LAUSR

We read with great interest the recent article by Scangos and colleagues on their closed-loop deep brain stimulation (DBS) study that targeted ventral capsule/ventral striatum (VC/VS) for the treatment of major depressive disorder (MDD) in a single participant [1]. The study consisted of an open-loop stage (Stage I) and a closed-loop stage (Stage II). In the open-loop stage, gamma power in bilateral amygdala was identified as a biomarker for the high symptom state using cross-validated logistic regression models. VC/VS was identified as an upstream stimulation target based on sophisticated structural (diffusion-based tractography) and functional mapping (stimulation-evoked potentials). In the closed-loop stage, a DBS system was implanted to detect gamma activity in the right amygdala and to stimulate the right VC/VS in a closed loop to reduce amygdala gamma activity and alleviate symptoms of depression. The participant experienced a precipitous drop in symptom severity in the first week of closed-loop stimulation compared to the week prior and remained in a low symptom state for the majority of the closedloop stimulation period. The authors suggested that while immediate benefits of DBS to VC/VS have been repeatedly demonstrated, these effects are difficult to sustain. With a closed-loop system, the acute benefit of stimulation can be maximized, and attenuation of its efficacy can be avoided with infrequent stimulation. Overall, the work effectively integrates multiple experimental and engineering techniques, which exemplifies the future of personalized psychiatric treatment using closed-loop DBS. We are impressed with the sustained clinical outcome of closed-loop DBS in this n-of-1 study, and we suggest that the precise mechanism underlying the successful intervention could be further elucidated with a dynamical systems approach and a closer examination of the nonlinear relation between gamma activity and symptom severity. First, analyzing the impact of closed-loop stimulation on depressive symptoms as a bistable dynamical system may provide novel insight into the therapeutic mechanism. In Scangos et al., 2021 [1], Fig. 2i demonstrates the key clinical outcome, i.e., precipitous symptom reduction in the first week of closed-loop stimulation compared to theweek before the onset of closed-loop stimulation. Such precipitous change is often a sign of phase transition in bistable ormultistable nonlinear dynamical systems [2]. This observation is particularly interesting in the context of the Stage I results of the study, where Scangos et al. demonstrated that the symptomology of the patient fluctuated between two distinct states (Fig.1b and Fig. 2c of the original paper [1]), i.e., a high symptom state and a low symptom state (Fig. 1a, reproduced using data from the GitHub repository of the paper). Thus, it is clear that the participant was in the high symptom state during the week before the onset of closed-loop stimulation: an average of 77.33 for the visual analog scale for depression (VAS-