Leanne Tamm

Maturation of brain function associated with response inhibition.

OBJECTIVE To investigate the developmental trajectory of response inhibition and, more specifically, whether there is a dissociation of function in the prefrontal cortex over the course of development of executive function and associated response inhibition abilities. METHOD Nineteen typically developing subjects, ranging in age from 8 to 20, performed a Go/NoGo task while behavioral and functional magnetic resonance imaging (fMRI) data were collected. RESULTS All subjects performed the task with few errors of omission and commission. No relationship between accuracy and age emerged, but the ability to inhibit responses significantly improved with age. Analyses of fMRI data revealed a positive correlation between activation and age in the left inferior frontal gyrus/insula/orbitofrontal gyrus, and a negative correlation between activation and age in the left middle/superior frontal gyri. CONCLUSION These data provide the first evidence of dissociable processes occurring in the prefrontal cortex during development of executive functions associated with response inhibition: (1) Younger subjects activate more extensively than older subjects in discrete regions of the prefrontal cortex, presumably due to increased demands and inefficient recruitment of brain regions subserving executive functions including working memory. (2) Older subjects show increasingly focal activation in specific regions thought to play a more critical role in response inhibition.

Effect of Stimulant Medication on Children with Attention Deficit Disorder: A “Review of Reviews”

The University of California, Irvine ADD Center recently conducted a synthesis of the literature on the use of stimulants with children with attention deficit disorder (ADD), using a unique “review of reviews” methodology. In this article, we compare three reviews from each of three review types (traditional, meta-analytic, general audience) and illustrate how coding variables can highlight sources of divergence. In general, divergent conclusions stemmed from variations in goal rather than from variations in the sources selected to review. Across quantitative reviews, the average effect size for symptomatic improvement (.83) was twice that for benefits on IQ and achievement measures (.35). A summary of what should and should not be expected of the use of stimulants with ADD children, derived from the literature synthesis, is provided.

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.

Reaction Time Variability in ADHD: A Review

For the past decade, intra-individual variability in reaction times on computerized tasks has become a central focus of cognitive research on Attention-Deficit/Hyperactivity Disorder (ADHD). Numerous studies document increased reaction time variability among children and adults with ADHD, relative to typically developing controls. However, direct comparisons with other disorders with heightened reaction time variability are virtually nonexistent, despite their potential to inform our understanding of the phenomenon. A growing literature examines the sensitivity of reaction time variability to theoretically and clinically relevant manipulations. There is strong evidence that stimulus treatment reduces reaction time variability during a range of cognitive tasks, but the literature is mixed regarding the impact of motivational incentives and variation in stimulus event rate. Most studies of reaction time variability implicitly assume that heightened reaction time variability reflects occasional lapses in attention, and the dominant neurophysiological interpretation suggests this variability is linked to intrusions of task-negative brain network activity during task performance. Work examining the behavioral and neurophysiological correlates of reaction time variability provides some support for these hypotheses, but considerably more work is needed in this area. Finally, because conclusions from each of domains reviewed are limited by the wide range of measures used to measure reaction time variability, this review highlights the need for increased attention to the cognitive and motivational context in which variability is assessed and recommends that future work always supplement macro-level variability indices with metrics that isolate particular components of reaction time variability.

Experimental cross-validation of DSM-IV types of attention-deficit/hyperactivity disorder.

OBJECTIVE To examine the discriminant validity of DSM-IV attention-deficit/hyperactivity disorder (ADHD) types by testing the hypothesis that types are associated with specific kinds of functional impairment and to compare overlap of DSM-IV and DSM-III-R ADHD. METHOD Consecutive referrals (n = 692) to a pediatric subspecialty clinic for ADHD were classified into 1 of each of the 3 DSM-IV types of ADHD using parent and teacher checklist ratings of ADHD symptoms. The resulting types were compared on clinical correlates and on whether the children also met criteria for DSM-III-R ADHD. RESULTS The validity of DSM-IV types was supported by dimension-specific impairment and other distinct correlates. Academic problems aggregated in the 2 types defined by extreme inattention, and externalizing problems aggregated in the 2 types defined by extreme hyperactivity. CONCLUSION DSM-IV appeared superior to DSM-III-R in subcategorical homogeneity and in exhaustiveness (ability to classify all apparent cases).

Responsiveness of children with attention deficit-hyperactivity disorder to reward and response cost: Differential impact on performance and motivation

Using a within-subject design and both high- and low-interest tasks, this study examined the effects of reward (R), response cost (RC), and no contingency (NR) on performance and motivation of 22 children with attention deficit-hyperactivity disorder (ADHD) and 22 controls. Dependent variables included performance measures, self-rated performance and motivation, and a new measure of behavioral motivation based on a 2-min postcontingency task. Both contingencies benefited some aspects of the performance of ADHD children; relative to R, RC showed stronger effects but at the expense of decreased self-rated motivation on the low-interest task. The performance of controls did not differ across tasks, whereas ADHD children performed relatively better on the high-interest task. Neither contingency decreased motivation measures relative to NR for either group. For ADHD children, motivational effects appeared to be influenced by self-perceptions of performance.

Comparison of fMRI activation at 3 and 1.5 T during perceptual, cognitive, and affective processing

Previous studies comparing fMRI data acquired at 1.5 T and higher field strengths have focused on examining signal increases in the visual and motor cortices. No information is, however, available on the relative gain, or the comparability of data, obtained at higher field strengths for other brain regions such as the prefrontal and other association cortices. In the present study, we investigated fMRI activation at 1.5 and 3 T during visual perception, visuospatial working memory, and affect-processing tasks. A 23% increase in striate and extrastriate activation volume was observed at 3 T compared with that for 1.5 T during the visual perception task. During the working memory task significant increases in activation volume were observed in frontal and parietal association cortices as well as subcortical structures, including the caudate, globus pallidus, putamen, and thalamus. Increases in working memory-related activation volume of 82, 73, 83, and 36% were observed in the left frontal, right frontal, left parietal, and right parietal lobes, respectively, for 3 T compared with 1.5 T. These increases were characterized by increased activation at 3 T in several prefrontal and parietal cortex regions that showed activation at 1.5 T. More importantly, at 3 T, activation was detected in several regions, such as the ventral aspects of the inferior frontal gyrus, orbitofrontal gyrus, and lingual gyrus, which did not show significant activation at 1.5 T. No difference in height or extent of activation was detected between the two scanners in the amygdala during affect processing. Signal dropout in the amygdala from susceptibility artifact was greater at 3 T, with a 12% dropout at 3 T compared with a 9% dropout at 1.5 T. The spatial smoothness of T2* images was greater at 3 T by less than 1 mm, suggesting that the greater extent of activation at 3 T beyond these spatial scales was not due primarily to increased intrinsic spatial correlations at 3 T. Rather, the increase in percentage of voxels activated reflects increased sensitivity for detection of brain activation at higher field strength. In summary, our findings suggest that functional imaging of prefrontal and other association cortices can benefit significantly from higher magnetic field strength.

fMRI Study of Cognitive Interference Processing in Females with Fragile X Syndrome

Females with fragile X syndrome, the most common form of inherited developmental and learning problems, are known to be impaired in executive function. The current study is the first to investigate the performance of females with fragile X on a cognitive interference task utilizing functional magnetic resonance imaging (fMRI). Fourteen females with fragile X and 14 age-matched healthy controls were imaged while they performed a counting Stroop interference task. Compared to controls, females with fragile X appeared to have longer reaction times during the interference condition of the task, and adopted a strategy trading speed for accuracy. Females with fragile X also had a significantly different pattern of activation than controls. Whereas controls showed significant activation in the inferior/ middle frontal gyrus and inferior/superior parietal lobe, females with fragile X showed more extensive activation in the anterior region of the prefrontal cortex, and failed to show expected activation in the inferior/superior parietal lobe. Further, between-group analyses revealed that females with fragile X had reduced activation in the left orbitofrontal gyrus, thought to be involved in modulating goal-directed behavior. Females with fragile X also demonstrated a markedly different pattern of deactivation from controls. These findings suggest that deficits in cognitive interference processing during the counting Stroop task observed in females with fragile X may arise from inability to appropriately recruit and modulate lateral prefrontal and parietal resources.

Randomized Controlled Trial of Osmotic-Release Methylphenidate with Cognitive-Behavioral Therapy in Adolescents with Attention-Deficit/Hyperactivity Disorder and Substance Use Disorders.

OBJECTIVE To evaluate the efficacy and safety of osmotic-release methylphenidate (OROS-MPH) compared with placebo for attention-deficit/hyperactivity disorder (ADHD), and the impact on substance treatment outcomes in adolescents concurrently receiving cognitive-behavioral therapy (CBT) for substance use disorders (SUD). METHOD This was a 16-week, randomized, controlled, multi-site trial of OROS-MPH + CBT versus placebo + CBT in 303 adolescents (aged 13 through 18 years) meeting DSM-IV diagnostic criteria for ADHD and SUD. Primary outcome measures included the following: for ADHD, clinician-administered ADHD Rating Scale (ADHD-RS), adolescent informant; for substance use, adolescent-reported days of use in the past 28 days. Secondary outcome measures included parent ADHD-RS and weekly urine drug screens (UDS). RESULTS There were no group differences on reduction in ADHD-RS scores (OROS-MPH: -19.2, 95% confidence interval [CI], -17.1 to -21.2; placebo, -21.2, 95% CI, -19.1 to -23.2) or reduction in days of substance use (OROS-MPH: -5.7 days, 95% CI, 4.0-7.4; placebo: -5.2 days, 95% CI, 3.5-7.0). Some secondary outcomes favored OROS-MPH, including lower parent ADHD-RS scores at 8 (mean difference = 4.4, 95% CI, 0.8-7.9) and 16 weeks (mean difference =6.9; 95% CI, 2.9-10.9) and more negative UDS in OROS-MPH (mean = 3.8) compared with placebo (mean = 2.8; p = .04). CONCLUSIONS OROS-MPH did not show greater efficacy than placebo for ADHD or on reduction in substance use in adolescents concurrently receiving individual CBT for co-occurring SUD. However, OROS-MPH was relatively well tolerated and was associated with modestly greater clinical improvement on some secondary ADHD and substance outcome measures. Clinical Trial Registration Information-Attention Deficit Hyperactivity Disorder (ADHD) in Adolescents with Substance Use Disorders (SUD); http://www.clinicaltrials.gov; NCT00264797.

Abnormal prefrontal cortex function during response inhibition in Turner syndrome: functional magnetic resonance imaging evidence.

BACKGROUND Turner syndrome (TuS) arises from the partial or complete absence of one X chromosome. Although neuropsychological studies report impaired attentional function and response inhibition in TuS, the neural correlates of these cognitive problems are unknown. METHODS Eleven female subjects with TuS and 11 individually matched normal control subjects were imaged using functional magnetic resonance imaging while performing a Go/NoGo task. RESULTS Groups did not differ on accuracy or reaction time; however, the TuS group activated more in the bilateral superior and middle frontal gyri than control subjects. Control subjects did not activate more than the TuS group in any region. CONCLUSION These findings suggest that female subjects with TuS compensate for executive dysfunction via recruitment of additional prefrontal cortex regions involved in inhibition, attention, and working memory, functions necessary for successful performance of Go/NoGo tasks. Elucidating brain function in TuS will advance our understanding of the influence of X-chromosome genes on neurodevelopment and brain function and contribute to planning future intervention strategies.