Altered Interictal Bed Nucleus of Stria Terminalis Connectivity in Patients With Temporal Lobe Epilepsy

Background and Objectives: Temporal lobe epilepsy (TLE) is a highly prevalent neurological disorder, with 30–50% of patients developing drug-resistant epilepsy (DRE). Pharmacoresistant seizures remodel critical arousal and respiratory networks, impairing autonomic function and chemoreception, and putting patients at increased risk for adverse respiratory events and sudden unexpected death (SUDEP). Given that the bed nucleus of stria terminalis (BNST) serves as a key relay between brainstem respiratory nuclei and cortical arousal networks, we characterized interictal BNST connectivity alterations in patients with TLE. Methods: We conducted a case-control study of patients with drug-resistant TLE evaluated for epilepsy surgery at Vanderbilt University Medical Center, compared to healthy controls with no history of neurological disease. Inclusion criteria for patients included clinical TLE diagnosis and age 18–65 years. Using resting-state fMRI (multiband factor=3, TR=1.3s), we measured functional connectivity (FC) and effective connectivity via Granger causality (GC) between BNST and whole-brain, cortical networks, and brainstem nuclei. Graph theoretical network metrics assessed BNST hub properties. Statistical analyses employed multiple comparison corrections and age-corrected z-scores. Results: Thirty-seven patients with TLE (mean age 42.5 ± 12.1 years, 43.2% female) and 33 healthy controls (mean age 36.2 ± 12.0 years, 54.5% female) were studied. Patients demonstrated bilateral reductions in BNST connectivity and causal influence with the whole brain (FC: −2.31 ± 2.87, P = 0.0032; GC: −0.18 ± 0.08, P = 0.0025). While FC showed preserved BNST-brainstem connectivity, GC revealed ipsilateral disruptions in BNST influence over ventral tegmental area (0.023 ± 0.026, P = 0.0067), median raphe (−0.009 ± 0.029, P = 0.0038), and cuneiform nuclei (0.012 ± 0.062, P = 0.0153). Critical respiratory circuits showed divergent reorganization: dorsal raphe-parabrachial complex pathways exhibited 57.2% efferent reduction (P = 0.0028) with 204.6% compensatory afferent increase (P = 0.0020), while dorsal raphe-locus coeruleus circuits showed bilateral deterioration (66.2% reduction DR→LC, P = 0.0015; 56.4% reduction LC→DR, P = 0.0189). Graph analyses confirmed compromised BNST network integration bilaterally (P < 0.05). Discussion: Our findings reveal network reorganization in TLE that compromises autonomic and arousal circuit integrity, leading to failed respiratory-autonomic integration that may underlie respiratory vulnerability and increased SUDEP risk; however, we did not directly study SUDEP cases.