Dysconnectivity of the Nucleus Accumbens and Amygdala in Youths with Thought Problems: A Dimensional Approach.

Background: Youths with thought problems (TP) are at risk to develop psychosis and obsessive-compulsive disorder (OCD). Yet, the pathophysiological mechanisms underpinning TP are still unclear. Functional magnetic resonance imaging (fMRI) studies have shown that striatal and limbic alterations are associated with psychosis-like and obsessive-like symptoms in individuals at clinical risk for psychosis, schizophrenia, and OCD. More specifically, nucleus accumbens (NAcc) and amygdala are mainly involved in these associations. The current study aims to investigate the neural correlates of TP in youth populations using a dimensional approach and explore potential cognitive functions and neurotransmitters associated with it. Methods: Seed-to-voxels functional connectivity analyses using NAcc and amygdala as regions-of-interest were conducted with resting-state fMRI data obtained from 1360 young individuals, and potential confounders related to TP such as anxiety and cognitive functions were included as covariates in multiple regression analyses. Replicability was tested in using an adult cohort. In addition, functional decoding and neurochemical correlation analyses were performed to identify the associated cognitive functions and neurotransmitters. Results: The altered functional connectivities between the right NAcc and posterior parahippocampal gyrus, between the right amygdala and lateral prefrontal cortex, and between the left amygdala and the secondary visual area were the best predictors of TP in multiple regression model. These functional connections are mainly involved in social cognition and reward processing. Conclusions: The results show that alterations in the functional connectivity of the NAcc and the amygdala in neural pathways involved in social cognition and reward processing are associated with severity of TP in youths.

The company you keep: The neglected role of affiliating with delinquent friends in the development of the cannabis-violence link.

A growing body of research suggests a potential role of cannabis use on aggressive behaviors. In literature on adolescents, the lack of consideration of important confounders, such as adolescent's affiliation with delinquent peers, limits the possibility to determine whether there might be a direct or indirect link between cannabis use and aggression. Therefore, we sought to examine the effect of delinquent peers on the association between cannabis use and violence. We re-analyzed data from 850 ninth graders who were followed from mid-adolescence to early adulthood. Generalized Estimations Equations (GEE) were conducted to examine whether affiliation with delinquent peers may mediate the relationship between cannabis use and violence. Cross-Lagged Panel Models were also conducted to estimate the directionality of these relationships over time. We additionally tested whether similar relationships may be identifiable when examining rule-breaking behaviors and/or alcohol use. GEE models revealed that both cannabis use and affiliation with delinquent peers were statistically associated with aggressive behaviors. Cannabis use, alcohol use and delinquent peers also predicted rule-breaking behaviors. More precisely, cross-lagged models showed that affiliation with delinquent peers played a partially mediating role in the cannabis-aggression link, and that similar cross-lagged estimates were observed when examining rule-breaking behaviors instead of aggression. Our results indicate that cannabis use may be associated with aggression as well as rule-breaking behaviors, suggesting a broader effect on conduct problems. More importantly, our study highlights the non-negligible role of affiliating with delinquent peers during adolescence.

Executive function and underlying brain network distinctions for callous-unemotional traits and conduct problems in adolescents.

The complexity of executive function (EF) impairments in youth antisocial phenotypes of callous-unemotional (CU) traits and conduct problems (CP) challenge identifying phenotypic specific EF deficits. We can redress these challenges by (1) accounting for EF measurement error and (2) testing distinct functional brain properties accounting for differences in EF. Thus, we employed a latent modeling approach for EFs (inhibition, shifting, fluency, common EF) and extracted connection density from matching contemporary EF brain models with a sample of 112 adolescents (ages 13-17, 42% female). Path analysis indicated CU traits associated with lower inhibition. Inhibition network density positively associated with inhibition, but this association was strengthened by CU and attenuated by CP. Common EF associated with three-way interactions between density*CP by CU for the inhibition and shifting networks. This suggests those higher in CU require their brain to work harder for lower inhibition, whereas those higher in CP have difficulty engaging inhibitory brain responses. Additionally, those with CP interacting with CU show distinct brain patterns for a more general EF capacity. Importantly, modeling cross-network connection density in contemporary EF models to test EF involvement in core impairments in CU and CP may accelerate our understanding of EF in these phenotypes.

Altered functional connectivity of the amygdala across variants of callous-unemotional traits: A resting-state fMRI study in children and adolescents.

Over the past years, research has shown that primary (high callousness and low anxiety) and secondary (high callousness and anxiety) variants of CU traits may be associated with opposite amygdala activity (hypo- and hyper-reactivity, respectively). However, their differences in amygdala functional connectivity remains largely unexplored. We conducted a Latent Profile Analysis on a large sample of adolescents (n = 1416) to identify homogeneous subgroups with different levels of callousness and anxiety. We then performed a seed-to-voxel connectivity analysis on resting-state fMRI data to compare subgroups on connectivity patterns of the amygdala. We examined the results in relation to conduct problems to identify potential neural risk factors. The Latent Profile Analysis revealed four subgroups, including the primary and secondary variants, anxious, and typically developing adolescents. The seed-to-voxel analyses showed that the primary variant was mainly characterized by increased connectivity between the left amygdala and left thalamus. The secondary variant exhibited deficient connectivity between the amygdala and the dorsomedial prefrontal cortex, temporo-parietal junction, premotor, and postcentral gyrus. Both variants showed increased connectivity between the left amygdala and the right thalamus but exhibited opposite functional connectivity between the left amygdala and the parahippocampal gyrus. Dimensional analyses indicated that conduct problems may play a mediating role between callousness and amygdala-dmPFC functional connectivity across youths with already high levels of callousness. Our study highlights that both variants differ in the functional connectivity of the amygdala. Our results support the importance of disentangling the heterogeneity of adolescents at risk for conduct problems in neuroimaging.

Neural bases of frustration-aggression theory: A multi-domain meta-analysis of functional neuroimaging studies.

BACKGROUND: Early evidence suggests that unexpected non-reward may increase the risk for aggressive behaviors. Despite the growing interest in understanding brain functions that may be implicated in aggressive behaviors, the neural processes underlying such frustrative events remain largely unknown. Furthermore, meta-analytic results have produced discrepant results, potentially due to substantial differences in the definition of anger/aggression constructs. METHODS: Therefore, we conducted a coordinate-based meta-analysis, using the activation likelihood estimation algorithm, on neuroimaging studies examining reward omission and retaliatory behaviors in healthy subjects. Conjunction analyses were further examined to discover overlapping brain activations across these meta-analytic maps. RESULTS: Frustrative non-reward deactivated the orbitofrontal cortex, ventral striatum and posterior cingulate cortex, whereas increased activations were observed in midcingulo-insular regions. Retaliatory behaviors recruited the left fronto-insular and anterior midcingulate cortices, the dorsal caudate and the primary somatosensory cortex. Conjunction analyses revealed that both strongly activated midcingulo-insular regions. LIMITATIONS: Spatial overlap between neural correlates of frustration and retaliatory behaviors was conducted using a conjunction analysis. Therefore, neurobiological markers underlying the temporal sequence of the frustration-aggression theory should be interpreted with caution. CONCLUSIONS: Nonetheless, our results underscore the role of anterior midcingulate/pre-supplementary motor area and fronto-insular cortex in both frustration and retaliatory behaviors. A neurobiological framework for understanding frustration-based impulsive aggression is provided.

Clarifying the role of Cortico-Cortical and Amygdalo-Cortical brain dysconnectivity associated with Conduct Problems.

A recent meta-analysis of resting-state functional connectivity studies revealed that individuals exhibiting antisocial behaviors or conduct problems may show disrupted brain connectivity in networks underpinning socio-affective and attentional processes. However, studies included in the meta-analysis generally rely on small sample sizes and substantially differ in terms of psychometric scales and neuroimaging methodologies. Therefore, we aimed to identify reliable functional brain connectivity alterations associated with severity of conduct problems using a large sample of adolescents and two measures of conduct problems. In a sample of 1416 children and adolescents, mass-univariate analyses of connectivity measures between 333 cortical parcels were conducted to examine the relationship between resting-state functional cortical-cortical connectome and the severity of conduct problems using the Child Behavior Checklist (CBCL) and the Strengths and Difficulties Questionnaire (SDQ). At a liberal threshold, results showed that the functional brain connectivity significantly associated with conduct problems largely differ between the two scales. Indeed, only 21 pairs of brain regions overlapped between the CBCL and SDQ. Permutation feature importance of these 21 brain connectivity measures revealed that connectivity between precentral/postcentral gyri and lateral prefrontal cortex (both ventral and dorsal) were the most important features in explaining variance in conduct problems. The current study highlights that psychometric measures may yield distinct functional connectivity results. Moreover, severity of conduct problems in children and adolescents was mainly associated with deficient functional connectivity of somatomotor and ventral attention networks indicating potential alterations in motor, cognitive and reward processes.

Disrupted functional connectivity of the brain reward system in substance use problems: A meta-analysis of functional neuroimaging studies.

Extensive literature suggests that the brain reward system is crucial in understanding the neurobiology of substance use disorders. However, evidence of reliable deficits in functional connectivity across studies on substance use problems remains limited. Therefore, a voxel-wise seed-based meta-analysis using brain regions of the reward system as seeds of interest was conducted on 96 studies representing 5757 subjects with substance use problems. The ventromedial prefrontal cortex exhibited hyperconnectivity with the ventral striatum and hypoconnectivity with the amygdala and hippocampus. The executive striatum showed hyperconnectivity with the motor thalamus and dorsolateral prefrontal cortex and hypoconnectivity with the anterior cingulate cortex and anterior insula. Finally, the limbic striatum was found to be hyperconnected to the orbitofrontal cortex and hypoconnected to the precuneus compared with healthy subjects. The current study provided meta-analytical evidence of deficient functional connectivity between brain regions of the reward system and cortico-striato-thalamocortical loops in addiction. These results are consistent with deficits in motivation and habit formation occurring in addiction, and they highlight alterations in brain regions involved in socio-emotional processing and attention salience.

The origins of evil: From lesions to the functional architecture of the antisocial brain.

In the past decades, a growing body of evidence has suggested that some individuals may exhibit antisocial behaviors following brain lesions. Recently, some authors have shown that lesions underpinning antisocial behaviors may disrupt a particular brain network during resting-state. However, it remains unknown whether these brain lesions may alter specific mental processes during tasks. Therefore, we conducted meta-analytic co-activation analyses on lesion masks of 17 individuals who acquired antisocial behaviors following their brain lesions. Each lesion mask was used as a seed of interest to examine their aberrant co-activation network using a database of 143 whole-brain neuroimaging studies on antisocial behaviors (n = 5,913 subjects). We aimed to map the lesion brain network that shows deficient activity in antisocial population against a null distribution derived from 655 control lesions. We further characterized the lesion-based meta-analytic network using term-based decoding (Neurosynth) as well as receptor/transporter density maps (JuSpace). We found that the lesion meta-analytic network included the amygdala, orbitofrontal cortex, ventro- and dorso-medial prefrontal cortex, fusiform face area, and supplementary motor area (SMA), which correlated mainly with emotional face processing and serotoninergic system (5-HT1A and 5-HTT). We also investigated the heterogeneity in co-activation networks through data-driven methods and found that lesions could be grouped in four main networks, encompassing emotional face processing, general emotion processing, and reward processing. Our study shows that the heterogeneous brain lesions underpinning antisocial behaviors may disrupt specific mental processes, which further increases the risk for distinct antisocial symptoms. It also highlights the importance and complexity of studying brain lesions in relationship with antisocial behaviors.

Meta-analytical transdiagnostic neural correlates in common pediatric psychiatric disorders.

In the last decades, neuroimaging studies have attempted to unveil the neurobiological markers underlying pediatric psychiatric disorders. Yet, the vast majority of neuroimaging studies still focus on a single nosological category, which limit our understanding of the shared/specific neural correlates between these disorders. Therefore, we aimed to investigate the transdiagnostic neural correlates through a novel and data-driven meta-analytical method. A data-driven meta-analysis was carried out which grouped similar experiments' topographic map together, irrespectively of nosological categories and task-characteristics. Then, activation likelihood estimation meta-analysis was performed on each group of experiments to extract spatially convergent brain regions. One hundred forty-seven experiments were retrieved (3124 cases compared to 3100 controls): 79 attention-deficit/hyperactivity disorder, 32 conduct/oppositional defiant disorder, 14 anxiety disorders, 22 major depressive disorders. Four significant groups of experiments were observed. Functional characterization suggested that these groups of aberrant brain regions may be implicated internally/externally directed processes, attentional control of affect, somato-motor and visual processes. Furthermore, despite that some differences in rates of studies involving major depressive disorders were noticed, nosological categories were evenly distributed between these four sets of regions. Our results may reflect transdiagnostic neural correlates of pediatric psychiatric disorders, but also underscore the importance of studying pediatric psychiatric disorders simultaneously rather than independently to examine differences between disorders.

Developmental multi-trajectory of irritability, anxiety, and hyperactivity as psychological markers of heterogeneity in childhood aggression.

BACKGROUND: A growing body of evidence suggests that child aggression is likely to be driven by multiple developmental pathways. However, little is known about the complex interactions between developmental trajectories of child psychological factors (such as anxiety, irritability, and hyperactivity/impulsivity dimensions) and their associations with aggression from childhood to adolescence. Therefore, the current study aimed to identify clusters of individuals with different developmental multi-trajectory, investigate their early risk factors, and describe their longitudinal associations with physical aggression. METHOD: The sample comprised 4898 children derived from the Fragile Families and Child Wellbeing Study. A parallel process growth mixture model was used to identify developmental multi-trajectory groups at 5, 9 and 15 years old. Associations between multi-trajectory group membership and physical aggression were examined with Generalized Estimating Equations models. Finally, multinomial logistic regression was performed to assess perinatal and early risk factors for multi-trajectory groups. RESULTS: Multi-trajectory groups differed in the magnitude of risk for exhibiting physical aggression, compared to typically developing children. The risk for physical aggression was the most prominent in children who were hyperactive/impulsive and irritable [odds ratio (OR) 6.47; 95% confidence interval (CI) 5.44-7.70] and hyperactive/impulsive, irritable, and anxious (OR 7.68; CI 6.62-8.91). Furthermore, maternal cigarette and alcohol use during pregnancy and maternal depression consistently predicted multi-trajectory groups characterized by problematic levels of at least two co-occurrent psychological symptoms. CONCLUSIONS: Identified combinations of developmental trajectories of psychological characteristics were associated with different magnitude in risk for exhibiting physical aggression. These results may highlight the heterogeneity of developmental trajectories associated with childhood aggression.

Multiple developmental pathways underlying conduct problems: A multitrajectory framework.

In the past decades, there has been an overemphasis of a descriptive/behavioral approach to study conduct disorder. In an equifinal perspective, we aimed to examine the developmental multitrajectory groups of psychological features (irritability, interpersonal callousness, hyperactivity/impulsivity, and depressive-anxiety symptoms) and their associations with conduct problems. In a population-based cohort (n = 1,309 participants followed from 5 months to 17 years old), latent-class growth analysis was performed for each psychological feature to identify a two-trajectory model (from ages 6 to 12 years). Based on parameter estimates of the two-trajectory models for each of the four psychological features, a parallel process growth mixture model identified eight significant developmental patterns that were subsequently compared with typically developing children. Furthermore, we observed that while interpersonal callousness conferred an increased risk for childhood and adolescence conduct problems, its co-occurrence with hyperactivity/impulsivity, irritability, and/or depressive-anxiety symptoms heightened the general risk, but also predicted distinct subtypes of conduct problems (i.e., aggressive and rule-breaking behaviors). Thus, by studying complex developmental combinations of psychological features, we observed qualitatively distinct pathways towards conduct problems. A multitrajectory framework of psychological features should be considered as a significant step towards unveiling the multiple etiological pathways leading to conduct disorder and its substantial clinical heterogeneity.

Preliminary Evidence for Heterogeneity of Beliefs About Auditory Verbal Hallucinations Intent.

ABSTRACT: Perceptions of patient's auditory verbal hallucinations (AVHs), commonly termed voices, have important impacts on their everyday lives. Despite research emphasizing the consequences of malevolent voices, preliminary results suggest that beliefs about voices may not be mutually exclusive. As such, we aimed to characterize the heterogeneity of beliefs about AVHs and describe their clinical correlates. We recruited 78 patients referred to a Voices group therapy for refractory and distressing voices. Based on the Revised Beliefs About Voices Questionnaire, clustering analysis yielded four subgroups of patients with distinct pattern of beliefs about AVHs. These subgroups differed significantly in terms of affective disturbances, engagement, and resistance to their voices. Furthermore, no significant changes in beliefs about voices were observed after 6 weeks. Results of the current study suggest that the heterogeneity regarding the beliefs about AVHs should be targeted in treatment to reduce their associated negative outcomes.

Functional connectivity abnormalities of the long-axis hippocampal subregions in schizophrenia during episodic memory.

Past evidence suggests that hippocampal subregions, namely the anterior and posterior parts, may be engaged in distinct networks underlying the memory functions which may be altered in patients with schizophrenia. However, of the very few studies that have investigated the hippocampal longitudinal axis subdivisions functional connectivity in patients with schizophrenia, the majority was based on resting-state data, and yet, none aimed to examine these during an episodic memory task. A total of 41 patients with schizophrenia and 45 healthy controls were recruited for a magnetic resonance imaging protocol in which they performed an explicit memory task. Seed-based functional connectivity analysis was employed to assess connectivity abnormalities between hippocampal subregions and voxel-wise connectivity targets in patients with schizophrenia. We observed a significantly reduced connectivity between the posterior hippocampus and regions from the default mode network, but increased connectivity with the primary visual cortex, in patients with schizophrenia compared to healthy subjects. Increased connectivity between the anterior hippocampus and anterior temporal regions also characterized patients with schizophrenia. In the current study, we provided evidence and support for studying hippocampal subdivisions along the longitudinal axis in schizophrenia. Our results suggest that the abnormalities in hippocampal subregions functional connectivity reflect deficits in episodic memory that may be implicated in the pathophysiology of schizophrenia.

Aggression and delinquent behavior in a large representative sample of high school students: Cannabis use and victimization as key discriminating factors.

PURPOSE: Since conduct problems (CP) vary distinctly across youths, better subtyping CP may be an important vehicle to study specific risk factors associated to differential patterns of CP. In a sample of 63,196 adolescents, we employed a two-step method to the identify such CP patterns and to help classify youths based on several sociodemographic and psychopathological risk factors associated with CP. METHODS: K-means clustering methods were first used to reduce the heterogeneity of CP by analyzing patterns of aggressive (AGG) and rule-breaking (RB) behaviors. A multi-class Classification and Regression Tree approach was further employed to examine the hierarchical interactions between risk factors specific to the emergence of different CP patterns. RESULTS: Results revealed a three-cluster solution: (i) Low AGG-RB, (ii) High AGG and low RB, and (iii) High AGG-RB. The frequency of cannabis use, level of victimization and hyperactivity symptoms were the three factors best discriminating youths' membership to distinct patterns of CP. The model displayed a moderate to strong discriminatory capacity. CONCLUSION: Although this study provides evidence of key factors that may increase the risk of youths following specific patterns of disruptive behavior, additional research is necessary to clarify the etiology, longitudinal trajectories and outcomes related to these patterns.

Neurofunctional abnormalities in antisocial spectrum: A meta-analysis of fMRI studies on Five distinct neurocognitive research domains.

Past functional magnetic resonance imaging on antisocial subjects have shown important inconsistencies and methodological problems (e.g. heterogeneity in fMRI tasks domain, small sample sizes, analyses on regions-of-interest). We aimed to conduct a meta-analysis of whole-brain fMRI studies on antisocial individuals based on distinct neurocognitive domains. A voxel-based meta-analysis via permutation of subject images (SDM-PSI) was performed on studies using fMRI tasks in the domains of acute threat response, cognitive control, social cognition, punishment and reward processing. Overall, 83 studies were retrieved. Using a liberal statistical threshold, several key regions were identified in the meta-analysis, principally during acute threat response, social cognition and cognitive control tasks. Additionally, we observed that the right amygdala was negatively associated with both callous-unemotional traits and severity of antisocial behaviors, in meta-analyses on region-of-interest and on dimensional studies, respectively. The findings show that the most prominent functional brain deficits arise during acute threat response, social cognitions and cognitive control neurocognitive domains. These results provide substantial insights for our understanding of aberrant neural processing across specific contexts.

Medial Orbitofrontal De-Activation During Tonic Cold Pain Stimulation: A fMRI Study Examining the Opponent-Process Theory.

BACKGROUND: While the concomitant administration of painful and rewarding stimuli tends to reduce the perception of one another, recent evidence shows that pleasant pain relief is experience after the interruption of noxious stimuli. On neurobiological grounds, these opponent processes should translate into decreased activity in brain reward regions during nociceptive stimulation and increased activity in these regions after its interruption. While growing evidence supports the latter assumption, evidence is lacking in humans in support of the former. METHODS: Twenty-six healthy individuals underwent a functional magnetic resonance imaging (fMRI) session during which they were administered a cold pain stimulation, using a novel paradigm which consisted in a cold gel applied on the right foot of participants. RESULTS: After the interruption of noxious stimulation, participants experienced significant levels of pleasant pain relief. During cold pain stimulation, brain activations were observed in key regions of the pain matrix (eg, thalamus, primary somatosensory cortex and insula). Conversely, the medial orbitofrontal cortex was found to be de-activated. Medial orbitofrontal de-activations were negatively correlated with subclinical pain symptoms. DISCUSSION: Our results show that a key brain reward region (eg, medial orbitofrontal cortex) is de-activated during cold pain stimulation, a result which is consistent with one of the central assumptions of the opponent-process theory. On methodological grounds, our results show that the cold gel applied to the foot can be used to trigger activations in the pain matrix, and that the interruption of the cold pressor test elicits significant levels of pleasant pain relief. fMRI studies on pain-reward interactions in chronic pain patients are warranted.

Violent Behavior Is Associated With Emotion Salience Network Dysconnectivity in Schizophrenia.

Background: Despite individuals with schizophrenia being at an elevated risk of violence compared to the general population, limited efforts have been invested in investigating the neurobiological etiology explaining the increase. Among the few studies examining functional disruptions pertaining to violent schizophrenia patients using fMRI, only one study has considered functional connectivity. The current state of knowledge does not allow to infer deficits in functional connectivity specific to distinct cognitive/emotional states that have been associated with the emergence of violence in schizophrenia, such as negative emotion processing. This study sought to identify disrupted connectivity among men with schizophrenia and a history of violence (SCZ+V), compared to men with schizophrenia without a history of violence (SCZ-V) and healthy controls, during negative emotion processing using fMRI. Methods: Twenty SCZ+V, 19 SCZ-V, and 21 healthy men were scanned while viewing negative images. Results: Negative images elicited an increased connectivity between the dorsal anterior cingulate cortex (dACC) and the bilateral rostral prefrontal cortex (rPFC), as well as a decreased functional connectivity between the frontal regions (bilateral rPFC and dACC) and the putamen and hippocampus in SCZ+V men as compared to SCZ-V men and healthy controls. Concurrently, the centrality of the dACC within the network was reduced in SCV+V subjects. Conclusions: These results suggest an inefficient integration of the information by the dACC between frontal and limbic regions in SCZ+V men during negative emotion processing and highlight the importance of the ACC in the neurobiological bases of violent behavior in schizophrenia.

Developmental joint trajectories of anxiety-depressive trait and trait-aggression: implications for co-occurrence of internalizing and externalizing problems.

BACKGROUND: In youth, anxiety-depressive traits (ADT) and trait-aggression (TA) are important risk factors of exhibiting maladaptive behaviors in adulthood (i.e. violence and substance use). However, the developmental co-occurrence of these traits in youth remains unknown. We thus sought to investigate the developmental trajectories of ADT and TA within a data-driven approach. The aim was two-fold: (i) to examine the developmental trajectories of ADT and TA in youth from ages 10 to 16, and (ii) to investigate both childhood predictors and problematic outcomes of the identified joint trajectories. METHOD: The sample comprised 1354 children provided from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN) Consortium. Group-based trajectory modeling was first employed to identify individual trajectory models of ADT and TA independently (from ages 10 to 16). Then, joint trajectory models were built on the found trajectories. Last, logistic regressions were used to evaluate the childhood characteristics and negative outcomes of the joint trajectory groups. RESULTS: Our results showed five trajectory groups with varying levels of ADT and TA. A significant co-occurrence between ADT and TA was found in three of the trajectory groups. Notably, higher levels of childhood psychopathology and more severe/frequent childhood abuse were found in the groups with moderate to high ADT and high TA. The groups with higher ADT and high TA were also more likely to exhibit violence and substance use. CONCLUSIONS: This study exposes the importance of assessing ADT and TA simultaneously and early in childhood to prevent and manage the risk of problematic behaviors in adolescence.

Limbic Hyperactivity in Response to Emotionally Neutral Stimuli in Schizophrenia: A Neuroimaging Meta-Analysis of the Hypervigilant Mind.

OBJECTIVE: It has long been assumed that paranoid ideation may stem from an aberrant limbic response to threatening stimuli. However, results from functional neuroimaging studies using negative emotional stimuli have failed to confirm this assumption. One of the potential reasons for the lack of effect is that study participants with psychosis may display aberrant brain responses to neutral material rather than to threatening stimuli. The authors conducted a functional neuroimaging meta-analysis to test this hypothesis. METHODS: A literature search was performed with PubMed, Google Scholar, and Embase to identify functional neuroimaging studies examining brain responses to neutral material in patients with psychosis. A total of 23 studies involving schizophrenia patients were retrieved. Using t-maps of peak coordinates to calculate effect sizes, a random-effects model meta-analysis was performed with the anisotropic effect-size version of Seed-based d Mapping software. RESULTS: In schizophrenia patients relative to healthy control subjects, increased activations were observed in the left and right amygdala and parahippocampus and the left putamen, hippocampus, and insula in response to neutral stimuli. CONCLUSIONS: Given that several limbic regions were found to be more activated in schizophrenia patients than in control subjects, the results of this meta-analysis strongly suggest that these patients confer aberrant emotional significance to nonthreatening stimuli. In theory, this abnormal brain reactivity may fuel delusional thoughts. Studies are needed in individuals at risk of psychosis to determine whether aberrant limbic reactivity to neutral stimuli is an early neurofunctional marker of psychosis vulnerability.