Stage-Specific Brain Aging in First-Episode Schizophrenia and Treatment-Resistant Schizophrenia.

BACKGROUND: Brain age is a popular brain-based biomarker that offers a powerful strategy for using neuroscience in clinical practice. We investigated the brain-predicted age difference (PAD) in patients with schizophrenia (SCZ), first-episode schizophrenia spectrum disorders (FE-SSDs), and treatment-resistant schizophrenia (TRS) using structural magnetic resonance imaging data. The association between brain-PAD and clinical parameters was also assessed. METHODS: We developed brain age prediction models for the association between 77 average structural brain measures and age in a training sample of controls (HCs) using ridge regression, support vector regression, and relevance vector regression. The trained models in the controls were applied to the test samples of the controls and 3 patient groups to obtain brain-based age estimates. The correlations were tested between the brain PAD and clinical measures in the patient groups. RESULTS: Model performance indicated that, regardless of the type of regression metric, the best model was support vector regression and the worst model was relevance vector regression for the training HCs. Accelerated brain aging was identified in patients with SCZ, FE-SSDs, and TRS compared with the HCs. A significant difference in brain PAD was observed between FE-SSDs and TRS using the ridge regression algorithm. Symptom severity, the Social and Occupational Functioning Assessment Scale, chlorpromazine equivalents, and cognitive function were correlated with the brain PAD in the patient groups. CONCLUSIONS: These findings suggest additional progressive neuronal changes in the brain after SCZ onset. Therefore, pharmacological or psychosocial interventions targeting brain health should be developed and provided during the early course of SCZ.

A Learnable Counter-Condition Analysis Framework for Functional Connectivity-Based Neurological Disorder Diagnosis.

To understand the biological characteristics of neurological disorders with functional connectivity (FC), recent studies have widely utilized deep learning-based models to identify the disease and conducted post-hoc analyses via explainable models to discover disease-related biomarkers. Most existing frameworks consist of three stages, namely, feature selection, feature extraction for classification, and analysis, where each stage is implemented separately. However, if the results at each stage lack reliability, it can cause misdiagnosis and incorrect analysis in afterward stages. In this study, we propose a novel unified framework that systemically integrates diagnoses (i.e., feature selection and feature extraction) and explanations. Notably, we devised an adaptive attention network as a feature selection approach to identify individual-specific disease-related connections. We also propose a functional network relational encoder that summarizes the global topological properties of FC by learning the inter-network relations without pre-defined edges between functional networks. Last but not least, our framework provides a novel explanatory power for neuroscientific interpretation, also termed counter-condition analysis. We simulated the FC that reverses the diagnostic information (i.e., counter-condition FC): converting a normal brain to be abnormal and vice versa. We validated the effectiveness of our framework by using two large resting-state functional magnetic resonance imaging (fMRI) datasets, Autism Brain Imaging Data Exchange (ABIDE) and REST-meta-MDD, and demonstrated that our framework outperforms other competing methods for disease identification. Furthermore, we analyzed the disease-related neurological patterns based on counter-condition analysis.

Site-Invariant Meta-Modulation Learning for Multisite Autism Spectrum Disorders Diagnosis.

Large amounts of fMRI data are essential to building generalized predictive models for brain disease diagnosis. In order to conduct extensive data analysis, it is often necessary to gather data from multiple organizations. However, the site variation inherent in multisite resting-state functional magnetic resonance imaging (rs-fMRI) leads to unfavorable heterogeneity in data distribution, negatively impacting the identification of biomarkers and the diagnostic decision. Several existing methods have alleviated this shift of domain distribution (i.e., multisite problem). Statistical tuning schemes directly regress out site disparity factors from the data prior to model training. Such methods have a limitation in processing data each time through variance estimation according to the added site. In the model adjustment approaches, domain adaptation (DA) methods adjust the features or models of the source domain according to the target domain during model training. Thus, it is inevitable that it needs updating model parameters according to the samples of a target site, causing great limitations in practical applicability. Meanwhile, the approach of domain generalization (DG) aims to create a universal model that can be quickly adapted to multiple domains. In this study, we propose a novel framework for disease diagnosis that alleviates the multisite problem by adaptively calibrating site-specific features into site-invariant features. Specifically, it applies directly to samples from unseen sites without the need for fine-tuning. With a learning-to-learn strategy that learns how to calibrate the features under the various domain shift environments, our novel modulation mechanism extracts site-invariant features. In our experiments over the Autism Brain Imaging Data Exchange (ABIDE I and II) dataset, we validated the generalization ability of the proposed network by improving diagnostic accuracy in both seen and unseen multisite samples.

Medical Transformer: Universal Encoder for 3-D Brain MRI Analysis.

Transfer learning has attracted considerable attention in medical image analysis because of the limited number of annotated 3-D medical datasets available for training data-driven deep learning models in the real world. We propose Medical Transformer, a novel transfer learning framework that effectively models 3-D volumetric images as a sequence of 2-D image slices. To improve the high-level representation in 3-D-form empowering spatial relations, we use a multiview approach that leverages information from three planes of the 3-D volume, while providing parameter-efficient training. For building a source model generally applicable to various tasks, we pretrain the model using self-supervised learning (SSL) for masked encoding vector prediction as a proxy task, using a large-scale normal, healthy brain magnetic resonance imaging (MRI) dataset. Our pretrained model is evaluated on three downstream tasks: 1) brain disease diagnosis; 2) brain age prediction; and 3) brain tumor segmentation, which are widely studied in brain MRI research. Experimental results demonstrate that our Medical Transformer outperforms the state-of-the-art (SOTA) transfer learning methods, efficiently reducing the number of parameters by up to approximately 92% for classification and regression tasks and 97% for segmentation task, and it also achieves good performance in scenarios where only partial training samples are used.

Deep Learning-based Brain Age Prediction in Patients With Schizophrenia Spectrum Disorders.

BACKGROUND AND HYPOTHESIS: The brain-predicted age difference (brain-PAD) may serve as a biomarker for neurodegeneration. We investigated the brain-PAD in patients with schizophrenia (SCZ), first-episode schizophrenia spectrum disorders (FE-SSDs), and treatment-resistant schizophrenia (TRS) using structural magnetic resonance imaging (sMRI). STUDY DESIGN: We employed a convolutional network-based regression (SFCNR), and compared its performance with models based on three machine learning (ML) algorithms. We pretrained the SFCNR with sMRI data of 7590 healthy controls (HCs) selected from the UK Biobank. The parameters of the pretrained model were transferred to the next training phase with a new set of HCs (n = 541). The brain-PAD was analyzed in independent HCs (n = 209) and patients (n = 233). Correlations between the brain-PAD and clinical measures were investigated. STUDY RESULTS: The SFCNR model outperformed three commonly used ML models. Advanced brain aging was observed in patients with SCZ, FE-SSDs, and TRS compared to HCs. A significant difference in brain-PAD was observed between FE-SSDs and TRS with ridge regression but not with the SFCNR model. Chlorpromazine equivalent dose and cognitive function were correlated with the brain-PAD in SCZ and FE-SSDs. CONCLUSIONS: Our findings indicate that there is advanced brain aging in patients with SCZ and higher brain-PAD in SCZ can be used as a surrogate marker for cognitive dysfunction. These findings warrant further investigations on the causes of advanced brain age in SCZ. In addition, possible psychosocial and pharmacological interventions targeting brain health should be considered in early-stage SCZ patients with advanced brain age.

Electronic Cigarette Vaping Did Not Enhance the Neural Process of Working Memory for Regular Cigarette Smokers.

BACKGROUND: Electronic cigarettes (e-cigs) as substitute devices for regular tobacco cigarettes (r-cigs) have been increasing in recent times. We investigated neuronal substrates of vaping e-cigs and smoking r-cigs from r-cig smokers. METHODS: Twenty-two r-cig smokers made two visits following overnight smoking cessation. Functional magnetic resonance imaging (fMRI) data were acquired while participants watched smoking images. Participants were then allowed to smoke either an e-cig or r-cig until satiated and fMRI data were acquired. Their craving levels and performance on the Montreal Imaging Stress Task and a 3-back alphabet/digit recognition task were obtained and analyzed using two-way repeated-measures analysis of variance. Regions-of-interest (ROIs) were identified by comparing the abstained and satiated conditions. Neuronal activation within ROIs was regressed on the craving and behavioral data separately. RESULTS: Craving was more substantially reduced by smoking r-cigs than by vaping e-cigs. The response time (RT) for the 3-back task was significantly shorter following smoking r-cigs than following vaping e-cigs (interaction: F (1, 17) = 5.3, p = 0.035). Neuronal activations of the right vermis (r = 0.43, p = 0.037, CI = [-0.05, 0.74]), right caudate (r = 0.51, p = 0.015, CI = [0.05, 0.79]), and right superior frontal gyrus (r = -0.70, p = 0.001, CI = [-0.88, -0.34]) were significantly correlated with the RT for the 3-back task only for smoking r-cigs. CONCLUSION: Our findings suggest that insufficient satiety from vaping e-cigs for r-cigs smokers may be insignificant effect on working memory function.

Altered functional connectivity in psychotic disorder not otherwise specified.

BACKGROUND: Few studies have investigated functional connectivity (FC) in patients with psychotic disorder not otherwise specified (PNOS). We sought to identify distinct FC differentiating PNOS from schizophrenia (SZ). METHODS: In total, 49 patients with PNOS, 42 with SZ, and 55 healthy controls (HC) matched for age, sex, and education underwent functional magnetic resonance imaging (fMRI) brain scans and clinical evaluation. Using six functional networks consisting of 40 regions of interest (ROIs), we conducted ROI to ROI and intra- and inter-network FC analyses using resting-state fMRI (rs-fMRI) data. Correlations of altered FC with symptomatology were explored. RESULTS: We found common brain connectomics in PNOS and SZ including thalamo-cortical (especially superior temporal gyrus) hyperconnectivity, thalamo-cerebellar hypoconnectivity, and reduced within-thalamic connectivity compared to HC. Additionally, features differentiating the two patient groups included hyperconnectivity between the thalamic subregion and anterior cingulate cortex in PNOS compared to SZ and hyperconnectivity of the thalamic subregions with the posterior cingulate cortex and precentral gyrus in SZ compared to PNOS. CONCLUSIONS: These findings suggest that PNOS and SZ exhibit both common and differentiating changes in neuronal connectivity. Furthermore, they may support the hypothesis that PNOS should be treated as a separate clinical syndrome with distinct neural connectomics.