Subcortico-Cortical Dysconnectivity in ADHD: A Voxel-Wise Mega-Analysis Across Multiple Cohorts.

OBJECTIVE: A large body of functional MRI research has examined a potential role for subcortico-cortical loops in the pathogenesis of attention deficit hyperactivity disorder (ADHD), but has produced inconsistent findings. The authors performed a mega-analysis of six neuroimaging data sets to examine associations between ADHD diagnosis and traits and subcortico-cortical connectivity. METHODS: Group differences were examined in the functional connectivity of four subcortical seeds in 1,696 youths with ADHD diagnoses (66.39% males; mean age, 10.83 years [SD=2.17]) and 6,737 unaffected control subjects (47.05% males; mean age, 10.33 years [SD=1.30]). The authors examined associations between functional connectivity and ADHD traits (total N=9,890; 50.3% males; mean age, 10.77 years [SD=1.96]). Sensitivity analyses were used to examine specificity relative to commonly comorbid internalizing and non-ADHD externalizing problems. The authors further examined results within motion-matched subsamples, and after adjusting for estimated intelligence. RESULTS: In the group comparison, youths with ADHD showed greater connectivity between striatal seeds and temporal, fronto-insular, and supplementary motor regions, as well as between the amygdala and dorsal anterior cingulate cortex, compared with control subjects. Similar findings emerged when ADHD traits were considered and when alternative seed definitions were adopted. Dominant associations centered on the connectivity of the caudate bilaterally. Findings were not driven by in-scanner motion and were not shared with commonly comorbid internalizing and externalizing problems. Effect sizes were small (largest peak d, 0.15). CONCLUSIONS: The findings from this large-scale mega-analysis support established links with subcortico-cortical circuits, which were robust to potential confounders. However, effect sizes were small, and it seems likely that resting-state subcortico-cortical connectivity can capture only a fraction of the complex pathophysiology of ADHD.

Exposure and response prevention versus stress management training for adults and adolescents with obsessive compulsive disorder: A randomized clinical trial.

OBJECTIVE: Though exposure and response prevention (ERP) is a well-proven treatment for OCD across the lifespan, prior RCTs have not studied adolescent and adult patients with the same ERP protocol relative to an active comparator that controls for non-specific effects of treatment. This approach assesses differences in the effect of OCD-specific exposures in affected adolescents and adults and in response to ERP compared to a stress-management control therapy (SMT). METHODS: This assessor-blinded, parallel, 2-arm, randomized, ambulatory clinical superiority trial randomized adolescents (aged 12-18) and adults (24-46) with OCD (N = 126) to 12 weekly sessions of ERP or SMT. OCD severity was measured before, during and after treatment using the child or adult version of the Yale-Brown Obsessive Compulsive Scale (C/Y-BOCS), depending on participant age. We predicted that ERP would produce greater improvement in OCD symptoms than SMT and that there would be no significant post-treatment differences across age groups. RESULTS: ERP (n = 63) produced significantly greater improvements on C/Y-BOCS scores at post-treatment than SMT (n = 63) (Effect size = -0.72, CI = -0.52 to -0.91, p < .001). ERP also produced more treatment responders (ERP = 86%, SMT = 32%; χ2 = 46.37, p < .001) and remitters than SMT (ERP = 39%, SMT = 7%; χ2 = 16.14, p < .001). Finally, there were no statistically significant post-treatment differences in C/Y-BOCS scores between adolescents and adults assigned to ERP. CONCLUSION: A single ERP protocol is superior to SMT in treating both adolescents and adults with OCD. OCD-specific therapy is necessary across the lifespan for optimal outcomes in this highly disabling disorder, though non-specific treatments like SMT are still all-too-commonly provided.

Longitudinal trajectories of childhood and adolescent attention deficit hyperactivity disorder diagnoses in three cohorts.

Background: Attention deficit/hyperactivity disorder (ADHD) is usually conceptualized as a childhood-onset neurodevelopmental disorder, in which symptoms either decrease steadily into adulthood or remain stable. A recent study challenged this view, reporting that for most with ADHD, diagnostic status fluctuates with age. We ask if such a 'fluctuating' ADHD symptom trajectory subgroup is present in other population-based and clinic-based cohorts, centered on childhood and adolescence. Methods: Cohorts were the population-based Adolescent Brain Cognitive Development (ABCD: N = 9735), Neurobehavioral Clinical Research (NCR: N = 258), and the Nathan Kline Institute-Rockland (NKI-Rockland: N = 149). All participants had three or more assessments spanning different age windows. Participants were categorized into developmental diagnostic subgroups: fluctuant ADHD (defined by two or more switches between meeting and not meeting ADHD criteria), remitting ADHD, persisting ADHD, emerging ADHD and never affected. Data were collected between 2011 and 2022. Analyses were performed between May 2022 and April 2023. Findings: A subgroup with fluctuant child and adolescent ADHD diagnoses was found in all cohorts (29.3% of participants with ADHD in ABCD, 26.6% in NCR and 17% in NKI-Rockland). While the proportion of those with fluctuant ADHD increased with the number of assessments, it never constituted the dominant subgroup. Interpretation: We provide further evidence in three cohorts for the existence of a fluctuant ADHD diagnostic subgroup during childhood and adolescence, albeit in a minority of cases. Such fluctuant child and adolescent ADHD diagnoses may suggest a natural history more akin to relapsing-remitting mood disorders and/or a marked sensitivity to environmental shifts that occur across development. Funding: Intramural programs of the NHGRI and NIMH.

Disorder-specific cingulo-opercular network hyperconnectivity in pediatric OCD relative to pediatric anxiety.

BACKGROUND: Prior investigation of adult patients with obsessive compulsive disorder (OCD) has found greater functional connectivity within orbitofrontal-striatal-thalamic (OST) circuitry, as well as altered connectivity within and between large-scale brain networks such as the cingulo-opercular network (CON) and default mode network (DMN), relative to controls. However, as adult OCD patients often have high rates of co-morbid anxiety and long durations of illness, little is known about the functional connectivity of these networks in relation to OCD specifically, or in young patients near illness onset. METHODS: In this study, unmedicated female patients with OCD (ages 8-21 years, n = 23) were compared to age-matched female patients with anxiety disorders (n = 26), and healthy female youth (n = 44). Resting-state functional connectivity was used to determine the strength of functional connectivity within and between OST, CON, and DMN. RESULTS: Functional connectivity within the CON was significantly greater in the OCD group as compared to the anxiety and healthy control groups. Additionally, the OCD group displayed greater functional connectivity between OST and CON compared to the other two groups, which did not differ significantly from each other. CONCLUSIONS: Our findings indicate that previously noted network connectivity differences in pediatric patients with OCD were likely not attributable to co-morbid anxiety disorders. Moreover, these results suggest that specific patterns of hyperconnectivity within CON and between CON and OST circuitry may characterize OCD relative to non-OCD anxiety disorders in youth. This study improves understanding of network dysfunction underlying pediatric OCD as compared to pediatric anxiety.

Defining brain-based OCD patient profiles using task-based fMRI and unsupervised machine learning.

While much research has highlighted phenotypic heterogeneity in obsessive compulsive disorder (OCD), less work has focused on heterogeneity in neural activity. Conventional neuroimaging approaches rely on group averages that assume homogenous patient populations. If subgroups are present, these approaches can increase variability and can lead to discrepancies in the literature. They can also obscure differences between various subgroups. To address this issue, we used unsupervised machine learning to identify subgroup clusters of patients with OCD who were assessed by task-based fMRI. We predominantly focused on activation of cognitive control and performance monitoring neurocircuits, including three large-scale brain networks that have been implicated in OCD (the frontoparietal network, cingulo-opercular network, and default mode network). Participants were patients with OCD (n = 128) that included both adults (ages 24-45) and adolescents (ages 12-17), as well as unaffected controls (n = 64). Neural assessments included tests of cognitive interference and error processing. We found three patient clusters, reflecting a "normative" cluster that shared a brain activation pattern with unaffected controls (65.9% of clinical participants), as well as an "interference hyperactivity" cluster (15.2% of clinical participants) and an "error hyperactivity" cluster (18.9% of clinical participants). We also related these clusters to demographic and clinical correlates. After post-hoc correction for false discovery rates, the interference hyperactivity cluster showed significantly longer reaction times than the other patient clusters, but no other between-cluster differences in covariates were detected. These findings increase precision in patient characterization, reframe prior neurobehavioral research in OCD, and provide a starting point for neuroimaging-guided treatment selection.

Resting-State Connectivity and Response to Psychotherapy Treatment in Adolescents and Adults With OCD: A Randomized Clinical Trial.

OBJECTIVE: Cortical-subcortical hyperconnectivity related to affective-behavioral integration and cortical network hypoconnectivity related to cognitive control have been demonstrated in obsessive-compulsive disorder (OCD); the study objective was to examine whether these connectivity patterns predict treatment response. METHODS: Adolescents (ages 12-17) and adults (ages 24-45) were randomly assigned to 12 sessions of exposure and response prevention (ERP) or stress management therapy (SMT), an active control. Before treatment, resting-state connectivity of ventromedial prefrontal cortical (vmPFC), cingulo-opercular, frontoparietal, and subcortical regions was assessed with functional MRI. OCD severity was assessed with the Yale-Brown Obsessive Compulsive Scale before, during, and after treatment. Usable fMRI and longitudinal symptom data were obtained from 116 patients (68 female; 54 adolescents; 60 medicated). RESULTS: ERP produced greater decreases in symptom scores than SMT. ERP was selectively associated with less vmPFC-subcortical (caudate and thalamus) connectivity in both age groups and primarily in unmedicated participants. Greater symptom improvement with both ERP and SMT was associated with greater cognitive-control (cingulo-opercular and frontoparietal) and subcortical (putamen) connectivity across age groups. Developmental specificity was observed across ERP and SMT treatments, such that greater improvements with ERP than SMT were associated with greater frontoparietal-subcortical (nucleus accumbens) connectivity in adolescents but greater connectivity between frontoparietal regions in adults. Comparison of response-predictive connections revealed no significant differences compared with a matched healthy control group. CONCLUSIONS: The results suggest that less vmPFC-subcortical connectivity related to affect-influenced behavior may be important for ERP engagement, whereas greater cognitive-control and motor circuit connectivity may generally facilitate response to psychotherapy. Finally, neural predictors of treatment response may differ by age.

Evidence from "big data" for the default-mode hypothesis of ADHD: a mega-analysis of multiple large samples.

We sought to identify resting-state characteristics related to attention deficit/hyperactivity disorder, both as a categorical diagnosis and as a trait feature, using large-scale samples which were processed according to a standardized pipeline. In categorical analyses, we considered 1301 subjects with diagnosed ADHD, contrasted against 1301 unaffected controls (total N = 2602; 1710 males (65.72%); mean age = 10.86 years, sd = 2.05). Cases and controls were 1:1 nearest neighbor matched on in-scanner motion and key demographic variables and drawn from multiple large cohorts. Associations between ADHD-traits and resting-state connectivity were also assessed in a large multi-cohort sample (N = 10,113). ADHD diagnosis was associated with less anticorrelation between the default mode and salience/ventral attention (B = 0.009, t = 3.45, p-FDR = 0.004, d = 0.14, 95% CI = 0.004, 0.014), somatomotor (B = 0.008, t = 3.49, p-FDR = 0.004, d = 0.14, 95% CI = 0.004, 0.013), and dorsal attention networks (B = 0.01, t = 4.28, p-FDR < 0.001, d = 0.17, 95% CI = 0.006, 0.015). These results were robust to sensitivity analyses considering comorbid internalizing problems, externalizing problems and psychostimulant medication. Similar findings were observed when examining ADHD traits, with the largest effect size observed for connectivity between the default mode network and the dorsal attention network (B = 0.0006, t = 5.57, p-FDR < 0.001, partial-r = 0.06, 95% CI = 0.0004, 0.0008). We report significant ADHD-related differences in interactions between the default mode network and task-positive networks, in line with default mode interference models of ADHD. Effect sizes (Cohen's d and partial-r, estimated from the mega-analytic models) were small, indicating subtle group differences. The overlap between the affected brain networks in the clinical and general population samples supports the notion of brain phenotypes operating along an ADHD continuum.

Treatment biomarkers for ADHD: Taking stock and moving forward.

The development of treatment biomarkers for psychiatric disorders has been challenging, particularly for heterogeneous neurodevelopmental conditions such as attention-deficit/hyperactivity disorder (ADHD). Promising findings are also rarely translated into clinical practice, especially with regard to treatment decisions and development of novel treatments. Despite this slow progress, the available neuroimaging, electrophysiological (EEG) and genetic literature provides a solid foundation for biomarker discovery. This article gives an updated review of promising treatment biomarkers for ADHD which may enhance personalized medicine and novel treatment development. The available literature points to promising pre-treatment profiles predicting efficacy of various pharmacological and non-pharmacological treatments for ADHD. These candidate predictive biomarkers, particularly those based on low-cost and non-invasive EEG assessments, show promise for the future stratification of patients to specific treatments. Studies with repeated biomarker assessments further show that different treatments produce distinct changes in brain profiles, which track treatment-related clinical improvements. These candidate monitoring/response biomarkers may aid future monitoring of treatment effects and point to mechanistic targets for novel treatments, such as neurotherapies. Nevertheless, existing research does not support any immediate clinical applications of treatment biomarkers for ADHD. Key barriers are the paucity of replications and external validations, the use of small and homogeneous samples of predominantly White children, and practical limitations, including the cost and technical requirements of biomarker assessments and their unknown feasibility and acceptability for people with ADHD. We conclude with a discussion of future directions and methodological changes to promote clinical translation and enhance personalized treatment decisions for diverse groups of individuals with ADHD.

ADHD and its neurocognitive substrates: A two sample Mendelian randomization study.

Attention-deficit/hyperactivity disorder (ADHD) is associated with a wide array of neural and cognitive features, and other psychiatric disorders, identified mainly through cross-sectional associations studies. However, it is unclear if the disorder is causally associated with these neurocognitive features. Here, we applied a two-sample bidirectional Mendelian randomization (MR) study to summary GWAS data to explore the presence and direction of a causal effect between ADHD and a range of neurocognitive features and other psychiatric disorders. The inverse variance weighted method was used in the main analysis, and two MR methods (MR-Egger, weighted median) were used for robustness checks. We found that genetic risk for ADHD was causally associated with a decreased area of lateral orbitofrontal cortex. Conversely, we found that brain volume and some features of intrinsic functional connectivity had causal effects on ADHD risk. Bidirectional causal links were found between ADHD and adult general intelligence, as well as depression and autistic spectrum disorders. Such work highlights the important ties between ADHD and general cognitive ability, and suggest some neural features, previously merely associated with the disorder, may play a causal role in its pathogenesis.

The Anatomy of Friendship: Neuroanatomic Homophily of the Social Brain among Classroom Friends.

Homophily refers to the tendency to like similar others. Here, we ask if homophily extends to brain structure. Specifically: do children who like one another have more similar brain structures? We hypothesized that neuroanatomic similarity tied to friendship is most likely to pertain to brain regions that support social cognition. To test this hypothesis, we analyzed friendship network data from 1186 children in 49 classrooms. Within each classroom, we identified "friendship distance"-mutual friends, friends-of-friends, and more distantly connected or unconnected children. In total, 125 children (mean age = 7.57 years, 65 females) also had good quality neuroanatomic magnetic resonance imaging scans from which we extracted properties of the "social brain." We found that similarity of the social brain varied by friendship distance: mutual friends showed greater similarity in social brain networks compared with friends-of-friends (ß = 0.65, t = 2.03, P = 0.045) and even more remotely connected peers (ß = 0.77, t = 2.83, P = 0.006); friends-of-friends did not differ from more distantly connected peers (ß = -0.13, t = -0.53, P = 0.6). We report that mutual friends have similar "social brain" networks, adding a neuroanatomic dimension to the adage that "birds of a feather flock together."

An examination of the relationships between attention/deficit hyperactivity disorder symptoms and functional connectivity over time.

Previous cross-sectional work has demonstrated resting-state connectivity abnormalities in children and adolescents with attention/deficit hyperactivity disorder (ADHD) relative to typically developing controls. However, it is unclear to what extent these neural abnormalities confer risk for later symptoms of the disorder, or represent the downstream effects of symptoms on functional connectivity. Here, we studied 167 children and adolescents (mean age at baseline = 10.74 years (SD = 2.54); mean age at follow-up = 13.3 years (SD = 2.48); 56 females) with varying levels of ADHD symptoms, all of whom underwent resting-state functional magnetic resonance imaging and ADHD symptom assessments on two occasions during development. Resting-state functional connectivity was quantified using eigenvector centrality mapping. Using voxelwise cross-lag modeling, we found that less connectivity at baseline within right inferior frontal gyrus was associated with more follow-up symptoms of inattention (significant at an uncorrected cluster-forming threshold of p ≤ 0.001 and a cluster-level familywise error corrected threshold of p < 0.05). Findings suggest that previously reported cross-sectional abnormalities in functional connectivity within inferior frontal gyrus in patients with ADHD may represent a longitudinal risk factor for the disorder, in line with efforts to target this region with novel therapeutic methods.

A Longitudinal Study of Resting-State Connectivity and Response to Psychostimulant Treatment in ADHD.

OBJECTIVE: Psychostimulants are first-line pharmacological treatments for attention deficit hyperactivity disorder (ADHD), although symptom reduction varies widely between patients and these individual differences in treatment response are poorly understood. The authors sought to examine whether the resting-state functional connectivity within and between cingulo-opercular, striato-thalamic, and default mode networks was associated with treatment response to psychostimulant medication, and whether this relationship changed with development. METHODS: Patients with ADHD (N=110; 196 observations; mean age at first observation, 10.83 years, SD=2.2) and typically developing control subjects (N=142; 330 observations; mean age at first observation, 10.49 years, SD=2.81) underwent functional neuroimaging on up to five occasions during development (age range, 6-17 years). For patients, symptoms were assessed on and off psychostimulant medication (methylphenidate-based treatments: N=132 observations, 67%; amphetamine-based treatments: N=64 observations, 33%) using the Diagnostic Interview for Children and Adolescents for parents. Linear mixed-effects models examined whether resting-state connectivity was associated with treatment response and its interaction with age. Comparisons with typically developing control subjects were performed to contextualize any significant associations. RESULTS: Resting-state connectivity within the cingulo-opercular network was associated with a significant interaction between treatment response and age. Specifically, worse responses to treatment compared with better responses to treatment among patients and compared with typically developing control subjects were associated with an atypical increase in cingulo-opercular connectivity with increasing age from childhood to adolescence. CONCLUSIONS: This work delineates how resting-state connectivity may be associated over development with response to psychostimulants in ADHD. Functioning and development within the cingulo-opercular network may warrant further investigation as a contributor to differential response to psychostimulants.

Treatment-Specific Associations Between Brain Activation and Symptom Reduction in OCD Following CBT: A Randomized fMRI Trial.

OBJECTIVE: The authors sought to examine whether brain activity is associated with treatment response to cognitive-behavioral therapy (CBT) in adolescents and adults with obsessive-compulsive disorder (OCD), and whether any associations are treatment specific relative to an active control psychotherapy (stress management therapy; SMT). METHODS: Eighty-seven patients with OCD (age range 12-45 years; 57 female, 39 medicated) were randomly assigned to receive 12 weeks of CBT or SMT. Prior to treatment, functional MRI scans were conducted in patients performing an incentive flanker task, which probes brain activation to both cognitive control and reward processing. Voxelwise linear mixed-effects models examined whether baseline brain activation was differentially associated with change in scores on the Yale-Brown Obsessive Compulsive Scale (standard or Children's version) over the course of CBT or SMT treatment. RESULTS: Within the CBT group, a better treatment response was significantly associated with greater pretreatment activation within the right temporal lobe and rostral anterior cingulate cortex during cognitive control and within the ventromedial prefrontal, orbitofrontal, lateral prefrontal, and amygdala regions during reward processing. In contrast, reduced pretreatment activation within a largely overlapping set of regions was significantly associated with a better treatment response to SMT. CONCLUSIONS: The study findings demonstrate that associations between brain activation and treatment response were treatment specific to CBT relative to a control psychotherapy and that these associations were stable from adolescence to mature adulthood. Such treatment-specific associations are important for the development of biomarkers to personalize treatment in OCD.

Error Processing and Inhibitory Control in Obsessive-Compulsive Disorder: A Meta-analysis Using Statistical Parametric Maps.

BACKGROUND: Error processing and inhibitory control enable the adjustment of behaviors to meet task demands. Functional magnetic resonance imaging studies report brain activation abnormalities in patients with obsessive-compulsive disorder (OCD) during both processes. However, conclusions are limited by inconsistencies in the literature and small sample sizes. Therefore, the aim here was to perform a meta-analysis of the existing literature using unthresholded statistical maps from previous studies. METHODS: A voxelwise seed-based d mapping meta-analysis was performed using t-maps from studies comparing patients with OCD and healthy control subjects (HCs) during error processing and inhibitory control. For the error processing analysis, 239 patients with OCD (120 male; 79 medicated) and 229 HCs (129 male) were included, while the inhibitory control analysis included 245 patients with OCD (120 male; 91 medicated) and 239 HCs (135 male). RESULTS: Patients with OCD, relative to HCs, showed longer inhibitory control reaction time (standardized mean difference = 0.20, p = .03, 95% confidence interval = 0.016, 0.393) and more inhibitory control errors (standardized mean difference = 0.22, p = .02, 95% confidence interval = 0.039, 0.399). In the brain, patients showed hyperactivation in the bilateral dorsal anterior cingulate cortex, supplementary motor area, and pre-supplementary motor area as well as right anterior insula/frontal operculum and anterior lateral prefrontal cortex during error processing but showed hypoactivation during inhibitory control in the rostral and ventral anterior cingulate cortices and bilateral thalamus/caudate, as well as the right anterior insula/frontal operculum, supramarginal gyrus, and medial orbitofrontal cortex (all seed-based d mapping z value >2, p < .001). CONCLUSIONS: A hyperactive error processing mechanism in conjunction with impairments in implementing inhibitory control may underlie deficits in stopping unwanted compulsive behaviors in the disorder.

Frontostriatal Dysfunction During Decision Making in Attention-Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder.

BACKGROUND: The aim of the current paper is to provide the first comparison of computational mechanisms and neurofunctional substrates in adolescents with attention-deficit/hyperactivity disorder (ADHD) and adolescents with obsessive-compulsive disorder (OCD) during decision making under ambiguity. METHODS: Sixteen boys with ADHD, 20 boys with OCD, and 20 matched control subjects (12-18 years of age) completed a functional magnetic resonance imaging version of the Iowa Gambling Task. Brain activation was compared between groups using three-way analysis of covariance. Hierarchical Bayesian analysis was used to compare computational modeling parameters between groups. RESULTS: Patient groups shared reduced choice consistency and relied less on reinforcement learning during decision making relative to control subjects, while adolescents with ADHD alone demonstrated increased reward sensitivity. During advantageous choices, both disorders shared underactivation in ventral striatum, while OCD patients showed disorder-specific underactivation in the ventromedial orbitofrontal cortex. During outcome evaluation, shared underactivation to losses in patients relative to control subjects was found in the medial prefrontal cortex and shared underactivation to wins was found in the left putamen/caudate. ADHD boys showed disorder-specific dysfunction in the right putamen/caudate, which was activated more to losses in patients with ADHD but more to wins in control subjects. CONCLUSIONS: The findings suggest shared deficits in using learned reward expectancies to guide decision making, as well as shared dysfunction in medio-fronto-striato-limbic brain regions. However, findings of unique dysfunction in the ventromedial orbitofrontal cortex in OCD and in the right putamen in ADHD indicate additional, disorder-specific abnormalities and extend similar findings from inhibitory control tasks in the disorders to the domain of decision making under ambiguity.

Neural dysfunction during temporal discounting in paediatric Attention-Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder.

Both Attention-Deficit/Hyperactivity Disorder (ADHD) and Obsessive-Compulsive Disorder (OCD) are associated with choice impulsivity, i.e. the tendency to prefer smaller immediate rewards over larger delayed rewards. However, the extent to which this impulsivity is mediated by shared or distinct underlying neural mechanisms is unclear. Twenty-six boys with ADHD, 20 boys with OCD and 20 matched controls (aged 12-18) completed an fMRI version of an individually adjusted temporal discounting (TD) task which requires choosing between a variable amount of money now or £100 in one week, one month or one year. Activations to immediate and delayed reward choices were compared between groups using a three-way ANCOVA. ADHD patients had steeper discounting rates on the task relative to controls. OCD patients did not differ from controls or patients with ADHD. Patients with ADHD and OCD showed predominantly shared activation deficits during TD in fronto-striato-insular-cerebellar regions responsible for self-control and temporal foresight, suggesting that choice impulsivity is mediated by overlapping neural dysfunctions in both disorders. OCD patients alone showed dysfunction relative to controls in right orbitofrontal and rostrolateral prefrontal cortex, extending previous findings of abnormalities in these regions in OCD to the domain of choice impulsiveness.

Shared and disorder-specific task-positive and default mode network dysfunctions during sustained attention in paediatric Attention-Deficit/Hyperactivity Disorder and obsessive/compulsive disorder.

Patients with Attention-Deficit/Hyperactivity Disorder (ADHD) and obsessive/compulsive disorder (OCD) share problems with sustained attention, and are proposed to share deficits in switching between default mode and task positive networks. The aim of this study was to investigate shared and disorder-specific brain activation abnormalities during sustained attention in the two disorders. Twenty boys with ADHD, 20 boys with OCD and 20 age-matched healthy controls aged between 12 and 18 years completed a functional magnetic resonance imaging (fMRI) version of a parametrically modulated sustained attention task with a progressively increasing sustained attention load. Performance and brain activation were compared between groups. Only ADHD patients were impaired in performance. Group by sustained attention load interaction effects showed that OCD patients had disorder-specific middle anterior cingulate underactivation relative to controls and ADHD patients, while ADHD patients showed disorder-specific underactivation in left dorsolateral prefrontal cortex/dorsal inferior frontal gyrus (IFG). ADHD and OCD patients shared left insula/ventral IFG underactivation and increased activation in posterior default mode network relative to controls, but had disorder-specific overactivation in anterior default mode regions, in dorsal anterior cingulate for ADHD and in anterior ventromedial prefrontal cortex for OCD. In sum, ADHD and OCD patients showed mostly disorder-specific patterns of brain abnormalities in both task positive salience/ventral attention networks with lateral frontal deficits in ADHD and middle ACC deficits in OCD, as well as in their deactivation patterns in medial frontal DMN regions. The findings suggest that attention performance in the two disorders is underpinned by disorder-specific activation patterns.

Real-time fMRI neurofeedback in adolescents with attention deficit hyperactivity disorder.

Attention Deficit Hyperactivity Disorder (ADHD) is associated with poor self-control, underpinned by inferior fronto-striatal deficits. Real-time functional magnetic resonance neurofeedback (rtfMRI-NF) allows participants to gain self-control over dysregulated brain regions. Despite evidence for beneficial effects of electrophysiological-NF on ADHD symptoms, no study has applied the spatially superior rtfMRI-NF neurotherapy to ADHD. A randomized controlled trial tested the efficacy of rtfMRI-NF of right inferior prefrontal cortex (rIFG), a key region that is compromised in ADHD and upregulated with psychostimulants, on improvement of ADHD symptoms, cognition, and inhibitory fMRI activation. To control for region-specificity, an active control group received rtfMRI-NF of the left parahippocampal gyrus (lPHG). Thirty-one ADHD boys were randomly allocated and had to learn to upregulate their target brain region in an average of 11 rtfMRI-NF runs over 2 weeks. Feedback was provided through a video-clip of a rocket that had to be moved up into space. A transfer session without feedback tested learning retention as a proximal measure of transfer to everyday life. Both NF groups showed significant linear activation increases with increasing number of runs in their respective target regions and significant reduction in ADHD symptoms after neurotherapy and at 11-month follow-up. Only the group targeting rIFG, however, showed a transfer effect, which correlated with ADHD symptom reductions, improved at trend level in sustained attention, and showed increased IFG activation during an inhibitory fMRI task. This proof-of-concept study demonstrates for the first time feasibility, safety, and shorter- and longer-term efficacy of rtfMRI-NF of rIFG in adolescents with ADHD. Hum Brain Mapp 38:3190-3209, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Comparative Multimodal Meta-analysis of Structural and Functional Brain Abnormalities in Autism Spectrum Disorder and Obsessive-Compulsive Disorder.

BACKGROUND: Autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD) share inhibitory control deficits possibly underlying poor control over stereotyped and repetitive and compulsive behaviors, respectively. However, it is unclear whether these symptom profiles are mediated by common or distinct neural profiles. This comparative multimodal meta-analysis assessed shared and disorder-specific neuroanatomy and neurofunction of inhibitory functions. METHODS: A comparative meta-analysis of 62 voxel-based morphometry and 26 functional magnetic resonance imaging (fMRI) studies of inhibitory control was conducted comparing gray matter volume and activation abnormalities between patients with ASD (structural MRI: 911; fMRI: 188) and OCD (structural MRI: 928; fMRI: 247) and control subjects. Multimodal meta-analysis compared groups across voxel-based morphometry and fMRI. RESULTS: Both disorders shared reduced function and structure in the rostral and dorsomedial prefrontal cortex including the anterior cingulate. OCD patients had a disorder-specific increase in structure and function of left basal ganglia (BG) and insula relative to control subjects and ASD patients, who had reduced right BG and insula volumes versus OCD patients. In fMRI, ASD patients showed disorder-specific reduced left dorsolateral-prefrontal activation and reduced posterior cingulate deactivation, whereas OCD patients showed temporoparietal underactivation. CONCLUSIONS: The multimodal comparative meta-analysis shows shared and disorder-specific abnormalities. Whereas the rostrodorsomedial prefrontal cortex was smaller in structure and function in both disorders, this was concomitant with increased structure and function in BG and insula in OCD patients, but a reduction in ASD patients, presumably reflecting a disorder-specific frontostriatoinsular dysregulation in OCD in the form of poor frontal control over overactive BG, and a frontostriatoinsular maldevelopment in ASD with reduced structure and function in this network. Disorder-differential mechanisms appear to drive overlapping phenotypes of inhibitory control abnormalities in patients with ASD and OCD.

Structural and Functional Brain Abnormalities in Attention-Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder: A Comparative Meta-analysis.

IMPORTANCE: Patients with attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) share impaired inhibitory control. However, it is unknown whether impairments are mediated by shared or disorder-specific neurostructural and neurofunctional abnormalities. OBJECTIVE: To establish shared and disorder-specific structural, functional, and overlapping multimodal abnormalities in these 2 disorders through a voxel-based meta-analytic comparison of whole-brain gray matter volume (GMV) and functional magnetic resonance imaging (fMRI) studies of inhibition in patients with ADHD and OCD. DATA SOURCES: Literature search using PubMed, ScienceDirect, Web of Knowledge, and Scopus up to September 30, 2015. STUDY SELECTION: Whole-brain voxel-based morphometry (VBM) or fMRI studies during inhibitory control comparing children and adults with ADHD or OCD with controls. DATA EXTRACTION AND SYNTHESIS: Voxel-wise meta-analyses of GMV or fMRI differences were performed using Seed-based d-Mapping. Regional structure and function abnormalities were assessed within each patient group and then a quantitative comparison was performed of abnormalities (relative to controls) between ADHD and OCD. MAIN OUTCOMES AND MEASURES: Meta-analytic disorder-specific and shared abnormalities in GMV, in inhibitory fMRI, and in multimodal functional and structural measures. RESULTS: The search revealed 27 ADHD VBM data sets (including 931 patients with ADHD and 822 controls), 30 OCD VBM data sets (928 patients with OCD and 942 controls), 33 ADHD fMRI data sets (489 patients with ADHD and 591 controls), and 18 OCD fMRI data sets (287 patients with OCD and 284 controls). Patients with ADHD showed disorder-contrasting multimodal structural (left z = 1.904, P < .001; right z = 1.738, P < .001) and functional (left z = 1.447, P < .001; right z = 1.229, P < .001) abnormalities in bilateral basal ganglia/insula, which were decreased in GMV and function in patients with ADHD relative to those with OCD (and controls). In OCD patients, they were enhanced relative to controls. Patients with OCD showed disorder-specific reduced function and structure in rostral and dorsal anterior cingulate/medial prefrontal cortex (fMRI z = 2.113, P < .001; VBM z = 1.622, P < .001), whereas patients with ADHD showed disorder-specific underactivation predominantly in the right ventrolateral prefrontal cortex (z = 1.229, P < .001). Ventromedial prefrontal GMV reduction was shared in both disorders relative to controls. CONCLUSIONS AND RELEVANCE: Shared impairments in inhibitory control, rather than representing a transdiagnostic endophenotype in ADHD and OCD, were associated with disorder-differential functional and structural abnormalities. Patients with ADHD showed smaller and underfunctioning ventrolateral prefrontal/insular-striatal regions whereas patients with OCD showed larger and hyperfunctioning insular-striatal regions that may be poorly controlled by smaller and underfunctioning rostro/dorsal medial prefrontal regions.