Brain temperature and tissue microstructure in treatment-resistant epilepsy

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PROJECT SUMMARY/ABSTRACT Epilepsy affects over 70 million people worldwide with a global incidence of 2.4 million new cases per year. In many of these patients, neuroinflammation (NI) is a key pathological contributor to focal seizure generation and maintenance. Sustained NI degrades the blood–brain barrier, leads to neuronal death, and ultimately decreases seizure threshold. Finding ways to image and treat NI is especially important for the >30% of patients with treatment-resistant epilepsy (TRE) who cannot achieve seizure freedom with standard antiseizure medications. Cannabidiol (CBD) effectively reduces seizure frequency and severity in many TRE patients, though how it exerts these benefits is poorly understood. Atypically high brain temperature (>38°C) is a surrogate measure for the biochemical consequences of NI, and may be a useful for studying the effects of CBD on human NI. Brain temperature can be non-invasively measured by volumetric magnetic resonance spectroscopic imaging and thermometry (MRSI-t) with high repeatability and reproducibility. This project builds on our experience using MRSI-t for brain temperature mapping. In our preliminary studies, we imaged patients with TRE using MRSI-t and found atypically high brain temperature in regions involved in the development of seizures. To date, however, no study has investigated whether elevations in brain temperature measured by MRSI-t indicate underlying tissue damage or whether these elevations resolve after treatment. In AIM 1, we propose to define the relationship between brain temperature and microstructural tissue damage. Microstructural integrity will be assessed using multi-shell diffusion data analyzed by neurite orientation dispersion and density imaging (NODDI), a promising tool that has been validated by histopathological studies. In AIM 2, we will quantify CBD-induced changes in brain temperature using repeated MRSI-t in TRE patients. We hypothesize that elevated brain temperature is associated with microstructural damage, and that these temperature aberrations decrease after treatment with CBD. The proposed research will provide initial insights into how CBD exerts its therapeutic effects in humans. The long-term goal of this proposal is to assess whether brain temperature measured by MRSI-t offers unique and valuable information for visualizing NI and evaluating treatment effectiveness in TRE. By combining MRSI-t and NODDI, the utility of brain temperature mapping will be evaluated using an imaging method that has been validated by tissue analyses. The proposed aims will be completed in conjunction with a formal research training plan sponsored by Dr. Jerzy P. Szaflarski, Dr. Mark Bolding, and Dr. David Redden. The training plan will enhance the applicant’s expertise in 1) biostatistics, 2) MRI methods, 3) mentorship skills and professional development, 4) neurobiology and neuroimmunology, and 5) epilepsy. This proposal is a vehicle for mentored training that will provide a solid foundation for the skills needed for the applicant’s career as a productive, independent scientist. .