363. Angular gyrus as a key hub of treatment refractoriness and neuromodulation response in major depressive disorder: a data-driven structural covariance network analysis

Abstract

Abstract Background Treatment-resistant depression (TRD) represents a severe subtype of major depressive disorder (MDD) characterized by inadequate response to antidepressant treatments. Although large-scale network (e.g., default mode network) dysfunction, has been implicated in MDD, the structural network substrates underlying antidepressant treatment refractoriness and neuromodulation response remain unclear. Aims & Objectives We aimed to identify brain regions that emerge as critical hubs when antidepressant treatment resistance is examined using a data-driven approach. Method A total of 162 patients with major depressive disorder (MDD), including individuals with at least one failed antidepressant trial and those without failed trials (non-TRD), underwent T1-weighted structural MRI. Whole-brain voxel-wise gray matter volume (GMV) maps were obtained using voxel-based morphometry. To identify regions associated with antidepressant treatment refractoriness, voxel-wise regression analyses were conducted with the Maudsley Staging Method treatment subscale (MSM-T) as a continuous variable, controlling for age, sex, education, and total intracranial volume. Regions showing significant GMV by MSM-T interactions were identified and defined as hub clusters. These hubs were subsequently used as seed regions to construct structural covariance networks (SCNs) by examining voxel-wise covariance between seed GMV and whole-brain GMV. Individual-level SCN integrity was quantified using a structural covariance index (SCI), reflecting the overall covariance strength between the seed region and its associated SCN clusters. A subset of patients received 20 sessions of left prefrontal 10-Hz rTMS or intermittent theta-burst stimulation (iTBS) and underwent post-treatment MRI. Changes in GMV and SCN integrity were assessed using paired analyses and correlated with depression severity (HDRS-17) and treatment-related symptom improvement. Results Whole-brain voxel-wise analyses revealed that bilateral angular gyrus (AG) gray matter volume, especially the left side, emerged as a significant hub positively associated with MSM-T. Structural covariance analyses demonstrated that brain regions within this AG-centered network showed a significant negative association with MSM-T, including bilateral postcentral gyrus and right precentral gyrus (sensorimotor cortex), left superior frontal gyrus (BA6), bilateral occipital lingual regions including the lingual gyrus and an extension to cerebellar dentate nucleus (FWE-corrected p<0.05). Baseline SCI between left AG, left lingual gyrus and cerebellar dentate nucleus significantly associated with HDRS-17. Following neuromodulation, changes in AG-centered SCI were significantly correlated with clinical improvement after rTMS, but not iTBS. Discussion & Conclusions The first analyses identified the left angular gyrus as a central structural hub whose covariance with sensorimotor, frontal, and occipital-cerebellar regions progressively deteriorates with increasing antidepressant treatment refractoriness. This AG-centered network disruption provides a structural network signature of TRD and highlights network-level decoupling, rather than focal atrophy, as a key neurobiological feature of refractoriness.