Carlos Cabral

Detecting the Psychosis Prodrome Across High-Risk Populations Using Neuroanatomical Biomarkers

To date, the MRI-based individualized prediction of psychosis has only been demonstrated in single-site studies. It remains unclear if MRI biomarkers generalize across different centers and MR scanners and represent accurate surrogates of the risk for developing this devastating illness. Therefore, we assessed whether a MRI-based prediction system identified patients with a later disease transition among 73 clinically defined high-risk persons recruited at two different early recognition centers. Prognostic performance was measured using cross-validation, independent test validation, and Kaplan-Meier survival analysis. Transition outcomes were correctly predicted in 80% of test cases (sensitivity: 76%, specificity: 85%, positive likelihood ratio: 5.1). Thus, given a 54-month transition risk of 45% across both centers, MRI-based predictors provided a 36%-increase of prognostic certainty. After stratifying individuals into low-, intermediate-, and high-risk groups using the predictors decision score, the high- vs low-risk groups had median psychosis-free survival times of 5 vs 51 months and transition rates of 88% vs 8%. The predictors decision function involved gray matter volume alterations in prefrontal, perisylvian, and subcortical structures. Our results support the existence of a cross-center neuroanatomical signature of emerging psychosis enabling individualized risk staging across different high-risk populations. Supplementary results revealed that (1) potentially confounding between-site differences were effectively mitigated using statistical correction methods, and (2) the detection of the prodromal signature considerably depended on the available sample sizes. These observations pave the way for future multicenter studies, which may ultimately facilitate the neurobiological refinement of risk criteria and personalized preventive therapies based on individualized risk profiling tools.

Detecting Neuroimaging Biomarkers for Depression: A Meta-analysis of Multivariate Pattern Recognition Studies

BACKGROUND Multiple studies have examined functional and structural brain alteration in patients diagnosed with major depressive disorder (MDD). The introduction of multivariate statistical methods allows investigators to utilize data concerning these brain alterations to generate diagnostic models that accurately differentiate patients with MDD from healthy control subjects (HCs). However, there is substantial heterogeneity in the reported results, the methodological approaches, and the clinical characteristics of participants in these studies. METHODS We conducted a meta-analysis of all studies using neuroimaging (volumetric measures derived from T1-weighted images, task-based functional magnetic resonance imaging [MRI], resting-state MRI, or diffusion tensor imaging) in combination with multivariate statistical methods to differentiate patients diagnosed with MDD from HCs. RESULTS Thirty-three (k = 33) samples including 912 patients with MDD and 894 HCs were included in the meta-analysis. Across all studies, patients with MDD were separated from HCs with 77% sensitivity and 78% specificity. Classification based on resting-state MRI (85% sensitivity, 83% specificity) and on diffusion tensor imaging data (88% sensitivity, 92% specificity) outperformed classifications based on structural MRI (70% sensitivity, 71% specificity) and task-based functional MRI (74% sensitivity, 77% specificity). CONCLUSIONS Our results demonstrate the high representational capacity of multivariate statistical methods to identify neuroimaging-based biomarkers of depression. Future studies are needed to elucidate whether multivariate neuroimaging analysis has the potential to generate clinically useful tools for the differential diagnosis of affective disorders and the prediction of both treatment response and functional outcome.

Classifying Schizophrenia Using Multimodal Multivariate Pattern Recognition Analysis: Evaluating the Impact of Individual Clinical Profiles on the Neurodiagnostic Performance

Previous studies have shown that structural brain changes are among the best-studied candidate markers for schizophrenia (SZ) along with functional connectivity (FC) alterations of resting-state (RS) patterns. This study aimed to investigate effects of clinical and sociodemographic variables on the classification by applying multivariate pattern analysis (MVPA) to both gray matter (GM) volume and FC measures in patients with SZ and healthy controls (HC). RS and structural magnetic resonance imaging data (sMRI) from 74 HC and 71 SZ patients were obtained from a Mind Research Network COBRE dataset available via COINS (http://coins.mrn.org/dx). We used a MVPA framework using support-vector machines embedded in a repeated, nested cross-validation to generate a multi-modal diagnostic system and evaluate its generalizability. The dependence of neurodiagnostic performance on clinical and sociodemographic variables was evaluated. The RS classifier showed a slightly higher accuracy (70.5%) compared to the structural classifier (69.7%). The combination of sMRI and RS outperformed single MRI modalities classification by reaching 75% accuracy. The RS based moderator analysis revealed that the neurodiagnostic performance was driven by older SZ patients with an earlier illness onset and more pronounced negative symptoms. In contrast, there was no linear relationship between the clinical variables and neuroanatomically derived group membership measures. This study achieved higher accuracy distinguishing HC from SZ patients by fusing 2 imaging modalities. In addition the results of RS based moderator analysis showed that age of patients, as well as their age at the illness onset were the most important clinical features.

Aberrant Functional Whole-Brain Network Architecture in Patients With Schizophrenia: A Meta-analysis

Findings from multiple lines of research provide evidence of aberrant functional brain connectivity in schizophrenia. By using graph-analytical measures, recent studies indicate that patients with schizophrenia exhibit changes in the organizational principles of whole-brain networks and that these changes relate to cognitive symptoms. However, there has not been a systematic investigation of functional brain network changes in schizophrenia to test the consistency of these changes across multiple studies. A comprehensive literature search was conducted to identify all available functional graph-analytical studies in patients with schizophrenia. Effect size measures were derived from each study and entered in a random-effects meta-analytical model. All models were tested for effects of potential moderator variables as well as for the presence of publication bias. The results of a total of n = 13 functional neuroimaging studies indicated that brain networks in patients with schizophrenia exhibit significant decreases in measures of local organization (g = -0.56, P = .02) and significant decreases in small-worldness (g = -0.65, P = .01) whereas global short communication paths seemed to be preserved (g = 0.26, P = .32). There was no evidence for a publication bias or moderator effects. The present meta- analysis demonstrates significant changes in whole brain network architecture associated with schizophrenia across studies.

Structural brain changes are associated with response of negative symptoms to prefrontal repetitive transcranial magnetic stimulation in patients with schizophrenia

Impaired neural plasticity may be a core pathophysiological process underlying the symptomatology of schizophrenia. Plasticity-enhancing interventions, including repetitive transcranial magnetic stimulation (rTMS), may improve difficult-to-treat symptoms; however, efficacy in large clinical trials appears limited. The high variability of rTMS-related treatment response may be related to a comparably large variation in the ability to generate plastic neural changes. The aim of the present study was to determine whether negative symptom improvement in schizophrenia patients receiving rTMS to the left dorsolateral prefrontal cortex (DLPFC) was related to rTMS-related brain volume changes. A total of 73 schizophrenia patients with predominant negative symptoms were randomized to an active (n=34) or sham (n=39) 10-Hz rTMS intervention applied 5 days per week for 3 weeks to the left DLPFC. Local brain volume changes measured by deformation-based morphometry were correlated with changes in negative symptom severity using a repeated-measures analysis of covariance design. Volume gains in the left hippocampal, parahippocampal and precuneal cortices predicted negative symptom improvement in the active rTMS group (all r⩽−0.441, all P⩽0.009), but not the sham rTMS group (all r⩽0.211, all P⩾0.198). Further analyses comparing negative symptom responders (⩾20% improvement) and non-responders supported the primary analysis, again only in the active rTMS group (F(9, 207)=2.72, P=0.005, partial η 2=0.106). Heterogeneity in clinical response of negative symptoms in schizophrenia to prefrontal high-frequency rTMS may be related to variability in capacity for structural plasticity, particularly in the left hippocampal region and the precuneus.

Brain Subtyping Enhances The Neuroanatomical Discrimination of Schizophrenia

Identifying distinctive subtypes of schizophrenia could ultimately enhance diagnostic and prognostic accuracy. We aimed to uncover neuroanatomical subtypes of chronic schizophrenia patients to test whether stratification can enhance computer-aided discrimination of patients from control subjects. Unsupervised, data-driven clustering of structural MRI (sMRI) data was used to identify 2 subtypes of schizophrenia patients drawn from a US-based open science repository (n = 71) and we quantified classification improvements compared to controls (n = 74) using supervised machine learning. We externally validated the unsupervised and supervised learning models in a heterogeneous German validation sample (n = 316), and characterized symptom, cognition, and longitudinal symptom change signatures. Stratification improved classification accuracies from 68.5% to 73% (subgroup 1) and 78.8% (subgroup 2), respectively. Increased accuracy was also found when models were externally validated, and an average gain of 9% was found in supplementary analyses. The first subgroup was associated with cortical and subcortical volume reductions coupled with substantially longer illness duration, whereas the second subgroup was mainly characterized by cortical reductions, reduced illness duration, and comparatively less negative symptoms. Individuals within each subgroup could be identified using just 10 clinical questions at an accuracy of 81.2%, and differential cognitive and symptom course signatures were suggested in multivariate analyses. Our findings suggest that sMRI-based subtyping enhances the neuroanatomical discrimination of schizophrenia by identifying generalizable brain patterns that align with a clinical staging model of the disorder. These findings could be used to improve illness stratification for biomarker-based computer-aided diagnoses.

EPA-1644 – Differential diagnosis of schizophrenia vs. borderline personality disorder using pattern classification methods in structural mri images

Introduction Everyday clinical routine is frequently challenged by difficulty to choose among differential diagnostic options, since many psychiatric disorders share similar phenotypes. E.g., borderline personality disorder (BPD) and schizophrenia (SZ) can both be associated with psychotic syndromes. Objectives Our objective was to evaluate the effectiveness of combining sMRI data and pattern classification methods to differentiate between BPD and SZ. Aims We aim to introduce objective diagnostic measures to improve the reliability of clinical evaluations. Methods sMRI data of 114 female patients were used to train a multivariate disease classifier. MR images were processed using voxel-based morphometry and high-dimensional registration to the MNI template. Grey matter volume maps were fed into a machine learning pipeline consisting of adjustment for possible age effects, PCA for dimensionality reduction and linear ν-support vector classification. Diagnostic performance of the classifier was determined by repeated nested 10-fold cross-validation. Results We were able to correctly classify unseen test subjects’ diagnosis with 74% accuracy. Classification sensitivity and specificity was 74%. Volume reductions in SZ vs. BPD were predominantly located in the left peri- and intrasylvian regions, orbitofrontal regions, the nucleus caudatus and the right cerebellum. Volume reductions in BPD compared to SZ were found predominantly in the left cerebellum, in limbic areas and the left inferior occipital gyrus. Conclusions Our results suggest that SZ can be differentiated from BPD at the single-subject level using sMRI and pattern classification methods. In future, this method might enhance clinical evaluations and improve accuracy and reliability of differential diagnosis.

EPA-1579 - Classifying schizophrenia using joint multivariate pattern recognition analysis of brain function and structure

Background Previous studies have shown that structural brain changes are among the best-studied candidate markers for schizophrenia (SZ) along with global functional connectivity (FC) alterations of resting-state (RS) networks. Only few studies tried to combine these data domains to outperform unimodal pattern classification approaches. We aimed at distinguishing SZ patients from healthy controls (HC) at the single-subject level by applying multivariate pattern recognition analysis to both gray matter (GM) volume and FC measures. Methods The RS functional and structural MRI data from 74 HC and 71 patients with SZ were obtained from the publicly available COBRE database. The machine learning pipeline wrapped into repeated nested cross-validation was used to train a multi-modal diagnostic system and evaluate its generalization capacity in new subjects . Results Both functional and structural classifiers were able to distinguish between HC and SZ patients with similar accuracies. The RS classifier was showing a slightly higher accuracy (75%) comparing to GM volume classifier (74.4%). Ensemble-based data fusion outperformed pattern classification based on single MRI modalities by reaching 76.6% accuracy, as determined by cross-validation. Further analysis showed that RS classification was less sensitive to age-related effects across the life span than GM volume . Discussion Our findings suggest that age plays an important role in discriminating SZ patients from HC, but that RS is more robust towards age-differences compared to GM volume. Single neuroimaging modalities provide useful insight into brain function or structure, while multimodal fusion emphasizes the strength of each and provides higher accuracy in discriminating SZ patients from HC.