Abstracts

Rationale: We previously reported an Australian family with a GABA type A receptor gamma2 subunit gene (GABRG2) pathogenic variant related to febrile seizures, febrile seizures plus and absence seizures. This family have decreased cortical inhibition (transcranial magnetic stimulation) and increased cortical metabolism (positron emission tomography). In mice with the Gabrg2 mutation, deficits in somatosensory cortex inhibition are more pronounced than ventral thalamus and correlate with anatomical changes in cortical interneuron positioning.Although these investigations provide clues about mechanisms underlying the GABRG2 mutation, it is unknown whether brain connectivity is affected in humans with this gene mutation. To study this issue, we quantified changes in functional MRI (fMRI) connectivity in people with GABRG2 mutation. We focused on regions previously studied in Gabrg2 mice: the somatosensory cortex and ventral thalamus, as well as the putamen (as GABA_A antagonists enhances connectivity of somatosensory cortex and striatum).Based on previous research, we hypothesize that fMRI connectivity within the somatosensory cortex, but not putamen or ventral thalamus, is elevated in people with GABRG2 mutation. We also hypothesize that fMRI connectivity is altered between brain regions in people with GABRG2 mutation. Methods: We recruited five adults with a confirmed GABRG2 mutation (mean age 36.4±4.2 s.d; clinical information in Table 1) located at long (q) arm of chromosome 5 at position 34 that acts at inhibitory GABA_A receptors via ligand-gated chloride channels. Subjects with GABRG2 mutation were compared to five matched controls (mean age 36.8±4.1 s.d).We employed two methods of connectivity using 10 minutes of resting-state fMRI data (temporal resolution=3s; spatial voxel resolution=3mm³): i) Regional Homogeneity: to calculate local connectivity within each brain node (somatosensory cortex, thalamus and putamen). ii) Partial correlation: to calculate Pearson correlations between the mean fMRI time-series of each node-pair. Results: Primary analysis: fMRI connectivity within somatosensory cortex was increased in individuals with the GABRG2 variant compared to controls (Hedges’ g=1.46; CI95=0.43-2.41; Fig. 1A). fMRI connectivity between putamen and thalamus was also elevated in people with GABRG2 mutation (Hedges’ g=1.98; CI95=0.11-3.45; Fig. 1F).Post-hoc analysis: To test whether our primary result was specific to the somatosensory cortex, thalamus and putamen or it reflected a ‘whole-brain process’, we analyzed two additional brain nodes: i) primary visual cortex and ii) precuneus. There was no difference in fMRI connectivity of these two brain regions between GABRG2 subjects and controls. Conclusions: This preliminary study suggests that people with a genetic predisposition to generalized seizures and a GABRG2 mutation display network-specific hyperconnectivity within somatosensory cortex, and between thalamo-striatal regions. These results align with rodent research: this network model can be used to validate the emerging hypothesis that generalized seizures arise from the somatosensory cortex and are modulated in striato-thalamic circuits. Funding: This study was supported by the National Health and Medical Research Council (NHMRC) of Australia (#628952). The Florey Institute of Neuroscience and Mental Health acknowledges the strong support from the Victorian Government and in particular the funding from the Operational Infrastructure Support Grant. We also acknowledge the facilities, and the scientific and technical assistance of the National Imaging Facility (NIF) at the Florey node and The Victorian Biomedical Imaging Capability (VBIC).