SAP - Identifying the effects of cognitive-behavioral therapy on the structural connectome in depression

Depression is widely recognized as one of the most debilitating conditions worldwide (James et al., 2018; Vos et al., 2020). Although various treatment approaches, including pharmacotherapy and psychotherapy, are available and provide relief to many (Bundesärztekammer (BÄK) et al., 2022), a substantial portion of patients either fail to respond or experience relapse, highlighting the limited stability of remission and the frequent need for multiple treatment attempts (Malhi & Mann, 2018). Improving treatment outcomes and developing more personalized therapeutic strategies require a deeper understanding of the underlying mechanisms through which these treatments exert their effects. Emerging evidence suggests that alterations in the brain’s structural network, or structural connectome, may represent a key pathophysiological mechanism underlying depression (Korgaonkar et al., 2014; Repple et al., 2020). Considering the brain as a connectome conceptualizes it as a network composed of nodes, representing distinct brain regions, and edges, representing the white matter fiber tracts connecting these regions. In practice, nodes are typically defined by parcellation of T1-weighted structural MRI, whereas edges are derived from diffusion-weighted imaging (Hagmann, 2005; Sporns et al., 2005). This approach enables the use of graph metrics to investigate the architecture of the brain's structural network (Rubinov & Sporns, 2010) as well as the identification of specific subnetworks associated with effects of interest (Zalesky et al., 2010). Previous cross-sectional studies on the structural connectome have reported lower structural brain connectivity in patients with MDD compared to HC (Korgaonkar et al., 2014; Myung et al., 2016; Yao et al., 2019), with more pronounced deficits observed in patients with earlier onset and more severe depressive symptoms (Repple et al., 2020, 2023). These findings are further corroborated by microstructural analyses in MDD showing lowered white matter integrity (van Velzen et al., 2020) as well as a decline in white matter integrity over time compared to HC (Flinkenflügel et al., 2024). These results support the notion that depression may be characterized by disrupted information processing within the connectome (Sporns et al., 2005). Despite evidence of structural connectome alterations in depression, it remains uncer-tain whether these abnormalities can be modified by particular treatments and whether such modifications are linked to treatment outcomes in depression. Cognitive-behavioral therapy (CBT) is a first-line treatment for depression (Bundesärztekammer (BÄK) et al., 2022) that focuses on actively restructuring maladaptive schemas, fostering more realistic and reflective beliefs, and promoting cognitive flexibility (Beck, 1979, 2008). While previous MRI studies have demonstrated CBT-associated changes in both functional activity and connectivity (Borgers et al., 2025; Jamieson et al., 2024; König et al., 2025; Li et al., 2022) as well as CBT-associated changes in white matter microstructure and gray matter volume (Flinkenflügel et al., 2025; Zwiky et al., 2025), the effect of CBT on the structural connectome in depression has yet to be elucidated. To address these gaps, this prospective, naturalistic study aims to investigate the as-sociation between longitudinal changes in the structural connectome and treatment outcome following CBT in patients with depression. In the present study, we aim to investigate changes in measures of brain structural connectivity in patients with depression following CBT, as compared to healthy controls (HC). Specifically, we expect (1) significant group-specific, time-dependent effects (group × time interactions) in brain structural connectivity, characterized by a longitudinal increase in structural connectivity in patients undergoing CBT, whereas healthy controls are expected to show no comparable change. Furthermore, we hypothesize (2) that increases in structural connectivity in the patient group will be significantly associated with reductions in depressive symptom severity following CBT.