A comprehensive hierarchical comparison of structural connectomes in Major Depressive Disorder cases v. controls in two large population samples.

BACKGROUND: The brain can be represented as a network, with nodes as brain regions and edges as region-to-region connections. Nodes with the most connections (hubs) are central to efficient brain function. Current findings on structural differences in Major Depressive Disorder (MDD) identified using network approaches remain inconsistent, potentially due to small sample sizes. It is still uncertain at what level of the connectome hierarchy differences may exist, and whether they are concentrated in hubs, disrupting fundamental brain connectivity. METHODS: We utilized two large cohorts, UK Biobank (UKB, N = 5104) and Generation Scotland (GS, N = 725), to investigate MDD case-control differences in brain network properties. Network analysis was done across four hierarchical levels: (1) global, (2) tier (nodes grouped into four tiers based on degree) and rich club (between-hub connections), (3) nodal, and (4) connection. RESULTS: In UKB, reductions in network efficiency were observed in MDD cases globally (d = -0.076, pFDR = 0.033), across all tiers (d = -0.069 to -0.079, pFDR = 0.020), and in hubs (d = -0.080 to -0.113, pFDR = 0.013-0.035). No differences in rich club organization and region-to-region connections were identified. The effect sizes and direction for these associations were generally consistent in GS, albeit not significant in our lower-N replication sample. CONCLUSION: Our results suggest that the brain's fundamental rich club structure is similar in MDD cases and controls, but subtle topological differences exist across the brain. Consistent with recent large-scale neuroimaging findings, our findings offer a connectomic perspective on a similar scale and support the idea that minimal differences exist between MDD cases and controls.

Associations of negative affective biases and depressive symptoms in a community-based sample.

BACKGROUND: Major depressive disorder (MDD) was previously associated with negative affective biases. Evidence from larger population-based studies, however, is lacking, including whether biases normalise with remission. We investigated associations between affective bias measures and depressive symptom severity across a large community-based sample, followed by examining differences between remitted individuals and controls. METHODS: Participants from Generation Scotland (N = 1109) completed the: (i) Bristol Emotion Recognition Task (BERT), (ii) Face Affective Go/No-go (FAGN), and (iii) Cambridge Gambling Task (CGT). Individuals were classified as MDD-current (n = 43), MDD-remitted (n = 282), or controls (n = 784). Analyses included using affective bias summary measures (primary analyses), followed by detailed emotion/condition analyses of BERT and FAGN (secondary analyses). RESULTS: For summary measures, the only significant finding was an association between greater symptoms and lower risk adjustment for CGT across the sample (individuals with greater symptoms were less likely to bet more, despite increasingly favourable conditions). This was no longer significant when controlling for non-affective cognition. No differences were found for remitted-MDD v. controls. Detailed analysis of BERT and FAGN indicated subtle negative biases across multiple measures of affective cognition with increasing symptom severity, that were independent of non-effective cognition [e.g. greater tendency to rate faces as angry (BERT), and lower accuracy for happy/neutral conditions (FAGN)]. Results for remitted-MDD were inconsistent. CONCLUSIONS: This suggests the presence of subtle negative affective biases at the level of emotion/condition in association with depressive symptoms across the sample, over and above those accounted for by non-affective cognition, with no evidence for affective biases in remitted individuals.

Neuroimaging reveals a potential brain-based pre-existing mechanism that confers vulnerability to development of chronic painful chemotherapy-induced peripheral neuropathy.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition impacting 30% of cancer survivors. This study is the first to explore whether a brain-based vulnerability to chronic sensory CIPN exists. METHODS: This prospective, multicentre cohort study recruited from three sites across Scotland. Brain functional MRI (fMRI) scans (3 Tesla) were carried out on chemotherapy naïve patients at a single fMRI centre in Edinburgh, Scotland. Nociceptive stimuli (with a 256 mN monofilament) were administered during the fMRI. Development of chronic sensory/painful CIPN (CIPN+) was determined based upon European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 changes conducted 9 months after chemotherapy, and imaging data analysed using standard software. RESULTS: Of 30 patients recruited (two lung, nine gynaecological, and 19 colorectal malignancies), data from 20 patients at 9 months after chemotherapy was available for analysis. Twelve were classified as CIPN+ (mean age, 63.2[9.6] yr, 9.6; six female), eight as CIPN- (mean age 62.9 [SD 5.5] yr, four female). In response to punctate stimulation, group contrast analysis showed that CIPN+ compared with CIPN- had robust activity in sensory, motor, attentional, and affective brain regions. An a priori chosen region-of-interest analysis focusing on the periaqueductal grey, an area hypothesised as relevant for developing CIPN+, showed significantly increased responses in CIPN- compared with CIPN+ patients. No difference in subcortical volumes between CIPN+ and CIPN- patients was detected. CONCLUSIONS: Before administration of any chemotherapy or appearance of CIPN symptoms, we observed altered patterns of brain activity in response to nociceptive stimulation in patients who later developed chronic sensory CIPN. This suggests the possibility of a pre-existing vulnerability to developing CIPN centred on brainstem regions of the descending pain modulatory system.

Pandemic-related emergency psychiatric presentations for self-harm of children and adolescents in 10 countries (PREP-kids): a retrospective international cohort study.

To examine the differences in hospital emergency psychiatric presentations for self-harm of children and adolescents during the covid-19 lockdown in March and April 2020 compared with the same period in 2019. Retrospective cohort study. We used electronic patient records from 23 hospital emergency departments in ten countries grouped into 14 areas. We examined data on 2073 acute hospital presentations by 1795 unique children and adolescents through age 18. We examined the total number of emergency psychiatric hospital presentations and the proportion of children and adolescents presenting with severe self-harm as our two main outcome measures. In addition, we examined sociodemographic and clinical characteristics and clinical management variables for those presenting with self-harm. To compare the number of hospital presentations between 2020 and 2019 a negative binomial model was used. For other variables, individual participant data (IPD) meta-analyses were carried out. Emergency psychiatric hospital presentations decreased from 1239 in 2019 to 834 in 2020, incident rate ratio 0.67, 95% CI 0.62-0.73; p < 0.001. The proportion of children and adolescents presenting with self-harm increased from 50% in 2019 to 57% in 2020, odds ratio 1.33, 1.07-1.64; p = 0.009 but there was no difference in the proportion presenting with severe self-harm. Within the subpopulation presenting with self-harm the proportion of children and adolescents presenting with emotional disorders increased from 58 to 66%, odds ratio 1.58, 1.06-2.36; p = 0.025. The proportion of children and adolescents admitted to an observation ward also decreased from 13 to 9% in 2020, odds ratio 0.52, 0.28-0.96; p = 0.036. Service planners should consider that, during a lockdown, there are likely to be fewer emergency psychiatric presentations. Many children and adolescents with psychiatric emergencies might not receive any service. A focus on developing intensive community care services with outreach capabilities should be prioritised.

Spectral clustering based on structural magnetic resonance imaging and its relationship with major depressive disorder and cognitive ability.

There is increasing interest in using data-driven unsupervised methods to identify structural underpinnings of common mental illnesses, including major depressive disorder (MDD) and associated traits such as cognition. However, studies are often limited to severe clinical cases with small sample sizes and most do not include replication. Here, we examine two relatively large samples with structural magnetic resonance imaging (MRI), measures of lifetime MDD and cognitive variables: Generation Scotland (GS subsample, N = 980) and UK Biobank (UKB, N = 8,900), for discovery and replication, using an exploratory approach. Regional measures of FreeSurfer derived cortical thickness (CT), cortical surface area (CSA), cortical volume (CV) and subcortical volume (subCV) were input into a clustering process, controlling for common covariates. The main analysis steps involved constructing participant K-nearest neighbour graphs and graph partitioning with Markov stability to determine optimal clustering of participants. Resultant clusters were (1) checked whether they were replicated in an independent cohort and (2) tested for associations with depression status and cognitive measures. Participants separated into two clusters based on structural brain measurements in GS subsample, with large Cohen's d effect sizes between clusters in higher order cortical regions, commonly associated with executive function and decision making. Clustering was replicated in the UKB sample, with high correlations of cluster effect sizes for CT, CSA, CV and subCV between cohorts across regions. The identified clusters were not significantly different with respect to MDD case-control status in either cohort (GS subsample: pFDR = .2239-.6585; UKB: pFDR = .2003-.7690). Significant differences in general cognitive ability were, however, found between the clusters for both datasets, for CSA, CV and subCV (GS subsample: d = 0.2529-.3490, pFDR  < .005; UKB: d = 0.0868-0.1070, pFDR  < .005). Our results suggest that there are replicable natural groupings of participants based on cortical and subcortical brain measures, which may be related to differences in cognitive performance, but not to the MDD case-control status.

Blunted medial prefrontal cortico-limbic reward-related effective connectivity and depression.

Major depressive disorder is a leading cause of disability and significant mortality, yet mechanistic understanding remains limited. Over the past decade evidence has accumulated from case-control studies that depressive illness is associated with blunted reward activation in the basal ganglia and other regions such as the medial prefrontal cortex. However it is unclear whether this finding can be replicated in a large number of subjects. The functional anatomy of the medial prefrontal cortex and basal ganglia has been extensively studied and the former has excitatory glutamatergic projections to the latter. Reduced effect of glutamatergic projections from the prefrontal cortex to the nucleus accumbens has been argued to underlie motivational disorders such as depression, and many prominent theories of major depressive disorder propose a role for abnormal cortico-limbic connectivity. However, it is unclear whether there is abnormal reward-linked effective connectivity between the medial prefrontal cortex and basal ganglia related to depression. While resting state connectivity abnormalities have been frequently reported in depression, it has not been possible to directly link these findings to reward-learning studies. Here, we tested two main hypotheses. First, mood symptoms are associated with blunted striatal reward prediction error signals in a large community-based sample of recovered and currently ill patients, similar to reports from a number of studies. Second, event-related directed medial prefrontal cortex to basal ganglia effective connectivity is abnormally increased or decreased related to the severity of mood symptoms. Using a Research Domain Criteria approach, data were acquired from a large community-based sample of subjects who participated in a probabilistic reward learning task during event-related functional MRI. Computational modelling of behaviour, model-free and model-based functional MRI, and effective connectivity dynamic causal modelling analyses were used to test hypotheses. Increased depressive symptom severity was related to decreased reward signals in areas which included the nucleus accumbens in 475 participants. Decreased reward-related effective connectivity from the medial prefrontal cortex to striatum was associated with increased depressive symptom severity in 165 participants. Decreased striatal activity may have been due to decreased cortical to striatal connectivity consistent with glutamatergic and cortical-limbic related theories of depression and resulted in reduced direct pathway basal ganglia output. Further study of basal ganglia pathophysiology is required to better understand these abnormalities in patients with depressive symptoms and syndromes.

Deactivation in anterior cingulate cortex during facial processing in young individuals with high familial risk and early development of depression: fMRI findings from the Scottish Bipolar Family Study.

BACKGROUND: Studies have identified perturbations in facial processing in bipolar disorder and major depressive disorder (MDD), but their relationship to genetic risk and early development of illness is unclear. METHODS: The Scottish Bipolar Family Study is a prospective longitudinal investigation examining young individuals (age 16-25) at familial risk of mood disorder. Participants underwent functional MRI using an implicit facial processing task employing angry and neutral faces. An explicit facial expression recognition task was completed outside the scanner. Clinical outcomes obtained 2 years after the scan were used to categorise participants into controls (n = 54), high-risk individuals who had developed MDD (HR MDD; n = 30) and high-risk individuals who remained well (HR Well, n = 43). RESULTS: All groups demonstrated activation patterns typically observed during facial processing, including activation of the amygdala, hippocampus, fusiform gyrus and middle frontal regions. Notably, the HR MDD group showed reduced activation of the anterior cingulate gyrus versus both the control and HR Well group for angry faces, and versus the HR Well group for neutral faces. Outside the scanner, the HR MDD group was less accurate in recognising fearful expressions than the HR Well group. CONCLUSIONS: Here, we demonstrate functional abnormalities of the anterior cingulate cortex alongside facial emotional recognition deficits in high-risk individuals in the early stages of depression compared with both controls and at-risk individuals who remained well. These neural changes were associated with a current or future diagnosis of MDD and were not simply associated with increased familial risk.

Loneliness in the Digital World: protocol for a co-produced ecological momentary assessment study in adolescents.

INTRODUCTION: Loneliness has been identified as an important public health issue, peaking during adolescence. Previous research has suggested that social interaction is a key factor in loneliness, and positive social interaction can act as a protective factor against loneliness. However, it is unclear whether there are differing impacts of in-person and online social interaction on adolescents' loneliness and mental health. Ecological Momentary Assessment (EMA) designs are ideally suited for better understanding these associations. METHOD AND ANALYSIS: In the 'Loneliness in the Digital World' study, we will use a co-developed EMA design to capture daily social interactions, loneliness and mental health such as positive and negative emotions, depression and anxiety in approximately 200 adolescents aged 12-15 years. We will combine this with comprehensive information gathered from online surveys. Analysing the data using techniques such as dynamic structural equation modelling, we will examine, among other research questions, the associations between online and in-person social interaction and feelings of loneliness. The results can help inform interventions to support adolescents with high levels of loneliness and poor mental health. ETHICS AND DISSEMINATION: We received the ethics approval for the data collection from The Academic and Clinical Central Office for Research and Development, followed by the College of Medicine and Veterinary Medicine Ethics panel at University of Edinburgh, and finally reviewed by East of Scotland Research Ethics Service. The results will be disseminated through journal publications, conferences and seminar presentations and to relevant stakeholders such as teachers.

Disrupted limbic-prefrontal effective connectivity in response to fearful faces in lifetime depression.

BACKGROUND: Multiple brain imaging studies of negative emotional bias in major depressive disorder (MDD) have used images of fearful facial expressions and focused on the amygdala and the prefrontal cortex. The results have, however, been inconsistent, potentially due to small sample sizes (typically N<50). It remains unclear if any alterations are a characteristic of current depression or of past experience of depression, and whether there are MDD-related changes in effective connectivity between the two brain regions. METHODS: Activations and effective connectivity between the amygdala and dorsolateral prefrontal cortex (DLPFC) in response to fearful face stimuli were studied in a large population-based sample from Generation Scotland. Participants either had no history of MDD (N=664 in activation analyses, N=474 in connectivity analyses) or had a diagnosis of MDD during their lifetime (LMDD, N=290 in activation analyses, N=214 in connectivity analyses). The within-scanner task involved implicit facial emotion processing of neutral and fearful faces. RESULTS: Compared to controls, LMDD was associated with increased activations in left amygdala (PFWE=0.031,kE=4) and left DLPFC (PFWE=0.002,kE=33), increased mean bilateral amygdala activation (ß=0.0715,P=0.0314), and increased inhibition from left amygdala to left DLPFC, all in response to fearful faces contrasted to baseline. Results did not appear to be attributable to depressive illness severity or antidepressant medication status at scan time. LIMITATIONS: Most studied participants had past rather than current depression, average severity of ongoing depression symptoms was low, and a substantial proportion of participants were receiving medication. The study was not longitudinal and the participants were only assessed a single time. CONCLUSIONS: LMDD is associated with hyperactivity of the amygdala and DLPFC, and with stronger amygdala to DLPFC inhibitory connectivity, all in response to fearful faces, unrelated to depression severity at scan time. These results help reduce inconsistency in past literature and suggest disruption of 'bottom-up' limbic-prefrontal effective connectivity in depression.

Evaluation of intensive community care services for young people with psychiatric emergencies: study protocol for a multi-centre parallel-group, single-blinded randomized controlled trial with an internal pilot phase.

BACKGROUND: Over 3000 young people under the age of 18 are admitted to Tier 4 Child and Adolescent Mental Health Services (CAMHS) inpatient units across the UK each year. The average length of hospital stay for young people across all psychiatric units in the UK is 120 days. Research is needed to identify the most effective and efficient ways to care for young people (YP) with psychiatric emergencies. This study aims to evaluate the clinical effectiveness and cost-effectiveness of intensive community care service (ICCS) compared to treatment as usual (TAU) for young people with psychiatric emergencies. METHODS: This is a multicentre two-arm randomized controlled trial (RCT) with an internal pilot phase. Young people aged 12 to < 18 considered for admission at participating NHS organizations across the UK will be randomized 1:1 to either TAU or ICCS. The primary outcome is the time to return to or start education, employment, or training (EET) at 6 months post-randomization. Secondary outcomes will include evaluations of mental health and overall well-being and patient satisfaction. Service use and costs and cost-effectiveness will also be explored. Intention-to-treat analysis will be adopted. The trial is expected to be completed within 42 months, with an internal pilot phase in the first 12 months to assess the recruitment feasibility. A process evaluation using visual semi-structured interviews will be conducted with 42 young people and 42 healthcare workers. DISCUSSION: This trial is the first well-powered randomized controlled trial evaluating the clinical and cost-effectiveness of ICCS compared to TAU for young people with psychiatric emergencies in Great Britain. TRIAL REGISTRATION: ISRCTN ISRCTN42999542, Registration on April 29, 2020.

The application of nonlinear Dynamic Causal Modelling for fMRI in subjects at high genetic risk of schizophrenia.

Nonlinear Dynamic Causal Modelling (DCM) for fMRI provides computational modelling of gating mechanisms at the neuronal population level. It allows for estimations of connection strengths with nonlinear modulation within task-dependent networks. This paper presents an application of nonlinear DCM in subjects at high familial risk of schizophrenia performing the Hayling Sentence Completion Task (HSCT). We analysed scans of 19 healthy controls and 46 subjects at high familial risk of schizophrenia, which included 26 high risk subjects without psychotic symptoms and 20 subjects with psychotic symptoms. The activity-dependent network consists of the intra parietal cortex (IPS), inferior frontal gyrus (IFG), middle temporal gyrus (MTG), anterior cingulate cortex (ACC) and the mediodorsal (MD) thalamus. The connections between the MD thalamus and the IFG were gated by the MD thalamus. We used DCM to investigate altered connection strength of these connections. Bayesian Model Selection (BMS) at the group and family level was used to compare the optimal bilinear and nonlinear models. Bayesian Model Averaging (BMA) was used to assess the connection strengths with the gating from the MD thalamus and the IFG. The nonlinear models provided the better explanation of the data. Furthermore, the BMA analysis showed significantly lower connection strength of the thalamocortical connection with nonlinear modulation from the MD thalamus in high risk subjects with psychotic symptoms and those who subsequently developed schizophrenia. These findings demonstrate that nonlinear DCM provides a method to investigate altered connectivity at the level of neural circuits. The reduced connection strength with thalamic gating may be a neurobiomarker implicated in the development of psychotic symptoms. This study suggests that nonlinear DCM could lead to new insights into functional and effective dysconnection at the network level in subjects at high familial risk.

Keeping up with the kids: the value of co-production in the study of irritability in youth depression and its underlying neural circuitry.

Irritability is a core symptom of adolescent depression, characterized by an increased proneness to anger or frustration. Irritability in youth is associated with future mental health problems and impaired social functioning, suggesting that it may be an early indicator of emotion regulation difficulties. Adolescence is a period during which behavior is significantly impacted by one's environment. However, existing research on the neural basis of irritability typically use experimental paradigms that overlook the social context in which irritability occurs. Here, we bring together current findings on irritability in adolescent depression and the associated neurobiology and highlight directions for future research. Specifically, we emphasize the importance of co-produced research with young people as a means to improve the construct and ecological validity of research within the field. Ensuring that our research design and methodology accurately reflect to lives of young people today lays a strong foundation upon which to better understand adolescent depression and identify tractable targets for intervention.

Striatal correlates of Bayesian beliefs in self-efficacy in adolescents and their relation to mood and autonomy: a pilot study.

Major depressive disorder often originates in adolescence and is associated with long-term functional impairment. Mechanistically characterizing this heterogeneous illness could provide important leads for optimizing treatment. Importantly, reward learning is known to be disrupted in depression. In this pilot fMRI study of 21 adolescents (16-20 years), we assessed how reward network disruption impacts specifically on Bayesian belief representations of self-efficacy (SE-B) and their associated uncertainty (SE-U), using a modified instrumental learning task probing activation induced by the opportunity to choose, and an optimal Hierarchical Gaussian Filter computational model. SE-U engaged caudate, nucleus accumbens (NAcc), precuneus, posterior parietal and dorsolateral prefrontal cortex (PFWE < 0.005). Sparse partial least squares analysis identified SE-U striatal activation as associating with one's sense of perceived choice and depressive symptoms, particularly anhedonia and negative feelings about oneself. As Bayesian uncertainty modulates belief flexibility and their capacity to steer future actions, this suggests that these striatal signals may be informative developmentally, longitudinally and in assessing response to treatment.

The role of brain structure in the association between pubertal timing and depression risk in an early adolescent sample (the ABCD Study®): A registered report.

BACKGROUND: Earlier pubertal timing is associated with higher rates of depressive disorders in adolescence. Neuroimaging studies report brain structural associations with both pubertal timing and depression. However, whether brain structure mediates the relationship between pubertal timing and depression remains unclear. METHODS: The current registered report examined associations between pubertal timing (indexed via perceived pubertal development), brain structure (cortical and subcortical metrics, and white matter microstructure) and depressive symptoms in a large sample (N = âˆ¼5000) of adolescents (aged 9-13 years) from the Adolescent Brain Cognitive Development (ABCD) Study. We used three waves of follow-up data when the youth were aged 10-11 years, 11-12 years, and 12-13 years, respectively. We used generalised linear-mixed models (H1) and structural equation modelling (H2 & H3) to test our hypotheses. HYPOTHESES: We hypothesised that earlier pubertal timing at Year 1 would be associated with increased depressive symptoms at Year 3 (H1), and that this relationship would be mediated by global (H2a-b) and regional (H3a-g) brain structural measures at Year 2. Global measures included reduced cortical volume, thickness, surface area and sulcal depth. Regional measures included reduced cortical thickness and volume in temporal and fronto-parietal areas, increased cortical volume in the ventral diencephalon, increased sulcal depth in the pars orbitalis, and reduced fractional anisotropy in the cortico-striatal tract and corpus callosum. These regions of interest were informed by our pilot analyses using baseline ABCD data when the youth were aged 9-10 years. RESULTS: Earlier pubertal timing was associated with increased depressive symptoms two years later. The magnitude of effect was stronger in female youth and the association remained significant when controlling for parental depression, family income, and BMI in females but not in male youth. Our hypothesised brain structural measures did not however mediate the association between earlier pubertal timing and later depressive symptoms. CONCLUSION: The present results demonstrate that youth, particularly females, who begin puberty ahead of their peers are at an increased risk for adolescent-onset depression. Future work should explore additional biological and socio-environmental factors that may affect this association so that we can identify targets for intervention to help these at-risk youth.

Structural brain correlates of childhood trauma with replication across two large, independent community-based samples.

INTRODUCTION: Childhood trauma and adversity are common across societies and have strong associations with physical and psychiatric morbidity throughout the life-course. One possible mechanism through which childhood trauma may predispose individuals to poor psychiatric outcomes is via associations with brain structure. This study aimed to elucidate the associations between childhood trauma and brain structure across two large, independent community cohorts. METHODS: The two samples comprised (i) a subsample of Generation Scotland (n=1,024); and (ii) individuals from UK Biobank (n=27,202). This comprised n=28,226 for mega-analysis. MRI scans were processed using Free Surfer, providing cortical, subcortical, and global brain metrics. Regression models were used to determine associations between childhood trauma measures and brain metrics and psychiatric phenotypes. RESULTS: Childhood trauma associated with lifetime depression across cohorts (OR 1.06 GS, 1.23 UKB), and related to early onset and recurrent course within both samples. There was evidence for associations between childhood trauma and structural brain metrics. This included reduced global brain volume, and reduced cortical surface area with highest effects in the frontal (ß=-0.0385, SE=0.0048, p(FDR)=5.43x10-15) and parietal lobes (ß=-0.0387, SE=0.005, p(FDR)=1.56x10-14). At a regional level the ventral diencephalon (VDc) displayed significant associations with childhood trauma measures across both cohorts and at mega-analysis (ß=-0.0232, SE=0.0039, p(FDR)=2.91x10-8). There were also associations with reduced hippocampus, thalamus, and nucleus accumbens volumes. DISCUSSION: Associations between childhood trauma and reduced global and regional brain volumes were found, across two independent UK cohorts, and at mega-analysis. This provides robust evidence for a lasting effect of childhood adversity on brain structure.

Self-Harm in Children and Adolescents Who Presented at Emergency Units During the COVID-19 Pandemic: An International Retrospective Cohort Study.

OBJECTIVE: To compare psychiatric emergencies and self-harm at emergency departments (EDs) 1 year into the pandemic, to early pandemic and pre-pandemic, and to examine the changes in the characteristics of self-harm presentations. METHOD: This retrospective cohort study expanded on the Pandemic-Related Emergency Psychiatric Presentations (PREP-kids) study. Routine record data in March to April of 2019, 2020, and 2021 from 62 EDs in 25 countries were included. ED presentations made by children and adolescents for any mental health reasons were analyzed. RESULTS: Altogether, 8,174 psychiatric presentations were recorded (63.5% female; mean [SD] age, 14.3 [2.6] years), 3,742 of which were self-harm presentations. Rate of psychiatric ED presentations in March to April 2021 was twice as high as in March to April 2020 (incidence rate ratio [IRR], 1.93; 95% CI, 1.60-2.33), and 50% higher than in March to April 2019 (IRR, 1.51; 95% CI, 1.25-1.81). Rate of self-harm presentations doubled between March to April 2020 and March to April 2021 (IRR, 1.98; 95% CI, 1.68-2.34), and was overall 1.7 times higher than in March to April 2019 (IRR, 1.70; 95% CI, 1.44-2.00). Comparing self-harm characteristics in March to April 2021 with March to April 2019, self-harm contributed to a higher proportion of all psychiatric presentations (odds ratio [OR], 1.30; 95% CI, 1.05-1.62), whereas female representation in self-harm presentations doubled (OR, 1.98; 95% CI, 1.45-2.72) and follow-up appointments were offered 4 times as often (OR, 4.46; 95% CI, 2.32-8.58). CONCLUSION: Increased pediatric ED visits for both self-harm and psychiatric reasons were observed, suggesting potential deterioration in child mental health. Self-harm in girls possibly increased and needs to be prioritized. Clinical services should continue using follow-up appointments to support discharge from EDs. DIVERSITY & INCLUSION STATEMENT: One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Effects of a mis-sense DISC1 variant on brain activation in two cohorts at high risk of bipolar disorder or schizophrenia.

Bipolar disorder and schizophrenia share a number of clinical features and genetic risk variants of small effect, suggesting overlapping pathogenic mechanisms. The effect of single genetic risk variants on brain function is likely to differ in people at high familial risk versus controls as these individuals have a higher overall genetic loading and are therefore closer to crossing a threshold of disease liability. Therefore, whilst the effects of genetic risk variants on brain function may be similar across individuals at risk of both disorders, they are hypothesized to differ compared to that seen in control subjects. We sought to examine the effects of the DISC1 Leu(607) Phe polymorphism on brain activation in young healthy individuals at familial risk of bipolar disorder (n = 84), in a group of controls (n = 78), and in a group at familial risk of schizophrenia (n = 47), performing a language task. We assessed whether genotype effects on brain activation differed according to risk status. There was a significant genotype × group interaction in a cluster centered on the left pre/postcentral gyrus, extending to the inferior frontal gyrus. The origin of this genotype × group effect originated from a significant effect of the presumed risk variant (Phe) on brain activation in the control group, which was absent in both high-risk groups. Differential effects of this polymorphism in controls compared to the two familial groups suggests a commonality of effect across individuals at high-risk of the disorders, which is likely to be dependant upon existing genetic background.

Impairment in acquisition of conditioned fear in schizophrenia.

Individuals with schizophrenia show impairments in associative learning. One well-studied, quantifiable form of associative learning is Pavlovian fear conditioning. However, to date, studies of fear conditioning in schizophrenia have been inconclusive, possibly because they lacked sufficient power. To address this issue, we pooled data from four independent fear conditioning studies that included a total of 77 individuals with schizophrenia and 74 control subjects. Skin conductance responses (SCRs) to stimuli that were paired (the CS + ) or not paired (CS-) with an aversive, unconditioned stimulus were measured, and the success of acquisition of differential conditioning (the magnitude of CS + vs. CS- SCRs) and responses to CS + and CS- separately were assessed. We found that acquisition of differential conditioned fear responses was significantly lower in individuals with schizophrenia than in healthy controls (Cohen's d = 0.53). This effect was primarily related to a significantly higher response to the CS- stimulus in the schizophrenia compared to the control group. Moreover, the magnitude of this response to the CS- in the schizophrenia group was correlated with the severity of delusional ideation (p = 0.006). Other symptoms or antipsychotic dose were not associated with fear conditioning measures. In conclusion, individuals with schizophrenia who endorse delusional beliefs may be over-responsive to neutral stimuli during fear conditioning. This finding is consistent with prior models of abnormal associative learning in psychosis.

Comparing personalized brain-based and genetic risk scores for major depressive disorder in large population samples of adults and adolescents.

BACKGROUND: Major depressive disorder (MDD) is a polygenic disorder associated with brain alterations but until recently, there have been no brain-based metrics to quantify individual-level variation in brain morphology. Here, we evaluated and compared the performance of a new brain-based 'Regional Vulnerability Index' (RVI) with polygenic risk scores (PRS), in the context of MDD. We assessed associations with syndromal MDD in an adult sample (N = 702, age = 59 ± 10) and with subclinical depressive symptoms in a longitudinal adolescent sample (baseline N = 3,825, age = 10 ± 1; 2-year follow-up N = 2,081, age = 12 ± 1). METHODS: MDD-RVIs quantify the correlation of the individual's corresponding brain metric with the expected pattern for MDD derived in an independent sample. Using the same methodology across samples, subject-specific MDD-PRS and six MDD-RVIs based on different brain modalities (subcortical volume, cortical thickness, cortical surface area, mean diffusivity, fractional anisotropy, and multimodal) were computed. RESULTS: In adults, MDD-RVIs (based on white matter and multimodal measures) were more strongly associated with MDD (ß = 0.099-0.281, PFDR = 0.001-0.043) than MDD-PRS (ß = 0.056-0.152, PFDR = 0.140-0.140). In adolescents, depressive symptoms were associated with MDD-PRS at baseline and follow-up (ß = 0.084-0.086, p = 1.38 × 10-4-4.77 × 10-4) but not with any MDD-RVIs (ß < 0.05, p > 0.05). CONCLUSIONS: Our results potentially indicate the ability of brain-based risk scores to capture a broader range of risk exposures than genetic risk scores in adults and are also useful in helping us to understand the temporal origins of depression-related brain features. Longitudinal data, specific to the developmental period and on white matter measures, will be useful in informing risk for subsequent psychiatric illness.

Lockdown stringency and paediatric self-harm presentations during COVID-19 pandemic: retrospective cohort study.

BACKGROUND: Lockdown during the pandemic has had significant impacts on public mental health. Previous studies suggest an increase in self-harm and suicide in children and adolescents. There has been little research on the roles of stringent lockdown. AIMS: To investigate the mediating and predictive roles of lockdown policy stringency measures in self-harm and emergency psychiatric presentations. METHOD: This was a retrospective cohort study. We analysed data of 2073 psychiatric emergency presentations of children and adolescents from 23 hospital catchment areas in ten countries, in March to April 2019 and 2020. RESULTS: Lockdown measure stringency mediated the reduction in psychiatric emergency presentations (incidence rate ratio of the natural indirect effect [IRRNIE] = 0.41, 95% CI [0.35, 0.48]) and self-harm presentations (IRRNIE = 0.49, 95% CI [0.39, 0.60]) in 2020 compared with 2019. Self-harm presentations among male and looked after children were likely to increase in parallel with lockdown stringency. Self-harm presentations precipitated by social isolation increased with stringency, whereas school pressure and rows with a friend became less likely precipitants. Children from more deprived neighbourhoods were less likely to present to emergency departments when lockdown became more stringent. CONCLUSIONS: Lockdown may produce differential effects among children and adolescents who self-harm. Development in community or remote mental health services is crucial to offset potential barriers to access to emergency psychiatric care, especially for the most deprived youths. Governments should aim to reduce unnecessary fear of help-seeking and keep lockdown as short as possible. Underlying mediation mechanisms of stringent measures and potential psychosocial inequalities warrant further research.