Depression is a highly heterogeneous syndrome that bears only modest correlations with its biological substrates, motivating a renewed interest in rethinking our approach to diagnosing depression for research purposes and new efforts to discover subtypes of depression anchored in biology. Here, we review the major causes of diagnostic heterogeneity in depression, with consideration of both clinical symptoms and behaviors (symptomatology and trajectory of depressive episodes) and biology (genetics and sexually dimorphic factors). Next, we discuss the promise of using data-driven strategies to discover novel subtypes of depression based on functional neuroimaging measures, including dimensional, categorical, and hybrid approaches to parsing diagnostic heterogeneity and understanding its biological basis. The merits of using resting-state functional magnetic resonance imaging functional connectivity techniques for subtyping are considered along with a set of technical challenges and potential solutions. We conclude by identifying promising future directions for defining neurobiologically informed depression subtypes and leveraging them in the future for predicting treatment outcomes and informing clinical decision making. <<<

Sheila Shanmugan, Jakob Seidlitz, Zaixu Cui, Azeez Adebimpe, Danielle S Bassett, Maxwell A Bertolero, Christos Davatzikos, Damien A Fair, Raquel E Gur, Ruben C Gur, Bart Larsen, Hongming Li, Adam Pines, Armin Raznahan, David R Roalf, Russell T Shinohara, Jacob Vogel, Daniel H Wolf, Yong Fan, Aaron Alexander-Bloch, Theodore D Satterthwaite <<<

Prior work has shown that there is substantial interindividual variation in the spatial distribution of functional networks across the cerebral cortex, or functional topography. However, it remains unknown whether there are sex differences in the topography of individualized networks in youth. Here, we leveraged an advanced machine learning method (sparsity-regularized non-negative matrix factorization) to define individualized functional networks in 693 youth (ages 8 to 23 y) who underwent functional MRI as part of the Philadelphia Neurodevelopmental Cohort. Multivariate pattern analysis using support vector machines classified participant sex based on functional topography with 82.9% accuracy ( < 0.0001). Brain regions most effective in classifying participant sex belonged to association networks, including the ventral attention, default mode, and frontoparietal networks. Mass univariate analyses using generalized additive models with penalized splines provided convergent results. Furthermore, transcriptomic data from the Allen Human Brain Atlas revealed that sex differences in multivariate patterns of functional topography were spatially correlated with the expression of genes on the X chromosome. These results highlight the role of sex as a biological variable in shaping functional topography. <<<

Transcranial magnetic stimulation (TMS) is used to treat multiple psychiatric and neurological conditions by manipulating activity in particular brain networks and circuits, but individual responses are highly variable. In clinical settings, TMS coil placement is typically based on either group average functional maps or scalp heuristics. Here, we found that this approach can inadvertently target different functional networks in depressed patients due to variability in their functional brain organization. More precise TMS targeting should be feasible by accounting for each patient's unique functional neuroanatomy. To this end, we developed a targeting approach, termed targeted functional network stimulation (TANS). The TANS approach improved stimulation specificity in silico in 8 highly sampled patients with depression and 6 healthy individuals and in vivo when targeting somatomotor functional networks representing the upper and lower limbs. Code for implementing TANS and an example dataset are provided as a resource. <<<