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

Abstract

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.

Multimodal connectome biomarkers of cognitive and affective dysfunction in the common epilepsies

“…Our study showed that working memory and language impairment in frontal lobe epilepsy was associated with reduced activation across attentional and executive systems, together with an attenuated deactivation of default mode regions, suggesting a reorganization of functional recruitment at the systems level. While atypical activation patterns were similar to those in TLE patients, reductions in default mode network deactivations appeared more marked in frontal lobe epilepsy patients, whereas those with TLE presented with less activations in posterior language areas during semantic tasks 101 . Collectively, these findings provide emerging evidence of both shared and syndrome specific impacts of different location-related epilepsies on brain functional networks.…”

“…In ETE (middle row), a study focusing on children with frontal lobe lesions demonstrated that despite the absence of significant differences in structural network parameters in patients, structural modularity increased with stronger cognitive impairment (middle left) 130 . Additionally, when comparing fMRI activation patterns in a verbal working memory task, frontal lobe epilepsy patients showed targeted reductions in the recruitment of specific networks, notably fronto-parietal and dorsal attention systems, while effects in TLE patients were more widespread (middle right) 101 . As for IGE (bottom row), a study in patients with juvenile myoclonic epilepsy and their unaffected siblings studied left hippocampal shape/positional anomalies, and found associations to atypical activation during a verbal memory task (bottom left)…”

Altered functional connectome hierarchy with gene expression signatures in newly-diagnosed focal epilepsy

“…49 Intrinsic connectivity gradients have recently been used to capture task-related functional reorganisation of episodic memory processes, as well as language and working memory systems in temporal lobe epilepsy. 50,51 To link our gradient findings of stronger differentiation between unimodal and transmodal systems in NDfE and PS to the histologically measured distribution of gene expression in the brain, we first used a PLS regression to identify weighted gene combinations with cortical expression maps that best matched maps of principal gradient differences between groups (PLS-1). 21 We then ran a series of enrichment analyses to examine diseases and functional processes that have been associated with identified gene combinations in previous genetics and functional genomics research.…”

Multimodal connectome biomarkers of cognitive and affective dysfunction in the common epilepsies

“…In extratemporal epilepsy (ETE; middle row), a study focusing on children with frontal lobe seizures demonstrated that despite the absence of significant differences in structural network parameters in patients, structural modularity increased with more marked cognitive impairment (middle left) ( Vaessen et al, 2014 ) . When comparing fMRI activation patterns in a verbal working memory task, frontal lobe epilepsy patients showed targeted reductions in the recruitment of specific networks, notably fronto-parietal and dorsal attention systems, while effects in TLE patients were more widespread (middle right) ( Caciagli et al, 2022 ). As for idiopathic generalized epilepsy syndromes (IGE; bottom row), a study in patients with juvenile myoclonic epilepsy and their unaffected siblings investigated left hippocampal shape/positional anomalies and found associations to atypical activation during a verbal memory task (bottom left) ( Caciagli et al, 2019 ).…”