Atypical connectome topography and signal flow in temporal lobe epilepsy

Abstract

Temporal lobe epilepsy (TLE) is one of the most common pharmaco-resistant epilepsies in adults. While hippocampal pathology is the hallmark of this condition, emerging evidence indicates that brain alterations extend beyond the mesiotemporal epicenter and affect macroscale brain function and cognition. We studied macroscale functional reorganization in TLE, explored structural substrates, and examined cognitive associations. We investigated a multisite cohort of 95 patients with pharmaco-resistant TLE and 95 healthy controls using state-of-the-art multimodal 3T magnetic resonance imaging (MRI). We quantified macroscale functional topographic organization using connectome dimensionality reduction techniques and estimated directional functional flow using generative models of effective connectivity. We observed atypical functional topographies in patients with TLE relative to controls, manifesting as reduced functional differentiation between sensory/motor networks and transmodal systems such as the default mode network, with peak alterations in bilateral temporal and ventromedial prefrontal cortices. TLE-related topographic changes were consistent in all three included sites and reflected reductions in hierarchical flow patterns between cortical systems. Integration of parallel multimodal MRI data indicated that these findings were independent of TLE-related cortical grey matter atrophy, but mediated by microstructural alterations in the superficial white matter immediately beneath the cortex. The magnitude of functional perturbations was robustly associated with behavioral markers of memory function. Overall, this work provides converging evidence for macroscale functional imbalances, contributing microstructural alterations, and their associations with cognitive dysfunction in TLE.

Differential Reorganization of Episodic and Semantic Memory Systems in Epilepsy-Related Mesiotemporal Pathology

“…Consistent with previous work based on rs-fMRI data 111 , we found neocortical gradient compressions in regions susceptible to TLE-related compromise 111,113 , suggesting atypical functional topographic segregation in TLE. Prior rs-fMRI studies reported simultaneous increases in short-and decrease in long-range connections in temporo-limbic and dorsomedial regions in TLE 111,112 , a finding that is compatible with a large body of structural covariance and diffusion MRI studies suggesting reduced connectivity to regions beyond the temporo-limbic diseased epicentre 35,111 . We also observed an extended hippocampal principal gradient, supporting the concept of subcortical gradient expansion as a functional connectome phenotype in TLE 84 .…”

“…Previous studies have also linked network alterations in TLE patients to cognitive impairment 47,85,112,114,116 . Consistent with a recent study from our group 46 , distinct episodic task impairment was observed in TLE, while semantic task performance remained relatively intact.…”

“…In TLE, previous work has mainly reported associations between structural compromise of the MTL and memory impairment measured behaviourally and shown atypical functional activation patterns in the MTL and beyond 111, 112 . Here, we extend this literature by showing a marked reorganization of functional networks during episodic retrieval states.…”

Connectome reorganization associated with temporal lobe pathology and its surgical resection

“…Indeed, recent stepwise functional connectivity studies and applications of dimensional decompositions have described an imbalance of functional integration and segregation between sensory and transmodal systems in TLE. 66,67 Our study applied gradient mapping for the first time to structural connectivity data in epilepsy. Using diffusion MRI, we demonstrated shifts in macroscale connectome organization implicating strategic regions such as the disease epicenter itself, as well as distant, yet direct, temporo-parietal connections, reflecting an increased segregation of these regions from the rest of the brain.…”

Pharmaco-resistant temporal lobe epilepsy gradually perturbs the cortex-wide excitation-inhibition balance

“…Here, E/I imbalances across different brain systems result in spontaneous seizures as well as inter-ictal epileptic phenomena, and can also impart cognitive and psychosocial consequences in patients. [9][10][11] Although the pathophysiological mechanisms by which structural and functional brain changes in epilepsy [12][13][14] cause epileptogenic events remain incompletely understood, E/I imbalance emerging from localized as well as distributed networks likely acts as a driver. 15,16 In temporal lobe epilepsy (TLE), the most common pharmaco-resistant focal epilepsy in adults, E/I imbalance is thought to originate primarily from temporolimbic circuits.…”