Transdiagnostic psychopathology in the light of robust single-trial event-related potentials.

Recent evidence indicates that event-related potentials (ERPs) as measured on the electroencephalogram (EEG) are more closely related to transdiagnostic, dimensional measures of psychopathology (TDP) than to diagnostic categories. A comprehensive examination of correlations between well-studied ERPs and measures of TDP is called for. In this study, we recruited 50 patients with emotional disorders undergoing 14 weeks of transdiagnostic group psychotherapy as well as 37 healthy comparison subjects (HC) matched in age and sex. HCs were assessed once and patients three times throughout treatment (N = 172 data sets) with a battery of well-studied ERPs and psychopathology measures consistent with the TDP framework The Hierarchical Taxonomy of Psychopathology (HiTOP). ERPs were quantified using robust single-trial analysis (RSTA) methods and TDP correlations with linear regression models as implemented in the EEGLAB toolbox LIMO EEG. We found correlations at several levels of the HiTOP hierarchy. Among these, a reduced P3b was associated with the general p-factor. A reduced error-related negativity correlated strongly with worse symptomatology across the Internalizing spectrum. Increases in the correct-related negativity correlated with symptoms loading unto the Distress subfactor in the HiTOP. The Flanker N2 was related to specific symptoms of Intrusive Cognitions and Traumatic Re-experiencing and the mismatch negativity to maladaptive personality traits at the lowest levels of the HiTOP hierarchy. Our study highlights the advantages of RSTA methods and of using validated TDP constructs within a consistent framework. Future studies could utilize machine learning methods to predict TDP from a set of ERP features at the subject level.

Robust single-trial event-related potentials differentiate between distress and fear disorders.

Recent evidence indicates that measures of brain functioning as indexed by event-related potentials (ERPs) on the electroencephalogram align more closely to transdiagnostic measures of psychopathology than to categorical taxonomies. The Hierarchical Taxonomy of Psychopathology (HiTOP) is a transdiagnostic, dimensional framework aiming to solve issues of comorbidity, symptom heterogeneity, and arbitrary diagnostic boundaries. Based on shared features, the emotional disorders are allocated into subfactors Distress and Fear. Evidence indicates that disorders that are close in the HiTOP hierarchy share etiology, symptom profiles, and treatment outcomes. However, further studies testing the biological underpinnings of the HiTOP are called for. In this study, we assessed differences between Distress and Fear in a range of well-studied ERP components. In total, 50 patients with emotional disorders were divided into two groups (Distress, N = 25; Fear, N = 25) according to HiTOP criteria and compared against 37 healthy comparison (HC) subjects. Addressing issues in traditional ERP preprocessing and analysis methods, we applied robust single-trial analysis as implemented in the EEGLAB toolbox LIMO EEG. Several ERP components were found to differ between the groups. Surprisingly, we found no difference between Fear and HC for any of the ERPs. This suggests that some well-established results from the literature, e.g., increased error-related negativity in OCD, are not a shared neurobiological correlate of the Fear subfactor. Conversely, for Distress, we found reductions compared to Fear and HC in several ERP components across paradigms. Future studies could utilize HiTOP-validated psychopathology measures to more precisely define subfactor groups.

Clonidine augmentation in patients with schizophrenia: A double-blind, randomized placebo-controlled trial.

INTRODUCTION: Noradrenergic imbalance in the brain of schizophrenia patients may underlie both symptomatology and deficits in basic information processing. The current study investigated whether augmentation with the noradrenergic α2-agonist clonidine might alleviate these symptoms. METHODS: In a double-blind placebo-controlled randomized clinical trial, 32 chronic schizophrenia patients were randomly assigned to six-weeks augmentation with either 50 µg clonidine or placebo to their current medication. Effects on symptom severity and both sensory- and sensorimotor gating were assessed at baseline, 3- and 6-weeks. Results were compared with 21 age- and sex-matched healthy controls (HC) who received no treatment. RESULTS: Only patients treated with clonidine showed significantly reduced PANSS negative, general and total scores at follow-up compared to baseline. On average, also patients treated with placebo showed minor (non-significant) reductions in these scores, likely indicating a placebo effect. Sensorimotor gating of patients was significantly lower at baseline compared to controls. It increased in patients treated with clonidine over the treatment period, whereas it decreased in both the HC and patients treated with placebo. However, neither treatment nor group effects were found in sensory gating. Clonidine treatment was very well tolerated. CONCLUSION: Only patients treated with clonidine showed a significant decrease on two out of the three PANSS subscales, while additionally retained their levels of sensorimotor gating. Given that there are only a few reports on effective treatment for negative symptoms in particular, our current results support augmentation of antipsychotics with clonidine as a promising, low-cost and safe treatment strategy for schizophrenia.

Clustering of antipsychotic-naïve patients with schizophrenia based on functional connectivity from resting-state electroencephalography.

Schizophrenia is associated with aberrations in the Default Mode Network (DMN), but the clinical implications remain unclear. We applied data-driven, unsupervised machine learning based on resting-state electroencephalography (rsEEG) functional connectivity within the DMN to cluster antipsychotic-naïve patients with first-episode schizophrenia. The identified clusters were investigated with respect to psychopathological profile and cognitive deficits. Thirty-seven antipsychotic-naïve, first-episode patients with schizophrenia (mean age 24.4 (5.4); 59.5% males) and 97 matched healthy controls (mean age 24.0 (5.1); 52.6% males) underwent assessments of rsEEG, psychopathology, and cognition. Source-localized, frequency-dependent functional connectivity was estimated using Phase Lag Index (PLI). The DMN-PLI was factorized for each frequency band using principal component analysis. Clusters of patients were identified using a Gaussian mixture model and neurocognitive and psychopathological profiles of identified clusters were explored. We identified two clusters of patients based on the theta band (4-8 Hz), and two clusters based on the beta band (12-30 Hz). Baseline psychopathology could predict theta clusters with an accuracy of 69.4% (p = 0.003), primarily driven by negative symptoms. Five a priori selected cognitive functions conjointly predicted the beta clusters with an accuracy of 63.6% (p = 0.034). The two beta clusters displayed higher and lower DMN connectivity, respectively, compared to healthy controls. In conclusion, the functional connectivity within the DMN provides a novel, data-driven means to stratify patients into clinically relevant clusters. The results support the notion of biological subgroups in schizophrenia and endorse the application of data-driven methods to recognize pathophysiological patterns at earliest stage of this syndrome.

Prediction of Behavioral Improvement Through Resting-State Electroencephalography and Clinical Severity in a Randomized Controlled Trial Testing Bumetanide in Autism Spectrum Disorder.

BACKGROUND: Mechanism-based treatments such as bumetanide are being repurposed for autism spectrum disorder. We recently reported beneficial effects on repetitive behavioral symptoms that might be related to regulating excitation-inhibition (E/I) balance in the brain. Here, we tested the neurophysiological effects of bumetanide and the relationship to clinical outcome variability and investigated the potential for machine learning-based predictions of meaningful clinical improvement. METHODS: Using modified linear mixed models applied to intention-to-treat population, we analyzed E/I-sensitive electroencephalography (EEG) measures before and after 91 days of treatment in the double-blind, randomized, placebo-controlled Bumetanide in Autism Medication and Biomarker study. Resting-state EEG of 82 subjects out of 92 participants (7-15 years) were available. Alpha frequency band absolute and relative power, central frequency, long-range temporal correlations, and functional E/I ratio treatment effects were related to the Repetitive Behavior Scale-Revised (RBS-R) and the Social Responsiveness Scale 2 as clinical outcomes. RESULTS: We observed superior bumetanide effects on EEG, reflected in increased absolute and relative alpha power and functional E/I ratio and in decreased central frequency. Associations between EEG and clinical outcome change were restricted to subgroups with medium to high RBS-R improvement. Using machine learning, medium and high RBS-R improvement could be predicted by baseline RBS-R score and EEG measures with 80% and 92% accuracy, respectively. CONCLUSIONS: Bumetanide exerts neurophysiological effects related to clinical changes in more responsive subsets, in whom prediction of improvement was feasible through EEG and clinical measures.

Effects of methylphenidate on mismatch negativity and P3a amplitude of initially psychostimulant-naïve, adult ADHD patients.

BACKGROUND: Deficient information processing in ADHD theoretically results in sensory overload and may underlie the symptoms of the disorder. Mismatch negativity (MMN) and P3a amplitude reflect an individual's detection and subsequent change in attention to stimulus change in their environment. Our primary aim was to explore MMN and P3a amplitude in adult ADHD patients and to examine the effects of methylphenidate (MPH) on these measures. METHODS: Forty initially psychostimulant-naïve, adult ADHD patients without comorbid ASD and 42 matched healthy controls (HC) were assessed with an MMN paradigm at baseline. Both groups were retested after 6 weeks, in which patients were treated with MPH. RESULTS: Neither significant group differences in MMN nor P3a amplitude were found at baseline. Although 6-week MPH treatment significantly reduced symptomatology and improved daily functioning of the patients, it did not significantly affect MMN amplitude; however, it did significantly reduce P3a amplitude compared to the HC. Furthermore, more severe ADHD symptoms were significantly associated with larger MMN amplitudes in the patients, both at baseline and follow-up. CONCLUSION: We found no evidence for early information processing deficits in patients with ADHD, as measured with MMN and P3a amplitude. Six-week treatment with MPH decreased P3a but not MMN amplitude, although more severe ADHD-symptoms were associated with larger MMN amplitudes in the patients. Given that P3a amplitude represents an important attentional process and that glutamate has been linked to both ADHD and MMN amplitude, future research should investigate augmenting MPH treatment of less responsive adults with ADHD with glutamatergic antagonists.

Atypical Semantic Fluency and Recall in Children and Adolescents with Autism Spectrum Disorders Associated with Autism Symptoms and Adaptive Functioning.

It is unclear whether children with autism spectrum disorders have atypical semantic fluency and lower memory for the semantics of words. Therefore, we examined semantic typicality, fluency and recall for the categories of fruits and animals in 60 children with autism aged 7-15 years (boys: 48/girls: 12) compared to 60 typically developing controls. Relative to controls, the autism group had reduced animal fluency, fruit typicality and recall for fruits. Notably, these measures were associated with more autistic-like symptoms and/or lower adaptive functioning across the autism and control groups. In conclusion, atypical semantics of fruits in the autism group may reflect development of idiosyncratic semantic networks while their lower semantic fluency and recall suggest impaired executive language functions.

Stratifying the autistic phenotype using electrophysiological indices of social perception.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties in social communication, but also great heterogeneity. To offer individualized medicine approaches, we need to better target interventions by stratifying autistic people into subgroups with different biological profiles and/or prognoses. We sought to validate neural responses to faces as a potential stratification factor in ASD by measuring neural (electroencephalography) responses to faces (critical in social interaction) in N = 436 children and adults with and without ASD. The speed of early-stage face processing (N170 latency) was on average slower in ASD than in age-matched controls. In addition, N170 latency was associated with responses to faces in the fusiform gyrus, measured with functional magnetic resonance imaging, and polygenic scores for ASD. Within the ASD group, N170 latency predicted change in adaptive socialization skills over an 18-month follow-up period; data-driven clustering identified a subgroup with slower brain responses and poor social prognosis. Use of a distributional data-driven cutoff was associated with predicted improvements of power in simulated clinical trials targeting social functioning. Together, the data provide converging evidence for the utility of the N170 as a stratification factor to identify biologically and prognostically defined subgroups in ASD.

In-depth characterization of neuroradiological findings in a large sample of individuals with autism spectrum disorder and controls.

BACKGROUND: Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions associated with quantitative differences in cortical and subcortical brain morphometry. Qualitative assessment of brain morphology provides complementary information on the possible underlying neurobiology. Studies of neuroradiological findings in ASD have rendered mixed results, and await robust replication in a sizable and independent sample. METHODS: We systematically and comprehensively assessed neuroradiological findings in a large cohort of participants with ASD and age-matched controls (total N = 620, 348 ASD and 272 controls), including 70 participants with intellectual disability (47 ASD, 23 controls). We developed a comprehensive scoring system, augmented by standardized biometric measures. RESULTS: There was a higher incidence of neuroradiological findings in individuals with ASD (89.4 %) compared to controls (83.8 %, p = .042). Certain findings were also more common in ASD, in particular opercular abnormalities (OR 1.9, 95 % CI 1.3-3.6) and mega cisterna magna (OR 2.4, 95 % CI 1.4-4.0) reached significance when using FDR, whereas increases in macrocephaly (OR 2.0, 95 % CI 1.2-3.2), cranial deformities (OR 2.4, 95 % CI: 1.0-5.8), calvarian / dural thickening (OR 1.5, 95 % CI 1.0-2.3), ventriculomegaly (OR 3.4, 95 % CI 1.3-9.2), and hypoplasia of the corpus callosum (OR 2.7, 95 % CI 1.1-6.3) did not survive this correction. Furthermore, neuroradiological findings were more likely to occur in isolation in controls, whereas they clustered more frequently in ASD. The incidence of neuroradiological findings was higher in individuals with mild intellectual disability (95.7 %), irrespective of ASD diagnosis. CONCLUSION: There was a subtly higher prevalence of neuroradiological findings in ASD, which did not appear to be specific to the condition. Individual findings or clusters of findings may point towards the neurodevelopmental mechanisms involved in individual cases. As such, clinical MRI assessments may be useful to guide further etiopathological (genetic) investigations, and are potentially valuable to fundamental ASD research.

Mismatch negativity and P3a amplitude in children with familial high risk of schizophrenia or bipolar disorder - A Danish register-based EEG study.

BACKGROUND: Infrequent deviants in a rapid sequence of sounds elicit a negative cortical potential over the frontocentral midline (mismatch negativity, MMN) followed by a positive deflection (P3a). Both cortical potentials are consistently attenuated in patients with schizophrenia (SZ), and, to a lesser degree, in patients with bipolar disorder (BP). OBJECTIVE: Since it is unclear when MMN and P3a deficits arise relative to the emergence of symptoms, we examined whether MMN and P3a alterations are already detectable in children with familial high risk. METHODS: Using 128-channel electroencephalography, we recorded auditory MMN and P3a evoked by a deviation in sound duration, frequency, or both in 51 children with familial high-risk for SZ (FHR-SZ), 41 children with familial high-risk for BP (FHR-BP), and 39 population-based children (PBC) at a mean age of 12.10. RESULTS: MMN amplitude evoked by a duration deviant was larger in children with FHR-BP compared to PBC and FHR-SZ. P3a amplitude in response to a duration ∗ frequency deviant was larger in children with FHR-BP compared to children with FHR-SZ, but not compared to PBC. MMN- and P3a-peak latency did not differ between groups. CONCLUSIONS: At an age of around 12 years, children with FHR-BP display enhanced neural sensitivity to change detection of duration deviants, while FHR-SZ showed a normal response pattern. Longitudinal recordings in high-risk children during adolescence are required to elucidate the temporal trajectories of MMN and P3a responses and how they relate to the emergence of first clinical symptoms in SZ and BP.

Prepulse Inhibition and P50 Suppression in Relation to Creativity and Attention: Dispersed Attention Beneficial to Quantitative but Not Qualitative Measures of Divergent Thinking.

The current study investigated whether lower sensory and sensorimotor gating were related to higher levels of creativity and/or attentional difficulties in a natural population of primary school children (9- to 13-year-old). Gating abilities were measured with P50 suppression and prepulse inhibition of the startle reflex (PPI). The final sample included 65 participants in the P50 analyses and 37 participants in the PPI analyses. Our results showed that children with a high P50 amplitude to testing stimuli scored significantly higher on the divergent outcome measures of fluency and flexibility but not originality compared to children with a lower amplitude. No significant differences were found on any of the creativity measures when the sample was split on average PPI parameters. No significant differences in attention, as measured with a parent questionnaire, were found between children with low or high levels of sensory or sensorimotor gating. The data suggest that quantitative, but not qualitative measures of divergent thinking benefit from lower psychophysiological gating and that attentional difficulties stem from specific instead of general gating deficits. Future studies should take the effect of controlled attention into consideration.

Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study.

Neuronal excitation-inhibition (E/I) imbalances are considered an important pathophysiological mechanism in neurodevelopmental disorders. Preclinical studies on tuberous sclerosis complex (TSC), suggest that altered chloride homeostasis may impair GABAergic inhibition and thereby E/I-balance regulation. Correction of chloride homeostasis may thus constitute a treatment target to alleviate behavioral symptoms. Recently, we showed that bumetanide-a chloride-regulating agent-improved behavioral symptoms in the open-label study Bumetanide to Ameliorate Tuberous Sclerosis Complex Hyperexcitable Behaviors trial (BATSCH trial; Eudra-CT: 2016-002408-13). Here, we present resting-state EEG as secondary analysis of BATSCH to investigate associations between EEG measures sensitive to network-level changes in E/I balance and clinical response to bumetanide. EEGs of 10 participants with TSC (aged 8-21 years) were available. Spectral power, long-range temporal correlations (LRTC), and functional E/I ratio (fE/I) in the alpha-frequency band were compared before and after 91 days of treatment. Pre-treatment measures were compared against 29 typically developing children (TDC). EEG measures were correlated with the Aberrant Behavioral Checklist-Irritability subscale (ABC-I), the Social Responsiveness Scale-2 (SRS-2), and the Repetitive Behavior Scale-Revised (RBS-R). At baseline, TSC showed lower alpha-band absolute power and fE/I than TDC. Absolute power increased through bumetanide treatment, which showed a moderate, albeit non-significant, correlation with improvement in RBS-R. Interestingly, correlations between baseline EEG measures and clinical outcomes suggest that most responsiveness might be expected in children with network characteristics around the E/I balance point. In sum, E/I imbalances pointing toward an inhibition-dominated network are present in TSC. We established neurophysiological effects of bumetanide although with an inconclusive relationship with clinical improvement. Nonetheless, our results further indicate that baseline network characteristics might influence treatment response. These findings highlight the possible utility of E/I-sensitive EEG measures to accompany new treatment interventions for TSC. Clinical Trial Registration: EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016.

Event-related potentials and use of psychotropic medication in major psychiatric disorders.

BACKGROUND: Attention deficits measured using event-related potentials (ERPs) have been frequently reported in several major psychiatric disorders, e.g. mood disorder (MD), psychotic disorder (PD) and substance use disorder (SUD). However, comparisons between these specific categories are lacking. Here we investigated if electrophysiological parameters of basic information processing are associated with the above-mentioned categories of psychiatric disorders, or instead were associated with general psychopathology. METHODS: 579 subjects with MD, PD or SUD and healthy controls (HC) were included. Participants were tested in a passive auditory and an active visual oddball paradigm to assess mismatch negativity (MMN), P3A and P3B amplitudes. Additionally, we examined associations between these measures and psychoactive medication treatments. RESULTS: All patients had significantly lower P3B amplitudes compared to healthy controls, while only SUD patients had lower P3A amplitudes than MD, PD and HC. PD patients also produced significantly less MMN than both MD and SUD patients. Additionally, we found significantly higher P3B amplitude in HC compared to patients without psychopharmacological treatment and patients treated with two or more psychoactive compounds (polypharmacy), but no significant associations with medication on P3A and MMN amplitudes. CONCLUSIONS: Our results add to the theory that P3B deficits are associated with general psychopathology, whereas P3A and MMN deficits appear to be associated with substance abuse and psychotic disorders respectively.

Reduced mismatch negativity in children and adolescents with autism spectrum disorder is associated with their impaired adaptive functioning.

Children and adolescents on the autism spectrum display sensory disturbances, rigid and repetitive behavior, social communication problems and a high prevalence of impaired adaptive functioning. Autism is associated with slowed behavioral and neural habituation to repeated sensory input and decreased responses to sensory deviations. Mismatch negativity (MMN) reflects a pre-attentive difference in the neural response to sensory deviations relative to regularities and studies overall suggest that children and adolescents with autism tend to have smaller MMN. However, it remains unclear whether reduced MMN in autism is coupled to severity of specific autistic symptoms or more generally to lower level of adaptive functioning. To address these questions, the present study used electroencephalography (EEG) to assess whether auditory MMN in 59 children and adolescents with autism aged 7-14 years compared to 59 typically developing children and adolescents were related to specific autistic symptoms or level in adaptive functioning. As hypothesized, the autism group had a lower MMN amplitude than controls. Smaller MMN amplitudes were specifically associated with lower adaptive functioning in the autistic subjects but not in controls while no apparent relationships were observed with autistic-like social interaction and communication problems, atypical language, rigidity, stereotypy or sensory sensitivity symptoms. Our findings indicate that a blunted response to changes in sensory input may underlie or contribute to the generalized difficulties with adapting to daily life circumstances seen in children and adolescents with autism. LAY SUMMARY: Children and adolescents on the autism spectrum have a high prevalence of impaired adaptive functioning. Neuroimaging studies have reported that children and adolescents with autism display attenuated brain activity when discriminating sensory input. However, it is unknown whether this attenuation is related to autistic symptoms and/or adaptive functioning. The present study used electroencephalogram (EEG) to show that attenuated brain response in discrimination of novel compared to repetitive sounds in children and adolescents with autism is related to their impaired adaptive functioning.

Resting state EEG power spectrum and functional connectivity in autism: a cross-sectional analysis.

BACKGROUND: Understanding the development of the neuronal circuitry underlying autism spectrum disorder (ASD) is critical to shed light into its etiology and for the development of treatment options. Resting state EEG provides a window into spontaneous local and long-range neuronal synchronization and has been investigated in many ASD studies, but results are inconsistent. Unbiased investigation in large and comprehensive samples focusing on replicability is needed. METHODS: We quantified resting state EEG alpha peak metrics, power spectrum (PS, 2-32 Hz) and functional connectivity (FC) in 411 children, adolescents and adults (n = 212 ASD, n = 199 neurotypicals [NT], all with IQ > 75). We performed analyses in source-space using individual head models derived from the participants' MRIs. We tested for differences in mean and variance between the ASD and NT groups for both PS and FC using linear mixed effects models accounting for age, sex, IQ and site effects. Then, we used machine learning to assess whether a multivariate combination of EEG features could better separate ASD and NT participants. All analyses were embedded within a train-validation approach (70%-30% split). RESULTS: In the training dataset, we found an interaction between age and group for the reactivity to eye opening (p = .042 uncorrected), and a significant but weak multivariate ASD vs. NT classification performance for PS and FC (sensitivity 0.52-0.62, specificity 0.59-0.73). None of these findings replicated significantly in the validation dataset, although the effect size in the validation dataset overlapped with the prediction interval from the training dataset. LIMITATIONS: The statistical power to detect weak effects-of the magnitude of those found in the training dataset-in the validation dataset is small, and we cannot fully conclude on the reproducibility of the training dataset's effects. CONCLUSIONS: This suggests that PS and FC values in ASD and NT have a strong overlap, and that differences between both groups (in both mean and variance) have, at best, a small effect size. Larger studies would be needed to investigate and replicate such potential effects.

Subtly altered topological asymmetry of brain structural covariance networks in autism spectrum disorder across 43 datasets from the ENIGMA consortium.

Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture network connectivity between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1455 individuals with ASD and 1560 controls, across 43 independent datasets of the ENIGMA consortium's ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered average asymmetry of networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, involving higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve executive functions, language-related and sensorimotor processes. These findings provide a network-level characterization of altered left-right brain asymmetry in ASD, based on a large combined sample. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.

Effects of methylphenidate on sensory and sensorimotor gating of initially psychostimulant-naïve adult ADHD patients.

Deficient information processing in ADHD theoretically results in sensory overload, which in turn may underlie its symptoms. If this sensory overload is caused by deficient filtering of environmental stimuli, then one would expect finding deficits in P50 gating and prepulse inhibition of the startle reflex (PPI). Previous reports on these measures in ADHD have shown inconsistent findings, which may have been caused by either medication use or comorbidity (e.g. ASD). The primary aim of this study was therefore to explore P50 suppression and PPI in adult, psychostimulant-naïve patients with ADHD without major comorbidity, and to examine the effects of 6 weeks treatment with methylphenidate (MPH) on these measures. A total of 42 initially psychostimulant-naive, adult ADHD patients without major comorbidity and 42 matched healthy controls, were assessed for their P50 gating, PPI, and habituation/sensitization abilities at baseline and after 6 weeks of treatment with methylphenidate. Although six weeks of treatment with MPH significantly reduced symptomatology as well as improved daily life functioning in our patients, it neither significantly affected PPI, P50 suppression nor sensitization, but habituation unexpectedly decreased. The absence of PPI and P50 suppression deficits in our patients in the psychostimulant-naïve state indicates no gating deficits. In turn, this suggests that the difficulties to inhibit distraction of attention by irrelevant stimuli that many patients with (adult) ADHD report, have a different origin than the theoretical causes of sensory overload frequently reported in studies on patients with schizophrenia.

"Include me if you can"-reasons for low enrollment of pediatric patients in a psychopharmacological trial.

BACKGROUND: Low recruitment in clinical trials is a common and costly problem which undermines medical research. This study aimed to investigate the challenges faced in recruiting children and adolescents with obsessive-compulsive disorder and autism spectrum disorder for a randomized, double-blind, placebo-controlled clinical trial and to analyze reasons for non-participation. The trial was part of the EU FP7 project TACTICS (Translational Adolescent and Childhood Therapeutic Interventions in Compulsive Syndromes). METHODS: Demographic data on pre-screening patients were collected systematically, including documented reasons for non-participation. Findings were grouped according to content, and descriptive statistical analyses of the data were performed. RESULTS: In total, n = 173 patients were pre-screened for potential participation in the clinical trial. Of these, only five (2.9%) were eventually enrolled. The main reasons for non-inclusion were as follows: failure to meet all inclusion criteria/meeting one or more of the exclusion criteria (n = 73; 42.2%), no interest in the trial or trials in general (n = 40; 23.1%), and not wanting changes to current therapy/medication (n = 14; 8.1%). CONCLUSIONS: The findings from this study add valuable information to the existing knowledge on reasons for low clinical trial recruitment rates in pediatric psychiatric populations. Low enrollment and high exclusion rates raise the question of whether such selective study populations are representative of clinical patient cohorts. Consequently, the generalizability of the results of such trials may be limited. The present findings will be useful in the development of improved recruitment strategies and may guide future research in establishing the measurement of representativeness to ensure enhanced external validity in psychopharmacological clinical trials in pediatric populations. TRIAL REGISTRATION: EudraCT 2014-003080-38 . Registered on 14 July 2014.

Developmental changes in fronto-striatal glutamate and their association with functioning during inhibitory control in autism spectrum disorder and obsessive compulsive disorder.

Autism spectrum disorder (ASD) and obsessive compulsive disorder (OCD) show overlapping symptomatology and deficits in inhibitory control, which are associated with altered functioning and glutamatergic signaling in fronto-striatal circuitry. These parameters have never been examined together. The purpose of the current study was to investigate functioning during inhibitory control and its association with fronto-striatal glutamate concentrations across these disorders using a multi-center, longitudinal approach. Adolescents with ASD (n = 24), OCD (n = 15) and controls (n = 35) underwent two magnetic resonance imaging (MRI) sessions with a one-year interval. This included proton magnetic resonance spectroscopy (1H-MRS; n = 74) and functional MRI during an inhibitory control task (n = 53). We investigated 1H-MRS data and fMRI data separately as well as integrated in a multimodal analysis using linear models focusing on diagnosis and continuous measures of overlapping compulsivity symptoms. ACC glutamate was reduced over time in the ASD group compared with controls, while striatal glutamate decreased over time independent of diagnosis. Increased compulsive behavior seemed to be associated with increased striatal activity during failed inhibitory control. The integrated analyses showed differential involvement of increased striatal glutamate during failed but decreased striatal glutamate during successful inhibitory control in the OCD group compared to controls and ASD, suggesting different underlying mechanisms for OCD compared to ASD.