UH3NS109557

Thalamocortical Responsive Neurostimulation for the Treatment of Lennox-Gastaut Syndrome - Project Summary / Abstract

Lennox-Gastaut Syndrome (LGS) is a devastating form of childhood onset epilepsy with cognitive dysfunction and very frequent generalized onset seizures (GOS), often leading to injury. Driven by the lack of effective therapies and the demonstrated safety and efficacy of brain-responsive stimulation for medically intractable focal onset seizures (FOS), this study will test whether brain-responsive neurostimulation of thalamocortical networks (RNS-TCN) is a feasible strategy to treat LGS.

Specifically, the project aims to:

1. Acquire preliminary evidence for safety and efficacy in treating GOS of LGS with RNS-TCN.
2. Create an interactive therapy-decision support system based on patient-specific computational network models and machine learning to identify optimal lead placement and stimulation parameters.

Using the RNS® system, which is FDA approved for FOS, an early feasibility IDE study will be conducted at 6 epilepsy centers in 20 patients with LGS and medically intractable GOS. The patients will be enrolled in two cohorts of 10, with safety and efficacy milestones in the first cohort governing the enrollment of the second cohort.

Patients will have two depth leads placed bilaterally in the centromedian nucleus of the thalamus and two subdural strip leads placed bilaterally on the medial prefrontal cortex. These targets are selected because they are implicated in the onset and spread of GOS in LGS. Leads will be located within each target such that stimulation maximally engages the thalamocortical network, guided by finite-element biophysical models created from structural magnetic resonance imaging and diffusion-weighted imaging. The finite-element biophysical models will also be used to identify the initial RNS-TCN stimulation pathway and current amplitude.

During the blinded evaluation period, patients will be randomized to receive either high-frequency short burst (HFSB) or low-frequency long burst (LFLB) RNS-TCN, then enter a washout period before crossing over to receive the other treatment condition. During the open-label period, stimulation parameters can be modified at the discretion of the physician. Parameter adjustments will be informed by using a Bayesian optimization model developed specifically for each patient.

All clinical and electrophysiological data collected during the study will be used to identify a biomarker of clinical response; if found, these will aid future epilepsy research and clinical practice. If safety is favorable and there is preliminary evidence for efficacy, then this early experience will inform the design of a future larger feasibility study.

In addition to treating a population in need, this project engages in fundamental discovery of biomarkers in generalized network epilepsies and develops novel automated therapy selection policies that have the potential to improve the lives of patients with LGS and other seizure disorders.

Neuropace

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.310 - Trans-NIH Research Support

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Mountain View, California 940435237 United States

Single Zip Code

BRAIN Initiative: Clinical Studies to Advance Next-Generation Invasive Devices for Recording and Modulation in the Human Central Nervous System (UH3 - Clinical Trial Required) (RFA-NS-18-023)

Amendment Since initial award the total obligations have increased 1071% from $831,388 to $9,737,772.