Brain Sciences

Background: Blood-brain barrier dysfunction in active multiple sclerosis (MS) lesions leads to pathological changes in the cerebrospinal fluid (CSF). This study aimed to investigate the possible association between routine CSF findings, especially CSF chloride, at the time of the first lumbar puncture and the relapse risk and disability progression of relapsing–remitting MS (RRMS). Methods: This retrospective study included 77 patients with RRMS at the MS Center of our institution from January 2012 to December 2020. The Anderson and Gill (AG) model and Spearman correlation analysis were used to explore predictors of relapse and disability during follow-up. Results: In the multivariate AG model, patients with elevated CSF chloride level (hazard ratio [HR], 1.1; 95% confidence interval [CI]: 1.06–1.22; p = 0.001) had a high risk of MS relapse. Using median values of CSF chloride (123.2 mmol/L) as a cut-off, patients with CSF chloride level ≥ 123.2 mmol/L had a 120% increased relapse risk compared with those with CSF chloride level < 123.2 mmol/L (HR = 2.20; 95% CI: 1.19–4.05; p = 0.012). Conclusions: Elevated CSF chloride levels might be a biologically unfavorable predictive factor for disease relapse in RRMS. Full article

Recently, genuine motor abnormalities have been recognized as prodromal and predictive signs of psychosis onset and progression. Therefore, physical exercise could represent a potentially relevant clinical tool in promoting the reshaping of neural connections in motor circuitry. The aim of this review is to provide an overview of the literature on neuroimaging findings as a result of physical treatment in psychosis cohorts. Twenty-one studies, all research articles, were included and discussed in this narrative review. Here, we first outlined how the psychotic brain is susceptible to structural plastic changes after aerobic physical training in pathognomic brain areas (i.e., temporal, hippocampal and parahippocampal regions). Secondly, we focused on functional changes, both region-specific and in terms of connections, to gain insights into the involvement of distant but inter-related neural regions in the plastic process occurring after treatment. Third, we attempted to bridge neural plastic changes occurring after physical interventions with clinical and cognitive outcomes of psychotic patients in order to assess the relevance of such neural reshaping in the psychiatric rehabilitation field. In conclusion, we suggest that the current state of the art is presenting physical intervention as effective in promoting neural changes for patients with psychosis; it is not only useful at the onset of the pathology but also in improving the course of the illness and its functional outcome. However, more evidence is needed to improve our knowledge of the efficacy of physical exercise in plastically reorganizing the psychotic brain in the long term, especially within regions lacking specific investigations, such as motor circuitry. Full article

Electroacupuncture (EA) is an efficient treatment for visceral hypersensitivity (VH). However, the mechanism underlying VH remains obscure. This study aimed to examine the effect of EA at Housanli acupoint on PAR2 and PAR4 expression in the periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and spinal cord dorsal horn (SCDH) axes, as well as on expression of the proinflammatory cytokines IL-1β and TNF-α, COX-2 enzyme, c-Fos, and the neuropeptides CGRP and SP in the same areas of the descending pain modulatory system. To induce VH in male goats, a 2,4,6-trinitrobenzene-sulfonic acid (TNBS)–ethanol solution was administered to the ileal wall. The visceromotor response (VMR) and nociceptive response at different colorectal distension pressures were measured to evaluate VH. Goats in the TNBS group displayed significantly increased VMR and nociceptive response scores, and elevated protein and mRNA levels of PAR2 and PAR4 in the descending pain modulatory system compared to those in the control group. EA alleviated VMR and nociceptive responses, decreased the protein and mRNA expression levels of PAR2, and elevated those of PAR4 in the descending pain modulatory system. EA may relieve VH by reducing PAR2 expression and increasing PAR4 expression in the descending pain modulatory system. Full article

Paired associative stimulation (PAS) is a non-invasive brain stimulation technique that modulates synaptic plasticity in the human motor cortex (M1). Since previous studies have primarily used motor-evoked potentials (MEPs) as outcome measure, cortical correlates of PAS-induced plasticity remain unknown. Therefore, the aim of this observational study was to investigate cortical correlates of a standard PAS induced plasticity in the primary motor cortex by using a combined TMS-EEG approach in a cohort of eighteen healthy subjects. In addition to the expected long-lasting facilitatory modulation of MEPs amplitude, PAS intervention also induced a significant increase in transcranial magnetic stimulation-evoked potentials (TEPs) P30 and P60 amplitude. No significant correlation between the magnitude of PAS-induced changes in TEP components and MEP amplitude were observed. However, the linear regression analysis revealed that the combined changes in P30 and P60 component amplitudes significantly predicted the MEP facilitation after PAS. The findings of our study offer novel insight into the neurophysiological changes associated with PAS-induced plasticity at M1 cortical level and suggest a complex relationship between TEPs and MEPs changes following PAS. Full article

Although the progressive clinical trajectory of motor neurone disease (MND) is widely understood, multiple challenges remain preventing optimal end-of-life care for this population with unique needs from the patient, carer and service provider perspectives. This paper reports on the experiences, gaps in service and unmet needs of MND patients and family carers and explores public health palliative care approaches that would facilitate coordinated and integrated care to respond to their changing needs. This is a qualitative study of responses to questions in an online consumer survey (353 respondents) in Western Australia (2020), focusing on a subset of 29 current and bereaved carers of people with MND who have used health services in the last five years. The analysis identified themes, highlighting the insufficient integration of services across health and social care; poor and unequal access to coordinated palliative care; significant gaps in the knowledge base of the workforce and a failure to meet the consumer expectations of person-centred care. For palliative care to be accessible to those living with MND and other under-served conditions, there needs to be a shift to more comprehensive, inclusive and sustainable options, such as the public health approach to palliative/end-of-life care that engages the assets of local communities in partnership with health services, one example being the “Compassionate Communities Connectors” model of care. Further considerations include advocacy for policy changes, fostering partnerships and developing indicators for evaluating the impact of the proposed models of care. The end result is not only better care but substantial savings for the health system. Full article

Wisconsin card-sorting tasks provide unique opportunities to study cognitive flexibility and its limitations, which express themselves behaviorally as perseverative errors (PE). PE refer to those behavioral errors on Wisconsin card-sorting tasks that are committed when cognitive rules are maintained even though recently received outcomes demand to switch to other rules (i.e., cognitive perseveration). We explored error-suppression effects (ESE) across three Wisconsin card-sorting studies. ESE refer to the phenomenon that PE are reduced on repetitive trials compared to non-repetitive trials. We replicated ESE in all three Wisconsin card-sorting studies. Study 1 revealed that non-associative accounts of ESE, in particular the idea that cognitive inhibition may account for them, are not tenable. Study 2 suggested that models of instrumental learning are among the most promising associative accounts of ESE. Instrumental learning comprises goal-directed control and the formation of corresponding associative memories over and above the formation of habitual memories according to dual-process models of instrumental learning. Study 3 showed that cognitive, rather than motor, representations of responses should be conceptualized as elements entering goal-directed instrumental memories. Collectively, the results imply that ESE on Wisconsin card-sorting tasks are not only a highly replicable phenomenon, but they also indicate that ESE provide an opportunity to study cognitive mechanisms of goal-directed instrumental control. Based on the reported data, we present a novel theory of cognitive perseveration (i.e., the ‘goal-directed instrumental control’ GIC model), which is outlined in the Concluding Discussion. Full article

L-menthol is known to activate transient receptor potential melastatin 8 (TRPM8) and induce analgesia to thermal stimuli. However, since thermal stimulation leads to the interaction among the other TRP channels, it was unclear whether L-menthol causes analgesia to stimuli other than thermal stimuli. Therefore, we aimed to investigate whether activating TRPM8 via topical application of 10% menthol solution attenuates pain-related somatosensory-evoked potentials (pSEPs) and affects numerical rating scale (NRS) score using intra-epidermal electrical stimulation (IES). We applied 10% L-menthol or control solution on the dorsum of the right hand of 25 healthy participants. The pSEP and NRS, elicited by IES, and sensory threshold were measured before and after each solution was applied. The results showed that the topical application of 10% L-menthol solution significantly reduced N2–P2 amplitude in pSEPs compared with the control solution. Moreover, the N2 latency was significantly prolonged upon the topical application of L-menthol solution. NRS scores were similar under both conditions. These results suggest that topical application of L-menthol does not alter subjective sensation induced using IES, although it may attenuate afferent signals at free nerve endings even with stimuli that do not directly activate TRP channels. Full article

Acetylcholine is a critical modulatory neurotransmitter for cognitive function. Cholinergic drugs improve cognitive performance and enhance neuronal activity in the sensory and association cortices. An alternative means of improving cognitive function is through the use of deep brain stimulation. Prior animal studies have demonstrated that stimulation of the nucleus basalis of Meynert through DBS improves cognitive performance on a visual working memory task to the same degree as cholinesterase inhibitors. Additionally, unlike current pharmacological treatments for neurocognitive disorders, DBS does not lose efficacy over time and adverse effects are rare. These findings suggest that DBS may be a promising alternative for treating cognitive impairments in neurodegenerative disorders such as Alzheimer’s disease. Thus, further research and human trials should be considered to assess the potential of DBS as a therapeutic treatment for these disorders. Full article

Given the complex and multifaceted nature of resecting giant tumors in the anterior, middle, and, to a lesser extent, the posterior fossa, we present two example strategies for navigating the intricacies of such tumors. The foundational premise of these two approaches is based on a two-stage method that aims to improve the visualization and excision of the tumor. In the first case, we utilized a combined endoscopic endonasal approach and a staged modified pterional, pretemporal, with extradural clinoidectomy, and transcavernous approach to successfully remove a giant pituitary adenoma. In the second case, we performed a modified right-sided pterional approach with pretemporal access and extradural clinoidectomy. This was followed by a transcortical, transventricular approach to excise a giant anterior clinoid meningioma. These cases demonstrate the importance of performing staged operations to address the challenges posed by these giant tumors. Full article

The paradigm is gradually shifting, with radiosurgery and endovascular embolization being increasingly chosen over surgical resection in the selected cases of brain arteriovenous malformations. Routinely used X-ray monitoring of liquid embolic infusion has very good spatial and temporal resolution but is not without significant drawbacks regarding poor visualization of the complex AVM angioarchitecture, especially after many embolizations in the past and therefore limiting the technical ability of the embocure—total occlusion of the feeding arteries, nidus, and draining veins. The purpose of this study was to evaluate the use of real-time MRI guidance in endovascular embolization with Onyx (instead of X-ray) in a single swine rete mirabile (RM) AVM model in order to provide the scaffolding for the real-time MRI guidance method. Onyx propagation was observed in real-time dynamic GE-EPI scan with initial ipsilateral RM filling followed by main cerebral arterial branch distribution. The relatively bright signal within RM and the brain prior to Onyx injection provided a good background for the dark, low signal of the embolic agent spreading in rete mirabile and brain arteries. X-ray picture confirmed Onyx cast distribution at the end of the procedure. In this initial experience, real-time MRI seems to be a promising method that may significantly improve liquid embolic agent infusion monitoring in the future, although requiring further development before clinical use. Full article

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. There is a wide range of sleep disturbances in patients with PD, such as insomnia and rapid eye movement (REM) sleep behavior disorder (or REM behavior disorder (RBD)). RBD is a sleep disorder in which a patient acts out his/her dreams and includes abnormal behaviors during the REM phase of sleep. On the other hand, melatonin is the principal hormone that is secreted by the pineal gland and significantly modulates the circadian clock and mood state. Furthermore, melatonin has a wide range of regulatory effects and is a safe treatment for sleep disturbances such as RBD in PD. However, the molecular mechanisms of melatonin involved in the treatment or control of RBD are unknown. In this study, we reviewed the pathophysiology of PD and sleep disturbances, including RBD. We also discussed the potential molecular mechanisms of melatonin involved in its therapeutic effect. It was concluded that disruption of crucial neurotransmitter systems that mediate sleep, including norepinephrine, serotonin, dopamine, and GABA, and important neurotransmitter systems that mediate the REM phase, including acetylcholine, serotonin, and norepinephrine, are significantly involved in the induction of sleep disturbances, including RBD in PD. It was also concluded that accumulation of α-synuclein in sleep-related brain regions can disrupt sleep processes and the circadian rhythm. We suggested that new treatment strategies for sleep disturbances in PD may focus on the modulation of α-synuclein aggregation or expression. Full article

N-acetylneuraminic acid (Neu5Ac) is a functional metabolite and has been demonstrated to be a risk factor for cardiovascular diseases. It is not clear whether Neu5Ac is associated with a higher risk of cerebrovascular disorders, especially moyamoya disease (MMD). We sought to elucidate the association between serum Neu5Ac levels and MMD in a case–control study and to create a clinical risk model. In our study, we included 360 MMD patients and 89 matched healthy controls (HCs). We collected the participants’ clinical characteristics, laboratory results, and serum Neu5Ac levels. Increased level of serum Neu5Ac was observed in the MMD patients (p = 0.001). After adjusting for traditional confounders, the risk of MMD (odds ratio [OR]: 1.395; 95% confidence interval [CI]: 1.141–1.706) increased with each increment in Neu5Ac level (per μmol/L). The area under the curve (AUC) values of the receiver operating characteristic (ROC) curves of the basic model plus Neu5Ac binary outcomes, Neu5Ac quartiles, and continuous Neu5Ac are 0.869, 0.863, and 0.873, respectively. Furthermore, including Neu5Ac in the model offers a substantial improvement in the risk reclassification and discrimination of MMD and its subtypes. A higher level of Neu5Ac was found to be associated with an increased risk of MMD and its clinical subtypes. Full article

Purpose: The accurate preoperative histopathological grade diagnosis of adult gliomas is of great significance for the formulation of a surgical plan and the implementation of a subsequent treatment. The aim of this study is to establish a predictive model for classifying adult gliomas into grades 2–4 based on preoperative conventional multimodal MRI radiomics. Patients and Methods: Patients with pathologically confirmed gliomas at Huashan Hospital, Fudan University, between February 2017 and July 2019 were retrospectively analyzed. Two regions of interest (ROIs), called the maximum anomaly region (ROI1) and the tumor region (ROI2), were delineated on the patients’ preoperative MRIs utilizing the tool ITK-SNAP, and Pyradiomics 3.0 was applied to execute feature extraction. Feature selection was performed utilizing a least absolute shrinkage and selection operator (LASSO) filter. Six classifiers, including Gaussian naive Bayes (GNB), random forest (RF), K-nearest neighbor (KNN), support vector machine (SVM) with a linear kernel, adaptive boosting (AB), and multilayer perceptron (MLP) were used to establish predictive models, and the predictive performance of the six classifiers was evaluated through five-fold cross-validation. The performance of the predictive models was evaluated using the AUC and other metrics. After that, the model with the best predictive performance was tested using the external data from The Cancer Imaging Archive (TCIA). Results: According to the inclusion and exclusion criteria, 240 patients with gliomas were identified for inclusion in the study, including 106 grade 2, 68 grade 3, and 66 grade 4 gliomas. A total of 150 features was selected, and the MLP classifier had the best predictive performance among the six classifiers based on T2-FLAIR (mean AUC of 0.80 ± 0.07). The SVM classifier had the best predictive performance among the six classifiers based on DWI (mean AUC of 0.84 ± 0.05); the SVM classifier had the best predictive performance among the six classifiers based on CE-T1WI (mean AUC of 0.85 ± 0.06). Among the six classifiers, based on ROI1, the MLP classifier had the best prediction performance (mean AUC of 0.78 ± 0.07); among the six classifiers, based on ROI2, the SVM classifier had the best prediction performance (mean AUC of 0.82 ± 0.07). Among the six classifiers, based on the multimodal MRI of all the ROIs, the SVM classifier had the best prediction performance (average AUC of 0.85 ± 0.04). The SVM classifier, based on the multimodal MRI of all the ROIs, achieved an AUC of 0.81 using the external data from TCIA. Conclusions: The prediction model, based on preoperative conventional multimodal MRI radiomics, established in this study can conveniently, accurately, and noninvasively classify adult gliomas into grades 2–4, providing certain assistance for the precise diagnosis and treatment of patients and optimizing their clinical management. Full article

Recent data on the distribution and influence of copper, zinc and cadmium in glial cells are summarized. This review also examines the relationship between those metals and their role in neurodegenerative diseases like Alzheimer disease, multiple sclerosis, Parkinson disease and Amyotrophic lateral sclerosis, which have become a great challenge for today’s physicians. The studies suggest that among glial cells, iron has the highest concentration in oligodendrocytes, copper in astrocytes and zinc in the glia of hippocampus and cortex. Previous studies have shown neurotoxic effects of copper, iron and manganese, while zinc can have a bidirectional effect, i.e., neurotoxic but also neuroprotective effects depending on the dose and disease state. Recent data point to the association of metals with neurodegeneration through their role in the modulation of protein aggregation. Metals can accumulate in the brain with aging and may be associated with age-related diseases. Full article

Perinatal brain damage, one of the most common causes of lifelong impairment, is predominantly caused by a lack of oxygen and glucose during early development. These conditions, in turn, affect cells of the nervous tissue through various stages of their maturation. To quantify the influence of these factors on cell differentiation and mitochondrial parameters, we exposed neural cell precursors to oxygen and glucose deprivation (OGD) during three stages of their differentiation: day 1, day 7, and day 14 (D1, D7, and D14, respectively). The obtained results show that OGD slows down cellular differentiation and causes cell death. Regardless of the level of cell maturity, the overall area of the mitochondria, their length, and the branching of their filaments decreased uniformly when exposed to OGD-related stress. Moreover, the cells in all stages of differentiation exhibited an increase in ROS production, hyperpolarization of the mitochondrial membrane, and autophagy. Interestingly, day 7 was the only stage in which a significant increase in mitochondrial fission, along with measurable instances of mitophagy, were detected. Taken together, the results of this study suggest that, apart from common reactions to a sudden lack of oxygen and glucose, cells in specific stages of neural differentiation can also exhibit increased preferences for mitochondrial fission and mitophagy. Such findings could play a role in guiding the future development of novel therapeutic approaches targeting perinatal brain damage during specific stages of nervous system development. Full article

Bipolar depression remains a clinical challenge with a quarter of patients failing to respond to initial conventional treatments. Although ketamine has been extensively studied in unipolar depression, its role in bipolar disorder remains inconclusive. The aim of our scoping review was to comprehensively synthesize the current clinical literature around ketamine use in bipolar depression. A total of 10 clinical studies (5 randomized controlled trials and 5 open label studies) were selected. The preliminary evidence, albeit weak, suggests that ketamine is a promising treatment and calls for further interest from the research community. Overall, ketamine treatment appeared to be tolerable with minimal risk for manic/hypomanic switching and showed some effectiveness across parameters of depression and suicidality. Moreover, ketamine is a potential treatment agent in patients with treatment-resistant bipolar depression with promising data extracted from extant controlled trials and real-world effectiveness studies. Future studies are needed to identify ketamine’s role in acute and maintenance treatment phases of bipolar depression. Moreover, future researchers should study the recurrence prevention and anti-suicidal effects of ketamine in the treatment of bipolar depression. Full article

Extensive music practice has been suggested to enhance the development of cognitive abilities over and above musical expertise. Executive functions (EFs) have been particularly investigated, given their generalizability across different domains and their crucial role in almost all aspects of cognition. However, the relationship between musical expertise and EFs is still not completely understood, as several studies have reported conflicting results. The present study aims to investigate the relationship between musical expertise and EFs, determining which facets—if any—of EFs might be particularly relevant to extensive music practice. Thirty-five student pianists completed a set of neuropsychological tasks which assessed EFs (the Trail Making Task, Design Fluency, Numerical Stroop, and the Tower of London). They also performed a short musical excerpt inspired by the piano literature. Musical expertise was assessed by considering three parameters, namely the highest academic degree in music, the lifetime amount of music practice, and the quality of the sample-based musical performance. The results indicate that postgraduate piano students did not show advantages in EFs compared to undergraduate piano students. More extensive lifetime practice in music was solely associated with faster visual reaction times on the Numerical Stroop task. The Trail Making and Design Fluency scores were significant predictors of the quality of the sample-based musical performance. In conclusion, the present data suggests that EFs and the amount of music practice do not seem to be correlated in student pianists. Nevertheless, some facets of EFs and the quality of musical performance may share substantial amounts of variance. Full article

Culture greatly influences our attitudes, beliefs, and behaviors, affecting how we communicate and make decisions. There is an ongoing debate regarding the belief that people from Eastern cultures possess greater self-control abilities when compared to people from Western cultures. In this study, we conducted a meta-analysis using the Activation Likelihood Estimation (ALE) algorithm to compare 30 studies (719 subjects, 373 foci) that used fMRI to investigate the performance in Go–Nogo and Stop Signal Tasks of participants from Western and/or Eastern countries. Our meta-analysis found differences between the networks activated in Eastern and Western culture participants. The right prefrontal cortex showed distinct patterns, with the Inferior Frontal gyrus more active in the Eastern group and the middle and superior frontal gyri more active in the Western group. Our findings suggest that Eastern culture subjects have a higher tendency to activate brain regions involved in proactive inhibitory control, while Western culture subjects rely more on reactive inhibitory brain regions during cognitive control tasks. This implies that proactive inhibition may play a crucial role in promoting the collective and interdependent behavior typical of Eastern cultures, while reactive inhibition may be more important for efficient cognitive control in subjects of Western cultures that prioritize individualism and independence. Full article

Around the world, more the 700,000 individuals die by suicide every year. It is necessary to understand the mechanisms associated with suicidal behavior. Recently, an increase in gene expression studies has been in development. Through a systematic review, we aimed to find a candidate gene in gene expression studies on postmortem brains of suicide completers. Databases were systematically searched for published studies. We performed an online search using PubMed, Scopus and Web of Science databases to search studies up until May 2023. The terms included were “gene expression”, “expressed genes”, “microarray”, “qRT–PCR”, “brain samples” and “suicide”. Our systematic review included 59 studies covering the analysis of 1450 brain tissues from individuals who died by suicide. The majority of gene expression profiles were obtained of the prefrontal cortex, anterior cingulate cortex, dorsolateral prefrontal cortex, ventral prefrontal cortex and orbital frontal cortex area. The most studied mRNAs came of genes in glutamate, γ-amino-butyric acid and polyamine systems. mRNAs of genes in the brain-derived neurotrophic factor, tropomyosin-related kinase B (TrkB), HPA axis and chemokine family were also studied. On the other hand, psychiatric comorbidities indicate that suicide by violent death can alter the profile of mRNA expression. Full article