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WO2005002467A2 - Arene de stimulation - Google Patents

Arene de stimulation Download PDF

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Publication number
WO2005002467A2
WO2005002467A2 PCT/IL2004/000611 IL2004000611W WO2005002467A2 WO 2005002467 A2 WO2005002467 A2 WO 2005002467A2 IL 2004000611 W IL2004000611 W IL 2004000611W WO 2005002467 A2 WO2005002467 A2 WO 2005002467A2
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WO
WIPO (PCT)
Prior art keywords
animal
coil
cage
current
coil current
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IL2004/000611
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English (en)
Other versions
WO2005002467A3 (fr
Inventor
Alon Shalev
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Brainsgate Ltd
Original Assignee
Brainsgate Ltd
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Filing date
Publication date
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Publication of WO2005002467A2 publication Critical patent/WO2005002467A2/fr
Publication of WO2005002467A3 publication Critical patent/WO2005002467A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A61N1/0526—Head electrodes
    • A61N1/0546—Nasal electrodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A61N1/0526—Head electrodes
    • A61N1/0548—Oral electrodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36014—External stimulators, e.g. with patch electrodes
    • A61N1/36017—External stimulators, e.g. with patch electrodes with leads or electrodes penetrating the skin

Definitions

  • the present invention relates generally to medical procedures and electronic devices.
  • the invention relates to the use of electrical devices for implantation in the head, for example, in the nasal cavity.
  • the invention also relates to apparatus and methods for administering drugs, for treating stroke and migraine, and for improving cerebral blood flow.
  • the blood-brain barrier is a unique feature of the central nervous system (CNS) which isolates the brain from the systemic blood circulation. To maintain the homeostasis of the CNS, the BBB prevents access to the brain of many substances circulating in the blood.
  • the BBB is formed by a complex cellular system of endothelial cells, astroglia, pericytes, perivascular macrophages, and a basal lamina. Compared to other tissues, brain endothelia have the most intimate cell-to-cell connections: endothelial cells adhere strongly to each other, forming structures specific to the CNS called "tight junctions" or zonula occludens.
  • a continuous uniform basement membrane surrounds the brain capillaries. This basal lamina encloses contractile cells called pericytes, which form an intermittent layer and probably play some role in phagocytosis activity and defense if the BBB is breached.
  • Astrocytic end feet which cover the brain capillaries, build a continuous sleeve and maintain the integrity of the BBB by the synthesis and secretion of soluble growth factors (e.g., gamma-glutamyl transpeptidase) essential for the endothelial cells to develop their BBB characteristics.
  • the normal BBB prevents the passage of ionized water soluble drugs with a molecular weight greater than 180 dalton (Da).
  • Most currently-available effective chemotherapeutic agents have a molecular weight between 200 and 1200 Da. Therefore, based both on their lipid solubilities and molecular masses, the passage of many agents is impeded by the BBB.
  • Specific transport proteins exist for required molecules, such as glucose and amino acids. Additionally, absorptive endocytosis and transcytosis occur for cationized plasma proteins.
  • Non-surgical treatment of neurological disorders is generally limited to systemic introduction of compounds such as neuropharmaceuticals and other neurologically-active agents that might remedy or modify neurologically-related activities and disorders.
  • Such treatment is limited, however, by the relatively small number of known compounds that pass through the BBB. Even those that do cross the BBB often produce adverse reactions in other parts of the body or in non-targeted regions of the brain.
  • efforts to cross the BBB specifically, with regard to overcoming the limited access of drugs to the brain. Such efforts have included, for example, chemical modification, development of more hydrophobic analogs, or linking an active compound to a specific carrier.
  • Treatment is accomplished directly via stimulation of the sphenopalatine ganglion and/or indirectly by the facilitation of drug transport across the blood brain barrier via stimulation of the sphenopalatine ganglion.
  • US Patent 6,526,318 to Ansarinia and related PCT Patent Publication WO 01/97905 to Ansarinia describes a method for treating a patient by placing at least one electrode on or proximate to at least one of the patient's sphenopalatine ganglia, sphenopalatine nerves, or vidian nerves, and activating the electrode to apply an electrical signal and/or a medical solution to at least one of those ganglia or nerves.
  • U.S. Patent 6,405,079 to Ansarinia whose disclosure is incorporated herein by reference, describes methods for treating medical conditions by implanting one or more electrodes in regions of the sinus and applying electrical stimulation and or medical solutions to the implantation site.
  • an electrical stimulator drives current into the sphenopalatine ganglion (SPG) or into neural tracts originating or reaching the SPG.
  • the stimulator drives the current in order to control and/or modify SPG-related behavior, e.g., in order to induce changes in cerebral blood flow and/or to modulate permeability of the blood-brain barrier (BBB).
  • BBB blood-brain barrier
  • implantation and stimulation sites, methods of implantation, and parameters of stimulation are described herein by way of illustration and not limitation, and that the scope of the present invention includes other possibilities which would be obvious to someone of ordinary skill in the art who has read the present patent application.
  • preferred embodiments of the invention are generally described herein with . respect to electrical transmission of power and electrical stimulation of tissue, other modes of energy transport may be used as well.
  • energy includes, but is not limited to, direct or induced electromagnetic energy, RF transmission, ultrasonic transmission, optical power, and low power laser energy (via, for example, a fiber optic cable).
  • the SPG is a neuronal center located in the brain behind the nose. It consists of parasympathetic neurons innervating the middle cerebral and anterior cerebral lumens, the facial skin blood vessels, and the lacrimal glands. Activation of this ganglion is believed to cause vasodilation of these vessels.
  • a second effect of such stimulation is the opening of pores in the vessel walls, causing plasma protein extravasation (PPE).
  • the SPG is a target of manipulation in clinical medicine, mostly in attempted treatments of severe headaches such as cluster headaches.
  • the ganglion is blocked either on a short-term basis, by applying lidocaine, or permanently, by ablation with a radio frequency probe. In both cases the approach is through the nostrils.
  • similar methods for approaching the SPG are utilized, to enable the electrical stimulation or electrical blocking thereof.
  • a method and apparatus are provided to enhance delivery of therapeutic molecules across the BBB by stimulation of the SPG and/or its outgoing parasympathetic tracts and/or another parasympathetic center.
  • the apparatus typically stimulates the parasympathetic nerve fibers of the SPG, thereby inducing the middle and anterior cerebral arteries to dilate, and also causing the walls of these cerebral arteries walls to become more permeable to large molecules. In this manner, the movement of large pharmaceutical molecules from within blood vessels to the cerebral tissue is substantially increased.
  • this method can serve as a neurological drug delivery facilitator, without the sacrifices in molecular weight required by techniques of the prior art.
  • substantially all pharmacological treatments aimed at cerebral cells for neurological and psychiatric disorders are amenable for use with these embodiments of the present invention.
  • these embodiments may be adapted for use in the treatment of disorders such as brain tumors, epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, schizophrenia, depression, stress, anxiety, and any other CNS disorders that are directly or indirectly affected by changes in cerebral blood flow or by BBB permeability changes.
  • disorders such as brain tumors, epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, schizophrenia, depression, stress, anxiety, and any other CNS disorders that are directly or indirectly affected by changes in cerebral blood flow or by BBB permeability changes.
  • BBB permeability changes patients with these and other disorders are generally helped by the vasodilation secondary to stimulation of the SPG, and the resultant improvement in oxygen supply to neurons and other tissue.
  • this treatment is given on a long-term basis, e.g., in the chronic treatment of Alzheimer's patients.
  • the treatment is performed on a short-term basis, e.g., to mirumize the damage following an acute stroke event and initiate neuronal and therefore functional rehabilitation.
  • Blocking of nerve transmission in the SPG or in related neural tracts is used in accordance with some preferred embodiments of the present invention to treat or prevent migraine headaches.
  • apparatus for use with a non-human animal, the animal having implanted therein (a) an implanted coil and, electrically coupled to the coil, (b) an electrode in contact with target tissue in a head of the animal, the apparatus including: a cage to contain the animal; a cage coil, surrounding at least a portion of the cage; and a coil current driver, which drives cage coil current through the cage coil thereby inductively driving induced current through the implanted coil, into the electrode, and into the target tissue.
  • the target tissue includes an ethmoidal nerve of the animal, and the coil current driver drives the cage coil current at a magnitude sufficient to stimulate the ethmoidal nerve.
  • the target tissue includes a nerve of the animal, and the coil current driver drives the cage coil current at a magnitude sufficient to stimulate the nerve.
  • the target tissue includes a ganglion of the animal, and the coil current driver drives the cage coil current at a magnitude sufficient to stimulate the ganglion.
  • the apparatus includes a camera, coupled to the cage, which records images of the animal in conjunction with the coil current driver driving the cage coil current.
  • the apparatus includes a motion detector, coupled to the cage, which detects motion of the animal in conjunction with the coil current driver driving the cage coil current.
  • the apparatus includes a stimulation indicator adapted to be coupled to an external surface of the animal and to generate an indication of flow of a current in the implanted coil.
  • the stimulation indicator includes an LED.
  • the stimulation indicator includes a sound generator.
  • the stimulation indicator includes a stimulation indicator coil, adapted to be coupled to the external surface of the animal, and the stimulation indicator coil drives the stimulation indicator to generate the indication responsive to a level at the stimulation indicator coil of a field caused by the cage coil current.
  • the stimulation indicator is adapted to generate the indication when it is driven by current in the implanted coil.
  • a method for use with a non-human animal the animal having implanted therein (a) an implanted coil and, coupled to the coil, (b) an electrode in contact with target tissue in a head of the ariimal, the method including: placing the animal in a cage; and driving a cage coil current in a cage coil, which surrounds at least a portion of the cage, thereby inductively driving induced current through the implanted coil, into the electrode, and into the target tissue.
  • the method includes administering, to the ariimal, a drug targeting a central nervous system (CNS) of the animal, and driving the cage coil current includes configuring the cage coil current to induce an increase in permeability of a blood-brain barrier (BBB) of the animal, so as to facilitate passage of the drug from a systemic blood circulation of the ariimal, through the BBB, and into the CNS.
  • CNS central nervous system
  • BBB blood-brain barrier
  • Fig. 1 is a schematic pictorial view of a fully implantable stimulator for stimulation of the SPG, in accordance with a preferred embodiment of the present invention
  • Fig. 2 is a schematic pictorial view of another stimulator for stimulation of the SPG, in accordance with a preferred embodiment of the present invention
  • Fig. 3 is a schematic block diagram illustrating circuitry for use with the stimulator shown in Fig. 1, in accordance with a preferred embodiment of the present invention
  • Fig. 4 is a schematic block diagram illustrating circuitry for use with the stimulator shown in Fig. 2, in accordance with a preferred embodiment of the present invention
  • Figs. 5A and 5B are schematic illustrations depicting different modes of operation of stimulators such as those shown in Figs. 1 and 2, in accordance with preferred embodiments of the present invention
  • Fig. 6 is a schematic illustration of a mode of operation of the stimulators shown in
  • FIG. 7 is a schematic block diagram illustrating circuitry for use with the stimulator shown in Fig. 1, where the stimulator is driven by an external controller and energy source using a modulator and a demodulator, in accordance with a preferred embodiment of the present invention
  • Fig. 8 depicts sample modulator and demodulator functions for use with the circuitry of Fig. 7, in accordance with a preferred embodiment of the present invention
  • Figs. 9, 10A, and 10B are schematic diagrams illustrating further circuitry for use with implantable stimulators, in accordance with respective preferred embodiments of the present invention
  • FIG. 11 and 12 are bar graphs showing experimental data collected in accordance with a preferred embodiment of the present invention
  • Fig. 13 is a schematic illustration of a sensor for application to a blood vessel, in accordance with a preferred embodiment of the present invention
  • Fig. 14 is a block diagram of a stimulation arena, in accordance with an embodiment of the present invention
  • Fig. 15 is a schematic illustration of a stimulation arena, in accordance with an embodiment of the present invention.
  • FIG. 1 is a schematic pictorial view of a fully-implantable stimulator 4, for stimulation of the sphenopalatine ganglion (SPG) 6 or other parasympathetic site of a patient, in accordance with a preferred embodiments of the present invention.
  • SPG sphenopalatine ganglion
  • a human nasal cavity 2 is shown, and stimulator 4 is implanted adjacent to SPG 6.
  • Branches of parasympathetic neurons coming from SPG 6 extend to the middle cerebral and anterior cerebral arteries (not shown).
  • one or more relatively short electrodes 7 extend from stimulator 4 to contact or to be in a vicinity of SPG 6 or of nerves innervating SPG 6 (e.g., postganglionic parasympathetic trunks thereof).
  • stimulator 4 is implanted on top of the bony palate, in the bottom of the nasal cavity.
  • the stimulator is implanted at the lower side of the bony palate, at the top of the oral cavity.
  • one or more flexible electrodes 7 originating in the stimulator are passed through the palatine bone or posterior to the soft palate, so as to be in a position to stimulate the SPG or its parasympathetic tracts.
  • the stimulator may be directly attached to the SPG and or to its postganglionic parasympathetic trunk(s).
  • stimulator 4 is delivered to a desired point within nasal cavity 2 by removably attaching stimulator 4 to the distal end of a rigid or slightly flexible introducer rod (not shown) and inserting the rod into one of the patient's nasal passages until the stimulator is properly positioned.
  • the placement process may be facilitated by fluoroscopy, x-ray guidance, fine endoscopic surgery (FES) techniques or by any other effective guidance method known in the art, or by combinations of the aforementioned.
  • FES fine endoscopic surgery
  • the ambient temperature and/or cerebral blood flow is measured concurrently with insertion.
  • the cerebral blood flow may be measured with, for example, a laser Doppler unit positioned at the patient's forehead or transcranial Doppler measurements.
  • Nerification of proper implantation of the electrodes onto the appropriate neural structure may be performed by activating the device, and generally simultaneously monitoring cerebral blood flow.
  • the passage of certain molecules from cerebral blood vessels into the brain is hindered by the BBB.
  • the endothelium of the capillaries, the plasma membrane of the blood vessels, and the foot processes of the astrocytes all impede uptake by the brain of the molecules.
  • the BBB generally allows only small molecules (e.g., hydrophilic molecules of molecular weight less than about 200 Da, and lipophilic molecules of less than about 500 Da) to pass from the circulation into the brain.
  • stimulator 4 may be used to transiently remove a substantial obstacle to the passage of drugs from the blood to the brain.
  • the stimulator may cyclically apply current for about two minutes, and subsequently have a rest period of between about 1 and 20 minutes. It is hypothesized that two neurotransmitters play an important role in this change in properties of the BBB ⁇ vasoactive intestinal polypeptide (VLP) and nitric oxide (NO).
  • VLP vasoactive intestinal polypeptide
  • NO nitric oxide
  • VIP is a short peptide
  • NO is a gaseous molecule
  • VTP is believed to be a major factor in facilitating plasma protein extravasation (PPE), while NO is responsible for vasodilation.
  • stimulator 4 is adapted to vary parameters of the current applied to the SPG, as appropriate, in order to selectively influence the activity of one or both of these neurotransmitters. For example, stimulation of the parasympathetic nerve at different frequencies can induce differential secretion ⁇ low frequencies cause secretion of NO, while high frequencies (e.g., above about 10 Hz) cause secretion of peptides (VIP).
  • stimulator 4 may be configured to induce parasympathetic electrical block, in order to cause vasoconstriction by mimicking the overall effect of chemical block on the SPG.
  • This vasoconstrictive effect may be used, for example, to controUably prevent or reverse the formation of migraine headaches.
  • This technique of electrical treatment of migraines stands in contrast to methods of the prior art, in which pharmacological agents such as lidocaine are used to induce SPG block.
  • FIG. 2 is a schematic illustration of a stimulator control unit 8 positioned external to a patient's body, in accordance with a preferred embodiment of the present invention.
  • At least one flexible electrode 10 preferably extends from control unit 8, through a nostril 12 of the patient, and to a position within the nasal cavity 14 that is adjacent to SPG 6.
  • electrodes 7 (Fig. 1) and 10 may each comprise one or more electrodes, e.g., two electrodes, or an array of microelectrodes.
  • stimulator 4 comprises a metal housing that can function as an electrode
  • typically one electrode 7 is used, operating in a monopolar mode. Regardless of the total number of electrodes in use, typically only a single or a double electrode extends to SPG 6.
  • Electrodes 7 or 10 or a metal housing of stimulator 4 are preferably temporarily or permanently implanted in contact with other parts of nasal cavity 2.
  • Each of electrodes 7 and/or 10 preferably comprises a suitable conductive material, for example, a physiologically-acceptable material such as silver, iridium, platinum, a platinum iridium alloy, titanium, nitinol, or a nickel-chrome alloy.
  • a physiologically-acceptable material such as silver, iridium, platinum, a platinum iridium alloy, titanium, nitinol, or a nickel-chrome alloy.
  • one or more of the electrodes have lengths ranging from about 1 to 5 mm, and diameters ranging from about 50 to 100 microns.
  • Each electrode is preferably insulated with a physiologically-acceptable material such as polyethylene, polyurethane, or a co-polymer of either of these.
  • each one of electrodes 7 and/or 10 comprises a substantially smooth surface, except that the distal end of each such electrode is configured or treated to have a large surface area.
  • the distal tip may be porous platinized.
  • at least the tip of electrode 7 or 10, and/or a metal housing of stimulator 4 includes a coating comprising an anti-inflammatory drug, such as beclomethasone sodium phosphate or beclomethasone phosphate.
  • FIG. 3 is a schematic block diagram illustrating circuitry comprising an implanted unit 20 and an external unit 30, for use with stimulator 4 (Fig. 1), in accordance with a preferred embodiment of the present invention.
  • Implanted unit 20 preferably comprises a feedback block 22 and one or more sensing or signal application electrodes 24.
  • Implanted unit 20 typically also comprises an electromagnetic coupler 26, which receives power and/or sends or receives data signals to or from an electromagnetic coupler 28 in external unit 30.
  • External unit 30 preferably comprises a microprocessor 32 which receives an external control signal 34 (e.g., from a physician or from the patient), and a feedback signal 36 from feedback block 22.
  • Control signal 34 may include, for example, operational parameters such as a schedule of operation, patient parameters such as the patient's weight, or signal parameters, such as desired frequencies or amplitudes of a signal to be applied to the SPG. If appropriate, control signal 34 can comprise an emergency override signal, entered by the patient or a healthcare provider to terminate stimulation or to modify it in accordance with a predetermined program.
  • Microprocessor 32 preferably processes control signal 34 and feedback signal 36 so as to determine one or more parameters of the electric current to be applied through electrodes 24. Responsive to this determination, microprocessor 32 typically generates an electromagnetic control signal 42 that is conveyed by electromagnetic coupler 28 to electromagnetic coupler 26.
  • Control signal 42 preferably corresponds to a desired current or voltage to be applied by electrodes 24 to SPG 6, and, in a preferred embodiment, inductively drives the electrodes.
  • the configuration of couplers 26 and 28 and/or other circuitry in units 20 or 30 may determine the intensity, frequency, shape, monophasic or biphasic mode, or DC offset of the signal (e.g., a series of pulses) applied to designated tissue.
  • Power for microprocessor 32 is typically supplied by a battery 44 or, optionally, another DC power supply. Grounding is provided by battery 44 or a separate ground 46. If appropriate, microprocessor 32 generates a display signal 38 that drives a display block 40 of external unit 30.
  • the display is activated to show feedback data generated by feedback block 22, or to provide a user interface for the external unit.
  • Implanted unit 20 is preferably packaged in a case made of titanium, platinum or an epoxy or other suitable biocompatible material. Should the case be made of metal, then the case may serve as a ground electrode and, therefore, stimulation typically is performed in a monopolar mode. Alternatively, should the case be made of biocompatible plastic material, two electrodes 24 are typically driven to apply current to the SPG.
  • the waveform applied by one or more of electrodes 24 to designated tissue comprises a waveform with an exponential decay, a ramp up or down, a square wave, a sinusoid, a saw tooth, a DC component, or any other shape known in the art to be suitable for application to tissue.
  • the waveform comprises one or more bursts of short shaped or square pulses ⁇ each pulse preferably less than about 1 ms in duration.
  • appropriate waveforms and parameters thereof are determined during an initial test period of external unit 30 and implanted unit 20.
  • the waveform is dynamically updated according to measured physiological parameters, measured during a period in which unit 20 is stimulating the SPG, and/or during a non-activation (i.e., standby) period.
  • the waveform may take the form of a slowly varying shape, such as a slow saw tooth, or a constant DC level, intended to block outgoing parasympathetic messaging.
  • Fig. 4 is a schematic block diagram of circuitry for use, for example, in conjunction with control unit 8 (Fig. 2), in accordance with a preferred embodiment of the present invention.
  • An external unit 50 comprises a microprocessor 52 supplied by a battery 54 or another DC power source. Grounding may be provided by battery 54 or by a separate ground 56.
  • Microprocessor 52 preferably receives control and feedback signals 58 and 68 (analogous to signal 34 and 36 described hereinabove), and generates responsive thereto a stimulation signal 64 conveyed by one or more electrodes 66 to the SPG or other tissue.
  • feedback signal 68 comprises electrical feedback measured by one or more of electrodes 66 and/or feedback from other sensors on or in the patient's brain or elsewhere coupled to the patient's body.
  • microprocessor 52 generates a display signal 60 which drives a display block 62 to output relevant data to the patient or the patient's physician.
  • Fig. 5 A is a graph schematically illustrating a mode of operation of one or more of the devices shown in Figs. 1-4, in accordance with a preferred embodiment of the present invention.
  • the effect of the applied stimulation is monitored by means of a temperature transducer at the SPG or elsewhere in the head, e.g., in the nasal cavity. As shown in Fig.
  • stimulation of the SPG or related tissue is initiated at a time TI, and this is reflected by a measurable rise in temperature (due to increased blood flow).
  • a predetermined or dynan ⁇ cally-varying threshold e.g., 37 oC
  • stimulation is terminated (time T2), responsive to which the temperature falls.
  • time T3 the stimulation is reinitiated (time T3).
  • suitable temperatures or other physiological parameters are determined for each patient so as to provide the optimal treatment.
  • control instructions may also be received from the patient, e.g., to initiate stimulation upon the onset of a migraine headache.
  • FIG. 5B is a graph schematically illustrating a mode of operation of one or more of the devices shown in Figs. 1-4, in accordance with another preferred embodiment of the present invention.
  • the amplitude of the waveform applied to the SPG is varied among a continuous set of values (SI), or a discrete set of values (S2), responsive to the measured temperature, in order to achieve the desired performance.
  • SI continuous set of values
  • S2 discrete set of values
  • Other feedback parameters measured in the head e.g., intracranial pressure and/or cerebral blood flow
  • measured systemic parameters e.g., heart rate
  • FIG. 6 is a graph schematically illustrating a mode of operation of one or more of the devices shown in Figs. 1-4, in accordance with a preferred embodiment of the present invention.
  • a drug is administered to the patient at a constant rate, e.g., intravenously, prior to the initiation of stimulation of the SPG at time TI.
  • this prior generation of heightened concentrations of the drug in the blood tends to provide relatively rapid transfer of the drug across the BBB and into the brain, without unnecessarily prolonging the enhanced permeability of the BBB while waiting for the blood concentration of the drug to reach an appropriate level.
  • Fig. 7 is a schematic block diagram showing circuitry for parasympathetic stimulation, which is particularly useful in combination with the embodiment shown in Fig. 1, in accordance with a preferred embodiment of the present invention.
  • An external unit 80 preferably comprises a microprocessor 82 that is powered by a battery 84 and/or an AC power source. Microprocessor 82 is grounded through battery 84 or through an optional ground 86.
  • an external control signal 88 is input to microprocessor 82, along with a feedback signal 108 from one or more biosensors 106, which are typically disposed in a vicinity of an implanted unit 100 or elsewhere on or in the patient's body. Responsive to signals 88 and 108, microprocessor 82 preferably generates a display signal 89 which drives a display 90, as described hereinabove. hi addition, microprocessor 82 preferably processes external control signal 88 and feedback signal 108, to determine parameters of an output signal 92, which is modulated by a modulator 94. The output therefrom preferably drives a current through an electromagnetic coupler 96, which inductively drives an electromagnetic coupler 98 of implanted unit 100.
  • biosensor 106 comprises implantable or external medical apparatus including, for example, one or more of the following: • a blood flow sensor, • a temperature sensor, • a chemical sensor, • an ultrasound sensor, • transcranial Doppler (TCD) apparatus, • laser-Doppler apparatus, • a systemic or intracranial blood pressure sensor (e.g., comprising a piezoelectric crystal fixed to a major cerebral blood vessel, capable of detecting a sudden blood pressure increase indicative of a clot), • a kinetics sensor, comprising, for example, an acceleration, velocity, or level sensor (e.g., a mercury switch), for indicating body dispositions such as a sudden change in body attitude (as in collapsing), • an electroencephalographic (EEG) sensor comprising EEG electrodes attached to, or implante
  • EEG electroencephalographic
  • Fig. 8 is a schematic illustration showing operational modes of modulator 94 and/or demodulator 102, in accordance with a preferred embodiment of the present invention.
  • the amplitude and frequency of signal 92 in Fig. 7 can have certain values, as represented in the left graph; however, the amplitude and frequency are modulated so that signal 103 has different characteristics.
  • Fig. 9 is a schematic illustration of further apparatus for stimulation of the SPG, in accordance with a preferred embodiment of the present invention.
  • substantially all of the processing and signal generation is performed by circuitry in an implanted unit 110 in the patient, and, preferably, communication with a controller 122 in an external unit 111 is performed only intermittently.
  • the implanted unit 110 preferably comprises a microprocessor 112 coupled to a battery 114.
  • Microprocessor 112 generates a signal 116 that travels along at least one electrode 118 to stimulate the SPG.
  • a feedback signal 120 from a biosensor (not shown) and/or from electrode 118 is received by microprocessor 112, which is adapted to modify stimulation parameters responsive thereto.
  • microprocessor 112 and controller 122 are operative to communicate via electromagnetic couplers 126 and 124, in order to exchange data or to change parameters.
  • FIG. 10A is a schematic illustration of a stimulator 150, in accordance with a preferred embodiment of the present invention.
  • substantially all of the electronic components are encapsulated in a biocompatible metal case 154.
  • An inductive coil 156 and at least one electrode 162 are preferably coupled to circuit 158 by means of a feed-through coupling 160.
  • the inductive coil is preferably isolated by an epoxy coating 152, which allows for higher efficiency of the electromagnetic coupling.
  • Fig. 10B is a schematic illustration of another configuration of an implantable stimulator, in accordance with a preferred embodiment of the present invention.
  • substantially all of the electronic components are encapsulated in a biocompatible metal case 174.
  • One or more feed-throughs are preferably provided to enable coupling between at least one electrode 182 and the electronic circuit, as well as between inductive coil 176 and another inductive coil (not shown) in communication therewith.
  • the energy source for electronic circuits 158 and 178 may comprise, for example, a primary battery, a rechargeable battery, or a super capacitor.
  • any kind of energizing means may be used to charge the energy source, such as (but not limited to) standard means for inductive charging or a miniature electromechanical energy converter that converts the kinetics of the patient movement into electrical charge.
  • an external light source e.g., a simple LED, a laser diode, or any other light source
  • ultrasound energy is directed onto the implanted unit, and transduced to drive battery charging means.
  • Figs. 11 and 12 are bar graphs showing experimental results obtained during rat experiments performed in accordance with a preferred embodiment of the present invention.
  • a common technique in monitoring bio-distribution of materials in a system includes monitoring the presence and level of radio-labeled tracers. These tracers are unstable isotopes of common elements (e.g., Tc, In, Cr, Ga, and Gd), conjugated to target materials. The chemical properties of the tracer are used as a predictor for the behavior of other materials with similar physiochemical properties, and are selected based on the particular biological mechanisms that are being evaluated. Typically, a patient or experimental animal is placed on a Gamma camera, or target tissue samples can be harvested and placed separately into a well counter. For the purpose of the present set of experiments which were performed, the well counter method was chosen due to its higher sensitivity and spatial resolution.
  • Figs. 11 and 12 show results obtained using 99Tc-DTPA penetration assays using ordinary brain sampling techniques (Fig. 11) and peeled brain techniques (Fig. 12).
  • the x-axis of each graph represents different experimental runs, and the y-axis of each graph is defined as: [(hemisphere radioactivity) / (hemisphere weight)] / [(total injected radioactivity) / (total animal weight)].
  • the results obtained demonstrate an average 2.5- fold increase in the penetration of 99Tc-DTPA to the rat brain. It is noted that these results were obtained by unilateral stimulation of the SPG. The inventors believe that bilateral SPG stimulation will approximately double drug penetration, relative to unilateral SPG stimulation. In both Fig. 11 and Fig. 12, some animals were designated as control animals, and other animals were designated as test animals.
  • Fig. 11 shows results from a total of four test hemispheres and four control hemispheres.
  • Fig. 12 shows results from six test hemispheres and fourteen control hemispheres. The juxtaposition of control and test bars in the bar graphs is not meant to imply pairing of control and test hemispheres.
  • FIG. 13 is a schematic illustration of acoustic or optical clot detection apparatus 202, for use, for example, in providing feedback to any of the microprocessors or other circuitry described hereinabove, in accordance with a preferred embodiment of the present invention.
  • the detection is preferably performed by coupling to a major blood vessel 200 (e.g., the internal carotid artery or aorta) a detecting element comprising an acoustic or optical transmitter/receiver 206, and an optional reflecting surface 204.
  • Natural physiological liquids may serve as a mediating fluid between the device and the vessel.
  • the transmitter/receiver generates an ultrasound signal or electromagnetic signal which is reflected and returned, and a processor evaluates changes in the returned signal to detect indications of a newly-present clot.
  • a transmitter is placed on side of the vessel and a receiver is placed on the other side of the vessel.
  • more than one such apparatus 202 are placed on the vessel, in order to improve the probability of successful clot detection for possible estimation of the clot's direction of motion within the vessel, and to lower the false alarm (i.e. false detection) rate.
  • Embodiments of the present invention have many medical applications. For example, chemotherapeutic drugs need to pass into cerebral tissue in order to treat brain tumors.
  • chemotherapeutic drugs have molecular weights of 200-1200 Da, and thus their transport through the blood-brain barrier (BBB) is highly restricted.
  • BBB blood-brain barrier
  • an intracarotid infusion of high osmotic load has been used in the prior art in order to open the tight junctions of the BBB for a very short period (e.g., 25 minutes), during which the medications are given.
  • This procedure is not simple — it is invasive, requires general anesthesia, requires subsequent intensive care, and is in any case relatively expensive. For these reasons, such intracarotid infusions are used only in very few healthcare facilities, even though some reports claim a substantial improvement in life expectancy in patients receiving chemotherapy in this manner.
  • embodiments of the present invention which facilitate increased trans- BBB drug delivery, and therefore more efficient chemotherapy, also enable a reduction or elimination of the need for radiotherapy. It is noted that such irradiation of the brain is indicated in the literature to be a significant cause of long-term cognitive and other deficits.
  • the better delivery of drugs is also a factor in the treatment of other disorders, such as Parkinson's disease, Alzheimer's disease, and other neurological diseases.
  • the trans-BBB delivery of various growth factors is facilitated using the techniques described herein.
  • Growth factors are typically large molecules that stimulate the growth of neurons, and may be used to treat degenerative disorders, such as Parkinson's disease, Alzheimer's disease, and Motor Neuron Diseases (e.g., Lou Gehrig's disease).
  • Another preferred application of the present invention includes facilitating drug delivery across the BBB in order to treat inflammation in the brain, e.g., for cases of infectious diseases of the brain in immunocompromised patients. Similarly, medications to treat AIDS may be more effectively administered to sites in the brain through the BBB, when appropriate, through the use of methods and apparatus described herein.
  • a further application of some embodiments of the present invention includes the delivery through the BBB of viruses that are agents of gene therapy (e.g., for treating Parkinson's disease).
  • GM2 gangliosidosis Another aspect of some preferred embodiments of the invention relates to the modulation of cerebral blood flow.
  • Stroke is the United States' third leading cause of death, killing about 160,000 Americans every year. More than 3 million people in the United States have survived strokes, of whom more than 2 million suffer crippling paralysis, speech loss and lapses of memory.
  • About 85% of strokes are ischemic, i.e., a blood vessel is occluded and its territory is deprived of oxygen supply. A cerebral region that is totally deprived of blood supply is surrounded by a second region of partial lack of supply, whose vitality is at risk.
  • This second region is one of the main targets of some embodiments of the invention ⁇ stimulation of the SPG will dilate its vessels and significantly improve that region's likelihood of survival. If the intervention is given early enough in the event (e.g., a few hours post-stroke), it might help also the core region of the stroke, as the thrombus is not yet organized, and dilation of the vessels may reintroduce blood supply to the tissue. Alternatively, SPG stimulation may allow the clot to move from a big vessel to a small vessel, and thus deprive blood supply only from a much smaller volume of the brain (which would, in any case, have probably been deprived of blood supply had the clot remained in place). Population-based studies have shown that about 5% of men and 16% of women suffer migraine attacks.
  • An embodiment of the present invention uses electrical means to induce the vasoconstrictive effect and treat migraine. For example, it may use techniques to block nerve messaging, such as applying a slowly-varying voltage, or in some cases, a constant level DC voltage.
  • Alzheimer's disease is becoming a major source of disability and financial load with the increase in life expectancy.
  • vascular factors have been considered prominent in the pathophysiology of the disease. Current therapy is generally concentrated along one line — cholinomimetic medications, which can, at most, slow down the deterioration of cognitive function in patients.
  • Fig. 14 is a block diagram of a stimulation arena 300, in accordance with an embodiment of the present invention.
  • Fig. 15 is a schematic illustration of stimulation arena 300, in accordance with an embodiment of the present invention.
  • Stimulation arena 300 is typically, but not necessarily, used in combination with the techniques described herein, and/or in the patent applications and publications incorporated herein by reference.
  • Stimulation arena 300 comprises an experimental arena 310, such as a cage 311, for holding an animal 312, typically a small animal such as a mouse, rat, or gerbil (animal not shown in Fig. 15). Additionally, stimulation arena 300 comprises means, such as a transmitter coil 314, for wirelessly driving an implant 316 within animal 312. Implant 316 typically comprises a small implanted coil 318 electrically coupled, typically by one or more wires, to at least one electrode 320. Electrode 320 is implanted in animal 312 in a vicinity of a site to be stimulated. For example, electrode 320 may be implanted in a head of the animal.
  • Stimulation sites include, but are not limited to: • a sphenopalatine ganglion (SPG) (also called a pterygopalatine ganglion); • an anterior ethmoidal nerve; • a posterior ethmoidal nerve; • a communicating branch between the anterior ethmoidal nerve and the SPG (retro-orbital branch); • a communicating branch between the posterior ethmoidal nerve and the SPG (retro-orbital branch) • a nerve of the pterygoid canal (also called a vidian nerve), such as a greater superficial petrosal nerve (a preganglionic parasympathetic nerve) or a lesser deep petrosal nerve (a postganglionic sympathetic nerve); • a greater palatine nerve; • a lesser palatine nerve; • a sphenopalatine nerve; • a communicating branch between the maxillary nerve and the sphenopalatine ganglion; • a nasopalatine nerve; • a posterior nasal nerve;
  • Coil 318 is typically implanted at an easily accessible site within animal 312, such as subcutaneously in the anhnal's back.
  • transmitter coil 314 typically comprises a cage coil 322, wrapped around the walls of the cage.
  • cage 311 may be generally cylindrical in shape, as shown in Fig. 15, and cage coil 322 is wrapped around the cylinder.
  • a coil current driver 324 is activated, typically by user controls 326, to drive current through cage coil 322, and thereby inductively drive implanted coil 318 to drive current through electrode 320 and into the stimulation site.
  • User controls 326 typically allow selection of signal parameters such as pulse rate, pulse duration, pulse frequency, and pulse amplitude.
  • experimental arena 310 comprises one or more audiovisual input devices 330, adapted to monitor animal 312.
  • input devices 330 may comprise a video camera 332, e.g., mounted at the top of the experimental arena, adapted to record video and optionally audio of the animal's behavior throughout the inductive application of current to the implanted coil.
  • input devices 330 additionally are active prior to and/or following an experiment.
  • experimental arena 310 comprises a biosensor transceiver 334, e.g., mounted on the experimental arena.
  • Biosensor transceiver 334 typically receives input from: (a) a biosensor unit 336, placed on or implanted in the animal, and adapted to evaluate the effect of the current applied to the stimulation site, and/or (b) an activation indicator 338, such as an accelerometer or other motion detector on or in the animal, which records motion of the animal and facilitates a determination of an effect of the signal application.
  • a stimulation indicator is attached to the animal, and the stimulation indicator generates an indication when current is being driven through implanted coil 318.
  • the stimulation indicator may comprise (a) an LED mounted on the animal's back, and (b) an electronic circuit coupled to the LED.
  • the stimulation indicator may be driven by implanted coil 318 (e.g., via a transcutaneous coupling), or it may be driven by a dedicated stimulation indicator coil incorporated in the electronic circuit and typically mounted on an external surface of the animal. In this latter case, the dedicated coil is typically mounted with an axis thereof parallel to a corresponding axis of implanted coil 318.
  • the stimulation indicator comprises a sound generator.
  • Control station 328 typically performs data collection, data playback, and realtime monitoring of an experiment. For some applications, control station 328 additionally activates coil current driver 324, and/or sets the signal parameters of the stimulation.
  • Control station 328 typically comprises a general-purpose computer, such as a personal computer, which is programmed in software 340 to carry out the functions described herein. Software 340 may be downloaded to the workstation in electronic form, over a network, for example, or it may alternatively be provided on tangible media, such as magnetic or optical media or other non-volatile memory.
  • Control station 328 typically comprises I/O devices 342, a processing unit 344, a power supply 346, and log devices 348 for data collection.
  • an experimental laboratory deploys a plurality of experimental arenas
  • One or more control stations 328 and/or user controls 326 typically activate, configure, and monitor experimental arenas 310 in real-time.
  • Cage 311 is typically ventilated, designed for continuous extensive usage, and has a detachable base-plate (not shown) for easy maintenance.
  • implant 316 is implanted in the animal. The animal is typically then allowed several days to recover.
  • one or more stimulation arenas 300 are used for in vivo screening of drugs targeting the central nervous system (CNS).
  • the automated features of stimulation arena 300 enable long-term testing of a CNS drug.
  • the deployment of a plurality of stimulation arenas 300 enables simultaneous testing of a CNS drug in multiple animals.
  • the parameters of stimulation are configured to cause an increase in BBB permeability of the animals, so as to facilitate passage of the screened drug from the systemic blood circulation into the CNS.
  • implant 316 is selected to be similar to a human implant that is expected to be used in conjunction with the delivery of the tested drugs to humans.
  • Drug-testing applications for which stimulation arena 300 is typically used include, but are not limited to: • Testing of existing drugs having regulatory approval, which are known to have an effect on the CNS, but have poor CNS penetration without the use of the stimulation techniques described herein and/or in the patent applications and publications incorporated herein by reference; • Testing of existing drugs having regulatory approval, which have an effect on other organs in the body; • Screening of promising molecules that have demonstrated effectiveness in tissue cultures, but cannot cross the BBB without the use of the stimulation techniques described herein and or in the patent applications and publications incorporated herein by reference; and • Screening of large molecules such as antibodies or of molecules with low BBB-penetration abilities, such as DNA anti-sense molecules.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biophysics (AREA)
  • Otolaryngology (AREA)
  • Electrotherapy Devices (AREA)

Abstract

L'invention concerne un appareil (300) destiné à être utilisé sur un animal (312) non humain. On implante dans ledit animal (312) (a) une bobine (318) implantée et, couplée électriquement à la bobine (318), (b) une électrode (320) en contact avec des tissus cibles situés dans la tête de l'animal (312). L'appareil (300) comprend une cage (311) permettant de retenir l'animal (312), une bobine (322) de cage entourant au moins une partie de la cage (311) et un dispositif de commande (324) du courant de la bobine, lequel commande le courant de la bobine de la cage (311) à travers la bobine (322) de la cage, tout en dirigeant de manière inductive du courant induit à travers la bobine implantée (318), dans l'électrode (320), et dans les tissus cible.
PCT/IL2004/000611 2003-07-07 2004-07-07 Arene de stimulation Ceased WO2005002467A2 (fr)

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US7117033B2 (en) 2000-05-08 2006-10-03 Brainsgate, Ltd. Stimulation for acute conditions
US7561919B2 (en) 2002-11-14 2009-07-14 Brainsgate Ltd. SPG stimulation via the greater palatine canal
WO2010090852A3 (fr) * 2009-01-21 2010-10-14 Zurlin Technologies Holdings, Llc Thérapie électronique continue ou discontinue appliquée aux voies respiratoires (ecat) pour assurer le traitement de troubles respiratoires survenant durant le sommeil
WO2010138994A1 (fr) * 2009-06-02 2010-12-09 Commonwealth Scientific Industrial Research Organisation Transmission d'energie a des dispositifs portes par des animaux
US7908000B2 (en) 2004-02-20 2011-03-15 Brainsgate Ltd. Transmucosal electrical stimulation
ES2376597A1 (es) * 2010-06-11 2012-03-15 Universitat Politècnica De Catalunya Sistema modular para la alimentación por campo magnético en telemetr�?a animal.
US9072906B2 (en) 2008-07-30 2015-07-07 Ecole Polytechnique Federale De Lausanne Apparatus and method for optimized stimulation of a neurological target
US9604055B2 (en) 2009-12-01 2017-03-28 Ecole Polytechnique Federale De Lausanne Microfabricated surface neurostimulation device and methods of making and using the same
US9675796B2 (en) 2013-11-10 2017-06-13 Brainsgate Ltd. Implant and delivery system for neural stimulator
US9889304B2 (en) 2014-08-27 2018-02-13 Aleva Neurotherapeutics Leadless neurostimulator
US9925376B2 (en) 2014-08-27 2018-03-27 Aleva Neurotherapeutics Treatment of autoimmune diseases with deep brain stimulation
US10065031B2 (en) 2014-08-27 2018-09-04 Aleva Neurotherapeutics Deep brain stimulation lead
US10271907B2 (en) 2015-05-13 2019-04-30 Brainsgate Ltd. Implant and delivery system for neural stimulator
US10406350B2 (en) 2008-11-12 2019-09-10 Ecole Polytechnique Federale De Lausanne Microfabricated neurostimulation device
US10575765B2 (en) 2014-10-13 2020-03-03 Glusense Ltd. Analyte-sensing device
US10695556B2 (en) 2010-04-01 2020-06-30 Ecole Polytechnique Federale De Lausanne Device for interacting with neurological tissue and methods of making and using the same
US10871487B2 (en) 2016-04-20 2020-12-22 Glusense Ltd. FRET-based glucose-detection molecules
US10966620B2 (en) 2014-05-16 2021-04-06 Aleva Neurotherapeutics Sa Device for interacting with neurological tissue and methods of making and using the same
US11266830B2 (en) 2018-03-02 2022-03-08 Aleva Neurotherapeutics Neurostimulation device
US11311718B2 (en) 2014-05-16 2022-04-26 Aleva Neurotherapeutics Sa Device for interacting with neurological tissue and methods of making and using the same
US12357792B2 (en) 2019-01-04 2025-07-15 Shifamed Holdings, Llc Internal recharging systems and methods of use
US12357817B2 (en) 2021-04-06 2025-07-15 Aerin Medical Inc. Nasal neuromodulation devices and methods
US12440656B2 (en) 2020-04-23 2025-10-14 Shifamed Holdings, Llc Power management for interatrial shunts and associated systems and methods

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US9233245B2 (en) 2004-02-20 2016-01-12 Brainsgate Ltd. SPG stimulation

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US7117033B2 (en) 2000-05-08 2006-10-03 Brainsgate, Ltd. Stimulation for acute conditions
US7561919B2 (en) 2002-11-14 2009-07-14 Brainsgate Ltd. SPG stimulation via the greater palatine canal
US8954149B2 (en) 2004-02-20 2015-02-10 Brainsgate Ltd. External stimulation of the SPG
US7908000B2 (en) 2004-02-20 2011-03-15 Brainsgate Ltd. Transmucosal electrical stimulation
US8010189B2 (en) 2004-02-20 2011-08-30 Brainsgate Ltd. SPG stimulation for treating complications of subarachnoid hemorrhage
US10952627B2 (en) 2008-07-30 2021-03-23 Ecole Polytechnique Federale De Lausanne Apparatus and method for optimized stimulation of a neurological target
US10166392B2 (en) 2008-07-30 2019-01-01 Ecole Polytechnique Federale De Lausanne Apparatus and method for optimized stimulation of a neurological target
US9072906B2 (en) 2008-07-30 2015-07-07 Ecole Polytechnique Federale De Lausanne Apparatus and method for optimized stimulation of a neurological target
US10406350B2 (en) 2008-11-12 2019-09-10 Ecole Polytechnique Federale De Lausanne Microfabricated neurostimulation device
US11123548B2 (en) 2008-11-12 2021-09-21 Ecole Polytechnique Federale De Lausanne Microfabricated neurostimulation device
WO2010090852A3 (fr) * 2009-01-21 2010-10-14 Zurlin Technologies Holdings, Llc Thérapie électronique continue ou discontinue appliquée aux voies respiratoires (ecat) pour assurer le traitement de troubles respiratoires survenant durant le sommeil
WO2010138994A1 (fr) * 2009-06-02 2010-12-09 Commonwealth Scientific Industrial Research Organisation Transmission d'energie a des dispositifs portes par des animaux
US9604055B2 (en) 2009-12-01 2017-03-28 Ecole Polytechnique Federale De Lausanne Microfabricated surface neurostimulation device and methods of making and using the same
US10695556B2 (en) 2010-04-01 2020-06-30 Ecole Polytechnique Federale De Lausanne Device for interacting with neurological tissue and methods of making and using the same
US11766560B2 (en) 2010-04-01 2023-09-26 Ecole Polytechnique Federale De Lausanne Device for interacting with neurological tissue and methods of making and using the same
WO2012007605A3 (fr) * 2010-06-11 2012-03-15 Universitat Politecnica De Catalunya Système modulaire pour l'alimentation par champ magnétique en télémétrie animale
ES2376597A1 (es) * 2010-06-11 2012-03-15 Universitat Politècnica De Catalunya Sistema modular para la alimentación por campo magnético en telemetr�?a animal.
US9675796B2 (en) 2013-11-10 2017-06-13 Brainsgate Ltd. Implant and delivery system for neural stimulator
US10512771B2 (en) 2013-11-10 2019-12-24 Brainsgate Ltd. Implant and delivery system for neural stimulator
US11311718B2 (en) 2014-05-16 2022-04-26 Aleva Neurotherapeutics Sa Device for interacting with neurological tissue and methods of making and using the same
US10966620B2 (en) 2014-05-16 2021-04-06 Aleva Neurotherapeutics Sa Device for interacting with neurological tissue and methods of making and using the same
US11167126B2 (en) 2014-08-27 2021-11-09 Aleva Neurotherapeutics Deep brain stimulation lead
US9889304B2 (en) 2014-08-27 2018-02-13 Aleva Neurotherapeutics Leadless neurostimulator
US10441779B2 (en) 2014-08-27 2019-10-15 Aleva Neurotherapeutics Deep brain stimulation lead
US10201707B2 (en) 2014-08-27 2019-02-12 Aleva Neurotherapeutics Treatment of autoimmune diseases with deep brain stimulation
US10065031B2 (en) 2014-08-27 2018-09-04 Aleva Neurotherapeutics Deep brain stimulation lead
US9925376B2 (en) 2014-08-27 2018-03-27 Aleva Neurotherapeutics Treatment of autoimmune diseases with deep brain stimulation
US11730953B2 (en) 2014-08-27 2023-08-22 Aleva Neurotherapeutics Deep brain stimulation lead
US10575765B2 (en) 2014-10-13 2020-03-03 Glusense Ltd. Analyte-sensing device
US10271907B2 (en) 2015-05-13 2019-04-30 Brainsgate Ltd. Implant and delivery system for neural stimulator
US10871487B2 (en) 2016-04-20 2020-12-22 Glusense Ltd. FRET-based glucose-detection molecules
US11266830B2 (en) 2018-03-02 2022-03-08 Aleva Neurotherapeutics Neurostimulation device
US11738192B2 (en) 2018-03-02 2023-08-29 Aleva Neurotherapeutics Neurostimulation device
US12357792B2 (en) 2019-01-04 2025-07-15 Shifamed Holdings, Llc Internal recharging systems and methods of use
US12440656B2 (en) 2020-04-23 2025-10-14 Shifamed Holdings, Llc Power management for interatrial shunts and associated systems and methods
US12357817B2 (en) 2021-04-06 2025-07-15 Aerin Medical Inc. Nasal neuromodulation devices and methods

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