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Dimensional Neuroimaging Endophenotypes: Neurobiological Representations of Disease Heterogeneity Through Machine Learning

Machine learning has been increasingly used to obtain individualized neuroimaging signatures for disease diagnosis, prognosis, and response to treatment in neuropsychiatric and neurodegenerative disorders. Therefore, it has contributed to a better understanding of disease heterogeneity by identifying disease subtypes that present significant differences in various brain phenotypic measures. In this review, we first present a systematic literature overview of studies using machine learning and multimodal MRI to unravel disease heterogeneity in various neuropsychiatric and neurodegenerative disorders, including Alzheimer disease, schizophrenia, major depressive disorder, autism spectrum disorder, multiple sclerosis, as well as their potential in transdiagnostic settings. Subsequently, we summarize relevant machine learning methodologies and discuss an emerging paradigm which we call dimensional neuroimaging endophenotype (DNE). DNE dissects the neurobiological heterogeneity of neuropsychiatric and neurodegenerative disorders into a low dimensional yet informative, quantitative brain phenotypic representation, serving as a robust intermediate phenotype (i.e., endophenotype) largely reflecting underlying genetics and etiology. Finally, we discuss the potential clinical implications of the current findings and envision future research avenues.

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