Disorganization of language and working memory systems in frontal versus temporal lobe epilepsy

Cognitive impairment is a common comorbidity of epilepsy, and adversely impacts people with both frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE). While the underlying neural substrates in TLE have been extensively investigated, functional imaging studies in FLE are scarce. In this study, we profiled cognitive dysfunction in FLE, and directly compared FLE and TLE patients to establish commonalities and differences. We investigated 172 adult participants (56 with FLE, 64 with TLE, and 52 controls), using neuropsychological tests and four functional MRI tasks probing the neural correlates of expressive language (verbal fluency, verb generation) and working memory (verbal and visuo-spatial). Patient groups were comparable in disease duration and anti-epileptic drug load. We devised a multiscale approach to map the landscape of brain activation and deactivation during cognition, and track reorganization in FLE and TLE. Voxel-based analyses were complemented with profiling of task effects (i) across intrinsic functional systems, and (ii) along the principal functional connectivity gradient, which encodes a continuous transition from lower-level sensory to higher-order transmodal brain areas. We show that cognitive impairment in FLE is associated with reduced activation across attentional and executive systems, and reduced deactivation of the default mode system, indicative of a large-scale disorganization of task-related recruitment. Functional abnormalities in FLE were modulated by disease load. Patterns of dysfunction in FLE were broadly similar to those in TLE, but some traits were syndrome-specific: altered default-mode deactivation was more prominent in FLE, while impaired recruitment of posterior language areas during a task with semantic demands was more marked in TLE. Our study elucidates neural processes underlying language and working memory impairment in FLE, identifies shared and syndrome-specific alterations in the two most common focal epilepsies, and sheds light on system behavior that may be amenable to future remediation strategies.