Objective Seizures in temporal lobe epilepsy (TLE) disturb brain networks and lead to connectivity disturbances. We previously hypothesised that recurrent seizures in TLE may lead to abnormal connections involving subcortical activating structures including the ascending reticular activating system (ARAS), contributing to neocortical dysfunction and neurocognitive impairments. However, no studies of ARAS connectivity have been previously reported in patients with epilepsy.
Methods We used resting-state functional MRI recordings in 27 patients with TLE (67% right sided) and 27 matched controls to examine functional connectivity (partial correlation) between eight brainstem ARAS structures and 105 cortical/subcortical regions. ARAS nuclei included: cuneiform/subcuneiform, dorsal raphe, locus coeruleus, median raphe, parabrachial complex, pontine oralis, pedunculopontine and ventral tegmental area. Connectivity patterns were related to disease and neuropsychological parameters.
Results In control subjects, regions showing highest connectivity to ARAS structures included limbic structures, thalamus and certain neocortical areas, which is consistent with prior studies of ARAS projections. Overall, ARAS connectivity was significantly lower in patients with TLE than controls (p<0.05, paired t-test), particularly to neocortical regions including insular, lateral frontal, posterior temporal and opercular cortex. Diminished ARAS connectivity to these regions was related to increased frequency of consciousness-impairing seizures (p<0.01, Pearson’s correlation) and was associated with impairments in verbal IQ, attention, executive function, language and visuospatial memory on neuropsychological evaluation (p<0.05, Spearman’s rho or Kendell’s tau-b).
Conclusions Recurrent seizures in TLE are associated with disturbances in ARAS connectivity, which are part of the widespread network dysfunction that may be related to neurocognitive problems in this devastating disorder.
- functional connectivity
- reticular activating system
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Contributors Data were primarily collected by VLM and analysed by DJE and VLM, with data analysis assistance provided by P-FDH. Neuropsychological data were primarily collected and interpreted by MLJ. JCG, PEK and BWA-K participated in the data interpretation. DJE produced the first draft of the manuscript. All authors read, provided input and approved the final manuscript.
Funding This work was supported by the National Institutes of Health grants K99 NS097618 (DJE) and R01 NS075270 (VLM) and by an American Epilepsy Society/Epilepsy Foundation grant (DJE).
Competing interests None declared.
Ethics approval This study was approved by the Vanderbilt University Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
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