Discussion
depression, TRD, SCC, anxiety
DEMYELINATION, PATHOPHYSIOLOGY
In this study investigating long-term multimodal changes with SCC DBS, we derived the SDC as a common objective biomarker that accurately captured clinically defined ‘sick’ and ‘stable response’ states in all patients, as well as responding to changes in DBS stimulation. In addition, the transition to reach the ‘stable response’ state identified from the SDC was correlated with structural and functional irregularities in the targeted white matter tracts and was further concordant with a data-driven analysis of complex facial expressions. While this cohort experienced typical moment-to-moment mood variations as well as short-lived (experiential and LFP) effects with initial DBS exposureNotably, the post hoc analysis of the relapsed responder demonstrates the potential value of the SDC in a clinical setting. Specifically, the SDC predicted the relapse approximately 5 weeks before structured interviews indicated the pending clinical change. Conversely, we also observed a different participant (P003) where the SDC indicated a transition to stable recovery well before the HDRS-17. Further analysis of the individual HDRS-17 items revealed that the apparent mismatch of the HDRS-17 and SDC was because of increasing anxiety symptoms without changes in core depression symptoms, a dissociation confirmed by clinical notes made by the study psychiatrist (Extended Data Fig. Multiple previous studies have also identified prominent (but not exclusive) beta band changes in acute SCC LFP dynamics with short-term stimulation exposureThe long-term effects observed here with chronic DBS resemble the effects of slower-acting antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs). The effect of SSRIs on 5-hydroxytryptamine neural activity in the dorsal raphe nucleus (DRN, one of the downstream targets of SCC DBS) has been shown to change over time, with acute suppression followed by restoration over 2 weeks (ref. While all patients were implanted to affect the same four white matter bundles, the degree of increased radial diffusivity and decreased FA (typically suggesting demyelination) within this target network was correlated with longer recovery times. Further supporting the role of region-specific white matter integrity in depression pathophysiology is complementary postmortem findings in TRD suicides, which identify local myelin and oligodendroglia abnormalities in and around the SCC region and its projectionsA patient’s appearance is a core component of a physician’s clinical assessment during diagnosis and recovery, and our personalized facial expression analysis of depression states provides a robust independent readout of these clinical impressions that concords with the SDC. While there was a clear overlap of the face action units (AUs) that changed across participants, the inability to derive a single sick/well classifier (either due to inherent variability or small sample size limitations) meant that the model could only be used as a descriptive tool instead of a prospective estimate of the current depression state. The common changes across participants do involve AUs previously linked to classic constructs of both sadness and happinessThe current study has several limitations. First, the LFP analysis here is limited to six of ten participants due to prototype device challenges (that is, data artefacts and protocol changes after pilot implantations). Nonetheless, the derived SDC biomarker was reliable across all participants, including the held-out participant. Second, the results presented are from LFP collected with therapeutic stimulation temporarily turned OFF to eliminate significant stimulation-related artefacts