WO2004069331A2 - Neural stimulation - Google Patents

Neural stimulation Download PDF

Info

Publication number
WO2004069331A2
WO2004069331A2 PCT/US2004/002847 US2004002847W WO2004069331A2 WO 2004069331 A2 WO2004069331 A2 WO 2004069331A2 US 2004002847 W US2004002847 W US 2004002847W WO 2004069331 A2 WO2004069331 A2 WO 2004069331A2
Authority
WO
WIPO (PCT)
Prior art keywords
patient
stimulation
blocking
nerve
site
Prior art date
Application number
PCT/US2004/002847
Other languages
French (fr)
Other versions
WO2004069331A3 (en
WO2004069331B1 (en
Inventor
Mark B. Knudson
Timothy R. Conrad
Luke B. Evnin
Richard R. Wilson
Katherine S. Tweden
Original Assignee
Enteromedics Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/358,093 external-priority patent/US20040172084A1/en
Application filed by Enteromedics Inc. filed Critical Enteromedics Inc.
Priority to DK04707122.0T priority Critical patent/DK1601414T3/en
Priority to AT04707122T priority patent/ATE547148T1/en
Priority to EP04707122A priority patent/EP1601414B1/en
Publication of WO2004069331A2 publication Critical patent/WO2004069331A2/en
Publication of WO2004069331A3 publication Critical patent/WO2004069331A3/en
Publication of WO2004069331B1 publication Critical patent/WO2004069331B1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36053Implantable neurostimulators for stimulating central or peripheral nerve system adapted for vagal stimulation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F5/00Orthopaedic methods or devices for non-surgical treatment of bones or joints; Nursing devices; Anti-rape devices
    • A61F5/0003Apparatus for the treatment of obesity; Anti-eating devices
    • A61F5/0013Implantable devices or invasive measures
    • A61F5/0026Anti-eating devices using electrical stimulation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/02Details
    • A61N1/04Electrodes
    • A61N1/05Electrodes for implantation or insertion into the body, e.g. heart electrode
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/321Electromedical belts
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36007Applying electric currents by contact electrodes alternating or intermittent currents for stimulation of urogenital or gastrointestinal organs, e.g. for incontinence control
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36071Pain
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36082Cognitive or psychiatric applications, e.g. dementia or Alzheimer's disease
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/372Arrangements in connection with the implantation of stimulators
    • A61N1/37211Means for communicating with stimulators
    • A61N1/37235Aspects of the external programmer

Definitions

  • This invention pertains to treatments of disorders associated, at least in part, with neural activity. These may include, without limitation, gastrointestinal, pancreo-biliary, cardio-respiratory and central nervous system disorders (including neurological and psychiatric, psychological and panic disorders). More particularly, this invention pertains to treatment of such disorders through management of neural impulse stimulation and blocking.
  • FGIDs Functional Gastrointestinal Disorders
  • FGIDs are a diagnostic grouping having diagnostic criteria based on symptomatology, because the pathophysiology of these diseases is multifactorial with some pathophysiologic mechanisms in common. FGIDs are thought to be due to altered autonomic nervous system balance and to be pathophysiological combinations of: (1) abnormal GI motility; (2) visceral hypersensitivity; and, (3) brain-gut interactions. Tougas, "The Autonomic Nervous System in Functional Bowel Disorders", Gut, Vol. 47 (Suppl IV), pp.
  • the FGIDs of interest to the present invention are functional dyspepsia (dysmotility-like) and irritable bowel syndrome (LBS).
  • Functional dyspepsia (dysmotility-like), is diagnosed when a patient's symptoms, in the absence of other organic disease likely to explain the symptoms, include persistent or recurrent pain or discomfort centered in the upper abdomen that may be accompanied by upper abdominal fullness, early satiety, bloating or nausea.
  • Talley et al. "Rome II: A Multinational Consensus Document on Gastrointestinal Disorders - Functional Gastroduodenal Disorders" Gut, Vol. 45 (Suppl II), pp. 137- 1142 (1999).
  • IBS Irritable Bowel Syndrome
  • the second FGID of interest, IBS is diagnosed when a patient's symptoms include persistent abdominal pain or discomfort, in the absence of other explanatory organic disease, along with at least two of the following: relief of pain with defecation, onset of symptoms associated with a change in frequency of stools and/or onset of symptoms associated with a change in appearance/form of stools! Thompson WG, et al., "Rome II: A Multinational Consensus Document on
  • GI motility abnormalities In addition to colonic dysmotility, a number of other GI motility abnormalities have been identified, including delayed gastric emptying, gastroparesis, and small intestine motility abnormalities. Vassallo MJ, et al.,
  • Kellow JE, et al "Dysmotility of the Small Intestine in irritable Bowel Syndrome", Gut, (1988);29:1236-1243.
  • Evans PR et al, "Jejunal Sensorimotor Dysfunction in Irritable Bowel Syndrome: Clinical and Psychosocial Features", Gastroenterol, (1996);110:393-404.
  • Schmidt T et al, "Ambulatory 24-Hour Jejunal Motility in Diarrhea-Predominant Irritable Bowel Syndrome", J Gastroenterol (1996);31 :581-589.
  • Simren M et al, "Abnormal Propagation Pattern of Duodenal Pressure Waves in the Irritable Bowel Syndrome (IBS)", Dig Pis Sci, (2000);45 :2151 -2161.
  • a recently approved drug to treat selected patients with FGIPs is tegaserod maleate sold under the tradename "Zelnorm ® " by Novartis Pharmaceuticals Corp., East Hanover, New Jersey, USA.
  • the product literature on Zelnorm recognizes the enteric nervous system is a key element in treating IBS.
  • the literature suggests Zelnorm ' acts to enhance basal motor activity and to normalize impaired motility.
  • Novartis product description, Zelnorm ® July 2002 (T2002-19).
  • Zelnorm' s approved use is limited to females with constipation-related IBS. It is for short-term use only.
  • gastroparesis or delayed gastric emptying
  • upper GI symptoms such as nausea, vomiting fullness, bloating and early satiety.
  • Gastroparesis can be caused by many underlying conditions. The most important, because of chronicity and prevalence, are diabetes, idiopathic and post-surgical Hornbuckle K, et al. "The Diagnosis and Work-Up of the Patient with Gastroparesis", J Clin Gastroenterol (2000);30: 117-124.
  • GI dysmotility in the form of delayed gastric emptying is, by definition, present in these patients.
  • the current treatments for gastroparesis are far from satisfactory. They include supportive care, such as dietary modification, prokinetic drugs, and; when required, interventions such as intravenous fluids and placement of a nasogastric tube may be needed.
  • Gastroesophageal Reflux Disease The fourth indication, GERD, can be associated with a wide spectrum of symptoms, including dyspepsia, reflux of gastric contents into the mouth, dysphagia, persistent cough, refractory hyperreactive airway disease and even chronic serous otitis media.
  • Sontag SJ, et al "Asthmatics with Gastroesophageal Reflux: Long Term Results of a Randomized Trial of Medical and Surgical Antireflux Therapies", Am J Gastroenterol (2003);98:987-999.
  • GERD is considered to be a chronic condition for which long-term medical therapy and/or surgical therapy is often deemed necessary, in significant part because esophageal adenocarcinoma is sometimes a consequence of GERD.
  • DeVault KR et al, "Updated Guidelines for the Diagnosis and Treatment of Gastroesophageal Reflux Pisease", Am J Gastroenterol. (1999);94:1434-1442.
  • Lagergren J, et al "Symptomatic Gastroesophageal Reflux as a Risk Factor for Esophageal Adenocarcinoma", New Engl J Med, (1999);340:825-831.
  • TLESRs transient lower esophageal relaxations
  • gastric distention is thought to be associated with an increase in TLESRs.
  • Mittal RK et al, "Mechanism of Disease: The Esophagogastric Junction", New Engl J Med. (1997);336:924-932.
  • Scheffer RC et al, "Elicitation of Transient Lower Oesophageal Sphincter Relaxations in Response to Gastric Distension", Neuro gastroenterol Mo til, (2002);14:647-655.
  • GERD is generally considered to be the result of a motility disorder which permits the abnormal and prolonged exposure of the esophageal lumen to acidic gastric contents.
  • Hunt "The Relationship Between The Control Of pH And healing And Symptom Relief In Gastro-Oesophageal Reflux Disease", Ailment Pharmacol Ther., 9 (Suppl. 1) pp. 3 - 7 (1995).
  • Many factors are believed to contribute to the onset of GERD. These include transient lower esophageal sphincter relaxations (as previously described), decreased LES resting tone, delayed stomach emptying and an ineffective esophageal clearance.
  • H 2 -receptor antagonists which control gastric acid secretion in the basal state
  • proton pump inhibitors which control meal-stimulated acid secretion
  • Surgery treatments are also employed for the treatment of GERD and include techniques for bulking the lower esophageal sphincter such as fundoplication and techniques described in US Pat. No. 6,098,629 Johnson et al, Aug 8, 2000.
  • Other surgical techniques include placement of pacemakers for stimulating muscle contractions in the esophageal sphincter, the stomach muscles or in the pyloric valve.
  • U.S. Pat. No. 6,104,955 to Bourgeois U.S. Pat. No. 5,861,014 to Familoni.
  • a summary of GERD treatments can be found in DeVault, et al, "Updated Guidelines for the Diagnosis and Treatment of Gastroesophageal Reflux Disease", Amer. J.
  • dysmotility is described as hyper- or hypo-contractility.
  • dysmotility is a broader concept to refer to all abnormalities of gastric emptying or bowel transfer regardless of cause.
  • U.S. Pat. No. 6,610,713 to Tracey dated August 26, 2003 describes inhibiting release of a proinflammatory cytokine by treating a cell with a cholinergic agonist by stimulating efferent vagus nerve activity to inhibit the inflammatory cytokine cascade.
  • a substantial body of literature is developed on nerve stimulation. For example, in Dapoigny et al, "Vagal influence on colonic motor activity in conscious nonhuman primates", Am. J.
  • vagal influence on colonic motor activity was investigated in conscious monkeys.
  • vagal cooling was implanted distal to the vagal block.
  • vagal stimulation electrode was implanted distal to the vagal block. It was noted that vagal efferent stimulation increased contractile frequency and that the vagus has either a direct or indirect influence on fasting and fed colonic motor activity throughout the colon, and that a non-adrenergic, noncholinergic inhibitory pathway is under vagal control.
  • Colonic and gastric stimulation are also described in a number of articles associated with M. P. Mintchev.
  • Mintchev, et al "Electrogastrographic impact of multi-site functional gastric electrical stimulation", J. of Medical Eng. & Tech.. Vol. 23, No. 1 pp. 5 - 9 (1999); Rashev, et al, "Three- dimensional static parametric modeling of phasic colonic contractions for the purpose of microprocessor-controlled functional stimulation", J. of Medical Eng. & Tech.. Vol. 25, No. 3 pp. 85 - 96 (2001); Lin et al, "Hardware - software co-design of portable functional gastrointestinal stimulator system", J. of Medical Eng. & Tech., Vol. 27, No. 4 pp.
  • the present invention utilizes vagal stimulation to improve vagal tone (similar in concept to improving cardiac electrical tone through cardiac pacing) and/or to treat GI disorders by altering the nature of duodenum contents by stimulation pancreatic and biliary output.
  • the invention is also applicable to treating other diseases such as neuropsychiatric disorders.
  • Vagal tone has been shown to be associated with dyspepsia. Hjelland, et al, "Vagal tone and meal-induced abdominal symptoms in healthy subjects", Digestion, 65: 172 - 176 (2002). f Also, Hausken, et al, "Low Vagal Tone and Antral
  • the present invention includes, in several embodiments, a blocking of a nerve (such as the vagal nerve) to avoid antidromic influences during stimulation.
  • Cryogenic nerve blocking of the vagus is described in Dapoigny et al, "Vagal influence on colonic motor activity in conscious nonhuman primates", Am. J. Physiol, 262: G231 - G236 (1992). Electrically induced nerve blocking is described in Van Den Honert, et al, “Generation of Unidirectionally Propagated Action Potentials in a Peripheral Nerve by Brief Stimuli", Science, Vol. 206, pp. 1311 - 1312.
  • a method and apparatus for treating at least one of a plurality of gastrointestinal disorders of a patient characterized at least in part by an altered autonomic balance or altered motility.
  • the method includes electrically stimulating an enteric nervous system of the patient to enhance a functional tone of the enteric nervous system.
  • Enteric rhythm management treats GI diseases in which dysmotility is thought to play a major role.
  • This therapy is based on the physiological actions of pancreatic exocrine secretion and bile on the composition (osmolality and pH) and the digestion (enzymatic activity and, in the case of fats, emulsification) of intraduodenal chyme, thereby presenting a novel approach to regulating the motility of the GI tract and, in particular, gastric emptying and the digestion and propulsion of chyme through the duodenum and into the jejunum and ileum.
  • ERM as a therapy for GI diseases involving dysmotility is based on the following: (1) pacing the delivery of pancreatic exocrine secretion and bile can be used to either up- or down-regulate at least two aspects of GI motility - gastric emptying and small bowel transit - by modulating the osmolality, the pH and the digestion, including emulsification as needed, of intra-duodenal chyme; (2) pacing the efferent activity of the intra-abdominal vagus nerve as needed while blocking afferent activity of that same nerve as needed can be used to treat GI dysmotility in patients with either increased or decreased vagal tone as a component of their disease; and, (3) treating GI dysmotility disorders can and often does require flexibility in adjusting treatment algorithms based on symptomatic response because of inter-patient differences with a diagnostic group and because of intra-patient variability over time.
  • enteric rhythm management in gastroparesis are: 1) to regulate the composition and digestion of duodenal chyme and, by so doing, to facilitate gastric emptying through the modulatory effect of duodenal chemo- and mechanoreceptors on the pylorus and 2) to up-regulate or down-regulate vagal tone to optimize gastricintestinal motility and symptom relief.
  • ERM utilizing a physiologic enteric pacing device will, as described earlier, allow pacing of the delivery of pancreatic exocrine secretion and bile, thereby initiating pyloric relaxation, gastric emptying and consequent reduction in gastric distention, leading to a decrease in the underlying mechanism of GERD, that is, TLESRs.
  • Kellow JE, et al "Rome II: A Multinational Consensus Document on Gastrointestinal Disorders - Principles of Applied Neurogastroenterology: Physiology/Motility-Sensation", Gut, (1999);45(Suppl II): II 17-1124.
  • Paterson CA, et al "Determinants of Occurrence and Volume of Transpyloric Flow During Gastric Emptying of Liquids in Dogs: Importance of Vagal Input", Dig Pis Sci, (2000);45:1509-1516. Tougas G, "The Autonomic Nervous System in Functional Bowel Disorders", Gut, (2000);47(Suppl IV):iv78-iv80.
  • ERM involves pacing and thereby regulating the timing and the volume of pancreatic exocrine secretion and bile delivered to the intraluminal contents of the duodenum. In one embodiment, this is accomplished with a small, laparoscopically implantable and programmable medical device called a physiologic enteric pacing device. Three leads are positioned intra-abdominally and then connected to a subcutaneous, programmable pulse generator. A pacing lead may be placed on the anterior vagal trunk and another pacing lead may be placed on the posterior vagal trunk. One or more intra-abdominal electrode, i.e. blocking electrodes, may be placed on the vagus nerve proximal to the pacing leads.
  • intra-abdominal electrode i.e. blocking electrodes
  • An additional embodiment of the present invention pertains to treating at least one of a plurality of gastrointestinal disorders of a patient by electrically stimulating a vagus nerve of the patient at a stimulation site proximal to at least one site of vagal innervation of a gastrointestinal organ.
  • the electrical stimulation includes applying a stimulation signal at the stimulation site.
  • a proximal electrical blocking signal is applied to the vagus nerve at a proximal blocking site proximal to the stimulation site.
  • the proximal blocking signal is selected to at least partially block nerve impulses proximal to the proximal blocking site.
  • the invention further includes a treatment apparatus having a stimulation electrode adapted for placement on a nerve of a patient at a stimulation site and a stimulation signal generator for generating a stimulation signal at the stimulation electrode and selected to electrically stimulate a nerve to induce bi-directional propagation of nervous impulses in a stimulated nerve.
  • the apparatus includes a blocking member for placement on the nerve at a blocking site and creating localized conditions at the blocking site that at least partially diminish transmission of nerve impulses past the blocking site.
  • a still further embodiment of the present invention includes a method for treating at least one of a plurality of disorders of a patient where the disorders are associated with a gastrointestinal tract of a patient where the disorders are characterized at least in part by hyper-tonal vagal activity innervating at least one of a plurality of alimentary tract organs of the patient at an innervation site.
  • the method includes applying a neural conduction block to a vagus nerve of the patient at a blocking site proximal to the innervation site.
  • the neural conduction block is selected to at least partially block nerve impulses on the vagus nerve distal to the blocking site.
  • a yet further embodiment pertains to a treatment apparatus having an electrically controllable neural conduction electrode adapted to be placed on a vagus nerve of a patient at a blocking site proximal to an innervation site.
  • a blocking signal generator generates a blocking signal selected to at least partially block nerve impulses on the vagus nerve distal to the blocking site.
  • a still additional embodiment of the present invention includes a method for treating at least one of a plurality of disorders of a patient by electrically stimulating a vagus nerve at a stimulation site with a stimulation signal selected to have a therapeutic effect on a target organ.
  • An electrical blocking signal is applied to the vagus nerve at a blocking site on a side of said stimulation site opposite the target organ.
  • the blocking signal is selected to at least partially block nerve impulses to a second organ on a side of said blocking site opposite the stimulation site.
  • the target organ may be gastrointestinal or central nervous with the other organ being cardio-respiratory.
  • FIG. 1 is a schematic representation of a gastric-emptying feedback loop with a patient-controlled stimulator for stimulating an organ of the loop;
  • Fig. 2 is a view similar to Fig. 1 with an automatic controller replacing the patient-controller of Fig. 1 and with feedback circuits to the automatic controller schematically represented;
  • Fig. 3 is a schematic illustration of an alimentary tract (GI tract plus non-GI organs such as the pancreas and liver) and its relation to vagal and enteric innervation;
  • Fig. 4 is the view of Fig. 3 showing the application of a pacing electrode according to an embodiment of the present invention;
  • Fig. 5 is a schematic representation of pacing system
  • Fig. 6 is the view of Fig. 4 showing the application of a nerve conduction block electrode proximal to the pacing electrode
  • Fig. 7 is the view of Fig. 6 showing the application of a nerve conduction block electrode distal to the pacing electrode
  • Fig. 8 is the view of Fig. 3 showing the application of a nerve conduction block electrode according to an embodiment of the present invention.
  • a gastric emptying feedback loop is shown schematically for ease of illustration.
  • the feedback loop illustrates a patient's stomach S which is provided with food from the esophagus E.
  • a lower esophageal sphincter LES is shown positioned between the esophagus E and the stomach S.
  • the lower esophageal sphincter normally provides control of reflux of stomach contents into the esophagus E.
  • the stomach discharges into the superior duodenum D which is an upper portion of the intestines.
  • the superior duodenum D and the stomach S are separated by a pyloric valve PV which opens to permit gastric emptying from the stomach into the duodenum D.
  • FIG. 1 Also schematically illustrated in Fig. 1 are nerve paths N providing signal flow paths from both the superior duodenum D and the stomach S to the brain B.
  • An efferent Vagal nerve VN connects the brain B to the pancreas P of the patient.
  • a conduit pancreatic duct PD extends from the pancreas P and discharges into the superior duodenum D.
  • the presence of food contents within the duodenum D may prevent passage of gastric content of the stomach S past the pyloric valve PV into the duodenum D.
  • contents can be forced retrograde past the lower esophageal sphincter LES and into the esophagus E creating the symptoms and discomfort of GERD.
  • the contents discharging from the stomach S into the duodenum D are acidic (and high osmolality) and reside in the duodenum D until pH is elevated (close to a neutral pH of 6 - 7) and osmolality is normalized.
  • the elevation of pH and reduction of osmolality of chyme in the duodenum D results from exocrine secretion being administered from the pancreas P and from bile from the liver into the duodenum D. This raises the pH and lowers the osmolality of the duodenum D content permitting discharge from the duodenum D and thereby permitting gastric emptying across the pyloric valve PV.
  • gastroesophageal reflux disease results from a derangement of the feedback loops involved in upper GI digestion and motility control.
  • This problem encompasses receptors and reflexes that regulate the propulsive contractions of the stomach, upper duodenum and biliary tree and the secretions of the exocrine pancreas.
  • the interaction of these receptors and reflexes control gastric emptying (by coordinating gastric propulsive contractions and sphincter [primarily pyloric] tone) and regulate the pH and osmolality of the chyme in the duodenum.
  • ingestate delivered to the stomach is mixed by low intensity gastric mixing contractions with the enzymatic, ionic, including hydrogen ion (H + ), and water secretions of the glands of the stomach.
  • H + hydrogen ion
  • the fluid now called chyme
  • This material is at a very low pH (about 2) and high osmolality, which activates receptors, including those for H + and osmotic pressure, which are abundant in the wall of the ampulla.
  • This receptor activation initiates the series of reflexes that cause pancreatic exocrine secretion to be delivered into the superior duodenum and ampulla.
  • This fluid contains digestive enzymes, water and buffering compounds to raise the pH, and reduce the osmolality, of the chyme.
  • control system If the control system is down regulated by, for example, by increased pH of gastric contents entering the ampulla, feedback may thereby be reduced from the H + receptors in the duodenum that stimulate pancreatic exocrine secretion and bile delivery to the duodenum, then movement of chyme from the superior duodenum is delayed, causing delay of gastric emptying.
  • Mabayo, et al "Inhibition of Food Passage by Osmeprazole in the Chicken", European J. of Pharmacology, pp. 161 - 165 (1995).
  • the drugs used to treat this disease raise pH further dampening the hydrogen-receptor-pancreatic secretion loop, further delaying gastric emptying.
  • Benini "Gastric Emptying and Pyspeptic Symptoms in Patients with Gastroesophageal Reflux", Amer. J. of Gastroenterology, pp. 1351 - 1354 (1996).
  • the present invention is directed towards reestablishing the link between gastric emptying and pancreatic secretion delivery, thereby addressing the main pathology of this disease by shortening chyme residence time in the superior duodenum so that intestinal contents move into the distal digestive tract in a more normal manner.
  • this is done by stimulating the H+ ion receptors or by stimulation of the pancreas directly or via its para-sympathetic innervation (pre-ganglionic Vagal nerves).
  • Stimulation of pancreatic exocrine secretion has been shown by direct stimulation of the thoracic vagus nerves in dogs. Kaminski et al, "The Effect of Electrical Vagal Stimulation on Canine Pancreatic Exocrine Function", Surgery, pp. 545 - 552 (1975). This results in a more rapid (normal) neutralization of chyme in the ampulla, allowing it move down the duodenum more quickly so that gastric emptying is returned to a more normal pace.
  • Acidity can be assessed by measuring bicarbonate. It will be understood that references to -H includes such indirect measurements. Also, effects of the therapy described herein can be assessed and/or controlled by measuring an indication of pancreatic exocrine secretion or bile (e.g., HCO 3 " ).
  • An alternative embodiment uses gastrocopic delivery of a paralyzing agent (e.g. botulism toxin) to the pyloric valve along with use of H2 antagonists or PPI's to manage the acidity of the chyme reaching the duodenum.
  • a paralyzing agent e.g. botulism toxin
  • the gall bladder can be stimulated to encourage bile movement into the duodenum. Shown schematically in the figures, the gall bladder GB resides below the liver L. The gall bladder is connected to the small intestine (specifically the duodenum P) via a bile duct BP. The bile duct BP can discharge directly into the duodenum P or via the pancreatic duct PP as shown.
  • the bile can normalize the chyme to accelerate duodenal emptying.
  • Bile consists of bile acids (detergents that emulsify lipids), cholesterol, phospholipids, electrolytes such as (Na + , K + , Ca +2 , CF, HCO 3 " ) and H 2 0. Chapter 4, "The Liver and Biliary Tract", Gastrointestinal System, 2 nd Ed., M.S. Long editor, Mosby Publisher, London (2002).
  • the gall bladder GB or bile duct can be stimulated indirectly via stimulation of the vagal nerve VN or directly stimulated by an electrode 11 (shown in phantom lines).
  • an electrical stimulator 10, 20 which may be implanted is provided which alternatively may be directly connected to the Vagal nerve VN or the pancreas P to stimulate the pancreas directly or indirectly to excrete exocrine into the duodenum P (or more distally into the small intestine - e.g., into the jejunum) and increase the pH of chyme in the duodenum P as described. Alternatively, the same can be done to promote bile release. The frequency may be varied to maximize the response and selectively stimulate exocrine instead of endocrine secretions.
  • the patient may activate the stimulator 10 by remote transmitter to stimulate an electrical charge either after eating (e.g., about 60 to 90 minutes after eating) or on onset of GERD symptoms.
  • the stimulator 10 may activate the stimulator 10 by remote transmitter to stimulate an electrical charge either after eating (e.g., about 60 to 90 minutes after eating) or on onset of GERD symptoms.
  • Fig. 2 illustrates an additional embodiment where the patient activated loop is replaced with an automatic loop having a programmable stimulator 20 which receives as an input signals from sensors in the duodenum to measure pH, osmolality or strain (e.g., from baro-sensors) on the duodenum indicating filling or may measure acidity in the esophagus or strain on the lower esophageal sphincter LES or stomach S all of which may be provided to the implantable controller 20 which can be provided with desirable software to process the incoming signals and generate a stimulating signal to either the vagal nerve, the pancreas P or the duodenum P (or jejunum) directly in response to such received signals.
  • a programmable stimulator 20 which receives as an input signals from sensors in the duodenum to measure pH, osmolality or strain (e.g., from baro-sensors) on the duodenum indicating filling or may measure acidity in the esophagus or strain on the
  • U.S. Pat. No. 5,540,730 teaches a neuro stimulator to stimulate a vagus nerve to treat a motility disorder.
  • U.S. Pat. No. 5,292,344 teaches gastrointestinal sensors, including pH sensors.
  • the foregoing invention is applicable to treatment of a plurality of GI diseases associated with delayed gastric emptying or altered autonomic activity. These include functional gastrointestinal disorders and gastroparesis. Furthermore, applicants have determined that duodenal content impacts a plurality of motility disorders throughout the bowels and can diseases associated with dysmotility (e.g., irritable bowel syndrome). Accordingly it is an object of the present invention to use the teachings of the aforementioned parent application to treat GI disorders associated with delayed gastric emptying and abnormal intestinal transport.
  • Fig. 3 is a schematic illustration of an alimentary tract (GI tract plus non-GI organs such as the pancreas and ball bladder, collectively labeled PG) and its relation to vagal and enteric innervation.
  • the lower esophageal sphincter (LES) acts as a gate to pass food into the stomach S and, assuming adequate function of all components, prevent reflux.
  • the pylorus PV controls passage of chyme from the stomach S into the intestines I (collectively shown in the figures and including the large intestine or colon and the small intestine including the duodenum, jejunum and ileum).
  • the biochemistry of the contents of the intestines I is influenced by the pancreas P and gall bladder PG which discharge into the duodenum. This discharge is illustrated by dotted arrow A.
  • the vagus nerve VN transmits signals to the stomach S, pylorus PV, pancreas and gall bladder PG directly. Originating in the brain, there is a common vagus nerve VN in the region of the diaphragm (not shown). In the region of the diaphragm, the vagus VN separates into anterior and posterior components with both acting to innervate the GI tract. In Figs. 3, 5 - 8, the anterior and posterior vagus nerves are not shown separately. Instead, the vagus nerve VN is shown schematically to include both anterior and posterior nerves. The vagus nerve VN contains both afferent and efferent components sending signals away from and to, respectively, its innervated organs.
  • the enteric nervous system ENS is an interconnected network of nerves, receptors and actuators throughout the GI tract. There are many millions of nerve endings of the enteric nervous system ENS in the tissues of the GI organs. For ease of illustration, the enteric nervous system ENS is illustrated as a line enveloping the organs innervated by the enteric nervous system ENS
  • vagus nerve VN innervates, at least in part, the enteric nervous system ENS (schematically illustrated by vagal trunk VN3 which represents many vagus- ENS innervation throughout the cut).
  • receptors in the intestines I connect to the enteric nervous system ENS.
  • Arrow B in the figures illustrates the influence of duodenal contents on the enteric nervous system ENS as a feedback to the secretion function of the pancreas, liver and gall bladder.
  • receptors in the intestine I respond the biochemistry of the intestine contents (which are chemically modulated by the pancreao-biliary output of Arrow A). This biochemistry includes pH and osmolality.
  • vagal trunks VN1 , VN2, VN4 and VN6 illustrate schematically the direct vagal innervation of the GI organs of the LES, stomach S, pylorus PV and intestines I.
  • Trunk VN3 illustrates direct communication between the vagus VN and the ENS.
  • Trunk VN5 illustrates direct vagal innervation of the pancreas and gall bladder.
  • Enteric nerves ENS1 - ENS4 represent the multitude of enteric nerves in the stomach S, pylorus PV, pancreas and gall bladder PG and intestines I.
  • the enteric nervous system ENS can act independently of the vagus and the central nervous system. For example, in patients with a severed vagus nerve (vagotomy - an historical procedure for treating ulcers), the enteric nervous system can operate the gut. Most enteric nerve cells are not directly innervated by the vagus. Gershon, "The Second Brain", Harper Collins Publishers, Inc, New York, NY p. 19 (1998)
  • FIG. 3 the vagus VN and its trunks (illustrated as VN1 - VN6) and the enteric nervous system ENS are shown in phantom lines to illustrate reduced vagal and enteric nerve tone (i.e., sub-optimal nerve transmission levels).
  • Reduced vagal and enteric tone contribute directly to the ineffectiveness of the GI organs as well as indirectly (through reduced pancreatic/biliary output).
  • the reduced pancreatic/biliary output is illustrated by the dotted presentation of arrow A.
  • the vagus can be stimulated to stimulate pancreatic or biliary output. Therefore, the reduced output of arrow A results in a reduced feedback illustrated by the dotted presentation of arrow B.
  • a stimulating or pacing electrode PE is applied to the vagus VN. While only one electrode is shown in Fig. 4, separate electrodes could be applied to both the anterior and posterior vagus nerves (or to the common vagus or vagal branches), hi a preferred embodiment, the electrode PE is placed a few centimeters below the diaphragm and proximal to stomach and pancreo/biliary innervation. While this placement is presently preferred for ease of surgical access, other placement locations may be used.
  • vagal tone is optimized by either up- or down-regulation.
  • tone refers to basal activity of a nerve or nervous system facilitating appropriate physiologic response to a patient's internal environment.
  • low vagal tone implies a reduction in vagus nerve activity resulting in decreased response of the alimentary tract to ingested food.
  • pacing is not limited to mean timed events coordinated with specifically timed physiologic events. Instead, pacing means any electrical stimulation of a nerve trunk to induce bi-directional propagation of nervous impulses in the stimulated nerve. The operating effectiveness of the vagus is enhanced so that local physiological signals generated in the enteric nervous system (or sent to the brain from the organs) are more appropriately responded to within the alimentary tract.
  • pacing of the vagus enhances the functional tone of the enteric nervous system.
  • the stimulation pacing is elevating the degree of functionality of the vagus and enteric nerves.
  • pacing is not meant to mean timed pulsed coordinated with muscular contractions or synchronized with other invents. Pacing means elevating the activity level of the nerves.
  • Tonal enhancement of the vagus and enteric nerves is illustrated by the solid lines for the nerves VN, ENS in Fig. 4.
  • Vagal trunk VN5 is in solid line to illustrate enhanced tone of the many vagal nerve components communicating with the enteric nervous system ENS.
  • Pirect vagal innervation of the LES, stomach S, pylorus PV and intestines I remains shown as low tone indicated by phantom lines VN1, VN2, VN4, VN6.
  • the tonal pacing described herein is not intended to trigger or drive the muscular contractility of these organs.
  • the stimulation is not intended to be timed to trigger contractility and is not provided with an energy level sufficient to drive peristaltic contractions. Instead, these functions remain controlled by the central and enteric nerves systems.
  • the enhanced nerve tone provided by the present invention permits these functions to occur.
  • Pacing to enhance vagal tone is not initiated in response to any senses event (or in anticipation of an immediate need to GI activity). Instead, the pacing can be done intermittently over the day to provide an enhanced level of operating functionality to the vagus.
  • the stimulation pacing can be done during awake hours. For example, every ten minutes, pacing signals can be sent to the pacing electrodes.
  • the pacing signals have a duration of 30 seconds with a current of 4mA, a frequency of 12 Hz and an impulse duration of 2 msec. These parameters are representative only. A wide range of signal parameters may be used to stimulate the vagus nerve. Examples of these are recited in the afore-referenced literature
  • the present invention permits ERM to be uniquely designed and modified by an attending physician to meet the specific needs of individual patients.
  • pacing can be limited to discrete intervals in the morning, afternoon and evening with the patient free to coordinate meals around these events.
  • the pacing also enhances the pancreatic and biliary output for the reasons discussed above. Namely, while ERM does not drive muscular events over nerve trunks VN1, VN2, VN4, VN6, the enhanced tone stimulates pancreo-biliary output over trunk VN5 (illustrated by the solid line of VN5 in Fig. 4). This enhanced output is illustrated as solid arrow A' in Fig. 4. As a consequence there is a greater feedback to the intestinal receptors as illustrated by solid arrow B' in Fig. 4. This enhanced biochemistry feedback further enhances the tone of the enteric nervous system ENS.
  • a representative pacing circuit 100 is schematically shown in Fig. 5. Similar to cardiac pacing devices, an implantable controller 102 contains an induction coil 104 for inductive electrical coupling to a coil 106 of an external controller 108.
  • the implantable controller 102 includes anterior and posterior pulse generators 110, 112 electrically connected through conductors 114, 116 to anterior and posterior pacing electrodes 118, 120 for attachment to anterior and posterior trunks, respectively, of the vagus nerve VN.
  • the implantable controller 102 also includes a battery 122 and a CPU 124 which includes program storage and memory.
  • the timing and parameters of the pulse at the electrodes 118, 120 can be adjusted by inductively coupling the external controller 108 to the implantable controller 102 and inputting pacing parameters (e.g., pulse width, frequency and amplitude). While a fully implantable controller 102 is desirable, it is not necessary.
  • the electrodes 118, 120 can be implanted connected to a receiving antenna placed near the body surface.
  • the control circuits i.e., the elements 124, 110, 112 and 108) can be housed in an external pack worn by the patient with a transmitting antenna held in place on the skin over the area of the implanted receiving antenna.
  • Such a design is forward-compatible in that the implanted electrodes can be later substituted with the implantable controller 102 at a later surgery if desired.
  • the controller 102 can also include circuits generating nerve conduction block signals (as will be described) which connect to electrodes which may be positioned on a nerve proximally, distally (or both) of the electrodes 118, 120.
  • Fig. 6 shows an alternative embodiment using a nerve conduction blocking electrode PBE proximal to the pacing electrode for providing a conduction block.
  • a nerve block is, functionally speaking, a reversible vagotomy. Namely, application of the block at least partially prevents nerve transmission across the site of the block. Removal of the block restores normal nerve activity at the site.
  • a block is any localized imposition of conditions that at least partially diminish transmission of impulses.
  • the vagal block may be desirable in some patients since unblocked pacing may result in afferent vagal and antidromic efferent signals having undesired effect on organs innervated by the vagus proximal to the GI tract (e.g., undesirable cardiac response). Further, the afferent signals of the pacing electrode PE can result in a central nervous system response that tends to offset the benefits of the pacing electrode on the ENS and pancreo/biliary function, thereby reducing the GI and enteric rhythm management effectiveness of vagal pacing.
  • the block may be intermittent and applied only when the vagus is paced by the pacing electrode PE.
  • the preferred nerve conduction block is an electronic block created by a signal at the vagus by an electrode PBE controlled by the implantable controller (such as controller 102 or an external controller).
  • the nerve conduction block can be any reversible block.
  • cryogenics either chemically or electronically induced
  • An electronic cryogenic block may be a Peltier solid-state device which cools in response to a current and may be electrically controlled to regulate cooling. Prug blocks may include a pump-controlled subcutaneous drug delivery.
  • the block parameters can be altered by a controller and can be coordinated with the pacing signals to block only during pacing.
  • a representative blocking signal is a 500Hz signal with other parameters (e.g., timing and current) matched to be the same as the pacing signal. While an alternating current blocking signal is described, a direct current (e.g., -70mV PC) could be used.
  • a direct current e.g., -70mV PC
  • the nerve conduction block is preferably within the parameters disclosed in Solomonow, et al, "Control of Muscle Contractile Force through Indirect High-Frequency Stimulation", Am. J. of Physical Medicine. Vol. 62, No. 2, pp. 71 - 82 (1983).
  • the nerve conduction block is applied with electrical signal selected to block the entire cross-section of the nerve (e.g., both afferent, efferent, myelinated and nonmyelinated fibers) at the site of applying the blocking signal (as opposed to selected sub-groups of nerve fibers or just efferent and not afferent or visa versa) and, more preferably, has a frequency selected to exceed the 200 Hz threshold frequency described in Solomonow et al.
  • preferred parameters are a frequency of 500 Hz (with other parameters, as non-limiting examples , being amplitude of 4 mA, pulse width of 0.5 msec, and duty cycle of 5 minutes on and 10 minutes off).
  • the present invention gives a physician great latitude in selected pacing and blocking parameters for individual patients.
  • vagus VN and enteric nervous system ENS in Fig. 6 distal to the block PBE are shown in solid lines to illustrate enhanced tone (except for the direct innervation VN1, VN2, VN4, VN6 to the GI tract organs).
  • arrows A', B' are shown in solid lines to illustrate the enhanced pancreo-biliary output and resultant enhanced feedback stimulation to the enteric nervous system ENS.
  • the proximal vagus nerve segment VNP proximal to the block PBE is shown in phantom lines to illustrate it is not stimulated by the pacing electrode PE while the blocking electrode PBE is activated.
  • Fig. 7 illustrates the addition over Fig. 6 of a nerve conductive block PBE distal to the pacing electrode PE.
  • the proximal block PBE prevents adverse events resulting from afferent signals and heightens the GI effectiveness by blocking antidromic interference as discussed with reference to Fig. 6.
  • the distal block PBE is provided in the event there is a desire to isolate the pacing effect of electrode PE. For example, a physician may which to enhance the vagus and enteric activity in the region proximal to the duodenum but may wish to avoid stimulating pancreo-biliary output.
  • a patient may have a GI problem without apparent colon dysfunction (e.g., gastroparesis functional dyspepsia without bowel symptoms).
  • Placing the distal block PBE on a branch of the vagus between the pacing electrode PE and the pancreas and gall bladder PG prevents increased pancreo-biliary output and resultant feedback (illustrated by dotted arrows A and B in Fig. 7 and dotted distal vagal nerve segment VNP and vagal trunk VN5).
  • Fig. 8 illustrates an alternative embodiment of the invention.
  • the vagus nerve may be hyperactive contributing to diarrhea-dominant IBS.
  • Use of a blocking electrode alone in the vagus permits down-regulating the vagus nerve VN, the enteric nervous system ENS and pancreo- biliary output. The block down-regulates efferent signal transmission.
  • the hyperactive vagus is illustrated by the solid line of the proximal vagus nerve segment VNP.
  • the remainder of the vagus and enteric nervous system are shown in reduced thickness to illustrate down-regulation of tone.
  • the pancreo-biliary output (and resulting feedback) is also reduced.
  • the blocking electrode BE is shown high on the vagus relative to the GI tract innervation (e.g., just below the diaphragm), the sole blocking electrode could be placed lower (e.g., just proximal to pancreo/biliary innervation VN5). Blocking of the entire vagus as described above can be used to down-regulate the vagus for various benefits including: pancreatitis and obesity treatments. Further, blocking the vagus interrupts the vagally-mediated neurogenic inflammatory arc.
  • the present invention can electrically simulate the effects of PPY by using the vagal block to down-regulate afferent vagal activity to create a desired sensation of satiety. Since the down-regulation does not require continuous blocking signals, the beneficial efferent signals are permitted.
  • vagal pacing or stimulation to treat a wide variety of diseases.
  • U.S. Pat. No. 5,188,104 dated February 23, 1993 describes vagal stimulation to treat eating disorders.
  • U.S. Pat. No. 5,231,988 dated August 3, 1993 describes vagal stimulation to treat endocrine disorders.
  • U.S. Pat. No. 5,215,086 dated June 1, 1993 describes vagal stimulation to treat migraines.
  • U.S. Pat. No. 5,269,303 dated Pecember 14, 1993 describes vagal stimulation to treat dementia.
  • U.S. Pat. No. 5,330,515 dated July 19, 1994 describes vagal stimulation to treat pain.
  • pacing a vagus nerve in the thoracic cavity or neck combined with a blocking electrode on the vagus nerve distal to the pacing electrode can be used to treat neuropsychiatric disorders (such as depression and schizophrenia) and Parkinson's and epilepsy and dementia.
  • the blocking electrode is placed distal to the stimulating electrode 25 shown in Figs. 4 and 2, respectively, of each of U.S. Pat. Nos. 5,269,303 and 5,299,569.
  • the present invention thereby enables the teachings of the afore-referenced patents listed in foregoing two paragraphs.
  • the parameters of the stimulating and blocking electrodes can be inputted via a controller and, thereby, modified by a physician.
  • Fig. 2 illustrates a feedback for controlling a stimulating electrode. Feedbacks for stimulating electrodes are also described in the patents.
  • the blocking electrode can also be controlled by an implanted controller and feedback system. For example, physiologic parameters (e.g., heart rate, blood pressure, etc.) can be monitored.
  • the blocking signal can be regulated by the controller to maintain measured parameters in a desired range. For example, blocking can be increased to maintain heart rate within a desired rate range during stimulation pacing.
  • proximal and distal blocking electrodes in combination with one or more pacing electrode permits a physician to alter an operating permutation of the electrodes. This permits regional and local up- or down-regulation of the nervous system and organs. Further, pacing parameters (duty cycle, current, frequency, pulse length) can all be adjusted. Therefore, the treating physician has numerous options to alter a treatment to meet the needs of a specific patient.
  • a physician can combine the present invention with other therapies (such as drug therapies like prokinetic agents).

Abstract

A plurality of disorders are treated by neural stimulation with optional neural blocking. These include gastrointestinal disorders as well as neuropsychiatric and cardio-respiratory disorders. The apparatus includes stimulating and blocking electrodes. Stimulating electrodes proving a stimulation signal on a nerve. Blocking electrodes at least partially block nerve impulses at a blocking site.

Description

NEURAL STIMULATION TREATMENT
This application is being filed on 30 January 2004, as a PCT International Patent application in the name of EnteroMedics Inc-, a U.S., national corporation, applicant for the designation of all countries except the US, and Mark B. Knudson, Timothy R. Conrad, Luke B. Evnin, Richard R. Wilson, and Katherine S. Tweden, all US citizens, applicants for the designation of the US only.
BACKGROUND OF THE INVENTION 1. Field of the Invention
This invention pertains to treatments of disorders associated, at least in part, with neural activity. These may include, without limitation, gastrointestinal, pancreo-biliary, cardio-respiratory and central nervous system disorders (including neurological and psychiatric, psychological and panic disorders). More particularly, this invention pertains to treatment of such disorders through management of neural impulse stimulation and blocking.
2. Description of the Prior Art
A. Functional Gastrointestinal Disorders (FGIDs) Functional Gastrointestinal Disorders (FGIDs) are a diagnostic grouping having diagnostic criteria based on symptomatology, because the pathophysiology of these diseases is multifactorial with some pathophysiologic mechanisms in common. FGIDs are thought to be due to altered autonomic nervous system balance and to be pathophysiological combinations of: (1) abnormal GI motility; (2) visceral hypersensitivity; and, (3) brain-gut interactions. Tougas, "The Autonomic Nervous System in Functional Bowel Disorders", Gut, Vol. 47 (Suppl IV), pp. iv78-iv80 (2000) and Drossman, "Rome II: A Multinational Consensus Document on Gastrointestinal Disorders - The Functional Gastrointestinal Disorders and the Rome π Process", Gut, Vol. 45 (Suppl II):II1-II5 (1999). The FGIDs of interest to the present invention are functional dyspepsia (dysmotility-like) and irritable bowel syndrome (LBS).
1. Functional Dyspepsia (Dysmotility-Like)
Functional dyspepsia (dysmotility-like), is diagnosed when a patient's symptoms, in the absence of other organic disease likely to explain the symptoms, include persistent or recurrent pain or discomfort centered in the upper abdomen that may be accompanied by upper abdominal fullness, early satiety, bloating or nausea. Talley et al., "Rome II: A Multinational Consensus Document on Gastrointestinal Disorders - Functional Gastroduodenal Disorders" Gut, Vol. 45 (Suppl II), pp. 137- 1142 (1999).
A spectrum of dysmotilities has been documented in patients with functional dyspepsia. These include delayed gastric emptying of solids and liquids, reduced vagal tone, gastric dysrhythmias and impaired gastric accommodation. Furthermore, some studies have found good correlation between symptoms and indices of dysmotility, while others have not. Stanghellini V, et al., "Delayed Gastric Emptying of Solids in Patients with Functional Dyspepsia", Gastroenterol , (1996) 110:1036-1042. Undeland KA, et al, "Wide Gastric Antrum and Low Vagal Tone in Patients with Diabetes Mellitus Type 1 Compared to Patients with Functional Dyspepsia and Healthy Individuals", Dig Pis Sci, (1996) 41:9-16. Tack J, et al, "Role of Impaired Gastric Accommodation to a Meal in Functional Dyspepsia", Gastroenterol (1998) 115:1346-1352. Wilmer A, et al., "Ambulatory Gastrojejunal Manometry in Severe Motility-like Dyspepsia: Lack of Correlation between Dysmotility, Symptoms and Gastric Emptying", Gut, (1998) 42:235-242. Tack J, et al, "Symptom Pattern and Gastric Emptying Rate Assessed by the Octanoic Acid Breath Test in Functional Dyspepsia" [abstract]. Gastroenterol, (1998) 114:A301. Cuomo R, et al, "Functional Dyspepsia Symptoms, Gastric Emptying and Satiety Provocation Test: Analysis of Relationships", Scand J Gastroenterol , (2001) 36:1030-1036. Sarnelli G, et al., "Symptoms Associated with Impaired Gastric Emptying of Solids and Liquids in Functional Dyspepsia", Am J Gastroenterol, (2003) 98:783-788.
2. Irritable Bowel Syndrome (IBS) The second FGID of interest, IBS, is diagnosed when a patient's symptoms include persistent abdominal pain or discomfort, in the absence of other explanatory organic disease, along with at least two of the following: relief of pain with defecation, onset of symptoms associated with a change in frequency of stools and/or onset of symptoms associated with a change in appearance/form of stools! Thompson WG, et al., "Rome II: A Multinational Consensus Document on
Gastrointestinal Disorders - Functional Bowel Disorders and Functional Abdominal Pain", Gut, (1999) ;45(Suppl II):II43-II47.
In addition to colonic dysmotility, a number of other GI motility abnormalities have been identified, including delayed gastric emptying, gastroparesis, and small intestine motility abnormalities. Vassallo MJ, et al.,
"Colonic Tone and Motility in Patients with Irritable Bowel Syndrome", Mayo Clin Proc, (1992);67:725-731. Van Wijk HJ, et al, "Gastric Emptying and Dyspeptic Symptoms in the Irritable Bowel Syndrome", Scand J Gastroenterol (1992);27:99- 102. Evans PR, et al, "Gastroparesis and Small Bowel Dysmotility in Irritable Bowel Syndrome", Dig Pis Sci (1997);42:2087-2093. Cann PA, et al. "Irritable Bowel Syndrome: Relationship of Disorders in the Transit of a Single Solid Meal to Symptoms Patterns", Gut, (1983);24:405-411. Kellow JE, et al, "Dysmotility of the Small Intestine in irritable Bowel Syndrome", Gut, (1988);29:1236-1243. Evans PR, et al, "Jejunal Sensorimotor Dysfunction in Irritable Bowel Syndrome: Clinical and Psychosocial Features", Gastroenterol, (1996);110:393-404. Schmidt T, et al, "Ambulatory 24-Hour Jejunal Motility in Diarrhea-Predominant Irritable Bowel Syndrome", J Gastroenterol (1996);31 :581-589. Simren M, et al, "Abnormal Propagation Pattern of Duodenal Pressure Waves in the Irritable Bowel Syndrome (IBS)", Dig Pis Sci, (2000);45 :2151 -2161.
A related finding is that patients with constipation-predominant IBS have evidence of decreased vagal tone, while diarrhea-predominant IBS is associated with evidence of increased sympathetic activity. Aggarwal A, et al, "Predominant Symptoms in Irritable Bowel Syndrome Correlate with Specific Autonomic Nervous system Abnormalities", Gastroenterol (1994);106:945-950.
There is no cure for IBS. Treatments include supportive palliative care (antidiarrheals, dietary modification and counseling).
A recently approved drug to treat selected patients with FGIPs is tegaserod maleate sold under the tradename "Zelnorm®" by Novartis Pharmaceuticals Corp., East Hanover, New Jersey, USA. The product literature on Zelnorm recognizes the enteric nervous system is a key element in treating IBS. The literature suggests Zelnorm ' acts to enhance basal motor activity and to normalize impaired motility. Novartis product description, Zelnorm®, July 2002 (T2002-19). Zelnorm' s approved use is limited to females with constipation-related IBS. It is for short-term use only.
B. Gastroparesis
The third disease indication discussed here, gastroparesis (or delayed gastric emptying) is associated with upper GI symptoms such as nausea, vomiting fullness, bloating and early satiety. Gastroparesis can be caused by many underlying conditions. The most important, because of chronicity and prevalence, are diabetes, idiopathic and post-surgical Hornbuckle K, et al. "The Diagnosis and Work-Up of the Patient with Gastroparesis", J Clin Gastroenterol (2000);30: 117-124. GI dysmotility in the form of delayed gastric emptying is, by definition, present in these patients.
In patients with Type 1 diabetes mellitus and delayed gastric emptying, there appears to be a relationship between delayed gastric emptying and low vagal tone. Merio R, et al, "Slow Gastric Emptying in Type 1 Diabetes: Relation to Autonomic and Peripheral Neuropathy, Blood Glucose, and Glycemic Control", Diabetes Care, (1997);20:419-423. A related finding is that patients with Type 1 diabetes have low vagal tone in association with increased gastric antral size, possibly contributing to the dysmotility-associated symptoms seen in these patients. Undeland KA, et al, "Wide Gastric Antrum and Low Vagal Tone in Patients with Diabetes Mellitus Type 1 Compared to Patients with Functional Dyspepsia and Healthy Individuals", Dig Dis Scl (1996);41:9-16.
The current treatments for gastroparesis are far from satisfactory. They include supportive care, such as dietary modification, prokinetic drugs, and; when required, interventions such as intravenous fluids and placement of a nasogastric tube may be needed.
C. Gastroesophageal Reflux Disease (GERD) The fourth indication, GERD, can be associated with a wide spectrum of symptoms, including dyspepsia, reflux of gastric contents into the mouth, dysphagia, persistent cough, refractory hyperreactive airway disease and even chronic serous otitis media. Sontag SJ, et al, "Asthmatics with Gastroesophageal Reflux: Long Term Results of a Randomized Trial of Medical and Surgical Antireflux Therapies", Am J Gastroenterol (2003);98:987-999. Poelmans J, et al, "Prospective Study on the Incidence of Chronic Ear Complaints Related to Gastroesophageal Reflux and on the Outcome of Antireflux Therapy", Ann Otol Rhinol Laryngol (2002); 111:933- 938.
GERD is considered to be a chronic condition for which long-term medical therapy and/or surgical therapy is often deemed necessary, in significant part because esophageal adenocarcinoma is sometimes a consequence of GERD. DeVault KR, et al, "Updated Guidelines for the Diagnosis and Treatment of Gastroesophageal Reflux Pisease", Am J Gastroenterol. (1999);94:1434-1442. Lagergren J, et al, "Symptomatic Gastroesophageal Reflux as a Risk Factor for Esophageal Adenocarcinoma", New Engl J Med, (1999);340:825-831.
The underlying pathophysiological mechanisms in GERD are considered to be transient lower esophageal relaxations (TLESRs) in the presence of either an inadequate pressure gradient between the stomach and the esophagus across the lower esophageal sphincter and/or low amplitude esophageal activity at times when gastric contents do reflux into the esophagus. In addition, gastric distention is thought to be associated with an increase in TLESRs. Mittal RK, et al, "Mechanism of Disease: The Esophagogastric Junction", New Engl J Med. (1997);336:924-932. Scheffer RC, et al, "Elicitation of Transient Lower Oesophageal Sphincter Relaxations in Response to Gastric Distension", Neuro gastroenterol Mo til, (2002);14:647-655.
GERD is generally considered to be the result of a motility disorder which permits the abnormal and prolonged exposure of the esophageal lumen to acidic gastric contents. Hunt, "The Relationship Between The Control Of pH And Healing And Symptom Relief In Gastro-Oesophageal Reflux Disease", Ailment Pharmacol Ther., 9 (Suppl. 1) pp. 3 - 7 (1995). Many factors are believed to contribute to the onset of GERD. These include transient lower esophageal sphincter relaxations (as previously described), decreased LES resting tone, delayed stomach emptying and an ineffective esophageal clearance.
Certain drags have had some effectiveness at controlling GERD but fail to treat underlying causes of the disease. Examples of such drugs are H2-receptor antagonists (which control gastric acid secretion in the basal state) and proton pump inhibitors (which control meal-stimulated acid secretion). Hunt, id. Both classes of drugs can raise intragastric pH to or about 4 for varying durations. Hunt, supra.
Surgery treatments are also employed for the treatment of GERD and include techniques for bulking the lower esophageal sphincter such as fundoplication and techniques described in US Pat. No. 6,098,629 Johnson et al, Aug 8, 2000. Other surgical techniques include placement of pacemakers for stimulating muscle contractions in the esophageal sphincter, the stomach muscles or in the pyloric valve. U.S. Pat. No. 6,104,955 to Bourgeois, U.S. Pat. No. 5,861,014 to Familoni. A summary of GERD treatments can be found in DeVault, et al, "Updated Guidelines for the Diagnosis and Treatment of Gastroesophageal Reflux Disease", Amer. J. of Gastroenterology, Vol. 94, No. 6, pp. 1434 - 1442 (1999). Notwithstanding multiple attempts at various types of treatment, GERD continues to be a serious disease proving to be difficult to treat by any of the foregoing prior art techniques. In view of the foregoing and notwithstanding various efforts exemplified in the prior art, there remains a need for an effective treatment for GERD. It is an object of the present invention to provide a novel treatment and novel apparatus for the treatment of GERD.
D. Electrical Stimulation to Treat GI Disorders
Treatment of gastrointestinal diseases through nerve stimulation have been suggested. For example, U.S. Past. No. 6,238,423 to Bardy dated May 29, 2001 describes a constipation treatment involving electrical stimulation of the muscles or related nerves of the gut. U.S. Pat. No. 6,571,127 to Ben-Haim et al. dated May 27, 2003 describes increasing motility by applying an electrical field to the GI tract. U.S. Pat. No. 5,540,730 to Terry, Jr. et al, dated July 30, 1996 describes a motility treatment involving vagal stimulation to alter GI contractions in response to a sense condition indicative of need for treatment. The '730 patent also uses a definition of dysmotility more restrictive than in the present application. In the '730 patent, dysmotility is described as hyper- or hypo-contractility. In the present application, dysmotility is a broader concept to refer to all abnormalities of gastric emptying or bowel transfer regardless of cause. U.S. Pat. No. 6,610,713 to Tracey dated August 26, 2003 describes inhibiting release of a proinflammatory cytokine by treating a cell with a cholinergic agonist by stimulating efferent vagus nerve activity to inhibit the inflammatory cytokine cascade. A substantial body of literature is developed on nerve stimulation. For example, in Dapoigny et al, "Vagal influence on colonic motor activity in conscious nonhuman primates", Am. J. Phvsiol, 262: G231 - G236 (1992), vagal influence on colonic motor activity was investigated in conscious monkeys. To block antidromic interference, the vagus was blocked via vagal cooling and a vagal stimulation electrode was implanted distal to the vagal block. It was noted that vagal efferent stimulation increased contractile frequency and that the vagus has either a direct or indirect influence on fasting and fed colonic motor activity throughout the colon, and that a non-adrenergic, noncholinergic inhibitory pathway is under vagal control. Colonic and gastric stimulation are also described in a number of articles associated with M. P. Mintchev. These include: Mintchev, et al, "Electrogastrographic impact of multi-site functional gastric electrical stimulation", J. of Medical Eng. & Tech.. Vol. 23, No. 1 pp. 5 - 9 (1999); Rashev, et al, "Three- dimensional static parametric modeling of phasic colonic contractions for the purpose of microprocessor-controlled functional stimulation", J. of Medical Eng. & Tech.. Vol. 25, No. 3 pp. 85 - 96 (2001); Lin et al, "Hardware - software co-design of portable functional gastrointestinal stimulator system", J. of Medical Eng. & Tech., Vol. 27, No. 4 pp. 164 - 177 (2003); Amaris et al, "Microprocessor controlled movement of solid colonic content using sequential neural electrical stimulation", Gut, 50: pp 475 - 479 (2002) and Rashev et al, "Microprocessor- Controlled Colonic Peristalsis", Digestive Diseases and Sciences, Vol. 47, No. 5, pp. 1034 - 1048 (2002).
The foregoing references describe nerve stimulation to stimulate muscular contraction in the GI tract. As will be more fully discussed, the present invention utilizes vagal stimulation to improve vagal tone (similar in concept to improving cardiac electrical tone through cardiac pacing) and/or to treat GI disorders by altering the nature of duodenum contents by stimulation pancreatic and biliary output. The invention is also applicable to treating other diseases such as neuropsychiatric disorders.
Vagal tone has been shown to be associated with dyspepsia. Hjelland, et al, "Vagal tone and meal-induced abdominal symptoms in healthy subjects", Digestion, 65: 172 - 176 (2002). f Also, Hausken, et al, "Low Vagal Tone and Antral
Dysmotility in Patients with Functional Dyspepsia", Psychosomatic Medicine, 55: 12 - 22 (1993). Also, decreased vagal tone has been associated with irritable bowel syndrome. Heitkemper, et al, "Evidence for Automatic Nervous System Imbalance in Women with Irritable Bowel Syndrome", Digestive Diseases and Sciences, Vol. 43, No. 9, pp. 2093 - 2098 (1998).
Also, as will be discussed, the present invention includes, in several embodiments, a blocking of a nerve (such as the vagal nerve) to avoid antidromic influences during stimulation. Cryogenic nerve blocking of the vagus is described in Dapoigny et al, "Vagal influence on colonic motor activity in conscious nonhuman primates", Am. J. Physiol, 262: G231 - G236 (1992). Electrically induced nerve blocking is described in Van Den Honert, et al, "Generation of Unidirectionally Propagated Action Potentials in a Peripheral Nerve by Brief Stimuli", Science, Vol. 206, pp. 1311 - 1312. An electrical nerve block is described in Solomonow, et al, "Control of Muscle Contractile Force through Indirect High-Frequency Stimulation", Am. J. of Physical Medicine, Vol. 62, No. 2, pp. 71 - 82 (1983) and Petrofsky, et al, "Impact of Recruitment Order on Electrode Design for Neural Prosthetics of Skeletal Muscle", Am. J. of Physical Medicine, Vol. 60, No.5, pp. 243 - 253 (1981). A neural prosthesis with an electrical nerve block is also described in U.S. Patent Application Publication No. US 2002/0055779 Al to Andrews published May 9, 2002. A cryogenic vagal block and resulting effect on gastric emptying are described in Paterson CA, et al, "Deteraiinants of Occurrence and Volume of Transpyloric Flow During Gastric Emptying of Liquids in Dogs: Importance of Vagal Input", Dig Pis Sci, (2000);45: 1509-1516.
SUMMARY OF THE INVENTION
According to a preferred embodiment of the present invention, a method and apparatus are disclosed for treating at least one of a plurality of gastrointestinal disorders of a patient characterized at least in part by an altered autonomic balance or altered motility. The method includes electrically stimulating an enteric nervous system of the patient to enhance a functional tone of the enteric nervous system.
Enteric rhythm management (ERM) treats GI diseases in which dysmotility is thought to play a major role. This therapy is based on the physiological actions of pancreatic exocrine secretion and bile on the composition (osmolality and pH) and the digestion (enzymatic activity and, in the case of fats, emulsification) of intraduodenal chyme, thereby presenting a novel approach to regulating the motility of the GI tract and, in particular, gastric emptying and the digestion and propulsion of chyme through the duodenum and into the jejunum and ileum. ERM as a therapy for GI diseases involving dysmotility is based on the following: (1) pacing the delivery of pancreatic exocrine secretion and bile can be used to either up- or down-regulate at least two aspects of GI motility - gastric emptying and small bowel transit - by modulating the osmolality, the pH and the digestion, including emulsification as needed, of intra-duodenal chyme; (2) pacing the efferent activity of the intra-abdominal vagus nerve as needed while blocking afferent activity of that same nerve as needed can be used to treat GI dysmotility in patients with either increased or decreased vagal tone as a component of their disease; and, (3) treating GI dysmotility disorders can and often does require flexibility in adjusting treatment algorithms based on symptomatic response because of inter-patient differences with a diagnostic group and because of intra-patient variability over time.
The goals of enteric rhythm management in gastroparesis are: 1) to regulate the composition and digestion of duodenal chyme and, by so doing, to facilitate gastric emptying through the modulatory effect of duodenal chemo- and mechanoreceptors on the pylorus and 2) to up-regulate or down-regulate vagal tone to optimize gastricintestinal motility and symptom relief.
In patient with GERD, ERM utilizing a physiologic enteric pacing device will, as described earlier, allow pacing of the delivery of pancreatic exocrine secretion and bile, thereby initiating pyloric relaxation, gastric emptying and consequent reduction in gastric distention, leading to a decrease in the underlying mechanism of GERD, that is, TLESRs.
Kellow JE, et al, "Rome II: A Multinational Consensus Document on Gastrointestinal Disorders - Principles of Applied Neurogastroenterology: Physiology/Motility-Sensation", Gut, (1999);45(Suppl II): II 17-1124. Paterson CA, et al, "Determinants of Occurrence and Volume of Transpyloric Flow During Gastric Emptying of Liquids in Dogs: Importance of Vagal Input", Dig Pis Sci, (2000);45:1509-1516. Tougas G, "The Autonomic Nervous System in Functional Bowel Disorders", Gut, (2000);47(Suppl IV):iv78-iv80. Guyton AC, et al, "Propulsion and Mixing of Food in the Alimentary Tract", Textbook of Medical Physiology, 10th ed. Philadelphia: W. B. Saunders and Company, 200:728-737. Guyton AC, et al, "Secretory Functions of the Alimentary Tract", Textbook of Medical Physiology, 10th ed. Philadelphia: W. B. Saunders and Company, 200:738- 753. Schwartz MP, et al, "Human Duodenal Motor Activity in Response to Acid and Different Nutrients", Dig Pis Sci (2001);46:1472-1481. Schwartz MP, et al, "Chemospecific Alterations in Duodenal Perception and Motor Response in Functional Dyspepsia", Am J Gastroenterol (2001);96:2596-2602.
ERM involves pacing and thereby regulating the timing and the volume of pancreatic exocrine secretion and bile delivered to the intraluminal contents of the duodenum. In one embodiment, this is accomplished with a small, laparoscopically implantable and programmable medical device called a physiologic enteric pacing device. Three leads are positioned intra-abdominally and then connected to a subcutaneous, programmable pulse generator. A pacing lead may be placed on the anterior vagal trunk and another pacing lead may be placed on the posterior vagal trunk. One or more intra-abdominal electrode, i.e. blocking electrodes, may be placed on the vagus nerve proximal to the pacing leads.
An additional embodiment of the present invention pertains to treating at least one of a plurality of gastrointestinal disorders of a patient by electrically stimulating a vagus nerve of the patient at a stimulation site proximal to at least one site of vagal innervation of a gastrointestinal organ. The electrical stimulation includes applying a stimulation signal at the stimulation site. A proximal electrical blocking signal is applied to the vagus nerve at a proximal blocking site proximal to the stimulation site. The proximal blocking signal is selected to at least partially block nerve impulses proximal to the proximal blocking site.
The invention further includes a treatment apparatus having a stimulation electrode adapted for placement on a nerve of a patient at a stimulation site and a stimulation signal generator for generating a stimulation signal at the stimulation electrode and selected to electrically stimulate a nerve to induce bi-directional propagation of nervous impulses in a stimulated nerve. The apparatus includes a blocking member for placement on the nerve at a blocking site and creating localized conditions at the blocking site that at least partially diminish transmission of nerve impulses past the blocking site.
A still further embodiment of the present invention includes a method for treating at least one of a plurality of disorders of a patient where the disorders are associated with a gastrointestinal tract of a patient where the disorders are characterized at least in part by hyper-tonal vagal activity innervating at least one of a plurality of alimentary tract organs of the patient at an innervation site. The method includes applying a neural conduction block to a vagus nerve of the patient at a blocking site proximal to the innervation site. The neural conduction block is selected to at least partially block nerve impulses on the vagus nerve distal to the blocking site. A yet further embodiment pertains to a treatment apparatus having an electrically controllable neural conduction electrode adapted to be placed on a vagus nerve of a patient at a blocking site proximal to an innervation site. A blocking signal generator generates a blocking signal selected to at least partially block nerve impulses on the vagus nerve distal to the blocking site.
A still additional embodiment of the present invention includes a method for treating at least one of a plurality of disorders of a patient by electrically stimulating a vagus nerve at a stimulation site with a stimulation signal selected to have a therapeutic effect on a target organ. An electrical blocking signal is applied to the vagus nerve at a blocking site on a side of said stimulation site opposite the target organ. The blocking signal is selected to at least partially block nerve impulses to a second organ on a side of said blocking site opposite the stimulation site. In specific examples, the target organ may be gastrointestinal or central nervous with the other organ being cardio-respiratory.
BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic representation of a gastric-emptying feedback loop with a patient-controlled stimulator for stimulating an organ of the loop;
Fig. 2 is a view similar to Fig. 1 with an automatic controller replacing the patient-controller of Fig. 1 and with feedback circuits to the automatic controller schematically represented;
Fig. 3 is a schematic illustration of an alimentary tract (GI tract plus non-GI organs such as the pancreas and liver) and its relation to vagal and enteric innervation; Fig. 4 is the view of Fig. 3 showing the application of a pacing electrode according to an embodiment of the present invention;
Fig. 5 is a schematic representation of pacing system; Fig. 6 is the view of Fig. 4 showing the application of a nerve conduction block electrode proximal to the pacing electrode; Fig. 7 is the view of Fig. 6 showing the application of a nerve conduction block electrode distal to the pacing electrode; and
Fig. 8 is the view of Fig. 3 showing the application of a nerve conduction block electrode according to an embodiment of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
With reference now to the various drawing figures in which identical elements are numbered identically throughout, a description of the preferred embodiment of the present invention will now be described. A. Invention of Parent Application
Figs 1 and 2 and the description which follow are from the aforementioned U.S. patent application Ser. No. 10/358,093 filed February 3, 2003 filed February 3, 2003 and entitled "Method and Apparatus for Treatment of Gastroesophageal Disease (GERD)".
With initial reference to Fig. 1, a gastric emptying feedback loop is shown schematically for ease of illustration. The feedback loop illustrates a patient's stomach S which is provided with food from the esophagus E. A lower esophageal sphincter LES is shown positioned between the esophagus E and the stomach S. The lower esophageal sphincter normally provides control of reflux of stomach contents into the esophagus E.
On a proximal or lower end of the stomach S the stomach discharges into the superior duodenum D which is an upper portion of the intestines. The superior duodenum D and the stomach S are separated by a pyloric valve PV which opens to permit gastric emptying from the stomach into the duodenum D.
Also schematically illustrated in Fig. 1 are nerve paths N providing signal flow paths from both the superior duodenum D and the stomach S to the brain B. An efferent Vagal nerve VN connects the brain B to the pancreas P of the patient. A conduit (pancreatic duct PD) extends from the pancreas P and discharges into the superior duodenum D.
The presence of food contents within the duodenum D (such contents being referred to as "chyme") may prevent passage of gastric content of the stomach S past the pyloric valve PV into the duodenum D. As long as such gastric contents cannot be passed into the duodenum D, such contents can be forced retrograde past the lower esophageal sphincter LES and into the esophagus E creating the symptoms and discomfort of GERD. The contents discharging from the stomach S into the duodenum D are acidic (and high osmolality) and reside in the duodenum D until pH is elevated (close to a neutral pH of 6 - 7) and osmolality is normalized.
The elevation of pH and reduction of osmolality of chyme in the duodenum D results from exocrine secretion being administered from the pancreas P and from bile from the liver into the duodenum D. This raises the pH and lowers the osmolality of the duodenum D content permitting discharge from the duodenum D and thereby permitting gastric emptying across the pyloric valve PV.
According to the present invention gastroesophageal reflux disease (GERD) results from a derangement of the feedback loops involved in upper GI digestion and motility control. This problem encompasses receptors and reflexes that regulate the propulsive contractions of the stomach, upper duodenum and biliary tree and the secretions of the exocrine pancreas. The interaction of these receptors and reflexes control gastric emptying (by coordinating gastric propulsive contractions and sphincter [primarily pyloric] tone) and regulate the pH and osmolality of the chyme in the duodenum. This chemo-regulation is mediated through control of bile delivery and stimulation of secretion by the exocrine pancreas of fluid delivered to the superior duodenum. Chey et al, "Neural Hormonal Regulation of Exocrine Pancreatic Secretion", Pancreatology, pp. 320 - 335 (2001).
Normally, ingestate delivered to the stomach is mixed by low intensity gastric mixing contractions with the enzymatic, ionic, including hydrogen ion (H +), and water secretions of the glands of the stomach. When the material is adequately reduced in size and is a smooth consistency, the fluid, now called chyme, is delivered to the ampulla of the small intestine by the much stronger propulsive, or emptying, contractions of the stomach coupled with transitory relaxation of the pyloric sphincter. This material is at a very low pH (about 2) and high osmolality, which activates receptors, including those for H+ and osmotic pressure, which are abundant in the wall of the ampulla. This receptor activation initiates the series of reflexes that cause pancreatic exocrine secretion to be delivered into the superior duodenum and ampulla. This fluid contains digestive enzymes, water and buffering compounds to raise the pH, and reduce the osmolality, of the chyme.
Once a neutral pH and physiological osmolality are achieved, then propulsive contractions in the superior duodenum move the chyme out of the superior portion into the length of the duodenum; At which point the stretch and baro-receptors in the ampulla allow the pyloric sphincter to relax and another bolus of gastric contents is delivered into the ampulla by the peristaltic gastric emptying contractions. This material, at a very low pH (less than 2), activates hydrogen ion (H +) on receptors of the ampulla (upper most portion of the duodenum) causing the pancreatic fluids to be delivered to the material in the ampulla restarting the cycle as described above. Chapter 3, "The Stomach", Gastrointestinal System, 2nd Ed., M.S. Long editor, Mosby Publisher, London (2002).
If the control system is down regulated by, for example, by increased pH of gastric contents entering the ampulla, feedback may thereby be reduced from the H+ receptors in the duodenum that stimulate pancreatic exocrine secretion and bile delivery to the duodenum, then movement of chyme from the superior duodenum is delayed, causing delay of gastric emptying. Mabayo, et al, "Inhibition of Food Passage by Osmeprazole in the Chicken", European J. of Pharmacology, pp. 161 - 165 (1995).
In GERD, this reflex is inhibited in such a way that the stomach empties more slowly so that the gastric emptying contractions force gastric contents to flow retrograde into the esophagus. This is a result of the situation in which the gastric emptying contractions are vigorous but must operate against a contracted pyloric sphincter. These vigorous peristaltic contractions eventually begin to force gastric contents to flow retrograde into the esophagus because of the inherent imbalance between a very strong pyloric sphincter and a much weaker gastroesophageal sphincter. The delay in gastric emptying is directly related to a slow down in the transport of chyme out of the ampulla and superior duodenum. The drugs used to treat this disease raise pH further dampening the hydrogen-receptor-pancreatic secretion loop, further delaying gastric emptying. Benini, "Gastric Emptying and Pyspeptic Symptoms in Patients with Gastroesophageal Reflux", Amer. J. of Gastroenterology, pp. 1351 - 1354 (1996).
The present invention is directed towards reestablishing the link between gastric emptying and pancreatic secretion delivery, thereby addressing the main pathology of this disease by shortening chyme residence time in the superior duodenum so that intestinal contents move into the distal digestive tract in a more normal manner. According to a first embodiment, this is done by stimulating the H+ ion receptors or by stimulation of the pancreas directly or via its para-sympathetic innervation (pre-ganglionic Vagal nerves). Stimulation of pancreatic exocrine secretion has been shown by direct stimulation of the thoracic vagus nerves in dogs. Kaminski et al, "The Effect of Electrical Vagal Stimulation on Canine Pancreatic Exocrine Function", Surgery, pp. 545 - 552 (1975). This results in a more rapid (normal) neutralization of chyme in the ampulla, allowing it move down the duodenum more quickly so that gastric emptying is returned to a more normal pace.
Acidity (pH) can be assessed by measuring bicarbonate. It will be understood that references to -H includes such indirect measurements. Also, effects of the therapy described herein can be assessed and/or controlled by measuring an indication of pancreatic exocrine secretion or bile (e.g., HCO3 ").
An alternative embodiment uses gastrocopic delivery of a paralyzing agent (e.g. botulism toxin) to the pyloric valve along with use of H2 antagonists or PPI's to manage the acidity of the chyme reaching the duodenum. As an additional alternative to pancreatic stimulation, the gall bladder can be stimulated to encourage bile movement into the duodenum. Shown schematically in the figures, the gall bladder GB resides below the liver L. The gall bladder is connected to the small intestine (specifically the duodenum P) via a bile duct BP. The bile duct BP can discharge directly into the duodenum P or via the pancreatic duct PP as shown. The bile can normalize the chyme to accelerate duodenal emptying. Bile consists of bile acids (detergents that emulsify lipids), cholesterol, phospholipids, electrolytes such as (Na+, K+, Ca +2, CF, HCO3 ") and H20. Chapter 4, "The Liver and Biliary Tract", Gastrointestinal System, 2nd Ed., M.S. Long editor, Mosby Publisher, London (2002). The gall bladder GB or bile duct can be stimulated indirectly via stimulation of the vagal nerve VN or directly stimulated by an electrode 11 (shown in phantom lines).
As illustrated in the figures, an electrical stimulator 10, 20 which may be implanted is provided which alternatively may be directly connected to the Vagal nerve VN or the pancreas P to stimulate the pancreas directly or indirectly to excrete exocrine into the duodenum P (or more distally into the small intestine - e.g., into the jejunum) and increase the pH of chyme in the duodenum P as described. Alternatively, the same can be done to promote bile release. The frequency may be varied to maximize the response and selectively stimulate exocrine instead of endocrine secretions. Rδsch et al, "Frequency-Pependent Secretion of Pancreatic Amylase, Lipase, Trypsin, and Chymotrypsin Puring Vagal Stimulation in Rats", Pancreas, pp. 499 - 506 (1990). See, also, Berthoud et al, "Characteristics of Gastric and Pancreatic Reponses to Vagal Stimulation with Varied Frequencies: Evidence for Pifferent Fiber Calibers?", J. Auto. Nervous Svs., pp. 77 - 84 (1987) (showed frequency-response relationship with insulin, i.e., significantly less insulin was released at lower frequencies - 2 Hz v. 8 Hz - also, frequency-response curves evidenced distinctly different profiles for gastric, pancreatic and cardiovascular responses.) Slight insulin release can maximize pancreatic exocrine secretion. Chey et al, "Neural Hormonal Regulation of Exocrine Pancreatic Secretion", Pancreatology, pp. 320 - 335 (2001).
With a patient control stimulation as shown in Fig. 1, the patient may activate the stimulator 10 by remote transmitter to stimulate an electrical charge either after eating (e.g., about 60 to 90 minutes after eating) or on onset of GERD symptoms. It will be appreciated that there are a wide variety of nerve stimulators and organ stimulators available for implantation and are commercially available and which include comiectors for connecting directly to nerves.
Fig. 2 illustrates an additional embodiment where the patient activated loop is replaced with an automatic loop having a programmable stimulator 20 which receives as an input signals from sensors in the duodenum to measure pH, osmolality or strain (e.g., from baro-sensors) on the duodenum indicating filling or may measure acidity in the esophagus or strain on the lower esophageal sphincter LES or stomach S all of which may be provided to the implantable controller 20 which can be provided with desirable software to process the incoming signals and generate a stimulating signal to either the vagal nerve, the pancreas P or the duodenum P (or jejunum) directly in response to such received signals. It will be appreciated that stimulators and controllers are well within the skill of the art. U.S. Pat. No. 5,540,730 teaches a neuro stimulator to stimulate a vagus nerve to treat a motility disorder. U.S. Pat. No. 5,292,344 teaches gastrointestinal sensors, including pH sensors.
B. Application of Parent Application to Treatments Other than GERD In addition to treatment of GERP, the foregoing invention is applicable to treatment of a plurality of GI diseases associated with delayed gastric emptying or altered autonomic activity. These include functional gastrointestinal disorders and gastroparesis. Furthermore, applicants have determined that duodenal content impacts a plurality of motility disorders throughout the bowels and can diseases associated with dysmotility (e.g., irritable bowel syndrome). Accordingly it is an object of the present invention to use the teachings of the aforementioned parent application to treat GI disorders associated with delayed gastric emptying and abnormal intestinal transport.
C. Additional Disclosure of the Present Application
1. Enteric Innervation
Fig. 3 is a schematic illustration of an alimentary tract (GI tract plus non-GI organs such as the pancreas and ball bladder, collectively labeled PG) and its relation to vagal and enteric innervation. The lower esophageal sphincter (LES) acts as a gate to pass food into the stomach S and, assuming adequate function of all components, prevent reflux. The pylorus PV controls passage of chyme from the stomach S into the intestines I (collectively shown in the figures and including the large intestine or colon and the small intestine including the duodenum, jejunum and ileum). The biochemistry of the contents of the intestines I is influenced by the pancreas P and gall bladder PG which discharge into the duodenum. This discharge is illustrated by dotted arrow A.
The vagus nerve VN transmits signals to the stomach S, pylorus PV, pancreas and gall bladder PG directly. Originating in the brain, there is a common vagus nerve VN in the region of the diaphragm (not shown). In the region of the diaphragm, the vagus VN separates into anterior and posterior components with both acting to innervate the GI tract. In Figs. 3, 5 - 8, the anterior and posterior vagus nerves are not shown separately. Instead, the vagus nerve VN is shown schematically to include both anterior and posterior nerves. The vagus nerve VN contains both afferent and efferent components sending signals away from and to, respectively, its innervated organs.
In addition to influence from the vagus nerve VN, the GI and alimentary tracts are greatly influenced by the enteric nervous system ENS. The enteric nervous system ENS is an interconnected network of nerves, receptors and actuators throughout the GI tract. There are many millions of nerve endings of the enteric nervous system ENS in the tissues of the GI organs. For ease of illustration, the enteric nervous system ENS is illustrated as a line enveloping the organs innervated by the enteric nervous system ENS
The vagus nerve VN innervates, at least in part, the enteric nervous system ENS (schematically illustrated by vagal trunk VN3 which represents many vagus- ENS innervation throughout the cut). Also, receptors in the intestines I connect to the enteric nervous system ENS. Arrow B in the figures illustrates the influence of duodenal contents on the enteric nervous system ENS as a feedback to the secretion function of the pancreas, liver and gall bladder. Specifically, receptors in the intestine I respond the biochemistry of the intestine contents (which are chemically modulated by the pancreao-biliary output of Arrow A). This biochemistry includes pH and osmolality. In the figures, vagal trunks VN1 , VN2, VN4 and VN6 illustrate schematically the direct vagal innervation of the GI organs of the LES, stomach S, pylorus PV and intestines I. Trunk VN3 illustrates direct communication between the vagus VN and the ENS. Trunk VN5 illustrates direct vagal innervation of the pancreas and gall bladder. Enteric nerves ENS1 - ENS4 represent the multitude of enteric nerves in the stomach S, pylorus PV, pancreas and gall bladder PG and intestines I.
While communicating with the vagus nerve VN, the enteric nervous system ENS can act independently of the vagus and the central nervous system. For example, in patients with a severed vagus nerve (vagotomy - an historical procedure for treating ulcers), the enteric nervous system can operate the gut. Most enteric nerve cells are not directly innervated by the vagus. Gershon, "The Second Brain", Harper Collins Publishers, Inc, New York, NY p. 19 (1998)
In Fig. 3, the vagus VN and its trunks (illustrated as VN1 - VN6) and the enteric nervous system ENS are shown in phantom lines to illustrate reduced vagal and enteric nerve tone (i.e., sub-optimal nerve transmission levels). Reduced vagal and enteric tone contribute directly to the ineffectiveness of the GI organs as well as indirectly (through reduced pancreatic/biliary output). The reduced pancreatic/biliary output is illustrated by the dotted presentation of arrow A. As previously discussed, the vagus can be stimulated to stimulate pancreatic or biliary output. Therefore, the reduced output of arrow A results in a reduced feedback illustrated by the dotted presentation of arrow B. 2. Enteric Rhythm Management (ERM)
The benefits of the present invention are illustrated in Fig. 4 where a stimulating or pacing electrode PE is applied to the vagus VN. While only one electrode is shown in Fig. 4, separate electrodes could be applied to both the anterior and posterior vagus nerves (or to the common vagus or vagal branches), hi a preferred embodiment, the electrode PE is placed a few centimeters below the diaphragm and proximal to stomach and pancreo/biliary innervation. While this placement is presently preferred for ease of surgical access, other placement locations may be used. By pacing the vagus through the pacing electrode, vagal tone is optimized by either up- or down-regulation. With reference to the parasympathetic and enteric nervous systems, "tone" refers to basal activity of a nerve or nervous system facilitating appropriate physiologic response to a patient's internal environment. For example, low vagal tone implies a reduction in vagus nerve activity resulting in decreased response of the alimentary tract to ingested food. As used in the present application, "pacing" is not limited to mean timed events coordinated with specifically timed physiologic events. Instead, pacing means any electrical stimulation of a nerve trunk to induce bi-directional propagation of nervous impulses in the stimulated nerve. The operating effectiveness of the vagus is enhanced so that local physiological signals generated in the enteric nervous system (or sent to the brain from the organs) are more appropriately responded to within the alimentary tract. Pue to its innervation of the enteric nervous system, pacing of the vagus enhances the functional tone of the enteric nervous system. By enhancing the functional tone it will be noted that the stimulation pacing is elevating the degree of functionality of the vagus and enteric nerves. In this context, "pacing" is not meant to mean timed pulsed coordinated with muscular contractions or synchronized with other invents. Pacing means elevating the activity level of the nerves.
Tonal enhancement of the vagus and enteric nerves is illustrated by the solid lines for the nerves VN, ENS in Fig. 4. Vagal trunk VN5 is in solid line to illustrate enhanced tone of the many vagal nerve components communicating with the enteric nervous system ENS. Pirect vagal innervation of the LES, stomach S, pylorus PV and intestines I remains shown as low tone indicated by phantom lines VN1, VN2, VN4, VN6. The tonal pacing described herein is not intended to trigger or drive the muscular contractility of these organs. The stimulation is not intended to be timed to trigger contractility and is not provided with an energy level sufficient to drive peristaltic contractions. Instead, these functions remain controlled by the central and enteric nerves systems. The enhanced nerve tone provided by the present invention permits these functions to occur.
Pacing to enhance vagal tone is not initiated in response to any senses event (or in anticipation of an immediate need to GI activity). Instead, the pacing can be done intermittently over the day to provide an enhanced level of operating functionality to the vagus. By way of non-limiting example, the stimulation pacing can be done during awake hours. For example, every ten minutes, pacing signals can be sent to the pacing electrodes. The pacing signals have a duration of 30 seconds with a current of 4mA, a frequency of 12 Hz and an impulse duration of 2 msec. These parameters are representative only. A wide range of signal parameters may be used to stimulate the vagus nerve. Examples of these are recited in the afore-referenced literature
As will be further discussed, the present invention permits ERM to be uniquely designed and modified by an attending physician to meet the specific needs of individual patients. For example, pacing can be limited to discrete intervals in the morning, afternoon and evening with the patient free to coordinate meals around these events.
In addition to enhancing vagal and enteric tone directly, the pacing also enhances the pancreatic and biliary output for the reasons discussed above. Namely, while ERM does not drive muscular events over nerve trunks VN1, VN2, VN4, VN6, the enhanced tone stimulates pancreo-biliary output over trunk VN5 (illustrated by the solid line of VN5 in Fig. 4). This enhanced output is illustrated as solid arrow A' in Fig. 4. As a consequence there is a greater feedback to the intestinal receptors as illustrated by solid arrow B' in Fig. 4. This enhanced biochemistry feedback further enhances the tone of the enteric nervous system ENS.
3. Implantable Pacing Circuit
A representative pacing circuit 100 is schematically shown in Fig. 5. Similar to cardiac pacing devices, an implantable controller 102 contains an induction coil 104 for inductive electrical coupling to a coil 106 of an external controller 108. The implantable controller 102 includes anterior and posterior pulse generators 110, 112 electrically connected through conductors 114, 116 to anterior and posterior pacing electrodes 118, 120 for attachment to anterior and posterior trunks, respectively, of the vagus nerve VN. The implantable controller 102 also includes a battery 122 and a CPU 124 which includes program storage and memory. The timing and parameters of the pulse at the electrodes 118, 120 can be adjusted by inductively coupling the external controller 108 to the implantable controller 102 and inputting pacing parameters (e.g., pulse width, frequency and amplitude). While a fully implantable controller 102 is desirable, it is not necessary. For example, the electrodes 118, 120 can be implanted connected to a receiving antenna placed near the body surface. The control circuits (i.e., the elements 124, 110, 112 and 108) can be housed in an external pack worn by the patient with a transmitting antenna held in place on the skin over the area of the implanted receiving antenna. Such a design is forward-compatible in that the implanted electrodes can be later substituted with the implantable controller 102 at a later surgery if desired.
Although not shown in Fig. 5, the controller 102 can also include circuits generating nerve conduction block signals (as will be described) which connect to electrodes which may be positioned on a nerve proximally, distally (or both) of the electrodes 118, 120.
4. Nerve Conduction Block
Fig. 6 shows an alternative embodiment using a nerve conduction blocking electrode PBE proximal to the pacing electrode for providing a conduction block. A nerve block is, functionally speaking, a reversible vagotomy. Namely, application of the block at least partially prevents nerve transmission across the site of the block. Removal of the block restores normal nerve activity at the site. A block is any localized imposition of conditions that at least partially diminish transmission of impulses.
The vagal block may be desirable in some patients since unblocked pacing may result in afferent vagal and antidromic efferent signals having undesired effect on organs innervated by the vagus proximal to the GI tract (e.g., undesirable cardiac response). Further, the afferent signals of the pacing electrode PE can result in a central nervous system response that tends to offset the benefits of the pacing electrode on the ENS and pancreo/biliary function, thereby reducing the GI and enteric rhythm management effectiveness of vagal pacing.
The block may be intermittent and applied only when the vagus is paced by the pacing electrode PE. The preferred nerve conduction block is an electronic block created by a signal at the vagus by an electrode PBE controlled by the implantable controller (such as controller 102 or an external controller). The nerve conduction block can be any reversible block. For example, cryogenics (either chemically or electronically induced) or drug blocks can be used. An electronic cryogenic block may be a Peltier solid-state device which cools in response to a current and may be electrically controlled to regulate cooling. Prug blocks may include a pump-controlled subcutaneous drug delivery.
With such an electrode conduction block, the block parameters (signal type and timing) can be altered by a controller and can be coordinated with the pacing signals to block only during pacing. A representative blocking signal is a 500Hz signal with other parameters (e.g., timing and current) matched to be the same as the pacing signal. While an alternating current blocking signal is described, a direct current (e.g., -70mV PC) could be used. The foregoing specific examples of blocking signals are representative only. Other examples and ranges of blocking signals are described in the afore-mentioned literature. For example, the nerve conduction block is preferably within the parameters disclosed in Solomonow, et al, "Control of Muscle Contractile Force through Indirect High-Frequency Stimulation", Am. J. of Physical Medicine. Vol. 62, No. 2, pp. 71 - 82 (1983). Particularly, the nerve conduction block is applied with electrical signal selected to block the entire cross-section of the nerve (e.g., both afferent, efferent, myelinated and nonmyelinated fibers) at the site of applying the blocking signal (as opposed to selected sub-groups of nerve fibers or just efferent and not afferent or visa versa) and, more preferably, has a frequency selected to exceed the 200 Hz threshold frequency described in Solomonow et al. Further, preferred parameters are a frequency of 500 Hz (with other parameters, as non-limiting examples , being amplitude of 4 mA, pulse width of 0.5 msec, and duty cycle of 5 minutes on and 10 minutes off). As will be more fully described, the present invention gives a physician great latitude in selected pacing and blocking parameters for individual patients.
Similar to Fig. 4, the vagus VN and enteric nervous system ENS in Fig. 6 distal to the block PBE are shown in solid lines to illustrate enhanced tone (except for the direct innervation VN1, VN2, VN4, VN6 to the GI tract organs). Similarly, arrows A', B' are shown in solid lines to illustrate the enhanced pancreo-biliary output and resultant enhanced feedback stimulation to the enteric nervous system ENS. The proximal vagus nerve segment VNP proximal to the block PBE is shown in phantom lines to illustrate it is not stimulated by the pacing electrode PE while the blocking electrode PBE is activated.
5. Proximal and Distal Blocking
Fig. 7 illustrates the addition over Fig. 6 of a nerve conductive block PBE distal to the pacing electrode PE. The proximal block PBE prevents adverse events resulting from afferent signals and heightens the GI effectiveness by blocking antidromic interference as discussed with reference to Fig. 6. In Fig. 7, the distal block PBE is provided in the event there is a desire to isolate the pacing effect of electrode PE. For example, a physician may which to enhance the vagus and enteric activity in the region proximal to the duodenum but may wish to avoid stimulating pancreo-biliary output. For example, a patient may have a GI problem without apparent colon dysfunction (e.g., gastroparesis functional dyspepsia without bowel symptoms). Placing the distal block PBE on a branch of the vagus between the pacing electrode PE and the pancreas and gall bladder PG prevents increased pancreo-biliary output and resultant feedback (illustrated by dotted arrows A and B in Fig. 7 and dotted distal vagal nerve segment VNP and vagal trunk VN5).
6. Blocking As An Independent Therapy
Fig. 8 illustrates an alternative embodiment of the invention. In certain patients, the vagus nerve may be hyperactive contributing to diarrhea-dominant IBS. Use of a blocking electrode alone in the vagus permits down-regulating the vagus nerve VN, the enteric nervous system ENS and pancreo- biliary output. The block down-regulates efferent signal transmission. In Fig. 8, the hyperactive vagus is illustrated by the solid line of the proximal vagus nerve segment VNP. The remainder of the vagus and enteric nervous system are shown in reduced thickness to illustrate down-regulation of tone. The pancreo-biliary output (and resulting feedback) is also reduced. In Fig. 8, the blocking electrode BE is shown high on the vagus relative to the GI tract innervation (e.g., just below the diaphragm), the sole blocking electrode could be placed lower (e.g., just proximal to pancreo/biliary innervation VN5). Blocking of the entire vagus as described above can be used to down-regulate the vagus for various benefits including: pancreatitis and obesity treatments. Further, blocking the vagus interrupts the vagally-mediated neurogenic inflammatory arc.
7. Application to Obesity
The foregoing discussion has been described in a preferred embodiment of treating FGIOs, gastroparesis and GERP. Obesity is also treatable with the present invention.
Recent literature describes potential obesity treatments relative to gut hormone fragment peptide YY3-36. See, e.g., Batterham, et al, "Inhibition of Food Intake in Obese Subjects by Peptide YY3-36", New England J. Med., pp. 941 - 948 (September 4, 2003) and Korner et al, "To Eat or Not to Eat - How the Gut Talks to the Brain", New England J. Med., pp. 926 - 928 (September 4, 2003). The peptide YY3-36 (PPY) has the effect of inhibiting gut motility through the phenomena of the ileal brake. Vagal afferents create a sensation of satiety.
The present invention can electrically simulate the effects of PPY by using the vagal block to down-regulate afferent vagal activity to create a desired sensation of satiety. Since the down-regulation does not require continuous blocking signals, the beneficial efferent signals are permitted.
8. Application to Other Therapies There are numerous suggestions for vagal pacing or stimulation to treat a wide variety of diseases. For example, U.S. Pat. No. 5,188,104 dated February 23, 1993 describes vagal stimulation to treat eating disorders. U.S. Pat. No. 5,231,988 dated August 3, 1993 describes vagal stimulation to treat endocrine disorders. U.S. Pat. No. 5,215,086 dated June 1, 1993 describes vagal stimulation to treat migraines. U.S. Pat. No. 5,269,303 dated Pecember 14, 1993 describes vagal stimulation to treat dementia. U.S. Pat. No. 5,330,515 dated July 19, 1994 describes vagal stimulation to treat pain. U.S. Pat. No. 5,299,569 dated April 5, 1994 describes vagal stimulation to treat neuropsychiatric disorders. U.S. Pat. No. 5,335,657 dated August 9, 1994 describes vagal stimulation to treat sleep disorders. U.S. Pat. No. 5,707,400 dated January 13, 400 describes vagal stimulation to treat refractory hypertension. U.S. Pat. No. 6,473,644 dated October 29, 2002 describes vagal stimulation to treat heart failure. U.S. Pat. No. 5,571,150 dated November 5, 1996 describes vagal stimulation to treat patients in comas. As previously described, U.S. Pat. No. 5,540,730 dated July 30, 1996 describes vagal stimulation to treat motility disorders and U.S. Pat. No. 6,610,713 dated August 26, 2003 describes vagal stimulation to inhibit inflammatory cytokine production.
All of the foregoing suffer from undesired effects of vagal pacing on cardiovascular, gastrointestinal or other organs. Nerve conduction blocking permits longer pulse durations which would otherwise have adverse effects on other organs such as those of the cardiovascular or gastrointestinal systems. In accordance with the present invention, all of the foregoing disclosures can be modified by applying a blocking electrode and blocking signal as disclosed herein to prevent adverse side effects. By way of specific example, pacing a vagus nerve in the thoracic cavity or neck combined with a blocking electrode on the vagus nerve distal to the pacing electrode can be used to treat neuropsychiatric disorders (such as depression and schizophrenia) and Parkinson's and epilepsy and dementia. In such treatments, the blocking electrode is placed distal to the stimulating electrode 25 shown in Figs. 4 and 2, respectively, of each of U.S. Pat. Nos. 5,269,303 and 5,299,569. The present invention thereby enables the teachings of the afore-referenced patents listed in foregoing two paragraphs.
As described, the parameters of the stimulating and blocking electrodes can be inputted via a controller and, thereby, modified by a physician. Also, Fig. 2 illustrates a feedback for controlling a stimulating electrode. Feedbacks for stimulating electrodes are also described in the patents. The blocking electrode can also be controlled by an implanted controller and feedback system. For example, physiologic parameters (e.g., heart rate, blood pressure, etc.) can be monitored. The blocking signal can be regulated by the controller to maintain measured parameters in a desired range. For example, blocking can be increased to maintain heart rate within a desired rate range during stimulation pacing.
9. Opportunity for Physician to Alter Treatment for Specific Patient Gastrointestinal disorders are complex. For many, the precise mechanism is of the disorder is unknown. Piagnosis and treatment are often iterative processes. The present invention is particularly desirable for treating such disorders.
Use of proximal and distal blocking electrodes in combination with one or more pacing electrode permits a physician to alter an operating permutation of the electrodes. This permits regional and local up- or down-regulation of the nervous system and organs. Further, pacing parameters (duty cycle, current, frequency, pulse length) can all be adjusted. Therefore, the treating physician has numerous options to alter a treatment to meet the needs of a specific patient.
In addition, a physician can combine the present invention with other therapies (such as drug therapies like prokinetic agents).
With the foregoing detailed description of the present invention, it has been shown how the objects of the invention have been attained in a preferred manner. Modifications and equivalents of disclosed concepts such as those which might readily occur to one skilled in the art, are intended to be included in the scope of the claims which are appended hereto.

Claims

We claim:
1. A method for treating at least one of a plurality of gastrointestinal disorders of a patient where said disorders are characterized at least in part by abnormal gastrointestinal system activity attributable at least in part to altered autonomic balance, said method comprising: electrically stimulating an enteric nervous system of said patient to enhance a functional tone of said enteric nervous system, and applying said stimulation with frequency of occurrence selected to elevate nerve activity sufficient to relieve symptoms.
2. A method according to claim 1 further comprising: electrically stimulating pancreo-biliary organs of said alimentary tract to stimulate discharge of secretions of said pancreo-biliary organs into a duodenum of said patient by an amount sufficient to enhance a transport of contents through a gastrointestinal organ of said alimentary tract.
3. A method according to claim 1 further comprising: electrically stimulating pancreo-biliary organs of said alimentary tract to induce discharge of secretions of said pancreo-biliary organs into a duodenum of said patient by an amount sufficient for receptors in a gastrointestinal organ of said patient to respond to said secretions to contribute to an enhancement of said functional tone of said enteric nervous system.
4. A method according to each of claims 1 or 2 wherein: said electrical stimulation is created by placing an electrode on a vagus nerve of said patient and applying an electrical stimulating current to said electrode and create a stimulation signal in said vagus nerve.
5. A method according to claim 4 further comprising: applying a proximal nerve conduction block on said vagus intermediate a site of said electrical stimulation and a central nervous system of said patient with said nerve block selected to block passage of said stimulation signal to said central nervous system.
6. A method according to claim 5 wherein said nerve conduction block is a cryogenic block.
7. A method according to claim 5 wherein said proximal nerve conduction block is a pharmocologic block.
8. A method according to claim 5 wherein said proximal nerve conduction block is an electrical conduction block.
9. A method according to claim 8 wherein: said electrical conduction block is selected to function during periods of application of said electrical stimulating current to said electrode.
10. A method according to claim 5 further comprising: applying a distal nerve conduction block on said vagus with said site of said electrical stimulation disposed between said proximal and distal nerve blocks.
11. A method for treating at least one of a plurality of gastrointestinal disorders of a patient, said method comprising: electrically stimulating a vagus nerve of said patient at a stimulation site proximal to at least one site of vagal innervation of a gastrointestinal organ of said patient, said electrical stimulation including applying a stimulation signal at said site; applying a proximal electrical blocking signal to said vagus nerve at a proximal blocking site proximal to said stimulation site with said proximal blocking signal selected to at least partially block nerve impulses proximal to said proximal blocking site.
12. A method according to claim 11 further comprising: applying a distal electrical blocking signal to said vagus nerve at a distal blocking site distal to said stimulation site with said distal blocking signal selected to at least partially block efferent transmission of said stimulation signal distal to said distal blocking site.
13. A method according to claim 11 wherein said proximal blocking signal is variable by a controller to regulate transmission of afferent proximal to said proximal blocking site.
14. A method according to claim 12 wherein said distal blocking signal is variable by a controller to regulate transmission of efferent proximal to said distal blocking site.
15. An apparatus for treating at least one of a plurality of disorders of a patient attributable at least in part to neural activity, said apparatus comprising: a stimulation electrode adapted for placement on a nerve of a patient at a stimulation site; a stimulation signal generator for generating a stimulation signal at said stimulation electrode and selected to electrically stimulate a nerve to induce bi-directional propagation of nervous impulses in a stimulated nerve; a blocking member for placement on said nerve at a blocking site and creating localized conditions at said blocking site that at least partially diminish transmission of nerve impulses past said blocking site.
16. An apparatus according to claim 15 wherein said blocking member includes a drug-delivery member for delivery of a pharmacologic lock at said blocking site.
17. An apparatus according to claim 15 wherein said blocking member is an electrically controlled blocking member.
18. An apparatus according to claim 17 wherein said blocking member is cryogenic.
19. An apparatus according to claim 17 wherein said blocking member creates and electrical signal at said blocking site with an electrical frequency selected to at least partially diminish said transmission.
20. An apparatus according to claim 15 comprising a controller for selectively controlling parameters of said blocking and said stimulation.
21. An apparatus according to claim 20 wherein said controller is implantable within said patient's body.
22. An apparatus according to claim 20 wherein said controller is inductively coupled to said stimulation electrode and said blocking member to electrically controlling said electrode and member remote from an interior of said patient's body.
23. A x apparatus according to claim 15 wherein said blocking member is one of at least two blocking members for disposition on said nerve on opposite sides of said stimulation electrode.
24. An apparatus according to claim 15 wherein said nerve is a vagus nerve.
25. An apparatus according to claim 20 including a sensor to sense a physiologic parameter of an organ and said controller comiected to said sensor to regulate said blocking in response to said sensed parameter.
26. A method for treating at least one of a plurality of disorders of a patient, said method comprising: electrically stimulating a vagus nerve of said patient at a stimulation site with a stimulation signal selected to have a therapeutic effect on a target organ; applying an electrical blocking signal to said vagus nerve at a blocking site on a side of said stimulation site opposite said target organ; said blocking signal selected to at least partially block nerve impulses to a second organ on a side of said blocking site opposite said stimulation site.
27. A method according to claim 26 wherein said blocking signal is variable by a controller to regulate transmission nerve impulses past said blocking site.
28. A method according to claim 27 comprising sensing a physiologic parameter of said second organ and regulating said blocking signal in response to said sensed parameter.
29. A method according to claim 28 wherein said target organ is a gastrointestinal organ and said second organ is a heart.
30. A method according to claim 29 wherein said disorder is any one of a plurality of gastrointestinal diseases.
31. A method according to claim 28 wherein said target organ is a brain and said second organ is a heart.
32. A method according to claim 31 wherein said disorder is any one of a plurality of diseases associated with the central nervous system.
33. A method according to claim 32 wherein said disease is selected from a group including dementia, schizophrenia, depression, borderline personality disorder, epilepsy and Parkinson's disease.
34. A method for treating at least one of a plurality of disorders of a patient where the disorders are associated with a gastrointestinal tract of a patient where said disorders are characterized at least in part by hyper-tonal vagal activity innervating at least one of a plurality of alimentary tract organs of said patient at an innervation site, said method comprising: applying a neural conduction block to a vagus nerve of said patient at a blocking site proximal to said innervation site with said neural conduction block selected to at least partially block nerve impulses on said vagus nerve at said blocking site.
35. A method according to claim 34 wherein application of said neural conduction block is variable by a controller to alter a characteristic of said block.
36. A method according to claim 34 wherein said neural conduction block is a cryogenic block.
37. A method according to claim 34 wherein said proximal neural conduction block is a pharmacologic block.
38. A method according to claim 34 wherein said proximal neural conduction block is an electrical conductive block.
39. A method according to claim 34 wherein said at least one of a plurality of disorders is obesity.
40. A method according to claim 39 wherein said neural conduction block is regulated to heighten a sensation of satiety of said patient.
41. A method according to claim 39 wherein said at least one of a plurality of disorders is constipation.
42. A method according to claim 39 wherein said at least one of a plurality of disorders is irritable bowel syndrome.
43. An apparatus for treating at least one of a plurality of disorders of a patient where the disorders are associated with a gastrointestinal tract of a patient where said disorders are characterized at least in part by hyper-tonal vagal activity iiinervating at least one of a plurality of alimentary tract organs of said patient at an innervation site, said apparatus comprising: an electrically controllable neural conduction electrode adapted to be placed on a vagus nerve of said patient at a blocking site proximal to said innervation site; a blocking signal generator for generating a blocking signal selected to at least partially block nerve impulses on said vagus nerve at said blocking site.
44. An apparatus according to claim 43 comprising a controller for selectively controlling parameters of said blocking stimulation.
45. An apparatus according to claim 44 wherein said controller is implantable within said patient's body.
" 46. An apparatus according to claim 44 wherein said controller is inductively coupled to said blocking electrode to electrically controlling said electrode and member remote from an interior of said patient's body.
47. A method for treating a gastrointestinal disease of a patient comprising: treating a body organ to accelerate a discharge of contents through at least a portion of a small intestine of the patient to thereby encourage discharge of contents from a stomach of the patient across a pyloric valve of the patient and into said small intestine.
48. A method according to claim 47 wherein said portion is a duodenum of said patient.
49. A method according to claim 47 wherein said treating is a stimulation selected to increase a pH of said contents of said portion of said small intestine.
50. A method according to claim 47 wherein said treating is a stimulation selected to decrease an osmolality of said contents of said portion of said small intestine.
51. A method according to claim 47 wherein said organ is a pancreas of said patient and said treating is a stimulation of said organ selected to stimulate delivery of an exocrine secretion from said pancreas to said portion of said small intestine.
52. A method according to claim 51 wherein said pancreas is stimulated directly.
53. A method according to claim 51 wherein said pancreas is indirectly stimulated by stimulating at least a nerve of said pancreas.
54. A method according to claim 51 wherein said stimulation is initiated by said patient.
55. A method according to claim 51 wherein said stimulation is initiated by a controller operatively connected to stimulating electrodes and having an input operatively comiected to a sensor.
56. A method according to claim 55 wherein said sensor senses a pH level of said portion of said small intestine.
57. A method according to claim 55 wherein said sensor senses a degree of filling of said portion of said small intestine.
58. A method according to claim 55 wherein said sensor senses a degree of osmolality within said portion of said small intestine.
59. A method according to claim 55 wherein said sensor senses a degree of motility within said portion of said small intestine.
60. A method according to claim 47 wherein said treatment includes delivery of a paralyzing agent to said pyloric valve.
61. A method according to claim 60 wherein said delivery is done in conjunction with agents to manage acidity of a content of said portion of said small intestine.
62. A method according to claim 61 wherein said agents are selected from a group including H antagonists and PPI's.
63. A method according to claim 51 wherein said stimulation is an electrical stimulation.
64. A method according to claim 63 wherein said stimulation is at a frequency selected to encourage exocrine secretion without excess endocrine secretion.
65. A method according to claim 47 wherein said treating is a stimulation selected to encourage bile delivery to the portion of said small intestine.
66. An apparatus for treating a gastro-intestinal disease of a patient comprising: a generator for generating a stimulation signal; a conductor for electrically connecting said signal generator to a body organ to accelerate a discharge of contents from a portion of said small intestine of the patient to thereby encourage discharge of contents from a stomach of the patient across a pyloric valve of the patient and into said portion of said small intestine.
67. An apparatus according to claim 66 wherein said conductor is selected to engage and stimulate a pancreas to produce and deliver exocrine secretion to said portion of said small intestine.
68. An apparatus according to claim 66 wherein said conductor is selected to engage and stimulate a pancreas to produce and deliver endocrine digestive compounds to the blood of said patient.
69. An apparatus according to claim 66 comprising a controller to initiate said signal generator.
70. An apparatus according to claim 69 wherein said controller is a patient operated controller.
71. An apparatus according to claim 69 wherein said controller is an automatic controller having sensors connected to body organs to sense initiating events and to send a signal to said controller in response to said events.
72. An apparatus according to claim 67 wherein said stimulation is at a frequency selected to encourage exocrine secretion without excess endocrine secretion.
73. An apparatus according to claim 66 wherein said conductor is selected to stimulate delivery of bile to said portion of said small intestine.
PCT/US2004/002847 2003-02-03 2004-01-30 Neural stimulation WO2004069331A2 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
DK04707122.0T DK1601414T3 (en) 2003-02-03 2004-01-30 Neural stimulation
AT04707122T ATE547148T1 (en) 2003-02-03 2004-01-30 NERVE STIMULATION DEVICE
EP04707122A EP1601414B1 (en) 2003-02-03 2004-01-30 Apparatus for neural stimulation

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US10/358,093 US20040172084A1 (en) 2003-02-03 2003-02-03 Method and apparatus for treatment of gastro-esophageal reflux disease (GERD)
US10/358,093 2003-02-03
US10/675,818 US20040176812A1 (en) 2003-02-03 2003-09-29 Enteric rhythm management
US10/674,330 US7489969B2 (en) 2003-02-03 2003-09-29 Vagal down-regulation obesity treatment
US10/675,818 2003-09-29
US10/674,330 2003-09-29
US10/674,324 US20040172085A1 (en) 2003-02-03 2003-09-29 Nerve stimulation and conduction block therapy
US10/674,324 2003-09-29

Publications (3)

Publication Number Publication Date
WO2004069331A2 true WO2004069331A2 (en) 2004-08-19
WO2004069331A3 WO2004069331A3 (en) 2005-01-20
WO2004069331B1 WO2004069331B1 (en) 2005-03-17

Family

ID=32854477

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/002847 WO2004069331A2 (en) 2003-02-03 2004-01-30 Neural stimulation

Country Status (3)

Country Link
US (10) US7444183B2 (en)
EP (1) EP1601414B1 (en)
WO (1) WO2004069331A2 (en)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7678068B2 (en) 2002-12-02 2010-03-16 Gi Dynamics, Inc. Atraumatic delivery devices
US7682330B2 (en) 2003-12-09 2010-03-23 Gi Dynamics, Inc. Intestinal sleeve
US7695446B2 (en) 2002-12-02 2010-04-13 Gi Dynamics, Inc. Methods of treatment using a bariatric sleeve
US7758535B2 (en) 2002-12-02 2010-07-20 Gi Dynamics, Inc. Bariatric sleeve delivery devices
US7766861B2 (en) 2002-12-02 2010-08-03 Gi Dynamics, Inc. Anti-obesity devices
US7815591B2 (en) 2004-09-17 2010-10-19 Gi Dynamics, Inc. Atraumatic gastrointestinal anchor
US7837643B2 (en) 2004-07-09 2010-11-23 Gi Dynamics, Inc. Methods and devices for placing a gastrointestinal sleeve
US7976488B2 (en) 2005-06-08 2011-07-12 Gi Dynamics, Inc. Gastrointestinal anchor compliance
US8057420B2 (en) 2003-12-09 2011-11-15 Gi Dynamics, Inc. Gastrointestinal implant with drawstring
US8137301B2 (en) 2002-12-02 2012-03-20 Gi Dynamics, Inc. Bariatric sleeve
US8801647B2 (en) 2007-02-22 2014-08-12 Gi Dynamics, Inc. Use of a gastrointestinal sleeve to treat bariatric surgery fistulas and leaks
US9526648B2 (en) 2010-06-13 2016-12-27 Synerz Medical, Inc. Intragastric device for treating obesity
US9993297B2 (en) 2013-01-31 2018-06-12 Digma Medical Ltd. Methods and systems for reducing neural activity in an organ of a subject
US10413436B2 (en) 2010-06-13 2019-09-17 W. L. Gore & Associates, Inc. Intragastric device for treating obesity
US10420665B2 (en) 2010-06-13 2019-09-24 W. L. Gore & Associates, Inc. Intragastric device for treating obesity
US10537387B2 (en) 2014-04-17 2020-01-21 Digma Medical Ltd. Methods and systems for blocking neural activity in an organ of a subject, preferably in the small intestine or the duodenum
US10575904B1 (en) 2016-08-14 2020-03-03 Digma Medical Ltd. Apparatus and method for selective submucosal ablation
US10779980B2 (en) 2016-04-27 2020-09-22 Synerz Medical, Inc. Intragastric device for treating obesity
WO2021119741A1 (en) * 2019-12-17 2021-06-24 The Bionics Institute Of Australia Methods and system for modulating glycaemia
US11109913B2 (en) 2016-08-14 2021-09-07 Digma Medical Ltd. Apparatus and method for nerve ablation in the wall of the gastointestinal tract
US11135078B2 (en) 2010-06-13 2021-10-05 Synerz Medical, Inc. Intragastric device for treating obesity

Families Citing this family (380)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7076307B2 (en) * 2002-05-09 2006-07-11 Boveja Birinder R Method and system for modulating the vagus nerve (10th cranial nerve) with electrical pulses using implanted and external components, to provide therapy neurological and neuropsychiatric disorders
US9101765B2 (en) 1999-03-05 2015-08-11 Metacure Limited Non-immediate effects of therapy
US8666495B2 (en) 1999-03-05 2014-03-04 Metacure Limited Gastrointestinal methods and apparatus for use in treating disorders and controlling blood sugar
US6587719B1 (en) * 1999-07-01 2003-07-01 Cyberonics, Inc. Treatment of obesity by bilateral vagus nerve stimulation
US7300449B2 (en) * 1999-12-09 2007-11-27 Mische Hans A Methods and devices for the treatment of neurological and physiological disorders
US6600953B2 (en) 2000-12-11 2003-07-29 Impulse Dynamics N.V. Acute and chronic electrical signal therapy for obesity
US8914114B2 (en) 2000-05-23 2014-12-16 The Feinstein Institute For Medical Research Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation
EP1300401B1 (en) * 2000-06-30 2009-12-09 Dainippon Sumitomo Pharma Co., Ltd. Thiazole derivatives for use as antiinflammatories
US6609025B2 (en) * 2001-01-02 2003-08-19 Cyberonics, Inc. Treatment of obesity by bilateral sub-diaphragmatic nerve stimulation
WO2002053093A2 (en) * 2001-01-05 2002-07-11 Impulse Dynamics Nv Regulation of eating habits
AU2002255245A1 (en) * 2001-04-18 2002-10-28 Impulse Dynamics Nv Analysis of eating habits
US7689284B2 (en) 2001-05-01 2010-03-30 Intrapace, Inc. Pseudounipolar lead for stimulating a digestive organ
US20050143784A1 (en) * 2001-05-01 2005-06-30 Imran Mir A. Gastrointestinal anchor with optimal surface area
US7747322B2 (en) 2001-05-01 2010-06-29 Intrapace, Inc. Digestive organ retention device
US7702394B2 (en) * 2001-05-01 2010-04-20 Intrapace, Inc. Responsive gastric stimulator
US7616996B2 (en) 2005-09-01 2009-11-10 Intrapace, Inc. Randomized stimulation of a gastrointestinal organ
US7756582B2 (en) * 2001-05-01 2010-07-13 Intrapace, Inc. Gastric stimulation anchor and method
US7979127B2 (en) 2001-05-01 2011-07-12 Intrapace, Inc. Digestive organ retention device
US8150519B2 (en) 2002-04-08 2012-04-03 Ardian, Inc. Methods and apparatus for bilateral renal neuromodulation
US7756583B2 (en) 2002-04-08 2010-07-13 Ardian, Inc. Methods and apparatus for intravascularly-induced neuromodulation
US20080213331A1 (en) 2002-04-08 2008-09-04 Ardian, Inc. Methods and devices for renal nerve blocking
US8347891B2 (en) 2002-04-08 2013-01-08 Medtronic Ardian Luxembourg S.A.R.L. Methods and apparatus for performing a non-continuous circumferential treatment of a body lumen
US9308044B2 (en) 2002-04-08 2016-04-12 Medtronic Ardian Luxembourg S.A.R.L. Methods for therapeutic renal neuromodulation
US8175711B2 (en) 2002-04-08 2012-05-08 Ardian, Inc. Methods for treating a condition or disease associated with cardio-renal function
US20140018880A1 (en) 2002-04-08 2014-01-16 Medtronic Ardian Luxembourg S.A.R.L. Methods for monopolar renal neuromodulation
US7620451B2 (en) 2005-12-29 2009-11-17 Ardian, Inc. Methods and apparatus for pulsed electric field neuromodulation via an intra-to-extravascular approach
US6978174B2 (en) 2002-04-08 2005-12-20 Ardian, Inc. Methods and devices for renal nerve blocking
US8774913B2 (en) 2002-04-08 2014-07-08 Medtronic Ardian Luxembourg S.A.R.L. Methods and apparatus for intravasculary-induced neuromodulation
US7617005B2 (en) 2002-04-08 2009-11-10 Ardian, Inc. Methods and apparatus for thermally-induced renal neuromodulation
US8131371B2 (en) 2002-04-08 2012-03-06 Ardian, Inc. Methods and apparatus for monopolar renal neuromodulation
US7162303B2 (en) 2002-04-08 2007-01-09 Ardian, Inc. Renal nerve stimulation method and apparatus for treatment of patients
US7853333B2 (en) 2002-04-08 2010-12-14 Ardian, Inc. Methods and apparatus for multi-vessel renal neuromodulation
US20070129761A1 (en) 2002-04-08 2007-06-07 Ardian, Inc. Methods for treating heart arrhythmia
US8774922B2 (en) 2002-04-08 2014-07-08 Medtronic Ardian Luxembourg S.A.R.L. Catheter apparatuses having expandable balloons for renal neuromodulation and associated systems and methods
US9308043B2 (en) 2002-04-08 2016-04-12 Medtronic Ardian Luxembourg S.A.R.L. Methods for monopolar renal neuromodulation
US8145316B2 (en) 2002-04-08 2012-03-27 Ardian, Inc. Methods and apparatus for renal neuromodulation
US20070135875A1 (en) 2002-04-08 2007-06-14 Ardian, Inc. Methods and apparatus for thermally-induced renal neuromodulation
US7653438B2 (en) 2002-04-08 2010-01-26 Ardian, Inc. Methods and apparatus for renal neuromodulation
US8145317B2 (en) 2002-04-08 2012-03-27 Ardian, Inc. Methods for renal neuromodulation
US9636174B2 (en) 2002-04-08 2017-05-02 Medtronic Ardian Luxembourg S.A.R.L. Methods for therapeutic renal neuromodulation
CA2485271A1 (en) * 2002-05-09 2003-11-20 Daemen College Electrical stimulation unit and waterbath system
US20040082859A1 (en) 2002-07-01 2004-04-29 Alan Schaer Method and apparatus employing ultrasound energy to treat body sphincters
US7844338B2 (en) 2003-02-03 2010-11-30 Enteromedics Inc. High frequency obesity treatment
US20040172084A1 (en) 2003-02-03 2004-09-02 Knudson Mark B. Method and apparatus for treatment of gastro-esophageal reflux disease (GERD)
US7613515B2 (en) * 2003-02-03 2009-11-03 Enteromedics Inc. High frequency vagal blockage therapy
US7444183B2 (en) * 2003-02-03 2008-10-28 Enteromedics, Inc. Intraluminal electrode apparatus and method
US7684865B2 (en) * 2003-03-14 2010-03-23 Endovx, Inc. Methods and apparatus for treatment of obesity
US8792985B2 (en) 2003-07-21 2014-07-29 Metacure Limited Gastrointestinal methods and apparatus for use in treating disorders and controlling blood sugar
US20090259236A2 (en) 2003-07-28 2009-10-15 Baronova, Inc. Gastric retaining devices and methods
US8821521B2 (en) * 2003-07-28 2014-09-02 Baronova, Inc. Gastro-intestinal device and method for treating addiction
US9700450B2 (en) * 2003-07-28 2017-07-11 Baronova, Inc. Devices and methods for gastrointestinal stimulation
US8048169B2 (en) 2003-07-28 2011-11-01 Baronova, Inc. Pyloric valve obstructing devices and methods
US9498366B2 (en) * 2003-07-28 2016-11-22 Baronova, Inc. Devices and methods for pyloric anchoring
WO2005018417A2 (en) * 2003-08-13 2005-03-03 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Compressive device for percutaneous treatment of obesity
US20050070970A1 (en) * 2003-09-29 2005-03-31 Knudson Mark B. Movement disorder stimulation with neural block
US7054690B2 (en) * 2003-10-22 2006-05-30 Intrapace, Inc. Gastrointestinal stimulation device
US9050469B1 (en) 2003-11-26 2015-06-09 Flint Hills Scientific, Llc Method and system for logging quantitative seizure information and assessing efficacy of therapy using cardiac signals
US20060195139A1 (en) * 2004-03-23 2006-08-31 Michael Gertner Extragastric devices and methods for gastroplasty
US7255675B2 (en) * 2004-03-23 2007-08-14 Michael Gertner Devices and methods to treat a patient
US20070233170A1 (en) * 2004-03-23 2007-10-04 Michael Gertner Extragastric Balloon
US7946976B2 (en) * 2004-03-23 2011-05-24 Michael Gertner Methods and devices for the surgical creation of satiety and biofeedback pathways
US20060142790A1 (en) * 2004-03-23 2006-06-29 Michael Gertner Methods and devices to facilitate connections between body lumens
WO2006049725A2 (en) * 2004-03-23 2006-05-11 Minimus Surgical Systems Surgical systems and devices to enhance gastric restriction therapies
US10912712B2 (en) 2004-03-25 2021-02-09 The Feinstein Institutes For Medical Research Treatment of bleeding by non-invasive stimulation
EP1734941A2 (en) * 2004-03-25 2006-12-27 The Feinstein Institute for Medical Research Neural tourniquet
WO2005105003A1 (en) 2004-04-26 2005-11-10 Synecor, Llc Restrictive and/or obstructive implant for inducing weight loss
US7803195B2 (en) 2004-06-03 2010-09-28 Mayo Foundation For Medical Education And Research Obesity treatment and device
JP2008504282A (en) * 2004-06-23 2008-02-14 ザ ファインスタイン インスティテュート フォー メディカル リサーチ Method for treating bowel obstruction by pharmacological activity of cholinergic receptors
US7664551B2 (en) * 2004-07-07 2010-02-16 Medtronic Transneuronix, Inc. Treatment of the autonomic nervous system
US20060020277A1 (en) * 2004-07-20 2006-01-26 Gostout Christopher J Gastric reshaping devices and methods
US20060020298A1 (en) * 2004-07-20 2006-01-26 Camilleri Michael L Systems and methods for curbing appetite
US8612016B2 (en) 2004-08-18 2013-12-17 Metacure Limited Monitoring, analysis, and regulation of eating habits
US20060070334A1 (en) * 2004-09-27 2006-04-06 Blue Hen, Llc Sidewall plank for constructing a trailer and associated trailer sidewall construction
IN266764B (en) 2004-10-15 2015-05-29 Bfkw Llc
US7833279B2 (en) * 2004-11-12 2010-11-16 Enteromedics Inc. Pancreatic exocrine secretion diversion apparatus and method
EP2298410B1 (en) 2004-12-27 2013-10-09 The Feinstein Institute for Medical Research Treating inflammatory disorders by electrical vagus nerve stimulation
US11207518B2 (en) * 2004-12-27 2021-12-28 The Feinstein Institutes For Medical Research Treating inflammatory disorders by stimulation of the cholinergic anti-inflammatory pathway
US8600521B2 (en) 2005-01-27 2013-12-03 Cyberonics, Inc. Implantable medical device having multiple electrode/sensor capability and stimulation based on sensed intrinsic activity
US8565867B2 (en) 2005-01-28 2013-10-22 Cyberonics, Inc. Changeable electrode polarity stimulation by an implantable medical device
US9314633B2 (en) 2008-01-25 2016-04-19 Cyberonics, Inc. Contingent cardio-protection for epilepsy patients
US8260426B2 (en) 2008-01-25 2012-09-04 Cyberonics, Inc. Method, apparatus and system for bipolar charge utilization during stimulation by an implantable medical device
US7561918B2 (en) * 2005-01-28 2009-07-14 Cyberonics, Inc. Autocapture in a neurostimulator
US7454245B2 (en) * 2005-01-28 2008-11-18 Cyberonics, Inc. Trained and adaptive response in a neurostimulator
US9821158B2 (en) 2005-02-17 2017-11-21 Metacure Limited Non-immediate effects of therapy
US8700163B2 (en) * 2005-03-04 2014-04-15 Cyberonics, Inc. Cranial nerve stimulation for treatment of substance addiction
US8463404B2 (en) 2005-03-24 2013-06-11 Metacure Limited Electrode assemblies, tools, and methods for gastric wall implantation
US7835796B2 (en) * 2005-04-29 2010-11-16 Cyberonics, Inc. Weight loss method and device
US7310557B2 (en) * 2005-04-29 2007-12-18 Maschino Steven E Identification of electrodes for nerve stimulation in the treatment of eating disorders
US7899540B2 (en) * 2005-04-29 2011-03-01 Cyberonics, Inc. Noninvasively adjustable gastric band
AU2006323195A1 (en) * 2005-05-10 2007-06-14 Michael Gertner Obesity treatment systems
EP1890763A4 (en) 2005-06-02 2017-05-03 Metacure Limited Gi lead implantation
US7711419B2 (en) * 2005-07-13 2010-05-04 Cyberonics, Inc. Neurostimulator with reduced size
US20070016262A1 (en) 2005-07-13 2007-01-18 Betastim, Ltd. Gi and pancreatic device for treating obesity and diabetes
WO2007013065A2 (en) 2005-07-25 2007-02-01 Rainbow Medical Ltd. Electrical stimulation of blood vessels
US20070027504A1 (en) * 2005-07-27 2007-02-01 Cyberonics, Inc. Cranial nerve stimulation to treat a hearing disorder
US7840280B2 (en) 2005-07-27 2010-11-23 Cyberonics, Inc. Cranial nerve stimulation to treat a vocal cord disorder
US7856273B2 (en) * 2005-07-28 2010-12-21 Cyberonics, Inc. Autonomic nerve stimulation to treat a gastrointestinal disorder
US20070027484A1 (en) * 2005-07-28 2007-02-01 Cyberonics, Inc. Autonomic nerve stimulation to treat a pancreatic disorder
US7672727B2 (en) 2005-08-17 2010-03-02 Enteromedics Inc. Neural electrode treatment
US7822486B2 (en) 2005-08-17 2010-10-26 Enteromedics Inc. Custom sized neural electrodes
US20070073354A1 (en) 2005-09-26 2007-03-29 Knudson Mark B Neural blocking therapy
US8442841B2 (en) 2005-10-20 2013-05-14 Matacure N.V. Patient selection method for assisting weight loss
US20070092591A1 (en) * 2005-10-24 2007-04-26 Cyberonics, Inc. Vacuum mandrel for use in fabricating an implantable electrode
US7957796B2 (en) 2005-10-28 2011-06-07 Cyberonics, Inc. Using physiological sensor data with an implantable medical device
US8509914B2 (en) * 2005-10-28 2013-08-13 Cyberonics, Inc. Insert for implantable electrode
US20090234417A1 (en) * 2005-11-10 2009-09-17 Electrocore, Inc. Methods And Apparatus For The Treatment Of Metabolic Disorders
US8041428B2 (en) * 2006-02-10 2011-10-18 Electrocore Llc Electrical stimulation treatment of hypotension
US8295932B2 (en) 2005-12-05 2012-10-23 Metacure Limited Ingestible capsule for appetite regulation
RS55632B1 (en) * 2005-12-13 2017-06-30 Incyte Holdings Corp Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors
US7996079B2 (en) 2006-01-24 2011-08-09 Cyberonics, Inc. Input response override for an implantable medical device
US7657310B2 (en) 2006-01-26 2010-02-02 Cyberonics, Inc. Treatment of reproductive endocrine disorders by vagus nerve stimulation
US7801601B2 (en) 2006-01-27 2010-09-21 Cyberonics, Inc. Controlling neuromodulation using stimulus modalities
US7467016B2 (en) * 2006-01-27 2008-12-16 Cyberonics, Inc. Multipolar stimulation electrode with mating structures for gripping targeted tissue
CA2637787A1 (en) 2006-02-03 2007-08-16 Synecor, Llc Intravascular device for neuromodulation
JP2009525806A (en) * 2006-02-10 2009-07-16 エレクトロコア、インコーポレイテッド Electrical stimulation treatment for hypotension
US8027718B2 (en) * 2006-03-07 2011-09-27 Mayo Foundation For Medical Education And Research Regional anesthetic
WO2007115103A1 (en) 2006-03-29 2007-10-11 Catholic Healthcare West Microburst electrical stimulation of cranial nerves for the treatment of medical conditions
US8180462B2 (en) 2006-04-18 2012-05-15 Cyberonics, Inc. Heat dissipation for a lead assembly
US20100057178A1 (en) * 2006-04-18 2010-03-04 Electrocore, Inc. Methods and apparatus for spinal cord stimulation using expandable electrode
US8209034B2 (en) * 2008-12-18 2012-06-26 Electrocore Llc Methods and apparatus for electrical stimulation treatment using esophageal balloon and electrode
US20080183237A1 (en) * 2006-04-18 2008-07-31 Electrocore, Inc. Methods And Apparatus For Treating Ileus Condition Using Electrical Signals
US8401650B2 (en) 2008-04-10 2013-03-19 Electrocore Llc Methods and apparatus for electrical treatment using balloon and electrode
US8556925B2 (en) 2007-10-11 2013-10-15 Vibrynt, Inc. Devices and methods for treatment of obesity
US20090281498A1 (en) * 2006-04-19 2009-11-12 Acosta Pablo G Devices, system and methods for minimally invasive abdominal surgical procedures
US20090287227A1 (en) * 2006-04-19 2009-11-19 Newell Matthew B Minimally invasive ,methods for implanting obesity treatment devices
US8398668B2 (en) 2006-04-19 2013-03-19 Vibrynt, Inc. Devices and methods for treatment of obesity
US20090275972A1 (en) * 2006-04-19 2009-11-05 Shuji Uemura Minimally-invasive methods for implanting obesity treatment devices
US8070768B2 (en) 2006-04-19 2011-12-06 Vibrynt, Inc. Devices and methods for treatment of obesity
US20090281376A1 (en) * 2006-04-19 2009-11-12 Acosta Pablo G Devices, system and methods for minimally invasive abdominal surgical procedures
US8187297B2 (en) 2006-04-19 2012-05-29 Vibsynt, Inc. Devices and methods for treatment of obesity
US8342183B2 (en) * 2006-04-19 2013-01-01 Vibrynt, Inc. Devices and methods for treatment of obesity
US7976554B2 (en) * 2006-04-19 2011-07-12 Vibrynt, Inc. Devices, tools and methods for performing minimally invasive abdominal surgical procedures
US20090281386A1 (en) * 2006-04-19 2009-11-12 Acosta Pablo G Devices, system and methods for minimally invasive abdominal surgical procedures
US20090272388A1 (en) * 2006-04-19 2009-11-05 Shuji Uemura Minimally-invasive methods for implanting obesity treatment devices
US20110172767A1 (en) * 2006-04-19 2011-07-14 Pankaj Rathi Minimally invasive, direct delivery methods for implanting obesity treatment devices
US8585733B2 (en) * 2006-04-19 2013-11-19 Vibrynt, Inc Devices, tools and methods for performing minimally invasive abdominal surgical procedures
US20070255335A1 (en) * 2006-04-28 2007-11-01 Medtronic, Inc. Controller for gastric constriction device with selectable electrode configurations
US7869885B2 (en) 2006-04-28 2011-01-11 Cyberonics, Inc Threshold optimization for tissue stimulation therapy
US20070255336A1 (en) * 2006-04-28 2007-11-01 Medtronic, Inc. Gastric constriction device with selectable electrode combinations
US7962220B2 (en) 2006-04-28 2011-06-14 Cyberonics, Inc. Compensation reduction in tissue stimulation therapy
US9020597B2 (en) 2008-11-12 2015-04-28 Endostim, Inc. Device and implantation system for electrical stimulation of biological systems
US7734341B2 (en) * 2006-06-06 2010-06-08 Cardiac Pacemakers, Inc. Method and apparatus for gastrointestinal stimulation via the lymphatic system
US20070282376A1 (en) 2006-06-06 2007-12-06 Shuros Allan C Method and apparatus for neural stimulation via the lymphatic system
US8478420B2 (en) 2006-07-12 2013-07-02 Cyberonics, Inc. Implantable medical device charge balance assessment
US20080027524A1 (en) 2006-07-26 2008-01-31 Maschino Steven E Multi-electrode assembly for an implantable medical device
US8905999B2 (en) 2006-09-01 2014-12-09 Cardiac Pacemakers, Inc. Method and apparatus for endolymphatic drug delivery
US20080071173A1 (en) * 2006-09-18 2008-03-20 Aldrich William N Visualizing Formation of Ablation Lesions
JP4314259B2 (en) * 2006-09-29 2009-08-12 株式会社東芝 Nonvolatile semiconductor memory
US20080086180A1 (en) * 2006-10-05 2008-04-10 Omry Ben-Ezra Techniques for gall bladder stimulation
US9345879B2 (en) 2006-10-09 2016-05-24 Endostim, Inc. Device and implantation system for electrical stimulation of biological systems
US20150224310A1 (en) * 2006-10-09 2015-08-13 Endostim, Inc. Device and Implantation System for Electrical Stimulation of Biological Systems
US11577077B2 (en) 2006-10-09 2023-02-14 Endostim, Inc. Systems and methods for electrical stimulation of biological systems
US9724510B2 (en) * 2006-10-09 2017-08-08 Endostim, Inc. System and methods for electrical stimulation of biological systems
US7738961B2 (en) * 2006-10-09 2010-06-15 Endostim, Inc. Method and apparatus for treatment of the gastrointestinal tract
US7869867B2 (en) 2006-10-27 2011-01-11 Cyberonics, Inc. Implantable neurostimulator with refractory stimulation
US8874216B2 (en) * 2006-11-03 2014-10-28 Gep Technology, Inc. Apparatus and methods for minimally invasive obesity treatment
WO2008085290A2 (en) * 2006-12-28 2008-07-17 Vibrynt, Inc. Devices and methods for treatment of obesity
TWI384986B (en) * 2007-01-17 2013-02-11 Lg Life Sciences Ltd Maleic acid monosalt of antiviral agent and pharmaceutical composition containing the same
US8301239B2 (en) * 2007-01-18 2012-10-30 Cardiac Pacemakers, Inc. Systems, devices and methods for acute autonomic stimulation
US7706875B2 (en) 2007-01-25 2010-04-27 Cyberonics, Inc. Modulation of drug effects by vagus nerve stimulation
US7974707B2 (en) 2007-01-26 2011-07-05 Cyberonics, Inc. Electrode assembly with fibers for a medical device
US20080183264A1 (en) * 2007-01-30 2008-07-31 Cardiac Pacemakers, Inc. Electrode configurations for transvascular nerve stimulation
US20080183265A1 (en) * 2007-01-30 2008-07-31 Cardiac Pacemakers, Inc. Transvascular lead with proximal force relief
US20080183255A1 (en) * 2007-01-30 2008-07-31 Cardiac Pacemakers, Inc. Side port lead delivery system
US8244378B2 (en) * 2007-01-30 2012-08-14 Cardiac Pacemakers, Inc. Spiral configurations for intravascular lead stability
US20080183186A1 (en) * 2007-01-30 2008-07-31 Cardiac Pacemakers, Inc. Method and apparatus for delivering a transvascular lead
US20080183187A1 (en) * 2007-01-30 2008-07-31 Cardiac Pacemakers, Inc. Direct delivery system for transvascular lead
US7949409B2 (en) * 2007-01-30 2011-05-24 Cardiac Pacemakers, Inc. Dual spiral lead configurations
US7917230B2 (en) * 2007-01-30 2011-03-29 Cardiac Pacemakers, Inc. Neurostimulating lead having a stent-like anchor
US8755896B2 (en) * 2007-02-05 2014-06-17 University Of Southern California Treatment of consumption disorders with biostimulation
US9037244B2 (en) * 2007-02-13 2015-05-19 Virender K. Sharma Method and apparatus for electrical stimulation of the pancreatico-biliary system
US8529431B2 (en) 2007-02-14 2013-09-10 Bfkw, Llc Bariatric device and method
US8068918B2 (en) 2007-03-09 2011-11-29 Enteromedics Inc. Remote monitoring and control of implantable devices
AU2008224943A1 (en) * 2007-03-13 2008-09-18 The Feinstein Institute For Medical Research Treatment of inflammation by non-invasive stimulation
US7904175B2 (en) 2007-04-26 2011-03-08 Cyberonics, Inc. Trans-esophageal vagus nerve stimulation
US7962214B2 (en) 2007-04-26 2011-06-14 Cyberonics, Inc. Non-surgical device and methods for trans-esophageal vagus nerve stimulation
US7869884B2 (en) 2007-04-26 2011-01-11 Cyberonics, Inc. Non-surgical device and methods for trans-esophageal vagus nerve stimulation
US7974701B2 (en) 2007-04-27 2011-07-05 Cyberonics, Inc. Dosing limitation for an implantable medical device
US8417329B2 (en) * 2007-05-09 2013-04-09 Metacure Ltd. Analysis and regulation of food intake
US20080281365A1 (en) * 2007-05-09 2008-11-13 Tweden Katherine S Neural signal duty cycle
US20080300657A1 (en) * 2007-05-31 2008-12-04 Mark Raymond Stultz Therapy system
SI2740731T1 (en) 2007-06-13 2016-07-29 Incyte Holdings Coroporation Crystalline salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo(2,3-d)pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile
WO2009013749A2 (en) * 2007-07-24 2009-01-29 Betastim, Ltd. Duodenal eating sensor
US7818069B2 (en) * 2007-07-27 2010-10-19 Cyberonics, Inc. Ribbon electrode
EP2190528B1 (en) 2007-08-20 2014-10-08 Medtronic, Inc. Evaluating therapeutic stimulation electrode configurations based on physiological responses
US20090054947A1 (en) * 2007-08-20 2009-02-26 Medtronic, Inc. Electrode configurations for directional leads
WO2009025824A1 (en) 2007-08-20 2009-02-26 Medtronic, Inc. Implantable medical lead with biased electrode
US8391970B2 (en) 2007-08-27 2013-03-05 The Feinstein Institute For Medical Research Devices and methods for inhibiting granulocyte activation by neural stimulation
US8888797B2 (en) * 2007-09-07 2014-11-18 Baronova, Inc. Device for intermittently obstructing a gastric opening and method of use
WO2009038802A1 (en) * 2007-09-20 2009-03-26 Theodore Khalili Sensor and pacemaker imbedded with a gastric banding
EP3821848A1 (en) * 2007-10-11 2021-05-19 Implantica Patent Ltd. Apparatus for the treatment of gallstones
US20090248033A1 (en) 2007-10-11 2009-10-01 Milux Holding S.A. Method for the treatment of gallstones
US8868203B2 (en) 2007-10-26 2014-10-21 Cyberonics, Inc. Dynamic lead condition detection for an implantable medical device
US8942798B2 (en) 2007-10-26 2015-01-27 Cyberonics, Inc. Alternative operation mode for an implantable medical device based upon lead condition
US20090204173A1 (en) * 2007-11-05 2009-08-13 Zi-Ping Fang Multi-Frequency Neural Treatments and Associated Systems and Methods
US20090149799A1 (en) * 2007-12-05 2009-06-11 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Method for chemical modulation of neural activity
US8170660B2 (en) * 2007-12-05 2012-05-01 The Invention Science Fund I, Llc System for thermal modulation of neural activity
US8989858B2 (en) * 2007-12-05 2015-03-24 The Invention Science Fund I, Llc Implant system for chemical modulation of neural activity
US8165668B2 (en) * 2007-12-05 2012-04-24 The Invention Science Fund I, Llc Method for magnetic modulation of neural conduction
UY31531A1 (en) * 2007-12-17 2009-08-03 SALTS DERIVED FROM 8-OXOADENINE PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND THEIR USE IN THERAPY AS TOLL TYPE RECEIVER MODULATORS (TLR)
US8337404B2 (en) 2010-10-01 2012-12-25 Flint Hills Scientific, Llc Detecting, quantifying, and/or classifying seizures using multimodal data
WO2009094609A1 (en) 2008-01-25 2009-07-30 Sharma Virender K Device and implantation system for electrical stimulation of biological systems
US8571643B2 (en) 2010-09-16 2013-10-29 Flint Hills Scientific, Llc Detecting or validating a detection of a state change from a template of heart rate derivative shape or heart beat wave complex
US8382667B2 (en) 2010-10-01 2013-02-26 Flint Hills Scientific, Llc Detecting, quantifying, and/or classifying seizures using multimodal data
US8565885B2 (en) * 2008-01-30 2013-10-22 The Board Of Regents Of The University Of Texas System Ileal electrical stimulation
US8538535B2 (en) 2010-08-05 2013-09-17 Rainbow Medical Ltd. Enhancing perfusion by contraction
US9005106B2 (en) 2008-01-31 2015-04-14 Enopace Biomedical Ltd Intra-aortic electrical counterpulsation
EP2254659B1 (en) * 2008-02-14 2017-06-14 Enteromedics Inc. Treatment of excess weight by neural downregulation in combination with compositions
US7925352B2 (en) 2008-03-27 2011-04-12 Synecor Llc System and method for transvascularly stimulating contents of the carotid sheath
US9662490B2 (en) 2008-03-31 2017-05-30 The Feinstein Institute For Medical Research Methods and systems for reducing inflammation by neuromodulation and administration of an anti-inflammatory drug
US9211409B2 (en) 2008-03-31 2015-12-15 The Feinstein Institute For Medical Research Methods and systems for reducing inflammation by neuromodulation of T-cell activity
EP2300099A1 (en) 2008-04-04 2011-03-30 Enteromedics Inc. Methods and systems for glucose regulation
US8682449B2 (en) 2008-04-10 2014-03-25 ElectroCore, LLC Methods and apparatus for transcranial stimulation
US8204603B2 (en) * 2008-04-25 2012-06-19 Cyberonics, Inc. Blocking exogenous action potentials by an implantable medical device
US20090275997A1 (en) * 2008-05-01 2009-11-05 Michael Allen Faltys Vagus nerve stimulation electrodes and methods of use
US7890182B2 (en) 2008-05-15 2011-02-15 Boston Scientific Neuromodulation Corporation Current steering for an implantable stimulator device involving fractionalized stimulation pulses
EP2318089A4 (en) 2008-07-11 2011-08-10 Gep Technology Inc Apparatus and methods for minimally invasive obesity treatment
US8768469B2 (en) 2008-08-08 2014-07-01 Enteromedics Inc. Systems for regulation of blood pressure and heart rate
US10603489B2 (en) 2008-10-09 2020-03-31 Virender K. Sharma Methods and apparatuses for stimulating blood vessels in order to control, treat, and/or prevent a hemorrhage
WO2010042686A1 (en) 2008-10-09 2010-04-15 Sharma Virender K Method and apparatus for stimulating the vascular system
US8457747B2 (en) 2008-10-20 2013-06-04 Cyberonics, Inc. Neurostimulation with signal duration determined by a cardiac cycle
US8417344B2 (en) * 2008-10-24 2013-04-09 Cyberonics, Inc. Dynamic cranial nerve stimulation based on brain state determination from cardiac data
US8255057B2 (en) 2009-01-29 2012-08-28 Nevro Corporation Systems and methods for producing asynchronous neural responses to treat pain and/or other patient conditions
CN102215909B (en) * 2008-11-18 2014-09-10 赛博恩特医疗器械公司 Devices and methods for optimizing electrode placement for anti-inflamatory stimulation
WO2010068797A1 (en) * 2008-12-10 2010-06-17 Waverx, Inc. Devices, systems and methods for preventing and treating sensation loss
US20100160995A1 (en) * 2008-12-18 2010-06-24 Jerome Dargent Method for treating obesity
WO2010075482A2 (en) * 2008-12-27 2010-07-01 John Hancock High specific gravity intragastric device
US8652129B2 (en) 2008-12-31 2014-02-18 Medtronic Ardian Luxembourg S.A.R.L. Apparatus, systems, and methods for achieving intravascular, thermally-induced renal neuromodulation
WO2010080886A1 (en) 2009-01-09 2010-07-15 Recor Medical, Inc. Methods and apparatus for treatment of mitral valve in insufficiency
US20100191304A1 (en) 2009-01-23 2010-07-29 Scott Timothy L Implantable Medical Device for Providing Chronic Condition Therapy and Acute Condition Therapy Using Vagus Nerve Stimulation
US20100191271A1 (en) * 2009-01-29 2010-07-29 Lilip Lau Assembly and method for automatically controlling pressure for a gastric band
US20100191265A1 (en) * 2009-01-29 2010-07-29 Cavu Medical, Inc. Assembly and method for automatically controlling pressure for a gastric band
US9101773B2 (en) * 2009-02-06 2015-08-11 Cardiac Pacemakers, Inc. Cross-channel noise detector in implantable medical devices
US8326426B2 (en) * 2009-04-03 2012-12-04 Enteromedics, Inc. Implantable device with heat storage
CN102448365B (en) 2009-04-03 2016-02-10 内测公司 Strengthen the feedback system of obstructive and other obesity process
EP2586488B1 (en) 2009-04-22 2017-03-15 Nevro Corporation Selective high frequency spinal cord modulation for inhibiting pain with reduced side effects, and associated systems
EP2756864B1 (en) 2009-04-22 2023-03-15 Nevro Corporation Spinal cord modulation systems for inducing paresthetic and anesthetic effects
US8239028B2 (en) * 2009-04-24 2012-08-07 Cyberonics, Inc. Use of cardiac parameters in methods and systems for treating a chronic medical condition
US8827912B2 (en) 2009-04-24 2014-09-09 Cyberonics, Inc. Methods and systems for detecting epileptic events using NNXX, optionally with nonlinear analysis parameters
US8612002B2 (en) 2009-12-23 2013-12-17 Setpoint Medical Corporation Neural stimulation devices and systems for treatment of chronic inflammation
US8996116B2 (en) 2009-10-30 2015-03-31 Setpoint Medical Corporation Modulation of the cholinergic anti-inflammatory pathway to treat pain or addiction
US9211410B2 (en) 2009-05-01 2015-12-15 Setpoint Medical Corporation Extremely low duty-cycle activation of the cholinergic anti-inflammatory pathway to treat chronic inflammation
US8591396B2 (en) * 2009-05-04 2013-11-26 Covidien Lp Magnetic gastric reduction device
US8414559B2 (en) 2009-05-07 2013-04-09 Rainbow Medical Ltd. Gastroretentive duodenal pill
TWI484962B (en) 2009-05-22 2015-05-21 Incyte Corp 3-(4-(7h-pyrrolo(2,3-d)pyrimidin-4-yl)-1h-pyrazol-1-yl)octane-or heptane-nitrile as jak inhibitors
EP2440284B1 (en) 2009-06-09 2018-09-12 Setpoint Medical Corporation Nerve cuff with pocket for leadless stimulator
US8954166B2 (en) * 2009-06-21 2015-02-10 Eugene Eustis Pettinelli Induced modulation of neuronal transmission
US8498710B2 (en) 2009-07-28 2013-07-30 Nevro Corporation Linked area parameter adjustment for spinal cord stimulation and associated systems and methods
US9249145B2 (en) * 2009-09-01 2016-02-02 Incyte Holdings Corporation Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors
US9833621B2 (en) 2011-09-23 2017-12-05 Setpoint Medical Corporation Modulation of sirtuins by vagus nerve stimulation
US11051744B2 (en) 2009-11-17 2021-07-06 Setpoint Medical Corporation Closed-loop vagus nerve stimulation
US8321012B2 (en) 2009-12-22 2012-11-27 The Invention Science Fund I, Llc Device, method, and system for neural modulation as vaccine adjuvant in a vertebrate subject
WO2011092710A2 (en) 2010-02-01 2011-08-04 Metacure Limited Gastrointestinal electrical therapy
US8447404B2 (en) 2010-03-05 2013-05-21 Endostim, Inc. Device and implantation system for electrical stimulation of biological systems
US11717681B2 (en) 2010-03-05 2023-08-08 Endostim, Inc. Systems and methods for treating gastroesophageal reflux disease
LT3050882T (en) 2010-03-10 2018-06-11 Incyte Holdings Corporation Piperidin-4-yl azetidine derivatives as jak1 inhibitors
US8478428B2 (en) 2010-04-23 2013-07-02 Cyberonics, Inc. Helical electrode for nerve stimulation
US8831732B2 (en) 2010-04-29 2014-09-09 Cyberonics, Inc. Method, apparatus and system for validating and quantifying cardiac beat data quality
US8649871B2 (en) 2010-04-29 2014-02-11 Cyberonics, Inc. Validity test adaptive constraint modification for cardiac data used for detection of state changes
US8562536B2 (en) 2010-04-29 2013-10-22 Flint Hills Scientific, Llc Algorithm for detecting a seizure from cardiac data
KR102303885B1 (en) 2010-05-21 2021-09-24 인사이트 홀딩스 코포레이션 Topical formulation for a jak inhibitor
US8825164B2 (en) 2010-06-11 2014-09-02 Enteromedics Inc. Neural modulation devices and methods
US8679009B2 (en) 2010-06-15 2014-03-25 Flint Hills Scientific, Llc Systems approach to comorbidity assessment
US8641646B2 (en) 2010-07-30 2014-02-04 Cyberonics, Inc. Seizure detection using coordinate data
WO2012045030A2 (en) 2010-10-01 2012-04-05 Intrapace, Inc. Feedback systems and methods to enhance obstructive and other obesity treatments, optionally using multiple sensors
US8684921B2 (en) 2010-10-01 2014-04-01 Flint Hills Scientific Llc Detecting, assessing and managing epilepsy using a multi-variate, metric-based classification analysis
EP2632373B1 (en) 2010-10-25 2018-07-18 Medtronic Ardian Luxembourg S.à.r.l. System for evaluation and feedback of neuromodulation treatment
US9034884B2 (en) 2010-11-19 2015-05-19 Incyte Corporation Heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines as JAK inhibitors
CA2818542A1 (en) 2010-11-19 2012-05-24 Incyte Corporation Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as jak inhibitors
US8649874B2 (en) 2010-11-30 2014-02-11 Nevro Corporation Extended pain relief via high frequency spinal cord modulation, and associated systems and methods
US9504390B2 (en) 2011-03-04 2016-11-29 Globalfoundries Inc. Detecting, assessing and managing a risk of death in epilepsy
AU2012242533B2 (en) 2011-04-14 2016-10-20 Endostim, Inc. Systems and methods for treating gastroesophageal reflux disease
US9498162B2 (en) 2011-04-25 2016-11-22 Cyberonics, Inc. Identifying seizures using heart data from two or more windows
WO2012149167A2 (en) 2011-04-26 2012-11-01 Christopher Gerard Kunis Method and device for treatment of hypertension and other maladies
US9402550B2 (en) 2011-04-29 2016-08-02 Cybertronics, Inc. Dynamic heart rate threshold for neurological event detection
CN103619405B (en) 2011-05-09 2015-11-25 赛博恩特医疗器械公司 The individual pulse being used for the treatment of the cholinergic anti-inflammatory pathway of chronic inflammatory disease activates
US10758723B2 (en) 2011-05-19 2020-09-01 Neuros Medical, Inc. Nerve cuff electrode for neuromodulation in large human nerve trunks
US11413458B2 (en) 2011-05-19 2022-08-16 Neuros Medical, Inc. Nerve cuff electrode for neuromodulation in large human nerve trunks
CA2834180C (en) 2011-05-19 2019-04-30 Neuros Medical, Inc. High-frequency electrical nerve block
US9295841B2 (en) 2011-05-19 2016-03-29 Meuros Medical, Inc. High-frequency electrical nerve block
AU2012273164B2 (en) 2011-06-20 2015-05-28 Incyte Holdings Corporation Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors
US9999767B2 (en) 2011-06-27 2018-06-19 E-Motion Medical, Ltd. Esophageal stimulation system
EP2723445B1 (en) * 2011-06-27 2016-12-07 E-Motion Medical Ltd. Esophageal stimulation devices
CN102952138B (en) * 2011-08-17 2016-07-06 上海特化医药科技有限公司 The salt of a kind of pyrazolopyrimidinone compound, polymorph and pharmaceutical composition, preparation method and application
TW201313721A (en) 2011-08-18 2013-04-01 Incyte Corp Cyclohexyl azetidine derivatives as JAK inhibitors
WO2013033673A1 (en) 2011-09-02 2013-03-07 Endostim, Inc. Endoscopic lead implantation method
US9925367B2 (en) 2011-09-02 2018-03-27 Endostim, Inc. Laparoscopic lead implantation method
UA111854C2 (en) 2011-09-07 2016-06-24 Інсайт Холдінгс Корпорейшн METHODS AND INTERMEDIATE COMPOUNDS FOR JAK INHIBITORS
AU2012304370B2 (en) 2011-09-08 2016-01-28 Nevro Corporation Selective high frequency spinal cord modulation for inhibiting pain, including cephalic and/or total body pain with reduced side effects, and associated systems and methods
WO2013035092A2 (en) 2011-09-09 2013-03-14 Enopace Biomedical Ltd. Wireless endovascular stent-based electrodes
US9549677B2 (en) 2011-10-14 2017-01-24 Flint Hills Scientific, L.L.C. Seizure detection methods, apparatus, and systems using a wavelet transform maximum modulus algorithm
WO2013082587A1 (en) * 2011-12-02 2013-06-06 Enterx, Inc. Method for modulating the enteric nervous system to treat a disorder
US8382775B1 (en) 2012-01-08 2013-02-26 Vibrynt, Inc. Methods, instruments and devices for extragastric reduction of stomach volume
US9314362B2 (en) 2012-01-08 2016-04-19 Vibrynt, Inc. Methods, instruments and devices for extragastric reduction of stomach volume
US10576278B2 (en) 2012-02-21 2020-03-03 Virender K. Sharma System and method for electrical stimulation of anorectal structures to treat urinary dysfunction
US8706234B2 (en) 2012-02-21 2014-04-22 Virender K. Sharma System and method for electrical stimulation of anorectal structures to treat anal dysfunction
US9782583B2 (en) 2012-02-21 2017-10-10 Virender K. Sharma System and method for electrical stimulation of anorectal structures to treat urinary dysfunction
JP6195856B2 (en) 2012-03-08 2017-09-13 メドトロニック アーディアン ルクセンブルク ソシエテ ア レスポンサビリテ リミテ Biomarker sampling and related systems and methods for neuromodulators
WO2013134548A2 (en) 2012-03-08 2013-09-12 Medtronic Ardian Luxembourg S.A.R.L. Ovarian neuromodulation and associated systems and methods
US9572983B2 (en) 2012-03-26 2017-02-21 Setpoint Medical Corporation Devices and methods for modulation of bone erosion
WO2013143599A1 (en) * 2012-03-30 2013-10-03 Ethicon Endo-Surgery, Inc. Devices and methods for the treatment of metabolic disorders.
WO2013143600A1 (en) * 2012-03-30 2013-10-03 Ethicon Endo-Surgery, Inc. Devices and methods for the treatment of metabolic disorders.
US8676331B2 (en) 2012-04-02 2014-03-18 Nevro Corporation Devices for controlling spinal cord modulation for inhibiting pain, and associated systems and methods, including controllers for automated parameter selection
US10448839B2 (en) 2012-04-23 2019-10-22 Livanova Usa, Inc. Methods, systems and apparatuses for detecting increased risk of sudden death
AR091079A1 (en) 2012-05-18 2014-12-30 Incyte Corp DERIVATIVES OF PIRROLOPIRIMIDINA AND PIRROLOPIRIDINA REPLACED WITH PIPERIDINILCICLOBUTILO AS JAK INHIBITORS
US9456916B2 (en) 2013-03-12 2016-10-04 Medibotics Llc Device for selectively reducing absorption of unhealthy food
US9833614B1 (en) 2012-06-22 2017-12-05 Nevro Corp. Autonomic nervous system control via high frequency spinal cord modulation, and associated systems and methods
AU2013305543A1 (en) 2012-08-23 2015-03-19 Endostim, Inc. Device and implantation system for electrical stimulation of biological systems
US20140110296A1 (en) 2012-10-19 2014-04-24 Medtronic Ardian Luxembourg S.A.R.L. Packaging for Catheter Treatment Devices and Associated Devices, Systems, and Methods
PE20151157A1 (en) 2012-11-15 2015-08-19 Incyte Corp SUSTAINED RELEASE RUXOLITINIB DOSAGE FORMS
CA2896309A1 (en) 2012-12-24 2014-07-03 E-Motion Medical, Ltd. Gi tract stimulation devices and methods
US10220211B2 (en) 2013-01-22 2019-03-05 Livanova Usa, Inc. Methods and systems to diagnose depression
JP5945061B2 (en) * 2013-02-13 2016-07-05 ハバロン メヂ アンド ビューティー カンパニー リミテッド Portable high-frequency treatment device with built-in battery
US9498619B2 (en) 2013-02-26 2016-11-22 Endostim, Inc. Implantable electrical stimulation leads
CA2903418C (en) 2013-03-06 2021-03-23 Incyte Corporation Processes and intermediates for making a jak inhibitor
US9011365B2 (en) 2013-03-12 2015-04-21 Medibotics Llc Adjustable gastrointestinal bifurcation (AGB) for reduced absorption of unhealthy food
US9067070B2 (en) 2013-03-12 2015-06-30 Medibotics Llc Dysgeusia-inducing neurostimulation for modifying consumption of a selected nutrient type
US9056195B2 (en) 2013-03-15 2015-06-16 Cyberonics, Inc. Optimization of cranial nerve stimulation to treat seizure disorderse during sleep
WO2014150894A1 (en) 2013-03-15 2014-09-25 Baronova, Inc. Locking gastric obstruction device and method of use
US11229789B2 (en) 2013-05-30 2022-01-25 Neurostim Oab, Inc. Neuro activator with controller
EP3441109A1 (en) 2013-05-30 2019-02-13 Graham H. Creasey Flexible dermal patch for a topical nerve stimulator system
US9895539B1 (en) 2013-06-10 2018-02-20 Nevro Corp. Methods and systems for disease treatment using electrical stimulation
KR20220103810A (en) 2013-08-07 2022-07-22 인사이트 코포레이션 Sustained release dosage forms for a jak1 inhibitor
WO2015034867A2 (en) 2013-09-03 2015-03-12 Endostim, Inc. Methods and systems of electrode polarity switching in electrical stimulation therapy
CN108836586B (en) 2013-11-06 2021-04-06 伊诺佩斯生医有限公司 Wireless intravascular stent-based electrode
US10149978B1 (en) 2013-11-07 2018-12-11 Nevro Corp. Spinal cord modulation for inhibiting pain via short pulse width waveforms, and associated systems and methods
EP3071291A4 (en) * 2013-11-20 2017-08-02 Endostim, Inc. Systems and methods for electrical stimulation of biological systems
EP3092032A2 (en) * 2014-01-06 2016-11-16 Ohio State Innovation Foundation Neuromodulatory systems and methods for treating functional gastrointestinal disorders
WO2015134747A1 (en) 2014-03-06 2015-09-11 Mayo Foundation For Medical Education And Research Apparatus and methods of inducing weight loss using blood flow control
US10194979B1 (en) 2014-03-28 2019-02-05 Medtronic Ardian Luxembourg S.A.R.L. Methods for catheter-based renal neuromodulation
US9980766B1 (en) 2014-03-28 2018-05-29 Medtronic Ardian Luxembourg S.A.R.L. Methods and systems for renal neuromodulation
US10194980B1 (en) 2014-03-28 2019-02-05 Medtronic Ardian Luxembourg S.A.R.L. Methods for catheter-based renal neuromodulation
WO2015153427A1 (en) * 2014-03-31 2015-10-08 Regents Of The University Of Minnesota Systems and methods for electrical stimulation of the gastrointestinal tract for treatment of post-operative ileus
US9585611B2 (en) 2014-04-25 2017-03-07 Cyberonics, Inc. Detecting seizures based on heartbeat data
US9302109B2 (en) 2014-04-25 2016-04-05 Cyberonics, Inc. Cranial nerve stimulation to treat depression during sleep
WO2015184305A1 (en) 2014-05-30 2015-12-03 Incyte Corporation TREATMENT OF CHRONIC NEUTROPHILIC LEUKEMIA (CNL) AND ATYPICAL CHRONIC MYELOID LEUKEMIA (aCML) BY INHIBITORS OF JAK1
US11311725B2 (en) 2014-10-24 2022-04-26 Setpoint Medical Corporation Systems and methods for stimulating and/or monitoring loci in the brain to treat inflammation and to enhance vagus nerve stimulation
WO2016073728A1 (en) 2014-11-05 2016-05-12 Enterastim, Inc. Conditional gastrointestinal stimulation for improved motility
WO2016081468A2 (en) 2014-11-17 2016-05-26 Endostim, Inc. Implantable electro-medical device programmable for improved operational life
WO2016126807A1 (en) 2015-02-03 2016-08-11 Setpoint Medical Corporation Apparatus and method for reminding, prompting, or alerting a patient with an implanted stimulator
US11077301B2 (en) 2015-02-21 2021-08-03 NeurostimOAB, Inc. Topical nerve stimulator and sensor for bladder control
US10118035B2 (en) 2015-02-24 2018-11-06 Elira, Inc. Systems and methods for enabling appetite modulation and/or improving dietary compliance using an electro-dermal patch
US10376145B2 (en) 2015-02-24 2019-08-13 Elira, Inc. Systems and methods for enabling a patient to achieve a weight loss objective using an electrical dermal patch
US10335302B2 (en) 2015-02-24 2019-07-02 Elira, Inc. Systems and methods for using transcutaneous electrical stimulation to enable dietary interventions
US10864367B2 (en) 2015-02-24 2020-12-15 Elira, Inc. Methods for using an electrical dermal patch in a manner that reduces adverse patient reactions
US9956393B2 (en) 2015-02-24 2018-05-01 Elira, Inc. Systems for increasing a delay in the gastric emptying time for a patient using a transcutaneous electro-dermal patch
US10765863B2 (en) 2015-02-24 2020-09-08 Elira, Inc. Systems and methods for using a transcutaneous electrical stimulation device to deliver titrated therapy
US11318310B1 (en) 2015-10-26 2022-05-03 Nevro Corp. Neuromodulation for altering autonomic functions, and associated systems and methods
US10531907B2 (en) 2015-11-20 2020-01-14 Covidien Lp Devices, systems, and methods for treating ulcerative colitis and other inflammatory bowel diseases
US10596367B2 (en) 2016-01-13 2020-03-24 Setpoint Medical Corporation Systems and methods for establishing a nerve block
WO2017127758A1 (en) 2016-01-20 2017-07-27 Setpoint Medical Corporation Implantable microstimulators and inductive charging systems
CN114904142A (en) 2016-01-20 2022-08-16 赛博恩特医疗器械公司 Control of vagal nerve stimulation
US11471681B2 (en) 2016-01-20 2022-10-18 Setpoint Medical Corporation Batteryless implantable microstimulators
US10583304B2 (en) 2016-01-25 2020-03-10 Setpoint Medical Corporation Implantable neurostimulator having power control and thermal regulation and methods of use
WO2017132174A1 (en) 2016-01-25 2017-08-03 Nevro Corp. Treatment of congestive heart failure with electrical stimulation, and associated systems and methods
US10799701B2 (en) 2016-03-30 2020-10-13 Nevro Corp. Systems and methods for identifying and treating patients with high-frequency electrical signals
US11446504B1 (en) 2016-05-27 2022-09-20 Nevro Corp. High frequency electromagnetic stimulation for modulating cells, including spontaneously active and quiescent cells, and associated systems and methods
WO2018094207A1 (en) 2016-11-17 2018-05-24 Endostim, Inc. Modular stimulation system for the treatment of gastrointestinal disorders
US11083613B2 (en) 2017-01-23 2021-08-10 Baronova, Inc. Gastric obstruction device deployment assembly and methods of delivering and deploying a gastric obstruction device
WO2019036470A1 (en) 2017-08-14 2019-02-21 Setpoint Medical Corporation Vagus nerve stimulation pre-screening test
EP3706856A4 (en) 2017-11-07 2021-08-18 Neurostim Oab, Inc. Non-invasive nerve activator with adaptive circuit
US10596161B2 (en) 2017-12-08 2020-03-24 Incyte Corporation Low dose combination therapy for treatment of myeloproliferative neoplasms
US11116965B2 (en) 2017-12-13 2021-09-14 Neuros Medical, Inc. Nerve cuff deployment devices
US11864907B2 (en) 2018-01-16 2024-01-09 Boston Scientific Scimed, Inc. Devices, systems, and methods for monitoring gastrointestinal motility
UA127488C2 (en) 2018-01-30 2023-09-06 Інсайт Корпорейшн Processes for preparing (1 -(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidine-4-one)
AU2019245420A1 (en) 2018-03-30 2020-11-12 Incyte Corporation Treatment of hidradenitis suppurativa using JAK inhibitors
BR112020020867A2 (en) 2018-04-09 2021-01-26 Neuros Medical, Inc. apparatus and methods for adjusting electrical dose
WO2020068830A1 (en) 2018-09-24 2020-04-02 Vivek Sharma Auricular nerve stimulation to address patient disorders, and associated systems and methods
US11260229B2 (en) 2018-09-25 2022-03-01 The Feinstein Institutes For Medical Research Methods and apparatuses for reducing bleeding via coordinated trigeminal and vagal nerve stimulation
JP2020089723A (en) * 2018-12-07 2020-06-11 アヴェント インコーポレイテッド Device and method for selectively and reversibly modulating nervous system structure to inhibit perception of pain
US11602634B2 (en) 2019-01-17 2023-03-14 Nevro Corp. Sensory threshold adaptation for neurological therapy screening and/or electrode selection, and associated systems and methods
US11590352B2 (en) 2019-01-29 2023-02-28 Nevro Corp. Ramped therapeutic signals for modulating inhibitory interneurons, and associated systems and methods
JP2022538419A (en) 2019-06-26 2022-09-02 ニューロスティム テクノロジーズ エルエルシー Noninvasive neuroactivation device with adaptive circuitry
CR20220280A (en) 2019-11-22 2022-09-02 Incyte Corp Combination therapy comprising an alk2 inhibitor and a jak2 inhibitor
WO2021126921A1 (en) 2019-12-16 2021-06-24 Neurostim Solutions, Llc Non-invasive nerve activator with boosted charge delivery
AU2021219722A1 (en) 2020-02-11 2022-09-08 Neuros Medical, Inc. System and method for quantifying qualitative patient-reported data sets
US11559385B2 (en) 2020-04-24 2023-01-24 Jt Godfrey, Llc Device for use with body tissue sphincters
US11628052B2 (en) 2020-05-13 2023-04-18 Jt Godfrey, Llc Device for use with body tissue sphincters
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms
US11400299B1 (en) 2021-09-14 2022-08-02 Rainbow Medical Ltd. Flexible antenna for stimulator

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5263480A (en) * 1991-02-01 1993-11-23 Cyberonics, Inc. Treatment of eating disorders by nerve stimulation
US20010012828A1 (en) * 1999-10-12 2001-08-09 Aoki Kei Roger Intraspinal botulinum toxin for treating pain
US20020055779A1 (en) * 1996-03-05 2002-05-09 Brian J. Andrews Neural prosthesis

Family Cites Families (223)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US181958A (en) * 1876-09-05 Improvement in mop-heads
US127953A (en) * 1872-06-18 Improvement in processes for purifying iron, steel, and other metals
US181959A (en) * 1876-09-05 Improvement in combined spading, plowing, and stalk-cutting machines
US3128760A (en) * 1961-08-21 1964-04-14 Winston Electronics Ltd Vagotomy test apparatus
US3411507A (en) * 1964-04-01 1968-11-19 Medtronic Inc Method of gastrointestinal stimulation with electrical pulses
US4315503A (en) 1976-11-17 1982-02-16 Electro-Biology, Inc. Modification of the growth, repair and maintenance behavior of living tissues and cells by a specific and selective change in electrical environment
US4114625A (en) * 1976-12-02 1978-09-19 Onat Mustafa V Anti-vomiting, anti-aspirating oral-nasal gastric tube
US4198963A (en) * 1978-10-19 1980-04-22 Michigan Instruments, Inc. Cardiopulmonary resuscitator, defibrillator and monitor
US4441210A (en) 1981-09-18 1984-04-03 Hochmair Erwin S Transcutaneous signal transmission system and methods
US5370675A (en) 1992-08-12 1994-12-06 Vidamed, Inc. Medical probe device and method
CA1215128A (en) 1982-12-08 1986-12-09 Pedro Molina-Negro Electric nerve stimulator device
US4702254A (en) 1983-09-14 1987-10-27 Jacob Zabara Neurocybernetic prosthesis
US5025807A (en) 1983-09-14 1991-06-25 Jacob Zabara Neurocybernetic prosthesis
US4867164A (en) 1983-09-14 1989-09-19 Jacob Zabara Neurocybernetic prosthesis
AT385894B (en) * 1985-10-04 1988-05-25 Basem Dr Nashef TUBULAR PROBE
US5226426A (en) * 1990-12-18 1993-07-13 Inbae Yoon Safety penetrating instrument
US5188104A (en) 1991-02-01 1993-02-23 Cyberonics, Inc. Treatment of eating disorders by nerve stimulation
US5269303A (en) 1991-02-22 1993-12-14 Cyberonics, Inc. Treatment of dementia by nerve stimulation
US5199430A (en) * 1991-03-11 1993-04-06 Case Western Reserve University Micturitional assist device
US5215086A (en) 1991-05-03 1993-06-01 Cyberonics, Inc. Therapeutic treatment of migraine symptoms by stimulation
US5335657A (en) 1991-05-03 1994-08-09 Cyberonics, Inc. Therapeutic treatment of sleep disorder by nerve stimulation
US5299569A (en) 1991-05-03 1994-04-05 Cyberonics, Inc. Treatment of neuropsychiatric disorders by nerve stimulation
US5226429A (en) 1991-06-20 1993-07-13 Inamed Development Co. Laparoscopic gastric band and method
US5231988A (en) * 1991-08-09 1993-08-03 Cyberonics, Inc. Treatment of endocrine disorders by nerve stimulation
IT1260485B (en) * 1992-05-29 1996-04-09 PROCEDURE AND DEVICE FOR THE TREATMENT OF THE OBESITY OF A PATIENT
US5330515A (en) 1992-06-17 1994-07-19 Cyberonics, Inc. Treatment of pain by vagal afferent stimulation
US5292344A (en) 1992-07-10 1994-03-08 Douglas Donald D Percutaneously placed electrical gastrointestinal pacemaker stimulatory system, sensing system, and pH monitoring system, with optional delivery port
US5344438A (en) 1993-04-16 1994-09-06 Medtronic, Inc. Cuff electrode
US5601604A (en) 1993-05-27 1997-02-11 Inamed Development Co. Universal gastric band
US5620955A (en) 1993-06-18 1997-04-15 Peptide Technologies Corporation Bombesin receptor antagonists and uses thereof
US5437291A (en) * 1993-08-26 1995-08-01 Univ Johns Hopkins Method for treating gastrointestinal muscle disorders and other smooth muscle dysfunction
US6974578B1 (en) 1993-12-28 2005-12-13 Allergan, Inc. Method for treating secretions and glands using botulinum toxin
US6405732B1 (en) 1994-06-24 2002-06-18 Curon Medical, Inc. Method to treat gastric reflux via the detection and ablation of gastro-esophageal nerves and receptors
US5514175A (en) 1994-11-09 1996-05-07 Cerebral Stimulation, Inc. Auricular electrical stimulator
US5571150A (en) 1994-12-19 1996-11-05 Cyberonics, Inc. Treatment of patients in coma by nerve stimulation
US6558708B1 (en) 1995-05-17 2003-05-06 Cedars-Sinai Medical Center Methods for manipulating upper gastrointestinal transit, blood flow, and satiety, and for treating visceral hyperalgesia
US5540730A (en) * 1995-06-06 1996-07-30 Cyberonics, Inc. Treatment of motility disorders by nerve stimulation
US5707400A (en) 1995-09-19 1998-01-13 Cyberonics, Inc. Treating refractory hypertension by nerve stimulation
US5747060A (en) 1996-03-26 1998-05-05 Euro-Celtique, S.A. Prolonged local anesthesia with colchicine
US6735471B2 (en) * 1996-04-30 2004-05-11 Medtronic, Inc. Method and system for endotracheal/esophageal stimulation prior to and during a medical procedure
US6532388B1 (en) 1996-04-30 2003-03-11 Medtronic, Inc. Method and system for endotracheal/esophageal stimulation prior to and during a medical procedure
US5690691A (en) 1996-05-08 1997-11-25 The Center For Innovative Technology Gastro-intestinal pacemaker having phased multi-point stimulation
US6865423B2 (en) 1996-06-13 2005-03-08 The Victoria University Of Manchester Stimulation of muscles
US6243607B1 (en) 1996-09-05 2001-06-05 University Technologies International Inc. Gastro-intestinal electrical pacemaker
US5716385A (en) 1996-11-12 1998-02-10 University Of Virginia Crural diaphragm pacemaker and method for treating esophageal reflux disease
JP3246374B2 (en) 1997-01-13 2002-01-15 株式会社日立製作所 Magnetic recording device using magnetoresistive element
US6026326A (en) 1997-01-13 2000-02-15 Medtronic, Inc. Apparatus and method for treating chronic constipation
US5749907A (en) 1997-02-18 1998-05-12 Pacesetter, Inc. System and method for identifying and displaying medical data which violate programmable alarm conditions
US5830434A (en) 1997-02-26 1998-11-03 Medical University Of South Carolina Foundation For Research Development Methods of treating non-insulin dependent diabetes mellitus with pancreatic polypeptide
DE69832713T2 (en) 1997-02-26 2006-07-27 Alfred E. Mann Foundation For Scientific Research, Santa Clarita BATTERY OPERATING DEVICE FOR IMPLANTING IN A PATIENT
US5938596A (en) 1997-03-17 1999-08-17 Medtronic, Inc. Medical electrical lead
US5836994A (en) 1997-04-30 1998-11-17 Medtronic, Inc. Method and apparatus for electrical stimulation of the gastrointestinal tract
US5861014A (en) 1997-04-30 1999-01-19 Medtronic, Inc. Method and apparatus for sensing a stimulating gastrointestinal tract on-demand
US6216039B1 (en) 1997-05-02 2001-04-10 Medtronic Inc. Method and apparatus for treating irregular gastric rhythms
US5919216A (en) 1997-06-16 1999-07-06 Medtronic, Inc. System and method for enhancement of glucose production by stimulation of pancreatic beta cells
US6093167A (en) 1997-06-16 2000-07-25 Medtronic, Inc. System for pancreatic stimulation and glucose measurement
ATE426430T1 (en) 1997-07-16 2009-04-15 Metacure N V DEVICE FOR CONTROLLING A SMOOTH MUSCLE
IT1293974B1 (en) 1997-08-13 1999-03-15 Sorin Biomedica Cardio Spa ACTIVE IMPLANTABLE DEVICE.
US6479523B1 (en) 1997-08-26 2002-11-12 Emory University Pharmacologic drug combination in vagal-induced asystole
US5967977A (en) * 1997-10-03 1999-10-19 Medtronic, Inc. Transesophageal medical lead
US6104955A (en) 1997-12-15 2000-08-15 Medtronic, Inc. Method and apparatus for electrical stimulation of the gastrointestinal tract
US6091992A (en) 1997-12-15 2000-07-18 Medtronic, Inc. Method and apparatus for electrical stimulation of the gastrointestinal tract
US6364899B1 (en) 1998-01-23 2002-04-02 Innercool Therapies, Inc. Heat pipe nerve cooler
US7468060B2 (en) 1998-02-19 2008-12-23 Respiratory Diagnostic, Inc. Systems and methods for treating obesity and other gastrointestinal conditions
BR9911299A (en) * 1998-06-15 2001-03-13 Sepracor Inc Processes for treating bulimia, for treating disorders mediated by vagal activity, for treating irritable bowel syndrome, for treating bradycardia or bradyarrhythmia, for treating asthma, for treating urinary incontinence, for treating apnea or apnea disorders, or for apnea disorders, to prevent or controlling bulimia, disorders mediated by vagal activity, irritable bowel syndrome, bradycardia or bradyarrhythmia, asthma, urinary incontinence, and, apnea or apnea disorders, in a patient
US6148222A (en) 1998-07-10 2000-11-14 Cardiocommand, Inc. Esophageal catheters and method of use
US6002964A (en) 1998-07-15 1999-12-14 Feler; Claudio A. Epidural nerve root stimulation
WO2000006249A2 (en) 1998-07-27 2000-02-10 Case Western Reserve University Method and apparatus for closed-loop stimulation of the hypoglossal nerve in human patients to treat obstructive sleep apnea
US7599736B2 (en) 2001-07-23 2009-10-06 Dilorenzo Biomedical, Llc Method and apparatus for neuromodulation and physiologic modulation for the treatment of metabolic and neuropsychiatric disease
DE19847446B4 (en) 1998-10-08 2010-04-22 Biotronik Gmbh & Co. Kg Nerve electrode assembly
US20050137644A1 (en) * 1998-10-26 2005-06-23 Boveja Birinder R. Method and system for vagal blocking and/or vagal stimulation to provide therapy for obesity and other gastrointestinal disorders
US7076307B2 (en) * 2002-05-09 2006-07-11 Boveja Birinder R Method and system for modulating the vagus nerve (10th cranial nerve) with electrical pulses using implanted and external components, to provide therapy neurological and neuropsychiatric disorders
US6611715B1 (en) 1998-10-26 2003-08-26 Birinder R. Boveja Apparatus and method for neuromodulation therapy for obesity and compulsive eating disorders using an implantable lead-receiver and an external stimulator
US20030212440A1 (en) * 2002-05-09 2003-11-13 Boveja Birinder R. Method and system for modulating the vagus nerve (10th cranial nerve) using modulated electrical pulses with an inductively coupled stimulation system
US6366814B1 (en) 1998-10-26 2002-04-02 Birinder R. Boveja External stimulator for adjunct (add-on) treatment for neurological, neuropsychiatric, and urological disorders
US6097984A (en) * 1998-11-25 2000-08-01 Medtronic, Inc. System and method of stimulation for treating gastro-esophageal reflux disease
US6624150B2 (en) 1999-02-26 2003-09-23 Inspire Pharmaceuticals, Inc. Method of treating gastrointestinal tract disease with purinergic receptor agonists
IL129032A (en) 1999-03-17 2006-12-31 Moshe Dudai Gastric band
US6261280B1 (en) 1999-03-22 2001-07-17 Medtronic, Inc Method of obtaining a measure of blood glucose
US6098629A (en) 1999-04-07 2000-08-08 Endonetics, Inc. Submucosal esophageal bulking device
US6895278B1 (en) 1999-04-14 2005-05-17 Transneuronix, Inc. Gastric stimulator apparatus and method for use
US6341236B1 (en) 1999-04-30 2002-01-22 Ivan Osorio Vagal nerve stimulation techniques for treatment of epileptic seizures
CA2376903A1 (en) 1999-06-25 2001-01-04 Emory University Devices and methods for vagus nerve stimulation
US6587719B1 (en) 1999-07-01 2003-07-01 Cyberonics, Inc. Treatment of obesity by bilateral vagus nerve stimulation
US7149773B2 (en) 1999-07-07 2006-12-12 Medtronic, Inc. System and method of automated invoicing for communications between an implantable medical device and a remote computer system or health care provider
US6308105B1 (en) 1999-07-15 2001-10-23 Medtronic Inc. Medical electrical stimulation system using an electrode assembly having opposing semi-circular arms
US6473644B1 (en) 1999-10-13 2002-10-29 Cyberonics, Inc. Method to enhance cardiac capillary growth in heart failure patients
US6853862B1 (en) 1999-12-03 2005-02-08 Medtronic, Inc. Gastroelectric stimulation for influencing pancreatic secretions
AU784539B2 (en) * 1999-12-06 2006-04-27 Geistlich Pharma Ag Methods of treating tumors
IT1315260B1 (en) 1999-12-07 2003-02-03 Valerio Cigaina REMOVABLE GASTRIC BANDAGE
US6418346B1 (en) * 1999-12-14 2002-07-09 Medtronic, Inc. Apparatus and method for remote therapy and diagnosis in medical devices via interface systems
SE9904626D0 (en) 1999-12-16 1999-12-16 Pacesetter Ab Programming system for medical devices
US6261572B1 (en) * 2000-01-11 2001-07-17 Allergan Sales, Inc. Method for treating a pancreatic disorder with a neurotoxin
US6600953B2 (en) * 2000-12-11 2003-07-29 Impulse Dynamics N.V. Acute and chronic electrical signal therapy for obesity
US6612983B1 (en) 2000-03-28 2003-09-02 Medtronic, Inc. Pancreatic secretion response to stimulation test protocol
US6826428B1 (en) 2000-04-11 2004-11-30 The Board Of Regents Of The University Of Texas System Gastrointestinal electrical stimulation
US6610713B2 (en) 2000-05-23 2003-08-26 North Shore - Long Island Jewish Research Institute Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation
US6306423B1 (en) 2000-06-02 2001-10-23 Allergan Sales, Inc. Neurotoxin implant
JP2004509714A (en) * 2000-09-26 2004-04-02 トランスニューロニックス インコーポレイテッド Method and apparatus for treating obesity by electrical stimulation of the gastrointestinal tract utilizing detected activity
US7623926B2 (en) 2000-09-27 2009-11-24 Cvrx, Inc. Stimulus regimens for cardiovascular reflex control
US6591137B1 (en) 2000-11-09 2003-07-08 Neuropace, Inc. Implantable neuromuscular stimulator for the treatment of gastrointestinal disorders
US6832114B1 (en) * 2000-11-21 2004-12-14 Advanced Bionics Corporation Systems and methods for modulation of pancreatic endocrine secretion and treatment of diabetes
US20020094962A1 (en) 2000-12-01 2002-07-18 Gary Ashley Motilide compounds
US6609025B2 (en) 2001-01-02 2003-08-19 Cyberonics, Inc. Treatment of obesity by bilateral sub-diaphragmatic nerve stimulation
US6754536B2 (en) * 2001-01-31 2004-06-22 Medtronic, Inc Implantable medical device affixed internally within the gastrointestinal tract
US7389145B2 (en) 2001-02-20 2008-06-17 Case Western Reserve University Systems and methods for reversibly blocking nerve activity
US6684105B2 (en) 2001-08-31 2004-01-27 Biocontrol Medical, Ltd. Treatment of disorders by unidirectional nerve stimulation
US6907295B2 (en) 2001-08-31 2005-06-14 Biocontrol Medical Ltd. Electrode assembly for nerve control
US6761715B2 (en) 2001-04-26 2004-07-13 Ronald J. Carroll Method and device for neurocryo analgesia and anesthesia
US7702394B2 (en) 2001-05-01 2010-04-20 Intrapace, Inc. Responsive gastric stimulator
US7676274B2 (en) 2001-05-01 2010-03-09 Second Sight Medical Products, Inc. High-density array of micro-machined electrodes for neural stimulation
JP4289886B2 (en) * 2001-05-09 2009-07-01 バイオインターラクションズ リミテッド Wound closure system and method
US6928320B2 (en) 2001-05-17 2005-08-09 Medtronic, Inc. Apparatus for blocking activation of tissue or conduction of action potentials while other tissue is being therapeutically activated
US6901295B2 (en) * 2001-07-14 2005-05-31 Virender K. Sharma Method and apparatus for electrical stimulation of the lower esophageal sphincter
US20060116736A1 (en) 2001-07-23 2006-06-01 Dilorenzo Daniel J Method, apparatus, and surgical technique for autonomic neuromodulation for the treatment of obesity
US6622038B2 (en) 2001-07-28 2003-09-16 Cyberonics, Inc. Treatment of movement disorders by near-diaphragmatic nerve stimulation
US20040036377A1 (en) 2001-08-15 2004-02-26 Steven Mezinis High voltage lc electric and magnetic field motivator
WO2003015863A2 (en) 2001-08-17 2003-02-27 Advanced Bionics Corporation Gradual recruitment of muscle/neural excitable tissue using high-rate electrical stimulation parameters
US6600956B2 (en) 2001-08-21 2003-07-29 Cyberonics, Inc. Circumneural electrode assembly
US6760626B1 (en) 2001-08-29 2004-07-06 Birinder R. Boveja Apparatus and method for treatment of neurological and neuropsychiatric disorders using programmerless implantable pulse generator system
US7974693B2 (en) 2001-08-31 2011-07-05 Bio Control Medical (B.C.M.) Ltd. Techniques for applying, configuring, and coordinating nerve fiber stimulation
US7885709B2 (en) 2001-08-31 2011-02-08 Bio Control Medical (B.C.M.) Ltd. Nerve stimulation for treating disorders
US7778703B2 (en) * 2001-08-31 2010-08-17 Bio Control Medical (B.C.M.) Ltd. Selective nerve fiber stimulation for treating heart conditions
US7734355B2 (en) 2001-08-31 2010-06-08 Bio Control Medical (B.C.M.) Ltd. Treatment of disorders by unidirectional nerve stimulation
US7254444B2 (en) * 2001-10-17 2007-08-07 Encore Medical Asset Corporation Electrical nerve stimulation device
US7187978B2 (en) 2001-11-01 2007-03-06 Medtronic, Inc. Method and apparatus for programming an implantable medical device
US7050856B2 (en) 2002-01-11 2006-05-23 Medtronic, Inc. Variation of neural-stimulation parameters
US7035691B2 (en) 2002-01-15 2006-04-25 Therapeutic Innovations, Inc. Resonant muscle stimulator
WO2003062130A2 (en) * 2002-01-17 2003-07-31 Gugliotti, Carmine Kitchen sink top-mounted rigid stem-portable dispenser soap system
US20080147137A1 (en) 2002-01-23 2008-06-19 Biocontrol Medical Ltd. Inhibition of sympathetic nerves
US6721603B2 (en) 2002-01-25 2004-04-13 Cyberonics, Inc. Nerve stimulation as a treatment for pain
US20030144708A1 (en) 2002-01-29 2003-07-31 Starkebaum Warren L. Methods and apparatus for retarding stomach emptying for treatment of eating disorders
US6985773B2 (en) 2002-02-07 2006-01-10 Cardiac Pacemakers, Inc. Methods and apparatuses for implantable medical device telemetry power management
US7317948B1 (en) 2002-02-12 2008-01-08 Boston Scientific Scimed, Inc. Neural stimulation system providing auto adjustment of stimulus output as a function of sensed impedance
US7689276B2 (en) 2002-09-13 2010-03-30 Leptos Biomedical, Inc. Dynamic nerve stimulation for treatment of disorders
US7236822B2 (en) 2002-03-22 2007-06-26 Leptos Biomedical, Inc. Wireless electric modulation of sympathetic nervous system
US7239912B2 (en) 2002-03-22 2007-07-03 Leptos Biomedical, Inc. Electric modulation of sympathetic nervous system
US7551964B2 (en) 2002-03-22 2009-06-23 Leptos Biomedical, Inc. Splanchnic nerve stimulation for treatment of obesity
US7689277B2 (en) 2002-03-22 2010-03-30 Leptos Biomedical, Inc. Neural stimulation for treatment of metabolic syndrome and type 2 diabetes
US7702386B2 (en) 2002-03-22 2010-04-20 Leptos Biomedical, Inc. Nerve stimulation for treatment of obesity, metabolic syndrome, and Type 2 diabetes
US8145316B2 (en) 2002-04-08 2012-03-27 Ardian, Inc. Methods and apparatus for renal neuromodulation
US20040015201A1 (en) 2002-04-22 2004-01-22 Transneuronix, Inc. Process for electrostimulation treatment of obesity
US20040193229A1 (en) 2002-05-17 2004-09-30 Medtronic, Inc. Gastric electrical stimulation for treatment of gastro-esophageal reflux disease
WO2003101533A1 (en) * 2002-05-29 2003-12-11 Oklahoma Foundation For Digestive Research Spinal cord stimulation as treatment for functional bowel disorders
US6746474B2 (en) * 2002-05-31 2004-06-08 Vahid Saadat Apparatus and methods for cooling a region within the body
US7292890B2 (en) 2002-06-20 2007-11-06 Advanced Bionics Corporation Vagus nerve stimulation via unidirectional propagation of action potentials
US6938135B1 (en) * 2002-10-04 2005-08-30 Veritas Operating Corporation Incremental backup of a data volume
WO2004036377A2 (en) 2002-10-15 2004-04-29 Medtronic Inc. Configuring and testing treatment therapy parameters for a medical device system
US7236830B2 (en) 2002-12-10 2007-06-26 Northstar Neuroscience, Inc. Systems and methods for enhancing or optimizing neural stimulation therapy for treating symptoms of Parkinson's disease and/or other movement disorders
US7238357B2 (en) 2002-11-05 2007-07-03 Allergan, Inc. Methods for treating ulcers and gastroesophageal reflux disease
US6736722B1 (en) 2002-12-04 2004-05-18 Deere & Company Unloader tube cleaning system for harvesting apparatus
US6990376B2 (en) 2002-12-06 2006-01-24 The Regents Of The University Of California Methods and systems for selective control of bladder function
US7933654B2 (en) 2002-12-17 2011-04-26 Massachusetts Eye & Ear Infirmary Vestibular stimulator
US8064994B2 (en) 2003-01-14 2011-11-22 The United States Of America As Represented By The Department Of Veterans Affairs Cervical vagal stimulation induced weight loss
US7444183B2 (en) 2003-02-03 2008-10-28 Enteromedics, Inc. Intraluminal electrode apparatus and method
US7844338B2 (en) 2003-02-03 2010-11-30 Enteromedics Inc. High frequency obesity treatment
US7613515B2 (en) * 2003-02-03 2009-11-03 Enteromedics Inc. High frequency vagal blockage therapy
US20040172084A1 (en) 2003-02-03 2004-09-02 Knudson Mark B. Method and apparatus for treatment of gastro-esophageal reflux disease (GERD)
US20060015151A1 (en) 2003-03-14 2006-01-19 Aldrich William N Method of using endoscopic truncal vagoscopy with gastric bypass, gastric banding and other procedures
US7430449B2 (en) 2003-03-14 2008-09-30 Endovx, Inc. Methods and apparatus for testing disruption of a vagal nerve
US7783358B2 (en) 2003-03-14 2010-08-24 Endovx, Inc. Methods and apparatus for treatment of obesity with an ultrasound device movable in two or three axes
US7684865B2 (en) 2003-03-14 2010-03-23 Endovx, Inc. Methods and apparatus for treatment of obesity
US7142250B1 (en) 2003-04-05 2006-11-28 Apple Computer, Inc. Method and apparatus for synchronizing audio and video streams
DE10318071A1 (en) 2003-04-17 2004-11-25 Forschungszentrum Jülich GmbH Device for desynchronizing neuronal brain activity
US7444184B2 (en) 2003-05-11 2008-10-28 Neuro And Cardial Technologies, Llc Method and system for providing therapy for bulimia/eating disorders by providing electrical pulses to vagus nerve(s)
US7742818B2 (en) * 2003-05-19 2010-06-22 Medtronic, Inc. Gastro-electric stimulation for increasing the acidity of gastric secretions or increasing the amounts thereof
US7620454B2 (en) * 2003-05-19 2009-11-17 Medtronic, Inc. Gastro-electric stimulation for reducing the acidity of gastric secretions or reducing the amounts thereof
US7149574B2 (en) 2003-06-09 2006-12-12 Palo Alto Investors Treatment of conditions through electrical modulation of the autonomic nervous system
WO2004110549A2 (en) 2003-06-13 2004-12-23 Biocontrol Medical Ltd. Applications of vagal stimulation
US7263405B2 (en) * 2003-08-27 2007-08-28 Neuro And Cardiac Technologies Llc System and method for providing electrical pulses to the vagus nerve(s) to provide therapy for obesity, eating disorders, neurological and neuropsychiatric disorders with a stimulator, comprising bi-directional communication and network capabilities
US20050070970A1 (en) * 2003-09-29 2005-03-31 Knudson Mark B. Movement disorder stimulation with neural block
US20050070974A1 (en) * 2003-09-29 2005-03-31 Knudson Mark B. Obesity and eating disorder stimulation treatment with neural block
US7991479B2 (en) 2003-10-02 2011-08-02 Medtronic, Inc. Neurostimulator programmer with clothing attachable antenna
US8265770B2 (en) * 2003-10-02 2012-09-11 Medtronic, Inc. Driver circuitry switchable between energy transfer and telemetry for an implantable medical device
US20050143378A1 (en) * 2003-12-29 2005-06-30 Yun Anthony J. Treatment of conditions through pharmacological modulation of the autonomic nervous system
US7054690B2 (en) * 2003-10-22 2006-05-30 Intrapace, Inc. Gastrointestinal stimulation device
WO2005051486A1 (en) 2003-11-28 2005-06-09 University Technologies International Inc. Method and apparatus for gastrointestinal motility control
US7177693B2 (en) * 2004-01-07 2007-02-13 Medtronic, Inc. Gastric stimulation for altered perception to treat obesity
WO2006017634A2 (en) 2004-08-04 2006-02-16 Ndi Medical, Llc Devices, systems, and methods employing a molded nerve cuff electrode
US8452407B2 (en) * 2004-08-16 2013-05-28 Boston Scientific Neuromodulation Corporation Methods for treating gastrointestinal disorders
US8214047B2 (en) 2004-09-27 2012-07-03 Advanced Neuromodulation Systems, Inc. Method of using spinal cord stimulation to treat gastrointestinal and/or eating disorders or conditions
US8239029B2 (en) 2004-10-21 2012-08-07 Advanced Neuromodulation Systems, Inc. Stimulation of the amygdalohippocampal complex to treat neurological conditions
US20060161217A1 (en) 2004-12-21 2006-07-20 Jaax Kristen N Methods and systems for treating obesity
US8260426B2 (en) 2008-01-25 2012-09-04 Cyberonics, Inc. Method, apparatus and system for bipolar charge utilization during stimulation by an implantable medical device
US9339190B2 (en) 2005-02-17 2016-05-17 Metacure Limited Charger with data transfer capabilities
US7899540B2 (en) 2005-04-29 2011-03-01 Cyberonics, Inc. Noninvasively adjustable gastric band
US7774069B2 (en) 2005-04-29 2010-08-10 Medtronic, Inc. Alignment indication for transcutaneous energy transfer
US7310557B2 (en) 2005-04-29 2007-12-18 Maschino Steven E Identification of electrodes for nerve stimulation in the treatment of eating disorders
US7561923B2 (en) 2005-05-09 2009-07-14 Cardiac Pacemakers, Inc. Method and apparatus for controlling autonomic balance using neural stimulation
US7343539B2 (en) 2005-06-24 2008-03-11 The United States Of America As Represented By The United States National Aeronautics And Space Administration ARA type protograph codes
US20070016262A1 (en) 2005-07-13 2007-01-18 Betastim, Ltd. Gi and pancreatic device for treating obesity and diabetes
US20070027484A1 (en) 2005-07-28 2007-02-01 Cyberonics, Inc. Autonomic nerve stimulation to treat a pancreatic disorder
US7822486B2 (en) 2005-08-17 2010-10-26 Enteromedics Inc. Custom sized neural electrodes
US7672727B2 (en) 2005-08-17 2010-03-02 Enteromedics Inc. Neural electrode treatment
US7551960B2 (en) 2005-09-08 2009-06-23 Medtronic, Inc. External presentation of electrical stimulation parameters
US7620455B2 (en) 2005-10-25 2009-11-17 Cyberonics, Inc. Cranial nerve stimulation to treat eating disorders
US20070100377A1 (en) 2005-10-28 2007-05-03 Cyberonics, Inc. Providing multiple signal modes for a medical device
US8041428B2 (en) 2006-02-10 2011-10-18 Electrocore Llc Electrical stimulation treatment of hypotension
CA2637787A1 (en) 2006-02-03 2007-08-16 Synecor, Llc Intravascular device for neuromodulation
US20070191912A1 (en) 2006-02-10 2007-08-16 Vision Quest Industries, Inc. Interactive electrical stimulator device and server-based support system
CN101400403A (en) 2006-02-10 2009-04-01 电子核心公司 Methods and apparatus for treating anaphylaxis using electrical modulation
WO2007115103A1 (en) 2006-03-29 2007-10-11 Catholic Healthcare West Microburst electrical stimulation of cranial nerves for the treatment of medical conditions
US8187297B2 (en) 2006-04-19 2012-05-29 Vibsynt, Inc. Devices and methods for treatment of obesity
WO2007137026A2 (en) 2006-05-18 2007-11-29 Cedars-Sinai Medical Center Electrical stimulation of the lower esophageal sphincter
US7738961B2 (en) 2006-10-09 2010-06-15 Endostim, Inc. Method and apparatus for treatment of the gastrointestinal tract
US7729760B2 (en) 2006-10-27 2010-06-01 Cyberonics, Inc. Patient management system for providing parameter data for an implantable medical device
US7706875B2 (en) 2007-01-25 2010-04-27 Cyberonics, Inc. Modulation of drug effects by vagus nerve stimulation
US9037244B2 (en) 2007-02-13 2015-05-19 Virender K. Sharma Method and apparatus for electrical stimulation of the pancreatico-biliary system
US8068918B2 (en) 2007-03-09 2011-11-29 Enteromedics Inc. Remote monitoring and control of implantable devices
US20080300657A1 (en) 2007-05-31 2008-12-04 Mark Raymond Stultz Therapy system
US8103399B2 (en) 2007-06-05 2012-01-24 Snap-On Incorporated System and method for transferring vehicle service data
WO2009064408A1 (en) 2007-11-12 2009-05-22 Dilorenzo Daniel J Method and apparatus for programming of autonomic neuromodulation for the treatment of obesity
EP2254659B1 (en) 2008-02-14 2017-06-14 Enteromedics Inc. Treatment of excess weight by neural downregulation in combination with compositions
US7917226B2 (en) 2008-04-23 2011-03-29 Enteromedics Inc. Antenna arrangements for implantable therapy device
US8204603B2 (en) 2008-04-25 2012-06-19 Cyberonics, Inc. Blocking exogenous action potentials by an implantable medical device
US20090275997A1 (en) 2008-05-01 2009-11-05 Michael Allen Faltys Vagus nerve stimulation electrodes and methods of use
WO2010128167A1 (en) 2009-05-08 2010-11-11 Universite Libre De Bruxelles Gastrointestinal device
JP2013505080A (en) 2009-09-21 2013-02-14 メドトロニック,インコーポレイテッド Waveform for electrical stimulation treatment
US9089708B2 (en) 2010-05-27 2015-07-28 Ndi Medical, Llc Waveform shapes for treating neurological disorders optimized for energy efficiency
JP5684384B2 (en) 2010-07-19 2015-03-11 カーディアック ペースメイカーズ, インコーポレイテッド System for stimulating the vagus nerve
US20130184775A1 (en) 2010-10-01 2013-07-18 Indiana University Research & Technology Corporation Long term vagal nerve stimulation for therapeutic and diagnostic treatment
US9474482B2 (en) 2010-11-01 2016-10-25 G-Tech Medical, Inc. Method for diagnosis and treatment of disorders of the gastrointestinal tract, and apparatus for use therewith
US9014813B2 (en) 2010-11-03 2015-04-21 Cleveland Clinic Foundation Apparatus for energy efficient stimulation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5263480A (en) * 1991-02-01 1993-11-23 Cyberonics, Inc. Treatment of eating disorders by nerve stimulation
US20020055779A1 (en) * 1996-03-05 2002-05-09 Brian J. Andrews Neural prosthesis
US20010012828A1 (en) * 1999-10-12 2001-08-09 Aoki Kei Roger Intraspinal botulinum toxin for treating pain

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8486153B2 (en) 2002-12-02 2013-07-16 Gi Dynamics, Inc. Anti-obesity devices
US9901474B2 (en) 2002-12-02 2018-02-27 Gi Dynamics, Inc. Anti-obesity devices
US7695446B2 (en) 2002-12-02 2010-04-13 Gi Dynamics, Inc. Methods of treatment using a bariatric sleeve
US7758535B2 (en) 2002-12-02 2010-07-20 Gi Dynamics, Inc. Bariatric sleeve delivery devices
US7766861B2 (en) 2002-12-02 2010-08-03 Gi Dynamics, Inc. Anti-obesity devices
US9750596B2 (en) 2002-12-02 2017-09-05 Gi Dynamics, Inc. Bariatric sleeve
US9278020B2 (en) 2002-12-02 2016-03-08 Gi Dynamics, Inc. Methods of treatment using a bariatric sleeve
US9155609B2 (en) 2002-12-02 2015-10-13 Gi Dynamics, Inc. Bariatric sleeve
US7935073B2 (en) 2002-12-02 2011-05-03 Gi Dynamics, Inc. Methods of treatment using a bariatric sleeve
US7678068B2 (en) 2002-12-02 2010-03-16 Gi Dynamics, Inc. Atraumatic delivery devices
US8882698B2 (en) 2002-12-02 2014-11-11 Gi Dynamics, Inc. Anti-obesity devices
US8870806B2 (en) 2002-12-02 2014-10-28 Gi Dynamics, Inc. Methods of treatment using a bariatric sleeve
US8137301B2 (en) 2002-12-02 2012-03-20 Gi Dynamics, Inc. Bariatric sleeve
US8162871B2 (en) 2002-12-02 2012-04-24 Gi Dynamics, Inc. Bariatric sleeve
US9084669B2 (en) 2003-12-09 2015-07-21 Gi Dynamics, Inc. Methods and apparatus for anchoring within the gastrointestinal tract
US8057420B2 (en) 2003-12-09 2011-11-15 Gi Dynamics, Inc. Gastrointestinal implant with drawstring
US8303669B2 (en) 2003-12-09 2012-11-06 Gi Dynamics, Inc. Methods and apparatus for anchoring within the gastrointestinal tract
US8628583B2 (en) 2003-12-09 2014-01-14 Gi Dynamics, Inc. Methods and apparatus for anchoring within the gastrointestinal tract
US8771219B2 (en) 2003-12-09 2014-07-08 Gi Dynamics, Inc. Gastrointestinal implant with drawstring
US7682330B2 (en) 2003-12-09 2010-03-23 Gi Dynamics, Inc. Intestinal sleeve
US8834405B2 (en) 2003-12-09 2014-09-16 Gi Dynamics, Inc. Intestinal sleeve
US9585783B2 (en) 2003-12-09 2017-03-07 Gi Dynamics, Inc. Methods and apparatus for anchoring within the gastrointestinal tract
US7981163B2 (en) 2003-12-09 2011-07-19 Gi Dynamics, Inc. Intestinal sleeve
US7815589B2 (en) 2003-12-09 2010-10-19 Gi Dynamics, Inc. Methods and apparatus for anchoring within the gastrointestinal tract
US9095416B2 (en) 2003-12-09 2015-08-04 Gi Dynamics, Inc. Removal and repositioning devices
US9744061B2 (en) 2003-12-09 2017-08-29 Gi Dynamics, Inc. Intestinal sleeve
US9237944B2 (en) 2003-12-09 2016-01-19 Gi Dynamics, Inc. Intestinal sleeve
US7837643B2 (en) 2004-07-09 2010-11-23 Gi Dynamics, Inc. Methods and devices for placing a gastrointestinal sleeve
US7815591B2 (en) 2004-09-17 2010-10-19 Gi Dynamics, Inc. Atraumatic gastrointestinal anchor
US7976488B2 (en) 2005-06-08 2011-07-12 Gi Dynamics, Inc. Gastrointestinal anchor compliance
US8425451B2 (en) 2005-06-08 2013-04-23 Gi Dynamics, Inc. Gastrointestinal anchor compliance
US8801647B2 (en) 2007-02-22 2014-08-12 Gi Dynamics, Inc. Use of a gastrointestinal sleeve to treat bariatric surgery fistulas and leaks
US9526648B2 (en) 2010-06-13 2016-12-27 Synerz Medical, Inc. Intragastric device for treating obesity
US11607329B2 (en) 2010-06-13 2023-03-21 Synerz Medical, Inc. Intragastric device for treating obesity
US10413436B2 (en) 2010-06-13 2019-09-17 W. L. Gore & Associates, Inc. Intragastric device for treating obesity
US10420665B2 (en) 2010-06-13 2019-09-24 W. L. Gore & Associates, Inc. Intragastric device for treating obesity
US10512557B2 (en) 2010-06-13 2019-12-24 W. L. Gore & Associates, Inc. Intragastric device for treating obesity
US11596538B2 (en) 2010-06-13 2023-03-07 Synerz Medical, Inc. Intragastric device for treating obesity
US11351050B2 (en) 2010-06-13 2022-06-07 Synerz Medical, Inc. Intragastric device for treating obesity
US11135078B2 (en) 2010-06-13 2021-10-05 Synerz Medical, Inc. Intragastric device for treating obesity
US10888377B2 (en) 2013-01-31 2021-01-12 Digma Medical Ltd. Methods and systems for reducing neural activity in an organ of a subject
US10925671B2 (en) 2013-01-31 2021-02-23 Digma Medical Ltd. Methods and systems for reducing neural activity in an organ of a subject
US11311337B2 (en) 2013-01-31 2022-04-26 Digma Medical Ltd. Methods and systems for reducing neural activity in an organ of a subject
US9993297B2 (en) 2013-01-31 2018-06-12 Digma Medical Ltd. Methods and systems for reducing neural activity in an organ of a subject
US10537387B2 (en) 2014-04-17 2020-01-21 Digma Medical Ltd. Methods and systems for blocking neural activity in an organ of a subject, preferably in the small intestine or the duodenum
US10779980B2 (en) 2016-04-27 2020-09-22 Synerz Medical, Inc. Intragastric device for treating obesity
US11109913B2 (en) 2016-08-14 2021-09-07 Digma Medical Ltd. Apparatus and method for nerve ablation in the wall of the gastointestinal tract
US10575904B1 (en) 2016-08-14 2020-03-03 Digma Medical Ltd. Apparatus and method for selective submucosal ablation
US11564743B1 (en) 2016-08-14 2023-01-31 Digma Medical Ltd. Apparatus and method for selective submucosal ablation
WO2021119741A1 (en) * 2019-12-17 2021-06-24 The Bionics Institute Of Australia Methods and system for modulating glycaemia

Also Published As

Publication number Publication date
US8369952B2 (en) 2013-02-05
US7693577B2 (en) 2010-04-06
US20130197600A1 (en) 2013-08-01
US20040172088A1 (en) 2004-09-02
US20070135857A1 (en) 2007-06-14
EP1601414A2 (en) 2005-12-07
US7720540B2 (en) 2010-05-18
US20070135858A1 (en) 2007-06-14
US7986995B2 (en) 2011-07-26
US20070135846A1 (en) 2007-06-14
US20070135856A1 (en) 2007-06-14
US20070142870A1 (en) 2007-06-21
EP1601414B1 (en) 2012-02-29
US20040167583A1 (en) 2004-08-26
US8862233B2 (en) 2014-10-14
US20150012065A1 (en) 2015-01-08
US7167750B2 (en) 2007-01-23
WO2004069331A3 (en) 2005-01-20
US7444183B2 (en) 2008-10-28
US9586046B2 (en) 2017-03-07
WO2004069331B1 (en) 2005-03-17
US7630769B2 (en) 2009-12-08
US20110270344A1 (en) 2011-11-03

Similar Documents

Publication Publication Date Title
US9682233B2 (en) Nerve stimulation and blocking for treatment of gastrointestinal disorders
EP1601414B1 (en) Apparatus for neural stimulation
EP1603634B1 (en) Electrode band
US7844338B2 (en) High frequency obesity treatment
WO2004069332A9 (en) Intraluminal electrode
AU2011265519B2 (en) Electrode band

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
B Later publication of amended claims

Effective date: 20041202

WWE Wipo information: entry into national phase

Ref document number: 2004707122

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2004707122

Country of ref document: EP

DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)