Deep Brain Stimulation for Post-Traumatic Stress Disorder: A Review of the Experimental and Clinical Literature

<b><i>Introduction:</i></b> Up to 30% of patients with post-traumatic stress disorder (PTSD), especially combat veterans, remain refractory to conventional treatment. For them, deep brain stimulation (DBS) has been suggested. Here, we review the literature on animal models of PTSD in which DBS has been used to treat PTSD-type behavior, and we review and discuss patient reports of DBS for PTSD. <b><i>Methods:</i></b> A broad search was performed to find experimental animal articles and clinical reports on PubMed, Ovid MEDLINE, Cochrane Library, and PsycINFO, using combinations and variations of search words pertinent to DBS and PTSD. <b><i>Results:</i></b> The search yielded 30 articles, 24 on DBS in rat models of PTSD, and 6 publications between 2016 and 2020 reporting on a total of 3 patients. DBS in rat models targeted 4 brain areas: medial prefrontal cortex (mPFC), ventral striatum, amygdala, and hippocampus. Clinical publications reported on 2 male combat veterans who received DBS in basolateral amygdala, and 1 female with PTSD due to domestic abuse, who received DBS of mPFC. All 3 patients benefitted to various extents from DBS, at follow-ups of 4 years, 6 months, and 7 months, respectively. <b><i>Conclusions:</i></b> PTSD is the only potential clinical indication for DBS that shows extensive animal research <i>prior</i> to human applications. Nevertheless, DBS for PTSD remains highly investigational. Despite several years of government funding of DBS research in view of treating severe PTSD in combat veterans, ethical dilemmas, recruitment difficulties, and issues related to use of DBS in such a complex and heterogenous disorder remain prevalent.

ZAP-X Gyroscopic Radiosurgery System: A Preliminary Analysis of Clinical Applications within a Retrospective Case Series

<b><i>Introduction:</i></b> The ZAP-X Gyroscopic Radiosurgery system (ZAP Surgical Systems, Inc., San Carlos, CA, USA) is a novel high-dose targeted stereotactic radiosurgery platform for outpatient use that includes self-shielding, X-ray image guidance, and the capacity to aim the radiation beam gyroscopically at an intracranial lesion using 5 independent degrees of freedom. The ZAP-X Gyroscopic Radiosurgery system accomplishes these actions while meeting widely accepted standards for dose gradient and accuracy. This retrospective study examined data of patients treated with gyroscopic radiosurgery (GRS) to document clinical outcomes. <b><i>Methods:</i></b> Medical records of all outpatients treated with GRS over a 20-month period from January 2019 to August 2020 were searched to extract relevant details, including follow-up data until August 2021 (32-month study interval). Patients with &#x3c;6 months of radiographical follow-up data were excluded unless death occurred. Data collection included pretreatment clinical history, pathological diagnosis, radiographical features, treatment parameters, and long-term clinical and radiographical follow-up. <b><i>Results:</i></b> Sixty-eight patients received outpatient treatment with GRS during the 20-month treatment interval, with 59 patients remaining after exclusion for the minimum follow-up threshold, with a mean (standard deviation [SD]) fractionation of 1.85 (1.63). Eighty-two lesions were treated across a very heterogeneous patient population, including meningiomas (42.4%), metastases (39.0%), gliomas (6.8%), schwannomas (1.7%), and pituitary tumor (1.7%). Mean (SD) radiographical follow-up data (14.7 [6.60] months) were available for 56 patients. During that interval, 13 treated lesions in 13 patients (15.9%) demonstrated progression, 9 of which were stable during the initial posttreatment imaging surveillance period. Mean lesion volume was stable from pretreatment (2.54 cm³ [4.37 cm³]) to most recent follow-up (2.80 cm³ [8.20 cm³]) (<i>t</i> [79] = −0.310; <i>p</i> = 0.76). Minor adverse clinical events were noted in 3 (5.1%) of the 59 patients during the posttreatment phase that may have been related to the treatment. Ten (16.9%) patients died within the 32-month study interval. <b><i>Discussion/Conclusion:</i></b> This preliminary assessment of the first series of patients treated with the Zap-X Gyroscopic Radiosurgery system documents its overall feasibility in clinical applications. Although the duration of follow-up was brief, GRS appeared to be both safe and effective. Additional analysis, with an ongoing prospective registry, is underway.

Mask-Based versus Frame-Based Gamma Knife ICON Radiosurgery in Brain Metastases: A Prospective Randomized Trial

<b><i>Background:</i></b> Radiosurgery is performed with a diversity of instruments relying usually either on a stereotactic frame or a mask for patient head fixation. Comfort and safety efficacy of the 2 systems have never been rigorously evaluated and compared. <b><i>Material and Method:</i></b> Between February 2016 and January 2017, 58 patients presenting with nonsmall cell lung cancer brain metastases have been treated by Gamma Knife radiosurgery (GKS) with random use of a frame or a mask for fixation were included patients older than 18, with &#x3c;5 brain metastases (at the exclusion of brainstem and optic pathway’s locations) and no earlier history of radiotherapy. The primary outcome measure was the pain scale assessment (PSA) at the beginning of the GKS procedure. <b><i>Results:</i></b> The PSA at the beginning of the GKS procedure was not different between the 2 groups. The PSA at the day before GKS, before magnetic resonance imaging, just after frame application, and the day after radiosurgery (departure) has shown no difference between the 2 groups. At the end of the radiosurgery itself (just after frame or mask removal) and 1 h after, the mean pain scale was higher in patients treated with the frame (<i>p</i> &#x3c; 0.05 and <i>p</i> &#x3c; 0.001, respectively) but 2 patients were not able to tolerate the mask discomfort and had to be treated with frame. Tumor control and morbidity probability were demonstrated to be no difference between the 2 groups in this population of patients with BM not in highly functional area. The median of the extra dose to the body due to the cone-beam computed tomography was 7.5 mGy with a maximum of 35 mGy in patients treated with a mask fixation (null in the others treated with frame). Mask fixation was associated to longer treatment time although the beam on time was not different between the 2 groups. <b><i>Conclusion:</i></b> In selected patients, with brain oligo-metastases out of critical location, single-dose mask-based GKS can be done with a comfort and a safety efficacy comparable to frame-based GKS. There seems to be no clear patient data that confirm the value of the mask system with regards to comfort.

Anterior Nucleus of Thalamus Deep Brain Stimulation: A Clinical-Based Analysis of the Ideal Target in Drug-Resistant Epilepsy

<b><i>Introduction:</i></b> Deep brain stimulation of the anterior nucleus of thalamus (ANT-DBS) is an approved procedure for drug-resistant epilepsy. However, the preferred location inside ANT is not well known. In this study, we investigated the relationship between stereotactical coordinates of stimulated contacts and clinical improvement, in order to define the ideal target for ANT-DBS. <b><i>Methods:</i></b> Individual contact’s coordinates were obtained in the Montreal Neurological Institute (MNI) 152 space, with the utilization of advanced normalization tools and co-registration of pre- and postoperative MRI and CT images in open-source toolbox lead-DBS with the “Atlas of the Human Thalamus.” Each contact’s pair was either classified as a responder (≥50% seizure reduction and absence of intolerable adverse effects) or nonresponder, with a minimum follow-up of 11 continuous months of stimulation. <b><i>Results:</i></b> A total of 19 contacts’ pairs were tested in 14 patients. The responder rate was 9 out of 14 patients (64.3%). In 4 patients, a change in contacts’ pairs was needed to achieve this result. A highly encouraging location inside ANT (HELIA) was delimited in MNI space, corresponding to an area in the anterior and inferior portion of the anteroventral (AV) nucleus, medially to the endpoint of the mammillothalamic tract (ANT-mtt junction) (<i>x</i> [3.8; 5.85], <i>y</i> [−2.1; −6.35] and <i>z</i> [6.2; 10.1] in MNI space). Statistically significant difference was observed between responders and nonresponders, in terms of the number of coordinates inside this volume. Seven responders and two nonresponders had at least 5 of 6 coordinates (2 electrodes) inside HELIA (77.8% sensitivity and 80% specificity). In 3 patients, changing to contacts that were better placed inside HELIA changed the status from nonresponder to responder. <b><i>Conclusions:</i></b> A relationship between stimulated contacts’ coordinates and responder status was observed in drug-resistant epilepsy. The possibility to target different locations inside HELIA may help surpass anatomical variations and eventually obtain increased clinical benefit.

Use of Topical Vancomycin Powder to Reduce Surgical Site Infections after Deep Brain Stimulation Surgery: UCSF Experience and Meta-Analysis

<b><i>Objective:</i></b> Surgical site infection (SSI) is the most common serious complication of deep brain stimulation (DBS) implantation surgery. Here, we report a single-surgeon experience on the efficacy of topical, intrawound vancomycin powder (VP) in reducing SSI for DBS surgery and present the first systematic review and meta-analysis examining the effect of topical vancomycin on SSI in patients after DBS surgery. <b><i>Methods:</i></b> For the retrospective review, all unique patients undergoing DBS surgery at UCSF for new hardware implantation or internal pulse generator (IPG) replacement by a single surgeon from September 2013 to March 2019, with at least 1 year of follow-up data, were included. For the meta-analysis, we included all primary studies that compared SSIs with and without application of topical vancomycin in DBS surgeries. <b><i>Results:</i></b> 368 unique patients met inclusion criteria; 195 patients received topical VP (VP group) and 173 did not (control). 99/195 patients in the VP group underwent new DBS implantation and 96/195 had IPG replacement. 71/173 patients in the control group had new DBS implantation and 102/173 had IPG replacement. There were 10 total cases of SSI: 4 patients from the VP group (3 new implants and 1 IPG replacement) and 6 patients from the control group (3 new implants and 3 IPG replacements), resulting in SSI rates of 2.1 and 3.5%, respectively (<i>p</i> value = 0.337). Including our retrospective analysis, 6 studies met inclusion criteria for the systematic review and meta-analysis. In the 4 studies that examined primary DBS implants, 479 total patients received topical VP and 436 did not; mean odds ratio for SSI with topical vancomycin was 0.802 (95% confidence interval [CI] 0.175–3.678). Across the 5 studies that examined IPG implantations or replacements, 606 total patients received topical VP while 1,173 patients did not; mean odds ratio for SSI with topical vancomycin was 0.492 (95% CI 0.164–1.475). In either case, topical VP application did not significantly decrease risk of SSI. <b><i>Conclusion:</i></b> Surgical infections after DBS surgery are uncommon events, with studies demonstrating mixed results on whether topical vancomycin reduces this risk. Our single-institution retrospective analysis and systematic review of prior studies both demonstrated no significant SSI rate reduction with topical VP. This is likely due to low baseline SSI rates, resulting in a small effect size for prevention. Given the cost-effectiveness, simplicity, and low risk, topical, intrawound VP remains a treatment option to further reduce risk of SSI, particularly in settings with higher baseline infection rates.

Multicenter Validation of Individual Preoperative Motor Outcome Prediction for Deep Brain Stimulation in Parkinson’s Disease

Background: Subthalamic nucleus deep brain stimulation (STN DBS) is an established therapy for Parkinson’s disease (PD) patients suffering from motor response fluctuations despite optimal medical treatment, or severe dopaminergic side effects. Despite careful clinical selection and surgical procedures, some patients do not benefit from STN DBS. Preoperative prediction models are suggested to better predict individual motor response after STN DBS. We validate a preregistered model, DBS-PREDICT, in an external multicenter validation cohort. Methods: DBS-PREDICT considered eleven, solely preoperative, clinical characteristics and applied a logistic regression to differentiate between weak and strong motor responders. Weak motor response was defined as no clinically relevant improvement on the Unified Parkinson’s Disease Rating Scale (UPDRS) II, III, or IV, 1 year after surgery, defined as, respectively, 3, 5, and 3 points or more. Lower UPDRS III and IV scores and higher age at disease onset contributed most to weak response predictions. Individual predictions were compared with actual clinical outcomes. Results: 322 PD patients treated with STN DBS from 6 different centers were included. DBS-PREDICT differentiated between weak and strong motor responders with an area under the receiver operator curve of 0.76 and an accuracy up to 77%. Conclusion: Proving generalizability and feasibility of preoperative STN DBS outcome prediction in an external multicenter cohort is an important step in creating clinical impact in DBS with data-driven tools. Future prospective studies are required to overcome several inherent practical and statistical limitations of including clinical decision support systems in DBS care.

Is Real-Time Inverse Planning Optimizing Dose to the Normal Brain? A Prospective Comparative Trial in a Series of Brain Metastases Treated by Stereotactic Radiosurgery

<b><i>Background:</i></b> Radiosurgery has demonstrated good safety and efficacy in the treatment of multiple brain metastases (BMs). However, multi-target dose planning can be challenging and time-consuming. A recently developed real-time inverse treatment planning (IP) by convex optimization has been demonstrated to produce high-quality treatment plans with good conformity and selectivity in single-target plans. We intended to test the capacity of this IP to rapidly generate efficient plans while optimizing the preservation of normal tissue in multiple BM. <b><i>Methods:</i></b> Seventy-nine patients (mean age 62.4, age range 22–85) with a total of 272 BMs were treated by Gamma Knife Radiosurgery. All subjects were treated using a forward planning (FP) technique by an expert neurosurgeon. The new Intuitive Plan was applied and able to automatically generate an alternative plan for each patient. All planning variables were collected from the IP to be compared with the corresponding measurements obtained from the FP. A paired sample <i>t</i> test was applied to compare the 2 plans for the following variables: brain volumes receiving 10 Gy (V10) (primary endpoint), and 12 Gy (V12), planning indices (selectivity, coverage, gradient, and Paddick Conformity Index [PCI]), beam-on time (BOT), and integral doses. Additionally, the noninferiority margin for each item was calculated, and the 2 plans were compared for noninferiority using a paired <i>t</i> test. <b><i>Results:</i></b> The mean age of patients was 62.4 years old (age range 22–85), with a sex ratio of 1.02. The average number of lesions per patient was 3.4 (range 1–12). The mean prescription dose was 21.46 Gy (range 14–24 Gy). Noninferiority of the IP was concluded for V10, V12, prescription isodose volume, BOT, PCI, and selectivity. The V10 (and V12) was significantly lower with the IP (<i>p</i> &#x3c; 0.001). These volumes were 8.69 cm³ ± 11.39 and 5.47 cm³ ± 7.03, respectively, for the FP and 7.57 cm³ ± 9.44 and 4.78 cm³ ± 5.86 for the IP. Only the coverage was significantly lower with the IP (−2.3%, <i>p</i> &#x3c; 0.001), but both selectivity (+17%) and PCI (+15%) were significantly higher with the IP than FP (<i>p</i> &#x3c; 0.001). <b><i>Conclusion:</i></b> This IP demonstrated its capacity to generate multi-target plans rapidly, with a dose to the brain (V10) and BOT noninferior to the one of a human expert planner. These results would benefit from confirmation in a larger prospective series.

Deep Brain Stimulation of the Pallidofugal Pathways to Rescue Severe Life-Threatening Dyskinesias after STN-DBS Lead Implantation

We present a patient with severe life-threatening dyskinesias due to a persistent microlesion effect after STN-DBS electrode implantation. The pallidofugal pathways were identified using patient-specific tractography, and steering the current toward this white matter structure resulted in complete resolution of the severe dyskinesias.

Effectiveness of Deep Brain Stimulation in Reducing Body Mass Index and Weight: A Systematic Review

<b><i>Background:</i></b> Obesity has become a major public health concern worldwide, with current behavioral, pharmacological, and surgical treatments offering varying rates of success and adverse effects. Neurosurgical approaches to treatment of refractory obesity include deep brain stimulation (DBS) on either specific hypothalamic or reward circuitry nuclei, which might contribute to weight reduction through different mechanisms. We aimed to determine the safety and clinical effect of DBS in medical refractory obesity. <b><i>Summary:</i></b> Adhering to PRISMA guidelines, we performed a systematic review to identify all original studies – observational and experimental – in which DBS was performed to treat refractory obesity. From database inception to April 2021, we conducted our search in PubMed, Scopus, and LILACS databases using the following MeSH terms: “Obesity” OR “Prader-Willi Syndrome” AND “Deep Brain Stimulation.” The main outcomes were safety and weight loss measured with the body mass index (BMI). The Grading of Recommendations Assessment, Development, and Evaluation methods were applied to evaluate the quality of evidence. This study protocol was registered with PROSPERO ID: CRD42019132929. Seven studies involving 12 patients met the inclusion criteria; the DBS target was the nucleus accumbens in four (57.1%), the lateral hypothalamic area in two (29.6%), and the ventral hypothalamus in one (14.3%). Further, 33% of participants had obesity secondary to Prader-Willi syndrome (PWS) and 66.6% had primary obesity. The global BMI average at baseline was 46.7 (SD: 9.6, range: 32.2–59.1), and after DBS, 42.8 (SD: 8.8, range: 25–53.9), with a mean difference of 3.9; however, the delta in PWS patients was −2.3 and 10 in those with primary obesity. The incidence of moderate side effects was 33% and included manic symptoms (<i>N</i> = 2), electrode fracture (<i>N</i> = 1), and seizure (<i>N</i> = 1); mild complications (41.6%) included skin infection (<i>N</i> = 2), difficulties falling asleep (<i>N</i> = 1), nausea (<i>N</i> = 1), and anxiety (<i>N</i> = 1). <b><i>Key Messages:</i></b> Despite available small case series and case reports reporting a benefit in the treatment of refractory obesity with DBS, this study emphasizes the need for prospective studies with longer follow-ups in order to further address the efficacy and indications.