Abstracts

Rationale: Benign epilepsy with centrotemporal spikes (BECTS) is the most common focal childhood epilepsy syndrome, characterized by a transient period of seizures, abundant spikes during non-REM (NREM) sleep, and motor and cognitive deficits. The mechanisms underlying the neuropsychological deficits remain unknown. Several observations suggest that spikes can be generated by hijacking the same thalamocortical circuit that generates sleep spindles. These brief bursts of oscillatory sigma band (10-16 Hz) activity are present only in NREM sleep and are critical for memory consolidation. We hypothesized that children with active BECTS would have: i) a focal disruption in spindle activity at the epileptiform focus; ii) that spindle density would be inversely related to spike rate; and, iii) that spindle density would improve over disease resolution. Methods: We recorded EEG during a daytime nap (1024 Hz sampling rate) in patients with active BECTS (within 1 year of seizure, n=10), patients with resolving BECTS ( >1 year without seizure, n=13), and healthy individuals (controls, n=13). The sleep data were artifact rejected and scored for sleep stage using standard techniques. We detected spindles during NREM sleep with a wavelet-based algorithm modified to avoid false spindle detections due to epileptiform spikes. We also applied the Persyst 13 spike detector (Persyst Development Corporation, San Diego) to N2 in the same participants. Results: Using a subset of BECTS and control data with manually detected spindles as the gold standard (n=6 active, n=6 resolving, n=6 controls, 100s of data per subject), we found that the modified detector more accurately detected spindles, with improved sensitivity (p=7e-15) and positive predictive value (p=0.0015), compared to the original detector. Applying the modified detector to central electrodes (C3 and C4, the stereotyped focus of spikes in BECTS) in the full BECTS dataset (n=10 active, n=13 resolving, n=13 controls, 10 minutes of NREM each), we found that active subjects had reduced spindle density (number per minute) compared with resolving (p=0.002, age adjusted p=0.02) and control participants (p=0.01, age adjusted p=0.05). There were no group differences in spindle density at other electrodes excluding central and temporal channels (p>0.1). Spindle density in central electrodes decreased exponentially with spike rate (p=0.004), suggesting a shared, non-linear, pathophysiologic mechanism of spikes and spindles. Moreover, spindle density in the central electrodes increased with duration seizure free (p=0.015), suggesting that spindle deficits resolve with epilepsy resolution. Conclusions: Spindles are cardinal oscillations of NREM sleep and an essential mechanism to coordinate the synaptic plasticity required for memory consolidation during healthy sleep. Here we find that children with a common, focal, developmental epilepsy syndrome - BECTS - have focal, transient deficits in sleep spindles that inversely correlate with spike rate. These observations support the hypothesis that spindles deficits are an electrophysiological feature of BECTS. Future work will evaluate whether spindle deficits contribute to the characteristic motor and language deficits observed in this syndrome and whether these deficits can be improved by increasing spindles pharmacologically or with neurostimulation. Funding: K23-NS092923, NSF DMS #1451384