Patent Application
20200268536
The present invention relates generally to metabolic disease and neuropsychiatric disease and, more particularly, to stimulation of gastric and autonomic including sympathetic and parasympathetic neural tissue for the treatment of disease, including but not limited to obesity, eating disorders including anorexia and bulimia, depression, anxiety, epilepsy, metabolic conditions, diabetes, hyperglycemia, hypoglycemia, irritable bowel syndrome, immunological conditions, asthma, respiratory conditions, cardiovascular conditions, cardiac conditions, vascular conditions, headaches, substance abuse, substance addiction, smoking cessation, drug withdrawal, hyperhidrosis, reflex sympathetic dystrophy, pain, and other medical and neurological and psychiatric conditions.
Physiologic studies have demonstrated the presence of a sympathetic nervous system afferent pathway transmitting gastric distention information to the hypothalamus. [Barone, Zarco de Coronado et al. (1995). Gastric distension modulates hypothalamic neurons via a sympathetic afferent path through the mesencephalic periaqueductal gray. Brain Research Bulletin. 38: 239-51.] However, prior techniques have generally not addressed the problems associated with satiety, morbidity, mortality of intracranial modulation and the risk of ulcers. Unlike prior techniques, by specifically targeting sympathetic afferent fibers, the present invention effects the sensation of satiety and avoids the substantial risks of morbidity and mortality of intracranial modulation, particularly dangerous in the vicinity of the hypothalamus. Furthermore, this invention avoids the risk of ulcers inherent in vagus nerve stimulation.
A. Satiety. Stimulation of intracranial structures has been proposed and described for the treatment of obesity (U.S. Pat. No. 5,782,798). Stimulation of the left ventromedial hypothalamic (VMH) nucleus resulted in delayed eating by dogs who had been food deprived. Following 24 hours of food deprivation, dogs with VMH stimulation waited between 1 and 18 hours after food presentation before consuming a meal. Sham control dogs ate immediately upon food presentation. Dogs that received 1 hour of stimulation every 12 hours for 3 consecutive days maintained an average daily food intake of 35% of normal baseline levels. [Brown, Fessler et al. (1984). Changes in food intake with electrical stimulation of the ventromedial hypothalamus in dogs. Journal of Neurosurgery. 60: 1253-7.] B. Candidate Peripheral Nerve Pathways for Modulating Satiety.
B1. Sympathetic Afferents. The effect of gastric distension on activity in the lateral hypothalamus-lateral preoptic area-medial forebrain bundle (LPA-LH-MFB) was studied to determine the pathways for this gastric afferent input to the hypothalamus. [Barone, Zarco de Coronado et al. (1995). Gastric distension modulates hypothalamic neurons via a sympathetic afferent path through the mesencephalic periaqueductal gray. Brain Research Bulletin. 38: 239-51.] The periaqueductal gray matter (PAG) was found to be a relay station for this information. [Barone, Zarco de Coronado et al. (1995). Gastric distension modulates hypothalamic neurons via a sympathetic afferent path through the mesencephalic periaqueductal gray. Brain Research Bulletin. 38: 239-51.] This modulation of the hypothalamus was attenuated but not permanently eliminated by bilateral transection of the vagus nerve. This modulation was, however, significantly reduced or eliminated by bilateral transection of the cervical sympathetic chain or spinal transection at the first cervical level. [Barone, Zarco de Coronado et al. (1995). Gastric distension modulates hypothalamic neurons via a sympathetic afferent path through the mesencephalic periaqueductal gray. Brain Research Bulletin. 38: 239-51.] These signals containing gastric distension and temperature stimulation are mediated to a large degree by sympathetic afferents, and the PAG is a relay station for this gastric afferent input to the hypothalamus. [Barone, Zarco de Coronado et al. (1995). Gastric distension modulates hypothalamic neurons via a sympathetic afferent path through the mesencephalic periaqueductal gray. Brain Research Bulletin. 38: 239-51.] For example, in the LPA-LH-MFB study, 26.1% of the 245 neurons studied were affected by gastric stimulation, with 17.6% increasing in firing frequency and 8.6% decreasing during gastric distension. [Barone, Zarco de Coronado et al. (1995). Gastric distension modulates hypothalamic neurons via a sympathetic afferent path through the mesencephalic periaqueductal gray. Brain Research Bulletin. 38: 239-51.] The response of 8 of 8 neurons sensitive to gastric distension were maintained, though attenuated after bilateral vagus nerves were cut. In 2 of these 8 cells, the effect was transiently eliminated for 2-4 minutes after left vagus transection, and then activity recovered. In 3 LH-MFB cells, two increased and the other decreased firing rate with gastric distension. Following bilateral sympathetic ganglion transection, the response of two were eliminated, and the third (which increased firing with distension) had a significantly attenuated response. [Barone, Zarco de Coronado et al. (1995). Gastric distension modulates hypothalamic neurons via a sympathetic afferent path through the mesencephalic periaqueductal gray. Brain Research Bulletin. 38: 239-51.] Vagus stimulation resulted in opposite or similar responses as gastric distension on the mesencephalic cells.
B2. Vagus Nerve Afferents. Gastric vagal input to neurons throughout the hypothalamus has been characterized. [Yuan and Barber (1992). Hypothalamic unitary responses to gastric vagal input from the proximal stomach. American Journal of Physiology. 262: G74-80.] Nonselective epineural vagus nerve stimulation (VNS) has been described for the treatment of Obesity (U.S. Pat. No. 5,188,104). This suffers from several significant limitations that are overcome by the present invention.
The vagus nerve is well known to mediate gastric hydrochloric acid secretion. Dissection of the vagus nerve off the stomach is often performed as part of major gastric surgery for ulcers. Stimulation of the vagus nerve may pose risks for ulcers in patients, of particular concern, as obese patients often have gastroesophageal reflux disease (GERD); further augmentation of gastric acid secretion would only exacerbate this condition.
C. Assessment of Sympathetic and Vagus Stimulation. The present invention teaches a significantly more advanced neuroelectric interface technology to stimulate the vagus nerve and avoid the efferent vagus side effects, including speech and cardiac side effects common in with existing VNS technology as well as the potential ulcerogenic side effects. However, since sympathetic afferent activity appears more responsive to gastric distension, this may represent a stronger channel for modulating satiety. Furthermore, by pacing stimulating modulators on the greater curvature of the stomach, one may stimulate the majority of the circular layer of gastric musculature, thereby diffusely increasing gastric tone.
D. Neuromuscular Stimulation. The muscular layer of the stomach is comprised of 3 layers: (1) an outer longitudinal layer, (2) a circular layer in between, and (3) a deeper oblique layer. [Gray (1974). Gray's Anatomy. T. Pick and R. Howden. Philadelphia, Running Press.] The circular fibers, which lie deep to the superficial longitudinal fibers, would appear to be the layer of choice for creating uniform and consistent gastric contraction with elevated wall tension and luminal pressure. Therefore, modulators should have the ability to deliver stimulation through the longitudinal layer. If the modulator is in the form of an electrode, then the electrodes should have the ability to deliver current through the longitudinal layer.
Gray's Anatomy describes innervation as including the right and left pneumogastric nerves (not the vagus nerves), being distributed on the back and front of the stomach, respectively. A great number of branches from the sympathetic nervous system also supply the stomach. [Gray (1974). Gray's Anatomy. T. Pick and R. Howden. Philadelphia, Running Press.] Metabolic Modulation (Efferent) Electrical stimulation of the VMH enhances lipogenesis in the brown adipose tissue (BAT), preferentially over the white adipose tissue (WAT) and liver, probably through a mechanism involving activation of the sympathetic innervation of the BAT. [Takahashi and Shimazu (1982). Hypothalamic regulation of lipid metabolism in the rat: effect of hypothalamic stimulation on lipogenesis. Journal of the Autonomic Nervous System. 6: 225-35.] The VMH is a hypothalamic component of the sympathetic nervous system. [Ban (1975). Fiber connections in the hypothalamus and some autonomic functions. Pharmacology, Biochemistry & Behavior. 3: 3-13.] A thermogenic response in BAT was observed with direct sympathetic nerve stimulation. [Flaim, Horwitz et al. (1977). Coupling of signals to brown fat: a- and b-adrenergic responses in intact rats. Amer. J. Physiol. 232: R101-R109.] The BAT had abundant sympathetic innervation with adrenergic fibers that form nest-like networks around every fat cell, [Derry, Schonabum et al. (1969). Two sympathetic nerve supplies to brown adipose tissue of the rat. Canad. J. Physiol. Pharmacol. 47: 57-63.] whereas WAT has no adrenergic fibers in direct contact with fat cells except those related to the blood vessels. [Daniel and Derry (1969). Criteria for differentiation of brown and white fat in the rat. Canad. J. Physiol. Pharmacol. 47: 941-945.]
The present invention teaches apparatus and methods for treating a multiplicity of diseases, including obesity, depression, epilepsy, diabetes, and other diseases. The invention taught herein employs a variety of energy modalities to modulate central nervous system structures, peripheral nervous system structures, and peripheral tissues and to modulate physiology of neural structures and other organs, including gastrointestinal, adipose, pancreatic, and other tissues. The methods for performing this modulation, including the sites of stimulation and the modulator configurations are described. The apparatus for performing the stimulation are also described. This invention teaches a combination of novel anatomic approaches and apparatus designs for direct and indirect modulation of the autonomic nervous system, which is comprised of the sympathetic nervous system and the parasympathetic nervous system.
For the purposes of this description the term GastroPace™ should be interpreted to mean the devices constituting the system of the present embodiment of this invention, including the obesity application as well as others described, implied, enabled, facilitated, and derived from those taught in the present invention.
A. Obesity and Eating Disorders. The present invention teaches several mechanisms, including neural modulation and direct contraction of the gastric musculature, to effect the perception of satiety. This modulation is useful in the treatment of obesity and eating disorders, including anorexia nervosa and bulimia.
Direct stimulation of the gastric musculature increases the intraluminal pressure within the stomach; and this simulates the physiologic condition of having a full stomach, sensed by stretch receptors in the muscle tissue and transmitted via neural afferent pathways to the hypothalamus and other central nervous system structures, where the neural activity is perceived as satiety.
This may be accomplished with the several alternative devices and methods taught in the present invention. Stimulation of any of the gastric fundus, greater curvature of stomach, pyloric antrum, or lesser curvature of stomach, or other region of the stomach or gastrointestinal tract, increases the intraluminal pressure. Increase of intraluminal pressure physiologically resembles fullness of the respective organ, and satiety is perceived.
The present invention also includes the restriction of the flow of food to effect satiety. This is accomplished by stimulation of the pylorus. The pylorus is the sphincter-like muscle at the distal juncture of the stomach with the duodenum, and it regulates food outflow from the stomach into the duodenum. By stimulating contraction of the pylorus, food outflow from the stomach is slowed or delayed. The presence of a volume of food in the stomach distends the gastric musculature and causes the person to experience satiety.
B. Depression and Anxiety. An association has been made between depression and overeating, particularly with the craving of carbohydrates; and is believed to be an association between the sense of satiety and relief of depression. Stimulation of the gastric tissues, in a manner that resembles or is perceived as satiety, as described above, provides relief from this craving and thereby relief from some depressive symptoms. There are several mechanisms, including those taught above for the treatment of obesity that are applicable to the treatment of depression, anxiety, agoraphobia, social anxiety, panic attacks, and other neurological and psychiatric conditions.
An object of the present invention, as taught in the parent case, is the modulation of the autonomic nervous system for physiologic modulation, including modulation of limbic physiology, which has efficacy in the treatment of depression, anxiety and other psychiatric conditions. By altering the level of sympathetic nervous system activity, or the level of parasympathetic nervous system activity, or the ratio of sympathetic to parasympathetic nervous system activity (as reflected in metrics such as the autonomic index), the level of activity in the locus ceruleus, solitary nucleus, cingulate nucleus, the limbic system, the supraorbital cortex, and other regions may be modulated, thereby influencing affect or mood as well as level of anxiety. Furthermore, the reduction of systemic sympathetic activity may be used to alleviate the symptoms of anxiety, which is employed in both the treatment of anxiety and in the conditioning of patients to control anxiety.
C. Epilepsy. The present invention includes electrical stimulation of peripheral nervous system and other structures and tissues to modulate the activity in the central nervous system to control seizure activity.
This modulation takes the form of peripheral nervous system stimulation using a multiplicity of novel techniques and apparatus. Direct stimulation of peripheral nerves is taught; this includes stimulation of the vagus, trigeminal, accessory, and sympathetic nerves. Indiscriminate stimulation of the vagus nerves has been described for some disorders, but the limitations in this technique are substantial, including cardiac rhythm disruptions, speech difficulties, and gastric and duodenal ulcers. The present invention overcomes these persistent limitations by teaching a method and apparatus for the selective stimulation of structures, including the vagus nerve as well as other peripheral nerves, and other neural, neuromuscular, and other tissues.
The present invention further includes noninvasive techniques for neural modulation. This includes the use of tactile stimulation to activate peripheral or cranial nerves. This noninvasive stimulation includes the use of tactile stimulation, including light touch, pressure, vibration, and other modalities that may be used to activate the peripheral or cranial nerves. Temperature stimulation, including hot and cold, as well as constant or variable temperatures, are included in the present invention.
D. Diabetes. The response of the gastrointestinal system, including the pancreas, to a meal includes several phases. The first phase, the anticipatory stage, is neurally mediated. Prior to the actual consumption of a meal, saliva production increases and the gastrointestinal system prepares for the digestion of the food to be ingested. Innervation of the pancreas, in an analogous manner, controls production of insulin.
Modulation of pancreatic production of insulin may be performed by modulation of at least one of afferent or efferent neural structures. Afferent modulation of at least one of the vagus nerve, the sympathetic structures innervating the gastrointestinal tissue, the sympathetic trunk, and the gastrointestinal tissues themselves is used as an input signal to influence central and peripheral nervous system control of insulin secretion.
E. Irritable bowel Syndrome. An object of the present invention, as taught in the parent case, is the modulation of the autonomic nervous system for physiologic modulation, including modulation of gastrointestinal physiology, which has efficacy in the treatment of irritable bowel syndrome. By altering the level of sympathetic nervous system activity, or the level of parasympathetic nervous system activity, or the ratio of sympathetic to parasympathetic nervous system activity (as reflected in metrics such as the autonomic index), the level of gastrointestinal motility and absorption may be modulated.
Modulation including down-regulation of the activity of the gastrointestinal tract, through autonomic modulation, as taught in the parent case has application to the treatment of irritable bowel syndrome. Said autonomic modulation includes but is not limited to inhibition or blocking of sympathetic nervous system activity and to enhancement or stimulation of parasympathetic nervous system activity.
The response of the gastrointestinal system to sympathetic stimulation, such as that induced by stress or sympathomimetic agents including caffeine, may include symptoms such as elevated motility and altered absorption. Modulation of gastrointestinal physiology is taught for applications including but not limited to the maintenance of baseline levels of gastrointestinal motility, secretion, absorption, and hormone release. Modulation of gastrointestinal physiology is also taught for applications including but not limited to the real-time control of levels of gastrointestinal motility, secretion, absorption, and hormone release, in response to physiological needs as well as in response to perturbations. Such external perturbation that can induce symptoms that are alleviated by the present invention include but are not limited to stress, consumption of caffeine, alcohol, or other substance, consumption of allergenic substance, or consumption of infectious or toxic agent. By intervening with the application of autonomic modulation to counter these undesirable autonomic responses to external agents, these side effects are reduced or prevented.
F. Immunomodulation. An object of the present invention, as taught in the parent case, is the modulation of the autonomic nervous system for physiologic modulation, including modulation of immune system physiology. By altering the level of sympathetic nervous system activity, or the level of parasympathetic nervous system activity, or the ratio of sympathetic to parasympathetic nervous system activity (as reflected in metrics such as the autonomic index), the level of activity of the immune system may be modulated. Both polarities of modulation have efficacy in the treatment of disease as well as in prophylactic applications.
Modulation, including up-regulation of the immune system, through autonomic modulation, as taught in the parent case invention has application to the treatment of infection, cancer, autoimmune immunodeficiency syndrome (AIDS), human immunodeficiency virus) infection (HIV), severe combined immunodeficiency (SCID), other causes of immunodeficiency, other causes of immunosuppression, mitigation of effects of iatrogenic immunosuppression (including that used with organ transplantation or for treating autoimmune disorders), and other causes of decreased immune system activity.
Modulation, including down-regulation, of the immune system, through autonomic modulation, as taught in the parent case invention has application to the treatment of autoimmune disease, including but not limited to multiple sclerosis, reflex sympathetic dystrophy (RSD), type I diabetes (the pathophysiology of which may include an autoimmune component), rheumatoid arthritis, graft versus host disease, psoriasis, allergic reactions, dermatitis, other allergic conditions, other diseases involving signs or symptoms due to an autoimmune or other immune pathology, and other diseases with untoward effects arising from excessive or detrimental immune responses . . . .
Modulation, including down-regulation, of the immune system, through autonomic modulation, as taught in the parent case invention has application to the treatment of some complications from infection, including but not limited to Lyme disease, streptococcal pharyngitis (strep throat), rheumatic heart disease, fungal infections, parasitic infections, bacterial infections, viral infections, other infections, and other exposures to infectious or allergenic agents.
Modulation, including down-regulation, of the immune system, through autonomic modulation, as taught in the parent case invention has application to the augmentation of other therapies, and may be used to suppress immune function in patients with organ transplantation.
G. Asthma. An object of the present invention, as taught in the parent case, is the modulation of the autonomic nervous system for physiologic modulation, including modulation of pulmonary physiology. By altering the level of sympathetic nervous system activity, or the level of parasympathetic nervous system activity, or the ratio of sympathetic to parasympathetic nervous system activity (as reflected in metrics such as the autonomic index), the level of activity of the immune system may be modulated. Both polarities of modulation have efficacy in the treatment of disease as well as in prophylactic applications.
Modulation, including stimulation of the sympathetic nervous system, as taught in the parent case invention has application to the treatment of asthma, including exercise induced asthma and other forms of asthma. Through stimulation of the sympathetic nervous system, the beta-2 efferent pathways of the sympathetic nervous system are activated, effecting bronchodilation, providing a therapeutic action opposing the bronchoconstrictive process that underlies the increased airway resistance which results in the potentially life-threatening signs and symptoms of this disease. This same therapy is also applied to the treatment of bronchospasm and laryngospasm, in which elevated sympathetic efferent activity mitigates the constrictive effects on the airway.
Modulation, including stimulation of the sympathetic nervous system and stimulation of the parasympathetic nervous system, as taught in the parent case invention has application to the treatment of asthma, including exercise induced asthma through an additional mechanism. Through inhibition of the sympathetic nervous system, the activity of the immune system may be down-regulated, reducing the sensitivity of the pulmonary mast cells to allergens, thereby reducing the susceptibility to and the severity of asthma signs and symptoms.
H. Cardiovascular Disease—Cardiac. An object of the present invention, as taught in the parent case, is the modulation of the autonomic nervous system for physiologic modulation, including modulation of cardiovascular physiology, including cardiac physiology in particular. By altering the level of sympathetic nervous system activity, or the level of parasympathetic nervous system activity, or the ratio of sympathetic to parasympathetic nervous system activity (as reflected in metrics such as the autonomic index), cardiac parameters may be modulated. Both polarities of modulation have efficacy in the treatment of cardiac disease as well as in prophylactic applications.
Modulation, including stimulation of the sympathetic nervous system, inhibition of the parasympathetic system, or increase in the autonomic index, as taught in the parent case invention has application to the treatment of cardiac disease, including hear failure and bradycardia. Through stimulation of the sympathetic nervous system, the beta-1 efferent pathways of the sympathetic nervous system are activated, effecting increase inotropic activity, providing a therapeutic action to mitigate decreased myocardial contractility found in cardiac disease, including congestive heart failure, post myocardial infarction sequelae, and other cardiac disorders. Sympathetic stimulation is also used to effect increased chronotropic behavior, thereby elevating heart rate. This has application to numerous cardiac conditions, including bradycardia and heart block. This has further application to the treatment of hypotension and to neurogenic shock, which may be augmented by autonomic neuromodulation directed toward the vascular system, as described below.
Modulation, including inhibition of the sympathetic nervous system, stimulation of the parasympathetic system, or decrease in the autonomic index, as taught in the parent case invention has application to the treatment of cardiac disease. The negative inotropic effect of such autonomic modulation has application to cardiac disease, including among others, diastolic disease, in which the heart muscle does not fully relax, thereby impairing proper atrial and ventricular filling during the diastolic portion of the cardiac cycle. This additionally has application to the treatment of hypertension, through each of negative inotropic and negative chronotropic effects. This further has application to the prevention and control of the progression of congestive heart failure, through the reduction of the normal sympathetic physiologic response to heart failure, which itself contributes to progression of the disease. The negative chronotropic effect of such modulation also has application to the treatment of tachycardia and other cardiac rhythm abnormalities.
I. Cardiovascular Disease—Vascular. An object of the present invention, as taught in the parent case, is the modulation of the autonomic nervous system for physiologic modulation, including modulation of cardiovascular physiology including vascular physiology in particular. By altering the level of sympathetic nervous system activity, or the level of parasympathetic nervous system activity, or the ratio of sympathetic to parasympathetic nervous system activity (as reflected in metrics such as the autonomic index), the level of activity including the muscular tone of the vascular system may be modulated. Both polarities of modulation have efficacy in the treatment of disease as well as in prophylactic applications.
Modulation, including stimulation of the sympathetic nervous system, inhibition of the parasympathetic nervous system, or increase in the autonomic index, as taught in the parent case invention has application to the treatment of hypotension and neurogenic shock, and other conditions in which vascular tone or blood pressure is below normal. This further has application to therapeutically increase vascular tone or blood pressure, including to levels above normal, such as in the treatment of cerebral vasospasm, ischemic stroke, peripheral vascular disease, or other condition. Through stimulation of the sympathetic nervous system, the alpha-1 efferent pathways of the sympathetic nervous system are activated, effecting vasoconstriction, providing a therapeutic action to correct low blood pressure as well as to provide a normalizing to correct low vascular tone characterizing neurogenic shock as well as to elevate blood pressure to treat the above listed conditions. A particular advantage of this therapy is conveyed by the ability to selectively rather than systemically induce vasoconstriction, thereby elevating systemic blood pressure while avoiding vasoconstriction in selected circulatory regions, as desired in the treatment of cerebral vasospasm.
Modulation, including inhibition of the sympathetic nervous system, stimulation of the parasympathetic nervous system, or decrease in the autonomic index, as taught in the parent case invention has application to the treatment of hypertension, including essential hypertension, renally mediated hypertension, atherosclerosis mediated hypertension, other forms of systemic hypertension, and pulmonary hypertension. Through this therapy, vasodilation is achieved, which is also used to treat coronary artery disease, peripheral vascular disease, cerebral vascular disease, myocardial infarction, and stroke. This has further use in other therapy in which enhanced circulation is desired, such as for enhanced circulation and drug delivery in the treatment of infections and as an adjuvant to accelerate healing processes, such as ulcers, postoperative wounds, trauma, and other conditions.
J. Headaches. An object of the present invention, as taught in the parent case, is the modulation of the autonomic nervous system for physiologic modulation, including modulation of cerebral vascular physiology, including intraparenchymal circulation and meningeal circulation. By altering the level of sympathetic nervous system activity, or the level of parasympathetic nervous system activity, or the ratio of sympathetic to parasympathetic nervous system activity (as reflected in metrics such as the autonomic index), the level of activity of the cerebral vascular system may be modulated. Both polarities of modulation have efficacy in the treatment of headaches as well as in prophylactic applications.
Modulation, including stimulation of the sympathetic nervous system, inhibition of the parasympathetic nervous system, or increase in the autonomic index, as taught in the parent case invention has application to the treatment of headaches, including migraine headaches, cluster headaches, and other headaches. Through stimulation of the sympathetic nervous system, the alpha-1 efferent pathways of the sympathetic nervous system are activated, effecting cerebral vasoconstriction, providing decrease in the blood volume within the intracranial vascular structures as well as the remainder of the intracranial compartment. This acts through additional mechanisms including but not limited to reduction of the mechanical tension on the dura, reduction of the intracranial pressure, and alteration in the blood flow and neural activity within the brain, altering neural and vascular patterns that can progress to generate headaches or other undesirable neural states.
Modulation, including inhibition of the sympathetic nervous system, stimulation of the parasympathetic nervous system, or decrease in the autonomic index, as taught in the parent case invention has application to the prophylaxis and treatment of headaches, including migraine headaches, cluster headaches, and other headaches. Through inhibition of the sympathetic nervous system, the activity of alpha-1 efferent pathways of the sympathetic nervous system are reduced, effecting cerebral vasodilation, providing variation in the vascular tone as well as altered blood flow and neural activity, which has application to disrupt neural and vascular patterns that can generate headaches or other undesirable neural states.
K. Smoking Cessation and Drug Withdrawal. An object of the present invention, as taught in the parent case, is the modulation of the autonomic nervous system, which has application to stabilize or oppose the physiologic response to the introduction or withdrawal of pharmacological or other bioactive agents, including nicotine, caffeine, stimulants, depressants, and other medical and recreational drugs.
When patients cease smoking, the nicotine plasma levels drop, reducing the level of stimulation of the nicotinic receptors in the sympathetic nervous system. This alteration causes a physiologic response characterized by significant levels of anxiety and a withdrawal response in the person. By modulating the sympathetic nervous system activity using the method and apparatus taught in the parent case or using variants thereof, this response can be mitigated. This has application to controlling addiction to nicotine and in the facilitation of smoking cessation.
When patients cease intake of alcohol, narcotics, sedatives, hypnotics, or other drugs to which they may be addicted, a withdrawal response ensues. This response can be life threatening. In alcohol withdrawal, delirium tremens can be accompanied by dangerous elevations in heart rate. By modulating sympathetic and/or parasympathetic activity to control the autonomic index, this response can be reduced or prevented.
L. Hyperhidrosis. An object of the present invention, as taught in the parent case, is the modulation of the autonomic nervous system, which has application to prevent or control the symptoms of hyperhidrosis.
In hyperhidrosis, an abnormally active or responsive sympathetic nervous system results is excessive perspiration, typically most problematic when involving the hands and axillae. Current treatments employ surgical ablation of the corresponding region of the sympathetic trunk, which results in irreversible cessation of sympathetic activity in the corresponding anatomical region. By modulating the sympathetic nervous system activity using the method and apparatus taught in the parent case or using variants thereof, the symptoms arising from this condition can be prevented or reduced.
M. Reflex Sympathetic Dystrophy and Pain. An object of the present invention, as taught in the parent case, is the modulation of the autonomic nervous system, which has application to prevent the development or progression of reflex sympathetic dystrophy and to control the symptoms once the condition has developed.
Reflex sympathetic dystrophy is a potentially debilitating condition that typically develops following trauma to a peripheral nerve, in which a crush or transection injury disrupts the afferent pain fibers and the sympathetic efferent fibers. The most widely accepted theory as to the etiology underlying this condition holds that during the healing phase, sympathetic efferent fibers develop connections with the pain carrying afferent fibbers, resulting in the perception of pain in response to sympathetic activity. Current therapy involves pharmacologic agents and is largely ineffective, leaving a population of otherwise often healthy people who are debilitated by severe chronic medication refractory pain. By modulating the sympathetic nervous system activity using the method and apparatus taught in the parent case or using variants thereof, the symptoms arising from reflex sympathetic dystrophy can be prevented or reduced.
Inhibition of sympathetic system activity is used to reduce the level of neural activity that is pathologically fed back into pain afferent fibers, thereby reducing symptoms. This therapy may be applied preventatively to modulate sympathetic nervous system activity and minimize the degree of neural connection between the sympathetic efferent neurons and the pain carrying afferent neurons.
N. General—Control and Temporal Modulation. Various forms of temporal modulation may be performed to achieve the desired efficacy in the treatment of these and other diseases, conditions, or augmentation applications. Constant intensity modulation, time varying modulation, cyclical modulation, altering polarity modulation, up-regulation interspersed with down-regulation, intermittent modulation, and other permutations are include in the present invention. The use of a single or multiplicity of these temporal profiles provides resistance of the treatment or enhancement to habituation by the nervous system, thereby preserving or prolonging the effect of the modulation. The use of a multiplicity of modulation sites provides resistance of the treatment or enhancement to habituation by the nervous system, thereby preserving or prolonging the effect of the modulation; by distributing or varying the intensity of the neuromodulation among a plurality of sites enables the delivery of therapy or augmentation that is more resistant to adaptation or habituation by the nervous system. Furthermore, the control of neural state, including level of sympathetic nervous system activity, level of parasympathetic nervous system activity, autonomic index, or other characteristic or metric of neural function in either or both of an open-loop or closed-loop manner is taught herein. The use of open-loop or closed-loop control to maintain at least one neural state at a constant or time varying target level is used to better control physiology, reduce habituation, reduce side effects, apportion side effect to preferable time windows such as while sleeping), and optimize response to therapy.
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
Furthermore, all patents claiming priority to U.S. Provisional Application 60/095,413 and U.S. application Ser. No. 09/340,326, now U.S. Pat. No. 6,366,813, which were filed prior to Dec. 15, 2004 or which are in content continuations of these are incorporated by reference. Specifically, this includes U.S. Provisional Application 60/095,413 filed Aug. 5, 1998, U.S. Utility application Ser. No. 09/340,326 filed Jun. 25, 1999 and now U.S. Pat. No. 6,366,813, U.S. Utility application Ser. No. 10/008,576 filed Nov. 11, 2001 and now U.S. Pat. No. 6,819,956, U.S. Provisional Application 60/427,699 filed Nov. 20, 2002, U.S. Provisional Application 60/436,792 filed Dec. 27, 2002, U.S. Utility application Ser. No. 10/718,248 filed Nov. 20, 2003, U.S. Provisional Application 60/438,286 filed Jan. 6, 2003, U.S. Utility application Ser. No. 10/753,205 filed Jan. 6, 2004, U.S. Provisional Application 60/460,140 filed Apr. 3, 2003, U.S. Utility application Ser. No. 10/818,333 filed Apr. 5, 2004, U.S. Provisional Application 60/562,487 filed Apr. 14, 2004, U.S. application Ser. No. 10/889,844 filed Jul. 12, 2004, U.S. Application 60/614,241 filed Sep. 28, 2004, U.S. Provisional Application 60/307,124 Jul. 23, 2001, U.S. application Ser. No. 10/198,871 filed Jul. 19, 2002, and other which may not have published yet.
Figure A02 depicts biochemical pathways involved in mechanism of action of the effect of sympathetic nervous system modulation on adipose tissue and lipolysis.
The present invention encompasses a multimodality technique, method, and apparatus for the treatment of several diseases, including but not limited to obesity, eating disorders, depression, epilepsy, and diabetes.
These modalities may be used for diagnostic and therapeutic uses, and these modalities include but are not limited to stimulation of gastric tissue, stimulation of gastric musculature, stimulation of gastric neural tissue, stimulation of sympathetic nervous tissue, stimulation of parasympathetic nervous tissue, stimulation of peripheral nervous tissue, stimulation of central nervous tissue, stimulation of cranial nervous tissue, stimulation of skin receptors, including Pacinian corpuscles, nociceptors, Golgi tendons, and other sensory tissues in the skin, subcutaneous tissue, muscles, and joints.
Stimulation may be accomplished by electrical means, optical means, electromagnetic means, radiofrequency means, electrostatic means, magnetic means, vibrotactile means, pressure means, pharmacologic means, chemical means, electrolytic concentration means, thermal means, or other means for altering tissue activity.
Already encompassed in the above description are several specific applications of this broad technology. These specific applications include electrical stimulation of gastric tissue, including at least one of muscle and neural, for the control of appetite and satiety, and for the treatment of obesity. Additional specific uses include electrical stimulation of gastric tissue for the treatment of depression. Further uses include electrical stimulation of pancreatic tissue for the treatment of diabetes.
A. Satiety Modulation.
A1. Sympathetic Afferent Stimulation. Selected stimulation of the sympathetic nervous system is an objective of the present invention. A variety of modulator designs and configurations are included in the present invention and other designs and configurations may be apparent to those skilled in the art and these are also included in the present invention. Said modulator may take the form of electrode or electrical source, optical source, electromagnetic source, radiofrequency source, electrostatic source, magnetic source, vibrotactile source, pressure source, pharmacologic source, chemical source, electrolyte source, thermal source, or other energy or stimulus source.
One objective of the modulator design for selective sympathetic nervous system stimulation is the avoidance of stimulation of the vagus nerve. Stimulation of the vagus nerve poses the risk enhanced propensity for development of gastric or duodenal ulcers.
Other techniques in which electrical stimulation has been used for the treatment of obesity have included stimulation of central nervous system structures or peripheral nervous system structures. Other techniques have used sequential stimulation of the gastric tissue to interrupt peristalsis; however, this broad stimulation of gastric tissue necessarily overlaps regions heavily innervated by the vagus nerve and consequently poses the same risks of gastric and duodenal ulcers that stimulation of the vagus nerve does.
One objective of the present invention is the selective stimulation of said afferent neural fibers that innervate gastric tissue. Avoidance of vagus nerve stimulation is an object of this modulator configuration. Other alternative approaches to gastric pacing involving gastric muscle stimulation secondarily cause stimulation of the vagus nerve as well as stimulation of gastric tissues in acid-secreting regions, consequently posing the undesirable side effects of gastric and duodenal ulcers secondary to activation of gastric acid stimulation.
There are a number of approaches to selective stimulation of the sympathetic nervous system. This invention includes stimulation of the sympathetic fibers at sites including the zones of innervation of the stomach, the gastric innervation zones excluding those innervated by vagus branches, the distal sympathetic branches proximal to the stomach, the sympathetic trunk, the intermediolateral nucleus, the locus ceruleus, the hypothalamus, and other structures comprising or influencing sympathetic afferent activity.
Stimulation of the sympathetic afferent fibers elicits the perception of satiety, and achievement of chronic, safe, and efficacious modulation of sympathetic afferents is one of the major objectives of the present invention.
Alternating and augmenting stimulation of the sympathetic nervous system and vagus nerve is included in the present invention. By alternating stimulation of the vagus nerve and the sympathetic afferent fibers, one may induce the sensation of satiety in the implanted patient while minimizing the potential risk for gastric and duodenal ulcers.
Since vagus and sympathetic afferent fibers carry information that is related to gastric distention, a major objective of the present invention is the optimization stimulation of the biggest fibers, the afferent sympathetic nervous system fibers, and other afferent pathways such that a maximal sensation of satiety is perceived in the implanted individual and such that habituation of this sensation of satiety is minimized. This optimization is performed in any combination of matters including temporal patterning of the individual signals to each neural pathway, including but not limited to the vagus nerve and sympathetic afferents, as well as temporal patterning between a multiplicity of stimulation channels involving the same were neural pathways. The present invention teaches a multiplicity of apparatus and method for stimulation of afferent sympathetic fibers, as detailed below. Other techniques and apparatus may become apparent to those skilled in the art, without departing from the present invention.
A1a. Sympathetic Afferents—Gastric Region.
Implantable pulse generator 1 is shown with modulator 2 and modulator 3 in contact with the corresponding portion of stomach 8 in the respective figures, detailed below. Implantable pulse generator further comprises attachment fixture 4 and attachment fixture 5. Additional or fewer attachment fixtures may be included without departing from the present invention. Attachment means 6 and attachment means 7 are used to secure attachment fixture 4 and attachment fixture 5, respectively to appropriate portion of stomach 8. Attachment means 6 and attachment means 7 may be comprised from surgical suture material, surgical staples, adhesives, or other means without departing from the present invention.
Modulator 2 and modulator 3 are used to stimulate at least one of gastric longitudinal muscle layer, gastric circular muscle layer, gastric nervous tissue, or other tissue. Modulator 2 and modulator 3 may be fabricated from nonpenetrating material or from penetrating material, including needle tips, arrays of needle tips, wires, conductive sutures, other conductive material, or other material, without departing from the present invention.
A1b. Sympathetic Afferents—Sympathetic Trunk. The present invention teaches apparatus and method for stimulation of sympathetic afferent fibers using stimulation in the region of the sympathetic trunk. As shown in
A1c. Sympathetic Afferents—Other. The present invention teaches apparatus and method for stimulation of sympathetic afferent fibers using stimulation of nerves arising from the sympathetic trunk. As shown in
A2. Gastric Musculature Stimulation. A further object of the present invention is the stimulation of the gastric musculature. This may be performed using either or both of closed loop and open loop control. In the present embodiment, a combination of open and closed loop control is employed. The open loop control provides a baseline level of gastric stimulation. This stimulation maintains tone of the gastric musculature. This increases the wall tension the stomach and plays a role in the perception of satiety in the implanted patient. Additionally, stimulation of the gastric musculature causes contraction of the structures, thereby reducing the volume of the stomach. This gastric muscle contraction, and the consequent reduction of stomach volume effectively restricts the amount of food that may be ingested. Surgical techniques have been developed and are known to those practicing in the field of surgical treatment of obesity. Several of these procedures are of the restrictive type, but because of their surgical nature they are fixed in magnitude and difficult if not impossible to reverse. The present invention teaches a technique which employs neural modulation and gastric muscle stimulation which by its nature is the variable and reversible. This offers the advantages postoperative adjustment of magnitude, fine tuning for the individual patient, varying of magnitude to suit the patient's changing needs and changing anatomy over time, and the potential for reversal or termination of treatment. Furthermore, since the gastric wall tension is generated in a physiological manner by the muscle itself, it does not have the substantial risk of gastric wall necrosis and rupture inherent in externally applied pressure, as is the case with gastric banding.
This muscle stimulation and contraction accomplishes several objectives: (1) functional reduction in stomach volume, (2) increase in stomach wall tension, (3) reduction in rate of food bolus flow. All of these effects are performed to induce the sensation of satiety.
A3. Gastric Pylorus Stimulation.
A4. Parasympathetic Stimulation. The parasympathetic nervous system is complementary to the sympathetic nervous system and plays a substantial role in controlling digestion and cardiac activity. Several routes are described in the present invention to modulate activity of the parasympathetic nervous system.
A4a. Parasympathetic Stimulation—Vagus Nerve. Others have advocated the use of vagus nerve stimulation for the treatment of a number of disorders including obesity. Zabara and others have described systems in which the vagus nerve in the region of the neck is stimulated. This is plagued with a host of problems, including life-threatening cardiac complications as well as difficulties with speech and discomfort during stimulation. The present invention is a substantial advance over that discussed by Zabara et al, in which unrestricted fiber activation using epineural stimulation is described. That technique results in indiscriminate stimulation of efferent and afferent fibers. With vagus nerve stimulation, efferent fiber activation generates many undesirable side effects, including gastric and duodenal ulcers, cardiac disturbances, and others.
In the present invention, as depicted in
A.4.a.i. Innovative Stimulation Anatomy.
A.4.a.ii. Innovative Stimulation Device. The present invention further includes devices designed specifically for the stimulation of afferent fibers.
The present invention further includes stimulation of other tissues that influence vagus nerve activity. These include tissues of the esophagus, stomach, small and large intestine, pancreas, liver, gallbladder, kidney, mesentery, appendix, bladder, uterus, and other intraabdominal tissues. Stimulation of one or a multiplicity of these tissues modulates activity of the vagus nerve afferent fibers without significantly altering activity of efferent fibers. This method and the associated apparatus facilitate the stimulation of vagus nerve afferent fibers without activating vagus nerve efferent fibers, thereby overcoming the ulcerogenic and cardiac side effects of nonselective vagus nerve stimulation. This represents a major advance in vagus nerve modulation and overcomes the potentially life-threatening complications of nonselective stimulation of the vagus nerve.
A4b. Parasympathetic Stimulation—Other. The present invention teaches stimulation of the cervical nerves or their roots or branches for modulation of the parasympathetic nervous system. Additionally, the present invention teaches stimulation of the sacral nerves or their roots or branches for modulation of the parasympathetic nervous system.
A5. Multichannel Satiety Modulation.
Using the apparatus depicted in
In addition to the apparatus and methods depicted in
B. Metabolic ModulationB.1. Sympathetic Efferent Stimulation. One objective of the modulator configuration employed in the present invention is the selected stimulation of sympathetic efferent nerve fibers. The present invention includes a multiplicity of potential modulator configurations and combinations of thereof. The present embodiment includes modulators placed at a combination of sites to interface with the sympathetic efferent fibers. These sites include the musculature of the stomach, the distal sympathetic branches penetrating into the stomach, postganglionic axons and cell bodies, preganglionic axons and cell bodies, the sympathetic chain and portions thereof, the intermediolateral nucleus, the locus ceruleus, the hypothalamus, and other structures comprising or influencing activity of the sympathetic nervous system.
Stimulation of the sympathetic efferents is performed to elevate the metabolic rate and lipolysis in the adipose tissue, thereby enhancing breakdown of fat and weight loss in the patient.
B.1.a. Sympathetic Efferent Stimulation Sympathetic Trunk.
Right sympathetic trunk 71 and left sympathetic trunk are lateral to mediastinum 82. Right greater splanchnic nerve 73 and right lesser splanchnic nerve 75 arise from right sympathetic trunk 71. Left greater splanchnic nerve 74 and left lesser splanchnic nerve 76 arise from left sympathetic trunk 72. Right subdiaphragmatic greater splanchnic nerve 78, left subdiaphragmatic greater splanchnic nerve 79, right subdiaphragmatic lesser splanchnic nerve 80, and left subdiaphragmatic lesser splanchnic nerve 81 are extensions below the diaphragm 77 of the right greater splanchnic nerve 73, left greater splanchnic nerve 74, right lesser splanchnic nerve 75, and left lesser splanchnic nerve 76, respectively.
B.1.b. Sympathetic Efferent Stimulation—Splanchnic Nerves.
Thoracic splanchnic nerve interface 87, 88, 89, 90 are implanted adjacent to and in communication with the right greater splanchnic nerve 73, left greater splanchnic nerve 74, right lesser splanchnic nerve 75, and left lesser splanchnic nerve 76, arise, respectively. Abdominal splanchnic nerve interface 91, 92, 93, and 94 are implanted adjacent to and in communication with the right subdiaphragmatic greater splanchnic nerve 78, left subdiaphragmatic greater splanchnic nerve 79, right subdiaphragmatic lesser splanchnic nerve 80, and left subdiaphragmatic lesser splanchnic nerve 81, respectively.
Stimulation of at least one of right sympathetic trunk 71, left sympathetic trunk 72, right greater splanchnic nerve 73, left greater splanchnic nerve 74, right lesser splanchnic nerve 75, and left lesser splanchnic nerve 76, right subdiaphragmatic greater splanchnic nerve 78, left subdiaphragmatic greater splanchnic nerve 79, right subdiaphragmatic lesser splanchnic nerve 80, and left subdiaphragmatic lesser splanchnic nerve 81 enhances metabolism of adipose tissue. Stimulation of these structures may be performed using at least one of electrical energy, electrical fields, optical energy, mechanical energy, magnetic energy, chemical compounds, pharmacological compounds, thermal energy, vibratory energy, or other means for modulating neural activity.
B.1.c. Sympathetic Efferent Stimulation—Spinal Cord.
Stimulation, inhibition, or other modulation of the spinal cord 151 is used to modulate fibers of the sympathetic nervous system, including those in the intermediolateral nucleus 121 and efferent and efferent fibers connected to the intermediolateral nucleus 121. Modulation of at least one of portions of the spinal cord 151, intermediolateral nucleus 121, ventral spinal root 124, dorsal spinal root 125, spinal ganglion 126, spinal nerve 127, gray ramus communicantes 130, white ramus communicantes 131 and other structures facilitates modulation of activity of the sympathetic trunk 132. Modulation of activity of the sympathetic trunk 132, in turn, is used to modulate at least one of metabolic activity, satiety, and appetite. This may be achieved using intermediolateral nucleus neuromodulatory interface 152, placed in or adjacent to the intermediolateral nucleus 121. The less invasive design employing neuromodulatory interfaces (144, 145, 146, 147, 148, 149, 150) shown positioned in the in epidural space 137 is taught in the present invention.
B.1.d. Sympathetic Efferent Stimulation—Other. The present invention further includes modulation of all sympathetic efferent nerves, nerve fibers, and neural structures. These sympathetic efferent neural structures include but are not limited to distal sympathetic nerve branches, mesenteric nerves, sympathetic efferent fibers at all spinal levels, rami communicantes at all spinal levels, paravertebral nuclei, prevertebral nuclei, and other sympathetic structures.
B.2. Noninvasive Stimulation. The present invention teaches a device for metabolic control using tactile stimulation. Tactile stimulation of afferent neurons causes alterations in activity of sympathetic neurons which influence metabolic activity of adipose tissue. The present invention teaches tactile stimulation of skin, dermal and epidermal sensory structures, subcutaneous tissues and structures, and deeper tissues to modulate activity of afferent neurons.
This device for metabolic control employs vibratory actuators. Alternatively, electrical stimulation, mechanical stimulation, optical stimulation, acoustic stimulation, pressure stimulation, and other forms of energy that modulate afferent neural activity, are used.
C. Multimodal Metabolic Modulation. To maximize efficacy while tailoring treatment to minimize side effects, the preferred embodiment includes a multiplicity of treatment modalities, including afferent, efferent, and neuromuscular modulation.
Afferent signals are generated to simulate satiety. This is accomplished through neural, neuromuscular, and hydrostatic mechanisms. Electrical stimulation of the vagus via vagus nerve interface 45 afferents provides one such channel to transmit information to the central nervous system for the purpose of eliciting satiety. Electrical stimulation of the sympathetic afferents via sympathetic nerve interface 46 provides another such channel to transmit information to the central nervous system for the purpose of eliciting satiety. Electrical stimulation of gastric circular muscle layer may also be employed to induce satiety.
In
In
In
E. System/Pulse Generator Design. Neuromodulatory interfaces that use electrical energy to modulate neural activity may deliver a broad spectrum of electrical waveforms. One preferred set of neural stimulation parameter sets includes pulse frequencies ranging from 0.1 Hertz to 1000 Hertz, pulse widths from 1 microsecond to 500 milliseconds. Pulses are charge balanced to insure no net direct current charge delivery. The preferred waveform is bipolar pulse pair, with an interpulse interval of 1 microsecond to 1000 milliseconds. Current regulated stimulation is preferred and includes pulse current amplitudes ranging from 1 microamp to 1000 milliamps. Alternatively, voltage regulation may be used, and pulse voltage amplitudes ranging from 1 microamp to 1000 milliamps. These parameters are provided as exemplary of some of the ranges included in the present invention; variations from these parameter sets are included in the present invention.
In
It is obvious to the reader that modulation of the right greater splanchnic nerve 73, the performance of which is exemplified by Abdominal Splanchnic Neuromodulatory Interface 91, will in turn effect modulation of connected structures, including proximal and distal portions of Right Subdiaphragmatic Greater Splanchnic Nerve 78. Proximal or retrograde conduction of neural signals will effect modulation of Right Greater Splanchnic Nerve 73 and more proximal structures. Distal or anterograde conduction of neural signals will effect modulation of distal structures including but not limited to celiac plexus 154, celiac ganglion 155, superior mesenteric plexus 156, superior mesenteric ganglion 157, renal plexus 158, renal ganglion 159, inferior mesenteric plexus 160, iliac plexus 161, and other structures connected by neural pathways.
It is obvious to the reader that modulation of the left greater splanchnic nerve 74, the performance of which is exemplified by Abdominal Splanchnic Neuromodulatory Interface 92, will in turn effect modulation of connected structures, including proximal and distal portions of Left Subdiaphragmatic Greater Splanchnic Nerve 79. Proximal or retrograde conduction of neural signals will effect modulation of Left Greater Splanchnic Nerve 74 and more proximal structures. Distal or anterograde conduction of neural signals will effect modulation of distal structures including but not limited to celiac plexus 154, celiac ganglion 155, superior mesenteric plexus 156, superior mesenteric ganglion 157, renal plexus 158, renal ganglion 159, inferior mesenteric plexus 160, iliac plexus 161, and other structures connected by neural pathways.
Pulse generator 101 generates neuromodulatory signal which is transmitted by connecting cable 168 to abdominal splanchnic neuromodulatory interface 166, which modulates at least one of celiac plexus 154 and celiac ganglion 155. Implantable Pulse generator 102 generates neuromodulatory signal which is transmitted by connecting cable 169 to abdominal splanchnic neuromodulatory interface 167, which modulates at least one of celiac plexus 154 and celiac ganglion 155.
Pulse generator 101 generates neuromodulatory signal which is transmitted by connecting cable 172 to abdominal splanchnic neuromodulatory interface 170, which modulates at least one of superior mesenteric plexus 156, superior mesenteric ganglion 157, renal plexus 158, renal ganglion 159, inferior mesenteric plexus 160, and iliac plexus 161. Pulse generator 102 generates neuromodulatory signal which is transmitted by connecting cable 173 to abdominal splanchnic neuromodulatory interface 171, which modulates at least one of superior mesenteric plexus 156, superior mesenteric ganglion 157, renal plexus 158, renal ganglion 159, inferior mesenteric plexus 160, and iliac plexus 161.
Pulse generator 101 generates neuromodulatory signal which is transmitted by connecting cable 176 to neuromodulator array 174, which modulates at least one of celiac plexus 154, celiac ganglion 155, superior mesenteric plexus 156, superior mesenteric ganglion 157, renal plexus 158, renal ganglion 159, inferior mesenteric plexus 160, and iliac plexus 161.
Pulse generator 102 generates neuromodulatory signal which is transmitted by connecting cable 177 to neuromodulator array 175, which modulates at least one of celiac plexus 154, celiac ganglion 155, superior mesenteric plexus 156, superior mesenteric ganglion 157, renal plexus 158, renal ganglion 159, inferior mesenteric plexus 160, and iliac plexus 161.
Abdominal Splanchnic Neuromodulatory Interface 178 modulate at least one of sympathetic trunk, 132, Right Lumbar Sympathetic Ganglia 162, and Right Sacral Sympathetic Ganglia 164. Abdominal Splanchnic Neuromodulatory Interface 179 modulates at least one of sympathetic trunk, 132, Left Lumbar Sympathetic Ganglia 163, and Left Sacral Sympathetic Ganglia 165
Abdominal Splanchnic Neuromodulatory Interface 180 modulates at least one neural structure in neural connection to sympathetic trunk 132, including but not limited to right greater splanchnic nerve 73, right lesser splanchnic nerve 75, right least splanchnic nerve, or other structure. Abdominal Splanchnic Neuromodulatory Interface 181 modulates at least one neural structure in neural connection to sympathetic trunk 132, including but not limited to left greater splanchnic nerve 74, left lesser splanchnic nerve 76, left least splanchnic nerve, or other structure.
Abdominal Splanchnic Neuromodulatory Interface 182, Abdominal Splanchnic Neuromodulatory Interface 183, Abdominal Splanchnic Neuromodulatory Interface 184, Abdominal Splanchnic Neuromodulatory Interface 185, and Abdominal Splanchnic Neuromodulatory Interface 186 each modulate abdominal structures including but not limited to celiac plexus 154, celiac ganglion 155, superior mesenteric plexus 156, superior mesenteric ganglion 157, renal plexus 158, renal ganglion 159, inferior mesenteric plexus 160, and iliac plexus 161.
Modulation is performed to modulate metabolic rate, satiety, blood pressure, heart rate, peristalsis, insulin release, CCK release, and other gastrointestinal functions. Modulation using the system and method taught, as well as equivalent modifications and variations thereof, allows the treatment of disease including obesity, bulimia, anorexia, diabetes, hypoglycemia, hyperglycemia, irritable bowel syndrome, hypertension, hypotension, shock, gastroparesis, and other disorders. Modulation includes at least one of stimulatory and inhibitory effect on neural structures.
Implantable pulse generator 99 is connected via connecting cable 213, 215, 217, 219, 221, and 235 to Right Cervical Plexus Neuromodulator Array 193, Right Intercostal Neuromodulator Array 195, Right Intercostal Neuromodulator Array 197, Right Intercostal Neuromodulator Array 199, Right Intercostal Neuromodulator Array 201, and Right Vagal Neuromodulator Array 233, respectively.
Implantable pulse generator 100 is connected via connecting cable 214, 216, 218, 220, 222, and 236 to Left Cervical Plexus Neuromodulator Array 194, Left Intercostal Neuromodulator Array 196, Left Intercostal Neuromodulator Array 198, Left Intercostal Neuromodulator Array 200, and Left Intercostal Neuromodulator Array 202, and Left Vagal Neuromodulator Array 234, respectively.
Implantable pulse generator 101 is connected via connecting cable 223, 225, 227, 229, and 231 to Right Abdominal Para Plexus Neuromodulator Array 203, Right Abdominal Greater Splanchnic Neuromodulator Array 205, Right Abdominal Lesser Splanchnic Neuromodulator Array 207, Right Abdominal Sympathetic Trunk Neuromodulator Array 209, and Right Abdominal Sympathetic Trunk Neuromodulator Array 211, respectively
Implantable pulse generator 102 is connected via connecting cable 224, 226, 228, 230, and 232 to Left Abdominal Para Plexus Neuromodulator Array 204, Left Abdominal Greater Splanchnic Neuromodulator Array 206, Left Abdominal Lesser Splanchnic Neuromodulator Array 208, Left Abdominal Sympathetic Trunk Neuromodulator Array 210, and Left Abdominal Sympathetic Trunk Neuromodulator Array 212, respectively
Right Cervical Plexus Neuromodulator Array 193 modulates neural activity in Right Cervical Plexus 237. Right Intercostal Neuromodulator Array 195, Right Intercostal Neuromodulator Array 197, Right Intercostal Neuromodulator Array 199, and Right Intercostal Neuromodulator Array 201 each modulate neural activity in at least one of Right Sympathetic Trunk 71, Right Greater Splanchnic Nerve 73, and Right Lesser Splanchnic Nerve 75. Right Vagal Neuromodulator Array 233 modulates neural activity in Right Vagus Nerve 95.
Left Cervical Plexus Neuromodulator Array 194 modulates neural activity in Left Cervical Plexus 238. Left Intercostal Neuromodulator Array 196, Left Intercostal Neuromodulator Array 198, Left Intercostal Neuromodulator Array 200, and Left Intercostal Neuromodulator Array 202 each modulate neural activity in at least one of Left Sympathetic Trunk 72, Left Greater Splanchnic Nerve 74, and Left Lesser Splanchnic Nerve 76. Left Vagal Neuromodulator Array 234 modulates neural activity in Left Vagus Nerve 96.
Right Abdominal Para Plexus Neuromodulator Array 203 modulates at least one of Celiac Plexus 154, Celiac Ganglion 155, Superior Mesenteric Plexus 156, Superior Mesenteric Ganglion 157, Renal Plexus 158, Renal Ganglion 159, Inferior Mesenteric Plexus 160, and Iliac Plexus 161. Right Abdominal Greater Splanchnic Neuromodulator Array 205 modulates Right Subdiaphragmatic Greater Splanchnic Nerve 78. Right Abdominal Lesser Splanchnic Neuromodulator Array 207 modulates Right Subdiaphragmatic Lesser Splanchnic Nerve 80. Right Abdominal Sympathetic Trunk Neuromodulator Array 209 and Right Abdominal Sympathetic Trunk Neuromodulator Array 211 each modulate at least one of Right Lumbar Sympathetic Ganglia 162, Right Sacral Sympathetic Ganglia 164, and Right Sympathetic Trunk 71.
Left Abdominal Pam Plexus Neuromodulator Array 204 modulates at least one of Celiac Plexus 154, Celiac Ganglion 155, Superior Mesenteric Plexus 156, Superior Mesenteric Ganglion 157, Renal Plexus 158, Renal Ganglion 159, Inferior Mesenteric Plexus 160, and Iliac Plexus 161. Left Abdominal Greater Splanchnic Neuromodulator Array 206 modulates Left Subdiaphragmatic Greater Splanchnic Nerve 79. Left Abdominal Lesser Splanchnic Neuromodulator Array 208 modulates Left Subdiaphragmatic Lesser Splanchnic Nerve 81. Left Abdominal Sympathetic Trunk Neuromodulator Array 210 and Left Abdominal Sympathetic Trunk Neuromodulator Array 212 each modulate at least one of Left Lumbar Sympathetic Ganglia 163, Left Sacral Sympathetic Ganglia 165, and Left Sympathetic Trunk 72.
Elements comprising neuromodulators and neuromodulator arrays provide at least one of activating or inhibiting influence on neural activity of respective neurological target structures. Additional or fewer connecting cables and neuromodulator arrays may be employed without departing from the present invention.
These connections provided by connecting cables may facilitate communication and/or power transmission via electrical energy, ultrasound energy, optical energy, radiofrequency energy, electromagnetic energy, thermal energy, mechanical energy, chemical agent, pharmacological agent, or other signal or power means without departing from the parent or present invention.
Neuromodulator and neuromodulatory interface may be used interchangeably in this specification. Neuromodulator is a subset of modulator and modulates neural tissue.
External Transmitting and Receiving Unit 239 comprises modules including Controller 240, Memory 241, Bidirectional Transceiver 242, and User Interface 243. Additional or fewer modules may be included without departing from the present invention.
Neuromodulatory interfaces include an energy storage element, such as capacitor, battery, or inductor, for storage of power for delivery to at least one of tissue and on-board electronic components.
External Transmitting and Receiving Unit 239 comprises modules including Controller 240, Memory 241, Bidirectional Transceiver 242, and User Interface 243. Additional or fewer modules and additional or fewer neuromodulatory interfaces may be included without departing from the present invention.
In addition to the thoracic anatomical structures shown on
In addition to the abdominal anatomical structures shown on
The activities of these structures are modulated by corresponding neuromodulatory interfaces. Any of the previously described neuromodulatory interfaces in the parent case and the present case may be positioned to modulate these neural structures. Additional or alternate designs for neuromodulatory interfaces may be employed without departing from the present or parent invention.
Implantable pulse generator 99 is connected via connecting cable 213, 215, 217, 219, 221, 235, 258, 260, and 268 to Right Cervical Plexus Neuromodulator Array 193, Right Intercostal Neuromodulator Array 195, Right Intercostal Neuromodulator Array 197, Right Intercostal Neuromodulator Array 199, Right Intercostal Neuromodulator Array 201, and Right Vagal Neuromodulator Array 233, Right Superficial Cardiac Plexus Neuromodulator Array 250, Right Deep Cardiac Plexus Neuromodulator Array 252, Right Anterior Pulmonary Nerve Neuromodulator Array 266, respectively.
Implantable pulse generator 100 is connected via connecting cable 214, 216, 218, 220, 222, 236, 259, 261, and 269 to Left Cervical Plexus Neuromodulator Array 194, Left Intercostal Neuromodulator Array 196, Left Intercostal Neuromodulator Array 198, Left Intercostal Neuromodulator Array 200, and Left Intercostal Neuromodulator Array 202, and Left Vagal Neuromodulator Array 234, Left Superficial Cardiac Plexus Neuromodulator Array 251, Left Deep Cardiac Plexus Neuromodulator Array 253, Left Anterior Pulmonary Nerve Neuromodulator Array 267, respectively.
Implantable pulse generator 101 is connected via connecting cable 223, 225, 227, 229, 231, 262, and 264 to Right Abdominal Para Plexus Neuromodulator Array 203, Right Abdominal Greater Splanchnic Neuromodulator Array 205, Right Abdominal Lesser Splanchnic Neuromodulator Array 207, Right Abdominal Sympathetic Trunk Neuromodulator Array 209, and Right Abdominal Sympathetic Trunk Neuromodulator Array 211, Right Renal Plexus Neuromodulator Array 254, and Right Renal Nerve Branch Neuromodulator Array 256, respectively.
Implantable pulse generator 102 is connected via connecting cable 224, 226, 228, 230, 232. 263, and 265 to Left Abdominal Para Plexus Neuromodulator Array 204, Left Abdominal Greater Splanchnic Neuromodulator Array 206, Left Abdominal Lesser Splanchnic Neuromodulator Array 208, Left Abdominal Sympathetic Trunk Neuromodulator Array 210, and Left Abdominal Sympathetic Trunk Neuromodulator Array 212, Left Renal Plexus Neuromodulator Array 255, and Left Renal Nerve Branch Neuromodulator Array 257, respectively
Right Cervical Plexus Neuromodulator Array 193 modulates neural activity in Right Cervical Plexus 237. Right Intercostal Neuromodulator Array 195, Right Intercostal Neuromodulator Array 197, Right Intercostal Neuromodulator Array 199, and Right Intercostal Neuromodulator Array 201 each modulate neural activity in at least one of Right Sympathetic Trunk 71, Right Greater Splanchnic Nerve 73, and Right Lesser Splanchnic Nerve 75. Right Vagal Neuromodulator Array 233 modulates neural activity in Right Vagus Nerve 95.
Right Superficial Cardiac Plexus Neuromodulator Array 250 modulates neural activity in at least one of Superficial Cardiac Plexus 244 and other structures. Right Deep Cardiac Plexus Neuromodulator Array 252 modulates neural activity in at least one of Deep Cardiac Plexus 245 and other structures. Right Anterior Pulmonary Nerve Neuromodulator Array 266 modulates neural activity in at least one of Right Anterior Pulmonary Nerve 246 and other structures.
Left Cervical Plexus Neuromodulator Array 194 modulates neural activity in Left Cervical Plexus 238. Left Intercostal Neuromodulator Array 196, Left Intercostal Neuromodulator Array 198, Left Intercostal Neuromodulator Array 200, and Left Intercostal Neuromodulator Array 202 each modulate neural activity in at least one of Left Sympathetic Trunk 72, Left Greater Splanchnic Nerve 74, and Left Lesser Splanchnic Nerve 76. Left Vagal Neuromodulator Array 234 modulates neural activity in Left Vagus Nerve 96.
Left Superficial Cardiac Plexus Neuromodulator Array 251 modulates neural activity in at least one of Superficial Cardiac Plexus 244 and other structures. Left Deep Cardiac Plexus Neuromodulator Array 253 modulates neural activity in at least one of Deep Cardiac Plexus 245 and other structures. Left Anterior Pulmonary Nerve Neuromodulator Array 267 modulates neural activity in at least one of Left Anterior Pulmonary Nerve 247 and other structures.
Right Abdominal Para Plexus Neuromodulator Array 203 modulates neural activity in at least one of Celiac Plexus 154, Celiac Ganglion 155, Superior Mesenteric Plexus 156, Superior Mesenteric Ganglion 157, Renal Plexus 158, Renal Ganglion 159, Inferior Mesenteric Plexus 160, and Iliac Plexus 161. Right Abdominal Greater Splanchnic Neuromodulator Array 205 modulates neural activity in Right Subdiaphragmatic Greater Splanchnic Nerve 78. Right Abdominal Lesser Splanchnic Neuromodulator Array 207 modulates neural activity in Right Subdiaphragmatic Lesser Splanchnic Nerve 80. Right Abdominal Sympathetic Trunk Neuromodulator Array 209 and Right Abdominal Sympathetic Trunk Neuromodulator Array 211 each modulate neural activity in at least one of Right Lumbar Sympathetic Ganglia 162, Right Sacral Sympathetic Ganglia 164, and Right Sympathetic Trunk 71.
Right Renal Plexus Neuromodulator Array 254 modulates neural activity in at least one of Right Renal Nerve Branch 248, Renal Plexus 158, Renal Ganglion 159, and other structures. Right Renal Nerve Branch Neuromodulator Array 256 modulates neural activity in at least one of Right Renal Nerve Branch 248, Renal Plexus 158, Renal Ganglion 159, and other structures.
Left Abdominal Para Plexus Neuromodulator Array 204 modulates neural activity in at least one of Celiac Plexus 154, Celiac Ganglion 155, Superior Mesenteric Plexus 156, Superior Mesenteric Ganglion 157, Renal Plexus 158, Renal Ganglion 159, Inferior Mesenteric Plexus 160, and Iliac Plexus 161. Left Abdominal Greater Splanchnic Neuromodulator Array 206 modulates neural activity in Left Subdiaphragmatic Greater Splanchnic Nerve 79. Left Abdominal Lesser Splanchnic Neuromodulator Array 208 modulates neural activity in Left Subdiaphragmatic Lesser Splanchnic Nerve 81. Left Abdominal Sympathetic Trunk Neuromodulator Array 210 and Left Abdominal Sympathetic Trunk Neuromodulator Array 212 each modulate neural activity in at least one of Left Lumbar Sympathetic Ganglia 163, Left Sacral Sympathetic Ganglia 165, and Left Sympathetic Trunk 72.
Left Renal Plexus Neuromodulator Array 255 modulates neural activity in at least one of Left Renal Nerve Branch 249, Renal Plexus 158, Renal Ganglion 159, and other structures. Left Renal Nerve Branch Neuromodulator Array 257 modulates neural activity in at least one of Left Renal Nerve Branch 249, Renal Plexus 158, Renal Ganglion 159, and other structures.
Elements comprising neuromodulators and neuromodulator arrays provide at least one of activating or inhibiting influence on neural activity of respective neurological target structures. Additional or fewer connecting cables and neuromodulator arrays may be employed without departing from the present invention.
These connections provided by connecting cables may facilitate communication and/or power transmission via electrical energy, ultrasound energy, optical energy, radiofrequency energy, electromagnetic energy, thermal energy, mechanical energy, chemical agent, pharmacological agent, or other signal or power means without departing from the parent or present invention.
Neuromodulators and neuromodulatory interfaces may be used interchangeably in this specification.
Care is taken to avoid perforating visceral pleura 283. Skin incision is made at entry point 285 through the majority of the thickness of skin 280 close to parietal pleura 282 to assist in minimizing the amount of force required to enter pleural space 286, thereby minimizing the velocity and acceleration of catheter insertion trocar bulb tip 275 during this procedure and reducing the risk of perforation of visceral pleura 283. A novelty of the present invention, shown in
Catheter insertion retriever 271 is inserted through an incision in skin 280 at the site of exit point 287. Surgeon or assistant grasps catheter insertion retriever handle 277, and with catheter insertion retriever shaft 286 penetrating skin 280, positions catheter insertion retriever grasper 279 to grasp catheter insertion trocar bulb tip 275 and to pull or guide attached catheter 272 through incision in skin 280 at exit point 287.
As shown in
In both
Neuromodulatory interface array catheter 284 comprises a connector contact array 300 located near connector end 289, a neuromodulatory interface array 301 located near neuromodulatory interface end 290, and catheter body 291, which provides mechanical connection and signal transmission between connector contact array 300 and neuromodulatory interface array 301. Said signal transmission may be in the form of electrical fields or energy, electrical voltage, electrical current, optical energy, magnetic fields or energy, electromagnetic fields or energy, mechanical force or energy, vibratory force or energy, chemical agent or activation, pharmacological agent or activation, or other signal transmission means.
Neuromodulatory interface array 301 is comprised of at least one of neuromodulatory interface 296, 297, 298, and 299. Additional or fewer numbers of neuromodulatory interface may comprise neuromodulatory interface array 301 without departing from the present invention. Neuromodulator interface 296, 297, 298, 299 modulate activity of neural structures using at least one of electrical fields or energy, electrical voltage, electrical current, optical energy, magnetic fields or energy, electromagnetic fields or energy, mechanical force or energy, vibratory force or energy, chemical agent or activation, pharmacological agent or activation, or other neural modulation means.
Connector contact array 300 is comprised of at least one of connector element 292, 293, 294, and 295. Additional or fewer numbers of connector element may comprise connector contact array 300 without departing from the present invention.
Tracings showing the level of sympathetic stimulation 305 and sympathetic inhibition 306 are shown. During the time window in which sympathetic stimulation 305 is active, the sympathetic index 303 is seen to be increased and the autonomic index 302 is increased. During the time window in which sympathetic inhibition 306 is active, the sympathetic index 303 is seen to be decreased and the autonomic index 302 is decreased.
Tracings showing the level of parasympathetic stimulation 307 and parasympathetic inhibition 308 are shown. During the time window in which parasympathetic stimulation 307 is active, the parasympathetic index 304 is seen to be increased and the autonomic index 302 is decreased. During the time window in which parasympathetic inhibition 308 is active, the parasympathetic index 304 is seen to be decreased and the autonomic index 302 is increased.
Sympathetic and parasympathetic inhibition is accomplished by blockage of neural fibers. This is be performed using high frequency stimulation, with a best mode involving biphasic charge balanced waveforms delivered at frequencies over 100 Hz, though significantly higher as well as lower frequencies may be employed without departing form the present invention.
E. Intracranial—Subclavicular components.
As one skilled in the relevant art would find apparent from the following description, the configuration illustrated in
Neuromodulator array 316 includes but is not limited to neuromodulator array 318, 319, 320, 321, 322, 323, modulator 2, 3, 24, 25, 26, 27, 28, 29, 30, 31, neuromodulatory interface 34, nerve cuff 36, longitudinal electrode array 38, regeneration electrode array 44, vagus nerve interface 45, sympathetic nerve interface 46, epineural electrode 49, 50, 51, sympathetic trunk neuromodulatory interface 83, 84, 85, 86, thoracic splanchnic neuromodulatory interface 87, 88, 89, 90, abdominal splanchnic neuromodulatory interface 91, 92, 93, 94, vagus neuromodulatory interface 97, 98, epineural cuff electrode neuromodulatory interface 117, longitudinal electrode neuromodulatory interface 118, 119, regeneration tube neuromodulatory interface 120, anterior central spinal neuromodulatory interface 143, anterior right lateral spinal neuromodulatory interface 144, anterior left lateral spinal neuromodulatory interface 145, posterior central spinal neuromodulatory interface 146, posterior right lateral spinal neuromodulatory interface 147, posterior left lateral spinal neuromodulatory interface 148, right lateral spinal neuromodulatory interface 149, left lateral spinal neuromodulatory interface 150, intermediolateral nucleus neuromodulatory interface 152, abdominal splanchnic neuromodulatory interface 170, 171, neuromodulator array 174, 175, abdominal splanchnic neuromodulatory interface 178, 179, 180, 181, 182, 193, 184, 185, 186, right cervical plexus neuromodulatory array 193, left cervical plexus neuromodulatory array 194, right intercostal neuromodulatory array 195, 197, 199, 201, left intercostal neuromodulatory array 196, 198, 200, 202, right abdominal para plexus neuromodulatory array 203, left abdominal para plexus neuromodulatory array 204, right abdominal superior splanchnic neuromodulatory array 205, left abdominal superior splanchnic neuromodulatory array 206, right abdominal inferior splanchnic neuromodulatory array 207, left abdominal inferior splanchnic neuromodulatory array 208, right abdominal sympathetic trunk neuromodulatory array 209, 211, left abdominal sympathetic trunk neuromodulatory array 210, 212, right vagal neuromodulator array 233, left vagal neuromodulator array 234, right superficial cardiac plexus neuromodulator array 250, left superficial cardiac plexus neuromodulator array 251, right deep cardiac plexus neuromodulator array 252, left deep cardiac plexus neuromodulator array 253, right renal plexus neuromodulator array 254, left renal plexus neuromodulator array 255, right renal nerve branch neuromodulator array 256, left renal nerve branch neuromodulator array 257, right anterior pulmonary nerve neuromodulator array 266, left anterior pulmonary nerve neuromodulator array 267, neuromodulatory interface 296, 297, 298, 299, neuromodulatory interface array 301, neuromodulator array 316, 325, 326, 327, 328, 329, 330, 331, 332, and other apparatus or methods which modulate neural activity. A single or plurality of elements of neuromodulator array 316 may also be used as elements of a sensor array instead of or in addition to their function in modulating neural activity.
In the embodiment illustrated in
Physiological sensor array 319 senses at least one of any physiological parameters comprising temperature, hear rate, heart rate variability, any cardiac parameter, blood pressure, respiratory rate, respiratory function parameters and pressures, metabolic rate, respiratory quotient, glucose level, insulin level, organ perfusion, or other physiological parameter. Additional or fewer sensors and/or neuromodulators may be used without departing from the present invention.
Superficial intracranial electrode array 341 and 342 modulate and sense activity from superficial regions of the nervous system, including the cortex, subdural space, epidural space, calvaral space, subgaleal space, subcutaneous space and/or scalp region. Deep intracranial electrode array 343 and 344 modulate and sense activity from deep brain regions, including but not limited to subcortical nuclei and white matter tracts, brainstem structures, and medial and lateral and other components of the hypothalamus and all satiety centers.
Neural sensor array 318 generates neural signals representative of neural activity, including but not limited to signals from cortical, white matter, and deep brain nuclear signals. Neural activity to be sensed and neural activity to be modulated includes but is not limited to that found in the sympathetic nervous system, parasympathetic nervous system, autonomic nervous system, baroreceptor neural circuit components, primary motor cortex, premotor cortex, supplementary motor cortex, other motor cortical regions, somatosensory cortex, other sensory cortical regions, Broca's area, Wernicke's area, other cortical regions, white matter tracts associated with these cortical areas, other white matter tracts, the globus pallidus internal segment (GPi, GPi,e, GPi,e), the globus pallidus external segment, the caudate, the putamen, locus ceruleus, and other cortical and subcortical areas, ventral medial Vim thalamic nucleus, other portion of the thalamus, subthalamic nucleus (STN), caudate, putamen, other basal ganglia components, cingulate gyrus, other subcortical nuclei, nucleus locus ceruleus, pedunculopontine nuclei of the reticular formation, red nucleus, substantia nigra, other brainstem structure, cerebellum, internal capsule, external capsule, corticospinal tract, pyramidal tract, ansa lenticularis, other central nervous system structure, other peripheral nervous system structure, other intracranial region, other extracranial region, other neural structure, sensory organs, muscle tissue, or other non-neural structure.
This is one embodiment. Numerous permutations of electrode stimulation site configuration may be employed, including more or fewer electrodes in each of these said regions, without departing from the present invention. Electrodes may be implanted within or adjacent to other regions in addition to or instead of those listed above without departing from the present invention.
As one of ordinary skill in the relevant art will find apparent, the present invention may include additional or different types of sensors that sense neural responses for the type and particular patient. Such sensors generate sensed signals that may be conditioned to generate conditioned signals, as described below. Examples of the placement of these electrodes is described above with reference to the embodiment illustrated in these figures. Many others are contemplated by the present invention.
Neural sensor array 318 is connected to recording and stimulating circuit 315 with neural sensor array connecting cable 375. In one embodiment, neural sensor array 318 comprises, at least one of neuromodulatory interface 34, nerve cuff 36, longitudinal electrode array 38, regeneration electrode array 44, vagus nerve interface 45, sympathetic nerve interface 46, epineural electrode 49, 50, and 51, sympathetic trunk neuromodulatory interface 83, 84, 85, and 86, thoracic splanchnic neuromodulatory interface 87, 88, 89, and 90, abdominal splanchnic neuromodulatory interface 91, 92, 93, and 94, vagus neuromodulatory interface 97 and 98, epineural cuff electrode neuromodulatory interface 117, longitudinal electrode neuromodulatory interface 118, longitudinal electrode regeneration port neuromodulatory interface 119, regeneration tube neuromodulatory interface 120, and any other potential component comprising neuromodulator array 316, which is described above. A single or multiplicity of peripheral nerve interface 380, comprising vagus neuromodulatory interface 97 and 98, vagus nerve interface 45, sympathetic nerve interface 46, or other neural interface may be located in the cervical region, thoracic region, lumbar region, sacral region, abdominal region, pelvic region, the head, cranial nerves, neck, torso, upper extremities, and lower extremities, without departing from the present invention. Peripheral nerve interface 380, when located in the neck region, can interface with the vagus nerve, sympathetic ganglia, spinal accessory nerve, or nerve arising from cervical roots.
In one embodiment, peripheral nerve interface 380 are each comprised of three epineural platinum-iridium ring electrodes, each in with an internal diameter approximately 30% larger than that of the epineurium, longitudinally spaced along the nerve. Electrodes of differing dimensions and geometries and constructed from different materials may alternatively be used without departing from the present invention. Alternative electrode configurations include but are not limited to epineural, intrafascicular, or other intraneural electrodes; and materials include but are not limited to platinum, gold, stainless steel, carbon, and other element or alloy.
As will become apparent from the following description, signals representing various sensory input modalities 324 from sensor arrays 323 may provide valuable feedback information.
It should be understood that this depiction is for simplicity only, and that any combination of ipsilateral, contralateral or bilateral combination of each of the multiple sensory input modalities and multiple stimulation output channels may be employed. In addition, neurological control system 999 may be a single device, multiple communicating devices, or multiple independent devices. Accordingly, these and other configurations are considered to be within the scope of the present invention. It is anticipated that neurological control system 999, if implemented as distinct units, would likely be implanted in separate procedures (soon after clinical introduction) to minimize the likelihood of drastic neurological complications.
In the exemplary embodiment illustrated in
Intracranial catheters 347 and 348 include neuromodulator arrays 325, 326, 327, and 328, which may comprise intracranial recording electrodes and/or intracranial stimulating electrodes. In accordance with one embodiment of the present invention, intracranial recording electrodes are used to record cortical activity as a measure of response to treatment and as a predictor of impeding treatment magnitude requirements. In the illustrative embodiment, neuromodulator arrays 327 and 328, which may be implemented as superficial intracranial electrode array 341 and 342 are depicted in a location superficial to neuromodulator arrays 325 and 326, which may be implemented as deep intracranial electrode arrays 343 and 344.
In the illustrative embodiment, intracranial catheters 347 and 348 are provided to mechanically support and facilitate communication of electrical, optical, or other signal and/or power modality between intracranial and extracranial structures. In this embodiment, intracranial catheters 347 and 348 contain one or more wires, optical fibers, telemetry links or other means facilitating connecting stimulating and recording circuit 315 to the intracranial components 345 and 346, including but not limited to neuromodulator array 316, which may comprise intracranial stimulating electrodes, intracranial recording electrodes, as well as extracranial stimulating electrodes and extracranial recording electrodes, and other sensors and modulators. The wires contained within intracranial catheters 347 and 348 transmit neuromodulation signal (NMS) 998 or stimulating electrode output signal (SEOS) to superficial intracranial electrode arrays 341 and 342 and to deep intracranial electrode arrays 343 and 344. Wires are understood to also include other communications medium, comprising optical fibers, ultrasound conduits, wireless telemetry modules, and the like. Such wires additionally transmit stimulating electrode input signal (SEIS) and recording electrode input signal (REIS), to and from superficial intracranial electrode arrays 341 and 342 and to and from deep intracranial electrode arrays 343 and 344. Other recording and stimulating or modulating modalities may be used in addition to or instead of electrode arrays without departing from the present invention.
Stimulating and recording circuit 315 is protected within circuit enclosure 361. Circuit enclosure 361 and contained components, including stimulating and recording circuit 315 comprise stimulating and recording unit 362. It should be understood that more or fewer of either type of electrode as well as additional electrode types and locations may be incorporated or substituted without departing from the spirit of the present invention. Furthermore, stimulating and recording circuit 315 can be placed extra cranially in a subclavian pocket as shown in
Connecting cable 349 and 350 generally provide electrical, optical, chemical or other signal connection between intracranial or intracranial locations. A set of electrical wires is one mans which provides the for electrical communication between the intracranial and extracranial components; however, it should be understood that alternate systems and techniques such as radiofrequency links, optical (including infrared) links with transcranial optical windows, magnetic links, and electrical links using the body components as conductors, may be used without departing from the present invention. Specifically, in the illustrative embodiment, connecting cable 349 and 350 provide electrical connection between intracranial components 345 and 346 and stimulating and recording circuit 315. In embodiments wherein stimulating and recording circuit 315 has an intracranial location, connecting cable 349 and 350 would likely be entirely intracranial. Alternatively, connecting in embodiments wherein stimulating and recording circuit 315 is implanted under scalp 359 or within or attached to calvarium 360, connecting cable 349 and 350 may be confined entirely to subcutaneous region under the scalp 359.
A catheter anchor 363 and 364 provide mechanical connection between intracranial catheter 347 and 348 and calvarium 360. Catheter anchor 363 and 364 are preferably deep to the overlying scalp 359. Such a subcutaneous connecting cable 349 and 350 provides connection between stimulating and recording circuit 26 and at least one of superficial intracranial electrode array 341 and 342, deep intracranial electrode array 343 and 344, other neuromodulator array 316, neural sensor array 318, physiological sensor array 319, metabolic sensor array 321, or other sensor array 323. Connecting cable 349 and 350 may also connect any other sensors, including but not limited to any of sensory input modalities 324, or other stimulating electrodes, neuromodulators, medication dispensers, or actuators with stimulating and recording circuit 315.
Sensory feedback is provided to stimulating and recording circuit 315 from a multiplicity of sensors, collectively referred to as sensory input modalities 324. Neural sensor array 318 comprises superficial intracranial electrode array 341 and 342, deep intracranial electrode array 343 and 344, and other intracranial and extracranial recording electrode arrays and other neural sensors and neuromodulators. Additional sensors, some of which are located extracranially in the embodiment, comprise the remainder of sensory input modalities 324. Sensory input modalities 324 provide information to stimulating and recording circuit 315. As will be described in greater detail below, such information is processed by stimulating and recording circuit 315 to deduce the disease state and progression and its response to therapy. Disease state comprises qualities, parameters, or metrics related to any disease, disorder, or condition mentioned or related to those mentioned in the present invention or any materials incorporated by reference. For example, disease state comprises metabolic state, cardiovascular parameters, respiratory parameters, affect qualities or parameters, psychosis qualities or parameters, insulin and glucose levels or parameters, irritable bowel syndrome qualities or parameters, or any quality or metric related to a disease, disorder, condition, neurological, psychiatric, or physiological state.
In one embodiment of the invention, physiological sensor array 319 comprises an acoustic transducer array 336 to monitor any number of vibratory characteristics such as high frequency head or body vibration, muscle vibration, speech production, blood flow, air flow, and/or other physiological parameter. Acoustic transducer array 336 comprises at least one of an acoustic sensor or an acoustic transducer and is connected to stimulating and recording circuit 315 with acoustic transducer array connecting cable 358.
In one embodiment of the invention, physiological sensor array 319 comprises temperature sensor array 365 to monitor local temperature, body temperature, or ambient temperature. Temperature sensor array 365 is connected to stimulating and recording circuit 315 with temperature sensor array connecting cable 366.
In one embodiment of the invention, physiological sensor array 319 comprises respiratory sensor array 367 to monitor at least one of pulmonary pleura pressure, inter-bronchial pressure, inter-alveolar pressure, transpleural pressure, transbronchial pressure, thransthoracic pressure, other pressure related to pulmonary or respiratory function, bronchial air flow, alveolar airflow, tracheal airflow, or other airflow or blood flow related to pulmonary or respiratory function. Respiratory sensor 367 may be implemented as at least one of a pressure sensor, flow sensor, Doppler transceiver and/or sensor, acoustic sensor and/or transducer, electrical impedance sensor and/or transducer, mechanical impedance sensor and/or transducer, or other sensor or transducer. Respiratory sensor array 367 is connected to stimulating and recording circuit 315 with respiratory sensor array connecting cable 368.
In one embodiment of the invention, physiological sensor array 319 comprises pressure sensor array 369 to monitor a pressure related to function of at least one of pulmonary function, respiratory function, cardiac function, cardiovascular function, vascular function, gastrointestinal function, alimentary function, gastric function, pyloric function, duodenum function, jejunum function, ileum function, small intestinal function, large intestine function, cecum function, sigmoid function, rectum function, bladder function, ovulatory function, ejaculatory function, other pressure listed in this specification, or other physiological function. Pressure sensor array 369 is connected to stimulating and recording circuit 315 with pressure sensor array connecting cable 370.
In one embodiment of the invention, physiological sensor array 319 comprises cardiovascular sensor array 371 to monitor at least one parameter related to cardiac, cardiovascular, or vascular function or physiology. Example parameters sensed by cardiovascular sensor array 371 comprise intracardiac pressure, right atrium pressure, left atrium pressure, right ventricle pressure, left ventricle pressure, intramural pressure, transmural pressure, pericardial pressure, intraluminal pressure, transvalvular pressure, transthoracic pressure, aortic pressure, pulmonary arterial pressure, central venous pressure, pulmonary venous pressure, arterial pressure, venous pressure, left ventricular end diastolic pressure, LVEDP, intracardiac blood flow, aortic blood flow, pulmonary arterial blood flow, or other pressure or flow related to cardiac function, cardiovascular function, or vascular function. Cardiovascular sensor array 371 may be implemented as at least one of a pressure sensor, flow sensor, Doppler transceiver and/or sensor, acoustic sensor and/or transducer, electrical impedance sensor and/or transducer, mechanical impedance sensor and/or transducer, or other sensor or transducer. Cardiovascular sensor array 371 is connected to stimulating and recording circuit 315 with cardiovascular sensor array connecting cable 372.
In one embodiment of the invention, physiological sensor array 319 comprises glucose sensor array 373 to monitor at least one parameter related to glucose, glycogen, and insulin level and metabolism. Example parameters sensed by glucose sensor array 373 comprise blood glucose level, tissue glucose level, other fluid glucose level, blood glycogen level, tissue glycogen level, other fluid glycogen level, blood insulin level, tissue insulin level, other fluid insulin level, other substance level reflective of levels or metabolism of glucose, glycogen, or insulin. Glucose sensor array 373 may be implemented using chemical, biological, optical, electronic, affinity array, or other known or new technologies for sensing such levels. Glucose sensor array 373 is connected to stimulating and recording circuit 315 with glucose sensor array connecting cable 374.
In one embodiment of the invention, physiological sensor array 319 comprises sensors to monitor head or body position and movement with respect to gravity; these may include accelerometers, gravity sensors, goniometers, hall effect sensors, or other sensors to measure at least one of head, neck, torso, abdomen, and limb position. Accelerometer may be mounted to any structure or structures that enables it to accurately sense a position or movement. Such structures include, for example, the skull base, calvarium, clavicle, mandible, extraocular structures, soft tissues and vertebrae. Accelerometer is connected to stimulating and recording circuit 315 with an accelerometer connecting cable. Accelerometer may be used to sense body position, such as recumbency, and provide information useful to determine circadian rhythm and sleep-wake cycle.
An electromyography (EMG) sensor array 320 is also included in certain embodiments of the invention. EMG sensor array 320 preferably includes a positive proximal EMG electrode, a reference proximal EMG electrode, and a negative proximal EMG electrode. As one skilled in the relevant art would find apparent, EMG sensor array may include any number of type of electrodes. EMG sensor array 320 is non-implanted overlying muscle tissue or is implanted in or adjacent to muscle tissue. EMG electrode array 320 may be located to sense activity of skeletal muscle, smooth muscle, or cardiac muscle and may therefore be used for many sensory modalities comprising motor function, visceral function including gastrointestinal and alimentary function, respiratory function, cardiac function, and other physiological function.
Acoustic transducer array 336 may also be implemented in the present invention. Acoustic transducer array 336 senses muscle vibration and may be used to augment, supplement or replace EMG recording. Also, acoustic transducer array 336 may be used to sense movement, including tremor and voluntary activity. Acoustic transducer array 336 may be used to sense respiratory function, including onset of symptoms of asthma.
It should also be understood from the preceding description that the number of each type of sensor may also be increased or decreased, some sensor types may be eliminated, and other sensor types may be included without departing from the spirit of the present invention.
F. System/Pulse Generator Design.
Stimulating and recording unit 362, comprises stimulating and recording circuit 315, circuit enclosure 361, header 317, and a single or plurality of attachment fixture 4 and 5. Stimulating and recording unit 362 is also a preferred embodiment of implantable pulse generator 99, 100, 101, 102, which are understood to be implanted or alternatively nonimplanted.
The neurological control system 999 includes one or more implantable or noninvasive components including one or more sensors each configured to sense a particular characteristic indicative of a neurological, psychiatric, or metabolic condition.
G. Stimulation Parameters
The amplitude of the first phase, depicted here as cathodic, is given by pulse amplitude 1 PA1; the amplitude of the second phase, depicted here as anodic, is given by pulse amplitude 2 PA2. The durations of the first and second phases are pulse width 1 PW1 and pulse width 1 PW2, respectively. Phase 1 and phase 2 are separated by a brief delay d. Waveforms repeat with a stimulation period T, defining the stimulation frequency as f=1/T.
The area under the curve for each phase represents the charge Q transferred, and in the preferred embodiment, these quantities are equal and opposite for the cathodic (Q1) and anodic (Q2) pulses, i.e. Q=Q1=Q2. For rectangular pulses, the charge transferred per pulse is given by Q1=PA1*PW1 and Q2=PA2*PW2. The charge balancing constraint given by −Q1=Q2 imposes the relation PA1*PW1=−PA2*PW2. Departure from the charge balancing constraint, as is desired for optimal function of certain electrode materials, in included in the present invention.
The stimulus amplitudes PA1 and PA2, durations PW1 and PW2, frequency f, or a combination thereof may be varied to modulate the intensity of the said stimulus. A series of stimulus waveforms may be delivered as a burst, in which case the number of stimuli per burst, the frequency of waveforms within the said burst, the frequency at which the bursts are repeated, or a combination thereof may additionally be varied to modulate the stimulus intensity.
Typical values for stimulation parameters include f=100-300 Hz, PA1 and PA2 range from 10 microamps to 10 milliamps, PW1 and PW2 range from 50 microseconds to 100 milliseconds. These values are representative, and departure from these ranges is included in the apparatus and method of the present invention.
Safe stimulation current waveforms may be achieved for stimulus waveforms which satisfy charge injection limits. For stimulation of peripheral nerves, sympathetic nerves, sympathetic trunk, sympathetic plexus, vagus nerve, and other neural structures, such as may be performed using peripheral nerve interface 380, charge injection limits may be selected to be approximately or less than 50 microcoulombs per square centimeter for stainless steel electrodes and approximately or less than 25 microcoulombs per square centimeter for Platinum-Iridium (Pt/Ir) electrodes.
For a design as shown in
An example set of dimensions for a Platinum-Iridium implementation of this electrode are a diameter of 127 microns and an exposed length of 2,000 microns (2 mm), resulting in a gross surface area of 797,560 square microns. This may increase substantially if the surface is roughened. The 25 microcoulomb per square centimeter charge injection limit for such a Platinum-Iridium electrode would be 0.199 microcoulombs, which would be satisfied by stimulation waveform of amplitude 1.99 milliamperes and pulse width 100 microseconds. For an example electrode resistance of 4,000 ohms, the required stimulation voltage would be 7.97 volts.
These dimensions are for example only, and much larger or smaller electrode dimensions and configurations, including those shown in
H. Recording Signals
I. Control
In one preferred embodiment, sympathetic index is modulated to control at least one of metabolic rate, body temperature, food intake, blood pressure, heart rate, respiratory gas flow, pulmonary function parameters, cardiac parameters, cardiovascular parameters, vascular parameters, and other parameters.
In
In
In
In
Neuromodulator Arrays comprise designs taught in
1. Epineural Neuromodulator Arrays/Epineural Neuromodulatory Interfaces: Neuromodulator Arrays include neuromodulators which perform epineural modulation such as that shown in
2. Intraneural Neuromodulator Arrays/Intraneural Neuromodulatory Interfaces: Still further Neuromodulator Array designs comprising the invention taught in the present application and the parent applications include Intraneural neural interfaces, such as that taught in
In
In prior applications in this portfolio, apparatus, methods, and surgical techniques were taught for minimally invasive surgical placement of portions or the entirety of a neuromodulation system for the modulation of sympathetic nervous system and for the modulation of other neural tissues including parasympathetic nervous system, other peripheral nervous structures, spinal cord, and other tissues including muscle tissue and gastrointestinal tissues and layers. Further detail of these and other apparatus, methods, and techniques are described in the present application. Some of this detail was presumed to be known to clinical practitioners, including neurosurgeons, and others skilled in the art, and so was not presented in as much detail in the parent application. The apparatus and method taught in the parent case is enabling to an engineer or engineering team skilled it the art of developing neuromodulation systems, and the anatomical placement of electrodes is enabling to a competent clinical practitioner, who has an armamentarium of surgical implantation techniques at his or her disposal. For sake of completeness, example apparatus and procedures are presented in the present application.
In the parent case,
In
In
Cannula 382 with stylet 383 inserted within are shown piercing skin 280 in the lumbar region, the intervening structures and the ligamentum flavum 388, with the cannula tip 384 entering the epidural space 137 in the lumbosacral region. Cannula 382 may enter or pierce skin 280 in the lumbar region as shown or anywhere else on the body. In the technique shown in
Cannula 385 with stylet 386 inserted within are shown piercing skin 280 in the thoracic or cervical region, the intervening structures and the ligamentum flavum 388, with the cannula tip 385 entering the epidural space 137 in the cervicothoracic region. Cannula 385 may enter or pierce skin 280 in the thoracic region as shown or cervical region or anywhere else on the body. In the technique shown in
A dorsal approach procedure is performed as follows. The patient is typically placed prone or in a lateral position on the operating table. The skin comprising and adjacent to the operative site is sterilely prepped and draped. This comprises the dorsal portion of the thoracolumbosacral trunk and extends laterally to the flank and anterolateral abdomen to include the skin overlying the location where a subcutaneous pocket may be made for implantation of the implantable pulse generator (IPG). Using intraoperative x-ray, fluoroscopic, or frameless stereotactic guidance, one or more cannula 382, 385 with stylet 383, 386 inserted are advanced percutaneously through the skin 280. Cannula 382, 385 with stylet 383, 386 are typically inserted through skin 280 with the cannula tip 384, 387 angled in a rostral or cephalic direction (toward the head) and the bevel of the tip angled also in a cephalic direction. For placement in an epidural location, cannula 382, 385 with stylet 383, 386 are typically advanced either midline between the vertebral spinous process 139 (shown in cross section in
After the stylet 383, 386 or syringe is removed from the cannula 382, 385, neuromodulatory interface 391, 392 is advanced through cannula 382, 385 into the desired position. Neuromodulatory interface 391, 392 may be at the tip or elsewhere along a connecting cable 393, 394 or Neuromodulatory interface 391, 392 may be separate and wireless. Neuromodulatory interface 391, 392 with connecting cable 393, 394 may be advanced through cannula 382, 385, and the desired position is usually in the epidural space 137, though it could be positioned outside the spinal canal or within the meningeal layer of dura mater 136 or within the spinal cord 151. By manipulating the position and angle of entry of the cannula 382, 385 in the transverse plane and by moving the cannula 382, 385 and twisting the connecting cable 393, 394, the surgeon can direct the positioning of the neuromodulatory interface 391, 392.
Using this technique described or other technique for the placement neuromodulatory interface 391, 392, one may implant one or more of anterior central spinal neuromodulatory interface 143, anterior right lateral spinal neuromodulatory interface 144, anterior left lateral spinal neuromodulatory interface 145, right lateral spinal neuromodulatory interface 149, left lateral spinal neuromodulatory interface 150, posterior central spinal neuromodulatory interface 146, posterior right lateral spinal neuromodulatory interface 147, posterior left lateral spinal neuromodulatory interface 148, and neuromodulatory interface 391, 392 of other design and configured to be implanted in other positions. By advancing cannula 382, 385 through meningeal layer of dura mater 136, the intermediolateral nucleus neuromodulatory interface 152 may be implanted within the spinal cord 151 in the intermediolateral nucleus 121 (shown in cross section in
A dorsal approach procedure is performed as follows. The patient is typically placed prone or in a lateral position on the operating table. The skin comprising and adjacent to the operative site is sterilely prepped and draped. This comprises the dorsal portion of the thoracolumbosacral trunk and extends laterally to the flank and anterolateral abdomen to include the skin overlying the location where a subcutaneous pocket may be made for implantation of the implantable pulse generator (IPG). Using intraoperative x-ray, fluoroscopic, or frameless stereotactic guidance, one or more cannula 382, 385 with stylet 383, 386 inserted are advanced percutaneously through the skin 280. Cannula 382, 385 with stylet 383, 386 may be inserted through skin 280 with the cannula tip 384, 387 angled perpendicular to the skin, in a rostral or cephalic direction (toward the head), caudally toward the feet, laterally, or medially from a paramidline entry point.
This technique may be used for placement of neuromodulatory interface 391 and 392 in communication with a neural plexus or component of the nervous system, including but not limited to the celiac plexus 154, Superior Mesenteric Plexus 156, Renal Plexus 159, Inferior Mesenteric Plexus 160, Iliac Plexus 161, Right Lumbar Sympathetic Ganglia 162, Left Lumbar Sympathetic Ganglia 163, Right Sacral Sympathetic Ganglia 164, Left Sacral Sympathetic Ganglia 165, and other neural structures and body tissues.
Using the techniques implied in the present figures and depicted in more detail in
Using the techniques implied in the present figures and depicted in more detail in
By this technique, one may implant or place:
250 Right Superficial Cardiac Plexus Neuromodulator Array
251 Left Superficial Cardiac Plexus Neuromodulator Array
252 Right Deep Cardiac Plexus Neuromodulator Array
253 Left Deep Cardiac Plexus Neuromodulator Array
254 Right Renal Plexus Neuromodulator Array
255 Left Renal Plexus Neuromodulator Array
256 Right Renal Nerve Branch Neuromodulator Array
257 Left Renal Nerve Branch Neuromodulator Array
And other arrays into position to be in communication with the above listed structures or other desired targets.
To target an epidural location, cannula 382, 385 with stylet 383, 386 are typically advanced either midline between the vertebral spinous process 139 (shown in cross section in
After the stylet 383, 386 or syringe is removed from the cannula 382, 385, neuromodulatory interface 391, 392 is advanced through cannula 382, 385 into the desired position. Neuromodulatory interface 391, 392 may be at the tip or elsewhere along a connecting cable 393, 394 or Neuromodulatory interface 391, 392 may be separate and wireless. Neuromodulatory interface 391, 392 with connecting cable 393, 394 may be advanced through cannula 382, 385, and the desired position is usually in the epidural space 137, though it could be positioned outside the spinal canal or within the meningeal layer of dura mater 136 or within the spinal cord 151. By manipulating the position and angle of entry of the cannula 382, 385 in the transverse plane and by moving the cannula 382, 385 and twisting the connecting cable 393, 394, the surgeon can direct the positioning of the neuromodulatory interface 391, 392.
Using this technique described or other technique for the placement neuromodulatory interface 391, 392, one may implant one or more of anterior central spinal neuromodulatory interface 143, anterior right lateral spinal neuromodulatory interface 144, anterior left lateral spinal neuromodulatory interface 145, right lateral spinal neuromodulatory interface 149, left lateral spinal neuromodulatory interface 150, posterior central spinal neuromodulatory interface 146, posterior right lateral spinal neuromodulatory interface 147, posterior left lateral spinal neuromodulatory interface 148, and neuromodulatory interface 391, 392 of other design and configured to be implanted in other positions. By advancing cannula 382, 385 through meningeal layer of dura mater 136, the intermediolateral nucleus neuromodulatory interface 152 may be implanted within the spinal cord 151 in the intermediolateral nucleus 121 (shown in cross section in
In
Multimodal Targeting: As taught in the present invention, neuromodulatory interfaces may be placed at locations to modulate targets which induce satiety (for example with spinal cord stimulation, including but not limited to levels T5, T6, T7, and other cervical, thoracic, lumbar, sacral levels, midline and other positions) and to modulate targets which increase metabolism (including the splanchnic nerves and their branches and nerve roots as they enter and exit the spinal cord and canal). One preferred embodiment includes a system with two neuromodulators:
(A) two spinal cord stimulation (SCS) electrode arrays: one SCS electrode array configured for implantation as taught for appetite suppression (for inducing satiety) and a second SCS electrode array for placement in communication with nerve roots supplying at least one of the splanchnic nerves.
(B) two linear catheter cylindrical electrode (LCCE) arrays: one LCCE electrode array configured for implantation as taught for appetite suppression (for inducing satiety) and a second LCCE electrode array for placement in communication with nerve roots supplying at least one of the splanchnic nerves. A LCCE electrode array may be configured to have similar dimensions as a SCS electrode array, or I may have a longer electrode spacing and length, enabling a single array (of 2, 4, 8, 16, 32) channels to span multiple vertebral segments (with an array length of at least 5 cm, 10 cm, 15 cm, 20 cm, and 30 cm), allowing for greater flexibility in recruiting appropriate sympathetic targets during intraoperative testing or screening as well as for postoperative fine tuning and maintenance, including compensation for electrode migration. A LCCE electrode array may also have much narrower dimensions than present SCS arrays, including diameters of less than 1 mm, 0.75 mm. 0.5 mm, 0.25 mm).
(C) two linear catheter cylindrical electrode (LCCE) arrays: one LCCE electrode array configured for implantation as taught for appetite suppression (for inducing satiety) and a second LCCE electrode array for placement in communication with at least one portion of the splanchnic nerves. The second LCCE electrode array may be placed using fluoroscopic guidance, or with biplanar or uniplanar X-Ray machines, or using computed tomography (CT), or magnetic resonance imaging (MRI) for localization. A series of dilators may be used to create a minimally invasive access trajectory to the splanchnic nerve.
(D) one linear catheter cylindrical electrode (LCCE) array and one nerve electrode array: one LCCE electrode array configured for implantation as taught for appetite suppression (for inducing satiety) and a nerve electrode array for placement in communication one portion of the splanchnic nerves. The nerve electrode array may be at least one of several designs without departing from the present invention, including but not limited to nerve cuff, linear catheter array, helical electrode array, intraneural electrode, epineural electrode, or other design.
Renal Nerve Stimulation: Renal nerve stimulation as taught in the present invention may be used to control blood pressure, catecholamines, and electrolytes. By delivering electrical stimulation, such as with frequencies greater than 30 Hz, and preferably greater than 50 H or 100 Hz or 300 Hz or 1000 Hz, renal nerve activity is suppressed, reducing sympathetic innervation to the renal influence on blood pressure including filtration rates as well as hormonal mechanisms, including but not limited to angiotensin, aldosterone, cortisol, catecholamines, and others. Another approach to reduction of renal nerve activity is temporary or permanent nerve ablation. A disadvantage of ablative approaches is attenuation of the normal physiological ability to maintain blood pressure to the brain during movement among a variety of postural positions. For example, as a person arises from lying flat to a standing position, the sympathetic nervous system provides some activation to maintain acceptable cerebral blood pressure. If the renal nerve is ablated, this adaptive mechanism is compromised. The use of closed-loop neuromodulation, as taught in the present invention, overcomes this limitation. A closed-loop controller is taught which uses as inputs, blood pressure, heart rate, tissue oxygenation levels, body position (flat, sitting, standing, torso angle, head angle, and other measurements) and employs a control law (such as a linear control law, proportional control law, nonlinear control law, adaptive control law), and uses the measured physiological parameters as an input to a feedback driven control law and which uses body position as an input to a feedforward control law, enables such a controller to anticipate changes in actual blood pressure and requirements of blood pressure resulting from positional changes and to respond to alterations in blood pressure or deviations in blood pressure from the desired values using feedback. Similar control of pulse and tissue oxygenation may be performed using feedforward and feedback control of these parameters, separately or in conjunction with control of blood pressure and/or other parameters.
Pulmonary Nerve Stimulation: Use of closed-loop neuromodulation for the control of asthma is taught in the present invention. By delivering electrical stimulation, such as with frequencies greater than 30 Hz, and preferably greater than 50 H or 100 Hz or 300 Hz or 1000 Hz, innervation of the bronchial tree musculature is suppressed, reducing the muscle tone within the bronchial tree, including the trachea, bronchi, and distal branches. Another approach is temporary or permanent nerve ablation. A closed-loop controller is taught which uses as inputs from at least one sensor, including but not limited to sensors which transducer at least one of blood oxygenation, tissue oxygenation, pulmonary blood flow, respiratory rate (breathing rate), airway pressure, airway flow rates, sound from airway flow, vibration from airway flow, heart rate, tissue, body position (flat, sitting, standing, torso angle, head angle, and other measurements) and employs a control law (such as a linear control law, proportional control law, nonlinear control law, adaptive control law), and uses the measured physiological parameters as an input to a feedback driven control law and which may employ user input and physiological parameters as an input to a feedforward control law, enables such a controller to anticipate changes in actual airway resistance and requirements of oxygen delivery suggested from user input, breathing rates, and other physiological parameters listed herein and to respond to alterations in airway resistance or deviations in airway resistance from the desired values using feedback.
The symptoms of an asthmatic attack may be sensed by changes in air flow in the bronchial tree, including but not limited to changes in turbulence, change in laminar flow, change in air velocity, change in air pressure, change in total air flow, change in pressure gradient, change in airway resistance, and other changes. The symptoms of an asthmatic attack may be sensed by changes blood oxygenation, tissue oxygenation, by user input, by input from a physician or family member or another individual, and by other senses parameters.
Temporally Optimized Stimulation Parameter Selection
As taught in the present invention, temporal patterning of neuromodulatory signal (NMS) may be performed in a spectrum of potential methods and using a variety of potential apparati. Intermittent stimulation may be delivered based upon a pattern which may comprise a singularity, multiplicity, or combination thereof of patterns comprising fixed temporal pattern or a variable temporal pattern or a random temporal pattern. Temporal patterning may comprise modulation which is a function of prandial activity; such patterning may comprise at least one of preprandial modulation, prandial modulation, postprandial modulation, modulation in between mealtimes, daytime modulation, nighttime modulation, other modulation, or a combination thereof.
For a system in which the therapeutic modality is appetite, various patterns may be employed to deliver optimal therapy, comprising preprandial, prandial, interprandial, postprandial, baseline, daytime, nighttime, or other time window.
For a system in which the therapeutic modality is metabolic rate, various patterns may be employed to deliver optimal therapy, comprising preprandial, prandial, interprandial, postprandial, baseline, daytime, nighttime, or other time window. Various sensors may be employed to sense status relative to prandial or to glucose state, including physiologic sensors, vital sign sensors, temperature sensors, heart rate sensors, blood pressure sensors, heart rate variability sensors, body position sensors, and user input sensors, and other sensors. Sensors which sense activity of the muscles of mastication, jaw movement, masseter activity, temporalis activity, sounds generated from chewing, vibrations generated from chewing, bolus passage in the gastrointestinal tract, and other sensors may be employed. These sensors may be configured to be implanted or non-implanted or noninvasive and may be swallowed, worn, carried, or be remote from the user.
For a system in which the therapeutic modality is at least one of glucose metabolic pathway and glucose metabolism, various patterns may be employed to deliver optimal therapy, comprising preprandial, prandial, interprandial, postprandial, baseline, daytime, nighttime, or other time window.
Temporal patterning of modulation provides benefits comprising but not limited to tachyphylaxis minimization and safety, including but not limited to sympathetic drive restriction.
Specific Features for Optimization of Stimulation for Safety
For therapeutic modalities such as metabolic rate modulation, careful control of the magnitude of sympathetic stimulation and the sympathetic index are advantageous to minimize potential adverse effects from excessive sympathetic activation. Such side effects or adverse effects may comprise but are not limited to elevations in blood pressure within the normal range as well as outside the normal range (hypertension), elevations in heart rate within the normal range as well as outside the normal range (tachycardia).
One preferred embodiment comprises a system which limits aspects of Neuromodulatory Signal (NMS) to maintain safety, said limits including but not limited to amplitude, dusty cycle, area under the curve per unit time. These limits are characterized in at least one of an open loop and a closed loop manner, with preset limits, dynamic limits, or constraints which are a function of other parameters, including neural state variables, physiological parameters, including neural activity, blood pressure, heart rate, heart rate variability, renal blood flow, creatinine level, sodium level, potassium level, pH, and other physiological parameter.
Furthermore, such side effects or adverse effects may comprise but are not limited to vasoconstriction within the normal range as well as outside the normal range, which may result in relative or absolute ischemia or hypoxia and which may be systemic, focal, or involve a singularity or multiplicity of organs or components of the central circulation, peripheral circulation, cardiac circulation, cerebral circulation, mesenteric circulation, renal circulation, or other component of the circulatory system. Careful monitoring of effects of neuromodulation on relevant regions of the circulatory system may provide advantageous levels of safety not provided by known systems available today. One object of the present invention is the teaching of methods and corresponding apparatus which facilitate the delivery of safe neuromodulation which is designed and patterned to be intrinsically safe as an open-loop system and to perform additional monitoring and control to further insure safety as a closed-loop system. Such monitoring comprises but is not limited to periodic monitoring of metrics of renal function, including blood urea nitrogen (BUN), creatinine, and electrolytes, including but not limited to sodium, potassium, chloride, bicarbonate, and others. This safety monitoring may be performed by implanted sensors and by external sensors. Furthermore, said safety monitoring may be performed through monitoring by other tests comprising a blood draw and other including laboratory tests, which can be performed by the patient, by a nurse, by a physician, or by other health care professional. This may be transmitted to the control circuit using radiofrequency signal, using infrared signal, or may be typed in or entered directly by a healthcare professional or transmitted automatically via radiofrequency, infrared, bluetooth, or other transmission signal. Such metrics sensed as part of this safety monitoring process may be used as at least of inputs, feedback, and other signals to a control law or to a safety check module. At least one of said control law and safety check module limit the effective magnitude of the neuromodulatory signal to maintain physiological parameters within at least one of their safe and normal range. Said effective magnitude is modulated, influenced, or set by stimulation parameters which comprises at least of voltage, current, pulse width, duty cycle, and temporal patterning of the neuromodulation signal (NMS).
For example, if modulation of the sympathetic nervous system causes vasoconstriction of the mesenteric or renal structures, relative or absolute ischemia may occur, thereby potentially causing tissue damage. Novel functions and apparatus taught in the present invention provide protection from stimulation which could otherwise cause such undesirable effects. Such novel functions may be implemented in at least one of a variety of methods and apparatus; one such implementation is in the form of safety parameters, which may be used to govern modulation parameters, which include but are not limited to control of neuromodulation amplitude, pulse width, stimulation frequency, burst frequency, burst duration, envelope frequency, envelope duration, duty cycle, and the maximum on-time duration, minimum on-time duration, maximum-off-time duration, minimum off-time duration, of these or other parameters, and other parameters, and which may be fixed, variable, adaptive, and adjustable. For example, stimulation may be provided for at least one of the following times, pre-prandially for DPrePMin to DPrePMax minutes for 0, 1, 2, 3, or more times per day, prandially for DPMin to DPMax, for a single or multiplicity of times during 0, 1, 2, 3, post-prandially for DPostPMin to DPostPMax minutes for 0, 1, 2, 3, or more times post-prandially; or inter-prandially for DIPMin to DIPMax minutes for 0, 1, 2, 3, 4, 5, 6, or more times during any inter-prandial period; for DDMin to DDMax minutes during any single or multiplicity of time or times during the day or in the evening, and for DNMin to DNMax minutes during any single or multiplicity of time or times during the night. DPrePMin, DPrePMax, DPMin, DPMax, DPostPMin, DPostPMax, DIPMin, DIPMax, DDMin, DDMax, DNMin, DNMax, which are described as durations in minutes may be any of a variety of durations (microseconds, milliseconds, seconds, minutes, hours, days, weeks, months, years) without departing from the present invention. The minimal durations, comprising DPrePMin, DPMin, DPostPMin, DIPMin, DDMin, DNMin may be 0, 1, 2, 3, 4, 5, 10, 15, 20, 30, 45, 60 seconds, any value in between, or 1, 2, 3, 4, 5, 10, 15, 30, 45, 60 90, 120 minutes, any value in between, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 22, 23, 24 hours or any value which is lesser, greater, or in between. The maximal durations, comprising DPrePMax, DPMax, DPostPMax, DIPMax, DDMax, DNMax may be 0, 1, 2, 3, 4, 5, 10, 15, 20, 30, 45, 60 seconds, any value in between, or 1, 2, 3, 4, 5, 10, 15, 30, 45, 60 90, 120 minutes, any value in between, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 22, 23, 24 hours or any value which is lesser, greater, or in between. The durations and the stimulation parameters for each of the defined time periods may be the same, different, variable, adjustable, functions of similar input variable, functions of different input variables, or controlled in other manners. For none, a singular, or plurality of these defined durations, a vector of said durations could also be used to describe a set of values for the corresponding multiplicity of intervals, i.e. DPrePMin, ={vector of DPreP1Min} of [DPreP1Min, DPreP2Min, DPreP3Min, DPreP4Min, DPrePNMin], where N indicates the number of such intervals. Further, for a singular, or plurality of these defined durations, a matrix of said durations could be used to describe a set of values for the corresponding multiplicity of intervals, i.e.
where (i,j) specifies the matric element (1:N, 1:M) in the N×M matrix corresponding to the index of the specified interval. Using such a structure, varying minima and maxima may be set for each of a varying number of intervals such as pre-prandial, prandial post-prandial, inter-prandial, day, evening, night intervals. This matrix structure is exemplary for and representative of that which is also taught for all durations and their respective parameters and durations, safety parameters, and the minima and maxima thereof.
For example, one such preferred embodiment regimen may comprise:
(1) stimulation for a single or multiplicity of durations including 15 minutes (or any duration from DDiMin to DDiMax) upon awakening or thereafter as determined by user input, predetermined or sensed or timed circadian clock, chronological clock, or sensed by change in body position or body angle or by physiological parameter change and in which the subscript “i” could be a single or a vector of values;
(2a) stimulation for a single or multiplicity of pre-prandial durations including for 30 minutes (or any duration from DPrePMin to DPrePMax) prior to breakfast;
(2b) stimulation for a single or multiplicity of prandial durations including for 10 minutes (or any duration from DPMin to DPMax) during breakfast;
(2c) stimulation for a single or multiplicity of prandial durations including for 15 minutes (or any duration from DPostMin to DPostMax) after breakfast;
(3) stimulation for a single or multiplicity of durations including 45 minutes (or any duration from DIPMin to DIPMax) between breakfast and lunch;
(4a) stimulation for a single or multiplicity of pre-prandial durations including for 30 minutes (or any duration from DPrePMin to DPrePMax) prior to lunch;
(4b) stimulation for a single or multiplicity of prandial durations including for 10 minutes (or any duration from DPMin to DPMax) during lunch;
(4c) stimulation for a single or multiplicity of prandial durations including for 15 minutes (or any duration from DPostMin to DPostMax) after lunch;
(5) stimulation for a single or multiplicity of durations including 45 minutes (or any duration from DIPMin to DIPMax) between lunch and dinner;
(6a) stimulation for a single or multiplicity of pre-prandial durations including for 30 minutes (or any duration from DPrePMin to DPrePMax) prior to dinner;
(6b) stimulation for a single or multiplicity of prandial durations including for 10 minutes (or any duration from DPMin to DPMax) during dinner;
(6c) stimulation for a single or multiplicity of prandial durations including for 15 minutes (or any duration from DPostMin to DPostMax) after dinner;
(7) stimulation for a single or multiplicity of durations including 45 minutes (or any duration from DIPMin to DIPMax) between dinner and a snack;
(8a) stimulation for a single or multiplicity of pre-prandial durations including for 30 minutes (or any duration from DPrePMin to DPrePMax) prior to a snack;
(8b) stimulation for a single or multiplicity of prandial durations including for 5 minutes (or any duration from DPMin to DPMax) during a snack;
(8c) stimulation for a single or multiplicity of prandial durations including for 15 minutes (or any duration from DPostMin to DPostMax) after a snack;
(9) stimulation for a single or multiplicity of durations including for 30 minutes (or any duration from DDMin to DDMax) during a single or plurality of daytime or evening periods;
(10) stimulation for a single or multiplicity of durations including for 30 minutes (or any duration from DNMin to DNMax) during a single or plurality of night time periods;
In
Safety state sensors 397 comprise any sensor, input device, transmission device, receiving device or other element which facilitates the sensing or acquisition of information or signals representative of information which may be processed to extract information which may be used to assess, monitor, or control metrics, parameters, or neuromodulation signals (NMS) 998 which relate to or insure safety of Neurological Control system 999. Such metrics include but are not limited to those shown in
Safety state sensors 397 comprise but are not limited to implanted sensors 403, external sensors 404, telemetered inputs 405, manual inputs 406, and other sensors, inputs, and receivers.
Implanted sensors 403 comprise but are not limited to physiological sensor array 319, metabolic sensor array 321, alimentary sensor array 322 (shown in more detail in
External sensors 404 comprise but are not limited to physiological sensor array 319, metabolic sensor array 321, alimentary sensor array 322 (shown in more detail in
Telemetered inputs 405, comprise but are not limited to a singularity or multiplicity of modulation authorization code 407, renal function metrics 408, physiological sensor array 319, metabolic sensor array 321, alimentary sensor array 322 (shown in more detail in
Manual inputs 406, comprise but are not limited to a singularity or multiplicity of modulation authorization code 407, renal function metrics 408, physiological sensor array 319, metabolic sensor array 321, alimentary sensor array 322 (shown in more detail in
In one preferred embodiment shown in
One objective of the present invention is to closely monitor the physiology of the patient or user of Neurological Control System (NMS) 999 to facilitate early detection of potential adverse effects and to monitor physiological trends such that physiological state 408, neural state 409, and safety state 410 may be at least one of anticipated, predicted, and controlled to prevent adverse effects. For example, sympathetic activation of vascular structures may cause vasoconstriction. Vasoconstriction, if effected for prolonged periods of time may cause ischemia and necrosis if not regulated or controlled. An objective of the present invention is the close monitoring of physiological functions and metrics which provide insight into causative processes underlying adverse effects and monitoring of early signs of adverse effects.
Safety state sensors 397 comprise sensors which sense at least one of physiological state 408, neural state 409, safety state 410, and other state or signal, comprising signals from implanted sensors 403, external sensors 404, telemetered sensors 504, and manual inputs 406, and other sensors or input devices. Safety State Sensors 397 may be configured to sense at least one of any singular or plurality of signals or arrays thereof, comprising those depicted in
Sensors comprising but not limited to those which sense states comprising but not limited to physiological state 408, neural state 409, safety state 410, are configured to sense at least one of: physiological signals, metabolic signals, modulation authorization codes, renal function metrics. Physiological state 408 comprises a singularity or plurality of at least one of vital signs (comprising heart rate, blood pressure, respiratory rate, temperature, urine output, heart rate variability, pulse oximetry, oxygen concentration in at least one component or region of the body or external support system including ventilator or tubing or component thereof.
Minimally Invasive Stimulation:
Power: Neuromodulatory interfaces 391, 392 may have internal energy storage elements comprising at least one of internal battery power storage, internal fuel cell power storage, internal capacitive poser storage, internal inductive power storage, or other internal power storage means. Neuromodulatory interfaces 391, 392 may have external energy storage elements comprising at least one of external battery power storage, external fuel cell power storage, external capacitive poser storage, external inductive power storage, or other external power storage means. Neuromodulatory interfaces 391, 392 may have augmented energy storage elements which may be implanted or non-implanted and which may be separate from the neuromodulatory interface and may at least one of supply, store, and relay power to neuromodulatory interfaces 391, 392.
Control signals: Control signals comprise Control Output (U), Neuromodulatory Signal (NMS), signals to or from patient interface module, signals to or from supervisory module, or signals to or from other modules. At least one of Control Output (U), Neuromodulatory Signal (NMS), other control signals, output stage internal signal, neural state (X), or other signal, may be transmitted as at least one of the power signal, an impedance drawn on the power signal, as a form of modulation of the power signal, as amplitude modulation of the power signal, as frequency modulation of the power signal, as phase modulation of the power signal, and as a separate signal, which may be implemented as radiofrequency (RF) energy, microwave energy, millimeter wave energy, sub-millimeter wave energy, direct current (DC) energy, alternating current (AC) energy, optical energy, infrared energy, near infrared energy, visible energy, ultraviolet energy, vibratory energy, sonic energy, ultrasonic energy, subsonic energy, thermal energy, chemical energy, fuel cell energy, motion energy, energy derived from physiological sources, or other forms of energy. Neuromodulatory interfaces 391, 392 may be surgically implanted via an open or minimally invasive procedure, including placement using laparoscopic, ventriculoscopic, or other endoscopic technique or they may be inserted using a catheter guide tube or be injected. They may have a tethering tail which provides a mechanical means for removal, a catheter which includes connecting cable 393, 394 with electrical wires to facilitate signal transmission from an implanted or external Neuromodulatory Signal (NMS) source, or may be wireless with active or passive electronics facilitating receipt of at least one of Neuromodulatory Signal (NMS) and power as well as transmission of signal via wireless means.
Relevant anatomy shown in
Percutaneous Stimulation:
Applications: The present invention teaches the use of percutaneous neuromodulation including at least one of stimulation and inhibition of autonomic structures and other neural and gastrointestinal structures for at least one of the characterization of metabolic conditions, the diagnosis of metabolic conditions, the trialing of metabolic conditions, Obesity, diabetes, hyperlipidemia, hypercholesterolemia and the treatment of metabolic conditions and for the treatment of any other conditions described or referred to in the this specification or others incorporated by reference.
The present invention teaches the use of percutaneous neuromodulation including at least one of stimulation and inhibition of autonomic structures and other neural and gastrointestinal structures for at least one of the characterizations of metabolic conditions, the diagnosis of metabolic conditions, the trialing of metabolic conditions, and the treatment of metabolic conditions.
Non-Invasive Stimulation:
Multiple neuromodulator configurations are depicted, and more or fewer or a singularity or multiplicity are included in the present invention. Neuromodulator groups 425, 426, 427, 428, 429 are shown in proximity to skin 280. Any of neuromodulator groups 425, 426, 427, 428, 429 may be at least one of in contact with, in close proximity to, or distant from skin 280, without departing from the present invention. Further, any of neuromodulator groups 425, 426, 427, 428, 429 could be configured with percutaneous elements, including electrodes or other energy delivery elements, or be implanted, without departing from the present invention. Further, each of neuromodulator groups 425, 426, 427, 428, 429 may comprise a at least one of a single or a plurality of neuromodulator arrays, comprising neuromodulator array 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, and a single or plurality of neuromodulator 421. Energy delivery elements include but are not limited to macroelectrodes, microelectrodes, percutaneous electrodes, magnetic coils, microfabricated electrodes, microfabricated coils, optical fibers, ultrasound transducers, sonic transducers, auditory transducers, speakers, vibratory transducers, piezoelectric transducers, solenoids, electromechanical transducers, mechanical transducers, pressure transducers, thermal transducers, heat sources, cold sources, chemical sources, pharmaceutical sources, biochemical sources, and biochemical compound reservoir,
Energy delivery elements further include but are not limited to biochemical compound simulator, molecular signal transducer, low frequency molecular signal transducer, high frequency molecular signal transducer, molecular signal transducer electrode, molecular signal transducer magnetic coil.
Neuromodulator group 425 is shown comprising Neuromodulator Band 422 which provides at least one of mechanical and electrical connection between Neuromodulator Array 411, 412, 413 each of which comprise arrays of a single or plurality of Neuromodulator 421.
Neuromodulator group 426 is shown comprising Neuromodulator Array 414 and may comprise a single or plurality of at least one of Neuromodulator Array 414 and neuromodulator 421. Neuromodulator Array 414 is shown comprising a plurality of Neuromodulator 421 and may comprise a single or plurality of Neuromodulator 421.
Neuromodulator group 427 is shown comprising Neuromodulator Band 423 which provides at least one of mechanical and electrical connection between Neuromodulator Array 415 and 416, each of which comprise arrays of a single or plurality of Neuromodulator 421. Neuromodulator group 427 may comprise additional or fewer instances of neuromodulator array 415, 416, and additional or fewer instances of neuromodulator 421 without departing from the present invention.
Neuromodulator group 428 is shown comprising Neuromodulator Band 424 which provides at least one of mechanical and electrical connection between Neuromodulator Array 417 and 418, each of which comprise arrays of a single or plurality of Neuromodulator 421. Neuromodulator group 427 may comprise additional or fewer instances of neuromodulator array 417, 418, and additional or fewer instances of neuromodulator 421 without departing from the present invention.
Neuromodulator group 429 is shown comprising Neuromodulator Array 419 and may comprise a single or plurality of at least one of Neuromodulator Array 419 and neuromodulator 421. Neuromodulator Array 419 is shown comprising a plurality of Neuromodulator 421 and may comprise a single or plurality of Neuromodulator 421. Neuromodulator group 429 could further include a Neuromodulator Band 422, 423, 424, and which provides at least one of mechanical and electrical connection between Neuromodulator Array 419 additional instances of neuromodulator array and neuromodulator 421. Neuromodulator group 429 may comprise additional or fewer instances of neuromodulator array 419, and additional or fewer instances of neuromodulator 421 without departing from the present invention.
Neuromodulator group 430 is shown comprising Neuromodulator Array 420 and may comprise a single or plurality of at least one of Neuromodulator Array 420 and neuromodulator 421. Neuromodulator Array 420 is shown comprising a plurality of Neuromodulator 421 and may comprise a single or plurality of Neuromodulator 421. Neuromodulator group 430 could further include a Neuromodulator Band 422, 423, 424, and which provides at least one of mechanical and electrical connection between Neuromodulator Array 420 additional instances of neuromodulator array and neuromodulator 421. Neuromodulator group 430 may comprise additional or fewer instances of neuromodulator array 420, and additional or fewer instances of neuromodulator 421 without departing from the present invention.
Neuromodulator group 430, shown comprising array 420, is shown within the confines of the outer surface of skin 280; tis may be inserted surgically, through minimally invasive technique, through natural orifices, through ingestion such as by swallowing by the patient, through placement per os (PO) including use of an endoscope or other device or procedure, through placement per rectum (PR) including placement manually or through use of an endoscope or other device or procedure, or other technique for placement within the confines of the body. Using this technique, Neuromodulator group 430 may remain in the intraluminal space or be inserted transluminally into another space. Neuromodulator group 430 may be placed within the hollow visceral organs including any segment or portion of the gastrointestinal tract. Neuromodulator group 430 may be inserted through the hollow visceral organs including any segment or portion of the gastrointestinal tract and placed in another space, such as within the cervical region, thoracic region, thoracic cavity, peritoneal region, peritoneal cavity, pelvic region, pelvic cavity, adjacent to or affixed to the prevertebral fascia, adjacent to or affixed to the esophagus, adjacent to or affixed to the trachea, adjacent to or affixed to the mediastinum, adjacent to or affixed to the aorta, adjacent to or affixed to the vena cava, adjacent to or affixed to an artery, adjacent to or affixed to a vein, adjacent to or affixed to a nerve, adjacent to or affixed to a ganglion, adjacent to or affixed to a plexus, adjacent to or affixed to an organ, adjacent to or affixed to a neural target, adjacent to or affixed to a physiological target, adjacent to or affixed to an adrenal gland, adjacent to or affixed to a kidney, adjacent to or affixed to the stomach, adjacent to or affixed to the pylorus, adjacent to or affixed to a celiac plexus, adjacent to or affixed to a mesenteric plexus, adjacent to or affixed to a renal nerve, adjacent to or affixed to another target.
Neuromodulator group 430, shown comprising array 420, is shown within the confines of the outer surface of skin 280; tis may be inserted surgically, through minimally invasive technique, through vascular structures, including use of an endovascular technique or device or procedure, or other technique for placement within the confines of the body. Using this technique, Neuromodulator group 430 may remain in the intravascular space or be inserted transvascularly into another space. Neuromodulator group 430 may be placed within the hollow visceral organs including any segment or portion of the gastrointestinal tract. Neuromodulator group 430 may be inserted through the hollow visceral organs including any segment or portion of the gastrointestinal tract and placed in another space, such as within the cervical region, thoracic region, thoracic cavity, peritoneal region, peritoneal cavity, pelvic region, pelvic cavity, adjacent to or affixed to the prevertebral fascia, adjacent to or affixed to the esophagus, adjacent to or affixed to the trachea, adjacent to or affixed to the mediastinum, adjacent to or affixed to the aorta, adjacent to or affixed to the vena cava, adjacent to or affixed to an artery, adjacent to or affixed to a vein, adjacent to or affixed to a nerve, adjacent to or affixed to a ganglion, adjacent to or affixed to a plexus, adjacent to or affixed to an organ, adjacent to or affixed to a neural target, adjacent to or affixed to a physiological target, adjacent to or affixed to an adrenal gland, adjacent to or affixed to a kidney, adjacent to or affixed to the stomach, adjacent to or affixed to the pylorus, adjacent to or affixed to a celiac plexus, adjacent to or affixed to a mesenteric plexus, adjacent to or affixed to a renal nerve, adjacent to or affixed to another target.
Neuromodulation Field Alignment
Multimodal Surface Neuromodulator (MSM) 431 is shown with components comprising MSM Outer Surface 432, MSM Modulator Element A 433, MSM Modulator Element B 434, MSM Modulator Element C 435, MSM Modulator Element D 436, MSM Modulator Element E 437, MSM Modulator Coil 438, and MSM Power and Control Electronics 439. Multimodal Surface Neuromodulator (MSM) 431 may comprise additional of fewer MSM Modulator elements and other elements or components without departing from the present invention. Each of MSM Outer Surface 432, MSM Modulator Element A 433, MSM Modulator Element B 434, MSM Modulator Element C 435, MSM Modulator Element D 436, and MSM Modulator Element E 437 may each deliver a modulatory signal of the same or of different modulatory modalities.
Said modulatory modalities include but are not limited to noninvasive modulation and invasive modulation, modulation comprising at least one of stimulation, inhibition, activation, and blocking, modulation including tactile stimulation, including light touch, pressure, vibration, thermal stimulation, including hot and cold, as well as constant or variable temperatures, electrical stimulation, including direct current stimulation, alternating current stimulation, interferential stimulation, magnetic stimulation, including transcranial magnetic stimulation (TMS), transcutaneous magnetic stimulation, implanted magnetic stimulation, electromagnetic stimulation, including stimulation with radiofrequency energy (including but not limited to extremely low frequency (ELF) 3-30 Hz, super low frequency (SLF) 30-300 Hz, ultra low frequency (ULF) 300-3000 Hz, very low frequency (VLF) 3-30 kHz, low frequency (LF) 30-300 kHz, medium frequency (MF) 300 kHz-3 MHz, high frequency (HF) 3-30 MHz, very high frequency (VHF) 30-300 MHz, ultra-high frequency (UHF) 300 MHz-3 GHz, super high frequency (SHF) 3-30 GHz, extremely high frequency (EHF) 30-300 GHz, tremendously high frequency (THF) 300 GHz-3 THz, microwave bands, millimeter wave bands, and other bands), and other electromagnetic frequency bands, optical stimulation, including infrared light (IR) 300 GHz-430 THz (including far-infrared (FIR) 300 GHz-30 THz, mid-infrared (MIR) 30 THz-120 THz, and near infrared (NIR) 120 THz-400 THz bands), visible light 400-789 THz (including red 400-484 THz, orange 484-508 THz, yellow 508-526 THz, green 526-606 THz, blue 606-668 THz, violet 668-789 THz), ultraviolet light (UV) 400 nm-100 nm (including ultraviolet A (UV-A) 400 nm-315 nm, ultraviolet B (UV-B) 315 nm-280 nm, and ultraviolet C (UV-C) 280 nm-200 nm, and vacuum UV (UV-V) 200 nm-100 nm), X-rays, gamma rays, and other stimulation with photons of these and other wavelengths, pressure wave stimulation including ultrasonic, high frequency ultrasonic, sonic, subsonic, and other pressure wave frequencies, chemical stimulation, stimulation using pharmacological agents, stimulation using electromagnetic signals which emulate signals generated by chemical and biological compounds, and other modalities which control, modulate, or influence neural activity, neural signals, or other physiological activity.
Neuromodulator Group 440, Neuromodulator Group, 441, Neuromodulator Group, 442, Neuromodulator Band, 443, Neuromodulator Band 444, Neuromodulator Band 445 are shown; additional or fewer instances of each of these may comprise the Autonomic Vector Control System (AVCS) 465 without departing from the present invention.
Many of the other components of Autonomic Vector Control System (AVCS) 465 shown in
Autonomic Vector Control (AVC) as taught in the present invention is novel and useful in many respects and enables treatment efficacy and safety not otherwise possible. Built upon the novel construct of autonomic nodes, three modalities of progressively increasing sophistication and dimensionality are enabled by the present invention: (1) Autonomic Node Modulation, (2) Autonomic Vector Modulation and (2) Autonomic Matrix Modulation.
Autonomic Node Construct:
Heretofore, the autonomic nervous system has been understood and described as a one-dimensional entity with two linearly opposing components, the sympathetic and the parasympathetic nervous systems. Congruent with this understanding, the autonomic nervous system has been described as simplistic balance between two activities, a “fight and flight” sympathetic response and a “rest and digest” parasympathetic response. This simplistic view has remained unchanged over the decades. A novel aspect of the present invention is based upon the innovative construct in which the autonomic nervous system can be more precisely modeled as a multivariable vector of autonomic nodes. Applying this innovative model in the design of a novel therapy has made possible the design of the present invention which facilitates the surprising but important innovations, including modulation of specific nodes of the autonomic nervous system and the precise control of specific physiological functions controlled by respective autonomic nodes and combinations thereof.
In this construct, nodes may be defined as components segmented by spinal level, by target organ, by physiological function, by pathway including autonomic pathway and other pathways (sympathetic, parasympathetic, enteric, somatosensory, motor, visual, auditory, and other pathway, including but not limited to pathways listed elsewhere in the present application), by neurotransmitter (glutamine, acetylcholine, glycine, GABA, dopamine, serotonin, norepinephrine (noradrenaline), histamine, adenosine, adenosine triphosphate (ATP), and others, including but not limited to neurotransmitters listed elsewhere in the present application), by receptor (cholinergic, nicotinic, muscarinic, dopaminergic (including but not limited to D1 and D2 receptors), serotonergic, and others, including but not limited to receptors listed elsewhere in the present application), and by other dimensions of distinction.
In addition to these autonomic dimensions of distinction, the autonomic nervous system network comprises a multiplicity of neural pathways each of which potentially represent a distinct anatomical pathway element within a corresponding vector of anatomically distinct nodes along an anatomical pathway dimension. This may be orthogonal to or have some dependence upon a vector comprising anatomical spinal levels. This construct provides the foundation for a high dimensionality model for autonomic physiology and which facilitates the design, discovery, characterization, and validation of novel therapies which have far more efficacy and safety than present pharmacological and neuromodulatory therapies. Present pharmacotherapies are restricted only by the dimension of receptor specificity and therefore have limited anatomical specificity and often have dose limiting side effects. Present neuromodulatory therapies are generally restricted by nerve and therefore have limited pathway specificity. By employing a high dimensionality model and framework, a greater degree of modulatory specificity is achieved, permitting simultaneously greater efficacy and safety and in doing so, enabling the creation of novel therapies previously not possible or not sufficiently safe to be feasible.
A further dimension for assessment and for modulation of the autonomic vector is characterizable according to cranial level and spinal level, including but not limited to cranial nerves CN1, CN2, CN3, CN4, CN5, CN6, CN7, CN8, CN9, CN10, CN11, CN12, cervical spinal levels, C1, C2, C3, C4, C5, C6, C7, C8, thoracic spinal levels T1, T2, T3, T4, T5, T6, T7, T8, T9 T10, T1, T12, lumbar spinal levels L1, L2, L3, L4, L5, sacral spinal levels S1, S2, S3, S4, S5, and coccygeal spinal level Cx1. These spinal levels may be further subdivided by modality, or modalities may comprise a separate dimension or multiplicity of dimensions.
A further dimension which is anatomically orthogonal to the spinal levels is the dimension along the proximal-distal axis along the neural pathways, herein termed proximality-distality. For the sympathetic nervous system, the elements include but are not limited to the hypothalamus, locus ceruleus, intermediolateral nucleus, spinal nerve, dorsal root ganglion, paravertebral ganglia (including but not limited to the stellate ganglia, sympathetic trunk ganglia, lumbar ganglia), sympathetic trunk, sympathetic white rami, sympathetic grey rami, splanchnic nerves, prevertebral ganglia (including celiac ganglia, superior mesenteric ganglia, inferior mesenteric ganglia) and effector organs. For the parasympathetic nervous system, the elements include but are not limited to the hypothalamus, solitary nucleus, Edinger-Westphal nucleus, superior salivary nucleus, inferior salivary nucleus; preganglionic nerves: oculomotor nerve (parasympathetic roots), facial nerve (greater petrosal nerve), facial nerve (chorda tympani), glossopharyngeal nerve (lesser petrosal nerve), vagus nerves, pelvic nerves; paired head and neck ganglia (including but not limited to the ciliary ganglia, pterygopalatine ganglia, submandibular ganglia, and otic ganglia); postganglionic nerves: short ciliary nerves, nasopalatine nerve, pterygopalatine nerve, greater palatine nerve, lesser palatine nerve, auriculotemporal nerve, lingual nerve, pelvic splanchnic nerve, inferior hypogastric plexus.
Characterizing the autonomic nervous system (including the sympathetic nervous system and parasympathetic nervous system) and the enteric nervous system as a multidimensional matrix and further characterizing efficacy and side effects associated with each autonomic node allows for true optimization of neuromodulation performance, realizing maxima of efficacy and minima of side effects. This facilitates a dramatically more precise and granular conceptualization of autonomic physiology, and enables the informed design, development, validation, and characterization of a next generation of neuromodulation-based therapies, including but not limited to Autonomic Node Modulation 480, Autonomic Vector Modulation 472, and Autonomic Matrix Modulation 479, described below.
Autonomic Node Modulation:
The generation and delivery of the neuromodulatory vector taught in the present invention facilitates precise modulation of individual autonomic nodes as well as groups of autonomic nodes, and the neuromodulatory vector further facilitates independent modulation of at least one of individual nodes and groups of autonomic nodes with a single or a multiplicity of independent neuromodulatory signals comprising the neuromodulatory vector.
Autonomic Nodal Control for Autonomic Vector Modulation:
Each of Multimodal Surface Neuromodulator (MSM) 431 possesses the capability to deliver at least one modulatory modality at a focal location, including but not limited to a node within the autonomic nervous system. The novel configuration taught in the present invention comprises an array of Multimodal Surface Neuromodulator (MSM) 431 configured to concurrently modulate a vector of autonomic nodes.
One application of this is in the treatment of obesity in which one representative autonomic neuromodulatory vector increases metabolic rate while concurrently decreasing or stabilizing at least one of heart rate and blood pressure. This novel construct and combination of innovative apparatus and methods allows for maximization and/or optimization of efficacy in weight loss as well as minimization and/or optimization of side effects including possible tachycardia and hypertension as well as others.
Autonomic Nodal Differential Modality Control for Autonomic Matrix Modulation:
Each of Multimodal Surface Neuromodulator (MSM) 431 possesses the capability to deliver multiple modalities at the same location. Through the use of a single or multiplicity of modulatory modalities, each Multimodal Surface Neuromodulator (MSM) 431 may stimulate, inhibit, activate, block, or modulate at least one component of the autonomic nervous system at that node.
In some anatomical locations, furthermore, differential modulation of distinct autonomic and other neural pathways is facilitated. For example, this may involve one Multimodal Surface Neuromodulator (MSM) 431 configured to deliver an electrical modulatory signal which activates sympathetic nervous system fibers and an ultrasound modulatory signal which inhibits parasympathetic fibers. Alternatively or concurrently, at least one Multimodal Surface Neuromodulator (MSM) 431 could be configured to deliver a sonic modulatory signal to stimulate sympathetic nervous system components in a node and to inhibit sympathetic nervous system pathways in the same or adjacent regions and which may comprise the same node or distinct nodes.
Neuromodulator assemblies of neuromodulator belts are shown in a variety of exemplary configurations; other configurations may be implemented without departing from the present invention. This figure demonstrates field lines which for modulation using energy forms including but not limited to electrical, magnetic, optical, subsonic, sonic, ultrasound, high frequency ultrasound, thermal, vibratory, and others.
Optimization of Ligand Specific Signal Generation
A further dimension taught in the present invention is the use of electrical, magnetic, electromagnetic, and other signals which mimic the signals produced by the electron cloud of neurotransmitters, and other atoms and molecules and which, when used in conjunction with the novel autonomic vector modulation taught in the present invention, provides a further dimension of modulation specificity. This additional dimension allows for even greater selective modulation for optimization of efficacy, for optimization of side effects and side effect profile, and for simultaneous optimization of efficacy and side effects.
For example, by delivering a signal which mimics stimulatory effects of the preganglionic neurotransmitter at the autonomic ganglion or of the postganglionic neurotransmitter at the end effector organ or any other neurotransmitter in the autonomic matrix, the autonomic end organ may be stimulated. By concurrently or simultaneously or in a temporally patterned manner preceding or following previously said stimulation, delivering a signal which mimics an inhibitory neurotransmitter or blocks an activating neurotransmitter in the autonomic matrix, a very high degree of specificity in modulation is realized; and this facilitates optimization and maximization of efficacy, optimization and minimization of side effects, and concurrent optimization of efficacy and side effects.
Said energy signals (including electric fields, magnetic fields, electromagnetic field, and other energy fields) which may mimic neurotransmitters may be in any frequency range, including those ranges listed elsewhere in this specification and may include activation stimulation and/or blockage or inhibition of autonomic (or somatic, enteric, or other) pathways or a single or plurality of autonomic vector elements using signals including but not limited to high frequency stimulation, such as with stimulation frequency F>=50 Hz, F>=100 Hz, F>=1,000 Hz, F>=10,000 Hz, F>=100,000 Hz, F>=1 MHz, F>=10 MHz, F>=100 MHz, F>=1 GHz, F>=10 GHZ.
Optimization of Ligand Specific Signal Generation
Stimulation or augmentation of one or multiple autonomic vector elements using signals including but not limited to lower frequency stimulation, such as with stimulation frequency F<=30 Hz, F<=50 Hz, F<=100 Hz, F<=1,000 Hz, and other ranges is also taught in the present invention.
Use of more than one stimulation signal, for simplicity called a carrier signal, to establish a beat frequency to allow modulation, including stimulation and inhibition, at the frequency difference between the two carrier signals. This may be used for modulation (including stimulation and inhibition) of structures including but not limited to the brain, intracranial structures, cranial nerves, spinal cord, peripheral nerves, autonomic structures, autonomic nerves, splanchnic nerves, greater splanchnic nerves, lesser splanchnic nerves, sympathetic nerves, vagus nerves, celiac plexus, mesenteric plexus, nerves innervating the pancreas, nerves innervating the gastrointestinal tract, nerves innervating the gastric antrum, nerves innervating the gastric pylorus, any other structures listed in this application, any other neural structures in the body.
An array of such modulators as shown in
Autonomic Vector Modulation Utilizing Interference Frequency Vectors:
MIF=MCFi−MCFi
The modulation carrier frequencies (MCFa, . . . , MCFi, . . . , MCFj, . . . , MCFN) 466 may be chosen to be outside of the frequency ranges in which stimulation and inhibition of the target tissue occurs. For example, modulation carrier frequencies (MCF) 466 of 1 MHz may be used to accomplish this. Alternatively or additionally, modulation carrier frequencies (MCF) 466 of higher or lower may be used, including but not limited to 100 KHz-1 KHz, 1 KHz-10 KHz, 10 KHz-100 KHz, 100 KHz-1 MHz, 1 MHz-10 MHz, 10 MHz-100 MHZ, 100 MHz-1 GHz, 1 GHz-10 GHz, 10 GHZ-100 GHz, 100 GHz-1 THz, 1 THz-10 THz, 10 THz-100 THz.
Modulation carrier frequencies (MCF) 466 may be selected to generate a single or plurality of modulator interference frequency (MIF) 467, such that the modulator interference frequency (MIF) 467 are within a frequency range that generates at least one of stimulation and inhibition of the target tissue. For example, a modulator interference frequency (MIF) 467 of 30 Hz may be used to stimulate target tissue. For example, a modulator interference frequency (MIF) 467 of 180 Hz may be used to inhibit target tissue. Alternatively or additionally, a single or plurality of modulator interference frequency (MIF) 467 may be generated in at least one of the ranges 0-10 Hz, 10 Hz-100 Hz, 100 Hz-1 KHz, 1 KHz-10 KHz, 10 KHz-100 KHz, 100 KHz-1 MHz, 1 MHz-10 MHz, 10 MHz-100 MHz, 100 MHz-1 GHz, 1 GHz-10 GHz, and other frequency ranges, including but not limited to those listed elsewhere in this specification.
Modulator Interference Frequency (MIF) 467 is delivered to target structure 468, which may be at least one of Right Sympathetic Trunk 71, Left Sympathetic Trunk 72, Right Greater Splanchnic Nerve 73, Left Greater Splanchnic Nerve 74, Right Lesser Splanchnic Nerve 75, Left Lesser Splanchnic Nerve 76, Right Subdiaphragmatic Greater Splanchnic Nerve 78, Left Subdiaphragmatic Greater Splanchnic Nerve 79, Right Subdiaphragmatic Lesser Splanchnic Nerve 80, Left Subdiaphragmatic Lesser Splanchnic Nerve 81, Intercostal Nerve 69, Intercostal Nerve 70, Right Vagus Nerve 95, Left Vagus Nerve 96, Intermediolateral Nucleus 121, Spinal Cord White Matter 122, Ventral Spinal Root 124, Dorsal Spinal Root 125, Spinal Ganglion 126, Spinal Nerve 127, Spinal Nerve Anterior Ramus 128, Spinal Nerve Posterior Ramus 129, Grey Ramus Communicantes 130, White Ramus Communicantes 131, Sympathetic Trunk 132, Ventral Horn of Spinal Gray Matter 141, Dorsal Horn of Spinal Gray Matter 142, Spinal Cord 151, Celiac Plexus 154, Celiac Ganglion 155, Superior Mesenteric Plexus 156, Superior Mesenteric Ganglion 157, Renal Plexus 158, Renal Ganglion 159, Inferior Mesenteric Plexus 160, Iliac Plexus 161, Right Lumbar Sympathetic Ganglia 162, Left Lumbar Sympathetic Ganglia 163, Right Sacral Sympathetic Ganglia 164, Left Sacral Sympathetic Ganglia 165, Abdominal Neural Plexus 187, Abdominal Neural Ganglion 188, Right Lumbar Sympathetic Trunk 189, Left Lumbar Sympathetic Trunk 190, Right Cervical Plexus 237, Left Cervical Plexus 238, Superficial Cardiac Plexus 244, Deep Cardiac Plexus 245, Right Anterior Pulmonary Nerve 246, Left Anterior Pulmonary Nerve 247, Right Renal Nerve Branch 248, Left Renal Nerve Branch 249, Stomach 8, Gastric Fundus 9, Greater Curvature of Stomach 10, Pyloric Antrum 11, Gastric Pylorus 12, Duodenum 13, Lower Esophageal Sphincter 14, Esophagus 15, Cardiac Notch of Stomach 16, Lesser Curvature of Stomach 17, Nerve 35, Transected Nerve End 37, Vagus Nerve 47, Sympathetic Nerve Branch 48, Intercostal Nerve 69, Intercostal Nerve 70, and other structure.
In
In
Autonomic Vector Control System and Modulation Zone Focusing and Confinement:
In
Modulator Interference Frequency k (MIFk) 467, for k=1 to m,
where m may be chosen to be 0 to 1,000, or 1 to 100, or 1 to 24, or 0 to 12, or 0 to 10, or 0 to 8, or other range as desired. The range of k−1 to m may be chosen to correspond to the vector size of the autonomic vector being modulated, or m may be chosen to be larger or smaller than the autonomic vector being modulated.
In
469 Modulator Interference Frequency 1 (MIF1)
470 Modulator Interference Frequency 2 (MIF2)
471 Modulator Interference Frequency 3 (MIF3)
A single or multiplicity of paradigms may be applied in the selection of Modulator Interference Frequency k (MIFk) 467. Modulator Interference Frequency k (MIFk) 467 may be selected to comprise a Neuromodulation Signal Vector (NSV) 996, comprising elements as may be defined below:
Neuromodulation Signal (NMS) Vector=[NMSk], for k=1 to m=[Modulator Interference Frequency k (MIFk), for k=1 to m
modulation using a vector of k elements, where k represents the size of the vector and which may also represent the dimensionality of the Neuromodulation Signal (NMS) Vector for the case in which each of the elements are orthogonal or independent, which may or may not be the case for a particular application.
In this preferred embodiment, Neuromodulation Signal Vector (NSV) 996 comprises a single or multiplicity of elements, each element of which may be a single or multiplicity of Neuromodulation signal (NMS) 998.
For any pair of modulators i and j, respective modulator carrier frequency i (MCFi) and modulator carrier frequency j (MCFj) may be chosen such that the modulator interference frequency (MIF) 467 is the difference between the two:
MIF=MCFi−MCFi
One preferred embodiment includes any single or multiplicity of modulation modalities, as enumerated above. Field lines depicted in each of
Autonomic Vector Modulation Utilizing Passive Implants:
Enhanced focality may be accomplished through the use of active or of passive implants which are powered internally or externally. The use of external power delivered through the skin to passive implants provides a greater degree of safety and both technical and regulatory simplicity in the implementation of the Autonomic Vector Control System (AVCS) 465. Micro-implants with passive elements including a diode and energy resonant and coupling elements such as an induction coil and a resistor and capacitor, or a subset or superset of these, may be used to receive energy through magnetic, indictive, electromagnetic, and other coupling mechanisms. These implants may then more focally deliver energy to specific autonomic nodes to provide a Neuromodulation Signal Vector (NSV) 996 with enhanced spatial precision.
Autonomic Vector Modulation Utilizing Other Energy Modalities:
The Autonomic Vector Control System (AVCS) 465 may be implemented using any single or plurality of energy modalities without departing from the present invention, said energy modalities include but are not limited to electrical energy, magnetic energy, electromagnetic energy, ultrasonic energy, sonic energy, subsonic energy, vibrotactile energy, vibrational energy, optical energy, any other energy form described or listed in the present invention and/or specification, and other energy forms. Additionally, energy and/or signals may be delivered percutaneously using transmission means that are conductive to that energy form, with as percutaneous wires, optical fibers, conductive gels, natural structures which provide conductivity, and other means.
Autonomic Vector Modulation Utilizing Multimodality Modulation:
Modulation of autonomic vectors may be performed utilizing multiple modalities as taught in the present inventions. Combinations of modalities, including but not limited to at least one energy form disclosed or mentioned in the present invention, and all permutations thereof, are included in the present invention.
Multiple previous attempts by well-funded research groups have failed to demonstrate efficacy in metabolic control utilizing a variety of modulation modalities. One preferred embodiment teaches the use of multiple modalities to achieve an optimal balance of modulation of sympathetic pathways and parasympathetic pathways. By utilizing a vector of excitatory neuromodulation modalities to stimulate sympathetic cells, fibers, or pathways and by using a vector of inhibitory neuromodulation modalities to suppress or block parasympathetic fibers, selected components of the autonomic vector may be increased, including those specific to metabolism and metabolic rate or to other desired physiological functions taught in the present invention.
Similarly, by utilizing a vector of excitatory neuromodulation modalities to stimulate parasympathetic cells, fibers, or pathways and by using a vector of inhibitory neuromodulation modalities to suppress or block sympathetic fibers, selected components of the autonomic vector may be decreased, including those specific to metabolism and metabolic rate or to other desired physiological functions taught in the present invention. Furthermore, additional pathways, including somatic and somatovisceral pathways may be modulated separately or concurrently with Autonomic Vector Modulation 472 by Autonomic Vector Control System (AVCS) 465 to further augment efficacy and safety.
Target structure 468 may comprise any neural or physiological structure in the body 464 including but not limited to any neural structure or other structure in the present invention. Additionally, target structure 468 may include brown adipose tissue (BAT) in any location including but not limited to the thorax, abdomen, neck, back, arms, or legs, supraclavicular regions, head, brain, spinal cord, peripheral nerves, and any other structure, and in any other location.
In one preferred embodiment, a combination of at least one modality including sonic, ultrasonic, electrical, direct current electrical, alternating current electrical, magnetic, and optical energy are delivered to the supraclavicular brown adipose tissue (BAT) 476 fat pads. Modulation may be delivered directly to the brown adipose tissue (BAT) 476 or indirectly via the innervating pathways, including but not limited to neural structures, hormonal pathways, adrenergic signals, epinephrine, norepinephrine, sympathetic nervous system, parasympathetic nervous system, autonomic nervous system, enteric nervous system, and other pathway.
In another preferred embodiment, a combination of at least one modality including sonic, ultrasonic, electrical, direct current electrical, alternating current electrical, magnetic, and optical energy are delivered to the white adipose tissue (WAT) 477. Modulation may be delivered directly to the white adipose tissue (WAT) 477 or indirectly via the innervating pathways, including but not limited to neural structures, hormonal pathways, adrenergic signals, epinephrine, norepinephrine, sympathetic nervous system, parasympathetic nervous system, autonomic nervous system, enteric nervous system, and other pathway.
In another preferred embodiment, a combination of at least one modality including sonic, ultrasonic, electrical, direct current electrical, alternating current electrical, magnetic, and optical energy are delivered to the mastoid region of the skull in order to modulate the vestibular nerve directly or indirectly via the innervating pathways, including but not limited to neural structures, sympathetic nervous system, parasympathetic nervous system, autonomic nervous system, sensory nervous system, motor nervous system, visceral afferent nervous system, visceral efferent nervous system, and other pathway.
On one preferred embodiment, a combination of at least one modality including sonic, ultrasonic, electrical, direct current electrical, alternating current electrical, magnetic, and optical energy are delivered to target structure 468 in a manner that induces plastic changes, such as neural plasticity, resulting in durable changes in physiology that persist beyond the duration of the neuromodulation signal. One advantage of this modality is that it permits the use of intermittent stimulation, which is less susceptible to habituation or tachyphylaxis, phenomena in which the physiological response taper down with successive stimuli. For example, by inducing at least one of plastic changes such as a reduction in parasympathetic nervous system activity and plastic changes such as an increase in sympathetic nervous system activity, a durable increase in autonomic index or an increase in specific components of the autonomic vector may be effected and which persist after termination of the neuromodulation signal. Conversely, by inducing at least one of plastic changes such as a reduction in sympathetic nervous system activity and plastic changes such as an increase in parasympathetic nervous system activity, a durable decrease in autonomic index or a decrease in specific components of the autonomic vector may be effected and which persist after termination of the neuromodulation signal.
Autonomic Vector Modulation: Representative Indications and Applications:
Autonomic Vector Modulation 472, as that taught in the present invention and performed by Autonomic Vector Control System (AVCS) 465, may be used to provide optimal and maximal efficacy and optimal and minimal side effects in the treatment of a multiplicity disorders, including but not limited to at least one of the prevention and treatment of: Cardiac Failure, right heart failure, left heart failure, congestive heart failure (CHF), systolic heart disease, diastolic heart disease, Takotsubo's cardiomyopathy, acute respiratory distress syndrome (ARDS), obesity, asthma, hypertension, hypotension, sepsis, inflammation, traumatic brain injury (TBI), necrotizing enterocolitis (NEC), dysautonomia, reduction of stress-induced disease processes, reduction of inflammation induced disease processes, and other neurological, autonomic, somatic, and other diseases and conditions.
Autonomic Vector Modulation 472, as that taught in the present invention and performed by Autonomic Vector Control System (AVCS) 465, may also be used for physiological training and performance enhancement, including cardiovascular training, weight loss, weight optimization, attention enhancement, cognitive enhancement, memory enhancement, relaxation, meditation, stress reduction, lifespan augmentation, lifespan extension, and other health promotion objectives.
Life extension: modulation of metabolic parameters, including but not limited to those taught in the present invention above and further specifically including autonomic and other physiologic modulation of heart rate, blood pressure, energy metabolism including cell respiration, glucose metabolism, lipid metabolism, oxygen consumption, carbon dioxide production, and other neural and physiological pathways are taught for slowing down the organism metabolic process I order to conserve energy and to extend lifespan.
Autonomic Vector Modulation: Tachyphylaxis Minimization:
Autonomic Vector Modulation 472, as that taught in the present invention and performed by Autonomic Vector Control System (AVCS) 465, may be used to provide temporally patterned modulation that takes advantage of coupling between autonomic nodes and other neural nodes in the nervous system network to alternate or partition in time or in space the neuromodulatory signal (NMS) 998 elements of Neuromodulation Signal Vector (NSV) 996 such that tachyphylaxis that would develop if a solely scalar signal delivered may be avoided or minimized by delivering a multiplicity of coordinated signals comprising Neuromodulation Signal Vector (NSV) 996. Neuromodulation Signal Vector (NSV) 996 may be generated by Autonomic Vector Control System (AVCS) 465 to perform Autonomic Vector Modulation 472 which delivers individual neuromodulatory signals (NMS) 998 which are of a lower amplitude, lower duty cycle, lower amplitude and lower duty cycle, and which dynamically adjust to maximize use of nodes robustly coupled to the desired physiological effect and minimize use of nodes less robustly coupled to the desired effect in order to dynamically maximize efficacy and safety, dynamically minimize side effects, and dynamically adjust to minimize tachyphylaxis.
Energy Field Orientation:
Application of electrical fields parallel to sympathetic nervous system structures is taught to optimize modulatory coupling between said neuromodulator and nervous system tissue. Such a configuration may allow for a decreased stimulation threshold, thereby improving coupling between neuromodulator and nervous system component. This is useful for axons, comprising non-myelinated fibers and myelinated fibers. Electrical fields may alternately be applied perpendicular to sympathetic nervous system structures.
Electrical fields may applied parallel to single or plurality of nervous system structures comprising fibers, tracts, nuclei, single or plurality of ganglia, prevertebral ganglia, paravertebral ganglia, spinal root, spinal nerve, grey ramus, white ramus, sympathetic trunk, sympathetic chain, splanchnic nerve, vagus nerve, peripheral nerve, cranial nerve, autonomic structure, sympathetic structure, parasympathetic structure, axons, dendrites, soma, cortex, cerebral structure, cerebellar structure, brainstem structure, or other structures.
Electrical fields may applied perpendicular to single or plurality of nervous system structures comprising fibers, tracts, nuclei, single or plurality of ganglia, prevertebral ganglia, paravertebral ganglia, spinal root, spinal nerve, grey ramus, white ramus, sympathetic trunk, sympathetic chain, splanchnic nerve, vagus nerve, peripheral nerve, cranial nerve, autonomic structure, sympathetic structure, parasympathetic structure, axons, dendrites, soma, cortex, cerebral structure, cerebellar structure, brainstem structure, or other structures.
Electrical fields may applied oblique to single or plurality of nervous system structures comprising fibers, tracts, nuclei, single or plurality of ganglia, prevertebral ganglia, paravertebral ganglia, spinal root, spinal nerve, grey ramus, white ramus, sympathetic trunk, sympathetic chain, splanchnic nerve, vagus nerve, peripheral nerve, cranial nerve, autonomic structure, sympathetic structure, parasympathetic structure, axons, dendrites, soma, cortex, cerebral structure, cerebellar structure, brainstem structure, or other structures.
Ablation:
Further embodiments of the present invention comprise neuromodulation of targets for which the modulating effect is fully reversible, partially reversible, and irreversible.
Further embodiments of the present invention comprise neuromodulation of targets for which the modulating effect is immediately reversible, reversible in a delayed time manner, reversible with gradual return of function, reversible with graded return of function, reversible with return of function in a linear manner, reversible with return of function in a non-linear manner, reversible with return of function in an exponential manner, reversible with return of function in a continuous manner, reversible with return of function in a discrete manner, reversible with return of function in a piecewise continuous manner, reversible with return of function over a predetermined tome course, reversible with return of function over a random tie course, reversible with return of function over a another time course.
Trialing:
Electrical neuromodulation as taught herein may be used for at least one of diagnosis, trialing, and therapy. In one embodiment, neuromodulation may be used to assess the system response of the physiology of the patient or user to assess information including diagnostic information. Trialing may then be performed to assess whether and to what degree the said patient or user will respond to the therapy and therefore is likely to be a responder. Therapeutic neuromodulation may then be performed to deliver at least one of acute, subacute, intermittent, periodic, sporadic, and chronic therapy.
At least one of trialing and therapy may be done with percutaneous single contact or multiple contact electrode catheters or other electrode configurations, and theses may be done with electrode catheters which are tunneled in the subcutaneous space or which follow a direct linear percutaneous trajectory. Said electrode catheters may be configured in any of several ways without departing form the present invention, and these may comprise flexible or rigid catheters, catheters with omnidirectional electrodes, catheters with unidirectional electrodes, catheters with directional electrodes, electrode wires with pattered insulation, electrode wires with insulation along the length with the exception of the region of the exposed electrode at the tip or along the length or other location, or other configuration.
Calibration:
Neuromodulation may be performed in a closed loop manner for a variety of applications including but not limited to the validation of the anatomical target. Neuromodulation may be performed using any of the modalities taught herein as well as other modalities, including those known to those versed in the art. For example, at least one of thermal, radiofrequency, ultrasonic, high frequency ultrasonic, sonic, and other modalities may be used to reversible stimulate or inhibit a prospective target. The physiological response may then be sensed directly or indirectly, and the degree of response fed into a control law which may then be used to adjust the degree of neuromodulation to assess the physiological response and then if desired to perform partially or completely irreversible neuromodulation.
Noninvasive Modulation of Neural and Other Structures:
Transcutaneous modulation of neural structures is taught for the treatment of conditions and diseases comprising but not limited to those listed and referenced in the present and related applications.
In
Energy forms include but are not limited to electrical, vibratory, subsonic, sonic, ultrasonic, high frequency ultrasonic, optical, magnetic, electromagnetic, pressure wave, kinetic, thermal including heating and or cooling, other energy forms in the present invention and specification, and other energy forms.
Autonomic Vector Control System—System Configurations and Considerations:
Preferred embodiments include a single or a plurality of neuromodulators configured to modulate a singularity or a plurality of neural pathways, including but not limited to autonomic pathways, comprising sympathetic pathways, parasympathetic pathways, sympathetic and parasympathetic pathways. a combination of including. By appropriately modulating an autonomic vector, autonomic indices corresponding to metabolic subvector components may be down modulated while maintaining an overall balance in autonomic activity. This may be applied to the slowing down of metabolic processes that correlate with subcellular genetic and organelle processes that correlate with ageing at the cellular level. Through chronic application of metabolic subvector inhibition, using at least one of implanted, percutaneous, noninvasive, and other neuromodulators, one can reduce metabolic stresses at the cellular and organ level, thereby contributing to longevity at the organism level.
A preferred embodiment includes the use of an external nonimplanted power supply in communication with an implanted passive electronic circuit and neuromodulator. This allows for simpler product design and regulatory approval processes while facilitating easier programming and updating of control parameters, which may be embodies in the external controller. This external power and internal passive circuit and neuromodulator configuration may be applied to one or any of the neuromodulator locations, indications, proposes, functions, functionalities, form factors, implantation procedures, array configurations, vector configurations, or any other aspect of the instant invention and any of the inventions included by reference without departing from the present invention. An external power supply may transmit power to the passive implant using energy modalities including but not limited to tactile energy, including light touch, pressure, vibration, thermal energy, including hot and cold, as well as constant or variable temperatures, electrical energy, including direct current, alternating current, interferential signals, magnetic stimulation, including static magnetic fields, time varying magnetic fields, alternating magnetic fields, pulsed magnetic fields, transcranial magnetic stimulation (TMS) signals, transcutaneous magnetic stimulation signals, electromagnetic stimulation, including stimulation with radiofrequency energy, very low frequency signals, extremely low frequency (ELF) signals, sub-ELF signals, radiofrequency signals, microwave signals, infrared light signals, visible light signals, ultraviolet light signals X-Ray signals, gamma ray signals, and other electromagnetic frequency bands, optical stimulation, including visible light, infrared light, ultraviolet light, and other stimulation with photons of these and other wavelengths, pressure wave signals including ultrasonic, high frequency ultrasonic, sonic, subsonic, and other pressure wave frequencies, and other energy forms. In one preferred embodiment, an external magnetic signal may be transmitted through the skin to an implanted passive device which employs an antenna and a passive network to convert the alternating magnetic field into electrical energy for use in stimulating neural tissue. At least one of a half-wave bridge and a full wave bridge may be included in the passive implant to rectify the alternating signals in order to create a DC signal for powering on board circuitry or for delivering a signal which may have a DC component. In one preferred embodiment, a charge-balanced alternating signal is delivered to the neural tissues.
It will be appreciated by those skilled in the art that while the invention has been described above in connection with the particular embodiments and examples, the invention is not necessarily so limited, and that numerous other embodiments, examples uses, modifications, and departures from the embodiments, examples, and uses are intended to be encompassed by the claims attached hereto The entire disclosure of each patent and publication cited herein is incorporated by reference, as if each such patent or publication were individually incorporated by reference herein.
All patents and patent applications listed are hereby incorporated by reference. This application is a continuation of and incorporates by reference U.S. Provisional Patent Application Ser. No. 61/919,835 (Docket GIPROG 06.01p1), filed Dec. 23, 2013, entitled “METHOD, APPARATUS, SURGICAL TECHNIQUE, AND OPTIMAL STIMULATION PARAMETERS FOR NONINVASIVE & MINIMALLY INVASIVE AUTONOMIC NEUROMODULATION FOR THE TREATMENT OF OBESITY, PULMONARY DISORDERS, HYPERTENSION, AND OTHER CONDITIONS”, and naming as inventor Daniel John DiLorenzo, which is incorporated by reference. This application is a continuation of and incorporates by reference U.S. Provisional Patent Application Ser. No. 62/569,975 (Docket GIPROG 06.01p2), filed Oct. 9, 2017, entitled “METHOD, APPARATUS, SURGICAL TECHNIQUE, AND OPTIMAL STIMULATION PARAMETERS FOR NONINVASIVE & MINIMALLY INVASIVE AUTONOMIC VECTOR NEUROMODULATION FOR THE TREATMENT OF OBESITY, PULMONARY DISORDERS, HYPERTENSION, AND OTHER CONDITIONS”, and naming as inventor Daniel John DiLorenzo, which is incorporated by reference. This application is a continuation of and incorporates by reference U.S. Provisional Patent Application Ser. No. 62/635,467 (Docket GIPROG 06.01p3), filed Feb. 28, 2018, entitled “METHOD, APPARATUS, SURGICAL TECHNIQUE, AND OPTIMAL STIMULATION PARAMETERS FOR NONINVASIVE & MINIMALLY INVASIVE AUTONOMIC VECTOR NEUROMODULATION FOR THE TREATMENT OF OBESITY, PULMONARY DISORDERS, HYPERTENSION, AND OTHER CONDITIONS”, and naming as inventor Daniel John DiLorenzo, which is incorporated by reference. This application is a continuation of and incorporates by reference U.S. Provisional Patent Application Ser. No. 62/780,332 (Docket GIPROG 06.01p4), filed Dec. 17, 2018, entitled “METHOD, APPARATUS, SURGICAL TECHNIQUE, AND OPTIMAL STIMULATION PARAMETERS FOR NONINVASIVE & MINIMALLY INVASIVE AUTONOMIC VECTOR NEUROMODULATION FOR THE TREATMENT OF OBESITY, PULMONARY DISORDERS, HYPERTENSION, AND OTHER CONDITIONS”, and naming as inventor Daniel John DiLorenzo, which is incorporated by reference. This application is a continuation in Part of and incorporates by reference U.S. patent application Ser. No. 12/317,448 (Docket GIELEC 01.01), filed Dec. 22, 2008, entitled “METHOD AND APPARATUS FOR CONFORMAL ELECTRODES FOR AUTONOMIC NEUROMODULATION FOR THE TREATMENT OF OBESITY AND OTHER CONDITIONS”, which is a continuation of U.S. Provisional Patent Application Ser. No. 61/008,804 (Docket GIELEC 01.01p1), filed Dec. 21, 2007, entitled “METHOD AND APPARATUS FOR CONFORMAL ELECTRODES FOR AUTONOMIC NEUROMODULATION FOR THE TREATMENT OF OBESITY AND OTHER CONDITIONS”, and which is a continuation in Part of U.S. patent application Ser. No. 12/291,685 (Docket GIPROG 01.01), filed Nov. 12, 2008, entitled “METHOD AND APPARATUS FOR PROGRAMMING OF AUTONOMIC NEUROMODULATION FOR THE TREATMENT OF OBESITY”, which claims priority to U.S. Provisional Patent Application Ser. No. 61/002,735, filed Nov. 12, 2007, entitled “METHOD AND APPARATUS FOR PROGRAMMING OF AUTONOMIC NEUROMODULATION FOR THE TREATMENT OF OBESITY” and U.S. Provisional Patent Application Ser. No. 61/003,686, filed Nov. 19, 2007, entitled “METHOD AND APPARATUS FOR OPERATION OF AUTONOMIC NEUROMODULATION FOR THE TREATMENT OF OBESITY”, all naming as inventor Daniel John DiLorenzo, and all of which are incorporated by reference. This application is a continuation in part of and incorporates by reference U.S. patent application Ser. No. 12/291,685 (Docket GIPROG 01.01), filed Nov. 12, 2008, entitled “METHOD AND APPARATUS FOR PROGRAMMING OF AUTONOMIC NEUROMODULATION FOR THE TREATMENT OF OBESITY”, which names as inventor Daniel John DiLorenzo, which is incorporated by reference. This application is a continuation in part of and incorporates by reference U.S. patent application Ser. No. 11/716,451 (Docket GISTIM 03.01), entitled METHOD, APPARATUS, SURGICAL TECHNIQUE, AND STIMULATION PARAMETERS FOR AUTONOMIC NEUROMODULATION FOR THE TREATMENT OF OBESITY, filed Mar. 9, 2007, which names as inventor Daniel John DiLorenzo, and which is incorporated by reference, which is a continuation of and claims the benefit of U.S. Provisional Patent Application Ser. No. 60/786,250 Filed Mar. 27, 2006. This application is a continuation in part of and incorporates by reference U.S. patent application Ser. No. 11/317,099 (Docket GISTIM 02.02), filed Dec. 22, 2005, entitled “METHOD, APPARATUS, AND SURGICAL TECHNIQUE FOR AUTONOMIC NEUROMODULATION FOR THE TREATMENT OF OBESITY”, which names as inventor Daniel John DiLorenzo. This application is a continuation in Part of and incorporates by reference U.S. patent application Ser. No. 12/462,903 (Docket GISTIM 01.03), filed Aug. 9, 2009, entitled “Methods and Apparatus for Neuromodulation and Physiologic Modulation for the Treatment of Obesity and Metabolic and Neuropsychiatric Disease”, which is a continuation of U.S. patent application Ser. No. 12/387,638 (Docket GISTIM 01.04), filed May 5, 2009, entitled “Methods and Apparatus for Neuromodulation and Physiologic Modulation for the Treatment of Obesity and Metabolic and Neuropsychiatric Disease”, which is a continuation of U.S. patent application Ser. No. 10/982,549 (Docket GISTIM 01.02), now U.S. Pat. No. 7,529,582, filed Jun. 21, 2004, entitled “Method And Apparatus For Neuromodulation And Physiologic Modulation For The Treatment Of Metabolic And Neuropsychiatric Disease”, which is a continuation of U.S. patent application Ser. No. 10/198,871 (Docket GISTIM 01.01), filed Jul. 19, 2002, now U.S. Pat. No. 7,599,736, entitled “Method and Apparatus for the Neuromodulation and Physiologic Modulation for the Treatment of Metabolic and Neuropsychiatric Disease”, which is a continuation of U.S. Provisional Patent Application No. 60/307,124, filed Jul. 19, 2001, entitled “Physiologic Modulation for the Control of Obesity, Depression, Epilepsy, and Diabetes”, all naming as inventor, Daniel John DiLorenzo. This application is a continuation in Part of and incorporates by reference U.S. patent application Ser. No. 13/290,071 (Docket GISTIM 03.01.DIV06), filed Nov. 5, 2011, naming as inventor Daniel John DiLorenzo. This application is a continuation in Part of and incorporates by reference U.S. patent application Ser. No. 13/290,078 (Docket GISTIM 03.01.DIV10), filed Nov. 5, 2011, naming as inventor Daniel John DiLorenzo. This application is a continuation in Part of and incorporates by reference U.S. patent application Ser. No. 11/901,295 (Docket GISTIM 04.01), filed Sep. 15, 2007, naming as inventor Daniel John DiLorenzo. This application is a continuation in Part of and incorporates by reference U.S. patent application Ser. No. 12/880,146 (Docket GISTIM 05.01), filed Sep. 12, 2010, naming as inventor Daniel John DiLorenzo. This application is a continuation in Part of and incorporates by reference U.S. patent application Ser. No. 12/880,147 (Docket GISTIM 05.91), filed Sep. 12, 2010, naming as inventor Daniel John DiLorenzo. This application is a continuation in Part of and incorporates by reference U.S. patent application Ser. No. 12/291,685 (Docket GIPROG 01.01), filed Nov. 12, 2008, naming as inventor Daniel John DiLorenzo. This application is a continuation in Part of and incorporates by reference U.S. patent application Ser. No. 12/317,448 (Docket GIELEC 01.01), filed Dec. 22, 2008, naming as inventor Daniel John DiLorenzo. This application incorporates by reference U.S. patent application Ser. No. 11/187,315, entitled CLOSED-LOOP SYMPATHETIC NEUROMODULATION FOR OPTIMAL CONTROL OF DISEASE, filed Jul. 23, 2005 and naming as inventor Daniel J. DiLorenzo. This application incorporates by reference U.S. Pat. No. 6,366,813 B1, entitled APPARATUS AND METHOD FOR CLOSED-LOOP INTRACRANIAL STIMULATION FOR OPTIMAL CONTROL OF NEUROLOGICAL DISEASE., filed Jun. 25, 1999, issued Apr. 2, 2002, and naming as inventor Daniel J. DiLorenzo. This application incorporates by reference U.S. Pat. No. 6,819,956 B2, entitled OPTIMAL METHOD AND APPARATUS FOR NEURAL MODULATION FOR THE TREATMENT OF NEUROLOGICAL DISEASE, PARTICULARLY MOVEMENT DISORDERS., filed Nov. 11, 2001, issued Nov. 16, 2004, and naming as inventor Daniel J. DiLorenzo. This application incorporates by reference U.S. Patent Application Number US 2005/0021104 A1, entitled APPARATUS AND METHOD FOR CLOSED-LOOP INTRACRANIAL STIMULATION FOR OPTIMAL CONTROL OF NEUROLOGICAL DISEASE., filed Apr. 5, 2004, and naming as inventor Daniel J. DiLorenzo. This application incorporates by reference all Patent Applications naming as inventor Daniel J. DiLorenzo. This application incorporates by reference all Patents naming as inventor Daniel J. DiLorenzo. This application incorporates by reference all patents and non-patent documents and references cited in the specification and in the information disclosure statements.
