Large, rare chromosomal deletions and duplications known as copy number variants (CNVs) have been implicated in neurodevelopmental disorders similar to attention-deficit hyperactivity disorder (ADHD). We aimed to establish whether burden of CNVs was increased in ADHD, and to investigate whether identified CNVs were enriched for loci previously identified in autism and schizophrenia. We undertook a genome-wide analysis of CNVs in 410 children with ADHD and 1156 unrelated ethnically matched controls from the 1958 British Birth Cohort. Children of white UK origin, aged 5-17 years, who met diagnostic criteria for ADHD or hyperkinetic disorder, but not schizophrenia and autism, were recruited from community child psychiatry and paediatric outpatient clinics. Single nucleotide polymorphisms (SNPs) were genotyped in the ADHD and control groups with two arrays; CNV analysis was limited to SNPs common to both arrays and included only samples with high-quality data. CNVs in the ADHD group were validated with comparative genomic hybridisation. We assessed the genome-wide burden of large (>500 kb), rare (<1% population frequency) CNVs according to the average number of CNVs per sample, with significance assessed via permutation. Locus-specific tests of association were undertaken for test regions defined for all identified CNVs and for 20 loci implicated in autism or schizophrenia. Findings were replicated in 825 Icelandic patients with ADHD and 35,243 Icelandic controls. Data for full analyses were available for 366 children with ADHD and 1047 controls. 57 large, rare CNVs were identified in children with ADHD and 78 in controls, showing a significantly increased rate of CNVs in ADHD (0·156 vs 0·075; p=8·9×10(-5)). This increased rate of CNVs was particularly high in those with intellectual disability (0·424; p=2·0×10(-6)), although there was also a significant excess in cases with no such disability (0·125, p=0·0077). An excess of chromosome 16p13.11 duplications was noted in the ADHD group (p=0·0008 after correction for multiple testing), a finding that was replicated in the Icelandic sample (p=0·031). CNVs identified in our ADHD cohort were significantly enriched for loci previously reported in both autism (p=0·0095) and schizophrenia (p=0·010). Our findings provide genetic evidence of an increased rate of large CNVs in individuals with ADHD and suggest that ADHD is not purely a social construct. Action Research; Baily Thomas Charitable Trust; Wellcome Trust; UK Medical Research Council; European Union.

A prominent theory claims that the right temporoparietal junction (rTPJ) is especially associated with embodied processes relevant to perspective-taking. In the present study, we use high-definition transcranial direct current stimulation to provide evidence that the rTPJ is causally associated with the embodied processes underpinning perspective-taking. Eighty-eight young human adults were stratified to receive either rTPJ or dorsomedial PFC anodal high-definition transcranial direct current stimulation in a sham-controlled, double-blind, repeated-measures design. Perspective-tracking (line-of-sight) and perspective-taking (embodied rotation) were assessed using a visuo-spatial perspective-taking task that required understanding what another person could see or how they see it, respectively. Embodied processing was manipulated by positioning the participant in a manner congruent or incongruent with the orientation of an avatar on the screen. As perspective-taking, but not perspective-tracking, is influenced by bodily position, this allows the investigation of the specific causal role for the rTPJ in embodied processing. Crucially, anodal stimulation to the rTPJ increased the effect of bodily position during perspective-taking, whereas no such effects were identified during perspective-tracking, thereby providing evidence for a causal role for the rTPJ in the embodied component of perspective-taking. Stimulation to the dorsomedial PFC had no effect on perspective-tracking or taking. Therefore, the present study provides support for theories postulating that the rTPJ is causally involved in embodied cognitive processing relevant to social functioning.SIGNIFICANCE STATEMENTThe ability to understand another's perspective is a fundamental component of social functioning. Adopting another perspective is thought to involve both embodied and nonembodied processes. The present study used high-definition transcranial direct current stimulation (HD-tDCS) and provided causal evidence that the right temporoparietal junction is involved specifically in the embodied component of perspective-taking. Specifically, HD-tDCS to the right temporoparietal junction, but not another hub of the social brain (dorsomedial PFC), increased the effect of body position during perspective-taking, but not tracking. This is the first causal evidence that HD-tDCS can modulate social embodied processing in a site-specific and task-specific manner.

Theories of right temporoparietal junction (rTPJ) function in social cognition include self–other distinction, self-inhibition, or embodied rotation, whereas the dorsomedial prefrontal cortex (dmPFC) is associated with integrating social information. However, no study has provided causal evidence for dissociable roles of the rTPJ and dmPFC in social cognition. A total of 52 healthy young adults were stratified to receive either dmPFC or rTPJ anodal high-definition transcranial direct current stimulation (HD-tDCS) in a sham-controlled, double-blinded, repeated measures design. Self–other processing was assessed across implicit and explicit level 1 (line-of-sight) and level 2 (mental rotation) visual perspective taking (VPT) tasks, and self–other effects on memory. DmPFC stimulation selectively increased the influence of the allocentric perspective during egocentric perspective taking, indexed by an increase in congruency effect across explicit VPT tasks. Moreover, dmPFC stimulation removed the self-reference effect in episodic memory by increasing the recognition of other and decreasing the recognition of self-encoded words. Stimulation of the rTPJ resulted in improved inhibition of the egocentric-perspective during level 2 VPT only, indexed by a reduction of the congruency effect when taking the allocentric perspective. This research supports theories suggesting that the rTPJ facilitates embodied mental rotation of the self into an alternate perspective, whereas the dmPFC integrates social information relevant to self-directed processes.

The dorsomedial prefrontal cortex (dmPFC) is a key hub of the ‘social brain’, but little is known about specific processes supported by this region. Using focal high-definition transcranial direct current stimulation (HD-tDCS) and a social cognitive battery with differing demands on self-other processing, we demonstrate specific involvement of the dmPFC in tasks placing high demands on self-other processing. Specifically, excitatory (anodal) HD-tDCS enhanced the integration of external information into the self for explicit higher-order socio-cognitive tasks across cognitive domains; i.e. visual perspective taking (VPT) and episodic memory. These effects were task specific, as no stimulation effects were found for attributing mental states from the eyes or implicit VPT. Inhibitory (cathodal) HD-tDCS had weaker effects in the opposite direction towards reduced integration of external information into the self. We thus demonstrate for the first time a specific and causal role of the dmPFC in integrating higher-order information from others/external source into that of the self across cognitive domains.