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ABSTRACT Importance Pediatric cerebral cavernous malformation (CCM) is a rarely encountered vascular entity. Comparative study on surgical excision and nonsurgical management outcomes of CCM in pediatrics is limited. Objective To determine the demographic characteristics, hemorrhage rate, and long‐term outcomes of pediatric patients with CCM. Methods A retrospective study of pediatric patients with CCM in Chinese PLA General Hospital was conducted between January 2004 and January 2019. We compared the clinical characteristics, radiological features, and outcomes of the surgical and nonsurgical groups. Results Seventy‐nine children were included, with 69.6% being boys, and the average age was 11.8 ± 5.5 years. The annual retrospective hemorrhagic rate was 5.7% per patient per year. Fifty‐six children (70.9%) underwent surgical excision, and they were more likely to present with seizure symptoms (P = 0.011), have a higher proportion of larger lesion size (P = 0.008), less likely to have durations ≤10 days (P = 0.048), and less likely to have supratentorial deep CCM (P = 0.014) compared to children who received nonsurgical management. Total resection was achieved in most surgical cases (55, 98.2%). During the 143.9 ± 50.8 months of follow‐up, 44 patients (78.6%) achieved improvement, 12 patients (17.8%) remained the same, and two (3.6%) experienced worsening. In the nonsurgical management group, 14 children (60.9%) experienced symptom improvement, eight (34.8%) remained the same, and one (4.3%) worsened, with a re‐hemorrhagic risk of 8.7%. Interpretation Surgical removal of pediatric CCM can eliminate the risk of hemorrhage and lead to satisfactory outcomes. For children undergoing nonsurgical management, long‐term close monitoring is essential due to the life‐long risk of hemorrhage.

Abstract Empathy enables understanding and sharing of others’ feelings. Human neuroimaging studies have identified critical brain regions supporting empathy for pain, including the anterior insula (AI), anterior cingulate (ACC), amygdala, and inferior frontal gyrus (IFG). However, to date, the precise spatio-temporal profiles of empathic neural responses and inter-regional communications remain elusive. Here, using intracranial electroencephalography, we investigated electrophysiological signatures of vicarious pain perception. Others’ pain perception induced early increases in high-gamma activity in IFG, beta power increases in ACC, but decreased beta power in AI and amygdala. Vicarious pain perception also altered the beta-band-coordinated coupling between ACC, AI, and amygdala, as well as increased modulation of IFG high-gamma amplitudes by beta phases of amygdala/AI/ACC. We identified a necessary combination of neural features for decoding vicarious pain perception. These spatio-temporally specific regional activities and inter-regional interactions within the empathy network suggest a neurodynamic model of human pain empathy.

Time delay (TD) across corticomuscular coupling (CMC) is a significant index to assess the information transmission between brain and muscle during movement execution. Larger methods have been widely used to calculate the time delay by estimating phase information, but fail to account for both linear and nonlinear characteristics in the bidirectional coupled systems. For this, this study proposed a novel time-delay estimation method, defined as time-delay information transfer index (TDITI), to explore the TD characteristics between two signal deriving from one system with time-delay coupling. To verify this, we introduced two models to generate a series of simulation signal with linearly unidirectional/ bidirectional coupling or nonlinearly unidirectional/ bidirectional coupling. Simulation results manifested that the TDITI method, compared with the information transfer index (ITI) and coherence methods, can not only describe the TD in the linearly or nonlinearly unidirectional systems, but was also suitable for the bidirectional coupled systems. We also found its robustness to data length, coupling strength and signal-noise ratio. After that, we applied it to explore the TD of CMC by synchronizing the electroencephalogram (EEG) and electromyogram (EMG) signal during steady-state task. Experimental results showed that the CMC between cortex and muscle were direction-dependent, and the average delay time from EEG to EMG (∼25 ms) was shorter than that in the opposition (∼30 ms). Both simulation and experimental data expound the effectiveness of the TDITI method to describe the time delay in the unidirectional or bidirectional coupled systems, and this study extends our perspective to the mechanism of motor control.

Introduction Deep brain stimulation (DBS) and vagus nerve stimulation (VNS) can improve motor function in patients with poststroke hemiplegia. No comparison study exists.Methods and analysis This is a randomised, double-blind, controlled clinical trial involving 64 patients who had their first stroke at least 6 months ago and are experiencing poststroke limb dysfunction. These patients must receive necessary support at home and consent to participate. The aim is to evaluate the effectiveness and safety of DBS and VNS therapies. Patients are excluded if they have implantable devices that are sensitive to electrical currents, severe abnormalities in their lower limbs or are unable to comply with the trial procedures. The study has two parallel, distinct treatment arms: the Stimulation Group and the Sham Group. Initially, the Stimulation Group will undergo immediate electrical stimulation postsurgery, while the Sham Group will receive non-stimulation 1 month later. After 3 months, these groups will swap treatments, with the Stimulation Group discontinuing stimulation and the Sham Group initiating stimulation. Six months later, both groups will resume active stimulation. Our primary outcomes will meticulously assess motor function improvements, using the Fugl-Meyer Assessment, and safety, monitored by tracking adverse reaction rates. Furthermore, we will gain a comprehensive view of patient outcomes by evaluating secondary measures, including clinical improvement (National Institutes of Health Stroke Scale), surgical complications/side effects, quality of life (36-item Short Form Questionnaire) and mental health status (Hamilton Anxiety Rating Scale/Hamilton Depression Rating Scale). To ensure a thorough understanding of the long-term effects, we will conduct follow-ups at 9 and 12 months postsurgery, with additional long-term assessments at 15 and 18 months. These follow-ups will assess the sustained performance and durability of the treatment effects. The statistical analysis will uncover the optimal treatment strategy for poststroke hemiplegia, providing valuable insights for clinicians and patients alike.Ethics and dissemination This study was reviewed and approved by the Ethical Committee of Chinese PLA General Hospital (S2022-789-01). The findings will be submitted for publication in peer-reviewed journals with online accessibility, ensuring adherence to the conventional scientific publishing process while clarifying how the research outcomes will be disseminated and accessed.Trial registration number NCT06121947.

BackgroundDeep brain stimulation (DBS) is a potential treatment for improving movement disorder. However, few large-sample studies can reveal its efficacy and safety. This study aims to initially explore the efficacy and safety of DBS in the mesencephalic locomotor region (MLR) on motor function in patients with post-stroke hemiplegia.Methods/designThis multicenter, prospective, double-blind, randomized crossover clinical trial aims to assess the safety and effectiveness of Deep Brain Stimulation (DBS) in the mesencephalic locomotor region (MLR) for patients with moderate to severe post-stroke hemiplegia. Sixty-two patients with stable disease after a year of conservative treatment will be enrolled and implanted with deep brain electrodes. Post-surgery, patients will be randomly assigned to either the DBS group or the control group, with 31 patients in each. The DBS group will receive electrical stimulation 1 month later, while the control group will undergo sham stimulation. Stimulation will be discontinued after 3 and 6 months, followed by a 2-week washout period. Subsequently, the control group will receive electrical stimulation, while the DBS group will undergo sham stimulation. Both groups will resume electrical stimulation at the 9th and 12th-month follow-ups. Post-12-month follow-up, motor-related scores will be collected for analysis, with the Fugl-Meyer Assessment Upper Extremity Scale (FMA-UE) as the primary metric. Secondary outcomes include balance function, neuropsychiatric behavior, fall risk, daily living activities, and quality of life. This study aims to provide insights into the therapeutic benefits of DBS for post-stroke hemiplegia patients.Result/conclusionWe proposed this study for the first time to comprehensively explore the effectiveness and safety of DBS in improving motor function for post-stroke hemiplegia, and provide evidence for DBS in the treatment of post-stroke hemiplegia. Study limitations are related to the small sample size and short study period.Clinical Trial RegistrationClinicaltrials.gov, identifier NCT05968248.

Deep brain stimulation (DBS) is an effective therapy for Meige syndrome (MS). However, the DBS efficacy varies across MS patients and the factors contributing to the variable responses remain enigmatic. We aim to explain the difference in DBS efficacy from a network perspective. We collected preoperative T1-weighted MRI images of 76 MS patients who received DBS in our center. According to the symptomatic improvement rates, all MS patients were divided into two groups: the high improvement group (HIG) and the low improvement group (LIG). We constructed group-level structural covariance networks in each group and compared the graph-based topological properties and interregional connections between groups. Subsequent functional annotation and correlation analyses were also conducted. The results indicated that HIG showed a higher clustering coefficient, longer characteristic path length, lower small-world index, and lower global efficiency compared with LIG. Different nodal betweennesses and degrees between groups were mainly identified in the precuneus, sensorimotor cortex, and subcortical nuclei, among which the gray matter volume of the left precentral gyrus and left thalamus were positively correlated with the symptomatic improvement rates. Moreover, HIG had enhanced interregional connections within the somatomotor network and between the somatomotor network and default-mode network relative to LIG. We concluded that the high and low DBS responders have notable differences in large-scale network architectures. Our study sheds light on the structural network underpinnings of varying DBS responses in MS patients.

[INLINE:1] The safety and effectiveness of magnetic resonance-guided focused ultrasound thalamotomy has been broadly established and validated for the treatment of essential tremor. In 2018, the first magnetic resonance-guided focused ultrasound system in Chinese mainland was installed at the First Medical Center of the PLA General Hospital. This prospective, single center, open-label, single-arm study was part of a worldwide prospective multicenter clinical trial (ClinicalTrials.gov Identifier: NCT03253991) conducted to confirm the safety and efficacy of magnetic resonance-guided focused ultrasound for treating essential tremor in the local population. From 2019 to 2020, 10 patients with medication refractory essential tremor were recruited into this open-label, single arm study. The treatment efficacy was determined using the Clinical Rating Scale for Tremor. Safety was evaluated according to the incidence and severity of adverse events. All of the subjects underwent a unilateral thalamotomy targeting the ventral intermediate nucleus. At the baseline assessment, the estimated marginal mean of the Clinical Rating Scale for Tremor total score was 58.3 ± 3.6, and this improved after treatment to 23.1 ± 6.4 at a 12-month follow-up assessment. A total of 50 adverse events were recorded, and 2 were defined as serious. The most common intraoperative adverse events were nausea and headache. The most frequent postoperative adverse events were paresthesia and equilibrium disorder. Most of the adverse events were mild and usually disappeared within a few days. Our findings suggest that magnetic resonance-guided focused ultrasound for the treatment of essential tremor is effective, with a good safety profile, for patients in Chinese mainland.

Abstract Cushing’s disease is a rare neuroendocrine disorder with excessive endogenous cortisol, impaired cognition, and psychiatric symptoms. Evidence from resting-state fMRI revealed the abnormalities of static brain connectivity in patients with Cushing’s disease (CD patients). However, it is unknown whether the CD patients’ dynamic functional connectivity would be abnormal and whether the dynamic features are associated with deficits in cognition and psychopathological symptoms. Here, we evaluated 50 patients with Cushing’s disease and 57 healthy participants by using resting-state fMRI and dynamic functional connectivity (dFNC) approach. We focused on the dynamic features of default mode network (DMN), salience network (SN), and central executive network (CEN) because these are binding sites for the cognitive-affective process, as well as vital in understanding the pathophysiology of psychiatric disorders. The dFNC was further clustered into four states by k-mean clustering. CD patients showed more dwell time in State 1 but less time in State 4. Intriguingly, group differences in dwell time in these two states can explain the cognitive deficits of CD patients. Moreover, the inter-network connections between DMN and SN and the engagement time in State 4 negatively correlated with anxiety and depression but positively correlated with cognitive performance. Finally, the classifier trained by the dynamic features of these networks successfully classified CD patients from healthy participants. Together, our study revealed the dynamic features of CD patients’ brains and found their associations with impaired cognition and emotional symptoms, which may open new avenues for understanding the cognitive and affective deficits induced by Cushing’s disease.

Cushing’s disease (CD) represents a state of cortisol excess, serving as a model to investigate the effects of prolonged hypercortisolism on functional brain. Potential alterations in the functional connectome of the brain may explain frequently reported cognitive deficits and affective disorders in CD patients. This study aims to elucidate the effects of chronic hypercortisolism on the principal functional gradient, which represents a hierarchical architecture with gradual transitions across cognitive processes, by integrating connectomics and transcriptomics approaches. Utilizing resting-state functional magnetic resonance imaging data from 140 participants (86 CD patients, 54 healthy controls) recruited at a single center, we explored the alterations in the principal gradient in CD patients. Further, we thoroughly explored the underlying associative mechanisms of the observed characteristic alterations with cognitive function domains, biological attributes, and neuropsychiatric representations, as well as gene expression profiles. Compared to healthy controls, CD patients demonstrated changes in connectome patterns in both primary and higher-order networks, exhibiting an overall converged trend along the principal gradient axis. The gradient values in CD patients’ right prefrontal cortex and bilateral sensorimotor cortices exhibited a significant correlation with cortisol levels. Moreover, the cortical regions showing gradient alterations were principally associated with sensory information processing and higher-cognitive functions, as well as correlated with the gene expression patterns which involved synaptic components and function. The findings suggest that converged alterations in the principal gradient in CD patients may mediate the relationship between hypercortisolism and cognitive impairments, potentially involving genes regulating synaptic components and function.

ObjectiveTremor-dominant Parkinson’s disease (TD-PD) can be further separated into levodopa-responsive and levodopa-resistant types, the latter being considered to have a different pathogenesis. Previous studies indicated that deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the globus pallidus internus (GPi) individually was not sufficient for tremor control, especially for the levodopa-resistant TD-PD (LRTD-PD). The thalamic ventral intermediate nucleus (VIM) has been regarded as a potent DBS target for different kinds of tremors. Therefore, we focused on the LRTD-PD subgroup and performed one-pass combined DBSs of STN and VIM to treat refractory tremors, aiming to investigate the safety and effectiveness of this one-trajectory dual-target DBS scheme.MethodsWe retrospectively collected five LRTD-PD patients who underwent a one-pass combined DBS of STN and VIM via a trans-frontal approach. The targeting of VIM was achieved by probabilistic tractography. Changes in severity of symptoms (measured by the Unified Parkinson Disease Rating Scale part III, UPDRS-III), levodopa equivalent daily doses (LEDD), and disease-specific quality of life (measured by the 39-item Parkinson’s Disease Questionnaire, PDQ-39) were evaluated.ResultsThree-dimensional reconstruction of electrodes illustrated that all leads were successfully implanted into predefined positions. The mean improvement rates (%) were 53 ± 6.2 (UPDRS-III), 82.6 ± 11.4 (tremor-related items of UPDRS), and 52.1 ± 11.4 (PDQ-39), respectively, with a mean follow-up of 11.4 months.ConclusionOne-pass combined DBS of STN and VIM via the trans-frontal approach is an effective and safe strategy to alleviate symptoms for LRTD-PD patients.

Introduction Deep brain stimulation (DBS) has been validated as a safe and effective treatment for refractory cervical dystonia (CD). Globus pallidus internus (GPi) and subthalamic nucleus (STN) are the two main stimulating targets. However, there has been no prospective study to clarify which target is the better DBS candidate for CD. The objective of this trial is to compare directly the efficacy and safety of GPi-DBS and STN-DBS, thereby instructing the selection of DBS target in clinical practice.Methods and analysis This multicentre, prospective, randomised, controlled study plans to enrol 98 refractory CD patients. Eligible CD patients will be randomly allocated to GPi-DBS group or STN-DBS group, with the DBS electrodes implanted into the posteroventral portion of GPi or the dorsolateral portion of STN, respectively. The primary outcome will be the improvement of symptomatic severity, measured by the changes in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) severity subscale and the Tsui scale at 3 months, 6 months and 12 months after surgery. The secondary outcomes include the improvement of the TWSTRS-disability subscale, TWSTRS-pain subscale, quality of life, mental and cognitive condition, as well as the differences in stimulation parameters and adverse effects. In addition, this study intends to identify certain predictors of DBS efficacy for CD.Ethics and dissemination The trial has been approved by the Medical Ethics Committee of Chinese PLA General Hospital (S2022-613-01). The results of this study will be published in international peer-reviewed journals and shared in professional medical conferences.Trial registration number NCT05715138.

ObjectiveThe purpose of this study was to study mechanisms of VNS modulation from a single neuron perspective utilizing a practical observation platform with single neuron resolution and widefield, real-time imaging coupled with an animal model simultaneously exposing the cerebral cortex and the hippocampus.MethodsWe utilized the observation platform characterized of widefield of view, real-time imaging, and high spatiotemporal resolution to obtain the neuronal activities in the cerebral cortex and the hippocampus during VNS in awake states and under anesthesia.ResultsSome neurons in the hippocampus were tightly related to VNS modulation, and varied types of neurons showed distinct responses to VNS modulation.ConclusionWe utilized such an observation platform coupled with a novel animal model to obtain more information on neuron activities in the cerebral cortex and the hippocampus, providing an effective method to further study the mechanisms of therapeutic effects modulated by VNS.

Background: The physiopathologic mechanism of Meige syndrome (MS) has not been clarified, and neuroimaging studies centering on cerebellar changes in MS are scarce. Moreover, even though deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been recognized as an effective surgical treatment for MS, there has been no reliable biomarker to predict its efficacy. Objective: To characterize the volumetric alterations of gray matter (GM) in the cerebellum in MS and to identify GM measurements related to a good STN-DBS outcome. Methods: We used voxel-based morphometry and lobule-based morphometry to compare the regional and lobular GM differences in the cerebellum between 47 MS patients and 52 normal human controls (HCs), as well as between 31 DBS responders and 10 DBS non-responders. Both volumetric analyses were achieved using the Spatially Unbiased Infratentorial Toolbox (SUIT). Further, we performed partial correlation analyses to probe the relationship between the cerebellar GM changes and clinical scores. Finally, we plotted the receiver operating characteristic (ROC) curve to select biomarkers for MS diagnosis and DBS outcomes prediction. Results: Compared to HCs, MS patients had GM atrophy in lobule Crus I, lobule VI, lobule VIIb, lobule VIIIa, and lobule VIIIb. Compared to DBS responders, DBS non-responders had lower GM volume in the left lobule VIIIb. Moreover, partial correlation analyses revealed a positive relationship between the GM volume of the significant regions/lobules and the symptom improvement rate after DBS surgery. ROC analyses demonstrated that the GM volume of the significant cluster in the left lobule VIIIb could not only distinguish MS patients from HCs but also predict the outcomes of STN-DBS surgery with high accuracy. Conclusion: MS patients display bilateral GM shrinkage in the cerebellum relative to HCs. Regional GM volume of the left lobule VIIIb can be a reliable biomarker for MS diagnosis and DBS outcomes prediction.

Cavernoma is the second most common cerebrovascular lesion. Cavernoma involving the cranial nerves is very rare. Only 15 cases of cavernoma presenting with trigeminal neuralgia (TN) have been previously reported. Here, we report a rare case of cavernoma manifesting with TN. A young female patient with a 15-day history of right-sided lancinating pain in the face, difficulty in opening the mouth, and hearing dysesthesia. Magnetic resonance imaging (MRI) revealed a well-demarcated lesion in the cerebellopontine angle related closely to the root of the trigeminal nerve. The initial impression was that of a neurinoma. The lesion was surgically resected via the retrosigmoid approach, postoperative pathological analysis confirmed the diagnosis of cavernoma, and the patient's pain and difficulty in opening the mouth resolved completely. We presented the 16th documented case of cavernoma with TN. Although cavernoma involving the trigeminal nerve is extremely rare, this diagnosis should be taken into consideration when a lesion in the cerebellopontine angle is detected on MRI, and the clinical manifestation is consistent with that of secondary TN. Specialized MRI sequences, such as susceptibility weighted imaging (SWI), gradient echo T2, and constructive interference in steady-state (CISS)-weighted imaging, aid in establishing the diagnosis. Resection via craniotomy may be the primary management strategy for cavernoma causing TN. In addition, gamma knife radiosurgery (GKRS) and percutaneous balloon compression (PBC) may ameliorate the pain to some extent.

Intracranial brain-computer interfaces (BCIs) can assist severely disabled persons in text communication and environmental control with high precision and speed. Nevertheless, sustainable BCI implants require minimal invasiveness. One of the implantation strategies is to adopt localized and robust cortical activities to drive BCI communication and to make a precise presurgical planning. The visual motion response is a good candidate for inclusion in this strategy because of its focal activity over the middle temporal visual area (MT). Here, we developed an intracranial BCI for spelling, utilizing only three electrodes over the MT area. The best recording electrodes were decided by preoperative functional magnetic resonance imaging (MRI) localization of the MT, and local neural activities were further enhanced by differential rereferencing of these electrodes. The BCI spelling system was validated both offline and online by five epilepsy patients, achieving the fastest speed of 62 bits/min, i.e., 12 characters/min. Moreover, the response patterns of dual-directional visual motion stimuli provided an additional dimension of BCI target encoding and paved the way for a higher information transfer rate of intracranial BCI spelling.

Assimilation of atlas is a rare skeletal malformation causing nerve compression with high risk of fatal. However, the genetic etiology of assimilation of atlas AOA is currently lacking. In this paper, the whole-exome sequencing (WES) analysis was employed to study a Chinese family having a sporadic proband son of assimilation of atlas AOA but other healthy family members. We identified a novel variant in ciliary rootlet coiled-coil gene (NM_014675.5 (CROCC): c.4702C>T (r.4702c>u, p.(Arg1568Cys)). The variant had different genotypes between the proband and healthy family members but with high conservations of “damage” to protein structure based on MutationTaster and SIFT prediction. CROCC gene can be obtained in both healthy (n=220) and non-mutated assimilation of atlas AOA patient samples (n=68) but absented in five sporadic patients with the novel variant. Furthermore, abnormal of cilia was observed after editing the target sequence on CROCC using CRISPR-Cas9. These results suggested that assimilation of atlas AOA might be caused by the mutation of CROCC: c.4702C>T (r.4702c>u, p.(Arg1568Cys)). With strong amino acid conservation and interaction regulation, the variant mutation could cause the signal disorder of skeletal development which may lead to the defective bone formation and finally cause the development of assimilation of atlas AOA.

Abstract Introduction Stress‐related brain disorders can be associated with glucocorticoid disturbance and hippocampal alteration. However, it remains largely unknown how cortisol affects the structure and function of hippocampus. Cushing's disease (CD) provides a unique “hyperexpression model” to explore the effects of excessive cortisol on hippocampus as well as the relation between these effects and neuropsychological deficits. Methods We acquired high‐resolution T1‐weighted and resting‐state functional magnetic resonance imaging in 47 CD patients and 53 healthy controls. We obtained the volume and functional connectivity of the hippocampal rostral and caudal subregions in both groups. Relationships between hippocampal alterations, neuroendocrine, and neuropsychological assessments were identified. Results Relative to control subjects, the CD patients had smaller volumes of all four hippocampal subregions. Furthermore, whole brain resting‐state functional connectivity analyses with these four different hippocampal regions as seeds revealed altered hippocampal functional connectivity with high‐order networks, involving the DMN, frontoparietal, and limbic networks in CD patients. The intrinsic hippocampal functional connectivity was associated with the quality of life of the CD patients. Conclusions Our findings elucidate the cumulative effect of excess cortisol on the morphology and function of hippocampus and reinforce the need for effective interventions in stress‐related brain disease to halt potential hippocampal damage.

In the interaction between a tumor and the immune system, immune checkpoints play an important role, and in tumor immune escape, co-inhibitory immune checkpoints are important. Immune checkpoint inhibitors (ICIs) can enhance the immune system’s killing effect on tumors. To date, impressive progress has been made in a variety of tumor treatments; PD1/PDL1 and CTLA4 inhibitors have been approved for clinical use in some tumors. However, glioblastoma (GBM) still lacks an effective treatment. Recently, a phase III clinical trial using nivolumab to treat recurrent GBM showed no significant improvement in overall survival compared to bevacizumab. Therefore, the use of immune checkpoints in the treatment of GBM still faces many challenges. First, to clarify the mechanism of action, how different immune checkpoints play roles in tumor escape needs to be determined; which biomarkers predict a benefit from ICIs treatment and the therapeutic implications for GBM based on experiences in other tumors also need to be determined. Second, to optimize combination therapies, how different types of immune checkpoints are selected for combined application and whether combinations with targeted agents or other immunotherapies exhibit increased efficacy need to be addressed. All of these concerns require extensive basic research and clinical trials. In this study, we reviewed existing knowledge with respect to the issues mentioned above and the progress made in treatments, summarized the state of ICIs in preclinical studies and clinical trials involving GBM, and speculated on the therapeutic prospects of ICIs in the treatment of GBM.

MRgFUS has just been made available for the 1.7 million Parkinson's disease patients in China. Despite its non-invasive and rapid therapeutic advantages for involuntary tremor, some concerns have emerged about outcomes variability, non-specificity, and side-effects, as little is known about its impact on the long-term plasticity of brain structure. We sought to dissect the characteristics of long-term changes in brain structure caused by MRgFUS lesion and explored potential biological mechanisms. One-year multimodal imaging follow-ups were conducted for nine tremor-dominant Parkinson's disease patients undergoing unilateral MRgFUS thalamotomy. A structural connectivity map was generated for each patient to analyze dynamic changes in brain structure. The human brain transcriptome was extracted and spatially registered for connectivity vulnerability. Genetic functional enrichment analysis was performed and further clarified using in vivo emission computed tomography data. MRgFUS not only abolished tremors but also significantly disrupted the brain network topology. Network-based statistics identified a U-shape MRgFUS-sensitive subnetwork reflective of hand tremor recovery and surgical process, accompanied by relevant cerebral blood flow and gray matter alteration. Using human brain gene expression data, we observed that dopaminergic signatures were responsible for the preferential vulnerability associated with these architectural alterations. Additional PET/SPECT data not only validated these gene signatures, but also suggested that structural alteration was significantly correlated with D1 and D2 receptors, DAT, and F-DOPA measures. There was a long-term dynamic loop between structural alteration and dopaminergic signature for MRgFUS thalamotomy, which may be closely related to the long-term improvements in clinical tremor.

Cortisol, the end product of the hypothalamic–pituitary–adrenal axis, regulates cognitive function and emotion processing. Cushing's disease, which is characterized by a unique excess of cortisol upon clinical diagnosis, serve as an excellent in vivo “hyperexpression” model to investigate the neurobiological mechanisms of cortisol in the human brain. Previous studies have shown the association between cortisol and functional connectivity within an a priori brain network. However, the whole-brain connectivity pattern that accompanies endogenous cortisol variation is still unclear, as are its associated genetic underpinnings. Here, using resting-state functional magnetic resonance imaging in 112 subjects (60 patients with Cushing's disease and 52 healthy subjects), we performed a voxel-level brain-wide association analysis to investigate the functional connectivity pattern associated with a wide variation in cortisol levels at 8 a.m. The results showed that the regions associated with cortisol as of 8 a.m. were primarily distributed in brain functional hubs involved in self-referential processing, such as the medial prefrontal cortex, anterior and posterior cingulate cortex, and caudate. We also found that regions in the middle temporal, inferior parietal and ventrolateral prefrontal cortex, which is important for social communication tasks, and in the visual and supplementary motor cortex, which is involved in primary sensorimotor perception, were adversely affected by excessive cortisol. The connectivity between these regions was also significantly correlated with neuropsychiatric profiles, such anxiety and depression. Finally, combined neuroimaging and transcriptome analysis showed that functional cortisol-sensitive brain variations were significantly coupled to regional expression of glucocorticoid and mineralocorticoid receptors. These findings reveal cortisol-biased functional signatures in the human brain and shed light on the transcriptional regulation constraints on the cortisol-related brain network.

Summary: Scant understanding of the glioblastoma microenvironment and molecular bases hampers development of efficient treatment strategies. Analyses of gene signatures of human gliomas demonstrate that the SETD2 mutation is correlated with poor prognosis of IDH1/2 wild-type (IDH-WT) adult glioblastoma patients. To better understand the crosstalk between SETD2 mutant (SETD2-mut) glioblastoma cells and the tumor microenvironment, we leverage single-cell transcriptomics to comprehensively map cellular populations in glioblastoma. In this study, we identify a specific subtype of high-grade glioma-associated microglia (HGG-AM). Further analysis shows that transforming growth factor (TGF)-β1 derived from SETD2-mut/IDH-WT tumor cells activates HGG-AM, exhibiting pro-inflammation and proliferation signatures. Particularly, HGG-AM secretes interleukin (IL)-1β via the apolipoprotein E (ApoE)-mediated NLRP1 inflammasome, thereby promoting tumor progression. HGG-AM present extensive proliferation and infiltration to supplement the activated microglia pool. Notably, TGF-β1/TβRI depletion dramatically reduces HGG-AM density and suppresses tumor growth. Altogether, our studies identify a specific microglia subpopulation and establish the cellular basis of interactions between HGG-AM and glioblastoma cells.

Abstract Background Glioma‐related epilepsy (GRE) is defined as symptomatic epileptic seizures secondary to gliomas, it brings both heavy financial and psychosocial burdens to patients with diffuse glioma and significantly decreases their quality of life. To date, there have been no clinical guidelines that provide recommendations for the optimal diagnostic and therapeutic procedures for GRE patients. Methods In March 2017, the Joint Task Force for GRE of China Association Against Epilepsy and Society for Neuro‐Oncology of China launched the guideline committee for the diagnosis and treatment of GRE. The guideline committee conducted a comprehensive review of relevant domestic and international literatures that were evaluated and graded based on the Oxford Centre for Evidence‐Based Medicine Levels of Evidence, and then held three consensus meetings to discuss relevant recommendations. The recommendations were eventually given according to those relevant literatures, together with the experiences in the diagnosis and treatment of over 3000 GRE cases from 24 tertiary level hospitals that specialize in clinical research of epilepsy, glioma, and GRE in China. Results The manuscript presented the current standard recommendations for the diagnostic and therapeutic procedures of GRE. Conclusions The current work will provide a framework and assurance for the diagnosis and treatment strategy of GRE to reduce complications and costs caused by unnecessary treatment. Additionally, it can serve as a reference for all professionals involved in the management of patients with GRE.

PurposeHemangiopericytomas are aggressive tumors known for their recurrence. The purpose of this study was to evaluate the management of residual, recurrent, and metastatic intracranial hemangiopericytomas using CyberKnife (CK) stereotactic radiotherapy (SRT).Materials and MethodsData were collected from 15 patients (28 tumors; eight men and seven women; 32–58 years) with residual, recurrent, or metastatic intracranial hemangiopericytomas, who were treated with stereotactic radiotherapy using CyberKnife between January 2014 and August 2019. All patients had previously been treated with surgical resection. Initial tumor volumes ranged from 0.84 to 67.2 cm3, with a mean volume of 13.06 cm3. The mean marginal and maximum radiosurgical doses to the tumors were 21.1 and 28.76 Gy, respectively. The mean follow-up time for tumors was 34.5 months, ranging from 13 to 77 months.Results15 patients were alive after treatment; the mean post-diagnosis survival at censoring was 45.6 months (range 13–77 months). The volumes of the 28 tumors in the 15 followed patients were calculated after treatment. Postoperative magnetic resonance imaging revealed a mean tumor volume of 6.72 cm3 and a range of 0–67.2 cm3, with the volumes being significantly lower than pretreatment values. Follow-up imaging studies demonstrated tumor disappearance in seven (25%) of 28 tumors, reduction in 14 (50%), stability in one (3.57%), and recurrence in six (21.4%). Total tumor control was achieved in 22 (78.5%) of 28 tumors. The tumor grade and fraction time were not significantly associated with progression-free survival. Intracranial metastasis occurred in three patients, and extraneural metastasis in one patient.ConclusionsOn the basis of the current results, stereotactic radiotherapy using CyberKnife is an effective and safe option for residual, recurrent, and metastatic intracranial hemangiopericytomas. Long-term close clinical and imaging follow-up is also necessary.

A growing body of evidence suggests that altered brain structure plays a crucial role in the pathogenesis of neuropsychological abnormalities induced by hypercortisolism in patients with Cushing’s disease. While most studies mainly focus on gray matter, white matter structure has been largely overlooked. In the current study, we conducted a cross-sectional diffusion tensor imaging study on 58 patients with Cushing’s disease and 54 matched healthy individuals to profile the microstructural pattern using automated fiber quantification and investigate its association with neuroendocrine and neuropsychological deficits. The study revealed that microstructural pattern showed a widespread mean diffusivity, radial diffusivity increase, fractional anisotropy decrease and partial axial diffusivity increase among tracts notably in corpus callosum forceps, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, uncinate fasciculus and arcuate fasciculus, while within the same tract abnormalities localized to specific positions. Moreover, compromised microstructural pattern of white matter in specific tracts and locations along the trajectory were associated with ACTH and cortisol concentration and cognitive decline in patients with Cushing’s disease. Collectively, our study elucidates the form of white matter pathology induced by hypercortisolism and its association with cognitive decline which may provide further targets for early identification and intervention of Cushing’s disease.

Background/Aims: Autophagy is essential for maintaining cellular homeostasis and the survival of terminally differentiated cells as neurons. In this study, we aim to investigate whether mitofusin 2, a mitochondrial fusion protein, mediates autophagy in cerebral ischemia/reperfusion (I/R) injury. Methods: Primary cultured neurons were treated with oxygen-glucose deprivation/reperfusion to mimic cerebral I/R injury in vitro. Autophagosomes were visualized upon TEM. Autophagy-markers were then detected to monitor autophagy by western-blot and real-time PCR, and the autophagic flux was tracked with a mRFP-GFP-LC3 construct by fluorescence as well as autophagy inhibitors and agonists. The up- and downregulation of Mfn2 were through transfecting a lentivirusexpression vector respectively. And neuronal injury was detected by cell counting kit and TUNEL assay. Results: Results showed I/R increased autophagosome formation and inhibited autolysosome degradation. Furthermore, use of autophagy related agents demonstrated that I/R injury was caused by insufficient autophagy and aggravated by impaired autophagic degradation. The results also indicated that mitofusin 2 could ameliorate I/R injury through increasing autophagosome formation and promoting the fusion of autophagosomes and lysosomes. In contrast, downregulation of mitofusin 2 aggravated the I/R injury by inhibiting autophagosome formation and the fusion of autophagosomes and lysosomes. Additionly, mitofusin 2 overexpression did not lead to autolysosome accumulation induced by I/R. Conclusions: In summary, this study explicitly demonstrated that mitofusin 2 could ameliorate I/R injury mainly through promoting autophagy, which represented a potential novel strategy for neuroprotection against cerebral I/R damage.

The negative feedback system (NFS) was regarded as the basic unit of regulation of physiological homeostasis for more than 70 years. However, NFS-based depiction possesses some limitations. The self-coupled system (SCS), a non-stop system in which the output of the current moment becomes the input of the next moment, can also be utilized to depict homeostasis. In SCS-based depiction, all of the related regulatory mechanisms of a homeostasis are regarded as an entity. Then, homeostatic dynamics can be expressed by simple mathematical language. A new disease group was revealed and some useful inferences were obtained through mathematical deduction. They were supported by published studies. SCS-based depiction of homeostasis should be a requisite supplement to medical knowledge systems based on NFS.

Background: Deep brain stimulation (DBS) is considered an effective treatment option for Parkinson's disease (PD). Several studies have demonstrated the efficacy of neurostimulation in patients with advanced PD. The subthalamic nucleus (STN), the internal globus pallidus (GPi), ventral intermediate nucleus (Vim), and pedunculopontine nucleus (PPN) are reportedly effective DBS targets for control of Parkinsonian tremors. However, there is no consensus on the ideal target for DBS in patients with Parkinson's disease. Only a few studies have directly compared the efficacy of DBS of the Vim, STN, and GPi. Therefore, we searched PubMed, Embase, Cochrane Library, and other databases for observational studies, extracted data on unified Parkinson's disease rating scale (UPDRS) scores and performed a comprehensive network meta-analysis of different strategies of DBS and compared the efficiency of DBS at different targets.Methods: Forest plot was used to examine the overall efficiency of DBS; cumulative probability value was used to rank the strategies under examination. A node-splitting model was employed to assess consistency of reported outcomes inconsistency. A total of 16 studies which focused on UPDRS improvement were included in the network meta-analysis.Results: By comparing the overall efficiency associated with each target, we confirmed the efficacy of DBS therapy in PD. Our findings revealed similar efficacy of DBS targeted at GPi and STN in the on-medication phase [GPi-3.9 (95% CI −7.0 to −0.96); STN-3.1 (−5.9 to −0.38)]; however, in the off-medication phase, Vim-targeted DBS was associated with better improvement in UPDRS scores and could be a choice as a DBS target for tremor-dominant Parkinsonism.Conclusions: Our findings will help improve clinical application of DBS.

The accurate identification of the human brain tumor boundary and the complete resection of the tumor are two essential factors for the removal of the glioma tumor in brain surgery. We present a visible resonance Raman (VRR) spectroscopy technique for differentiating the brain tumor margin and glioma grading. Eighty-seven VRR spectra from twenty-one human brain specimens of four types of brain tissues, including the control, glioma grade II, III, and IV tissues, were observed. This study focuses on observing the characteristics of new biomarkers and their changes in the four types of brain tissue. We found that two new RR peaks at 1129 cm−1 and 1338 cm−1 associated with molecular vibrational bonds in four types of brain tissues are significantly different in peak intensities of VRR spectra. These two resonance enhanced peaks may arise from lactic acid/phosphatidic acid and adenosine triphosphate (ATP)/nicotinamide adenine dinucleotide, respectively. We found that lactic acid and ATP concentrations vary with glioma gratings. The higher the grade of malignancy, the more the increase in lactic acid and ATP concentrations. These two RR peaks may be considered as new molecular biomarkers and used to evaluate glioma grades and identify the margin of gliomas from the control tissues. The metabolic process of lactic acid and ATP in glioma cells based on the VRR spectral changes may reveal the Warburg hypothesis.

Classical trigeminal neuralgia (TN) is a severe neuropathic facial pain disorder associated with increased risks of anxiety and depression. Converging evidence suggests that chronic pain pathophysiology involves dysfunctional pain-related and emotion-related networks. However, whether these systems are also among the culprit networks for TN remains unclear. Here, we aimed to assess TN-related anatomical and functional brain anomalies in pain-related and emotion-related networks. We investigated differences in gray matter (GM) volume and the related resting-state functional connectivity (rsFC) between 29 classical TN patients and 34 matched healthy controls. Relationships between brain measurement alterations, clinical pain and emotional states were identified. A longitudinal observation was further conducted to determine whether alterations in the brain could renormalize following pain relief. Reduced GM volumes in the bilateral amygdala, periaqueductal gray (PAG) and right insula were found in TN patients compared with healthy control subjects. Whole-brain rsFC analyses with the four above-mentioned anatomical regions as seeds identified three significantly altered functional circuits, including amygdala-DLPFC, amygdala-mPFC and amygdala-thalamus/putamen circuitry. The amygdala-DLPFC and amygdala-mPFC circuits were associated with clinical pain duration and emotional state ratings, respectively. Further longitudinal analysis found that rsFC strength abnormalities in two fronto-limbic circuits (left amygdala/left DLPFC and right amygdala/right PFC) were resolved after pain relief. Together, structural and functional deficits in pain-related and emotion-related networks were associated with TN patients, as demonstrated by our multimodal results. Pain relief had protective effects on brain functional connectivity within fronto-limbic circuits. Our study provides novel insights into the pathophysiology of TN, which may ultimately facilitate advances in TN intervention.

Among sphingosine 1-phosphate receptors (S1PRs) family, S1PR1 has been shown to be the most highly expressed subtype in neural stem cells (NSCs) and plays a crucial role in the migratory property of NSCs. Recent studies suggested that S1PR1 was expressed abundantly in the hippocampus, a specific neurogenic region in rodent brain for endogenous neurogenesis throughout life. However, the potential association between S1PR1 and neurogenesis in hippocampus following traumatic brain injury (TBI) remains unknown. In this study, the changes of hippocampal S1PR1 expression after TBI and their effects on neurogenesis and neurocognitive function were investigated, focusing on particularly the extracellular signal-regulated kinase (Erk) signaling pathway which had been found to regulate multiple properties of NSCs. The results showed that a marked upregulation of S1PR1 occurred with a peak at 7 days after trauma, revealing an enhancement of proliferation and neuronal differentiation of NSCs in hippocampus due to S1PR1 activation. More importantly, it was suggested that mitogen-activated protein kinase-Erk kinase (MEK)/Erk cascade was required for S1PR1-meidated neurogenesis and neurocognitive recovery following TBI. This study lays a preliminary foundation for future research on promoting hippocampal neurogenesis and improving TBI outcome.