WO2003072186A2 - Neurostimulation for affecting sleep disorders - Google Patents
Neurostimulation for affecting sleep disorders Download PDFInfo
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- WO2003072186A2 WO2003072186A2 PCT/US2003/002860 US0302860W WO03072186A2 WO 2003072186 A2 WO2003072186 A2 WO 2003072186A2 US 0302860 W US0302860 W US 0302860W WO 03072186 A2 WO03072186 A2 WO 03072186A2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
- A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
- A61N1/36082—Cognitive or psychiatric applications, e.g. dementia or Alzheimer's disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
- A61N1/0526—Head electrodes
- A61N1/0529—Electrodes for brain stimulation
Definitions
- neurostimulation including deep brain stimulation
- modulation of neural structures for both the excitation and inhibition of the neural elements
- Today's surgical lesioning techniques while technologically improved and more precise, have the fundamental limitation of being inherently irreversible and are essentially a "one shot" procedure with little chance of alleviating or preventing potential side effects.
- Sleep disorders can include narcolepsy and its clinical manifestations such as sleep attacks, cataplexy, sleep paralysis, hypnagogic hallucinations; insomnia; sleep apnea; hypersomnia; and related disorders.
- Narcolepsy is a particularly dangerous problem given its incidence of 0.05% in the U.S. population, according to the American Association of Sleeping Disorders.
- Circadian rhythms are not merely passive reflections of the environmental light-dark cycle, but instead depend upon an underlying endogenous clock.
- the suprachiasmatic nucleus is not merely passive reflections of the environmental light-dark cycle, but instead depend upon an underlying endogenous clock.
- SCN of the hypothalamus
- the mammalian circadian clock that synchronizes the functions of different organ systems to each other and to the environmental light-dark cycle.
- other structures also influence the human circadian rhythm.
- the retina is the dominant circadian clock in invertebrates, such as sea slugs.
- the pineal gland is the dominant circadian clock in birds. In mammals, these ancient circadian pacemakers work in concert with the SCN.
- Melatonin is a hormone synthesized in the pineal gland and released at night.
- Serotonine is an important neurotransmitter involved in the mechanisms related to the generation of the different stages of awakeness-sleep cycle.
- Kereb, A. et al. Pharmacological and morphological evidence for a serotoninergic input to cholinergic nucleus basalis neurons. Eur. J. Neurosci, v5, p 541-47, 1993.
- Previous research has proven that lesions in the Raphe Nucleus, which is rich in serotonine, can produce intense insomnia which is reversed with the injection of serotonine precursors (5-hidroxitriptofano) (Jouvet, M., The role of monoamine and acethylcholine-containing neurons in the regulation of the sleep- waking cycle. Ergebn. Physiol V 64, 165-307, 1972).
- serotoninergic fiber which originates from the Raphe Nucleus, together with the noradrenergic fibers, is tonic activated during the alert phase, decreasing its activity during non-REM sleep and remaining silent in REM sleep (Jacobs, B.L.; Fornal. C. A., Activity of brain serotoninergic neurons in the behaving animal.
- Jouvet et al. in 1984 described a region just ventral to the Locus Coeruleus which lesion causes total inhibition of the motor behavior during the dreams.
- Sakai named it the Perilocus Coeruleus region or Alfa-Coeruleus nucleus (Sakai, K., Central mechanisms of paradoxical sleep. Brain Development 8, 402-7, 1986.)
- the lesion of this region cancels the inhibition of the motor neurons during REM sleep and releases the motor manifestation during the dreams (Jouvet et al., 1972).
- Narcolepsy is a disabling illness affecting more than 1 in 2,000 Americans. Most individuals with the disorder are not diagnosed, and are thus, not treated. The disease is principally characterized by a permanent and overwhelming feeling of sleepiness and fatigue. Other symptoms involve abnormalities of dreaming sleep, such as dream-like hallucinations and finding oneself physically weak or paralyzed for a few seconds.
- narcoleptic patients in this country are still undiagnosed, and narcoleptic subjects are most often diagnosed only after many years of struggle. In one recent study, the mean number of years between the onset of symptoms and correct diagnosis was 14 years. Since the symptoms of narcolepsy usually appear during adolescence, this means that most narcoleptic patients are diagnosed too late to prevent the dramatic impact of the disease on their personal and professional development.
- narcolepsy The main symptoms of narcolepsy are excessive daytime sleepiness and abnormal REM sleep, i.e., intrusion of REM sleep into the waking state or into the transition periods between waking and sleep.
- Many narcoleptics are sleepy during most or all of the day, specifically during times when normal people may only have a tendency to become somnolent. An example would be the tendency of a normal person to become somnolent after a heavy meal, whereas a narcoleptic would fall asleep.
- narcolepsy Patients with narcolepsy are subject to narcoleptic sleep attacks, cataplexy, sleep paralysis and hypnagogic hallucinations; however, an individual patient may not have all these symptoms. Sleep attacks may occur at any time the day and in embarrassing and dangerous situation, such as while walking, climbing, a ladder or even driving. These attacks are brief but can occur anytime and in any situation. Narcolepsy is not only a serious and common medical problem, it also offers basic sleep researchers a unique opportunity to gather new information on the central mechanisms regulating REM sleep and alertness. Since the 1960s it has been known that several of the disabling symptoms of narcolepsy, such as sleep paralysis, cataplexy and hypnagogic hallucinations, are pathological equivalents of REM sleep.
- the patient's knees buckle and may give way upon laughing, elation, surprise or anger.
- the head may drop or the jaw may become slack.
- the patient might fall down and become completely paralyzed for a few seconds to several minutes. Reflexes are abolished during the attack.
- Narcolepsy can be diagnosed using specific medical procedures. The diagnosis of narcolepsy is usually easy if all the symptoms of the illness are present. More often, however, the symptoms of dissociated REM sleep such as cataplexy are mild. In such cases, a nocturnal polysomnogram, followed by the multiple sleep latency test (MSLT), is suggested. This test, performed at a sleep disorders clinic, will confirm the daytime sleepiness by showing a short sleep latency of usually less than 5 minutes, as well as an abnormally short latency prior to the first REM period (SOREMPs). Other causes of daytime sleepiness, such as sleep apnea or periodic leg movements, are also excluded by the nocturnal recordings.
- MSLT multiple sleep latency test
- the narcolepsy responds best to strategically placed 15 to 20 minutes naps and the use of stimulants drugs (e.g., dextraamphetamine sulfate or methylphenidate hydrochloride (Ritalin), or pemoline) and a tricyclic antidepressant (e.g., imipramine or clormipramine).
- stimulants drugs e.g., dextraamphetamine sulfate or methylphenidate hydrochloride (Ritalin), or pemoline
- a tricyclic antidepressant e.g., imipramine or clormipramine.
- the combined use of these stimulants and tricyclic antidepressant drugs is often indicated. The occurrence of tolerance is frequent and the treatment fails quite often.
- the stimulants drugs and the tricyclic antidepressants increase the level of cathecolamines, and their chronic administration may produce hypertension.
- Sleep Apnea is a disorder of breathing during sleep. Typically it is accompanied by loud snoring. Apnea during sleep consist of brief periods throughout the night in which breathing stops. People with sleep apnea do not get enough oxygen during sleep. There are two major types of apnea: obstructive sleep apnea and central sleep apnea.
- Obstructive sleep apnea is the most common type and is due to an obstruction in the throat during sleep. Bed partners notice pauses of approximately 10 to 60 seconds between loud snores. The narrowing of the upper airway can be a result of several factors including inherent physical characteristics, excess weight, and alcohol consumption before sleep.
- Central sleep apnea is caused by a delay in the signal from the brain to breath. With both obstructive and central apnea the subj ect suffering therefrom must wake up briefly to breathe, sometimes hundreds of times during the night. Usually there is no memory of these brief awakenings. This type of sleep apnea can be treated with electrical stimulation of the above- mentioned nuclei.
- apnea central or obstructive.
- trazadone has been reported to have some effects on the treatment of the symptoms.
- Other medications may include acetazolamide, theophylline and clomipramine, which have produced questionable results.
- Insomnia is a sleep disorder that comes in many different manifestations and symptoms, including difficulty falling asleep, no problem falling asleep but difficulty staying asleep, i.e., many nocturnal awakenings, or even waking up too early. Normally a normal adult without any stress factors needs from 7 to 9 hours of good quality of sleep; the actual amount of sleep needed varies from person to person.
- Transient insomnia which last for a few nights
- short-term insomnia in which poor sleep lasts from two to four weeks of poor sleep
- chronic insomnia in which poor sleep occurs most nights and may last a month or longer.
- Transient and short-term insomnia generally occur in people who are temporarily experiencing one or more of the following: stress, environmental noise, extreme temperatures, change in the surrounding environment, sleep/wake schedule problems such as those due to jet lag or medication side effects, for example.
- Chronic insomnia is more complex and often results from a combination of factors, including underlying physical or mental disorders.
- One of the most common causes of chronic insomnia is depression.
- Other underlying causes include arthritis, kidney disease, heart failure, asthma, sleep apnea, restless legs syndrome, Parkinson's disease, and hyperthyroidism.
- chronic insomnia may also be due to behavioral factors, including the misuse of caffeine, alcohol, or other substances; disrupted sleep/wake cycles as may occur with shift work or other nighttime activity schedules; and chronic stress.
- Transient and short-term insomnia may not require treatment since episodes last only a few days at a time. For example, if insomnia is due to a temporary change in the sleep/wake schedule, as with jet lag, the person's biological clock will often get back to normal on its own. However, for some people who experience daytime sleepiness and impaired performance as a result of transient insomnia, the use of short-acting sleeping pills may improve sleep and next-day alertness. As with all drugs, there are potential side effects. The use of over-the-counter sleep medicines is not usually recommended for the treatment of insomnia.
- Treatment for chronic insomnia first consists of diagnosing and treating underlying medical or psychological problems. Further treatment includes identifying a patient's behavior(s) that may worsen insomnia and advising the patient to stop or reduce such behavior. Finally, sleeping pills may be prescribed, however, the long-term use of sleeping pills for chronic insomnia is controversial. Jet Lag Syndrome
- Jet lag also called desynchronosis, is a temporary condition that some people experience following air travel across several time zones in a short period of time. Jet lag causes the traveler's internal clock to be out of sync with the external environment. People experiencing jet lag have a difficult time maintaining their internal, routine sleep-wake pattern in their new location, because external stimuli, such as sunshine and local timetables, dictate a different pattern. For this reason, the person experiencing jet lag can feel lethargic one moment and excited the next. Jet lag creates a double bind for vacationers and business people who must cross several time zones to reach their destination, but who are also intent on maximizing sightseeing or productivity. As travelers attempt to adjust their internal clock to a new external environment, symptoms result with varying intensity.
- Jet lag occurs while rapidly crossing time zones, or, more specifically, it occurs after crossing the Earth's meridians. Meridians demarcate geographic position in relation to the Earth's poles and, ultimately, define time zones. Jet lag is a unique sleep disorder because its onset is not necessarily caused by abnormal sleep patterns, like insomnia. Therefore, travelers who sleep normally prior to transmeridian travel are not immune to jet lag. Again, the symptoms of jetlag result when a person's internal clock attempts to acclimate to a new external environment. This acclimation involves circadian rhythms that, among other functions, are associated with the body's management of sleep.
- jet lag is a transient sleep disorder and is classified differently than other, more serious disorders. Although jet lag occasionally lasts for a week or more, travelers usually return to their normal sleep-wake pattern after a day or two. For many travelers, jet lag can catalyze the effects of certain conditions associated with the head and nervous system that are not related to specific sleep-wake patterns.
- Jet Lag syndrome is still a matter of debate since no clear therapeutic effect has been observed with any drug or behavioral treatment.
- Melatonine is the hormone produced in the pituitary gland that may act "re setting" the biological clock of the hypothalamus and controlling the symptoms.
- the causes of the above-described sleep disorders include the sudden intrusion of the REM sleep during the awake period.
- the rationale of the presently provided methods of treatment is to abort or activate REM sleep by modulating specific nuclei in the brain stem, depending upon the sleep disorder or abnormal awakeness-sleep cycle to be treated, as discussed infra.
- Several papers highlight the role of Locus Coeruleus in the generation of REM Sleep. The inhibition of this specific nucleus in experimental trials interrupts the REM Sleep and its clinical manifestations, thus controlling and avoiding the dangerous consequences of those sleep disorders.
- the same neurophysiological response happens when lesions are provoked in this nucleus or related nuclei.
- this invention provides a method of affecting a sleep disorder in a subject having the sleep disorder, said method comprising: a) identifying at least one nucleus in a brain of the subject, said nucleus being a nucleus of the sleep circuitry of the brain; and b) stimulating the at least one identified nucleus so as to modulate the nucleus, thereby affecting the sleep disorder.
- the present invention provides a method of re-establishing a normal awakeness-sleep cycle in a subject having an abnormal awakeness-sleep cycle, said method comprising: a) identifying at least one nucleus in a brain of the subject, said nucleus being a nucleus of the sleep circuitry of the brain; and b) stimulating the at least one identified nucleus so as to modulate the nucleus, thereby re-establishing the normal awakeness-sleep cycle in the subject.
- the present invention provides a use of an electrode system adapted to be implanted within a brain of a subject having a sleep disorder, wherein the electrode is implanted proximate to at least one nucleus of the brain, said nucleus being a nucleus of the sleep circuitry of the brain, and provided with a stimulation signal to stimulate the at least one nucleus to affect the sleep disorder.
- the present invention provides a use of an electrode system adapted to be implanted within a brain of a subject having a sleep disorder for affecting the sleep disorder.
- the present invention provides a use of a chemical stimulus to be infused into a brain of a subject having a sleep disorder, wherein the chemical stimulus is infused proximate to at least one nucleus of the brain, said nucleus being a nucleus of the sleep circuitry of the brain, to affect the sleep disorder.
- the chemical stimulus may be a neurotransmitter, a neuro transmitter mimic, an agent for affecting sleep disorders or abnormal awakeness-sleep cycles, including but not limited to those listed drugs in Table 2 infra.
- the present invention provides a use of an electrode system adapted to be implanted within a brain of a subject having an abnormal awakeness-sleep cycle, wherein the electrode is implanted proximate to at least one nucleus of the brain, said nucleus being a nucleus of the sleep circuitry of the brain, and provided with a stimulation signal to stimulate the at least one nucleus to affect the abnormal awakeness- sleep cycle.
- proximate is defined to mean at or near the vicinity of the identified nucleus.
- the present invention provides a use of an electrode system adapted to be implanted within a brain of a subject having an abnormal awakeness-sleep cycle for affecting the abnormal awakeness-sleep cycle.
- the present invention provides a use of a chemical stimulus to be infused into a brain of a subject having an abnormal awakeness-sleep cycle, wherein the chemical stimulus is infused proximate to at least one nucleus of the brain, said nucleus being a nucleus of the sleep circuitry of the brain, to affect the abnormal awakeness-sleep cycle.
- Figure 1 illustrates the noradrenergic connections of the Locus Coeruleus in the several central nervous system relay envolved in the regulation of the awakefulness-sleep cycle.
- LC locus coeruleus.
- RF Dorsal raphe nucleus.
- T Thalamus.
- H Posterior hypothalamus.
- CTX Cortex.
- Figure 2 shows the medial surface of the brain. Also illustrated is a deep brain electrode inserted into the Locus Coeruleus Nuclei. A cannula which has a directional ball at the tip to allow angulation of the electrode may be used as shown.
- Surgical treatments for the above-described sleep disorders have been largely limited to stereotactic lesioning, such as cingulotomy, capsulotomy, subcaudate tractotomy, and limbic leucotomy.
- stereotactic lesioning such as cingulotomy, capsulotomy, subcaudate tractotomy, and limbic leucotomy.
- Such procedures have also been applied to date in the treatment of affective disorders and anxiety disorders. If one critically examines the results of these procedures in the literature, it becomes apparent, when applied to a carefully selected patient population in conjunction with modern stereotactic surgical equipment and imaging techniques, that these procedures are both efficacious and safe.
- these neurosurgical procedures may be the only treatment options available. Therefore, electrical and/or chemical neurosurgical neuromodulating techniques, with their inherent reversibility and adjustability, offer a safer and potentially more effective alternative to lesioning procedures.
- the present invention finds particular utility in its application to sleep disorders manifesting in humans. However, it is also to be appreciated that the present invention is applicable to other animals which exhibit behavior that is modulated by the brain. This may include, for example, primates, canines, felines, elephants, dolphins, etc. Utilizing the various embodiments of the present invention, one skilled in the art may modulate the functional outcome of the brain to achieve a desirable result.
- modulation/modulating includes changing an existing pattern of brain (e.g., including identified nuclei of the sleep circuitry of the brain) activity by electrical and/or chemical stimulation, wherein said pattern is an abnormal pattern, i.e., not found in subject who does not suffer from a sleep disorder or an abnormal awakeness-sleep cycle, as well as activating or inhibiting a specific nucleus.
- One technique that offers the ability to affect neuronal function in a reversible and dynamic fashion is the delivery of electrical stimulation for neuromodulation directly to target tissues via an implanted electrode assembly.
- Another technique which offers the ability to affect neuronal function in a reversible and dynamic fashion, is the delivery of drugs or neuromodulating chemicals directly to target tissues via a subcutaneously implanted pump and/or a slow release matrix.
- drugs listed in Table 2 infra, including either traditional disorder-treating agents, neurotransmitters or chemicals mimicking neurotransmitters, or combinations thereof, may be precisely administered by the methods described herein to the target nuclei at such low doses as to completely avoid the side effects so common to modern pharmacotherapy and to provide a physiological neuromodulation.
- Such doses may also be tailored in magnitude with respect to a particular patient's varying symptomatology.
- a chemical neuromodulating system may also be implanted as a primary treatment strategy or in combination with an electrically based one.
- a combination therapeutic approach provided herein, one combining electrical and chemical means, would be penultimate to generating healthy neuronal tissue itself.
- an implantable device may be configured to also have chemical and/or electrical sensing functions that are coupled to the chemical and electrical output of the modulating device.
- EEG electroencephalography
- MEG magnetoencephalography
- fMRI functional magnetic resonance imaging
- PET positron emission tomography
- U.S. Provisional Application No. 60/353,695 is a method of medical imaging, comprising: placing a fiducial marker proximate to an area of a body to be imaged; obtaining a first image of the area of the body using a first medical imaging technique, the first image including a first image of the fiducial marker; obtaining a second image of the area of the body using a second medical imaging technique, the second image including a second image of the fiducial marker, the second medical imaging technique being different than the first medical imaging technique; superimposing the first image of the area of the body and the second image of the area of the body; and aligning the first image of the first fiducial marker with the second image of the fiducial marker.
- Useful medical imaging techniques to obtain functional images include but are not limited to functional MRI, PET or MEG.
- Useful medical imaging techniques to obtain structural images include but are not limited to volumetric MRI, CT. The methods described therein may be applied to target nuclei for modulation by the presently described methods of affecting sleep disorders and abnormal sleep-awakeness cycles.
- the present invention provides methods which use a neurostimulation device in order to affect sleep disorders to regulate, prevent, treat, alleviate the symptoms of and/or reduce the effects of such sleep disorders. Also provided are methods which use chemical stimulation in order to affect sleep disorders.
- the methods of affecting a sleep disorder in a subject having the sleep disorder comprise: a) identifying at least one nucleus in a brain of the subject, said nucleus being a nucleus of the sleep circuitry of the brain; and b) stimulating the at least one identified nucleus so as to modulate the nucleus, thereby affecting the sleep disorder.
- nucleus or nuclei are defined as a concentration of neurons in the brain or a union of neurons. More specifically, the following stereotactic targets for affecting sleep disorders are identified and stimulated: the Locus Coeruleus, Dorsal Raphe Nucleus, Posterior Hypothalamus, Supra-Chiasmatic Nucleus of Hypothalamus, Nucleus Reticularis Pontis Oralis and Caudalis, and Basal Forebrain.
- the above-described nuclei are located in the posterior portion of the brainstem, close to the fourth ventricle (Nucleus Coeruleus) or in the base of the encephalus and can be reached using conventional stereotactic functional neurosurgical methods.
- stimulation of the above nuclei can also be performed in order to re-establish a normal awakeness-sleep cycle in pathologies related to a disfunction of the normal circadian cycle (narcolepsy, imnsonia) or even respiratory disturbance during the awakeness-sleepness cycle (sleep apnea).
- the methods described herein may further be utilized to affect patients with an abnormal awakeness-sleepness cycle, such as severe jet lag phenomenon, sleep deprivation or side effects of medication(s), to regulate, prevent, treat, alleviate the symptoms of and/or reduce the effects of such an abnormal awakeness-sleepness cycle.
- any of the related nuclei in the circuitry of sleep, enumerated supra may also be modulated to achieve a desired effect to affect any of the above-described disorders.
- Modulation of the Locus Coeruleus and related nuclei may include electrical stimulation or inhibition, chemical modulation via an infusion system, or both electrical and chemical stimulation or inhibition.
- An electrode system which may be used to effect electrical stimulation is described infra.
- At least one sensor which may be a cortical or subcortical sensor, e.g., subdural electrodes, may also be used to monitor the brain's sleep rhythms in order to allow for a closed-loop feedback and autoregulation of the system.
- Further sensory monitors may also include internal or external vital sign monitors for heart rate, respiration, REM, body tone, brain activity, etc. Brain activity may be monitored by electrocorticography.
- An example of this latter method of treatment using a closed-loop feedback system includes a system for Narcolepsy in which sensor(s) monitor the brain's sleep rhythm and result in inhibition of the Locus Coeruleus if the sensor(s) detect that the brain is approaching REM sleep (a particular sleep pattern phase). This system would be programmed to be in an off mode at night to encourage physiological sleep.
- a closed-loop feedback system may be used monitor the brain's sleep rhythm, wherein detection of a correct/particular sleep pattern phase results in activation of the identified the nucleus/nuclei at the appropriate time, e.g., in jet lag, detection of a sleep pattern requiring activation/excitation of the nuclei would result in activation of the Locus Coeruleus. Sleep pattern phases are well known to one of skill in the art.
- Table 1 summarizes the sleep circuitry nuclei which require either inhibition, activation, or modulation depending upon the particular disease to be affected.
- Coordinates for target sites to be stimulated for treatment of sleep disorders may be obtained from atlases of the brain, including Heidelbergenbrand, G. and Bailey, P., 1959,
- the stereotactic coordinates for several nuclei in the sleep circuitry of the brain, relative to the AC-PC Line, are as follows:
- Axis X Medial- lateral: 0 to 6mm from Mid AC-PC line
- Axis Y (Antero-Posterior): 5-9 mm
- Posterior to PC Axis Z (Dorsal-Ventral): 7- 17mm from Mid AC-PC line
- Axis X Medial-lateral: 0 to 8mm from Mid AC-PC line
- Axis Y (Antero-Posterior): 3-9 mm
- Posterior to PC Axis Z (Dorsal- Ventral): 2- 10mm from Mid AC-PC line
- Axis X Medial-lateral: 0 to 6mm from Mid AC-PC line
- Axis Y (Antero-Posterior): 2-8 mm
- Posterior to PC Axis Z (Dorsal- Ventral): 5-22mm from Mid AC-PC line
- Axis X Medial-lateral: 0 to 6mm from Mid AC-PC line
- Axis Y (Antero-Posterior): 8-14 mm
- Posterior to AC Axis Z (Dorsal- Ventral): 0-8mm from Mid AC-PC line Basal Forebrain
- Axis X Medial-lateral: 0 to 20mm from Mid AC-PC line
- Axis Y Antero-Posterior: 0-36 mm
- Anterior to AC Axis Z (Dorsal- Ventral): 0-25mm from Mid AC-PC line
- Axis X Medial-lateral: 0 to 10 mm from Mid AC-PC line
- Axis Z (Dorsal-Ventral): -5 to +25mm from Mid AC-PC line
- One embodiment of the present invention relates generally to modulating the pathological electrical and chemical activity of the brain by electrical stimulation and/or direct placement of neuromodulating chemicals within the corresponding areas of abnormal function and activity.
- a method is provided for surgical treatment of disorders by implantation of stimulating electrodes and/or drug or chemical delivery by microinfusion at the locations detailed herein.
- chemicals may be delivered by a pump or slow release matrix.
- Pumps which may be used in the present methods include commercially available pumps such as the Synchromed pump manufactured by Medtronic, Inc., as well as any commercially available micropumps.
- the slow release matrix also commercially available may be implanted subcutaneously in the skull of the subject, wherein the chemical is infused proximate to the identified nucleus.
- the proximal end of the electrode and/or catheter is coupled to an electrical signal source and/or drug delivery pump which, in turn, is operated to stimulate the predetermined treatment site in regions described above such that the desired functional outcome is achieved or the clinical effects of the sleep disorders are reduced.
- Sleep disorders which may be affected by the methods described herein include but are not limited to narcolepsy, whose symptoms are manifested by at least one of sleep attacks, sleep paralysis, cataplexy, or hypnagogic hallucinations; insomnia; sleep apnea; hypersomnia; and jet lag phenomenon.
- Abnormal awakeness-sleep cycles which may also be affected by the methods provided herein, include but are not limited to sleep deprivation, jet lag and side effects of medication(s).
- the methods of the present invention in which stimulation is effected by electrical stimulation may be performed by an electrode system.
- the electrode system includes a cannula which can redirect the electrode in a direction to allow maximal coverage of the
- the impulse generator of the electrode system must include an internal synchronizable clock which can be externally programmed via telemetry in order to resynchronize sleep patterns.
- Synchronizable clocks i.e., timed systems which are programmed to turn on and off at a particular time(s) to be in sync with the body's physiology are known and available for stimulation systems, e.g., such as those used for treatment of epilepsy.
- neuromodulation electrodes e.g., such as those manufactured by Medtronic, Inc. and described in U.S. Patent No. 6,356,784, issued March 12, 2002 to Lozano et al, which is hereby incorporated by reference in its entirety, may be used in the methods of the present invention.
- DBS electrode leads manufactures by Medtronic, Inc. may be employed in the methods described herein.
- electrodes may be custom designed, to be cylindrical, ovoid, plate or grid like electrodes.
- the stimulation parameters include monopolar, bipolar or multipolar, intensities of 0.1 ⁇ V to about 20 V intensity, frequency off 2 Hz to about 2500 Hz, pulse width of 10 microseconds to about 1,000 microseconds. This range of electrical intensities may be used to effectively stimulate the various identified nuclei of the brain to affect sleep disorders using the methods provided herein.
- the stimulation controller i.e. pulse generator
- the stimulation controller is activated thereby applying to the target site an oscillating electrical signal having specified pulsing parameters.
- the oscillating electrical signal may be applied continuously or intermittently and the pulsing parameters, such as the pulse width, amplitude, frequency, voltage, current, intensity, pole combinations, and/or waveform may be adjusted to affect a desired result.
- the oscillating electrical signal is operated at a voltage between about 0.1 ⁇ N to about 20 V More preferably, the oscillating electrical signal is operated at a voltage between about 1 N to about 15 N.
- the electric signal is operated at a frequency range between about 2 Hz to about 2500 Hz. More preferably, the electric signal is operated at a frequency range between about 2 Hz to about 200 Hz.
- the pulse width of the oscillating electrical signal is between about 10 microseconds to about 1,000 microseconds. More preferably, the pulse width of the oscillating electrical signal is between about 50 microseconds to about 500 microseconds.
- the waveform may be, for example, biphasic square wave, sine wave, or other electrically safe and feasible combination.
- the application of the oscillating electrical signal is : monopolar when the electrode is monopolar, bipolar when the electrode is bipolar, and multipolar when the electrode is multipolar.
- a grid electrode such as subdural grids manufactured by AD-Tech in different sizes and shapes , which can remain supracortically, and optionally have one or more intracranial extensions, may be used to deliver electrical stimulation to the target nuclei in the methods of the present invention.
- Chemicals such as neurotransmitters including but not limited to acetylcholine, dopamine, epinephrine, norepinephrine, serotonine, GABA, and inhibitors of noradrenaline, or any agent for affecting a sleep disorder or mixtures thereof may be delivered to the identified target nuclei by commercially available catheters and cannulas, e.g., such as those presently used for vascular surgery for aneurysms, which may be modified for drug delivery. Additional catheters which may be used in the present methods include a catheter described in U.S. Patent No. 6,356,784 to Lozano et al., which is incorporated by reference in its entirety herein.
- microcannulas/microcatheters such as those used in microdialysis procedures, may be used to deliver drugs in the methods of the present invention.
- Table 2 provides a list of neurotransmitters and drugs known to act on the central nervous system, in the circuitry of the awakeness-sleep cycle, which may be delivered to the identified nuclei to affect sleep disorders using the methods of the present invention.
- the neurotransmitters delivered will vary according to the type of sleep disorder to be affected and the nuclei proximate to which the chemicals are infused.
- Table 2 List of possible neurotransmitters and drugs with action in the central nervous system, in the circuitry involved in the regulation of the awakeness-sleep cycle.
- Cholinergic agonists Dimethylphenylpierazinium, Oxotremorine, Muscarine, McN-A-343,
- Cholinergic antagonists Trimethaphan, atropine, pirenzepine, atropine, hexahydrosiladifenidol, Quinuclidynil, benzoate, pirezepine, Dihydro-B-erythroidine.
- Adrenergic antagonists Alpha adrenergic antagonists: Phenoxybenzamine; Beta adrenergic antagonists: Propranolol, Metoprolol, praxosin, Rawolscine, yohimbine, metoprolol, practolol, butoxamine, phenyllephrine, clonidine, dobutamine, terbutalina.
- Adrenergic agonists Reserpine, imipramine, methyldopa, amphetamine, cocaine.
- Serotoninergic agonists 5-hydroxitriptamin, LSD, 8-OH DPAT, 5-HT2, 5-HT3.
- Serotoninergic antagonists Metergoline, Spiperone methysergide, MDL-7222
- Dopaminergic agonists L-dopa, SKF 38393, apomorphine; quimpirole
- Dopaminergic antagonists neuroleptics, SCH 23390, Butyrophenones, S-sulpiride
- Gabaergic agonists Muscinol, Bacoflen
- Gabergic antagonists Biccuculine, picrotoxin
- Glutamate agonists Quisqualate, AMPA, NMDAspartate, Kainate
- Glutamate antagonists CNQX, CPP, Lactonized kainite
- any of the above-described chemicals may be microinfused using a device comprising an electrode device and a microcatheter.
- the electrode-microcatheter system used in the methods described herein may be configured to have multiple ports for dmg delivery, and may include a recording/multi-contact stimulating electrode, as described by in U.S. Patent No. 5,676,655, issued on October 14, 1997 to Howard, in et al., which is incorporated by reference in its entirety herein.
- Effective doses of the administered chemicals will vary from in patients depending upon the sleep disorder to be affected, however, the range of effective doses includes from 0.1 nL to 1 cc in each bolus or in continuous injection.
- the electrode device which may be used in the above- described methods may further comprise at least one of a pH probe, a sensor to detect bleeding, and oximetry systems to optimally alter the delivery of the modulator (electric or chemical stimulation) in a closed-loop manner.
Abstract
Description
Claims
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US10/502,820 US8612005B2 (en) | 2002-02-01 | 2003-01-31 | Neurostimulation for affecting sleep disorders |
AU2003241269A AU2003241269A1 (en) | 2002-02-01 | 2003-01-31 | Neurostimulation for affecting sleep disorders |
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US35369702P | 2002-02-01 | 2002-02-01 | |
US60/353,697 | 2002-02-01 |
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WO2003072186A2 true WO2003072186A2 (en) | 2003-09-04 |
WO2003072186A3 WO2003072186A3 (en) | 2004-03-25 |
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PCT/US2003/002860 WO2003072186A2 (en) | 2002-02-01 | 2003-01-31 | Neurostimulation for affecting sleep disorders |
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AU (1) | AU2003241269A1 (en) |
WO (1) | WO2003072186A2 (en) |
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US8612005B2 (en) | 2013-12-17 |
WO2003072186A3 (en) | 2004-03-25 |
US20050177192A1 (en) | 2005-08-11 |
AU2003241269A1 (en) | 2003-09-09 |
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