Impaired striatal glutamate/GABA regulation in violent offenders with antisocial personality disorder and psychopathy.

Men with antisocial personality disorder (ASPD) with or without psychopathy (+/-P) are responsible for most violent crime in society. Development of effective treatments is hindered by poor understanding of the neurochemical underpinnings of the condition. Men with ASPD with and without psychopathy demonstrate impulsive decision-making, associated with striatal abnormalities in functional neuroimaging studies. However, to date, no study has directly examined the potential neurochemical underpinnings of such abnormalities. We therefore investigated striatal glutamate: GABA ratio using Magnetic Resonance Spectroscopy in 30 violent offenders (16 ASPD-P, 14 ASPD + P) and 21 healthy non-offenders. Men with ASPD +/- P had a significant reduction in striatal glutamate : GABA ratio compared to non-offenders. We report, for the first time, striatal Glutamate/GABA dysregulation in ASPD +/- P, and discuss how this may be related to core behavioral abnormalities in the disorders.

Neurobiological basis of reinforcement-based decision making in adults with ADHD treated with lisdexamfetamine dimesylate: Preliminary findings and implications for mechanisms influencing clinical improvement.

BACKGROUND: ADHD is often described as a disorder of altered reward sensitivity, yet few studies have examined the extent to which: (i) treatments for ADHD impact reward-related mechanisms; and (ii) changes in the reward system are associated with clinical improvement. This study addresses these issues - examining the extent to which clinical improvement following lisdexamfetamine (LDX) treatment is associated with changes in brain reward system activation. METHODS: Twenty adults (M = 11, 55%, F = 9, 45%), ages 19-52 (M = 33.9, SD = 10.0) with ADHD participated in a randomized cross-over study with lisdexamfetamine (LDX) and placebo (PB). Changes in brain activation were assessed during functional magnetic resonance (fMRI) scans: after receiving 3-5 weeks of treatment with LDX and 3-5 weeks of no drug/PB. fMRI contrasts were derived from the passive-avoidance (PA) learning task, which assessed reward-related learning using computational variables. We analyzed the following conditions: the Choice-Phase, modulated by the expected value (EV; i.e., object-choose and object-reject), and the Feedback-Phase, modulated by the prediction error (PE; i.e., reward and punish). Clinical symptom severity was assessed via interview with the ADHD-Rating Scale (ADHD-RS-IV). To address the primary objective, we performed group-level mass-univariate regression analyses between LDX and PB of percent change of the ADHD-RS total scores and the four contrast images under the Choice- and Feedback-conditions. Significance was set at a whole-brain voxel-wise threshold of p < 0.05 with family-wise error (FWE) correction and an extent (cluster) threshold of 50 contiguous voxels. RESULTS: Improvement in ADHD symptoms with LDX was accompanied by significantly increased activation in a series of brain regions previously implicated in reinforcement processing in the choice and feedback conditions (e.g., left caudate and putamen, right orbitofrontal cortex, left middle frontal, superior frontal, and precentral gyri). CONCLUSIONS: These findings, while preliminary, are the first to show that ADHD symptom improvement with stimulant treatment is associated with increased responsiveness of brain systems engaged in reward processing. Results support the hypothesis that LDX treatment may restore balance to dysfunction (e.g., hypoactivation) within the brain reward circuitry in adults with ADHD. Trial RegistrationClinicaltrials.gov Identifier: NCT01924429.

Atypical neurocognitive functioning in children and adolescents with obsessive-compulsive disorder (OCD).

Atypical neurocognitive functioning has been found in adult patients with obsessive-compulsive disorder (OCD). However, little work has been done in children and adolescents with OCD. In this study, we investigated neurocognitive functioning in a large and representative sample of newly diagnosed children and adolescents with OCD compared to non-psychiatric controls. Children and adolescents with OCD (n = 119) and non-psychiatric controls (n = 90) underwent psychopathological assessment, intelligence testing, and a neurocognitive test battery spanning cognitive flexibility, planning and decision-making, working memory, fluency, and processing speed. The MANOVA main effect revealed that children and adolescents with OCD performed significantly worse than the control group (p < .001, [Formula: see text] = 0.256). Atypical patient performance was particularly found for indices of cognitive flexibility, decision-making, working memory, and processing speed. We found no evidence of differences in planning or fluency. Moreover, we found no significant associations between neurocognitive performance and OCD symptom severity or comorbidity status. Our results indicate that children and adolescents with OCD show selective atypical neurocognitive functioning. These difficulties do not appear to drive their OCD symptoms. However, they may contribute to lifespan difficulties and interfere with treatment efficacy, an objective of our research currently.

Oxytocin normalizes the implicit processing of fearful faces in psychopathy: a randomized crossover study using fMRI.

Adults with antisocial personality disorder with (ASPD + P) and without (ASPD - P) psychopathy commit the majority of violent crimes. Empathic processing abnormalities are particularly prominent in psychopathy, but effective pharmacological interventions have yet to be identified. Oxytocin modulates neural responses to fearful expressions in healthy populations. The current study investigates its effects in violent antisocial men. In a placebo-controlled, randomized crossover design, 34 violent offenders (19 ASPD + P; 15 ASPD - P) and 24 healthy non-offenders received 40 IU intranasal oxytocin or placebo and then completed an fMRI morphed faces task examining the implicit processing of fearful facial expressions. Increasing intensity of fearful facial expressions failed to appropriately modulate activity in the bilateral mid-cingulate cortex in violent offenders with ASPD + P, compared with those with ASPD - P. Oxytocin abolished these group differences. This represents evidence of neurochemical modulation of the empathic processing of others' distress in psychopathy.

Structural brain alterations associated with suicidal thoughts and behaviors in young people: results from 21 international studies from the ENIGMA Suicidal Thoughts and Behaviours consortium.

Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample of young people with mood disorders, in which STB were assessed using different instruments, MRI metrics were compared among healthy controls without STBs (HC; N = 519), clinical controls with a mood disorder but without STBs (CC; N = 246) and young people with current suicidal ideation (N = 223). In separate analyses, MRI metrics were compared among HCs (N = 253), CCs (N = 217), and suicide attempters (N = 64). Third, in a larger transdiagnostic sample with various assessment instruments (HC = 606; CC = 419; Ideation = 289; HC = 253; CC = 432; Attempt=91). In the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and a history of actual suicide attempts (N = 163) than those without a lifetime suicide attempt (N = 323; FDR-p = 0.035, Cohen's d = 0.34). No associations with suicidal ideation were found. When examining more heterogeneous samples, we did not observe significant associations. Lower frontal pole surface area may represent a vulnerability for a (non-interrupted and non-aborted) suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk.

Research Audit on Clinical Utility of Dimensional Disruptive Mood and Behavior Psychopathologies in Child and Adolescent Psychiatry Practice.

To investigate the utility of dimensional psychopathologies of disruptive mood and behavior disorders (DBDs) by applying latent profile analysis (LPA) for characterization of youth referred to the tertiary outpatient clinic of child and adolescent psychiatry clinic and pharmacological treatment choices. One hundred fifty-eight children and adolescents with significant DBDs symptoms participated. Core dimensional psychopathologies of DBDs (irritability, callous-unemotional trait, and reactive-proactive aggressive behavior), DSM diagnoses, prescribed medications, and behavioral and emotional problems (Child Behavior Checklist, CBCL) were measured at baseline (clinic intake) and at 3-month follow-up. Latent Profile Analysis (LPA) was applied to characterize the study population based on the levels and interrelations among the core dimensional DBDs psychopathologies. Following LPA, the differences in clinical and treatment features between the latent classes were analyzed. LPA revealed two latent classes based on severity of DBDs symptoms. Class 1 (the moderate group) was characterized by relatively low scores on all trans-diagnostic indicators, whereas class 2 (the severe/critical group) showed higher levels of the dimensional psychopathologies and the majority of CBCL subscales. In addition, the severe/critical group was more often prescribed antipsychotic medications, and also experienced more frequent medication changes (addition, increasing the dose, and trial of different medications). Our findings suggested that application of LPA to a cluster of dimensional DBDs psychopathologies may provide valuable characterization of the youths referred to a tertiary outpatient child and adolescent psychiatric clinic, and offer insight into the providers' decision making on psychotropic medications, by overall severity of these psychopathologies rather than by single categorical diagnosis or single externalizing psychopathology.

Reduced cortical volume of the default mode network in adolescents with generalized anxiety disorder.

BACKGROUND: Widespread structural alterations have been shown to be implicated in individuals with generalized anxiety disorder (GAD). However, there have been inconsistent findings in cortical volume (CV) differences. Most structural neuroimaging studies looking at GAD used region-based approach with relatively small sample sizes, let alone be specific to adolescents with GAD. We believe this is the first study to look at CV measures using a network-based approach in a larger sample of adolescents with GAD. The goal of the current study was to focus on three different brain networks (i.e., Limbic, Frontoparietal, and Default Mode Network [DMN]) in adolescents with GAD. METHOD: The study involved 81 adolescents with GAD and 112 typically developing (TD) comparison individuals matched on age (15.98 and 15.63 respective means), sex (42F/39M and 45F/67M), and IQ (101.90 and 103.94 respective means). Participants underwent structural MRI. Freesurfer was used to estimate CV (both network-specific and region-specific within networks) and region-specific sub-cortical volume measures. Multivariate analysis of covariance (MANCOVA; with sex, age, IQ, and intracranial volume [ICV] as potential covariates) was used to estimate group differences. RESULTS: We found significantly lower CV for the DMN in adolescents with GAD, compared with TD individuals. Adolescents with GAD also showed significantly lower hemispheric mean CV of the default-mode regions (particularly the prefrontal and temporal regions) and the hippocampus, compared with TD individuals. CONCLUSION: The current findings suggest structural alterations in adolescents with GAD. These structural alterations will need to be addressed when implementing and developing treatments for patients with GAD.

Alcohol and Cannabis Use Disorder Symptom Severity, Conduct Disorder, and Callous-Unemotional Traits and Impairment in Expression Recognition.

Background: Alcohol and cannabis are commonly used by adolescents in the United States. Both alcohol use disorder (AUD) and cannabis use disorder (CUD) have been associated with reduced emotion expression recognition ability. However, this work has primarily occurred in adults and has not considered neuro-cognitive risk factors associated with conduct problems that commonly co-occur with, and precede, substance use. Yet, conduct problems are also associated with reduced emotion expression recognition ability. The current study investigated the extent of negative association between AUD and CUD symptom severity and expression recognition ability over and above any association of expression recognition ability with conduct problems [conduct disorder (CD) diagnostic status]. Methods: In this study, 152 youths aged 12.5-18 years (56 female; 60 diagnosed with CD) completed a rapid presentation morphed intensity facial expression task to investigate the association between relative severity of AUD/CUD and expression recognition ability. Results: Cannabis use disorder identification test (CUDIT) scores were negatively associated with recognition accuracy for higher intensity (particularly sad and fearful) expressions while CD diagnostic status was independently negatively associated with recognition of sad expressions. Alcohol use disorder identification test (AUDIT) scores were not significantly associated with expression recognition ability. Conclusions: These data indicate that relative severity of CUD and CD diagnostic status are statistically independently associated with reduced expression recognition ability. On the basis of these data, we speculate that increased cannabis use during adolescence may exacerbate a neuro-cognitive risk factor for the emergence of aggression and antisocial behavior.

Psychopathy.

Psychopathy is a personality disorder characterized by a constellation of affective, interpersonal, lifestyle and antisocial features whose antecedents can be identified in a subgroup of young people showing severe antisocial behaviour. The prevalence of psychopathy in the general population is thought to be ~1%, but is up to 25% in prisoners. The aetiology of psychopathy is complex, with contributions of both genetic and environmental risk factors, and gene-environment interactions and correlations. Psychopathy is characterized by structural and functional brain abnormalities in cortical (such as the prefrontal and insular cortices) and subcortical (for example, the amygdala and striatum) regions leading to neurocognitive disruption in emotional responsiveness, reinforcement-based decision-making and attention. Although no effective treatment exists for adults with psychopathy, preliminary intervention studies targeting key neurocognitive disturbances have shown promising results. Given that psychopathy is often comorbid with other psychiatric disorders and increases the risk of physical health problems, educational and employment failure, accidents and criminality, the identification of children and young people at risk for this personality disorder and preventative work are important. Indeed, interventions that target the antecedents of psychopathic features in children and adolescents have been found to be effective.

Reduced neural differentiation of rewards and punishment during passive avoidance learning in adolescents with generalized anxiety disorder.

BACKGROUND: It has been proposed that individuals with generalized anxiety disorder (GAD) show dysfunctional computations related to approach-avoidance decision-making. However, few studies have examined the neural basis of this impairment, particularly in adolescents with GAD. The goal of the current study was to address this gap in the literature. METHOD: The study involved 51 adolescents with GAD and 51 typically developing (TD) comparison individuals matched on age (16.10 and 15.75 respective means), gender (30 F/21 M and 24 F/27 M), and IQ (103.20 and 103.18 respective means). Participants underwent functional magnetic resonance imaging during a passive avoidance task. RESULTS: We found a significant Group-by-Reinforcement interaction within reward-related brain regions including the caudate, putamen, mid cingulate/paracentral lobule, and superior and middle frontal gyrus. TD adolescents showed a greater differential response to reward versus punishment feedback within these regions relative to adolescents with GAD. In particular, this reflected reduced responses to rewards in the adolescents with GAD. There were no group differences in neural responses when making approach/avoidance responses. CONCLUSION: The results of this study suggest reduced differential responsiveness to reinforcement as a component of the pathophysiology seen in adolescents with GAD. This dysfunction likely underpins decision-making impairments that may exacerbate the participants' worry.

Reduced top-down attentional control in adolescents with generalized anxiety disorder.

BACKGROUND: Generalized anxiety disorder (GAD) can significantly impair quality of life and is associated with a relatively poor long-term prognosis. Anxiety disorders are often associated with hyper-responsiveness to threat, perhaps coupled with impaired executive functioning. However, GAD, particularly adolescent GAD, has been the focus of little functional neuroimaging work compared to other anxiety disorders. Here, we examine the neural association of adolescent GAD with responsiveness to threat and response control. METHODS: The study involved 35 adolescents with GAD and 34 healthy comparison individuals (N = 69) matched on age, gender, and IQ. Participants were scanned during an affective number Stroop task. RESULTS: We found significant Group-by-Task Condition interactions in regions involved in response control/motor responding (bilateral precentral gyri and cerebellum) and/or cognitive control/attention (dorsomedial and lateral frontal cortex, posterior cingulate cortex, cuneus, and precuneus). In line with predictions, the youth with GAD showed significantly less recruitment during task trials than the healthy comparison individuals. However, no indications of specific heightened responses to threat were seen. CONCLUSIONS: GAD involves reduced capacity for engaging regions involved in response control/motor responding and/or cognitive control/attention. This might reflect either a secondary consequence of the patient's worry or an early risk factor for the development of worry.

Recent neuro-imaging findings with respect to conduct disorder, callous-unemotional traits and psychopathy.

PURPOSE OF REVIEW: To review recent neuro-imaging findings with respect to conduct disorder and callous-unemotional traits in childhood and comparable psychopathy in adult-hood that deepen the literature in important ways. RECENT FINDINGS: Recent structural findings particularly bring clarity to the literature. First, they reinforce previous work indicating that severity of psychopathy is positively associated with extent of cavum septum pellucidum. This suggests psychopathy is associated with early neurodevelopmental disruption within limbic structures. Second, they clarify the direction of the association between conduct disorder and particularly callous-unemotional traits and white matter tract abnormalities even if it remains less transparent exactly which tracts are disrupted. However, conclusions based on recent functional imaging studies are more equivocal with inconsistencies in direction of emotional (albeit with notably more work confirming the previous reports of hypo-responsiveness in limbic regions) and reward responsiveness. SUMMARY: The recent data are, for the most part, consistent with a view that callous-unemotional traits/psychopathy represents an early appearing neuro-developmental disorder particularly associated with compromised emotional (limbic) functioning. However, some patients presenting with severe antisocial behavior may also show hyper-threat sensitivity, perhaps reflecting trauma exposure, and require different clinical interventions.

Dysfunctional neurocognition in individuals with clinically significant psychopathic traits
.

The main goal of this review is to consider the main forms of dysfunctional neurocognition seen in individuals with clinically significant psychopathic traits (ie, reduced guilt/empathy and increased impulsive/antisocial behavior). A secondary goal is to examine the extent to which these forms of dysfunction are seen in both adults with psychopathic traits and adolescents with clinically significant antisocial behavior that may also involve callous-unemotional traits (reduced guilt/empathy). The two main forms of neurocognition considered are emotional responding (to distress/pain cues and emotional stimuli more generally) and reward-related processing. Highly related forms of neurocognition, the response to drug cues and moral judgments, are also discussed. It is concluded that dysfunction in emotional responsiveness and moral judgments confers risk for aggression across adolescence and into adulthood. However, reduced reward-related processing, including to drug cues, is only consistently found in adolescents with clinically significant antisocial behavior, not adults with psychopathy.
.

El objetivo central de este artículo es considerar las principales formas de disfunción neurocognitiva que se observan en sujetos con rasgos psicopáticos clínicamente significativos (por ejemplo, disminución de la empatía / culpa y aumento del comportamiento impulsivo / antisocial). En segundo lugar, se analiza en qué medida aparecen estas formas de disfunción tanto en adultos con rasgos psicopáticos como en adolescentes con un comportamiento antisocial clínicamente significativo que también puede implicar características insensibles / frías (disminución de la empatía / culpa). Las dos formas principales de neurocognición examinadas son la reactividad emocional (a los signos de angustia y dolor, y los estímulos emocionales en general) y el sistema de recompensa. También se discuten formas muy relacionadas de la neurocognición, como son la respuesta a estímulos de drogas y los juicios morales. En conclusión, la aparición de una disfunción en la reactividad emocional y los juicios morales confiere un riesgo de agresión durante la adolescencia y la edad adulta. Sin embargo, en adolescentes con comportamiento antisocial clínicamente significativo se encuentra de manera consistente una reducción del procesamiento relacionado con la recompensa, incluyendo la respuesta a drogas ; lo que no aparece en adultos con psicopatía.

Cet article a pour principal objectif d'envisager les principales formes de dysfonction neurocognitive observées chez des sujets présentant des traits psychopathiques cliniquement significatifs (par exemple, empathie/culpabilité réduite et comportement impulsif/antisocial majoré). Secondairement, il sera analysé dans quelle mesure ces formes de dysfonction sont observées à la fois chez des adultes ayant des traits psychopathiques et chez des adolescents ayant un comportement antisocial cliniquement significatif qui peut aussi impliquer des traits insensibles/froids (empathie/culpabilité réduite). Les deux principales formes de neurocognition examinées sont la réactivité émotionnelle (aux signes de détresse et de douleur et aux stimuli émotionnels plus généralement) et le système de récompense. Des formes de neurocognition très reliées, la réponse aux stimuli des drogues et aux jugements moraux, sont aussi discutées. En conclusion, une dysfonction observée dans la réactivité émotionnelle et les jugements moraux confère un risque pour l'agression au cours de l'adolescence et à l'âge adulte. Néanmoins, une diminution du système de récompense, y compris les stimuli des drogues, est régulièrement observée chez des adolescents au comportement antisocial cliniquement significatif et pas chez les adultes psychopathes.

Threat Responsiveness as a Function of Cannabis and Alcohol Use Disorder Severity.

Objective: Two of the most commonly abused substances by adolescents in the United States are alcohol and cannabis, both of which are associated with adverse medical and psychiatric outcomes throughout the lifespan. Both are assumed to impact the development of emotional processing although findings on the direction of this impact have been mixed. Preclinical animal work and some functional magnetic resonance imaging (fMRI) work with humans have suggested cannabis use disorder (CUD) and alcohol use disorder (AUD) are associated with increased threat responsiveness. However, other fMRI work has indicated CUD/AUD are associated with diminished threat responsiveness. In this study, we report on a study examining the relationship of severity of CUD/AUD and threat responsiveness in an adolescent population. Methods: The study involved 87 (43 male) adolescents with varying levels of CUD/AUD symptomatology (N = 45 above clinical cutoffs for CUD or AUD). They were scanned with fMRI during a looming threat task that involved images of threatening and neutral human faces or animals that appeared to be either looming or receding. Results: Increasing levels of CUD symptomatology were associated with decreased responding to looming stimuli within regions, including rostral frontal and fusiform gyrus as well as the amygdala. There were no relationships with AUD symptomatology. Conclusions: These data indicate that CUD in particular is associated with a decrease in responsiveness to the looming threat cue possibly relating to the putative neurotoxic impact of cannabis abuse.

Intensity, not emotion: The role of poverty in emotion labeling ability in middle childhood.

Poverty exposure has been linked to difficulties in emotion expression recognition, which further increases risks for negative emotional outcomes among children. The current study aimed to investigate whether the difficulties in emotion expression recognition among children experiencing poverty may be emotion specific or expression intensity specific. Thus, the current study investigated the relationship between poverty exposure and emotion labeling ability in an ethnically and economically diverse sample of children (N = 46) in middle childhood. A novel experimental design measured emotion labeling ability at different valences of emotion (fearful, angry, and happy) and at varying intensities (0-100%) of emotion presentation. Using a hierarchical logistic regression, we found a significant interaction between the percentage of time since birth a child has lived in poverty and the intensity of the emotional stimulus in affecting correct emotion identification. Children who lived longer in poverty gained less accuracy for equivalent increases in intensity compared with children who had not lived in poverty. On average, children who chronically lived in poverty required emotional intensity set at 60% in order to reach levels of accuracy observed at 30% intensity among children who were never exposed to poverty. We found no significant emotion-specific effect. These findings demonstrate that children who experience chronic poverty require more intense expressions to recognize emotions across valences. This further elaborates the existing understanding of a relationship between poverty exposure and emotion recognition, informing future studies examining expression recognition as a mechanism involved in developing psychopathology.

Impaired functional but preserved structural connectivity in limbic white matter tracts in youth with conduct disorder or oppositional defiant disorder plus psychopathic traits.

Youths with conduct disorder or oppositional defiant disorder and psychopathic traits (CD/ODD+PT) are at high risk of adult antisocial behavior and psychopathy. Neuroimaging studies demonstrate functional abnormalities in orbitofrontal cortex and the amygdala in both youths and adults with psychopathic traits. Diffusion tensor imaging in psychopathic adults demonstrates disrupted structural connectivity between these regions (uncinate fasiculus). The current study examined whether functional neural abnormalities present in youths with CD/ODD+PT are associated with similar white matter abnormalities. Youths with CD/ODD+PT and comparison participants completed 3.0 T diffusion tensor scans and functional magnetic resonance imaging scans. Diffusion tensor imaging did not reveal disruption in structural connections within the uncinate fasiculus or other white matter tracts in youths with CD/ODD+PT, despite the demonstration of disrupted amygdala-prefrontal functional connectivity in these youths. These results suggest that disrupted amygdala-frontal white matter connectivity as measured by fractional anisotropy is less sensitive than imaging measurements of functional perturbations in youths with psychopathic traits. If white matter tracts are intact in youths with this disorder, childhood may provide a critical window for intervention and treatment, before significant structural brain abnormalities solidify.