Neural predictors of cognitive-behavior therapy outcome in anxiety-related disorders: a meta-analysis of task-based fMRI studies.

BACKGROUND: Cognitive-behavior therapy (CBT) is a well-established first-line intervention for anxiety-related disorders, including specific phobia, social anxiety disorder, panic disorder/agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder. Several neural predictors of CBT outcome for anxiety-related disorders have been proposed, but previous results are inconsistent. METHODS: We conducted a systematic review and meta-analysis of task-based functional magnetic resonance imaging (fMRI) studies investigating whole-brain predictors of CBT outcome in anxiety-related disorders (17 studies, n = 442). RESULTS: Across different tasks, we observed that brain response in a network of regions involved in salience and interoception processing, encompassing fronto-insular (the right inferior frontal gyrus-anterior insular cortex) and fronto-limbic (the dorsomedial prefrontal cortex-dorsal anterior cingulate cortex) cortices was strongly associated with a positive CBT outcome. CONCLUSIONS: Our results suggest that there are robust neural predictors of CBT outcome in anxiety-related disorders that may eventually lead (probably in combination with other data) to develop personalized approaches for the treatment of these mental disorders.

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.

Greater male than female variability in regional brain structure across the lifespan.

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.

Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA.

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).

Neural signatures of conditioning, extinction learning, and extinction recall in posttraumatic stress disorder: a meta-analysis of functional magnetic resonance imaging studies.

BACKGROUND: Establishing neurobiological markers of posttraumatic stress disorder (PTSD) is essential to aid in diagnosis and treatment development. Fear processing deficits are central to PTSD, and their neural signatures may be used as such markers. METHODS: Here, we conducted a meta-analysis of seven Pavlovian fear conditioning fMRI studies comparing 156 patients with PTSD and 148 trauma-exposed healthy controls (TEHC) using seed-based d-mapping, to contrast neural correlates of experimental phases, namely conditioning, extinction learning, and extinction recall. RESULTS: Patients with PTSD, as compared to TEHCs, exhibited increased activation in the anterior hippocampus (extending to the amygdala) and medial prefrontal cortex during conditioning; in the anterior hippocampus-amygdala regions during extinction learning; and in the anterior hippocampus-amygdala and medial prefrontal areas during extinction recall. Yet, patients with PTSD have shown an overall decreased activation in the thalamus during all phases in this meta-analysis. CONCLUSION: Findings from this metanalysis suggest that PTSD is characterized by increased activation in areas related to salience and threat, and lower activation in the thalamus, a key relay hub between subcortical areas. If replicated, these fear network alterations may serve as objective diagnostic markers for PTSD, and potential targets for novel treatment development, including pharmacological and brain stimulation interventions. Future longitudinal studies are needed to examine whether these observed network alteration in PTSD are the cause or the consequence of PTSD.

An overlapping pattern of cerebral cortical thinning is associated with both positive symptoms and aggression in schizophrenia via the ENIGMA consortium.

BACKGROUND: Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample. METHOD: To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls. RESULTS: The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression. CONCLUSION: These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.

Voxel-based meta-analysis via permutation of subject images (PSI): Theory and implementation for SDM.

Coordinate-based meta-analyses (CBMA) are very useful for summarizing the large number of voxel-based neuroimaging studies of normal brain functions and brain abnormalities in neuropsychiatric disorders. However, current CBMA methods do not conduct common voxelwise tests, but rather a test of convergence, which relies on some spatial assumptions that data may seldom meet, and has lower statistical power when there are multiple effects. Here we present a new algorithm that can use standard voxelwise tests and, importantly, conducts a standard permutation of subject images (PSI). Its main steps are: a) multiple imputation of study images; b) imputation of subject images; and c) subject-based permutation test to control the familywise error rate (FWER). The PSI algorithm is general and we believe that developers might implement it for several CBMA methods. We present here an implementation of PSI for seed-based d mapping (SDM) method, which additionally benefits from the use of effect sizes, random-effects models, Freedman-Lane-based permutations and threshold-free cluster enhancement (TFCE) statistics, among others. Finally, we also provide an empirical validation of the control of the FWER in SDM-PSI, which showed that it might be too conservative. We hope that the neuroimaging meta-analytic community will welcome this new algorithm and method.

What do results from coordinate-based meta-analyses tell us?

Coordinate-based meta-analyses (CBMA) methods, such as Activation Likelihood Estimation (ALE) and Seed-based d Mapping (SDM), have become an invaluable tool for summarizing the findings of voxel-based neuroimaging studies. However, the progressive sophistication of these methods may have concealed two particularities of their statistical tests. Common univariate voxelwise tests (such as the t/z-tests used in SPM and FSL) detect voxels that activate, or voxels that show differences between groups. Conversely, the tests conducted in CBMA test for "spatial convergence" of findings, i.e., they detect regions where studies report "more peaks than in most regions", regions that activate "more than most regions do", or regions that show "larger differences between groups than most regions do". The first particularity is that these tests rely on two spatial assumptions (voxels are independent and have the same probability to have a "false" peak), whose violation may make their results either conservative or liberal, though fortunately current versions of ALE, SDM and some other methods consider these assumptions. The second particularity is that the use of these tests involves an important paradox: the statistical power to detect a given effect is higher if there are no other effects in the brain, whereas lower in presence of multiple effects.

Electro-physiological data fusion for stress detection.

In this work we describe the performance evaluation of a system for stress detection. The analysed data is acquired by following an experimental protocol designed to induce cognitive stress to the subjects. The experimental set-up included the recording of electroencephalography (EEG) and facial (corrugator and zygomatic) electromyography (EMG). In a preliminary analysis we are able to correlate EEG features (alpha asymmetry and alpha/beta ratio using only 3 channels) with the stress level of the subjects statistically (by using averages over subjects) but also on a subject-to-subject basis by using computational intelligence techniques reaching classification rates up to 79% when classifying 3 minutes takes. On a second step, we apply fusion techniques to the overall multi-modal feature set fusing the formerly mentioned EEG features with EMG energy. We show that the results improve significantly providing a more robust stress index every second. Given the achieved performance the system described in this work can be successfully applied for stress therapy when combined with virtual reality.

Precuneus and insular hypoactivation during cognitive processing in first-episode psychosis: Systematic review and meta-analysis of fMRI studies.

INTRODUCTION: The neural correlates of the cognitive dysfunction in first-episode psychosis (FEP) are still unclear. The present review and meta-analysis provide an update of the location of the abnormalities in the fMRI-measured brain response to cognitive processes in individuals with FEP. METHODS: Systematic review and voxel-based meta-analysis of cross-sectional fMRI studies comparing neural responses to cognitive tasks between individuals with FEP and healthy controls (HC) according to PRISMA guidelines. RESULTS: Twenty-six studies were included, comprising 598 individuals with FEP and 567 HC. Individual studies reported statistically significant hypoactivation in the dorsolateral prefrontal cortex (6 studies), frontal lobe (8 studies), cingulate (6 studies) and insula (5 studies). The meta-analysis showed statistically significant hypoactivation in the left anterior insula, precuneus and bilateral striatum. CONCLUSIONS: While the studies tend to highlight frontal hypoactivation during cognitive tasks in FEP, our meta-analytic results show that the left precuneus and insula primarily display aberrant activation in FEP that may be associated with salience attribution to external stimuli and related to deficits in perception and regulation.

An fMRI Study Using a Combined Task of Interval Discrimination and Oddball Could Reveal Common Brain Circuits of Cognitive Change.

Recent functional neuroimaging studies suggest that the brain networks responsible for time processing are involved during other cognitive processes, leading to a hypothesis that time-related processing is needed to perform a range of tasks across various cognitive functions. To examine this hypothesis, we analyze whether, in healthy subjects, the brain structures activated or deactivated during performance of timing and oddball-detection type tasks coincide. To this end, we conducted two independent signed differential mapping (SDM) meta-analyses of functional magnetic resonance imaging (fMRI) studies assessing the cerebral generators of the responses elicited by tasks based on timing and oddball-detection paradigms. Finally, we undertook a multimodal meta-analysis to detect brain regions common to the findings of the two previous meta-analyses. We found that healthy subjects showed significant activation in cortical areas related to timing and salience networks. The patterns of activation and deactivation corresponding to each task type partially coincided. We hypothesize that there exists a time and change-detection network that serves as a common underlying resource used in a broad range of cognitive processes.

Cortical gray matter reduction precedes transition to psychosis in individuals at clinical high-risk for psychosis: A voxel-based meta-analysis.

Gray matter and cortical thickness reductions have been documented in individuals at clinical high-risk for psychosis and may be more pronounced in those who transition to psychosis. However, these findings rely on small samples and are inconsistent across studies. In this review and meta-analysis we aimed to investigate neuroanatomical correlates of clinical high-risk for psychosis and potential predictors of transition, using a novel meta-analytic method (Seed-based d Mapping with Permutation of Subject Images) and cortical mask, combining data from surface-based and voxel-based morphometry studies. Individuals at clinical high-risk for psychosis who later transitioned to psychosis were compared to those who did not and to controls, and included three statistical maps. Overall, individuals at clinical high-risk for psychosis did not differ from controls, however, within the clinical high-risk for psychosis group, transition to psychosis was associated with less cortical gray matter in the right temporal lobe (Hedges' g = -0.377), anterior cingulate and paracingulate (Hedges' g = -0.391). These findings have the potential to help refine prognostic and etiopathological research in early psychosis.

Can we increase the subjective well-being of the general population? An umbrella review of the evidence.

INTRODUCTION: Subjective well-being (SWB) refers to being satisfied with one's life, having positive affect and having little negative affect. We may understand it as a subjective definition of good life, or in colloquial terms "happiness", and it has been associated with several important benefits such as lower mortality. In the last decades, several randomized controlled trials (RCT) have investigated the efficacy of several interventions in increasing SWB in the general population but results from different disciplines have not been integrated. METHODS: We conducted an umbrella review of systematic reviews and meta-analyses of RCT that assess the efficacy of any kind of interventions in increasing SWB in the general population, including both positive psychology interventions (PPI) and other interventions. We (re)calculated the meta-analytic statistics needed to objectively assess the quality of the evidence of the efficacy of each type of intervention in improving each component of SWB according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: There was moderate-quality evidence that PPI might induce small decreases of negative affect, and low-quality evidence that they might induce moderate increases of positive affect. We found similar results for those PPI specifically consisting in conducting acts of kindness (especially spending money on or giving items to others), for which there was low-quality evidence that they might induces small increases of life satisfaction, but not for PPI specifically consisting in practicing gratitude. Quality of the evidence of the efficacy for the other interventions included in the umbrella review (yoga, resilience training, physical activity, leisure, control enhancement, psychoeducation, and miscellaneous) was very low. CONCLUSION: There is some evidence that PPI, and specially conducting acts of kindness such as spending money on others, may increase the SWB of the general population. The quality of the evidence of the efficacy for other interventions (e.g., yoga, physical activity, or leisure) is still very low. Registration number: PROSPERO CRD42020111681.

Structural brain correlates in major depression, anxiety disorders and post-traumatic stress disorder: A voxel-based morphometry meta-analysis.

The high comorbidity of Major Depressive Disorder (MDD), Anxiety Disorders (ANX), and Posttraumatic Stress Disorder (PTSD) has hindered the study of their structural neural correlates. The authors analyzed specific and common grey matter volume (GMV) characteristics by comparing them with healthy controls (HC). The meta-analysis of voxel-based morphometry (VBM) studies showed unique GMV diminutions for each disorder (p < 0.05, corrected) and less robust smaller GMV across diagnostics (p < 0.01, uncorrected). Pairwise comparison between the disorders showed GMV differences in MDD versus ANX and in ANX versus PTSD. These results endorse the hypothesis that unique clinical features characterizing MDD, ANX, and PTSD are also reflected by disorder specific GMV correlates.

Focusing on Comorbidity-A Novel Meta-Analytic Approach and Protocol to Disentangle the Specific Neuroanatomy of Co-occurring Mental Disorders.

BACKGROUND: In mental health, comorbidities are the norm rather than the exception. However, current meta-analytic methods for summarizing the neural correlates of mental disorders do not consider comorbidities, reducing them to a source of noise and bias rather than benefitting from their valuable information. OBJECTIVES: We describe and validate a novel neuroimaging meta-analytic approach that focuses on comorbidities. In addition, we present the protocol for a meta-analysis of all major mental disorders and their comorbidities. METHODS: The novel approach consists of a modification of Seed-based d Mapping-with Permutation of Subject Images (SDM-PSI) in which the linear models have no intercept. As in previous SDM meta-analyses, the dependent variable is the brain anatomical difference between patients and controls in a voxel. However, there is no primary disorder, and the independent variables are the percentages of patients with each disorder and each pair of potentially comorbid disorders. We use simulations to validate and provide an example of this novel approach, which correctly disentangled the abnormalities associated with each disorder and comorbidity. We then describe a protocol for conducting the new meta-analysis of all major mental disorders and their comorbidities. Specifically, we will include all voxel-based morphometry (VBM) studies of mental disorders for which a meta-analysis has already been published, including at least 10 studies. We will use the novel approach to analyze all included studies in two separate single linear models, one for children/adolescents and one for adults. DISCUSSION: The novel approach is a valid method to focus on comorbidities. The meta-analysis will yield a comprehensive atlas of the neuroanatomy of all major mental disorders and their comorbidities, which we hope might help develop potential diagnostic and therapeutic tools.

Precuneus and insular hypoactivation during cognitive processing in first-episode psychosis: Systematic review and meta-analysis of fMRI studies.

INTRODUCTION: The neural correlates of the cognitive dysfunction in first-episode psychosis (FEP) are still unclear. The present review and meta-analysis provide an update of the location of the abnormalities in the fMRI-measured brain response to cognitive processes in individuals with FEP. METHODS: Systematic review and voxel-based meta-analysis of cross-sectional fMRI studies comparing neural responses to cognitive tasks between individuals with FEP and healthy controls (HC) according to PRISMA guidelines. RESULTS: Twenty-six studies were included, comprising 598 individuals with FEP and 567 HC. Individual studies reported statistically significant hypoactivation in the dorsolateral prefrontal cortex (6 studies), frontal lobe (8 studies), cingulate (6 studies) and insula (5 studies). The meta-analysis showed statistically significant hypoactivation in the left anterior insula, precuneus and bilateral striatum. CONCLUSIONS: While the studies tend to highlight frontal hypoactivation during cognitive tasks in FEP, our meta-analytic results show that the left precuneus and insula primarily display aberrant activation in FEP that may be associated with salience attribution to external stimuli and related to deficits in perception and regulation.

Meta-analysis of non-statistically significant unreported effects.

Published studies in Medicine (and virtually any other discipline) sometimes report that a difference or correlation did not reach statistical significance but do not report its effect size or any statistic from which the latter may be derived. Unfortunately, meta-analysts should not exclude these studies because their exclusion would bias the meta-analytic outcome, but also they cannot be included as null effect sizes because this strategy is also associated to bias. To overcome this problem, we have developed MetaNSUE, a novel method based on multiple imputations of the censored information. We also provide an R package and an easy-to-use Graphical User Interface for non-R meta-analysts.

Meta-analysis of Voxel-Based Neuroimaging Studies using Seed-based d Mapping with Permutation of Subject Images (SDM-PSI).

Most methods for conducting meta-analysis of voxel-based neuroimaging studies do not assess whether effects are not null, but whether there is a convergence of peaks of statistical significance, and reduce the assessment of the evidence to a binary classification exclusively based on p-values (i.e., voxels can only be "statistically significant" or "non-statistically significant"). Here, we detail how to conduct a meta-analysis using Seed-based d Mapping with Permutation of Subject Images (SDM-PSI), a novel method that uses a standard permutation test to assess whether effects are not null. We also show how to grade the strength of the evidence according to a set of criteria that considers a range of statistical significance levels (from more liberal to more conservative), the amount of data or the detection of potential biases (e.g., small-study effect and excess of significance). To exemplify the procedure, we detail the conduction of a meta-analysis of voxel-based morphometry studies in obsessive-compulsive disorder, and we provide all the data already extracted from the manuscripts to allow the reader to replicate the meta-analysis easily. SDM-PSI can also be used for meta-analyses of functional magnetic resonance imaging, diffusion tensor imaging, position emission tomography and surface-based morphometry studies.