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High grade gliomas (HGGs) are aggressive brain tumors associated with poor prognosis despite advances in surgical treatment and therapy. Navigated tumor resection has yielded improved outcomes for patients. We compare 5-ALA, fluorescein sodium (FS), and intraoperative MRI (IMRI) with no image guidance to determine the best intraoperative navigation method to maximize rates of gross total resection (GTR) and outcomes. A frequentist network meta-analysis was performed following standard PRISMA guidelines (PROSPERO registration CRD42021268659). Surface-under-the-cumulative ranking (SUCRA) analysis was executed to hierarchically rank modalities by the outcomes of interest. Heterogeneity was measured by the I

Understanding factors that influence technology diffusion is central to clinical translation of novel therapies. We characterized the pattern of adoption for laser interstitial thermal therapy (LITT), also known as stereotactic laser ablation (SLA), in neuro-oncology using the National Inpatient Sample (NIS) database. We identified patients age ≥ 18 in the NIS (2012–2018) with a diagnosis of primary or metastatic brain tumor that underwent LITT or craniotomy. We compared characteristics and outcomes for patients that underwent these procedures. LITT utilization increased ~ 400% relative to craniotomy during the study period. Despite this increase, the total number of LITT procedures performed for brain tumor was 2 comorbidities (OR 0.64, CI95 0.51–0.79) or to be older (OR 0.92, CI95 0.86–0.99) and more likely to be female (OR 1.35, CI95 1.08–1.69), Caucasian compared to Black (OR 1.94, CI95 1.12–3.36), and covered by private insurance compared to Medicare or Medicaid (OR 1.38, CI95 1.09–1.74). LITT hospital stays were 50% shorter than craniotomy (IRR 0.52, CI95 0.45–0.61). However, charges related to the procedures were comparable between LITT and craniotomy ($1397 greater for LITT, CI95 $−5790 to $8584). For neuro-oncology indications, LITT utilization increased ~ 400% relative to craniotomy. Relative to craniotomy-treated patients, LITT-treated patients were likelier to be young, female, non-Black race, covered by private insurance, or with

Management of cerebral venous thrombosis (CVT) involves minimizing expansion of the thrombus and promoting the recanalization of the venous sinus. While current guidelines include indications of endovascular management and anticoagulation with heparin and warfarin, the use of direct-acting oral anticoagulants (DOACs) has increased. In this study, we aim to conduct a network meta-analysis comparing these 3 therapeutic options: standard anticoagulation, DOACs, and endovascular treatments (EVTs).Seventeen of 2265 studies identified from 4 publication databases met inclusion criteria for this network meta-analysis. Outcomes analyzed included modified Rankin Scale score, complications, mortality, and 6-month recanalization rates using a frequentist network meta-analysis approach. For each outcome, the preferential order of each intervention was ranked hierarchically based on P-score calculations used for frequentist network meta-analyses.Modified Rankin Scale outcomes were not significantly different based on the type of treatment modality (i.e., standard anticoagulation, DOACs, or EVT). Evaluation of complications demonstrated that patients treated with EVT were significantly more likely to experience a worse outcome than individuals treated with standard anticoagulation (odds ratio [OR] = 1.83, P = 0.04). Other comparisons did not demonstrate a significant difference in adverse events. For all-cause mortality outcomes, EVT demonstrated significantly greater odds of mortality than standard anticoagulation (OR = 1.89, P = 0.02). Mortality between DOACs and standard anticoagulation was not significantly different. When comparing 6-month recanalization rates, DOACs and EVT were significantly more effective than standard anticoagulation (OR = 1.93, OR = 2.2, P0.05). EVT followed by DOACs was preferred over standard anticoagulation for 6-month recanalization rates.This network meta-analysis evaluates the outcomes in CVT treatment, comparing standard anticoagulation, DOACs, and EVT, with evidence that DOACs have similar outcomes to standard anticoagulation in the treatment of CVT. EVT resulted in an increased risk of overall mortality but improved 6-month recanalization rates.

We sought to determine whether racial and socioeconomic disparities in the utilization of deep brain stimulation (DBS) for Parkinson's disease (PD) have improved over time. We examined DBS utilization and analyzed factors associated with placement of DBS. The odds of DBS placement increased across the study period, whereas White patients with PD were 5 times more likely than Black patients to undergo DBS. Individuals, regardless of racial background, with 2 or more comorbidities were 14 times less likely to undergo DBS. Privately insured patients were 1.6 times more likely to undergo DBS. Despite increasing DBS utilization, significant disparities persist in access to DBS. ANN NEUROL 2022;92:246-254.

Epilepsy is the most common form of chronic neurologic disease. Here, we review the available randomized controlled trials (RCTs) that examined the efficacy of resective epilepsy surgery in select patients suffering from medically intractable epilepsy (defined as persistent epilepsy despite two or more antiepileptic drugs [AEDs]). Three RCTs (two adult RCTs and one pediatric RCT) consistently supported the efficacy of resective surgery as treatment for epilepsy with semiology localized to the mesial temporal lobe. In these studies, 58–100% of the patients who underwent resective surgery achieved seizure freedom, in comparison to 0–13% of medically treated patients. In another RCT, the likelihood of seizure freedom after resective surgery was independent of the surgical approach (transSylvian [64%] versus subtemporal [62%]). Two other RCTs demonstrated that hippocampal resection is essential to optimize seizure control. But, no significant gain in seizure control was achieved beyond removing 2.5 cm of the hippocampus. Across RCTs, minor complications (deficit lasting 3 months) ranged 2–5% and 5–11% respectively. However, nonincapacitating superior subquadrantic visual-field defects (not typically considered a minor or major complication) were noted in up to 55% of the surgical cohort. The available RCTs provide compelling support for resective surgery as a treatment for mesial temporal lobe epilepsy and offer insights toward optimal surgical strategy.

The physiologic basis underlying the long-term consequences of repetitive, mild traumatic brain injury (mTBI) remains poorly understood. Mild traumatic brain injury often results in brief loss of consciousness, impaired attention and concentration, memory problems, impulsivity, and headache, without objective findings on clinical imaging or examination. The effects of mTBI can persist and become cumulative with repetitive injury, suggesting global alterations in cortical networks. Using transparent polymer skulls, we performed mesoscopic Ca2+ imaging in mice to evaluate how repetitive mTBI alters patterns of neuronal interactions across the dorsal cerebral cortex. Spatial Independent Component Analysis (sICA) and Localized semi-Nonnegative Matrix Factorization (LocaNMF) were used to quantify changes in cerebral functional connectivity (FC). Repetitive, mild, controlled cortical impacts induce temporary neuroinflammatory responses, characterized by increased density of microglia exhibiting de-ramified morphology. These temporary neuro-inflammatory changes were not associated with compromised cognitive performance in the Barnes maze or motor function as assessed by rotarod. However, long-term alterations in functional connectivity were observed. Widespread, bilateral changes in FC occurred immediately following impact and persisted for up to 7 weeks, the duration of the experiment. Network alterations include decreases in global efficiency, clustering coefficient, and nodal strength, thereby disrupting functional interactions and information flow throughout the dorsal cerebral cortex. A subnetwork analysis shows the largest disruptions in FC were concentrated near the impact site. Therefore, repetitive mTBI induces a transient neuroinflammation, without alterations in cognitive or motor behavior, and a reorganized cortical network evidenced by the widespread, chronic alterations in cortical FC.Significance StatementMore than 2.5 million individuals in the United States suffer minor traumatic brain injuries annually. Because these injuries are typically not associated with visible anatomic injuries or objective clinical findings, they were thought benign and fully recoverable. However, there is increasing awareness of the long-term deleterious consequences, particularly in patients who suffer repeated mTBI. Using long-term, mesoscopic neuronal Ca2+ imaging to characterize the dorsal cerebral cortical connectome following repetitive mTBI, we show extensive, persistent changes in functional connectivity, not only at the site of injury but throughout the cortex. These findings provide new insights into the pathophysiology of mTBI.

OBJECTIVE The aim of this study was to characterize the clinical utilization and associated charges of autologous bone flap (ABF) versus synthetic flap (SF) cranioplasty and to characterize the postoperative infection risk of SF versus ABF using the National Readmissions Database (NRD). METHODS The authors used the publicly available NRD to identify index hospitalizations from October 2015 to December 2018 involving elective ABF or SF cranioplasty after traumatic brain injury (TBI) or stroke. Subsequent readmissions were further characterized if patients underwent neurosurgical intervention for treatment of infection or suspected infection. Survey Cox proportional hazards models were used to assess risk of readmission. RESULTS An estimated 2295 SF and 2072 ABF cranioplasties were performed from October 2015 to December 2018 in the United States. While the total number of cranioplasty operations decreased during the study period, the proportion of cranioplasties utilizing SF increased (p < 0.001), particularly in male patients (p = 0.011) and those with TBI (vs stroke, p = 0.012). The median total hospital charge for SF cranioplasty was $31,200 more costly than ABF cranioplasty (p < 0.001). Of all first-time readmissions, 20% involved surgical treatment for infectious reasons. Overall, 122 SF patients (5.3%) underwent surgical treatment of infection compared with 70 ABF patients (3.4%) on readmission. After accounting for confounders using a multivariable Cox model, female patients (vs male, p = 0.003), those discharged nonroutinely (vs discharge to home or self-care, p < 0.001), and patients who underwent SF cranioplasty (vs ABF, p = 0.011) were more likely to be readmitted for reoperation. Patients undergoing cranioplasty during more recent years (e.g., 2018 vs 2015) were less likely to be readmitted for reoperation because of infection (p = 0.024). CONCLUSIONS SFs are increasingly replacing ABFs as the material of choice for cranioplasty, despite their association with increased hospital charges. Female sex, nonroutine discharge, and SF cranioplasty are associated with increased risk for reoperation after cranioplasty.

BACKGROUND Symptomatic disseminated myxopapillary ependymoma (MPE) in a young person presents a daunting challenge because the risks of prolonged prone positioning and spinal cord injury may outweigh the likelihood of attaining the benefit of gross total resection. OBSERVATIONS The authors reported the case of a 15-year-old girl with five discrete recurrent spinal cord ependymomas. The patient received a 25-hour surgical procedure for gross total resection of the tumors and fusion over an approximately 33-hour period. She experienced complete resolution of all preoperative neurological symptoms and subsequently received adjuvant radiation therapy. At 52 months after surgery, she was still experiencing neurologically intact, progression-free survival. This case illustrated one of the most extensive recurrent tumor resections for MPE with prolonged disease-free survival reported to date. It may also represent the longest prone position spinal case reported and was notable for a lack of any of the complications commonly associated with the prolonged prone position. LESSONS The authors discussed the complexity of surgical decision-making in a symptomatic patient with multiple disseminated metastases, technical considerations for resection of intradural and intramedullary spinal cord tumors, and considerations for avoiding complications during prolonged positioning necessary for spinal surgery.

We examined the efficacy of vagal nerve stimulation (VNS) for patients suffering from medically intractable epilepsy. Four randomized controlled trials (RCTs - 3 adult RCTs and 1 pediatric RCT) were identified in our comprehensive literature search. Across the 4 studies, high frequency VNS stimulation (frequency >20 Hz) consistently achieved a greater seizure frequency reduction (23.4-33.1%) relative to low frequency VNS stimulation (1 Hz, .6-15.2%). We identified 2 RCTs examining whether the parameters of stimulation influenced seizure control. These studies reported that VNS achieved seizure control comparable to those reported by the first 4 RCTs (22-43% seizure frequency reduction), irrespective of the parameters utilized for VNS stimulation. In terms of VNS associated morbidity, these morbidities were consistently higher in adults who underwent high frequency VNS stimulation (eg dysphonia 37-66%, dyspnea 6-25.3%). However, no such differences were observed in the pediatric population. Moreover

IntroductionCortical spreading depolarisation (CSD) is characterised by a near-complete loss of the ionic membrane potential of cortical neurons and glia propagating across the cerebral cortex, which generates a transient suppression of spontaneous neuronal activity. CSDs have become a recognised phenomenon that imparts ongoing secondary insults after brain injury. Studies delineating CSD generation and propagation in humans after traumatic brain injury (TBI) are lacking. Therefore, this study aims to determine the feasibility of using a multistrip electrode array to identify CSDs and characterise their propagation in space and time after TBI.Methods and analysisThis pilot, prospective observational study will enrol patients with TBI requiring therapeutic craniotomy or craniectomy. Subdural electrodes will be placed for continuous electrocorticography monitoring for seizures and CSDs as a research procedure, with surrogate informed consent obtained preoperatively. The propagation of CSDs relative to structural brain pathology will be mapped using reconstructed CT and electrophysiological cross-correlations. The novel use of multiple subdural strip electrodes in conjunction with brain morphometric segmentation is hypothesised to provide sufficient spatial information to characterise CSD propagation across the cerebral cortex and identify cortical foci giving rise to CSDs.Ethics and disseminationEthical approval for the study was obtained from the Hennepin Healthcare Research Institute’s ethics committee, HSR 17-4400, 25 October 2017 to present. Study findings will be submitted for publication in peer-reviewed journals and presented at scientific conferences.Trial registration numberNCT03321370.

Understanding factors that influence technology diffusion is central to clinical translation of novel therapies. We characterized the pattern of adoption for laser interstitial thermal therapy (LITT), also known as stereotactic laser ablation (SLA), in neuro-oncology using the National Inpatient Sample (NIS) database.We identified patients age ≥ 18 in the NIS (2012-2018) with a diagnosis of primary or metastatic brain tumor that underwent LITT or craniotomy. We compared characteristics and outcomes for patients that underwent these procedures.LITT utilization increased ~ 400% relative to craniotomy during the study period. Despite this increase, the total number of LITT procedures performed for brain tumor was 1% of craniotomy. After adjusting for this time trend, LITT patients were less likely to have 2 comorbidities (OR 0.64, CIFor neuro-oncology indications, LITT utilization increased ~ 400% relative to craniotomy. Relative to craniotomy-treated patients, LITT-treated patients were likelier to be young, female, non-Black race, covered by private insurance, or with 2 comorbidities. While the total hospital charges were comparable, LITT was associated with a shorter hospitalization relative to craniotomy.

Injuries from Less-lethal Weapons during the George Floyd Protests In this analysis involving patients treated in Minnesota during protests after George Floyd’s death, 89 patients were identified w...

INTRODUCTION Neuro-cognitive decline is near universal in glioblastoma patients and negatively impacts the quality of life for afflicted patients. Yet, there is little information on longitudinal effects of brain tumor growth on cerebral cortical function and network connectivity. OBJECTIVE To address this knowledge gap, we examined in vivo Ca2+ imaging in a transgenic murine glioblastoma model. METHODS Mesoscopic Ca2+ imaging was performed after implant of GL261 glioblastoma cells into a transgenic mice strain (Thy1-GCaMP6f) that expresses the fast calcium indicator GCaMP6f in Layer II/III and Layer V pyramidal neurons. Independent component analysis (ICA), correlation matrix and graph theory approaches were used to assess changes in network connectivity. RESULTS ICA defined canonical cerebral network consisting of nodal convergence and connectivity between nodes. The overall network structure remained unaltered after tumor implant. A decrease in the strength of connectivity was observed immediately following tumor implant. This temporary suppression was followed by progressive, global increase in the strength of nodal connectivity (p < 0.0001). By two weeks post-tumor implant, 50% of the nodes exhibited increased connectivity compared to baseline. Progressive activation of select nodes was also observed in the weeks following tumor implant (p < 0.01). In aggregate, these results suggest that activation of select network nodes as well as enhanced connectivity as means to compensate for the deleterious effects of glioblastoma growth. CONCLUSIONS Our results indicate that focal brain tumor growth induces a reorganization of both local and remote cortical activity. The finding bears pertinence to the pathogenesis of neuro-cognitive decline and tumor-associated epilepsy.

Epilepsy is the most common form of chronic neurologic disease. Here, we review the available randomized controlled trials (RCTs) that examined the efficacy of resective epilepsy surgery in select patients suffering from medically intractable epilepsy (defined as persistent epilepsy despite two or more antiepileptic drugs [AEDs]). Three RCTs (two adult RCTs and one pediatric RCT) consistently supported the efficacy of resective surgery as treatment for epilepsy with semiology localized to the mesial temporal lobe. In these studies, 58-100% of the patients who underwent resective surgery achieved seizure freedom, in comparison to 0-13% of medically treated patients. In another RCT, the likelihood of seizure freedom after resective surgery was independent of the surgical approach (transSylvian [64%] versus subtemporal [62%]). Two other RCTs demonstrated that hippocampal resection is essential to optimize seizure control. But, no significant gain in seizure control was achieved beyond removing 2.5 cm of the hippocampus. Across RCTs, minor complications (deficit lasting 3 months) and major complications (deficit 3 months) ranged 2-5% and 5-11% respectively. However, nonincapacitating superior subquadrantic visual-field defects (not typically considered a minor or major complication) were noted in up to 55% of the surgical cohort. The available RCTs provide compelling support for resective surgery as a treatment for mesial temporal lobe epilepsy and offer insights toward optimal surgical strategy.

Deciphering neurologic function is a daunting task, requiring understanding the neuronal networks and emergent properties that arise from the interactions among single neurons. Mechanistic insights into neuronal networks require tools that simultaneously assess both single neuron activity and the consequent mesoscale output. The development of cranial window technologies, in which the skull is thinned or replaced with a synthetic optical interface, has enabled monitoring neuronal activity from subcellular to mesoscale resolution in awake, behaving animals when coupled with advanced microscopy techniques. Here we review recent achievements in cranial window technologies, appraise the relative merits of each design and discuss the future research in cranial window design.

INTRODUCTION Neuro-cognitive decline is near universal in glioblastoma patients and negatively impacts the quality of life for afflicted patients. Yet, there is little information on longitudinal effects of brain tumor growth on cerebral cortical function and network connectivity. OBJECTIVE To address this knowledge gap, we examined in vivo Ca2+ flux imaging in a transgenic murine glioblastoma model. METHODS Mesoscopic Ca2+ imaging was performed after implant of GL261 glioblastoma cells into a transgenic mice strain (Thy1-GCaMP6f) that expresses the fast calcium indicator GCaMP6f in Layer II/III and Layer V pyramidal neurons. Independent component analysis (ICA), correlation matrix and graph theory approaches were used to assess changes in network connectivity. RESULTS ICA defined canonical cerebral network consisting of nodal convergence and connectivity between nodes. The overall network structure remained unaltered after tumor implant. A decrease in the strength of connectivity was observed immediately following tumor implant. This temporary suppression was followed by progressive, global increase in the strength of nodal connectivity (p < 0.0001). By two weeks post-tumor implant, 50% of the nodes exhibited increased connectivity compared to baseline. Progressive activation of select nodes was also observed in the weeks following tumor implant (p < 0.01). In aggregate, these results suggest that activation of select network nodes as well as enhanced connectivity as means to compensate for the deleterious effects of glioblastoma growth. CONCLUSIONS Our results indicate that focal brain tumor growth induces a reorganization of both local and remote cortical activity. The finding bear pertinence to the pathogenesis of neuro-cognitive decline and tumor associated epilepsy.

The Ca2+channelopathies caused by mutations of theCACNA1Agene that encodes the pore-forming subunit of the human Cav2.1 (P/Q-type) voltage-gated Ca2+channel include episodic ataxia type 2 (EA2). Although, in EA2 the emphasis has been on cerebellar dysfunction, patients also exhibit episodic, nonmotoric abnormalities involving the cerebral cortex. This study demonstrates episodic, low-frequency oscillations (LFOs) throughout the cerebral cortex oftottering(tg/tg) mice, a widely used model of EA2. Ranging between 0.035 and 0.11 Hz, the LFOs intg/tgmice can spontaneously develop very high power, referred to as a high-power state. The LFOs intg/tgmice are mediated in part by neuronal activity as tetrodotoxin decreases the oscillations and cortical neuron discharge contain the same low frequencies. The high-power state involves compensatory mechanisms because acutely decreasing P/Q-type Ca2+channel function in either wild-type (WT) ortg/tgmice does not induce the high-power state. In contrast, blockingl-type Ca2+channels, known to be upregulated intg/tgmice, reduces the high-power state. Intriguingly, basal excitatory glutamatergic neurotransmission constrains the high-power state because blocking ionotropic or metabotropic glutamate receptors results in high-power LFOs intg/tgbut not WT mice. The high-power LFOs are decreased markedly by acetazolamide and 4-aminopyridine, the primary treatments for EA2, suggesting disease relevance. Together, these results demonstrate that the high-power LFOs in thetg/tgcerebral cortex represent a highly abnormal excitability state that may underlie noncerebellar symptoms that characterizeCACNA1Amutations.

Docosahexaenoic acid (DHA) has neuroprotective effects in several neurodegenerative disease conditions. However, the underlying mechanisms are not well understood. In the present study, we investigated the effects of DHA on astrocyte Ca(2+) signaling under in vitro ischemic conditions (oxygen/glucose deprivation and reoxygenation, OGD/REOX). OGD (2h) triggered a Ca(2+) (ER) store overload (∼1.9-fold). Ca(2+) uptake by the Ca(2+) (ER) stores was further augmented during REOX and Ca(2+) (ER) was elevated by ∼4.7-fold at 90min REOX. Interestingly, Ca(2+) (ER) stores abruptly released Ca(2+) at ∼120min REOX and emptied at 160min REOX. Depletion of Ca(2+) (ER) stores led to delayed elevation of intracellular Ca(2+) concentration (Ca(2+) (cyt) ) and cell death. Activation of the purinergic receptor P2Y1 was responsible for the release of Ca(2+) (ER) . Most importantly, DHA blocked the initial Ca(2+) (ER) store overload, the delayed depletion of Ca(2+) (ER) , and rise in Ca(2+) (cyt) , which was in part via inhibiting d-myo-inositol 1,4,5-triphosphate receptors. The DHA metabolite DiHDoHE exhibited similar effects. DHA also attenuated expression of phosphorylated eukaryotic initiation factor 2α and activating transcription factor-4, two ER stress markers, following in vitro ischemia. Taken together, these findings suggest that DHA has protective effects in astrocytes following in vitro ischemia, in part, by inhibiting Ca(2+) dysregulation and ER stress.

We investigated mechanisms underlying the Na+/H+ exchanger isoform 1 (NHE1)-mediated neuronal damage in transient focal ischemia. Physiological parameters, body and tympanic temperatures, and regional cerebral blood flow during 30 min of middle cerebral artery occlusion were similar in wild-type NHE1 (NHE1+/+) and NHE1 heterozygous (NHE1+/-) mice. NHE1+/+ mice developed infarct volume of 57.3 +/- 8.8 mm(3) at 24 h reperfusion (Rp), which progressed to 86.1 +/- 10.0 mm(3) at 72 h Rp. This delayed cell death was preceded by release of mitochondrial cytochrome c (Cyt. C), nuclear translocation of apoptosis-inducing factor (AIF), activation of caspase-3, and TUNEL-positive staining and chromatin condensation in the ipsilateral hemispheres of NHE1+/+ brains. In contrast, NHE1+/- mice had a significantly smaller infarct volume and improved neurological function. A similar neuroprotection was obtained with NHE1 inhibitor HOE 642. The number of apoptotic cells, release of AIF and Cyt. C or levels of active caspase-3 was significantly reduced in NHE1+/- brains. These data imply that NHE1 activity may contribute to ischemic apoptosis. Ischemic brains did not exhibit changes of NHE1 protein expression. In contrast, up-regulation of NHE1 expression was found in NHE1+/+ neurons after in vitro ischemia. These data suggest that NHE1 activation following cerebral ischemia contributes to mitochondrial damage and ischemic apoptosis.

Background: Altered Cl− homeostasis and GABAergic function are associated with nociceptive input hypersensitivity. This study investigated the role of two major intracellular Cl− regulatory proteins, Na+-K+-Cl− cotransporter 1 (NKCC1) and K+-Cl− cotransporter 2 (KCC2), in neuropathic pain following spinal cord injury (SCI). Results: Sprague-Dawley rats underwent a contusive SCI at T9 using the MASCIS impactor. The rats developed hyperalgesia between days 21 and 42 post-SCI. Thermal hyperalgesia (TH) was determined by a decrease in hindpaw thermal withdrawal latency time (WLT) between days 21 and 42 post-SCI. Rats with TH were then treated with either vehicle (saline containing 0.25% NaOH) or NKCC1 inhibitor bumetanide (BU, 30 mg/kg, i.p.) in vehicle. TH was then re-measured at 1 h post-injection. Administration of BU significantly increased the mean WLT in rats (p < 0.05). The group administered with the vehicle alone showed no anti-hyperalgesic effects. Moreover, an increase in NKCC1 protein expression occurred in the lesion epicenter of the spinal cord during day 2–14 post-SCI and peaked on day 14 post-SCI (p < 0.05). Concurrently, a down-regulation of KCC2 protein was detected during day 2–14 post-SCI. The rats with TH exhibited a sustained loss of KCC2 protein during post-SCI days 21–42. No significant changes of these proteins were detected in the rostral region of the spinal cord. Conclusion: Taken together, expression of NKCC1 and KCC2 proteins was differentially altered following SCI. The anti-hyperalgesic effect of NKCC1 inhibition suggests that normal or elevated NKCC1 function and loss of KCC2 function play a role in the development and maintenance of SCI-induced neuropathic pain.

Spinocerebellar ataxia type 5 (SCA5), a dominant neurodegenerative disease characterized by profound Purkinje cell loss, is caused by mutations in SPTBN2, a gene that encodes β-III spectrin. SCA5 is the first neurodegenerative disorder reported to be caused by mutations in a cytoskeletal spectrin gene. We have developed a mouse model to understand the mechanistic basis for this disease and show that expression of mutant but not wild-type β-III spectrin causes progressive motor deficits and cerebellar degeneration. We show that endogenous β-III spectrin interacts with the metabotropic glutamate receptor 1α (mGluR1α) and that mice expressing mutant β-III spectrin have cerebellar dysfunction with altered mGluR1α localization at Purkinje cell dendritic spines, decreased mGluR1-mediated responses, and deficient mGluR1-mediated long-term potentiation. These results indicate that mutant β-III spectrin causes mislocalization and dysfunction of mGluR1α at dendritic spines and connects SCA5 with other disorders involving glutamatergic dysfunction and synaptic plasticity abnormalities.

The role of parallel fibers (PFs) in cerebellar physiology remains controversial. Early studies inspired the “beam” hypothesis whereby granule cell (GC) activation results in PF-driven, postsynaptic excitation of beams of Purkinje cells (PCs). However, the “radial” hypothesis postulates that the ascending limb of the GC axon provides the dominant input to PCs and generates patch-like responses. Using optical imaging and single-cell recordings in the mouse cerebellar cortex in vivo, this study reexamines the beam versus radial controversy. Electrical stimulation of mossy fibers (MFs) as well as microinjection of NMDA in the granular layer generates beam-like responses with a centrally located patch-like response. Remarkably, ipsilateral forepaw stimulation evokes a beam-like response in Crus I. Discrete molecular layer lesions demonstrate that PFs contribute to the peripherally generated responses in Crus I. In contrast, vibrissal stimulation induces patch-like activation of Crus II and GABAA antagonists fail to convert this patch-like activity into a beam-like response, implying that molecular layer inhibition does not prevent beam-like responses. However, blocking excitatory amino acid transporters (EAATs) generates beam-like responses in Crus II. These beam-like responses are suppressed by focal inhibition of MF-GC synaptic transmission. Using EAAT4 reporter transgenic mice, we show that peripherally evoked patch-like responses in Crus II are aligned between parasagittal bands of EAAT4. This is the first study to demonstrate beam-like responses in the cerebellar cortex to peripheral, MF, and GC stimulation in vivo. Furthermore, the spatial pattern of the responses depends on extracellular glutamate and its local regulation by EAATs.

Docosahexaenoic acid (DHA) has neuroprotective effects in several neurodegenerative disease conditions. However, the underlying mechanisms are not well understood. In the present study, we investigated the effects of DHA on astrocyte Ca(2+) signaling under in vitro ischemic conditions (oxygen/glucose deprivation and reoxygenation, OGD/REOX). OGD (2h) triggered a Ca(2+) (ER) store overload (∼1.9-fold). Ca(2+) uptake by the Ca(2+) (ER) stores was further augmented during REOX and Ca(2+) (ER) was elevated by ∼4.7-fold at 90min REOX. Interestingly, Ca(2+) (ER) stores abruptly released Ca(2+) at ∼120min REOX and emptied at 160min REOX. Depletion of Ca(2+) (ER) stores led to delayed elevation of intracellular Ca(2+) concentration (Ca(2+) (cyt) ) and cell death. Activation of the purinergic receptor P2Y1 was responsible for the release of Ca(2+) (ER) . Most importantly, DHA blocked the initial Ca(2+) (ER) store overload, the delayed depletion of Ca(2+) (ER) , and rise in Ca(2+) (cyt) , which was in part via inhibiting d-myo-inositol 1,4,5-triphosphate receptors. The DHA metabolite DiHDoHE exhibited similar effects. DHA also attenuated expression of phosphorylated eukaryotic initiation factor 2α and activating transcription factor-4, two ER stress markers, following in vitro ischemia. Taken together, these findings suggest that DHA has protective effects in astrocytes following in vitro ischemia, in part, by inhibiting Ca(2+) dysregulation and ER stress.

At the molecular and circuitry levels, the cerebellum exhibits a striking parasagittal zonation as exemplified by the spatial distribution of molecules expressed on Purkinje cells and the topography of the afferent and efferent projections. The physiology and function of the zonation is less clear. Activity-dependent optical imaging has proven a useful tool to examine the physiological properties of the parasagittal zonation in the intact animal. Recent findings show that zebrin II-positive and zebrin II-negative zones differ markedly in their responses to parallel fiber inputs. These findings suggest that cerebellar cortical excitability, information processing, and synaptic plasticity depend on the intrinsic properties of different parasagittal zones.