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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.

Background Studies of brain functional connectivity (FC) typically involve massive univariate tests, performing statistical analysis on each individual connection. In this study, we apply a novel whole-matrix regression approach referred to as covariate assisted principal regression to identify resting-state FC brain networks associated with attention-deficit/hyperactivity disorder (ADHD) and response control. Methods Participants included 8- to 12-year-old children with ADHD (n = 115; 29 girls) and typically developing control children (n = 102; 35 girls) who completed a resting-state functional magnetic resonance imaging scan and a Go/NoGo task. We modeled three sets of covariates to identify resting-state networks associated with an ADHD diagnosis, sex, and response inhibition (commission errors) and variability (ex-Gaussian parameter tau). Results The first network includes FC between striatal-cognitive control (CC) network subregions and thalamic-default mode network (DMN) subregions and is positively related to age. The second consists of FC between CC-visual-somatomotor regions and between CC-DMN subregions and is positively associated with response variability in boys with ADHD. The third consists of FC within the DMN and between DMN-CC-visual regions and differs between boys with and without ADHD. The fourth consists of FC between visual-somatomotor regions and between visual-DMN regions and differs between girls and boys with ADHD and is associated with response inhibition and variability in boys with ADHD. Unique networks were also identified in each of the three models, suggesting some specificity to the covariates of interest. Conclusions These findings demonstrate the utility of our novel covariance regression approach to studying functional brain networks relevant for development, behavior, and psychopathology.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with a behavioral phenotype characterized by impaired development of social-communicative skills as well as excessive repetitive and stereotyped behaviors. Despite high phenotypic heterogeneity in ASD, a meaningful subpopulation of children with ASD (~90%) show significant general motor impairment.. More focused studies on the nature of motor impairment in ASD reveal that children with ASD are particularly impaired on tasks such as ball catching and motor imitation that require efficient visual-motor integration (VMI). Motor computational approaches also provide evidence for VMI-impairment showing that children with ASD form internal sensorimotor representations that bias proprioceptive over visual-feedback. Impaired integration of visual information to form internal representations of others’ and the external world may explain observed impairments on VMI-tasks and motor imitation of others. Motor imitation is crucial for acquiring both social and motor skills and impaired imitation skill may contribute to the observed core behavioral phenotype of ASD. The current review examines evidence supporting VMI-impairment as a core feature of ASD that may contribute to both impaired motor imitation and social-communicative skill development. We propose that understanding the neurobiological mechanisms underlying VMI-impairment in ASD may be key to discovery of therapeutics to address disability in children and adults with ASD.

Copying other people’s mannerisms (i.e., mimicry) occurs spontaneously during social interactions, and is thought to contribute to sharing emotions, affiliation with partners and interaction quality. While previous research shows decreased mimicry of emotional facial expressions in autism spectrum disorders (ASD), we know relatively little about how non-emotional, non-facial behavioural mimicry manifests and, more importantly, what it means for autistic individuals’ social interactions. In a controlled, semi-naturalistic interaction setting, this study examined how often autistic and neurotypical (NT) children mimicked a virtual partner’s non-facial mannerisms as they engaged in an interactive story-telling activity. Subsequently, children reported how affiliated they felt towards their interaction partner using an established implicit measure of closeness and a set of questions. Results revealed reduced mimicry (p = .001, φ = .38) and less affiliation (p = .01, φ = .33) in ASD relative to NT children. Mimicry was associated with affiliation for NT (r(23) = .64, p = .0009), but not ASD, children (r(31) = .07, p = .72). These results suggest an autism-associated reduction in mimicry and that mimicry during social interactions may not substantially contribute to affiliation in autism.

Sensory differences and anxiety disorders are highly prevalent in autistic individuals with and without ADHD. Studies have shown that sensory differences and anxiety are associated and that intolerance of uncertainty (IU) plays an important role within this relationship. However, those studies predominantly assessed sensory reactivity using questionnaires (i.e., observational reports), which can be subjective, and do not differentiate between perceptual, affective, and behavioural levels of sensory processing. Psychophysical approaches can offer useful additional insight, by providing objective measures of sensory differences at the perceptual level. In the current study, we used psychophysical vibrotactile tasks to assess how alterations in sensory perception contribute to observationally assessed sensory reactivity, IU, and anxiety. 38 autistic children (aged 8-12 years; 27 with co-occurring ADHD) were included in the analyses. Consistent with previous findings, parent-report measures of sensory reactivity, anxiety, and child-reported IU, were intercorrelated. Mediation analyses showed that IU fully mediated an association between sensory reactivity and anxiety, and that anxiety partially mediated an association between sensory reactivity and IU. Of the measured vibrotactile thresholds, only simultaneous frequency discrimination (SFD) thresholds significantly correlated with parent-reported sensory reactivity. Interestingly, we found that sensory reactivity fully mediated an association between SFD threshold and anxiety, and between SFD threshold and IU. Taken together, these findings suggest a mechanistic pathway whereby low-level perceptual alterations contribute to sensory differences at the affective level, leading in turn to increased IU and anxiety. This stepwise association can inform therapeutic interventions for IU and anxiety in autistic individuals with or without ADHD.

Sensory differences are highly prevalent in autistic individuals. However, few studies have compared their presentation between autistic males and autistic females. We used psychophysics to assess and compare tactile perceptual sensitivity between autistic and non-autistic boys and girls aged between 8 and 12 years of age. While there were sex-differences of amplitude discrimination, frequency discrimination and order judgement thresholds, these sex-differences were not autism-specific. Mean RTs and detection thresholds were elevated in autism but were comparable between the sexes. Tactile sensitivity measures that are elevated in autism but are otherwise comparable between autistic males and autistic females suggest the possibility that certain sensory features could be used as sex-indifferent markers of autism. Further investigation with larger and more representative samples should be conducted before any stronger conclusions are made.

Intolerance of uncertainty (IU) is a multidimensional construct involving maladaptive responses to uncertainty. IU is strongly associated with autism and anxiety, yet no studies have examined its symptom profile in autistic children. This study compares IU symptom profiles in autistic and NT children and in autistic children with and without anxiety using the Intolerance of Uncertainty Scale for Children. Compared to NT peers, autistic children exhibited heightened IU symptoms in all domains, affective, behavioral, and cognitive; affective symptoms had the highest association with autism. Autistic children with anxiety also exhibited elevated IU symptoms in all domains compared to those without anxiety; behavioral IU symptoms had the highest association with anxiety. IU symptom profiles should be considered in assessment and treatment.

BackgroundThe tendency to prefer smaller, immediate rewards over larger, delayed rewards is known as Delay Discounting (DD). Developmental deviations in DD may play a key role in characterizing psychiatric and neurodevelopmental disorders. Recent work provided empirical support for DD as a transdiagnostic process in various psychiatric disorders. However, there is a lack of research relating developmental changes in DD from mid-childhood to adolescence to psychiatric and neurodevelopmental disorders.MethodsThe current study addresses this gap in a robust psychiatric sample of 1843 children and adolescents aged 5-18 (M = 10.6, SD = 3.17; 1219 males, 624 females). General Additive Models (GAMs) characterized the shape of age-related changes in monetary and food reward discounting for nine psychiatric disorders compared to neurotypical youth (NT; n=123). We found that over 40% of our sample possessed a minimum of at least three psychiatric or neurodevelopmental disorders. We used bootstrap-enhanced Louvain community detection to map the underlying comorbidity patterns impacting DD. We derived five subtypes based on diagnostic categories present in our sample. DD patterns were then compared across each of the subtypes. Further, we evaluated the effect of cognitive ability, emotional and behavioral problems and total household income (THI) in relation to DD across development.ResultsHigher discounting was found in six out of the nine disorders we examined relative to NT. DD was consistently elevated across development for most disorders with the exception of depressive disorders, with age-specific DD differences compared to NTs. Community detection analyses revealed that one comorbidity subtype consisting primarily of Attention-Deficit/Hyperactivity Disorder (ADHD) Combined Presentation and anxiety disorders displayed the highest overall emotional/behavioral problems and greater DD for the food reward. An additional comorbidity subtype composed mainly of ADHD Predominantly Inattentive Presentation, learning and developmental disorders showed the greatest DD for both food and monetary rewards compared to the other subtypes. Notably, this subtype had general deficits in reasoning ability, given their low performance on cognitive and academic achievement measures. Additionally, for this ADHD-I and developmental disorders subtype, THI was related to DD across the age span such that participants with high THI showed no differences in DD compared to NTs, while participants with low THI showed significantly worse DD trajectories than all others. Our results also support prior work showing that DD follows non-linear developmental patterns.ConclusionsWe demonstrate preliminary evidence for DD as a transdiagnostic marker of psychiatric and neurodevelopmental disorders in children and adolescents. Comorbidity subtypes provide insight into heterogeneity in DD across disorders and offer a unique way to identify high-risk individuals. Importantly, our findings suggest that DD is strongly related to overall intellectual reasoning ability and that, among those with lower intellectual reasoning, DD is particularly heightened in children from households with lower THI. The findings suggest that self-regulation may be particularly impaired in individuals with psychiatric and neurodevelopmental disorders with low household income.

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.

Motor stereotypies are rhythmic, repetitive, prolonged, predictable, and purposeless movements that stop with distraction. Although once believed to occur only in children with neurodevelopmental disorders such as autism, the presence and persistence of complex motor stereotypies (CMS) in otherwise typically developing children (primary CMS) has been well-established. Little, however, is known about the underlying pathophysiology of these unwanted actions. The aim of the present study was to use resting-state functional magnetic resonance imaging to evaluate functional connectivity within frontal-striatal circuits that are essential for goal-directed and habitual activity in children with primary complex motor stereotypies. Functional connectivity between prefrontal cortical and striatal regions, considered essential for developing goal-directed behaviors, was reduced in children with primary CMS compared to their typically developing peers. In contrast, functional connectivity between motor/premotor and striatal regions, critical for developing and regulating habitual behaviors, did not differ between groups. This documented alteration of prefrontal to striatal connectivity could provide the underlying mechanism for the presence and persistence of complex motor stereotypies in otherwise developmentally normal children.

Aim: Compare transcranial magnetic stimulation (TMS)-derived measures of motor cortex (M1) physiology between children with and without Tourette syndrome (TS) and dimensionally analyze TMS measures with TS-related tic and urge symptom severity.Method: 60 8-12-year-old children (30 TS, 3 girls, 10 years, 10 months [1 year, 3 months]; 30 typically developing children - TDC, 7 girls, 10 years, 7 months [1 year, 3 months]) participated. Within TS, 15 children (1 girl, 10 years, 11 months [1 year, 3 months]) had comorbid Attention-Deficit/Hyperactivity Disorder (ADHD), rated with the Conners 3rd Edition and the parent-reported ADHD rating scale. Tic severity was rated with the Yale Global Tic Severity Scale (YGTSS), and premonitory urge severity with the Individualized Premonitory Urge for Tics Scale (I-PUTS) for children with TS. M1 short interval cortical inhibition (SICI) and intracortical facilitation (ICF) were compared between diagnostic groups and, within TS, correlated with symptom severity using repeated measures regressions.Results: Accounting for ADHD, we found no difference in SICI or ICF in TS vs. TDC (p>.1). Within TS, reduced M1 SICI predicted greater total (p=.012) and global (p=.002) tic severity. There were no associations with urge severity (p>.5). Interpretation: Reduced M1 SICI is robustly associated with increased tic, but not urge, severity.

The stop-signal paradigm has become ubiquitous in investigations of inhibitory control. Tasks inspired by the paradigm, referred to as stop-signal tasks, require participants to make responses on go trials and to inhibit those responses when presented with a stop-signal on stop trials. Currently, the most popular version of the stop-signal task is the ‘choice-reaction’ variant, where participants make choice responses, but must inhibit those responses when presented with a stop-signal. An alternative to the choice-reaction variant of the stop-signal task is the ‘anticipated response inhibition’ task. In anticipated response inhibition tasks, participants are required to make a planned response that coincides with a predictably timed event (such as lifting a finger from a computer key to stop a filling bar at a predefined target). Anticipated response inhibition tasks have some advantages over the more traditional choice-reaction stop-signal tasks and are becoming increasingly popular. However, currently, there are no openly available versions of the anticipated response inhibition task, limiting potential uptake. Here, we present an open-source, free, and ready-to-use version of the anticipated response inhibition task, which we refer to as the OSARI (the Open-Source Anticipated Response Inhibition) task.

Objective Compared to typically developing (TD) peers, children with attention deficit hyperactivity disorder (ADHD) manifest reduced short interval cortical inhibition (SICI) in the dominant motor cortex measured with transcranial magnetic stimulation (TMS). This multimodal study investigates the inhibitory neurophysiology and neurochemistry by evaluating the relationship between SICI and γ-amino butyric acid (GABA+) levels, measured with magnetic resonance spectroscopy (MRS). Methods Across two sites, 37 children with ADHD and 45 TD children, ages 8–12 years, participated. Single and paired pulse TMS to left motor cortex quantified SICI during REST and at times of action selection (GO) and inhibition (STOP) during a modified Slater-Hammel stop signal reaction task. MRS quantified GABA+ levels in the left sensorimotor cortex. Relationships between SICI and GABA+, as well as stopping efficiency and clinical symptoms, were analyzed with correlations and repeated-measure, mixed-models. Results In both groups, higher GABA+ levels correlated with less SICI. In TD children only, higher GABA+ levels correlated with larger TMS motor evoked potentials (MEPs) at REST. In GO and STOP trials, higher GABA+ was associated with smaller MEP amplitudes, for both groups. Overall, GABA+ levels did not differ between groups or correlate with ADHD clinical symptoms. Conclusions In children with higher motor cortex GABA+, motor cortex is less responsive to inhibitory TMS (SICI). Comparing the relationships between MRS-GABA+ levels and responses to TMS at REST vs. GO/STOP trials suggests differences in inhibitory neurophysiology and neurotransmitters in children with ADHD. These differences are more prominent at rest than during response inhibition task engagement. Significance Evaluating relationships between GABA+ and SICI may provide a biomarker useful for understanding behavioral diagnoses.

Alterations of tactile processing have long been identified in autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). However, the extent to which these alterations are disorder-specific, rather than disorder-general, and how they relate to the core symptoms of each disorder, remains unclear. We measured and compared tactile detection, discrimination, and order judgment thresholds between a large sample of children with ASD, ADHD, ASD + ADHD combined and typically developing controls. The pattern of results suggested that while difficulties with tactile detection and order judgement were more common in children with ADHD, difficulties with tactile discrimination were more common in children with ASD. Interestingly, in our subsequent correlation analyses between tactile perception and disorder-specific clinical symptoms, tactile detection and order judgment correlated exclusively with the core symptoms of ADHD, while tactile discrimination correlated exclusively with the symptoms of ASD. When taken together, these results suggest that disorder-specific alterations of lower-level sensory processes exist and are specifically related to higher-level clinical symptoms of each disorder., He et al. assessed different parameters of tactile processing in children diagnosed with autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). They found evidence for disorder-specific alterations of lower-level sensory processing, which can be related back to higher-level clinical symptoms.

Children with autism spectrum disorder (ASD) have difficulties perceiving and producing skilled gestures, or praxis. The inferior parietal lobule (IPL) is crucial to praxis acquisition and expression, yet how IPL connectivity contributes to autism-associated impairments in praxis as well as social-communicative skill remains unclear. Using resting-state functional magnetic resonance imaging, we applied independent component analysis to test how IPL connectivity relates to praxis and social-communicative skills in children with and without ASD. Across all children (with/without ASD), praxis positively correlated with connectivity of left posterior-IPL with the left dorsal premotor cortex and with the bilateral posterior/medial parietal cortex. Praxis also correlated with connectivity of right central-IPL connectivity with the left intraparietal sulcus and medial parietal lobe. Further, in children with ASD, poorer praxis and social-communicative skills both correlated with weaker right central-IPL connectivity with the left cerebellum, posterior cingulate, and right dorsal premotor cortex. Our findings suggest that IPL connectivity is linked to praxis development, that contributions arise bilaterally, and that right IPL connectivity is associated with impaired praxis and social-communicative skills in autism. The findings underscore the potential impact of IPL connectivity and impaired skill acquisition on the development of a range of social-communicative and motor functions during childhood, including autism-associated impairments.

Autism is more commonly diagnosed in males than females, with an approximate ratio of 4:1. While some theories posit that males may be more susceptible to diagnosis for biological reasons, others suggest that females on the autism spectrum are being underdiagnosed due to sociological reasons such as the diagnostic criteria being biased towards the detection of autistic symptoms in boys. Sensory differences (i.e., “hyper- or hyporeactivity to sensory input or unusual interest in sensory aspects of the environment”) have been recently added to the diagnostic criteria for autism in the Diagnostic Statistical Manual of Mental Disorders, 5th Edition. Although sensory differences are highly prevalent in autistic individuals, few studies have compared their presentation between autistic males and females. In the current study, we used psychophysics to assess tactile perceptual sensitivity in 76 autistic (58 males and 18 female) and 197 typically developing children (140 males and 57 females) aged between 8 to 13 years of age. While we observed differences in tactile sensitivity between autistic children and typically developing controls, we did not observe any Diagnosis by Sex interaction effects. That is, tactile sensitivity, which is lower in autistic children compared to typically developing controls, was comparable between autistic males and females. Given that the other core symptoms of autism (i.e., the social communication difficulties and restricted/repetitive behaviours) are known to present differently between autistic males and females, the finding that tactile sensitivity was generally comparable between the sexes suggest that the sensory differences of autism, such as tactile sensitivity, could be used as a sex-indifferent biomarker.

This study examined the developmental trajectory of neurodevelopmental motor signs among boys and girls with attention-deficit/hyperactivity disorder (ADHD) and typically-developing (TD) children. Seventy children with ADHD and 48 TD children, aged 8–17 years, were evaluated on at least two time-points using the Physical and Neurological Assessment of Subtle Signs (PANESS). Age-related changes in subtle motor signs (overflow, dysrhythmia, speed) were modeled using linear mixed-effects models to compare the developmental trajectories among four subgroups (ADHD girls and boys and TD girls and boys). Across visits, both boys and girls with ADHD showed greater overflow, dysrhythmia, and slower speed on repetitive motor tasks compared to TD peers; whereas, only girls with ADHD were slower on sequential motor tasks than TD girls. Developmental trajectory analyses revealed a greater reduction in overflow with age among boys with ADHD than TD boys; whereas, trajectories did not differ among girls with and without ADHD, or among boys and girls with ADHD. For dysrhythmia and speed, there were no trajectory differences between the subgroups, with all groups showing similar reductions with age. Children with ADHD show developmental trajectories of subtle motor signs that are consistent with those of TD children, with one clear exception: Boys with ADHD show more significant reductions in overflow from childhood to adolescence than do their TD peers. Our findings affirm the presence of subtle motor signs in children with ADHD and suggest that some of these signs, particularly motor overflow in boys, resolve through adolescence while dysrhythmia and slow speed, may persist.

Impairments in visuomotor integration (VMI) may contribute to anomalous development of motor, as well as social-communicative, skills in children with autism spectrum disorder (ASD). However, it is relatively unknown whether VMI impairments are specific to children with ASD versus children with other neurodevelopmental disorders. As such, this study addressed the hypothesis that children with ASD, but not those in other clinical control groups, would show greater deficits in high-VMI dynamic grip-force tracking versus low-VMI static presentation. Seventy-nine children, aged 7-17 years, participated: 22 children with ASD, 17 children with fetal alcohol spectrum disorder (FASD), 18 children with Attention-Deficit Hyperactivity Disorder (ADHD), and 22 typically developing (TD) children. Two grip-force tracking conditions were examined: (1) a low-VMI condition (static visual target) and (2) a high-VMI condition (dynamic visual target). Low-frequency force oscillations

Objective Previous studies of Tai Chi or mindfulness-based interventions in attention-deficit/hyperactivity disorder (ADHD) have relied on self- or parent-reported outcome measures; however, there is a critical need for the validation of objective biomarkers of treatment. Therefore, we implemented a mindful movement intervention for children with ADHD, hypothesizing that an ADHD-relevant motor control measure could serve as a predictive biomarker of treatment-related improvement. Methods Thirty-four participants were included, 8 to 12 year olds diagnosed with DSM-5 ADHD. Participants engaged in the mindful movement treatment, an 8-week program with 2 classes a week for 60 minutes. At pre- and post-treatment, ADHD symptoms and associated impairment and motor control via the Physical and Neurological Examination for Subtle Signs (PANESS) were assessed. Results The results showed a significant reduction for PANESS Gaits and Station (p ≤ 0.001), total overflow (p = 0.009), and total score (p = 0.001) after treatment, with the largest effect for Gaits and Stations. The results also showed a significant reduction in symptoms of inattention (p ≤ 0.001), hyperactivity/impulsivity (p ≤ 0.001), oppositional defiant disorder (p = 0.001), and executive dysfunction (p ≤ 0.001). There were significant positive correlations between change in PANESS Gaits and Stations and change in both inattentive (p = 0.02) and hyperactive/impulsive symptoms (p = 0.02). There was also a significant positive correlation between change in the PANESS total score and change in inattentive (p = 0.007) and hyperactive/impulsive symptoms (p = 0.042). The change in the PANESS total score (β = 0.295, p = 0.002) predicted post-treatment ADHD severity above the change in inattentive or hyperactive/impulsive symptoms. Conclusion The results suggest the effectiveness of a mindful movement treatment on ADHD symptoms and suggest the PANESS as a candidate motor biomarker for future mindful movement trials. Clinical trial registration ClinicalTrials.gov, NCT02234557, https://clinicaltrials.gov/ct2/show/NCT02234557.

Whole-brain network analysis is commonly used to investigate the topology of the brain in a variety of neuroimaging modalities. This approach is notable for its applicability to a large number of domains, such as understanding how brain network organization relates to cognition and behavior, examining disrupted brain network organization in disease, and assessing developmental trajectories across the lifespan. A benefit to this approach is the ability to summarize overall brain network organization with a single number (e.g., global efficiency). However, important local differences in network structure might exist without any corresponding observable differences in overall topology, making a whole-brain analysis strategy unlikely to detect relevant local findings. Here, we propose the network-based statistic (NBS) jackknife as a means of combining the utility of global network analysis strategies with the ability to detect relevant local differences in network structure. We describe the NBS jackknife framework, and demonstrate three specific testing scenarios in a series of examples. Finally, we provide an empirical example comparing global efficiency between children with ADHD and typically developing (TD) children. We demonstrate using functional connectivity data that there are no group differences in whole-brain global efficiency. Using the NBS jackknife, however, we identify group differences in global efficiency specific to the salience and subcortical subnetworks. The NBS jackknife framework has been implemented in a public, open source R package, netjack, available at https://cran.r-project.org/package=netjack.

Children with ADHD show developmentally abnormal levels of mirror overflow-unintentional movements occurring symmetrically opposite of intentional movements. Because mirror overflow correlates with ADHD behavioral symptoms, the study of disinhibition in motor control may shed light on physiologic mechanisms underlying impaired behavioral/cognitive control. This is a case-controlled study of EEG recording from 25 children with ADHD and 25 typically developing (TD) controls performing unilateral sequential finger tapping, with overflow movements measured using electronic goniometers. Consistent with previously published findings, children with ADHD showed increased mirror overflow as compared with TD peers. EEG findings revealed less lateralized alpha modulation (event-related desynchronization; ERD) and decreased magnitude of beta ERD in ADHD; both alpha and beta ERD reflect cortical activation. Moderation analysis revealed a significant association between beta ERD and overflow, independent of diagnosis; and an equivocal (p = .08) effect of diagnosis on the relationship between alpha ERD and overflow, with a significant effect in children with ADHD but not TD children. These results suggest two mechanisms involved with mirror overflow: one reflected in beta ipsilateral to the intentional movement and relevant to both children with ADHD and controls, and the other seemingly more specific to ADHD (alpha, contralateral to movement).

Autism spectrum disorder (ASD) consists of altered performance of a range of skills, including social/communicative and motor skills. It is unclear whether this altered performance results from atypical acquisition or learning of the skills or from atypical "online" performance of the skills. Atypicalities of skilled actions that require both motor and cognitive resources, such as abnormal gesturing, are highly prevalent in ASD and are easier to study in a laboratory context than are social/communicative skills. Imitation has long been known to be impaired in ASD; because learning via imitation is a prime method by which humans acquire skills, we tested the hypothesis that children with ASD show alterations in learning novel gestures via imitation. Eighteen participants with ASD and IQ > 80, ages 8-12.9 years, and 19 typically developing peers performed a task in which they watched a video of a model performing a novel, meaningless arm/hand gesture and copied the gesture. Each gesture video/copy sequence was repeated 4-6 times. Eight gestures were analyzed. Examination of learning trajectories revealed that while children with ASD made nearly as much progress in learning from repetition 1 to repetition 4, the shape of the learning curves differed. Causal modeling demonstrated the shape of the learning curve influenced both the performance of overlearned gestures and autism severity, suggesting that it is in the index of learning mechanisms relevant both to motor skills and to autism core features. Autism Res 2020, 13: 777-784.. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Imitation is a route by which humans learn a wide range of skills, naturally and in therapies. Imitation is known to be altered in autism spectrum disorder (ASD), but learning via imitation has not been rigorously examined. We found that the shape of the learning curve is altered in ASD, in a way that has a significant impact both on measures of autism severity and of other motor skills.

The exclusion of high-motion participants can reduce the impact of motion in functional Magnetic Resonance Imaging (fMRI) data. However, the exclusion of high-motion participants may change the distribution of clinically relevant variables in the study sample, and the resulting sample may not be representative of the population. Our goals are two-fold: 1) to document the biases introduced by common motion exclusion practices in functional connectivity research and 2) to introduce a framework to address these biases by treating excluded scans as a missing data problem. We use a study of autism spectrum disorder in children without an intellectual disability to illustrate the problem and the potential solution. We aggregated data from 545 children (8-13 years old) who participated in resting-state fMRI studies at Kennedy Krieger Institute (173 autistic and 372 typically developing) between 2007 and 2020. We found that autistic children were more likely to be excluded than typically developing children, with 28.5% and 16.1% of autistic and typically developing children excluded, respectively, using a lenient criterion and 81.0% and 60.1% with a stricter criterion. The resulting sample of autistic children with usable data tended to be older, have milder social deficits, better motor control, and higher intellectual ability than the original sample. These measures were also related to functional connectivity strength among children with usable data. This suggests that the generalizability of previous studies reporting naïve analyses (i.e., based only on participants with usable data) may be limited by the selection of older children with less severe clinical profiles because these children are better able to remain still during an rs-fMRI scan. We adapt doubly robust targeted minimum loss based estimation with an ensemble of machine learning algorithms to address these data losses and the resulting biases. The proposed approach selects more edges that differ in functional connectivity between autistic and typically developing children than the naïve approach, supporting this as a promising solution to improve the study of heterogeneous populations in which motion is common.

BackgroundIndividuals with Tourette syndrome (TS) often report that they express tics as a means of alleviating the experience of unpleasant sensations. These sensations are perceived as an urge to act and are referred to as premonitory urges. Premonitory urges have been the focus of recent efforts to develop interventions to reduce tic expression in those with TS.ObjectiveThe aim of this study was to examine the contribution of brain γ-aminobutyric acid (GABA) and glutamate levels of the right primary sensorimotor cortex (SM1), supplementary motor area (SMA), and insular cortex (insula) to tic and urge severity in children with TS.MethodsEdited magnetic resonance spectroscopy was used to assess GABA+ (GABA + macromolecules) and Glx (glutamate + glutamine) of the right SM1, SMA, and insula in 68 children with TS (MAge = 10.59, SDAge = 1.33) and 41 typically developing control subjects (MAge = 10.26, SDAge = 2.21). We first compared GABA+ and Glx levels of these brain regions between groups. We then explored the association between regional GABA+ and Glx levels with urge and tic severity.ResultsGABA+ and Glx of the right SM1, SMA, and insula were comparable between the children with TS and typically developing control subjects. In children with TS, lower levels of SMA GABA+ were associated with more severe and more frequent premonitory urges. Neither GABA+ nor Glx levels were associated with tic severity.ConclusionsThese results broadly support the role of GABAergic neurotransmission within the SMA in the experience of premonitory urges in children with TS. © 2021 International Parkinson and Movement Disorder Society

Background. Individuals with Tourette syndrome (TS) often report that they express tics as a means of alleviating the experience of unpleasant sensations. These sensations are perceived as an urge to act and are referred to as premonitory urges. Premonitory urges have been the focus of recent efforts to develop interventions to reduce tic expression in those with TS. Increasing evidence points to the role of both structural and functional alterations of prefrontal and limbic brain regions regarding the experience of premonitory urges to tic in TS. This study examined the contribution of brain GABA and glutamate levels of the right primary sensorimotor cortex (SM1), supplementary motor area (SMA), and insular cortex (insula) to tic and urge severity in children with TS.Methods. Edited magnetic resonance spectroscopy was used to assess GABA+ (GABA + macromolecules) and Glx (glutamate + glutamine) of the right SM1, SMA and insula in 68 children with TS (MAge = 10.59, SDAge = 1.33) and 41 typically developing controls (MAge = 10.26, SDAge = 2.21). We first compared GABA+ and Glx levels of these brain regions between groups. We then explored the association between regional GABA+ and Glx levels with urge and tic severity. Results. GABA+ and Glx of the right SM1, SMA and insula were comparable between the children with TS and typically developing controls. In children with TS, lower levels of SMA GABA+ was associated with more severe and more frequent premonitory urges. Neither GABA+ nor Glx levels were associated with tic severity. Conclusions. These results broadly support the role of GABAergic neurotransmission within the SMA in the experience of premonitory urges in children with TS.