Efficacy of deep brain stimulation for treatment-resistant obsessive-compulsive disorder: systematic review and meta-analysis.

Deep brain stimulation (DBS) is an established and growing intervention for treatment-resistant obsessive-compulsive disorder (TROCD). We assessed current evidence on the efficacy of DBS in alleviating OCD and comorbid depressive symptoms including newly available evidence from recent trials and a deeper risk of bias analysis than previously available. PubMed and EMBASE databases were systematically queried using Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. We included studies reporting primary data on multiple patients who received DBS therapy with outcomes reported through the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Primary effect measures included Y-BOCS mean difference and per cent reduction as well as responder rate (≥35% Y-BOCS reduction) at last follow-up. Secondary effect measures included standardised depression scale reduction. Risk of bias assessments were performed on randomised controlled (RCTs) and non-randomised trials. Thirty-four studies from 2005 to 2021, 9 RCTs (n=97) and 25 non-RCTs (n=255), were included in systematic review and meta-analysis based on available outcome data. A random-effects model indicated a meta-analytical average 14.3 point or 47% reduction (p<0.01) in Y-BOCS scores without significant difference between RCTs and non-RCTs. At last follow-up, 66% of patients were full responders to DBS therapy. Sensitivity analyses indicated a low likelihood of small study effect bias in reported outcomes. Secondary analysis revealed a 1 standardised effect size (Hedges' g) reduction in depressive scale symptoms. Both RCTs and non-RCTs were determined to have a predominantly low risk of bias. A strong evidence base supports DBS for TROCD in relieving both OCD and comorbid depression symptoms in appropriately selected patients.

Defining functional brain networks underlying obsessive-compulsive disorder (OCD) using treatment-induced neuroimaging changes: a systematic review of the literature.

Approximately 2%-3% of the population suffers from obsessive-compulsive disorder (OCD). Several brain regions have been implicated in the pathophysiology of OCD, but their various contributions remain unclear. We examined changes in structural and functional neuroimaging before and after a variety of therapeutic interventions as an index into identifying the underlying networks involved. We identified 64 studies from 1990 to 2020 comparing pretreatment and post-treatment imaging of patients with OCD, including metabolic and perfusion, neurochemical, structural, functional and connectivity-based modalities. Treatment class included pharmacotherapy, cognitive-behavioural therapy/exposure and response prevention, stereotactic lesions, deep brain stimulation and transcranial magnetic stimulation. Changes in several brain regions are consistent and correspond with treatment response despite the heterogeneity in treatments and neuroimaging modalities. Most notable are decreases in metabolism and perfusion of the caudate, anterior cingulate cortex, thalamus and regions of prefrontal cortex (PFC) including the orbitofrontal cortex (OFC), dorsolateral PFC (DLPFC), ventromedial PFC (VMPFC) and ventrolateral PFC (VLPFC). Modulating activity within regions of the cortico-striato-thalamo-cortical system may be a common therapeutic mechanism across treatments. We identify future needs and current knowledge gaps that can be mitigated by implementing integrative methods. Future studies should incorporate a systematic, analytical approach to testing objective correlates of treatment response to better understand neurophysiological mechanisms of dysfunction.

Cost-effectiveness and threshold analysis of deep brain stimulation vs. treatment-as-usual for treatment-resistant depression.

Treatment-resistant depression (TRD) affects approximately 2.8 million people in the U.S. with estimated annual healthcare costs of $43.8 billion. Deep brain stimulation (DBS) is currently an investigational intervention for TRD. We used a decision-analytic model to compare cost-effectiveness of DBS to treatment-as-usual (TAU) for TRD. Because this therapy is not FDA approved or in common use, our goal was to establish an effectiveness threshold that trials would need to demonstrate for this therapy to be cost-effective. Remission and complication rates were determined from review of relevant studies. We used published utility scores to reflect quality of life after treatment. Medicare reimbursement rates and health economics data were used to approximate costs. We performed Monte Carlo (MC) simulations and probabilistic sensitivity analyses to estimate incremental cost-effectiveness ratios (ICER; USD/quality-adjusted life year [QALY]) at a 5-year time horizon. Cost-effectiveness was defined using willingness-to-pay (WTP) thresholds of $100,000/QALY and $50,000/QALY for moderate and definitive cost-effectiveness, respectively. We included 274 patients across 16 studies from 2009-2021 who underwent DBS for TRD and had ≥12 months follow-up in our model inputs. From a healthcare sector perspective, DBS using non-rechargeable devices (DBS-pc) would require 55% and 85% remission, while DBS using rechargeable devices (DBS-rc) would require 11% and 19% remission for moderate and definitive cost-effectiveness, respectively. From a societal perspective, DBS-pc would require 35% and 46% remission, while DBS-rc would require 8% and 10% remission for moderate and definitive cost-effectiveness, respectively. DBS-pc will unlikely be cost-effective at any time horizon without transformative improvements in battery longevity. If remission rates ≥8-19% are achieved, DBS-rc will likely be more cost-effective than TAU for TRD, with further increasing cost-effectiveness beyond 5 years.

Intracranial Directed Connectivity Links Subregions of the Prefrontal Cortex to Major Depression.

Understanding the neural basis of major depressive disorder (MDD) is vital to guiding neuromodulatory treatments. The available evidence supports the hypothesis that MDD is fundamentally a disease of cortical disinhibition, where breakdowns of inhibitory neural systems lead to diminished emotion regulation and intrusive ruminations. Recent research also points towards network changes in the brain, especially within the prefrontal cortex (PFC), as primary sources of MDD etiology. However, due to limitations in spatiotemporal resolution and clinical opportunities for intracranial recordings, this hypothesis has not been directly tested. We recorded intracranial EEG from the dorsolateral (dlPFC), orbitofrontal (OFC), and anterior cingulate cortices (ACC) in neurosurgical patients with MDD. We measured daily fluctuations in self-reported depression severity alongside directed connectivity between these PFC subregions. We focused primarily on delta oscillations (1-3 Hz), which have been linked to GABAergic inhibitory control and intracortical communication. Depression symptoms worsened when connectivity within the left vs. right PFC became imbalanced. In the left hemisphere, all directed connectivity towards the ACC, from the dlPFC and OFC, was positively correlated with depression severity. In the right hemisphere, directed connectivity between the OFC and dlPFC increased with depression severity as well. This is the first evidence that delta oscillations flowing between prefrontal subregions transiently increase intensity when people are experiencing more negative mood. These findings support the overarching hypothesis that MDD worsens with prefrontal disinhibition.

Beta activity in human anterior cingulate cortex mediates reward biases.

The rewards that we get from our choices and actions can have a major influence on our future behavior. Understanding how reward biasing of behavior is implemented in the brain is important for many reasons, including the fact that diminution in reward biasing is a hallmark of clinical depression. We hypothesized that reward biasing is mediated by the anterior cingulate cortex (ACC), a cortical hub region associated with the integration of reward and executive control and with the etiology of depression. To test this hypothesis, we recorded neural activity during a biased judgment task in patients undergoing intracranial monitoring for either epilepsy or major depressive disorder. We found that beta (12-30 Hz) oscillations in the ACC predicted both associated reward and the size of the choice bias, and also tracked reward receipt, thereby predicting bias on future trials. We found reduced magnitude of bias in depressed patients, in whom the beta-specific effects were correspondingly reduced. Our findings suggest that ACC beta oscillations may orchestrate the learning of reward information to guide adaptive choice, and, more broadly, suggest a potential biomarker for anhedonia and point to future development of interventions to enhance reward impact for therapeutic benefit.

Disruption of neural periodicity predicts clinical response after deep brain stimulation for obsessive-compulsive disorder.

Recent advances in surgical neuromodulation have enabled chronic and continuous intracranial monitoring during everyday life. We used this opportunity to identify neural predictors of clinical state in 12 individuals with treatment-resistant obsessive-compulsive disorder (OCD) receiving deep brain stimulation (DBS) therapy ( NCT05915741 ). We developed our neurobehavioral models based on continuous neural recordings in the region of the ventral striatum in an initial cohort of five patients and tested and validated them in a held-out cohort of seven additional patients. Before DBS activation, in the most symptomatic state, theta/alpha (9 Hz) power evidenced a prominent circadian pattern and a high degree of predictability. In patients with persistent symptoms (non-responders), predictability of the neural data remained consistently high. On the other hand, in patients who improved symptomatically (responders), predictability of the neural data was significantly diminished. This neural feature accurately classified clinical status even in patients with limited duration recordings, indicating generalizability that could facilitate therapeutic decision-making.

Alternative patterns of deep brain stimulation in neurologic and neuropsychiatric disorders.

Deep brain stimulation (DBS) is a widely used clinical therapy that modulates neuronal firing in subcortical structures, eliciting downstream network effects. Its effectiveness is determined by electrode geometry and location as well as adjustable stimulation parameters including pulse width, interstimulus interval, frequency, and amplitude. These parameters are often determined empirically during clinical or intraoperative programming and can be altered to an almost unlimited number of combinations. Conventional high-frequency stimulation uses a continuous high-frequency square-wave pulse (typically 130-160 Hz), but other stimulation patterns may prove efficacious, such as continuous or bursting theta-frequencies, variable frequencies, and coordinated reset stimulation. Here we summarize the current landscape and potential clinical applications for novel stimulation patterns.

Cost-effectiveness analysis of radiosurgical capsulotomy versus treatment as usual for treatment-resistant obsessive-compulsive disorder.

OBJECTIVE: Stereotactic radiosurgical capsulotomy (SRS-C) is an effective neurosurgical option for patients with treatment-resistant obsessive-compulsive disorder (TROCD). Unlike other procedures such as deep brain stimulation and radiofrequency ablation, the cost-effectiveness of SRS-C for TROCD has not been investigated. The authors herein report the first cost-effectiveness analysis of SRS-C for TROCD. METHODS: Using a decision analytic model, the authors compared the cost-effectiveness of SRS-C to treatment as usual (TAU) for TROCD. Treatment response and complication rates were derived from a review of relevant clinical trials. Published algorithms were used to convert Yale-Brown Obsessive Compulsive Scale scores into utility scores reflecting improvements in quality of life. Costs were approached from the healthcare sector perspective and were drawn from Medicare reimbursement rates and available healthcare economics data. A Monte Carlo simulation and probabilistic sensitivity analysis were performed to estimate the incremental cost-effectiveness ratio. RESULTS: One hundred fifty-eight TROCD patients across 9 studies who had undergone SRS-C and had at least 36 months of follow-up were included in the model. Compared to TAU, SRS-C was more cost-effective, with an estimated incremental cost-effectiveness ratio of $28,960 per quality-adjusted life year (QALY) gained. Within the 3-year time horizon, net QALYs gained were greater in the SRS-C group than the TAU group by 0.27 (95% CI 0.2698-0.2702, p < 0.0001). At willingness-to-pay thresholds of $50,000 and $100,000 per QALY, the Monte Carlo simulation revealed that SRS-C was more cost-effective than TAU in 83% and 100% of iterations, respectively. CONCLUSIONS: Compared to TAU, SRS-C for TROCD is more cost-effective under a range of possible cost and effectiveness values.

Association of clinical outcomes and connectivity in awake versus asleep deep brain stimulation for Parkinson disease.

OBJECTIVE: Deep brain stimulation (DBS) for Parkinson disease (PD) is traditionally performed with awake intraoperative testing and/or microelectrode recording. Recently, however, the procedure has been increasingly performed under general anesthesia with image-based verification. The authors sought to compare structural and functional networks engaged by awake and asleep PD-DBS of the subthalamic nucleus (STN) and correlate them with clinical outcomes. METHODS: Levodopa equivalent daily dose (LEDD), pre- and postoperative motor scores on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III), and total electrical energy delivered (TEED) at 6 months were retroactively assessed in patients with PD who received implants of bilateral DBS leads. In subset analysis, implanted electrodes were reconstructed using the Lead-DBS toolbox. Volumes of tissue activated (VTAs) were used as seed points in group volumetric and connectivity analysis. RESULTS: The clinical courses of 122 patients (52 asleep, 70 awake) were reviewed. Operating room and procedure times were significantly shorter in asleep cases. LEDD reduction, MDS-UPDRS III score improvement, and TEED at the 6-month follow-up did not differ between groups. In subset analysis (n = 40), proximity of active contact, VTA overlap, and desired network fiber counts with motor STN correlated with lower DBS energy requirement and improved motor scores. Discriminative structural fiber tracts involving supplementary motor area, thalamus, and brainstem were associated with optimal clinical improvement. Areas of highest structural and functional connectivity with VTAs did not significantly differ between the two groups. CONCLUSIONS: Compared to awake STN DBS, asleep procedures can achieve similarly optimal targeting-based on clinical outcomes, electrode placement, and connectivity estimates-in more efficient procedures and shorter operating room times.

Stereo-EEG-guided network modulation for psychiatric disorders: Surgical considerations.

BACKGROUND: Deep brain stimulation (DBS) and other neuromodulatory techniques are being increasingly utilized to treat refractory neurologic and psychiatric disorders. OBJECTIVE: /Hypothesis: To better understand the circuit-level pathophysiology of treatment-resistant depression (TRD) and treat the network-level dysfunction inherent to this challenging disorder, we adopted an approach of inpatient intracranial monitoring borrowed from the epilepsy surgery field. METHODS: We implanted 3 patients with 4 DBS leads (bilateral pair in both the ventral capsule/ventral striatum and subcallosal cingulate) and 10 stereo-electroencephalography (sEEG) electrodes targeting depression-relevant network regions. For surgical planning, we used an interactive, holographic visualization platform to appreciate the 3D anatomy and connectivity. In the initial surgery, we placed the DBS leads and sEEG electrodes using robotic stereotaxy. Subjects were then admitted to an inpatient monitoring unit for depression-specific neurophysiological assessments. Following these investigations, subjects returned to the OR to remove the sEEG electrodes and internalize the DBS leads to implanted pulse generators. RESULTS: Intraoperative testing revealed positive valence responses in all 3 subjects that helped verify targeting. Given the importance of the network-based hypotheses we were testing, we required accurate adherence to the surgical plan (to engage DBS and sEEG targets) and stability of DBS lead rotational position (to ensure that stimulation field estimates of the directional leads used during inpatient monitoring were relevant chronically), both of which we confirmed (mean radial error 1.2±0.9 mm; mean rotation 3.6±2.6°). CONCLUSION: This novel hybrid sEEG-DBS approach allows detailed study of the neurophysiological substrates of complex neuropsychiatric disorders.

Elimination of anxiety after laser interstitial thermal ablation of the dominant cingulate gyrus for epilepsy.

Background: Anxiety is a common symptom of mental health disorders. Surgical treatment of anxiety-related disorders is limited by our understanding of the neural circuitry responsible for emotional regulation. Limbic regions communicate with other cortical and subcortical regions to generate emotional responses and behaviors toward anxiogenic stimuli. Epilepsy involving corticolimbic regions may disrupt normal neural circuitry and present with mood disorders. Anxiety presenting in patients with mesial temporal lobe epilepsy is common; however, anxiety in patients with cingulate epilepsy is not well described. Neurosurgical cases with rare clinical presentations may provide insight into the basic functionality of the human mind and ultimately lead to improvements in surgical treatments. Case Description: We present the case of a 24-year-old male with a 20-year history of nonlesional and cingulate epilepsy with an aura of anxiety and baseline anxiety. Noninvasive work-up was discordant. Intracranial evaluation using stereoelectroencephalography established the epileptogenic zone in the left anterior and mid-cingulate gyrus. Stimulation of the cingulate reproduced a sense of anxiety typical of the habitual auras. We performed laser interstitial thermal therapy of the left anterior and mid-cingulate gyrus. At 8 months following ablation, the patient reported a substantial reduction in seizure frequency and complete elimination of his baseline anxiety and anxious auras. Conclusion: This case highlights the role of the cingulate cortex (CC) in regulating anxiety. Ablation of the epileptic focus resolved both epilepsy-related anxiety and baseline features.a Future studies assessing the role of the CC in anxiety disorders may enable improvements in surgical treatments for anxiety disorders.

Predictive value of magnetoencephalography in guiding the intracranial implant strategy for intractable epilepsy.

OBJECTIVE: Magnetoencephalography (MEG) is a useful component of the presurgical evaluation of patients with epilepsy. Due to its high spatiotemporal resolution, MEG often provides additional information to the clinician when forming hypotheses about the epileptogenic zone (EZ). Because of the increasing utilization of stereo-electroencephalography (sEEG), MEG clusters are used to guide sEEG electrode targeting with increasing frequency. However, there are no predefined features of an MEG cluster that predict ictal activity. This study aims to determine which MEG cluster characteristics are predictive of the EZ. METHODS: The authors retrospectively analyzed all patients who had an MEG study (2017-2021) and underwent subsequent sEEG evaluation. MEG dipoles and sEEG electrodes were reconstructed in the same coordinate space to calculate overlap among individual contacts on electrodes and MEG clusters. MEG cluster features-including number of dipoles, proximity, angle, density, magnitude, confidence parameters, and brain region-were used to predict ictal activity in sEEG. Logistic regression was used to identify important cluster features and to train a binary classifier to predict ictal activity. RESULTS: Across 40 included patients, 196 electrodes (42.2%) sampled MEG clusters. Electrodes that sampled MEG clusters had higher rates of ictal and interictal activity than those that did not sample MEG clusters (ictal 68.4% vs 39.8%, p < 0.001; interictal 71.9% vs 44.6%, p < 0.001). Logistic regression revealed that the number of dipoles (odds ratio [OR] 1.09, 95% confidence interval [CI] 1.04-1.14, t = 3.43) and confidence volume (OR 0.02, 95% CI 0.00-0.86, t = -2.032) were predictive of ictal activity. This model was predictive of ictal activity with 77.3% accuracy (sensitivity = 80%, specificity = 74%, C-statistic = 0.81). Using only the number of dipoles had a predictive accuracy of 75%, whereas a threshold between 14 and 17 dipoles in a cluster detected ictal activity with 75.9%-85.2% sensitivity. CONCLUSIONS: MEG clusters with approximately 14 or more dipoles are strong predictors of ictal activity and may be useful in the preoperative planning of sEEG implantation.

Robot-Assisted Deep Brain Stimulation: High Accuracy and Streamlined Workflow.

BACKGROUND: A number of stereotactic platforms are available for performing deep brain stimulation (DBS) lead implantation. Robot-assisted stereotaxy has emerged more recently demonstrating comparable accuracy and shorter operating room times compared with conventional frame-based systems. OBJECTIVE: To compare the accuracy of our streamlined robotic DBS workflow with data in the literature from frame-based and frameless systems. METHODS: We retrospectively reviewed 126 consecutive DBS lead placement procedures using a robotic stereotactic platform. Indications included Parkinson disease (n = 94), essential tremor (n = 21), obsessive compulsive disorder (n = 7), and dystonia (n = 4). Procedures were performed using a stereotactic frame for fixation and the frame pins as skull fiducials for robot registration. We used intraoperative fluoroscopic computed tomography for registration and postplacement verification. RESULTS: The mean radial error for the target point was 1.06 mm (SD: 0.55 mm, range 0.04-2.80 mm) on intraoperative fluoroscopic computed tomography. The mean operative time for an asleep, bilateral implant without implantable pulse generator placement was 238 minutes (SD: 52 minutes), and skin-to-skin procedure time was 116 minutes (SD: 42 minutes). CONCLUSION: We describe a streamlined workflow for DBS lead placement using robot-assisted stereotaxy with a comparable accuracy profile. Obviating the need for checking and switching coordinates, as is standard for frame-based DBS, also reduces the chance for human error and facilitates training.

Case Report: Dual Target Deep Brain Stimulation With Externalized Programming for Post-traumatic Complex Movement Disorder.

Introduction: Movement disorders can be common, persistent, and debilitating sequelae of severe traumatic brain injury. Post-traumatic movement disorders are usually complex in nature, involving multiple phenomenological manifestations, and can be difficult to control with medical management alone. Deep brain stimulation (DBS) has been used to treat these challenging cases, but distorted brain anatomy secondary to trauma can complicate effective targeting. In such cases, use of diffusion tractography imaging and inpatient testing with externalized DBS leads can be beneficial in optimizing outcomes. Case Description: We present the case of a 42-year-old man with severe, disabling post-traumatic tremor who underwent bilateral, dual target DBS to the globus pallidus internus (GPi) and a combined ventral intermediate nucleus of the thalamus (Vim)/dentato-rubro-thalamic tracts (DRTT) target. DRTT fiber tracts were reconstructed preoperatively to assist in surgical targeting given the patient's distorted anatomy. Externalization and survey of the four leads extra-operatively with inpatient testing allowed for internalization of the leads that demonstrated benefit. Six months after surgery, the patient's tremor and dystonic burden had decreased by 67% in the performance sub-score of The Essential Tremor Rating Scale (TETRAS). Conclusion: A patient-tailored approach including target selection guided by individualized anatomy and tractography as well as extra-operative externalized lead interrogation was shown to be effective in optimizing clinical outcome in a patient with refractory post-traumatic tremor.