Re: Recovery My File With Crack
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Patients with treatment-resistant depression (TRD) experience a wide variety of debilitating symptoms, including persistent negative mood, anhedonia, psychomotor retardation and suicidal thoughts. While many patients with TRD who receive experimental subcallosal cingulate (SCC) deep brain stimulation (DBS) have responded to continuous stimulation with durable symptom relief4,5,6,7,8, the clinical management of these patients is often complex due to a number of interacting factors. In particular, the progress of antidepressant response is nonlinear and different for each individual1,2, often involving periods of mood fluctuation for which there is no absolute unanimous clinical interpretation. Without objective markers of depression severity, psychiatrists rely on clinical intuition to decide whether to change stimulation parameters or apply a watchful waiting approach. Currently, clinical teams use interviews and symptom surveys such as the Hamilton Depression Rating Scale (HDRS) to quantify depression severity, but these gold-standard rater-dependent measures are often obscured by various non-specific factors such as subjective recall biases9,10 and reactions to environmental circumstances. For example, while depression diagnostic criteria are based on negative mood and anhedonia that are sustained over a period of weeks, patients may experience normal transient short-term mood fluctuations due to a variety of factors (for example, stressful life events, interrupted sleep or transitory anxiety) that are reflected in the HDRS and confound the measurement of core depression symptom changes. Therefore, objective markers of brain changes underlying DBS-mediated recovery are necessary to standardize treatment approaches and aid in scaling SCC DBS to an approved therapy for TRD.
This Article demonstrates a biomarker that accurately identifies depressive and recovered states, tracks individual recovery trajectories and predicts relapses, provides evidence of differential acute and sustained neuronal network adaptations and is concordant with objective changes in facial expression over the course of recovery. Furthermore, a multimodal analysis based on this brain signal shows that specific structural and functional deficits in the targeted white matter network reflect baseline disease severity (number of lifetime depressive episodes) and time to respond to DBS, demonstrating individual differences that account for variable recovery trajectories with SCC DBS. Taken together, these results advance the existing practice of SCC DBS by providing actionable objective information to support personalized clinical management, provide new insight into the complex relationship between functional, structural and behavioural factors involved in patient-specific recovery, and motivate further research in using multimodal measurements to advance the treatment of depressive disorders.
The study cohort consisted of ten consecutively recruited participants who were implanted with an experimental DBS implanted pulse generator (IPG) that served both stimulation and recording functions. DBS leads were inserted at the intersection of four major white matter pathways (Fig. 1a,b) identified from earlier studies11,12. All participants met study inclusion criteria before implantation with a minimum depression severity HDRS-17 score equal to or higher than 20 (Extended Data Table 1). Stimulation was turned on following a 4-week postsurgery recovery phase, and the primary endpoint of the study was defined as the HDRS-17 score at 24 weeks of chronic SCC DBS. At a cohort level, participants experienced a significant reduction in HDRS-17 score from the presurgery baseline with a mean HDRS-17 of 22.3 (s.d. 1.64), to the end of the 24-week observation phase with a mean HDRS-17 of 7.3 (s.d. 3.62). At an individual level, nine out of ten participants were deemed to be responders (greater than 50% decrease in HDRS-17) and 7 out of 10 were deemed to be in remission (HDRS-17 less than 8). Despite the consistent clinical outcomes at the 24-week endpoint, individual patients showed variable recovery trajectories, with some achieving clinical response much earlier than others (Fig. 1c).
Multiple previous studies have also identified prominent (but not exclusive) beta band changes in acute SCC LFP dynamics with short-term stimulation exposure14,15 or with resting-state or emotional-challenge experiments without stimulation22,23,24,25. For example, previous studies demonstrate decreases in beta band power after brief bilateral intraoperative SCC stimulation14,15, consistent with the decreases in beta band power observed within the first month of chronic stimulation in the current cohort. The eventual transition to an increase in beta band power after chronic stimulation suggests that sustained, antidepressant responses are distinct from transient behavioural stimulation effects and thus are probably mediated by different mechanisms, including stimulation-induced plasticity26,27. Our findings support the broader hypothesis that beta band activity signals the establishment and maintenance of a status quo cognitive state28. In this context, we posit that the early desynchronization of beta band activity may correspond to release from the depressive maladaptive state enabling more flexible behaviour (reflected by increased HDRS variability), followed by an increase in beta band activity signalling the return of a new homeostatic set point after adaptation to chronic DBS (corresponding to stable recovery)28. Beyond the SCC, beta band activity has emerged as an important marker of dysfunction across many studies investigating mood disorders, including intracranial recordings in humans29,30, non-invasive electroencephalogram31 and rodent models32. Of note, the different regions investigated in these studies constitute the targets of our treatment network33, suggesting that the beta band changes we observed may reflect network-wide changes across multiple regions.
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 projections36,37,38. Furthermore, dACC FA is significantly associated with functional connectivity deficits between the stimulation target and MCC, which are directly connected via the cingulum bundle33,39. Importantly, our finding of a negative correlation between white matter deficits and the number of lifetime depressive episodes is consistent with a large depression cohort study that reported lower FA and higher radial diffusivity with recurrent patients compared with single-episode patients, as well as previous studies relating the cumulative effects of depressive episodes on brain microstructure40. Network reorganization may be a potential mechanism of the transition from acute to chronic response with SCC DBS, consistent with animal studies suggesting that chronic stimulation may lead to neuroplastic changes, resulting in remyelination of targeted tracts26,41 or engagement of homeostatic plasticity mechanisms to produce long-term changes42. The availability of new magnetic resonance imaging (MRI)-compatible DBS IPGs will enable direct measurements of structural and functional connectivity changes within the stimulated network over time to test these hypotheses.
The 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 artefacts50. However, while there is practical convenience to estimating a biomarker without interrupting therapeutic stimulation, the lack of negative clinical effects associated with relatively short SCC DBS discontinuation makes it feasible to calculate this biomarker during transient periods without the technical confound. Third, we have not explicitly modelled acute moment-to-moment distress20,30, which would validate the specificity and potentially enhance the behavioural interpretability of our chronic biomarker. Future studies with increased data collection frequency will allow the modelling of potential LFP signatures of transient mood or anxiety symptoms. Finally, the analysis here is retrospective, leaving open questions about the exact use of the SDC in determining the precise timing of optimal stimulation adjustments or the introduction of adjunct rehabilitative interventions such as cognitive behavioural therapy or mindfulness training.
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