Dominique Durand - US grants

Research is underway that is designed to provide information on the mechanisms of the effects of applied and naturally generated electrical fields on the stimulation, and on the optimal parameters of electrical stimulation for prosthetic and therapeutic devices. This research area should have direct application to problems concerning electric field effects on the development of seizures in epilepsy. Several sophisticated techniques are being used, including ;itin vitro;ro brain slice preparations, current density analysis, and computer models of nerve cells and neural networks, to accomplish the research tasks.

The objective of the proposed research is to study the effects of acute doses of ethanol on the electrical parameters of neuronal membrane and the mechanisms leading to the long-term effects of ethanol. The electrical membrane properties are essential parameters of neuronal integration in the central nervous system. This concept of integration deals with the effectiveness of synaptic inputs and their summation in the dendrites, and relies on the electrotonic properties of neuronal membrane. Although acute ethanol intoxication causes deficits in memory and information processing, very little is known about the effects of ethanol on neuronal integration. Preliminary studies in the hippocampus have suggested that clinically relevant acute doses of ethanol (20 to 100mM) increase the membrane capacitance of CA1 pyramidal cells. However, the determination of the electrical membrane properties requires detailed analysis of the morphological and electrical structure of the neurons studied. Therefore, the first objective is to measure the acute effects of clinically relevant doses of ethanol (20 to 100mM) on the electrical membrane properties of granule cells in the dentate gyrus using the in-vitro hippocampal slice preparation. This preparation is particularly useful, because it allows direct access to the neurons for intracellular records, morphological identification of the same cell, and the ethanol containing solution can be applied directly on the tissue slice. The second objective is to analyze the effect of ethanol on neuronal integration with computer modeling techniques applied to th granule cells. Powerful computer models of neurons have been developed to accurately simulate neuronal behavior. The effects of ethanol on the membrane properties and other electrophysiological parameters will be implemented to study the interaction between both acute and long-term effects of ethanol and neuronal integration. Chronic ethanol treatment (5 months) also affects the membrane electrotonic parameters and particularly a decrease in the membrane specific capacitance of granule cells was measured. However, the mechanisms leading to the development of long-term effects are unknown. Acute tolerance (adaptation during the course of a single ethanol exposure) has been reported to share the same mechanisms with chronic tolerance (adaptation during continuous presence of ethanol). The final objective is to measure the electrical neuronal parameters during this acute tolerance phase in order to understand the process leading to long-term effects of ethanol.

Electrical stimulation has been used effectively to excite nerves, muscles and brain nerve cells. A more difficult problem is to inhibit the firing of neurons using electrical stimulation. A method for blocking neuronal firing would be extremely important any time abnormal neuronal firing interferes with the normal physiological functions such as in spasticity and in epilepsy. Electrical fields have been used to block neuronal firing in axons. Moreover, electrical fields applied in several parts of the brain have been shown to modify the excitability of neurons. This research project proposes that these electrical field techniques be studied for the purpose of controlling abnormal neuronal firing in neural tissue. Preliminary experiments have shown that neuronal firing can be blocked when low-intensity, long current pulses are applied with electrodes. Neural recording techniques as well as computer modeling methods will be used to understand the mechanisms. The in vitro brain slice preparation will be used for this project, since it is possible to directly position the electrodes in the tissue to ensure a proper orientation of the electrical field. The short-term impact of this project is to provide an understanding of the role of electrical fields in controlling abnormal neuronal activity. The long-term impact of this project is to generate the background knowledge for the design of the method for controlling and blocking abnormal epileptic activity.***//

The objective of the proposed project is to determine the effect of clinically relevant concentrations of ethanol on the firing threshold of small central neurons. Although ethanol has known anesthetic properties, the mechanisms of the action of ethanol on the firing threshold of small central neurons has never been accurately measured. Computer simulation experiments predict that the threshold of granule cells should be increased with ethanol. Preliminary experiments in the hippocampus using the strength-duration curve have also shown that ethanol can increase threshold at clinically relevant doses (50 mM) at a wide range of pulse width and amplitude. The mechanism for the increase in threshold is not clear, but computer simulations show that a decrease in membrane capacitance produced by ethanol could be responsible for this change in threshold. Both a voltage and a current threshold contribute to the observed firing threshold in membrane. These thresholds have traditionally been measured with the strength-duration curve which relates the amplitude to the pulse width of the current just necessary to fire the cell. This method, however, is very insensitive to large changes in threshold when both the voltage and the current thresholds have been modified. Synaptic thresholds have also been estimated by measuring the amplitude of an EPSP just necessary to generate a spike. Ethanol has been should to increase this value of the threshold as well. However, this value is only an estimate and is highly dependent on the rise time of the membrane voltage and has no direct relationship to the true value of the voltage threshold. It is therefore proposed to study the effect of ethanol on the firing threshold of granule cells at various clinically relevant concentrations (20 to 100 mM) by measuring the current- voltage relationship of the membrane using voltage clamp techniques. Both the voltage and the current threshold can be obtained with this technique and the synaptic threshold can also be directly measured. The analysis of the difference between the direct firing threshold and the synaptic threshold is important for the determination of the locus of action of ethanol. The measurements will be made using the in-vitro hippocampal preparation technique. This preparation is particularly useful since it allows direct access to the neurons and the ethanol solution can be applied directly to the tissue. The threshold parameters will also be measured during the acute tolerance phase. Acute tolerance (adaptation during the course of a single exposure) has been reported to share the same mechanisms with chronic tolerance (adaptation during the repeated exposure to ethanol). Therefore, the determination of the ethanol effects during this acute tolerance period will provide information about the process leading to the development of the long-term effects of ethanol.

This project will study: i) the mechanisms of activation of neural tissue by magnetic stimulation; ii) calculate induced fields in various volume conductors; iii) simulate on the computer the effects of these fields using models of axons and neurons; and iv) design a coil capable of focussing the induced fields. This project also intends to test directly the efficacy of this coil in both the peripheral nervous system and the central nervous system (CNS). This combination of a theoretical with an experimental approach should generate useful and important information about the mechanisms of magnetic stimulation and the efficacy of focussing magnetic fields for the excitation of the nervous system. This non-invasive method of stimulation should provide clinicians with a powerful tool to study and map normal brain function as well as diagnose certain types of neural diseases provided that the mechanisms of the interactions between magnetic fields and neural tissue can be understood.

9315886 Durand This award will fund a project to investigate parameter estimation techniques for use with neurophysiological systems. The investigators will compare and test current and new parameter estimation techniques; that is, Linear Associative Memories. These techniques will be applied to the estimation of electrotonic and membrane ionic channel parameters. This proposal was submitted to the Biosystems Analysis and Control Initiative which encouraged the submission of proposals that through the study of neurophysiological systems could advance engineering science and advance the knowledge of biological systems through the use of engineering analysis techniques. The research being funded by this award has the potential to assist in the modeling of neurophysiological data and advance the field of engineering in the area of parameter estimation. ***

Functional nerve stimulation (FNS) is a means to restore lost function to patients with spinal cord injury. By directly stimulating the nerve, it is possible to maximize muscle contraction and minimize injected charge. An effective neural electrode must meet the following criteria: 1) The electrode must be able to activate any subset of the neural axon population, either deep or surface, selectively and independently and; 2) The electrode must not cause significant damage to the nerve. Current nerve cuff designs place electrodes around the nerve. These exhibit some degree of selectivity, but, cannot provide adequate functional control since it is not possible to selectively activate portions deep in the nerve without stimulation of the surface of the nerve. Intraneural electrodes have been developed to provide access to the deep portions of the nerve. Two of the current intraneural approaches are regeneration electrodes and wire electrodes. The regeneration design places a silicon substrate penetrated by holes between two severed ends of a nerve. The axons then regenerate through the holes. Wire electrodes are electrical wires threaded through the neural fascicles, penetrating the epineurium and a second protective layer, the perineurium. Both the threaded wire and regeneration designs provide selective stimulation of neural regions, but produce significant damage to the fascicles and axons. We propose a new design which combines the advantages of the standard nerve cuff and intraneural electrodes. This new device slowly places electrodes inside the nerve, but between the fascicles without perforation of the perineurium. The interaction takes place over the course of several days by taking advantage of the mechanical energy stored in the cuff prior to installation. Preliminary experiments have shown that the slow rate of penetration causes minimal damage and trauma to the nerve while still placing electrodes deep in the nerve. The aims of this proposal are 1) to show that chronic damage from the electrode is minimal, 2) to determine the selectivity of the design for electrical stimulation of the sciatic nerve in the cat, 3) develop finite element model of fields generated within the nerve and use this model to optimize the electrode design, and 4) to develop a electrode that utilizes currently available silicon technology to maximize the selectivity and function of the electrode. The end-product of this project will be an electrode capable of producing selective activation of neural regions by placing multiple contact points within the nerve with minimal axon damage. The same electrode could then be used for recording neuronal activity such as sensory signals and this Slowly Penetrating Interfascicular Nerve Electrode (SPINE) could, therefore, become a general purpose neural cuff design capable of both selective activation and recording.

The goal of this research project entitled "Electric Field Interaction With Neuronal Tissue" is to study the mechanisms by which electric fields can control and modify the activity of neurons. Electric fields can be easily generated near and around neurons in the brain by placing electrodes in specific locations and injecting known amounts of current. Previous experiments have shown that currents applied at very small amplitudes are capable of preventing the activity of neurons and to interfere with their firing patterns. The research is aimed at the determination of the basic mechanisms underlying these effects. The results of the research proposal will allow us to better understand how electric fields can control the activity of neurons and may lead to the design of a method to prevent abnormal neuronal activity such as in epileptic seizures.

The principal objective of the proposed project is to design and test coils that can produce localized magnetic fields for neural excitation. Magnetic stimulation is a fairly recent method to activate excitable tissue in the peripheral and the central nervous system non-invasively. Despite the potential usefulness of this technique, the most important problem with magnetic stimulation to date is the large spread of the induced field produced by coils compared to the size of neuronal structures. Localization of induced fields as proposed here refers to a reduction of the spatial extent of the induced fields produced by magnetic coils. Such a reduction would. provide concentrated regions of higher flux linkage and thereby improve selectivity and efficiency of magnetic stimulation. Further, some of the basic mechanisms underlying activation of peripheral nerves and neural tissue in the brain are still unclear. In particular, elements excited and sites of excitation are still not well known in both peripheral nerves and the CNS. Another problem is the absence of accurate methods to predict threshold strengths based on information about the induced fields. The knowledge of the above mentioned basic mechanisms would enable design of better coils for use in magnetic stimulation. Moreover, it is now known that tissue inhomogeneities in excitable tissue (e.g.. branching, bending and termination) would localize excitation sites to anatomical structures. However, the exact mechanisms of effects of such inhomogeneities with localized fields are unknown. Therefore, we propose to develop methods to predict threshold strengths during magnetic stimulation and to analyze effects of tissue inhomogeneities using theoretical models, computer simulations and in vitro experiments. We also propose to design optimal coils such that both energies required for threshold excitation of neuronal.structures and the spatial extents of the fields are minimized. Localization of magnetic fields will firstly be used in in vitro hippocampal slice preparations to measure the effects of magnetically-induced fields in the CNS. This preparation is particularly useful since the neurons are directly accessible for intra- and extracellular recording and will allow direct measurement of excitation mechanisms. It is important to use coils that produce localized fields for this preparation because the spatial extent of the fields from regular solenoidal coils are large compared to the small size of the tissue. Hence, concentration of flux linkage is required for efficient excitation. Finally, we propose to test localized coils using in vivo experiments for bladder contraction in dogs. Since stimulation of the nerves to the bladder using large coils stimulates nerves to the sphincter and other abdominal and pelvic structures, we intend to use coils that produce localized fields for selective contraction of the bladder. This would allow magnetic stimulation to be used not only as a diagnostic tool for non-invasive excitation of the nervous system but also as a functional tool for patients with impaired bowel and bladder function. This combination of coil design and optimization based on theoretical models, computer simulations with related experiments should generate useful and important information about the mechanisms of magnetic stimulation for excitation of the nervous system and thereby increase its functionality.

Obstructive Sleep Apnea (OSA) is the recurrent occlusion of the upper airways during sleep due to the decreased neuromuscular tone in the tongue and the pharyngeal muscles. A 1993 study in Wisconsin has shown that 2 to 4 percent of the population is affected. This number reaches 9 percent in another study conducted in Australia. This is clearly a serious problem which affects a large segment of the population and can lead to severe disorders such as stroke. The current methods used to treat this sleep disorder provide only partial solutions and only in a limited number of cases. We propose to develop a closed-loop control nerve prosthetic device as a treatment for OSA to be tested in a dog model. The hypoglossal nerve innervates the genioglossus, the muscle mainly responsible for protrusion of the tongue. The spontaneous activity of the hypoglossal nerve will be recorded during normal sleeping conditions and used as the feedback signal to trigger the stimulation of the genioglossus. Electrical stimulation will be delivered to the hypoglossal nerve with the same electrode used for recording and will be synchronized with inspirations to keep the airways open. Electrical stimulation of this nerve has already been proposed and tested experimentally by other groups. The innovative part of this project is to use the stimulating electrode to record the nerve activity in order to detect the occlusion and trigger the stimulation. This project has an element of risk because chronic recording of hypoglossal nerve activity in a non-anesthetized animal has never been reported as well as the design of a neural prosthetic system capable of recording and stimulation with the same electrode. Successful completion of this project could lead to the design of a neuronal prosthesis capable of restoring a normal pattern of breathing without causing arousal from sleep in humans.

DESCRIPTION (provided by applicant): Interest in the field of neural prosthetics has grown significantly in the last 20 years. Yet only few applications such as cochlear prosthesis have found their way into patient therapy. One of the major reasons for this lack of success is the interface between nerve and electrodes. Recent development in electrode design suggest that either reshaping the nerve into a flat configuration or maintaining the nerve in an already flat shape can improve the ability to interface with peripheral nerves. The Flat Nerve Interface Electrode (FINE) design is the result of research carried out during the last grant period. The central hypothesis of this proposal is that fascicular signals from peripheral nerves can be recovered and used to control the peripheral nervous system function with a multiple contact FINE cuff. This hypothesis will be tested with three specific aims: Aim 1: Signals from various fascicles within the nerve can be recovered, Aim 2: Neural activity within nerve can be controlled with multiple contact nerve electrodes, and Aim 3: Joint dynamics can be controlled by neural signals. The end product of this proposal will be a platform technology for closed-loop control of neural function that relies on a single approach for recording and stimulation with multicontact electrodes placed on peripheral nerves. The team assembled relies on expertise in various fields such as engineering, orthopedics and mathematics. This neurotechnology is applicable to many disorders of the nervous systems such as stroke, paralysis and autonomic nervous system disorders and to the control of artificial prosthetic limbs. In particular, peripheal nerve interfaces could provide a complementary approach to brain microelectrodes for the detection and control of neural function. 1

DESCRIPTION:(adapted from applicant's abstract) This project aims to develop an experimental therapy for obstructive sleep apnea (OSA) using electrical stimulation of the hypoglossal nerve. The PI proposes to use a multi-channel stimulation technique for selective activation of portions of the hypoglossal nerve to activate individual tongue muscles selectively. Such stimulation might increase control over the tongue muscles and improve efficiency for electrical stimulation to remove pharyngeal obstruction. There are 3 aims to be tested in dogs. Aim 1 will determine the maximum muscle selectivity that can be obtained with a multi-contact electrode on the hypoglossal nerve. Aim 2 will evaluate the mechanical dilation of the airways due to selective stimulation. Aim 3 will determine the optimum electrode geometries and stimulation paradigms for airway dilation in chronic dogs. It is anticipated that the experimental delineation and validation of these methods will lead to a design of a neuroprosthetic device for the treatment of OSA.

DESCRIPTION (provided by applicant): Epilepsy is characterized by the abnormal synchronization of large numbers of neurons. The synchronization and propagation of epileptic seizures are thought to rely on synaptic transmission. However, non-synaptic mechanisms such as neuronal swelling, electric field effects, potassium diffusion, gap junctions and glial cell function also contribute to the generation and spread of epileptiform activity. Non-synaptic epilepsy is generated by lowering calcium in the extracellular space thereby eliminating synaptic transmission. As a result, the clinical relevance of non-synaptic mechanisms has been questioned. We have recently generated novel models of non-synaptic activity in the presence of normal calcium and normal synaptic transmission. We propose to analyze the role of non-synaptic mechanisms in neuronal synchronization in order to understand and potentially develop novel therapies to prevent abnormal neural activity. We have recently shown that the frequency, amplitude and duration of non-synaptic epileptiform events can be controlled independently suggesting that different mechanisms are responsible. In particular, preliminary experiments show that gap junctions are not responsible for the propagation of non-synaptic events generated in zero-calcium medium, but that potassium diffusion (potentially mediated by the activity of glial cells) plays a crucial role. The goal of this proposal is to analyze and control non-synaptic epileptiform activity. Specifically, we propose to 1) determine the common mechanisms underlying three models of non-synaptic epilepsy, 2) establish the conditions sufficient for the generation of non-synaptic epileptogenesis, 3) analyze the mechanisms underlying the propagation of non-synaptic epileptiform activity, 4) develop a computer model of non-synaptic propagation to test hypotheses not directly testable by experimentation, and 5) develop methods for controlling epileptiform activity. Multi-disciplinary experimental approaches such as computer simulation and fluorescence imaging will be combined with pharmacology and in-vitro slice electrophysiology to achieve these goals. Current therapeutic agents are not capable of controlling seizure activity in 25 percent of all epileptic patients. The results of our studies should provide valuable insight into mechanisms underlying epileptogenesis as well as new tools for the control and suppression of epileptic seizures.

DESCRIPTION (provided by applicant): Epilepsy is characterized by the abnormal synchronization of large numbers of neurons. The synchronization and propagation of epileptic seizures are thought to rely on synaptic transmission. However, non-synaptic mechanisms such as neuronal swelling, electric field effects, potassium diffusion, gap junctions and glial cell function also contribute to the generation and spread of epileptiform activity. Non-synaptic epilepsy is generated by lowering calcium in the extracellular space thereby eliminating synaptic transmission. As a result, the clinical relevance of non-synaptic mechanisms has been questioned. We have recently generated novel models of non-synaptic activity in the presence of normal calcium and normal synaptic transmission. We propose to analyze the role of non-synaptic mechanisms in neuronal synchronization in order to understand and potentially develop novel therapies to prevent abnormal neural activity. We have recently shown that the frequency, amplitude and duration of non-synaptic epileptiform events can be controlled independently suggesting that different mechanisms are responsible. In particular, preliminary experiments show that gap junctions are not responsible for the propagation of non-synaptic events generated in zero-calcium medium, but that potassium diffusion (potentially mediated by the activity of glial cells) plays a crucial role. The goal of this proposal is to analyze and control non-synaptic epileptiform activity. Specifically, we propose to 1) determine the common mechanisms underlying three models of non-synaptic epilepsy, 2) establish the conditions sufficient for the generation of non-synaptic epileptogenesis, 3) analyze the mechanisms underlying the propagation of non-synaptic epileptiform activity, 4) develop a computer model of non-synaptic propagation to test hypotheses not directly testable by experimentation, and 5) develop methods for controlling epileptiform activity. Multi-disciplinary experimental approaches such as computer simulation and fluorescence imaging will be combined with pharmacology and in-vitro slice electrophysiology to achieve these goals. Current therapeutic agents are not capable of controlling seizure activity in 25 percent of all epileptic patients. The results of our studies should provide valuable insight into mechanisms underlying epileptogenesis as well as new tools for the control and suppression of epileptic seizures.

DESCRIPTION (provided by applicant): Epilepsy is one of the most prevalent neurological disorders. Patients with epilepsy experience recurrent seizures that can cause a variety of symptoms ranging from muscle stiffness to loss of consciousness. Partial epilepsy is the most common syndrome in adult epilepsy patients and mesial temporal lobe epilepsy (MTLE) is the most common form of partial epilepsy. Epilepsy is characterized by the abnormal synchronization of large numbers of neurons. Current therapeutic agents cannot control seizures in 25% of all epileptic patients. Although electrical stimulation of the brain has been very effective to suppress some symptoms of Parkinson's disease, the level of seizure suppression by brain stimulation has been limited. The reason for this low therapeutic outcome could be attributed to an inadequate target for stimulation, lack of understanding of the mechanisms and non-optimum stimulation parameters. During the previous grant period, we have developed a novel method to suppress seizures by activating a fiber tract target at low frequency that has been tested in several animal models and in patients with mesial temporal lobe epilepsy. We now propose to study the mechanisms underlying this powerful suppression method in order to improve the suppression and guide the clinical implementation. Specifically, we propose to 1) unravel the cellular mechanisms of the suppression and the after effects, 2) study the specific role of inhibitory neurons using optogenetics methodology and 3) determine the axonal pathways involved in the suppression. The results of this neuro-technology project should provide valuable insights into the mechanisms underlying seizure suppression as well as capitalizing on the previous grant period to develop a novel therapeutic method for the control of seizures in patients with mesial temporal lobe epilepsy.

This workshop will address the need for the neural engineering community to meet and address some of the major problems facing the progress in the area of Neural Interfacing in before the 6th International Neural Engineering Conference that will take place in San Diego just prior to the Society for Neuroscience meeting. There are currently unsolved problems at the interface between the nervous system (both peripheral and central) that prevent clinical implementation for therapy. These problems involve both engineering and neuroscience and in particular, biocompatibility, mechanical properties, materials properties, electrochemistry, neural tissue repair and immune response. In particular outstanding benefits will be derived from the area of neuro-prosthetics, understanding the brain circuitry, engineering the brain and neuro-modulation where it is possible to intervene directly to control or modulate the nervous system. A report will be developed based on the meeting discussions to provide guidance for possible future programs.

? DESCRIPTION (provided by applicant): Hypertension is a major risk factor for cardiovascular disease affecting about 30% of the population in the United States and its prevalence in expected to rise. One of the main reasons for the failure to treat this disease is the lack of understanding of the mechanisms. The role played by the carotid sinus in maintaining blood pressure has recently been under intense investigation. A widely accepted hypothesis that its activity is increased in hypertension remains untested due to the lack of a technology for recordings in very small nerves. The central hypothesis of this proposal is that the time course of the development of hypertension can be studied with a novel stable nanowire interface with the carotid sinus nerve (CSN) in a chronic spontaneously hypertensive (SH) rat preparation. The mechanical properties of the interface will be optimized by matching the mechanical properties of the implant to that of the nerve. The biocompatibility of the interface will be enhanced by adsorbing collagen onto the surface of the insulation to match the endoneurium environment. The wire will be implanted in SH rat chronic preparation for periods of three months and the hypothesis will be tested with two specific aims: The first aim is to develop a nanowire interface to record activity in the carotid sinus nerve. The second aim is to test the hypothesis that the CSN activity is indeed increasing and that its time either precedes the development of hypertension or is simultaneous with it. The relevance of the proposal is that it provides a novel method to monitor the activity of such a small nerve and to relate its activity to the development of one of the most pervasive disease, hypertension. In addition, this technique is applicable to other parts of the autonomic nervous system such as the vagus nerve in order to monitor and restore the function of internal organs.

? DESCRIPTION (provided by applicant): Hypertension is a major risk factor for cardiovascular disease affecting about 30% of the population in the United States and its prevalence in expected to rise. One of the main reasons for the failure to treat this disease is the lack of understanding of the mechanisms. The role played by the carotid sinus in maintaining blood pressure has recently been under intense investigation. A widely accepted hypothesis that its activity is increased in hypertension remains untested due to the lack of a technology for recordings in very small nerves. The central hypothesis of this proposal is that the time course of the development of hypertension can be studied with a novel stable nanowire interface with the carotid sinus nerve (CSN) in a chronic spontaneously hypertensive (SH) rat preparation. The mechanical properties of the interface will be optimized by matching the mechanical properties of the implant to that of the nerve. The biocompatibility of the interface will be enhanced by adsorbing collagen onto the surface of the insulation to match the endoneurium environment. The wire will be implanted in SH rat chronic preparation for periods of three months and the hypothesis will be tested with two specific aims: The first aim is to develop a nanowire interface to record activity in the carotid sinus nerve. The second aim is to test the hypothesis that the CSN activity is indeed increasing and that its time either precedes the development of hypertension or is simultaneous with it. The relevance of the proposal is that it provides a novel method to monitor the activity of such a small nerve and to relate its activity to the development of one of the most pervasive disease, hypertension. In addition, this technique is applicable to other parts of the autonomic nervous system such as the vagus nerve in order to monitor and restore the function of internal organs.

Abstract Epilepsy is one of the most prevalent neurological disorders. Patients with epilepsy experience recurrent seizures that can cause a variety of symptoms ranging from auras to loss of consciousness. Epilepsy is characterized by the abnormal firing of large numbers of neurons and current therapeutic agents cannot control seizures in 25% of all epileptic patients. We have previously shown that a novel brain stimulation method targeting fiber tracts (fornix) instead of grey matter at low frequency (1-20Hz) is effective to suppress seizures in animal models and patients with mesial temporal lobe epilepsy (MTLE). We propose to target another prominent fiber tract, the corpus callosum (CC) to suppress cortical seizures and to compare this technology to two state-the-art methods that stimulate at high frequency either the focus directly or the anterior nucleus of the thalamus. Specifically, we propose to determine if stimulation of the CC at low frequency can decrease focal seizures by selectively activating the CC fibers innervating the focus in an acute model (Aim 1) or in focal chronic model of epilepsy with tetanus toxin (Aim 2). We then propose to determine if fiber tract stimulation can improve seizure control of activity generated by multiple foci compared to stimulation of the anterior nucleus of the thalamus (Aim3) or with kainic acid in chronic model (Aim4). Finally, we will study the mechanisms of the CC stimulation using in-vitro cortical brain slices obtained from animals in previous aims. The project will be carried with a collaboration between scientists, engineers and clinicians and if successful could be translated into a novel patient-specific therapeutic modality for the control of cortical seizures in patients with intractable epilepsy.

Abstract A seizure is an abnormal neural activity in the brain and the main characteristic of epilepsy. About one-third of the patients have seizures resistant to anti-epileptic medication and therefore, an alternative treatment is necessary. Recent studies show that neurons can be recruited and seizures can propagate by a mechanism known as electric field coupling. Our laboratory has shown that canceling the electric field in the extracellular space can prevent neural propagation and recruitment. We now propose to develop a novel neurotechnology that not only can control the propagation of seizures but prevent the seizure from being generated by controlling the extracellular electric field. With a combined methodology of in-vitro electrophysiology with state-of-the-art neural imaging, computer modeling and in-vivo preparations in rodents, we will implement the seizure control system and study its mechanism with four specific aims: 1) Prevent neuronal synchronization in hyperexcitable neural tissue, 2) Develop a novel technology of extracellular voltage clamp to control seizures in-vivo, 3) Determine the mechanisms of seizure control by an extracellular voltage clamp system, 4) Determine the role of the extracellular space in the clamping efficiency. Current electrical responsive control therapy detects a seizure and then applies stimulation. The proposed neurotechnology will prevent the synchronization between neurons to stop the generation of seizures before they arise at very low current amplitude thereby providing a novel therapeutic paradigm for treating epilepsy.