Neurobehavioral therapy in functional seizures: Investigation of mechanism of action with resting-state functional magnetic resonance imaging

Objective: Functional seizures (FS) often disrupt the key regions integral to cognitive processing and emotional regulation (anterior insula, anterior cingulate, and temporoparietal junction). We investigated the potential neurophysiologic mechanism of action (MOA) of neurobehavioral therapy (NBT) using resting-state functional MRI seed-based whole-brain functional connectivity within these regions in adults with FS. We hypothesized that NBT would induce changes in functional connectivity in parallel with improving seizure frequency and behavioral outcomes. Methods: Forty patients with traumatic brain injury and FS (TBI+FS) underwent 12 weekly sessions of NBT and provided pre-/post-intervention resting-state functional magnetic resonance imaging (MRI), seizure logs, and behavioral assessments. Fifty-five individuals with TBI without FS (TBI-only) completed the same measures, received standard medical care but not NBT, and functional MRI similar to 12 weeks apart. For each key region, two-sample t-tests assessed direct group comparison. Repeated measures analysis of covariance assessed how group differences evolved over time and how these changes were modulated by the changes in seizure frequency, diagnosis duration, or behavioral scores (false discovery rate corrected at p < .05). Results: With NBT, seed-based whole-brain functional connectivity was significantly higher between right anterior insula and left supplementary motor area in TBI+FS compared to TBI-only, and between left anterior insula and left postcentral gyrus in seizure-free TBI+FS compared to those who were not seizure-free. Percentage decrease in seizure frequency with NBT was associated with lower functional connectivity between bilateral insula and left superior medial frontal gyrus in patients with FS. Improvements in behavioral measures did not correspond to changes in functional connectivity. Significance: The study underscores the relationship between the changes in resting-state functional connectivity of the anterior insula in FS and treatment response to NBT and illustrates the potential neurophysiologic MOA of NBT for the treatment of FS; it suggests an independence of this MOA from the potential effects of NBT on behavioral measures.