Biological Psychiatry : Genotype, Circuits, and Cognition in Autism and Attention-Deficit/Hyperactivity Disorder

vendredi 2 décembre 2011

Le numéro d’août 2011 de Biological Psychiatry est consacré à la question du génotype et de la cognition dans l’autisme et le TDAH.

Les articles sont consultables sur le site de l’éditeur.

1. Ahmad R H. The What, Where, and When of Catechol-O-Methyltransferase. Biological Psychiatry ;2011 ;70(3):214-215.

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2. Ducharme S, Hudziak JJ, Botteron KN, Ganjavi H, Lepage C, Collins DL, Albaugh MD, Evans AC, Karama S. Right Anterior Cingulate Cortical Thickness and Bilateral Striatal Volume Correlate with Child Behavior Checklist Aggressive Behavior Scores in Healthy Children. Biological Psychiatry ;2011 ;70(3):283-290.

Background The anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and basal ganglia have been implicated in pathological aggression. This study aimed at identifying neuroanatomical correlates of impulsive aggression in healthy children. Methods Data from 193 representative 6- to 18-year-old healthy children were obtained from the National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development after a blinded quality control. Cortical thickness and subcortical volumes were obtained with automated software. Aggression levels were measured with the Aggressive Behavior scale (AGG) of the Child Behavior Checklist. AGG scores were regressed against cortical thickness and basal ganglia volumes using first- and second-order linear models while controlling for age, gender, scanner site, and total brain volume. Gender by AGG interactions were analyzed. Results There were positive associations between bilateral striatal volumes and AGG scores (right : r = .238, p = .001 ; left : r = .188, p = .01). A significant association was found with right ACC and subgenual ACC cortical thickness in a second-order linear model (p < .05, corrected). High AGG scores were associated with a relatively thin right ACC cortex. An AGG by gender interaction trend was found in bilateral OFC and ACC associations with AGG scores. Conclusions This study shows the existence of relationships between impulsive aggression in healthy children and the structure of the striatum and right ACC. It also suggests the existence of gender-specific patterns of association in OFC/ACC gray matter. These results may guide research on oppositional-defiant and conduct disorders.

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3. Dumontheil I, Roggeman C, Ziermans T, Peyrard-Janvid M, Matsson H, Kere J, Klingberg T. Influence of the COMT Genotype on Working Memory and Brain Activity Changes During Development. Biological Psychiatry ;2011 ;70(3):222-229.

Background The Valine158Methionine (Val158Met) polymorphism of the COMT gene leads to lower enzymatic activity and higher dopamine availability in Met carriers. The Met allele is associated with better performance and reduced prefrontal cortex activation during working memory (WM) tasks in adults. Dopaminergic system changes during adolescence may lead to a reduction of basal dopamine levels, potentially affecting Met allele benefits during development. Methods We investigated the association of COMT genotype with behavioral (n = 322) and magnetic resonance imaging data (n = 81–84) collected during performance of a visuospatial WM task and potential changes in these effects during development (reflected in age × genotype interactions). Data were collected from a cross-sectional and longitudinal typically developing sample of 6- to 20-year-olds. Results Visuospatial WM capacity exhibited an age × genotype interaction, with a benefit of the Met allele emerging after 10 years of age. There was a parallel age × genotype interaction on WM-related activation in the right inferior frontal gyrus and intraparietal sulcus (IPS), with increases in activation with age in the Val/Val group only. Main effects of COMT genotype were also observed in the IPS, with greater gray matter volumes bilaterally and greater right IPS activation in the Val/Val group compared with the Met carriers. Conclusions These results suggest that COMT genotype effects on WM brain activity and behavior are not static during development. The full developmental picture should be considered when trying to understand the impact of genetic polymorphisms on the mature cognition of healthy adult or psychiatric populations.

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4. Kurth F, Narr KL, Woods RP, O’Neill J, Alger JR, Caplan R, McCracken JT, Toga AW, Levitt JG. Diminished Gray Matter Within the Hypothalamus in Autism Disorder : A Potential Link to Hormonal Effects ?. Biological Psychiatry ;2011 ;70(3):278-282.

Background Subjects with autism suffer from impairments of social interaction, deviations in language usage, as well as restricted and stereotyped patterns of behavior. These characteristics are found irrespective of age, IQ, and gender of affected subjects. However, brain changes due to age, IQ, and gender might pose potential confounds in autism neuroimaging analyses. Methods To investigate gray matter differences in autism that are not related to these potential confounds, we performed a voxel-based morphometry analysis in 52 affected children and adolescents and 52 matched control subjects. Results We observed diminished gray matter in a region of the hypothalamus, which synthesizes the behaviorally relevant hormones oxytocin and arginine vasopressin. Conclusions This finding provides support for further investigations of the theory of abnormal functioning of this hormonal system in autism and potentially for experimental therapeutic approaches with oxytocin and related neuropeptides.

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5. Michael W O. Expanding Findings on D-Cycloserine Augmentation of Therapeutic Learning : A Role for Social Learning Relative to Autism Spectrum Disorders ?. Biological Psychiatry ;2011 ;70(3):210-211.

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6. Näätänen R, Kujala T. The Mismatch Negativity and Its Magnetic Equivalent : An Index of Language Impairment or More General Cognitive Decline in Autism ?. Biological Psychiatry ;2011 ;70(3):212-213.

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7. Riem MME, Bakermans-Kranenburg MJ, Pieper S, Tops M, Boksem MAS, Vermeiren RRJM, van Ijzendoorn MH, Rombouts SARB. Oxytocin Modulates Amygdala, Insula, and Inferior Frontal Gyrus Responses to Infant Crying : A Randomized Controlled Trial. Biological Psychiatry ;2011 ;70(3):291-297.

Background Oxytocin facilitates parental caregiving and mother–infant bonding and might be involved in responses to infant crying. Infant crying provides information about the physical status and mood of the infant and elicits parental proximity and caregiving. Oxytocin might modulate the activation of brain structures involved in the perception of cry sounds—specifically the insula, the amygdala, and the thalamocingulate circuit—and thereby affect responsiveness to infant crying. Method In a randomized controlled trial we investigated the influence of intranasally administered oxytocin on neural responses to infant crying with functional magnetic resonance imaging. Blood oxygenation level–dependent responses to infant crying were measured in 21 women who were administered oxytocin and 21 women who were administered a placebo. Results Induced oxytocin levels reduced, experimentally, activation in the amygdala and increased activation in the insula and inferior frontal gyrus pars triangularis. Conclusions Our findings suggest that oxytocin promotes responsiveness to infant crying by reducing activation in the neural circuitry for anxiety and aversion and increasing activation in regions involved in empathy.

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8. Roberts TPL, Cannon KM, Tavabi K, Blaskey L, Khan SY, Monroe JF, Qasmieh S, Levy SE, Edgar JC. Auditory Magnetic Mismatch Field Latency : A Biomarker for Language Impairment in Autism. Biological Psychiatry ;2011 ;70(3):263-269.

Background Auditory processing abnormalities are frequently observed in autism spectrum disorders (ASD), and these abnormalities may have sequelae in terms of clinical language impairment (LI). The present study assessed associations between language impairment and the amplitude and latency of the superior temporal gyrus magnetic mismatch field (MMF) in response to changes in an auditory stream of tones or vowels. Methods Fifty-one children with ASD, and 27 neurotypical control subjects, all aged 6 to 15 years, underwent neuropsychological evaluation, including tests of language function, as well as magnetoencephalographic recording during presentation of tones and vowels. The MMF was identified in the difference waveform obtained from subtraction of responses to standard from deviant stimuli. Results Magnetic mismatch field latency was significantly prolonged (p < .001) in children with ASD, compared with neurotypical control subjects. Furthermore, this delay was most pronounced (∼50 msec) in children with concomitant LI, with significant differences in latency between children with ASD with LI and those without (p < .01). Receiver operator characteristic analysis indicated a sensitivity of 82.4% and specificity of 71.2% for diagnosing LI based on MMF latency. Conclusions Neural correlates of auditory change detection (the MMF) are significantly delayed in children with ASD, and especially those with concomitant LI, suggesting a neurobiological basis as well as a clinical biomarker for LI in ASD.

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9. Rubia K, Halari R, Mohammad A-M, Taylor E, Brammer M. Methylphenidate Normalizes Frontocingulate Underactivation During Error Processing in Attention-Deficit/Hyperactivity Disorder. Biological Psychiatry ;2011 ;70(3):255-262.

Background Children with attention-deficit/hyperactivity disorder (ADHD) have deficits in performance monitoring often improved with the indirect catecholamine agonist methylphenidate (MPH). We used functional magnetic resonance imaging to investigate the effects of single-dose MPH on activation of error processing brain areas in medication-naive boys with ADHD during a stop task that elicits 50% error rates. Methods Twelve medication-naive boys with ADHD were scanned twice, under either a single clinical dose of MPH or placebo, in a randomized, double-blind design while they performed an individually adjusted tracking stop task, designed to elicit 50% failures. Brain activation was compared within patients under either drug condition. To test for potential normalization effects of MPH, brain activation in ADHD patients under either drug condition was compared with that of 13 healthy age-matched boys. Results During failed inhibition, boys with ADHD under placebo relative to control subjects showed reduced brain activation in performance monitoring areas of dorsomedial and left ventrolateral prefrontal cortices, thalamus, cingulate, and parietal regions. MPH, relative to placebo, upregulated activation in these brain regions within patients and normalized all activation differences between patients and control subjects. During successful inhibition, MPH normalized reduced activation observed in patients under placebo compared with control subjects in parietotemporal and cerebellar regions. Conclusions MPH normalized brain dysfunction in medication-naive ADHD boys relative to control subjects in typical brain areas of performance monitoring, comprising left ventrolateral and dorsomedial frontal and parietal cortices. This could underlie the amelioration of MPH of attention and academic performance in ADHD.

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10. Salatino-Oliveira A, Genro JP, Zeni C, Polanczyk GV, Chazan R, Guimarães AP, Callegari-Jacques SM, Rohde LA, Hutz MH. Catechol-O-Methyltransferase Valine158Methionine Polymorphism Moderates Methylphenidate Effects on Oppositional Symptoms in Boys with Attention-Deficit/Hyperactivity Disorder. Biological Psychiatry ;2011 ;70(3):216-221.

Background The catechol-O-methyltransferase enzyme plays a key role in the function of prefrontal cortex, accounting for most of the degradation of dopamine. Previous studies have documented the improvement of oppositional symptoms in attention-deficit/hyperactivity disorder (ADHD) patients with methylphenidate (MPH) treatment. However, the effect of the COMT gene in the response to MPH on oppositional symptoms has not been investigated. Methods A total of 251 children with ADHD fulfilled inclusion criteria to participate in the study. Dosages of short-acting MPH were augmented until no further clinical improvement was detected or until there were significant adverse events (MPH dose always > .3 mg/kg/day). The outcome measure was the parent-rated oppositional subscale of the Swanson, Nolan and Pelham Scale-Version IV (SNAP-IV). The scale was applied by child psychiatrists blinded to genotype at baseline and in the first and third months. The COMT valine158methionine polymorphism was genotyped by polymerase chain reaction based methods. Results We detected significant improvement in SNAP-IV oppositional scores from baseline to the first and three months of treatment [n = 112 ; F(2,231) = 5.35, p = .005]. A significant effect of the presence of methionine allele in oppositional defiant disorder scores during treatment [F(1,148) = 5.02, p = .027] and a significant interaction between the methionine allele and treatment over time for the SNAP-IV oppositional scores during this period of treatment [F(2,229) = 6.40, p = .002] were both observed. Conclusions These results suggest an effect of the COMT genotype on the trajectory of oppositional defiant disorder symptoms improvement with MPH treatment in boys with ADHD.

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11. Scerri TS, Morris AP, Buckingham L-L, Newbury DF, Miller LL, Monaco AP, Bishop DVM, Paracchini S. DCDC2, KIAA0319 and CMIP Are Associated with Reading-Related Traits. Biological Psychiatry ;2011 ;70(3):237-245.

Background Several susceptibility genes have been proposed for dyslexia (reading disability ; RD) and specific language impairment (SLI). RD and SLI show comorbidity, but it is unclear whether a common genetic component is shared. Methods We have investigated whether candidate genes for RD and SLI affect specific cognitive traits or have broad effect on cognition. We have analyzed common risk variants within RD (MRPL19/C2ORF3, KIAA0319, and DCDC2) and language impairment (CMIP and ATP2C2) candidate loci in the Avon Longitudinal Study of Parents and Children cohort (n = 3725), representing children born in southwest England in the early 1990s. Results We detected associations between reading skills and KIAA0319, DCDC2, and CMIP. We show that DCDC2 is specifically associated with RD, whereas variants in CMIP and KIAA0319 are associated with reading skills across the ability range. The strongest associations were restricted to single-word reading and spelling measures, suggesting that these genes do not extend their effect to other reading and language-related skills. Inclusion of individuals with comorbidity tends to strengthen these associations. Our data do not support MRPL19/C2ORF3 as a locus involved in reading abilities nor CMIP/ATP2C2 as genes regulating language skills. Conclusions We provide further support for the role of KIAA0319 and DCDC2 in contributing to reading abilities and novel evidence that the language-disorder candidate gene CMIP is also implicated in reading processes. Additionally, we present novel data to evaluate the prevalence and comorbidity of RD and SLI, and we recommend not excluding individuals with comorbid RD and SLI when designing genetic association studies for RD.

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12. Shih P, Keehn B, Oram JK, Leyden KM, Keown CL, Müller R-A. Functional Differentiation of Posterior Superior Temporal Sulcus in Autism : A Functional Connectivity Magnetic Resonance Imaging Study. Biological Psychiatry ;2011 ;70(3):270-277.

Background Socio-communicative impairments are salient features of autism spectrum disorder (ASD). Abnormal development of posterior superior temporal sulcus (pSTS)—a key processing area for language, biological motion, and social context—could play a role in these deficits. Methods Functional connectivity magnetic resonance imaging was used to examine the synchronization of low-frequency blood oxygen level-dependent fluctuations during continuous performance on a visual search task. Twenty-one children and adolescents with ASD and 26 typically developing individuals—matched on age and IQ—participated in the study. Three subregions of pSTS were delineated with a data-driven approach, and differentiation of pSTS was examined by comparing the connectivity of each subregion. Results In typically developing individuals, differentiation of networks was positively associated with age and anatomical maturation (cortical thinning in pSTS, greater white matter volume). In the ASD group, differentiation of pSTS connectivity was significantly reduced, and correlations with anatomical measures were weak or absent. Moreover, pSTS differentiation was inversely correlated with autism symptom severity. Conclusions Atypical maturation of pSTS suggests altered trajectories for functional segregation and integration of networks in ASD, potentially related to impaired cognitive and sensorimotor development. Furthermore, our findings provide a novel explanation for atypically increased connectivity in ASD that has been observed in some functional connectivity magnetic resonance imaging studies.

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13. Sonuga-Barke EJS, Kumsta R, Schlotz W, Lasky-Su J, Marco R, Miranda A, Mulas F, Oades RD, Banaschewski T, Mueller U, Andreou P, Christiansen H, Gabriels I, Uebel H, Kuntsi J, Franke B, Buitelaar J, Ebstein R, Gill M, Anney R, Roeyers H, Rothenberger A, Sergeant J, Steinhausen HC, Asherson P, Faraone SV. A Functional Variant of the Serotonin Transporter Gene (SLC6A4) Moderates Impulsive Choice in Attention-Deficit/Hyperactivity Disorder Boys and Siblings. Biological Psychiatry ;2011 ;70(3):230-236.

Background Impulsive drive for immediate reward (IDIR) and delay aversion are dissociable elements of the preference for immediate over delayed rewards seen in attention-deficit/hyperactivity disorder (ADHD). We hypothesized that IDIR would be associated with dopamine regulating genes and delay aversion would be associated with serotonin-regulating genes. Methods Impulsive drive for immediate reward and delay aversion were measured in 459 male children and adolescents (328 ADHD and 131 unaffected siblings) with a laboratory choice task. The sample was genotyped for the 5HTT (SLC6A4) promoter serotonin-transporter-linked polymorphic region polymorphism and a DAT1 (SLC6A3) 40-base pair variable number tandem repeat located in the 3′-untranslated region of the gene. Results There was no effect of dopamine transporter (DAT)1 on IDIR. As predicted, serotonin-transporter-linked polymorphic region s-allele carriers were more delay averse. This effect was driven by the s/l genotype in the ADHD group. These results were not altered by taking account of the rs25531 A/G single nucleotide polymorphism and were independent of age, IQ, and oppositional defiant disorder symptoms. Conclusions The results support the genetic distinctiveness of IDIR and delay aversion in ADHD and implicate serotonin function in delay aversion. Possible explanations of the heterosis effect in the ADHD cases are presented.

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14. Yordanova J, Kolev V, Albrecht B, Uebel H, Banaschewski T, Rothenberger A. May Posterror Performance Be a Critical Factor for Behavioral Deficits in Attention-Deficit/Hyperactivity Disorder ?. Biological Psychiatry ;2011 ;70(3):246-254.

Background Although the performance of children with attention-deficit/hyperactivity disorder (ADHD) is impaired in a variety of cognitive tasks, the specific capacity of strategic readaptation after errors as a source of behavioral deficits is not sufficiently understood. This study used an extended and refined behavioral parameterization to assess performance monitoring and posterror adaptation in children with ADHD. Methods Twenty-eight healthy control subjects and 47 ADHD patients (7–16 years of age, all males, matched for age and IQ) performed a visual flanker task in which targets were congruent or incongruent with preceding flankers. Posterror adaptation was measured for response speed (posterror slowing), accuracy, and variability by using normalized individual rates of change. Markers of error detection and general performance were also analyzed. Results Postcorrect response speed and accuracy did not differ between the groups, in contrast to posterror behaviors. Whereas posterror slowing was not evident in any of the groups, the error rate and performance instability (reaction time variance) substantially increased after errors only in ADHD patients, not in control subjects. No reliable between-group differences were found for error detection and global performance. Conclusions In healthy children, posterror adaptation preserves performance at its ongoing level. No such adaptation was evident in ADHD, leading to consecutive errors and increased behavioral instability. Performance deficits in ADHD were only present after error but not after correct behaviors, which shapes the general profile of performance impairment in ADHD. The findings have practical implications for strategic designs of behavioral therapy in ADHD.

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