Phase Property of Envelope-Tracking EEG Response Is Preserved in Patients with Disorders of Consciousness.

When listening to speech, the low-frequency cortical response below 10 Hz can track the speech envelope. Previous studies have demonstrated that the phase lag between speech envelope and cortical response can reflect the mechanism by which the envelope-tracking response is generated. Here, we analyze whether the mechanism to generate the envelope-tracking response is modulated by the level of consciousness, by studying how the stimulus-response phase lag is modulated by the disorder of consciousness (DoC). It is observed that DoC patients in general show less reliable neural tracking of speech. Nevertheless, the stimulus-response phase lag changes linearly with frequency between 3.5 and 8 Hz, for DoC patients who show reliable cortical tracking to speech, regardless of the consciousness state. The mean phase lag is also consistent across these DoC patients. These results suggest that the envelope-tracking response to speech can be generated by an automatic process that is barely modulated by the consciousness state.

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.

Cerebral perfusion mediated by thalamo-cortical functional connectivity in non-dominant thalamus affects naming ability in aphasia.

Naming is a commonly impaired language domain in various types of aphasia. Emerging evidence supports the cortico-subcortical circuitry subserving naming processing, although neurovascular regulation of the non-dominant thalamic and basal ganglia subregions underlying post-stroke naming difficulty remains unclear. Data from 25 subacute stroke patients and 26 age-, sex-, and education-matched healthy volunteers were analyzed. Region-of-interest-wise functional connectivity (FC) was calculated to measure the strength of cortico-subcortical connections. Cerebral blood flow (CBF) was determined to reflect perfusion levels. Correlation and mediation analyses were performed to identify the relationship between cortico-subcortical connectivity, regional cerebral perfusion, and naming performance. We observed increased right-hemispheric subcortical connectivity in patients. FC between the right posterior superior temporal sulcus (pSTS) and lateral/medial prefrontal thalamus (lPFtha/mPFtha) exhibited significantly negative correlations with total naming score. Trend-level increased CBF in subcortical nuclei, including that in the right lPFtha, and significant negative correlations between naming and regional perfusion of the right lPFtha were observed. The relationship between CBF in the right lPFtha and naming was fully mediated by the lPFtha-pSTS connectivity in the non-dominant hemisphere. Our findings suggest that perfusion changes in the right thalamic subregions affect naming performance through thalamo-cortical circuits in post-stroke aphasia. This study highlights the neurovascular pathophysiology of the non-dominant hemisphere and demonstrates thalamic involvement in naming after stroke.

Microstructural profiles of thalamus and thalamocortical connectivity in patients with disorder of consciousness.

Thalamus and thalamocortical connectivity are crucial for consciousness; however, their microstructural changes in patients with a disorder of consciousness (DOC) have not yet been thoroughly characterized. In the present study, we applied the novel fixel-based analysis to comprehensively investigate the thalamus-related microstructural abnormalities in 10 patients with DOC using 7-T diffusion-weighted imaging data. We found that compared to healthy controls, patients with DOC showed reduced fiber density (FD) and fiber density and cross-section (FDC) in the mediodorsal, anterior, and ventral anterior thalamic nuclei, while fiber-bundle cross-section (FC) was not significantly altered in the thalamus. Impaired thalamocortical connectivity in the DOC cohort was mainly connected to the middle frontal gyrus, anterior cingulate gyrus, fusiform gyrus, and sensorimotor cortices, including the precentral gyrus and postcentral gyrus, with predominant microstructural abnormalities in FD and FDC. Correlation analysis showed that FC of the right mediodorsal thalamus was negatively correlated with the level of consciousness. Our results suggest that microstructural abnormalities of thalamus and thalamocortical connectivity in DOC were mainly attributed to axonal injury. In particular, the microstructural integrity of the thalamus is a vital factor in consciousness generation.

Tianzhi granule improves cognition and BPSD of vascular dementia: a randomized controlled trial.

BACKGROUND AND PURPOSE: Tianzhi granule (TZ) is usually used for patients with vascular dementia (VaD) in China. The aim was to assess the effect of TZ by a randomized clinical trial (RCT). METHODS: A 24-week RCT was conducted in 16 centres. Participants were grouped into TZ, donepezil or placebo. The co-primary outcomes were the Vascular Dementia Assessment Scale-cognitive subscale (VADAS-cog) and Clinician's Interview-based Impression of Change-plus caregiver information (CIBIC-plus). RESULTS: A total of 543 patients with mild to moderate VaD were enrolled, of whom 242 took TZ granules, 241 took donepezil, and 60 took placebo. The least-squares mean changes from baseline and 95% CI were 6.20 (5.31, 7.09) (TZ group), 6.53 (5.63, 7.42) (donepezil group) and 3.47 (1.76, 5.19) (placebo group), both TZ and donepezil showed small but significantly improvement compared with placebo group. The percent of improvement on the global impression which was measured by CIBIC-plus was 73.71% in TZ and 58.18% in placebo, there was significant different between TZ and placebo group (P = 0.004). No significant differences were observed between TZ and donepezil. No significant differences of adverse events were found. CONCLUSIONS: TZ and donepezil could bring symptomatic benefit for mild to moderate VaD. Trial registration The protocol had retrospectively registered at clinical trial.gov, Unique identifier: NCT02453932, date of registration: May 27, 2015; https://www.clinicaltrials.gov/ct2/show/NCT02453932?term=NCT02453932&rank=1.

Efficacy and safety of a novel acetylcholinesterase inhibitor octohydroaminoacridine in mild-to-moderate Alzheimer's disease: a Phase II multicenter randomised controlled trial.

Background: inhibition of acetylcholinesterase (AChE) has been a effective treatment for Alzheimer's disease (AD). Octohydroaminoacridine, a new AChE inhibitor, is a potential treatment for AD. Method: we conducted a multicenter, randomised, double blind, placebo-controlled, parallel-group Phase II clinical trial to investigate the effects of octohydroaminoacridine in patients with mild-to-moderate AD. Patients were randomised to receive placebo thrice daily, octohydroaminoacridine 1 mg/thrice daily (TID) (low-dose group), 2 mg/TID (middle-dose group) or 4 mg/TID (high-dose group). Doses in the middle-dose and high-dose group were titrated over 2-4 weeks. Changes from baseline to Week 16 were assessed with the AD Assessment Scale-Cognitive Subscale (ADAS-cog), Clinician's Interview-Based Impression of Change Plus (CIBIC+), activities of daily living (ADL) and the neuropsychiatric inventory (NPI). ADAS-cog was the primary end point of the study. A two-way analysis of covariance and least squares mean t-test were used. Results: at Week 16, the changes from baseline in ADAS-cog were 1.4, -2.1, -2.2 and -4.2 for placebo, low-, middle- and high-dose groups, respectively. Patients in the high-dose group had better performance in CIBIC+ and ADL scores at the end of the study. There was no significant difference in the change in NPI score among the groups. The effects of octohydroaminoacridine were dose dependent, and were effective within 16 weeks of treatment. No evidence was found for more adverse events that occurred in different drug groups than placebo group. Conclusions: octohydroaminoacridine significantly improved cognitive function and behaviour in patients with mild-to-moderate AD and this effect was dose dependent.

Intergenerational Transmission of Enhanced Seizure Susceptibility after Febrile Seizures.

Environmental exposure early in development plays a role in susceptibility to disease in later life. Here, we demonstrate that prolonged febrile seizures induced by exposure of rat pups to a hyperthermic environment enhance seizure susceptibility not only in these hyperthermia-treated rats but also in their future offspring, even if the offspring never experience febrile seizures. This transgenerational transmission was intensity-dependent and was mainly from mothers to their offspring. The transmission was associated with DNA methylation. Thus, our study supports a "Lamarckian"-like mechanism of pathogenesis and the crucial role of epigenetic factors in neurological conditions.

The Efficacy of Hyperbaric Oxygen Therapy on Middle Cerebral Artery Occlusion in Animal Studies: A Meta-Analysis.

BACKGROUND: Inconsistent results have been reported for hyperbaric oxygen therapy (HBO) for acute stroke. We conducted a systematic review and meta-analysis to evaluate the benefit of HBO in animal studies of middle cerebral artery occlusion (MCAO). METHODS: A systematic search of the literature published prior to September 2015 was performed using Embase, Medline (OvidSP), Web of Science and PubMed. Keywords included "hyperoxia" OR "hyperbaric oxygen" OR "HBO" AND "isch(a)emia" OR "focal cerebral ischemia" OR "stroke" OR "infarct" OR "middle cerebral artery occlusion (MCAO)." The primary endpoints were the infarct size and/or neurological outcome score evaluated after HBO treatment in MCAO. Heterogeneity was analyzed using Cochrane Library's RevMan 5.3.5. RESULTS: Fifty-one studies that met the inclusion criteria were identified among the 1198 studies examined. When compared with control group data, HBO therapy resulted in infarct size reduction or improved neurological function (32% decrease in infarct size; 95% confidence interval (CI), range 28%-37%; p < 0.00001). Mortality was 18.4% in the HBO group and 26.7% in the control group (RR 0.72, 95% CI, 0.54-0.98; p = 0.03). Subgroup analysis showed that a maximal neuro-protective effect was reached when HBO was administered immediately after MCAO with an absolute atmospheric pressure (ATA) of 2.0 (50% decrease; 95% CI, 43% -57% decrease; p < 0.0001) and more than 6 hours HBO treatment (53% decrease; 95% CI, 41% -64% decrease; p = 0.0005). CONCLUSIONS: HBO had a neuro-protective effect and improved survival in animal models of MCAO, especially in animals given more than 6 hours of HBO and when given immediately after MCAO with 2.0 ATA.

Ginkgo biloba on focal cerebral ischemia: a systematic review and meta-analysis.

Gingko biloba extract (EGB) has been used in traditional medicines for centuries, and although its application to cerebral ischemia has been of great interest in recent years, high quality evidence-based clinical trials have not been carried out. This systematic review and meta-analysis aimed to examine the neuroprotective effect of EGB on focal cerebral ischemia in animal models. A systematic literature search was performed using five databases spanning January 1980-July 2013. The outcome was assessed using the effect size, which was based on infarct size and/or neurological score. A total of 42 studies with 1,232 experimental animals matched our inclusion criteria. The results revealed that EGB improved the effect size by 34% compared to the control group. The animal species, the method and time to measure outcome, and the route and dosage of EGB administration affected the variability of the effect size. Mechanisms of EGB neuroprotection were reported as anti-apoptotic, anti-oxidative, and anti-inflammatory. In conclusion, EGB exerts a significant protective effect on experimental focal cerebral ischemia. However, possible experimental bias should be taken into account in future clinical studies.

EGB1212 post-treatment ameliorates hippocampal CA1 neuronal death and memory impairment induced by transient global cerebral ischemia/reperfusion.

Extracts of Ginkgo biloba have been used in traditional medicines for centuries, and have potential for clinical applications in cerebral ischemia/reperfusion injury. However, standardized extracts have proven protective only as pre-treatments, and the major mechanisms of action remain unclear. We explored the potential of the novel extract EGB1212, which meets the United States Pharmacopeia (USP) 31 standardization criteria for pharmaceutical use, as a post-treatment after global cerebral ischemia/reperfusion (GCI/R) injury in a rat model. The pre-treated group was administered EGB1212 for 7 d prior to common carotid artery occlusion (i.e., ischemia, for 20 min). Post-treated rats received the same but starting 2 h after ischemia and continuing for 7 d. Seven days after GCI/R, brains of each group were processed for H&E staining of hippocampal CA1 neurons. Remaining rats underwent the Morris water maze and Y-maze tests of spatial learning and memory, beginning eight days after reperfusion. To assess hippocampal autophagy, light chain (LC)-3-I/LC3-II and Akt/pAkt were determined via a Western blot of rat hippocampi harvested 12, 24, or 72 h after reperfusion. EGB1212 pre- and post-treatments both improved neuronal survival and spatial learning and memory functions. Pre-treatment effectively reduced LC3-II levels and post-treatment resulted in significantly elevated pAkt levels. We conclude that EGB1212 exerted significant neuroprotection in GCI/R in both preventative and post-treatment settings. This extract shows great potential for clinical applications.

A systematic review and meta-analysis of buyang huanwu decoction in animal model of focal cerebral ischemia.

Buyang Huanwu Decoction (BHD) is a well-known Chinese herbal prescription for ischemic stroke. The objective of this systematic review and meta-analysis is to provide the current evidence for neuroprotective effects of BHD and its possible mechanisms in animal models of focal ischemia. A systematic literature search, through October 2012, was performed using six databases. The outcome measures assessed were infarct size and/or neurological score. Fifty-six studies with 1270 animals that met the inclusion criteria were identified. The median score for methodological quality was 3 with a range of 2 to 6. Compared with vehicle or no treatment controls, BHD gave a 37% improvement in outcome for all doses ranging from 1.0 g/kg to 60 g/kg at each time point that BHD was administered (P < 0.01). Efficacy was higher in mouse models that utilized suture occlusion and temporary ischemia. The neuroprotective effects of BHD are involved in multiple mechanisms and act upon multiple cell types. In conclusion, BHD possesses substantial neuroprotective effects in experimental stroke probably as a result of the multitarget therapy strategy typically utilized in traditional Chinese medicine. Future research should examine the presence of possible experimental bias and an in-depth study of herbal compound preparations.

[Clinical study on effect of sanqi tongshu capsule in treating ischemic stroke: multicenter clinical trial].

OBJECTIVE: To observe the clinical effect and security of Sanqi Tongshu capsule in treating ischemic strkoe. METHOD: A multicenter, no dummy, open labeled clincal trail was conducted. 1 753 patient were enrolled in this clinical trial. All patients were treated with the Sanqi Tongshu capsule (200 mg, three times a day) for 28 days. The score of Europe Stroke Score (ESS) and Barthel Index (BI) were evaluated before and after treatment. The adverse reaction occurred in the therapeutic course was also observed. RESULT: Finally, 1742 cases and 1676 cases were respectively assessable by Full analysis set (FAS) analysis and Full analysis set (FAS) analysis. Clinical symptoms markedly improved in patients after treatment, and the score of ESS and BI had significantly improved (P<0.05). According to the score of ESS and BI, the total effect analysis indicated that the total effective rate in FAS and PPS were 81.86% and 84.43% respectively. The rate of adverse reaction was 3.44%, and the raction was so slight that didn't need to receive therapy or withdral drug. CONCLUSION: Sanqi Tongshu capsule is effect and secure in treating ischemic stroke without obvious adverse reaction.