Premika S.W. Boedhoe

ENIGMA and the Individual: Predicting Factors that Affect the Brain in 35 Countries Worldwide

In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) – a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date – of schizophrenia and major depression – ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others1, ENIGMAs genomic screens – now numbering over 30,000 MRI scans – have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants – and genetic variants in general – may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures – from tens of thousands of people – that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMAs efforts so far.

Distinct Subcortical Volume Alterations in Pediatric and Adult OCD: A Worldwide Meta- and Mega-Analysis.

OBJECTIVE Structural brain imaging studies in obsessive-compulsive disorder (OCD) have produced inconsistent findings. This may be partially due to limited statistical power from relatively small samples and clinical heterogeneity related to variation in illness profile and developmental stage. To address these limitations, the authors conducted meta- and mega-analyses of data from OCD sites worldwide. METHOD T1 images from 1,830 OCD patients and 1,759 control subjects were analyzed, using coordinated and standardized processing, to identify subcortical brain volumes that differ between OCD patients and healthy subjects. The authors performed a meta-analysis on the mean of the left and right hemisphere measures of each subcortical structure, and they performed a mega-analysis by pooling these volumetric measurements from each site. The authors additionally examined potential modulating effects of clinical characteristics on morphological differences in OCD patients. RESULTS The meta-analysis indicated that adult patients had significantly smaller hippocampal volumes (Cohens d=-0.13; % difference=-2.80) and larger pallidum volumes (d=0.16; % difference=3.16) compared with adult controls. Both effects were stronger in medicated patients compared with controls (d=-0.29, % difference=-4.18, and d=0.29, % difference=4.38, respectively). Unmedicated pediatric patients had significantly larger thalamic volumes (d=0.38, % difference=3.08) compared with pediatric controls. None of these findings were mediated by sample characteristics, such as mean age or scanning field strength. The mega-analysis yielded similar results. CONCLUSIONS The results indicate different patterns of subcortical abnormalities in pediatric and adult OCD patients. The pallidum and hippocampus seem to be of importance in adult OCD, whereas the thalamus seems to be key in pediatric OCD. These findings highlight the potential importance of neurodevelopmental alterations in OCD and suggest that further research on neuroplasticity in OCD may be useful.

A smaller amygdala is associated with anxiety in Parkinson’s disease: a combined FreeSurfer—VBM study

Background Up to 50% of all patients with Parkinsons disease (PD) suffer from anxiety symptoms, a much higher percentage than in the general population. This suggests that PD associated pathological alterations partly underlie these symptoms, although empirical evidence is limited. Methods Here we investigated the association between anxiety symptoms measured with the Beck Anxiety Inventory (BAI) and hippocampal and amygdalar volume in 110 early-stage patients with PD. Measures of anxiety in PD are often obscured by overlap with the somatic symptoms. We therefore also used a subscale of the BAI, established by our recent factor analysis, that reflects ‘psychological’ anxiety symptoms and is independent of the severity of PD-related motor and autonomic symptoms. We used FreeSurfer and voxel-based morphometry for the volumetric analyses. Results Both software packages showed a negative correlation between the ‘psychological’ subscale of the BAI, but not total BAI and volume of the left amygdala, independent of the severity of motor symptoms, autonomic dysfunction and dopaminergic or anxiolytic medication status. Conclusions These results confirm studies in non-PD samples showing lower left amygdalar volume in anxious patients. The results also indicate that the ‘psychological’ BAI subscale is a better reflection of neural correlates of anxiety in PD. Whether the left amygdalar volume decrease constitutes a premorbid trait, a PD-associated neurobiological susceptibility to anxiety or arises as a consequence of chronic anxiety symptoms remains to be determined by future prospective longitudinal studies. Nonetheless, we speculate that the Parkinson pathology is responsible for the reduction in amygdalar volume and the concomitant development of anxiety symptoms.

Cortical Abnormalities Associated with Pediatric and Adult Obsessive-Compulsive Disorder: Findings from the Enigma Obsessive-Compulsive Disorder Working Group

OBJECTIVE Brain imaging studies of structural abnormalities in OCD have yielded inconsistent results, partly because of limited statistical power, clinical heterogeneity, and methodological differences. The authors conducted meta- and mega-analyses comprising the largest study of cortical morphometry in OCD ever undertaken. METHOD T1-weighted MRI scans of 1,905 OCD patients and 1,760 healthy controls from 27 sites worldwide were processed locally using FreeSurfer to assess cortical thickness and surface area. Effect sizes for differences between patients and controls, and associations with clinical characteristics, were calculated using linear regression models controlling for age, sex, site, and intracranial volume. RESULTS In adult OCD patients versus controls, we found a significantly lower surface area for the transverse temporal cortex and a thinner inferior parietal cortex. Medicated adult OCD patients also showed thinner cortices throughout the brain. In pediatric OCD patients compared with controls, we found significantly thinner inferior and superior parietal cortices, but none of the regions analyzed showed significant differences in surface area. However, medicated pediatric OCD patients had lower surface area in frontal regions. Cohens d effect sizes varied from -0.10 to -0.33. CONCLUSIONS The parietal cortex was consistently implicated in both adults and children with OCD. More widespread cortical thickness abnormalities were found in medicated adult OCD patients, and more pronounced surface area deficits (mainly in frontal regions) were found in medicated pediatric OCD patients. These cortical measures represent distinct morphological features and may be differentially affected during different stages of development and illness, and possibly moderated by disease profile and medication.

Morphological Brain Alterations in Patients with Obsessive–Compulsive Disorder

Obsessive–compulsive disorder (OCD) is characterized by repetitive thoughts and behaviors that are experienced as unwanted. Structural magnetic resonance imaging (MRI) studies, using different techniques such as manual tracing, voxel-based morphometry (VBM), cortical thickness analysis, and diffusion tensor imaging (DTI), investigating brain abnormalities in OCD patients have been numerous. These studies have implicated the cortico-striato-thalamo-cortical (CSTC) circuit in the pathophysiology of the disorder. However, results have not always been consistent. Variability in study results may partially be explained by small sample sizes, clinical heterogeneity between patient samples, and methodological differences between studies. In this chapter, we review the most consistent findings on morphological brain alterations in patients with OCD, and we discuss the relationship within the implicated networks. The reviewed literature shows that the pathophysiology of OCD cannot be explained by alterations in function and structure of the classical CSTC regions exclusively and emphasizes the importance of other fronto-limbic and frontoparietal areas as well as the cerebellum. Moreover, these findings support the notion that the brain alterations found in OCD patients are represented at the network level rather than discrete brain regions. The widespread abnormalities across several different regions and circuits, and their interconnectivity, fit with the complex phenomenology of OCD, which includes different emotional, cognitive, and behavioral domains. A life span perspective on the structural brain abnormalities in OCD is warranted since variation in developmental stage, symptom profile, and disease stage seems to underlie variation in structural abnormalities.

A resting state fMRI analysis pipeline for pooling inference across diverse cohorts: an ENIGMA rs-fMRI protocol

Large-scale consortium efforts such as Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) and other collaborative efforts show that combining statistical data from multiple independent studies can boost statistical power and achieve more accurate estimates of effect sizes, contributing to more reliable and reproducible research. A meta- analysis would pool effects from studies conducted in a similar manner, yet to date, no such harmonized protocol exists for resting state fMRI (rsfMRI) data. Here, we propose an initial pipeline for multi-site rsfMRI analysis to allow research groups around the world to analyze scans in a harmonized way, and to perform coordinated statistical tests. The challenge lies in the fact that resting state fMRI measurements collected by researchers over the last decade vary widely, with variable quality and differing spatial or temporal signal-to-noise ratio (tSNR). An effective harmonization must provide optimal measures for all quality data. Here we used rsfMRI data from twenty-two independent studies with approximately fifty corresponding T1-weighted and rsfMRI datasets each, to (A) review and aggregate the state of existing rsfMRI data, (B) demonstrate utility of principal component analysis (PCA)-based denoising and (C) develop a deformable ENIGMA EPI template based on the representative anatomy that incorporates spatial distortion patterns from various protocols and populations.

NEUROIMAGING OF SUBCORTICAL BRAIN VOLUME ALTERATIONS IN PEADIATRIC AND ADULT OBSESSIVE-COMPULSIVE DISORDER: Preliminary findings from the ENIGMA Obsessive-Compulsive Disorder working group

Objective Structural MRI studies investigating the neural correlates of OCD have been numerous. Nevertheless, results of these studies have not always been consistent. Variability in study results may partially be explained by small sample sizes resulting in limited statistical power, clinical heterogeneity between patient samples, and methodological differences between studies. In this context, we initiated the ENIGMA-OCD working group. Our aim is to identify robust imaging markers of OCD using coordinated standardized image processing and statistical analysis protocols. Here, we perform the largest study to date of subcortical brain volumes in OCD patients and healthy controls using an individual participant data (IPD) based meta-analysis approach. Methods Structural T1-weightred MRI scans from 3722 subjects (361 paediatric OCD patients, 1574 adult OCD patients, 314 paediatric controls and 1473 adult controls) from 25 research sites worldwide were analysed using FreeSurfer 5.3. Segmentations of subcortical regions, lateral ventricles and total intracranial volumes (ICV) were visually inspected for accuracy and compared between patients and controls using regression models controlling for age, sex, and ICV. Each site followed standardized protocols designed to facilitate harmonized image analysis across multiple sites. Separate stratified analyses assessing effects of age of onset, disease duration, symptom dimensions, and symptom severity were performed. Results were combined in random-effects meta-analysis models. Meta-regression analyses were used to test whether mean age of each sample and field strength of MR images explained a significant proportion of the variance in effect seizes across sites in the meta-analysis. Results were considered significant if they exceeded a Bonferroni corrected P-value threshold (p=0.05/9 regions = 5.6x10-3). Results Adult patients, compared to adult controls, had significantly smaller hippocampal volumes (Cohen’s d= -0.15, p= 7.4x10-4) and bigger pallidum volumes (d= 0.16, p=1.8x10-3). This effect was notably stronger in medicated patients versus controls (d= -0.29, p=2.8x10-6 and d= 0.24, p=2.5x10-4, respectively). The hippocampus effect seemed to be driven by patients with comorbid depression d= 0.29, p=4.8x10-5). Also, symptom severity was associated with a smaller hippocampus (R= -0.08, p=4.9x10-3). Sample characteristics such as mean age and field strength did not moderate brain volume alterations. None of the subcortical structures, neither ICV nor lateral ventricles were significantly different between paediatric OCD cases and controls after Bonferroni correction. However, unmedicated paediatric patients show bigger thalamus volumes (d= 0.40, p=9.0x10-4) relative to control children. Additionally, longer disease duration and ad trend-significant level, younger age of onset was associated with bigger thalamus volume in paediatric OCD (d= 0.18, p=5.1x10-3 and d= -0.17, p=5.7x10-3, respectively). Conclusion Results of this subcortical meta-analysis indicate a key role of the pallidum in the pathophysiology of OCD. Different ENIGMA disease working groups, such as MDD, schizophrenia, and bipolar disorder also observed hippocampal abnormalities, which suggests that our findings regarding hippocampal abnormalities are aspecific for OCD. In addition, we showed that unmedicated paediatric OCD patients have significantly enlarged thalamus volumes. Moreover, our findings suggest a different pattern of subcortical abnormalities in paediatric OCD patients and adult OCD patients in line with the developmental nature of the disease.