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Individuals on the autism spectrum are often reported as being hyper- and/or hyporeactive to sensory input. These sensory symptoms were one of the key observations that led to the development of the altered excitation-inhibition (E-I) model of autism, which posits that an increase ratio of excitatory to inhibitory signaling may explain certain phenotypical expressions of autism spectrum disorders (ASD). While there has been strong support for the altered E-I model of autism, much of the evidence has come from animal models. With regard to in-vivo human studies, evidence for altered E-I balance in ASD come from studies adopting magnetic resonance spectroscopy (MRS). Spectral-edited MRS can be used to provide measures of the levels of GABA + (GABA + macromolecules) and Glx (glutamate + glutamine) in specific brain regions as proxy markers of inhibition and excitation respectively. In the current study, we found region-specific elevations of Glx in the primary sensorimotor cortex (SM1) in ASD. There were no group differences of GABA+ in either the SM1 or thalamus. Higher levels of Glx were associated with more parent reported difficulties of sensory hyper- and hyporeactivity, as well as reduced feed-forward inhibition during tactile perception in children with ASD. Critically, the finding of elevated Glx provides strong empirical support for increased excitation in ASD. Our results also provide a clear link between Glx and the sensory symptoms of ASD at both behavioral and perceptual levels.

The human cerebellum plays an essential role in motor control, is involved in cognitive function (i.e., attention, working memory, and language), and helps to regulate emotional responses. Quantitative in-vivo assessment of the cerebellum is important in the study of several neurological diseases including cerebellar ataxia, autism, and schizophrenia. Different structural subdivisions of the cerebellum have been shown to correlate with differing pathologies. To further understand these pathologies, it is helpful to automatically parcellate the cerebellum at the highest fidelity possible. In this paper, we coordinated with colleagues around the world to evaluate automated cerebellum parcellation algorithms on two clinical cohorts showing that the cerebellum can be parcellated to a high accuracy by newer methods. We characterize these various methods at four hierarchical levels: coarse (i.e., whole cerebellum and gross structures), lobe, subdivisions of the vermis, and the lobules. Due to the number of labels, the hierarchy of labels, the number of algorithms, and the two cohorts, we have restricted our analyses to the Dice measure of overlap. Under these conditions, machine learning based methods provide a collection of strategies that are efficient and deliver parcellations of a high standard across both cohorts, surpassing previous work in the area. In conjunction with the rank-sum computation, we identified an overall winning method. •First paper to evaluate the state-of-the-art in cerebellum parcellation.•Presenting results on both Adult and Pediatric Cohorts.•Adult Cohort contains healthy controls, and patients with either symptoms of cerebellar dysfunction or SCA 6.•Pediatric Cohort contains healthy controls, and patients with ADHD or Autism.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders characterized in current diagnostic criteria by two dominant symptoms, inattention and hyperactivity/impulsivity. Here we show that task-related alpha (8-12 Hz) interhemispheric connectivity changes, as assessed during a unimanual finger-tapping task, is correlated with inattentive symptom severity (r = 0.55, p = 0.01) but not with severity of hyperactive/impulsive symptoms. Prior published analyses of the same dataset have already show that alpha event-related desynchronization (ERD) in the hemisphere contralateral to unimanual tapping is related to hyperactive/impulsive symptom severity (r = 0.43, p = 0.04) but not to inattentive symptom severity. Our findings demonstrate a neurobiological dissociation in ADHD symptom severity, with implications for understanding the structure of endophenotypes in the disorder as well as for biomarker development.

Sensory and motor difficulties are common in autism. Altered excitation-inhibition (E-I) balance is a putative framework for understanding atypical sensory and motor function. We investigated whether sensory differences of autism mediate motor difficulties of autism via differences in E-I balance. 106 children were included in the study (Autism n = 44, Typical development children (TDC) n = 62, age 10.32 ± 1.49). E-I balance was assessed through magnetic resonance spectroscopy (MRS), quantifying Glutamate and Glutamine (Glx) and Gamma-Aminobutyric Acid (GABA) in primary sensorimotor cortex (SM1) and thalamus (Thal). Sensory function was evaluated using both objective vibrotactile perceptual sensitivity assessments and subjective parent ratings via the Sensory Experience Questionnaire (SEQ). Motor ability was assessed objectively through the Movement Assessment Battery for Children-second edition (MABC-2) and the Physical and Neurological Examination for Subtle Signs (PANESS). Our findings reveal that lower sensory reactivity and lower tactile thresholds are both predictive of better motor ability (R sig range between 0.32 and 0.57) with higher sensory scores reflecting poorer sensory filtering predicting worse motor function (R sig range −0.22 and −0.63). We identified significant associations between MRS-measured Glx and GABA+ levels and sensory reactivity (p < 0.001). Importantly, sensory reactivity sub-scores were found to fully mediate E-I balance to motor associations in domain-specific patterns: Hyper-reactivity mediated the impact of SM1 Glx levels, while hypo-reactivity mediated the impact of SM1 GABA levels. Additionally, sensory seeking mediated the impact of Thalamic GABA levels with all indirect paths ab p < 0.01. These results propose a model where regional metabolite-specific markers of E-I balance explain patterns of autism-associated sensory and motor difficulties, and where subsequently, distinct sensory phenotypes differentially mediate metabolite-motor associations (see Graphical Abstract for detail).

Recent studies suggest that the cerebellum may have a significant role in repetitive behaviors. In primary complex motor stereotypies, typically developing children have repetitive movements usually involving rhythmic flapping/waving arm/hand movements. Similarly, the deer mouse animal model exhibits inherited repetitive behaviors, with increased frequencies of spontaneous jumping and rearing. In this study, data from both children with motor stereotypies and deer mice were used to investigate the role of the cerebellum in repetitive behaviors. The 3.0-T MRI volumetric imaging of the cerebellum was obtained in 20 children with primary complex motor stereotypies and 20 healthy controls. In deer mice, cerebellar volume (n = 7/group) and cell counts (n = 9/group) were compared between high- and low-activity animals. Levels of cerebellar neurotransmitters were also determined via HPLC (n = 10/group). In children with stereotypies, (a) there were a statistically significant reduction (compared to controls) in the white matter volume of the posterior cerebellar lobule VI–VII that negatively correlated with motor control and (b) an 8% increase in the anterior vermis gray matter that positively correlated with motor Stereotypy Severity Scores (SSS). In deer mice, (a) there was a significant increase in the volume of the anterior vermal granular cell layer that was associated with higher activity and (b) dentate nucleus cell counts were higher in high activity animals. Similar increases in volume were observed in anterior vermis in children with stereotypies and a deer mouse model of repetitive behaviors. These preliminary findings support the need for further investigation of the cerebellum in repetitive behaviors.

Objective Children with attention‐deficit/hyperactivity disorder (ADHD) show excessive mirror overflow (particularly in the nondominant hand); however, patterns of age‐related decrease of overflow remain unclear. This study aimed to quantify age‐related changes in mirror overflow in youth with and without ADHD. Methods Average mirror overflow was examined during left‐hand finger tapping (LHFT; nondominant finger tapping) and right‐hand finger tapping (RHFT; dominant finger tapping) using electronic finger twitch transducers in a cross‐sectional sample of youth with ADHD (n = 77) and typically developing (TD) youth (n = 75) ages 8–18 years. Effects of age and ADHD diagnosis on LHFT, RHFT, and a summed “total” overflow (TOF) across hands were examined across the sample age range and within childhood (8–12 years) and adolescence (13–18 years). Results ADHD youth showed a decrease in overflow with age, including a large effect for TOF, with a very large age effect for LHFT but a more moderate age effect for RHFT. TD youth showed a moderate decrease in overflow with age for TOF, with a large decrease for LHFT but no significant decrease for RHFT. Additionally, we found that large effects of ADHD‐related excessive overflow in childhood diminished in adolescence. Interpretation Findings suggest that mirror overflow in ADHD youth diminishes into adolescence but does not resolve completely, suggesting ADHD‐associated increased mirror overflow may reflect both a developmentally resolving effect and a somewhat persistent atypicality. Future studies with larger and longitudinal samples would provide additional insight into mechanisms contributing to excessive mirror overflow and its relationship to both clinical and neurobiological aspects of ADHD‐associated disinhibition.

Objective The aim of this study was to identify a quantitative, brain‐based measure reflecting impaired response inhibition in children with attention‐deficit/hyperactivity disorder (ADHD). Methods In this cross‐sectional study, we used transcranial magnetic stimulation (TMS) to evoke potentials in hand muscle during both a simple reaction time and a response inhibition task in 8‐to‐12‐year‐old children, 41 with ADHD (42% girls, 76% white, mean age 10.3 years) and 38 typically developing controls (53% girls, 74% white, mean age 9.8 years). We used mixed‐model linear regressions of evoked potential amplitudes to compare motor cortex excitability at (1) task‐onset (“START”: 550 ms prior to action); (2) preparing‐to‐go (“GO”: 150 ms prior to action); and (3) selecting‐to‐stop (“STOP”: 150 ms after stop cue). We hypothesized that task‐related up‐modulation of motor cortex excitability (motor evoked potential amplitudes) would depend both on task (STOP > GO > START) and on diagnosis (controls > patients). Results Motor cortex up‐modulation was significantly greater for STOP trials than during GO or START. Children with ADHD had both worse response inhibition performance (longer stop‐signal reaction times) and significantly less task effect on motor cortex up‐modulation. The largest diagnostic difference in motor cortex activation occurred during STOP trials. Reduced up‐modulation during stopping was also associated with higher parent‐rated symptom severity. Interpretation Our findings suggest that motor cortex up‐modulation of excitability, assessed indirectly by TMS motor evoked potentials, reflects the cognitive load during response inhibition tasks and may be a quantitative, brain‐based indicator of impaired response inhibition in children with ADHD.

Dopamine-related abnormalities in the basal ganglia have been implicated in attention-deficit/hyperactivity disorder (ADHD). Iron plays a critical role in supporting dopaminergic function, and reduced brain iron and serum ferritin levels have been linked to ADHD symptom severity in children. Furthermore, the basal ganglia is a central brain region implicated in ADHD psychopathology and involved in motor and reward functions as well as emotional responding. The present study repurposed diffusion tensor imaging (DTI) to examine effects of an ADHD diagnosis and sex on iron deposition within the basal ganglia in children ages 8–12 years. We further explored associations between brain iron levels and ADHD symptom severity and affective symptoms. We observed reduced iron levels in children with ADHD in the bilateral limbic region of the striatum, as well as reduced levels of iron-deposition in males in the sensorimotor striatal subregion, regardless of diagnosis. Across the whole sample, iron-deposition increased with age in all regions. Brain-behavior analyses revealed that, across diagnostic groups, lower tissue-iron levels in bilateral limbic striatum correlated with greater ADHD symptom severity, whereas lower tissue-iron levels in the left limbic striatum only correlated with anxious, depressive and affective symptom severity. This study sheds light on the neurobiological underpinnings of ADHD, specifically highlighting the localization of tissue-iron deficiency in limbic regions, and providing support for repurposing DTI for brain iron analyses. Our findings highlight the need for further investigation of iron as a biomarker in the diagnosis and treatment of ADHD and sex differences.

The current study presents a novel method for imaging the cerebellar dentate nucleus, combining ultra-high field (7T) and quantitative susceptibility mapping (QSM) to enhance tissue boundary identification and segmentation. After assessing segmentation reliability, we assessed validity by evaluating volume and resting state functional connectivity (FC) of the dorsal vs. ventral dentate subregions. Neurotypical adults ( n  = 30, 15 females) completed 7T susceptibility-weighted imaging (SWI) and resting state fMRI. QSM maps were used to segment the dentate (whole, dorsal, ventral subregions). Reliability of the segmentation protocol was established across three raters (inter-rater) and one rater who performed the segmentations twice (intra-rater) using the Dice coefficient ( d ). Dorsal and ventral dentate volumes were calculated, and whole-brain seed-to-voxel FC patterns were assessed from the whole dentate, dorsal, and ventral subregions. Group-level contrasts for each subregion and between subregions were thresholded at voxel-level p  <.005, with a cluster-level FDR-correction of p  <.05. Segmentation reliability was high (inter-rater d  = 0.89, intra-rater d  = 0.93), and the dorsal subregion was significantly smaller than the ventral ( p  <.001). The dorsal dentate showed greater FC with regions involved in sensorimotor processing (cerebellar vermis I-V, IX-X, lobules VIII-IX, fusiform, cuneus), and the ventral dentate showed greater FC with regions involved in cognitive processing (cerebellar lobule VII, angular gyrus, middle and superior frontal gyri, middle and superior temporal gyri, temporal pole). We present an innovative, reliable, and valid method for imaging the dentate. Dentate volumes and FC were consistent with anatomical mapping from animal and human studies. Future directions include application to clinical populations with anomalous cerebellar development and injury.

Children with attention-deficit/hyperactivity disorder (ADHD) demonstrate reduced response inhibition, increased response time variability, and atypical frontal lobe white matter microstructure with emerging evidence of sex differences. This study aims to examine whether frontal lobe white matter microstructure is differentially impacted in ADHD by sex and whether this relates to Go/No-Go (GNG) task performance. Diffusion tensor imaging (DTI) from 187 children (8–12 years), including ADHD (n = 94) and typically developing controls (TD; n = 93). Participants completed three GNG tasks with varying cognitive demands and incentives (standard, cognitive, and motivational). Fractional anisotropy (FA) was examined as an index of white matter microstructure within bilateral frontal lobe regions of interest. Children with ADHD showed reduced FA in primary motor (M1) and supplementary motor area (SMA) regardless of sex. Sex-based dissociation for the effect of diagnosis was observed in medial orbitofrontal cortex (mOFC), with higher FA in girls with ADHD and lower FA in boys with ADHD. Both diagnosis and sex contributed to performance on measures of response inhibition and reaction time (RT) variability, with all children with ADHD demonstrating poorer performance on all GNG tasks, but boys with ADHD demonstrating more impulsivity on standard and motivational behavioral paradigms compared to girls with ADHD. Analyses revealed associations between reduced FA in M1, SMA, and mOFC and increased response inhibition and RT variability with some sex-based differences. These findings provide novel insights regarding the brain basis of ADHD and associated impairments in response inhibition and RT variability, and contribute to our understanding of sexual dimorphic behavioral outcomes.