Intra-Subject Variability, Intelligence, and ADHD Traits in a Community-Based Sample.

OBJECTIVE: The present study investigates the predictive validity of intra-subject variability (ISV) for ADHD traits in a community-based sample and the stability of the relationship between ISV and fluid intelligence (gf) across the continuum of ADHD traits. METHOD: Age-residualized data from 426 participants (8-18 years, 6% ADHD) was used to investigate whether ex-Gaussian and DDM parameters derived from simple choice-reaction-time tasks can predict continuously assessed ADHD traits. Multiple-Group-Analyses and Latent-Moderated-Structural-Equations were used to test whether ADHD traits moderate the relationship between ISV and gf. RESULTS: σ and µ of the ex-Gaussian model as well as DDM parameters drift rate (v) and boundary separation (a) significantly predicted general ADHD traits, while τ predicted attention difficulties specifically. Across the ADHD continuum, σ and v were significant predictors of gf. CONCLUSION: The results confirm the link between ISV and ADHD. The relationship between ISV and gf appears stable across the ADHD continuum.

Long-Term Effects of an Oligoantigenic Diet in Children with Attention-Deficit/Hyperactivity Disorder (ADHD) on Core Symptomatology.

In the early 1920s, it was discovered that nutrition is associated with what is known today as Attention-Deficit/Hyperactivity Disorder (ADHD) and that certain foods can worsen the symptoms. In previous studies, approximately 60% of the participants experience at least a 40% reduction in ADHD symptoms after an oligoantigenic diet (OD). The purpose of this study was to evaluate ADHD symptoms in children approximately 3.5 years after completing a 4-week oligoantigenic diet. Among 28 participants who completed the 4-week diet, 21 were re-assessed for this study after 3.5 years. The severity of ADHD symptoms was assessed with the ADHD-Rating-Scale-IV (ARS). Of 21 participants, 14 fulfilled the responder criterion, whereas 7 did not. At follow-up, 28% of the participants were taking medication. The mean ARS total score improved significantly from T1: M = 29.62 (SD = 9.80) to T2: M = 15.86 (SD = 8.56) between the time points before and after the diet (d = -1.91). There was also a lower ARS total score at the follow-up T5: M = 16.00 (SD = 10.52) compared to before the diet (d = -1.17). This study shows that individually adjusted nutrition significantly improved the ADHD symptomatology of the participants long-term. This suggests that an oligoantigenic diet with subsequent individual nutritional recommendations could become an additional treatment option for children with ADHD.

Evidence towards a continuum of impairment across neurodevelopmental disorders from basic ocular-motor tasks.

Findings of genetic overlap between Schizophrenia, Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) contributed to a renewed conceptualization of these disorders as laying on a continuum based on aetiological, pathophysiological and neurodevelopmental features. Given that cognitive impairments are core to their pathophysiology, we compared patients with schizophrenia, ADHD, ASD, and controls on ocular-motor and manual-motor tasks, challenging crucial cognitive processes. Group comparisons revealed inhibition deficits common to all disorders, increased intra-subject variability in schizophrenia and, to a lesser extent, ADHD as well as slowed processing in schizophrenia. Patterns of deviancies from controls exhibited strong correlations, along with differences that posited schizophrenia as the most impaired group, followed by ASD and ADHD. While vector correlations point towards a common neurodevelopmental continuum of impairment, vector levels suggest differences in the severity of such impairment. These findings argue towards a dimensional approach to Neurodevelopmental Disorders' pathophysiological mechanisms.

Sensorische Auffälligkeiten bei Autismus-Spektrum-Störung: Validierung und Adaptation des englischsprachigen "Sensory Perception Quotient" (SPQ) von Tavassoli und Kollegen.

Although the DSM-5 has emphasised the relevance of sensory abnormalities in autism spectrum disorders (ASD), there are hardly any measures to assess them in German speaking countries. The present study translated the "Sensory Perception Questionnaire" (SPQ) by Tavassoli et al. (2014) to German and validated this scale. The SPQ is a self-rating scale for adults which focuses on perceptual aspects rather than cognitive or motivational antecedents or consequences of such perceptual processes. A total of 188 subjects participated in this study, including n=85 participants with ASD and n=103 neurotypical controls. The autism spectrum quotient (AQ) and the empathy quotient (EQ) were also administered, the IQ was measured using the CFT20-R, and participants were clinically evaluated using the SKID-I. Alternative items were generated to improve the semantic and psychometric properties of the SPQ. Of the 92 original SPQ items, 33 separated the clinical groups significantly and linguistically clearly in the sense of sensory hyper-sensitivity. These items covered primarily the sensory modalities of hearing, touch and vision. Increased sensory hyper-sensitivity was associated with greater scores in the AQ and increased slightly with increasing age. Sensory hyper-sensitivity in participants with ASD was, however, not significantly correlated with the EQ and the IQ. Due to the item-analytical rather than dimensional item selection, the short versions presented here exhibit a clearly better group separation with comparable concurrent validities when compared to Tavassoli's short version of the scale. Pending replication and proper norming, the SPQ short version presented here can be employed for screening purposes and supplement the clinical diagnostic process.

Attention for Emotion-How Young Adults With Neurodevelopmental Disorders Look at Facial Expressions of Affect.

While Autism Spectrum Disorder (ASD), Attention-Deficit/Hyperactivity Disorder (ADHD) and Schizophrenia (SCZ) differ in many clinically relevant features such as symptomatology and course, they may also share genetic underpinnings, affective problems, deviancies in social interactions, and are all characterized by some kind of cognitive impairment. This situation calls for a joint investigation of the specifics of cognitive (dys-)functions of the three disorders. Such endeavor should focus, among other domains, on the inter-section of processing cognitive, affective and social information that is crucial in effective real-life interactions and can be accomplished when attentional preferences for human facial expressions of emotions is studied. To that end, attention to facial expressions of basic emotions was examined in young adults with ASD, ADHD, or SCZ in the present study. The three clinical groups were compared with an age-matched group of typically-developing participants (TD) during the free contemplation of five different facial emotions presented simultaneously, by varying identities, through the registration of eye movements. We showed, that dwell times and fixation counts differed for the different emotions in TD and in a highly similar way in ADHD. Patients with ASD differed from TD by showing a stronger differentiation between emotions and partially different attentional preferences. In contrast, the SCZ group showed an overall more restricted scanning behavior and a lack of differentiation between emotions. The ADHD group, showed an emotion-specific gazing pattern that was highly similar to that of controls. Thus, by analyzing eye movements, we were able to differentiate three different viewing patterns that allowed us to distinguish between the three clinical groups. This outcome suggests that attention for emotion may not tap into common pathophysiological processes and argues for a multi-dimensional approach to the grouping of disorders with neurodevelopmental etiology.

An German Short-Version of the "Sensory Perception Quotient" for Adults With Autism Spectrum Disorder.

Sensory features in autism spectrum disorder (ASD) have received increasing interest in clinical work and research during the recent years. With the Sensory Perception Quotient (SPQ), Tavasolli and colleagues have produced a self-rating scale for adults with ASD that measures sensory hyper-sensitivity in different sensory modalities, without also tapping cognitive or motivational aspects that precede or follow autistic sensory experiences. Here, we present the results of a translation of the SPQ to German and its short version as well as their validation in samples of autistic or neuro-typical participants. We, furthermore, present the psychometric properties and validities of Tavasolli's original SPQ-short version as well as an alternative short version based on different psychometric item-selection criteria. We can show here that our alternative SPQ-short version, overlapping with the original short-version in 61% of its items, exhibits superior reliabilities, reasonable concurrent validities with other related measures. It, furthermore, exhibits excellent differentiation between autistic and non-autistic samples, underscoring its utility as a screening instrument in research and a clinical instrument to supplement the ASD diagnostic process.

Visual search in neurodevelopmental disorders: evidence towards a continuum of impairment.

Disorders with neurodevelopmental aetiology such as Attention-Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD) and Schizophrenia share commonalities at many levels of investigation despite phenotypic differences. Evidence of genetic overlap has led to the concept of a continuum of neurodevelopmental impairment along which these disorders can be positioned in aetiological, pathophysiological and developmental features. This concept requires their simultaneous comparison at different levels, which has not been accomplished so far. Given that cognitive impairments are core to the pathophysiology of these disorders, we provide for the first time differentiated head-to-head comparisons in a complex cognitive function, visual search, decomposing the task with eye movement-based process analyses. N = 103 late-adolescents with schizophrenia, ADHD, ASD and healthy controls took a serial visual search task, while their eye movements were recorded. Patients with schizophrenia presented the greatest level of impairment across different phases of search, followed by patients with ADHD, who shared with patients with schizophrenia elevated intra-subject variability in the pre-search stage. ASD was the least impaired group, but similar to schizophrenia in post-search processes and to schizophrenia and ADHD in pre-search processes and fixation duration while scanning the items. Importantly, the profiles of deviancy from controls were highly correlated between all three clinical groups, in line with the continuum idea. Findings suggest the existence of one common neurodevelopmental continuum of performance for the three disorders, while quantitative differences appear in the level of impairment. Given the relevance of cognitive impairments in these three disorders, we argue in favour of overlapping pathophysiological mechanisms.

Preliminary Evaluation of the FETASS Training for Parents of Children With Autism Spectrum Disorder: A Pilot Study.

While several recent evaluation studies have shown the efficacy of parent training programs for children with neurodevelopmental disorders, manual-based training in German is still scarce. To address this gap, we developed a specific modularized training program for parents of children from preschool to pre-adolescent age with Autism Spectrum Disorder (FETASS). The overarching purpose of the FETASS intervention is to enhance social communication behavior and quality of life of the child by coaching parents. As a proximal target, the FETASS training aims to provide families with behavior management and communication strategies. The development of the training was influenced by published behavioral parent trainings and autism-specific interventions. The training comprises eight weekly sessions and targets families whose children have a diagnosis of Autism Spectrum Disorder (ASD) without intellectual and language impairments. As a preliminary pilot study, the purpose was to evaluate the acceptability of the training. Furthermore, the study aimed at initially evaluating social communication behavior, quality of life of the child, parental stress level, and parenting after training in comparison to a treatment as usual (TAU) group. Exploratively, long-term effects were investigated after 6 months of training as well. In total, 57 families participated (n[TAU] = 29, n[FETASS] = 28). Questionnaires about social communication behavior and quality of life of the child, parental stress, and parenting were administered at three time points (t1: baseline TAU/FETASS, t2: post TAU/FETASS; and t3: 6-month follow-up after FETASS). Primary outcome measures were the social communication behavior of the child and the parent's proxy report on quality of life of the child. Secondary outcome measures were changes in parental stress and parenting behavior. Acceptability of the training was very high and we had almost no dropouts during training. Results for the primary outcome measure of social communication behavior, overall quality of life of the child, and long-term effects on social communication behavior were not significant. While long-term findings for parent stress reduction and for the quality of life of the child are promising, further research has to be done in a future randomized controlled trial.

ADOS-Eye-Tracking: The Archimedean Point of View and Its Absence in Autism Spectrum Conditions.

Face perception and emotion categorization are widely investigated under laboratory conditions that are devoid of real social interaction. Using mobile eye-tracking glasses in a standardized diagnostic setting while applying the Autism Diagnostic Observation Schedule (ADOS-2), we had the opportunity to record gaze behavior of children and adolescents with and without Autism Spectrum Conditions (ASCs) during social interaction. The objective was to investigate differences in eye-gaze behavior between three groups of children and adolescents either (1) with ASC or (2) with unconfirmed diagnosis of ASC or (3) with neurotypical development (NTD) during social interaction with an adult interviewer in a diagnostic standard situation using the ADOS-2. In a case control study, we used mobile eye-tracking glasses in an ecologically valid and highly standardized diagnostic interview to investigate suspected cases of ASC. After completion of the ASC diagnostic gold standard including the ADOS-2, the participants were assigned to two groups based on their diagnosis (ASC vs. non-ASC) and compared with a matched group of neurotypically developed controls. The primary outcome measure is the percentage of total dwell times assessed for different areas of interest (AOI) with regard to the face and body of a diagnostic interviewer and the surrounding space. Overall, 65 children and adolescents within an age range of 8.3-17.9 years were included in the study. The data revealed significant group differences, especially in the central-face area. Previous investigations under laboratory conditions gave preferential attention to the eye region during face perception to describe differences between ASC and NTD. In this study - using an ecologically valid setting within a standard diagnostic procedure - the results indicate that neurotypically developed controls seem to process faces and facial expressions in a holistic manner originating from the central-face region. Conversely, participants on the Autism Spectrum (tAS) seem to avoid the central-face region and show unsystematic gaze behavior, not using the preferred landing position in the central-face region as the Archimedean point of face perception. This study uses a new approach, and it will be important to replicate these preliminary findings in future research.

Dissociating Slow Responses From Slow Responding.

Increased Intra-Subject Variability (ISV) is a candidate endophenotype of ADHD. ISV's relationship with response speed is highly relevant for ADHD as patients are highly variable but typically no slower than controls. This brief report addresses the relationship between variability and speed by employing dimensional analyses for differentiated performance measures, with a particular focus on the ex-Gaussian measures, across relevant ADHD studies and in young healthy adults (N = 70). For both patients with ADHD and healthy adults, we found that reaction time standard deviation and mean reaction time were strongly correlated, thus failing to dissociate, but ex-Gaussian tau (τ) shared only little variance with Gaussian mu (µ), thus dissociating slow responses (τ) from response speed or-if given-slow responding (µ). Our results highlight the utility of employing the ex-Gaussian measures to disentangle ISV and speed, particularly for ADHD data as patients make more slow responses but are not overall slower than typical controls.

Late attentional processes potentially compensate for early perceptual multisensory integration deficits in children with autism: evidence from evoked potentials.

Sensory processing deficits and altered long-range connectivity putatively underlie Multisensory Integration (MSI) deficits in Autism Spectrum Disorder (ASD). The present study set out to investigate non-social MSI stimuli and their electrophysiological correlates in young neurotypical adolescents and adolescents with ASD. We report robust MSI effects at behavioural and electrophysiological levels. Both groups demonstrated normal behavioural MSI. However, at the neurophysiological level, the ASD group showed less MSI-related reduction of the visual P100 latency, greater MSI-related slowing of the auditory P200 and an overall temporally delayed and spatially constrained onset of MSI. Given the task design and patient sample, and the age of our participants, we argue that electro-cortical indices of MSI deficits in ASD: (a) can be detected in early-adolescent ASD, (b) occur at early stages of perceptual processing, (c) can possibly be compensated by later attentional processes, (d) thus leading to normal MSI at the behavioural level.

Quantitative genome-wide association study of six phenotypic subdomains identifies novel genome-wide significant variants in autism spectrum disorder.

Autism spectrum disorders (ASD) are highly heritable and are characterized by deficits in social communication and restricted and repetitive behaviors. Twin studies on phenotypic subdomains suggest a differing underlying genetic etiology. Studying genetic variation explaining phenotypic variance will help to identify specific underlying pathomechanisms. We investigated the effect of common variation on ASD subdomains in two cohorts including >2500 individuals. Based on the Autism Diagnostic Interview-Revised (ADI-R), we identified and confirmed six subdomains with a SNP-based genetic heritability h2SNP = 0.2-0.4. The subdomains nonverbal communication (NVC), social interaction (SI), and peer interaction (PI) shared genetic risk factors, while the subdomains of repetitive sensory-motor behavior (RB) and restricted interests (RI) were genetically independent of each other. The polygenic risk score (PRS) for ASD as categorical diagnosis explained 2.3-3.3% of the variance of SI, joint attention (JA), and PI, 4.5% for RI, 1.2% of RB, but only 0.7% of NVC. We report eight genome-wide significant hits-partially replicating previous findings-and 292 known and novel candidate genes. The underlying biological mechanisms were related to neuronal transmission and development. At the SNP and gene level, all subdomains showed overlap, with the exception of RB. However, no overlap was observed at the functional level. In summary, the ADI-R algorithm-derived subdomains related to social communication show a shared genetic etiology in contrast to restricted and repetitive behaviors. The ASD-specific PRS overlapped only partially, suggesting an additional role of specific common variation in shaping the phenotypic expression of ASD subdomains.

Psychometric analyses of the Tower of London planning task reveal high reliability and feasibility in typically developing children and child patients with ASD and ADHD.

The Tower of London (TOL) is probably the most often used assessment tool for planning ability in healthy and clinical samples. Various versions, including our proposed standard problem set, have proven to be feasible and reliable in adults. In contrast, reliability information for typically developing (TD) children and neurodevelopmental disorders during childhood are largely missing. Also, it would be highly desirable to attain a problem set that can be used across the whole lifespan. Therefore, here we examine reliability of our proposed standard problem set using a computerized TOL version in 178 TD children (two different samples), 49 children with high-functioning autism spectrum disorder (ASD) and 56 children with attention-deficit/hyperactivity disorder (ADHD) (age ranges of each group 6 to 13 years), and 130 young adults (age range 18 to 32 years). Greatest lower bound estimates of reliability were adequate to high in the two samples of TD children (.76 and .80) and high to very high in patients (ASD: .90; ADHD: .83). In young adults, all reliability indices were adequate to high. Moreover, a subset of four- and five-move problems exhibited sufficient performance variability and high part-whole correlations with the complete problem set in all samples. These findings demonstrate the reliability of the presented TOL problem set in both clinical and non-clinical child samples. A clinically feasible subset of four- and five-move problems is reflective of overall planning performance at all ages, hence enabling comparisons of planning ability within and between developmental samples across almost the whole lifespan.

Media Use, Sleep Quality, and ADHD Symptoms in a Community Sample and a Sample of ADHD Patients Aged 8 to 18 Years.

Objective: Relationships between sleep, screen-based media, and ADHD symptomatology were investigated using a case- and community-based approach. Method: N = 357 healthy and N = 61 children with ADHD (12.72 ± 2.83 years) completed a sleep and media questionnaire. To measure ADHD symptomatology, parents filled out the Strengths and Weaknesses of ADHD symptoms and Normal behavior (SWAN) scale. Two samples were formed: a matched (N = 61 patients and N = 61 controls) and a community sample (N = 357 healthy participants and N = 20 patients). Results: Compared with controls, participants with ADHD reported delayed sleep onset and more screen time on school days. Adolescent patients showed more behavior promoting delayed sleep phase. In the community sample, media time, sleep deviation, and circadian rhythm were correlated with ADHD symptomatology. Furthermore, media time, sleep-wake behavior, and sleep deviation were predictive of ADHD symptomatology (variance explained = 4%-15%). Conclusion: Longer media time and inadequate sleep-wake behavior increase the risk of ADHD-like symptoms. However, research using objective assessments is needed to disentangle this distinct association and to provide possible directions for intervention.

Intuitive Moral Reasoning in High-Functioning Autism Spectrum Disorder: A Matter of Social Schemas?

Using a schema-theoretical perspective in the field of moral cognition, we assessed response behavior of adolescent (n = 15) and adult (n = 22) individuals with Autism Spectrum Disorder (ASD) in comparison with adolescent (n = 22) and adult (n = 22) neurotypically developed controls. We conceptualized the Intuitive Moral Reasoning Test-in five moral dilemmas, participants had to choose between two alternative actions and assess their decision with respect to emotional valence, arousal, moral acceptability and permissibility from both the perspective of the acting person and then of the victim. Patients with ASD displayed a different decision and response behavior, particularly when the dilemmas were based on extreme life situations in combination with a social schema involving close social relationships.

ADHD Traits in German School-Aged Children: Validation of the German Strengths and Weaknesses of ADHS Symptoms and Normal Behavior (SWAN-DE) Scale.

OBJECTIVE: The Strengths and Weaknesses of ADHS-Symptoms and Normal Behavior (SWAN) Scale has been developed to support the dimensional assessment of ADHD symptoms by capturing variance on both poles of the ADHD continuum. The present study provides the first validation of the German version of SWAN (SWAN-DE). METHOD: Based on a sample of N1 = 343 children from the general population and N2 = 62 children with ADHD, both aged between 8 and 18 years, normality, internal consistency, test-retest reliability, and different validity indices were examined. RESULTS: SWAN was characterized by normally distributed scores, good to excellent reliability, and factorial validity. It showed high diagnostic utility in discriminating between patients with ADHD and healthy controls and significant correlations to related clinical scales and neuropsychological constructs, such as intra-subject variability. CONCLUSION: The present study reveals the excellent psychometric properties of SWAN-DE, which can now be usefully applied in the German-speaking countries as well as in cross-national studies.

Inferior Frontal Gyrus Volume Loss Distinguishes Between Autism and (Comorbid) Attention-Deficit/Hyperactivity Disorder-A FreeSurfer Analysis in Children.

Objective: Autism spectrum (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental disorders with a high rate of comorbidity. To date, diagnosis is based on clinical presentation and distinct reliable biomarkers have been identified neither for ASD nor ADHD. Most previous neuroimaging studies investigated ASD and ADHD separately. Method: To address the question of structural brain differences between ASD and ADHD, we performed FreeSurfer analysis in a sample of children with ADHD (n = 30), with high-functioning ASD (n = 14), with comorbid high-functioning ASD and ADHD (n = 15), and of typically developed controls (TD; n = 36). With FreeSurfer, an automated brain imaging processing and analyzing suite, we reconstructed the cerebral cortex and calculated gray matter volumes as well as cortical surface parameters in terms of cortical thickness and mean curvature. Results: A significant main effect of the factor ADHD was detected for the left inferior frontal gyrus (Pars orbitalis) volume, with the ADHD group exhibiting smaller Pars orbitalis volumes. Dimensional measures of autism (SRS total raw score) and ADHD (DISYPS-II FBB-ADHD score) had no significant influence on the left Pars orbitalis volume. Both, ASD and ADHD tended to have an effect on cortical thickness or mean curvature, which did not survive correction for multiple comparisons. Conclusion: Our results underline that ADHD rather than ASD is associated with volume loss in the left inferior frontal gyrus (Pars orbitalis). This area might play a relevant role in modulating symptoms of inattention and/or impulsivity in ADHD. The effect of comorbid ADHD in ASD samples and vice versa, on cortical thickness and mean curvature, requires further investigation in larger samples.

Interindividual and Intraindividual Variation of Methylphenidate Concentrations in Serum and Saliva of Patients With Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Therapeutic drug monitoring is becoming increasingly important in psychiatric therapy, especially in children. However, for several reasons, it cannot yet be implemented as a daily routine in clinical or outpatient settings. To evaluate new, noninvasive procedures, blood and saliva (oral fluid) samples were collected from patients with attention-deficit/hyperactivity disorder (ADHD) who were also being administered methylphenidate (MPH). The study's main purposes were to correlate MPH concentrations in serum and saliva between subjects and to analyze intraindividual variation of serum concentration. METHODS: Thirty-six patients with ADHD (27 children and 9 adults) on MPH medication were included for drug analysis. MPH and its major metabolite ritalinic acid were quantified using liquid chromatography-tandem mass spectrometry measurements. The following correlations were investigated: (1) between drug concentrations in serum and saliva, and (2) between pH value and saliva to serum concentration ratio. Furthermore, the mean intraindividual MPH-concentration fluctuation in saliva under constant frame conditions was analyzed. RESULTS: After quantification, MPH concentrations were approximately 5 times higher in the saliva than in the serum, whereas the concentrations of ritalinic acid were much lower in saliva. We found significant correlations between concentrations of MPH in serum and saliva (r = 0.51, P < 0.05). Saliva MPH measures, compared with serum, were pH-dependent (r = -0.56, P < 0.01). Daily coefficient of variance of saliva concentration in children taking constant medication was 27.3% (11%-42%), whereas the coefficient of variance for the ratio of saliva to serum was 122% (2%-2060%). CONCLUSIONS: Our data indicate that the interindividual variation in saliva to serum concentrations is rather high, whereas the intraindividual variation is fairly low, as already shown in the literature for repeated citalopram serum measurements. Saliva may well serve as an alternative matrix for therapeutic drug monitoring of MPH in patients with ADHD, especially for follow-up examinations. Future research should focus on analyzing the relationship between drug levels in saliva and clinical effects as well as on understanding the mechanisms that generate saliva drug concentrations. These are essential steps before potential clinical use.

Common functional variants of the glutamatergic system in Autism spectrum disorder with high and low intellectual abilities.

The genetic architecture underlying Autism spectrum disorder (ASD) has been suggested to differ between individuals with lower (IQ ≤ 70; LIQ) and higher intellectual abilities (IQ > 70; HIQ). Among the identified pathomechanisms, the glutamatergic signalling pathway is of specific interest in ASD. We investigated 187 common functional variants of this neurotransmitter system for association with ASD and with symptom severity in two independent samples, a German (German-ALL: N = 583 families) and the Autism Genome Project cohort (AGP-ALL: N = 2001 families), split into HIQ, and LIQ subgroups. We did not identify any association withstanding correction for multiple testing. However, we report a replicated nominal significant under-transmission (OR < 0.79, p < 0.04) of the AKAP13 rs745191-T allele in both LIQ cohorts, but not in the much larger HIQ cohorts. At the phenotypic level, we nominally replicated associations of CAMK2A-rs2241694 with non-verbal communication in both combined LIQ and HIQ ASD cohorts. Variants PLD1-rs2124147 and ADCY1-rs2461127 were nominally associated with impaired non-verbal abilities and AKAP2-rs3739456 with repetitive behaviour in both LIQ cohorts. All four LIQ-associated genes are involved in G-protein coupled signal transduction, a downstream pathway of metabotropic glutamate receptor activation. We conclude that functional common variants of glutamatergic genes do not have a strong impact on ASD, but seem to moderately affect ASD risk and phenotypic expression. Since most of our nominally replicated hits were identified in the LIQ cohort, further investigation of the glutamatergic system in this subpopulation might be warranted.

Glutathione metabolism in the prefrontal brain of adults with high-functioning autism spectrum disorder: an MRS study.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by difficulties in social communication, unusually restricted, repetitive behavior and interests, and specific abnormalities in language and perception. The precise etiology of ASD is still unknown and probably heterogeneous. In a subgroup of patients, toxic environmental exposure might lead to an imbalance between oxidative stress and anti-oxidant systems. Previous serum and postmortem studies measuring levels of glutathione (GSH), the main cellular free radical scavenger in the brain, have supported the hypothesis that this compound might play a role in the pathophysiology of autism. METHODS: Using the method of single-voxel proton magnetic resonance spectroscopy (MRS), we analyzed the GSH signal in the dorsal anterior cingulate cortex (dACC) and the dorsolateral prefrontal cortex (DLPFC) of 24 ASD patients with normal or above average IQs and 18 matched control subjects. We hypothesized that we would find decreased GSH concentrations in both regions. RESULTS: We did not find overall group differences in neurometabolites including GSH, neither in the dorsal ACC (Wilks' lambda test; p = 0.429) nor in the DLPFC (p = 0.288). In the dACC, we found a trend for decreased GSH signals in ASD patients (p = 0.076). CONCLUSIONS: We were unable to confirm our working hypothesis regarding decreased GSH concentrations in the ASD group. Further studies combining MRS, serum, and cerebrospinal fluid measurements of GSH metabolism including other regions of interest or even whole brain spectroscopy are needed.