Human GABRG2 generalized epilepsy: Increased somatosensory and striatothalamic connectivity

Abstract

Objective: To map functional MRI (fMRI) connectivity within and between the somatosensory cortex, putamen, and ventral thalamus in individuals from a family with a GABAergic deficit segregating with febrile seizures and genetic generalized epilepsy.

Methods: We studied 5 adults from a family with early-onset absence epilepsy and/or febrile seizures and a GABA_A receptor subunit gamma2 pathogenic variant (GABRG2[R43Q]) vs 5 age-matched controls. We infer differences between participants with the GABRG2 pathogenic variant and controls in resting-state fMRI connectivity within and between the somatosensory cortex, putamen, and ventral thalamus.

Results: We observed increased fMRI connectivity within the somatosensory cortex and between the putamen and ventral thalamus in all individuals with the GABRG2 pathogenic variant compared with controls. Post hoc analysis showed less pronounced changes in fMRI connectivity within and between the primary visual cortex and precuneus.

Conclusions: Although our sample size was small, this preliminary study suggests that individuals with a GABRG2 pathogenic variant, raising risk of febrile seizures and generalized epilepsy, display underlying increased functional connectivity both within the somatosensory cortex and in striatothalamic networks. This human network model aligns with rodent research and should be further validated in larger cohorts, including other individuals with generalized epilepsy with and without known GABA pathogenic variants.

Figure. Functional connectivity within and between brain nodes in GABRG2 participants displayed by purple magenta color bars and healthy controls displayed by blue cyan color bars

Peak regional homogeneity across all voxels within the somatosensory cortex (A), putamen (B), and ventral thalamus (C), and partial correlations averaged across all voxels between the somatosensory cortex-putamen (D), somatosensory cortex-ventral thalamus (E), and ventral thalamus-putamen (F). Error bars denote the standard error across participants. There was little difference in head movement between groups (mean movement [SD] in GABRG2 = 0.12 mm ± 0.05; mean movement [SD] in controls = 0.16 mm ± 0.04). Our 3 brain regions of interest—(1) bilateral somatosensory cortex (yellow); (2) putamen (orange); and (3) ventral thalamus (red) (G)—were delineated using the NeuroSynth database (neurosynth.org) incorporating findings from a multitude of previous fMRI studies describing these brain regions and their behavioral correlates, as well as their functional connectivity patterns. *A and F had large effect size.