Continuous theta burst stimulation to dorsomedial prefrontal cortex in young adults with depression: Changes in resting frontostriatal functional connectivity relevant to positive mood.

Depression is associated with diminished positive affect (PA), postulated to reflect frontostriatal reward circuitry disruptions. Depression has consistently been associated with higher dorsomedial prefrontal cortex (dmPFC) activation, a region that regulates PA through ventral striatum (VS) connections. Low PA in depression may reflect dmPFC's aberrant functional connectivity (FC) with the VS. To test this, we applied theta burst stimulation (TBS) to dmPFC in 29 adults with depression (79% female, Mage = 21.4, SD = 2.04). Using a randomized, counterbalanced design, we administered 3 types of TBS at different sessions: intermittent (iTBS; potentiating), continuous (cTBS; depotentiating), and sham TBS (control). We used neuronavigation to target personalized dmPFC targets based on VS-dmPFC FC. PA and negative affect (NA), and resting-state fMRI were collected pre- and post-TBS. We found no changes in PA or NA with time (pre/post), condition (iTBS, cTBS, sham), or their interaction. Functional connectivity (FC) between the nucleus accumbens and dmPFC showed a significant condition (cTBS, iTBS, and sham) by time (pre-vs. post-TBS) interaction, and post-hoc testing showed decreased pre-to post-TBS for cTBS but not iTBS or sham. For cTBS only, reduced FC pre/post stimulation was associated with increased PA (but not NA). Our findings lend support to the proposed mechanistic model of aberrant FC between the dmPFC and VS in depression and suggest a way forward for treating depression in young adults. Future studies need to evaluate multi-session TBS to test clinical effects.

Lateral Prefrontal Stimulation of Active Cortex With Theta Burst Transcranial Magnetic Stimulation Affects Subsequent Engagement of the Frontoparietal Network.

BACKGROUND: A critical unanswered question about therapeutic transcranial magnetic stimulation is what patients should do during treatment to optimize its effectiveness. Here, we address this lack of knowledge in healthy participants, testing the hypotheses that stimulating the left dorsolateral prefrontal cortex (dlPFC) while participants perform a working memory task will provide stronger effects on subsequent activation, perfusion, connectivity, and performance than stimulating resting dlPFC. METHODS: After a baseline functional magnetic resonance imaging session to localize dlPFC activation and the associated frontoparietal network (FPN) engaged by an n-back task, healthy participants (N = 40, 67.5% female) underwent 3 counterbalanced sessions, separated by several weeks, during which they received intermittent theta burst stimulation (iTBS) followed by magnetic resonance imaging scans as follows: 1) iTBS to the dlPFC while resting passively (passive), 2) iTBS to the dlPFC while performing the n-back task (active), and 3) iTBS to a vertex site, while not engaged in the n-back task and resting passively (control). RESULTS: We found no difference in n-back performance between the 3 conditions. However, FPN activation was reduced while performing the n-back task in the active condition relative to the passive and control conditions. There was no differential activity in the FPN on comparing passive with control conditions, i.e., there was no effect of the site of stimulation. We found no effects of state or site of stimulation on perfusion or connectivity with the dlPFC. CONCLUSIONS: In this study, the state of the brain while receiving iTBS affected FPN activation, possibly reflecting greater efficiency of FPN network activation when participants were stimulated while engaging the FPN.

Changes in Brain Network Connections After Exposure and Response Prevention Therapy for Obsessive-Compulsive Disorder in Adolescents and Adults.

BACKGROUND: Functional alterations of tripartite neural networks during cognitive control (i.e., frontoparietal network [FPN], cingulo-opercular network, and default mode network) occur in patients with obsessive-compulsive disorder (OCD) and may contribute to illness expression. However, the degree to which changes in these networks are elicited by gold standard treatment (e.g., exposure and response prevention [EX/RP]) remains unknown. Understanding how EX/RP modulates network connectivity in adolescent versus adult patients with OCD may aid the identification of developmentally sensitive treatment targets that enhance cognitive control. METHODS: Data from a total of 169 adolescents (13-17 years) and adults (25-40 years; 57% female) were analyzed, including healthy control participants (n = 58) and patients with OCD (n = 111) who were randomized to either EX/RP or an active control therapy (stress management training). Participants performed a flanker task during functional magnetic resonance imaging pre- and posttreatment. To retain sensitivity to individual differences in connectivity, group iterative multiple model estimation was used to assess functional connectivity (i.e., density) within and between brain networks. RESULTS: Significant increases in FPN density and decreases in FPN-default mode network density were observed from pre- to posttreatment in patients who received EX/RP. The opposite patterns of change occurred in patients who received stress management training. These treatment-related changes in network density did not differ across age group. CONCLUSIONS: Results suggest EX/RP-specific changes in task-based connectivity in patients with OCD. Given baseline differences between healthy control participants and patients by age group, these treatment-related changes may indicate restoration of healthy FPN and default mode network development across patients, providing targets for improving response to EX/RP.

Exposure and response prevention versus stress management training for adults and adolescents with obsessive compulsive disorder: A randomized clinical trial.

OBJECTIVE: Though exposure and response prevention (ERP) is a well-proven treatment for OCD across the lifespan, prior RCTs have not studied adolescent and adult patients with the same ERP protocol relative to an active comparator that controls for non-specific effects of treatment. This approach assesses differences in the effect of OCD-specific exposures in affected adolescents and adults and in response to ERP compared to a stress-management control therapy (SMT). METHODS: This assessor-blinded, parallel, 2-arm, randomized, ambulatory clinical superiority trial randomized adolescents (aged 12-18) and adults (24-46) with OCD (N = 126) to 12 weekly sessions of ERP or SMT. OCD severity was measured before, during and after treatment using the child or adult version of the Yale-Brown Obsessive Compulsive Scale (C/Y-BOCS), depending on participant age. We predicted that ERP would produce greater improvement in OCD symptoms than SMT and that there would be no significant post-treatment differences across age groups. RESULTS: ERP (n = 63) produced significantly greater improvements on C/Y-BOCS scores at post-treatment than SMT (n = 63) (Effect size = -0.72, CI = -0.52 to -0.91, p < .001). ERP also produced more treatment responders (ERP = 86%, SMT = 32%; χ2 = 46.37, p < .001) and remitters than SMT (ERP = 39%, SMT = 7%; χ2 = 16.14, p < .001). Finally, there were no statistically significant post-treatment differences in C/Y-BOCS scores between adolescents and adults assigned to ERP. CONCLUSION: A single ERP protocol is superior to SMT in treating both adolescents and adults with OCD. OCD-specific therapy is necessary across the lifespan for optimal outcomes in this highly disabling disorder, though non-specific treatments like SMT are still all-too-commonly provided.

The behavioral and neural effects of parietal theta burst stimulation on the grasp network are stronger during a grasping task than at rest.

Repetitive transcranial magnetic stimulation (TMS) is widely used in neuroscience and clinical settings to modulate human cortical activity. The effects of TMS on neural activity depend on the excitability of specific neural populations at the time of stimulation. Accordingly, the brain state at the time of stimulation may influence the persistent effects of repetitive TMS on distal brain activity and associated behaviors. We applied intermittent theta burst stimulation (iTBS) to a region in the posterior parietal cortex (PPC) associated with grasp control to evaluate the interaction between stimulation and brain state. Across two experiments, we demonstrate the immediate responses of motor cortex activity and motor performance to state-dependent parietal stimulation. We randomly assigned 72 healthy adult participants to one of three TMS intervention groups, followed by electrophysiological measures with TMS and behavioral measures. Participants in the first group received iTBS to PPC while performing a grasping task concurrently. Participants in the second group received iTBS to PPC while in a task-free, resting state. A third group of participants received iTBS to a parietal region outside the cortical grasping network while performing a grasping task concurrently. We compared changes in motor cortical excitability and motor performance in the three stimulation groups within an hour of each intervention. We found that parietal stimulation during a behavioral manipulation that activates the cortical grasping network increased downstream motor cortical excitability and improved motor performance relative to stimulation during rest. We conclude that constraining the brain state with a behavioral task during brain stimulation has the potential to optimize plasticity induction in cortical circuit mechanisms that mediate movement processes.

Recreational cannabis use over time in individuals at clinical high risk for psychosis: Lack of associations with symptom, neurocognitive, functioning, and treatment patterns.

Recreational cannabis use has recently gained considerable interest as an environmental risk factor that triggers the onset of psychosis. To date, however, the evidence that cannabis is associated with negative outcomes in individuals at clinical high risk (CHR) for psychosis is inconsistent. The present study tracked cannabis usage over a 2-year period and examined its associations with clinical and neurocognitive outcomes, along with medication rates. CHR youth who continuously used cannabis had higher neurocognition and social functioning over time, and decreased medication usage, relative to non-users. Surprisingly, clinical symptoms improved over time despite the medication decreases.

A cognitive-behavioral suicide prevention treatment for adults with schizophrenia spectrum disorders in community mental health: Preliminary findings of an open pilot study.

Suicide is a leading cause of death among schizophrenia spectrum disorder populations. This open pilot study examined a modified cognitive-behavioral suicide prevention treatment for clients in community mental health. Providers (n=5) were trained to deliver the treatment and clients (n=5) received it in 10 individual therapy sessions. Clients experienced improvements in suicide ideation, depression, hopelessness, general symptoms of psychosis, entrapment, defeat, approaches to coping, psychological stress, impulsivity, and the number of treatment barriers from baseline to post-treatment. Qualitative findings reinforced quantitative results of client improvements and provided important suggestions to strengthen the intervention and its delivery in community mental health.

Aberrant Effective Connectivity During Eye Gaze Processing Is Linked to Social Functioning and Symptoms in Schizophrenia.

BACKGROUND: Patients with schizophrenia show abnormal gaze processing, which is associated with social dysfunction. These abnormalities are related to aberrant connectivity among brain regions that are associated with visual processing, social cognition, and cognitive control. In this study, we investigated 1) how effective connectivity during gaze processing is disrupted in schizophrenia and 2) how this may contribute to social dysfunction and clinical symptoms. METHODS: Thirty-nine patients with schizophrenia/schizoaffective disorder (SZ) and 33 healthy control participants completed an eye gaze processing task during functional magnetic resonance imaging. Participants viewed faces with different gaze angles and performed explicit and implicit gaze processing. Four brain regions-the secondary visual cortex, posterior superior temporal sulcus, inferior parietal lobule, and posterior medial frontal cortex-were identified as nodes for dynamic causal modeling analysis. RESULTS: Both the SZ and healthy control groups showed similar model structures for general gaze processing. Explicit gaze discrimination led to changes in effective connectivity, including stronger excitatory, bottom-up connections from the secondary visual cortex to the posterior superior temporal sulcus and inferior parietal lobule and inhibitory, top-down connections from the posterior medial frontal cortex to the secondary visual cortex. Group differences in top-down modulation from the posterior medial frontal cortex to the posterior superior temporal sulcus and inferior parietal lobule were noted, such that these inhibitory connections were attenuated in the healthy control group but further strengthened in the SZ group. Connectivity was associated with social dysfunction and symptom severity. CONCLUSIONS: The SZ group showed notably stronger top-down inhibition during explicit gaze discrimination, which was associated with more social dysfunction but less severe symptoms among patients. These findings help pinpoint neural mechanisms of aberrant gaze processing and may serve as future targets for interventions that combine neuromodulation with social cognitive training.

Neurobehavioral indices of gaze perception are associated with social cognition across schizophrenia patients and healthy controls.

BACKGROUND: Gaze perception is a basic building block of social cognition, which is impaired in schizophrenia (SZ) and contributes to functional outcomes. Few studies, however, have investigated neural underpinnings of gaze perception and their relation to social cognition. We address this gap. METHOD: We recruited 77 SZ patients and 71 healthy controls, who completed various social-cognition tasks. During functional magnetic resonance imaging, participants (62 SZ, 54 controls) completed a gaze-perception task, where they judged whether faces with varying gaze angles were self-directed or averted; as a control condition, participants identified stimulus gender. Activation estimates were extracted based on (a) task versus baseline, (b) gaze-perception versus gender-identification, (c) parametric modulation by perception of stimuli as self-directed versus averted, and (d) parametric modulation by stimulus gaze angle. We used latent variable analysis to test associations among diagnostic group, brain activation, gaze perception, and social cognition. RESULTS: Preferential activation to gaze perception was observed throughout dorsomedial prefrontal cortex, superior temporal sulcus, and insula. Activation was modulated by stimulus gaze angle and perception of stimuli as self-directed versus averted. More precise gaze perception and higher task-related activation were associated with better social cognition. Patients with SZ showed hyperactivation within left pre-/postcentral gyrus, which was associated with more precise gaze perception and fewer symptoms and thus may be a compensatory mechanism. CONCLUSIONS: Neural and behavioral indices of gaze perception were related to social cognition, across patients and controls. This suggests gaze perception is an important perceptual building block for more complex social cognition. Results are discussed in the context of dimensional psychopathology and clinical heterogeneity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Metabolomic signatures associated with weight gain and psychosis spectrum diagnoses: A pilot study.

Psychosis spectrum disorders (PSDs), as well as other severe mental illnesses where psychotic features may be present, like bipolar disorder, are associated with intrinsic metabolic abnormalities. Antipsychotics (APs), the cornerstone of treatment for PSDs, incur additional metabolic adversities including weight gain. Currently, major gaps exist in understanding psychosis illness biomarkers, as well as risk factors and mechanisms for AP-induced weight gain. Metabolomic profiles may identify biomarkers and provide insight into the mechanistic underpinnings of PSDs and antipsychotic-induced weight gain. In this 12-week prospective naturalistic study, we compared serum metabolomic profiles of 25 cases within approximately 1 week of starting an AP to 6 healthy controls at baseline to examine biomarkers of intrinsic metabolic dysfunction in PSDs. In 17 of the case participants with baseline and week 12 samples, we then examined changes in metabolomic profiles over 12 weeks of AP treatment to identify metabolites that may associate with AP-induced weight gain. In the cohort with pre-post data (n = 17), we also compared baseline metabolomes of participants who gained ≥5% baseline body weight to those who gained <5% to identify potential biomarkers of antipsychotic-induced weight gain. Minimally AP-exposed cases were distinguished from controls by six fatty acids when compared at baseline, namely reduced levels of palmitoleic acid, lauric acid, and heneicosylic acid, as well as elevated levels of behenic acid, arachidonic acid, and myristoleic acid (FDR < 0.05). Baseline levels of the fatty acid adrenic acid was increased in 11 individuals who experienced a clinically significant body weight gain (≥5%) following 12 weeks of AP exposure as compared to those who did not (FDR = 0.0408). Fatty acids may represent illness biomarkers of PSDs and early predictors of AP-induced weight gain. The findings may hold important clinical implications for early identification of individuals who could benefit from prevention strategies to reduce future cardiometabolic risk, and may lead to novel, targeted treatments to counteract metabolic dysfunction in PSDs.

Disorder-specific cingulo-opercular network hyperconnectivity in pediatric OCD relative to pediatric anxiety.

BACKGROUND: Prior investigation of adult patients with obsessive compulsive disorder (OCD) has found greater functional connectivity within orbitofrontal-striatal-thalamic (OST) circuitry, as well as altered connectivity within and between large-scale brain networks such as the cingulo-opercular network (CON) and default mode network (DMN), relative to controls. However, as adult OCD patients often have high rates of co-morbid anxiety and long durations of illness, little is known about the functional connectivity of these networks in relation to OCD specifically, or in young patients near illness onset. METHODS: In this study, unmedicated female patients with OCD (ages 8-21 years, n = 23) were compared to age-matched female patients with anxiety disorders (n = 26), and healthy female youth (n = 44). Resting-state functional connectivity was used to determine the strength of functional connectivity within and between OST, CON, and DMN. RESULTS: Functional connectivity within the CON was significantly greater in the OCD group as compared to the anxiety and healthy control groups. Additionally, the OCD group displayed greater functional connectivity between OST and CON compared to the other two groups, which did not differ significantly from each other. CONCLUSIONS: Our findings indicate that previously noted network connectivity differences in pediatric patients with OCD were likely not attributable to co-morbid anxiety disorders. Moreover, these results suggest that specific patterns of hyperconnectivity within CON and between CON and OST circuitry may characterize OCD relative to non-OCD anxiety disorders in youth. This study improves understanding of network dysfunction underlying pediatric OCD as compared to pediatric anxiety.

Structural connectivity of an interoception network in schizophrenia.

Interoception refers to the processing, integration, and interpretation of bodily signals by the brain. Interoception is key to not only basic survival, but also motivational and affective functioning. There is emerging evidence suggesting altered interoception in schizophrenia, but few studies have explored potential neural underpinnings. The current study aims to investigate the anatomical connectivity of a previously identified interoception network in individuals with schizophrenia, and the relationship between network structural connectivity and both emotional functioning and clinical symptoms. Thirty-five participants with schizophrenia (SZ) and 36 healthy control participants (HC) underwent diffusion tensor imaging (DTI) and performed tasks measuring emotional functioning. Probabilistic tractography was used to identify white matter tracts connecting key hubs in an interoception network. Microstructural integrity of these tracts was compared across groups and correlated with measures of emotional functioning and symptom severity. Compared with HC, SZ exhibited altered structural connectivity in the interoception network. In HC, the structural connectivity of the network was significantly correlated with emotion recognition, supporting a link between the interoception network and emotional functioning. However, this correlation was much weaker in SZ. These findings suggest that altered interoception may have implications for illness mechanisms of schizophrenia, especially in relation to emotional deficits.

Abnormally Enhanced Midfrontal Theta Activity During Response Monitoring in Youths With Obsessive-Compulsive Disorder.

BACKGROUND: Response monitoring, as reflected in electroencephalogram recordings after commission of errors, has been consistently shown to be abnormally enhanced in individuals with obsessive-compulsive disorder (OCD). This has traditionally been quantified as error-related negativity (ERN) and may reflect abnormal neurophysiological mechanisms underlying OCD. However, the ERN reflects the increase in phase-locked activities, particularly in the theta-band (4-8 Hz), and does not reflect non-phase-locked activities. To more broadly investigate midfrontal theta activity in a brain region that is essential for complex cognition, this study investigated theta abnormalities during response monitoring in participants with OCD to acheive a better understanding of the mechanism underlying the ERN. METHODS: Electroencephalogram data were recorded from 99 participants with pediatric OCD and 99 sex- and age-matched healthy control participants while they completed the arrow flanker task. Effects of group (OCD, healthy control) and response type (error, correct) on postresponse theta total power and intertrial phase coherence (ITPC) were examined using mixed analysis of covariance and Bayesian analyses controlling for sex and accuracy. RESULTS: Theta total power was larger on error than on correct trials and larger in OCD than healthy control participants, but there was no effect of response type between groups. Theta ITPC was larger on error than correct trials, but there was no group difference or response type difference between the groups. Correlations of theta total power and ITPC with clinical measures were overall small. CONCLUSIONS: Abnormally enhanced midfrontal theta total power, but not ITPC, may reflect ineffective heightened response monitoring or compensatory activity in pediatric OCD.

Combined Cognitive Training and Transcranial Direct Current Stimulation in Neuropsychiatric Disorders: A Systematic Review and Meta-analysis.

BACKGROUND: Treatments for cognitive dysfunction in neuropsychiatric conditions are urgently needed. Cognitive training and transcranial direct current stimulation (tDCS) hold promise, and there is growing interest in combined or multimodal treatments, though studies to date have had small samples and inconsistent results. METHODS: A systematic review and meta-analysis was completed. Retained studies included cognitive training combined with active or sham tDCS in a neuropsychiatric population and reported a posttreatment cognitive outcome. Meta-analyses included effect sizes comparing cognitive training plus active tDCS and cognitive training plus sham tDCS in 5 cognitive domains. Risk of bias in included studies and across studies was explored. RESULTS: Fifteen studies were included: 10 in neurodegenerative disorders and 5 in psychiatric disorders (n = 629). There were several tDCS montages, though two-thirds of studies placed the anode over the left dorsolateral prefrontal cortex. A wide variety of cognitive training types and outcome measures were reported. There was a small, statistically significant effect of combined treatment on measures of attention/working memory, as well as small and non-statistically significant effects favoring combined treatment on global cognition and language. There was no evidence of bias in individual studies but some evidence of nonreporting or small-study bias across studies. CONCLUSIONS: These results may provide preliminary support for the efficacy of combined cognitive training and tDCS on measures of attention/working memory. More data are needed, particularly via studies that explicitly align the cognitive ability of interest, stimulation target, training type, and outcome measures.

Defining brain-based OCD patient profiles using task-based fMRI and unsupervised machine learning.

While much research has highlighted phenotypic heterogeneity in obsessive compulsive disorder (OCD), less work has focused on heterogeneity in neural activity. Conventional neuroimaging approaches rely on group averages that assume homogenous patient populations. If subgroups are present, these approaches can increase variability and can lead to discrepancies in the literature. They can also obscure differences between various subgroups. To address this issue, we used unsupervised machine learning to identify subgroup clusters of patients with OCD who were assessed by task-based fMRI. We predominantly focused on activation of cognitive control and performance monitoring neurocircuits, including three large-scale brain networks that have been implicated in OCD (the frontoparietal network, cingulo-opercular network, and default mode network). Participants were patients with OCD (n = 128) that included both adults (ages 24-45) and adolescents (ages 12-17), as well as unaffected controls (n = 64). Neural assessments included tests of cognitive interference and error processing. We found three patient clusters, reflecting a "normative" cluster that shared a brain activation pattern with unaffected controls (65.9% of clinical participants), as well as an "interference hyperactivity" cluster (15.2% of clinical participants) and an "error hyperactivity" cluster (18.9% of clinical participants). We also related these clusters to demographic and clinical correlates. After post-hoc correction for false discovery rates, the interference hyperactivity cluster showed significantly longer reaction times than the other patient clusters, but no other between-cluster differences in covariates were detected. These findings increase precision in patient characterization, reframe prior neurobehavioral research in OCD, and provide a starting point for neuroimaging-guided treatment selection.

Resting-State Connectivity and Response to Psychotherapy Treatment in Adolescents and Adults With OCD: A Randomized Clinical Trial.

OBJECTIVE: Cortical-subcortical hyperconnectivity related to affective-behavioral integration and cortical network hypoconnectivity related to cognitive control have been demonstrated in obsessive-compulsive disorder (OCD); the study objective was to examine whether these connectivity patterns predict treatment response. METHODS: Adolescents (ages 12-17) and adults (ages 24-45) were randomly assigned to 12 sessions of exposure and response prevention (ERP) or stress management therapy (SMT), an active control. Before treatment, resting-state connectivity of ventromedial prefrontal cortical (vmPFC), cingulo-opercular, frontoparietal, and subcortical regions was assessed with functional MRI. OCD severity was assessed with the Yale-Brown Obsessive Compulsive Scale before, during, and after treatment. Usable fMRI and longitudinal symptom data were obtained from 116 patients (68 female; 54 adolescents; 60 medicated). RESULTS: ERP produced greater decreases in symptom scores than SMT. ERP was selectively associated with less vmPFC-subcortical (caudate and thalamus) connectivity in both age groups and primarily in unmedicated participants. Greater symptom improvement with both ERP and SMT was associated with greater cognitive-control (cingulo-opercular and frontoparietal) and subcortical (putamen) connectivity across age groups. Developmental specificity was observed across ERP and SMT treatments, such that greater improvements with ERP than SMT were associated with greater frontoparietal-subcortical (nucleus accumbens) connectivity in adolescents but greater connectivity between frontoparietal regions in adults. Comparison of response-predictive connections revealed no significant differences compared with a matched healthy control group. CONCLUSIONS: The results suggest that less vmPFC-subcortical connectivity related to affect-influenced behavior may be important for ERP engagement, whereas greater cognitive-control and motor circuit connectivity may generally facilitate response to psychotherapy. Finally, neural predictors of treatment response may differ by age.

Medial Frontal Cortex GABA Concentrations in Psychosis Spectrum and Mood Disorders: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies.

BACKGROUND: Abnormalities of GABAergic (gamma-aminobutyric acidergic) systems may play a role in schizophrenia and mood disorders. Magnetic resonance spectroscopy allows for noninvasive in vivo quantification of GABA; however, studies of GABA in schizophrenia have yielded inconsistent findings. This may stem from grouping together disparate voxels from functionally heterogeneous regions. METHODS: We searched PubMed for magnetic resonance spectroscopy studies of GABA in the medial frontal cortex (MFC) in patients with schizophrenia, bipolar disorder, and depression and in individuals meeting criteria for ultra-high risk for psychosis. Voxel placements were classified as rostral-, rostral-mid-, mid-, or posterior MFC, and meta-analyses were conducted for each group for each subregion. RESULTS: Of 341 screened articles, 23 studies of schizophrenia, 6 studies of bipolar disorder, 20 studies of depression, and 7 studies of ultra-high risk met the inclusion criteria. Meta-analysis revealed lower mid- (standardized mean difference [SMD] = -0.28, 95% CI, -0.48 to -0.07, p < .01) and posterior (SMD = -0.29, 95% CI, -0.49 to -0.09, p < .01) MFC GABA in schizophrenia and increased rostral MFC GABA in bipolar disorder (SMD = 0.76, 95% CI, 0.25 to -1.25, p < .01). In depression, reduced rostral MFC GABA (SMD = -0.36, 95% CI, -0.64 to -0.08, p = .01) did not survive correction for multiple comparisons. We found no evidence for GABA differences in individuals at ultra-high risk for psychosis. CONCLUSIONS: While limited by small numbers of published studies, these results substantiate the relevance of GABA in the pathophysiology of psychosis spectrum and mood disorders and underline the importance of voxel placement.

Mu Opioid Receptor Dynamics in Healthy Volunteers with a History of Childhood Maltreatment.

Evidence suggests that adults with a history of childhood maltreatment, the experience of emotional or physical neglect and/or abuse within the family during childhood, have blunted reward and stress processing, and higher risk of depression. The mu opioid receptor rich nucleus accumbens and amygdala are critical to reward and stress processing respectively. We hypothesized that nucleus accumbens and amygdala mu opioid receptor densities and activity (change in receptor binding due to endogenous opioid release or receptor conformation change) were negatively associated with childhood maltreatment in healthy young adults. Maltreatment was assessed with the Childhood Trauma Questionnaire (CTQ). Healthy participants, n = 75 (52% female) completed [11C]carfentanil positron emission tomography imaging labeling mu opioid receptors. The relationship between CTQ score and binding potential (BPND, proportional to density of unoccupied receptors) was evaluated with a linear mixed effects model. No significant relationship was found between CTQ score and BPND (f = 3.28; df = 1, 73; p = 0.074) or change in BPND (activity) (t = 1.48; df = 198.3; p = 0.14). This is the first investigation of mu opioid receptors in those with childhood maltreatment. We did not identify a significant relationship between mu opioid receptor dynamics and severity of maltreatment in those without psychopathology. Because this cohort has a low CTQ score average, this may indicate that those with low severity of maltreatment may not have associated changes in mu opioid receptor dynamics. Future directions include evaluating a cohort with increased severity of childhood maltreatment.