Abstracts

Rationale: In addition to recurrent seizures, patients with temporal lobe epilepsy (TLE) can experience a number of widespread neurocognitive deficits that are reliant on distant cortical areas distinct from regions of seizure onset. Thus, it is posited by the extended network inhibition hypothesis (ENIH) that subcortical structures, such as the thalamus, may contribute to these widespread deficits through abnormal connectivity. Moreover, evidence shows that the thalamus is essential for widespread network perturbations, seizure spread, and loss of consciousness in TLE. For example, in our previous work, we observed that abnormal functional connectivity (FC) between the central lateral thalamus and medial occipital lobes related to neurocognitive impairments and disease morbidity in TLE. However, we have yet to investigate functional connectivity of the thalamus to defined resting state networks. We aim to test the hypothesis that patients with TLE exhibit deterioration of thalamo-cortical connectivity.

Methods: Twenty minutes of fMRI resting state data were collected from an age matched cohort of 58 patients with TLE and 58 healthy control subjects. We used subject-specific thalamic and Desikan-Killany atlases. FC was determined by calculating Pearson correlations from the BOLD activation signal. Full scale IQ and verbal IQ scores were obtained as part of each patient’s standard clinical assessment. Partial correlations between functional connectivity (FC) and scores on neuropsychological evaluations were analyzed for patients with TLE. This analysis used a linear model that regressed out the effects of age.

Results: At rest, patients with TLE exhibited a significant net decrease in fMRI FC between the ventral thalamus and resting state networks including: the salience network (Fig. 1A, p = 0.0009 , two-sample t-test), and the ascending reticular activation system (ARAS) (Fig. 2A, p = 0.0006, two-sample t-test). Additionally, for patients with TLE, FC of the ventral thalamus and the salience network was found to be negatively correlated to verbal IQ (Fig. 1C, r = -0.36, p = 0.012, partial correlation) and full-scale IQ (Fig. 1B, r = -0.33 , p = 0.029, partial correlation); and, FC of the ventral thalamus and ARAS was found to be negatively correlated to verbal IQ (Fig. 2C, r = -0.36, p = 0.013, partial correlation).

Conclusions: This work provides evidence that recurrent seizures in the temporal lobe are associated with noted deterioration of ventral thalamic connectivity between subcortical arousal structures and the salience network. Additionally, this abnormal functional connectivity between the ventral thalamus and both, ARAS and the salience network are similarly significantly correlated to verbal IQ. These results may highlight a key subcortical-thalamo-cortical pathway that associated with higher cognitive abilities, particularly language and verbal processing, as posited in the ENIH. Further investigation into this pathway may provide insight into network properties of TLE, perhaps leading to the ventral thalamus as a neuromodulatory target in treatment of TLE.

Funding: This work was funded by NIH grants T32EB021937, T32GM007347, F31NS120401, R01NS112252, NS108445, NS110130