Perisylvian and Hippocampal Anomalies in Individuals With Pathogenic Variants.

Background And Objectives: Pathogenic variants in are associated with a spectrum of epilepsy-aphasia syndromes (EASs). Seizures as well as speech and language disorders occur frequently but vary widely in severity, both between individuals and across the life span. The link between this phenotypic spectrum and brain characteristics is unknown. Specifically, altered brain networks at the root of speech and language deficits remain to be identified. Patients with pathogenic variants in offer an opportunity to interrogate the impact of glutamate receptor dysfunction on brain development.

Methods: We characterized brain anomalies in individuals with pathogenic variants and EASs, hypothesizing alterations in perisylvian speech-language regions and the striatum. We compared structural MRI data from 10 individuals (3 children and 7 adults, 3 female) with pathogenic variants with data from age-matched controls (N = 51 and N = 203 in a secondary analysis). We examined cortical thickness and volume in 4 a priori hypothesized speech and language regions (inferior frontal, precentral, supramarginal, and superior temporal) and across the whole brain. Subcortical structures (hippocampus, basal ganglia, thalamus) and the corpus callosum were also compared.

Results: Individuals with pathogenic variants showed increased thickness and volume in the posterior part of Broca's area (inferior frontal gyrus, pars opercularis). For thickness, the effects were bilateral but more pronounced in the left (large effect size, η = 0.37) than the right (η = 0.12) hemisphere. Both volume and thickness were also higher in the bilateral superior temporal region while the supramarginal region showed increased thickness only. Whole-brain analyses confirmed left-sided thickness increases in Broca's area, with additional increases in the occipital and superior frontal cortices bilaterally. Hippocampal volume was reduced in the left hemisphere. There were no age-dependent effects or corpus callosum group differences.

Discussion: Anomalies in perisylvian regions, with largest differences in Broca's area, suggest an altered development of classical speech-language networks in -related EAS. Left hippocampal reduction suggests a role for this structure in early speech and language development and is consistent with gene expression in that region. Overall, elucidating the neural correlates of EAS provides insights into the impact of dysfunction, opening avenues for targeted intervention in developmental syndromes with compromised speech-language development.