Source EEG reveals that Rolandic epilepsy is a regional epileptic encephalopathy

Abstract

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.

Keywords: Childhood epilepsy with centrotemporal spikes; EEG; Electrical source imaging; Epileptic encephalopathy; Sleep spindle; Thalamus.

Graphical abstract

Fig. 1

Example of electrical source imaging procedure. (A) Digitized EEG electrode placement and anatomical landmarks (red circles), and (B) reconstructed anatomical surfaces: inner skull (blue), outer skull (light gray), and outer skin surfaces (dark gray). (C) Example cortical surface reconstruction with lateral inferior Rolandic cortex indicated (blue). (D) Example source activity during an interictal spike in the inferior Rolandic cortex (inset). Red heat-map indicates amplitude of interictal spike (corresponding to time indicated by red line in inset) averaged over time for each source. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Spindle rate is lower in subjects with Rolandic epilepsy. (A) Example spindle activity (10–15 Hz rhythms characteristic of NREM sleep) from 10 sources in the left inferior Rolandic cortex with detected spindles (orange). (B) Left and right lateral views of the brain with the inferior Rolandic region indicated (blue). Black circles indicate example source locations used to compute spindle rate. (C) Spindle rate in the inferior Rolandic cortices for active (red), resolved (yellow), and control (green) subjects. Bar heights indicate population mean, and circles indicate the spindle rate for each hemisphere of each patient. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Spindle rate correlates with other spectral estimates. (A) Averaged power spectra for each patient group, active (red), resolved (yellow), and control subjects (green). Solid lines indicate the mean, and shading indicates 95% confidence intervals. (B, C) Spindle rate in the inferior Rolandic cortex correlates with sigma power (B) and sigma bump (C). Shaded regions in the power spectra insets in the upper left of (B) and (C) represent areas used to compute sigma power and sigma bump, respectively. Black line indicates the linear fit, shading the 95% confidence intervals, and circles the values for each subject (see legend). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Rolandic epilepsy subjects produce fewer, but typical, spindles. (A) Left and (B) right hemispheres of a subject with sources (circles) in the inferior Rolandic cortices (blue). The subset of sources in the inferior Rolandic cortices with detected spindles are colored orange, otherwise black. (C) Example recordings from source in the left hemisphere (top) and the right hemisphere (bottom) with detected spindles in orange. Arrows between sources within each cortex indicate intra-hemispheric coherence, and arrows between sources from the left to the right cortices indicate inter-hemispheric coherence. Below the recordings from each hemisphere is the corresponding spindle indicator function that contains ones if at least one source is exhibiting a spindle at that moment in time and is used to compute the bilateral synchrony of spindles. (D-H) Spindle characteristics sigma power (D), duration (E), intra-hemispheric sigma band coherence (F), inter-hemispheric sigma band coherence (G), and bilateral synchrony (H). We find evidence of a difference between active and control subjects only for the bilateral synchrony (asterisks). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

Spindle rate deficit extends beyond inferior Rolandic cortices. Parcellation of the cortex into 31 regions per hemisphere. Lateral (A) and medial (B) regions with a significant reduction in spindle rate in active versus control subjects indicated in green. Asterisk (*) indicates significant differences after correction for multiple comparisons. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 6

Performance on neuropsychological assessments. Each subject’s performance (z-score, circles) on the (A) motor dexterity (dominant and nondominant scores averaged per subject), (B) processing speed, (C) IQ, and (D) phonological awareness tasks. In each boxplot, central mark indicates the median; bottom and top edges of the box indicate the 25th and 75th percentiles, respectively; and whiskers extend to the most extreme data points.

Fig. 7

Regional spindle rate correlates with neuropsychological assessments. (A) Schematic of the grooved pegboard experiment. Subjects perform a grooved pegboard task with their left and right hand. Performance is paired with spindle rate in the contralateral hemisphere (green). (B-D) As regional measure of spindle rate increases, motor performance (B), processing speed (C), and IQ (D) significantly increase. (E) Phonological awareness shows an increasing trend. Circles represent three disease groups: active (red filled), resolved (red unfilled), and control subjects (green). The solid line indicates the model fit, and shaded regions indicate 95% confidence intervals. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)