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We investigated the electrophysiological relationships in the cortico-basal ganglia network on a sub-centimeter scale to increase our understanding of neural functional relationships in Parkinson's disease (PD).Data was intraoperatively recorded from 2 sources in the human brain-a microelectrode in the subthalamic nucleus (STN) and a micro-electrocorticography grid on the motor association cortex-during bilateral deep brain stimulation (DBS) electrode placement. STN neurons and local field potential (LFP) were defined as functionally connected when the 99.7% confidence intervals of the action potential (AP)-aligned average LFP and control did not overlap.APs from STN neurons were functionally connected to the STN LFP for 18/46 STN neurons. This functional connection was observed between STN neuron APs and cortical LFP for 25/46 STN neurons. The cortical patterns of electrophysiological functional connectivity differed for each neuron.A subset of single neurons in the STN exhibited functional connectivity with electrophysiological activity in the STN and at a distance with the motor association cortex surveyed on a sub-centimeter spatial scale. These connections show a per neuron differential topography on the cortex.The cortico-basal ganglia circuit is organized on a sub-centimeter scale, and plays an important role in the mechanisms of PD and DBS.

OBJECTIVE Electrophysiologic mapping (EM) has been instrumental in advancing neuroscience and ensuring accurate lead placement for deep brain stimulation. However, EM is associated with increased operative time, expense, and potential risk. Intraoperative imaging to verify lead placement provides an opportunity to reassess the clinical role of EM. We investigated whether EM 1) provides new information that corrects suboptimal preoperative target selection by the physician or 2) simply corrects intraoperative stereotactic error, which can instead be quickly corrected with intraoperative imaging. METHODS Deep brain stimulation lead location errors were evaluated by measuring whether repositioning leads based on EM directed the final lead placement 1) away from or 2) toward the original target. We retrospectively identified 50 patients with 61 leads that required repositioning directed by EM. The stereotactic coordinates of each lead were determined with intraoperative computed tomography. RESULTS In 45 of 61 leads (74%), the electrophysiologically directed repositioning moved the lead toward the initial target. The mean radial errors between the preoperative plan and targeted contact coordinates before and after repositioning were 2.2 and 1.5 mm, respectively (P < 0.001). Microelectrode recording was more likely than test stimulation to direct leads toward the initial target (88% vs. 63%; P = 0.03). The nucleus targeted was associated with the likelihood of moving toward the initial target. CONCLUSIONS Electrophysiologic mapping corrected primarily for errors in lead placement rather than providing new information regarding errors in target selection. Thus, intraoperative imaging and improvements in stereotactic techniques may reduce or even eliminate dependence on EM.

We recently showed that perineuronal nets (PNNs) enmesh glucoregulatory neurons in the arcuate nucleus (Arc) of the mediobasal hypothalamus (MBH)1, but whether these PNNs play a role in either the pathogenesis of type 2 diabetes (T2D) or its treatment remains unclear. Here we show that PNN abundance within the Arc is markedly reduced in the Zucker diabetic fatty (ZDF) rat model of T2D, compared with normoglycaemic rats, correlating with altered PNN-associated sulfation patterns of chondroitin sulfate glycosaminoglycans in the MBH. Each of these PNN-associated changes is reversed following a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) at a dose that induces sustained diabetes remission in male ZDF rats. Combined with previous work localizing this FGF1 effect to the Arc area2-4, our finding that enzymatic digestion of Arc PNNs markedly shortens the duration of diabetes remission following icv FGF1 injection in these animals identifies these extracellular matrix structures as previously unrecognized participants in the mechanism underlying diabetes remission induced by the central action of FGF1.

BACKGROUND 5-ALA SDT is not a blood-brain barrier disruption technique, but rather a first-in-class drug-device therapy exploiting the heme synthesis pathway in recurrent glioblastoma (rGBM). Following IV 5-ALA administration, aberrant tumor metabolism results in protoporphyrin-IX (PpIX) accumulation. Activation of PpIX by non-invasive, non-ablative magnetic resonance-guided focused ultrasound (MRgFUS) induces reactive oxygen species and tumor cell death. This first-in-human Phase 0/1 study investigates the feasibility, safety, and biological effects of 5-ALA SDT in rGBM patients. METHODS Six hours prior to SDT, adult patients with rGBM were administered 10mg/kg of an IV formulation of 5-ALA (SONALA-001). Patients were assigned to one of three ascending acoustic energy levels of MRgFUS (200J/400J/800J, measured at transducer surface), followed by a four-day interval prior to planned tumor resection. In each patient, 50% of the enhancing and nonenhancing tumor volume was targeted with MRgFUS with the untreated tumor serving as an internal control. The Optimal Biological Dose (OBD) associated with 5-ALA SDT is the energy level associated with greatest tumor cell death. RESULTS 8 patients were accrued across all energy levels, and none demonstrated drug- or device-related adverse events. Compared to internal control tissue, the apoptosis biomarker, cleaved caspase-3, was elevated in all patients, but most prominently at the 200J energy level. The oxidative stress biomarkers 4-hydroxynonenal, glutathione, cysteine, and thiol were elevated in treated vs. control tissues at all energy levels. The mean Cmax for 5-ALA and PpIX in plasma were 305 µM and 65 nM, respectively. No off-target histological or radiographic alterations were detected in any patient. CONCLUSIONS This first-in-human Phase 0/1 study of a new therapeutic modality for rGBM patients demonstrates that 5-ALA SDT is safe at 200 to 800J and likely induces targeted cell death in rGBM patients via oxidative stress. At 10mg/kg of 5-ALA, the OBD is at or lower than 200J.

Historically, pancreatic islet beta cells have been viewed as principal regulators of glycemia, with type 2 diabetes (T2D) resulting when insulin secretion fails to compensate for peripheral tissue insulin resistance. However, glycemia is also regulated by insulin-independent mechanisms that are dysregulated in T2D. Based on evidence supporting its role both in adaptive coupling of insulin secretion to changes in insulin sensitivity and in the regulation of insulin-independent glucose disposal, the central nervous system (CNS) has emerged as a fundamental player in glucose homeostasis. Here, we review and expand upon an integrative model wherein the CNS, together with the islet, establishes and maintains the defended level of glycemia. We discuss the implications of this model for understanding both normal glucose homeostasis and T2D pathogenesis and highlight centrally targeted therapeutic approaches with the potential to restore normoglycemia to patients with T2D.

Cancer-related pain is a uniquely challenging entity for treating practitioners for a variety of reasons, including its often severe and medically refractory nature, the emotional and social circumstances surrounding the disease process, and the frequently associated limited life expectancy.

OBJECTIVE Spinal cord stimulation (SCS) has been shown to be a safe and effective therapy for patients with chronic pain. However, some patients do not obtain or maintain adequate pain relief after SCS. The goal of this study was to identify factors that affect patient outcome with regard to SCS. MATERIALS AND METHODS A retrospective analysis of electronic medical records at a single site was performed. Records for 181 patients who received SCS implants from 2014 through 2016 were collected with follow-up data captured up to August 2019. Patient outcome was measured by device explantation and patient benefit from the SCS. Study parameters included demographic characteristics, history of pain, SCS implant characteristics, and postimplantation events. RESULTS An earlier diagnosis of radiculopathy was associated with an increased risk of poor benefit (relative risk [RR], 1.81; 95% CI, 1.19-2.74; p = 0.008). Postimplantation falls were associated with an increased risk of poor benefit (RR, 2.17; 95% CI, 1.48-3.17; p = 0.009). Device manufacturer was associated with both patient benefit and explantation. Device 2 was associated with a reduced risk of poor benefit (RR, 0.52; 95% CI, 0.32-0.85; p = 0.009). Device 4 was associated with an increased risk of poor benefit (RR, 1.71; 95% CI, 1.14-2.55; p = 0.02) and increased risk of device explantation (RR, 2.69; 95% CI, 1.2-6.02; p = 0.03). CONCLUSIONS Patient outcome was associated with diagnosis, postimplantation falls, and device manufacturer. Further investigation is recommended to confirm associations through prospective studies that can more accurately quantify patient outcome over longer periods.

The brain plays an essential role in driving daily rhythms of behavior and metabolism in harmony with environmental light–dark cycles. Within the brain, the dorsomedial hypothalamic nucleus (DMH) has been implicated in the integrative circadian control of feeding and energy homeostasis, but the underlying cell types are unknown. Here, we identify a role for DMH leptin receptor-expressing (DMHLepR) neurons in this integrative control. Using a viral approach, we show that silencing neurotransmission in DMHLepR neurons in adult mice not only increases body weight and adiposity but also phase-advances diurnal rhythms of feeding and metabolism into the light cycle and abolishes the normal increase in dark-cycle locomotor activity characteristic of nocturnal rodents. Finally, DMHLepR-silenced mice fail to entrain to a restrictive change in food availability. Together, these findings identify DMHLepR neurons as critical determinants of the daily time of feeding and associated metabolic rhythms.

Cancer-related pain is a uniquely challenging entity for treating practitioners for a variety of reasons, including its often severe and medically refractory nature, the emotional and social circumstances surrounding the disease process, and the frequently associated limited life expectancy.

Prostheses that can restore limited vision in the profoundly blind have been under investigation for several decades. Studies using epicortical macroelectrodes and intracortical microelectrodes have validated that electrical stimulation of primary visual cortical can serve as the basis for a vision prosthesis. However, neither of these approaches has resulted in a clinically viable vision prosthesis. Epicortical macroelectrodes required high levels of electrical current to evoke visual percepts, while intracortical microelectrodes faced challenges with longevity and stability. We hypothesized that epicortical microelectrodes could evoke visual percepts at lower currents than macroelectrodes and provide improved longevity and stability compared with intracortical microelectrodes. To test this hypotheses we implanted epicortical microelectrode arrays over the primary visual cortex of a nonhuman primate. Electrical stimulation via this array was used to evaluate the ability of epicortical microstimulation to evoke differentiable visual percepts. Visual percepts were evoked using the epicortical microelectrode array, and at electrical currents notably lower than those required to evoke visual percepts on macroelectrode arrays. The electrical current thresholds for evoking visual percepts on the epicortical microelectrode array were consistent across multiple array implants and over several months. Normal vision of light perception was not impaired by multiple array implants or chronic electrical stimulation, demonstrating that no gross visual deficit resulted from the experiments. We specifically demonstrate that epicortical microelectrode interfaces can serve as the basis for a vision prosthesis and more generally may provide an approach to evoking perception in multiple sensory modalities.One Sentence SummaryElectrical stimulation of the brain via microelectrodes resting on the surface of primary visual cortex can evoke multiple differentiable visual percepts.

Facial pain occurs in approximately 80% of patients with head and neck cancers. Pain in these settings may result directly from the tumor, or indirectly as a side effect of oncological treatment of the tumor. Optimizing treatment for cancer pain of the face, therefore, involves a variety of diagnostic and treatment considerations, with the development of a successful treatment algorithm dependent on accurate diagnosis of the anatomical location of the pain, its relationship to the facial pain pathway, the type of pain being treated and, finally, patient's prognosis and preference for treatment modality. Beyond direct treatments to reduce tumor burden, a wide variety of neuro-ablative and neuro-augmentative approaches are available that may be tailored to a patient's specific pain syndrome and individual clinical context, taking into account the patient's treatment goals, life expectancy, other cancer-related medical problems, and end-of-life issues.

Defective glucoregulatory neurocircuit activity within the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of type 2 diabetes (T2D). In the ARC of T2D-Zucker Diabetic Fatty (ZDF) rats, we have identified significant changes in the composition and abundance of extracellular perineuronal nets (PNNs) that enmesh glucoregulatory neurocircuits. Imaging of ARC PNNs, which are comprised of the chondroitin sulfate (CS) proteoglycan aggrecan and attached CS glycosaminoglycans (GAGs), show that T2D-ZDF rats exhibit a 66.4% and 77.3% decrease in aggrecan in the medial and lateral ARC areas, respectively, compared to normoglycemic controls. Distinctive sulfation of the attached CS-GAG isomers (0S-, 4S-, 6S-, 4S6S-, 2S6S-CS) differentially influence the function of PNNs. Using LC-MS/MS, we provide the first description of hypothalamic CS-GAG sulfation patterns and show that in T2D-ZDF rats, levels of the ∆4S- isomer is increased, whereas ∆6S- and ∆2S6S-CS isomers are decreased, differences predicted to disrupt protein-GAG interactions involved in neurite outgrowth and favor tissue stiffening. To determine if ARC PNNs are targets for the antidiabetic effect of fibroblast growth factor 1 (FGF1), we performed intracerebroventricular (icv) injection of FGF1 in ZDF rats and report that both the hypothalamic CS-GAG sulfation patterns and content of ARC PNNs are normalized 24 d after treatment. Western blot analysis shows that the latter effect entails a 1.7-fold increase in aggrecan protein abundance. To assess the functional significance of ARC PNN restoration by FGF1, ZDF rats received an icv FGF1 injection followed by bilateral microinjection of either ChABC, a PNN digesting enzyme, or its vehicle control into the ARC. Our finding that the duration of sustained FGF1-induced blood glucose lowering was shortened following ARC PNN digestion (p Disclosure K.M. Alonge: Research Support; Self; Novo Nordisk Inc. Z. Mirzadeh: None. J. Scarlett: None. A. Logsdon: None. J.M. Brown: None. E. Cabrales: None. C.K. Chan: None. K. Kaiyala: None. M.A. Bentsen: None. W.A. Banks: None. M. Guttman: None. T.N. Wight: None. G.J. Morton: Research Support; Self; Novo Nordisk A/S. M.W. Schwartz: Research Support; Self; Novo Nordisk A/S. Funding National Institutes of Health (P30DK017047, F32DK122662, R01DK101997, R01DK089056, R01DK083042, K08DK114474, R01GM127579, K12NS080223, P30DK035816); Barrow Neurological Foundation (1800253005); University of Washington; Novo Nordisk (CMS431104); Novo Nordisk Foundation (NNF170C0024328, NNF10CC1016515)

Glucose-sensitive neurons have long been implicated in glucose homeostasis, but how glucose-sensing information is used by the brain in this process remains uncertain. Here, we propose a model in which (1) information relevant to the circulating glucose level is essential to the proper function of this regulatory system, (2) this input is provided by neurons located outside the blood-brain barrier (BBB) (since neurons situated behind the BBB are exposed to glucose in brain interstitial fluid, rather than that in the circulation), and (3) while the efferent limb of this system is comprised of neurons situated behind the BBB, many of these neurons are also glucose sensitive. Precedent for such an organizational scheme is found in the thermoregulatory system, which we draw upon in this framework for understanding the role played by brain glucose sensing in glucose homeostasis.

OBJECTIVEVentral intermediate nucleus deep brain stimulation (DBS) for essential tremor is traditionally performed with intraoperative test stimulation and conscious sedation, without general anesthesia (GA). Recently, the authors reported retrospective data on 17 patients undergoing DBS after induction of GA with standardized anatomical coordinates on T1-weighted MRI sequences used for indirect targeting. Here, they compare prospectively collected data from essential tremor patients undergoing DBS both with GA and without GA (non-GA).METHODSClinical outcomes were prospectively collected at baseline and 3-month follow-up for patients undergoing DBS surgery performed by a single surgeon. Stereotactic, euclidean, and radial errors of lead placement were calculated. Functional (activities of daily living), quality of life (Quality of Life in Essential Tremor [QUEST] questionnaire), and tremor severity outcomes were compared between groups.RESULTSFifty-six patients underwent surgery: 16 without GA (24 electrodes) and 40 with GA (66 electrodes). The mean baseline functional scores and QUEST summary indices were not different between groups (p = 0.91 and p = 0.59, respectively). Non-GA and GA groups did not differ significantly regarding mean postoperative percentages of functional improvement (non-GA, 47.9% vs GA, 48.1%; p = 0.96) or QUEST summary indices (non-GA, 79.9% vs GA, 74.8%; p = 0.50). Accuracy was comparable between groups (mean radial error 0.9 ± 0.3 mm for non-GA and 0.9 ± 0.4 mm for GA patients) (p = 0.75). The mean euclidean error was also similar between groups (non-GA, 1.1 ± 0.6 mm vs GA, 1.2 ± 0.5 mm; p = 0.92). No patient had an intraoperative complication, and the number of postoperative complications was not different between groups (non-GA, n = 1 vs GA, n = 10; p = 0.16).CONCLUSIONSDBS performed with the patient under GA to treat essential tremor is as safe and effective as traditional DBS surgery with intraoperative test stimulation while the patient is under conscious sedation without GA.

OBJECTIVERecent studies have shown similar clinical outcomes between Parkinson disease (PD) patients treated with deep brain stimulation (DBS) under general anesthesia without microelectrode recording (MER), so-called “asleep” DBS, and historical cohorts undergoing “awake” DBS with MER guidance. However, few studies include internal controls. This study aims to compare clinical outcomes after globus pallidus internus (GPi) and subthalamic nucleus (STN) DBS using awake and asleep techniques at a single institution.METHODSPD patients undergoing awake or asleep bilateral GPi or STN DBS were prospectively monitored. The primary outcome measure was stimulation-induced change in motor function off medication 6 months postoperatively, measured using the Unified Parkinson’s Disease Rating Scale part III (UPDRS-III). Secondary outcomes included change in quality of life, measured by the 39-item Parkinson’s Disease Questionnaire (PDQ-39), change in levodopa equivalent daily dosage (LEDD), stereotactic accuracy, stimulation parameters, and adverse events.RESULTSSix-month outcome data were available for 133 patients treated over 45 months (78 GPi [16 awake, 62 asleep] and 55 STN [14 awake, 41 asleep]). UPDRS-III score improvement with stimulation did not differ between awake and asleep groups for GPi (awake, 20.8 points [38.5%]; asleep, 18.8 points [37.5%]; p = 0.45) or STN (awake, 21.6 points [40.3%]; asleep, 26.1 points [48.8%]; p = 0.20) targets. The percentage improvement in PDQ-39 and LEDD was similar for awake and asleep groups for both GPi (p = 0.80 and p = 0.54, respectively) and STN cohorts (p = 0.85 and p = 0.49, respectively).CONCLUSIONSIn PD patients, bilateral GPi and STN DBS using the asleep method resulted in motor, quality-of-life, and medication reduction outcomes that were comparable to those of the awake method.

5-Aminoleveulinic acid sonodynamic therapy (5-ALA SDT) is a drug-device strategy that exploits the metabolic liabilities of cancer. Following systemic administration of 5-ALA, aberrant tumor metabolism leads to accumulation of protoporphyrin-IX (PpIX). Activation of PpIX by non-invasive, non-ablative magnetic resonance-guided focused ultrasound (MRgFUS) induces reactive oxygen species and tumor cell death. This first-in-human Phase 0/1 study investigates the feasibility, safety, and biological effects of 5-ALA SDT in recurrent glioblastoma (GBM) patients. Six hours prior to SDT, adult patients with recurrent GBM are administered Sonala-001 (10mg/kg), an IV formulation of 5-ALA. In a Dose-Escalation Arm, 9-18 patients are assigned to one of three ascending acoustic energy doses of MRgFUS (200J/400J/800J, measured at transducer surface), followed by a four-day interval to planned tumor resection. In each patient, half the tumor volume, including Gadolinium-enhancing and nonenhancing tumor, is targeted with MRgFUS and the other half serves as an internal control. Using tumor pharmacodynamic endpoints, the Minimum Biological Dose (MBD) associated with 5-ALA SDT response is identified. In a subsequent Time-Escalation Arm, 12 patients are treated at the MBD and assigned to one of two time-intervals between SDT and resection. As of May 1, accrual to the 200J dose level (n=3) is complete without significant drug- or device-related adverse events. No cellular or radiographic changes to non-targeted tissue were detected. The median Cmax for 5-ALA and PpIX were 307 µM and 319 nM, respectively. The oxidative stress biomarkers 4-hydroxynonenal, glutathione, cysteine, and thiol were significantly elevated in treated tissue vs. control. Similarly, the apoptosis biomarker cleaved caspase-3 was increased in treated tumor vs. control (median, 48.6% vs. 29.6%, p=0.05). This first-in-human experience with a new therapeutic modality for recurrent glioblastoma patients demonstrates that 5-ALA SDT is safe at 200J. Sonodynamic therapy leads to targeted oxidative stress and tumor cell death in human glioblastoma tissue.

OBJECTIVEAs the number of deep brain stimulation (DBS) procedures performed under general anesthesia (“asleep” DBS) increases, it is more important to assess the rates of adverse events, inpatient lengths of stay (LOS), and 30-day readmission rates in patients undergoing these procedures compared with those in patients undergoing traditional “awake” DBS without general anesthesia.METHODSAll patients in an institutional database who had undergone awake or asleep DBS procedures performed by a single surgeon between August 2011 and August 2014 were reviewed. Adverse events, inpatient LOS, and 30-day readmissions were analyzed.RESULTSA total of 490 electrodes were placed in 284 patients, of whom 126 (44.4%) underwent awake surgery and 158 (55.6%) underwent asleep surgery. The most frequent overall complication for the cohort was postoperative mental status change (13 patients [4.6%]), followed by hemorrhage (4 patients [1.4%]), seizure (4 patients [1.4%]), and hardware-related infection (3 patients [1.1%]). Mean LOS for all 284 patients was 1.19 ± 1.29 days (awake: 1.06 ± 0.46 days; asleep: 1.30 ± 1.67 days; p = 0.08). Overall, the 30-day readmission rate was 1.4% (1 awake patient, 3 asleep patients). There were no significant differences in complications, LOS, and 30-day readmissions between awake and asleep groups.CONCLUSIONSBoth awake and asleep DBS can be performed safely with low complication rates. The authors found no significant differences between the 2 procedure groups in adverse events, inpatient LOS, and 30-day readmission rates.

We recently showed that perineuronal nets (PNNs) enmesh glucoregulatory neurons in the arcuate nucleus (Arc) of the mediobasal hypothalamus (MBH)

Facial pain occurs in approximately 80% of patients with head and neck cancers. Pain in these settings may result directly from the tumor, or indirectly as a side effect of oncological treatment of the tumor. Optimizing treatment for cancer pain of the face, therefore, involves a variety of diagnostic and treatment considerations, with the development of a successful treatment algorithm dependent on accurate diagnosis of the anatomical location of the pain, its relationship to the facial pain pathway, the type of pain being treated and, finally, patient's prognosis and preference for treatment modality. Beyond direct treatments to reduce tumor burden, a wide variety of neuro-ablative and neuro-augmentative approaches are available that may be tailored to a patient's specific pain syndrome and individual clinical context, taking into account the patient's treatment goals, life expectancy, other cancer-related medical problems, and end-of-life issues.

Lasting remission of hyperglycemia can be achieved in rodent models of type 2 diabetes by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF-1), and the mediobasal hypothalamus (MBH) was recently identified as a target for this effect. To investigate the cellular basis of FGF-1 action in the MBH, we combined whole tissue RNA-sequencing with large-scale single cell and single nuclei RNA-sequencing to generate >60,000 single cell transcriptomes from diabetic ob/ob mice harvested 5d after a single icv injection of either FGF-1 or vehicle. Of the 4 known FGF receptor genes, 3 were expressed in the MBH, primarily by glial cells rather than neurons. Employing weighted gene co-expression network analysis, distinct modules that correlated with icv FGF-1 treatment were identified, again primarily in glial cells. In astrocytes, the response to FGF-1 closely paralleled the neuroprotective “A2” transcriptional phenotype induced by stroke, and both the proportion of differentiating oligodendrocytes and genes involved in extracellular matrix remodeling of the perivascular space were also upregulated by FGF-1. By comparison, the neuronal response to icv FGF-1 was one of generalized inhibition, including decreased expression of Agrp and Pmch (encoding agouti-related peptide and pro-melanin-concentrating hormone (MCH), respectively). Since Agrp and MCH neurons are activated in ob/ob mice, and since this effect predisposes to hyperglycemia, these findings support a model in which sustained inhibition of these and perhaps other neuronal subsets underlies diabetes remission induced by icv FGF-1. Moreover, this neuronal inhibition appears to be driven by neuroprotective glial responses elicited by FGF-1. These data add to growing evidence of a crucial role for neuron-glia interactions in hypothalamic control of glucose homeostasis. Disclosure M.A. Bentsen: None. D. Rausch: None. Z. Mirzadeh: Consultant; Self; Novo Nordisk A/S. J. Scarlett: None. J.M. Brown: None. K.M. Alonge: Research Support; Self; Novo Nordisk Inc. T.H. Meek: Employee; Self; Novo Nordisk Inc. A. Secher: Employee; Spouse/Partner; Gubra. Employee; Self; Novo Nordisk A/S. Speaker's Bureau; Spouse/Partner; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. R. Jorgensen: Employee; Self; Novo Nordisk A/S. T. Pers: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Funding National Institutes of Health; Novo Nordisk Foundation; Lundbeck Foundation; Novo Nordisk A/S

Abnormal development of neurocircuits in the hypothalamic arcuate nucleus (ARC) is a common feature of genetic and acquired (e.g., postnatal overnutrition) models of obesity and type 2 diabetes (T2D). In leptin-deficient ob/ob mice, developmental defects occur both in efferent projections from the ARC to downstream circuits and in afferent GABAergic input onto ARC neurons. A developmental critical period (CP) has been proposed based on the temporally-restricted requirement for leptin, during the first month of life, to enable normal projections of ARC Agrp neurons in ob/ob mice. We recently described the formation of perineuronal nets (PNNs) around ARC Agrp neurons during the latter half of this CP, shortly following the peak of the postnatal leptin surge. PNNs, which are extracellular matrix specializations that restrict CP plasticity in neurons they enmesh, were overabundant in the ARC of adult ob/ob mice, suggesting that ARC neurocircuit dysfunction contributes to their metabolic phenotype. To remodel ARC neurocircuits containing PNN-enmeshed cells, we engrafted a special population of GABAergic inhibitory interneurons derived from the embryonic brain medial ganglionic eminence (MGE). Here we show that MGE interneurons derived from E13.5 GAD67-GFP embyros and transplanted bilaterally into the ob/ob ARC survive, integrate into local circuits, and form GABAergic synapses. Preliminary metabolic phenotyping shows that compared to vehicle injection, transplanted MGE cells (∼5000 MGE cells/ARC) induce a sustained reduction of hyperglycemia lasting for at least one month (1-month average BG: veh 301±12 vs. MGE 189±12 mg/dl, n=4/group, p=0.022) without significant effects on food intake or body weight. These findings suggest that sustained diabetes remission can be achieved by remodeling ARC neurocircuits through MGE cell transplantation. Disclosure Z. Mirzadeh: Consultant; Self; Novo Nordisk A/S. E. Cabrales: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Funding National Institute of Neurological Disorders and Stroke

OBJECT Deep brain stimulation (DBS) performed under general anesthesia (“asleep” DBS) has not been previously reported for essential tremor. This is in part due to the inability to visualize the target (the ventral intermediate nucleus [VIM]) on MRI. The authors evaluate the efficacy of this asleep technique in treating essential tremor by indirect VIM targeting. METHODS The authors retrospectively reviewed consecutive cases of initial DBS for essential tremor performed by a single surgeon. DBS was performed with patients awake (n = 40, intraoperative test stimulation without microelectrode recording) or asleep (n = 17, under general anesthesia). Targeting proceeded with standardized anatomical coordinates on preoperative MRI. Intraoperative CT was used for stereotactic registration and lead position confirmation. Functional outcomes were evaluated with pre- and postoperative Bain and Findley Tremor Activities of Daily Living scores. RESULTS A total of 29 leads were placed in asleep patients, and 60 were placed in awake patients. Bain and Findley Tremor Activities of Daily Living Questionnaire scores were not significantly different preoperatively for awake versus asleep cohorts (p = 0.2). The percentage of postoperative improvement was not significantly different between asleep (48.6%) and awake (45.5%) cohorts (p = 0.35). Euclidean error (mm) was higher for awake versus asleep patients (1.7 ± 0.8 vs 1.2 ± 0.4, p = 0.01), and radial error (mm) trended higherfor awake versus asleep patients (1.3 ± 0.8 vs 0.9 ± 0.5, p = 0.06). There were no perioperative complications. CONCLUSIONS In the authors’ initial experience, asleep VIM DBS for essential tremor without intraoperative test stimulation can be performed safely and effectively.

OBJECT Recent studies show that deep brain stimulation can be performed safely and accurately without microelectrode recording ortest stimulation but with the patient under general anesthesia. The procedure couples techniques for direct anatomical targeting on MRI with intraoperative imaging to verify stereotactic accuracy. However, few authors have examined the clinical outcomes of Parkinson’s disease (PD) patients after this procedure. The purpose of this study was to evaluate PD outcomes following “asleep” deep brain stimulation in the globus pallidus internus (GPi). METHODS The authors prospectively examined all consecutive patients with advanced PD who underwent bilateral GPi electrode placement while under general anesthesia. Intraoperative CT was used to assess lead placement accuracy. The primary outcome measure was the change in the off-medication Unified Parkinson’s Disease Rating Scale motor score 6 months after surgery. Secondary outcomes included effects on the 39-Item Parkinson’s Disease Questionnaire (PDQ-39) scores, on-medication motor scores, and levodopa equivalent daily dose. Lead locations, active contact sites, stimulation parameters, and adverse events were documented. RESULTS Thirty-five patients (24 males, 11 females) had a mean age of 61 years at lead implantation. The mean radial error off plan was 0.8 mm. Mean coordinates for the active contact were 21.4 mm lateral, 4.7 mm anterior, and 0.4 mm superior to the midcommissural point. The mean off-medication motor score improved from 48.4 at baseline to 28.9 (40.3% improvement) at 6 months (p < 0.001). The PDQ-39 scores improved (50.3 vs 42.0; p = 0.03), and the levodopa equivalent daily dose was reduced (1207 vs 1035 mg; p = 0.004). There were no significant adverse events. CONCLUSIONS Globus pallidus internus leads placed with the patient under general anesthesia by using direct anatomical targeting resulted in significantly improved outcomes as measured by the improvement in the off-medication motor score at 6 months after surgery.

In leptin-deficient ob/ob mice, obesity and diabetes are associated with abnormal development of neurocircuits in the hypothalamic arcuate nucleus (ARC)1, a critical brain area for energy and glucose homoeostasis2,3. Because this developmental defect can be remedied by systemic leptin administration, but only if given before postnatal day 28, a critical period for leptin-dependent development of ARC neurocircuits has been proposed4. In other brain areas, critical-period closure coincides with the appearance of perineuronal nets (PNNs), extracellular matrix specializations that restrict the plasticity of neurons that they enmesh5. Here we report that in humans and rodents, subsets of neurons in the mediobasal aspect of the ARC are enmeshed in PNN-like structures. In mice, these neurons are densely packed into a continuous ring that encircles the junction of the ARC and median eminence, which facilitates exposure of ARC neurons to the circulation. Most of the enmeshed neurons are both γ-aminobutyric acid-ergic and leptin-receptor positive, including a majority of Agouti-related-peptide neurons. Postnatal formation of the PNN-like structures coincides precisely with closure of the critical period for maturation of Agouti-related-peptide neurons and is dependent on input from circulating leptin, because postnatal ob/ob mice have reduced ARC PNN-like material that is restored by leptin administration during the critical period. We conclude that neurons crucial to metabolic homoeostasis are enmeshed in PNN-like structures and organized into a densely packed cluster situated circumferentially at the ARC–median eminence junction, where metabolically relevant humoral signals are sensed.

The retrosigmoid approach for microvascular decompression of the trigeminal nerve (TN) is an established and highly effective technique for the treatment of trigeminal neuralgia due to vascular compression. It is common to place a pledget or other cushion material between the source of vascular compression, typically the superior cerebellar artery (SCA), and the TN after vessel mobilization and decompression. A previous study demonstrated the use of a tentorial sling on the SCA to maintain decompression of the TN, with encouraging results. 1 In this video, we demonstrate a novel technique using a Gore-Tex (W. L. Gore & Associates, Newark, Delaware) sling wrapped around the SCA and secured with a vascular clip on the petrous dura to maintain decompression of the TN ( Video 1 ). Informed consent was obtained from the patient. He tolerated the procedure well with excellent pain relief and was discharged on postoperative day 1.

OBJECTIVEDeep brain stimulation (DBS) is a well-established, evidence-based therapy with FDA approval for Parkinson’s disease and essential tremor. Despite the early successful use of DBS to target the sensory thalamus for intractable facial pain, subsequent studies pursuing various chronic pain syndromes reported variable efficacy, keeping DBS for pain as an investigational and “off-label” use. The authors report promising results for a contemporary series of patients with intractable facial pain who were treated with DBS.METHODSPain outcomes for 7 consecutive patients with unilateral, intractable facial pain undergoing DBS of the ventral posteromedial nucleus of the thalamus (VPM) and the periaqueductal gray (PAG) were retrospectively reviewed. Pain was assessed preoperatively and at multiple postoperative time points using the visual analog scale (VAS), the Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2), and the Pain Disability Index (PDI).RESULTSVAS scores significantly decreased from a mean ± SD of 9.0 ± 1.3 preoperatively to 2.6 ± 1.5 at 1 year postoperatively (p = 0.001). PDI scores decreased from a mean total of 48.5 to 28.5 (p = 0.01). SF-MPQ-2 scores decreased from a mean of 4.6 to 2.4 (p = 0.03). Notably, several patients did not experience maximum improvement until 6–9 months postoperatively, correlating with repeated programming adjustments.CONCLUSIONSDBS of the VPM and PAG is a potential therapeutic option for patients suffering from severe, intractable facial pain refractory to other interventions. Improved efficacy may be observed over time with close follow-up and active DBS programming adjustments.

Recently, lasting remission of hyperglycemia was achieved in rodent models of type 2 diabetes (T2D) by a single intracerebroventricular (icv) injection of FGF-1. While the mechanism underlying this effect is unknown, the lack of association with changes of body fat mass or risk of hypoglycaemia raises the possibility that icv FGF-1 normalizes the defended level of glycemia, rather than simply lowering blood glucose levels. Recent work from our lab has identified gluco-regulatory neurocircuits in the mediobasal hypothalamus (MBH) as targets for this FGF-1 effect. To investigate the mechanism underlying FGF-1 action in this brain area, we used large-scale single cell RNA-sequencing to identify and characterize FGF-1-responsive cells in mouse MBH. Based on >70,000 single cell MBH transcriptomes from diabetic ob/ob mice harvested 5d after a single icv injection of either FGF-1 or vehicle, we identified >20 cell clusters and >900 cell type-specific differentially expressed genes (p Disclosure M.A. Bentsen: None. D. Rausch: None. J. Scarlett: None. K.M. Alonge: None. P.N. Timshel: None. Z. Mirzadeh: None. A. Secher: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Gubra. R. Jorgensen: Employee; Self; Novo Nordisk Inc.. T. Pers: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S.

Background: Many surgeons utilize assistants to perform procedures in more than one operating room at a given time using a practice known as overlapping surgery. Debate has continued as to whether overlapping surgery improves the efficiency and access to care or risks patient safety and outcomes. Objective: To examine effects of overlapping surgery in deep brain stimulation (DBS) for movement disorders. Methods: In this retrospective analysis of overlapping and non-overlapping cases, we evaluated stereotactic accuracy, operative duration, length of hospital stay, and the presence of hemorrhage, wound-related complications, and hardware-related complications requiring revision in adults with movement disorders undergoing DBS. Results: Of 324 cases, 141 (43.5%) were overlapping and 183 (56.5%) non-overlapping. Stereotactic error, number of brain penetrations, and postoperative length of hospitalization did not differ significantly (p ≥ 0.08) between the overlapping and non-overlapping groups. Mean operative duration was significantly longer for overlapping (81/141 [57.4%], 189.5 ± 10.8 min) than for non-overlapping cases (79/183 [43.2%], 169.9 ± 7.6 min; p = 0.004). There were no differences in rates of wound-related complications or hemorrhages, but overlapping cases had a significantly higher rate of hardware-related complications requiring revision (7/141 [5.0%] vs. 0/183 [0%]; p = 0.002). Conclusions: Overlapping and non-overlapping cases had comparable DBS lead placement accuracy. Overlapping cases had a longer operative duration and had a higher rate of hardware-related complications requiring revision.

Alzheimer's disease is a major worldwide health problem with no effective therapy. Deep brain stimulation (DBS) has emerged as a useful therapy for certain movement disorders and is increasingly being investigated for treatment of other neural circuit disorders. Here we review the rationale for investigating DBS as a therapy for Alzheimer's disease. Phase I clinical trials of DBS targeting memory circuits in Alzheimer's disease patients have shown promising results in clinical assessments of cognitive function, neurophysiological tests of cortical glucose metabolism, and neuroanatomical volumetric measurements showing reduced rates of atrophy. These findings have been supported by animal studies, where electrical stimulation of multiple nodes within the memory circuit have shown neuroplasticity through stimulation-enhanced hippocampal neurogenesis and improved performance in memory tasks. The precise mechanisms by which DBS may enhance memory and cognitive functions in Alzheimer's disease patients and the degree of its clinical efficacy continue to be examined in ongoing clinical trials.

Background Deep brain stimulation (DBS) is well-established, evidence-based therapy for Parkinson disease, essential tremor, and primary dystonia. Clinical outcome studies have recently shown that "asleep" DBS lead placement, performed using intraoperative imaging with stereotactic accuracy as the surgical endpoint, has motor outcomes comparable to traditional "awake" DBS using microelectrode recording (MER), but with shorter case times and improved speech fluency. Objective To identify procedural variables in DBS surgery associated with improved surgical efficiency and stereotactic accuracy. Methods Retrospective review of 323 cases with 546 leads placed (August 2011-October 2014). In 52% (n = 168) of cases, patients were asleep under general anesthesia without MER. Multivariate regression identified independent predictors of reduced surgery time and improved stereotactic accuracy. Results MER was an independent contributor to increased procedure time (+44 min; P = .03). Stereotactic accuracy was better in asleep patients. Accuracy was improved with frame-based stereotaxy at head of bed 0° vs frameless stereotaxy at head of bed 30°. Improved accuracy was also associated with shorter procedures (r = 0.17; P = .049). Vector errors were evenly distributed around the planned target for the globus pallidus internus, but directionally skewed for the subthalamic (medial-posterior) and ventral intermediate nuclei (medial-anterior). Conclusion Distinct procedural variables in DBS surgery are associated with reduced case times and improved stereotactic accuracy.

Deep brain stimulation is typically performed with intraoperative microelectrode recording and test stimulation for target confirmation. Recent studies have shown accurate, clinically efficacious results after lead placement without microelectrode recording or test stimulation, using interventional magnetic resonance imaging (MRI) or intraoperative computed tomography (CT; iCT) for verification of accuracy. The latter relies on CT–MRI fusion. To validate CT–MRI fusion in this setting, we compared stereotactic coordinates determined intraoperatively using CT–MRI fusion with those obtained on postoperative MRI. Deep brain stimulation electrodes were implanted with patients under general anesthesia. Direct targeting was performed on preoperative MRI, which was merged with preimplantation iCT images for stereotactic registration and postimplantation iCT images for accuracy confirmation. Magnetic resonance imaging was obtained 6 weeks postoperatively for comparison. Postoperative MRI was obtained for 48 patients, with 94 leads placed over a 1-year period. Vector error of the targeted contact relative to the initial plan was 1.1 ± 0.7 mm on iCT and 1.6 ± 0.7 mm on postoperative MRI. Variance comparisons (F-tests) showed that the discrepancy between iCT- and postoperative MRI-determined errors was attributable to measurement error on postoperative MRI, as detected in inter-rater reliability testing. In multivariate analysis, improved lead placement accuracy was associated with frame-based stereotaxy with the head of the bed at 0° compared with frameless stereotaxy with the head of the bed at 30° (P = 0.037). Intraoperative CT can be used to determine lead placement accuracy in deep brain stimulation surgery. The discrepancy between coordinates determined intraoperatively by CT–MRI fusion and postoperatively by MRI can be accounted for by inherent measurement error. © 2014 International Parkinson and Movement Disorder Society

Object After complete resection and radiation therapy, the 10-year overall survival rates for adult patients with posterior fossa ependymomas approach 85%. This favorable outcome profile emphasizes the critical importance of functional preservation to this patient population. Here, the authors identify predictors of functional outcome following microsurgical resection of adult posterior fossa ependymomas. Methods The authors identified adult patients with newly diagnosed WHO Grade II posterior fossa ependymomas who underwent microsurgical resection at the Barrow Neurological Institute from 1990 to 2011. Clinical and radiographic variables were collected, including volumetric extent of resection, foramen of Luschka extension, cystic changes, peritumoral T2 signal changes, Karnofsky Performance Scale (KPS) score, National Institutes of Health Stroke Scale (NIHSS) score, progression-free survival (PFS), and overall survival (OS). Results Forty-five patients were identified, with a median clinical follow-up of 103 months. The median PFS and OS were 6.8 and 8.6 years, respectively. Extent of resection and adjuvant radiotherapy were predictive of improved PFS (p = 0.005) and were nonsignificantly associated with improved OS. Univariate analysis revealed that tumor size (p < 0.001), cystic changes (p < 0.01), postoperative T2 signal (p < 0.01), and CSF diversion (p = 0.048) predicted functional and neurological recovery rates, based on KPS and NIHSS scores, respectively. Multivariate regression analysis identified tumor size (p < 0.001), cystic changes (p = 0.01), and CSF diversion (p = 0.02) as independent predictors of slower functional recovery, while only tumor size (p = 0.007) was an independent predictor of neurological recovery. Specifically, by 6 weeks postoperatively, baseline KPS score was recovered by only 43.8% of patients with tumors larger than 30 cm3 (vs 72.4% patients with tumors < 30 cm3), 35.3% of patients with cystic tumors (vs 78.6% of patients with noncystic tumors), and 46.7% of patients requiring CSF diversion (vs 70% of patients not requiring CSF diversion). Conclusions Greater extent of resection and adjuvant radiotherapy significantly improve PFS in adult patients with posterior fossa ependymomas. Tumor size, cystic changes, and the need for CSF diversion were independent predictors of the rate of functional recovery in this patient population. Taken together, these functional outcome predictors may guide preoperative estimations of recovery following microsurgical resection.

Objective Although performing deep brain stimulation (DBS) with the patient under general anesthesia without microelectrode recording (MER) or intraoperative test stimulation (ITS) for movement disorders (“asleep” DBS) has become increasingly popular, its feasibility is based on the untested assumption that stereotactic accuracy correlates with positive clinical outcomes. To investigate outcomes after asleep DBS without MER or neurophysiological testing, we reviewed the medical literature on the topic. Methods We searched PubMed to identify all studies reporting clinical outcomes for patients who underwent DBS without MER or ITS for Parkinson disease (PD) or essential tremor (ET). Results We identified 9 studies with level 3b (n = 3) or level 4 evidence (n = 6). Eight PD studies (220 patients) reported asleep placement of 431 electrodes (341 subthalamic nucleus, 90 globus pallidus interna). Unified Parkinson Disease Rating Scale motor examination−III scores for 208 patients demonstrated significant improvement (40.2%−65%) at 6–12 months. The levodopa equivalent daily dose for 115 patients was significantly reduced (14%−49.3%) at 6–12 months in 103 patients. Two studies with a comparison cohort undergoing “awake” DBS with MER found no differences in postoperative Unified Parkinson Disease Rating Scale−III improvement or levodopa equivalent daily dose reduction. One study of asleep DBS for ET found no difference in functional outcomes between 17 patients undergoing asleep ventral intermediate nucleus DBS and 40 patients undergoing awake placement with ITS. Conclusions Initial evidence suggests that asleep DBS can be performed safely for PD and ET with good clinical outcomes. Long-term follow-up, larger cohorts, and double-armed studies are needed to validate these initial results.

Background: Deep brain stimulation (DBS) hardware infection is a serious complication, often resulting in multiple hardware salvage attempts, hospitalizations, and long-term antibiotic therapy. Objectives: We aimed to quantify the costs of DBS hardware-related infections in patients undergoing eventual device explantation. Methods: Of 362 patients who underwent 530 electrode placements (1 January 2010 to 30 December 2014), 16 (4.4%) had at least 2 hardware salvage procedures. Most (n = 15 [93.8%]) required complete explantation due to recurrent infection. Financial data (itemized hospital and physician costs) were available for 13 patients and these were analyzed along with the demographic data. Results: Each patient underwent 1-5 salvage procedures (mean 2.5 ± 1.4; median 2). The mean total cost for a patient undergoing the median number of revisions (n = 2), device explantation, and subsequent reimplantation after infection clearance was USD 75,505; just over half this cost (54.2% [USD 40,960]) was attributable to reimplantation, and nearly one-third (28.9% [USD 21,816]) was attributable to hardware salvage procedures. Operating-room costs were the highest cost category for hardware revision and explantation. Medical and surgical supplies accounted for the highest reimplantation cost. Conclusions: DBS infection incurs significant health care costs associated with hardware salvage attempts, explantation, and reimplantation. The highest cost categories are operating-room services and medical and surgical supplies.

Two neurogenic regions have been described in the adult brain, the lateral ventricle subventricular zone and the dentate gyrus subgranular zone. It has been suggested that neural stem cells also line the central canal of the adult spinal cord. Using transmission and scanning electron microscopy and immunostaining, we describe here the organization and cell types of the central canal epithelium in adult mice. The identity of dividing cells was determined by 3D ultrastructural reconstructions of [3H]thymidine-labeled cells and confocal analysis of bromodeoxyuridine labeling. The most common cell type lining the central canal had two long motile (9+2) cilia and was vimentin+, CD24+, FoxJ1+, Sox2+, and CD133+, but nestin- and glial fibrillary acidic protein (GFAP)-. These biciliated ependymal cells of the central canal (Ecc) resembled E2 cells of the lateral ventricles, but their basal bodies were different from those of E2 or E1 cells. Interestingly, we frequently found Ecc cells with two nuclei and four cilia, suggesting they are formed by incomplete cytokinesis or cell fusion. GFAP+ astrocytes with a single cilium and an orthogonally oriented centriole were also observed. The majority of dividing cells corresponded to biciliated Ecc cells. Central canal proliferation was most common during the active period of spinal cord growth. Pairs of labeled Ecc cells were observed within the central canal in adult mice 2.5 weeks post labeling. Our work suggests that the vast majority of postnatal dividing cells in the central canal are Ecc cells and their proliferation is associated with the growth of the spinal cord. J. Comp. Neurol. 520:35283552, 2012. (C) 2012 Wiley Periodicals, Inc.