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Mate Abraham, Annakarina Mundorf, Katja Brodmann, Nadja Freund

• \(\bf Background:\) Numerous cortical and subcortical structures have been studied extensively concerning alterations of their integrity as well as their neurotransmitters in depression. However, connections between these structures have received considerably less attention. \(\bf Objective:\) This systematic review presents results from recent neuroimaging as well as neuropathologic studies conducted on humans and other mammals. It aims to provide evidence for impaired white matter integrity in individuals expressing a depressive phenotype. \(\bf Methods:\) A systematic database search in accordance with the PRISMA guidelines was conducted to identify imaging and postmortem studies conducted on humans with a diagnosis of major depressive disorder, as well as on rodents and primates subjected to an animal model of depression. \(\bf Results:\) Alterations are especially apparent in frontal gyri, as well as in structures establishing interhemispheric connectivity between frontal regions. Translational neuropathological findings point to alterations in oligodendrocyte density and morphology, as well as to alterations in the expression of genes related to myelin synthesis. An important role of early life adversities in the development of depressive symptoms and white matter alterations across species is thereby revealed. Data indicating that stress can interfere with physiological myelination patterns is presented. Altered myelination is most notably present in regions that are subject to maturation during the developmental stage of exposure to adversities. \(\bf Conclusion:\) Translational studies point to replicable alterations in white matter integrity in subjects suffering from depression across multiple species. Impaired white matter integrity is apparent in imaging as well as neuropathological studies. Future studies should focus on determining to what extent influencing white matter integrity is able to improve symptoms of depression in animals as well as humans.