Emotion regulation skills-focused interventions for chronic pain: A systematic review and meta-analysis.

OBJECTIVES: To investigate the effect of emotion regulation skills-focused (ERSF) interventions to reduce pain intensity and improve psychological outcomes for people with chronic pain and to narratively report on safety and intervention compliance. METHODS: Six databases and four registries were searched for randomized controlled trials (RCTs) up to 29 April 2022. Risk of bias was evaluated using the Cochrane RoB 2.0 tool, and certainty of evidence was assessed according to the Grading, Assessment, Development and Evaluation (GRADE). Meta-analyses for eight studies (902 participants) assessed pain intensity (primary outcome), emotion regulation, affect, symptoms of depression and anxiety, and pain interference (secondary outcomes), at two time points when available, post-intervention (closest to intervention end) and follow-up (the first measurement after the post-intervention assessment). RESULTS: Compared to TAU, pain intensity improved post-intervention (weighted mean difference [WMD] = -10.86; 95% confidence interval [CI] [-17.55, -2.56]) and at follow-up (WMD = -11.38; 95% CI [-13.55, -9.21]). Emotion regulation improved post-intervention (standard mean difference [SMD] = 0.57; 95% CI [0.14, 1.01]), and depressive symptoms improved at follow-up (SMD = -0.45; 95% CI [-0.66, -0.24]). Compared to active comparators, anxiety symptoms improved favouring the comparator post-intervention (SMD = 0.10; 95% CI [0.03, 0.18]), and compared to CBT, pain interference improved post-intervention (SMD = -0.37; 95% CI [-0.69, -0.04]). Certainty of evidence ranged from very low to moderate. SIGNIFICANCE: The findings provide evidence that ERSF interventions reduce pain intensity for people with chronic pain compared to usual treatment. These interventions are at least as beneficial to reduce pain intensity as the current gold standard psychological intervention, CBT. However, the limited number of studies and certainty of evidence mean further high-quality RCTs are warranted. Additionally, further research is needed to identify whether ERSF interventions may be more beneficial for specific chronic pain conditions.

Differences in the neural correlates of schizophrenia with positive and negative formal thought disorder in patients with schizophrenia in the ENIGMA dataset.

Formal thought disorder (FTD) is a clinical key factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, the relationship between FTD symptom dimensions and patterns of regional brain volume loss in schizophrenia remains to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles by enrolling a large multi-site cohort acquired by the ENIGMA Schizophrenia Working Group (752 schizophrenia patients and 1256 controls), to unravel the neuroanatomy of FTD in schizophrenia and using virtual histology tools on implicated brain regions to investigate the cellular basis. Based on the findings of previous clinical and neuroimaging studies, we decided to separately explore positive, negative and total formal thought disorder. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but positive and negative FTD demonstrated a dissociation: negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD also showed associations with microglial cell types. These results provide an important step towards linking FTD to brain structural changes and their cellular underpinnings, providing an avenue for a better mechanistic understanding of this syndrome.

Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

Intrusive Traumatic Re-Experiencing Domain: Functional Connectivity Feature Classification by the ENIGMA PTSD Consortium.

Background: Intrusive traumatic re-experiencing domain (ITRED) was recently introduced as a novel perspective on posttraumatic psychopathology, proposing to focus research of posttraumatic stress disorder (PTSD) on the unique symptoms of intrusive and involuntary re-experiencing of the trauma, namely, intrusive memories, nightmares, and flashbacks. The aim of the present study was to explore ITRED from a neural network connectivity perspective. Methods: Data were collected from 9 sites taking part in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) PTSD Consortium (n= 584) and included itemized PTSD symptom scores and resting-state functional connectivity (rsFC) data. We assessed the utility of rsFC in classifying PTSD, ITRED-only (no PTSD diagnosis), and trauma-exposed (TE)-only (no PTSD or ITRED) groups using a machine learning approach, examining well-known networks implicated in PTSD. A random forest classification model was built on a training set using cross-validation, and the averaged cross-validation model performance for classification was evaluated using the area under the curve. The model was tested using a fully independent portion of the data (test dataset), and the test area under the curve was evaluated. Results: rsFC signatures differentiated TE-only participants from PTSD and ITRED-only participants at about 60% accuracy. Conversely, rsFC signatures did not differentiate PTSD from ITRED-only individuals (45% accuracy). Common features differentiating TE-only participants from PTSD and ITRED-only participants mainly involved default mode network-related pathways. Some unique features, such as connectivity within the frontoparietal network, differentiated TE-only participants from one group (PTSD or ITRED-only) but to a lesser extent from the other group. Conclusions: Neural network connectivity supports ITRED as a novel neurobiologically based approach to classifying posttrauma psychopathology.

Heritability of cognitive and emotion processing during functional MRI in a twin sample.

Despite compelling evidence that brain structure is heritable, the evidence for the heritability of task-evoked brain function is less robust. Findings from previous studies are inconsistent possibly reflecting small samples and methodological variations. In a large national twin sample, we systematically evaluated heritability of task-evoked brain activity derived from functional magnetic resonance imaging. We used established standardised tasks to engage brain regions involved in cognitive and emotional functions. Heritability was evaluated across a conscious and nonconscious Facial Expressions of Emotion Task (FEET), selective attention Oddball Task, N-back task of working memory maintenance, and a Go-NoGo cognitive control task in a sample of Australian adult twins (N ranged from 136 to 226 participants depending on the task and pairs). Two methods for quantifying associations of heritability and brain activity were utilised; a multivariate independent component analysis (ICA) approach and a univariate brain region-of-interest (ROI) approach. Using ICA, we observed that a significant proportion of task-evoked brain activity was heritable, with estimates ranging from 23% to 26% for activity elicited by nonconscious facial emotion stimuli, 27% to 34% for N-back working memory maintenance and sustained attention, and 32% to 33% for selective attention in the Oddball task. Using the ROI approach, we found that activity of regions specifically implicated in emotion processing and selective attention showed significant heritability for three ROIs, including estimates of 33%-34% for the left and right amygdala in the nonconscious processing of sad faces and 29% in the medial superior prefrontal cortex for the Oddball task. Although both approaches show similar levels of heritability for the Nonconscious Faces and Oddball tasks, ICA results displayed a more extensive network of heritable brain function, including additional regions beyond the ROI analysis. Furthermore, multivariate twin modelling of both ICA networks and ROI activation suggested a mix of common genetic and unique environmental factors that contribute to the associations between networks/regions. Together, the results indicate a complex relationship between genetic factors and environmental interactions that ultimately give rise to neural activation underlying cognition and emotion.

Childhood trauma moderates schizotypy-related brain morphology: analyses of 1182 healthy individuals from the ENIGMA schizotypy working group.

BACKGROUND: Schizotypy represents an index of psychosis-proneness in the general population, often associated with childhood trauma exposure. Both schizotypy and childhood trauma are linked to structural brain alterations, and it is possible that trauma exposure moderates the extent of brain morphological differences associated with schizotypy. METHODS: We addressed this question using data from a total of 1182 healthy adults (age range: 18-65 years old, 647 females/535 males), pooled from nine sites worldwide, contributing to the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Schizotypy working group. All participants completed both the Schizotypal Personality Questionnaire Brief version (SPQ-B), and the Childhood Trauma Questionnaire (CTQ), and underwent a 3D T1-weighted brain MRI scan from which regional indices of subcortical gray matter volume and cortical thickness were determined. RESULTS: A series of multiple linear regressions revealed that differences in cortical thickness in four regions-of-interest were significantly associated with interactions between schizotypy and trauma; subsequent moderation analyses indicated that increasing levels of schizotypy were associated with thicker left caudal anterior cingulate gyrus, right middle temporal gyrus and insula, and thinner left caudal middle frontal gyrus, in people exposed to higher (but not low or average) levels of childhood trauma. This was found in the context of morphological changes directly associated with increasing levels of schizotypy or increasing levels of childhood trauma exposure. CONCLUSIONS: These results suggest that alterations in brain regions critical for higher cognitive and integrative processes that are associated with schizotypy may be enhanced in individuals exposed to high levels of trauma.

Estimating multimodal brain variability in schizophrenia spectrum disorders: A worldwide ENIGMA study.

Objective: Schizophrenia is a multifaceted disorder associated with structural brain heterogeneity. Despite its relevance for identifying illness subtypes and informative biomarkers, structural brain heterogeneity in schizophrenia remains incompletely understood. Therefore, the objective of this study was to provide a comprehensive insight into the structural brain heterogeneity associated with schizophrenia. Methods: This meta- and mega-analysis investigated the variability of multimodal structural brain measures of white and gray matter in individuals with schizophrenia versus healthy controls. Using the ENIGMA dataset of MRI-based brain measures from 22 international sites with up to 6139 individuals for a given brain measure, we examined variability in cortical thickness, surface area, folding index, subcortical volume and fractional anisotropy. Results: We found that individuals with schizophrenia are distinguished by higher heterogeneity in the frontotemporal network with regard to multimodal structural measures. Moreover, individuals with schizophrenia showed higher homogeneity of the folding index, especially in the left parahippocampal region. Conclusions: Higher multimodal heterogeneity in frontotemporal regions potentially implies different subtypes of schizophrenia that converge on impaired frontotemporal interaction as a core feature of the disorder. Conversely, more homogeneous folding patterns in the left parahippocampal region might signify a consistent characteristic of schizophrenia shared across subtypes. These findings underscore the importance of structural brain variability in advancing our neurobiological understanding of schizophrenia, and aid in identifying illness subtypes as well as informative biomarkers.

Neural Correlates of Positive and Negative Formal Thought Disorder in Individuals with Schizophrenia: An ENIGMA Schizophrenia Working Group Study.

Formal thought disorder (FTD) is a key clinical factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, relationship between FTD symptom dimensions and patterns of regional brain volume deficiencies in schizophrenia remain to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles based on a large multi-site cohort through the ENIGMA Schizophrenia Working Group (752 individuals with schizophrenia and 1256 controls), to unravel the neuroanatomy of positive, negative and total FTD in schizophrenia and their cellular bases. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks for positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD was also linked to microglial cell types. These findings relate different dimensions of FTD to distinct brain structural changes and their cellular underpinnings, improve our mechanistic understanding of these key psychotic symptoms.

Functional brain changes after alternative pharmacological interventions in posttraumatic stress disorder: A systematic review of clinical trials.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a complex and heterogeneous mental health condition that can develop after exposure to a traumatic event. Clinical trials have used alternative pharmacological agents to treat PTSD, but their associated neural correlates remain unclear. The present systematic review aims to summarize the changes in brain function associated with the use of these alternative pharmacological agents in PTSD. METHODS: Clinical trials using functional magnetic resonance imaging, either at rest or during the performance of tasks, were included if they compared the effects of alternative pharmacological agents between PTSD patients and either trauma-exposed controls or never-exposed healthy controls. RESULTS: Sixteen studies were included, of which 11 used intranasal oxytocin, 2 used hydrocortisone, and 3 used delta-9-tetrahydrocannabinol (THC). Oxytocin administration was associated with the normalization of functional connectivity between the ventromedial prefrontal cortex and amygdala as well as enhanced the function of brain regions specifically involved in emotion processing (e.g., amygdala), working memory (e.g., dorsolateral prefrontal cortex), and reward (e.g., putamen). Hydrocortisone did not influence brain function at rest or during the performance of an autobiographical memory task, whereas THC was associated with the reduction of the amygdala and increased medial prefrontal cortex activation. CONCLUSIONS: This systematic review identified preliminary evidence for normalizing brain function after the use of alternative pharmacological agents. Importantly, sex-specific differences were noted, in particular when using oxytocin, that will require further investigation.

Internet-Delivered Dialectical Behavioral Therapy Skills Training for Chronic Pain: Protocol for a Randomized Controlled Trial.

BACKGROUND: Emotion dysregulation is key to the development and maintenance of chronic pain, feeding into a cycle of worsening pain and disability. Dialectical behavioral therapy (DBT), an evidence-based treatment for complex transdiagnostic conditions presenting with high emotion dysregulation, may be beneficial to manage and mitigate the emotional and sensory aspects of chronic pain. Increasingly, DBT skills training as a key component of standard DBT is being delivered as a stand-alone intervention without concurrent therapy to help develop skills for effective emotion regulation. A previous repeated-measure single-case trial investigating a novel technologically driven DBT skills training, internet-delivered DBT skills training for chronic pain (iDBT-Pain), revealed promising findings to improve both emotion dysregulation and pain intensity. OBJECTIVE: This randomized controlled trial aims to examine the efficacy of iDBT-Pain in comparison with treatment as usual to reduce emotion dysregulation (primary outcome) for individuals with chronic pain after 9 weeks and at the 21-week follow-up. The secondary outcomes include pain intensity, pain interference, anxiety symptoms, depressive symptoms, perceived stress, posttraumatic stress, harm avoidance, social cognition, sleep quality, life satisfaction, and well-being. The trial also examines the acceptability of the iDBT-Pain intervention for future development and testing. METHODS: A total of 48 people with chronic pain will be randomly assigned to 1 of 2 conditions: treatment and treatment as usual. Participants in the treatment condition will receive iDBT-Pain, consisting of 6 live web-based group sessions led by a DBT skills trainer and supervised by a registered psychologist and the iDBT-Pain app. Participants in the treatment-as-usual condition will not receive iDBT-Pain but will still access their usual medication and health interventions. We predict that iDBT-Pain will improve the primary outcome of emotion dysregulation and the secondary outcomes of pain intensity, pain interference, anxiety symptoms, depressive symptoms, perceived stress, harm avoidance, social cognition, sleep quality, life satisfaction, and well-being. A linear mixed model with random effects of individuals will be conducted to investigate the differences between the baseline, 9-week (primary end point), and 21-week (follow-up) assessments as a function of experimental condition. RESULTS: Recruitment started in February 2023, and the clinical trial started in March 2023. Data collection for the final assessment is planned to be completed by July 2024. CONCLUSIONS: If our hypothesis is confirmed, our findings will contribute to the evidence for the efficacy and acceptability of a viable intervention that may be used by health care professionals for people with chronic pain. The results will add to the chronic pain literature to inform about the potential benefits of DBT skills training for chronic pain and will contribute evidence about technologically driven interventions. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12622000113752; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=383208&isReview=true. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/41890.

Neural Correlates of Positive and Negative Formal Thought Disorder in Individuals with Schizophrenia: An ENIGMA Schizophrenia Working Group Study.

Formal thought disorder (FTD) is a key clinical factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, relationship between FTD symptom dimensions and patterns of regional brain volume deficiencies in schizophrenia remain to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles based on a large multi-site cohort through the ENIGMA Schizophrenia Working Group (752 individuals with schizophrenia and 1256 controls), to unravel the neuroanatomy of positive, negative and total FTD in schizophrenia and their cellular bases. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks for positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD was also linked to microglial cell types. These findings relate different dimensions of FTD to distinct brain structural changes and their cellular underpinnings, improve our mechanistic understanding of these key psychotic symptoms.

Depressive symptoms moderate functional connectivity within the emotional brain in chronic pain.

BACKGROUND: Depressive symptoms are often comorbid with chronic pain. These conditions share aberrant emotion processing and regulation, as well as having common brain networks. However, the relationship between depressive symptoms and chronic pain and the effects on emotional brain function are unclear. AIMS: The present study aimed to disentangle the effects of chronic pain and depressive symptoms on functional connectivity between regions implicated in both these conditions. METHOD: Twenty-six individuals with chronic pain (referred to as the pain group) and 32 healthy controls underwent resting-state functional magnetic resonance imaging and completed the Beck Depression Inventory. Main effects of group, depressive symptoms (total severity score) and their interaction on the functional connectivity of three seed regions (the left and right amygdalae and the medial prefrontal cortex; mPFC) with the rest of the brain were evaluated. In cases of significant interaction, moderation analyses were conducted. RESULTS: The group × depressive symptoms interaction was significantly associated with changes in connectivity between the right amygdala and the mPFC (family-wise error-corrected P-threshold (pFWEc = 0.008). In the moderation analysis, the pain group showed weaker connectivity between these regions at lower levels of depressive symptoms (P = 0.020), and stronger connectivity at higher levels of depressive symptoms (P = 0.003), compared with the healthy controls. In addition, the strength of connectivity decreased in the healthy controls (P = 0.005) and increased in the pain group (P = 0.014) as the severity of depressive symptoms increased. CONCLUSIONS: Depressive symptoms moderate the impact of chronic pain on emotional brain function, with potential implications for the choice of treatment for chronic pain.

Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Investigating the neural correlates of affective mentalizing and their association with general intelligence in patients with schizophrenia.

BACKGROUND AND HYPOTHESIS: Mentalizing impairment in schizophrenia has been linked to altered neural responses. This study aimed to replicate previous findings of altered activation of the mentalizing network in schizophrenia and investigate its possible association with impaired domain-general cognition. STUDY DESIGN: We analyzed imaging data from two large multi-centric German studies including 64 patients, 64 matched controls and a separate cohort of 300 healthy subjects, as well as an independent Australian study including 46 patients and 61 controls. All subjects underwent functional magnetic resonance imaging while performing the same affective mentalizing task and completed a cognitive assessment battery. Group differences in activation of the mentalizing network were assessed by classical as well as Bayesian two-sample t-tests. Multiple regression analysis was performed to investigate effects of neurocognitive measures on activation of the mentalizing network. STUDY RESULTS: We found no significant group differences in activation of the mentalizing network. Bayes factors indicate that these results provide genuine evidence for the null hypothesis. We found a positive association between verbal intelligence and activation of the medial prefrontal cortex, a key region of the mentalizing network, in three independent samples. Finally, individuals with low verbal intelligence showed altered activation in areas previously implicated in mentalizing dysfunction in schizophrenia. CONCLUSIONS: Mentalizing activation in patients with schizophrenia might not differ compared to large well-matched groups of healthy controls. Verbal intelligence is an important confounding variable in group comparisons, which should be considered in future studies of the neural correlates of mentalizing dysfunction in schizophrenia.

Imaging dissociation in post-traumatic stress disorder.

Symptom provocation paradigms have been successfully developed to identify the neural correlates associated with post-traumatic stress disorder (PTSD) symptoms, especially dissociative behaviours, but have critical limitations. Transiently stimulating the sympathetic nervous system and/or the hypothalamic-pituitary-adrenal (HPA) axis can enhance the stress response to symptom provocation and would help identify targets for personalised interventions.

Dissociation, trauma and the experience of visual hallucinations in post-traumatic stress disorder and schizophrenia.

Dissociative behaviours and hallucinations are often reported in trauma-exposed people with schizophrenia spectrum disorders and post-traumatic stress disorder (PTSD). Auditory hallucinations are the most commonly reported type of hallucination, but often co-occur with experiences in other sensory modalities. The phenomenology and the neurobiological systems involved in visual experiences are not well characterised. Are these experiences similar in nature, content or severity among people with schizophrenia and/or PTSD? What are the neurobiological bases of these visual experiences and what is the role of dissociative behaviours in the formation of these experiences? A study by Wearne and colleagues in BJPsych Open aimed to characterise these phenomenological systems in groups of people with PTSD, schizophrenia or both (schizophrenia + PTSD).

Evaluation of emotion-centric psychological interventions for chronic pain: protocol for a systematic review and meta-analysis.

INTRODUCTION: Chronic pain, defined as pain persisting longer than 3 months, is more than an unpleasant sensory experience. Persistent negative emotions and emotional comorbidities, such as depression and anxiety, plague people with chronic pain leading to worsening pain intensity and increasing disability. While cognitive-behavioural therapy (CBT) is the gold standard psychological treatment, recent evidence highlights that CBT lacks efficacy for the physical and emotional aspects of chronic pain. Increasingly, researchers are investigating emotion-centric psychological therapies. While treatment modalities vary, these interventions frequently target understanding emotions, and train individuals for an emotionally adaptive response. The aim of this systematic review and meta-analysis is to quantify the efficacy of emotion-centric interventions for the physical and emotional characteristics of chronic pain. METHODS/ANALYSIS: Electronic databases (EMBASE, PubMed, PsychINFO, Cochrane Central Register of Controlled Trials, CINAHL and Web of Science) will be systematically searched from inception to 28 April 2022 for randomised controlled trials. Studies that compare an emotion-centric intervention with another form of treatment or placebo/control for adults (≥18 years old) with chronic pain will be included. All treatment modes (eg, online or in-person), any duration and group-based or individual treatments will be included. Studies that do not investigate at least one emotion-centric treatment will be excluded. The primary outcome is pain intensity. Secondary outcomes include emotion dysregulation, depression, anxiety, affect, safety and intervention compliance. A quantitative synthesis using a random effects meta-analysis will be adopted. Risk of bias will be evaluated using Cochrane Risk of Bias V.2.0 with the certainty of evidence assessed according to Recommendation, Assessment, Development and Evaluation. Data permitting, subgroup analysis will be conducted for intervention type and pain condition. ETHICS AND DISSEMINATION: Ethical approval is not required for this systematic review. Results may inform an efficacy study examining a new emotion-centric intervention for chronic pain. Dissemination will be through peer-reviewed publications and in conference presentations. PROSPERO REGISTRATION NUMBER: CRD42021266815.

Polygenic risk for schizophrenia as a moderator of associations between childhood trauma and schizotypy.

Recent evidence shows that genetic and environmental risk factors for psychotic disorders are associated with higher levels of schizotypy (or psychosis proneness) in the general population. However, little is known about how these risk factors interact. We specifically examined whether genetic loading for schizophrenia moderates the association between childhood trauma severity and schizotypy. Schizotypy was measured using the Schizotypal Personality Questionnaire (SPQ), and childhood trauma severity was measured with the Childhood Trauma Questionnaire (CTQ) among a total of 168 participants (comprising 51 healthy individuals, 56 diagnosed with schizophrenia, and 61 with bipolar disorder). Polygenic risk scores (PRS) for schizophrenia were calculated for all participants and examined as a potential moderator of associations between total scores on the CTQ and schizotypy total scores and dimensions (i.e., cognitive-perceptual, interpersonal, disorganised). Multiple linear regression models revealed associations between childhood trauma and all dimensions of schizotypy, but no associations between PRS and schizotypy. A significant interaction between PRS and childhood trauma was evident for the interpersonal and disorganised dimensions of schizotypy, as well as the total score, reflecting positive associations between childhood trauma severity and these two schizotypal dimensions, only for individuals with low or average PRS for schizophrenia. This suggests that trauma may be able to increase risk for psychosis independently of any genetic vulnerability. The present findings are consistent with the idea of several risk pathways for the development of psychotic disorders.

Interactive effects of polygenic risk and cognitive subtype on brain morphology in schizophrenia spectrum and bipolar disorders.

Grey matter volume (GMV) may be associated with polygenic risk for schizophrenia (PRS-SZ) and severe cognitive deficits in people with schizophrenia, schizoaffective disorder (collectively SSD), and bipolar disorder (BD). This study examined the interactive effects of PRS-SZ and cognitive subtypes of SSD and BD in relation to GMV. Two-step cluster analysis was performed on 146 clinical cases (69 SSD and 77 BD) assessed on eight cognitive domains (verbal and visual memory, executive function, processing speed, visual processing, language ability, working memory, and planning). Among them, 55 BD, 51 SSD, and 58 healthy controls (HC), contributed to focal analyses of the relationships between cognitive subtypes, PRS-SZ and their interaction on GMV. Two distinct cognitive subtypes were evident among the combined sample of cases: a 'cognitive deficit' group (CD; N = 31, 20SSD/11BD) showed severe impairment across all cognitive indices, and a 'cognitively spared' (CS; N = 75; 31SSD/44BD) group showed intermediate cognitive performance that was significantly worse than the HC group but better than the CD subgroup. A cognitive subgroup-by-PRS-SZ interaction was significantly associated with GMV in the left precentral gyrus. Moderation analyses revealed a significant negative relationship between PRS-SZ and GMV in the CD group only. At low and average (but not high) PRS-SZ, larger precentral GMV was evident in the CD group compared to both CS and HC groups, and in the CS group compared to HCs. This study provides evidence for a relationship between regional GMV changes and PRS-SZ in psychosis spectrum cases with cognitive deficits, but not in cases cognitively spared.

Cell type-specific manifestations of cortical thickness heterogeneity in schizophrenia.

Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each individual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes; (2) endothelial cells; (3) oligodendrocyte progenitor cells (OPCs); (4) excitatory neurons; and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same individuals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells (r = -0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes (r = -0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-individual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.