Accelerated Brain Aging Mediates the Association Between Psychological Profiles and Clinical Pain in Knee Osteoarthritis.

Chronic pain is driven by factors across the biopsychosocial spectrum. Previously, we demonstrated that magnetic resonance images (MRI)-based brain-predicted age differences (brain-PAD: brain-predicted age minus chronological age) were significantly associated with pain severity in individuals with chronic knee pain. We also previously identified four distinct, replicable, multidimensional psychological profiles significantly associated with clinical pain. The brain aging-psychological characteristics interface in persons with chronic pain promises elucidating factors contributing to their poor health outcomes, yet this relationship is barely understood. That is why we examined the interplay between the psychological profiles in participants having chronic knee pain impacting function, brain-PAD, and clinical pain severity. Controlling for demographics and MRI scanner, we compared the brain-PAD among psychological profiles at baseline (n = 164) and over two years (n = 90). We also explored whether profile-related differences in pain severity were mediated by brain-PAD. Brain-PAD differed significantly between profiles (ANOVA's omnibus test, P = .039). Specifically, participants in the profile 3 group (high negative/low positive emotions) had an average brain-PAD ∼4 years higher than those in profile- (low somatic reactivity), with P = .047, Bonferroni-corrected, and than those in profile 2 (high coping), with P = .027, uncorrected. Repeated measures ANOVA revealed no significant change in profile-related brain-PAD differences over time, but there was a significant decrease in brain-PAD for profile 4 (high optimism/high positive affect), with P = .045. Moreover, profile-related differences in pain severity at baseline were partly explained by brain-PAD differences between profile 3 and 1, or 2; but brain-PAD did not significantly mediate the influence of variations in profiles on changes in pain severity over time. PERSPECTIVE: Accelerated brain aging could underlie the psychological-pain relationship, and psychological characteristics may predispose individuals with chronic knee pain to worse health outcomes via neuropsychological processes.

Brain-predicted age difference estimated using DeepBrainNet is significantly associated with pain and function-a multi-institutional and multiscanner study.

ABSTRACT: Brain age predicted differences (brain-PAD: predicted brain age minus chronological age) have been reported to be significantly larger for individuals with chronic pain compared with those without. However, a debate remains after one article showed no significant differences. Using Gaussian Process Regression, an article provides evidence that these negative results might owe to the use of mixed samples by reporting a differential effect of chronic pain on brain-PAD across pain types. However, some remaining methodological issues regarding training sample size and sex-specific effects should be tackled before settling this controversy. Here, we explored differences in brain-PAD between musculoskeletal pain types and controls using a novel convolutional neural network for predicting brain-PADs, ie, DeepBrainNet. Based on a very large, multi-institutional, and heterogeneous training sample and requiring less magnetic resonance imaging preprocessing than other methods for brain age prediction, DeepBrainNet offers robust and reproducible brain-PADs, possibly highly sensitive to neuropathology. Controlling for scanner-related variability, we used a large sample (n = 660) with different scanners, ages (19-83 years), and musculoskeletal pain types (chronic low back [CBP] and osteoarthritis [OA] pain). Irrespective of sex, brain-PAD of OA pain participants was ∼3 to 4.7 years higher than that of CBP and controls, whereas brain-PAD did not significantly differ among controls and CBP. Moreover, brain-PAD was significantly related to multiple variables underlying the multidimensional pain experience. This comprehensive work adds evidence of pain type-specific effects of chronic pain on brain age. This could help in the clarification of the debate around possible relationships between brain aging mechanisms and pain.

Image harmonization: A review of statistical and deep learning methods for removing batch effects and evaluation metrics for effective harmonization.

Magnetic resonance imaging and computed tomography from multiple batches (e.g. sites, scanners, datasets, etc.) are increasingly used alongside complex downstream analyses to obtain new insights into the human brain. However, significant confounding due to batch-related technical variation, called batch effects, is present in this data; direct application of downstream analyses to the data may lead to biased results. Image harmonization methods seek to remove these batch effects and enable increased generalizability and reproducibility of downstream results. In this review, we describe and categorize current approaches in statistical and deep learning harmonization methods. We also describe current evaluation metrics used to assess harmonization methods and provide a standardized framework to evaluate newly-proposed methods for effective harmonization and preservation of biological information. Finally, we provide recommendations to end-users to advocate for more effective use of current methods and to methodologists to direct future efforts and accelerate development of the field.

Applications of generative adversarial networks in neuroimaging and clinical neuroscience.

Generative adversarial networks (GANs) are one powerful type of deep learning models that have been successfully utilized in numerous fields. They belong to the broader family of generative methods, which learn to generate realistic data with a probabilistic model by learning distributions from real samples. In the clinical context, GANs have shown enhanced capabilities in capturing spatially complex, nonlinear, and potentially subtle disease effects compared to traditional generative methods. This review critically appraises the existing literature on the applications of GANs in imaging studies of various neurological conditions, including Alzheimer's disease, brain tumors, brain aging, and multiple sclerosis. We provide an intuitive explanation of various GAN methods for each application and further discuss the main challenges, open questions, and promising future directions of leveraging GANs in neuroimaging. We aim to bridge the gap between advanced deep learning methods and neurology research by highlighting how GANs can be leveraged to support clinical decision making and contribute to a better understanding of the structural and functional patterns of brain diseases.

Benchmarking the generalizability of brain age models: Challenges posed by scanner variance and prediction bias.

Machine learning has been increasingly applied to neuroimaging data to predict age, deriving a personalized biomarker with potential clinical applications. The scientific and clinical value of these models depends on their applicability to independently acquired scans from diverse sources. Accordingly, we evaluated the generalizability of two brain age models that were trained across the lifespan by applying them to three distinct early-life samples with participants aged 8-22 years. These models were chosen based on the size and diversity of their training data, but they also differed greatly in their processing methods and predictive algorithms. Specifically, one brain age model was built by applying gradient tree boosting (GTB) to extracted features of cortical thickness, surface area, and brain volume. The other model applied a 2D convolutional neural network (DBN) to minimally preprocessed slices of T1-weighted scans. Additional model variants were created to understand how generalizability changed when each model was trained with data that became more similar to the test samples in terms of age and acquisition protocols. Our results illustrated numerous trade-offs. The GTB predictions were relatively more accurate overall and yielded more reliable predictions when applied to lower quality scans. In contrast, the DBN displayed the most utility in detecting associations between brain age gaps and cognitive functioning. Broadly speaking, the largest limitations affecting generalizability were acquisition protocol differences and biased brain age estimates. If such confounds could eventually be removed without post-hoc corrections, brain age predictions may have greater utility as personalized biomarkers of healthy aging.

Clinical measures, radiomics, and genomics offer synergistic value in AI-based prediction of overall survival in patients with glioblastoma.

Multi-omic data, i.e., clinical measures, radiomic, and genetic data, capture multi-faceted tumor characteristics, contributing to a comprehensive patient risk assessment. Here, we investigate the additive value and independent reproducibility of integrated diagnostics in prediction of overall survival (OS) in isocitrate dehydrogenase (IDH)-wildtype GBM patients, by combining conventional and deep learning methods. Conventional radiomics and deep learning features were extracted from pre-operative multi-parametric MRI of 516 GBM patients. Support vector machine (SVM) classifiers were trained on the radiomic features in the discovery cohort (n = 404) to categorize patient groups of high-risk (OS < 6 months) vs all, and low-risk (OS ≥ 18 months) vs all. The trained radiomic model was independently tested in the replication cohort (n = 112) and a patient-wise survival prediction index was produced. Multivariate Cox-PH models were generated for the replication cohort, first based on clinical measures solely, and then by layering on radiomics and molecular information. Evaluation of the high-risk and low-risk classifiers in the discovery/replication cohorts revealed area under the ROC curves (AUCs) of 0.78 (95% CI 0.70-0.85)/0.75 (95% CI 0.64-0.79) and 0.75 (95% CI 0.65-0.84)/0.63 (95% CI 0.52-0.71), respectively. Cox-PH modeling showed a concordance index of 0.65 (95% CI 0.6-0.7) for clinical data improving to 0.75 (95% CI 0.72-0.79) for the combination of all omics. This study signifies the value of integrated diagnostics for improved prediction of OS in GBM.

Deep Generative Medical Image Harmonization for Improving Cross-Site Generalization in Deep Learning Predictors.

BACKGROUND: In the medical imaging domain, deep learning-based methods have yet to see widespread clinical adoption, in part due to limited generalization performance across different imaging devices and acquisition protocols. The deviation between estimated brain age and biological age is an established biomarker of brain health and such models may benefit from increased cross-site generalizability. PURPOSE: To develop and evaluate a deep learning-based image harmonization method to improve cross-site generalizability of deep learning age prediction. STUDY TYPE: Retrospective. POPULATION: Eight thousand eight hundred and seventy-six subjects from six sites. Harmonization models were trained using all subjects. Age prediction models were trained using 2739 subjects from a single site and tested using the remaining 6137 subjects from various other sites. FIELD STRENGTH/SEQUENCE: Brain imaging with magnetization prepared rapid acquisition with gradient echo or spoiled gradient echo sequences at 1.5 T and 3 T. ASSESSMENT: StarGAN v2, was used to perform a canonical mapping from diverse datasets to a reference domain to reduce site-based variation while preserving semantic information. Generalization performance of deep learning age prediction was evaluated using harmonized, histogram matched, and unharmonized data. STATISTICAL TESTS: Mean absolute error (MAE) and Pearson correlation between estimated age and biological age quantified the performance of the age prediction model. RESULTS: Our results indicated a substantial improvement in age prediction in out-of-sample data, with the overall MAE improving from 15.81 (±0.21) years to 11.86 (±0.11) with histogram matching to 7.21 (±0.22) years with generative adversarial network (GAN)-based harmonization. In the multisite case, across the 5 out-of-sample sites, MAE improved from 9.78 (±6.69) years to 7.74 (±3.03) years with histogram normalization to 5.32 (±4.07) years with GAN-based harmonization. DATA CONCLUSION: While further research is needed, GAN-based medical image harmonization appears to be a promising tool for improving cross-site deep learning generalization. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 1.

MRI signatures of brain age and disease over the lifespan based on a deep brain network and 14 468 individuals worldwide.

Deep learning has emerged as a powerful approach to constructing imaging signatures of normal brain ageing as well as of various neuropathological processes associated with brain diseases. In particular, MRI-derived brain age has been used as a comprehensive biomarker of brain health that can identify both advanced and resilient ageing individuals via deviations from typical brain ageing. Imaging signatures of various brain diseases, including schizophrenia and Alzheimer's disease, have also been identified using machine learning. Prior efforts to derive these indices have been hampered by the need for sophisticated and not easily reproducible processing steps, by insufficiently powered or diversified samples from which typical brain ageing trajectories were derived, and by limited reproducibility across populations and MRI scanners. Herein, we develop and test a sophisticated deep brain network (DeepBrainNet) using a large (n = 11 729) set of MRI scans from a highly diversified cohort spanning different studies, scanners, ages and geographic locations around the world. Tests using both cross-validation and a separate replication cohort of 2739 individuals indicate that DeepBrainNet obtains robust brain-age estimates from these diverse datasets without the need for specialized image data preparation and processing. Furthermore, we show evidence that moderately fit brain ageing models may provide brain age estimates that are most discriminant of individuals with pathologies. This is not unexpected as tightly-fitting brain age models naturally produce brain-age estimates that offer little information beyond age, and loosely fitting models may contain a lot of noise. Our results offer some experimental evidence against commonly pursued tightly-fitting models. We show that the moderately fitting brain age models obtain significantly higher differentiation compared to tightly-fitting models in two of the four disease groups tested. Critically, we demonstrate that leveraging DeepBrainNet, along with transfer learning, allows us to construct more accurate classifiers of several brain diseases, compared to directly training classifiers on patient versus healthy control datasets or using common imaging databases such as ImageNet. We, therefore, derive a domain-specific deep network likely to reduce the need for application-specific adaptation and tuning of generic deep learning networks. We made the DeepBrainNet model freely available to the community for MRI-based evaluation of brain health in the general population and over the lifespan.

A Multidimensional Neural Maturation Index Reveals Reproducible Developmental Patterns in Children and Adolescents.

Adolescence is a time of extensive neural restructuring, leaving one susceptible to atypical development. Although neural maturation in humans can be measured using functional and structural MRI, the subtle patterns associated with the initial stages of abnormal change may be difficult to identify, particularly at an individual level. Brain age prediction models may have utility in assessing brain development in an individualized manner, as deviations between chronological age and predicted brain age could reflect one's divergence from typical development. Here, we built a support vector regression model to summarize high-dimensional neuroimaging as an index of brain age in both sexes. Using structural and functional MRI data from two large pediatric datasets and a third clinical dataset, we produced and validated a two-dimensional neural maturation index (NMI) that characterizes typical brain maturation patterns and identifies those who deviate from this trajectory. Examination of brain signatures associated with NMI scores revealed that elevated scores were related to significantly lower gray matter volume and significantly higher white matter volume, particularly in high-order regions such as the prefrontal cortex. Additionally, those with higher NMI scores exhibited enhanced connectivity in several functional brain networks, including the default mode network. Analysis of data from a sample of male and female patients with schizophrenia revealed an association between advanced NMI scores and schizophrenia diagnosis in participants aged 16-22, confirming the NMI's utility as a marker of atypicality. Altogether, our findings support the NMI as an individualized, interpretable measure by which neural development in adolescence may be assessed.SIGNIFICANCE STATEMENT The substantial neural restructuring that occurs during adolescence increases one's vulnerability to aberration. A brain index that is capable of capturing one's conformance with typical development will allow for individualized assessment and enhance our understanding of typical and atypical development. In this analysis, we produce a neural maturation index (NMI) using support vector regression and a large pediatric sample. This index generalizes across multiple cohorts and shows potential in the identification of clinical groups. We also implement a novel method for examining the developmental trajectory through data-driven analysis. The signatures identified by the NMI reflect key stages of the extensive neural development that occurs during adolescence and support its utility as a metric of typical brain development.

Harmonization of large MRI datasets for the analysis of brain imaging patterns throughout the lifespan.

As medical imaging enters its information era and presents rapidly increasing needs for big data analytics, robust pooling and harmonization of imaging data across diverse cohorts with varying acquisition protocols have become critical. We describe a comprehensive effort that merges and harmonizes a large-scale dataset of 10,477 structural brain MRI scans from participants without a known neurological or psychiatric disorder from 18 different studies that represent geographic diversity. We use this dataset and multi-atlas-based image processing methods to obtain a hierarchical partition of the brain from larger anatomical regions to individual cortical and deep structures and derive age trends of brain structure through the lifespan (3-96 years old). Critically, we present and validate a methodology for harmonizing this pooled dataset in the presence of nonlinear age trends. We provide a web-based visualization interface to generate and present the resulting age trends, enabling future studies of brain structure to compare their data with this reference of brain development and aging, and to examine deviations from ranges, potentially related to disease.