Abstracts

Rationale: The sudden breakdown of arousal and autonomic systems suggests a major role for a fatal brainstem dysfunction in SUDEP. MR Imaging has shown brainstem atrophy in patients who later died of SUDEP in regions that were linked to autonomic dysfunction in living patients. This suggests that imaging could be a useful biomarker of SUDEP risk. The brainstem projects to and modulates the activation state of several widespread cortical/subcortical regions of which some have also been linked to SUDEP. The overall goal was to investigate A. the impact of brainstem atrophy on gray matter connectivity of cortical/subcortical structures and autonomic control. B. the impact on the modulation of cortical/subcortical functional connectivity. Methods: The study population consisted of 11 controls (mean age 30.7(7.8), m/f 6/5) and 18 patients with non-lesional focal epilepsy (LRE)(mean age: 40.2(14.1), m/f: 9/9) in whom HRV measurements and a 3T MRI (T1 in all subjects, task-free fMRI in 7 controls/ 12 LRE) had been acquired. The brainstem was extracted, and atrophy assessed using deformation-based-morphometry. The mean Jacobian determinants were extracted from 71 5x5x5 mm grids placed in brainstem regions associated with autonomic function and converted into age-corrected z-scores. Cortical and non-brainstem subcortical gray matter atrophy was assessed with voxel-based-morphometry and mean gray matter volumes modulated by their Jacobian determinants extracted from 380 regions and converted into age-corrected z-scores. The profile similarity index combined with graph analysis (negative strength) was used to characterize the impact of brainstem atrophy on gray matter connectivity (1). The fMRI was preprocessed in SPM12/Conn17 and the BOLD signal extracted from 396 ROIs (16 brainstem). A dynamic task-free analysis approach that combines sliding windows with graph and cluster analysis was used to identify activation states. Spearman rank correlations were used to assess connectivity HRV relationship Results: Reduced HRV was correlated with reduced brainstem to gray matter connectivity in the left amygdala, parahippocampus, bilateral lingual gyrus, anterior thalamus, lingual gyrus, temporal pole and at the brainstem level reticular formation of the dorsal medulla oblongata and pons, parabrachial nuclei and periaqueductal gray in LRE (FDR<0.05). Dynamic task-free fMRI analysis identified 17 states. The strength of the functional brainstem/cortical connectivity of state 15 was negatively associated with HRV (r =-0.5, p = 0.03) and positively with decreased brainstem (r=0.44, p = 0.049) and brainstem-cortical (0.49, p = 0.03) gray matter connectivity in all 19 subjects with fMRI. Conclusions: These findings indicate that impaired brainstem-cortex gray matter connectivity negatively affects the brain stem's ability to control cortical activation states which results in the appearance of a state with overshooting brain stem-cortex interactions that negatively affected HRV control. This state becomes more pronounced with worsening brainstem atrophy which indicates that it could reach a point where only a minor disturbance is needed to initiate a full breakdown.1. Front Aging Neurosci. 2017;19(9):418. doi: 10.3389/fnagi.2017.00418 Funding: Epilepsy Foundation grant 325981