Abstracts

Rationale: Psychogenic nonepileptic (functional) seizures (FS) clinically resemble epileptic seizures (ES) but are not associated with ictal discharge. FS are often preceded by traumatic brain injury (TBI) and linked to aberrant neurobehavioral stress responses, similar to TBI alone. The associated underlying neural mechanisms that maintain FS, their link to stress, and how these differ from ES remain unclear. Healthy physiologic fronto-limbic networks enable adaptive responses to psychosocial stress. We hypothesized that neural responses within these regions during a psychosocial stress task would differ between TBI+FS compared to TBI+ES, after controlling for TBI status (TBI-only).

Methods: Volunteers were recruited at Brown University and the University of Alabama at Birmingham. History of TBI, ES, and FS were verified based on medical history and video-EEG confirmed diagnosis. TBI+ES (N=21) and TBI+FS (N=21) were matched for age and sex and combined into an initial group (TBI+SZ; N=42). A TBI-only group (N=42) was age and sex matched to the TBI+SZ group. All participants completed control math task (CMT) and stress math task (SMT) conditions based on the Montreal Imaging Stress Task (MIST) during fMRI. Positive and negative auditory feedback during CMT and SMT, respectively, was provided irrespective of performance. FMRI data were acquired at each site’s Siemens Prisma MRI (same scanning parameters). Standard processing in AFNI modeled math and auditory events separately.

Results: A cluster volume extent threshold (341 mm³) was calculated to correct for multiple comparisons using 3dClustSim (with -acf) for a fronto-limbic regions of interest brain mask. The first 3dLME analysis identified neural responses that differed between TBI+SZ and TBI-only to isolate activation related to seizures, holding TBI constant. This analysis revealed a Group effect (TBI+SZ vs TBI-only) response (SMT - CMT) during math performance within the right anterior insula (AI). During auditory feedback, the second 3dLME analysis revealed a differential Group fMRI response within the posterior cingulate cortex (PCC) and right hippocampus/amygdala.

Planned secondary contrasts compared TBI+ES vs. TBI+FS groups within clusters identified by the initial 3dLMEs to identify effects of seizure type on responses while controlling for differences between TBI+SZ and TBI-only. The first contrast revealed a cluster of decreased response to math performance for TBI+FS within the right AI. The second contrast revealed clusters of increased response to auditory feedback for TBI+FS within the PCC and right hippocampus.

Conclusions: Physiologic responses to stressors were significantly decreased in AI during performance demands and increased in the PCC and hippocampus during evaluative feedback for TBI+FS compared to TBI+ES, controlling for TBI-only. AI is associated with interoception as part of the salience network, while PCC/hippocampus are part of the self-reference processing network. These findings implicate specific neurobehavioral mechanisms that may maintain functional neurological symptoms and possibly distinguish FS from ES.

Funding: Please list any funding that was received in support of this abstract.: This work was supported by the US Department of Defense (W81XH-17-0619) to WCL and JPS.