Brain glutathione and GABA+ levels in autistic children.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication challenges and repetitive behaviors. Altered neurometabolite levels, including glutathione (GSH) and gamma-aminobutyric acid (GABA), have been proposed as potential contributors to the biology underlying ASD. This study investigated whether cerebral GSH or GABA levels differ between a cohort of children aged 8-12 years with ASD (n = 52) and typically developing children (TDC, n = 49). A comprehensive analysis of GSH and GABA levels in multiple brain regions, including the primary motor cortex (SM1), thalamus (Thal), medial prefrontal cortex (mPFC), and supplementary motor area (SMA), was conducted using single-voxel HERMES MR spectroscopy at 3T. The results revealed no significant differences in cerebral GSH or GABA levels between the ASD and TDC groups across all examined regions. These findings suggest that the concentrations of GSH (an important antioxidant and neuromodulator) and GABA (a major inhibitory neurotransmitter) do not exhibit marked alterations in children with ASD compared to TDC. A statistically significant positive correlation was observed between GABA levels in the SM1 and Thal regions with ADHD inattention scores. No significant correlation was found between metabolite levels and hyper/impulsive scores of ADHD, measures of core ASD symptoms (ADOS-2, SRS-P) or adaptive behavior (ABAS-2). While both GSH and GABA have been implicated in various neurological disorders, the current study provides valuable insights into the specific context of ASD and highlights the need for further research to explore other neurochemical alterations that may contribute to the pathophysiology of this complex disorder.

Mindful Movement Intervention Applied to at Risk Urban School Children for Improving Motor, Cognitive, and Emotional-Behavioral Regulation.

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. Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-022-02063-7.

From urges to tics in children with Tourette syndrome: associations with supplementary motor area GABA and right motor cortex physiology.

Tourette syndrome (TS) is a childhood-onset disorder in which tics are often preceded by premonitory sensory urges. More severe urges correlate with worse tics and can render behavioral therapies less effective. The supplementary motor area (SMA) is a prefrontal region believed to influence tic performance. To determine whether cortical physiological properties correlate with urges and tics, we evaluated, in 8-12-year-old right-handed TS children (n = 17), correlations of urge and tic severity scores and compared both to cortical excitability (CE) and short- and long-interval cortical inhibition (SICI and LICI) in both left and right M1. We also modeled these M1 transcranial magnetic stimulation measures with SMA gamma-amino butyric acid (GABA) levels in TS and typically developing control children (n = 16). Urge intensity correlated strongly with tic scores. More severe urges correlated with lower CE and less LICI in both right and left M1. Unexpectedly, in right M1, lower CE and less LICI correlated with less severe tics. We found that SMA GABA modulation of right, but not left, M1 CE and LICI differed in TS. We conclude that in young children with TS, lower right M1 CE and LICI, modulated by SMA GABA, may reflect compensatory mechanisms to diminish tics in response to premonitory urges.

Psilocybin induces spatially constrained alterations in thalamic functional organizaton and connectivity.

BACKGROUND: Classic psychedelics, such as psilocybin and LSD, and other serotonin 2A receptor (5-HT2AR) agonists evoke acute alterations in perception and cognition. Altered thalamocortical connectivity has been hypothesized to underlie these effects, which is supported by some functional MRI (fMRI) studies. These studies have treated the thalamus as a unitary structure, despite known differential 5-HT2AR expression and functional specificity of different intrathalamic nuclei. Independent Component Analysis (ICA) has been previously used to identify reliable group-level functional subdivisions of the thalamus from resting-state fMRI (rsfMRI) data. We build on these efforts with a novel data-maximizing ICA-based approach to examine psilocybin-induced changes in intrathalamic functional organization and thalamocortical connectivity in individual participants. METHODS: Baseline rsfMRI data (n=38) from healthy individuals with a long-term meditation practice was utilized to generate a statistical template of thalamic functional subdivisions. This template was then applied in a novel ICA-based analysis of the acute effects of psilocybin on intra- and extra-thalamic functional organization and connectivity in follow-up scans from a subset of the same individuals (n=18). We examined correlations with subjective reports of drug effect and compared with a previously reported analytic approach (treating the thalamus as a single functional unit). RESULTS: Several intrathalamic components showed significant psilocybin-induced alterations in spatial organization, with effects of psilocybin largely localized to the mediodorsal and pulvinar nuclei. The magnitude of changes in individual participants correlated with reported subjective effects. These components demonstrated predominant decreases in thalamocortical connectivity, largely with visual and default mode networks. Analysis in which the thalamus is treated as a singular unitary structure showed an overall numerical increase in thalamocortical connectivity, consistent with previous literature using this approach, but this increase did not reach statistical significance. CONCLUSIONS: We utilized a novel analytic approach to discover psilocybin-induced changes in intra- and extra-thalamic functional organization and connectivity of intrathalamic nuclei and cortical networks known to express the 5-HT2AR. These changes were not observed using whole-thalamus analyses, suggesting that psilocybin may cause widespread but modest increases in thalamocortical connectivity that are offset by strong focal decreases in functionally relevant intrathalamic nuclei.

Frequency and Intensity of Premonitory Urges-to-Tic in Tourette Syndrome Is Associated With Supplementary Motor Area GABA+ Levels.

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. OBJECTIVE: The 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. 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 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. RESULTS: GABA+ 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. CONCLUSIONS: These 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.

Subtle Motor Signs as a Biomarker for Mindful Movement Intervention in Children with Attention-Deficit/Hyperactivity Disorder.

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 (ß = 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.

Reduced subcortical volumes among preschool-age girls and boys with ADHD.

Anomalous brain structure and function are implicated in children with attention-deficit/hyperactivity disorder (ADHD). Most neuroimaging research, however, has examined school-aged children, despite the typical onset of symptoms in early childhood. This study compared the volumes of subcortical structures (caudate nucleus, putamen, globus pallidus, and thalamus) among preschoolers with ADHD and typically developing (TD) children. High resolution T1-weighted 3D MPRAGE images covering the whole brain were acquired on a 3T scanner and subcortical volumes were automatically extracted. Analyses were conducted in a total of 87 medication-naïve preschoolers, ages 4-5 years (47 with ADHD, 40 controls; 63% boys). ADHD was diagnosed using modified DSM-IV criteria based on review of developmental history, structured psychiatric interview and caregiver ratings. Compared to typically developing children, subcortical volumes were reduced among preschoolers with ADHD, with largest reductions in the caudate, globus pallidus, and thalamus. Among girls (but not boys) with ADHD, putamen and thalamus volumes were associated with ADHD symptom severity. The observed patterns of subcortical differences in preschoolers with ADHD (larger reductions in girls), contrasted with differences observed among school-aged children, (larger reductions in boys) suggests that children with ADHD show sexual dimorphism in neuroanatomical development that parallels early trajectory of symptom onset and attenuation.

Mindful movement and skilled attention.

Bodily movement has long been employed as a foundation for cultivating mental skills such as attention, self-control or mindfulness, with recent studies documenting the positive impacts of mindful movement training, such as yoga and tai chi. A parallel "mind-body connection" has also been observed in many developmental disorders. We elaborate a spectrum of mindfulness by considering ADHD, in which deficient motor control correlates with impaired (disinhibited) behavioral control contributing to defining features of excessive distractibility and impulsivity. These data provide evidence for an important axis of variation for wellbeing, in which skillful cognitive control covaries with a capacity for skillful movement. We review empirical and theoretical literature on attention, cognitive control, mind wandering, mindfulness and skill learning, endorsing a model of skilled attention in which motor plans, attention, and executive goals are seen as mutually co-defining aspects of skilled behavior that are linked by reciprocal inhibitory and excitatory connections. Thus, any movement training should engage "higher-order" inhibition and selection and develop a repertoire of rehearsed procedures that coordinate goals, attention and motor plans. However, we propose that mindful movement practice may improve the functional quality of rehearsed procedures, cultivating a transferrable skill of attention. We adopt Langer's spectrum of mindful learning that spans from "mindlessness" to engagement with the details of the present task and contrast this with the mental attitudes cultivated in standard mindfulness meditation. We particularly follow Feldenkrais' suggestion that mindful learning of skills for organizing the body in movement might transfer to other forms of mental activity. The results of mindful movement training should be observed in multiple complementary measures, and may have tremendous potential benefit for individuals with ADHD and other populations.

Decreased connectivity and cerebellar activity in autism during motor task performance.

Although motor deficits are common in autism, the neural correlates underlying the disruption of even basic motor execution are unknown. Motor deficits may be some of the earliest identifiable signs of abnormal development and increased understanding of their neural underpinnings may provide insight into autism-associated differences in parallel systems critical for control of more complex behaviour necessary for social and communicative development. Functional magnetic resonance imaging was used to examine neural activation and connectivity during sequential, appositional finger tapping in 13 children, ages 8-12 years, with high-functioning autism (HFA) and 13 typically developing (TD), age- and sex-matched peers. Both groups showed expected primary activations in cortical and subcortical regions associated with motor execution [contralateral primary sensorimotor cortex, contralateral thalamus, ipsilateral cerebellum, supplementary motor area (SMA)]; however, the TD group showed greater activation in the ipsilateral anterior cerebellum, while the HFA group showed greater activation in the SMA. Although activation differences were limited to a subset of regions, children with HFA demonstrated diffusely decreased connectivity across the motor execution network relative to control children. The between-group dissociation of cerebral and cerebellar motor activation represents the first neuroimaging data of motor dysfunction in children with autism, providing insight into potentially abnormal circuits impacting development. Decreased cerebellar activation in the HFA group may reflect difficulty shifting motor execution from cortical regions associated with effortful control to regions associated with habitual execution. Additionally, diffusely decreased connectivity may reflect poor coordination within the circuit necessary for automating patterned motor behaviour. The findings might explain impairments in motor development in autism, as well as abnormal and delayed acquisition of gestures important for socialization and communication.

MRI parcellation of the frontal lobe in boys with attention deficit hyperactivity disorder or Tourette syndrome.

Dysfunction of frontal-striatal-thalamic-frontal circuitry has been hypothesized to underlie both attention deficit hyperactivity disorder (ADHD) and Tourette syndrome (TS). Several research groups have therefore used anatomic magnetic resonance imaging (aMRI) to obtain volumetric measurements of subregions of the frontal lobe in these disorders. Most previous studies have relied on subparcellation methods that utilize callosal landmarks to derive subregions of the frontal lobe. In contrast, we present here an investigation of frontal lobe morphometry in ADHD and TS based on a reliable frontal subparcellation protocol that combines contiguous sulcal/gyral boundaries to derive frontal lobe modules based on prior functional studies. This highly reliable procedure subdivides the frontal lobe into five major modules: prefrontal, premotor, motor (precentral gyrus), anterior cingulate, and deep white matter. The first four modules are also segmented into gray and gyral white matter compartments. The protocol was applied to T1-weighted, SPGR coronal MRI images of 13 school-aged boys with ADHD, 13 boys with TS, and 13 age- and gender-matched controls. In ADHD, we found volumetric reductions in both the gray and white matter of the prefrontal cortex. These findings, in conjunction with previous reports on basal ganglia abnormalities, suggest that prefrontal-striatal pathways may be anomalous in ADHD. In TS, we found volumetric decreases in the left deep frontal white matter. Decreases in deep white matter suggest the presence of abnormalities in long associational and projection fiber bundles in TS. The findings of this study both confirm and extend our knowledge of the neurobiology of ADHD and TS, indicating that the reliable parcellation method presented has the potential of increasing our understanding of the role of the frontal lobe in developmental and psychiatric disorders.