Abstracts

Rationale: Epilepsy is characterized by recurrent seizures, which exert severe cardiovascular and breathing consequences that may lead to sudden death. Sudden Unexpected Death in Epilepsy (SUDEP) accounts for an estimated 7–17% of deaths in individuals with epilepsy, and over half of deaths in intractable epilepsy patients. Although the physiological mechanisms underlying SUDEP are unclear, these likely include a combination of cardiovascular and respiratory dysfunction, contributing to impaired perfusion and hypoxia, respectively. Seizure-induced respiratory/cardiovascular alterations, which follow from impaired regulation, may cause additive injury to autonomic and respiratory regulatory brain sites. Consequently, the risk of SUDEP could be exacerbated if such regulatory brain structures were injured in GTC patients. The cingulate cortex (CC) is one such regulatory region, and is involved in both cardiovascular and, indirectly, respiratory regulation. The CC showed signs indicative of inflammatory processes in a previous study of GTC patients, but tissue integrity of this area is unclear. The objective was to determine cortical thickness, an index that can change with injury, of the CC in GTC patients relative to age- and gender-matched healthy control subjects. Methods: We assessed regional cortical tissue thickness using high-resolution magnetic resonance imaging scans (3.0-Tesla), collected from 53 GTC patients (Mage ± SE, 37.1 ± 1.7 years, 22 male) at UCLA, Case Western Reserve University, and University College, London. We compared GTC patients with a population set of 530 control subjects (Mage ± SD, 37.1 ± 0.5 years, 219 male) collected from UCLA and supplemented by the Open Access Series of Imaging Studies (OASIS), a control population database. We used the MATLAB-based SPM12 software to preprocess high-resolution T1-weighted scans, including intensity bias correction, and FreeSurfer 5.3 software to measure cortical thickness and perform statistical analysis of group differences and age-thickness correlations, accounting for age/sex (p Results: Increased cortical thickness in patients with GTCs relative to controls was observed bilaterally in two regions of the CC, including the genu and sub-genu region of the anterior CC (ACC), and the posterior CC (PCC). In sex-specific analyses, increased thickness of the cingulate was more pronounced in male over female GTC subjects (particularly in the PCC and isthmus of cingulate). No decreases in cortical thickness were observed in the CC. Conclusions: Both the ACC and PCC contribute to parasympathetic autonomic modulation. Thickening of the CC (possibly from glial activation and neuronal swelling) may reflect ongoing changes that impact protective parasympathetic processes over blood pressure and cardiac arrhythmia, a concern for SUDEP risk in GTC patients. Such expression could be manifested as excessive bradycardia or untimely release of parasympathetic influences on arrhythmia suppression. Previous studies have shown cortical changes in multiple other autonomic regions in addition to the CC; therefore, the CC structural changes in these GTC patients are likely accompanied by other types of injury in other brain areas. The functional implications of the structural changes need to be explored, especially in the context of CC influences on nearby limbic structures, including the insula. Funding: This work was supported by U01 NS090407 and the Amgen Foundation.