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.