Central Nervous System Control of Glucose Homeostasis: A Therapeutic Target for Type 2 Diabetes?

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.

Factors Contributing to Spinal Cord Stimulation Outcomes for Chronic Pain.

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.

Neurosurgical Treatments for Cancer Pain.

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.

Accuracy in Deep Brain Stimulation Electrode Placement: A Single-Surgeon Retrospective Analysis of Sterotactic Error in Overlapping and Non-Overlapping Surgical Cases.

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.

Deep brain stimulation for intractable neuropathic facial pain.

OBJECTIVE Deep 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. METHODS Pain 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). RESULTS VAS 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. CONCLUSIONS DBS 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.

Corridors of migrating neurons in the human brain and their decline during infancy.

The subventricular zone of many adult non-human mammals generates large numbers of new neurons destined for the olfactory bulb. Along the walls of the lateral ventricles, immature neuronal progeny migrate in tangentially oriented chains that coalesce into a rostral migratory stream (RMS) connecting the subventricular zone to the olfactory bulb. The adult human subventricular zone, in contrast, contains a hypocellular gap layer separating the ependymal lining from a periventricular ribbon of astrocytes. Some of these subventricular zone astrocytes can function as neural stem cells in vitro, but their function in vivo remains controversial. An initial report found few subventricular zone proliferating cells and rare migrating immature neurons in the RMS of adult humans. In contrast, a subsequent study indicated robust proliferation and migration in the human subventricular zone and RMS. Here we find that the infant human subventricular zone and RMS contain an extensive corridor of migrating immature neurons before 18 months of age but, contrary to previous reports, this germinal activity subsides in older children and is nearly extinct by adulthood. Surprisingly, during this limited window of neurogenesis, not all new neurons in the human subventricular zone are destined for the olfactory bulb--we describe a major migratory pathway that targets the prefrontal cortex in humans. Together, these findings reveal robust streams of tangentially migrating immature neurons in human early postnatal subventricular zone and cortex. These pathways represent potential targets of neurological injuries affecting neonates.

Cost of Deep Brain Stimulation Infection Resulting in Explantation.

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.

The rationale for deep brain stimulation in Alzheimer's disease.

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.

Combinations of genetic mutations in the adult neural stem cell compartment determine brain tumour phenotypes.

It has been suggested that intrinsic brain tumours originate from a neural stem/progenitor cell population in the subventricular zone of the post-natal brain. However, the influence of the initial genetic mutation on the phenotype as well as the contribution of mature astrocytes to the formation of brain tumours is still not understood. We deleted Rb/p53, Rb/p53/PTEN or PTEN/p53 in adult subventricular stem cells; in ectopically neurografted stem cells; in mature parenchymal astrocytes and in transplanted astrocytes. We found that only stem cells, but not astrocytes, gave rise to brain tumours, independent of their location. This suggests a cell autonomous mechanism that enables stem cells to generate brain tumours, whereas mature astrocytes do not form brain tumours in adults. Recombination of PTEN/p53 gave rise to gliomas whereas deletion of Rb/p53 or Rb/p53/PTEN generated primitive neuroectodermal tumours (PNET), indicating an important role of an initial Rb loss in driving the PNET phenotype. Our study underlines an important role of stem cells and the relevance of initial genetic mutations in the pathogenesis and phenotype of brain tumours.

Validation of CT-MRI fusion for intraoperative assessment of stereotactic accuracy in DBS surgery.

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.

Reciprocal Changes in Sagittal Spinal Alignment After L5-S1 Anterior Lumbar Interbody Fusion.

OBJECTIVE: Degenerative diseases of the lumbar spine decrease lumbar lordosis (LL). Anterior lumbar interbody fusion (ALIF) at the L5-S1 disc space improves segmental lordosis, LL, and sagittal balance. This study investigated reciprocal changes in spinopelvic alignment after L5-S1 ALIF. METHODS: A retrospective chart review identified patients who underwent L5-S1 ALIF with or without posterior fixation at a single institution (November 1, 2016 to October 1, 2021). Changes in pelvic tilt, sacral slope, proximal LL (L1-L4), distal LL (L4-S1), total LL (L1-S1), segmental lordosis, pelvic incidence-LL mismatch, thoracic kyphosis, cervical lordosis, and sagittal vertical axis were measured on preoperative and postoperative radiographs. RESULTS: Forty-eight patients were identified. Immediate postoperative radiographs were obtained at a mean (SD) of 17 (20) days after surgery; delayed radiographs were obtained 184 (82) days after surgery. After surgery, patients had significantly decreased pelvic tilt (15.71° [7.25°] vs. 17.52° [7.67°], P = 0.003) and proximal LL (11.86° [10.67°] vs. 16.03° [10.45°], P < 0.001) and increased sacral slope (39.49° [9.27°] vs. 36.31° [10.39°], P < 0.001), LL (55.35° [13.15°] vs. 51.63° [13.38°], P = 0.001), and distal LL (43.17° [9.33°] vs. 35.80° [8.02°], P < 0.001). Segmental lordosis increased significantly at L5-S1 and decreased significantly at L2-3, L3-4, and L4-5. Lordosis distribution index increased from 72.55 (19.53) to 81.38 (22.83) (P < 0.001). CONCLUSIONS: L5-S1 ALIF was associated with increased L5-S1 segmental lordosis accompanied by pelvic anteversion and a reciprocal decrease in proximal LL. These changes may represent a reversal of compensatory mechanisms, suggesting an overall relaxation of spinopelvic alignment after L5-S1 ALIF.

Radiographic and Clinical Outcomes After Stand-Alone Anterior Lumbar Interbody Fusion for Symptomatic L5-S1 Retrolisthesis.

BACKGROUND AND OBJECTIVES: Degenerative lumbar spondylolisthesis is associated with significant pain and disability. The literature on the treatment options and clinical outcomes for lumbar anterolisthesis is robust, but very few reports specifically evaluate lumbar retrolisthesis. This study investigated surgical outcomes for symptomatic L5-S1 retrolisthesis treated with stand-alone L5-S1 anterior lumbar interbody fusion (ALIF). METHODS: All patients with symptomatic L5-S1 retrolisthesis treated with stand-alone L5-S1 ALIF at a single institution over a 7-year period were identified. Exhaustive nonoperative management had failed for all patients. Patients with previous lumbar fusion were excluded. Preoperative and postoperative radiographic images and patient-reported outcome measures for 20 patients (14 males and 6 females; mean [SD] age, 50.3 [13.7] years) were analyzed. RESULTS: The mean (SD) follow-up was 43.0 (23.7) months (range, 12.1-102.5 months). Patients experienced postoperative improvements in L5-S1 retrolisthesis (P = .048), L5-S1 disk height and angle (P < .001), L5 foraminal height (P < .001), L5-S1 lordosis (P < .001), and lumbar lordosis (P = .01). There were no significant changes in spinopelvic parameters. At the most recent follow-up, minimal clinically important differences in Oswestry Disability Index score, 36-Item Short-Form Survey (SF-36), and numerical rating scale score for leg pain were achieved in 11 of 20 (55%), 7 of 14 (50%), and 7 of 13 (54%) patients, respectively. All patients demonstrated fusion with no graft subsidence at up to 32 months. No patient experienced intraoperative complications, was readmitted, or required a subsequent posterior decompression or fusion because of refractory symptoms. CONCLUSION: In our cohort, stand-alone L5-S1 ALIF was associated with radiographic and clinical improvement in patients with symptomatic L5-S1 retrolisthesis.

Technical Feasibility of Subaxial Cervical Pedicle Screws for Distal Anchoring of Occipitocervical Fixation Constructs in the Mid-Cervical Spine: Early Clinical Experience.

Occipitocervical fixation and fusion (OCF) is performed for patients who have destabilizing traumatic injuries or pathologies affecting the complex bony and ligamentous structures of the occipitoatlantal and atlantoaxial joint structures. Distal fixation failure and pseudoarthrosis are known risks of these constructs, especially for those constructs ending in the mid-cervical spine. We present the technical feasibility of using cervical pedicle screws (CPSs) as distal fixation anchors to strengthen OCF constructs ending in the mid-cervical spine and present a case series describing our early clinical experience with this technique. We used a freehand technique to place subaxial pedicle screws in the mid-cervical spine as the distal fixation point in OCF constructs. This technique involves performing a laminotomy to provide direct visualization of the pedicle borders to safely guide freehand pedicle screw placement. Our early clinical experience with this technique is presented. Three patients received OCF constructs ending in the mid-cervical subaxial spine between C3 and C6. CPSs were placed at the distal vertebra in each construct. Stable instrumentation and arthrodesis were confirmed postoperatively in all patients. This freehand technique uses direct visualization of the pedicle to aid in safe and accurate subaxial pedicle screw placement. CPS placement is clinically feasible and increases the robustness of OCF constructs in appropriately selected patients. Larger case series are needed to further validate the safety and effectiveness of this technique.

Microscale electrophysiological functional connectivity in human cortico-basal ganglia network.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SIGNIFICANCE: The cortico-basal ganglia circuit is organized on a sub-centimeter scale, and plays an important role in the mechanisms of PD and DBS.

Cilia organize ependymal planar polarity.

Multiciliated epithelial cells, called ependymal cells, line the ventricles in the adult brain. Most ependymal cells are born prenatally and are derived from radial glia. Ependymal cells have a remarkable planar polarization that determines orientation of ciliary beating and propulsion of CSF. Disruption of ependymal ciliary beating, by injury or disease, results in aberrant CSF circulation and hydrocephalus, a common disorder of the CNS. Very little is known about the mechanisms guiding ependymal planar polarity and whether this organization is acquired during ependymal cell development or is already present in radial glia. Here we show that basal bodies in ependymal cells in the lateral ventricle walls of adult mice are polarized in two ways: (1) rotational; angle of individual basal bodies with respect to their long axis and (2) translational; the position of basal bodies on the apical surface of the cell. Conditional ablation of motile cilia disrupted rotational orientation, but translational polarity was largely preserved. In contrast, translational polarity was dramatically affected when radial glial primary cilia were ablated earlier in development. Remarkably, radial glia in the embryo have a translational polarity that predicts the orientation of mature ependymal cells. These results suggest that ependymal planar cell polarity is a multistep process initially organized by primary cilia in radial glia and then refined by motile cilia in ependymal cells.

Functional outcome after language mapping for glioma resection.

BACKGROUND: Language sites in the cortex of the brain vary among patients. Language mapping while the patient is awake is an intraoperative technique designed to minimize language deficits associated with brain-tumor resection. METHODS: To study language function after brain-tumor resection with language mapping, we examined 250 consecutive patients with gliomas. Positive language sites (i.e., language regions in the cortex of the brain, 1 cm by 1 cm, which were temporarily inactivated by means of a bipolar electrode) were identified and categorized into cortical language maps. The tumors were resected up to 1 cm from the cortical areas where intraoperative stimulation produced a disturbance in language. Our resection strategy did not require identification of the stimulation-induced language sites within the field of exposure. RESULTS: A total of 145 of the 250 patients (58.0%) had at least one site with an intraoperative stimulation-induced speech arrest, 82 patients had anomia, and 23 patients had alexia. Overall, 3094 of 3281 cortical sites (94.3%) were not associated with stimulation-induced language deficits. A total of 159 patients (63.6%) had intact speech preoperatively. One week after surgery, baseline language function remained in 194 patients (77.6%), it worsened in 21 patients (8.4%), and 35 patients (14.0%) had new speech deficits. However, 6 months after surgery, only 4 of 243 surviving patients (1.6%) had a persistent language deficit. Cortical maps generated with intraoperative language data also showed surprising variability in language localization within the dominant hemisphere. CONCLUSIONS: Craniotomies tailored to limit cortical exposure, even without localization of positive language sites, permit most gliomas to be aggressively resected without language deficits. The composite language maps generated in our study suggest that our current models of human language organization insufficiently account for observed language function.

Electrophysiologic Mapping for Target Acquisition in Deep Brain Stimulation May Become Unnecessary in the Era of Intraoperative Imaging.

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.

Leptin receptor neurons in the dorsomedial hypothalamus regulate diurnal patterns of feeding, locomotion, and metabolism.

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.