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The article discusses the use of cannabis and its components, particularly delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), for various medical conditions, including psychiatric disorders.Topics include the use of cannabis and its components for medical purposes; the differences between THC and CBD in terms of psychoactive effects, and the need for more research, particularly randomized controlled trials, to assess the effectiveness and safety of CBD for psychiatric disorders.

Background: Sex differences in the symptomatology of adults with attention-deficit/hyperactivity disorder (ADHD) have often been overlooked when studying behavioral abnormalities. However, it is known that women exhibit considerably more stronger symptoms related to emotional competence than men. Since affective functions significantly influence the processing of risky decision-making and risk-engagement, we assume that risky behavior in ADHD is affected by sex differences. Therefore, we specifically investigated sex-specific effects on the interaction between emotionally induced changes in physiology and behavioral performance on a decision-making task. Methods: Skin conductance responses of twenty-nine adults with ADHD (n = 16 male; n = 13 female) and thirty-three adults in the control group (n = 14 male; n = 19 female) were recorded during the performance in a modified version of the Balloon Analogue Risk Task (BART). Additional questionnaires were used to reveal insights in the self-assessment of emotional competence, risk perception, and feedback sensitivity. Emotional arousal and decision-making behavior were analyzed using linear mixed-effects models. Results: Results showed different effects of sex on risk behaviors in controls and ADHD. In contrast to healthy controls, female adults with ADHD showed a significantly greater risk engagement in the BART compared to males with ADHD. This contrary sex relation was not observed in skin conductance responses and revealed a significantly different sex-dependent correlation of body response and behavioral task performance in ADHD. Comparisons with results from self-assessments furthermore indicate a reduced behavioral self-perception in women with ADHD, but not in men. Conclusion: In summary, we found an altered interaction between physiological activity and risky behavior in women with ADHD. Thus, the present study indicates a reduced sensitivity towards the own bodily responses in women with ADHD, which could consequently cause increased risky DM behavior in daily life. The current results suggest that more consideration needs to be given to sex-specific effects on physiological processes and behavior in adults with ADHD. [ABSTRACT FROM AUTHOR]

• Social anxiety disorder (SAD) has been linked to impaired fear regulation. • We investigated threat and safety reversal learning in young patients with SAD. • People with SAD showed unimpaired reversal learning across all measured domains. • Overall, higher social anxiety symptoms predicted more safety reversal learning. Social anxiety disorder (SAD) has been linked to maladaptive forms of fear regulation, including flexibly distinguishing between learned threat and safety signals. Few studies have examined this in young, unmedicated SAD patients, including its neural basis. We aimed to characterize the neural, subjective, and autonomic correlates of reversal learning in patients with SAD and compare them to matched patients with major depressive disorder and to healthy control participants. All participants completed a threat-safety reversal learning task during functional magnetic resonance imaging. Successful threat-safety updating was associated with significant activation of primary regions of interest (anterior cingulate, insula and ventromedial prefrontal cortex), however, no significant differences were observed between them, consistent with subjective reports of task-evoked anxiety and affect. Contrary to expectations, we did not observe threat and safety reversal learning to be significantly impaired in young people with SAD. [ABSTRACT FROM AUTHOR]

Safety learning generates associative links between neutral stimuli and the absence of threat, promoting the inhibition of fear and security-seeking behaviors. Precisely how safety learning is mediated at the level of underlying brain systems, particularly in humans, remains unclear. Here, we integrated a novel Pavlovian conditioned inhibition task with ultra-high field (7 Tesla) fMRI to examine the neural basis of safety learning in 49 healthy participants. In our task, participants were conditioned to two safety signals: a conditioned inhibitor that predicted threat omission when paired with a known threat signal (A+/AX-), and a standard safety signal that generally predicted threat omission (BC-). Both safety signals evoked equivalent autonomic and subjective learning responses but diverged strongly in terms of underlying brain activation (PFDR whole-brain corrected). The conditioned inhibitor was characterized by more prominent activation of the dorsal striatum, anterior insular, and dorsolateral PFC compared with the standard safety signal, whereas the latter evoked greater activation of the ventromedial PFC, posterior cingulate, and hippocampus, among other regions. Further analyses of the conditioned inhibitor indicated that its initial learning was characterized by consistent engagement of dorsal striatal, mid-brain, thalamic, premotor, and prefrontal subregions. These findings suggest that safety learning via conditioned inhibition involves a distributed cortico-striatal circuitry, separable from broader cortical regions involved with processing standard safety signals (e.g., CS ). This cortico-striatal system could represent a novel neural substrate of safety learning, underlying the initial generation of "stimulus-safety" associations, distinct from wider cortical correlates of safety processing, which facilitate the behavioral outcomes of learning. [ABSTRACT FROM AUTHOR]

Responding flexibly to sources of threat and safety is critical to the adaptive regulation of emotions, including fear. At a neural systems level, such flexibility is thought to rely on an extended neural circuitry involving the dorsal anterior cingulate cortex (dACC) and ventromedial prefrontal cortices (vmPFC), although precisely how this occurs remains unclear. Using a novel fear reversal task and functional magnetic resonance imaging (fMRI), we examined the neural correlates of threat and safety reversal learning and their associations with individual differences in anxious responding in a large sample of healthy adolescents and young adults. Overall, participants demonstrated successful threat and safety reversal learning, as indexed by subjective ratings. At a whole-brain level, threat reversal was associated with significant activation of the bilateral anterior insular cortex and dACC, in particular its rostral subregion. Conversely, safety reversal led to significant activation of the anterior vmPFC, together with posterior mid-line regions. Further analyses of regional responses suggested a more selective role for the rostral dACC in threat signal updating, as well as a direct association of its activity with participants' change in subjective anxious arousal to the reversed threat. Taken together, our findings complement existing neurocircuitry models of human fear regulation, particularly regarding the importance of midline cortical regions, and provide further insights into their specific contribution to flexible threat-safety signal processing. In particular, our results suggest that rostral dACC function may be more centrally involved in regulating levels of anxious arousal when flexibility is required. They also raise important questions regarding the vmPFC's role in safety learning, particularly involving its hypothesized subregional contributions to response inhibitory versus stimulus value processing functions. • Examined functional correlates of threat and safety reversal learning in large healthy cohort. • Investigated associations with individual differences in anxious arousal. • Key role for cortical midline regions in responding flexibly to reversed threat and safety signals. • A role for the dorsal anterior cingulate cortex in threat signal updating and subjective anxiety. • Address ventromedial prefrontal cortex subregional specificity in safety reversal learning. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to analyze the real‐time variability of suicidal ideation intensity and the relationship between real‐time and retrospective reports of suicidal ideation made on the Beck Scale for Suicidal Ideation (BSS), among young people with borderline personality disorder (BPD). Methods: Young people (15–25‐year olds) with BPD (N = 46), recruited from two government‐funded mental health services, rated the intensity of their suicidal ideation six times per day for 7 days before completing the BSS. Results: For 70% of participants, suicidal ideation changed in intensity approximately five times across the week, both within and between days. BSS ratings were most highly correlated with the highest real‐time ratings of suicidal ideation. However, this was not significantly different from the relationship between the BSS and both the average and most recent ratings. Median ratings of suicidal ideation intensity were higher on the BSS compared with an equivalent question asked in real time. Conclusion: Findings suggest that young people with BPD experience high levels of fluctuation in their intensity of suicidal ideation across a week and that retrospective reports of suicidal ideation might be more reflective of the most intense experience of suicidal ideation across the week. [ABSTRACT FROM AUTHOR]

Aim: Basic self disturbance is a putative core vulnerability marker of schizophrenia spectrum disorders. The primary aims of the Self, Neuroscience and Psychosis (SNAP) study are to: (1) empirically test a previously described neurophenomenological self‐disturbance model of psychosis by examining the relationship between specific clinical, neurocognitive, and neurophysiological variables in UHR patients, and (2) develop a prediction model using these neurophenomenological disturbances for persistence or deterioration of UHR symptoms at 12‐month follow‐up. Methods: SNAP is a longitudinal observational study. Participants include 400 UHR individuals, 100 clinical controls with no attenuated psychotic symptoms, and 50 healthy controls. All participants complete baseline clinical and neurocognitive assessments and electroencephalography. The UHR sample are followed up for a total of 24 months, with clinical assessment completed every 6 months. Results: This paper presents the protocol of the SNAP study, including background rationale, aims and hypotheses, design, and assessment procedures. Conclusions: The SNAP study will test whether neurophenomenological disturbances associated with basic self‐disturbance predict persistence or intensification of UHR symptomatology over a 2‐year follow up period, and how specific these disturbances are to a clinical population with attenuated psychotic symptoms. This may ultimately inform clinical care and pathoaetiological models of psychosis. [ABSTRACT FROM AUTHOR]

Antipsychotic medications are increasingly used for difficult-to-treat depression in young people. However, the evidence-base for this is unclear. Our aim was to assess the evidence for the efficacy of atypical antipsychotics in treating unipolar and bipolar depression in adolescents and young adults. We conducted a comprehensive systematic review and meta-analysis of randomized-control-trial studies (RCTs) of antipsychotic medications for 10- to 25-year-olds with unipolar and bipolar depression. The primary outcome of interest was change in depressive symptoms from baseline to trial endpoint. No studies were identified that evaluated the use of antipsychotics in the treatment of unipolar depression. However, we identified four studies, of quetiapine, lurasidone and olanzapine/fluoxetine combination, comprising a total of 866 randomized patients, that evaluated treatment of bipolar depression. All studies used the Children's Depression Rating Scale-Revised (CDRS-R). Our meta-analysis revealed the weighted mean difference (WMD) was −4.58 (95 % CI, −6.59 to −2.57) between antipsychotic and placebo-treated groups. Response and remission rates were also significantly in favor of antipsychotic treatment. There were few studies, several did not address risk-of-bias domains and there was a lack of non-industry sponsored studies. There is an absence of evidence for the use of antipsychotic medications in treatment of youth unipolar depression, and no recommendations can be made. There is some evidence for the efficacy of antipsychotics, specifically lurasidone and olanzapine/fluoxetine combination, in the treatment of young people with bipolar depression. However, this evidence is limited and more studies investigating the use of these medications in young people are needed. • Absence of trials for use of antipsychotics to treat youth unipolar depression • Limited evidence for use of atypical antipsychotics in youth bipolar depression • Quetiapine not shown to be effective • Lurasidone and Olanzapine/fluoxetine combination some evidence for efficacy • More studies required on a wider range of antipsychotics [ABSTRACT FROM AUTHOR]

Abstract: Aim: There is growing support for the role of inflammation and oxidative stress in the pathophysiology of major depressive disorder (MDD). This has led to the development of novel strategies targeting inflammation in the treatment of depression. Rosuvastatin and aspirin have well‐documented, anti‐inflammatory and antioxidant properties. The aim of the Youth Depression Alleviation: Augmentation with an anti‐inflammatory agent (YoDA‐A) study is to determine whether individuals receiving adjunctive anti‐inflammatory agents, aspirin and rosuvastatin experience a reduction in the severity of MDD compared with individuals receiving placebo. Methods: YoDA‐A is a 12‐week triple‐blind, randomized controlled trial funded by the National Health and Medical Research Council, Australia. Participants aged 15–25, with moderate‐to‐severe MDD, are allocated to receive either 10 mg/day rosuvastatin, 100 mg/day aspirin, or placebo, in addition to treatment as usual. Participants are assessed at baseline and at weeks 4, 8, 12 and 26. The primary outcome is change in the Montgomery–Åsberg Depression Rating Scale (MADRS) from baseline to week 12. Results: The study is planned to be completed in 2017. At date of publication, 85 participants have been recruited. Conclusion: Timely and targeted intervention for youth MDD is crucial. Given the paucity of new agents to treat youth MDD, adjunctive trials are not only pragmatic and ‘real‐world’, but additionally aim to target shortfalls in conventional medications. This study has the potential to first provide two new adjunctive treatment options for youth MDD; aspirin and rosuvastatin. Second, this study will serve as proof of principle of the role of inflammation in MDD. [ABSTRACT FROM AUTHOR]

Introduction: Psychosis and mania share conceptual, genetic and clinical features, which suggest the possibility that they have common antecedents. Participants identified to be at-risk for psychosis might also be at-risk for mania. We aimed to identify the rate and predictors of transition to mania in a cohort of youth with clinical or familial risk for psychosis.Methods: Among a cohort of 416 young people with an at-risk mental state for psychosis defined using the Ultra-High-Risk (UHR) criteria, 74.7% were followed up between 5 and 13years from their baseline assessment. We undertook a matched case-control examination of those who developed mania over the follow-up period compared to those who did not develop mania or psychosis. Transition to mania was determined using either a structured clinical interview, or diagnoses from a state-wide public mental health contact registry. Clinical characteristics and risk factors were examined at baseline using information from structured interviews, clinical file notes, rating scales and unstructured assessments.Results: Eighteen participants developed mania (UHR-Manic transition or UHR-M, 4.3%). In comparison with participants matched on age, gender and baseline-study who developed neither mania nor psychosis, more UHR-M participants had subthreshold manic symptoms or were prescribed antidepressants at baseline. They also had lower global functioning.Discussion: In addition to the UHR criteria, features such as subthreshold manic symptoms and antidepressant use may help identify at-risk groups that predict the onset of mania in addition to transition to psychosis. Presence of manic symptoms may also indicate syndrome specificity early in the prodromal phase. [ABSTRACT FROM AUTHOR]

Objective: Depression and suicidal ideation are closely intertwined. Yet, among young people with depression, the specific factors that contribute to changes in suicidal ideation over time are uncertain. Factors other than depressive symptom severity, such as comorbid psychopathology and personality traits, might be important contributors. Our aim was to identify contributors to fluctuations in suicidal ideation severity over a 12-week period in young people with major depressive disorder receiving cognitive behavioural therapy. Methods: Data were drawn from two 12-week randomised, placebo-controlled treatment trials. Participants (N = 283) were 15–25 years old, with moderate to severe major depressive disorder. The primary outcome measure was the Suicidal Ideation Questionnaire, administered at baseline and weeks 4, 8 and 12. A series of linear mixed models was conducted to examine the relationship between Suicidal Ideation Questionnaire score and demographic characteristics, comorbid psychopathology, personality traits and alcohol use. Results: Depression and anxiety symptom severity, and trait anxiety, independently predicted higher suicidal ideation, after adjusting for the effects of time, demographics, affective instability, non-suicidal self-injury and alcohol use. Conclusions: Both state and trait anxiety are important longitudinal correlates of suicidal ideation in depressed young people receiving cognitive behavioural therapy, independent of depression severity. Reducing acute psychological distress, through reducing depression and anxiety symptom severity, is important, but interventions aimed at treating trait anxiety could also potentially be an effective intervention approach for suicidal ideation in young people with depression. [ABSTRACT FROM AUTHOR]

This systematic review aimed to provide a comprehensive summary of the current literature on the neurobiological underpinnings of the experience of the negative moral emotions: shame, embarrassment and guilt. PsycINFO, PubMed and MEDLINE were used to identify existing studies. Twenty-one functional and structural magnetic resonance imaging and positron emission tomography studies were reviewed. Although studies differed considerably in methodology, their findings highlight both shared and distinct patterns of brain structure/function associated with these emotions. Shame was more likely to be associated with activity in the dorsolateral prefrontal cortex, posterior cingulate cortex and sensorimotor cortex; embarrassment was more likely to be associated with activity in the ventrolateral prefrontal cortex and amygdala; guilt was more likely to be associated with activity in ventral anterior cingulate cortex, posterior temporal regions and the precuneus. Although results point to some common and some distinct neural underpinnings of these emotions, further research is required to replicate findings. [ABSTRACT FROM AUTHOR]

Safety learning creates associations between conditional stimuli and the absence of threat. Studies of human fear conditioning have accumulated evidence for the neural signatures of safety over various paradigms, aligning on several common brain systems. While these systems are often interpreted as underlying safety learning in a generic sense, they may instead reflect the expression of learned safety, pertaining to processes of fear inhibition, positive affect, and memory. Animal models strongly suggest these can be separable from neural circuits implicated in the conditioning process itself (or safety acquisition). While acquisition-expression distinctions are ubiquitous in behavioural science, this lens has not been applied to safety learning, which remains a novel area in the field. In this mini-review, we overview findings from prevalent safety paradigms in humans, and synthesise these with insights from animal models to propose that the neurobiology of safety learning be conceptualised along an acquisition-expression model, with the aim of stimulating richer brain-based characterisations of this important process. [ABSTRACT FROM AUTHOR]

Background Identification of earlier stages of Bipolar Disorder (BD), even prior to the first manic episode, may help develop interventions to prevent or delay the onset of BD. However, reliable and valid instruments are necessary to ascertain such earlier stages of BD. The aim of the current review was to identify instruments that had predictive validity and utility for BD for use in early intervention (EI) settings for the prevention of BD. Methods We undertook a systematic examination of studies that examined participants without BD I or II at baseline and prospectively explored the predictive abilities of instruments for BD onset over a period of 6 months or more. The instruments and the studies were rated with respect to their relative validity and utility predicting onset of BD for prevention or early intervention. Odds ratios and area under the curve (AUC) values were derived when not reported. Results Six studies were included, identifying five instruments that examined sub-threshold symptoms, family history, temperament and behavioral regulation. Though none of the identified instruments had been examined in high-quality replicated studies for predicting BD, two instruments, namely the Child Behavioral Checklist – Pediatric BD phenotype (CBCL-PBD) and the General Behavioral Inventory – Revised (GBI-R), had greater levels of validity and utility. Limitation Non-inclusion of studies and instruments that incidentally identified BD on follow-up limited the breadth of the review. Conclusion Instruments that test domains such as subthreshold symptoms, behavioral regulation, family history, and temperament hold promise in predicting BD onset. [ABSTRACT FROM AUTHOR]

Background: People with depression often present with concurrent cognitive impairment. Computerized cognitive training (CCT) is a safe and efficacious strategy to maintain or enhance cognitive performance in a range of clinical populations. However, its efficacy in people with depression and how it varies across populations and design factors are currently unclear. Methods: We searched MEDLINE, EMBASE, and PsycINFO from inception to 13 July 2021 for randomised controlled trials examining the efficacy of CCT vs any control condition on cognitive, mood, psychiatric symptoms, psychosocial, and daily functioning in adults with depression. Eligible samples include studies specifically targeting people with major depressive disorder as well as those with other diagnoses where at least 50% of the sample meets the clinical criteria for depression, with the exception of major psychiatric disorders or dementia. The primary outcome is change in the overall cognitive performance. Multivariate analyses will be used to examine the effect sizes on each outcome category as well as possible effect modifiers and correlations between categories. The risk of bias will be assessed using the Cochrane risk of bias tool version 2. Discussion: To the best of our knowledge, this will be the first systematic review and meta-analysis of narrowly defined CCT across clinical populations with depression. We aim to investigate not only whether CCT is efficacious for cognition, but also how such effects vary across design factors, what other clinically relevant outcomes might respond to CCT, and the extent to which they differ across populations. Systematic review registration: PROSPERO CRD42020204209 [ABSTRACT FROM AUTHOR]

Background: Suicidal ideation (SI) is a common feature of depression and is closely associated with suicidal behaviour. Social support is implicated as an important determinant of suicide, but it is unclear how different social support dimensions influence SI in young people with depression. This study examines relationships between social support dimensions and SI in young people with major depressive disorder (MDD).Methods: 283 Australians aged 15-25, diagnosed with MDD, were recruited from two clinical trials conducted in youth-specific outpatient mental health services. The Multidimensional Scale of Perceived Social Support (MSPSS) was used to evaluate perceived support from Family, Friends, and a Significant Other. Suicidal ideation was assessed using the Suicidal Ideation Questionnaire (SIQ). Hierarchical regression was used to explore associations between social support and SI, controlling for demographics and depression severity.Results: A hierarchical regression model predicted 9% of the variability in SI, with depression severity being the most significant predictor. Family Support was inversely related to SI and uniquely contributed 2% of the variance; β = -0.15 (95% CI -0.27 - -0.02) p < .05. Demographics and support from Friends or a Significant Other were not significantly associated with SI.Limitations: Findings are correlational; it cannot be determined that increasing family support would decrease SI severity.Conclusion: Perceived Family Support was negatively associated with SI in young people with MDD. This suggests that family members might play important roles in suicide prevention efforts. More work is needed exploring ways to empower families to develop adaptive family functioning and support. [ABSTRACT FROM AUTHOR]

Human functional magnetic resonance imaging (fMRI) studies suggest that the ventromedial prefrontal cortex (vmPFC) contributes to the learned discrimination of threat and safety signals, although its precise contribution to these processes remains unclear. One hypothesis is that the vmPFC supports the positive affective processing of safety signals linked to their implicit stress-relieving properties. We set out to test this hypothesis and to examine the specificity of vmPFC responses to safety signal processing versus its high level of ‘default mode’ activity. Sixty participants completed an fMRI conditioning task that involved the generation of a conditioned threat (CS+) and safety (CS-) signal following the completion of a pre-conditioning baseline. Confirming past findings, activation of the vmPFC and other midline cortical and parietal areas – broadly resembling the default mode network – robustly discriminated between the CS- and CS+. However, when adjusting for this network's characteristic ‘baseline’ activity, only a subset of regions, including the vmPFC, was activated by the CS-. Regional selectivity for safety signal processing was confirmed by demonstrating a significant correlation between the magnitude of vmPFC responses and self-rated positive affect evoked by the CS-. Taken together, our current findings confirm a link between human vmPFC activity and the positive affective processing of safety signals. We discuss these findings with regards a broader model of human vmPFC function and its suggested higher-order contribution to emotionally adaptive behavior. [ABSTRACT FROM AUTHOR]

• Subcortical contributions to negative emotional salience processing remain unclear • We examined the dynamic causal influence of the amygdala and periaqueductal gray on negative emotional processing in the salience network • The amygdala showed an excitatory influence on the salience network • In comparison, the periaqueductal gray influence was inhibitory Core regions of the salience network (SN), including the anterior insula (aINS) and dorsal anterior cingulate cortex (dACC), coordinate rapid adaptive changes in attentional and autonomic processes in response to negative emotional events. In doing so, the SN incorporates bottom-up signals from subcortical brain regions, such as the amygdala and periaqueductal gray (PAG). However, the precise influence of these subcortical regions is not well understood. Using ultra-high field 7-Tesla functional magnetic resonance imaging, this study investigated the bottom-up interactions of the amygdala and PAG with the SN during negative emotional salience processing. Thirty-seven healthy participants completed an emotional oddball paradigm designed to elicit a salient negative emotional response via the presentation of random, task-irrelevant negative emotional images. Negative emotional processing was associated with prominent activation in the SN, spanning the amygdala, PAG, aINS, and dACC. Consistent with previous research, analysis using dynamic causal modelling revealed an excitatory influence from the amygdala to the aINS, dACC, and PAG. In contrast, the PAG showed an inhibitory influence on amygdala, aINS and dACC activity. Our findings suggest that the amygdala may amplify the processing of negative emotional stimuli in the SN to enable upstream access to attentional resources. In comparison, the inhibitory influence of the PAG possibly reflects its involvement in modulating sympathetic-parasympathetic autonomic arousal mediated by the SN. This PAG-mediated effect may be driven by amygdala input and facilitate bottom-up processing of negative emotional stimuli. Overall, our results show that the amygdala and PAG modulate divergent functions of the SN during negative emotional processing. [ABSTRACT FROM AUTHOR]

Evaluating suicidal ideation in young people seeking mental health treatment is an important component of clinical assessment and treatment planning. To reduce the burden of youth suicide, we need to improve our understanding of suicidal ideation, its underlying constructs, and how ideation translates into suicidal behaviour. Using exploratory factor analysis, we investigated the dimensionality of the Suicidal Ideation Questionnaire (SIQ) among 273 participants aged 15–25 with Major Depressive Disorder. Area under the receiver operating characteristic curve (AUROC) analysis was used to explore associations between latent factors and actual suicidal behaviour. Findings suggested that the SIQ assesses multiple factors underlying suicidal ideation. AUROC analyses demonstrated that latent factors relating to both active and passive suicidal ideation predicted past-month suicidal behaviour and suicide attempt. These findings contribute to an improved understanding of the complexities of suicidal ideation and relationships with suicidal behaviour in young people with depression. [ABSTRACT FROM AUTHOR]

Background Brain abnormalities in fronto-temporal structures have been implicated in major depressive disorder (MDD). This study aims to identify their anatomical distribution and their relation to the time course of the disease. Methods A whole-brain voxel based morphometry analysis was conducted to assess gray and white matter alterations in 56 participants with a lifetime history of MDD, including currently depressed (cMDD) and remitted patients (rMDD), and 33 matched healthy controls (HC). Results Compared to HC, MDD participants showed increased white matter volume (WMV) in the uncinate fasciculus (UF) and decreased gray matter density (GMD) on the ventromedial prefrontal cortex (vmPFC). The increased WMV in UF was driven by both cMDD and rMDD groups and positively correlated with depression scores. The GMD decrease in the vmPFC resulted mainly from abnormalities in rMDD and was not correlated with depression scores. Finally, temporal UF and vmPFC white matter showed strong structural covariance suggesting functional interactions between these two brain regions. Limitations The retrospective and cross-sectional design of the study limits the generalizability of the results. Information concerning ongoing treatment did not allow the exploration of interactions between medication and observed abnormalities. The duration of the remission period could have influenced abnormalities in the subgroup of remitted patients. Conclusions Fronto-temporal alterations in MDD consist of alterations in a cortico-limbic network involving the ventromedial prefrontal cortex and temporal white matter tracts. State-like abnormalities in the UF survive remission and persist as trait-like abnormalities together with alteration in the vmPFC. [ABSTRACT FROM AUTHOR]

Deficient safety learning has been implicated in the pathogenesis of anxiety disorders. Despite increased translational interest, there has been limited research on the basis of safety learning in humans. Here, we examined safety learning in seventy-three healthy participants via a modified Pavlovian conditioned inhibition paradigm, featuring a conditioned threat stimulus that was reinforced alone (A+), but not when combined with a second stimulus (the conditioned inhibitor, AX-). During a test phase, X and a control safety cue (C) were combined with a second threat stimulus to assess their inhibition of threat responses, measured via skin conductance (SCRs) and US-expectancy ratings. Both stimuli exhibited conditioned inhibition, but X suppressed ratings by a greater magnitude than C. Trait anxiety also predicted increased US-expectancy ratings of X. These findings suggest that a Pavlovian inhibitor accrues greater safety value than a merely unreinforced safety signal. Conditioned inhibition paradigms may have utility in the ongoing study of safety learning and its relevance to anxious psychopathology. • Safety learning was compared between a conditioned inhibitor and a conventional CS-. • Both inhibited threat responses at test, but the inhibitor showed greater suppression of US-expectancy ratings. • The inhibitor was easily re-learned as threatening when subsequently reinforced, contrary to conventional theory. • US-expectancy to the conditioned inhibitor was associated with higher trait anxiety. [ABSTRACT FROM AUTHOR]

• Novel paradigm developed to investigate the neural correlates of shame and guilt. • Shame was associated with decreased activity in superior temporal and precentral regions. • Guilt associated with decreased brain activity during peer feedback. • Guilt associated with activity in the precuneus, hippocampus, and supramarginal gyrus. • Implicated regions involved in social cognition and emotion regulation. • Neural activation associated with shame and guilt differentiated based on social evaluation. Shame and guilt are moral emotions that play an important role in social functioning. There is limited knowledge about the neural underpinnings of these emotions, particularly in young people. In the current study, 36 healthy females (mean age 18.8 ± 1.9 years) underwent functional Magnetic Resonance Imaging, during which they reflected on their decisions about social moral dilemmas, and subsequently received negative or positive peer feedback. Ratings of shame and guilt were used as parametric modulators of brain activity. Shame was associated with decreased activity in the superior temporal sulcus and precentral gyrus during reflection. Guilt was associated with decreased activity in the precuneus during positive feedback, and in the hippocampus and supramarginal gyrus during negative feedback. Results suggest that shame and guilt are associated with activity in brain regions involved in social cognition and emotion regulation; however, they have distinct underlying neural circuitry that may be differentiated based on social evaluation. [ABSTRACT FROM AUTHOR]

The free energy principle is a formal theory of adaptive self-organising systems that emerged from statistical thermodynamics, machine learning and theoretical neuroscience and has since been translated into biologically plausible 'process theories' of cognition and behaviour, which fall under the banner of 'active inference'. Despite the promise this theory holds for theorising, research and practical applications in psychology and psychiatry, its impact on these disciplines has only now begun to bear fruit. The aim of this treatment is to consider the extent to which active inference has informed theoretical progress in psychology, before exploring its contributions to our understanding and treatment of psychopathology. Despite facing persistent translational obstacles, progress suggests that active inference has the potential to become a new paradigm that promises to unite psychology's subdisciplines, while readily incorporating the traditionally competing paradigms of evolutionary and developmental psychology. To date, however, progress towards this end has been slow. Meanwhile, the main outstanding question is whether this theory will make a positive difference through applications in clinical psychology, and its sister discipline of psychiatry.

Background: Inter-individual variability in neurobiological and clinical characteristics in mental illness is often overlooked by classical group-mean case-control studies. Studies using normative modelling to infer person-specific deviations of grey matter volume have indicated that group means are not representative of most individuals. The extent to which this variability is present in white matter morphometry, which is integral to brain function, remains unclear., Methods: We applied Warped Bayesian Linear Regression normative models to T1-weighted magnetic resonance imaging data and mapped inter-individual variability in person-specific white matter volume deviations in 1,294 cases (58% male) diagnosed with one of six disorders (attention-deficit/hyperactivity, autism, bipolar, major depressive, obsessive-compulsive and schizophrenia) and 1,465 matched controls (54% male) recruited across 25 scan sites. We developed a framework to characterize deviation heterogeneity at multiple spatial scales, from individual voxels, through inter-regional connections, specific brain regions, and spatially extended brain networks., Results: The specific locations of white matter volume deviations were highly heterogeneous across participants, affecting the same voxel in fewer than 8% of individuals with the same diagnosis. For autism and schizophrenia, negative deviations (i.e., areas where volume is lower than normative expectations) aggregated into common tracts, regions and large-scale networks in up to 35% of individuals., Conclusions: The prevalence of white matter volume deviations was lower than previously observed in grey matter, and the specific location of these deviations was highly heterogeneous when considering voxel-wise spatial resolution. Evidence of aggregation within common pathways and networks was apparent in schizophrenia and autism but not other disorders., Competing Interests: Disclosures This manuscript has been submitted on bioRxiv. KMA is a scientific advisor to and shareholder in BrainKey Inc., a medical image analysis software company. BF has received educational speaking fees from Medice GmbH. CFB is a director and shareholder of SBGNeuro Ltd. OAA is a consultant to Cortechs.ai and received speaker’s honorarium from Lundbeck, Janssen, Otsuka and Sunovion. NC participed in advisory boards and received speaker’s honoraria from Angelini, Esteve, Janssen, Lundbeck, Novartis, Pfizer, and Viatris. Furthermore, they have been awarded research grants from the Ministry of Health, Ministry of Science and Innovation (CIBERSAM), and the Strategic Plan for Research and Innovation in Health (PERIS) for the period 2016–2020, as well as from Recercaixa and Marato TV3. MY received philanthropic donations from the David Winston Turner Endowment Fund, Wilson Foundation. He has also received funding to conduct sponsored Investigator-Initiated trials (including Incannex Healthcare Ltd). These funding sources had no role in the design, management, data analysis, presentation, or interpretation and write-up of the data. MY also sits on the Advisory Boards of Centre of The Urban Mental Health, University of Amsterdam; and Enosis Therapeutics. MB has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, Medical Benefits Fund, National Health and Medical Research Council, Medical Research Futures Fund, Beyond Blue, Rotary Health, A2 milk company, Meat and Livestock Board, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Abbot, Astra Zeneca, Janssen and Janssen, Lundbeck and Merck and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Eisai, Janssen and Janssen, Lundbeck Merck, Pfizer and Servier – all unrelated to this work. MB has received grant/research support from National Health and Medical Research Council, Wellcome Trust, Medical Research Future Fund, Victorian Medical Research Acceleration Fund, Centre for Research Excellence CRE, Victorian Government Department of Jobs, Precincts and Regions and Victorian COVID-19 Research Fund. He received honoraria from Springer, Oxford University Press, Cambridge University Press, Allen and Unwin, Lundbeck, Controversias Barcelona, Servier, Medisquire, HealthEd, ANZJP, EPA, Janssen, Medplan, Milken Institute, RANZCP, Abbott India, ASCP, Headspace and Sandoz. All other authors report no biomedical financial interests or potential conflicts of interest.

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Clinical trials suggest that long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) (fish oil) may reduce depressive symptoms in adults with major depressive disorder. Therefore, n-3 PUFAs may be a potential treatment for depression in youth., Methods: Participants were 15- to-25 year-old individuals with major depressive disorder who sought care in one of three government-funded mental health services for young people in metropolitan Melbourne, Perth, or Sydney, Australia. Participants were randomly assigned in a double-blind, parallel-arm design to receive either fish oil (840 mg of eicosapentaenoic acid and 560 mg of docosahexaenoic acid) or placebo capsules as adjunct to cognitive behavioral case management. All participants were offered 50-minute cognitive behavioral case management sessions every 2 weeks delivered by qualified therapists (treatment as usual) at the study sites during the intervention period. The primary outcome was change in the interviewer-rated Quick Inventory of Depressive Symptomatology, Adolescent Version, score at 12 weeks. Erythrocyte n-3 PUFA levels were assessed pre-post intervention., Results: A total of 233 young people were randomized to the treatment arms: 115 participants to the n-3 PUFA group and 118 to the placebo group. Mean change from baseline in the Quick Inventory of Depressive Symptomatology score was -5.8 in the n-3 PUFA group and -5.6 in the placebo group (mean difference, 0.2; 95% CI, -1.1 to 1.5; p = .75). Erythrocyte PUFA levels were not associated with depression severity at any time point. The incidence and severity of adverse events were similar in the two groups., Conclusions: This placebo-controlled trial and biomarker analysis found no evidence to support the use of fish oil for treatment in young people with major depressive disorder., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

In this paper, the case study of ketamine as a new treatment for severe depression is used to outline the challenges of repurposing established medicines and we suggest potential solutions. The antidepressant effects of generic racemic ketamine were identified over 20 years ago, but there were insufficient incentives for commercial entities to pursue its registration, or support for non-commercial entities to fill this gap. As a result, the evaluation of generic ketamine was delayed, piecemeal, uncoordinated, and insufficient to gain approval. Meanwhile, substantial commercial investment enabled the widespread registration of a patented, intranasal s-enantiomeric ketamine formulation (Spravato ® ) for depression. However, Spravato is priced at $600-$900/dose compared to ~$5/dose for generic ketamine, and the ~AUD$100 million annual government investment requested in Australia (to cover drug costs alone) has been rejected twice, leaving this treatment largely inaccessible for Australian patients 2 years after Therapeutic Goods Administration approval. Moreover, emerging evidence indicates that generic racemic ketamine is at least as effective as Spravato, but no comparative trials were required for regulatory approval and have not been conducted. Without action, this story will repeat regularly in the next decade with a new wave of psychedelic-assisted psychotherapy treatments, for which the original off-patent molecules could be available at low-cost and reduce the overall cost of treatment. Several systemic reforms are required to ensure that affordable, effective options become accessible; these include commercial incentives, public and public-private funding schemes, reduced regulatory barriers and more coordinated international public funding schemes to support translational research., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.R., C.G.D., M.L.C., N.G., M.H. and C.L. have all received competitive research grants from NHMRC and MRFF for clinical trials evaluating ketamine in depression. C.L. and M.H. have served on advisory boards for Janssen and C.L. has served on advisory boards for Douglas Pharmaceuticals. NG has received a panel honorarium from Janssen and served on Advisory Boards for Servier and Lundbeck. D.B. is an employee of Psylo. The remaining authors have no conflicts of interest to declare.

Major depressive disorder (MDD) is marked by altered processing of emotional stimuli, including facial expressions. Recent neuroimaging research has attempted to investigate how these stimuli alter the directional interactions between brain regions in those with MDD; however, methodological heterogeneity has made identifying consistent effects difficult. To address this, we systematically examined studies investigating MDD-associated differences present in effective connectivity during the processing of emotional facial expressions. We searched five databases: PsycINFO, EMBASE, PubMed, Scopus, and Web of Science, using a preregistered protocol (registration number: CRD42021271586). Of the 510 unique studies screened, 17 met our inclusion criteria. These studies identified that compared with healthy controls, participants with MDD demonstrated (1) reduced connectivity from the dorsolateral prefrontal cortex to the amygdala during the processing of negatively valenced expressions, and (2) increased inhibitory connectivity from the ventromedial prefrontal cortex to amygdala during the processing of happy facial expressions. Most studies investigating the amygdala and anterior cingulate cortex noted differences in their connectivity; however, the precise nature of these differences was inconsistent between studies. As such, commonalities observed across neuroimaging modalities warrant careful investigation to determine the specificity of these effects to particular subregions and emotional expressions. Future research examining longitudinal connectivity changes associated with treatment response may provide important insights into mechanisms underpinning therapeutic interventions, thus enabling more targeted treatment strategies., (© 2024. The Author(s).)

Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects., (© 2024. The Author(s).)

Dysfunctional activity of the rostral anterior cingulate cortex (rACC) - an extensively connected hub region of the default mode network - has been broadly linked to cognitive and affective impairments in depression. However, the nature of aberrant task-related rACC suppression in depression is incompletely understood. In this study, we sought to characterize functional connectivity of rACC activity suppression ('deactivation') - an essential feature of rACC function - during external task engagement in depression. Specifically, we aimed to explore neural patterns of functional decoupling and coupling with the rACC during its task-driven suppression. We enrolled 81 15- to 25-year-old young people with moderate-to-severe major depressive disorder (MDD) before they commenced a 12-week clinical trial that assessed the effectiveness of cognitive behavioral therapy plus either fluoxetine or placebo. Ninety-four matched healthy controls were also recruited. Participants completed a functional magnetic resonance imaging face matching task known to elicit rACC suppression. To identify brain regions associated with the rACC during its task-driven suppression, we employed a seed-based functional connectivity analysis. We found MDD participants, compared to controls, showed significantly reduced 'decoupling' of the rACC with extended task-specific regions during task performance. Specifically, less decoupling was observed in the occipital and fusiform gyrus, dorsal ACC, medial prefrontal cortex, cuneus, amygdala, thalamus, and hippocampus. Notably, impaired decoupling was apparent in participants who did not remit to treatment, but not treatment remitters. Further, we found MDD participants showed significant increased coupling with the anterior insula cortex during task engagement. Our findings indicate that aberrant task-related rACC suppression is associated with disruptions in adaptive neural communication and dynamic switching between internal and external cognitive modes that may underpin maladaptive cognitions and biased emotional processing in depression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Emotion regulation deficits are characteristic of youth depression and are underpinned by altered frontoamygdalar function. However, the causal dynamics of frontoamygdalar pathways in depression and how these dynamics relate to treatment prognosis remain unexplored. This study aimed to assess frontoamygdalar effective connectivity during cognitive reappraisal in youths with depression and to test whether pathway dynamics are predictive of individual response to combined cognitive behavioral therapy plus treatment with fluoxetine or placebo., Methods: One hundred seven young people with moderate to severe depression and 94 healthy control participants completed a functional magnetic resonance imaging cognitive reappraisal task. After the task, 87 participants with depression were randomized and received 12 weeks of cognitive behavioral therapy plus either fluoxetine or placebo. Dynamic causal modeling was used to map frontoamygdalar effective connectivity during reappraisal and to assess the predictive capacity of baseline frontoamygdalar effective connectivity on depression diagnosis and posttreatment depression remission., Results: Young people with depression showed weaker inhibitory modulation of ventrolateral prefrontal cortex to amygdala connectivity during reappraisal (0.29 Hz, posterior probability = 1.00). Leave-one-out cross-validation demonstrated that this effect was sufficiently large to predict individual diagnostic status (r = 0.20, p = .003). Posttreatment depression remission was associated with weaker excitatory ventromedial prefrontal cortex to amygdala connectivity (-0.56 Hz, posterior probability = 1.00) during reappraisal at baseline, though this effect did not predict individual remission status (r = -0.02, p = .561)., Conclusions: Frontoamygdalar effective connectivity shows promise in identifying youth depression diagnosis, and circuits responsible for negative affect regulation are implicated in responsiveness to first-line depression treatments., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The brain's default mode network has a central role in the processing of information concerning oneself. Dysfunction in this self-referential processing represents a key component of multiple mental health conditions, particularly social anxiety disorder (SAD). This case-control study aimed to clarify alterations to network dynamics present during self-appraisal in SAD participants. A total of 38 adolescents and young adults with SAD and 72 healthy control participants underwent a self-referential processing fMRI task. The task involved two primary conditions of interest: direct self-appraisal (thinking about oneself) and reflected self-appraisal (thinking about how others might think about oneself). Dynamic causal modeling and parametric empirical Bayes were then used to explore differences in the effective connectivity of the default mode network between groups. We observed connectivity differences between SAD and healthy control participants in the reflected self-appraisal but not the direct self-appraisal condition. Specifically, SAD participants exhibited greater excitatory connectivity from the posterior cingulate cortex (PCC) to medial prefrontal cortex (MPFC) and greater inhibitory connectivity from the inferior parietal lobule (IPL) to MPFC. In contrast, SAD participants exhibited reduced intrinsic connectivity in the absence of task modulation. This was illustrated by reduced excitatory connectivity from the PCC to MPFC and reduced inhibitory connectivity from the IPL to MPFC. As such, participants with SAD showed changes to afferent connections to the MPFC which occurred during both reflected self-appraisal as well as intrinsically. The presence of connectivity differences in reflected and not direct self-appraisal is consistent with the characteristic fear of negative social evaluation that is experienced by people with SAD., (© 2023. The Author(s).)

Background: Existing treatments for young people with severe depression have limited effectiveness. The aim of the Study of Ketamine for Youth Depression (SKY-D) trial is to determine whether a 4-week course of low-dose subcutaneous ketamine is an effective adjunct to treatment-as-usual in young people with major depressive disorder (MDD)., Methods: SKY-D is a double-masked, randomised controlled trial funded by the Australian Government's National Health and Medical Research Council (NHMRC). Participants aged between 16 and 25 years (inclusive) with moderate-to-severe MDD will be randomised to receive either low-dose ketamine (intervention) or midazolam (active control) via subcutaneous injection once per week for 4 weeks. The primary outcome is change in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale (MADRS) after 4 weeks of treatment. Further follow-up assessment will occur at 8 and 26 weeks from treatment commencement to determine whether treatment effects are sustained and to investigate safety outcomes., Discussion: Results from this trial will be important in determining whether low-dose subcutaneous ketamine is an effective treatment for young people with moderate-to-severe MDD. This will be the largest randomised trial to investigate the effects of ketamine to treat depression in young people., Trial Registration: Australian and New Zealand Clinical Trials Registry ID: ACTRN12619000683134. Registered on May 7, 2019. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377513 ., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The substantial individual heterogeneity that characterizes people with mental illness is often ignored by classical case-control research, which relies on group mean comparisons. Here we present a comprehensive, multiscale characterization of the heterogeneity of gray matter volume (GMV) differences in 1,294 cases diagnosed with one of six conditions (attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, depression, obsessive-compulsive disorder and schizophrenia) and 1,465 matched controls. Normative models indicated that person-specific deviations from population expectations for regional GMV were highly heterogeneous, affecting the same area in <7% of people with the same diagnosis. However, these deviations were embedded within common functional circuits and networks in up to 56% of cases. The salience-ventral attention system was implicated transdiagnostically, with other systems selectively involved in depression, bipolar disorder, schizophrenia and attention-deficit/hyperactivity disorder. Phenotypic differences between cases assigned the same diagnosis may thus arise from the heterogeneous localization of specific regional deviations, whereas phenotypic similarities may be attributable to the dysfunction of common functional circuits and networks., (© 2023. The Author(s).)

Most mental disorders have a typical onset between 12 and 25 years of age, highlighting the importance of this period for the pathogenesis, diagnosis, and treatment of mental ill-health. This perspective addresses interactions between risk and protective factors and brain development as key pillars accounting for the emergence of psychopathology in youth. Moreover, we propose that novel approaches towards early diagnosis and interventions are required that reflect the evolution of emerging psychopathology, the importance of novel service models, and knowledge exchange between science and practitioners. Taken together, we propose a transformative early intervention paradigm for research and clinical care that could significantly enhance mental health in young people and initiate a shift towards the prevention of severe mental disorders., (© 2023. The Author(s).)

Negative self-beliefs are a core feature of psychopathology, encompassing both negative appraisals about oneself directly (i.e. self-judgment) and negative inferences of how the self is appraised by others (i.e. social judgment). Challenging maladaptive self-beliefs via cognitive restructuring is a core treatment mechanism of gold-standard psychotherapies. However, the neural mechanisms underlying the restructuring of these two kinds of negative self-beliefs are poorly understood. Eighty-six healthy participants cognitively restructured self-judgment and social-judgment negative self-belief statements during 7 Tesla functional magnetic resonance imaging scanning. Cognitive restructuring broadly elicited activation in the core default mode network (DMN), salience and frontoparietal control regions. Restructuring self-judgment relative to social-judgment beliefs was associated with comparatively higher activation in the ventral posterior cingulate cortex (PCC)/retrosplenial cortex, while challenging social-judgment statements was associated with higher activation in the dorsal PCC/precuneus. While both regions showed increased functional connectivity with the supplementary and pre-supplementary motor areas during restructuring, the dorsal PCC displayed greater task-dependent connectivity with distributed regions involved in salience, attention and social cognition. Our findings indicate distinct patterns of PCC engagement contingent upon self- and social domains, highlighting a specialized role of the dorsal PCC in supporting neural interactions between the DMN and frontoparietal/salience networks during cognitive restructuring., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Adult attention-deficit/hyperactivity disorder (ADHD) is often associated with risky decision-making behavior. However, current research studies are often limited by the ability to adequately reflect daily behavior in a laboratory setting. Over the lifespan impairments in cognitive functions appear to improve, whereas affective functions become more severe. We assume that risk behavior in ADHD arises predominantly from deficits in affective processes. This study will therefore aim to investigate whether a dysfunction in affective pathways causes an abnormal risky decision-making (DM) behavior in adult ADHD., Methods: Twenty-eight participants with ADHD and twenty-eight healthy controls completed a battery of questionnaires regarding clinical symptoms, self-assessment of behavior and emotional competence. Furthermore, skin conductance responses were measured during the performance in a modified version of the Balloon Analogue Risk Task. A linear mixed-effects model analysis was used to analyze emotional arousal prior to a decision and after feedback display., Results: Results showed higher emotional arousal in ADHD participants before decision-making (β = -0.12, SE = 0.05, t = -2.63, p < 0.001) and after feedback display (β = -0.14, SE = 0.05, t = -2.66, p = 0.008). Although risky behavior was greater in HC than in ADHD, we found a significant interaction effect of group and anticipatory skin conductance responses regarding the response behavior (β = 107.17, SE = 41.91, t = 2.56, p = 0.011). Post hoc analyses revealed a positive correlation between anticipatory skin conductance responses and reaction time in HC, whereas this correlation was negative in ADHD. Self-assessment results were in line with the objective measurements., Conclusion: We found altered changes in physiological activity during a risky decision-making task. The results confirm the assumption of an aberrant relationship between bodily response and risky behavior in adult ADHD. However, further research is needed with respect to age and gender when considering physiological activities., Competing Interests: AP declares that she served on advisory boards, gave lectures, performed phase-3 studies, and received travel grants within the last five years from MEDICE Arzneimittel, Pütter GmbH and Co., KG, Takeda, Boehringer, Janssen-Cilag, and has authored books and articles on ADHD published by Elsevier, Hogrefe, Schattauer, Kohlhammer, Karger, Oxford Press, Thieme, Springer, and Schattauer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Halbe, Kolf, Heger, Hüpen, Bergmann, Aslan, Harrison, Davey, Philipsen and Lux.)

Suppression of the brain's default mode network (DMN) during external goal-directed cognitive tasks has been consistently observed in neuroimaging studies. However, emerging insights suggest the DMN is not a monolithic "task-negative" network but is comprised of subsystems that show functional heterogeneity. Despite considerable research interest, no study has investigated the consistency of DMN activity suppression across multiple cognitive tasks within the same individuals. In this study, 85 healthy 15- to 25-year-olds completed three functional magnetic resonance imaging tasks that were designed to reliably map DMN suppression from a resting baseline. Our findings revealed a distinct suppression subnetwork across the three tasks that comprised traditional DMN and adjacent regions. Specifically, common suppression was observed in the medial prefrontal cortex, the dorsal-to-mid posterior cingulate cortex extending to the precuneus, and the posterior insular cortex and parietal operculum. Further, we found the magnitude of suppression of these regions were significantly correlated within participants across tasks. Overall, our findings indicate that externally oriented cognitive tasks elicit common suppression of a distinct subnetwork of the broader DMN. The consistency to which the DMN is suppressed within individuals suggests a domain-general mechanism that may reflect a stable feature of cognitive function that optimizes external goal-directed behavior., (© The Author(s) 2022. Published by Oxford University Press.)

Objective: A major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behavior. Variation in suicide risk assessment instruments used across cohorts may represent a limitation to pooling data in international consortia., Method: Here, we examine this issue through two approaches: (a) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments and (b) by pooling data (N ∼ 6,000 participants) from cohorts from the Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) Major Depressive Disorder and ENIGMA-Suicidal Thoughts and Behaviour working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behavior., Results: We observed moderate-to-high correlations between measures, consistent with the wide range (κ range: 0.15-0.97; r range: 0.21-0.94) reported in the literature. Two common multi-item instruments, the Columbia Suicide Severity Rating Scale and the Beck Scale for Suicidal Ideation were highly correlated with each other (r = 0.83). Sensitivity analyses identified sources of heterogeneity such as the time frame of the instrument and whether it relies on self-report or a clinical interview. Finally, construct-specific analyses suggest that suicide ideation items from common psychiatric questionnaires are most concordant with the suicide ideation construct of multi-item instruments., Conclusions: Our findings suggest that multi-item instruments provide valuable information on different aspects of suicidal thoughts or behavior but share a modest core factor with single suicidal ideation items. Retrospective, multisite collaborations including distinct instruments should be feasible provided they harmonize across instruments or focus on specific constructs of suicidality. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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., (© 2022. Crown.)

Background: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life., Methods: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed., Results: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth., Conclusions: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)