Abstracts

Rationale: Children with benign epilepsy with centrotemporal spikes (BECTS) have only rare seizures which they outgrow in adolescence, yet often have language and attention deficits. We hypothesized that increased cortical excitability leads to atypical cortical plasticity in this group. We measured cortical excitability and plasticity in children with BECTS and in several healthy controls using transcranial magnetic stimulation paired with EMG and EEG (TMS-EMG/EEG) and compared these measures to cognitive tests. Methods: Fourteen children with BECTS (5-12 years) and 3 healthy controls (10-13 years) underwent cognitive tests to assess IQ (WASI-II), expressive & receptive language (EVT-2 and PPVT-4), attention (T.O.V.A.), language learning (CVLT-C), and fine-motor learning (repeated trials of grooved pegboard). With the TMS stimulation coil placed over the left central region, TMS-evoked potentials (TEPs) and motor evoked potentials (MEPs) were recorded by scalp EEG and surface EMG electrodes, respectively. Measures of cortical excitability were: right abductor pollicis brevis resting motor threshold (rMT), amplitude of the N100 (a TEP reflecting regional cortical inhibition), and magnitude of long-interval intracortical inhibition (LICI) of the MEP (another measure of cortical GABAergic tone) obtained by paired pulse TMS (ppTMS;interstimulus interval 100 ms, 120% rMT). Plasticity was measured by comparisons of the MEP and N100 amplitudes before and after a train of repetitive TMS (rTMS, 1 Hz, 1000 pulses, 120% rMT). We then tested whether cognitive test scores correlated with measures of excitability and plasticity. Results: Table 1 summarizes demographics and results. MEPs were elicited reliably in 8 of 17 subjects, all age >8 years. Subjects =11 years showed paradoxical facilitation with the ppTMS LICI protocol while those >11 years showed inhibition that is typical in adults (Figure 1a). Contrary to prior literature, there was not a clear relationship between age and N100 peak amplitude (R=0.32; p=0.29). In 7 of 8 children with BECTS, N100 amplitude increased after rTMS while in healthy children, N100 amplitude decreased. We combined all subjects for correlations with cognitive scores. There was no correlation between measures of excitability (rMT, LICI, N100 amplitude) or measures of plasticity (% change in MEP or TEP amplitude) and either motor or language learning. However, there was a strong correlation between the % change in N100 amplitude and IQ (R= -0.9, p=0.0002), expressive language (R=-0.76, p=0.007) and receptive language (R=-0.82, p=0.002) (Figure1b). Conclusions: We identify for the first time age-dependent changes in cortical inhibitory tone that include an inflection point where long-interval cortical facilitation shifts to long-interval cortical inhibition at ~11 years of age. Notably, the timing of the facilitation-to-inhibition shift approximates the age of epilepsy resolution for many BECTS patients, suggesting that developmental regulation of cortical inhibition may be a mechanism underlying resolution of this syndrome. Neither cortical excitability nor plasticity correlated with fine motor or language learning, but plasticity strongly correlated with static cognitive outcomes, like IQ. Healthy children and those with BECTS and the highest IQs had suppression or minimal change in their N100 amplitude with rTMS while those with lower IQs had augmentation of the N100 amplitude, suggesting that a failure in homeostatic plasticity may drive cognitive difficulties in some BECTS patients. Funding: Fiona Baumer conducted this work with support from a KL2 Mentored Career Development Award of the Stanford Clinical and Translational Science Award to Spectrum (NIH KL2 TR 001083) and (UL1 TR 001085) (FB).