Grant W. Mallory

A neurochemical closed-loop controller for deep brain stimulation: toward individualized smart neuromodulation therapies

Current strategies for optimizing deep brain stimulation (DBS) therapy involve multiple postoperative visits. During each visit, stimulation parameters are adjusted until desired therapeutic effects are achieved and adverse effects are minimized. However, the efficacy of these therapeutic parameters may decline with time due at least in part to disease progression, interactions between the host environment and the electrode, and lead migration. As such, development of closed-loop control systems that can respond to changing neurochemical environments, tailoring DBS therapy to individual patients, is paramount for improving the therapeutic efficacy of DBS. Evidence obtained using electrophysiology and imaging techniques in both animals and humans suggests that DBS works by modulating neural network activity. Recently, animal studies have shown that stimulation-evoked changes in neurotransmitter release that mirror normal physiology are associated with the therapeutic benefits of DBS. Therefore, to fully understand the neurophysiology of DBS and optimize its efficacy, it may be necessary to look beyond conventional electrophysiological analyses and characterize the neurochemical effects of therapeutic and non-therapeutic stimulation. By combining electrochemical monitoring and mathematical modeling techniques, we can potentially replace the trial-and-error process used in clinical programming with deterministic approaches that help attain optimal and stable neurochemical profiles. In this manuscript, we summarize the current understanding of electrophysiological and electrochemical processing for control of neuromodulation therapies. Additionally, we describe a proof-of-principle closed-loop controller that characterizes DBS-evoked dopamine changes to adjust stimulation parameters in a rodent model of DBS. The work described herein represents the initial steps toward achieving a “smart” neuroprosthetic system for treatment of neurologic and psychiatric disorders.

Moyamoya Disease in a Primarily White, Midwestern US Population Increased Prevalence of Autoimmune Disease

Background and Purpose— Moyamoya disease is an uncommon, cerebrovascular occlusive disease of unknown pathogenesis. Previously described Moyamoya cohorts include predominantly Asian populations or ethnically diverse North American cohorts. To gain further insight into the pathogenesis of moyamoya, we examined clinical characteristics of a primarily white, Midwestern US population Methods— Retrospective analysis of patients with angiographically confirmed moyamoya disease evaluated at our institution was performed. Prevalence of comorbidities, cerebrovascular risk factors, and autoimmune diseases were compared with the general population. Results— Ninety-four patients with moyamoya were evaluated; 72.3% were female. Ethnic composition was primarily white (85%). A significantly higher prevalence of autoimmune disease was seen, particularly type 1 diabetes mellitus (8.5% versus 0.4% in the general population) and thyroid disease (17.0% versus 8.0% in the institutional general patient population). Hyperlipidemia was also increased (27.7% versus 16.3% in the general population). Conclusions— This study of a unique, primarily white, Midwestern population of moyamoya patients demonstrates a significantly higher prevalence of autoimmune disease than in the general population. This supports a possible autoimmune component to the pathogenesis of moyamoya disease.

The Nucleus Accumbens as a Potential Target for Central Poststroke Pain

Although deep brain stimulation (DBS) has been found to be efficacious for some chronic pain syndromes, its usefulness in patients with central poststroke pain (CPSP) has been disappointing. The most common DBS targets for pain are the periventricular gray region (PVG) and the ventralis caudalis of the thalamus. Despite the limited success of DBS for CPSP, few alternative targets have been explored. The nucleus accumbens (NAC), a limbic structure within the ventral striatum that is involved in reward and pain processing, has emerged as an effective target for psychiatric disease. There is also evidence that it may be an effective target for pain. We describe a 72-year-old woman with a large right hemisphere infarct who subsequently experienced refractory left hemibody pain. She underwent placement of 3 electrodes in the right PVG, ventralis caudalis of the thalamus, and NAC. Individual stimulation of the NAC and PVG provided substantial improvement in pain rating. The patient underwent implantation of permanent electrodes in both targets, and combined stimulation has provided sustained pain relief at nearly 1 year after the procedure. These results suggest that the NAC may be an effective DBS target for CPSP.

Restoration of motor function following spinal cord injury via optimal control of intraspinal microstimulation: toward a next generation closed-loop neural prosthesis.

Movement is planned and coordinated by the brain and carried out by contracting muscles acting on specific joints. Motor commands initiated in the brain travel through descending pathways in the spinal cord to effector motor neurons before reaching target muscles. Damage to these pathways by spinal cord injury (SCI) can result in paralysis below the injury level. However, the planning and coordination centers of the brain, as well as peripheral nerves and the muscles that they act upon, remain functional. Neuroprosthetic devices can restore motor function following SCI by direct electrical stimulation of the neuromuscular system. Unfortunately, conventional neuroprosthetic techniques are limited by a myriad of factors that include, but are not limited to, a lack of characterization of non-linear input/output system dynamics, mechanical coupling, limited number of degrees of freedom, high power consumption, large device size, and rapid onset of muscle fatigue. Wireless multi-channel closed-loop neuroprostheses that integrate command signals from the brain with sensor-based feedback from the environment and the systems state offer the possibility of increasing device performance, ultimately improving quality of life for people with SCI. In this manuscript, we review neuroprosthetic technology for improving functional restoration following SCI and describe brain-machine interfaces suitable for control of neuroprosthetic systems with multiple degrees of freedom. Additionally, we discuss novel stimulation paradigms that can improve synergy with higher planning centers and improve fatigue-resistant activation of paralyzed muscles. In the near future, integration of these technologies will provide SCI survivors with versatile closed-loop neuroprosthetic systems for restoring function to paralyzed muscles.

Are there modifiable risk factors to prevent a cerebrospinal fluid leak following vestibular schwannoma surgery

OBJECT The following study was conducted to identify risk factors for a postoperative CSF leak after vestibular schwannoma (VS) surgery. METHODS The authors reviewed a prospectively maintained database of all patients who had undergone resection of a VS at the Mayo Clinic between September 1999 and May 2013. Patients who developed a postoperative CSF leak within 30 days of surgery were compared with those who did not. Data collected included patient age, sex, body mass index (BMI), tumor size, tumor side, history of prior tumor treatment, operative time, surgical approach, and extent of resection. Both univariate and multivariate regression analyses were performed to evaluate all variables as risk factors of a postoperative CSF leak. RESULTS A total of 457 patients were included in the study, with 45 patients (9.8%) developing a postoperative CSF leak. A significant association existed between increasing BMI and a CSF leak, with those classified as overweight (BMI 25-29.9), obese (BMI 30-39.9), or morbidly obese (BMI≥40) having a 2.5-, 3-, and 6-fold increased risk, respectively. Patients undergoing a translabyrinthine (TL) approach experienced a higher rate of CSF leaks (OR 2.5, 95% CI 1.3-4.6; p=0.005), as did those who had longer operative times (OR 1.04, 95% CI 1.02-1.07; p=0.0006). The BMI, a TL approach, and operative time remained independent risk factors on multivariate modeling. CONCLUSIONS Elevated BMI is a risk factor for the development of a postoperative CSF leak following VS surgery. Recognizing this preoperatively can allow surgeons to better counsel patients regarding the risks of surgery as well as perhaps to alter perioperative management in an attempt to decrease the likelihood of a leak. Patients undergoing a TL approach or having longer operative times are also at increased risk of developing a postoperative CSF leak.

Stereotactic radiosurgery for neurofibromatosis 2-associated vestibular schwannomas: toward dose optimization for tumor control and functional outcomes.

BACKGROUND Management of neurofibromatosis type 2 (NF2)-associated vestibular schwannomas (VSs) remains controversial. Stereotactic radiosurgery (SRS) with conventional dosing is less effective for NF2-related VS compared with sporadic lesions. OBJECTIVE To evaluate optimal SRS dose parameters for NF2-related VS and to report long-term outcomes. METHODS A prospective database was reviewed and outcome measures, including radiographic progression, American Academy of Otolaryngology-Head and Neck Surgery hearing class, and facial nerve function, were analyzed. Progression-free survival was estimated with Kaplan-Meier methods. Associations between tumor progression and radiosurgical treatment parameters, tumor volume, and patient age were explored with the use of Cox proportional hazards regression. RESULTS Between 1990 and 2010, 26 patients with 32 NF2-related VSs underwent SRS. Median marginal dose and tumor volume were 14 Gy and 2.7 cm, respectively. Twenty-seven tumors (84%) showed no growth (median follow-up, 7.6 years). Kaplan-Meier estimates for 5- and 10-year progression-free survival were 85% and 80%, respectively. Cox proportional hazards demonstrated a significant inverse association between higher marginal doses and tumor progression (hazard ratio, 0.49; 95% confidence interval, 0.17-0.92; P = .02). Audiometric data were available in 30 ears, with 12 having class A/B hearing before SRS. Only 3 maintained serviceable hearing at the last follow-up. Four underwent cochlear implantation. Initially, 3 achieved open-set speech recognition, although only 1 experienced long-term benefit. Facial nerve function remained stable in 50% of cases. CONCLUSION Higher marginal doses than commonly prescribed for sporadic VS were associated with improved tumor control in patients with NF2. Hearing outcomes were poor even when contemporary reduced marginal doses were used. However, SRS allows an anatomically preserved cochlear nerve and may permit hearing rehabilitation with cochlear implantation. Further consideration should be given to optimum dosing to achieve long-term control while maximizing functional outcomes. ABBREVIATIONS HB, House-BrackmannNF2, neurofibromatosis type 2SRS, stereotactic radiosurgeryVS, vestibular schwannoma.

Understanding the impact of obesity on short-term outcomes and in-hospital costs after instrumented spinal fusion

BACKGROUND Obesity rates continue to rise along with the number of obese patients undergoing elective spinal fusion. OBJECTIVE To evaluate the impact of obesity on resource utilization and early complications in patients undergoing surgery for degenerative spine disease. METHODS A single-institution retrospective analysis was conducted on patients with degenerative spine disease requiring instrumentation between 2008 and 2012. The 801 identified patients were grouped based on a body mass index (BMI) of <30 (nonobese, n = 478), ≥30 and <40 (obese, n = 283), and alternatively BMIs of ≥40 (morbidly obese, n = 40). Baseline characteristics, surgical outcomes and requirements, complications, and cost were compared. Logistic and linear regression analyses were used to determine the strength of association between obesity and outcomes for categorical and continuous data, respectively. RESULTS Significant differences were found in comorbidities between cohorts. Multivariate analysis revealed significant associations between obesity and longer anesthesia times (30 minutes, P = .008), and surgical times (24 minutes, P = .02). Additionally, there was a 2.8 times higher rate of wound complications in obese patients (4.2% vs 1.5, P = .03), and 2.5 times higher rate of major medical complications (7.8% vs 3.1, P = .01). Morbid obesity resulted in a 10 times higher rate of wound complications (P < .001). Morbid obesity resulted in a

Outcomes after percutaneous surgery for patients with multiple sclerosis-related trigeminal neuralgia.

9078 (P = .005) increase in overall cost of care. CONCLUSION Increased BMI is associated with longer operative times, increased complication rates, and increased cost independent of comorbidities. These effects are more pronounced with morbidly obese patients, further supporting a role for preoperative weight loss.

Surgical Outcomes and Predictors of Stroke in a North American White and African American Moyamoya Population

BACKGROUND Approximately 1% to 2% of patients with multiple sclerosis (MS) develop trigeminal neuralgia (TN). Percutaneous surgery is commonly performed in medically refractory cases. OBJECTIVE To analyze the pain outcomes and complications of patients with MS-related trigeminal neuralgia (MS-TN) having percutaneous surgery. METHODS Patients having balloon microcompression (BMC; n = 69) or glycerol rhizotomy (PRGR; n = 67) from 1997 to 2010 were reviewed retrospectively. Patients in the 2 groups were similar with regard to age, sex, pain location, and pain quality. Mean pain duration was longer in the PRGR group (54.6 vs 16 months; P < .001); more patients having BMC had prior surgery (87% vs. 48%; P < .001). Outcomes were defined as excellent (no pain, no medications), good (no pain with medications), and poor. Median follow-up was 13 months (range, 0.25-132 months). RESULTS Ninety-five patients initially had excellent (n = 45, 33%) or good (n = 50, 37%) outcomes. Pain relief was maintained in 58% of patients at 3 months and 28% at 2 years. There was no difference in excellent/good outcomes between the surgical groups (hazard ratio = 0.73; P = .14). No correlation was noted between pain relief and new or increased facial numbness (hazard ratio = 0.78; P = .19). Forty-four BMC patients (64%) had additional surgery compared with 36 PRGR patients (54%; P = .19). Complications were more frequent after BMC (17.4% vs 3.0%; P < .01). CONCLUSION Percutaneous surgery for patients with MS-TN is less likely to provide pain relief than similar operations performed for patients with idiopathic TN. New trigeminal deficits did not correlate with better facial pain outcomes, supporting the concept that many patients with MS-TN have centrally mediated pain.

Brain carcinoid metastases: outcomes and prognostic factors

BACKGROUND The majority of moyamoya surgical series have been confined to Asian and pediatric populations. Few have studied demographics, risk factors, and outcomes in adult North American populations. OBJECTIVE To examine outcomes after revascularization for moyamoya in white and African American adults and to assess for predictors of recurrent stroke. METHODS A retrospective review of 75 non-Asian patients undergoing 110 procedures at the Mayo Clinic was performed. Demographics, known moyamoya associations, cerebrovascular risk factors, and autoimmune diseases were recorded. Primary outcomes for vascular events were assessed with Kaplan-Meier analysis. Fisher exact methods were used to evaluate for associations with recurrent events. RESULTS Mean age was 42 years, and mean follow-up was 47 months. Seventy-one of the 75 patients were white. The majority had bilateral disease (n = 49). Perioperative ischemic events occurred in 5 patients (4.5%). The 5- and 10-year event rates were 5.8% and 9.9%. Significant associations were found with a history of thyroid disease (P = .05) and recurrent stroke. A trend was also found between hypertension and autoimmune disease with recurrent stroke. CONCLUSION Outcomes were favorable with revascularization in this subset with moyamoya. A significant association between a history of thyroid disease and recurrent stroke was found. Additionally, high prevalences of autoimmune disease, hypertension, and thyroid disease were found in our cohort, suggesting that they may play a role in the pathophysiology and progression of moyamoya disease in this population. A new classification for moyamoya is proposed based on these data.