Summary
Objective
This study aimed to identify non-invasive biomarkers of human epilepsy that can reliably detect and localize epileptic brain regions. Having non-invasive biomarkers would greatly enhance patient diagnosis, patient monitoring, and novel therapy development. At present time, only surgically invasive, direct brain recordings are capable of detecting these regions with precision, which severely limits the pace and scope of both clinical management and research progress in epilepsy.
Methods
We compared high versus low or non-spiking regions in 9 medically intractable epilepsy surgery patients by performing integrated metabolomic-genomic-histological analyses of electrically-mapped human cortical regions using high resolution magic angle spinning proton magnetic resonance spectroscopy, (HR-MAS 1H MRS), cDNA microarrays, and histological analysis.
Results
We found a highly consistent and predictive metabolite logistic regression model with reduced lactate and increased creatine plus phosphocreatine (Cr+PCr) and choline, suggestive of a chronically altered metabolic state in epileptic brain regions. Linking gene expression, cellular, and histological differences to these key metabolites using a hierarchical clustering approach predicted altered metabolic vascular coupling in the affected regions. Consistently, these predictions were validated histologically showing both neovascularization and newly discovered, millimeter-sized microlesions.
Significance
Using a systems biology approach on electrically-mapped human cortex provides new evidence for spatially-segregated, metabolic derangements in both neurovascular and synaptic architecture in human epileptic brain regions that could be a non-invasively detectable biomarker of epilepsy. These findings highlight both the immense power of a systems biology approach and identify a potentially important role that magnetic resonance spectroscopy can play in the research and clinical management of epilepsy.