Stewart H. Mostofsky

Purpose: Attention‐deficit/hyperactivity disorder (ADHD) is a highly prevalent and heterogeneous neurodevelopmental condition for which current diagnostic approaches rely on symptom‐based classifications that do not capture underlying neurobiology. This study examined whether transcranial magnetic stimulation (TMS) measures of motor cortex physiology could identify biologically meaningful ADHD subtypes and their associated neurocognitive profiles. Methods: A sample of 176 children ages 8–12 years (82 ADHD; 94 neurotypical controls) completed clinical assessments, cognitive and motor tasks, and TMS protocols. Three TMS metrics, resting motor threshold (RMT) and task‐related up‐modulation (TRUM) during response execution and inhibition, were used in hierarchical cluster analyses. Results: Results identified three primary ADHD clusters, each defined by distinct neurocognitive profiles. Despite comparable ADHD symptom severity across clusters, differences emerged in cognitive, motor, and behavioral domains. ADHD‐1 (low RMT, low TRUM) showed slower reaction times, suggesting inefficient motor initiation. ADHD‐2 (high RMT, intermediate TRUM) exhibited the greatest impairments in working memory, motor control, and attention, consistent with deficits in executive functioning. ADHD‐3 (intermediate RMT, high TRUM) demonstrated elevated oppositional symptoms, indicating increased behavioral dysregulation. Conclusion: These findings provide proof‐of‐concept that TMS‐derived measurements can parse heterogeneity within ADHD beyond traditional clinical symptom measures. RMT and TRUM appear to capture complementary aspects of cortical excitability and dynamic modulation, offering potential biomarkers for ADHD subtyping. This approach may support future precision medicine efforts by linking neurophysiological mechanisms to targeted interventions.

Background and Objectives: Children with autism spectrum disorder (ASD) often experience challenges integrating visual information to guide motor behavior, particularly in dynamic (speeded) contexts. We investigated the effects of varying stimulus tracking speed on visual‐motor integration (VMI), addressing our hypothesis that ASD diagnosis and symptom severity would be associated with impaired performance on dynamic, speeded (vs. slow/static) VMI. Methods: Fifty‐four children aged 8–12 years (ASD: n = 16; typically developing [TD] controls: n = 38) successfully completed a continuous grip‐force tracking task involving three conditions: static, slow, and fast visual trajectories. A linear mixed‐effects model was used to examine the effects of ASD (vs. TD) diagnosis on speeded VMI. We further examined the correlation between speeded VMI and both clinician‐rated (Autism Diagnostic Observation Schedule, Second Edition [ADOS‐2]) and parent‐reported Social Responsiveness Scales, Second Edition (SRS‐2) autism symptoms. Results: A significant interaction between diagnosis and condition was observed ( p = 0.03), indicating that group differences in tracking accuracy varied by stimulus speed. Children with ASD showed significantly greater tracking error than TD peers in the fast condition (ASD: 13.5 ± 1.0 [95% CI: 11.3–15.7]; TD: 10.5 ± 0.7 [95% CI: 9.1–12.0]; p = 0.02), but not in the static ( p = 0.80) or slow ( p = 0.55) conditions. Both groups showed increased error as speed increased, but the ASD group showed greater impairment under speeded conditions. Higher ADOS‐2 Total scores predicted greater error in the fast versus slow ( p = 0.009) and fast versus static ( p = 0.06) contrasts and in the fast condition alone ( p = 0.02). Elevated SRS‐2 Total scores were similarly associated with greater error in the fast versus slow ( p = 0.02) and fast versus static ( p = 0.02) comparisons, though not in the fast condition alone ( p = 0.23). Discussion: The findings support difficulty with speeded dynamic VMI as a scalable autism biomarker. Further development of these biomarkers could be helpful to guiding behavioral interventions, for instance, identifying children who would best respond to slowing visual cues during therapy. Future studies should refine assessment tools to extend assessments of dynamic VMI to younger and more affected children and explore developmentally appropriate interventions tailored for children showing difficulties with speeded VMI.

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.

An overreliance on proprioceptive (intrinsic) sensory input from the body, compared to visual (extrinsic) input from the environment, may underpin core features of autism spectrum disorder (ASD). We developed an engaging videogame (“HaptiKart”) as a tool to examine differences in sensory-motor bias (proprioceptive vs. visual) in children and adults with ASD and whether bias correlates with age, core autism features, and intellectual ability. Eighty-one participants (33 ASD, 48 typically-developing, TD) aged 8 to 31 years played “HaptiKart,” a driving videogame with a force-feedback steering wheel that provided “steering assist” during gameplay. In separate trials, proprioceptive and visual feedback were selectively delayed, and differences in driving error between the conditions were used to calculate perceptual bias scores. Effects of autism diagnosis and age on bias scores were examined, controlling for sex, as were associations of perceptual bias with autism symptom severity (ADOS-2, SRS-2), attention-deficit symptom severity (Conners4 ADHD Total Scores) ratings, and IQ (general ability index, GAI). The ASD group exhibited significantly higher proprioceptive bias than did the TD group (p=0.002). There was a trend for decreasing proprioceptive bias with age, but no significant diagnosis-by-age interaction. Increased proprioceptive bias correlated with higher autism severity and with lower IQ, but not ADHD symptoms. HaptiKart provides a highly scalable approach for measuring sensory-motor bias, revealing that individuals with ASD show elevated proprioceptive bias, correlating with autism severity. HaptiKart’s sensory-motor bias measure may thereby serve as a digital biomarker for addressing autism heterogeneity in ways that can improve targeted intervention. Author Summary: In this study, we explored how people with autism spectrum disorder (ASD) may rely more on body-based (proprioceptive) senses than on visual information when interacting with their surroundings. Using a custom video game, HaptiKart , we designed a fun and engaging driving task to measure this sensory preference. Players drove a virtual car using a steering wheel that could be set to delay either visual or proprioceptive feedback, allowing us to observe how each type of feedback affects driving accuracy. Our results showed that individuals with ASD had a stronger preference for proprioceptive feedback than those without ASD. This sensory preference was linked to greater autism symptom severity and lower IQ, suggesting that heightened reliance on body-centered feedback may contribute to learning and skill differences often seen in autism. These findings support the potential of HaptiKart as a simple, accessible tool to help clinicians better understand and address sensory biases in ASD, tailoring interventions to improve learning from visual information.

Background: Differences in responding to sensory stimuli, including sensory hyperreactivity (HYPER), hyporeactivity (HYPO), and sensory seeking (SEEK) have been observed in autistic individuals across sensory modalities, but few studies have examined the structure of these “supra-modal” traits in the autistic population. Methods: Leveraging a combined sample of 3868 autistic youth drawn from 12 distinct data sources (ages 3–18 years and representing the full range of cognitive ability), the current study used modern psychometric and meta-analytic techniques to interrogate the latent structure and correlates of caregiver-reported HYPER, HYPO, and SEEK within and across sensory modalities. Bifactor statistical indices were used to both evaluate the strength of a “general response pattern” factor for each supra-modal construct and determine the added value of “modality-specific response pattern” scores (e.g., Visual HYPER). Bayesian random-effects integrative data analysis models were used to examine the clinical and demographic correlates of all interpretable HYPER, HYPO, and SEEK (sub)constructs. Results: All modality-specific HYPER subconstructs could be reliably and validly measured, whereas certain modality-specific HYPO and SEEK subconstructs were psychometrically inadequate when measured using existing items. Bifactor analyses supported the validity of a supra-modal HYPER construct (ω_H = .800) but not a supra-modal HYPO construct (ω_H = .653), and supra-modal SEEK models suggested a more limited version of the construct that excluded some sensory modalities (ω_H = .800; 4/7 modalities). Modality-specific subscales demonstrated significant added value for all response patterns. Meta-analytic correlations varied by construct, although sensory features tended to correlate most with other domains of core autism features and co-occurring psychiatric symptoms (with general HYPER and speech HYPO demonstrating the largest numbers of practically significant correlations). Limitations: Conclusions may not be generalizable beyond the specific pool of items used in the current study, which was limited to caregiver report of observable behaviors and excluded multisensory items that reflect many “real-world” sensory experiences. Conclusion: Of the three sensory response patterns, only HYPER demonstrated sufficient evidence for valid interpretation at the supra-modal level, whereas supra-modal HYPO/SEEK constructs demonstrated substantial psychometric limitations. For clinicians and researchers seeking to characterize sensory reactivity in autism, modality-specific response pattern scores may represent viable alternatives that overcome many of these limitations.

To investigate developmental changes in emotion dysregulation (ED) and associated symptoms of emotional lability, irritability, anxiety, and depression, among girls and boys with and without ADHD from childhood through adolescence. Data were collected from a sample of 8–18-year-old children with (n = 264; 76 girls) and without (n = 153; 56 girls) ADHD, with multiple time-points from a subsample of participants (n = 121). Parents and youth completed rating scales assessing child ED, emotional lability, irritability, anxiety, and depression. Mixed effects models were employed to examine effects and interactions of diagnosis, sex [biological sex assigned at birth], age among boys and girls with and without ADHD. Mixed effects analyses showed sexually dimorphic developmental patterns between boys and girls, such that boys with ADHD showed a greater reduction in ED, irritability, and anxiety with age compared to girls with ADHD, whose symptom levels remained elevated relative to TD girls. Depressive symptoms were persistently elevated among girls with ADHD compared to boys with ADHD, whose symptoms decreased with age, relative to same-sex TD peers. While both boys and girls with ADHD showed higher levels of ED during childhood (compared to their sex-matched TD peers), mixed effects analyses revealed substantial sexually dimorphic patterns of emotional symptom change during adolescence: Boys with ADHD showed robust improvements in emotional symptoms from childhood to adolescence while girls with ADHD continued to show high and/or increased levels of ED, emotional lability, irritability, anxiety and depression.

Objectives Preliminary evidence has supported the notion that mindful movement-based practices may offer benefits for self-regulation, particularly for vulnerable children. However, this evidence has principally stemmed from subjective assessments of behavioral change, leaving the underlying mechanisms undetermined. The present study aimed to investigate the efficacy of an in-school mindful movement intervention (MMI) for at-risk children within an urban public school for enhancing motor, cognitive, and emotional-behavioral regulation, including control of disruptive and inattentive behaviors characteristic of ADHD. Method Participants included 38 (age 7–8 years) children who received twice weekly, in-school MMI, including a modified Tai Chi sequence, yoga and biomechanical warm-ups, imaginative play, and reflection. Parent and teacher ratings of disruptive behaviors, and objective measures of motor and cognitive control, were collected at baseline and after 5 months of MMI. Results Significant improvements in teacher ratings of inattentive, hyperactive/impulsive, oppositional, and other disruptive behaviors were observed. Significant improvements were also observed for objective measures of both cognitive control and motor control with particular reductions in both right and left dysrhythmia. Conclusions MMI was associated with improvements across objective and subjective assessments of motor, cognitive, and behavioral control. This proof-of-principle investigation provides preliminary support for the efficacy and feasibility of a novel MMI implemented as part of the school day in an urban school setting with 7–8-year-old children to augment development of at-risk youth.