The role of spinal neurons targeted by corticospinal neurons in central poststroke neuropathic pain.

BACKGROUND: Central poststroke pain (CPSP) is one of the primary sequelae following stroke, yet its underlying mechanisms are poorly understood. METHODS: By lesioning the lateral thalamic nuclei, we first established a CPSP model that exhibits mechanical and thermal hypersensitivity. Innocuous mechanical stimuli following the thalamic lesion evoked robust neural activation in somatosensory corticospinal neurons (CSNs), as well as in the deep dorsal horn, where low threshold mechanosensory afferents terminate. In this study, we used viral-based mapping and intersectional functional manipulations to decipher the role of somatosensory CSNs and their spinal targets in the CPSP pathophysiology. RESULTS: We first mapped the post-synaptic spinal targets of lumbar innervating CSNs using an anterograde trans-synaptic AAV1-based strategy and showed these spinal interneurons were activated by innocuous tactile stimuli post-thalamic lesion. Functionally, tetanus toxin-based chronic inactivation of spinal neurons targeted by CSNs prevented the development of CPSP. Consistently, transient chemogenetic silencing of these neurons alleviated established mechanical pain hypersensitivity and innocuous tactile stimuli evoked aversion linked to the CPSP. In contrast, chemogenetic activation of these neurons was insufficient to induce robust mechanical allodynia typically observed in the CPSP. CONCLUSION: The CSNs and their spinal targets are required but insufficient for the establishment of CPSP hypersensitivity. Our study provided novel insights into the neural mechanisms underlying CPSP and potential therapeutic interventions to treat refractory central neuropathic pain conditions.

Corticospinal-specific Shh overexpression in combination with rehabilitation promotes CST axonal sprouting and skilled motor functional recovery after ischemic stroke.

Ischemic stroke often leads to permanent neurological impairments, largely due to limited neuroplasticity in adult central nervous system. Here, we first showed that the expression of Sonic Hedgehog (Shh) in corticospinal neurons (CSNs) peaked at the 2nd postnatal week, when corticospinal synaptogenesis occurs. Overexpression of Shh in adult CSNs did not affect motor functions and had borderline effects on promoting the recovery of skilled locomotion following ischemic stroke. In contrast, CSNs-specific Shh overexpression significantly enhanced the efficacy of rehabilitative training, resulting in robust axonal sprouting and synaptogenesis of corticospinal axons into the denervated spinal cord, along with significantly improved behavioral outcomes. Mechanistically, combinatory treatment led to additional mTOR activation in CSNs when compared to that evoked by rehabilitative training alone. Taken together, our study unveiled a role of Shh, a morphogen involved in early development, in enhancing neuroplasticity, which significantly improved the outcomes of rehabilitative training. These results thus provide novel insights into the design of combinatory treatment for stroke and traumatic central nervous system injuries.

HSPB2 facilitates neural regeneration through autophagy for sensorimotor recovery after traumatic brain injury.

Autophagy is a promising target for promoting neural regeneration, which is essential for sensorimotor recovery following traumatic brain injury (TBI). Whether neuronal heat shock protein B2 (HSPB2), a small molecular heat shock protein, reduces injury and promotes recovery following TBI remains unclear. In this study, we demonstrated that HSPB2 was significantly increased in the neurons of a TBI mouse model, patients, and primary neuron cultures subjected to oxygen/glucose deprivation and reperfusion treatment. Upon creating a tamoxifen-induced neuron-specific HSPB2 overexpression transgenic mouse model, we found that elevated HSPB2 levels promoted long-term sensorimotor recovery and alleviated tissue loss after TBI. We also demonstrated that HSPB2 enhanced white matter structural and functional integrity, promoted central nervous system (CNS) plasticity, and accelerated long-term neural remodeling. Moreover, we found that autophagy occurred around injured brain tissues in patients, and the pro-regenerative effects of HSPB2 relied on its autophagy-promoting function. Mechanistically, HSPB2 may regulate autophagy possibly by forming the HSPB2/BCL2-associated athanogene 3/sequestosome-1 complex to facilitate the clearance of erroneously accumulated proteins in the axons. Treatment with the autophagy inhibitor chloroquine during the acute stage or delayed induction of HSPB2 remarkably impeded HSPB2's long-term reparative function, indicating the importance of acute-stage autophagy in long-term neuro-regeneration. Our findings highlight the beneficial role of HSPB2 in neuro-regeneration and functional recovery following acute CNS injury, thereby emphasizing the therapeutic potential of autophagy regulation for enhancing neuro-regeneration.

Perioperative risk factors associated with unplanned neurological intensive care unit readmission following elective supratentorial brain tumor resection.

OBJECTIVE: The aim of this study was to describe the clinical and procedural risk factors associated with the unplanned neurosurgical intensive care unit (NICU) readmission of patients after elective supratentorial brain tumor resection and serves as an exploratory analysis toward the development of a risk stratification tool that may be prospectively applied to this patient population. METHODS: This was a retrospective observational cohort study. The electronic medical records of patients admitted to an institutional NICU between September 2018 and November 2021 after elective supratentorial brain tumor resection were reviewed. Demographic and perioperative clinical factors were recorded. A prognostic model was derived from the data of 4892 patients recruited between September 2018 and May 2021 (development cohort). A nomogram was created to display these predictor variables and their corresponding points and risks of readmission. External validation was evaluated using a series of 1118 patients recruited between June 2021 and November 2021 (validation cohort). Finally, a decision curve analysis was performed to determine the clinical usefulness of the prognostic model. RESULTS: Of the 4892 patients in the development cohort, 220 (4.5%) had an unplanned NICU readmission. Older age, lesion type, Karnofsky Performance Status (KPS) < 70 at admission, longer duration of surgery, retention of endotracheal intubation on NICU entry, and longer NICU length of stay (LOS) after surgery were independently associated with an unplanned NICU readmission. A total of 1118 patients recruited between June 2021 and November 2021 were included for external validation, and the model's discrimination remained acceptable (C-statistic = 0.744, 95% CI 0.675-0.814). The decision curve analysis for the prognostic model in the development and validation cohorts showed that at a threshold probability between 0.05 and 0.8, the prognostic model showed a positive net benefit. CONCLUSIONS: A predictive model that included age, lesion type, KPS < 70 at admission, duration of surgery, retention of endotracheal intubation on NICU entry, and NICU LOS after surgery had an acceptable ability to identify elective supratentorial brain tumor resection patients at high risk for an unplanned NICU readmission. These risk factors and this prediction model may facilitate better resource allocation in the NICU and improve patient outcomes.

Perioperative Risk Factors Associated with Unplanned Neurological Intensive Care Unit Events Following Elective Infratentorial Brain Tumor Resection.

BACKGROUND: Our aim of this study was to identify risk factors and develop a prediction model for unplanned neurological intensive care unit (NICU) events after elective infratentorial brain tumor resection in order to propose an individualized admission to the NICU tailored to patient needs. METHODS: Patients admitted to our NICU between September 2018 and May 2021 after elective infratentorial brain tumor resection were reviewed. Prolonged NICU stays and unplanned NICU admissions were defined as unplanned NICU events. The prognostic model of unplanned NICU events was developed using a forward stepwise logistic regression analysis, and external validation was evaluated. The C-statistic was used to assess discrimination, and a smooth, nonparametric calibration line was used to assess calibration graphically in the model. RESULTS: Of the 1,710 patients in the development cohort, unplanned NICU events occurred in 162 (9.5%). Based on the lesion type, a Karnofsky Performance Status score <70 at admission, longer duration of surgery, bleeding in the operative area evident on postoperative computed tomography, higher fibrinogen and blood glucose levels at admission, and more intraoperative blood loss were independently associated with unplanned NICU events. The external validation test showed good discrimination (C-statistic = 0.811) and calibration (Hosmer-Lemeshow P = 0.141) for unplanned NICU events. CONCLUSIONS: Several patient and operative characteristics are associated with a greater likelihood of the occurrence of unplanned NICU events. In the future, we may be able to provide better help for the resource allocation of NICUs according to these risk factors and prediction models.

Rehabilitative training paired with peripheral stimulation promotes motor recovery after ischemic cerebral stroke.

Spontaneous recovery of ischemic stroke is very limited and often results in the loss of motor and sensory function. Till now, rehabilitative training is the most widely accepted therapy to improve long-term outcome. However, its effectiveness is often suboptimal, largely due to a sharp decline of neuroplasticity in adults. In this study, we hypothesized that a combination of proprioceptive stimulation and rehabilitative training will promote neuroplasticity and functional recovery post injury. To test this hypothesis, we first established a photothrombotic stroke model that lesions the hindlimb sensorimotor cortex. Next, we demonstrated that injecting Cre-dependent AAV-retro viruses into the dorsal column of PV-Cre mice achieves specific and efficient targeting of proprioceptors. With chemogenetics, this method enables chronic activation of proprioceptors. We then assessed effects of combinatorial treatment on motor and sensory functional recovery. Our results showed that pairing proprioceptive stimulation with rehabilitative training significantly promoted skilled motor, but not tactile sensory functional recovery. This further led to significant improvement when compared to rehabilitation training or proprioceptor stimulation alone. Mechanistically, combinatorial treatment promoted cortical layer V neuronal mTOR activity and sprouting of corticospinal axon into the area where proprioceptive afferents terminate in the denervated side of the spinal cord. Serving as a proof of principle, our study thus provided novel insights into the application of combining proprioceptive stimulation and rehabilitative training to improve functional recovery of ischemic stroke and other traumatic brain or spinal cord injuries.

Long term follow-up and outcomes in adult patients with thalamic gliomas.

OBJECTIVES: To investigate the optimal treatment and prognosis of thalamic glioma in adult patients. PATIENTS AND METHODS: We retrospectively analyzed the adult patients with thalamic glioma admitted to our hospital from May 2005 to September 2016. Patients were divided into two groups according to their treatment: surgery-based combined treatment and intensity modulated radiation therapy (IMRT)-based treatment. Univariate chi-square test and multivariate logistic regression were used to identify independent factors for the treatment modality. A log-rank test, adjusting for propensity score, was used to compare the overall survival (OS) and progression-free survival (PFS) of patients between the two groups. RESULTS: Fifty-eight adult patients with thalamic gliomas were included in the analysis. Of them, 31 were treated with surgery-based treatment, and 27 were treated with IMRT-based treatment. The overall survival (OS) and progression-free survival (PFS) of patients between the two groups were not significantly different (median OS 16.0 (range 1.0-163.0) months vs. 10.0 (range 1.0-118.0) months, p = 0.344 and median PFS 10.0 (range 1.0-163.0) months vs. 6.0 (range 1.0-118.0) months, p = 0.464, respectively) even after adjusting for potential confounding factors. CONCLUSIONS: The OS and PFS of adult patients with thalamic glioma were not significantly different between patients in the surgical group and in the IMRT group. IMRT might be an acceptable alternative to surgery for adult patients with unresectable thalamic glioma.

Clinical and Molecular Characteristics of Thalamic Gliomas: Retrospective Report of 26 Cases.

OBJECTIVE: Thalamic glioma is a type of midline glioma with poor outcomes. In the present study, we investigated the clinical and molecular features of thalamic gliomas in Chinese patients. METHODS: The data from 26 patients with thalamic glioma who had undergone surgery at Shanghai Huashan Hospital from January 2011 to August 2015 were retrospectively analyzed. Various clinical and molecular factors were evaluated to explore their effects on prognosis. H3K27M mutation status and its association with relevant molecular factors were also investigated. RESULTS: The mean age of the patients was 38.88 years, and no significant difference was found in sex. The most common initial symptoms were headaches (38.46%; 10 of 26) and motor deficits (30.77%; 8 of 26). The H3K27M mutation was identified in 12 patients, and mutant thalamic glioma showed less frequent O-6-methylguanine DNA methyltransferase (MGMT) promoter methylation compared with the wild-type group (P = 0.015; χ1 test). Multivariate analysis showed that the H3K27M mutation was an independent unfavorable prognostic factor for overall survival. MGMT promoter unmethylation and the TP53 mutation were identified as negative prognostic factors for progression-free survival. CONCLUSIONS: Our results revealed the clinical and molecular characteristics of thalamic glioma in China. Our data have shown the absence of MGMT promoter methylation in H3K27M mutant thalamic glioma, validating it as a hallmark of H3K27M mutant gliomas. In addition, H3K27M mutation was identified as the sole unfavorable prognostic factor on overall survival. MGMT promoter unmethylation and TP53 mutation were identified as independent prognostic factors for progression-free survival.

High-grade thalamic gliomas: Microsurgical treatment and prognosis analysis.

This retrospective study is aimed to investigate the efficacy of microsurgical treatment for high-grade thalamic gliomas, and to analyze the relevant prognosis. From May 2011 to Aug 2015, 49 patients with thalamic gliomas underwent microsurgical resection, and received chemotherapy and radiotherapy postoperatively. The postoperative symptoms and complications were documented, and the overall survival (OS) and the progression-free survival (PFS) data were collected. The prognostic factors were evaluated by univariate and multivariate analyses. Finally, there was no perioperative death. Twenty cases, 24 cases and 5 cases were achieved subtotal resection (>90%), partial resection (70-90%) and less than partial resection (<70%) respectively. All patients' pathological diagnosis was confirmed. The symptoms were improved in 32 cases, unchanged in 11 cases, and worsen in 6 cases. Postoperative complications were absent in 9 cases. The 6-month, 12-month, and 24-month OS were 71.4%, 38.9%, and 12.1% respectively; corresponding PFS were 66.6%, 27.1%, and 10.2% respectively. The median OS time and PFS time were 9.0 months (95% CI 6.9-11.1) and 9.0 months (95% CI 6.6-11.4) respectively. Multivariate analysis revealed extent of resection were independent prognostic factors for OS (p < .05), patients with postoperative adjuvant chemotherapy and radiotherapy had a significant prolonged OS (p < .001) and PFS (p < .001). The study shows that the short-term efficacy of microsurgery for high-grade thalamic gliomas is satisfactory. Microsurgery can effectively alleviate patients' symptoms and improve life quality. Postoperative adjuvant chemotherapy and radiotherapy are helpful for prolonging the survival time.

Classification of insular-basal ganglia gliomas based on the displacement of corticospinal tracts evaluated by diffusion tensor imaging.

BACKGROUND: Resection of insula-basal ganglia (IBG) gliomas is challenging because of their deep location and vicinity to critical structures, whereas diffusion tensor tractography (DTT) can noninvasively delineate the tracks of white matter fibers. This study aims to evaluate the role of cortico-spinal tract (CST) positions in prediction of the prognosis of patients with IBG gliomas. METHODS: We retrospectively reviewed 34 patients with IBG gliomas. DTT was used to reconstruct the CSTs for all patients, and the IBG gliomas were classified into three types (type I-III) based on the shifted patterns of the CSTs. RESULTS: The number of patients with type I IBG gliomas was 12 (35.3%), which was equal to the number of patients with type II IBG gliomas, and 10 cases (29.4%) presented with type III IBG gliomas. The six-month KPS score was significantly lower in the type III IBG group than that in the type I group (t=-11.43, P=0.013) and the type II group (t=-9.97, P=0.033). Postoperative MRI demonstrated that gross total or near total resection was achieved in 76.5% (26 cases) of all of the patients. CONCLUSIONS: The results suggest that the proposed classification of IBG gliomas can be used for predicting the long-term postoperative outcome profiles of IBG glioma patients.