Surgery: light – thermal – and electrical application – Light – thermal – and electrical application – Electrical therapeutic systems
Reexamination Certificate
2002-01-14
2003-04-29
Jastrzab, Jeffrey R. (Department: 3762)
Surgery: light, thermal, and electrical application
Light, thermal, and electrical application
Electrical therapeutic systems
Reexamination Certificate
active
06556868
ABSTRACT:
FIELD OF THE INVENTION
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
Vagal Afferents and Their Influence on Physiology and Behavior
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.
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).
Vagus Nerve Stimulation and the Brain
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).
Modulation of Memory by Arousal
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.
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.
Role of the Vagus Nerve in Mediating Arousal-Induced Memory Modulation
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, Toron
Browning Ronald A.
Clark Kevin B.
Jensen Robert A.
Naritoku Dean K.
Smith Douglas C.
Jastrzab Jeffrey R.
Senniger Powers Leavitt & Roedel
The Board of Trustees of Southern Illinois University
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