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Classical Pavlovian fear conditioning remains the most widely employed experimental model of fear and anxiety, and continues to inform contemporary pathophysiological accounts of clinical anxiety disorders. Despite its widespread application in human and animal studies, the neurobiological basis of fear conditioning remains only partially understood. Here we provide a comprehensive meta-analysis of human fear-conditioning studies carried out with functional magnetic resonance imaging (fMRI), yielding a pooled sample of 677 participants from 27 independent studies. As a distinguishing feature of this meta-analysis, original statistical brain maps were obtained from the authors of 13 of these studies. Our primary analyses demonstrate that human fear conditioning is associated with a consistent and robust pattern of neural activation across a hypothesized genuine network of brain regions resembling existing anatomical descriptions of the ‘central autonomic–interoceptive network’. This finding is discussed with a particular emphasis on the neural substrates of conscious fear processing. Our associated meta-analysis of functional deactivations—a scarcely addressed dynamic in fMRI fear-conditioning studies—also suggests the existence of a coordinated brain response potentially underlying the ‘safety signal’ (that is, non-threat) processing. We attempt to provide an integrated summary on these findings with the view that they may inform ongoing studies of fear-conditioning processes both in healthy and clinical populations, as investigated with neuroimaging and other experimental approaches.

While multiple studies have examined the brain functional correlates of reward, meta-analyses have either focused on studies using the monetary incentive delay (MID) task, or have adopted a broad strategy, combining data from studies using both monetary and non-monetary reward, as probed using a wide range of tasks. To meta-analyze fMRI studies that used monetary reward and in which there was a definable cue-reward contingency. Studies were limited to those using monetary reward in order to avoid potential heterogeneity from use of other rewards, especially social rewards. Studies using gambling or delay discounting tasks were excluded on the grounds that reward anticipation is not easily quantifiable. English-language fMRI studies (i) that reported fMRI findings on healthy adults; (ii) that used monetary reward; and (iii) in which a cue that was predictive of reward was compared to a no win (or lesser win) condition. Only voxel-based studies were included; those where brain coverage was incomplete were excluded. Ovid, Medline and PsycInfo, from 2000 to 2020, plus checking of review articles and meta-analyses. Data were pooled using Seed-based d Mapping with Permutation of Subject Images (SDM-PSI). Heterogeneity among studies was examined using the I2 statistic. Publication bias was examined using funnel plots and statistical examination of asymmetries. Moderator variables including whether the task was pre-learnt, sex distribution, amount of money won and width of smoothing kernel were examined. Pooled data from 45 studies of reward anticipation revealed activations in the ventral striatum, the middle cingulate cortex/supplementary motor area and the insula. Pooled data from 28 studies of reward delivery again revealed ventral striatal activation, plus cortical activations in the anterior and posterior cingulate cortex. There was relatively little evidence of publication bias. Among moderating variables, only whether the task was pre-learnt exerted an influence. According to this meta-analysis monetary reward anticipation and delivery both activate the ventral but not the dorsal striatum, and are associated with different patterns of cortical activation.

Cognitive-behavioural therapy (CBT) is considered to be effective for the symptoms of schizophrenia. However, this view is based mainly on meta-analysis, whose findings can be influenced by failure to consider sources of bias. To conduct a systematic review and meta-analysis of the effectiveness of CBT for schizophrenic symptoms that includes an examination of potential sources of bias. Data were pooled from randomised trials providing end-of-study data on overall, positive and negative symptoms. The moderating effects of randomisation, masking of outcome assessments, incompleteness of outcome data and use of a control intervention were examined. Publication bias was also investigated. Pooled effect sizes were -0.33 (95% CI -0.47 to -0.19) in 34 studies of overall symptoms, -0.25 (95% CI -0.37 to -0.13) in 33 studies of positive symptoms and -0.13 (95% CI -0.25 to -0.01) in 34 studies of negative symptoms. Masking significantly moderated effect size in the meta-analyses of overall symptoms (effect sizes -0.62 (95% CI -0.88 to -0.35) v. -0.15 (95% CI -0.27 to -0.03), P = 0.001) and positive symptoms (effect sizes -0.57 (95% CI -0.76 to -0.39) v. -0.08 (95% CI -0.18 to 0.03), P<0.001). Use of a control intervention did not moderate effect size in any of the analyses. There was no consistent evidence of publication bias across different analyses. Cognitive-behavioural therapy has a therapeutic effect on schizophrenic symptoms in the 'small' range. This reduces further when sources of bias, particularly masking, are controlled for.

Finding robust brain substrates of mood disorders is an important target for research. The degree to which major depression (MDD) and bipolar disorder (BD) are associated with common and/or distinct patterns of volumetric changes is nevertheless unclear. Furthermore, the extant literature is heterogeneous with respect to the nature of these changes. We report a meta-analysis of voxel-based morphometry (VBM) studies in MDD and BD. We identified studies published up to January 2015 that compared grey matter in MDD (50 data sets including 4101 individuals) and BD (36 data sets including 2407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Group comparisons and conjunction analyses identified regions in which the disorders showed common and distinct patterns of volumetric alteration. Both disorders were associated with lower grey-matter volume relative to healthy individuals in a number of areas. Conjunction analysis showed smaller volumes in both disorders in clusters in the dorsomedial and ventromedial prefrontal cortex, including the anterior cingulate cortex and bilateral insula. Group comparisons indicated that findings of smaller grey-matter volumes relative to controls in the right dorsolateral prefrontal cortex and left hippocampus, along with cerebellar, temporal and parietal regions were more substantial in major depression. These results suggest that MDD and BD are characterised by both common and distinct patterns of grey-matter volume changes. This combination of differences and similarities has the potential to inform the development of diagnostic biomarkers for these conditions.

We conducted a meta-analysis of voxel-based morphometry (VBM) studies in autism spectrum disorder (ASD) to clarify the changes in regional white-matter volume underpinning this condition, and generated an online database to facilitate replication and further analyses by other researchers. PubMed, ScienceDirect, Web of Knowledge and Scopus databases were searched between 2002 (the date of the first white-matter VBM study in ASD) and 2010. Manual searches were also conducted. Authors were contacted to obtain additional data. Coordinates were extracted from clusters of significant white-matter difference between patients and controls. A new template for white matter was created for the signed differential mapping (SDM) meta-analytic method. A diffusion tensor imaging (DTI)-derived atlas was used to optimally localize the changes in white-matter volume. Thirteen datasets comprising 246 patients with ASD and 237 healthy controls met inclusion criteria. No between-group differences were found in global white-matter volumes. ASD patients showed increases of white-matter volume in the right arcuate fasciculus and also in the left inferior fronto-occipital and uncinate fasciculi. These findings remained unchanged in quartile and jackknife sensitivity analyses and also in subgroup analyses (pediatric versus adult samples). Patients with ASD display increases of white-matter volume in tracts known to be important for language and social cognition. Whether the results apply to individuals with lower IQ or younger age and whether there are meaningful neurobiological differences between the subtypes of ASD remain to be investigated.

The relationship between brain diffusion microstructural changes and disability in multiple sclerosis (MS) remains poorly understood. We aimed to explore the predictive value of microstructural properties in white (WM) and grey matter (GM), and identify areas associated with mid-term disability in MS patients. We studied 185 patients (71% female; 86% RRMS) with the Expanded Disability Status Scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), and Symbol Digit Modalities Test (SDMT) at two time-points. We used Lasso regression to analyse the predictive value of baseline WM fractional anisotropy and GM mean diffusivity, and to identify areas related to each outcome at 4.1 years follow-up. Motor performance was associated with WM (T25FW: RMSE = 0.524, R 2  = 0.304; 9HPT dominant hand: RMSE = 0.662, R 2  = 0.062; 9HPT non-dominant hand: RMSE = 0.649, R 2  = 0.139), and SDMT with GM diffusion metrics (RMSE = 0.772, R 2  = 0.186). Cingulum, longitudinal fasciculus, optic radiation, forceps minor and frontal aslant were the WM tracts most closely linked to motor dysfunction, and temporal and frontal cortex were relevant for cognition. Regional specificity related to clinical outcomes provide valuable information that can be used to develop more accurate predictive models that could improve therapeutic strategies.

IntroductionEmotion dysregulation (ED) is a multidimensional construct involving the lack of awareness, understanding and acceptance of emotions, a reduced access to adaptive and appropriate strategies to modulate the intensity or duration of emotional responses, and the inability to control behaviors in accordance with desired goals when experiencing negative emotions. ED is outlined in the general population and several psychiatric disorders, including bipolar disorder (BD), and influences its clinical course and management, quality of life, and daily social functioning.ObjectivesThe objective of this systematic review was to examine the correlations between maladaptive (i.e., positive and negative rumination, negative focus, risk taking behaviors, suppression, and dampening) and adaptive (i.e., cognitive reframing, adaptive coping, and acceptance) strategies of emotion regulation (ER) and depressive and manic symptoms of BD.MethodsWe searched the literature from inception to April 12, 2022, and included studies focusing on ER/ED assessed with a validated scale. We conducted multiple pairwise meta-analyses for correlations between ED dimension (or overall ED) and the measures of depressive and manic symptoms of BD, and separate Bayesian network meta-analyses to examine which aspects of emotion regulation were most closely associated with depressive and manic symptoms of BD. The Pearson’s r coefficients were adjusted using sample-size weights and Fisher’s r-to-z transformed was conducted.ResultsA total of 13,826 records was identified and, after duplicate removal and title/abstract evaluation, 442 were explored at the full text. Sixteen studies were finally included. Results from pairwise meta-analyses are shown in Figure 1, results from network meta-analyses in Figure 2 and 3. Both depressive and manic BD symptomatology were found to be related to maladaptive ER strategies, with the only difference of positive rumination, associated only to manic symptoms. Negative rumination and risk-taking behaviors were the strategies more correlated to both manic and depressive symptoms, as confirmed by both pairwise metanalyses and network metanalyses. On the other hand, depressive symptomatology appeared more correlated with decreased adaptive strategies than manic symptomatology.Image:Image 2:Image 3:ConclusionsED has a significant correlation with BD symptomatology, therefore it should be explicitly considered during clinical assessment, diagnosis, and intervention on BD, and specific treatments should be implemented. More studies, and with longitudinal design, are needed to better explore these associations and their causal direction. In addition, future studies should mainly focus on the complex interactions between cognitive, social, and cultural aspects, and biological correlates to improve knowledge on a topic that is still poorly investigated.Disclosure of InterestV. Oliva: None Declared, M. De Prisco: None Declared, G. Fico Grant / Research support from: “La Caixa” Foundation (ID 100010434 - fellowship code LCF/BQ/DR21/11880019), Consultant of: Angelini, Janssen-Cilag and Lundbeck, A. Murru Grant / Research support from: Spanish Ministry of Science and Innovation (PI19/00672) integrated into the Plan Nacional de I+D+I and co-financed by the ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER), Consultant of: Angelini, Idorsia, Lundbeck, Pfizer, Takeda, M. Fornaro: None Declared, A. Serretti Consultant of: Abbott, Abbvie, Angelini, AstraZeneca, Clinical Data, Boehringer, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier, and Taliaz, J. Radua Grant / Research support from: Spanish Ministry of Science and Innovation (PI19/00394, CPII19/00009) integrated into the Plan Nacional de I+D+I and co-financed by the ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER) and the Instituto de Salud Carlos III, E. Vieta Grant / Research support from: Spanish Ministry of Science and Innovation (PI18/00805, PI21/00787) integrated into the Plan Nacional de I+D+I and co-financed by the ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER); the Instituto de Salud Carlos III; the CIBER of Mental Health (CIBERSAM); the Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (2017 SGR 1365), the CERCA Programme, and the Departament de Salut de la Generalitat de Catalunya for the PERIS grant SLT006/17/00357. Thanks the support of the European Union Horizon 2020 research and innovation program (EU.3.1.1. Understanding health, wellbeing and disease: Grant No 754907 and EU.3.1.3. Treating and managing disease: Grant No 945151), Consultant of: AB-Biotics, AbbVie, Angelini, Biogen, Boehringer-Ingelheim, Celon Pharma, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, Janssen, Lundbeck, Medincell, Novartis, Orion Corporation, Organon, Otsuka, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris

While multiple studies have examined the brain functional correlates of reward, meta-analyses have either focused on studies using the monetary incentive delay (MID) task, or have adopted a broad strategy, combining data from studies using both monetary and non-monetary reward, as probed using a wide range of tasks. To meta-analyze fMRI studies that used monetary reward and in which there was a definable cue-reward contingency. Studies were limited to those using monetary reward in order to avoid potential heterogeneity from use of other rewards, especially social rewards. Studies using gambling or delay discounting tasks were excluded on the grounds that reward anticipation is not easily quantifiable. Ovid, Medline and PsycInfo, from 2000 to 2020, plus checking of review articles and meta-analyses. Pooled data from 45 studies of reward anticipation revealed activations in the ventral striatum, the middle cingulate cortex/supplementary motor area and the insula. Pooled data from 28 studies of reward delivery again revealed ventral striatal activation, plus cortical activations in the anterior and posterior cingulate cortex. There was relatively little evidence of publication bias. Among moderating variables, only whether the task was pre-learnt exerted an influence. According to this meta-analysis monetary reward anticipation and delivery both activate the ventral but not the dorsal striatum, and are associated with different patterns of cortical activation.

IntroductionThis umbrella review is the frst to systematically examine psychological trauma as a transdiagnostic risk factor across psychiatric conditions.ObjectivesThis review aimed to be the frst to evaluate whether psychological trauma fulflilled criteria as a transdiagnostic risk factor cutting across various diagnostic categories and spectra. Transdiagnosticity will be assessed against the framework of the TRANSD criteria (Fusar-Poli, World Psychiatry 2019; 18 361-362). The paper additionally aimed to analyse the association of psychopathology with specifc trauma type.MethodsWe searched Pubmed, Scopus, and PsycNET databases from inception until 01/05/2021 for systematic reviews/meta-analyses evaluating the association between psychological trauma and at least one diagnosed mental disorder. We re-calculated the odds ratio (OR), then classifed the association as convincing, highly suggestive, suggestive, or weak, based on the number of cases and controls with and without psychological trauma, random-efects p value, the 95% conf- dence interval of the largest study, heterogeneity between studies, 95% prediction interval, small-study efect, and excess significance bias. Additional outcomes were the association between specifc trauma types and specific mental disorders, and a sensitivity analysis for childhood trauma. Transdiagnosticity was assessed using TRANSD criteria. The review was pre-registered in Prospero CRD42020157308 and followed PRISMA/MOOSE guidelines.ResultsFourteen reviews met inclusion criteria, comprising 16,277 cases and 77,586 controls. Psychological trauma met TRANSD criteria as a transdiagnostic factor across diferent diagnostic criteria and spectra. There was highly suggestive evidence of an association between psychological trauma at any time-point and any mental disorder (OR=2.92) and between childhood trauma and any mental disorder(OR=2.90). Regarding specifc trauma types, convincing evidence linked physical abuse (OR=2.36) and highly suggestive evidence linked sexual abuse (OR=3.47) with a range of mental disorders, and convincing evidence linked emotional abuse to anxiety disorders (OR=3.05); there were no data for emotional abuse with other disorders.Image:Image 2:ConclusionsThese fndings highlight the importance of preventing early traumatic events and providing trauma-informed care in early intervention and psychiatric services.Disclosure of InterestNone Declared

Background Fibromyalgia (FM) is a generalized, widespread chronic pain disorder affecting 2.7% of the general population. In recent years, different studies have observed a strong association between FM and psychological trauma. Therefore, a trauma-focused psychotherapy, such as Eye Movement Desensitization and Reprocessing (EMDR), combined with a non-invasive brain stimulation technique, such as multifocal transcranial current stimulation (MtCS), could be an innovative adjunctive treatment option. This double-blind randomized controlled trial (RCT) analyzes if EMDR therapy is effective in the reduction of pain symptoms in FM patients, and if its potential is boosted with the addition of MtCS. Methods Ninety-six patients with FM and a history of traumatic events will be randomly allocated to the treatment as usual (TAU) condition, EMDR + active-MtCS condition, or EMDR + sham-MtCS condition. Therapists and patients will be kept blind to MtCS conditions, and raters will be kept blind to both EMDR and MtCS. All patients will be evaluated at baseline, post-treatment, and follow-up at 6 months after post-treatment. Evaluations will assess the following variables: sociodemographic data, pain, psychological trauma, sleep disturbance, anxiety and affective symptoms, wellbeing, self-care, emotional regulation, self-esteem, and cognitive functioning. Discussion This study will provide evidence of whether EMDR therapy is effective in reducing pain symptoms in FM patients, and whether the effect of EMDR can be enhanced by MtCS. Trial registration number This trial was registered at ClinicalTrials.gov on 2 August 2019, identifier: NCT04084795.