Symptoms Of Neuropsychiatric Disorders Research Articles

Atrophy of posteromedial sulci in aging and Alzheimer’s disease differs by sulcal type and location

AbstractBackgroundRecent work has shown that the morphology of tertiary sulci — small, evolutionarily‐newer sulci that emerge last in gestation — is associated with individual differences in cognitive development and symptoms of neuropsychiatric disorders, but these sulci have not been investigated in aging. Here we extend these findings on tertiary sulci to the aging brain.MethodWe manually defined sulci on cortical surface reconstructions of T1 MRI scans in FreeSurfer and extracted the cortical thickness and mean anterior coordinate of each sulcus. We defined sulci in posteromedial cortex (PMC) in 72 younger adults (YA; age 18‐35) from the Human Connectome Project, 72 cognitively normal older adults (OA; age 65‐90) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), and 72 age‐matched amyloid positive older adults with AD from ADNI: 4,341 sulci total. We used a mixed‐effects ANOVA to examine the effects of group (YA, OA, AD) as a between‐subject variable, and sulcal type (tertiary or non‐tertiary) and hemisphere (left/right) as within‐subject variables on sulcal cortical thickness. We used LASSO regression with nested cross‐validation for feature selection to determine which sulcal measures are most related to ADNI Memory Composite (MEM) scores, and LOOCV linear regression to predict MEM scores from the best model. Because not all sulci are found in all participants, only the most consistent were included in the LASSO models.ResultIn PMC, tertiary sulci show more age‐ and AD‐related thinning compared to non‐tertiary (group x sulcal type interaction p<.0001; Fig. 1). Additionally, atrophy in PMC shows a more anterior bias in aging that is absent in AD (Fig. 2). The best model for predicting ADNI‐MEM scores relies on a subset of mostly posterior sulci, suggesting a posterior shift in atrophy may be more related to cognitive decline (Fig. 3).ConclusionThis is the first study to investigate tertiary sulci in aging and AD. Results show tertiary sulci in PMC are especially vulnerable to atrophy in aging and that a subset of PMC sulci are particularly associated with memory. The results provide insight into the anatomical specificity of age‐ and AD‐related atrophy in PMC and its association with cognitive decline.

Atrophy of posteromedial sulci in aging and Alzheimer’s disease differs by sulcal type and location

AbstractBackgroundRecent work has shown that the morphology of tertiary sulci — small, evolutionarily‐newer sulci that emerge last in gestation — is associated with individual differences in cognitive development and symptoms of neuropsychiatric disorders, but these sulci have not been investigated in aging. Here we extend these findings on tertiary sulci to the aging brain.MethodWe manually defined sulci on cortical surface reconstructions of T1 MRI scans in FreeSurfer and extracted the cortical thickness and mean anterior coordinate of each sulcus. We defined sulci in posteromedial cortex (PMC) in 72 younger adults (YA; age 18‐35) from the Human Connectome Project, 72 cognitively normal older adults (OA; age 65‐90) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), and 72 age‐matched amyloid positive older adults with AD from ADNI: 4,341 sulci total. We used a mixed‐effects ANOVA to examine the effects of group (YA, OA, AD) as a between‐subject variable, and sulcal type (tertiary or non‐tertiary) and hemisphere (left/right) as within‐subject variables on sulcal cortical thickness. We used LASSO regression with nested cross‐validation for feature selection to determine which sulcal measures are most related to ADNI Memory Composite (MEM) scores, and LOOCV linear regression to predict MEM scores from the best model. Because not all sulci are found in all participants, only the most consistent were included in the LASSO models.ResultIn PMC, tertiary sulci show more age‐ and AD‐related thinning compared to non‐tertiary (group x sulcal type interaction p<.0001; Fig. 1). Additionally, atrophy in PMC shows a more anterior bias in aging that is absent in AD (Fig. 2). The best model for predicting ADNI‐MEM scores relies on a subset of mostly posterior sulci, suggesting a posterior shift in atrophy may be more related to cognitive decline (Fig. 3).ConclusionThis is the first study to investigate tertiary sulci in aging and AD. Results show tertiary sulci in PMC are especially vulnerable to atrophy in aging and that a subset of PMC sulci are particularly associated with memory. The results provide insight into the anatomical specificity of age‐ and AD‐related atrophy in PMC and its association with cognitive decline.

Stress deficits in reward behaviour are associated with and replicated by dysregulated amygdala-nucleus accumbens pathway function in mice

Reduced reward interest/learning and reward-to-effort valuation are distinct, common symptoms in neuropsychiatric disorders for which chronic stress is a major aetiological factor. Glutamate neurons in basal amygdala (BA) project to various regions including nucleus accumbens (NAc). The BA-NAc neural pathway is activated by reward and aversion, with many neurons being monovalent. In adult male mice, chronic social stress (CSS) leads to reduced discriminative reward learning (DRL) associated with decreased BA-NAc activity, and to reduced reward-to-effort valuation (REV) associated, in contrast, with increased BA-NAc activity. Chronic tetanus toxin BA-NAc inhibition replicates the CSS-DRL effect and causes a mild REV reduction, whilst chronic DREADDs BA-NAc activation replicates the CSS effect on REV without affecting DRL. This study provides evidence that stress disruption of reward processing involves the BA-NAc neural pathway; the bi-directional effects implicate opposite activity changes in reward (learning) neurons and aversion (effort) neurons in the BA-NAc pathway following chronic stress.

Transcranial direct current stimulation (tDCS) in depression induces structural plasticity

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique involving administration of well-tolerated electrical current to the brain through scalp electrodes. TDCS may improve symptoms in neuropsychiatric disorders, but mixed results from recent clinical trials underscore the need to demonstrate that tDCS can modulate clinically relevant brain systems over time in patients. Here, we analyzed longitudinal structural MRI data from a randomized, double-blind, parallel-design clinical trial in depression (NCT03556124, N = 59) to investigate whether serial tDCS individually targeted to the left dorso-lateral prefrontal cortex (DLPFC) can induce neurostructural changes. Significant (FWEc p < 0.05) treatment-related gray matter changes were observed with active high-definition (HD) tDCS relative to sham tDCS within the left DLPFC stimulation target. No changes were observed with active conventional tDCS. A follow-up analysis within individual treatment groups revealed significant gray matter increases with active HD-tDCS in brain regions functionally connected with the stimulation target, including the bilateral DLPFC, bilateral posterior cingulate cortex, subgenual anterior cingulate cortex, and the right hippocampus, thalamus and left caudate brain regions. Integrity of blinding was verified, no significant differences in stimulation-related discomfort were observed between treatment groups, and tDCS treatments were not augmented by any other adjunct treatments. Overall, these results demonstrate that serial HD-tDCS leads to neurostructural changes at a predetermined brain target in depression and suggest that such plasticity effects may propagate over brain networks.

Prediction of Cognitive Decline by Behavioral Symptoms in Neuropsychiatric Disorders

Background: Neuropsychiatric disorders are described by their neurological, behavioral, and cognitive symptoms. However, behavioral symptoms may often be overlooked due to the current approach in neurology. Objectives: This study investigated the relationship between behavioral symptoms and cognitive functioning in neurological disorders. The second aim was to predict neurocognitive patterns by behavioral symptoms as independent variables. Methods: Behavioral symptoms were collected based on semi-structured neuropsychiatric interviews with 211 patients admitted to the neuropsychiatry department of Ayatollah Kashani hospital in Isfahan by both a neuropsychiatry fellow and an attending neuropsychiatrist. A neuropsychiatry fellow assessed all patients using the neuropsychiatry unit cognitive (NUCog) assessment tool. We used a generalized linear model (GLM) to indicate the effect of behavioral symptoms on the risk of decline in cognitive domains. Due to the use of all available samples, this study had no age limit, and the patients were 15 to 92 years old. Results: The regression coefficient of NUCog subscale scores for behavioral symptoms using GLM revealed that education level had a positive relationship with the scores of attention (P &lt; 0.001), visuoconstruction (P &lt; 0.001), memory (P &lt; 0.001), executive function (P &lt; 0.001), language (P &lt; 0.001), and the total score of NUCog (P &lt; 0.001). Patients with apathy had lower scores on the memory subscale (P = 0.002) and total NUCog (P = 0.021). Similarly, patients with delusion had lower scores on memory (P = 0.006) and executive function (P = 0.026). There was a negative relationship between agitation and attention (P = 0.049), visuoconstruction (P = 0.015), memory (P = 0.018), executive function (P = 0.005), and total score of NUCog (P = 0.007). Sleep disturbances were accompanied by lower memory scores (P = 0.056) and lower mean NUCog scores (P = 0.052). Visual hallucination was associated with declined performance in attention (P = 0.057). Conclusions: Behavioral assessment can help predict cognitive patterns in patients with neurobehavioral syndromes.

Mind reading improvements in mentalization-based therapy training.

The psychological strain of many psychiatric disorders arises from difficulties encountered in social interactions. Social withdrawal is often the first symptom of neuropsychiatric disorders. The authors explore the various options for training social cognition skills. Social cognition was assessed using the Movie for the Assessment of Social Cognition (MASC). After completion of mentalization-based therapy (MBT) training, MASC scores improved significantly in health care providers (p = .006, r = .57). Mentalizing (operationalized with reflective functioning [RF]) was assessed in the MBT group (Group A) and compared with RF in a control group (Group B). RF was significantly higher in Group A (RF = 4.35, SD = 1.19) than in Group B (RF = 3.43, SD = 1.70) (p = .0385; Cohen's d = 0.65). MBT might be a promising intervention in social cognition training. Mentalizing skills might be associated with attitude.

A Hierarchical Bayesian Implementation of the Experience-Weighted Attraction Model.

Social and decision-making deficits are often the first symptoms of neuropsychiatric disorders. In recent years, economic games, together with computational models of strategic learning, have been increasingly applied to the characterization of individual differences in social behavior, as well as their changes across time due to disease progression, treatment, or other factors. At the same time, the high dimensionality of these data poses an important challenge to statistical estimation of these models, potentially limiting the adoption of such approaches in patients and special populations. We introduce a hierarchical Bayesian implementation of a class of strategic learning models, experience-weighted attraction (EWA), that is widely used in behavioral game theory. Importantly, this approach provides a unified framework for capturing between- and within-participant variation, including changes associated with disease progression, comorbidity, and treatment status. We show using simulated data that our hierarchical Bayesian approach outperforms representative agent and individual-level estimation methods that are commonly used in extant literature, with respect to parameter estimation and uncertainty quantification. Furthermore, using an empirical dataset, we demonstrate the value of our approach over competing methods with respect to balancing model fit and complexity. Consistent with the success of hierarchical Bayesian approaches in other areas of behavioral science, our hierarchical Bayesian EWA model represents a powerful and flexible tool to apply to a wide range of behavioral paradigms for studying the interplay between complex human behavior and biological factors.

The contribution of nonhuman primate research to the understanding of emotion and cognition and its clinical relevance

Psychiatric disorders are often conceptualized as arising from dysfunctional interactions between neural systems mediating cognitive and emotional processes. Mechanistic insights into these interactions have been lacking in part because most work in emotions has occurred in rodents, often without concurrent manipulations of cognitive variables. Nonhuman primate (NHP) model systems provide a powerful platform for investigating interactions between cognitive operations and emotions due to NHPs’ strong homology with humans in behavioral repertoire and brain anatomy. Recent electrophysiological studies in NHPs have delineated how neural signals in the amygdala, a brain structure linked to emotion, predict impending appetitive and aversive stimuli. In addition, abstract conceptual information has also been shown to be represented in the amygdala and in interconnected brain structures such as the hippocampus and prefrontal cortex. Flexible adjustments of emotional behavior require the ability to apply conceptual knowledge and generalize to different, often novel, situations, a hallmark example of interactions between cognitive and emotional processes. Elucidating the neural mechanisms that explain how the brain processes conceptual information in relation to emotional variables promises to provide important insights into the pathophysiology accounting for symptoms in neuropsychiatric disorders.

Modeling behavioral symptoms of neuropsychiatric disorders through administration of acute low-dose MK-801

Modeling behavioral symptoms of neuropsychiatric disorders through administration of acute low-dose MK-801

Research in brief: Symptoms of neuropsychiatric disorders in people living with ALS and their family members

Changes in behaviour are common in Motor Neurone Disease (MND) with up to 15 per cent meeting criteria for frontotemporal dementia (FTD). Higher rates of neuropsychiatric disorders have been found in both MND patients and their family members suggesting a possible overlap between MND, FTD and neuropsychiatric disorders. In this preliminary analysis, we found generally low rates of neuropsychiatric disorders in MND patients and their family members, consistent with healthy controls (HC) and their family members. Future research aims to examine associations between neuropsychiatric symptoms and cognitive and behavioural changes.

Prospective crowdsensing versus retrospective ratings of tinnitus variability and tinnitus–stress associations based on the TrackYourTinnitus mobile platform

Many symptoms of neuropsychiatric disorders, such as tinnitus, are subjective and vary over time. Usually, in interviews or self-report questionnaires, patients are asked to retrospectively report symptoms as well as their severity, duration and influencing factors. However, only little is known to what degree such retrospective reports reflect the actual experiences made in daily life. Mobile technologies can remedy this deficiency. In particular, mobile self-help services allow patients to prospectively record symptoms and their severity at the time (or shortly after) they occur in daily life. In this study, we present results we obtained with the mobile crowdsensing platform TrackYourTinnitus. In particular, we show that there is a discrepancy between prospective and retrospective assessments. To be more precise, we show that the prospective variation of tinnitus loudness does not differ between the users who retrospectively rate tinnitus loudness as “varying” and the ones who retrospectively rate it as “non-varying.” As another result, the subjectively reported stress-level was positively correlated with tinnitus (loudness and distress) in the prospective assessments, even for users who retrospectively rated that stress reduces their tinnitus or has no effect on it. The results indicate that mobile technologies, like the TrackYourTinnitus crowdsensing platform, go beyond the role of an assistive service for patients by contributing to more detailed information about symptom variability over time and, hence, to more elaborated diagnostics and treatments.

Effects of fingolimod administration in a genetic model of cognitive deficits.

Notwithstanding recent advances, cognitive impairments are among the most difficult-to-treat symptoms in neuropsychiatric disorders. Deficits in information processing contributing to memory and sociability impairments are found across neuropsychiatric-related disorders. Previously, we have shown that mutations in the DTNBP1 gene (encoding dystrobrevin-binding protein 1 [dysbindin-1]) lead to abnormalities in synaptic glutamate release in the prefrontal cortex (PFC) and hippocampus and to cognitive deficits; glutamatergic transmission is important for cortical recurrent excitation that allows information processing in the PFC. To investigate possible means of restoring glutamate release and improving cognitive impairments, we assess the effects of increasing endogenous levels of brain-derived neurotrophic factor (BDNF) in a dysbindin-1-deficient mouse model. Increasing endogenous levels of BDNF may aid in remediating cognitive deficits, given the roles of BDNF in synaptic transmission, plasticity, and neuroprotection. To increase BDNF, we use a novel strategy, repeated intraperitoneal injections of fingolimod (Gilenya). Sphingolipids have recently been shown to have therapeutic value in several neurology-related disorders. Both wild-type (WT) and mutant (MUT) genotypes were tested for sociability and recognition memory, followed by measuring endogenous BDNF levels and presynaptic [Ca2+ ]i within the PFC. Both genotypes were treated for 1 week with either saline or fingolimod. Relative to WT mice, MUT mice demonstrated impairments in sociability and recognition memory and lower presynaptic calcium. After fingolimod treatment, MUT mice exhibited significant improvements in sociability and recognition memory and increases in presynaptic calcium and endogenous concentrations of BDNF. These results show promise for counteracting the cognitive impairments seen in neuropsychiatric disorders and may shed light on the role of dysbindin-1. © 2016 Wiley Periodicals, Inc.

Neuroligin-2 and the tightrope of excitation/inhibition balance in the prefrontal cortex.

Excitation/inhibition imbalance is implicated in symptoms of neuropsychiatric disorders. We discuss a study by Liang et al. (Mol Psychiatry 20: 850-859, 2015) demonstrating that the conditional knockout of neuroligin-2, a postsynaptic adhesion protein, in the prefrontal cortex of adult mice results in alterations in inhibitory synaptic properties. However, behavioral impairments emerged prior to the development of detectable changes in excitation/inhibition ratio. This suggests there may be network-specific excitation/inhibition ratios, some of which are more vulnerable to disruption than others.

The Role of N-Methyl-D-Aspartate Receptor - Mediated Neurotransmission in Attention Deficit (Hyperactivity) Disorder (ADHD/ADD)

Attention deficit (hyperactivity) disorder (ADHD/ADD) is a costly, prevalent, chronic neurobiological disorder that is estimated to affect 3-12% of school-aged children and accounts for approximately half of all pediatric referrals to mental health services. ADHD/ADD has as core features difficulty in sustaining attention, hyperactivity and impulsivity and is associated with high levels of morbidity and disability including poor performance in school and work, difficulty with peer and family relationships, antisocial behavior, psychiatric comorbidity, and substance abuse. ADHD/ADD persists into adulthood in a large proportion of pediatric cases. Psychostimulants are the first line drug treatment for ADHD/ADD, however, some patients do not respond well to currently used medications. Furthermore, most parents of children with ADHD/ADD dislike the use of psychostimulants. Overall, there is a critical need for the testing and development of new pharmacotherapies for symptom suppression in this disorder. We review an innovative approach for ADHD/ADD treatment. Glutamate is the primary excitatory neurotransmitter in the central nervous system, an essential component of neurocircuits implicated in ADHD/ADD and an extensive modulator of dopamine. Herein, we suggest using a natural compound, Dserine, that modulates glutamatergic neurotransmission. This approach is based on the use of N-methyl-Daspartate- type glutamate receptor (NMDAR) agonists that preferentially target NR1-subtype receptors. This line of investigation is supported by recent findings stemming from preclinical and clinical studies in which glycine (GLY) site agonists of the NMDAR (e.g. D-serine) were investigated as potential pharmacotherapy for psychiatric, cognitive and motor symptoms in neuropsychiatric disorders. Keywords: Attention deficit hyperactivity disorder, cognition, D-serine, dopamine, glutamate, N-methyl-D-aspartate receptor.

Apathy in schizophrenia as a deficit in the generation of options for action.

Negative symptoms are a core feature of schizophrenia and have been grouped into 2 factors: a motivational factor, which we refer to as apathy, and a diminished expression factor. Recent studies have shown that apathy is closely linked to functional outcome. However, knowledge about its mechanisms and its relation to decision-making is limited. In the current study, we examined whether apathy in schizophrenia is associated with predecisional deficits, that is, deficits in the generation of options for action. We applied verbal protocol analysis to investigate the quantity of options generated in ill-structured real world scenarios in 30 patients with schizophrenia or schizoaffective disorder and 21 healthy control participants. Patients generated significantly fewer options than control participants and clinical apathy ratings correlated negatively with the quantity of generated options. We show that the association between measures of psychopathology and option generation is most pronounced in regard to apathy symptoms and that it is only partially mediated by deficits in verbal fluency. This study provides empirical support for dysfunctional option generation as a possible mechanism for apathy in schizophrenia. Our data emphasize the potential importance of predecisional stages in the development and persistence of apathy symptoms in neuropsychiatric disorders and might also inform the development of novel treatment options in the realm of cognitive remediation.

Treatment of Social Cognitive Dysfunctions in Neuropsychiatric Patients with Intellectual Disabilities: a Systematic Review

Introduction Social cognitive impairments are intrinsically related to symptoms of neuropsychiatric disorders and to inadequate social interaction. Consequently, daily functioning and quality of life is strongly impeded. Several social cognitive training programs have been developed, but for patients with mild intellectual disabilities and/or genetic syndromes, however, treatment options are rarely available. Objective Development of a high quality, evidence-based intervention for the enhancement of social cognition in patients with combined genetic and neuropsychiatric disorders. Aims The aim of the current investigation is to identify and review relevant intervention studies, and to pinpoint effective elements of treatment. Methods An extensive literature search was performed (PubMed, PsycINFO and WebOfKnowledge databases) and articles were selected and scrutinized according to the PRISMA guidelines. Results Out of 341 relevant records, 58 full-text articles were finally assessed of which only 26 met the inclusion criteria. Social cognitive interventions were predominantly developed for people with psychotic disorders (n=21), and incidentally for autism spectrum disorders, anxiety and mood disorders. Studies provided evidence for effectiveness of the concerning intervention, in terms of improvement in either (social) cognitive functioning, or on behavioural outcome measures. Regarding broad-based and multiple interventions, most studies did not provide information on the differential effectiveness of the treatment components. Conclusions Social cognitive treatment in neuropsychiatric patients with intellectual disability may profit from the inclusion of low level behavioural training programs targeted at basic perspective taking. Future evaluation studies should specify and test the constituents of a training program more explicitly and should include long term follow-up.

Characterization of electrically evoked field potentials in the medial prefrontal cortex and orbitofrontal cortex of the rat: Modulation by monoamines

Medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) play critical roles in cognition and behavioural control. Glutamatergic, GABAergic, and monoaminergic dysfunction in the prefrontal cortex has been hypothesised to underlie symptoms in neuropsychiatric disorders. Here we characterised electrically-evoked field potentials in the mPFC and OFC. Electrical stimulation evoked field potentials in layer V/VI of the mPFC and layer V of the OFC. The earliest component (approximately 2ms latency) was insensitive to glutamate receptor blockade and was presumed to be presynaptic. Later components were blocked by 6,7-dinitroquinoxaline-2,3-dione (DNQX (20µM)) and were assumed to reflect monosynaptic (latency 4–6ms) and polysynaptic activity (latency 6–40ms) mediated by glutamate via AMPA/kainate receptor. In the mPFC, but not the OFC, the monosynaptic component was also partly blocked by 2-amino-5-phosphonopentanoic acid (AP-5 (50–100µM)) indicating the involvement of NMDA receptors. Bicuculline (3–10µM) enhanced the monosynaptic component suggesting electrically-evoked and/or glutamate induced GABA release inhibits the monosynaptic component via GABAA receptor activation. There were complex effects of bicuculline on polysynaptic components. In the mPFC both the mono- and polysynaptic components were attenuated by 5-HT (10–100µM) and NA (30 and 60µM) and the monosynaptic component was attenuated by DA (100µM). In the OFC the mono- and polysynaptic components were also attenuated by 5-HT (100µM), NA (10–100µM) but DA (10–100µM) had no effect. We propose that these pharmacologically characterised electrically-evoked field potentials in the mPFC and OFC are useful models for the study of prefrontal cortical physiology and pathophysiology.

Differential and distributed effects of dopamine neuromodulations on resting-state network connectivity

Dopaminergic medications, used to treat neurochemical pathology and resultant symptoms in neuropsychiatric disorders, are of mixed efficacy and regularly associated with behavioural side effects. The possibility that dopamine exerts both linear and nonlinear ('inverted U-shaped') effects on cognitive neurocircuitry may explain this outcome variability. However, it has proven to be difficult to characterise neural manifestations of psychopharmacological effects in humans. We hypothesised that diverse effects of dopamine neuromodulation could be characterised using systems-level neuroimaging approaches. Using 'resting-state' functional magnetic resonance imaging (FMRI), combined with dopaminergic challenges, we examined the dopamine-dependent functional connectivity of brain 'resting-state networks' (RSNs). We compared RSN connectivity in 3 groups of healthy volunteers given dopamine antagonist (haloperidol; N=18) or agonistic (levodopa; N=16) drugs, or a placebo (N=15). As RSNs have been shown to be relevant for numerous psychological functions and dysfunctions, we investigated both linear and nonlinear effects on RSN connectivity of manipulating dopamine neurotransmission pharmacologically. A basal ganglia RSN displayed both linear and nonlinear effects of dopamine manipulation on functional connectivity, respectively, with lateral frontoparietal and medial frontal neocortical areas. Conversely, a cognitive 'default mode' network showed only linear dopaminergic effects on connectivity with lateral frontal and parietal cortices. Our findings highlight diverse functional effects of dopamine neuromodulations on systems-level neural interactions. The observation that dopamine modulates distinct large-scale network connectivity patterns differentially, in both linear and nonlinear fashions, provides support for the objective utility of RSN metrics in classifying the effects and efficacy of psychopharmacological medications.

P.2.005 The role of adolescent social behaviour in the development of impulse control in rats

Adolescence is a critical developmental period, during which maturational changes in the brain are associated with age-specific behavioral characteristics, to facilitate the transition into adulthood. Similar to human children, most young mammals spend a substantial part of postweaning development engaging in play with peers, such as running, chasing, climbing and play fighting. Play experience in a social context is crucial for the development of adaptive socio-affective responses and the acquisition of cognitive skills [1]. Conversely, social deficits are a core symptom of neuropsychiatric disorders that are apparent during childhood and adolescence, such as autism, early-onset schizophrenia, and disruptive behavior disorders. In the present study, we investigated the importance of social interaction during adolescence for the development of impulse control and decision making in rats. To that aim, rats were socially isolated for several weeks during adolescence, subsequently group-housed, and impulsive behavior and decision making were tested in adulthood. Two behavioral dimensions of impulsivity were measured, i.e. inhibitory control using the five-choice serial reaction time task (5-CSRTT) and impulsive choice using the delayed reward task (DRT). In the 5CSRT task, rats are required to wait during an inter-trial interval (ITI) while scanning a horizontal array of five apertures, and to nose poke in the spatial location of a brief visual stimulus in order to earn food reward. The number of responses before the onset of the visual stimulus, i.e. premature responses, is regarded as a measure of impulsivity. In the DRT, rats are faced with a choice between two response options. One option is associated with a small, immediate food reward, whereas the second option results in a larger delayed, but economically optimal food reward. Impulsive choice is associated with a higher preference for the small, immediate reward. Decision making was determined using the rat Gambling Task (rGT). In this paradigm, rats choose among four different options to earn as many sugar pellets as possible within a limited amount of time. Each option is associated with the delivery of a different amount of reward, probability and duration of punishing time-out periods during which reward cannot be earned. Monoaminergic involvement in task performance was investigated using systemic administration of the psychostimulant drug amphetamine, dopamine reuptake inhibitor GBR12909, noradrenaline reuptake inhibitor atomoxetine and serotonin reuptake inhibitor citalopram. The results show that socially isolated rats display hypersensitivity to an impulse control challenge (long intertrial interval), and insensitivity to GBR12909 in the 5CSRTT. No major long-term effects of adolescent social isolation on impulsive choice and decision making were found. These data indicate that adolescent social isolation induces a subtle, but selective impairment in inhibitory control, associated with altered dopamine function in rats. Social interaction during adolescence serves to facilitate the development of inhibitory control capacities.

A novel analytical framework for dissecting the genetic architecture of behavioral symptoms in neuropsychiatric disorders.

BackgroundFor diagnosis of neuropsychiatric disorders, a categorical classification system is often utilized as a simple way for conceptualizing an often complex clinical picture. This approach provides an unsatisfactory model of mental illness, since in practice patients do not conform to these prototypical diagnostic categories. Family studies show notable familial co-aggregation between schizophrenia and bipolar illness and between schizoaffective disorders and both bipolar disorder and schizophrenia, revealing that mental illness does not conform to such categorical models and is likely to follow a continuum encompassing a spectrum of behavioral symptoms.Results and MethodologyWe introduce an analytic framework to dissect the phenotypic heterogeneity present in complex psychiatric disorders based on the conceptual paradigm of a continuum of psychosis. The approach identifies subgroups of behavioral symptoms that are likely to be phenotypically and genetically homogenous. We have evaluated this approach through analysis of simulated data with simulated behavioral traits and predisposing genetic factors. We also apply this approach to a psychiatric dataset of a genome scan for schizophrenia for which extensive behavioral information was collected for each individual patient and their families. With this approach, we identified significant evidence for linkage among depressed individuals with two distinct symptom profiles, that is individuals with sleep disturbance symptoms with linkage on chromosome 2q13 and also a mutually exclusive group of individuals with symptoms of concentration problems with linkage on chromosome 2q35. In addition we identified a subset of individuals with schizophrenia defined by language disturbances with linkage to chromosome 2p25.1 and a group of patients with a phenotype intermediate between those of schizophrenia and schizoaffective disorder with linkage to chromosome 2p21.ConclusionsThe findings presented are novel and demonstrate the efficacy of this approach in detection of genes underlying such complex human disorders as schizophrenia and depression.