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.

Sex Differences and Behavioral Associations with Typically Developing Pediatric Regional Cerebellar Gray Matter Volume.

The cerebellum contributes to motor and higher-order control throughout neurodevelopment, with marked growth during childhood. Few studies have investigated differential associations of cerebellar morphometry with function in males and females. The present study examines sex differences in regional cerebellar gray matter volume (GMV) and the moderating effect of sex on the relationship between GMV and motor, cognitive, and emotional functions in a large cohort of typically developing (TD) children. Participants included 371 TD children (123 females, age 8-12 years). A convolutional neural network-based approach was employed for cerebellar parcellation. Volumes were harmonized using ComBat to adjust for hardware-induced variations. Regression analyses examined the effect of sex on GMV and whether sex moderated the relationship between GMV and motor, cognitive, and emotional functions. Males showed larger GMV in right lobules I-V, bilateral lobules VI, crus II/VIIb, and VIII, left lobule X, and vermis regions I-V and VIII-X. Greater motor function correlated with less vermis VI-VII GMV in females. Greater cognitive function correlated with greater left lobule VI GMV in females and less left lobule VI GMV in males. Finally, greater internalizing symptoms correlated with greater bilateral lobule IX GMV in females but less in males. These findings reveal sexually dimorphic patterns of cerebellar structure and associations with motor, cognitive, and emotional functions. Males generally show larger GMV than females. Larger GMV was associated with better cognitive functioning for females and better motor/emotional functioning for males.

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 large 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.

ADHD-related sex differences in frontal lobe white matter microstructure and associations with response control under conditions of varying cognitive load and motivational contingencies.

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.

Sex differences in atypical fronto-subcortical structural connectivity among children with attention-deficit/hyperactivity disorder: Associations with delay discounting.

PURPOSE: Atypical fronto-subcortical neural circuitry has been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD), including connections between prefrontal cortical regions involved in top-down cognitive control and subcortical limbic structures (striatum and amygdala) involved in bottom-up reward and emotional processing. The integrity of fronto-subcortical connections may also relate to interindividual variability in delay discounting, or a preference for smaller, immediate over larger, delayed rewards, which is associated with ADHD, with recent evidence of ADHD-related sex differences. METHODS: We applied diffusion tensor imaging to compare the integrity of the white matter connections within fronto-subcortical tracts among 187 8-12 year-old children either with ADHD ((n = 106; 29 girls) or typically developing (TD) controls ((n = 81; 28 girls). Analyses focused on diagnostic group differences in fractional anisotropy (FA) within fronto-subcortical circuitry implicated in delay discounting, connecting subregions of the striatum (dorsal executive and ventral limbic areas) and amygdala with prefrontal regions of interest (dorsolateral [dlPFC], orbitofrontal [OFC] and anterior cingulate cortex [ACC]), and associations with two behavioral assessments of delay discounting. RESULTS: Children with ADHD showed reduced FA in tracts connecting OFC with ventral striatum, regardless of sex, whereas reduced FA in the OFC-amygdala and ventral ACC-amygdala tracts were specific to boys with ADHD. Across diagnostic groups and sex, reduced FA in the dorsal ACC-executive striatum tract correlated with greater game time delay discounting. CONCLUSIONS: These results suggest a potential neurobiological substrate of heightened delay discounting in children with ADHD and support the need for additional studies including larger sample sizes of girls with ADHD to further elucidate ADHD-related sex differences in these relationships.

Biomarkers of tic severity in children with Tourette syndrome: Motor cortex inhibition measured with transcranial magnetic stimulation.

AIM: To compare transcranial magnetic stimulation (TMS)-derived measures of primary motor cortex (M1) physiology between children with and without Tourette syndrome, and to dimensionally analyze TMS measures with Tourette syndrome-related symptom severity. METHOD: We used a cross-sectional experimental design. Sixty 8- to 12-year-old children participated (30 with Tourette syndrome: three females, mean age 10 years 10 months, standard deviation [SD] 1 year 3 months; 30 typically developing children: seven females, mean age 10 years 7 months, SD 1 year 3 months). In the group with Tourette syndrome, 15 (one female, mean age 10 years 11 months, SD 1 year 3 months) had comorbid attention-deficit/hyperactivity disorder (ADHD), rated with the Conners, Third Edition and the parent-reported ADHD rating scales. Tic severity was rated with the Yale Global Tic Severity Scale and urge severity with the Individualized Premonitory Urge for Tics Scale. M1 short-interval cortical inhibition (SICI) and intracortical facilitation were compared between diagnostic groups and, within the group with Tourette syndrome, correlated with symptom severity using linear mixed-effects models for repeated measures. RESULTS: Accounting for ADHD, we found no difference in SICI or intracortical facilitation in those with Tourette syndrome versus typically developing children (p > 0.1). In the group with Tourette syndrome, reduced M1 SICI predicted greater total (p = 0.012) and global (p = 0.002) tic severity. There were no associations with urge severity (p > 0.5). INTERPRETATION: Reduced M1 SICI is robustly associated with increased tic, but not urge, severity. WHAT THIS PAPER ADDS: Increased tic severity is associated with reduced motor cortex short-interval cortical inhibition (SICI). Children with Tourette syndrome with increased urge severity also show increased tic severity. However, reduced motor cortex SICI is associated with tic, but not urge, severity.

Reduced basal ganglia tissue-iron concentration in school-age children with attention-deficit/hyperactivity disorder is localized to limbic circuitry.

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.

Dissociation in Neural Correlates of Hyperactive/Impulsive vs. Inattentive Symptoms in Attention-Deficit/Hyperactivity Disorder.

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.

Altered white matter diffusivity and subtle motor function in a pilot cohort of adolescents with sports-related concussion.

BACKGROUND AND OBJECTIVE: Adolescents with sports-related concussion (SRC) demonstrate acute and persistent deficits in subtle motor function. However, there is limited research examining related neurological underpinnings. This pilot study examined changes in motor-associated white matter pathways using diffusion tensor imaging (DTI) and their relationship with subtle motor function. METHODS: Twelve adolescents with SRC (12-17 years) within two-weeks post-injury and 13 never-injured neurotypical peers completed DTI scanning. A subset of 6 adolescents with SRC returned for a follow-up visit post-medical clearance from concussion. Subtle motor function was evaluated using the Physical and Neurological Examination of Subtle Signs (PANESS). RESULTS: Adolescents with SRC showed higher mean diffusivity (MD) of the superior corona radiata and greater subtle motor deficits compared to controls. Across all participants, greater subtle motor deficits were associated with higher (more atypical) MD of the superior corona radiata. Preliminary longitudinal analysis indicated reduction in fractional anisotropy of the corpus callosum but no change in the MD of the superior corona radiata from the initial visit to the follow-up visit post-medical clearance. CONCLUSIONS: These findings support preliminary evidence for a brain-behavior relationship between superior corona radiata microstructure and subtle motor deficits in adolescents with SRC that merits further investigation.

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.

Altered cortical activation associated with mirror overflow driven by non-dominant hand movement in attention-deficit/hyperactivity disorder.

Mirror overflow is involuntary movement that accompanies unilateral voluntary movement on the opposite side of the body, and is commonly seen in Attention-Deficit/Hyperactivity Disorder (ADHD). Children with ADHD show asymmetry in mirror overflow between dominant and non-dominant hand, yet there are competing mechanistic accounts of why this occurs. Using EEG during a sequential, unimanual finger-tapping task, we found that children with ADHD exhibited significantly more mirror overflow than typically developing (TD) controls, especially during the tapping of the non-dominant hand. Furthermore, source-level EEG oscillation analysis revealed that children with ADHD showed decreased alpha (8-12 Hz) event-related desynchronization (ERD) compared with controls in both hemispheres, but only during tapping of the non-dominant hand. Moreover, only the ERD ipsilateral to the mirror overflow during non-dominant hand movement correlated with both magnitude of overflow movements and higher ADHD symptom severity (Conners ADHD Hyperactivity/Impulsiveness scale) in children with ADHD. TD controls did not show these relationships. Our findings suggest that EEG differences in finger-tapping in ADHD are related primarily to voluntary movement in the non-dominant hand. Our results are also consistent with the Ipsilateral Corticospinal Tract (CST) Hypothesis, which posits that the atypical persistence of mirror overflow in ADHD may originate in the sensorimotor areas ipsilateral to mirror overflow and be transmitted via non-decussating CST fibers.

The Role of the Cerebellum in Repetitive Behavior Across Species: Childhood Stereotypies and Deer Mice.

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.

Region-specific elevations of glutamate + glutamine correlate with the sensory symptoms of autism spectrum disorders.

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.

Motor cortex modulation and reward in children with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder, the most prevalent developmental disorder in childhood, is a biologically heterogenous condition characterized by impaired attention and impulse control as well as motoric hyperactivity and anomalous motor skill development. Neuropsychological testing often demonstrates impairments in motivation and reward-related decision making in attention-deficit/hyperactivity disorder, believed to indicate dysfunction of the dopamine reward pathway. Development of reliable, non-invasive, easily obtained and quantitative biomarkers correlating with the presence and severity of clinical symptoms and impaired domains of function could aid in identifying meaningful attention-deficit/hyperactivity disorder subgroups and targeting appropriate treatments. To this end, 55 (37 male) 8-12-year-old children with attention-deficit/hyperactivity disorder and 50 (32 male) age-matched, typically-developing controls were enrolled in a transcranial magnetic stimulation protocol-used previously to quantify cortical disinhibition in both attention-deficit/hyperactivity disorder and Parkinson's Disease-with a child-friendly reward motivation task. The primary outcomes were reward task-induced changes in short interval cortical inhibition and up-modulation of motor evoked potential amplitudes, evaluated using mixed model, repeated measure regression. Our results show that both reward cues and reward receipt reduce short-interval cortical inhibition, and that baseline differences by diagnosis (less inhibition in attention-deficit/hyperactivity disorder) were no longer present when reward was cued or received. Similarly, both reward cues and reward receipt up-modulated motor evoked potential amplitudes, but, differentiating the two groups, this Task-Related-Up-Modulation was decreased in children with attention-deficit/hyperactivity disorder. Furthermore, more severe hyperactive/impulsive symptoms correlated significantly with less up-modulation with success in obtaining reward. These results suggest that in children with attention-deficit/hyperactivity disorder, short interval cortical inhibition may reflect baseline deficiencies as well as processes that normalize performance under rewarded conditions. Task-Related-Up-Modulation may reflect general hypo-responsiveness in attention-deficit/hyperactivity disorder to both reward cue and, especially in more hyperactive/impulsive children, to successful reward receipt. These findings support transcranial magnetic stimulation evoked cortical inhibition and task-induced excitability as biomarkers of clinically relevant domains of dysfunction in childhood attention-deficit/hyperactivity disorder.

Relationship between GABA levels and task-dependent cortical excitability in children with attention-deficit/hyperactivity disorder.

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.

Neuropsychiatric disease classification using functional connectomics - results of the connectomics in neuroimaging transfer learning challenge.

Large, open-source datasets, such as the Human Connectome Project and the Autism Brain Imaging Data Exchange, have spurred the development of new and increasingly powerful machine learning approaches for brain connectomics. However, one key question remains: are we capturing biologically relevant and generalizable information about the brain, or are we simply overfitting to the data? To answer this, we organized a scientific challenge, the Connectomics in NeuroImaging Transfer Learning Challenge (CNI-TLC), held in conjunction with MICCAI 2019. CNI-TLC included two classification tasks: (1) diagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD) within a pre-adolescent cohort; and (2) transference of the ADHD model to a related cohort of Autism Spectrum Disorder (ASD) patients with an ADHD comorbidity. In total, 240 resting-state fMRI (rsfMRI) time series averaged according to three standard parcellation atlases, along with clinical diagnosis, were released for training and validation (120 neurotypical controls and 120 ADHD). We also provided Challenge participants with demographic information of age, sex, IQ, and handedness. The second set of 100 subjects (50 neurotypical controls, 25 ADHD, and 25 ASD with ADHD comorbidity) was used for testing. Classification methodologies were submitted in a standardized format as containerized Docker images through ChRIS, an open-source image analysis platform. Utilizing an inclusive approach, we ranked the methods based on 16 metrics: accuracy, area under the curve, F1-score, false discovery rate, false negative rate, false omission rate, false positive rate, geometric mean, informedness, markedness, Matthew's correlation coefficient, negative predictive value, optimized precision, precision, sensitivity, and specificity. The final rank was calculated using the rank product for each participant across all measures. Furthermore, we assessed the calibration curves of each methodology. Five participants submitted their method for evaluation, with one outperforming all other methods in both ADHD and ASD classification. However, further improvements are still needed to reach the clinical translation of functional connectomics. We have kept the CNI-TLC open as a publicly available resource for developing and validating new classification methodologies in the field of connectomics.

Links between parent-reported measures of poor sleep and executive function in childhood autism and attention deficit hyperactivity disorder.

OBJECTIVES: This study sought to assess whether poor sleep is associated with aspects of executive function (EF) among children with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), or typical development (TD), after adjusting for demographic variables, stimulant medications, intelligence, anxiety, inattention, and hyperactivity. DESIGN: Cross-sectional. SETTING: Children recruited through ongoing studies at the Kennedy Krieger Institute. PARTICIPANTS: We studied 735 children (323 TD; 177 ASD; 235 ADHD) aged 8 to 12 years. MEASUREMENTS: We investigated associations of parent-reported sleep measures from the Children's Sleep Habits Questionnaire (CSHQ) with parent-report measures of EF and performance-based processing speed with each clinical population. EF was measured using 8 clinical T scores that fall under 2 domains (behavioral regulation and metacognition) from the Behavior Rating Inventory of EF (BRIEF) and the processing speed index from the Wechsler Intelligence Scale for Children-IV or -V. RESULTS: Higher CSHQ scores were associated with poorer EF on all BRIEF scales, across all child groups, after adjustment for demographic factors, stimulant medications, and IQ. Among children with ADHD, these associations largely remained after adjusting for anxiety. Among those ASD, anxiety partially accounted for these associations, especially for behavioral regulation EF outcomes. Co-occurring symptoms of inattention and hyperactivity/impulsivity further accounted for the associations between sleep and EF. Poor sleep was not significantly associated with processing speed. CONCLUSIONS: Strong links exist between parent-reported poor sleep and executive dysfunction in children with typical development. Targeting anxiety may alleviate executive dysfunction, especially among children with ASD.

Tubulin Polymerization Promoting Protein (TPPP) gene methylation and corpus callosum measures in maltreated children.

The goal of the current study was to evaluate the impact of Tubulin Polymerization Promoting Protein (TPPP) methylation on structural and fractional anisotropy (FA) corpus callosum (CC) measures. TPPP is involved in the development of white matter tracts in the brain and was implicated in stress-related psychiatric disorders in an unbiased whole epigenome methylation study. The cohort included 63 participants (11.73 y/o ±1.91) from a larger study investigating risk and resilience in maltreated children. Voxel-based morphometry (VBM) was used to process the structural data, fractional anisotropy (FA) was determined using an atlas-based approach, and DNA specimens were derived from saliva in two batches using the 450 K (N = 39) and 850 K (N = 24) Illumina arrays, with the data from each batch analyzed separately. After controlling for multiple comparisons and relevant covariates (e.g., demographics, brain volume, cell composition, 3 PCs), 850 K derived TPPP methylation values, in interaction with a dimensional measure of children's trauma experiences, predicted left and right CC body volumes and genu, body and splenium FA (p < .007, all comparisons). The findings in the splenium replicated in subjects with the 450 K data. The results extend prior investigations and suggest a role for TPPP in brain changes associated with stress-related psychiatric disorders.

Increased mirror overflow movements in ADHD are associated with altered EEG alpha/beta band desynchronization.

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).

Response control correlates of anomalous basal ganglia morphology in boys, but not girls, with attention-deficit/hyperactivity disorder.

Anomalous basal ganglia morphology may contribute to deficient motor response control in children with attention-deficit/hyperactivity disorder (ADHD). This study expands upon recent evidence of sex differences in subcortical morphology and motor response control deficits among children with ADHD to examine basal ganglia volume and shape in relation to motor response control. Participants included 8-12 year-old children with ADHD (n = 52, 21 girls) and typically developing (TD) controls (n = 45, 19 girls). High resolution T1-weighted 3D MPRAGE images covering the whole brain were acquired for all participants on a 3 T scanner. Participants performed two computer-based go/no-go tasks that differed in the extent to which working memory was necessary to guide response selection. Shape-based morphometric analyses were performed in addition to traditional volumetric comparisons and correlations with measures of motor response control were examined. Boys with ADHD consistently demonstrated increased commission error rate and response variability, regardless of task demands, suggesting broad response control deficits. In contrast, response control deficits among girls with ADHD varied depending on task demands and performance measures. Volumetric reductions and inward deformation (compression) on the dorsal surface of the globus pallidus and within subregions of the putamen receiving projections from limbic, executive and motor cortices were observed in boys, but not girls, with ADHD relative to TD children. Mediation analyses revealed that putamen and globus pallidus volumes mediated the relationship between diagnosis and commission error rate. Furthermore, reduced volumes of these structures and localized inward deformation within executive and motor circuits correlated with poorer response control, particularly under conditions of increased cognitive load. These findings suggest that anomalous basal ganglia morphology is related to impaired motor response control among boys with ADHD.