Decreased thalamocortical connectivity in resolved Rolandic epilepsy.

OBJECTIVE: Median nerve somatosensory evoked fields (SEFs) conduction times reflect the integrity of neural transmission across the thalamocortical circuit. We hypothesized median nerve SEF conduction time would be abnormal in children with Rolandic epilepsy (RE). METHODS: 22 children with RE (10 active; 12 resolved) and 13 age-matched controls underwent structural and diffusion MRI and median nerve and visual stimulation during magnetoencephalography (MEG). N20 SEF responses were identified in contralateral somatosensory cortices. P100 were identified in contralateral occipital cortices as controls. Conduction times were compared between groups in linear models controlling for height. N20 conduction time was also compared to thalamic volume and Rolandic thalamocortical structural connectivity inferred using probabilistic tractography. RESULTS: The RE group had slower N20 conduction compared to controls (p = 0.042, effect size 0.6 ms) and this difference was driven by the resolved RE group (p = 0.046). There was no difference in P100 conduction time between groups (p = 0.83). Ventral thalamic volume positively correlated with N20 conduction time (p = 0.014). CONCLUSIONS: Children with resolved RE have focally decreased Rolandic thalamocortical connectivity. SIGNIFICANCE: These results identify a persistent focal thalamocortical circuit abnormality in resolved RE and suggest that decreased Rolandic thalamocortical connectivity may support symptom resolution in this self-limited epilepsy.

Transient, developmental functional and structural connectivity abnormalities in the thalamocortical motor network in Rolandic epilepsy.

Rolandic epilepsy (RE) is the most common focal, idiopathic, developmental epilepsy, characterized by a transient period of sleep-potentiated seizures and epileptiform discharges in the inferior Rolandic cortex during childhood. The cause of RE remains unknown but converging evidence has identified abnormalities in the Rolandic thalamocortical circuit. To better localize this transient disease, we evaluated Rolandic thalamocortical functional and structural connectivity in the sensory and motor circuits separately during the symptomatic and asymptomatic phases of this disease. We collected high resolution structural, diffusion, and resting state functional MRI data in a prospective cohort of children with active RE (n = 17), resolved RE (n = 21), and controls (n = 33). We then computed the functional and structural connectivity between the inferior Rolandic cortex and the ventrolateral (VL) nucleus of the thalamus (efferent pathway) and the ventroposterolateral (VPL) nucleus of the thalamus (afferent pathway) across development in children with active, resolved RE and controls. We compared connectivity with age in each group using linear mixed-effects models. We found that children with active RE have increasing thalamocortical functional connectivity between the VL thalamus and inferior motor cortex with age (p = 0.022) that is not observed in controls or resolved RE. In contrast, children with resolved RE have increasing thalamocortical structural connectivity between the VL nucleus and the inferior motor cortex with age (p = 0.025) that is not observed in controls or active RE. No relationships were identified between VPL nuclei and the inferior sensory cortex with age in any group. These findings localize the functional and structural thalamocortical circuit disruption in RE to the efferent thalamocortical motor pathway. Further work is required to determine how these circuit abnormalities contribute to the emergence and resolution of symptoms in this developmental disease.

Source EEG reveals that Rolandic epilepsy is a regional epileptic encephalopathy.

Rolandic epilepsy is the most common form of epileptic encephalopathy, characterized by sleep-potentiated inferior Rolandic epileptiform spikes, seizures, and cognitive deficits in school-age children that spontaneously resolve by adolescence. We recently identified a paucity of sleep spindles, physiological thalamocortical rhythms associated with sleep-dependent learning, in the Rolandic cortex during the active phase of this disease. Because spindles are generated in the thalamus and amplified through regional thalamocortical circuits, we hypothesized that: 1) deficits in spindle rate would involve but extend beyond the inferior Rolandic cortex in active epilepsy and 2) regional spindle deficits would better predict cognitive function than inferior Rolandic spindle deficits alone. To test these hypotheses, we obtained high-resolution MRI, high-density EEG recordings, and focused neuropsychological assessments in children with Rolandic epilepsy during active (n = 8, age 9-14.7 years, 3F) and resolved (seizure free for > 1 year, n = 10, age 10.3-16.7 years, 1F) stages of disease and age-matched controls (n = 8, age 8.9-14.5 years, 5F). Using a validated spindle detector applied to estimates of electrical source activity in 31 cortical regions, including the inferior Rolandic cortex, during stages 2 and 3 of non-rapid eye movement sleep, we compared spindle rates in each cortical region across groups. Among detected spindles, we compared spindle features (power, duration, coherence, bilateral synchrony) between groups. We then used regression models to examine the relationship between spindle rate and cognitive function (fine motor dexterity, phonological processing, attention, and intelligence, and a global measure of all functions). We found that spindle rate was reduced in the inferior Rolandic cortices in active but not resolved disease (active P = 0.007; resolved P = 0.2) compared to controls. Spindles in this region were less synchronous between hemispheres in the active group (P = 0.005; resolved P = 0.1) compared to controls; but there were no differences in spindle power, duration, or coherence between groups. Compared to controls, spindle rate in the active group was also reduced in the prefrontal, insular, superior temporal, and posterior parietal regions (i.e., "regional spindle rate", P < 0.039 for all). Independent of group, regional spindle rate positively correlated with fine motor dexterity (P < 1e-3), attention (P = 0.02), intelligence (P = 0.04), and global cognitive performance (P < 1e-4). Compared to the inferior Rolandic spindle rate alone, models including regional spindle rate trended to improve prediction of global cognitive performance (P = 0.052), and markedly improved prediction of fine motor dexterity (P = 0.006). These results identify a spindle disruption in Rolandic epilepsy that extends beyond the epileptic cortex and a potential mechanistic explanation for the broad cognitive deficits that can be observed in this epileptic encephalopathy.

Interictal epileptiform discharges changed epilepsy-related brain network architecture in BECTS.

To investigate directed information flow of epileptiform activity in benign epilepsy with centrotemporal spikes (BECTS) during ictal epileptiform discharges (IEDs) and non-IEDs periods. In this multi-center study, a total of 188 subjects, including 50 BECTS and 138 normal children's controls (NCs) from three different centers (Center 1: females/males, 38/55; mean age, 9.33 ± 2.6 years; Center 2: females/males,7/10; mean age, 8.59 ± 2.32 years; Center 3: females/males, 14/14; mean age, 13 ± 3.42 years) were recruited. The BECTS were classified into IEDs (females/males, 12/15; mean age, 8.15 ± 1.68 years) and non-IEDs (females/males, 10/13; mean age, 9.09 ± 1.98 years) subgroups depending on presence of central-temporal spikes from an EEG-fMRI examination. Three new methods, structural equation parametric modeling, dynamic causal modeling and granger causality density (GCD) were used to determine optimal network architectures for BECTS. Three multicentric NCs determined a reliable and consistent network architecture by structural equation parametric modeling method. Further analyses were used for IEDs and non-IEDs to determine the brain network architecture by structural equation parametric modeling, dynamic causal modeling and GCD, respectively. The brain network architecture of IEDs substate, non-IEDs substate and NCs are different. IEDs promoted the driving effect of the Rolandic areas with more output information flows, and increased the targeted effect of the top of pre-/post-central gyrus with more input information flows. The information flow arises from the Rolandic areas, and subsequently propagates to the top of pre-/post-central gyrus and thalamus. From non-IEDs status to IEDs status, the thalamus load may play an important role in the modulation and regulation of epileptiform activity. These findings shed new light on pathophysiological mechanism of directed localization of epileptiform activity in BECTS.

Persistent abnormalities in Rolandic thalamocortical white matter circuits in childhood epilepsy with centrotemporal spikes.

OBJECTIVE: Childhood epilepsy with centrotemporal spikes (CECTS) is a common, focal, transient, developmental epilepsy syndrome characterized by unilateral or bilateral, independent epileptiform spikes in the Rolandic regions of unknown etiology. Given that CECTS presents during a period of dramatic white matter maturation and thatspikes in CECTS are activated during non-rapid eye movement (REM) sleep, we hypothesized that children with CECTS would have aberrant development of white matter connectivity between the thalamus and the Rolandic cortex. We further tested whether Rolandic thalamocortical structural connectivity correlates with spike rate during non-REM sleep. METHODS: Twenty-three children with CECTS (age = 8-15 years) and 19 controls (age = 7-15 years) underwent 3-T structural and diffusion-weighted magnetic resonance imaging and 72-electrode electroencephalographic recordings. Thalamocortical structural connectivity to Rolandic and non-Rolandic cortices was quantified using probabilistic tractography. Developmental changes in connectivity were compared between groups using bootstrap analyses. Longitudinal analysis was performed in four subjects with 1-year follow-up data. Spike rate was quantified during non-REM sleep using manual and automated techniques and compared to Rolandic connectivity using regression analyses. RESULTS: Children with CECTS had aberrant development of thalamocortical connectivity to the Rolandic cortex compared to controls (P = .01), where the expected increase in connectivity with age was not observed in CECTS. There was no difference in the development of thalamocortical connectivity to non-Rolandic regions between CECTS subjects and controls (P = .19). Subjects with CECTS observed longitudinally had reductions in thalamocortical connectivity to the Rolandic cortex over time. No definite relationship was found between Rolandic connectivity and non-REM spike rate (P > .05). SIGNIFICANCE: These data provide evidence that abnormal maturation of thalamocortical white matter circuits to the Rolandic cortex is a feature of CECTS. Our data further suggest that the abnormalities in these tracts do not recover, but are increasingly dysmature over time, implicating a permanent but potentially compensatory process contributing to disease resolution.