Demographic and clinical characteristics
Participants’ demographic and clinical characteristics are presented in Table 1. In total, 233 subjects including 92 boys with ASD + ADHD (mean age, 11.4 years; SD, 2.4 years) and 141 TD controls (mean age, 11.1 years; SD, 2.5 years) participated in this study. Most participants were right-handed, except for 10 patients with ASD + ADHD and seven TD controls. The ASD + ADHD group included 17 patients with specific learning disorders, 13 with oppositional defiant disorder, three with conduct disorder, two with epilepsy, one with developmental coordination disorder, and one with tic disorder. Forty of the patients with ASD + ADHD were medication-naïve, while 37 were medicated with osmotic release oral system-methylphenidate, ten with atomoxetine, nine with antipsychotics, four with carbamazepine, and one with guanfacine. Although there were no significant differences in age or handedness between the two groups, there were significant differences in IQ, inattention, hyperactivity-impulsivity scores as evaluated by the ADHD-RS and AQ, as well as in SCQ total scores (all p < 0.01; Table 1).
There were no significant differences in total intracranial, total grey matter, total cortical, subcortical grey matter, or cerebellum cortex volumes between the two groups (Table 1S). Similarly, there were no significant differences in the volumes of the basal ganglia, such as the nucleus accumbens, amygdala, caudate, hippocampus, pallium, putamen, and thalamus (Table 2S). However, compared to TD controls, patients with ASD + ADHD exhibited significantly decreased volumes in the left postcentral gyrus (p = 0.018, FDR-corrected) (Fig. 1). There were no significant differences in cortical thickness and surface area between regions. The volumes, cortical thickness, and surface areas of all regions are listed in the supplementary materials (Tables 3S, 4S, 5S).While the left postcentral gyrus volume was significantly lower in children and preadolescents with ASD + ADHD than in TD controls (p = 0.026, 0.004), there was no significant difference between patients and controls in the adolescent age group (p = 0.171) (Fig. 2).
In the present study, we investigated the structural features of the brain in children with ASD + ADHD using relatively large participant pools from two study sites. While we found no significant differences in prefrontal cortex, cerebellum, or basal ganglia volumes, patients with ASD + ADHD exhibited significantly smaller left postcentral gyrus than TD controls. Additionally, in patients with ASD + ADHD, the volume of the left postcentral gyrus was only significantly smaller in children and preadolescents, not in adolescents.
Few postcentral gyrus volume abnormalities have been previously reported in patients with ASD or ADHD. One study that included only 15 children and adolescents with ADHD and 15 aged-matched participants with ASD revealed increased postcentral gyrus volumes in these patients relative to the TD controls. However, this finding did not survive a correction for multiple comparisons35. On the other hand, another study reported that 29 children and adolescents with ADHD exhibited reduced volume in the postcentral gyrus compared to 29 TD controls36. This finding survived familywise error corrections. Thus, although prior reports point to structural abnormalities in the postcentral gyrus in ASD and ADHD, findings have been inconsistent. This may be due to the small sample sizes and differences in statistical thresholds used. In the present study, however, we used a relatively large sample size across two recruitment sites, and we report findings after multiple corrections. Our study may thus be able to add more valid evidence to the earlier reported inconsistent findings. In addition, the postcentral gyrus, which is the location of the primary somatosensory cortex, is involved in somatosensory functions. Sensory problems are core symptoms of ASD and are listed in the ASD diagnostic criteria of the DSM-51. Interestingly, children with comorbid ASD and ADHD reportedly experience more sensory processing problems than those with either ASD or ADHD alone37, and postcentral gyrus abnormalities may further reflect this increased risk for sensory processing deficits. Furthermore, sensory processing abnormalities contribute to social, communication, and repetitive behaviour deficits, which are the core features of ASD38 and are also associated with attentional deficits39. Therefore, in children with comorbid ASD and ADHD, sensory problems may stem from postcentral gyrus abnormalities, which in turn may lead to core ASD and ADHD symptoms (social, communication, repetitive behaviour, and attentional deficits).
Critically, developmental trajectories may also be different in patients with ASD and ADHD comorbidity. In the present study, the left postcentral gyrus volume was significantly lower in children and preadolescents with ASD + ADHD than in TD, but there was no difference in adolescents. This finding suggests that developmental delays in the left postcentral gyrus may improve with age. Although ASD and ADHD are lifelong disorders, their features can change with development, and a substantial proportion of individuals with ADHD and a smaller proportion of individuals with ASD exhibit improved symptoms with age40,41,42. These changes in symptoms may result from improvements in postcentral gyrus function with development. Additionally, longitudinal studies of brain development in ADHD have reported delayed cortical development43,44. Similarly, as suggested by the present study, brain structure maturation may also be delayed in patients with ASD + ADHD.
Interestingly, we found no significant differences in total brain, cerebellar, prefrontal cortex, corpus callosum, or basal ganglia volumes, although these are areas in which abnormalities are often reported in both ASD and ADHD14,45,46. This suggests that the primary pathophysiology in ADHD + ASD may differ from that in ASD or ADHD alone. For instance, in an fMRI study using a temporal discounting task, which assesses a key aspect of reward-related decision making, patients with comorbid ASD and ADHD exhibited more pronounced differences in brain-behaviour associations compared to TD controls and those with ASD or ADHD alone. This finding suggests that ASD and ADHD are neither phenocopies nor additive pathologies, but that comorbid ASD and ADHD represents a distinct neurofunctional pathology altogether47. Furthermore, response rates to methylphenidate in individuals with ASD + ADHD differ from those of children with ADHD alone. The National Institute of Mental Health Collaborative Multisite Multimodal Treatment Study of Children with ADHD reported response rates of 70–80%, as compared to the 49% reported in the Research Units of Paediatric Psychopharmacology Autism Network methylphenidate trial48,49. Methylphenidate acts to increase dopamine and noradrenaline concentrations by inhibiting their reuptake in the prefrontal cortex and reward system, both of which exhibit abnormalities in patients with ADHD. The less pronounced effect of methylphenidate in patients with ASD + ADHD may thus be due to the attention-deficit symptoms in this comorbid condition being related to the somatosensory gyrus rather than to action in the prefrontal cortex or reward system as in ADHD alone. Despite similar symptoms, the regions causing the symptoms, that is, the underlying brain morphology, may differ. It is thus possible that a diagnosis based solely on symptoms is not always in line with the relevant pathophysiology, and symptomatic diagnoses do not often lead to effective therapy. On the other hand, therapy based on pathogenesis, not on a symptomatic diagnosis, may lead to better outcomes. In cases where structural MRI shows abnormalities in the postcentral gyrus rather than the prefrontal cortex and the reward systems, as seen in this study, the effect of methylphenidate may be weaker. Such considerations may be helpful for the selection of medication in the context of prior therapeutic strategies.
The National Institute of Mental Health in the United States launched the Research Domain Criteria (RDoC) project as an answer to the problem that a diagnosis based on symptoms does not always lead to effective therapy. This project sought to create a framework for research on pathophysiology, especially in the fields of neuroscience and genomics50. Using this model, researchers and clinicians are expected to identify syndromes based on their pathophysiology and thus ultimately improve treatment outcomes for psychiatric diseases. Imaging studies may further help clarify the underlying neuronal mechanisms of psychiatric disorders and thus provide new frameworks for their classification. This may ultimately lead to the development of treatment strategies that consider underlying pathophysiology. Using this model, the field’s future understanding of conditions of the brain will undoubtedly improve, as will the precision of their treatment.
While our findings offer significant benefits to the field, our study has some limitations. First, it is limited by its inclusion of only patients with comorbid ASD and ADHD. To further investigate the more exact, detailed progress of these diseases, both combined and in isolation, additional longitudinal studies are required. Second, the present study does not include female patients with ASD + ADHD, and our findings can therefore not be generalized to all cases of ASD + ADHD. Third, some patients with ASD + ADHD in this study were under medication, for example with methylphenidate, which may have affected their brain structure51.
In the present study, we assessed the unique brain structure features of patients with ASD + ADHD. This approach, to the best of our knowledge, has not been used elsewhere, and the relatively large sample size used here presents a significant advantage. Patients with ASD + ADHD exhibited significantly decreased left postcentral gyrus volumes compared to TD controls; however, the left postcentral gyrus volume in patients with ASD + ADHD was only significantly smaller in children and preadolescents, not in adolescents. These findings suggest that the pathophysiology of ASD + ADHD may be primarily related to somatosensory deficits and delayed maturation of the left postcentral gyrus. Our results improve the field’s current understanding of the neurobiological mechanisms underlying comorbid ASD and ADHD and may lead to the development of novel treatment strategies that consider the relevant pathophysiology.