Yannis Paloyelis

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.

DAT1 and COMT Effects on Delay Discounting and Trait Impulsivity in Male Adolescents with Attention Deficit/Hyperactivity Disorder and Healthy Controls

Choice impulsivity has been linked to dopamine function and is consistently observed in attention deficit/hyperactivity disorder (ADHD) as a preference for smaller-immediate over larger-delayed rewards using choice-delay paradigms. More sophisticated delay discounting paradigms have yielded inconsistent results. Context and sample characteristics may have contributed to these variations. In this study we examine the effect of type (real vs hypothetical) and magnitude of reward as well as of variation in dopamine genes on choice impulsivity. We selected 36 male adolescents with ADHD-combined subtype (ADHD-CT) and 32 controls (mean age=15.42, SD=2.05) to form four roughly equally sized subgroups on the basis of DAT110/6 haplotype dosage (2 copies and <2 copies). Participants, who were also genotyped for the COMTval158met and DRD448bp−VNTR polymorphisms, performed a hypothetical and a real-time discounting task and provided self-ratings of trait impulsivity. The ADHD-CT group discounted rewards more steeply than controls only in the hypothetical task, with delay, but not reward magnitude, influencing choices. They also rated themselves as more impulsive compared with controls. DAT110/6 dosage and the COMTVal158Met genotype predicted trait impulsivity and discounting rates in the hypothetical task, but not in the real-time task. Our results directly link variation in genes putatively influencing dopamine signaling in the prefrontal cortex (COMTVal158Met) and the striatum (DAT110/6) with discounting rates in a hypothetical task (but not a real-time task) and self-ratings of trait impulsivity in ADHD-CT and healthy controls. The lack of magnitude effects in the hypothetical task suggests that discounting in this task may be influenced by different processes in ADHD-CT than in healthy controls.

Functional MRI in ADHD: a systematic literature review.

FMRI research in ADHD is a fast developing and very complex field. Every study appears to show differences in patterns of brain activation between cases and controls, but the interpretation of such differences is not as straightforward as it may seem. We present here a systematic review of the fMRI literature in ADHD; areas covered include executive functions, reward processing, the effects of methylphenidate, comorbidity and spontaneous brain activity in the resting state. To facilitate the interpretation of research in this area, we discuss important conceptual issues, such as the need to take group differences in performance into account or to consider the role of errors. We present common themes that emerge from these studies, and we discuss possible reasons for the many discrepancies that were observed. Finally, based on existing literature and current advancements in fMRI research, we discuss the role that fMRI could play in the future as a diagnostic tool or in treatment outcome predictions, and we make predictions for the future directions of research in this field.Functional MRI (fMRI) research in attention-deficit/hyperactivity disorder (ADHD) is a fast developing and very complex field. Every study appears to show differences in patterns of brain activation between cases and controls, but the interpretation of such differences is not as straightforward as it may seem. We present here a systematic review of the fMRI literature in ADHD; areas covered include executive functions, reward processing, the effects of methylphenidate, comorbidity and spontaneous brain activity in the resting state. To facilitate the interpretation of research in this area, we discuss important conceptual issues, such as the need to take group differences in performance into account or to consider the role of errors. We present common themes that emerge from these studies and we discuss possible reasons for the many discrepancies that were observed. Finally, based on existing literature and current advancements in fMRI research, we discuss the role that fMRI could play in the future as a diagnostic tool or in treatment outcome predictions, and we make predictions for the future directions of research in this field.

Are ADHD symptoms associated with delay aversion or choice impulsivity? A general population study.

OBJECTIVE The term delay aversion has been used both to describe a behavioral tendency of greater preference for smaller-immediate over larger-delayed rewards (choice impulsivity) and to refer to a secondary explanatory construct put forward by delay aversion theory. In this study, we examined the association of attention-deficit/hyperactivity disorder (ADHD) symptoms with choice impulsivity and tested the specific hypothesis derived from delay aversion theory. METHOD A total of 1,062 children aged 7.90 to 10.90 years (49% girls) made a fixed number of repeated choices between a smaller reward delivered immediately and a larger reward delivered after a delay (choice-delay task), under two conditions (including and excluding a postreward delay). We assessed the unique contribution of each ADHD symptom dimension to the prediction of choice impulsivity and delay aversion, controlling for age (or age and IQ). Sex effects were examined. RESULTS : Inattention ratings uniquely predicted preference for smaller-immediate rewards under both task conditions for both sexes. An index of delay aversion was associated with inattention only in boys; the effect size was small yet significant. Hyperactivity-impulsivity ratings were negatively associated with choice impulsivity in girls in the postreward delay condition, whereas no significant association with hyperactivity-impulsivity ratings was observed in boys. Categorical analyses using groups with high ADHD symptoms yielded similar results. CONCLUSIONS This is the first study to report a unique association between inattention symptoms and behavioral measures of choice impulsivity and delay aversion. The findings indicate the importance of the primary constitutional processes that underlie choice impulsivity and their potential role in behavioral inattention. Understanding the behavioral and brain processes underlying choice impulsivity may lead to the improved targeting of behavioral and pharmacological interventions.

A Spatiotemporal Profile of In Vivo Cerebral Blood Flow Changes Following Intranasal Oxytocin in Humans

BACKGROUND Animal and human studies highlight the role of oxytocin in social cognition and behavior and the potential of intranasal oxytocin (IN-OT) to treat social impairment in individuals with neuropsychiatric disorders such as autism. However, extensive efforts to evaluate the central actions and therapeutic efficacy of IN-OT may be marred by the absence of data regarding its temporal dynamics and sites of action in the living human brain. METHODS In a placebo-controlled study, we used arterial spin labeling to measure IN-OT-induced changes in resting regional cerebral blood flow (rCBF) in 32 healthy men. Volunteers were blinded regarding the nature of the compound they received. The rCBF data were acquired 15 min before and up to 78 min after onset of treatment onset (40 IU of IN-OT or placebo). The data were analyzed using mass univariate and multivariate pattern recognition techniques. RESULTS We obtained robust evidence delineating an oxytocinergic network comprising regions expected to express oxytocin receptors, based on histologic evidence, and including core regions of the brain circuitry underpinning social cognition and emotion processing. Pattern recognition on rCBF maps indicated that IN-OT-induced changes were sustained over the entire posttreatment observation interval (25-78 min) and consistent with a pharmacodynamic profile showing a peak response at 39-51 min. CONCLUSIONS Our study provides the first visualization and quantification of IN-OT-induced changes in rCBF in the living human brain unaffected by cognitive, affective, or social manipulations. Our findings can inform theoretical and mechanistic models regarding IN-OT effects on typical and atypical social behavior and guide future experiments (e.g., regarding the timing of experimental manipulations).

Striatal sensitivity during reward processing in attention-deficit/hyperactivity disorder

OBJECTIVE Attention-deficit/hyperactivity disorder (ADHD) has been linked to deficits in the dopaminergic reward-processing circuitry; yet, existing evidence is limited, and the influence of genetic variation affecting dopamine signaling remains unknown. We investigated striatal responsivity to rewards in ADHD combined type (ADHD-CT) using functional magnetic resonance imaging (fMRI), and whether it is modulated by variation in the dopamine transporter gene (DAT1). METHOD We tested 29 male adolescents with ADHD-CT and 30 age-, handedness-, and gender-matched healthy controls who were selected for DAT1(10/6) haplotype dosage. Based on previous research, we focused our analysis on the ventral striatum and the caudate nucleus. RESULTS Three main findings emerged. First, male adolescents with ADHD-CT did not differ from controls in terms of blood oxygen-level dependent (BOLD) fMRI response to reward-predicting cues (gain or loss-avoidance) in the ventral striatum. Second, male adolescents with ADHD-CT showed a relative increase, compared with controls, in the striatal BOLD response to successful outcomes. Third, DAT1(10/6) dosage differentially modulated neural activation to reward-predicting cues in the caudate nucleus in the ADHD-CT and control groups. CONCLUSIONS The findings challenge the idea of a deficit in anticipation-related activation in the ventral striatum in male adolescents with ADHD-CT, while suggesting that the processing of reward outcomes is dysfunctional, consistent with a recent neurobiological model of the disorder. Preliminary evidence suggests that polymorphic variations in genes affecting dopamine signaling need to be taken into consideration when investigating reward-related deficits in ADHD-CT.

Peripheral oxytocin and vasopressin: Biomarkers of psychiatric disorders? A comprehensive systematic review and preliminary meta-analysis

A large array of studies have investigated peripheral oxytocin (OT) and vasopressin (ADH) as potential biomarkers of psychiatric disorders, with highly conflicting and heterogenous findings. We searched Web of KnowledgeSM and Scopus® for English original articles investigating OT and/or ADH levels in different biological fluids (plasma/serum, saliva, urine and cerebrospinal fluid) across several psychiatric disorders. Sixty-four studies were included. We conducted 19 preliminary meta-analyses addressing OT alterations in plasma/serum, saliva, urine and cerebrospinal fluid of 7 psychiatric disorders and ADH alterations in plasma/serum, saliva, urine and cerebrospinal fluid of 6 psychiatric disorders compared to controls. Hedges g was used as effect size measure, together with heterogeneity analyses, test of publication biases and quality control. None of them (except serum OT in anorexia nervosa) revealed significant differences. There is no convincing evidence that peripheral ADH or OT might be reliable biomarkers in psychiatric disorders. However, the lack of significant results was associated with high methodological heterogeneity, low quality of the studies, small sample size, and scarce reliability of the methods used in previous studies, which need to be validated and standardized.

Partners' Empathy Increases Pain Ratings: Effects of Perceived Empathy and Attachment Style on Pain Report and Display

Pain can be influenced by its social context. We aimed to examine under controlled experimental conditions how empathy from a partner and personal attachment style affect pain report, tolerance, and facial expressions of pain. Fifty-four participants, divided into secure, anxious, and avoidant attachment style groups, underwent a cold pressor task with their partners present. We manipulated how much empathy the participants perceived that their partners had for them. We observed a significant main effect of perceived empathy on pain report, with greater pain reported in the high perceived empathy condition. No such effects were found for pain tolerance or facial display. We also found a significant interaction of empathy with attachment style group, with the avoidant group reporting and displaying less pain than the secure and the anxious groups in the high perceived empathy condition. No such findings were observed in the low empathy condition. These results suggest that empathy from ones partner may influence pain report beyond behavioral reactions. In addition, the amount of pain report and expression that people show in high empathy conditions depends on their attachment style. Perspective Believing that ones partner feels high empathy for ones pain may lead individuals to rate the intensity of pain as higher. Individual differences in attachment style moderate this empathy effect.

Affective touch and attachment style modulate pain: A laser-evoked potentials study

Affective touch and cutaneous pain are two sub-modalities of interoception with contrasting affective qualities (pleasantness/unpleasantness) and social meanings (care/harm), yet their direct relationship has not been investigated. In 50 women, taking into account individual attachment styles, we assessed the role of affective touch and particularly the contribution of the C tactile (CT) system in subjective and electrophysiological responses to noxious skin stimulation, namely N1 and N2-P2 laser-evoked potentials. When pleasant, slow (versus fast) velocity touch was administered to the (non-CT-containing) palm of the hand, higher attachment anxiety predicted increased subjective pain ratings, in the same direction as changes in N2 amplitude. By contrast, when pleasant touch was administered to CT-containing skin of the arm, higher attachment anxiety predicted attenuated N1 and N2 amplitudes. Higher attachment avoidance predicted opposite results. Thus, CT-based affective touch can modulate pain in early and late processing stages (N1 and N2 components), with the direction of effects depending on attachment style. Affective touch not involving the CT system seems to affect predominately the conscious perception of pain, possibly reflecting socio-cognitive factors further up the neurocognitive hierarchy. Affective touch may thus convey information about available social resources and gate pain responses depending on individual expectations of social support. This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’.

Aetiology for the covariation between combined type ADHD and reading difficulties in a family study: the role of IQ

BACKGROUND Twin studies using both clinical and population-based samples suggest that the frequent co-occurrence of attention deficit hyperactivity disorder (ADHD) and reading ability/disability (RD) is largely driven by shared genetic influences. While both disorders are associated with lower IQ, recent twin data suggest that the shared genetic variability between reading difficulties and ADHD inattention symptoms is largely independent from genetic influences contributing to general cognitive ability. The current study aimed to extend the previous findings that were based on rating scale measures in a population sample by examining the generalisability of the findings to a clinical population, and by measuring reading difficulties both with a rating scale and with an objective task. This study investigated the familial relationships between ADHD, reading difficulties and IQ in a sample of individuals diagnosed with ADHD combined type, their siblings and control sibling pairs. METHODS Multivariate familial models were run on data from 1,789 individuals at ages 6-19. Reading difficulties were measured with both rating scale and an objective task. IQ was obtained using the Wechsler Intelligence Scales (WISC-III/WAIS-III). RESULTS Significant phenotypic (.2-.4) and familial (.3-.5) correlations were observed among ADHD, reading difficulties and IQ. Yet, 53%-72% of the overlapping familial influences between ADHD and reading difficulties were not shared with IQ. CONCLUSIONS Our finding that familial influences shared with general cognitive ability, although present, do not account for the majority of the overlapping familial influences on ADHD and reading difficulties extends previous findings from a population-based study to a clinically ascertained sample with combined type ADHD.