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WO2008003318A1 - Système de modèle de recherche et procédé d'utilisation d'une stimulation électrique et/ou d'une stimulation chimique pour induire une dépression dans des animaux de recherche - Google Patents

Système de modèle de recherche et procédé d'utilisation d'une stimulation électrique et/ou d'une stimulation chimique pour induire une dépression dans des animaux de recherche Download PDF

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Publication number
WO2008003318A1
WO2008003318A1 PCT/DK2007/000338 DK2007000338W WO2008003318A1 WO 2008003318 A1 WO2008003318 A1 WO 2008003318A1 DK 2007000338 W DK2007000338 W DK 2007000338W WO 2008003318 A1 WO2008003318 A1 WO 2008003318A1
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Prior art keywords
model system
causing
depressive illness
area
research
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PCT/DK2007/000338
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English (en)
Inventor
Jens Christian Hedemann SØRENSEN
Carsten Reidies Bjarkam
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Aarhus Universitet
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Aarhus Universitet
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36082—Cognitive or psychiatric applications, e.g. dementia or Alzheimer's disease

Definitions

  • This invention relates to nervous tissue stimulation for inducing a condition resembling depressive illness in research animals by modulating the function of the nervous tissue at a predetermined stimulation site in the brain.
  • depressive illness Each year several people experience a depressive illness.
  • the types of depressive illness may be clinical depression, including Mild Depression (Dysthymia) and the spectrum of anxiety disorders, Major Depression, and Bipolar Disorder (Manic-Depression).
  • Major Depression is defined by a constellation of chronic symptoms that include sleep problems, appetite problems, anhedonia or lack of energy, feelings of worthlessness or hopelessness, difficulty concentrating, and suicidal thoughts.
  • Bipolar Disorder involves major depressive episodes alternating with high-energy periods of rash behaviour, poor judgment, and grand delusions.
  • electrical stimulation for treating neurological and psychiatric diseases, such as movement disorders, chronic pain, obsessive compulsive disorder, depression and epilepsy, has been widely discussed in the literature. It has been recognized that electrical stimulation holds significant advantages over lesioning since lesioning destroys the nervous system tissue. In many instances, the preferred effect is to modulate neuronal activity. Electrical stimulation permits such modulation of the target neural structures and, equally importantly, does not require the destruction of nervous tissue.
  • Such electrical stimulation procedures include deep brain stimulation (DBS), electroconvulsive therapy (ECT), repetitive transcranial (rTMS) magnetic stimulation and vagal nerve stimulation (VNS).
  • Deep brain stimulation has been applied to the treatment of central pain syndromes and movement disorders, and it is currently being explored as a therapy for epilepsy.
  • DBS Deep brain stimulation
  • U.S. Pat. No. 6,016,449 and U.S. Pat. No. 6,176,242 disclose a system for the electrical stimulation of areas in the brain for the treatment of certain neurological diseases such as epilepsy, migraine headaches and Parkinson's disease.
  • the invention concerns a research model system for causing depressive illness in an animal subject other than a human being, said system comprising a probe having a stimulation portion in communication with the subcallosal area, and a device to stimulate the probe thereby activating the subcallosal area and causing the depressive illness.
  • the invention concerns a research system for causing subjects with depressive illness in an animal subject other than a human being, said system comprising an electrical stimulation lead that is implanted into the subject's brain, said lead comprising at least one electrode that is in communication with an area homologous to Brodmann area 25 in humans and delivers an electrical signal to the homolog Brodmann area 25; and a signal generator that generates the electrical signal for transmission to the at least one electrode of the lead resulting in delivery of the electrical signals to the homolog Brodmann area 25 thereby causing the depressive illness.
  • a research system for causing subjects with depressive illness in an animal subject other than a human being, said system comprising a catheter that is implanted into a subject's brain, said catheter having a proximal end coupled to a pump and a discharge portion for infusing a dosage of a pharmaceutical by the catheter into the subcallosal area; and a pump to discharge the pharmaceutical through the discharge portion of the catheter into the predetermined site thereby chemically stimulating the subcallosal area and causing the depressive illness.
  • the invention furthermore relates to a method for causing subjects with depressive illness in an animal subject other than a human being.
  • the invention also relates to the use of the system for causing subjects with depressive illness in an animal subject other than human beings, where said subject is a research animal selected from the group comprising mammals e.g. primates, pigs, cats, dogs and research mice or research rats.
  • the invention also relates to the use of the system for causing subjects with depressive illness in an animal subject other than human beings, where said subject is a genetically modified research animal developed by genetical engineering e.g. knock out, knock in, iRNA or siRNA techniques from the animal group comprising mammals e.g. primates, pigs, cats, dogs and research mice or research rats.
  • the invention uses electrical stimulation and/or chemical stimulation, i.e. one or more pharmaceuticals, to cause depressive illness.
  • electrical stimulation can also be used, such as transcranial magnetic stimulation ("TMS").
  • TMS transcranial magnetic stimulation
  • the stimulation modulates areas of the brain that exhibit altered activity in subjects relative to psychiatrically normal control subjects, thereby causing depressive illness.
  • Such stimulation is likely to be produced by electrical stimulation, an excitatory neurotransmitter or agonist(s) thereof, an inhibitory neurotransmitter of antagonist(s) thereof, and/or a medication that increases the level of an excitatory neurotransmitter or decreases the level of an inhibitory neurotransmitter.
  • Another embodiment of the invention uses genetic techniques to stimulate the areas of the brain that exhibit altered activity in subjects relative to psychiatrically normal control subjects, thereby causing depressive illness.
  • Such stimulation is likely to be produced the injection of stem cells, iRNA, siRNA, viral vectors, genetically modified stem cells or encapsulated cells resulting in increase activity in the targeted brain area and thus causing depressive illness.
  • One embodiment of the present invention utilizes neurosurgical intervention to modulate the pathological activity of the subcallosal area in subjects to cause depressive illness.
  • Such interventions include applying electrical stimulation, herein termed “deep brain stimulation” or DBS, as is currently practiced to treat a number of disorders like Parkinson's disease.
  • DBS deep brain stimulation
  • Other stimulations can include chemical stimulation such as through the use of pharmaceutical or drug pumps, for example local delivery of neuroactive substances or genetically engineered substances to cause the pathological activity stemming from or coursing through this area.
  • stimulation i.e., electrical, magnetic, chemical or genetic modulates the grey matter and white matter tracts in a subcallosal area, as well as the white matter tracts that are associated with the subcallosal area (such as the white matter tracts that lead to and from the subcallosal area or that are adjacent to the subcallosal area), which in turn modulates the limbic system.
  • other stimulations may comprise magnetic stimulation and/or transplantation of cells or genetic manipulation based on iRNA and siRNA techniques. Such simulations can be verified by a research model system according to the invention.
  • the electrical activation for causing mood and/or anxiety disorder may be provided by applying a low frequency signal, such as a frequency below approx. 120 Hz and more preferably below 60 Hz.
  • a low frequency signal such as a frequency below approx. 120 Hz and more preferably below 60 Hz.
  • a high frequency e.g. above 120 Hz
  • a treatment of the depression is achieved.
  • the reverse simulation effect may be achieved resulting in depressive illness. This provides an effective research animal tool for studying the effectiveness of both the known treatments of depressive illness and developing new and improved treatments.
  • Certain embodiments of the present invention involve a method that comprises surgically implanting a device or research stimulation system in communication with a predetermined site, for example the subcallosal area, in the subject's brain.
  • the device or stimulation system is operated to stimulate the predetermined site thereby causing the depressive illness.
  • the device or stimulation system may include a probe, for example, an electrode assembly (i.e., electrical stimulation lead), pharmaceutical-delivery assembly (i.e., catheters or encapsulated cell devices) or combinations of these (i.e., a catheter having at least one electrical stimulation lead) and/or a signal generator or signal source (i.e., electrical signal source, chemical signal source (i.e., pharmaceutical delivery pump) or magnetic signal source).
  • the probe may be coupled to the electrical signal source, pharmaceutical delivery pump, or both which, in turn, is operated to stimulate the predetermined treatment site.
  • the probe and the signal generator or source can be incorporated together, wherein the signal generator and probe are formed into a unitary or single unit, such unit may comprise, one, two or more electrodes.
  • These devices are known in the art as microstimulators, for example, Bion(TM) which is manufactured by Advanced Bionics Corporation.
  • the predetermined site is the subcallosal area.
  • the subcallosal area includes, but is not limited to the subgenual cingulate area, subcallosal gyrus area, ventral/medial prefrontal cortex area, ventral/medial white matter, Brodmann area 24,
  • the predetermined site is a subgenual cingulate area, more preferably Brodmann area 25, Brodmann area 24 or Brodmann area 10.
  • Brodmann areas and other areas throughout this specification homolog areas in the brain of the animal subject other than human beings are meant.
  • Stimulation of the subcallosal area includes stimulation of the grey matter and white matter tracts associated with the subcallosal area that result in the depressive illness.
  • Associated white matter tracts includes the surrounding or adjacent white matter tracts leading to or from the subcallosal area or white matter tracts that are contiguous with the subcallosal area.
  • Modulating the subcallosal area via electrical and/or chemical stimulation (i.e., pharmaceutical or gentical) and/or magnetic stimulation can result in increasing, decreasing, masking, altering or overriding neuronal activity resulting in the depressive illness.
  • stimulation of the subcallosal area may result in modulation of neuronal activity of other areas of the brain, for example, Brodmann area 24, Brodmann area 25, Brodmann area 10, Brodmann area 9, the hypothalamus and the brain stem.
  • Another embodiment of the present invention comprises a method of causing the depressive illness comprising the steps of: surgically implanting an electrical stimulation lead having a proximal end and a stimulation portion, wherein after implantation the stimulation portion is in communication with a predetermined site; the stimulation lead is coupled to or in communication with a signal generator; and an electrical signal is generated using the signal generator to modulate the predetermined site thereby causing the depressive illness.
  • the method can comprise the steps of: surgically implanting a catheter having a proximal end coupled to a pump and a discharge portion for infusing a dosage of a pharmaceutical or genetically engineered substance, wherein after implantation the discharge portion of the catheter is in communication with the predetermined stimulation site; and operating the pump to discharge the pharmaceutical through the discharge portion of the catheter into the stimulation site thereby causing the depressive illness.
  • the pharmaceutical is selected from the group consisting of excitatory neurotransmitter and agonists thereof, an inhibitory neurotransmitter and antagonist thereof, an agent that decreases the level of an inhibitory neurotransmitter, an agent that increase the level of an excitatory neurotransmitter.
  • the genetically engineered substance is selected from the group consisting of injection of stem cells, iRNA, siRNA, viral vectors, genetically modified stem cells or encapsulated cells. It is envisioned that chemical stimulation or infusion of pharmaceuticals or genetically engineered substances can be performed independently of electrical stimulation and/or in combination with electrical stimulation.
  • Another embodiment of the present invention is a method of causing depressive illness comprising the steps of: surgically implanting an electrical stimulation lead having a proximal end and a stimulation portion, wherein after implantation the stimulation portion is in communication with a predetermined site; surgically implanting a catheter having a proximal end coupled to a pump and a discharge portion for infusing a dosage of a pharmaceutical and/or genetically engineered substance, wherein after implantation the discharge portion of the catheter is in communication with a predetermined infusion site; and coupling the proximal end of the lead to a signal generator; generating an electrical signal with the signal generator to modulate the predetermined site; and operating the pump to discharge the pharmaceutical and/or the genetically engineered substance through the discharge portion of the catheter into the infusion site thereby causing the depressive illness.
  • the therapeutic research system comprises an electrical stimulation lead that is implanted into the subject's brain.
  • the electrical stimulation lead comprises at least one electrode that is in communication with a predetermined site and delivers electrical signals to the predetermined site; and a signal generator that generates signals for transmission to the electrodes of the lead resulting in delivery of electrical signals to predetermined site thereby causing the depressive illness.
  • the electrical stimulation lead may comprise one electrode or a plurality of electrodes in or around the target area. Still further, the signal generator is implanted in the subject's body.
  • a therapeutic research model system includes a catheter having a proximal end coupled to a pump and a discharge portion for infusing a dosage of a pharmaceutical and/or genetically engineered substance, wherein after implantation the discharge portion of the catheter is in communication with a predetermined stimulation site; and a pump to discharge the pharmaceutical and/or genetically engineered substance through the discharge portion of the catheter into the predetermined stimulation site thereby causing the depressive illness.
  • another therapeutic research model system comprises a device that is surgically implanted into the subject such that the device is in communication with a predetermined site, for example the subcallosal area.
  • An exemplary device includes a microstimulator (i.e., Bion(TM) manufactured by Advanced Bionics Corporation) in which the device contains a generating portion and at least one electrode in a single unit.
  • a lead assembly is associated with at least one electrode of the microstimulator such that the lead can stimulate the predetermined site not in direct contact with the microstimulator.
  • Other therapeutic research model systems may include a probe that is in communication with the predetermined site and a device that stimulates the probe thereby causing the depressive illness.
  • the probe can be, for example, an electrode assembly (i.e., electrical stimulation lead), pharmaceutical and/or genetically engineered substance-delivery assembly (i.e., catheters) or combinations of these (i.e., a catheter having at least one electrical stimulation lead).
  • the probe is coupled to the device, for example, electrical signal source, pharmaceutical and/or genetically engineered substance delivery pump, or both which, in turn, is operated to stimulate the predetermined treatment site.
  • Figure 1 is a schematic diagram showing the resulting effect of electrical stimulation on the brain tissue nerve cells depending on the frequency input.
  • subjects who are to have an electrical stimulation lead or electrode implanted into the brain generally, first have a stereotactic head frame, such as the Leksell, CRW, or Compass, mounted to the subject's skull by fixed screws.
  • a stereotactic headframe for quadrupeds are disclosed in WO
  • a series of reference points are established to relative aspects of the frame and the patient's skull, so that either a person or a computer software system can adjust and calculate the correlation between the real world of the patient's head and the virtual space model of the subject's MRI scans.
  • the surgeon is able to target any region within the stereotactic space of the brain with precision (i.e., within 1 mm).
  • Initial anatomical target localization is achieved either directly using the MRI images, or indirectly using interactive anatomical atlas programs that map the atlas image onto the stereotactic image of the brain.
  • the anatomical targets may be stimulated directly or affected through stimulation in another region of the brain.
  • the anatomical target for causing a depressive state is described in US2005/033379.
  • the stimulation lead, and stimulation source implantation is also described in US2005/033379. In quadrupeds the stimulation source implantation can in addition take place in the neck and back region.
  • EEG electroencephalography
  • MEG magnetoencephalography
  • fMRI functional magnetic resonance imaging
  • PET positron emission tomography
  • the present invention finds utility in its application to model human psychological or psychiatric activity/disorders in an animal subject other than human beings, e.g. mammals such as a pig or a primate, as it is appreciated that the present invention is applicable to all experimental animals or genetic modifications thereof. This may include, for example, rodents, pigs, primates, canines, felines, ruminants etc. Utilizing the various embodiments of the present invention, one skilled in the art may be able to modulate the functional outcome of the brain to achieve a depression like state in the subject.
  • the probe can be a stimulation lead or electrode assembly or drug and/or genetically engineered substance -delivery catheter, or any combination thereof.
  • the electrode assembly may be one electrode, multiple electrodes, or an array of electrodes in or around the target area.
  • the proximal end of the probe can be coupled to a device, such as an electrical signal source, pharmaceutical delivery pump, or both which, in turn, is operated to stimulate the predetermined treatment site.
  • the probe can be incorporated into the device such that the probe and the signal generating device are a single unit.
  • Certain embodiments of the present invention involve a method of causing a depressive illness comprising the steps of: surgically implanting an electrical stimulation lead having a proximal end and a stimulation portion, wherein after implantation the stimulation portion is in communication with a predetermined site; coupling the proximal end of the lead to a signal generator; and generating an electrical signal with the signal generator to modulate the predetermined site thereby causing the depressive illness.
  • neuromodulation of the predetermined site of the present invention can be achieved using magnetic stimulation.
  • One such system that can be employed and that is well known in the art is described in U.S. Pat. No. 6,425,852, which is incorporated herein by reference.
  • the disease modulating system or deep brain stimulation system of the present invention is surgically implanted as described in the above sections.
  • One of skill in the art is cognizant that a variety of electrodes or electrical stimulation leads may be utilized in the present invention. It is desirable to use an electrode or lead which contacts or conforms to the target site for optimal delivery of electrical stimulation.
  • One such example is a single multi-contact electrode with eight contacts separated by 2-2.5 mm each contact having a span of approximately 2 mm.
  • Another example is an electrode with two 1 cm contacts with a 2 mm intervening gap.
  • another example of an electrode that can be used in the present invention is a 2 or 3 branched electrode/catheter to cover the predetermined site or target site.
  • each one of these three pronged catheters/electrodes have four contacts 1-2 mm contacts with a centre to centre separation of 2 of 2.5 mm and a span of 1.5 mm.
  • Similar designs with catheters to infuse drugs and/or genetically engineered substances with single outlet pore at the extremities of these types of catheters or along their shaft may also be designed and used in the present invention.
  • the present invention extends to methods of transplanting cells into a predetermined site to cause depressive illness. It is envisioned that the transplanted cells can deliver a biologically active molecule to the predetermined site or to induce a condition and/or modulate existing neuronal cells. Such transplantation methods are described in U.S. Application No. US 2004/0092010, which is incorporated herein by reference.
  • the predetermined site or target area is the subcallosal area, more preferably, the subgenual cingulate area, and more preferably the homolog Brodmann area 25/Brodmann area 24.
  • Stimulation of the subcallosal area i.e., subgenual cingulate area or Brodmann area 25/Brodmann area 24
  • the surrounding or adjacent white matter tracts leading to or from the subcallosal area or white matter tracts that are contiguous with the subcallosal area results in changes that cause or induce the depressive illness in the subject. It is contemplated that modulating the subcallosal area, more particularly a subgenual cingulate area, can result in the depressive illness.
  • Brodmann area 25 results in modulation of neuronal activity of other areas of the brain, for example, Brodmann area 9, Brodmann area 10, Brodmann area 24, the hypothalamus, and the brain stem.
  • the predetermined site or target area is stimulated in an effective amount or effective stimulation regimen to increase, modulate or induce the depressive illness.
  • a low frequency such as a frequency below approx. 60-120 Hz
  • a high frequency such as a frequency above 120 Hz
  • a low frequency causing an increase in the activity in the subcallosal area and thereby causing a depressive illness in the subject.
  • the target site is stimulated using stimulation parameters such as, pulse width of about 1 to about 500 microseconds, more preferable, about 1 to about 90 microseconds; frequency of about 1 to about 120 Hz, more preferably, about 1 to about 60 Hz; and voltage of about 0.5 to about 10 volts, more preferably about 1 to about 10 volts.
  • stimulation parameters such as, pulse width of about 1 to about 500 microseconds, more preferable, about 1 to about 90 microseconds; frequency of about 1 to about 120 Hz, more preferably, about 1 to about 60 Hz; and voltage of about 0.5 to about 10 volts, more preferably about 1 to about 10 volts.
  • stimulation parameters such as, pulse width of about 1 to about 500 microseconds, more preferable, about 1 to about 90 microseconds; frequency of about 1 to about 120 Hz, more preferably, about 1 to about 60 Hz; and voltage of about 0.5 to about 10 volts, more preferably about 1 to about 10 volts.
  • stimulation of the subcallosal area and/or the adjacent white matter modulates other targets in the limbic-cortical circuit or pathway thereby stimulating limbic- cortical circuits resulting in depression and/or anxiety in the subjects.
  • an implantable signal generator and electrical stimulating lead and an implantable pump and catheter(s) are used to deliver electrical stimulation and/or one or more stimulating drugs and/or genetically active substances to the above mentioned areas to cause depressive illness.
  • stimulating drugs comprise medications, anaesthetic agents, synthetic or natural peptides or hormones, neurotransmitters, cytokines and other intracellular and intercellular chemical signals and messengers, and the like.
  • certain neurotransmitters, hormones, and other drugs are excitatory for some tissues, yet are inhibitory to other tissues. Therefore, where, herein, a drug is referred to as an "excitatory” drug, this means that the drug is acting in an excitatory manner, although it may act in an inhibitory manner in other circumstances and/or locations.
  • an “inhibitory” drug is mentioned, this drug is acting in an inhibitory manner, although in other circumstances and/or locations, it may be an "excitatory” drug.
  • stimulation of an area herein includes stimulation of cell bodies and axons in the area.
  • excitatory neurotransmitter agonists i.e., norepinephrine, epinephrine, glutamate, acetylcholine, serotonin, dopamine
  • agonists thereof and agents that act to increase levels of an excitatory neurotransmitter(s) (i.e., edrophonium; Mestinon; trazodone; SSRIs (i.e., flouxetine, paroxetine, sertraline, citalopram and fluvoxamine); tricyclic antidepressants (i.e., imipramine, amitriptyline, doxepin, desipramine, trimipramine and nortriptyline), monoamine oxidase inhibitors (i.e., phenelzine, tranylcypromine, isocarboxasid)), generally have an excitatory effect on neural tissue, while inhibitory neurotransmitters (i.e., dopamine,
  • antagonists of inhibitory neurotransmitters i.e., bicuculline
  • agents that act to decrease levels of an inhibitory neurotransmitter(s) have been demonstrated to excite neural tissue, leading to increased neural activity.
  • excitatory neurotransmitter antagonists i.e., prazosin, and metoprolol
  • agents that decrease levels of excitatory neurotransmitters may inhibit neural activity.
  • lithium salts and anaesthetics i.e., lidocane
  • lidocane lithium salts and anaesthetics

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  • Hospice & Palliative Care (AREA)
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Abstract

La présente invention concerne un système de modèle de recherche pour provoquer une dépression dans un sujet animal autre qu'un être humain, ledit système comprenant une sonde ayant une partie de stimulation en communication avec l'aire sous-calleuse; et un dispositif pour stimuler la sonde, permettant ainsi d'activer l'aire sous-calleuse et de provoquer la dépression. Par un système et procédé de modèle de recherche selon l'invention, il est proposé un système de recherche permettant de provoquer une augmentation de l'activité dans les zones prédéterminées, de telle sorte qu'une expérimentation des procédés de traitement de la dépression peut être effectuée dans ce modèle de recherche.
PCT/DK2007/000338 2006-07-05 2007-07-04 Système de modèle de recherche et procédé d'utilisation d'une stimulation électrique et/ou d'une stimulation chimique pour induire une dépression dans des animaux de recherche Ceased WO2008003318A1 (fr)

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DKPA200600923 2006-07-05

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US8788064B2 (en) 2008-11-12 2014-07-22 Ecole Polytechnique Federale De Lausanne Microfabricated neurostimulation device
US8788042B2 (en) 2008-07-30 2014-07-22 Ecole Polytechnique Federale De Lausanne (Epfl) Apparatus and method for optimized stimulation of a neurological target
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US9925376B2 (en) 2014-08-27 2018-03-27 Aleva Neurotherapeutics Treatment of autoimmune diseases with deep brain stimulation
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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

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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8788042B2 (en) 2008-07-30 2014-07-22 Ecole Polytechnique Federale De Lausanne (Epfl) 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
US10166392B2 (en) 2008-07-30 2019-01-01 Ecole Polytechnique Federale De Lausanne Apparatus and method for optimized stimulation of a neurological target
US10952627B2 (en) 2008-07-30 2021-03-23 Ecole Polytechnique Federale De Lausanne Apparatus and method for optimized stimulation of a neurological target
US11123548B2 (en) 2008-11-12 2021-09-21 Ecole Polytechnique Federale De Lausanne Microfabricated neurostimulation device
US8788064B2 (en) 2008-11-12 2014-07-22 Ecole Polytechnique Federale De Lausanne Microfabricated neurostimulation device
US9440082B2 (en) 2008-11-12 2016-09-13 Ecole Polytechnique Federale De Lausanne Microfabricated neurostimulation device
US10406350B2 (en) 2008-11-12 2019-09-10 Ecole Polytechnique Federale De Lausanne Microfabricated neurostimulation device
US9192767B2 (en) 2009-12-01 2015-11-24 Ecole Polytechnique Federale De Lausanne Microfabricated surface neurostimulation device and methods of making and using the same
US8774937B2 (en) 2009-12-01 2014-07-08 Ecole Polytechnique Federale De Lausanne Microfabricated surface neurostimulation device and methods of making and using the same
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
US9549708B2 (en) 2010-04-01 2017-01-24 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
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
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