmitters, including
excitatory amino acids and monoamines. Naritoku et al. ((1995)
Epilepsy Research 22:53-62) demonstrated that fos is induced by
stimulation of the vagus nerve in widespread areas of the brain
(see FIG. 3), thus demonstrating that vagus nerve stimulation
activates many areas in the brain, and furthermore, appears to
induce the production of a protein that causes further
transcriptional events that may in turn mediate neural
plasticity.
[0043] Memory and Learning, and their Modulation
[0044] It is clear that learning and memory are not unitary
processes and that there are different types of memory that are
mediated by different brain structures. On one level of analysis,
it is possible to distinguish between two broad classes of
memories, "explicit" and "implicit." When explicit memory is to be
assessed, measures such as recall and recognition are used. These
measures depend on the conscious recollection of previously stored
information. Recognition performance is generally considered to be
among the most sensitive measures of explicit memory. Tests of
implicit memory infer learning from the effects that experience or
practice has on the subject's performance. For example, prior
exposure to words will enhance later performance in recognizing
these words when they are flashed very rapidly on a screen or
presented as word fragments.
[0045] Another distinction between types of memory is that between
"procedural" and "declarative" memories. These are typically
defined as "knowing how" and "knowing that." Procedural memories
include perceptual, cognitive, and motor skills, while declarative
memory includes such things as facts, events, and routes between
places. Both forms of memory can be modulated by various agents,
although declarative memories are more subject to disease-produced
amnesia than are procedural memories.
[0046] We know from our own every-day experiences that some
occurrences or events are remembered clearly while others are
remembered poorly or perhaps not at all. This is true of procedural
and declarative memories whether assessed implicitly or explicitly.
It is well established in laboratory animals that retention can be
either impaired or enhanced by experimental treatments such as
electrical brain stimulation, the administration of stimulant
drugs, or the administration of hormones (McGaugh et al. (1972)
Memory Consolidation, San Francisco, Albion Publishing Company).
What is commonly reported is that retention performance, measured
some time after the learning experience, can be modulated by
changing the parameters of training or by the administration of
chemical stimulation shortly after the time of training. Although
the underlying mechanisms that mediate memory modulation are not
well understood, it appears that several common principles may
mediate differences in the quality of remembering.
[0047] One major variable influencing retention performance appears
to be level of arousal. Early in the development of the behavioral
sciences, the Yerkes-Dodson principle was described (Yerkes et al.
(1908) Journal of Comparative Neurology and Psychology 18:459-482).
This principle is characterized by an inverted U-shaped
relationship between the amount of motivation or arousal and the
resultant level of behavioral performance. This relationship can be
seen between the level of arousal and the effectiveness of memory
storage processes. For example, either low or very high levels of
arousal produce relatively poor learning and memory. However, an
intermediate level of arousal results in relatively good memory for
a learning experience (McGaugh, J. L. (1973) Annual Review of
Pharmacology 13:229-241). A similar curve showing an inverted
U-shaped function is seen in the data obtained using laboratory
rats and vagus nerve stimulation delivered after training. It is
important to note that memory is modulated by post-training
treatment. In such an experiment, the learning occurs in a normal
state and then after training, the treatment is administered. Thus,
the primary effects of the treatment are on the storage of the
memory and not on other aspects of the experience such as
perception or level of motivation.
[0048] Traumatic Brain Injury
[0049] Another form of neural plasticity is recovery of function
following brain injury. As in the case of memory formation or brain
development, in this case too there is a change in the ways that
neurons interact with one another. When neurons are lost due to
disease or trauma, they are not replaced. Rather, the remaining
neurons must adapt to whatever loss occurred by altering their
function or functional relationship relative to other neurons.
Following injury, neural tissue begins to produce trophic repair
factors, such as nerve growth factor and neuron cell adhesion
molecules, which retard further degeneration and promote synaptic
maintenance and the development of new synaptic connections.
However, as the lost cells are not replaced, existing cells must
take over some of the functions of the missing cells, i.e., they
must "learn" to do something new. In part, recovery of function
from brain traumatic damage involves plastic changes that occur in
brain structures other than those damaged. Indeed, in many cases,
recovery from brain damage represents the taking over by healthy
brain regions of the functions of the damaged area. Thus, such
recovery can be viewed as the learning of new functions by
uninjured brain areas to compensate for the loss of function by
other regions. Studies of the effect of vagus nerve stimulation
onfos production demonstrate that such stimulation induces
transcriptional events that produce proteins which in turn
stimulate further cellular transcriptional activity (Hughes et al.
(1995) Pharmacol. Rev. 47:133-178). Increases in neuronal cellular
activity will enhance the recovery of function after traumatic
brain injury.
[0050] Traumatic brain injury results from a wide variety of causes
including, for example, blows to the head from objects; penetrating
injuries from missiles, bullets, and shrapnel; falls; skull
fractures with resulting penetration by bone pieces; and sudden
acceleration or deceleration injuries.
[0051] Traumatic brain injury represents a growing medical problem
in the United States and elsewhere. It is an extremely costly
illness, not only due to the expenses arising from the acute care
required, but also due to the costs associated with rehabilitation
and any resulting long-term disability. A therapy that would
accelerate the recovery process and/or improve outcome would be
highly beneficial to afflicted persons. As many as 40% of persons
with severe head injury proceed to develop epilepsy, which further
impedes functional recovery from traumatic brain injury. In
addition, epilepsy itself further limits function in this
population. A therapy that prevents the genesis of epilepsy would
therefore significantly benefit traumatically brain injured
persons.
[0052] Memory Disorders
[0053] A third form of neural plasticity relates to the treatment
of chronic memory disorders. These disorders arise from, for
example, Alzheimer's Disease, encephalitis, cerebral palsy,
Wemicke-Korsakoff (alcohol-related) syndrome, brain injury,
post-temporal lobectomy, Binswanger disease, Parkinson's disease,
Pick's disease, stroke, multi-stroke dementia, multiple sclerosis,
post arrest hypoxic injury, near drowning, etc.
SUMMARY OF THE INVENTION
[0054] As demonstrated in the non-limiting Examples disclosed
infra, vagus nerve stimulation employed with the appropriate
parameters can improve memory and learning in human and animal
subjects. When delivered shortly after a learning experience, vagus
nerve stimulation results in the initiation of nerve impulses that
travel to those brain structures where the nerve terminates,
predominantly the nucleus of the solitary tract. The resultant
release of neurotransmitters and activation of cells in the vagus
nerve target structures results in the activation of other brain
areas including those such as the amygdala and hippocampus that are
known to be involved in memory storage and the modulation of
memory. The result is facilitated memory storage (consolidation)
and improved retention performance when memory is measured at some
later time. Vagus nerve stimulation can also be employed in the
treatment of human and animal subjects suffering from various forms
of brain damage or from traumatic head injury.
[0055] It is well known that central nervous system neurons do not
regenerate following loss due to disease or injury. Therefore, in
order for there to be recovery of function, healthy areas of the
brain must "learn" to take over the functions of the damaged
area.
[0056] As discussed above, both phenomena are manifestations of
brain neural plasticity.
[0057] Briefly, therefore, the present invention provides a number
of methods of influencing various aspects of brain neural
plasticity. In one embodiment, the present invention is directed to
a method of modulating brain neural plasticity in a human or animal
subject. The method comprises applying a stimulating electrical
signal to the vagus nerve of a human or animal subject. The
stimulating electrical signal being effective to cause a
physiological, structural, or neuronal connective alteration in the
brain. Neural function in the brain is changed as a consequence of
the neuronal connective alteration; thereby changing behavior, or
the capacity for behavior, in the human or animal subject.
[0058] In another embodiment, the present invention is directed to
a method of improving learning or memory in a human or animal
subject. The method comprises
[0059] (a) applying a stimulating electrical signal to the vagus
nerve of a human or animal subject, the stimulating electrical
signal being effective to enhance memory storage or consolidation
processes in the human or animal subject; and (b) improving memory
storage or improving the retention of learning experiences, in the
human or animal subject.
[0060] In another embodiment, the present invention is directed to
a method of treating a human or animal subject suffering from a
symptom caused by traumatic brain injury or characteristic of
traumatic brain injury. The method comprises selecting a human or
animal subject suffering from a symptom caused by traumatic brain
injury or characteristic of traumatic brain injury; and applying a
stimulating electrical signal to the vagus nerve of the human or
animal subject, the stimulating electrical signal being effective
to alleviate the symptom caused by or characteristic of traumatic
brain injury. The method further comprises monitoring the human or
animal subject via a member selected from the group consisting of
clinical outcome, a clinical test, a laboratory test, and
combinations thereof, to determine if the symptom has been
alleviated, or if further stimulation of the vagus nerve is
required. If required, the vagus nerve is further stimulated and
the subject is further monitored as in the preceding steps, until
the symptom has been alleviated.
[0061] In another embodiment, the present invention is directed to
a method of preventing the development of epilepsy in a human or
animal subject. The method comprises selecting a human or animal
subject predisposed to, or rendered susceptible to, developing
epilepsy; and applying a stimulating electrical signal being
effective to prevent epilepsy to the vagus nerve of the human or
animal subject. The method further comprises monitoring the subject
to determine if further stimulation of the vagus nerve is required
to prevent epilepsy in the subject; and if required, further
stimulating the vagus nerve and monitoring the subject as in the
preceding steps, to prevent development of epilepsy in the
subject.
[0062] In another embodiment, the present invention is directed to
a method of treating a human or animal subject suffering from a
symptom selected from the group consisting of memory impairment, a
learning disorder, impairment of cognitive processing speed,
impairment of acquisition of perceptual skills, impairment of
acquisition of motor skills, and impairment of perceptual
processing. The method comprises selecting a human or animal
subject suffering from a symptom selected from the group consisting
of memory impairment, a learning disorder, impairment of cognitive
processing speed, impairment of acquisition of perceptual skills,
impairment of acquisition of motor skills, and impairment of
perceptual processing; and applying a stimulating electrical signal
to the vagus nerve of the human or animal subject. The electrical
signal is characterized as being effective to alleviate the symptom
in the human or animal subject. The method further comprises
monitoring the human or animal subject via a method selected from
the group consisting of a clinical test, a laboratory test,
determination of clinical outcome, and combinations thereof, to
determine if the symptom has been alleviated, or if further
stimulation of the vagus nerve is required to alleviate the
symptom; and if required, further stimulating the vagus nerve and
monitoring the human or animal subject as in the preceding steps,
until the symptom has been alleviated.
[0063] In another embodiment, the present invention is directed to
a method of treating a human or animal subject suffering from
persistent impairment of consciousness. The method comprises
selecting a human or animal subject suffering from persistent
impairment of consciousness; and applying a stimulating electrical
signal to the vagus nerve of the human or animal subject. The
stimulating electrical signal is characterized as being effective
to alleviate the persistent impairment of consciousness in the
human or animal subject. The method further comprises monitoring
the human or animal subject via determination of clinical outcome
to determine if the persistent impairment of consciousness has been
alleviated, or if further stimulation of the vagus nerve is
required to alleviate the persistent impairment of consciousness;
and if required, further stimulating the vagus nerve and monitoring
the human or animal subject as in the preceding steps, until the
persistent impairment of consciousness has been alleviated.
[0064] Further scope of the applicability of the present invention
will become apparent from the detailed description and drawings
provided below. However, it should be understood that the detailed
description and specific examples, while indicating preferred
embodiments of the present invention, are given by way of
illustration only since various changes and modifications within
the spirit and scope of the invention will become apparent to those
skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0065] The foregoing and other objects, features, and advantages of
the present invention will be better understood from the following
detailed description taken in conjunction with the accompanying
drawings, all of which are given by way of illustration only and
which are not limitative of the present invention, in which:
[0066] FIG. 1 is a bar graph showing the effect of vagus nerve
stimulation given shortly after a learning experience, collapsed
across Gamma and Delta Group patients. Eleven subjects silently
read paragraphs containing highlighted words. Word recognition
performance was enhanced by vagus nerve stimulation delivered
during the memory consolidation interval. Stimulation intensity was
0.5 mA, biphasic pulses, 30 Hz. Highlighted words that were paired
with vagus nerve stimulation were recognized with greater frequency
(t(9)=2.78,p<0.03) than baseline control words (not paired with
stimulation).
[0067] FIG. 2 is a bar graph showing the effect of vagus nerve
stimulation at tolerance intensities for the Gamma Group. Subjects
were tested 2 weeks, 4 weeks and 16 weeks after implantation of the
neurocybemetic prosthesis. Recognition performance of highlighted
words following stimulation was compared to baseline (no
stimulation). Vagus nerve stiumlation delivered during the memory
consolidation interval significantly enhanced retention performance
only at Test 1 given 2 weeks after implantation with a 0.5 mA
intensity. Stimulation was ramped up to tolerance level after Test
2 and stimulation intensity averaged 1.2 mA on Tests 2 and 3. It is
unclear whether the decrement in the magnitude of the effect is due
to the increased stimulation intensity or to a reduction in effect
with the passage of time.
[0068] FIG. 3 is a camera lucida drawing of fos immunolabeling in
the brain induced by vagus nerve stimulation for three hours (from
FIG. 4 of Naritoku et al. (1995) Epilepsy Research 22:53-62). The
sections are displayed from caudal to rostal levels (left to
right), with the relative abundance of labeled nuclei represented
by the density of the dots in the drawings. Note the immunolabeling
in the cingulate, and retrosplenial cortex, and in the amygdala. In
the thalamus, there is labeling in the habenula, lateral posterior
nucleus, and marginal zone of the medial geniculate body, and in
the hypothalamus there is labeling in the ventromedial and arcuate
nuclei. In the brainstem there is immunolabeling in the locus
ceruleus, A5 nuclei and cochlear nuclei (Abbreviations: A5=A5
nucleus; Arc=arcuate nucleus; Cg=cingulate cortex; HbN=Habenular
nucleus; LC=locus ceruleus; LPMC=Lateral postr thalamic nucleus;
MZMG=marginal zone of medial geniculate; PMCO=postr medial cortical
amygdalar nucleus; PVP=paraventricular nucleus of thalamus;
RS=retrosplenial cortex; RSG=retrosplenial granular cortex;
VC=ventral cochlear nucleus; VMH=ventromedial hypothalamic
nucleus).
[0069] FIG. 4 is a graph showing the antiepileptogenic effect of
vagus nerve stimulation in the rat electrical kindling experiment
described in Example 5.
DETAILED DESCRIPTION OF THE INVENTION
[0070] The following detailed description of the present invention
is provided to aid those skilled in the art in practicing the same.
Even so, the following detailed description should not be construed
to unduly limit the present invention as modifications and
variations in the embodiments discussed herein may be made by those
of ordinary skill in the art without departing from the spirit or
scope of the present inventive discovery.
[0071] The contents of each of the references cited in the present
specification are herein incorporated by reference in their
entirety.
[0072] Devices for Electrical Stimulation of the Vagus Nerve
[0073] The methods of the present invention rely upon modulated
electrical stimulation of the vagus nerve. Such electrical
stimulation can be achieved by a variety of different methods known
in the art. By way of example, such electrical stimulation can be
achieved via the use of a neurostimulating device which can be, but
does not necessarily have to be, implanted within the subject's
body. Forms of neurostimulating devices or accessories therefor
that can be employed in the methods disclosed herein are described
in U.S. Pat. Nos. 4,573,481; 4,702,254; 4,867,164; 4,920,979;
4,979,511; 5,025,807; 5,154,172; 5,179,950; 5,186,170; 5,215,089;
5,222,494; 5,235,980, 5,237,991; 5,251,634; 5,269,303; 5,304,206;
and 5,351,394.
[0074] While the reader is referred to the disclosures of these
documents for details of various neurostimulating devices useful in
the present methods, certain aspects thereof can be summarized as
follows for the reader's convenience.
[0075] The neurostimulator can utilize a conventional
microprocessor and other standard electrical and electronic
components, and in the case of an implanted device, communicates
with a programmer and/or monitor located externally to the
subject's body by asynchronous serial communication for controlling
or indicating states of the device. Passwords, handshakes, and
parity checks can be employed for data integrity. The
neurostimulator also includes means for conserving energy, which is
important in any battery operated device, and especially where the
device is implanted for medical treatment, and means for providing
various safety functions, such as preventing accidental reset of
the device.
[0076] The stimulus generator can be implanted in the patient's
body in a pocket formed by the surgeon just below the skin in the
chest in much the same manner as a cardiac pacemaker would be
implanted, although a primarily external neurostimulator can also
be employed. The neurostimulator also includes implantable
stimulating electrodes, together with a lead system for applying
the output signal of the stimulus generator to the patient's vagus
nerve. Components external to the patient's body include a
programming wand for telemetry of parameter changes to the stimulus
generator and monitoring signals from the generator, and a computer
and associated software for adjustment of parameters and control of
communication between the generator, the programming wand, and the
computer.
[0077] In conjunction with its microprocessor-based logic and
control circuitry, the stimulus generator can include a battery or
set of batteries which can be of any reliable, long-lasting type
conventionally employed for powering implantable medical electronic
devices, such as those employed in implantable cardiac pacemakers
or defibrillators. In a preferred embodiment of the stimulus
generator, the battery can be a single lithium thionyl chloride
cell. The terminals of the cell are connected to the input side of
a voltage regulator which smoothes the battery output to produce a
clean, steady output voltage, and provides enhancement thereof such
as voltage multiplication or division if required.
[0078] The voltage regulator supplies power to the logic and
control section, which includes a microprocessor and controls the
programmable functions of the device. Among these programmable
functions are output current, output signal frequency, output
signal pulse width, output signal on-time, output signal off-time,
daily treatment time for continuous or periodic modulation of vagal
activity, and output signal-start delay time. Such programmability
allows the output signal to be selectively crafted for application
to the stimulating electrode set to obtain the desired modulation
of vagal activity. Timing signals for the logic and control
functions of the generator are provided by a crystal
oscillator.
[0079] A built-in antenna enables communication between the
implanted stimulus generator and the external electronics,
including both programming and monitoring devices, to permit the
device to receive programming signals for parameter changes, and to
transmit telemetry information from and to the programming wand.
Once the system is programmed, it can operate continuously at the
programmed settings until they are reprogrammed by means of the
external computer and the programming wand.
[0080] The logic and control section of the stimulus generator
controls an output circuit or section which generates the
programmed signal levels appropriate for the condition being
treated. The output section and its programmed output signal are
coupled (directly, capacitively, or inductively) to an electrical
connector on the housing of the generator and to a lead assembly
connected to the stimulating electrodes. Thus, the programmed
output signal of the stimulus generator can be applied to the
electrode set implanted on the subject's vagus nerve to modulate
vagal activity in the desired manner.
[0081] The housing in which the stimulus generator is encased is
hermetically sealed and composed of a myaterial such as titanium,
which is biologically compatible with the fluids and tissues of the
subject's body.
[0082] The implanted stimulus generator can be placed in the
subject's chest in a cavity formed by the implanting surgeon just
below the skin, much as a pacemaker pulse generator would be
implanted. A stimulating nerve electrode set is conductively
connected to the distal end of an insulated electrically conductive
lead assembly attached at its proximal end to a connector. The
electrode set can be a bipolar stimulating electrode of the type
described in U.S. Pat. No. 4,573,481. The electrode assembly is
surgically implanted on the vagus nerve in the patient's neck. The
two electrodes are wrapped about the vagus nerve, and the assembly
can be secured to the nerve by a spiral anchoring tether such as
that disclosed in U.S. Pat. No. 4,979,511. The lead(s) is(are)
secured, while retaining the ability to flex with movement of the
chest and neck, by a suture connection to nearby tissue.
[0083] The stimulus generator can be programmed using a personal
computer employing appropriate software and a programming wand. The
wand and software permit non-invasive communication with the
generator after the latter is implanted, which is useful for both
activation and monitoring functions. Programming capabilities
should include the ability to modify the adjustable parameters of
the stimulus generator and its output signal, to test device
diagnostics, and to store and retrieve telemetered data.
[0084] Diagnostics testing should be implemented to verify proper
operation of the device. The nerve electrodes are capable of
indefinite use absent indication of a problem with them observed on
such testing.
[0085] Although an implantable device for vagus nerve stimulation
has been described, it will be apparent to those skilled in the art
from the foregoing description that variations and modifications
thereof can be readily made. For example, rather than employing a
totally implantable **device, one can employ an electronic
energization package that is primarily external to the body.
Stimulation can be achieved with an RF power device implemented to
provide the necessary energy level. The implanted components may be
limited to the lead/electrode assembly, a coil, and a DC rectifier.
Pulses programmed with the desired parameters would be transmitted
through the skin with an RF carrier, and the signal thereafter
rectified to regenerate a pulsed signal for application as the
stimulus to the vagus nerve to modulate vagal activity. This would
virtually eliminate the need for battery changes.
[0086] An external stimulus generator can be employed, with leads
extending percutaneously to the implanted nerve electrode set.
EXAMPLE 1
Modulation of Brain Neural Plasticity by Vagus Nerve
Stimulation
[0087] As noted above, the concept of neural plasticity encompasses
structural alterations in the brain that lead to changes in neural
function. Changes in neural function then lead to changes in
behavior, or in the capacity or potential for behavior.
[0088] The present inventors have concluded that brain neural
plasticity in humans and animals can be modulated by vagus nerve
stimulation by the following steps:
[0089] (a) applying to the vagus nerve of said human or animal a
stimulating electrical signal having parameters sufficient to cause
a physiological, structural, or neuronal connective alteration in
the brain;
[0090] (b) changing neural function in said brain as a consequence
of said alteration; and;
[0091] (c) changing behavior or the capacity for behavior in said
human or animal subject.
[0092] Specifically, brain neural plasticity can be modulated as
follows.
[0093] Apparatus
[0094] The neurostimulating device and electrodes can be implanted
as described in U.S. Pat. Nos. 5,154,172 and 5,269,303, although
any conventional devices known in the art can be employed.
[0095] Stimulation Parameters of the Output Signal
[0096] The preferred range of stimulation parameters of the output
signal of the stimulus generator for modulation of brain
neuroplasticity, and the typical value of each parameter of the
output signal programmed into the device can be as follows.
[0097] The pulse width can be in the range of from about 50
.mu.sec. to about 1,500 .mu.sec., preferably from about 100
.mu.sec. to about 1,000 .mu.sec., more preferably from about 250
.mu.sec. to about 750 .mu.sec., even more preferably from about 400
.mu.sec. to about 750 .mu.sec., and most preferably from about 400
.mu.sec. to about 600 .mu.sec. A pulse width of about 400 .mu.sec.
to about 750 .mu.sec. is appropriate when C fiber activation is
required or desired. If only A and B fiber activation is required
or desired, then a pulse width of about 50 .mu.sec. to about 250
.mu.sec. would be effective. The type of fiber activation can vary
between individual patients.
[0098] The output current can be in the range of from about 0.1 mA
to about 10 mA, more preferably from about 0.1 mA to about 6 mA,
most preferably from about 0.1 mA to about 4 mA.
[0099] The frequency of the output signal can be in the range of
from about 1 Hz to about 75 Hz, more preferably about 5 Hz to about
60 Hz, most preferably from about 10 Hz to about 40 Hz.
[0100] The pulses can be monophasic, biphasic, or a combination
thereof.
[0101] The train duration of the output current can be in the range
of from about 1 sec. to 1,5 about 4 hours, more preferably from
about 2.5 sec. to about 2.5 hours, most preferably from about 5
sec. to about 1 hour. The interval between trains can be in the
range of from about 1 sec. to about 1 week, more preferably from
about 1 sec. to about 1 day, most preferably from about 5 sec. to
about 4 hours. Trains can also be supplied on demand.
[0102] As will be recognized by those of ordinary skill in the art,
any or all of the foregoing vagus nerve stimulation parameters can
be titrated clinically to achieve the desired response in a
patient.
EXAMPLE 2
Improvement of Memory and Learning by Vagus Nerve Stimulation
[0103] Methods and Design
[0104] Learning Experiences
[0105] The learning experiences to which the methods described
herein can be applied include those which are physical, mental, or
a combination thereof. As discussed above, learning and memory, one
form of neural plasticity, can take many forms. Most commonly,
memories are classified as being either procedural or declarative.
Further, there are a number of different aspects to each kind of
memory. Procedural learning and memory, characterized as knowing
how to perform some act, can include the learning and remembering
of motor skills, perceptual abilities, and cognitive capabilities.
Declarative learning and memory, knowing specific kinds of factual
information, can include the knowledge of isolated and connected
facts, the events and episodes of one's lifetime, and the routes
and pathways of everyday life. As noted supra, each of these kinds
of memory is the result of neural plasticity taking place in the
brain, and because each can be modulated by peripherally
administered chemical agents which do not cross the blood-brain
barrier, their mode of action is likely to be through the action of
receptors in the viscera that trigger nerve impulses which travel
along the vagus nerve to targets in the brain. Hence, the storage
of these forms of memory can be modulated by direct stimulation of
the vagus nerve, bypassing the need to activate neural receptors in
the viscera.
[0106] Apparatus
[0107] The device and electrodes can be implanted as described in
U.S. Pat. Nos. 5,154,172 and 5,269,303, although any comparable
device known in the art can be employed.
[0108] Stimulation Parameters of the Output Signal
[0109] Vagus nerve stimulation subsequent to exposure of a human or
animal subject to a learning experience in order to improve
learning or memory in that subject can be performed by employing a
range of stimulation parameter values of the output signal of the
stimulus generator.
[0110] The pulse width can be in the range of from about 50
.mu.sec. to about 1,500 .mu.sec., preferably from about 100
.mu.sec. to about 1,000 .mu.sec., more preferably from about 250
.mu.sec. to about 750 .mu.sec., even more preferably from about 400
.mu.sec. to about 750 .mu.sec., and most preferably from about 400
.mu.sec. to about 600 .mu.sec. A pulse width of about 400 .mu.sec.
to about 750 .mu.sec. is appropriate when C fiber activation is
required or desired. If only A and B fiber activation is required
or desired, then a pulse width of about 50 .mu.sec. to about 250
.mu.sec. would be effective. The type of fiber activation can vary
between individual patients.
[0111] The output current employed for the signal should be of a
moderate or intermediate intensity, and can be in the range of from
about 0.1 mA to about 10 mA, more preferably from about 0.1 mA to
about 6 mA, most preferably from about 0.1 mA to about 4 mA.
[0112] The frequency of the output signal can be in the range of
from about 1 Hz to about 75 Hz, more preferably about 5 Hz to about
60 Hz, most preferably from about 10 Hz to about 40 Hz.
[0113] The output signal can be monophasic, biphasic, or a
combination thereof.
[0114] The train duration of the output current can be in the range
of from about 1 sec. to about 4 hours, more preferably from about
2.5 sec. to about 2 hours, more preferably from about 5 sec. to
about 1 hour, and most preferably about 30 sec. The interval
between trains can be in the range of from about 1 sec. to about 60
sec., more preferably from about 2.5 sec. to about 45 sec., most
preferably from about 5 sec. to about 30 sec.
[0115] The time period after exposure of the human or animal
subject to a learning experience in which electrical stimulation of
the vagus nerve to improve memory or learning can occur can be in
the range of from about 0.01 sec. to about 30 min., more preferably
about 0.05 sec. to about 20 min., most preferably about 0.1 sec. to
about 15 min. The memory consolidation period in humans typically
lasts for 30 minutes after the conclusion of acquisition.
[0116] As will be recognized by those of ordinary skill in the art,
any or all of the foregoing vagus nerve stimulation parameters can
be titrated by routine experimentation to achieve the desired
memory enhancement response in a particular subject.
[0117] The improved storage of the memory or retention of the
learning experience can be observed hours, days, weeks, months, or
years after exposing or subjecting a human or animal subject to the
learning experience.
[0118] Stimuli and Tests for Human Testing
[0119] Fourteen narrative paragraphs were used as stimuli in this
experiment. Each paragraph was approximately 200 words in length,
of appropriate reading level for each subject, and each was typed
on a separate page. When presented to the subjects, each paragraph
was covered with a cardboard mask that revealed only two lines of
text at a time. Subjects were instructed to read at a comfortable
pace and to move the mask down the page as the paragraph was read.
Subjects were told that they would be questioned about the
paragraphs later, and that the mask was being used to prevent
reviewing of the material. Two versions of each paragraph were
prepared. In one version, seven words were highlighted using a
yellow marking pen, and subjects were told that a memory test for
these words would follow questions about the paragraph. In the
other set of paragraphs, no words were highlighted. Words chosen
for highlighting were common nouns, and were distributed equally
throughout each paragraph.
[0120] In each block of seven paragraphs, the first paragraph was
shorter and simpler than the subsequent paragraphs, and served as a
warm-up paragraph. Data from these warm-up paragraphs were not
included in the analysis. For the six test paragraphs in each
block, three "loaded" paragraphs (paragraphs with highlighted words
to be remembered) were alternated with three "unloaded" paragraphs
(no highlighted words). In addition, in one of the two blocks of
paragraphs, stimulation of the vagus nerve occurred, while in the
other block, the loaded trials were not associated with vagus nerve
stimulation. Whether vagus nerve stimulation occurred in the first
or second block of paragraphs was counterbalanced across subjects.
The overall design of this experiment is summarized in Table 1.
1TABLE 1 Summary of Experimental Design 1 2 3 4 5 6 7 Break 8 9 10
11 12 13 14 1 X A B C D E F X G H I J K L 2 X B A D C F E X H G J I
L K 3 X A B C D E F X G H I J K L 4 X B A D C F E X H G J I L K
[0121] Letters A-L and X represent the paragraphs of text that were
read by the subjects; rows represent the four condition orders.
Underlines indicate that highlighted word was present in the
paragraphs; italics indicate that stimulation of the vagus nerve
was given following reading of the paragraph. Subjects were
assigned to an experimental condition via Latin-square
rotation.
[0122] Procedure for Human Testing
[0123] Each subject was given a brief summary of the procedure used
in this study at each visit (i.e., visits 2, 5, and 7), and any
questions were answered prior to testing. Visit 2 testing served as
a pre-implantation baseline consisting of paragraph reading
followed by inferential, logical, and retention queries. The
procedures for this visit were identical to those discussed below
for visits 5 and 7, except that vagus nerve stimulation was not
administered. The first series (5 stimulations) of vagus nerve
stimulations were given to subjects during visit 5 at an intensity
of 0.5 mA with a frequency of 30 Hz (Gamma) or minimal perceptible
current (0.25-1 mA) at 1 Hz (Delta). During this time, the reaction
of the subject was studied, and appropriate adjustments were made.
This enabled each subject to become acquainted with the sensations
produced by the stimulation, and helped to minimize possible
effects of novelty produced by the sensations associated with
stimulation. It is important to eliminate any novelty effects
produced by the stimulation.
[0124] At that time, during Visit 5, those subjects in the Gamma
Group received vagus nerve stimulation at 0.5 mA, 30 Hz. Those in
the Delta Group received threshold stimulation to perception (0.25
to 1.0 mA) once every 180 minutes. Following stimulation, a
one-hour rest period was given to ensure that any residual effects
resulting from these first exposures to the stimulation current
were minimized before memory testing procedures began. Ramping
procedures began following completion of the memory testing
procedure on Visit 5.
[0125] Following the one-hour rest period, subjects were asked to
read a practice paragraph (paragraph X in Table 1) to familiarize
them with the use of the cardboard mask during reading. A
two-minute rest period followed to allow dissipation of any arousal
that might have occurred. Pulse rate and blood pressure were
measured at the end of this rest period. The two blocks of six
paragraphs each were then administered. There was a five-minute
rest period following administration of the first block of
paragraphs and the beginning of the second. A warm-up paragraph was
also given at the start of the second block of paragraphs.
Immediately following completion of each paragraph, pulse rate and
blood pressure were recorded and two questions, one factual and one
logical-inferential, were asked about the content of that
paragraph. In addition, for the loaded paragraphs, subjects were
asked to recall the highlighted words following answering of the
two questions. For those paragraphs to be paired with vagus-nerve
stimulation, immediately after each subject in the Gamma Group
completed reading the paragraph and answering the questions, she/he
was given vagus nerve stimulation for 30 sec. Those subjects in the
Delta Group received no stimulation.
[0126] Following completion of the final paragraph and the
answering of questions, an unannounced recognition test of all
highlighted words was given. In this test, a list of all 42
highlighted target words was randomly interspersed with 210
distractor words (16.6% target words). The distractor words were
highly concrete imageable nouns (Pavio et al. (1968). Concreteness,
imagery, and meaningfulness values for 925 nouns. Journal of
Experimental Psychology, 76, (Suppl), 1-25). Subjects were asked to
mark all words which they believed had been previously presented as
highlighted words in the paragraphs they had read earlier. When
this test was completed, pulse rate and blood pressure were
measured and the ramp-up or ramp-down procedure was resumed.
[0127] Subjects were again tested during Visit 7 according to the
basic procedures described above for Visit 5. This time, however,
vagus nerve stimulation given after the reading of half the
paragraphs was for the subjects in the Gamma Group at the tolerance
intensity that each had been ramped up to. This ranged from 0.75 mA
to 1.5 mA. A final test was conducted on Visit 9. This time,
subjects in the Gamma Group received vagus nerve stimulation at
their individual tolerance intensity (0.75 mA to 1.5 mA), while all
subjects in the Delta Group received stimulation at 0.5 mA.
[0128] This experimental design enables each subject to establish
his/her own baseline against which stimulation effects are
measured. Each stimulation group provided a standard of comparison
to evaluate the general effects of device implantation and vagus
nerve stimulation on memory performance. This is crucial as the
pre-implantation baseline measures (Visit 4) rules out changes in
performance merely resulting from surgery or the presence of the
device. The pre-implantation baseline is not in itself an adequate
control for cognitive testing without an additional
post-implantation stimulation baseline. This control was provided
by paragraph reading followed by no vagus nerve stimulation in each
group. Further, this experimental design permits the comparison of
the effects of different current intensity levels. One half of the
patients (those in the Gamma Group) were treated with 0.5 mA
stimulation during Visit 5. The other half of the patients (the
Delta Group) received no stimulation at either Visit 5 or Visit 7.
On Visit 7, patients in the Gamma Group had their stimulation
intensity increased to their own individual tolerance level, not
exceeding the ceiling intensity of 1.5 mA. Stimulation intensity is
an important factor as the results from laboratory animal studies
(Clark et al. (1994) Society for Neuroscience Abstracts 20:802;
Clark et al. (1995) Neurobiology of Learning and Memory 63:213-216)
indicate that this is an important parameter. In that case, only
0.4 mA stimulation produced significant enhancement in retention
performance. Lastly, if vagus nerve stimulation has a capacity to
improve memory or other cognitive functions in humans, it is most
likely to do so for those specific events occurring during an
interval time-locked to the stimulus. The vagus nerve stimulation
stimulus selectively enhances certain information over the milieu
of other information during the memory consolidation period.
General neuropsychological tests for cognitive and memory
performance are not designed to evaluate the time-locked pairing of
salient cues (i.e., vagus nerve stimulation-induced arousal) with
the acquisition of information. Therefore, any memory-modulating
effect would be overlooked or masked (i.e., a lowered mean
retention performance) by retention queries for acquired
information other than that associated with or time-locked to vagus
nerve stimulation. The working memory paradigm described above is,
in contrast, sensitive to even subtle vagus nerve stimulation
influences on the formation of memories, since retention for words
time-locked to vagus nerve stimulation at three different
intensities are compared to retention for words time-locked to no
vagus nerve stimulation.
[0129] Results
[0130] Recognition memory performance of eleven patients was
analyzed in tests performed on Visits 5, 7, and 9 (two, four, and
sixteen weeks postimplantation, respectively). The results are
summarized in FIGS. 1 and 2.
[0131] Current Intensity at 0.5 mA
[0132] FIG. 1 shows the effect of vagus nerve stimulation (0.5 mA,
0.5 ms pulse width, 30 Hz), given shortly after a learning
experience, collapsed across Gamma- and Delta-group patients. To
counterbalance for time effects, patients (n=5) in the Gamma group
received the above mentioned stimulus at Visit 5 while those
patients (n=6) in Delta group received the identical stimulation at
Visit 9. Each subject read a series of paragraphs, some of which
contained highlighted words. In half the trials, reading a
paragraph with highlighted words was followed by vagus nerve
stimulation. In the other half of the trials, no stimulation was
given. Retention performance, measured as recognition of
highlighted words, showed that subjects remembered more words from
trials that were followed by vagus nerve stimulation than they did
in those trials in which no stimulation followed reading of the
paragraphs (t(9)=2.78, p<0.025). These data indicate that
regardless of the time after device implantation, vagus nerve
stimulation at 0.5 mA, when administered after a learning
experience, significantly enhanced retention performance of the
learned material.
[0133] Current Intensity at Subject Tolerance
[0134] At Visits 7 and 9, patients in the Gamma group received
vagus nerve stimulation at each individual's tolerance intensity
(e.g., 0.75 to 1.5 mA). FIG. 2 shows the effect of vagus nerve
stimulation at tolerance intensities for the Gamma group. Vagus
nerve stimulation given at tolerance intensities (0.75 to 1.5 mA)
shortly after a learning experience did not significantly enhance
recognition performance (t(9)=0.76, p<0.470). This finding
parallels those effects observed for animals in the inventors'
laboratory (Clark et al. (1994) Society for Neuroscience Abstracts
20:802; Clark et al. Neurobiology of Learning and Memory
63:213-216). Animals that received posttraining administration of
vagus nerve simulation showed significantly enhanced memory
performance at moderate current intensities (i.e. 0.4 mA), but not
at the comparatively higher stimulation intensity of 0.8 mA. Such
an input-output curve is analogous to the inverted U-shaped dose
response curves commonly found for memory modulating drugs. Thus,
these findings with human subjects suggest that vagus nerve
stimulation produces enhancement of memory storage processes in a
manner similar to that of other memory modulatory agents.
EXAMPLE 3
Treatment of Traumatic Brain Injury by Vagus Nerve Stimulation
[0135] Vagus nerve stimulation is expected to help sufferers of
traumatic brain injury in a number of ways.
[0136] First, vagus nerve stimulation induces increased neuronal
activity in widespread regions of the brain (Naritoku et al. (1995)
Epilepsy Research 22:53-62). Such stimulation can ameliorate the
problems of brain hypometabolism and decrease in brain activity
induced by brain injury, and aid in improving recovery of
cognition, motor skills, activities of daily living, and
memory.
[0137] Secondly, vagus nerve stimulation activates the protein fos
in brain neurons (Naritoku et al., supra). Since this protein
promotes subsequent transcription and translation of genes, thereby
increasing the production of cellular proteins, it enhances brain
neural plasticity and thereby contributes to recovery from
injury.
[0138] Thirdly, vagus nerve stimulation produces widespread
increases of monoamines in the brain, including the
neuro-transmitters serotonin and norepinephrine. Several studies
indicate that increases in monoamines are antiepileptogenic, i.e,
prevent epilepsy (Gellman et al. (1987) J. Pharmacol. Exp. Ther.
241:891-898). While drugs that increase monoamines, such as
amphetamines, cause undesired side effects, vagus nerve stimulation
represents a means of increasing monoamine transmission without
negative side effects.
[0139] Next, vagus nerve stimulation will aid in preventing the
development of epilepsy. Previous investigations on vagus nerve
stimulation have examined the treatment of established chronic
epilepsy. The methods disclosed herein are expected to be useful in
preventing the development of epilepsy itself. Several types of
data support this hypothesis.
[0140] First, at least part of the anti-seizure properties of vagus
nerve stimulation relates to activation of monoaminergic nuclei.
Krahl et al. ((1994) Society for Neuroscience Abstracts 20:1453)
have demonstrated that inactivation of monoaminergic nuclei reduces
the effectiveness of vagus nerve stimulation. Furthermore, the data
of Naritoku et al. ((1995) Epilepsy Res. 22:53-62) demonstrate that
vagus nerve stimulation activates the A5 and locus ceruleus
noradrenergic nuclei.
[0141] Secondly, increasing monoaminergic transmission prevents the
development of epilepsy in animals (Jobe et al. (1981) Biochem.
Pharmacol. 30:3137-3144). This property has been termed
"antiepileptogenic," as opposed to "antiepileptic" or
"anticonvulsant". An antiepileptogenic therapy is distinctly
different from antiepileptic or anticonvulsant therapies in that
the latter two therapies prevent seizures once epilepsy is
established, but do not prevent the development of epilepsy, as do
antiepilepto-genic therapies. The effects of vagus nerve
stimulation will prevent the processes that cause epilepsy.
Specifically, injections of high amounts of monoaminergic drugs
such as clonidine block the rate at which epilepsy can be
established in animal models using the kindling protocol, which
involves direct applications of small amounts of electrical
currents to limbic structures (Burchfiel et al. (1989) Neurosci.
Behav. Rev. 13:289-299; Gellman et al. (1987) J. Pharmacol. Exp.
Ther. 241:891-898).
[0142] Thirdly, increases in serotonin or norepinephrine brought
about by drugs such as fluoxetine reduce spontaneous and induced
seizures in animals and humans (Jobe et al. (1973) J. Pharmacol.
Exp. Ther. 184:1-10; Leander (1992) Epilepsia 33:573-576; Favale et
al. (1995) Neurology 45:1926-1927).
[0143] Finally, vagus nerve stimulation is expected to improve
memory in brain-injured patients. As demonstrated in Example 1,
supra, vagus nerve stimulation improves memory function in normal
human subjects.
[0144] Methods and Design
[0145] Types of Brain Injuries Amenable to Treatment by Vagus Nerve
Stimulation
[0146] Vagus nerve stimulation can be used to improve recovery of
patients suffering from traumatic brain injury such as that
incurred, for example, from blows to the head from various objects;
penetrating injuries from missiles, bullets, shrapnel, etc., falls;
skull fractures with resulting penetration by bone pieces; sudden
acceleration or deceleration injuries; and other causes well known
in the art. Exemplary symptoms of such brain injuries include, but
are not limited to, impaired level of consciousness, impaired
cognition, impaired cognitive processing speed, impaired language,
impaired motor activity, impaired memory, impaired motor skills,
and impaired sensory skills.
[0147] Apparatus
[0148] The device and electrodes can be implanted as described in
U.S. Pat. Nos. 5,154,172 and 5,269,303, although any conventional
devices known in the art can be employed.
[0149] Stimulation Parameters of the Output Signal
[0150] The preferred range of stimulation parameters of the output
signal of the stimulus generator for treatment of traumatic brain
injury, and the typical value of each parameter of the output
signal programmed into the device by the attending physician or
therapist, can be as follows.
[0151] The pulse width can be in the range of from about 50
.mu.sec. to about 1,500 .mu.sec., preferably from about 100
.mu.sec. to about 1,000 .mu.sec., more preferably from about 250
.mu.sec. to about 750 .mu.sec., even more preferably from about 400
.mu.sec. to about 750 .mu.sec., and most preferably from about 400
.mu.sec. to about 600 .mu.sec. A pulse width of about 400 .mu.sec.
to about 750 .mu.sec. is appropriate when C fiber activation is
required or desired. If only A and B fiber activation is required
or desired, then a pulse width of about 50 .mu.sec. to about 250
.mu.sec. would be effective. The type of fiber activation can vary
between individual patients.
[0152] The output current can be in the range of from about 0.1 mA
to about 10 mA, more preferably from about 0.1 mA to about 6 mA,
most preferably from about 0.1 mA to about 4mA.
[0153] The frequency of the output signal can be in the range of
from about 1 Hz to about 75 Hz, more preferably about 5 Hz to about
60 Hz, most preferably from about 10 Hz to about 40 Hz.
[0154] The pulses can be monophasic, biphasic, or a combination
thereof.
[0155] The train duration of the output current can be in the range
of from about 1 sec. to about 4 hours, more preferably from about
2.5 sec. to about 2.5 hours, most preferably from about 5 sec. to
about 1 hour. The interval between trains can be in the range of
from about 1 sec. to about 1 week, more preferably from about 1
sec. to about 1 day, most preferably from about 5 sec. to about 4
hours. Trains can also be supplied on demand if this is determined
to be preferable by the physician or therapist.
[0156] The stimulating electrical signal can be applied to the
vagus nerve any time after appearance of any of the symptoms noted
above, for example, within a time period of from about 1 hour to
about 3 months after appearance of the symptom.
[0157] Finally, the duration of the total therapy can vary
depending upon the nature and severity of the brain injury, as well
as the physical attributes and condition of the patient. Therapy
can vary from about one day to as long as continued clinical
improvement is obtained or desired, e.g., several months or years
to the remainder of the patient's life. The necessity for, or
desirability of, further therapy can be determined from results
obtained via administering a variety of different clinical or
laboratory tests to the patient. Examples of useful clinical tests
include tests of activities required for daily living, memory,
cognition, motor skills, development of epilepsy, FIM (Functional
Index Measurement) scores, and other standardized measurements of
functional outcome. Examples of useful laboratory tests include a
brain scan, a PET scan, a SPECT scan, an EEG, an evoked potential,
monitoring the level of a neurotransmitter such as norepinephrine,
serotonin, or dopamine, or metabolites thereof, in the brain, and
monitoring the level of a neurotransmitter in spinal fluid.
[0158] As will be recognized by those of ordinary skill in the art,
any or all of the foregoing vagus nerve stimulation parameters can
be titrated clinically to achieve the desired response in a
patient.
EXAMPLE 4
[0159] Prevention of Epilepsy by Vagus Nerve Stimulation
[0160] As noted above in Example 3, various types of data lead to
the conclusion that vagus nerve stimulation is expected to be
effective in preventing the development of epilepsy. Such therapy
is applicable not only in the treatment of patients suffering from
traumatic brain injury, but also in preventing the development of
epilepsy in other subjects prone to this disorder. This population
includes patients predisposed to, or rendered susceptible to,
developing epilepsy. These patients include, for example, those
suffering from a disease or condition such as traumatic brain
injury, post-encephalitic patients, post-stroke patients, and
patients having a family history or genetic background predisposing
them to developing epilepsy.
[0161] Methods and Design
[0162] Apparatus
[0163] The device and electrodes can be implanted as described in
U.S. Pat. Nos. 5,154,172 and 5,269,303, although any conventional
devices known in the art can be employed.
[0164] Stimulation Parameters of the Output Signal
[0165] The preferred range of stimulation parameters of the output
signal of the stimulus generator for the prevention of epilepsy,
and the typical value of each parameter of the output signal
programmed into the device by the attending physician or therapist,
can be as follows.
[0166] The pulse width can be in the range of from about 50
.mu.sec. to about 1,500 .mu.sec., preferably from about 100
.mu.sec. to about 1,000 .mu.sec., more preferably from about 250
.mu.sec. to about 750 .mu.sec., even more preferably from about 400
.mu.sec. to about 750 .mu.sec., and most preferably from about 400
.mu.sec. to about 600 .mu.sec. A pulse width of about 400 .mu.sec.
to about 750 .mu.sec. is appropriate when C fiber activation is
required or desired. If only A and B fiber activation is required
or desired, then a pulse width of about 50 .mu.sec. to about 250
.mu.sec. would be effective. The type of fiber activation can vary
between individual patients.
[0167] The output current can be in the range of from about 0.1 mA
to about 10 mA, more preferably from about 0.1 mA to about 6 mA,
most preferably from about 0.1 mA to about 4 mA.
[0168] The frequency of the output signal can be in the range of
from about 1 Hz to about 75 Hz, more preferably about 5 Hz to about
60 Hz, most preferably from about 10 Hz to about 40 Hz.
[0169] The pulses can be monophasic, biphasic, or a combination
thereof.
[0170] The train duration of the output current can be in the range
of from about 1 sec. to about 4 hours, more preferably from about
2.5 sec. to about 2.5 hours, most preferably from about 5 sec. to
about 1 hour. The interval between trains can be in the range of
from about 1 sec. to about 1 week, more preferably from about 1
sec. to about 1 day, most preferably from about 5 sec. to about 4
hours. Trains can also be supplied on demand if this is determined
to be preferable by the physician or therapist.
[0171] Finally, the duration of the total therapy can vary
depending upon the nature and severity of the underlying disorder
or condition, as well as the physical attributes and condition of
the patient. Therapy can vary from about one day or one year to as
long as continued clinical improvement is obtained or desired,
e.g., several months or years to the remainder of the patient's
life. In the case of preventing epilepsy, the total duration of
therapy can be in the range of from about one day to as long as
necessary to prevent development of epilepsy in the patient.
Monitoring of patients for clinical improvement can be performed by
conducting a procedure selected from an electroencephalogram, an
evoked potential, spectral mapping, voltage mapping, clinical
assessment, and combinations thereof.
[0172] As will be recognized by those of ordinary skill in the art,
any or all of the foregoing vagus nerve stimulation parameters can
be titrated clinically to achieve the desired response in a
patient.
EXAMPLE 5
Antiepileptogenic Effect of Vagus Nerve Stimulation in a Rat
Electrical Kindling Model
[0173] Electrical kindling is an important model of
epileptogenesis, i.e., the development of a chronic seizure focus.
Since repeated kindling sessions cause progressive increases in
severe seizure severity (Goddard et al. (1969) Exp. Neurol.
25:295-330), electrical kindling can be utilized to test for
antiepileptogenic properties of a given therapy (Schmutz et al.
(1988) J. Neural. Transm. 72:245-257; Silver et al. (1991) Ann.
Neurol. 29:356-363). The effectiveness of vagus nerve stimulation
in opposing epileptogenesis was therefore investigated using this
paradigm.
[0174] Experimental
[0175] Electrodes were implanted on the left vagus nerve of adult
male Sprague-Dawley rats (250-300 g) to provide vagus nerve
stimulation. A twisted pair depth electrode was implanted into the
right amygdala (coordinates from bregma: AP -2.4 mm; ventral -8.6m;
lateral -4.2 mm) using a stereotaxic device, and the animals were
allowed to recuperate for at least one week.
[0176] On the first day, the kindling threshold was determined by
applying 100 Hz biphasic square wave pulses to the depth electrode
for 30 sec. The current was increased in 10 .mu.A increments until
at least a 10 sec. aferdischarge was obtained. The resulting
threshold current was recorded for each animal and used for
subsequent sessions. Prior to each kindling session, vagus nerve
stimulation (1 mA/30 Hz/500 .mu.sec. biphasic square pulses) or
sham stimulation (i.e., identical handling, no vagus nerve
stimulation) was administered for one hour. Subsequently, daily
kindling stimuli were administered through the depth electrode
(biphasic square wave, 100 Hz). Seizures were scored on a standard
severity scale (Racine, R. J. (1972) Electroencephalogr. Clin.
Neurophysiol. 32:281) on a scale from 0 to 5, in which 5 represents
a fully kindled convulsive seizure. The results are shown in FIG.
4.
[0177] Results
[0178] As can be seen in FIG. 4, there were significant differences
in the progression of kindling stage for rats that received vagus
nerve stimulation pretreatment (-.box-solid.-, n=4), control
animals that did not receive vagus nerve stimulation
[0179] (-.circle-solid.-, n=5), and a third comparison group
(-.tangle-solidup.-, n=7) that received vagus nerve stimulation for
the first 6 days, but not for subsequent kindling sessions
(p=0.0001; repeated measures ANOVA).
[0180] Post-hoc analysis revealed that there was a significant
delay in animals that received vagus nerve stimulation compared to
control animals (p.ltoreq.0.01; Newman-Keuls test). The mean
stimuli to class 5 seizures was 11.3.+-.1.5 (days.+-.SD) in vagus
nerve stimulation-treated animals (-.box-solid.-) compared to
6.0.+-.1.2 in sham-treated animals (-.circle-solid.-; p=0.001;
t-test).
[0181] To assure that the treatment opposed epileptogenesis rather
than masking the resulting seizure, the third group received vagus
nerve stimulation for 6 kindling sessions, and then received no
vagus nerve stimulation during subsequent sessions. This is shown
by the middle curve (-.tangle-solidup.-) in FIG. 4. As expected,
the rate of kindling in this group was similar to that in the other
treated group that received the first six vagus nerve stimulations
(-.box-solid.-). If vagus nerve stimulation was simply masking the
seizure severity, the severity score would be expected to increase
to control values for the remaining kindling sessions. However, the
seizure severity scores remained significantly lower than those in
control animals (p.ltoreq.0.01, Neuman-Keuls test), and exhibited
an intermediate progression of severity increases. These results
demonstrate that the vagus nerve stimulation opposed, rather than
masked, epileptogenesis.
[0182] In summary, these kindling experiments indicate that vagus
nerve stimulation can oppose epileptogenesis, and may therefore be
a useful therapy to prevent the development of epilepsy in clinical
situations associated with a high risk for developing epilepsy.
EXAMPLE 6
Treatment of Memory Disorders and Chronic Memory Impairment by
Vagus Nerve Stimulation
[0183] Electrical stimulation of the vagus nerve can also be used
in therapies to treat subjects suffering from diseases or
conditions in which memory impairment or learning disorders are a
prominent feature. Examples of such diseases or conditions include
Alzheimer's Disease, Binswanger Disease, Pick's Disease,
Parkinson's Disease, cerebral palsy, post-meningitis,
post-encephalitis, traumatic brain injury, Wernicke-Korsakoff
syndrome, alcohol-related memory disorders, post-temporal
lobectomy, memory loss from multi-infarct (stroke) state, multiple
sclerosis, post-cardiac arrest injury, post-hypoxic injury, and
near drowning.
[0184] Electrical stimulation of the vagus nerve can also be used
in therapies to treat subjects suffering from disorders in which
impairment of cognitive processing speed, acquisition of perceptual
skills, acquisition of motor skills, or perceptual processing are a
prominent feature. Examples of these diseases or conditions include
mental retardation, multiple sclerosis, perinatal asphyxia,
intrauterine infections, cerebral palsy, post-meningitis,
post-encephalitis, dyslexia, constructional apraxia, post-cardiac
arrest injury, post-hypoxic injury, multi-infarct (stroke) state,
and near drowning.
[0185] Methods and Design
[0186] Apparatus
[0187] The device and electrodes can be implanted as described in
U.S. Pat. Nos. 5,154,172 and 5,269,303, although any conventional
devices known in the art can be employed.
[0188] Stimulation Parameters of the Output Signal
[0189] The preferred range of stimulation parameters of the output
signal of the stimulus generator for the treatment of memory
impairment, learning disorders, impairment of cognitive processing
speed, acquisition of perceptual skills, acquisition of motor
skills, or perceptual processing, and the typical value of each
parameter of the output signal programmed into the device by the
attending physician or therapist, can be as follows.
[0190] The pulse width can be in the range of from about 50
.mu.sec. to about 1,500 .mu.sec., preferably from about 100
.mu.sec. to about 1,000 .mu.sec., more preferably from about 250
.mu.sec. to about 750 .mu.sec., even more preferably from about 400
.mu.sec. to about 750 .mu.sec., and most preferably from about 400
.mu.sec. to about 600 .mu.sec. A pulse width of about 400 .mu.sec.
to about 750 .mu.sec. is appropriate when C fiber activation is
required or desired. If only A and B fiber activation is required
or desired, then a pulse width of about 50 .mu.sec. to about 250
.mu.sec. would be effective. The type of fiber activation can vary
between individual patients.
[0191] The output current can be in the range of from about 0.1 mA
to about 10 mA, more preferably from about 0.1 mA to about 6 mA,
most preferably from about 0.1 mA to about 4 mA.
[0192] The frequency of the output signal can be in the range of
from about 1 Hz to about 75 Hz, more preferably about 5 Hz to about
60 Hz, most preferably from about 10 Hz to about 40 Hz.
[0193] The pulses can be monophasic, biphasic, or a combination
thereof.
[0194] The train duration of the output current can be in the range
of from about 1 sec. to about 4 hours, more preferably from about
2.5 sec. to about 2.5 hours, most preferably from about 5 sec. to
about 1 hour. The interval between trains can be in the range of
from about 1 sec. to about 1 week, more preferably from about 1
sec. to about 1 day, most preferably from about 5 sec. to about 4
hours. Trains can also be supplied on demand if this is determined
to be preferable by the physician or therapist.
[0195] The stimulating electrical current can be applied to the
vagus nerve any time after appearance of the symptom(s) to be
treated.
[0196] Finally, the duration of the total therapy can vary
depending upon the nature and severity of the disorder, condition,
or impairment, as well as the physical attributes and condition of
the patient. Therapy can vary from about one day to as long as
continued clinical improvement is obtained or desired, e.g.,
several months or years to the remainder of the patient's life.
Clinical tests that can be employed to monitor the success of
therapy include standard neuropsychological tests such as WISC,
WAIS, Halsted-Reitan, and combinations thereof. Useful laboratory
tests include, for example, electroencephalograms, evoked
potentials, spectral mapping, voltage mapping, clinical assessment,
and combinations thereof.
[0197] As will be recognized by those of ordinary skill in the art,
any or all of the foregoing vagus nerve stimulation parameters can
be titrated clinically to achieve the desired response in a
patient.
EXAMPLE 7
Treatment of Persistent Impairment of Consciousness by Vagus Nerve
Stimulation
[0198] The present inventors have also concluded that vagus nerve
stimulation can be employed in the treatment of persistent
impairment of consciousness, such as that associated with coma or
vegetative states.
[0199] Methods and Design
[0200] Apparatus
[0201] The device and electrodes can be implanted as described in
U.S. Pat. Nos. 5,154,172 and 5,269,303, although any conventional
devices known in the art can be employed.
[0202] Stimulation Parameters of the Output Signal
[0203] The preferred range of stimulation parameters of the output
signal of the stimulus generator for the treatment of persistent
impairment of consciousness, and the typical value of each
parameter of the output signal programmed into the device by the
attending physician or therapist, can be as follows.
[0204] The pulse width can be in the range of from about 50
.mu.sec. to about 1,500 .mu.sec., preferably from about 100
.mu.sec. to about 1,000 .mu.sec., more preferably from about 250
.mu.sec. to about 750 .mu.sec., even more preferably from about 400
.mu.sec. to about 750 .mu.sec., and most preferably from about 400
.mu.sec. to about 600 .mu.sec. A pulse width of about 400 .mu.sec.
to about 750 .mu.sec. is appropriate when C fiber activation is
required or desired. If only A and B fiber activation is required
or desired, then a pulse width of about 50 .mu.sec. to about 250
.mu.sec. would be effective. The type of fiber activation can vary
between individual patients.
[0205] The output current can be in the range of from about 0.1 mA
to about 10 mA, more preferably from about 0.1 mA to about 6 mA,
most preferably from about 0.1 mA to about 4 mA.
[0206] The frequency of the output signal can be in the range of
from about 1 Hz to about 75 Hz, more preferably about 5 Hz to about
60 Hz, most preferably from about 10 Hz to about 40 Hz.
[0207] The pulses can be monophasic, biphasic, or a combination
thereof.
[0208] The train duration of the output current can be in the range
of from about 1 sec. to about 4 hours, more preferably from about
2.5 sec. to about 2.5 hours, most preferably from about 5 sec. to
about 1 hour. The interval between trains can be in the range of
from about 1 sec. to about 1 week, more preferably from about 1
sec. to about 1 day, most preferably from about 5 sec. to about 4
hours. Trains can also be supplied on demand if this is determined
to be preferable by the physician or therapist.
[0209] The stimulating electrical current can be applied to the
vagus nerve any time after appearance of symptoms associated with
persistent impairment of consciousness, for example within a time
period of from about one hour to about three months after appeance
of such symptoms.
[0210] Finally, the duration of the total therapy can vary
depending upon the nature and severity of the impairment, as well
as the physical attributes and condition of the patient. Therapy
can vary from about one day to as long as continued clinical
improvement is obtained or desired, e.g., several months or years
to the remainder of the patient's life.
[0211] As will be recognized by those of ordinary skill in the art,
any or all of the foregoing vagus nerve stimulation parameters can
be titrated clinically to achieve the desired response in a
patient.
[0212] The invention being thus described, it will be obvious that
the same can be varied in many ways. Such variations are not to be
regarded as a departure from the spirit and scope of the present
invention, and all such modifications as would be obvious to one
skilled in the art are intended to be included within the scope of
the following claims.
* * * * *