Sarah Durston

A neural basis for the development of inhibitory control

The present study explores the neural basis of the development of inhibitory control by combining functional neuroimaging with a parametric manipulation of a go-nogo paradigm. We demonstrate how the maturation of ventral fronto-striatal circuitry underlies the development of this ability. We used event-related fMRI to examine the effect of interference on neural processes involved in inhibitory control in children and adults. Nogo trials were preceded by either 1, 3 or 5 go trials and then compared to one another. Both children and adults showed an increase in errors with increasing interference. Successful response inhibition was associated with stronger activation of prefrontal and parietal regions for children than for adults. In adults, activation in ventral prefrontal regions increased with increasing interference from go trials. Unlike adults, the circuitry appeared to be maximally activated in children when suppressing a behavioral response regardless of the number of preceding responses. Furthermore, activation in ventral fronto-striatal regions correlated with both age and performance. These findings suggest that immature cognition is more susceptible to interference and this is paralleled by maturational differences in underlying fronto-striatal circuitry.

Converging evidence for a fronto-basal-ganglia network for inhibitory control of action and cognition.

Imagine you are at an intersection, waiting for the traffic lights. They turn green, and you are about to press the gas pedal, when suddenly a cyclist swerves into your lane. Before your foot has actually moved, you have to rapidly prevent it from moving as planned. This example highlights the

Anatomical MRI of the developing human brain: what have we learned?

OBJECTIVE To critically review and integrate the existing literature on magnetic resonance imaging (MRI) studies of the normally developing brain in childhood and adolescence and discuss the implications for clinical MRI studies. METHOD Changes in regional brain volume with age and differences between the sexes are summarized from reports in refereed journal articles pertaining to MRI of the developing human brain. RESULTS White matter volume increases with age. Gray matter volumes increase during childhood and then decrease before adulthood. On average, boys have larger brains than girls; after correction for overall brain volume the caudate is relatively larger in girls, and the amygdala is relatively larger in boys. Differences are of clinical interest given gender-related differences in the age of onset, symptomatology, and prevalence noted for nearly all childhood-onset psychiatric disorders. Attention-deficit/hyperactivity disorder is frequently used as an example to demonstrate these points. CONCLUSIONS Understanding the developmental trajectories of normal brain development and differences between the sexes is important for the interpretation of clinical imaging studies.

Magnetic resonance imaging of boys with attention-deficit/hyperactivity disorder and their unaffected siblings

OBJECTIVE To study the influence of increased familial risk for attention-deficit/hyperactivity disorder (ADHD) on brain morphology. METHOD Volumetric cerebral measures based on whole brain magnetic resonance imaging scans from 30 boys with ADHD, 30 of their unaffected siblings, and 30 matched controls were compared. RESULTS Both subjects with ADHD and their unaffected siblings displayed reductions in right prefrontal gray matter and left occipital gray and white matter of up to 9.1% (p < 0.05). Right cerebellar volume was reduced by 4.9% in subjects with ADHD (p = 0.026) but not in their unaffected siblings (p = 0.308). A 4.0% reduction in intracranial volume was found in subjects with ADHD (p = 0.031), while a trend was observed in their unaffected siblings (p = 0.068). CONCLUSIONS The volumetric reductions in cortical gray and white matter in subjects with ADHD are also present in their unaffected siblings, suggesting that they are related to an increased familial risk for the disorder. In contrast, the cerebellum is unaffected in siblings, suggesting that the reduction in volume observed in subjects with ADHD may be more directly related to the pathophysiology of this disorder.

Changes in the developmental trajectories of striatum in autism.

BACKGROUND Repetitive and stereotyped behavior has been associated with striatum in various neuropsychiatric disorders. However, striatal involvement has not yet been shown conclusively in autism. Issues include the use of neuroleptic medication and differences in mean age between samples, where conflicting results may reflect differences in developmental stage between samples. The objective was to examine brain development in a homogeneous sample of subjects with high-functioning autism. METHODS Magnetic resonance measures of brain structure of 188 individuals (99 subjects with high-functioning autism and 89 typically developing, matched control subjects) aged between 6 years and 25 years were compared. Measurements included the volume of brain structures, including striatum, as well as voxel-based assessment of gray matter density. RESULTS Developmental trajectories of the caudate nucleus, putamen, and nucleus accumbens differed between subjects with autism and control subjects. Results were not accounted for by overall changes in brain volume or neuroleptic medication. The development of the caudate nucleus differed from typical most, as its volume increased with age in autism, while it decreased for control subjects. Voxel-based analysis showed that changes in striatum localized to the head of the caudate nucleus. Overall, caudate nucleus volume was associated with repetitive behavior in autism. CONCLUSIONS We report changes in striatal development in autism, while caudate volume is associated with repetitive behaviors. This emphasizes the importance of striatum in the etiology of autism, in particular in the development of repetitive behavior that characterizes the disorder.

Unique developmental trajectories of cortical thickness and surface area

There is evidence that the timing of developmental changes in cortical volume and thickness varies across the brain, although the processes behind these differences are not well understood. In contrast to volume and thickness, the regional developmental trajectories of cortical surface area have not yet been described. The present study used a combined cross-sectional and longitudinal design with 201 MRI-scans (acquired at 1.5-T) from 135 typically developing children and adolescents. Scans were processed using FreeSurfer software and the Desikan-Killiany atlas. Developmental trajectories were estimated using mixed model regression analysis. Within most regions, cortical thickness showed linear decreases with age, whereas both cortical volume and surface area showed curvilinear trajectories. On average, maximum surface area occurred later in development than maximum volume. Global gender differences were more pronounced in cortical volume and surface area than in average thickness. Our findings suggest that developmental trajectories of surface area and thickness differ across the brain, both in their pattern and their timing, and that they also differ from the developmental trajectory of global cortical volume. Taken together, these findings indicate that the development of surface area and thickness is driven by different processes, at least in part.

Caudate Nucleus Is Enlarged in High-Functioning Medication-Naive Subjects with Autism

BACKGROUND Autism is defined by three symptom clusters, including repetitive and stereotyped behavior. Previous studies have implicated basal ganglia in these behaviors. Earlier studies investigating basal ganglia in autism have included subjects on neuroleptics known to affect basal ganglia volumes. Therefore, we investigated these structures in medication-naive subjects with autism. METHODS Volumetric magnetic resonance measures of caudate, putamen, and nucleus accumbens were compared in two independent samples of medication-naive, high-functioning subjects with autism or Asperger syndrome: 1) 21 affected children and adolescents and 21 matched control subjects; and 2) 21 affected adolescents and young adults and 21 matched control subjects. RESULTS Caudate nucleus was enlarged in both samples. This result remained significant after correction for total brain volume. CONCLUSIONS These results implicate caudate nucleus in autism, as an enlargement of this structure was disproportional to an increase in total brain volume in two independent samples of medication-naive subjects with autism.

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

BACKGROUND Neuroimaging 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. METHODS In 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. FINDINGS Our 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). INTERPRETATION With 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. FUNDING National Institutes of Health.

Evidence for a mechanistic model of cognitive control

Abstract A core deficit observed in a number of disorders of childhood is an inability to inhibit or suppress inappropriate thoughts and behaviors (e.g. attention deficit/hyperactivity disorder, obsessive compulsive disorder and Tourettes syndrome). Two regions of the brain that have been implicated in these disorders are the frontal lobes and the basal ganglia. The common problem in inhibitory control and the common brain regions implicated across this range of developmental disorders suggest a single underlying biological mechanism. Yet, the symptomatology observed across these disorders is distinct. A number of parallel circuits that involve basal ganglia and frontal cortex have been described. Each of these basal ganglia thalamocortical circuits controls a different set of cortically mediated behaviors that range from skeletal and eye movements to cognitive and emotional actions. An important neuromodulator in the basal ganglia thalamocortical circuitry is dopamine, particularly at the level of the prefrontal cortex and striatum. These circuits are assumed to facilitate cortically mediated behaviors by inhibiting conflicting behaviors and dopamine is assumed to play a significant neuromodulatory role in these circuits. Accordingly, we have recently developed a model of inhibitory mechanisms whereby the basal ganglia are involved in inhibition of behaviors while the frontal cortex is involved in representing and maintaining the conditions in which we respond or act. Dopamine is suggested to play an important role in the ability to maintain these internal representations against interference. Converging evidence for this model is presented from developmental, clinical, neuroimaging and lesion studies.

Increased gray-matter volume in medication-naive high-functioning children with autism spectrum disorder

BACKGROUND To establish whether high-functioning children with autism spectrum disorder (ASD) have enlarged brains in later childhood, and if so, whether this enlargement is confined to the gray and/or to the white matter and whether it is global or more prominent in specific brain regions. METHOD Brain MRI scans were acquired from 21 medication-naive, high-functioning children with ASD between 7 and 15 years of age and 21 comparison subjects matched for gender, age, IQ, height, weight, handedness, and parental education, but not pubertal status. RESULTS Patients showed a significant increase of 6% in intracranium, total brain, cerebral gray matter, cerebellum, and of more than 40% in lateral and third ventricles compared to controls. The cortical gray-matter volume was evenly affected in all lobes. After correction for brain volume, ventricular volumes remained significantly larger in patients. CONCLUSIONS High-functioning children with ASD showed a global increase in gray-matter, but not white-matter and cerebellar volume, proportional to the increase in brain volume, and a disproportional increase in ventricular volumes, still present after correction for brain volume. Advanced pubertal development in the patients compared to the age-matched controls may have contributed to the findings reported in the present study.