Gustavo Sudre

Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis

BACKGROUNDnNeuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis.nnnMETHODSnIn this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0·0156.nnnFINDINGSnOur sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohens d=-0·15), amygdala (d=-0·19), caudate (d=-0·11), hippocampus (d=-0·11), putamen (d=-0·14), and intracranial volume (d=-0·10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0·95) and thalamus (p=0·39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (<15 years) versus adults (>21 years): in the accumbens (Cohens d=-0·19 vs -0·10), amygdala (d=-0·18 vs -0·14), caudate (d=-0·13 vs -0·07), hippocampus (d=-0·12 vs -0·06), putamen (d=-0·18 vs -0·08), and intracranial volume (d=-0·14 vs 0·01). There was no difference between children and adults for the pallidum (p=0·79) or thalamus (p=0·89). Case-control differences in adults were non-significant (all p>0·03). Psychostimulant medication use (all p>0·15) or symptom scores (all p>0·02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0·5).nnnINTERPRETATIONnWith the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes.nnnFUNDINGnNational Institutes of Health.

White matter microstructure and the variable adult outcome of childhood attention deficit hyperactivity disorder.

Changes in cerebral cortical anatomy have been tied to the clinical course of attention deficit hyperactivity disorder (ADHD). We now ask if alterations in white matter tract microstructure are likewise linked with the adult outcome of childhood ADHD. Seventy-five young adults, 32 with ADHD persisting from childhood and 43 with symptom remission were contrasted against 74 never-affected comparison subjects. Using diffusion tensor imaging, we defined fractional anisotropy, a metric related to white matter microstructure, along with measures of diffusion perpendicular (radial) and parallel (axial) to the axon. Analyses were adjusted for head motion, age and sex, and controlled for multiple comparisons and medication history. Tract-based analyses showed that greater adult inattention, but not hyperactivity–impulsivity, was associated with significantly lower fractional anisotropy in the left uncinate (standardized β=−0.37, t=3.28, p=0.002) and inferior fronto-occipital fasciculi (standardized β=−0.37, t=3.29, p=0.002). The ADHD group with symptoms persisting into adulthood had significantly lower fractional anisotropy than the never-affected controls in these tracts, differences associated with medium to large effect sizes. By contrast, the ADHD group that remitted by adulthood did not differ significantly from controls. The anomalies were found in tracts that connect components of neural systems pertinent to ADHD, such as attention control (inferior fronto-occipital fasciculus) and emotion regulation and the processing of reward (the uncinate fasciculus). Change in radial rather than axial diffusivity was the primary driver of this effect, suggesting pathophysiological processes including altered myelination as future targets for pharmacological and behavioral interventions.

A multicenter study of the early detection of synaptic dysfunction in Mild Cognitive Impairment using Magnetoencephalography-derived functional connectivity

Synaptic disruption is an early pathological sign of the neurodegeneration of Dementia of the Alzheimers type (DAT). The changes in network synchronization are evident in patients with Mild Cognitive Impairment (MCI) at the group level, but there are very few Magnetoencephalography (MEG) studies regarding discrimination at the individual level. In an international multicenter study, we used MEG and functional connectivity metrics to discriminate MCI from normal aging at the individual person level. A labeled sample of features (links) that distinguished MCI patients from controls in a training dataset was used to classify MCI subjects in two testing datasets from four other MEG centers. We identified a pattern of neuronal hypersynchronization in MCI, in which the features that best discriminated MCI were fronto-parietal and interhemispheric links. The hypersynchronization pattern found in the MCI patients was stable across the five different centers, and may be considered an early sign of synaptic disruption and a possible preclinical biomarker for MCI/DAT.

Tracking Brain Development and Dimensional Psychiatric Symptoms in Children: A Longitudinal Population-Based Neuroimaging Study

OBJECTIVEnPsychiatric symptomatology during childhood predicts persistent mental illness later in life. While neuroimaging methodologies are routinely applied cross-sectionally to the study of child and adolescent psychopathology, the nature of the relationship between childhood symptoms and the underlying neurodevelopmental processes remains unclear. The authors used a prospective population-based cohort to delineate the longitudinal relationship between childhood psychiatric problems and brain development.nnnMETHODnA total of 845 children participated in the study. Psychiatric symptoms were measured with the parent-rated Child Behavior Checklist at ages 6 and 10. MRI data were collected at ages 8 and 10. Cross-lagged panel models and linear mixed-effects models were used to determine the associations between psychiatric symptom ratings and quantitative anatomic and white matter microstructural measures over time.nnnRESULTSnHigher ratings for externalizing and internalizing symptoms at baseline predicted smaller increases in both subcortical gray matter volume and global fractional anisotropy over time. The reverse relationship did not hold; thus, baseline measures of gray matter and white matter were not significantly related to changes in symptom ratings over time.nnnCONCLUSIONSnChildren presenting with behavioral problems at an early age show differential subcortical and white matter development. Most neuroimaging models tend to explain brain differences observed in psychopathology as an underlying (causal) neurobiological substrate. However, the present work suggests that future neuroimaging studies showing effects that are pathogenic in nature should additionally explore the possibility of the downstream effects of psychopathology on the brain.

Estimating the Heritability of Structural and Functional Brain Connectivity in Families Affected by Attention-Deficit/Hyperactivity Disorder.

Importance Despite its high heritability, few risk genes have been identified for attention-deficit/hyperactivity disorder (ADHD). Brain-based phenotypes could aid gene discovery. There is a myriad of structural and functional connections that support cognition. Disruption of such connectivity is a key pathophysiologic mechanism for ADHD, and identifying heritable phenotypes within these connections could provide candidates for genomic studies. Objective To identify the structural and functional connections that are heritable and pertinent to ADHD. Design, Setting, and Participants Members of extended multigenerational families enriched for ADHD were evaluated. Structural connectivity was defined by diffusion tensor imaging (DTI) of white matter tract microstructure and functional connectivity through resting-state functional magnetic resonance imaging (rsfMRI). Heritability and association with ADHD symptoms were estimated in 24 extended multigenerational families enriched for ADHD (305 members with clinical phenotyping, 213 with DTI, and 193 with rsfMRI data). Findings were confirmed in 52 nuclear families (132 members with clinical phenotypes, 119 with DTI, and 84 with rsfMRI). The study and data analysis were conducted from April 1, 2010, to September 1, 2016. Results In the 52 nuclear families, 86 individuals (65.2%) were male and the mean (SD) age at imaging was 20.9 (15.0) years; in the 24 multigenerational extended families, 145 individuals (47.5%) were male and mean age at imaging was 30.4 (19.7) years. Microstructural properties of white matter tracts connecting ipsilateral cortical regions and the corpus callosum were significantly heritable, ranging from total additive genetic heritability (h2)u2009=u20090.69 (SE, 0.13; Pu2009=u2009.0000002) for radial diffusivity of the right superior longitudinal fasciculus to h2u2009=u20090.46 (SE, 0.15; Pu2009=u2009.0009) for fractional anisotropy of the right inferior fronto-occipital fasciculus. Association with ADHD symptoms was found in several tracts, most strongly for the right superior longitudinal fasciculus (tu2009=u2009−3.05; Pu2009=u2009.003). Heritable patterns of functional connectivity were detected within the default mode (h2u2009=u20090.36; SE, 0.16; cluster level significance, Pu2009<u2009.002), cognitive control (h2u2009=u20090.32; SE, 0.15; Pu2009<u2009.002), and ventral attention networks (h2u2009=u20090.36; SE, 0.16; Pu2009<u2009.002). In all cases, subregions within each network showed heritable functional connectivity with the rest of that network. More symptoms of hyperactivity/impulsivity (tu2009=u2009−2.63; Pu2009=u2009.008) and inattention (tu2009=u2009−2.34; Pu2009=u2009.02) were associated with decreased functional connectivity within the default mode network. Some cross-modal correlations were purely phenotypic, such as that between axial diffusivity of the right superior longitudinal fasciculus and heritable aspects of the default mode network (phenotypic correlation, &rgr;pu2009=u2009−0.12; Pu2009=u2009.03). A genetic cross-modal correlation was seen between the ventral attention network and radial diffusivity of the right inferior fronto-occipital fasciculus (genetic correlation, &rgr;gu2009=u2009−0.45, Pu2009=u2009.02). Conclusions Analysis of data on multigenerational extended and nuclear families identified the features of structural and functional connectivity that are both significantly heritable and associated with ADHD. In addition, shared genetic factors account for some phenotypic correlations between functional and structural connections. Such work helps to prioritize the facets of the brain’s connectivity for future genomic studies.

Multimodal mapping of the brain’s functional connectivity and the adult outcome of attention deficit hyperactivity disorder

Significance Many children do not simply “outgrow” attention deficit hyperactivity disorder (ADHD). The disorder often persists and affects around one in 40 adults, presenting a major public health challenge. Defining the mechanisms that underpin this variable clinical outcome could stimulate novel approaches to boost recovery in ADHD. We map the brain’s functional architecture in 205 young adults followed clinically since childhood. We find clinically significant inattention persisting from childhood has a disruptive effect on the functional connections within and between the brain’s major networks. These disruptions are similar whether defined through direct observation of neuronal activity or measures of hemodynamic change. By contrast, adults who remit from childhood ADHD showed typical brain connectivity, suggesting convergence toward typical brain function may underpin recovery. We have a limited understanding of why many children with attention deficit hyperactivity disorder do not outgrow the disorder by adulthood. Around 20–30% retain the full syndrome as young adults, and about 50% show partial, rather than complete, remission. Here, to delineate the neurobiology of this variable outcome, we ask if the persistence of childhood symptoms into adulthood impacts on the brain’s functional connectivity. We studied 205 participants followed clinically since childhood. In early adulthood, participants underwent magnetoencephalography (MEG) to measure neuronal activity directly and functional MRI (fMRI) to measure hemodynamic activity during a task-free period (the “resting state”). We found that symptoms of inattention persisting into adulthood were associated with disrupted patterns of typical functional connectivity in both MEG and fMRI. Specifically, those with persistent inattention lost the typical balance of connections within the default mode network (DMN; prominent during introspective thought) and connections between this network and those supporting attention and cognitive control. By contrast, adults whose childhood inattentive symptoms had resolved did not differ significantly from their never-affected peers, both hemodynamically and electrophysiologically. The anomalies in functional connectivity tied to clinically significant inattention centered on midline regions of the DMN in both MEG and fMRI, boosting confidence in a possible pathophysiological role. The findings suggest that the clinical course of this common childhood onset disorder impacts the functional connectivity of the adult brain.

Automated quality assessment of structural magnetic resonance images in children: Comparison with visual inspection and surface-based reconstruction

Motion‐related artifacts are one of the major challenges associated with pediatric neuroimaging. Recent studies have shown a relationship between visual quality ratings of T1 images and cortical reconstruction measures. Automated algorithms offer more precision in quantifying movement‐related artifacts compared to visual inspection. Thus, the goal of this study was to test three different automated quality assessment algorithms for structural MRI scans. The three algorithms included a Fourier‐, integral‐, and a gradient‐based approach which were run on raw T1‐weighted imaging data collected from four different scanners. The four cohorts included a total of 6,662 MRI scans from two waves of the Generation R Study, the NIH NHGRI Study, and the GUSTO Study. Using receiver operating characteristics with visually inspected quality ratings of the T1 images, the area under the curve (AUC) for the gradient algorithm, which performed better than either the integral or Fourier approaches, was 0.95, 0.88, and 0.82 for the Generation R, NHGRI, and GUSTO studies, respectively. For scans of poor initial quality, repeating the scan often resulted in a better quality second image. Finally, we found that even minor differences in automated quality measurements were associated with FreeSurfer derived measures of cortical thickness and surface area, even in scans that were rated as good quality. Our findings suggest that the inclusion of automated quality assessment measures can augment visual inspection and may find use as a covariate in analyses or to identify thresholds to exclude poor quality data.

A multicohort, longitudinal study of cerebellar development in attention deficit hyperactivity disorder

BACKGROUNDnThe cerebellum supports many cognitive functions disrupted in attention deficit hyperactivity disorder (ADHD). Prior neuroanatomic studies have been often limited by small sample sizes, inconsistent findings, and a reliance on cross-sectional data, limiting inferences about cerebellar development. Here, we conduct a multicohort study using longitudinal data, to characterize cerebellar development.nnnMETHODSnGrowth trajectories of the cerebellar vermis, hemispheres and white matter were estimated using piecewise linear regression from 1,656 youth; of whom 63% had longitudinal data, totaling 2,914 scans. Four cohorts participated, all contained childhood data (age 4-12xa0years); two had adolescent data (12-25xa0years). Growth parameters were combined using random-effects meta-analysis.nnnRESULTSnDiagnostic differences in growth were confined to the corpus medullare (cerebellar white matter). Here, the ADHD group showed slower growth in early childhood compared to the typically developing group (left corpus medullare zxa0=xa02.49, pxa0=xa0.01; right zxa0=xa02.03, pxa0=xa0.04). This reversed in late childhood, with faster growth in ADHD in the left corpus medullare (zxa0=xa02.06, pxa0=xa0.04). Findings held when gender, intelligence, comorbidity, and psychostimulant medication were considered.nnnDISCUSSIONnAcross four independent cohorts, containing predominately longitudinal data, we found diagnostic differences in the growth of cerebellar white matter. In ADHD, slower white matter growth in early childhood was followed by faster growth in late childhood. The findings are consistent with the concept of ADHD as a disorder of the brains structural connections, formed partly by developing cortico-cerebellar white matter tracts.

Growing out of attention deficit hyperactivity disorder: Insights from the ‘remitted’ brain

HighlightsWe review neuroimaging studies of adults who have remitted from childhood ADHD.Most studies find adult remitters show neural features indistinguishable from controls.Fewer studies find that remission arises due to compensatory neural re‐organization.Some deep brain anomalies may persist from childhood even in those who remit. Abstract We consider developmental and cognitive models to explain why some children ‘grow out’ of attention deficit hyperactivity disorder (ADHD) by adulthood. The first model views remission as a convergence towards more typical brain function and structure. In support, some studies find that adult remitters are indistinguishable from those who were never affected in the neural substrates of ‘top‐down’ mechanisms of cognitive control, some ‘bottom‐up’ processes of vigilance/response preparation, prefrontal cortical morphology and intrinsic functional connectivity. A second model postulates that remission is driven by the recruitment of new brain systems that compensate for ADHD symptoms. It draws support from demonstrations of atypical, but possibly beneficial, patterns of connectivity within the cognitive control network in adult remitters. The final model holds that some childhood ADHD anomalies show lifelong persistence, regardless of adult outcome, supported by shared reports of anomalies in remitters and persisters in posterior cerebral and striato‐thalamic regions. The models are compatible: different processes driving remission might occur in different brain regions. These models provide a framework for future studies which might inform novel treatments to ‘accelerate’ remission.

The Semantics of Adjective Noun Phrases in the Human Brain

As a person reads, the brain performs complex operations to create higher order semantic representations from individual words. While these steps are effortless for competent readers, we are only beginning to understand how the brain performs these actions. Here, we explore semantic composition using magnetoencephalography (MEG) recordings of people reading adjective-noun phrases presented one word at a time. We track the neural representation of semantic information over time, through different brain regions. Our results reveal two novel findings: 1) a neural representation of the adjective is present during noun presentation, but this neural representation is different from that observed during adjective presentation 2) the neural representation of adjective semantics observed during adjective reading is reactivated after phrase reading, with remarkable consistency. We also note that while the semantic representation of the adjective during the reading of the adjective is very distributed, the later representations are concentrated largely to temporal and frontal areas previously associated with composition. Taken together, these results paint a picture of information flow in the brain as phrases are read and understood.