Significance: Pain comprises a complex interaction between motor action and somatosensation that is dependent on dynamic interactions between the brain and spinal cord. This makes understanding pain particularly challenging as it involves rich interactions between many circuits (e.g., neural and vascular) and signaling cascades throughout the body. As such, experimentation on a single region may lead to an incomplete and potentially incorrect understanding of crucial underlying mechanisms. Aim: We aimed to develop and validate tools to enable detailed and extended observation of neural and vascular activity in the brain and spinal cord. The first key set of innovations was targeted to developing novel imaging hardware that addresses the many challenges of multisite imaging. The second key set of innovations was targeted to enabling bioluminescent (BL) imaging, as this approach can address limitations of fluorescent microscopy including photobleaching, phototoxicity, and decreased resolution due to scattering of excitation signals. Approach: We designed 3D-printed brain and spinal cord implants to enable effective surgical implantations and optical access with wearable miniscopes or an open window (e.g., for one- or two-photon microscopy or optogenetic stimulation). We also tested the viability for BL imaging and developed a novel modified miniscope optimized for these signals (BLmini). Results: We describe "universal" implants for acute and chronic simultaneous brain-spinal cord imaging and optical stimulation. We further describe successful imaging of BL signals in both foci and a new miniscope, the "BLmini," which has reduced weight, cost, and form-factor relative to standard wearable miniscopes. Conclusions: The combination of 3D-printed implants, advanced imaging tools, and bioluminescence imaging techniques offers a coalition of methods for understanding spinal cord-brain interactions. Our work has the potential for use in future research into neuropathic pain and other sensory disorders and motor behavior.
INTRODUCTION: Patients with traumatic intracranial hemorrhage (tICH) are at increased risk of venous thromboembolism and may require anticoagulation. We evaluated the utility of surveillance computed tomography (CT) in patients with tICH who required therapeutic anticoagulation. METHODS: This single institution, retrospective study included adult patients with tICH who required anticoagulation within 4 weeks and had a surveillance head CT within 24 hours of reaching therapeutic anticoagulation levels. The primary outcome was hematoma expansion (HE) detected by the surveillance CT. Secondary outcomes included 1) changes in management in patients with HE on the surveillance head CT, 2) HE in the absence of clinical changes, and 3) mortality due to HE. We also compared mortality between patients who did and did not have a surveillance CT. RESULTS: Of 175 patients, 5 (2.9%) were found to have HE. Most (n = 4, 80%) had changes in management including anticoagulation discontinuation (n = 4), reversal (n = 1), and operative management (n = 1). Two patients developed symptoms or exam changes prior to the head CT. Of the 3 patients (1.7%) without preceding exam changes, each had only very minor HE and did not require operative management. No patient experienced mortality directly attributed to HE. There was no difference in mortality between patients who did and those who did not have a surveillance scan. CONCLUSIONS: Our findings suggest that most patients with tICH who are started on anticoagulation could be followed clinically, and providers may reserve CT imaging for patients with changes in exam/symptoms or those who have a poor clinical examination to follow.
Anticoagulants , Intracranial Hemorrhage, Traumatic , Tomography, X-Ray Computed , Humans , Anticoagulants/therapeutic use , Anticoagulants/adverse effects , Male , Female , Retrospective Studies , Aged , Middle Aged , Intracranial Hemorrhage, Traumatic/diagnostic imaging , Adult , Aged, 80 and over
Central nervous system (CNS) tumors are the most common solid malignancy in the pediatric population. Based on adoptive cellular therapy's clinical success against childhood leukemia and the preclinical efficacy against pediatric CNS tumors, chimeric antigen receptor (CAR) T cells offer hope of improving outcomes for recurrent tumors and universally fatal diseases such as diffuse intrinsic pontine glioma (DIPG). However, a major obstacle for tumors of the brain and spine is ineffective T cell chemotaxis to disease sites. Locoregional CAR T cell delivery via infusion through an intracranial catheter is currently under study in multiple early phase clinical trials. Here, we describe the Seattle Children's single-institution experience including the multidisciplinary process for the preparation of successful, repetitive intracranial T cell infusion for children and the catheter-related safety of our 307 intracranial CAR T cell doses.
Brain Neoplasms , Central Nervous System Neoplasms , Child , Humans , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , T-Lymphocytes , Brain Neoplasms/pathology , Central Nervous System Neoplasms/therapy , Catheters
BACKGROUND: Although lateral lumbar interbody fusion (LLIF) is an effective surgical option for lumbar arthrodesis, postoperative plexopathies are a common complication. We characterized post-LLIF plexopathies in a large cohort and analyzed potential risk factors for each. METHODS: A single-institutional cohort who underwent LLIF between May 2015 and December 2019 was retrospectively reviewed for postoperative lumbar plexopathies. Plexopathies were divided based on sensory and motor symptoms and duration, as well as by laterality relative to the surgical approach. We assessed these subgroups for associations with patient and surgical characteristics as well as psoas dimensions. We then evaluated risk of developing plexopathies after intraoperative neuromonitoring observations. RESULTS: A total of 127 patients were included. The overall rate of LLIF-induced sensory or motor lumbar plexopathy was 37.8% (48/127). Of all cases, 42 were ipsilateral to the surgical approach (33.1%); conversely, 6 patients developed contralateral plexopathies (4.7%). Most (31/48; 64.6%) resolved with a follow-up interval of 402 days in the plexopathy group. Of ipsilateral cases, 24 patients experienced persistent (>90 days) postoperative sensory symptoms (18.9%), whereas 20 experienced persistent weakness (15.7%). More levels fused predicted persistent sensory symptoms (odds ratio, 1.714 [1.246-2.359]; P = 0.0085), whereas surgical duration predicted persistent weakness (odds ratio, 1.004 [1.002-1.006]; P = 0.0382). Psoas anatomic variables were not significantly associated with plexopathy. Nonresolution of intraoperative evoked motor potential alerts was a significant risk factor for developing plexopathies (relative risk, 2.29 [1.17-4.45]). CONCLUSIONS: Post-LLIF plexopathies are common but usually resolve. Surgical complexity and unresolved neuromonitoring alerts are possible risk factors for persistent plexopathy.
Spinal Fusion , Humans , Retrospective Studies , Spinal Fusion/adverse effects , Spinal Fusion/methods , Neurosurgical Procedures , Risk Factors , Multivariate Analysis , Lumbar Vertebrae/surgery
Significance: Pain is comprised of a complex interaction between motor action and somatosensation that is dependent on dynamic interactions between the brain and spinal cord. This makes understanding pain particularly challenging as it involves rich interactions between many circuits (e.g., neural and vascular) and signaling cascades throughout the body. As such, experimentation on a single region may lead to an incomplete and potentially incorrect understanding of crucial underlying mechanisms. Aim: Here, we aimed to develop and validate new tools to enable detailed and extended observation of neural and vascular activity in the brain and spinal cord. The first key set of innovations were targeted to developing novel imaging hardware that addresses the many challenges of multi-site imaging. The second key set of innovations were targeted to enabling bioluminescent imaging, as this approach can address limitations of fluorescent microscopy including photobleaching, phototoxicity and decreased resolution due to scattering of excitation signals. Approach: We designed 3D-printed brain and spinal cord implants to enable effective surgical implantations and optical access with wearable miniscopes or an open window (e.g., for one- or two-photon microscopy or optogenetic stimulation). We also tested the viability for bioluminescent imaging, and developed a novel modified miniscope optimized for these signals (BLmini). Results: Here, we describe novel 'universal' implants for acute and chronic simultaneous brain-spinal cord imaging and optical stimulation. We further describe successful imaging of bioluminescent signals in both foci, and a new miniscope, the 'BLmini,' which has reduced weight, cost and form-factor relative to standard wearable miniscopes. Conclusions: The combination of 3D printed implants, advanced imaging tools, and bioluminescence imaging techniques offers a new coalition of methods for understanding spinal cord-brain interactions. This work has the potential for use in future research into neuropathic pain and other sensory disorders and motor behavior.
Background: Lateral lumbar interbody fusion (LLIF) is a minimally invasive fusion procedure that may be performed with or without supplemental instrumentation. However, there is a paucity of evidence on the effect of supplemental instrumentation technique on perioperative morbidity and fusion rate in LLIF. Methods: A single-institutional retrospective review of patients who underwent LLIF for lumbar spondylosis was conducted. Patients were grouped according to supplemental instrumentation technique: stand-alone LLIF, LLIF with laterally placed instrumentation, or LLIF with posterior percutaneous pedicle screw fixation (PPSF). Outcomes included fusion rates, peri-operative complication, and reoperation; estimated blood loss (EBL); surgery duration; length of stay; and length of follow-up. Results: 82 patients underwent LLIF at 114 levels. 35 patients (42.7%) received supplemental lateral instrumentation, 30 (36.6%) received supplemental PPSF, and 17 (20.7%) underwent stand-alone LLIF. More patients in the lateral instrumentation group had prior lumbar fusion at adjacent levels (23/35, 65.71%) versus stand-alone (3/17, 17.6%) or PPSF (2/30, 6.67%) groups (p = 0.003). 4/17 patients (23.5%) with stand-alone LLIF and 4/35 patients (11.42%) with lateral instrumentation underwent reoperation, versus 0/30 with PPSF (p = 0.030). There was no difference in fusion rates between groups (p = 0.717). Operation duration was longer in patients with PPSF (p < 0.005) and length of follow-up was longer for PPSF than lateral instrumentation (p = 0.001). Choice of instrumentation group was a statistically significant predictor of reoperation. Conclusions: While rates of complete radiographic fusion on imaging follow-up didn't differ, patients receiving PPSF were less likely than stand-alone or lateral instrumentation groups to require reoperation, though operative time was significantly longer. Further study of choice of supplemental instrumentation with LLIF is indicated.
Ventral Capsulotomy (VC) is a surgical intervention for treatment-resistant Obsessive-Compulsive Disorder (OCD). Despite clinical studies, little is known about patient perception and lived experience after neurosurgery for severe OCD. To examine the lived experiences of patients who have undergone VC for severe, treatment-resistant OCD through qualitative analysis. We conducted semi-structured interviews with six participants treated with VC for OCD. Interviews were analyzed using Interpretive Phenomenological Analysis. The following themes emerged: (1) After years of conventional treatments, patients felt neurosurgery was their "last hope" and described themselves as "desperate," (2) While some described the surgery as a "supernatural experience," patients also demonstrated understanding of the scientific procedure, its risks and potential benefits, (3) The surgical experience itself was positive or neutral, which was linked to trust in the clinical team, (4) Post-surgery, participants described months of heightened fear as they awaited lesion formation and functional improvement. (5) Patients consistently contextualized outcome in the context of their own life goals. Patients undergoing VC have positive views of this neurosurgical intervention, but psychiatric neurosurgical teams should anticipate patient discomfort with the time needed to achieve behavioral improvement following surgery and emphasize the importance of post-operative psychiatric care.
Background: Lateral lumbar interbody fusion (LLIF) is a minimally invasive surgical option for treating symptomatic degenerative lumbar spinal stenosis (DLSS) in select patients. However, the efficacy of LLIF for indirectly decompressing the lumbar spine in DLSS, as well as the best radiographic metrics for evaluating such changes, are incompletely understood. Methods: A single-institutional cohort of patients who underwent LLIF for DLSS between 5/2015 - 12/2019 was retrospectively reviewed. Diameter, area, and stenosis grades were measured for the central canal (CC) and neural foramina (NF) at each LLIF level based on preoperative and postoperative T2-weighted MRI. Baseline facet joint (FJ) space, degree of FJ osteoarthritis, presence of spondylolisthesis, interbody graft position, and posterior disc height were analyzed as potential predictors of radiographic outcomes. Changes to all metrics after LLIF were analyzed and compared across lumbar levels. Preoperative and intraoperative predictors of decompression were then assessed using multivariate linear regression. Results: A total of 102 patients comprising 153 fused levels were analyzed. Pairwise linear regression of stenosis grade to diameter and area revealed significant correlations for both the CC and NF. All metrics except CC area were significantly improved after LLIF (p < 0.05, 2-tailed t-test). Worse FJ osteoarthritis ipsilateral to the surgical approach was predictive of greater post-operative CC and NF stenosis grade (p < 0.05, univariate and multivariate ordinary least squares linear regression). Lumbar levels L3-5 had significantly higher absolute postoperative CC stenosis grades while relative change in CC stenosis at the L2-3 was significantly greater than other lumbar levels (p < 0.05, one-way ANOVA). There were no baseline or postoperative differences in NF stenosis grade across lumbar levels. Conclusions: Radiographically, LLIF is effective at indirect compression of the CC and NF at all lumbar levels, though worse FJ osteoarthritis predicted higher degrees of post-operative stenosis.
Hypoxic-ischemic (HI) brain injury is a major contributor to neurodevelopmental morbidities. Inter-alpha inhibitor proteins (IAIPs) have neuroprotective effects on HI-related brain injury in neonatal rats. However, the effects of treatment with IAIPs on sequential behavioral, MRI, and histopathological abnormalities in the young adult brain after treatment with IAIPs in neonates remain to be determined. The objective of this study was to examine the neuroprotective effects of IAIPs at different neurodevelopmental stages from newborn to young adults after exposure of neonates to HI injury. IAIPs were given as 11-sequential 30-mg/kg doses to postnatal (P) day 7-21 rats after right common carotid artery ligation and exposure to 90 min of 8% oxygen. The resulting brain edema and injury were examined by T2-weighted magnetic resonance imaging (MRI) and cresyl violet staining, respectively. The mean T2 values of the ipsilateral hemisphere from MRI slices 6 to 10 were reduced in IAIP-treated HI males + females on P8, P9, and P10 and females on P8, P9, P10, and P14. IAIP treatment reduced hemispheric volume atrophy by 44.5 ± 29.7% in adult male + female P42 rats and improved general locomotor abilities measured by the righting reflex over time at P7.5, P8, and P9 in males + females and males and muscle strength/endurance measured by wire hang on P16 in males + females and females. IAIPs provided beneficial effects during the learning phase of the Morris water maze with females exhibiting beneficial effects. IAIPs confer neuroprotection from HI-related brain injury in neonates and even in adult rats and beneficial MRI and behavioral benefits in a sex-dependent manner.
Brain Injuries , Hypoxia-Ischemia, Brain , Neuroprotective Agents , Animals , Brain , Brain Injuries/pathology , Disease Models, Animal , Female , Hypoxia-Ischemia, Brain/drug therapy , Ischemia/pathology , Male , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Rats , Rats, Wistar
Detection of neural signatures related to pathological behavioral states could enable adaptive deep brain stimulation (DBS), a potential strategy for improving efficacy of DBS for neurological and psychiatric disorders. This approach requires identifying neural biomarkers of relevant behavioral states, a task best performed in ecologically valid environments. Here, in human participants with obsessive-compulsive disorder (OCD) implanted with recording-capable DBS devices, we synchronized chronic ventral striatum local field potentials with relevant, disease-specific behaviors. We captured over 1,000 h of local field potentials in the clinic and at home during unstructured activity, as well as during DBS and exposure therapy. The wide range of symptom severity over which the data were captured allowed us to identify candidate neural biomarkers of OCD symptom intensity. This work demonstrates the feasibility and utility of capturing chronic intracranial electrophysiology during daily symptom fluctuations to enable neural biomarker identification, a prerequisite for future development of adaptive DBS for OCD and other psychiatric disorders.
Electrophysiology/methods , Obsessive-Compulsive Disorder/physiopathology , Adult , Biomarkers/metabolism , Electrodes , Feasibility Studies , Female , Humans , Male , Ventral Striatum/physiology
BACKGROUND: In a competitive landscape for neurosurgical residency admission, research productivity is increasingly important. Medical school applicants to neurosurgery report high numbers of "scholarly products" as published by the National Residency Match Program. Despite increased student involvement in research and productivity, to the best of our knowledge, no previous reported studies have examined student perspectives on their involvement in neurosurgical research. METHODS: For 2 consecutive years (February 2019 and February 2020), medical students (n = 55) from around the United States presented original research at the Student Neurosurgical Research Conference. Participants were administered a mixed-method survey designed to assess experiences and perspectives on engaging in neurosurgical research. Survey responses were analyzed independently by two researchers to assess for common themes and perspectives. RESULTS: Medical students engaged in all types of research work across nearly every neurosurgical subfield with "Basic/Bench Lab work" (38.5%) and "Chart Review" (23.1%) representing the majority of projects. Students commonly cited "curiosity/interest," and "residency application competitiveness" as main reasons for participation in research. About 66% of respondents reported experiencing anxiety/concern about research productivity "often" or "very often." Thematic analysis revealed that sources of research-related stress were (1) having enough publications to match into residency, and (2) having enough time in medical school to engage in research. CONCLUSION: Medical students engaging in neurosurgical research are highly motivated students driven by scientific curiosity and pressure to prepare for competitive residency applications. Students experience anxiety due to time constraints in medical curricula and increasing demands for scholarly productivity.
Radiation recall (RR) is a chemotherapy-induced reaction that leads to inflammation and necrosis in previously irradiated tissue. Gemcitabine is a cytidine analogue that is often used in conjunction with nab-paclitaxel in the treatment of pancreatic cancer. Herein, we present a case of a 56-year-old woman with stage III pancreatic adenocarcinoma diagnosed with gemcitabine-induced RR when she presented with lower back pain and new rim-enhancing collections within the right and left paraspinal musculature 5 months after radiation therapy to the pancreas. A PubMed search was performed for 'Radiation Recall Myositis' and a complete literature review performed. This case and review of the literature of published cases of RR myositis highlight the clinical course and presentation of RR myositis. This review highlights the importance of considering RR in the differential diagnosis when patients who are undergoing chemotherapy and radiation present with inflammatory changes in previously irradiated areas.
Adenocarcinoma , Myositis , Pancreatic Neoplasms , Adenocarcinoma/drug therapy , Albumins/therapeutic use , Antineoplastic Combined Chemotherapy Protocols , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Female , Humans , Middle Aged , Myositis/chemically induced , Myositis/diagnosis , Paclitaxel/therapeutic use , Pancreatic Neoplasms/drug therapy , Gemcitabine
Ossification of the posterior longitudinal ligament (OPLL) is a relatively rare disorder characterized by elongation of the posterior longitudinal ligament followed by the progressive development of ectopic osseous tissue along the ligament. OPLL is most commonly reported in the cervical spine, with fewer reported cases of thoracic or lumbar OPLL. The incidence of OPLL is high in east Asian populations with a much lower incidence in the United States. In this case report and review, we present the case of a 44-year-old female who was admitted to the hospital with a one-year history of progressive bilateral lower extremity weakness. Her lower extremity weakness had worsened over months and precipitated a gait disturbance that left her wheelchair-bound at the time of presentation. Additional presenting symptoms included lower back pain, stool incontinence, neck pain, and upper extremity paresthesias. Computed tomography of the spine revealed multiple areas of osteophyte formation and OPLL in the cervical spine from C2-5, thoracic spine from T6-10, and in the lumbar and sacral spine from L1-S1. There were notable areas of accompanying neural foraminal stenosis and central canal stenosis with visible spinal cord compression present in various locations. The patient did not undergo surgical intervention given the significant risk of multilevel surgery, and her symptoms were managed with medication. OPLL, particularly when not considered in lower-risk populations, can be a significant cause for progressive debilitating neurological abnormality. We report a rare case of OPLL occurring throughout the cervical, thoracic, lumbar, and sacral spine.
BACKGROUND: Obsessive-compulsive disorder (OCD) is a disabling condition characterized by intrusive thoughts and repetitive behaviors. A subset of individuals have severe, treatment-resistant illness and are nonresponsive to medication or behavioral therapies. Without response to conventional therapeutic options, surgical intervention becomes an appropriate consideration. OBJECTIVE: To report clinical outcomes and the safety profile of bilateral ventral anterior capsulotomy for OCD using magnetic resonance (MR)-guided laser interstitial thermal therapy (LITT) in 10 patients followed for 6 to 24 mo. METHODS: A total of 10 patients underwent LITT for severe OCD; 1 patient withdrew prior to follow-up. LITT is a minimally invasive ablative technique performed with precise targeting and use of thermography under MR guidance. Lesions of the ventral anterior limb of the internal capsule by other techniques have been shown to be efficacious in prior studies. RESULTS: A total of 7 of the 9 patients were considered full responders (77.8%; Yale-Brown Obsessive-Compulsive Scale change ≥35%). Adverse effects included transient apathy/amotivation postsurgery (2 patients). One patient had a small tract hemorrhage where the laser fiber traversed the cerebral cortex as well as persistent insomnia postsurgery. One individual died after a drug overdose 7 mo postsurgery, which was judged unrelated to the surgery. CONCLUSION: LITT ventral capsulotomy was generally well tolerated, with promising evidence of effectiveness in the largest such series to date. Results were comparable to those after gamma knife ventral capsulotomy, as well as ventral anterior limb deep brain stimulation.
Internal Capsule/surgery , Obsessive-Compulsive Disorder/surgery , Posterior Capsulotomy/methods , Adult , Cognition , Female , Humans , Internal Capsule/diagnostic imaging , Magnetic Resonance Imaging , Male , Middle Aged , Obsessive-Compulsive Disorder/diagnostic imaging , Radiosurgery/methods , Surgery, Computer-Assisted , Treatment Outcome , Young Adult
OBJECTIVE: Medical students interested in neurosurgery are increasingly involved in research, and research conferences have proven valuable for developing medical research experience and exposure. A research conference was designed for medical students interested in neurosurgery to present research. METHODS: Our team designed an annual research conference at the Warren Alpert Medical School of Brown University in conjunction with the Neurosurgery and Neurology Departments. In February 2019, we hosted the first Student Neurosurgical and Neurological Research Conference (SNRC), the first national research conference, to our knowledge, designed for medical students to present neurosurgical research in the United States. The conference consisted of student poster/oral presentations, keynote speeches from clinical faculty, and surgical skills workstations. In February 2020, we hosted the second SNRC. After each conference, participants (n = 55) completed a survey to assess student perspectives of the conference. RESULTS: Fifty-five medical students from around the nation attended the conferences to present their research. One hundred percent of participants affirmed that the conference fulfilled their primary reason for attending, which for most (54.5%) was the opportunity to present research. Thematic analysis revealed that students especially appreciated the "lower stress environment" and "opportunity to get feedback on their research." Notably, 97.6% of students felt the conference strengthened or increased their interest in neurosurgery. CONCLUSIONS: Participants felt that the SNRC was a valuable opportunity to present research in an environment conducive for practice and improvement. Research conferences primarily for medical students may support the development of young researchers while increasing and strengthening interest in the field of neurosurgery.
Biomedical Research/education , Biomedical Research/trends , Congresses as Topic/trends , Neurosurgical Procedures/education , Neurosurgical Procedures/trends , Students, Medical , Career Choice , Female , Humans , Male , Rhode Island , United States
Neuroinflammation contributes to hypoxic-ischemic (HI) brain injury. Inter-alpha inhibitor proteins (IAIPs) have important immunomodulatory properties. Human (h) plasma-derived IAIPs reduce brain injury and improve neurobehavioral outcomes after HI. However, the effects of hIAIPs on neuroinflammatory biomarkers after HI have not been examined. We determined whether hIAIPs attenuated HI-related neuroinflammation. Postnatal day-7 rats exposed to sham-placebo, or right carotid ligation and 8% oxygen for 90 minutes with placebo, and hIAIP treatment were studied. hIAIPs (30 mg/kg) or PL was injected intraperitoneally immediately, 24, and 48 hours after HI. Rat complete blood counts and sex were determined. Brain tissue and peripheral blood were prepared for analysis 72 hours after HI. The effects of hIAIPs on HI-induced neuroinflammation were quantified by image analysis of positively stained astrocytic (glial fibrillary acid protein [GFAP]), microglial (ionized calcium binding adaptor molecule-1 [Iba-1]), neutrophilic (myeloperoxidase [MPO]), matrix metalloproteinase-9 (MMP9), and MMP9-MPO cellular markers in brain regions. hIAIPs reduced quantities of cortical GFAP, hippocampal Iba-1-positive microglia, corpus callosum MPO, and cortical MMP9-MPO cells and the percent of neutrophils in peripheral blood after HI in male, but not female rats. hIAIPs modulate neuroinflammatory biomarkers in the neonatal brain after HI and may exhibit sex-related differential effects.
Mental disorders are a leading cause of disability worldwide, and available treatments have limited efficacy for severe cases unresponsive to conventional therapies. Neurosurgical interventions, such as lesioning procedures, have shown success in treating refractory cases of mental illness, but may have irreversible side effects. Neuromodulation therapies, specifically Deep Brain Stimulation (DBS), may offer similar therapeutic benefits using a reversible (explantable) and adjustable platform. Early DBS trials have been promising, however, pivotal clinical trials have failed to date. These failures may be attributed to targeting, patient selection, or the "open-loop" nature of DBS, where stimulation parameters are chosen ad hoc during infrequent visits to the clinician's office that take place weeks to months apart. Further, the tonic continuous stimulation fails to address the dynamic nature of mental illness; symptoms often fluctuate over minutes to days. Additionally, stimulation-based interventions can cause undesirable effects if applied when not needed. A responsive, adaptive DBS (aDBS) system may improve efficacy by titrating stimulation parameters in response to neural signatures (i.e., biomarkers) related to symptoms and side effects. Here, we present rationale for the development of a responsive DBS system for treatment of refractory mental illness, detail a strategic approach for identification of electrophysiological and behavioral biomarkers of mental illness, and discuss opportunities for future technological developments that may harness aDBS to deliver improved therapy.
