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We investigated the function of microRNA (miR)-532-5p in cerebral ischemia-reperfusion injury (CI/RI) and the underlying mechanisms using oxygen-glucose deprivation and reperfusion (OGD/R)-treated SH-SY5Y cells and middle cerebral artery occlusion (MCAO) model rats. MiR-532-5p levels were significantly downregulated in OGD/R-treated SH-SY5Y cells and the brain tissues of MCAO model rats. MiR-532-5p overexpression significantly reduced apoptosis, reactive oxygen species (ROS), and inflammation in the OGD/R-induced SH-SY5Y cells. Bioinformatics analysis using the targetscan and miRDB databases as well as dual luciferase reporter assays confirmed that miR-532-5p directly binds to the 3'UTR of C-X-C Motif Ligand 1 (CXCL1). Methylation-specific PCR (MSP) analysis showed that miR-532-5p expression was reduced in OGD/R-treated SH-SY5Y cells because of miR-532-5p promoter hypermethylation. Moreover, 5-azacytidine, a methylation inhibitor, restored miR-532-5p expression in OGD/R-treated SH-SY5Y cells. Brain tissues of MCAO model rats showed significantly increased cerebral infarction areas, cerebral water, neuronal apoptosis, and activated CXCL1/CXCR2/NF-κB signaling, but these effects were alleviated by intraventricular injection of miR-532-5p agomir. These findings demonstrate that miR-532-5p overexpression significantly reduces in vitro and in vivo CI/RI by targeting CXCL1. Thus, miR-532-5p is a potential therapeutic target for patients with CI/RI.

Parkinson’s disease (PD) is a common age-related neurodegenerative disease that affects the structural architecture of the cerebral cortex. Cortical thickness (CTh) via surface-based morphometry (SBM) analysis is a popular measure to assess brain structural alterations in the gray matter in PD. However, the results of CTh analysis in PD lack consistency and have not been systematically reviewed. We conducted a comprehensive coordinate-based meta-analysis (CBMA) of 38 CTh studies (57 comparison datasets) in 1,843 patients with PD using the latest seed-based d mapping software. Compared with 1,172 healthy controls, no significantly consistent CTh alterations were found in patients with PD, suggesting CTh as an unreliable neuroimaging marker for PD. The lack of consistent CTh alterations in PD could be ascribed to the heterogeneity in clinical populations, variations in imaging methods, and underpowered small sample sizes. These results highlight the need to control for potential confounding factors to produce robust and reproducible CTh results in PD.

To clarify the potential role of selenium (Se) on cerebral ischemia/reperfusion (I/R) injury, we utilized mouse middle cerebral artery occlusion (MCAO) followed by reperfusion as an animal model and oxygen–glucose deprivation and reoxygenation (OGD/R) to treat N2a cells as a cell model, respectively. MCAO model was established in mice and then divided into different groups with or without Se treatment. TTC staining was used to observe whether the cerebral I/R modeling was successful, and the apoptosis level was determined by TUNEL staining. The expression of GPx-4 and p22phox was assessed by western blot. In vitro experiments, the OGD/R induced oxidative stress in N2a cells was assessed by levels of GSH/GSSG, malondialdehyde, superoxide dismutase and iron content, respectively. QRT-PCR was used to detect the mRNA levels of Cox-2, Fth1, Mfn1 and mtDNA in N2a cells. JC-1 staining and flow cytometry was performed to detect the mitochondrial membrane potential. Se treatment alleviated cerebral I/R injury and improved the survival rate of mice. Additionally, Se treatment apparently attenuated oxidative stress and inhibited iron accumulation in MCAO model mice and OGD/R model of N2a cells. In terms of its mechanism, Se could up-regulate Mfn1 expression to alleviate oxidative stress and ferroptosis by promoting mitochondrial fusion in vivo and vitro. These findings suggest that Se may have great potential in alleviating cerebral I/R injury.

To explore the association between cerebral small vessel disease (cSVD) and cognitive impairment (CI) in Parkinson's disease (PD).81 PD patients were recruited into the study from September 2018 to December 2020. The demographic characteristics and radiologic and laboratory data were collected. Cognitive assessments were carried out using the Montreal Cognitive Assessment. The association between cSVD and cognitive impairment was analyzed using univariate and binary logistic regression analysis.The binary logistic regression analysis showed that, after correcting for age, educational years, hyperhomocysteinemia, hypertension, and diabetes mellitus, total cSVD scores (OR 1.55, 95% CI 1.07-2.27, P = 0.02), the presence of paraventricular white matter hyperintensity (PVH) (OR 11.78, 95% CI 3.08-45.01, P 0.001), white matter hyperintensity (WMH) (OR 7.95, 95% CI 2.28-27.79, P = 0.001), and perivascular space (PVS) (OR 6.66, 95% CI 2.08-21.40, P = 0.001) were independent risk factors for PD-CI.The presence of cSVD was associated with cognitive dysfunction in patients with PD. It may be beneficial to manage cSVD to prevent the progression of cognitive impairment in patients with PD.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. Studies have shown that MS disrupts several social cognitive abilities [including empathy and theory of mind (ToM)]. Overall ToM deficits in MS are well documented, but how the specific ToM subcomponents and empathic capacity are affected remains unclear. For this meta-analysis, we searched PubMed, Web of Science, and Embase from inception to July 2020. Effect sizes were calculated using Hedges g with a random-effects model. Thirty-three studies were included. Relative to healthy controls (HCs), patients with MS were moderately impaired in overall empathy (g = −0.67), overall ToM (g = −74), cognitive ToM (g = −0.72), and the overlapping domains of cognitive empathy/affective ToM (g = −0.79); no group differences were identified for affective empathy (g = −0.19). Compared with HCs, patients with relapsing-remitting MS (RRMS) and progressive MS were impaired in overall empathy, overall ToM, cognitive ToM, and cognitive empathy/affective ToM, without significant RRMS–progressive MS differences in impairment degree. We conducted the first meta-analytic review investigating the empathy and ToM functioning patterns in patients with MS and examined the overlapping and distinct subcomponents of these constructs. The findings suggest differential impairment of the core aspects of social cognitive processing in patients with MS, which may importantly inform the development of structured social cognitive MS interventions.

Brain structural abnormalities in idiopathic restless legs syndrome have long been debated. Voxel-based morphometry is an objective structural magnetic resonance imaging technique to investigate regional grey matter volume or density differences between groups. In the last decade, voxel-based morphometry studies have exhibited inconsistent and conflicting findings regarding the presence and localization of brain grey matter alterations in restless legs syndrome. We therefore conducted a coordinate-based meta-analysis to quantitatively examine whether there were consistent grey matter findings in restless legs syndrome using the latest algorithms, seed-based d mapping with permutation of subject images. We included 12 voxel-based morphometry studies (13 datasets, 375 patients and 385 healthy controls). Our coordinate-based meta-analysis did not identify evidence of consistent grey matter alterations in restless legs syndrome. Grey matter alterations via voxel-based morphometry analysis are not therefore recommended to be used as a reliable surrogate neuroimaging marker for restless legs syndrome. This lack of consistency may be attributed to differences in sample size, genetics, gender distribution and age at onset, clinical heterogeneity (clinical course, anatomical distribution of symptoms, disease severity, disease duration, abnormal sensory profiles and comorbidity), and variations in imaging acquisition, data processing and statistical strategies. Longitudinal studies with multimodal neuroimaging techniques are needed to determine whether structural changes are dynamic and secondary to functional abnormalities.

Migraine is one of the most common disabling diseases in the world. Its recurrent attacks may lead to abnormalities in the structure of the brain and retina. An increasing number of studies have investigated retinal nerve fiber layer (RNFL) thickness alterations in migraine by the optical coherence tomography (OCT); however, no consensus has yet reached. We searched Pubmed, Embase, and Web of Science databases to identify studies that investigated RNFL thickness in migraine by OCT measurement and performed a meta-analysis of eligible studies. Twenty-six studies were included in the meta-analysis, comprising 1530 migraine patients and 1105 healthy controls. The mean RNFL thickness was thinner in the migraine group compared to the control group (SMD =− 0.53). In the subgroup analyses, RNFL thickness were decreased most significantly in the superior (SMD = − 0.71) and inferior (SMD = − 0.63) quadrants among all quadrants. Migraine with aura (SMD = − 0.91) showed a greater effect size of RNFL thickness reduction than migraine without aura (SMD =− 0.47). Spectral-domain OCT (SMD = − 0.55) seems more sensitive to detect RNFL thickness reduction than time-domain OCT (SMD = − 0.44). In addition, age, sex, disease duration, attack frequency, and intraocular pressure were not significantly associated with RNFL thickness. The findings from our comprehensive meta-analysis with large datasets strengthen the clinical evidence of the RNFL thickness reduction in migraine. RNFL thickness via spectral-domain OCT measurement demonstrates the potential role in differentiating patients with migraine, especially migraine with aura, from healthy controls.

Background: A growing number of studies have used surface-based morphometry (SBM) analyses to investigate gray matter cortical thickness (CTh) abnormalities in Parkinson disease (PD). However, the results across studies are inconsistent and have not been systematically reviewed. A clear picture of CTh alterations in PD remains lacked. Coordinate-based meta-analysis (CBMA) is a powerful tool to quantitatively integrate the results of individual voxel-based neuroimaging studies to identify the functional or structural neural substrates of particular neuropsychiatric disorders. Recently, CBMA has been updated for integrating SBM studies. Methods: The online databases PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), WanFang, and SinoMed were comprehensively searched without language limitations from the database inception to February 2, 2020. We will include all SBM studies that compared regional CTh between patients with idiopathic PD and healthy control subjects at the whole-cortex level using Seed-based d Mapping with Permutation of Subject Images (SDM-PSI). In addition to the main CBMA, we will conduct several supplementary analyses to test the robustness of the results, such as jackknife analyses, subgroup analyses, heterogeneity analyses, publication bias analyses, and meta-regression analyses. Results: This CBMA will offer the latest evidence of CTh alterations in PD. Conclusions: Consistent and robust evidence of CTh alterations will feature brain morphometry of PD and may facilitate biomarker development. PROSPERO registration number: CRD42020148775

Background: Multiple system atrophy (MSA) is a fatal neurodegenerative disease that progresses very rapidly and has a poor prognosis. Some studies indicate that the level of inflammatory cytokines may be related to MSA. However, no consistent conclusion has been drawn yet. The purpose of our research is to perform a meta-analysis to investigate whether the level of inflammatory cytokines is altered in MSA. Methods: Case-control studies on inflammatory cytokine levels in MSA will be searched in the following 3 databases: PubMed, Embase, and Web of Science from the database start time to March 17, 2020. Two independent authors will conduct research selection, data extraction, and quality evaluation. Data synthesis, subgroup analysis, sensitivity analysis, and the meta-analysis will be performed using Stata15.0 software. Results: This study will provide a comprehensive review of all studies on inflammatory cytokine levels in MSA. Conclusion: To the best of our knowledge, this study will be the first meta-analysis that provides the quantitative evidence of inflammatory cytokine levels in MSA. Registration Number: INPLASY202060034.

Ischemic stroke is characterized by loss of brain function because of cerebral ischemia. Evidence has been shown that miR-217-5p is significantly downregulated in infarcted brain areas following focal cerebral ischemia. However, the role of miR-217-5p in ischemic stroke is still unclear. To mimic ischemia/reperfusion (I/R) injury conditions in vitro, SH-SY5Y cells were treated with oxygen-glucose deprivation/reperfusion (OGD/R). Our data found that PTEN was the directly target of miR-217-5p in SH-SY5Y cells. The level of miR-217-5p was significantly decreased, while the level of PTEN was notably increased in SH-SY5Y cells following OGD/R treatment. Overexpression of miR-217-5p markedly promoted the proliferation and cell cycle progression, and inhibited apoptosis in OGD/R-treated SH-SY5Y cells. In addition, overexpression of miR-217-5p significantly decreased the expressions of PTEN and FOXO1, but increased the expression of p-Akt in OGD/R-treated SH-SY5Y cells. Moreover, methylation specific PCR (MSP) results indicated the CpG islands in the promoter region of miR-217-5p were hypermethylated in SH-SY5Y cells under OGD/R. Meanwhile, the DNA methylation of miR-217-5p promoter region decreased expression of miR-217-5p. Our data indicated that miR-217-5p could attenuate ischemic injury by inhibiting PTEN. In addition, DNA methylation-mediated silencing of miR-217-5p may serve as a promising therapeutic target of ischemic stroke.

To assess the potential early risk factors of mild cognitive impairment after aneurysmal subarachnoid hemorrhage.We prospectively enrolled patients with aneurysmal subarachnoid hemorrhage treated with endovascular coiling during a 5-year period. The demographic characteristics and radiologic and laboratory data were collected. Cognitive assessments were carried out using the Montreal Cognitive Assessment at 6 months after ictus. Multivariate logistic regression was used to determine the risk factors associated with the development of mild cognitive impairment.Of 152 patients, 59 patients (39%) developed cognitive impairment 6 months later. Univariate analysis showed that the patients with anterior communicating artery or anterior cerebral artery aneurysms (P0.001) with Glasgow Outcome Scale score of 7 or less at ictus (P = 0.002), Hunt and Hess grade of 3 or higher (P = 0.002), and Fisher grade of 3 or higher (P = 0.032) were more likely to develop mild cognitive impairment. The risk of mild cognitive impairment was increased for patients who had delayed cerebral ischemia (P = 0.040) and hydrocephalus (P = 0.002). In multivariate logistic regression analysis, mild cognitive impairment was independently associated with anterior communicating artery or anterior cerebral aneurysms (odds ratio [OR], 11.046; 95% confidence interval [CI], 3.371-36.198; P0.001), delayed cerebral ischemia (OR, 6.153; 95% CI, 1.587-23.855; P = 0.009), and hydrocephalus (OR, 8.768; 95% CI, 2.115-36.345; P = 0.003).The location of the aneurysm, delayed cerebral ischemia, and hydrocephalus were independently associated with the occurrence of mild cognitive impairment after aneurysmal subarachnoid hemorrhage and can contribute to improved identification of patients at high risk for mild cognitive impairment.

Background Multiple sclerosis (MS) is an immune-mediated demyelinating disease that disrupts several social cognitive abilities, including the theory of mind (ToM) and facial emotion recognition (FER). It is unclear how specific ToM subcomponents, including cognitive and affective ToM, are affected in patients with MS and the social cognitive abilities in MS subtypes. Methods A search of PubMed, Web of Science, and Embase databases was conducted until June 2020. Effect sizes were calculated using Hedges g with a random-effects model. Results A total of 45 studies were included. Relative to health controls (HCs), patients with MS and its subtypes (including relapsing-remitting MS [RRMS] and progressive MS) exhibited impairments in ToM (g = −0.77, g = −0.70, g = −0.75, respectively), cognitive ToM (g = −0.72, g = −0.83, g = −0.73, respectively), affective ToM (g = −0.84, g = −0.63, g = −0. 50, respectively), and FER (g = −0.62, g = −0.53, g = −1.07, respectively). In addition, there was no difference between progressive primary MS and secondary progressive MS in overall ToM, cognitive ToM, affective ToM, and FER. Compared to patients with RRMS, patients with progressive MS showed no difference in overall ToM, cognitive ToM, and affective ToM but had more serious defects in FER (g = -0.57). Conclusions These quantitative results indicate that patients with MS and its subtypes have a differential impairment of the core aspects of social cognitive processing (including ToM and FER), which may help develop the structured social cognitive interventions in MS.

BACKGROUND Studies employing voxel-based morphometry have reported inconsistent findings on the association of gray matter (GM) abnormalities with chronic back pain (CBP). We, therefore, performed a meta-analysis of available studies to identify the most consistent GM regions associated with CBP. METHODS The PubMed, Embase, and Web of Science databases were searched from January 2000 to May 29, 2016. Comprehensive meta-analyses of whole-brain voxel-based morphometry studies to identify the most robust GM abnormalities in CBP were conducted using the Seed-based d Mapping software package. RESULTS A total of 10 studies, comprising 293 patients with CBP and 624 healthy controls, were included in the meta-analyses. The most robust findings of regional GM decreases in patients with CBP compared with healthy controls were identified in the bilateral medial prefrontal cortex extending to the anterior cingulate cortex, the right medial prefrontal cortex extending to the orbitofrontal cortex. Regional GM decreases in the left anterior insula were less robustly observed. CONCLUSIONS The present study demonstrates a pattern of GM alterations in CBP. These data further advance our understanding of the pathophysiology of CBP.

Whole-brain voxel-based morphometry (VBM) studies of progressive supranuclear palsy (PSP) have demonstrated heterogeneous findings regarding gray matter (GM) abnormalities. Here, we used Seed-based d Mapping, a coordinate-based meta-analytic approach to identify consistent regions of GM anomalies across studies of PSP. Totally, 18 original VBM studies, comprising 284 patients with PSP and 367 healthy controls were included. As compared to healthy controls, patients with PSP demonstrated significant GM reductions in both cortical and subcortical regions, including the frontal motor cortices, medial (including anterior cingulate cortex) and lateral frontal cortices, insula, superior temporal gyrus, striatum (putamen and caudate nucleus), thalamus, midbrain, and anterior cerebellum. Our study further suggests that many confounding factors, such as age, male ratio, motor severity, cognitive impairment severity, and illness duration of PSP patients, and scanner field-strength, could contribute to the heterogeneity of GM alterations in PSP across studies. Our comprehensive meta-analysis demonstrates a specific neuroanatomical pattern of GM atrophy in PSP with the involvement of the cortical-subcortical circuitries that mediate vertical supranuclear gaze palsy, motor disabilities (postural instability with falls and parkinsonism), and cognitive-behavioral disturbances. Confounding factors merit attention in future studies.

Recent resting-state functional magnetic resonance imaging (rs-fMRI) studies have provided strong evidence of abnormal spontaneous brain activity in amnestic mild cognitive impairment (aMCI). However, the conclusions have been inconsistent. A meta-analysis of whole-brain rs-fMRI studies that measured differences in the amplitude of low-frequency fluctuations (ALFF) between aMCI patients and healthy controls was conducted using the Seed-based d Mapping software package. Twelve studies reporting 14 datasets were included in the meta-analysis. Compared to healthy controls, patients with aMCI showed decreased ALFFs in the bilateral precuneus/posterior cingulate cortices, bilateral frontoinsular cortices, left occipitotemporal cortex, and right supramarginal gyrus and increased ALFFs in the right lingual gyrus, left middle occipital gyrus, left hippocampus, and left inferior temporal gyrus. A meta-regression analysis demonstrated that the increased severity of cognitive impairment in aMCI patients was associated with greater decreases in ALFFs in the cuneus/precuneus cortices. Our comprehensive meta-analysis suggests that aMCI is associated with widespread aberrant regional spontaneous brain activity, predominantly involving the default mode, salience, and visual networks, which contributes to understanding its pathophysiology.

Background Voxel-based morphometry (VBM) has been used to study human brain gray matter (GM) alterations in essential tremor (ET) for over one decade. However, the literature revealed heterogeneous findings. Methods We therefore conducted a coordinate-based meta-analysis to synthesize the VBM studies to examine which brain regions show the most reliable GM alterations in patients with ET relative to healthy controls. Results A total of 16 original VBM studies, comprising 387 patients with ET and 355 healthy controls, were included in this meta-analysis. This quantitative meta-analysis revealed no evidence of robust and reliable alterations in regional brain GM structures in ET. Meta-regression analyses indicate that many moderators (e.g., MR field strength, statistical methodology, age, onset age, gender, illness severity, illness duration, and family history) account for some of the heterogeneity in GM across studies. Conclusions High heterogeneity in GM alterations across studies may reflect true heterogeneity in ET regarding the clinic, etiology, and pathology, as well as possibly the VBM methodological variations. Currently, this heterogeneity limits the use of VBM as a reliable tool to distinguish ET from healthy controls. In order to improve reproducibility of VBM results in ET, future research may benefit from increasing the sample size, comprehensively subtyping ET phenotypes, and using well-designed and standardized imaging acquisition and analytical protocols. Furthermore, data sharing should be considered as a high priority.

Considerable evidence from previous voxel-based morphometry studies indicates widespread but heterogeneous gray matter (GM) deficits in amyotrophic lateral sclerosis (ALS). Here, we aimed to investigate the concurrence across voxel-based morphometry studies to help clarify the spatial pattern of GM abnormalities that underlie this condition. Comprehensive meta-analyses to assess regional GM anomalies in ALS were conducted with the Anisotropic Effect Size version of Signed Differential Mapping software package. Twenty studies, which reported 22 comparisons and were composed of 454 ALS patients and 426 healthy controls, were included in the meta-analyses. Regional GM atrophy in ALS was consistently found in the frontal, temporal, and somatosensory areas. Meta-regression demonstrated that the disease duration, disease severity, and age were significantly related to GM deficits in ALS patients. The present meta-analysis provides convergent evidence that ALS is a multisystem degenerative disorder that is accompanied by a unique and widespread pattern of robust cortical GM atrophy. Future studies should investigate whether this atrophy pattern is a diagnostic and prognostic marker.

Background Neurofilament light chain (NfL), an index of neuroaxonal injury, is a promising diagnostic and prognostic fluid biomarker with high translational value in many neurodegenerative disorders. Blood NfL measurement has been an exciting and active field of research in idiopathic Parkinson disease (PD) and atypical parkinsonisms. However, blood NfL levels in these parkinsonisms from existing literature were inconsistent. No comprehensive meta-analysis has ever been conducted. Methods Three major biomedical electronic databases PubMed, Embase, and Web of Science were comprehensively searched from inception to July 10, 2020. This protocol will be prepared based on the guidelines recommended by the statement of Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). Original observational studies that measured blood (serum/plasma) NfL concentrations in patients with parkinsonisms (multiple system atrophy [MSA], progressive supranuclear palsy [PSP], corticobasal syndrome [CBS], and dementia with Lewy bodies [DLB]), and healthy controls (HCs) will be included. Quality assessment of the included studies will be performed using the Newcastle Ottawa Scale (NOS). Meta-analyses will be conducted using the STATA software version 13.0. The standardized mean differences as the measure of effect size and 95% confidence intervals were calculated for each comparison of blood NfL levels. Heterogeneity analysis, sensitivity analysis, publication bias, subgroup analysis, and meta-regression analysis will be carried out to test the robustness of the results. Results The meta-analysis will obtain the effect sizes of blood NfL levels in the following comparisons: PD versus HC, MSA versus HC, PSP versus HC, CBS versus HC, DLB versus HC, MSA versus PD, PSP versus PD, CBS versus PD, and DLB versus PD. Conclusions The present meta-analysis will provide the quantitative evidence of NfL levels in idiopathic PD and atypical parkinsonisms, hoping to facilitate differential diagnoses in clinical practice. Registration number INPLASY202070091.

Background: Migraine is a common neurological disease, which seriously affects the quality of life and daily activities of patients. Although migraine is a transient phenomenon of cerebral vasoconstriction, it is well documented that recurrent attacks of migraine may lead to abnormalities in retinal structure. Optical coherence tomography (OCT) is a sensitive method to detect subtle damage in retinal nerve fiber layer (RNFL). There have been many studies investigating the difference in RNFL thickness with optical coherence tomography (OCT) between migraine patients and healthy controls. However, the results were not consistent. Our purpose is to perform a meta-analysis to investigate RNFL alterations in migraine. Methods: We will search PubMed, Embase, Web of science for studies assessing the differences in RNFL measured by OCT between patients with migraine and healthy controls. Case-control studies published in English will be included. Two reviewers will independently screen eligible articles, extract data, and assess quality. This meta-analysis will synthesize selected research data and compare the difference in RNFL thickness between patients with migraine and healthy controls. We will use Stata 15 in this meta-analysis. I2 statistics will be used to assess heterogeneity. If I2 ≤ 50%, the data are synthesized will use a fixed effect model. Otherwise, a random effect model will be performed. Publication bias will be determined by the Egger test. The methodological quality of all included studies will be evaluated by the Newcastle-Ottawa Scale (NOS). We will perform subgroup analysis, sensitivity analysis, and meta-regression analysis to test the robustness of the results. Results: We will obtain quantitative results regarding the difference in RNFL thickness between migraine patients and healthy controls. The results will be published in a peer-reviewed journal. Conclusions: The results of this study provide a high-quality synthesis of existing evidence and provide a basis for assessing the effect of migraine on the thickness of RNFL. Registration number: INPLASY 202060033

Background Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS). Recently, numerous studies have shown that MS disrupts a number of social cognitive abilities, including empathy, theory of mind (ToM), and facial emotion recognition. In contrast to well-documented deficits in the core social cognitive domains of ToM and facial emotion recognition, it is not clear the broad and specific subcomponents of empathy processing affected. In addition, the specific subcomponents of ToM affected in MS are also unclear. The aim of this study is to conduct a systematic review and meta-analysis to characterize the performance of empathy and ToM in MS. Methods A systematic literature search will be performed for eligible studies published up to July 1st, 2020 in 3 international databases (PubMed, Web of Science, and Embase). The work such as article retrieval, screen, quality evaluation, data collection will be conducted by 2 independent researchers. Meta-analysis will be performed using Stata 15.0 software. Results The results of this study will be published in a peer-reviewed journal. Conclusions This meta-analysis will provide a high-quality synthesis from existing evidence for the performance of empathy and ToM in MS. Prospero registration number INPLASY202070029.

Background Multiple sclerosis (MS) is an inflammatory and degenerative neurological disorder of the central nervous system. Cognitive impairment is frequent in MS patients, which not only includes deficits in abilities assessed by traditional neuropsychological batteries, but also often features impairments in social cognition (including theory of mind and facial emotion recognition). Recently, numerous studies have assessed social cognition performance in MS. However, there have been inconsistent findings. Besides, it is not clear how social cognitive abilities are affected in MS subtypes. The aim of this study is to conduct a meta-analysis to characterize social cognition performance in MS and its subtypes (clinically isolated syndrome, relapsing-remitting MS, progressive primary MS, and secondary progressive MS). Methods Literature sources will be divided into 2 sections: electronic sources and manual sources. A systematic literature search will be performed for eligible studies published up to June 10, 2020 in 3 international databases (Embase, PubMed, and Web of Science). In addition, manual sources will be searched, such as the references of all included studies. Two researchers will independently conduct the work such as article retrieval, screening, quality evaluation, data collection. Meta-analysis will be conducted using Stata 15.0 software. Results The results of this study will be published in a peer-reviewed journal. Conclusions This meta-analysis will provide a high-quality synthesis from existing evidence for social cognition performance in MS and its subtypes. Prospero registration number INPLASY202070028.

Background: Numerous studies using a variety of non-invasive neuroimaging techniques in vivo have demonstrated that chronic pain (CP) is associated with brain alterations. Cortical thickness (CTh) via surface-based morphometry (SBM) analysis of magnetic resonance imaging data is a valid and sensitive method to investigate the structure of brain gray matter. Many studies have employed SBM to measure CTh difference between patients with CP and pain-free controls and provided important insights into the brain basis of CP. However, the findings from these studies were inconsistent and have not been quantitatively reviewed. Methods: Three major electronic medical databases: PubMed, Web of Science, and Embase were searched for eligible studies published in English on April 3, 2020. This protocol was prepared based on the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols. The Seed-based d Mapping with Permutation of Subject Images software package will be employed to conducted a coordinate-based meta-analysis (CBMA) to identify consistent CTh differences between patients with CP and pain-free controls. Several complementary analyses, including sensitivity analysis, heterogeneity analysis, publication bias, subgroup analysis, and meta-regression analysis, will be further conducted to test the robustness of the results. Results: This CBMA will tell us whether CP with different subtypes shares common CTh alterations and what the pattern of its characterized alterations is. Conclusions: To the best of our knowledge, this will be the first CBMA of SBM studies that characterizes brain CTh alterations in CP. The CBMA will provide the quantitative evidence of common brain cortical morphometry of CP. The findings will help us to understand the neural basis underlying CP. Trial Registration number: INPLASY202050069

Background A number of studies have used regional homogeneity (ReHo) to depict local functional connectivity in chronic pain (CP). However, the findings from these studies were mixed and inconsistent. Methods A computerized literature search will be performed in PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), WanFang, and SinoMed databases until June 15, 2019 and updated on March 20, 2020. This protocol will follow the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P). The Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) software will be used for this voxel-wise meta-analysis. Results This meta-analysis will identify the most consistent ReHo alterations in CP. Conclusions To our knowledge, this will be the first voxel-wise meta-analysis that integrates ReHo findings in CP. This meta-analysis will offer the quantitative evidence of ReHo alterations that characterize brain local functional connectivity of CP. Prospero registration number CRD42019148523.

Background: Parkinson disease (PD) is a common neurodegenerative disorder. Elevations of neurofilament light chain (NfL) concentrations in the cerebrospinal fluid (CSF) and blood are a marker of neuronal/axonal injury and degeneration. However, CSF and blood NfL alterations in patients with PD from existing studies remain inconclusive. To better understand these conflicting data, we will conduct a meta-analysis. Methods: We will comprehensively search PubMed, Embase, and Web of Science databases from each database's inception to 7th June, 2020. This protocol will conform to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols. We will only include original studies published in English that evaluated differences of NfL concentrations in the CSF or blood between idiopathic PD patients and healthy controls. The Newcastle-Ottawa Scale will be used to evaluate the quality of the included studies. Meta-analyses will be carried out using the STATA software version 13.0. Between-group difference of NfL concentrations in the CSF and blood will be expressed as the weighted standardized mean difference. A random-effects model will be used. Supplementary analyses, such as heterogeneity analysis, sensitivity analysis, publication bias, subgroup analysis, and meta-regression analysis will be performed. Results: The meta-analysis will provide the differences of NfL concentrations in the CSF and blood between patients with PD and healthy controls and will show the magnitudes of their effect sizes. Conclusions: This meta-analysis will provide the evidence of NfL concentrations in the CSF and blood in PD and we hope that our study has an important impact on clinical practice. Registration number: INPLASY202060025

Background Voxel-based morphometry (VBM) is an objective structural magnetic resonance imaging (MRI) technique which allows researchers to investigate group-level differences in regional gray matter (GM) volume or density over the whole brain. In the last decade, VBM studies in restless leg syndrome (RLS) have exhibited inconsistent and conflicting findings. Methods Studies will be identified through a computerized literature search of the following databases: PubMed, Web of Science, and Embase until October 1, 2018 and updated on March 1, 2020. This protocol will be performed in accordance with the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P). In addition, we will follow the recent guidelines and recommendations for coordinate-based meta-analysis (CBMA). This CBMA will be performed with the seed-based d mapping with permutation of subject images (SDM-PSI) software. Results This CBMA will offer the latest evidence of GM alterations in RLS. Conclusions To our knowledge, this will be the first CBMA that pooled VBM findings in RLS. This quantitative evidence of GM alterations will characterize brain morphometry of RLS. Prospero registration number CRD42018117014.

Mild cognitive impairment (MCI) is inconclusively associated with regional gray matter (GM) abnormalities in Parkinson's disease (PD). We aimed to quantitatively evaluate whole-brain voxel-based morphometry (VBM) studies that have investigated brain GM changes in PD patients with MCI (PD-MCI). Seed-based d Mapping, a well-validated coordinate-based meta-analytic approach, was utilized. We included 20 VBM studies that reported 22 datasets containing 504 patients with PD-MCI and 554 PD patients without MCI (PD-NCI). The most reliable finding identified in this meta-analysis was that patients with PD-MCI exhibited greater GM atrophy in the left anterior insula than those with PD-NCI. Our findings further suggest that several moderators (age, gender, educational level, disease stage, severity of motor disability, and the severity of cognitive impairments) in PD-MCI individuals, as well as scanner field-strength, may drive heterogeneous GM changes across studies. GM abnormalities in the anterior insula, an important cognitive hub involved in switching between neural networks, contribute to understanding the neural substrates of MCI in PD, which may serve as a biomarker of PD-MCI.

To investigate the association of homocysteine (Hcy), folate, and white matter hyperintensities in Parkinson’s disease (PD) with different motor phenotypes. Of the PD patients, 176 were included. Based on the Unified Parkinson’s Disease Rating Scale, the PD patients were classified into postural instability gait disorder (PIGD) and non-PIGD phenotypes. According to the Fazekas score, patients were divided into the none/mild white matter hyperintensity (WMH) group and the moderate/severe WMH group. The relationship of Hcy, folate, and white matter hyperintensities (WMHs), and the motor phenotype of PD were analyzed. PD-PIGD patients had higher proportion of moderate/severe WMHs, Hcy levels, and lower folate levels than PD-non-PIGD patients (p all ≤ 0.001). In the subgroup analysis, patients with both PD-PIGD and moderate/severe WMHs had the highest Hcy and lowest folate levels compared with others. Binary logistic regression analysis showed that age, folate, and Hcy were independent risk factors for WMHs. In an a priori-determined stratified analysis, after adjustment for confounding factors, the odds ratio of WMHs was 8.01 (95% CI 2.700–23.767, p trend = 0.001) in the patients with Hcy levels in the highest quintile compared with the lowest quintile and 16.81 (95% CI 4.74–59.65, p trend

Objective Our objective was to explore the clinical characteristics of Parkinson's disease (PD) comorbidity with obstructive sleep apnea (OSA), explore the correlation between OSA and PD features and identify factors that are independent predictors of OSA in PD patients. Methods In sum, 239 PD patients were divided into two groups according to the presence of OSA (apnea–hypopnea index (AHI) score ≥5) (PD-OSA vs PD-non-OSA). Blinded to sleep apnea status, participants underwent an extensive assessment to determine demographic features, concomitant disease, disease severity, polysomnography (PSG) characteristics and non-motor symptoms (NMSs). Results Of the 239 patients, 66 (27.62%) had an AHI score ≥5, including 14.2% (34/239) with mild, 6.7% (16/239) with moderate, and 6.7% (16/239) with severe sleep apnea. The binary logistic regression analyses indicated that age and male gender were risk factors for OSA, while rapid eye movement (REM) sleep disorder (RBD) and higher Levodopa equivalent dose (LED) were protective factors for OSA. PD-OSA patients had higher Epworth Sleepiness Scale (ESS) scores than those of PD-non-OSA patients. No differences were found for other NMSs between groups. Conclusion Our data suggest that OSA in PD was lower in patients with RBD and higher LED. RBD and higher LDEs were significant protective factors for OSA in PD. OSA in PD was increased with age and male gender. Age and male gender were risk factors for OSA in PD. OSA can aggravate excessive daytime somnolence in PD patients but is not associated with other NMSs.

Background Many studies have revealed a widespread pattern of gray matter (GM) atrophy by using voxel-based morphometry (VBM) studies involving the pathophysiology of alcohol dependence. However, the spatial localization of GM abnormalities reported in previous studies is heterogeneous. Here, we aimed to investigate the concurrence across VBM studies to help clarify the structural abnormalities underpinning this condition. Methods A systematic search from January, 2000 to November, 2014 was performed to identify VBM studies that compared alcohol dependent patients and healthy controls. A quantitative meta-analysis of whole-brain VBM studies to estimate regional GM abnormalities in alcohol dependent patients was performed using the Anisotropic Effect Size version of the Signed Differential Mapping (AES-SDM) software package. Results Nine studies consisting of 296 alcohol dependent patients and 359 healthy controls were included in the present meta-analyses. Regional GM atrophy in alcohol dependent patients was found in the prefrontal cortex (including the anterior cingulate cortex), the dorsal striatum/insula, and the posterior cingulate cortex consistently across studies. The results remained largely unchanged in the following jackknife sensitivity analyses. Conclusions By conducting the first comprehensive meta-analysis of VBM studies, we identified consistent regional GM atrophy particularly within several neurofunctional networks associated with alcohol dependence. Our study demonstrated a characteristic pattern of GM abnormalities and provided further insights into understanding the underlying nature of alcohol dependence.

There is convincing evidence that abnormalities of regional brain function exist in Parkinson’s disease (PD). However, many resting-state functional magnetic resonance imaging (rs-fMRI) studies using amplitude of low-frequency fluctuations (ALFF) have reported inconsistent results about regional spontaneous neuronal activity in PD. Therefore, we conducted a comprehensive meta-analysis using the Seed-based d Mapping and several complementary analyses. We searched PubMed, Embase, and Web of Science databases for eligible whole-brain rs-fMRI studies that measured ALFF differences between patients with PD and healthy controls published from January 1st, 2000 until June 24, 2016. Eleven studies reporting 14 comparisons, comparing 421 patients and 381 healthy controls, were included. The most consistent and replicable findings in patients with PD compared with healthy controls were identified, including the decreased ALFFs in the bilateral supplementary motor areas, left putamen, left premotor cortex, and left inferior parietal gyrus, and increased ALFFs in the right inferior parietal gyrus. The altered ALFFs in these brain regions are related to motor deficits and compensation in PD, which contribute to understanding its neurobiological underpinnings and could serve as specific regions of interest for further studies.

Background Depressive symptoms are frequent in idiopathic restless legs syndrome (RLS). However, little is known, so far, about the neurological basis. The present study aimed to explore the neuroanatomical anomalies in depressed drug-naive RLS patients using voxel-based morphometry (VBM) analysis. Methods We recruited 16 drug-naive idiopathic RLS patients with depressive symptoms (RLS-D), 18 drug-naive idiopathic RLS patients without depressive symptoms (RLS-ND), and 18 normal controls. All participants underwent structural MRI scans on a 3-T MR system. The differences in regional gray matter (GM) density were determined across groups by VBM8. Additional regression analysis was used to identify any associations between regional GM density and clinical symptoms. Results GM density of the bilateral anterior cingulate cortex (ACC) was significantly reduced in RLS-D patients when compared to RLS-ND patients or to the healthy controls. However, there were no significant differences of GM density either when the whole RLS group or the RLS-ND group was compared to healthy controls, respectively. Particularly, we found GM density of right ACC was negatively correlated with the severity and duration of depressive symptoms in RLS-D patients. Conclusions Depressive symptoms are associated with GM anomalies in ACC in patients with RLS. We propose that ACC is perhaps an important neuroimaging marker for facilitating treatment strategies in patients with RLS when assessing depressive symptoms.