R01NS122827

Identifying Brain Networks to Predict Treatment Resistance and Post-Surgical Outcome: An ENIGMA-Epilepsy Initiative - Abstract

Epilepsy is a devastating neurological illness that affects over 50 million people worldwide. Approximately one-third of patients do not respond to anti-seizure medication (ASM) and require additional diagnostic work-up, including consideration for surgery.

Structural neuroimaging plays a pivotal role in the diagnostic evaluation of epilepsy, identifying visible lesions in many patients that co-localize with the seizure focus. However, up to 40% of patients have normal-appearing MRIs, and this number is growing. As a result, there is increased interest in identifying subtle brain network abnormalities that could help to delineate the epileptogenic network and aid in the prediction of treatment response (i.e., response to ASMs and surgical outcomes).

Unfortunately, methods for reliably identifying which patients will be drug-responsive versus drug-resistant, and which patients will achieve successful versus unsuccessful surgical outcomes are lacking. A major barrier to progress in this field has been obtaining quantitative imaging, including structural MRI (sMRI) and diffusion-weighted imaging (dMRI), clinical, and genetic data on large, geographically diverse samples of patients in whom different treatment outcomes can be evaluated.

In the past, sample sizes have been insufficient to detect subtle, but reliable, brain abnormalities in patients with focal or generalized epilepsies that are genuinely associated with epilepsy and not with vicissitudes related to small or geographically restricted samples. A new, large-scale data initiative, ENIGMA4-Epilepsy, coupled with technological advancements that enable improved data harmonization, are now lifting these barriers and allowing us to combine multi-site sMRI/dMRI, clinical, genetic data to predict important clinical outcomes, and making the results generalizable to a global epilepsy community.

In this grant, we will leverage data collected through ENIGMA-Epilepsy—a consortium of 24 epilepsy centers from 14 countries (more than 2,250 patient and 1,727 healthy control sMRI/dMRI datasets) and the Human Epilepsy Project (HEP). We will include new network models (i.e., individualized connectomes) and polygenic risk scores (PRS) to test whether a combination of imaging, clinical, and genetic risk can accurately predict two clinical outcomes: drug-resistance and post-operative seizure outcome.

Our scientific premise is that MRI-based assessment of whole-brain network properties, in combination with clinical data and PRS derived from genetic data, are able to predict (i) drug response in recently diagnosed epilepsy cases and (ii) postsurgical outcomes in individuals with drug-resistant epilepsy.

This R01 addresses NIH's call for more reproducible studies by introducing a highly-powered design capable of capturing variability across patients with diverse clinical characteristics and treatment outcomes. This grant is also directly aligned with NINDS's 2020 Epilepsy Benchmarks (IIIB), which encourage the identification of genetic, clinical, and imaging biomarkers capable of predicting treatment response in epilepsy.

San Diego University Of California

(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.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

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

La Jolla, California 92093 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 359% from $682,706 to $3,130,466.