Effect of topographic comparison of electroencephalographic microstates on the diagnosis and prognosis prediction of patients with prolonged disorders of consciousness.

AIMS: The electroencephalography (EEG) microstates are indicative of fundamental information processing mechanisms, which are severely damaged in patients with prolonged disorders of consciousness (pDoC). We aimed to improve the topographic analysis of EEG microstates and explore indicators available for diagnosis and prognosis prediction of patients with pDoC, which were still lacking. METHODS: We conducted EEG recordings on 59 patients with pDoC and 32 healthy controls. We refined the microstate method to accurately estimate topographical differences, and then classify and forecast the prognosis of patients with pDoC. An independent dataset was used to validate the conclusion. RESULTS: Through optimized topographic analysis, the global explained variance (GEV) of microstate E increased significantly in groups with reduced levels of consciousness. However, its ability to classify the VS/UWS group was poor. In addition, the optimized GEV of microstate E exhibited a statistically significant decrease in the good prognosis group as opposed to the group with a poor prognosis. Furthermore, the optimized GEV of microstate E strongly predicted a patient's prognosis. CONCLUSION: This technique harmonizes with the existing microstate analysis and exhibits precise and comprehensive differences in microstate topography between groups. Furthermore, this method has significant potential for evaluating the clinical prognosis of pDoC patients.

NODDI Identifies Cognitive Associations with In Vivo Microstructural Changes in Remote Cortical Regions and Thalamocortical Pathways in Thalamic Stroke.

The roles of cerebral structures distal to isolated thalamic infarcts in cognitive deficits remain unclear. We aimed to identify the in vivo microstructural characteristics of remote gray matter (GM) and thalamic pathways and elucidate their roles across cognitive domains. Patients with isolated ischemic thalamic stroke and healthy controls underwent neuropsychological assessment and magnetic resonance imaging. Neurite orientation dispersion and density imaging (NODDI) was modeled to derive the intracellular volume fraction (VFic) and orientation dispersion index. Fiber density (FD) was determined by constrained spherical deconvolution, and tensor-derived fractional anisotropy (FA) was calculated. Voxel-wise GM analysis and thalamic pathway tractography were performed. Twenty-six patients and 26 healthy controls were included. Patients exhibited reduced VFic in remote GM regions, including ipsilesional insular and temporal subregions. The microstructural metrics VFic, FD, and FA within ipsilesional thalamic pathways decreased (false discovery rate [FDR]-p < 0.05). Noteworthy associations emerged as VFic within insular cortices (ρ = -0.791 to -0.630; FDR-p < 0.05) and FD in tracts connecting the thalamus and insula (ρ = 0.830 to 0.971; FDR-p < 0.001) were closely associated with executive function. The VFic in Brodmann area 52 (ρ = -0.839; FDR-p = 0.005) and FA within its thalamic pathway (ρ = -0.799; FDR-p = 0.003) correlated with total auditory memory scores. In conclusion, NODDI revealed neurite loss in remote normal-appearing GM regions and ipsilesional thalamic pathways in thalamic stroke. Reduced cortical dendritic density and axonal density of thalamocortical tracts in specific subregions were associated with improved cognitive functions. Subacute microstructural alterations beyond focal thalamic infarcts might reflect beneficial remodeling indicating post-stroke plasticity.

Cortical responses to auditory stimulation predict the prognosis of patients with disorders of consciousness.

OBJECTIVE: This study aimed to assess the prognosis of patients with disorders of consciousness (DoC) using auditory stimulation with electroencephalogram (EEG) recordings. METHODS: We enrolled 72 patients with DoC in the study, which involved subjecting patients to auditory stimulation while EEG responses were recorded. Coma Recovery Scale-Revised (CRS-R) scores and Glasgow Outcome Scale (GOS) were determined for each patient and followed up for three months. A frequency spectrum analysis was performed on the EEG recordings. Finally, the power spectral density (PSD) index was used to predict the prognosis of patients with DoC based on a support vector machine (SVM) model. RESULTS: Power spectral analyses revealed that the cortical response to auditory stimulation showed a decreasing trend with decreasing consciousness levels. Auditory stimulation-induced changes in absolute PSD at the delta and theta bands were positively correlated with the CRS-R and GOS scores. Furthermore, these cortical responses to auditory stimulation had a good ability to discriminate between good and poor prognoses of patients with DoC. CONCLUSIONS: Auditory stimulation-induced changes in the PSD were highly predictive of DoC outcomes. SIGNIFICANCE: Our findings showed that cortical responses to auditory stimulation may be an important electrophysiological indicator of prognosis in patients with DoC.

Sensorimotor network connectivity correlates with motor improvement after repetitive transcranial magnetic stimulation in patients with Parkinson's disease.

BACKGROUND: Emerging evidence suggests that repetitive transcranial magnetic stimulation (rTMS) generally improves Parkinson's disease (PD) motor symptoms. However, personal responses to rTMS might be different. In this study, we explore the connectivity changes in PD patients with different responses to rTMS. METHODS: Among PD patients, 25 were treated with 10Hz-rTMS and seven were with sham rTMS over the supplementary motor area for 10 days. Resting-state functional connectivity magnetic resonance imaging (rs-fMRI) was performed in PD patients before and after rTMS stimulation. Neuropsychological scales such as Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) were collected synchronously with rs-fMRI. To explore the connectivity changes after rTMS, degree centrality was calculated. RESULTS: 13 out of 25 participants were responsive to 10Hz rTMS. Degree centrality patterns in the left sensorimotor regions are primarily responsible for the differences between responsive and non-responsive individuals. Improvement in motor symptoms was substantially related to the baseline degree centrality in the left PreCG and the left PoCG. The performance in distinguishing non-responders from responders was further validated by the ROC analysis utilizing DC characteristics. Lastly, we found that connectivity increased in left PreCG and PoCG in patients with a better response to the rTMS. CONCLUSION: Taken together, these results suggest that the sensorimotor network is involved in the motor improvement following rTMS treatment, with patients with lower sensorimotor connectivity showing a tendency for greater motor improvement to HF-rTMS.

Sleep patterns correlates with the efficacy of tDCS on post-stroke patients with prolonged disorders of consciousness.

BACKGROUND: The subclassification of prolonged disorders of consciousness (DoC) based on sleep patterns is important for the evaluation and treatment of the disease. This study evaluates the correlation between polysomnographic patterns and the efficacy of transcranial direct current stimulation (tDCS) in patients with prolonged DoC due to stroke. METHODS: In total, 33 patients in the vegetative state (VS) with sleep cycles or without sleep cycles were randomly assigned to either active or sham tDCS groups. Polysomnography was used to monitor sleep changes before and after intervention. Additionally, clinical scale scores and electroencephalogram (EEG) analysis were performed before and after intervention to evaluate the efficacy of tDCS on the patients subclassified according to their sleep patterns. RESULTS: The results suggest that tDCS improved the sleep structure, significantly prolonged total sleep time (TST) (95%CI: 14.387-283.527, P = 0.013) and NREM sleep stage 2 (95%CI: 3.157-246.165, P = 0.040) of the VS patients with sleep cycles. It also significantly enhanced brain function of patients with sleep cycles, which were reflected by the increased clinical scores (95%CI: 0.340-3.440, P < 0.001), the EEG powers and functional connectivity in the brain and the 6-month prognosis. Moreover, the changes in NREM sleep stage 2 had a significant positive correlation with each index of the ß band. CONCLUSION: This study reveals the importance of sleep patterns in the prognosis and treatment of prolonged DoC and provides new evidence for the efficacy of tDCS in post-stroke patients with VS patients subclassified by sleep pattern. Trial registration URL: https://www. CLINICALTRIALS: gov . Unique identifier: NCT03809936. Registered 18 January 2019.

Altered Intestinal Microbiomes and Lipid Metabolism in Patients With Prolonged Disorders of Consciousness.

The intestinal microbiota regulate the brain function of the host through the production of a myriad of metabolites and are associated with various neurological diseases. Understanding the intestinal microbiome of patients with prolonged disorders of consciousness (DoC) is important for the evaluation and treatment of the disease. To investigate the differences in the intestinal microbiome and short-chain fatty acids (SCFAs) among patients in a vegetative state (VS), a minimally conscious state (MCS), and emerged from MCS (EMCS), as well as the influence of antibiotics on these patients, 16S ribosomal RNA (16S rRNA) sequencing and targeted lipidomics were performed on fecal samples from patients; in addition, analysis of the electroencephalogram (EEG) signals was performed to evaluate the brain function of these patients. The results showed that the intestinal microbiome of the three groups differed greatly, and some microbial communities showed a reduced production of SCFAs in VS patients compared to the other two groups. Moreover, reduced microbial communities and five major SCFAs, along with attenuated brain functional connectivity, were observed in MCS patients who were treated with antibiotics compared to those who did not receive antibiotic treatment, but not in the other pairwise comparisons. Finally, three genus-level microbiota-Faecailbacterium, Enterococcus, and Methanobrevibacter-were considered as potential biomarkers to distinguish MCS from VS patients, with high accuracy both in the discovery and validation cohorts. Together, our findings improved the understanding of patients with prolonged DoC from the intestinal microbiome perspective and provided a new reference for the exploration of therapeutic targets.

The Cerebellum is Involved in Motor Improvements After Repetitive Transcranial Magnetic Stimulation in Parkinson's Disease Patients.

Accumulating evidence indicates that repetitive transcranial magnetic stimulation (rTMS) ameliorates motor symptoms in patients with Parkinson's disease (PD); however, patients' responses to rTMS are different. Here, we aimed to explore neural activity changes in patients with PD exhibiting different responses to high-frequency rTMS treatments using functional magnetic resonance imaging (fMRI). We treated 24 patients with PD using 10-session rTMS (10 Hz) over the supplementary motor area (SMA) for 10 days. Resting-state functional magnetic resonance imaging (rs-fMRI), the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) and other neuropsychological scales were performed at the baseline and endpoint of rTMS treatment. The changes in the fractional amplitude of low-frequency fluctuation (fALFF) were calculated. Significant improvements were observed in motor symptoms, especially in the sub-symptoms of bradykinesia. All the participants were subsequently stratified into responders and non-responders according to the UPDRS-III reduction. We identified increased fALFF values in the left Crus II of the cerebellar hemisphere and bilateral thalamus as responsive signs to rTMS. Furthermore, the motor response to rTMS over the SMA, measured by the reduction in UPDRS-III and bradykinesia scores, was positively associated with increased fALFF values in the left Crus2 of cerebellar hemisphere, left lobule VIIB of cerebellar hemisphere, right lobule VI of the cerebellar hemisphere, and the right postcentral gyrus. These findings provide evidence for the involvement of cerebellar activity in the motor response to rTMS treatment.

CSPGs promote the migration of meningeal fibroblasts via p38 mitogen-activated protein kinase signaling pathway under OGD conditions.

AIMS: Usually glial scar that occurs after central nervous system injury has significantly affected the local neural microenvironment. Meningeal fibroblasts play an essential role in the formation of the glial scar. However, how and why meningeal fibroblasts migrate to lesion sites is still unclear. MAIN METHODS: Astrocytes were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) injury. And then, we measured the glial fibrillary acidic protein(GFAP) and chondroitin sulfate proteoglycans (CSPGs) expression of reactive astrocytes by western blot and quantitative polymerase chain reaction (qPCR) after they were co-cultured with meningeal fibroblasts. Following, we clarified the possibility that CSPGs induce the migration of meningeal fibroblasts to glial scar by transwell migration assay and the activation of the p38 MAPK signaling pathway during the migration by western blot. KEY FINDINGS: We found that co-cultured meningeal fibroblasts could alleviate the significantly increased expression of GFAP and CSPGs in the activation of reactive astrocytes induced by OGD/R. Additionally, CSPGs secreted by reactive astrocytes could induce the migration of meningeal fibroblasts and the expression of phospho-p38 in meningeal fibroblasts when meningeal fibroblasts were co-cultured with supernatant of reactive astrocytes. What's more, we could observe a noticeable increase in CSPGs that chondroitinase ABC could reverse their functions. Moreover, phospho-p38 could cause the expression of phospho-cofilin and the migration of CSPGs-induced meningeal fibroblasts. SIGNIFICANCE: Our study provides reliable evidence for explaining scar formation mechanisms and further studying to improve regeneration after an injury to the central nervous system.

Neural Tracking of Sound Rhythms Correlates With Diagnosis, Severity, and Prognosis of Disorders of Consciousness.

Effective diagnosis and prognosis of patients with disorders of consciousness (DOC) provides a basis for family counseling, decision-making, and the design of rehabilitation programs. However, effective and objective bedside evaluation is a challenging problem. In this study, we explored electroencephalography (EEG) response tracking sound rhythms as potential neural markers for DOC evaluation. We analyzed the responses to natural speech and tones modulated at 2 and 41 Hz. At the population level, patients with positive outcomes (DOC-P) showed higher cortical synchronization to modulated tones at 41 Hz compared with patients with negative outcomes (DOC-N). At the individual level, phase coherence to modulated tones at 41 Hz was significantly correlated with Coma Recovery Scale-Revised (CRS-R) and Glasgow Outcome Scale-Extended (GOS-E) scores. Furthermore, SVM classifiers, trained using phase coherences in higher frequency bands or combination of the low frequency aSSR and speech tracking responses, performed very well in diagnosis and prognosis of DOC. These findings show that EEG response to auditory rhythms is a potential tool for diagnosis, severity, and prognosis of DOC.

Upregulation of ATG7 attenuates motor neuron dysfunction associated with depletion of TARDBP/TDP-43.

A shared neuropathological hallmark in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is nuclear clearance and cytoplasmic aggregation of TARDBP/TDP-43 (TAR DNA binding protein). We previously showed that the ability of TARDBP to repress nonconserved cryptic exons was impaired in brains of patients with ALS and FTD, suggesting that its nuclear depletion contributes to neurodegeneration. However, the critical pathways impacted by the failure to repress cryptic exons that may contribute to neurodegeneration remain undefined. Here, we report that transcriptome analysis of TARDBP-deficient neurons revealed downregulation of ATG7, a critical gene required for macroautophagy/autophagy. Mouse and Drosophila models lacking TARDBP/TBPH in motor neurons exhibiting age-dependent neurodegeneration and motor deficits showed reduction of ATG7 and accumulation of SQSTM1/p62 inclusions. Importantly, genetic upregulation of the autophagy pathway improved motor function and survival in TBPH-deficient flies. Together with our observation that ATG7 is reduced in ALS-FTD brain tissues, these findings identify the autophagy pathway as one key effector of nuclear depletion of TARDBP that contributes to neurodegeneration. We thus suggest that the autophagy pathway is a therapeutic target for ALS-FTD and other disorders exhibiting TARDBP pathology.Abbreviations: ALS: amyotrophic lateral sclerosis; ANOVA: analysis of variance; ChAT: choline acetyltransferase; CTSD: cathepsin D; FTD: frontotemporal dementia; LAMP1: lysosomal associated membrane protein 1; NMJ: neuromuscular junction; RBFOX3/NeuN: RNA binding fox-1 homolog 3; SQSTM1: sequestosome 1; TARDBP/TDP-43: TAR DNA binding protein 43.

Valproic Acid Enhances Reprogramming Efficiency and Neuronal Differentiation on Small Molecules Staged-Induction Neural Stem Cells: Suggested Role of mTOR Signaling.

Inducing somatic cells into neural stem cells (iNSCs) in specific ways provides a new cell therapy in a variety of neurological diseases. In the past, iNSCs were generated by transcription factors which increased the risk of mutagenesis, tumor formations, and immune reactions by viral transduction vectors. Therefore, in this study, different small molecules were used to induce mouse embryonic fibroblasts (MEFs) into iNSCs in different reprogramming stages, which showed high reprogramming efficiency without altering the genome. We demonstrated that the small molecules staged-induction neural stem cells (SMSINS) have the characteristics of neural stem cells (NSCs) in morphology, gene expression, self-renewal and differentiation potential. Furthermore, valproic acid (VPA), one of small molecules, was showed to enhance neural induction with highest efficiency compared with six other small molecules, which were also investigated in the present study. Moreover, our results suggested that activating the mammalian target of rapamycin (mTOR) signaling enhanced the induction efficiency and neuronal differentiation. Collectively, our findings indicated that using this induction program allowed us to obtain safe and efficient iNSCs which were free of genetic manipulation. The VPA-mediated mTOR signaling pathway may enhance reprogramming efficiency and neuronal differentiation. So we suggested that this program could be a new method of obtaining iNSCs for the treatment of neurological diseases by cell replacement therapy in the future.

Splicing repression is a major function of TDP-43 in motor neurons.

Nuclear depletion of TDP-43, an essential RNA binding protein, may underlie neurodegeneration in amyotrophic lateral sclerosis (ALS). As several functions have been ascribed to this protein, the critical role(s) of TDP-43 in motor neurons that may be compromised in ALS remains unknown. We show here that TDP-43 mediated splicing repression, which serves to protect the transcriptome by preventing aberrant splicing, is central to the physiology of motor neurons. Expression in Drosophila TDP-43 knockout models of a chimeric repressor, comprised of the RNA recognition domain of TDP-43 fused to an unrelated splicing repressor, RAVER1, attenuated motor deficits and extended lifespan. Likewise, AAV9-mediated delivery of this chimeric rescue repressor to mice lacking TDP-43 in motor neurons delayed the onset, slowed the progression of motor symptoms, and markedly extended their lifespan. In treated mice lacking TDP-43 in motor neurons, aberrant splicing was significantly decreased and accompanied by amelioration of axon degeneration and motor neuron loss. This AAV9 strategy allowed long-term expression of the chimeric repressor without any adverse effects. Our findings establish that splicing repression is a major function of TDP-43 in motor neurons and strongly support the idea that loss of TDP-43-mediated splicing fidelity represents a key pathogenic mechanism underlying motor neuron loss in ALS.

Can amide proton transfer-weighted imaging differentiate tumor grade and predict Ki-67 proliferation status of meningioma?

OBJECTIVES: To determine the utility of the amide proton transfer-weighted MR imaging in differentiating the WHO grade and predict proliferative activity of meningioma. METHODS: Fifty-three patients with WHO grade I meningiomas and 26 patients with WHO grade II meningiomas underwent conventional and APT-weighted sequences on a 3.0 Tesla MR before clinical intervention. The APT-weighted (APTw) parameters in the solid tumor region were obtained and compared between two grades using the t test; the receiver operating characteristic (ROC) curve was used to assess the best parameter for predicting the grade of meningiomas. Pearson's correlation coefficient was calculated between the APTwmax and Ki-67 labeling index in meningiomas. RESULTS: The APTwmax and APTwmean values were not significantly different between WHO grade I and grade II meningiomas (p = 0.103 and p = 0.318). The APTwmin value was higher and the APTwmax-min value was lower in WHO grade II meningiomas than in WHO grade I tumors (p = 0.027 and p = 0.019). But the APTwmin was higher and the APTwmax-min was lower in microcystic meningiomas than in WHO grade II meningiomas (p = 0.001 and p = 0.006). The APTwmin combined with APTwmax-min showed the best diagnostic performance in predicting the grade of meningiomas with an AUC of 0.772. The APTwmax value was positively correlated with Ki-67 labeling index (r = 0.817, p < 0.001) in meningiomas; the regression equation for the Ki-67 labeling index (%) (Y) and APTwmax (%) (X) was Y = 4.9 × X - 12.4 (R2 = 0.667, p < 0.001). CONCLUSION: As a noninvasive imaging method, the ability of APTw-MR imaging in differentiating the grade of meningiomas is limited, but the technology can be used to predict the proliferative activity of meningioma. KEY POINTS: • The APTw min value was higher and the APTw max-min value was lower in WHO grade II meningioma than in grade I tumors. • The APTw min value was higher and the APTw max-min value was lower in microcystic meningiomas than in WHO grade II meningiomas. • The APTw max value was positively correlated with meningioma proliferation index.

Discriminating MGMT promoter methylation status in patients with glioblastoma employing amide proton transfer-weighted MRI metrics.

OBJECTIVES: To explore the feasibility of using amide proton transfer-weighted (APTw) MRI metrics as surrogate biomarkers to identify the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status in glioblastoma (GBM). METHODS: Eighteen newly diagnosed GBM patients, who were previously scanned at 3T and had a confirmed MGMT methylation status, were retrospectively analysed. For each case, a histogram analysis in the tumour mass was performed to evaluate several quantitative APTw MRI metrics. The Mann-Whitney test was used to evaluate the difference in APTw parameters between MGMT methylated and unmethylated GBMs, and the receiver-operator-characteristic analysis was further used to assess diagnostic performance. RESULTS: Ten GBMs were found to harbour a methylated MGMT promoter, and eight GBMs were unmethylated. The mean, variance, 50th percentile, 90th percentile and Width10-90 APTw values were significantly higher in the MGMT unmethylated GBMs than in the MGMT methylated GBMs, with areas under the receiver-operator-characteristic curves of 0.825, 0.837, 0.850, 0856 and 0.763, respectively, for the discrimination of MGMT promoter methylation status. CONCLUSIONS: APTw signal metrics have the potential to serve as valuable imaging biomarkers for identifying MGMT methylation status in the GBM population. KEY POINTS: • APTw-MRI is applied to predict MGMT promoter methylation status in GBMs. • GBMs with unmethylated MGMT promoter present higher APTw-MRI than methylated GBMs. • Multiple APTw histogram metrics can identify MGMT methylation status. • Mean APTw values showed the highest diagnostic accuracy (AUC = 0.825).