Relationship between epileptiform discharges and social reciprocity or cognitive function in children with and without autism spectrum disorders: An MEG study

Center for Evolutionary Cognitive Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Department of Community Mental Health & Law, National Institute of Mental Health, National Center of Neurology and Psychiatry, Departments of Neuropsychiatry, Institute for Diversity & Adaptation of Human Mind (UTIDAHM), The University of Tokyo, UTokyo Center for Integrative Science of Human Behavior (CiSHuB), and The International Research Center for Neurointelligence (WPI-IRCN), Institutes for Advanced Study (UTIAS), University of Tokyo, Tokyo, Japan Email: ojio@ncnp.go.jp Received 12 February 2020; revised 3 June 2020; accepted 9 June 2020.

As one might readily infer, assessing the ongoing effects of IED on autistic social impairment in children with ASD is important to elucidate how IED and autistic symptomatology are related. Furthermore, from a clinical perspective, it would be of interest to ascertain whether the IED at the initial assessment predict later intelligence. Therefore, we specifically examined the association between the frequency of IED and social impairment or intelligence over the course of time in children with and without ASD.
We recruited 40 TD children and 26 children with ASD and excluded participants who had had a clinical diagnosis of any other neuropsychiatric disorder, including epilepsy. We also excluded those who were receiving antiepileptic drugs. At the initial assessment, we recorded magnetoencephalographic (MEG) data for 10 min and evaluated intelligence using the Kaufman Assessment Battery for Children (K-ABC). 4 For children in the ASD group, we also measured social impairment using the Social Responsiveness Scale (SRS). 5 Participants completed a second K-ABC evaluation (and SRS for the ASD group) after at least 300 days. For each participant, the IED were counted manually by application of the same general principles recommended by the International Federation of Clinical Neurophysiology (Fig. S1). Appendix S1 presents detailed information related to the methodology. 6 Differences between TD and ASD in terms of age, sex, cognitive performance, frequency (i.e., number of IED per 10 s), prevalence of IED at first measurement, and duration between first and second assessment were assessed (Table S1). Additional statistical analyses were conducted after excluding a female child with ASD who was unable to complete either the K-ABC or the MEG recording. To predict Mental Processing Scale (MPS) and Achievement Scale (ACH) scores or SRS-T scores from a linear mixedeffects analysis, we incorporated the frequency of IED at first measurement, number of days between first and second evaluation, their two-way interaction, sex, and age at the first assessment into the models as fixed effects. As a random effect, we used intercepts for subjects. Appendix S1 presents more detailed information related to the results.
In children with ASD, we found a significant main effect of the frequency of IED for SRS scores (z = −4.3, P < 0.001; see Table S2 for more details), and significant interaction effects between the number of days between measurements and the IED frequency for both MPS (estimated fixed effect was 0.01, z = 2.57, P = 0.10) and ACH (estimated fixed effect was 0.02, z = 4.2, P < 0.001) scores (Table S3 presents additional details). First, the results implied that higher frequency of IED at the baseline was significantly associated with better social reciprocity. This result resembles those obtained from a study by Hartley-McAndrew and Weinstock 7 but contradicts results reported by others. 8,9 Second, the higher frequency of IED was associated with higher intelligence and achievement at later assessments. To visualize these interaction effects,

Marginal predicted mean for MPS scores
Marginal predicted mean for ACH scores we computed the respective marginal means from predictions of previously fit models for MPS and ACH. The results are presented in Figure 1.
In TD children, the effects were not found to be significant. This report is the first of a study finding that higher frequency of IED predicts better intelligence or achievement at a later assessment. Considering a recent report suggesting the importance of sociality for development of intelligence in children with ASD, 10 the observed association between IED and intelligence might be driven by the positive effect of IED on sociality. It is noteworthy that if IED in ASD are detrimental, or if they cause cognitive or social dysfunction, then a higher IED frequency can be expected to correspond to lower sociality or intelligence. Regarding results obtained from the current study, that hypothesis is unlikely. Rather, it is apparently protective against primary changes in ASD. However, drawing such a firm conclusion based purely on our results from such a small sample size is inappropriate. Further research with greater statistical power and considering locations and types of IED might be necessary to verify this hypothesis.
Parents agreed to the participation of their children. Written informed consent for participation and publication was obtained before participation. The Ethics Committee of Kanazawa University Hospital approved the methods and procedures, all of which were performed in accordance with the Declaration of Helsinki. The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

Supporting information
Additional Supporting Information may be found in the online version of this article at the publisher's web-site: Appendix S1. Supporting information. Table S1. Participant characteristics. Table S2. Effects of IED frequency on change over time in social reciprocity in children with ASD. Table S3. Effects of IED frequency on change over time in intelligencechildren with ASD. Table S4. Effects of IED frequency on change over time in intelligence -TD children. Figure S1 An example of observed interictal epileptiform discharges (IED), where IED were defined as sharp transient and clearly different from background activity with an 'epileptiform' morphology and a logical spatial distribution (left). Magnetoencephalogram 2-D topography shows a clear pattern of sink (green) and source (red).