Common Neurobiological Substrate Research Articles

Linking emotional valence and anxiety in a mouse insula-amygdala circuit

Responses of the insular cortex (IC) and amygdala to stimuli of positive and negative valence are altered in patients with anxiety disorders. However, neural coding of both anxiety and valence by IC neurons remains unknown. Using fiber photometry recordings in mice, we uncover a selective increase of activity in IC projection neurons of the anterior (aIC), but not posterior (pIC) section, when animals are exploring anxiogenic spaces, and this activity is proportional to the level of anxiety of mice. Neurons in aIC also respond to stimuli of positive and negative valence, and the strength of response to strong negative stimuli is proportional to mice levels of anxiety. Using ex vivo electrophysiology, we characterized the IC connection to the basolateral amygdala (BLA), and employed projection-specific optogenetics to reveal anxiogenic properties of aIC-BLA neurons. Finally, we identified that aIC-BLA neurons are activated in anxiogenic spaces, as well as in response to aversive stimuli, and that both activities are positively correlated. Altogether, we identified a common neurobiological substrate linking negative valence with anxiety-related information and behaviors, which provides a starting point to understand how alterations of these neural populations contribute to psychiatric disorders.

Transdiagnostic and Disorder-Specific Resting-State Functional Network Alterations in Alcohol Use Disorder, Schizophrenia, Bipolar Affective Disorder and Obsessive-Compulsive Disorder

Introduction The ICD and DSM diagnostic categories do not represent entirely distinct entities because several cognitive impairments are shared across psychiatric disorders. Such shared cognitive impairments are hypothesized to be caused by common neurobiological substrates, one of which is transdiagnostic alterations in functional network connectivity (FNC). Objectives To investigate and compare the within-network functional connectivity (WNFC) and between-network functional connectivity (BNFC) in alcohol use disorder (AUD), schizophrenia (SCZ), bipolar affective disorder (BPAD), obsessive-compulsive disorder (OCD) and healthy controls (HC) using resting-state fMRI employing a data-driven exploratory approach. Methods The current study was a secondary analysis of data from the ADBS project in India. After pre-processing of fMRI data, a spatially and temporally constrained group-independent component analysis in the GIFT toolbox was performed using the NeuroMark templates to generate 53 independent components (ICs). These components were divided into seven functional domains including subcortical (SC), auditory (AU), sensorimotor (SM), visual (VI), cognitive-control (CC), default-mode (DM), and cerebellar (CB). To investigate the FNC correlations associated with group status (patients or HC) univariate models were applied which were subjected to corrections for multiple comparisons at an alpha=0.05 significance level using the FDR. Results The overall sample size was 249 [AUD=35, SCZ=44, BPAD=48, OCD=53, and HC=69]. Transdiagnostic WNFC alterations largely involved dysconnectivity in the CC, DM, and SC domains, resulting in ICs with both increased and decreased WNFC. Transdiagnostic BNFC alterations were primarily in the form of increased connectivity of the SC domain with various cortical domains whereas reduced connectivity was noted between AU, VI, SM, and CB domains. There was AUD-specific hyperconnectivity in the CC domain and SCZ-specific hyperconnectivity in the DM domain, and dysconnectivity in the SC domain. BPAD-specific hyperconnectivity was identified in DM and SC domains in addition to increased connectivity between CB and SM domains and decreased connectivity between CB and SC domains. All results were significant at p ≤ 0.05; [FDR] q= 0.05. Conclusions Our transdiagnostic WNFC alterations corresponded to the central executive network, default mode network, salience network, and CSTC loop, which provided transdiagnostic evidence for the triple network model of psychopathology and underlined the relevance of subcortical dysconnectivity in this model. Furthermore, our BNFC changes showed subcortical hyperconnectivity with many cortical networks, underscoring its relevance as a potential target for transdiagnostic therapeutic interventions. Disclosure of Interest None Declared

Orexin/Hypocretin System Dysfunction in ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations).

Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations (ESSENCE) is an umbrella term covering a wide range of neurodevelopmental difficulties and disorders. Thus, ESSENCE includes attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and other neurodevelopmental disorders (NDDs) and difficulties, with a variety of symptoms in cognitive, motor, sensory, social, arousal, regulatory, emotional, and behavioral developmental domains, frequently co-occurring and likely having partly common neurobiological substrates. The ESSENCE concept is a clinical paradigm that promotes organizing NDDs in everyday clinical practice according to their coexistence, symptom dimensions overlapping, and treatment possibilities. Despite increased knowledge regarding NDDs, the neurobiological mechanisms that underlie them and other ESSENCE-related problems, are not well understood. With its wide range of neural circuits and interactions with numerous neurotransmitters, the orexin/hypocretin system (Orx-S) is possibly associated with a variety of neurocognitive, psychobiological, neuroendocrine, and physiological functions and behaviors. Dysfunction of Orx-S has been implicated in various psychiatric and neurological disorders. This article provides an overview of Orx-S dysfunctions' possible involvement in the development, presentation, and maintenance of ESSENCE. We provide a focused review of current research evidence linking orexin neuropeptides with specific clinical NDDs symptoms, mostly in ADHD and ASD, within the Research Domain Criteria (RDoC) framework. We propose that Orx-S dysfunction might have an important role in some of these neurodevelopmental symptom domains, such as arousal, wakefulness, sleep, motor and sensory processing, mood and emotional regulation, fear processing, reward, feeding, attention, executive functions, and sociability. Our perspective is presented from a clinical point of view. Further, more thorough systematic reviews are needed as well as planning of extensive new research into the Orx-S's role in ESSENCE, especially considering RDoC elements.

Activity in the Dorsomedial Striatum Underlies Serial Reversal Learning Performance Under Probabilistic Uncertainty

BackgroundCorticostriatal circuits, particularly the dorsomedial striatum (DMS) and lateral orbitofrontal cortex, are critical for navigating reversal learning under probabilistic uncertainty. These same areas are implicated in the reversal learning impairments observed in individuals with psychosis as well as their psychotic symptoms, suggesting that they may share a common neurobiological substrate. To address this question, we used psychostimulant exposure and specific activation of the DMS during reversal learning in mice to assess corticostriatal activity. MethodsWe used amphetamine treatment to induce psychosis-relevant neurobiology in male mice during reversal learning and to examine pathway-specific corticostriatal activation. To determine the causal role of DMS activity, we used chemogenetics to drive midbrain inputs during a range of probabilistic contingencies. ResultsMice treated with amphetamine showed altered punishment learning, which was associated with decreased shifting after losses and increased perseverative errors after reversals. Reversal learning performance and strategies were dependent on increased activity in lateral orbitofrontal cortex to DMS circuits as well as in the DMS itself. Specific activation of midbrain to DMS circuits also decreased shifting after losses and reversal learning performance. However, these alterations were dependent on the probabilistic contingency. ConclusionsOur work suggests that the DMS plays a multifaceted role in reversal learning. Increasing DMS activity impairs multiple reversal learning processes dependent on the level of uncertainty, confirming its role in the maintenance and selection of incoming cortical inputs. Together, these outcomes suggest that elevated dopamine levels in the DMS could contribute to decision-making impairments in individuals with psychosis.

Applying dimensional psychopathology: transdiagnostic prediction of executive cognition using brain connectivity and inflammatory biomarkers.

The association between executive dysfunction, brain dysconnectivity, and inflammation is a prominent feature across major psychiatric disorders (MPDs), schizophrenia, bipolar disorder, and major depressive disorder. A dimensional approach is warranted to delineate their mechanistic interplay across MPDs. This single site study included a total of 1543 participants (1058 patients and 485 controls). In total, 1169 participants underwent diffusion tensor and resting-state functional magnetic resonance imaging (745 patients and 379 controls completed the Wisconsin Card Sorting Test). Fractional anisotropy (FA) and regional homogeneity (ReHo) assessed structural and functional connectivity, respectively. Pro-inflammatory cytokine levels [interleukin (IL)-1β, IL-6, and tumor necrosis factor-α] were obtained in 325 participants using blood samples collected with 24 h of scanning. Group differences were determined for main measures, and correlation and mediation analyses and machine learning prediction modeling were performed. Executive deficits were associated with decreased FA, increased ReHo, and elevated IL-1β and IL-6 levels across MPDs, compared to controls. FA and ReHo alterations in fronto-limbic-striatal regions contributed to executive deficits. IL-1β mediated the association between FA and cognition, and IL-6 mediated the relationship between ReHo and cognition. Executive cognition was better predicted by both brain connectivity and cytokine measures than either one alone for FA-IL-1β and ReHo-IL-6. Transdiagnostic associations among brain connectivity, inflammation, and executive cognition exist across MPDs, implicating common neurobiological substrates and mechanisms for executive deficits in MPDs. Further, inflammation-related brain dysconnectivity within fronto-limbic-striatal regions may represent a transdiagnostic dimension underlying executive dysfunction that could be leveraged to advance treatment.

Affective-cognitive-behavioral heterogeneity of Attention-Deficit/Hyperactivity Disorder (ADHD): Emotional dysregulation as a sentinel symptom differentiating “ADHD-simplex” and “ADHD-complex” syndromes?

BackgroundCurrent DSM and ICD classifications of Attention-Deficit/Hyperactivity Disorder (ADHD) exclude emotional dysregulation (ED) in their diagnostic criteria, despite ED symptoms frequently co-occurring in ADHD and likely sharing common neurobiological substrates. In this study, we examined whether consideration of ED symptoms could delineate more informative “ADHD+ED” subphenotypes. Method4106 children with ADHD were recruited. ED and inattentive (IA) and hyperactive/impulsive (HI) symptoms were profiled using latent class analyses (LCA). The derived latent class (LC) subphenotypes were evaluated and validated in relation to comorbidity patterns, executive functions, and functional impairments. ResultsFive LC subphenotypes with ED symptoms were identified: IA/HI + ED profile (LC1); HI + ED profile (LC2); IA + ED profile (LC3); IA/HI profile (LC4); and IA profile (LC5). Cross-validation of the LCA model using support vector machine analysis confirmed 83% accuracy. ED positive (ED+ve) subphenotypes were associated with higher rates of oppositional defiant disorder, mood disorders, anxiety disorders, as well as more severe autistic traits and sluggish cognitive tempo symptoms. Higher rates of ecological executive functioning impairments (BRIEF ratings) were found among ED+ve subphenotypes (though no differences were detected by laboratory-based measures). Functional impairments were also more severe among participants with ED+ve subphenotypes. LimitationsThe data for our LCA were cross-sectional and based primarily on parent ratings. ConclusionOur classification model has parcellated IA, HI, and ED symptoms into novel informative subphenotypes. These classifications provide preliminary evidence that ED symptoms could serve as sentinel features to identify a potential “ADHD-complex” syndrome, which demarcates a more pervasive condition of greater severity, complexity, and impairment.

Cortical Thickness and Clinical Findings in Prescholar Children With Autism Spectrum Disorder.

The term autism spectrum disorder (ASD) includes a wide variability of clinical presentation, and this clinical heterogeneity seems to reflect a still unclear multifactorial etiopathogenesis, encompassing different genetic risk factors and susceptibility to environmental factors. Several studies and many theories recognize as mechanisms of autism a disruption of brain development and maturation time course, suggesting the existence of common neurobiological substrates, such as defective synaptic structure and aberrant brain connectivity. Magnetic resonance imaging (MRI) plays an important role in both assessment of region-specific structural changes and quantification of specific alterations in gray or white matter, which could lead to the identification of an MRI biomarker. In this study, we performed measurement of cortical thickness in a selected well-known group of preschool ASD subjects with the aim of finding correlation between cortical metrics and clinical scores to understand the underlying mechanism of symptoms and to support early clinical diagnosis. Our results confirm that recent brain MRI techniques combined with clinical data can provide some useful information in defining the cerebral regions involved in ASD although large sample studies with homogeneous analytical and multisite approaches are needed.

Using big data of genetics, health claims, and brain imaging to challenge the categorical classification in mental illness.

Psychiatric disorders in first-degree relatives (FDRs) often differ from the index patient's diagnosis, suggesting that there is genetic contribution to psychiatric disorders in which related cases do not all map to the same diagnosis as the index case. Our aim is to look for psychiatric comorbidities across major mental illnesses using three approaches, genetics, clinical diagnosis, and brain imaging to address common associations and pathology among mental illnesses. Genome-wide association studies from the Psychiatric Genomics Consortium showed single gene polymorphisms are common across 5 major psychiatric disorders, including schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD). Clinically, results of Taiwan's nationwide population studies showed that other major psychiatric disorders were more likely to coaggregate in families with an index case of an individual with a psychiatric disorder, compared to control families. Finally, resting functional connectivity (FC) magnetic resonance imaging (MRI) and whole-brain connectomic analysis of SZ, BD I, BD II, MDD, and healthy controls revealed that the four groups of patients shared similar patterns of abnormal neural substrate in the brain that differed from controls. In conclusion, using big data from genetics, administrative health claims, and brain imaging, we identified concordance, indicating dimensional coherence of genetic heritability, clinical mutual associations, and common neurobiological substrates across major psychiatric disorders. These results will challenge the current diagnostic classification system and possibly move psychiatry beyond descriptive syndromes towards a nosology informed by disease cause.

The brain correlates of behavioral disturbances in frontotemporal dementia

AbstractBackgroundVarious studies have researched singular or clusters of behaviors in frontotemporal dementia (FTD) correlating them with regional brain atrophy in structural MRI data, or hypometabolism in FDG‐PET images, but a multimodal approach is lacking. We identify the brain correlates of modes of variation (i.e., factors) explaining the variability of behavioral and psychological symptoms (BPSD) in frontotemporal dementia (FTD) using multimodal imaging.MethodImaging and behavioral data from 93 FTD patients acquired at NIH were analyzed. They underwent extended neuropsychological assessment including several scales measuring BPSD (UCLA NPI, FrSBe, and Neurobehavioral rating scale), T1‐weighted MRI, and FDG‐PET imaging. Factor analysis was used on the behavioral data to identify modes of variation of BPSD potentially pointing to few common neurobiological substrates across the FTD sample. The identified modes were then related to intersubject brain variability using a newly developed fusion method run on maps of gray matter volume and FDG metabolism obtained.ResultA factor related to decreased emotional/cognitive interaction (loading scores of apathy, executive dysfunction, withdrawal) correlated with volume and function of the right anterior cingulate and orbito‐frontal cortex. A factor expressing variability on mutacism versus disinhibition/euphoria continuum was associated with dysfunction of the right superior primary motor cortex. A factor related to the presence of hallucinations/delusions/suspiciousness was associated with dysfunction of the right anterior insula.ConclusionBPSD variability in patients with FTD can be explained by 3 major modes of variations, each associated with intersubject brain structure/function variability of the right frontal lobe.

Corpus callosum morphology in major mental disorders: a magnetic resonance imaging study

Mental disorders diagnosis is based on specific clinical criteria. However, clinical studies found similarities and overlapping phenomenology across a variety of disorders, which suggests a common neurobiological substrate. Thus, there is a need to measure disease-related neuroanatomical similarities and differences across conditions. While structural alterations of the corpus callosum have been investigated in obsessive-compulsive disorder, schizophrenia, major depressive disorder and bipolar disorder, no study has addressed callosal aberrations in all diseases in a single study. Moreover, results from pairwise comparisons (patients vs. controls) show some inconsistencies, possibly related to the parcellation methods to divide the corpus callosum into subregions. The main aim of the present paper was to uncover highly localized callosal characteristics for each condition (i.e. obsessive-compulsive disorder, schizophrenia, major depressive disorder and bipolar disorder) as compared either to healthy control subjects or to each other. For this purpose, we did not rely on any sub-callosal parcellation method, but applied a well-validated approach measuring callosal thickness at 100 equidistant locations along the whole midline of the corpus callosum. One hundred and twenty patients (30 in each disorder) as well as 30 controls were recruited for the study. All groups were closely matched for age and gender, and the analyses were performed controlling for the impact of antipsychotic treatment and illness duration. There was a significant main effect of group along the whole callosal surface. Pairwise post hoc comparisons revealed that, compared to controls, patients with obsessive-compulsive disorder had the thinnest corpora callosa with significant effects almost on the entire callosal structure. Patients with schizophrenia also showed thinner corpora callosa than controls but effects were confined to the isthmus and the anterior part of the splenium. No significant differences were found in both major depressive disorder and bipolar disorder patients compared to controls. When comparing the disease groups to each other, the corpus callosum was thinner in obsessive-compulsive disorder patients than in any other group. The effect was evident across the entire corpus callosum, with the exception of the posterior body. Altogether, our study suggests that the corpus callosum is highly changed in obsessive-compulsive disorder, selectively changed in schizophrenia and not changed in bipolar disorder and major depressive disorder. These results shed light on callosal similarities and differences among mental disorders providing valuable insights regarding the involvement of the major brain commissural fibre tract in the pathophysiology of each specific mental illness.

Comorbidity and therapeutic response of body dysmorphic disorder (BDD) in autism spectrum disorder (ASD)

IntroductionAutism spectrum disorder (ASD) is a neurodevelopmental disorder with a biological basis overlapped with obsessive compulsive disorders and body dysmorphic disorder (BDD). The combination of pharmacological treatment and psychological interventions have been considered the gold-standardObjectivesOur main objective was to present the case of a patient with ASD and comorbid BDD. As a second objective, we reviewed recent works on the common neurobiological substrate and therapeutic options for both conditions.Methods(1)Clinical case: Patient with ASD and BDD, treated with fluoxetine 60 mg/day and aripiprazole 30 mg/day. (2)Non-systematic narrative review focused on neurobiological substrate and treatment of ASD and BDD. The electronic search was performed by the PubMed database (1990-2020) using the following key terms: “autism spectrum disorder”, “body dysmorphic disorder”, “dysmorphophobia”, “neurobiology”, “pharmacological treatment”, “psychological treatment” and “treatment”.ResultsOur patient is a 31-year-old single male fulfilling DSM-5 criteria for ASD, diagnosed in childhood, and BDD. He received pharmacological treatment and CBT. He also verbalized having been concerned with his lips and mouth for the last 10 years. This discomfort leads to passive ideas of death. Review: All articles (n=4) supported the use of selective serotonin reuptake inhibitors (SSRIs) and CBT in this comorbidity. None of them reported the use of antipsychotics. Oone article described the use of Repetitive transcranial magnetic stimulation (rTMS) and oxytocin.ConclusionsASD and BDD share the basis of corticostriatal circuits. ISRS and CBT may be effective in treatment. Other options (oxytocin or rTMS) should be further investigated. Examining this comorbidity could be useful for discovering possible endophenotypes.

Recreational Activities and d-Amphetamine Effects in High and Low Sensation Seekers

This study examined the behavioral effects of d-amphetamine and recreational activities, alone and in combination, in high and low impulsive sensation seekers. Healthy 18-27 year-old participants, scoring in the upper (N=8) or lower (N=8) third of college students on the impulsive sensation-seeking scale of the Zuckerman-Kuhlman Personality Questionnaire, completed eight test days in which sessions were completed before (i.e., baseline) and 60, 120 and 180 minutes after d-amphetamine (0, 10 mg/70 kg) administration. Between sessions, subjects completed recreational activities (movies, music, reading, videogames) identified as high or low in sensation value. Each of four conditions (low and high sensation value activities combined with placebo and active drug) was administered under double-blind conditions on 2 days according to a randomized-block design. Typical stimulant-like cardiovascular and task performance effects were engendered by d-amphetamine; consistent with previous research, the magnitude of drug effects were greater among high sensation seekers. High sensation value activities engendered independent stimulant-like effects on subject ratings. These results suggest that d-amphetamine and high sensation stimulus materials may activate a common neurobiological substrate, likely the mesolimbic dopamine system, and that individual differences in sensation seeking status play a role in vulnerability to stimulant drug abuse.

Distinct Populations of Neurons Activated by Heroin and Cocaine in the Striatum as Assessed by catFISH.

Despite the still prevailing notion of a shared substrate of action for all addictive drugs, there is evidence suggesting that opioid and psychostimulant drugs differ substantially in terms of their neurobiological and behavioral effects. These differences may reflect separate neural circuits engaged by the two drugs. Here we used the catFISH (cellular compartment analysis of temporal activity by fluorescence in situ hybridization) technique to investigate the degree of overlap between neurons engaged by heroin versus cocaine in adult male Sprague Dawley rats. The catFISH technique is a within-subject procedure that takes advantage of the different transcriptional time course of the immediate-early genes homer 1a and arc to determine to what extent two stimuli separated by an interval of 25 min engage the same neuronal population. We found that throughout the striatal complex the neuronal populations activated by noncontingent intravenous injections of cocaine (800 μg/kg) and heroin (100 and 200 μg/kg), administered at an interval of 25 min from each other, overlapped to a much lesser extent than in the case of two injections of cocaine (800 μg/kg), also 25 min apart. The greatest reduction in overlap between populations activated by cocaine and heroin was in the dorsomedial and dorsolateral striatum (∼30% and ∼22%, respectively, of the overlap observed for the sequence cocaine-cocaine). Our results point toward a significant separation between neuronal populations activated by heroin and cocaine in the striatal complex. We propose that our findings are a proof of concept that these two drugs are encoded differently in a brain area believed to be a common neurobiological substrate to drug abuse.

Error-related brain activity as a transdiagnostic endophenotype for obsessive-compulsive disorder, anxiety and substance use disorder.

Increased neural error-signals have been observed in obsessive-compulsive disorder (OCD), anxiety disorders, and inconsistently in depression. Reduced neural error-signals have been observed in substance use disorders (SUD). Thus, alterations in error-monitoring are proposed as a transdiagnostic endophenotype. To strengthen this notion, data from unaffected individuals with a family history for the respective disorders are needed. The error-related negativity (ERN) as a neural indicator of error-monitoring was measured during a flanker task from 117 OCD patients, 50 unaffected first-degree relatives of OCD patients, and 130 healthy comparison participants. Family history information indicated, that 76 healthy controls were free of a family history for psychopathology, whereas the remaining had first-degree relatives with depression (n = 28), anxiety (n = 27), and/or SUD (n = 27). Increased ERN amplitudes were found in OCD patients and unaffected first-degree relatives of OCD patients. In addition, unaffected first-degree relatives of individuals with anxiety disorders were also characterized by increased ERN amplitudes, whereas relatives of individuals with SUD showed reduced amplitudes. Alterations in neural error-signals in unaffected first-degree relatives with a family history of OCD, anxiety, or SUD support the utility of the ERN as a transdiagnostic endophenotype. Reduced neural error-signals may indicate vulnerability for under-controlled behavior and risk for substance use, whereas a harm- or error-avoidant response style and vulnerability for OCD and anxiety appears to be associated with increased ERN. This adds to findings suggesting a common neurobiological substrate across psychiatric disorders involving the anterior cingulate cortex and deficits in cognitive control.

31 - GENETIC FACTORS INFLUENCING THE COMMON NEUROBIOLOGICAL SUBSTRATE FOR MENTAL DISORDERS

Background A multitiered imaging study found grey matter loss to converge across diagnoses in three brain regions within the right and left anterior insula and in part of the dorsal anterior cingulate (Goodkind, Eickhoff et al. 2015, JAMA Psychiatry 72, 305–315). These regions thus form a common neurobiological substrate of mental disorders. The aim of our study was the identification of genetic factors contributing to the volumes of these regions in healthy individuals to obtain insights into the biological processes involved. Evidence from structural and functional connectivity analyses indicates that the common neurobiological substrate is a closely connected network. Thus, we analyzed the regions jointly. Methods Analyses were carried out in healthy subjects of five population-based cohorts: 1000BRAINS (n=539), CONNECT100 (n=93), BiDirect (n=589), SHIP-2 (n=1142), and SHIP-Trend (n=896). Voxel-based volumes were corrected for covariates (head/total brain size, sex, age, handedness). Principal component analysis on the corrected volumes was used to generate a common measure, the Component of the Common Substrate (CCS). Heritability of the CCS was estimated with GCTA. A genome-wide association study (GWAS) on the CCS was conducted in each cohort using imputed variants (1000 Genomes Phase I panel). GWAS was carried out in a two-stage design with the first four cohorts as discovery sample and SHIP-Trend for replication. GWAS were combined using a fixed-effects pooled analysis. Pathway analysis was conducted in MAGENTA using a narrow gene definition (0 kb flanking regions) and Reactome pathways; cutoff was the 75th percentile of gene p-values, p-values were corrected by FDR. Results The significant pooled estimate of the SNP-based heritability of the CCS across all cohorts was 25%. In the discovery-stage GWAS, three blocks of highly correlated variants at chromosome 5q35.2 reached genome-wide significance. Association of the lead variant in one block was significant in the replication cohort and was thus confirmed. Follow-up analyses showed that the association was driven by the insulae and supported in all three regions. Association with total grey matter volume was lower than with any CCS region. Associated variants did not overlap with protein-coding genes, yet poorly characterized non-coding RNAs map to the area. Further analyses identified six associated pathways that intersected with either neurodevelopment or with neurodegeneration. Finally, we examined whether genetic variants shaping the CCS overlapped with variants influencing the risk for mental disorders using LD score regression, polygenic risk scores and sign tests. No overlap of variants associated in recent publications with either schizophrenia, bipolar disorder or MDD was found. Discussion We discovered and replicated a significant association of intergenic SNPs with brain regions representing a common neurobiological substrate for mental disorders. No genetic correlation between variants associated with these brain volumes and variants associated with mental disorders was observed, in line with a previous publication that did not find a correlation between schizophrenia-associated and volume-associated variants from subcortical brain regions and intracranial volume (Franke et al. 2016, Nat Neurosci 19, 420–431). These regions were distinct from the regions studied here. The associations should be explored in future studies using other measures as well as functional imaging and neuropsychological approaches.

Chronic methamphetamine self-administration dysregulates 5-HT2A and mGlu2 receptor expression in the rat prefrontal and perirhinal cortex: Comparison to chronic phencyclidine and MK-801

Chronic methamphetamine (meth) abuse often turns into a compulsive drug-taking disorder accompanied by persistent cognitive deficits and re-occurring psychosis. Possible common neurobiological substrates underlying meth-induced deficits and schizophrenia remain poorly understood. Serotonin 2A (5-HT2A) and metabotropic glutamate 2 (mGlu2) receptors co-regulate psychosis-like behaviors and cognitive function in animals. Therefore, in the present study we examined the effects of chronic exposure to three different drugs known to produce persistent deficits in sensorimotor gating and cognition [meth, phencyclidine (PCP) and MK-801] on the expression of 5-HT2A and mGlu2 within the rat medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC) and perirhinal cortex (PRh). Adult male rats underwent 14 days of: (a) meth self-administration (6 h/day), (b) phencyclidine (PCP; 5 mg/kg, twice/day) administration, or (c) MK-801 (0.3 mg/kg, twice/day) administration. Seven days after the discontinuation of drug administration, tissues of interest were collected for protein expression analysis. We found that despite different pharmacological mechanism of action, chronic meth, PCP, and MK-801 similarly dysregulated 5-HT2A and mGlu2, as indicated by an increase in the 5-HT2A/mGlu2 expression ratio in the mPFC (all three tested drugs), PRh (meth and PCP), and dHPC (MK-801 only). Complementary changes in G-protein expression (increase in Gαq and decrease in Gαi) were also observed in the mPFC of meth animals. Finally, we found that 5-HT2A/mGlu2 cooperation can be mediated in part by the formation of the receptor heteromer in some, but not all cortical regions. In summary, these data suggest that a shift towards increased availability (and G-protein coupling) of cortical 5-HT2A vs. mGlu2 receptors may represent a common neurobiological mechanism underlying the emergence of psychosis and cognitive deficits observed in subjects with meth use disorder and schizophrenia.

Use of atomoxetine in eating disorders. A case report

IntroductionEating disorders (EDs) are an important public health problem and not all patients respond adequately to psychotherapy. In the last decade, researchers report a significant comorbidity of EDs and attention-deficit/hyperactivity disorder (ADHD), especially binge eating disorder and bulimia nervosa. Some studies postulate the hypothesis of a common neurobiological substrate, such as noradrenergic pathways among others.ObjectivesTo revise the possible use of atomoxetine, a highly selective noradrenergic reuptake inhibitor, for the treatment of EDs.MethodsWe describe the effect of atomoxetine in a young woman with purging disorder and history of ADHD in childhood added to cognitive behavioural therapy (CBT).Resultspatient had selective/restrictive eating behaviours, daily purges and occasional binges for last five years. At age 14 she was diagnosed with ADHD by impulsivity/aggressiveness and poor school performance, but she did not take drugs and left medical consultations. She came to our specific unit of EDs in november-2015. Her BMI was 24.88 kg/m2. We initiated CBT and atomoxetine (80 mg/day). In this first year of treatment binges and purges have disappeared and exposure to new foods and body image have improved partially. We found clear improvement in mood, motivation and attention/concentration in relation with introduction of atomoxetine. These facts have positive impact on the clinical evolution. Her current BMI is 26.90 kg/m2.ConclusionsIdentify comorbid ADHD to assess the use of specific drugs for this disorder could be beneficial in the treatment and prognosis of EDs. However, more studies are needed to determine effectivenes, particularly of non-stimulant drugs.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Are schizophrenia, autistic, and obsessive spectrum disorders dissociable on the basis of neuroimaging morphological findings?: A voxel-based meta-analysis.

Schizophrenia spectrum disorder (SCZD), autism spectrum disorder (ASD), and obsessive-compulsive spectrum disorder (OCSD) are considered as three separate psychiatric conditions with, supposedly, different brain alterations patterns. From a neuroimaging perspective, this meta-analytic study aimed to address whether this nosographical differentiation is actually supported by different brain patterns of gray matter (GM) or white matter (WM) morphological alterations. We explored two possibilities: (a) to find out whether GM alterations are specific for SCZD, ASD, and OCSD; and (b) to associate the identified brain alteration patterns with cognitive dysfunctions by means of an analysis of lesion decoding. Our analysis reveals that these psychiatric spectra do not present clear distinctive patterns of alterations; rather, they all tend to be distributed in two alteration clusters. Cluster 1, which is more specific for SCZD, includes the anterior insular, anterior cingulate cortex, ventromedial prefrontal cortex, and frontopolar areas, which are parts of the cognitive control system. Cluster 2, which is more specific for OCSD, presents occipital, temporal, and parietal alteration patterns with the involvement of sensorimotor, premotor, visual, and lingual areas, thus forming a network that is more associated with the auditory-visual, auditory, premotor visual somatic functions. In turn, ASD appears to be uniformly distributed in the two clusters. The three spectra share a significant set of alterations. Our new approach promises to provide insight into the understanding of psychiatric conditions under the aspect of a common neurobiological substrate, possibly related to neuroinflammation during brain development. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 1079-1095. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

You say 'prefrontal cortex' and I say 'anterior cingulate': meta-analysis of spatial overlap in amygdala-to-prefrontal connectivity and internalizing symptomology.

Connections between the amygdala and medial prefrontal cortex (mPFC) are considered critical for the expression and regulation of emotional behavior. Abnormalities in frontoamygdala circuitry are reported across several internalizing conditions and associated risk factors (for example, childhood trauma), which may underlie the strong phenotypic overlap and co-occurrence of internalizing conditions. However, it is unclear if these findings converge on the same localized areas of mPFC or adjacent anterior cingulate cortex (ACC). Examining 46 resting-state functional connectivity magnetic resonance imaging studies of internalizing conditions or risk factors (for example, early adversity and family history), we conducted an activation likelihood estimation meta-analysis of frontoamygdala circuitry. We included all reported amygdala to frontal coordinate locations that fell within a liberal anatomically defined frontal mask. Peak effects across studies were centered in two focal subareas of the ACC: pregenual (pgACC) and subgenual (sgACC). Using publicly available maps and databases of healthy individuals, we found that observed subareas have unique connectivity profiles, patterns of neural co-activation across a range of neuropsychological tasks, and distribution of tasks spanning various behavioral domains within peak regions, also known as ‘functional fingerprints'. These results suggest disruptions in unique amygdala–ACC subcircuits across internalizing, genetic and environmental risk studies. Based on functional characterizations and the studies contributing to each peak, observed amygdala–ACC subcircuits may reflect separate transdiagnostic neural signatures. In particular, they may reflect common neurobiological substrates involved in developmental risk (sgACC), or the broad expression of emotional psychopathology (pgACC) across disease boundaries.

Impact of partial dopamine depletion on cognitive flexibility in BDNF heterozygous mice.

Cognitive flexibility is a key component of executive function and is disrupted in major psychiatric disorders. Brain-derived neurotrophic factor (BDNF) exerts neuromodulatory effects on synaptic transmission and cognitive/affective behaviors. However, the causal mechanisms linking BDNF hypofunction with executive deficits are not well understood. Here, we assessed the consequences of BDNF hemizygosity on cognitive flexibility in mice performing an operant conditioning task. As dopaminergic-glutamatergic interaction in the striatum is important for cognitive processing, and BDNF heterozygous (BDNF(+/-)) mice display a higher dopamine tone in the dorsal striatum, we also assessed the effects of partial striatal dopamine depletion on task performance and glutamate release. BDNF(+/-) mice acquired discrimination learning as well as new rule learning during set-shifting as efficiently as wild-type mice. However, partial removal of striatal dopaminergic inputs with 6-hydroxydopamine (6-OHDA) impaired these cognitive processes by impeding the maintenance of a new learning strategy in both genotypes. BDNF mutants exhibited performance impairments during reversal learning, and these deficits were associated with increased perseveration to the previously acquired strategy. Partial dopamine depletion of the striatum reversed these cognitive impairments. Additionally, reduction in depolarization-evoked glutamate release noted in the dorsal striatum of BDNF(+/-) mice was not observed in 6-OHDA-infused BDNF mutants indicating normalization of glutamatergic transmission in these animals. Our data illustrate that BDNF signaling regulates cognitive control processes presumably by maintaining striatal dopamine-glutamate balance. Moreover, aberrations in BDNF signaling may act as a common neurobiological substrate that accounts for executive dysfunction observed in multiple psychiatric conditions.