Brain-wide magnetic resonance imaging analysis of neurobehavioral comorbidities in temporal lobe epilepsy

In temporal lobe epilepsy (TLE), patients often present with neurobehavioral comorbidities encompassing affective and cognitive difficulties. Whereas the latter have been related to atypical connectivity of mesiotemporal and frontotemporal circuits, the brain basis of affective symptoms remains incompletely understood. Here, we assessed functional network substrates of affective symptoms and examined their relationship to structural magnetic resonance imaging (MRI), cognition, and clinical parameters.

We studied 42 drug-resistant patients who underwent multimodal 3-T MRI as well as self-report questionnaires of affective and cognitive functions outside the scanner, alongside 41 age- and sex-matched healthy controls. Partial least squares (PLS), a brain-wide multivariate associative technique, examined relationships between resting-state functional MRI connectivity strength (FCS) and affective measures. Linear models assessed relationships with morphology and microstructure, as well as cognitive and clinical parameters.

Moderate to severe anxiety was present in 79% of patients, with concealing and adjustment as coping strategies, and 40% experienced depression. Quality of life scores were below published norm for epilepsy. PLS analysis revealed a latent component that accounted for 67% of the covariance between FCS and affective symptoms, linking weaker connectivity in temporoparietal and prefrontal cortices, as well as mesiotemporal, thalamic, and pallidal regions, to anxiety, low energy/fatigue, medication-related complaints, and reduced quality of life. Among cognitive domains, verbal memory positively correlated with the same brain areas. Cortices with the strongest covariance between FCS and affective variables presented with marked atrophy and myelin alterations (indexed by T1/fluid-attenuated inversion recovery decreases). Controlling for verbal memory and metrics of brain structure, the temporal-parietal network remained the most compromised.

Dysconnectivity of the temporal-parietal network emerges as a key contributor to affective symptoms in TLE, and limbic network dysfunction additionally impacts cognition. These findings emphasize the importance of multidisciplinary care targeting both emotion regulation and stress reduction, alongside cognitive rehabilitation, for improved well-being and quality of life.