Trial Of Deep Brain Stimulation Research Articles

Aperiodic (1/f) neural activity robustly tracks symptom severity changes in treatment-resistant depression.

A reliable physiological biomarker for Major Depressive Disorder is essential for developing and optimizing neuromodulatory treatment paradigms. This study investigates a passive electrophysiologic biomarker that tracks changes in depressive symptom severity on the order of minutes to hours. We analyze brief recordings from intracranial electrodes implanted deep in the brain during a clinical trial of deep brain stimulation for treatment-resistant depression in 5 human subjects (nfemale= 3, nmale = 2). This surgical setting allows for precise temporal and spatial sensitivity in the ventromedial prefrontal cortex, a challenging area to measure. We focused on the aperiodic slope of the power spectral density, a metric reflecting the balance of activity across all frequency bands and serving as a proxy for excitatory/inhibitory balance in the brain. Our findings demonstrate that shifts in aperiodic slope correlate with depression severity, with flatter (less negative) slopes indicating reduced depression severity. This significant correlation was observed in all N=5 subjects, particularly in the ventromedial prefrontal cortex. This biomarker offers a new way to track patient responses to Major Depressive Disorder treatment, paving the way for individualized therapies in both intracranial and non-invasive monitoring contexts.

Why are clinical trials of deep brain stimulation terminated? An analysis of clinicaltrials.gov (New Version)

Why are clinical trials of deep brain stimulation terminated? An analysis of clinicaltrials.gov (New Version)

Deep brain stimulation for Parkinson’s disease: systematic review with meta-analysis and trial sequential analysis

ObjectiveTo assess the benefits and harms of deep brain stimulation for Parkinson’s disease.DesignSystematic review with meta-analysis and trial sequential analysis.Data sourcesCochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, Latin...

Why are clinical trials of deep brain stimulation terminated? An analysis of clinicaltrials.gov

BackgroundAlthough deep brain stimulation (DBS) has established uses for patients with movement disorders and epilepsy, it is under consideration for a wide range of neurologic and neuropsychiatric conditions. ObjectiveTo review successful and unsuccessful DBS clinical trials and identify factors associated with early trial termination. MethodsThe ClinicalTrials.gov database was screened for all studies related to DBS. Information regarding condition of interest, study aim, trial design, trial success, and, if applicable, reason for failure was collected. Trials were compared and logistic regression was utilized to identify independent factors associated with trial termination. ResultsOf 325 identified trials, 79.7% were successful and 20.3% unsuccessful. Patient recruitment, sponsor decision, and device issues were the most cited reasons for termination. 242 trials (74.5%) were interventional with 78.1% successful. There was a statistically significant difference between successful and unsuccessful trials in number of funding sources (p = 0.0375). NIH funding was associated with successful trials while utilization of other funding sources (academic institutions and community organizations) was associated with unsuccessful trials. 83 trials (25.5%) were observational with 84.0% successful; there were no statistically significant differences between successful and unsuccessful observational trials. ConclusionOne in five clinical trials for DBS were found to be unsuccessful, most commonly due to patient recruitment difficulties. The source of funding was the only factor associated with trial success. As DBS research continues to grow, understanding the current state of clinical trials will help design successful future studies, thereby minimizing futile expenditures of time, cost, and patient engagement.

195 Targeting Thalamocortical Circuits For Closed-Loop Stimulation in Lennox-Gastaut Syndrome

INTRODUCTION: Lennox-Gastaut syndrome (LGS) is a severe, childhood-onset epilepsy associated with frequent seizures, cognitive impairment, and high burden of care. Electrical stimulation of the thalamus can be an effective treatment for LGS, but complete seizure control is rarely achieved. Outcomes may be improved by stimulating areas beyond the thalamus, including cortex, but the optimal targets are unknown. METHODS: Brain network maps from 3 group-level studies of LGS were averaged to define the area of peak overlap: combined electroencephalography-functional MRI (EEG-fMRI) of paroxysmal fast activity, [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) of hypometabolism, and structural connectivity associated with efficacy in a previous trial of deep brain stimulation. The resulting “hotspot” was used as a seed in a normative fMRI connectivity analysis to identify connected networks. Two patients underwent bilateral thalamocortical implantations guided by this hotspot. Simultaneous recordings from cortex and thalamus were analyzed for presence and synchrony of epileptiform activity. RESULTS: Peak overlap was in bilateral premotor cortex. Functional connectivity of this hotspot revealed a network of frontoparietal cortex resembling the diffuse abnormalities seen on EEG-fMRI and FDG-PET. Intracranial electrophysiology showed characteristic epileptiform activity of LGS in the cortical hotspot that preceded or co-occurred with similar thalamic activity. CONCLUSIONS: Premotor cortex shows peak involvement in LGS, and functional connectivity of this region resembles the wider epileptic brain network. Thus, it may be an optimal target for neuromodulation therapies, including thalamocortical stimulation. Compared to thalamus-only stimulation, addition of this cortical target may allow more rapid detections and responsive stimulations of seizures, and broader modulation of the brain network underlying LGS to achieve greater seizure control.

Pallidal versus subthalamic deep brain stimulation for Meige syndrome: A systematic review and meta-analysis

BackgroundGlobus pallidus internus (GPi) and subthalamic nucleus (STN) are two common deep brain stimulation (DBS) targets. This meta-analysis was to compared the efficacy and safety of these two DBS targets for the treatment of Meige syndrome (MS). MethodsA systematic search was performed using EMBASE, MEDLINE, the Cochrane Library, and ClinicalTrials.gov to identify DBS trials for MS. Review Manager 5.3 was used to perform meta-analysis and the mean difference (MD) was analyzed and calculated with a random effect model. Pearson's correlation coefficients and meta-regression analyses were utilized to identify relevant predictive markers. ResultsTwenty trials involving 188 participants with GPi-DBS and 110 individuals with STN-DBS were eligible. Both groups showed improvement of the Burke-Fahn-Marsden Dystonia Rating Scale-Movement (BFMDRS-M) and Disability (BFMDRS-D) scores (BFMDRS-M: MD = 10.57 [7.74–13.41] for GPi-DBS, and MD = 8.59 [4.08–13.11] for STN-DBS; BFMDRS-D: MD = 5.96 [3.15–8.77] for GPi-DBS, and MD = 4.71 [1.38–8.04] for STN-DBS; all P < 0.001) from baseline to the final follow-up, while no notable disparity in improvement rates was observed between them. Stimulation-related complications occurrence was also similar between two groups (38.54 ± 24.07% vs. 43.17 ± 29.12%, P = 0.7594). Simultaneously, preoperative BFMDRS-M score and disease duration were positively connected with the relative changes in BFMDRS-M score at the final visit. ConclusionBoth GPi-DBS and STN-DBS are effective MS therapies, with no differences in efficacy or the frequency of stimulation-related problems. Higher preoperative scores and longer disease duration probably predict greater improvement.

Deep brain stimulation for the treatment of substance use disorders: a promising approach requiring caution.

Substance use disorders are prevalent, causing extensive morbidity and mortality worldwide. Evidence-based treatments are of low to moderate effect size. Growth in the neurobiological understanding of addiction (e.g., craving) along with technological advancements in neuromodulation have enabled an evaluation of neurosurgical treatments for substance use disorders. Deep brain stimulation (DBS) involves surgical implantation of leads into brain targets and subcutaneous tunneling to connect the leads to a programmable implanted pulse generator (IPG) under the skin of the chest. DBS allows direct testing of neurobiologically-guided hypotheses regarding the etiology of substance use disorders in service of developing more effective treatments. Early studies, although with multiple limitations, have been promising. Still the authors express caution regarding implementation of DBS studies in this population and emphasize the importance of safeguards to ensure patient safety and meaningful study results. In this perspectives article, we review lessons learned through the years of planning an ongoing trial of DBS for methamphetamine use disorder.

Identity Theft, Deep Brain Stimulation, and the Primacy of Post-trial Obligations.

Patient narratives from two investigational deep brain stimulation trials for traumatic brain injury and obsessive-compulsive disorder reveal that injury and illness rob individuals of personal identity and that neuromodulation can restore it. The early success of these interventions makes a compelling case for continued post-trial access to these technologies. Given the centrality of personal identity to respect for persons, a failure to provide continued access can be understood to represent a metaphorical identity theft. Such a loss recapitulates the pain of an individual's initial injury or illness and becomes especially tragic because it could be prevented by robust policy. A failure to fulfill this normative obligation constitutes a breach of disability law, which would view post-trial access as a means to achieve social reintegration through this neurotechnological accommodation.

Deep Brain Stimulation for Alzheimer’s Disease and the Human Memory Circuit

AbstractBackgroundBrain lesions causing amnesia are in a memory circuit centered on the subiculum. Deep brain stimulation (DBS) sites connected to this circuit are linked to cognitive decline in Parkinson’s disease but cognitive improvement in Alzheimer’s Disease (AD). Insight into this paradox may come from directly comparing the topography of lesion and DBS‐induced effects.MethodsWe studied 53 amnesia‐causing lesion locations and 46 patients (92 DBS sites) from Phase 1 and Phase 2 randomized controlled trials of fornix DBS for AD. Connectivity between lesions and DBS sites was computed using a normative atlas of functional connectivity data from 1000 healthy subjects. Baseline cognitive scores were compared to 1‐year post‐DBS activation scores.ResultsConnectivity between AD patients' DBS sites and a subiculum region derived from amnesia‐causing brain lesions correlated with cognitive improvement (Spearman’s rho = 0.33, p = 0.027). There was a difference between sham‐first (Spearman’s rho = 0.33, p = 0.027) and stimulation‐first (Spearman’s rho = 0.25, p = 0.27) cohorts. Whole‐brain connectivity maps of the subiculum region and AD response fingerprints were aligned: 17/19 local maxima appeared in both maps, dice coefficient 0.71 (p&lt;0.00001). Both maps showed data‐driven peaks in an overlapping subiculum region. However, DBS data showed a significant interaction effect between patient age and subiculum connectivity upon outcome in a general linear model (p = 0.031). Randomization status was controlled as a covariate and was not significant. Specifically, higher subiculum connectivity in older patients led to improved cognition, while higher connectivity in younger patients resulted in worsening cognition. The data‐driven inflection point for this interaction effect was at age 65 at any subiculum connectivity value.ConclusionOur findings suggest that lesions causing amnesia and DBS sites modulating cognition converge on common neuroanatomy. However, patient age appears to be critical variable in determining whether DBS sites connected to the subiculum result in cognitive improvement or decline. Our results provide insight into the paradox of mixed outcomes across DBS cohorts and support restricting ADvance II enrollment of fornix‐targeted DBS to patients over 65. The underlying mechanisms remain unclear, and this study must be replicated in additional datasets.

Neuropsychological assessment protocol in an ongoing randomized controlled trial on posterior subthalamic area vs. ventral intermediate nucleus deep brain stimulation for essential tremor.

Patients with essential tremor (ET) may experience cognitive-affective impairment. Deep brain stimulation (DBS) of different targets, such as the ventral intermediate nucleus (VIM) of the thalamus or the posterior subthalamic area (PSA), has been shown to be beneficial for refractory ET. However, there is little evidence regarding the possible neuropsychological effects of PSA-DBS on patients with ET, and there are few studies comparing it with VIM-DBS in this population.In this study, we aim to present the evaluation protocol and neuropsychological battery as used in an ongoing trial of DBS for ET comparing the already mentioned targets. As part of a randomized, double-blind, crossover clinical trial comparing the effectiveness and safety of PSA-DBS vs. VIM-DBS, 11 patients with refractory ET will undergo a multi-domain neuropsychological battery assessment. This will include a pre-/post-implantation assessment (3 months after the stimulation of each target and 6 months after an open stage of DBS on the most optimal target). Evidence on the neuropsychological effects of DBS in patients with refractory ET is very scarce, particularly in lesser-explored targets such as PSA. This study could contribute significantly in this field, particularly on pre-procedure safety analysis for tailored patient/technique selection, and to complete the safety analysis of the procedure. Moreover, if proven useful, this proposed neuropsychological assessment protocol could be extensible to other surgical therapies for ET.

Subject and Family Perspectives from the Central Thalamic Deep Brain Stimulation Trial for Traumatic Brain Injury: Part II.

This is the second paper in a two-part series describing subject and family perspectives from the CENTURY-S (CENtral Thalamic Deep Brain Stimulation for the Treatment of Traumatic Brain InjURY-Safety) first-in-human invasive neurological device trial to achieve cognitive restoration in moderate to severe traumatic brain injury (msTBI). To participate, subjects were independently assessed to formally establish decision-making capacity to provide voluntary informed consent. Here, we report on post-operative interviews conducted after a successful trial of thalamic stimulation. All five msTBI subjects met a pre-selected primary endpoint of at least a 10% improvement in completion time on Trail-Making-Test Part B, a marker of executive function. We describe narrative responses of subjects and family members, refracted against that success. Interviews following surgery and the stimulation trial revealed the challenge of adaptation to improvements in cognitive function and emotional regulation as well as altered (and restored) relationships and family dynamics. These improvements exposed barriers to social reintegration made relevant by recoveries once thought inconceivable. The study's success sparked concerns about post-trial access to implanted devices, financing of device maintenance, battery replacement, and on-going care. Most subjects and families identified the need for supportive counseling to adapt to the new trajectory of their lives.

Publication Rates and Characteristics of Clinical Trials in Deep Brain and Responsive Neurostimulation

Introduction: Prompt dissemination of clinical trial results is essential for ensuring the safety and efficacy of intracranial neurostimulation treatments, including deep brain stimulation (DBS) and responsive neurostimulation (RNS). However, the frequency and completeness of results publication, and reasons for reporting delays, are unknown. Moreover, the patient populations, targeted anatomical locations, and stimulation parameters should be clearly reported for both reproducibility and to identify lacunae in trial design. Here, we examine DBS and RNS trials from 1997 to 2022, chart their characteristics, and examine rates and predictors of results reporting. Methods: Trials were identified using <ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link>. Associated publications were identified using <ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link> and <ext-link ext-link-type="uri" xlink:href="http://PubMed.gov" xmlns:xlink="http://www.w3.org/1999/xlink">PubMed.gov</ext-link>. Pearson’s χ² tests were used to assess differences in trial characteristics between published and unpublished trials. Results: Across 449 trials, representing a cumulative cohort of 42,769 patient interventions, there were 37 therapeutic indications and 44 stimulation targets. The most common indication and target were Parkinson’s disease (40.55%) and the subthalamic nucleus (35.88%), respectively. Only 0.89% of trials were in pediatric patients (11.58% were mixed pediatric and adult). Explored targets represented 75% of potential basal ganglia targets but only 29% of potential thalamic targets. Allowing a 1-year grace period after trial completion, 34/169 (20.12%) had results reported on <ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link>, and 107/169 (63.31%) were published. ∼80% of published trials included details about stimulation parameters used. Published and unpublished trials did not significantly differ by trial characteristics. Conclusion: We highlight key knowledge and performance gaps in DBS and RNS trial research. Over one-third of trials remain unpublished >1 year after completion; pediatric trials are scarce; most of the thalamus remains unexplored; about one-in-five trials fail to report stimulation parameters; and movement disorders comprise the most studied indications.

Long-term neuropsychological outcomes of deep brain stimulation in early-stage Parkinson's disease

IntroductionThe pilot trial of deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) randomized 30 patients (medication duration 0.5–4 years; without dyskinesia or motor fluctuations) to receive optimal drug therapy alone (early ODT) or subthalamic nucleus (STN) DBS plus ODT (early DBS + ODT). This study reports long-term neuropsychological outcomes from the early DBS pilot trial. MethodsThis is an extension of an earlier study that examined two-year neuropsychological outcomes in the pilot trial. The primary analysis was conducted on the five-year cohort (n = 28), and a secondary analysis was conducted on the 11-year cohort (n = 12). Linear mixed effects models for each analysis compared overall trend in outcomes for randomization groups. All subjects who completed the 11-year assessment were also pooled to evaluate long-term change from baseline. ResultsThere were no significant differences between groups in either the five- or 11-year analyses. Across all PD patients who completed the 11-year visit, there was significant decline in Stroop Color and Color-Word and Purdue Pegboard from baseline to 11 years. ConclusionsPrevious significant differences between the groups in phonemic verbal fluency and cognitive processing speed showing more decline for early DBS + ODT subjects one year after baseline diminished as PD progressed. No cognitive domains were worse for early DBS + ODT subjects compared to standard of care subjects. There were shared declines across all subjects on cognitive processing speed and motor control, likely reflecting disease progression. More study is needed to understand the long-term neuropsychological outcomes associated with early DBS in PD.

Participant perceptions of changes in psychosocial domains following participation in an adaptive deep brain stimulation trial

BackgroundThere has been substantial controversy in the neuroethics literature regarding the extent to which deep brain stimulation (DBS) impacts dimensions of personality, mood, and behavior.Objective/Hypothesis: Despite extensive debate in the theoretical literature, there remains a paucity of empirical data available to support or refute claims related to the psychosocial changes following DBS. MethodsA mixed-methods approach was used to examine the perspectives of patients who underwent DBS regarding changes to their personality, authenticity, autonomy, risk-taking, and overall quality of life. ResultsPatients (n = 21) who were enrolled in adaptive DBS trials for Parkinson's disease, essential tremor, obsessive-compulsive disorder, Tourette's syndrome, or dystonia participated. Qualitative data revealed that participants, in general, reported positive experiences with alterations in what was described as ‘personality, mood, and behavior changes.’ The majority of participants reported increases in quality of life. No participants reported ‘regretting the decision to undergo DBS.’ Conclusion(s)The findings from this patient sample do not support the narrative that DBS results in substantial adverse changes to dimensions of personality, mood, and behavior. Changes reported as “negative” or “undesired” were few in number, and transient in nature.

ID: 221289 Early Experience From the Remote Optimization Adjustment and Measurement for Deep Brain Stimulation Trial

There is a critical need for Deep Brain Stimulation (DBS) telemedicine systems that allow for remote adjustment of stimulation parameters. This would reduce the need for patients to travel to clinic which is a barrier to care. A third of DBS patients with Parkinson’s Disease (PD) cannot easily travel to a clinic, and a quarter report difficulty contacting their provider or staff for clinical questions [1]. While newly introduced DBS remote programming platforms [2] allow for DBS device interrogation and programming remotely, evidence directly comparing real world outcomes of remote and traditional in-clinic programming is lacking. The ROAM-DBS trial compares remote and in-clinic programming in the immediate post-operative period.

The Role of Family Members in Psychiatric Deep Brain Stimulation Trials: More Than Psychosocial Support

Family members can provide crucial support to individuals participating in clinical trials. In research on the “newest frontier” of Deep Brain Stimulation (DBS)—the use of DBS for psychiatric conditions—family member support is frequently listed as a criterion for trial enrollment. Despite the significance of family members, qualitative ethics research on DBS for psychiatric conditions has focused almost exclusively on the perspectives and experiences of DBS recipients. This qualitative study is one of the first to include both DBS recipients and their family members as interview participants. Using dyadic thematic analysis—an approach that takes both the individuals and the relationship as units of analyses—this study analyzes the complex ways in which family relationships can affect DBS trial participation, and how DBS trial participation in turn influences family relationships. Based on these findings, we propose ways to improve study designs to better take family relationships into account, and better support family members in taking on the complex, essential roles that they play in DBS trials for psychiatric conditions.

Treating Obsessive-Compulsive Disorder by Invasively Modulating Thoughts, Feelings, or Both

The defining characteristic of pathological compulsions is that they are carried out to reduce momentary distress, even though performing the compulsive act or thought is rationally not in the individual’s true best interest. This inability to flexibly adapt is a prominent component of obsessive-compulsive disorder (OCD) and closely related illnesses such as Tourette syndrome and is also observed in substance use disorders ( 1 Figee M. Pattij T. Willuhn I. Luigjes J. van den Brink W. Goudriaan A. et al. Compulsivity in obsessive-compulsive disorder and addictions. Eur Neuropsychopharmacol. 2016; 26: 856-868 Crossref PubMed Scopus (111) Google Scholar ). Following the 20th century experience with ablative procedures such as capsulotomy, deep brain stimulation (DBS) was applied to the treatment of OCD. Electrodes are most commonly placed within the anterior limb of the internal capsule (ALIC), modulating cortico-basal ganglia-thalamo-cortical parallel white matter loops relevant to limbic, associative, and motor functions, respectively. ALIC stimulation has proven to be a highly effective treatment for severe OCD ( 2 Smith AH, Mayberg HS, Figee M (in press): Neuromodulation and psychiatric disorders. In: Nestler EJ, Charney DS, editors. Neurobiology of Mental Illness, 6th ed. New York: Oxford University Press. Google Scholar ). DBS to a different anatomical location, the subthalamic nucleus (STN), was initially developed for Parkinson’s disease, but positive early experience in patients with comorbid Parkinson’s disease and OCD led to research establishing high-frequency stimulation straight to the STN as clinically efficacious for OCD ( 3 Mallet L. Polosan M. Jaafari N. Baup N. Welter M.L. Fontaine D. et al. Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. N Engl J Med. 2008; 359: 2121-2134 Crossref PubMed Scopus (687) Google Scholar ). In a similar manner, promising early pilot studies led to further exploration of other targets. These include the bed nucleus of the stria terminalis, the “extended amygdala” located between the ALIC and STN targets ( 4 Mosley P.E. Windels F. Morris J. Coyne T. Marsh R. Giorni A. et al. A randomised, double-blind, sham-controlled trial of deep brain stimulation of the bed nucleus of the stria terminalis for treatment-resistant obsessive-compulsive disorder. Transl Psychiatry. 2021; 11: 190 Crossref PubMed Scopus (38) Google Scholar ). More recently, evidence has emerged for the effectiveness of stimulation delivered deeper in the midbrain than the STN, adjacent to the ventral tegmental area (VTA)—a source of dopaminergic projections to the cortex (via the medial forebrain bundle [MFB]) and a recipient of proposed regulatory projections back from the cortex (via the “supralateral MFB”) ( 5 Meyer D.M. Spanier S. Kilian H.M. Reisert M. Urbach H. Sajonz B.E. et al. Efficacy of superolateral medial forebrain bundle deep brain stimulation in obsessive-compulsive disorder. Brain Stimul. 2022; 15: 582-585 Abstract Full Text Full Text PDF Scopus (3) Google Scholar ). SEE CORRESPONDING ARTICLE ON PAGE 1010 SEE CORRESPONDING ARTICLE ON PAGE 1010 The Rostral Zona Incerta: A Subcortical Integrative Hub and Potential Deep Brain Stimulation Target for Obsessive-Compulsive DisorderBiological PsychiatryVol. 93Issue 11PreviewThe zona incerta (ZI) is involved in mediating survival behaviors and is connected to a wide range of cortical and subcortical structures, including key basal ganglia nuclei. Based on these connections and their links to behavioral modulation, we propose that the ZI is a connectional hub for mediating between top-down and bottom-up control and a possible target for deep brain stimulation for obsessive-compulsive disorder. Full-Text PDF

Personal recovery associated with deep brain stimulation for treatment-resistant depression: A constructivist grounded theory study.

WHAT IS KNOWN ON THE SUBJECT?: Major depressive disorder is the most prevalent of all mental illnesses. 10%-20% of patients with depression and 1% of the population overall have treatment-resistant depression (TRD). DBS is an emerging investigational treatment for TRD with documented clinical efficacy and safety. The framework of the recovery model includes both clinical and personal recovery. Personal recovery is a self-process in which hope, empowerment and optimism are embraced to overcome the impact of mental illness on one's sense of self. Although clinical and functional outcomes of DBS for TRD have been well documented in the previous studies, personal recovery as an outcome has been explored only in a handful of studies. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This is the first qualitative study exploring personal recovery from DBS treatment specific to the target of subcallosal cingulate cortex in patients with TRD. Since the existing literature on personal recovery in DBS studies is limited, the contribution of this paper is crucial to this field. For individuals who responded to deep brain stimulation clinically, neither participants nor family believed it cured their depression, but rather there was a significant decrease in the severity of symptoms of depression. A holistic-oriented framework (that includes personal recovery) is significant for those individuals with TRD undergoing DBS. Personal and clinical recovery are two different constructs, and individuals may experience one or the other or both. The experience of participants who responded to deep brain stimulation recognized that the recovery from depression is a process of reconstructing self. This process involved a period of adjustment that evoked a deeper self-awareness, re-engagement with daily living and newfound gratitude in living. Individuals transitioned from an emotionally driven life to one where future goals were considered. Supportive relationships were instrumental in this process. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: A deep brain stimulation intervention for treatment-resistant depression offered individuals an opportunity for personal recovery where a reconstruction of self occurred. Personal recovery can be considered as an outcome in conjunction with clinical and functional outcomes in future DBS trials for TRD. The relevance of personal recovery in the prevention of relapses needs further investigation. To advocate for care and services that facilitate the process of recovery from depression, it is important to understand the personal dimensions and experience of recovery that may influence the process. To develop recovery-oriented interventions to help patients and families in recovery post-deep brain stimulation, further understanding of support and negotiating relationships during this life-altering experience is needed. ABSTRACT: Introduction Multiple trials of antidepressant treatments in patients with depression pose a major challenge to the mental health system. Deep brain stimulation (DBS) is an emerging and promising investigational treatment to reduce depressive symptoms in individuals with treatment-resistant depression (TRD). The clinical and functional outcomes of DBS for TRD have been well documented in previous studies; however, studies of personal recovery as an outcome of DBS specific to the target of subcallosal cingulate cortex in patients with TRD are limited. Aim To explore the processes of personal recovery in patients with treatment-resistant depression following subcallosal cingulate-deep brain stimulation. Method Participants were 18 patients with TRD who participated in the subcallosal cingulate (SCC)-DBS trial and 11 family members. They also participated in add-on individual cognitive behavioural therapy during the trial. A qualitative constructivist grounded theory approach was used to conceptualize the personal recovery process of patients and families. Results While every participant and their families' journey were unique following the deep brain stimulation intervention, a theoretical model of Balancing to Establish a Reconstructed Self emerged from the data. The themes underlying the model were (1) Balancing to Establish a Reconstructed Self: A Whole-Body Experience, (2) The Liminal Space in-between: Balancing with Cautious Optimism, (3) Hope: Transitioning from Emotion-Focussed Living to Goal-Oriented Planning and (4) Support: Negotiating Relationships. Discussion This is the first study examining recovery from patients' perspectives as an outcome of SCC-DBS intervention for TRD. The study shows that personal recovery is a gradual and continual process of reconstruction of the self, developing through supportive relationships. Clinical and personal recovery are two distinct constructs, and individuals may experience one or the other or both. Most patients who do respond clinically experience improvement in terms of having optimism and hope. Some patients, however, respond with significant symptom reduction but are not able to achieve personal recovery to experience joy or hope for improved quality of living. Implications for Practice Strategies for personal recovery for both patients and family need to be considered during and post deep brain stimulation intervention. Nurses working with these patients and families may benefit from education, training and support to assess and engage in conversations about their recovery process.

208 DBS-Induced Improvement in Cognitive Control is Mediated by Theta Oscillations in Human Intracranial Recordings

INTRODUCTION: Deficits in cognitive control, defined as the ability to adjust response or attention in the face of competing or changing demands, are thought to be responsible for inflexible behaviors in neuropsychiatric diseases. Here, we seek to understand frontotemporal networks underlying dysfunctional cognitive function using sEEG recordings and deep brain stimulation (DBS) in human subjects with treatment-resistant depression (TRD). METHODS: We employed a forced two-choice cognitive control task where the strength in the target and the distractor interference of a visual stimulus was parametrically and independently varied, resulting in granular variation in response congruence. This task was performed in 13 total subjects, 10 of whom underwent sEEG implants for epilepsy monitoring, whereas 3 subjects were participating in a clinical trial of DBS for TRD and were additionally implanted with DBS leads in the ventral capsule/ventral striatum and subcallosal cingulate. RESULTS: Reaction time (RT) and accuracy worsened with increasing levels of conflict across all subjects (Cohen’s d-accuracy = 0.7, Cohen’s d-RT = 0.2) prior to stimulation. Single-trial regression analyses revealed a parametric effect of task conflict with theta-band (4-7 Hz) power across the dorsolateral PFC (dlPFC), dorsal anterior cingulate cortex, orbitofrontal cortex (OFC) as well as the insula. DBS significantly improved behavioral performance, demonstrated by reduced RT (1080 土 10 ms to 840 土 50 ms), and improved accuracy(70 土 9.8% to 90 土 5%). While we observed an overall increase in theta power across the PFC and ACC in TRD participants following DBS, the effect of conflict in theta power was reversed (theta power decreased with increasing conflict in dlPFC and OFC). CONCLUSIONS: Leveraging this unique behavioral paradigm with concurrent distributed intracranial recordings and causal manipulation broadens our understanding of neural substrates of decision-making as well as the mechanisms of therapeutic action of DBS for TRD and other psychiatric disorders.

Artifact characterization and mitigation techniques during concurrent sensing and stimulation using bidirectional deep brain stimulation platforms.

Bidirectional deep brain stimulation (DBS) platforms have enabled a surge in hours of recordings in naturalistic environments, allowing further insight into neurological and psychiatric disease states. However, high amplitude, high frequency stimulation generates artifacts that contaminate neural signals and hinder our ability to interpret the data. This is especially true in psychiatric disorders, for which high amplitude stimulation is commonly applied to deep brain structures where the native neural activity is miniscule in comparison. Here, we characterized artifact sources in recordings from a bidirectional DBS platform, the Medtronic Summit RC + S, with the goal of optimizing recording configurations to improve signal to noise ratio (SNR). Data were collected from three subjects in a clinical trial of DBS for obsessive-compulsive disorder. Stimulation was provided bilaterally to the ventral capsule/ventral striatum (VC/VS) using two independent implantable neurostimulators. We first manipulated DBS amplitude within safe limits (2-5.3 mA) to characterize the impact of stimulation artifacts on neural recordings. We found that high amplitude stimulation produces slew overflow, defined as exceeding the rate of change that the analog to digital converter can accurately measure. Overflow led to expanded spectral distortion of the stimulation artifact, with a six fold increase in the bandwidth of the 150.6 Hz stimulation artifact from 147-153 to 140-180 Hz. By increasing sense blank values during high amplitude stimulation, we reduced overflow by as much as 30% and improved artifact distortion, reducing the bandwidth from 140-180 Hz artifact to 147-153 Hz. We also identified artifacts that shifted in frequency through modulation of telemetry parameters. We found that telemetry ratio changes led to predictable shifts in the center-frequencies of the associated artifacts, allowing us to proactively shift the artifacts outside of our frequency range of interest. Overall, the artifact characterization methods and results described here enable increased data interpretability and unconstrained biomarker exploration using data collected from bidirectional DBS devices.