NeuroSci, Volume 6, Issue 3 (September 2025) – 27 articles

Interest in ketamine as a novel treatment for substance use disorders (SUDs) has been increasing due to its N-methyl-D-aspartate (NMDA) glutamate receptor antagonism and mounting evidence that glutamate neurotransmission is involved in the pathogenesis of both depression and addictions. This narrative review provides an outline of clinical evidence reported in the literature from the 1970s to 2025 that examines the efficacy of ketamine for the treatment of SUDs, focusing primarily on randomized blinded controlled trials (RBCTs). Key cohort studies, retrospective studies, secondary analyses, case reports, and relevant basic neuroscience studies are reviewed to complement the more rigorous human controlled trial data. Thus far, ketamine has been tested in nine RBCTs targeting cocaine (three studies), alcohol (three studies), opioid use disorder (two studies), and nicotine (one study), suggesting efficacy for addiction in combination with psychotherapies, and often when doses produce subjectively reported mystical or psychedelic experiences. This review highlights promising preliminary evidence, and the need for more rigorous studies to elucidate the scope of drug addictions ketamine may target, its optimal dosing or route of administration, the importance of concurrent psychotherapies, professional supervision and safety monitoring, and which psychiatric comorbidities or contexts may contraindicate its use for SUDs. Full article

Objective: We aimed to quantify multiple sclerosis (MS)-related work productivity and to illustrate the longitudinal trends for relapses, disease progression, and utilization of health care resources in a nationally representative cohort of working North Americans living with MS. Background: The North American Registry for Care and Research in Multiple Sclerosis (NARCRMS) is a multicentered physician-reported registry which prospectively collects clinical information including imaging data over a long period of time from people with MS from sites across the U.S. and Canada. The Health Economics Outcomes Research (HEOR) Advisory Group has also incorporated Health-Related Productivity and Health Resource Utilization questionnaires, which collect information about health care economics of people with MS and its effects on daily life. Design/Methods: This is a prospective observational study utilizing data from NARCRMS. Socio-demographic, clinical, and health economic outcome data were collected through previously validated and structured questionnaires. Logistic regression was used to calculate the relative odds of symptom impact, with a generalized logit link for number of relapses. Cox proportional hazards regression was used to calculate hazard ratios for time to first relapse. Results: Six hundred and eighty-two (682) people with MS were enrolled in NARCRMS and had completed the HEOR questionnaires at the time of the analysis. Among the participants, 61% were employed full-time and 11% were employed part time. Fatigue was the leading symptom reported to impact both work and household chores. Among the employed participants, 13% reported having missed work with a median of 6.8 (IQR: 3.0–9.0) missed hours due to MS symptoms (absenteeism), while 35% reported MS having impacted their work output (presenteeism). The odds of higher disease severity (EDSS 2.0–6.5 vs. 0.0–1.5) were 2.29 (95% CI = 1.08, 4.88; p = 0.011) times higher for participants who identified reduction of work output. Fatigue was the most identified symptom attributed to work output reduction. Among all participants, 33% reported having missed planned household work with a median of 3.0 (IQR: 2.0–5.0) hours. The odds of higher disease severity were 2.49 (95% CI = 1.37, 4.53; p = 0.006) times higher for participants who identified reduction in household work output, and 1.70 (CI = 1.27, 2.49; p = 0.006) times higher for those whose fatigue affected housework output as compared to other symptoms. Conclusions: A preliminary review of the first 682 patients showed that people with MS had reduced work and housework productivity even at an early disease state. Multiple sclerosis (MS) can significantly impair individuals’ ability to function fully at work and at home, with fatigue overwhelmingly identified as the primary contributing factor. The economic value of finding an effective treatment for MS-related fatigue is substantial, underscoring the importance of these findings for policy development, priority setting, and the strategic allocation of healthcare resources for this chronic and disabling condition. Full article

Background: The literature shows that anterior communicating artery (AcoA) aneurysms are the most common intracranial aneurysms. To date, there has only been one postmortem study focused on the correlations between autopsy findings and imaging results in cases of intracranial aneurysms associated with anatomical variants of the circle of Willis (CW). Methods: We investigated the anatomical variants of the CW associated with the occurrence and rupture of AcoA aneurysms by performing comparative analyses, in the same patients, of postmortem autopsy data with antemortem computed tomography–angiography (CTA) results obtained in the first 48 h after the onset of subarachnoid hemorrhage. Our retrospective observational study identified the anatomical variants of the CW at autopsy in 16 deceased adult Romanian patients with AcoA aneurysms over a 12-year period (2010–2022). Results: The autopsy findings revealed that the AcoA ruptured aneurysms had a mean external diameter of 9.50 mm, and 71.4% of them presented three or four anatomical variants inside the same CW. The initial antemortem CTA examination correctly located the AcoA aneurysms in all cases (100%), and an anatomical variant of the CW was only noted in 18.75% of patients. The final postmortem re-analyzed the same CTA images identified in all cases (100%), focusing on both the AcoA aneurysm and all anatomical variants of the CW found during the autopsies. Conclusions: Although it was previously thought that the occurrence of AcoA aneurysms is related only to the hemodynamic changes induced by the nearby arterial anatomical variants, we identified the simultaneous involvement of at least one hypoplastic artery and one or two PCA fetal-type anatomical variants that were located in both the anterior and posterior parts of the CW. Furthermore, if sufficient time is devoted to the CT–angiography analysis and interpretation of the images, anatomical variants of the circle of Willis associated with AcoA aneurysms can be identified as accurately as they are in invasive postmortem autopsy examinations. Full article

This perspective paper proposes a theoretical framework for investigating potential associations between Long COVID and rising autism spectrum disorder (ASD) prevalence through established epidemiological methodologies. I propose examining temporal correlations, biological mechanisms, and rigorous methodological approaches, including Mendelian randomization, animal models, and evidence-based analyses, that could distinguish association from causation. The proposed framework recognizes autism as neurodiversity while suggesting investigation of environmental factors that may influence expression of genetic predispositions. Hypothesized key mechanisms include neuroinflammation, cytokine alterations, and immune dysfunction. I emphasize the critical distinction between demonstrating statistical associations and establishing causal influence, proposing specific experimental designs that could test causality. This paper presents conceptual frameworks requiring future empirical validation and does not include original data analysis. Full article

Seizure clusters can be observed in patients with epilepsy as well as in individuals without a previous history of epilepsy. However, there are no data on whether seizure clusters differ between these two populations. The purpose of this study was to investigate the clinical presentation, diagnostic findings, presence of seizure triggers, outcomes and complications of seizure clusters in patients with epilepsy and individuals without epilepsy in their medical history. The results indicate that epilepsy history was not independently associated with the number of seizures during cluster; however, increasing age was significantly associated with a lower seizure burden, and pneumonia demonstrated a marginal positive association. Structural brain lesions were prevalent in both groups; particularly chronic post-stroke lesions and frontal lobe lesions were significantly more common among epilepsy patients. Over half of patients without prior epilepsy received a new epilepsy diagnosis following the cluster event. No severe complications, including status epilepticus or postictal psychosis, were observed. Our findings suggest that age, acute comorbidities, and structural brain pathology likely exert greater influence on frequency of seizures during cluster. Chronic post-stroke lesions, which have not yet been reported as a risk factor for seizure clusters, were the most frequent brain pathology in both groups and may thus be considered as an additional risk factor for this clinical entity. Prospective and larger-scale studies are needed to further clarify these associations. Full article

The menstrual cycle affects the autonomic nervous system (ANS), cognition, and emotional valence in all biological women. There exists a complex relationship between hormonal fluctuations, ANS, cognition, and emotional valence during the different phases of the menstrual cycle, which includes menstruation, the follicular phase, ovulation, and the luteal phase. Hence, this narrative review is an attempt to comprehensively understand the effects of the menstrual cycle on the structural and functional integrity of the ANS. In order to provide a comprehensive understanding of the complex relationship between the menstrual cycle, hormonal fluctuations, and ANS function in biological women, this review examines key parameters, including heart rate variability (HRV), baroreflex sensitivity (BRS), muscle sympathetic nerve activity (MSNA), and pupillary light reflex (PLR), to investigate how these physiological systems are dynamically influenced by the cyclical changes in hormone levels and how these fluctuations impact various physiological and psychological outcomes, such as mood, cognition, and emotional regulation. There have been several studies previously performed to assess these parameters during different phases of the menstrual cycle. However, the results have been contradictory; therefore, this review explores possible reasons behind these inconsistent results, with likely reasons including irregularity in the menstrual cycles and differences in hormonal fluctuations between different women during similar phases of the menstrual cycle. Overall, there appears to be evidence to suggest that the menstrual cycle has both direct and indirect effects on ANS, cognition, and emotional valence, whilst measures of ANS may provide a means for assessing the effect of the menstrual cycle. Full article

Background: Spontaneous intracerebral hemorrhage (ICH) has the highest case fatality of all stroke types, yet recent epidemiological and outcome data from Central and Eastern Europe remain limited. Methods: We retrospectively analyzed prospectively collected data for 601 consecutive adults with primary ICH admitted to Sibiu County Clinical Emergency Hospital, Romania (2017–2023). Demographics, Glasgow Coma Scale (GCS), CT-derived hematoma volume (ABC/2), anatomical site, intraventricular extension (IVH), treatment, comorbidities, and in-hospital death were reported with exact counts and percentages; no imputation was performed. Results: Mean age was 68.4 ± 12.9 years, and 59.7% were male. Mean hematoma volume was 30.4 mL, and 23.0% exceeded 30 mL. IVH occurred in 40.1% and doubled mortality (50.6% vs. 16.7%). Overall case fatality was 29.6% and climbed to 74.5% for brain-stem bleeds. Men, although younger than women (66.0 vs. 71.9 years), died more often (35.4% vs. 21.1%; risk ratio 1.67, 95% CI 1.26–2.21). Systemic hazards amplified death risk: Oral anticoagulation, 44.2%; chronic alcohol misuse, 51.4%; thrombocytopenia, 41.0%; chronic kidney disease, 42.3%. Conservative management (74.9%) yielded 27.8% mortality overall and ≤15 for small-to-mid lobar or capsulo-lenticular bleeds; lobar surgery matched this (13.4%) only in large clots. Thalamic evacuation was futile (82.3% mortality), and cerebellar decompression performed late still carried 54.5% mortality versus 16.6% medically. Multivariable analysis confirmed that low GCS, IVH, large hematoma volume, thrombocytopenia, and chronic alcohol use independently predicted in-hospital mortality. Limitations: This retrospective study lacked post-discharge functional outcome data (e.g., mRS at 90 days). Conclusions: This study presents the largest Romanian single-center ICH cohort, establishing national benchmarks and underscoring modifiable risk factors. Early ICH lethality aligns with Western data but is amplified by exposures such as alcohol misuse, anticoagulation, thrombocytopenia, and CKD. Priorities include preventive strategies, timely surgical access, wider adoption of minimally invasive techniques, and development of a prospective regional registry. Full article

(1) Background: Choroid plexus papillomas (CPPs) are rare brain tumors that tend to occur in very young children. Mechanisms of CPP development remain unelucidated. Separately, the process of angiogenesis has been implicated in other primary brain tumors. We hypothesize that angiogenesis is a hallmark of CPP biology. This study aims to identify and validate angiogenic factors in CPPs. (2) Methods: Cerebrospinal fluid (CSF) and CPP tumor samples are collected. A multiplex immunoassay panel is used to identify differentially expressed cytokines in the CSF samples. Concurrently, patient-derived primary cell cultures and their supernatants are derived from CPP samples. Targeted proteome blot arrays and human umbilical vein endothelial cell (HUVEC) angiogenesis assays are used for validation studies. (3) Results: CSF profiling showed higher expressions of VEGF-A, MCP-1, MMP-1, TNF-α, and CD40L in CPP patient samples versus non-tumor controls. Next, assessment via online protein–protein network platforms reports that these cytokines are associated with endothelial cell regulation. Using an angiogenesis-focused approach, CPP-derived cell lines and supernatants showed similarly higher expressions of VEGF, MCP-1, and MMP-1. Next, sprouting of nodes and tubule formation were observed in HUVEC angiogenesis assay cultures when conditioned CPP cell culture media was added. (4) Conclusions: This proof-of-concept study demonstrates potential to explore angiogenesis in CPP. Full article

S100β is a significant signaling molecule and biomarker that is primarily expressed in the brain. At low physiological concentrations, S100β induces astrocyte maturation, microglial migration, and neural proliferation. However, high concentrations activate inflammatory and pro-apoptotic pathways. Due to this dual role, increased research is being invested into the role of S100β in neuronal homeostasis and inflammation. In fact, increased S100β expression is seen in many neuropathologies including Alzheimer’s disease, Parkinson’s disease, cerebral ischemia, and traumatic brain injury. High S100β is generally associated with worsened disease outcome. Here, we provide an overview of the structure and role of S100β in various pathways, particularly in the context of neurological disorders. Modulation of S100β levels also holds promise as a therapeutic strategy. Micro-RNAs (miRNA) post-transcriptionally regulate gene expression and provide a novel approach reduce excess S100β protein. However, much of this research is still in its infancy. We outline current studies identifying miRNA in human and animal models of various neurological disorders. S100β itself has several predicted miRNA interactions although most have not yet been directly validated. Together, we compile the literature identifying S100β and miRNAs to guide future research in this field. We also comment on the feasibility and future uses of miRNA for pharmaceutical regulation of S100β, particularly for neurological treatments. Full article

Background: Neuropathic pain (NP), resulting from damage to the somatosensory nervous system, affects 7–10% of the global population and remains poorly managed despite available therapies. Smoking has been associated with increased pain severity and disease burden, yet its role in neuropathy/NP has not been systematically reviewed. This systematic review synthesizes the existing literature on smoking status and its relationship with neuropathy/NP incidence, prevalence, and severity. Methods: The review was conducted in accordance with PRISMA guidelines and included studies that assessed smoking consumption, dependency, quantity, and cessation in individuals with neuropathy/NP. Summary estimates were stratified by exposure type, and pooled odds ratios and relative risks were calculated. Results: Across 62 studies comprising cohort, case–control, and cross-sectional designs, smoking was consistently associated with greater NP prevalence and pain severity. Smoking dependency was linked to increased incidence, while cessation was associated with reduced risk of NP. Despite considerable heterogeneity and risk of bias, particularly from subjective exposure measurement and inconsistent classification, this relationship remained statistically significant. Conclusions: Findings support the role of smoking as a modifiable risk factor in various etiologies of neuropathy/NP. Cessation may represent a low-cost, low-risk, low-tech adjunctive therapy; however, further robust cessation interventional trials are needed, particularly for less common infectious causes of chronic NP such as leprosy. Full article

Background: Traumatic brain injury (TBI) remains a significant contributor to global mortality and long-term neurological disability. Accurate prognostic biomarkers are crucial for enhancing prognostic accuracy and guiding personalized clinical management. Objective: This review assesses the prognostic value of arterial spin labeling (ASL), a non-invasive MRI technique, in adult and pediatric TBI, with a focus on quantitative cerebral blood flow (CBF) and arterial transit time (ATT) measures. A comprehensive literature search was conducted across PubMed, Embase, Scopus, and IEEE databases, including observational studies and clinical trials that applied ASL techniques (pCASL, PASL, VSASL, multi-PLD) in TBI patients with functional or cognitive outcomes, with outcome assessments conducted at least 3 months post-injury. Results: ASL-derived CBF and ATT parameters demonstrate potential as prognostic indicators across both acute and chronic stages of TBI. Hypoperfusion patterns correlate with worse neurocognitive outcomes, while region-specific perfusion alterations are associated with affective symptoms. Multi-delay and velocity-selective ASL sequences enhance diagnostic sensitivity in TBI with heterogeneous perfusion dynamics. Compared to conventional perfusion imaging, ASL provides absolute quantification without contrast agents, making it suitable for repeated monitoring in vulnerable populations. ASL emerges as a promising prognostic biomarker for clinical use in TBI. Conclusion: Integrating ASL into multiparametric models may improve risk stratification and guide individualized therapeutic strategies. Full article

Introduction: Despite clinical evidence for efficacy, there has been minimal uptake of transcranial direct current stimulation (tDCS) for musculoskeletal conditions. Thus, our objective was to explore the perceptions and experiences of people living with lower-limb musculoskeletal injury as well as healthy physically active populations and relate this to the usage of tDCS and key aspects of tDCS design that would improve the capacity for implementation. Methods: We conducted a qualitative descriptive study of 16 participants (44% women) using semi-structured focus groups to identify the descriptions and experiences of people living with lower-limb musculoskeletal injury and healthy physically active populations. A thematic template was used to create a coding structure. Codes were then grouped, and key themes were derived from the data. Results: Four primary themes were identified from focus groups. These were (i) the impact of musculoskeletal injuries on health and quality of life, (ii) performance and injury recovery as facilitators to using tDCS, (iii) barriers and facilitators to tCDS application and (iv) design and aesthetic factors for a tDCS device. Discussion: Our qualitative descriptive study identified four themes relevant to the successful implementation of tDCS into rehabilitative and performance practice. To increase the likelihood of successful tDCS implementation, these barriers should be addressed and facilitators promoted. This should include innovative approaches to device application and structure that allow for a stylish, user-friendly design. Full article

Optimal sensorimotor control depends on response timing. With age, it is broadly assumed that reaction time (RT) increases as cognitive function declines. However, it is not clear if the literature supports this assumption. The purpose of this work was to review the association between cognition and upper extremity RT in older adults. We conducted a search using Scopus database with four inclusion criteria: (1) healthy, community-dwelling adults over 60 years old, (2) upper extremity movement, (3) cognitive assessment, and (4) RT measure. Twenty-five of the 1608 articles screened met the inclusion criteria. Only nine studies directly or indirectly assessed the association between cognition and RT. Our interpretation of the literature was further limited by inconsistency in test selection and measurement interdependence that could be addressed by future studies. We present a conceptual framework to guide research assessing the influence of cognition on sensorimotor control with age. Full article

(1) Background: Evidence from non-human animal and spaceflight analog studies have suggested that traveling to outer space could have a significant impact on the structural properties of the hippocampus, a brain region within the medial temporal lobe that is critical for learning and memory. Here, we tested this hypothesis in a group of astronauts who participated in a six-month mission in the International Space Station (ISS). (2) Methods: We collected magnetic resonance imaging (MRI) scans from a sample of 17 (9 males, 8 females) astronauts before and after the ISS mission, and calculated percent gray matter volume changes in the whole hippocampus and its (anterior, body, and posterior) subregions in both hemispheres. (3) Following the six-month mission in the ISS, we found a significantly decreased volume in the whole left hippocampus; in addition, when looking at subregions separately, we detected a significantly decreased volume in the anterior subregion of the left hippocampus and the body subregion of the right hippocampus. We also found a significantly decreased volume in the whole right hippocampus of male astronauts as compared to female astronauts. (4) Conclusions: This study, providing the very first evidence of hippocampal volumetric changes in astronauts following a six-month mission to the ISS, could have significant implications for cognitive performance during future long-duration spaceflights. Full article

Amyotrophic lateral sclerosis (ALS) remains a progressive neurodegenerative disease, lacking effective causal therapies. The Wobbler mouse model harboring a spontaneous autosomal recessive mutation in the vacuolar protein sorting associated protein (Vps54), has emerged as a valuable model for investigating ALS pathophysiology and potential treatments. This model exhibits cellular and phenotypic parallels to human ALS, including protein aggregation, microglia and astrocyte activation, as well as characteristic disease progression at distinct stages. Exploring the underlying pathomechanisms and identifying therapeutic targets requires a comprehensive analysis of gene and protein expression. In this study, we examined the expression of three well-established housekeeping genes and proteins—calnexin, ß-actin, and ßIII-tubulin—in the cervical spinal cord of the Wobbler model. These candidates were selected based on their demonstrated stability across various systems like animal models or cell culture. Calnexin, an integral protein of the endoplasmic reticulum, ß-actin, a structural component of the cytoskeleton, and ß-tubulin III, a component of microtubules, were quantitatively assessed using quantitative reverse transcription-polymerase chain reaction (RT-PCR) for gene expression and Western blotting for protein expression. Our results revealed no significant differences in the expression of CANX, ACTB, and TUBB3 between spinal cords of wild-type and Wobbler mice at the symptomatic stage (p40) at both the gene and protein levels. These findings suggest that the pathophysiological alterations induced by the Wobbler mutation do not significantly affect the expression of these crucial housekeeping genes and proteins at p40. Overall, this study provides a basis for further investigations using the Wobbler mouse model, while highlighting the potential use of calnexin, ß-actin, and ßIII-tubulin as reliable reference genes and proteins in future research to aid in the discovery for effective therapeutic interventions. Full article

Human memory is inherently susceptible to errors, including the formation of false memories—instances where individuals mistakenly recall information they were never exposed to. While prior research has largely focused on neural activity associated with false memory, the structural brain correlates of this phenomenon remain relatively unexplored. This study bridges that gap by investigating gray matter structure as it relates to individual differences in false memory performance. Using publicly available magnetic resonance imaging datasets, we analyzed cortical thickness (CT) in neural regions implicated in memory processes. To assess false memory, we applied signal detection theory, which provides a robust framework for differentiating between true and false memory. Our findings reveal that increased CT in the parietal lobe and middle occipital gyrus correlates with greater susceptibility to false memories, highlighting its role in integrating and manipulating memory information. Conversely, CT in the middle frontal gyrus and occipital pole was associated with enhanced accuracy in memory recall, emphasizing its importance in perceptual processing and encoding true memories. These results provide novel insights into the structural basis of memory errors and offer a foundation for future investigations into the neural underpinnings of memory reliability. Full article

Pulsed radiofrequency (PRF) current applied to peripheral nerves is a modality used in interventional pain medicine, but its underlying mechanisms remain unclear. This study aimed to investigate whether ex vivo exposure of human monocytic THP-1 cells to PRF current or to heat induces β-endorphin production. Methods: THP-1 cells were exposed to PRF current for 15 min or incubated at elevated temperatures (42 °C to 50 °C) for 3 or 15 min. Flow cytometry was used to assess cell viability, and β-endorphin concentrations in culture supernatants were quantified by ELISA. In a separate experiment, cells were stimulated with lipopolysaccharide (LPS) to compare its effects on β-endorphin release. Results: A 3 min exposure to temperatures ≥ 46 °C reduced THP-1 cell viability, whereas a 15 min exposure to PRF current or to heat at 42 °C did not impair viability. Both PRF current and mild heat significantly enhanced β-endorphin release. β-Endorphin levels in the supernatant of LPS-stimulated cells were comparable to those of cells exposed to PRF current. Conclusions: Ex vivo application of PRF current or mild heat enhanced β-endorphin production from THP-1 cells without significant cytotoxicity. These preliminary findings warrant further investigation using primary human monocytes and in vivo models to assess therapeutic potential. Full article

Background: Cognitive impairment (CI) is a common and disabling symptom in patients with relapsing–remitting multiple sclerosis (RRMS), potentially emerging at any stage, including preclinical phases. Despite its impact on quality of life, CI often goes unrecognized, as clinical follow-up typically focuses on motor and sensory symptoms. Validated tools, such as the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and patient-reported outcomes (PROs), should be integrated into routine evaluations beyond the Expanded Disability Status Scale (EDSS). Objective: The objective of this study was to evaluate cognitive impairment and quality of life in patients with RRMS using the BICAMS and PROs. Methods: This cross-sectional, descriptive study included patients with RRMS under follow-up at a tertiary hospital in San Luis Potosí, Mexico. Participants underwent cognitive screening with the BICAMS battery and completed the MSQoL-54 (quality of life), FSMC (fatigue), and MSIS-29 (functional impact) scales. Statistical analyses included ANOVA, the Kruskal–Wallis test, and Pearson correlations. Results: Nineteen patients were evaluated (73.7% female, mean age 36.5 ± 8.9 years). BICAMS results showed variable cognitive performance, with no significant differences across treatment groups for processing speed (p = 0.222), verbal memory (p = 0.082), or visuospatial memory (p = 0.311). A significant correlation was found between verbal and visuospatial memory (r = 0.668, p = 0.002). Total quality of life differed significantly across treatments (F = 8.007, p = 0.029), with a strong correlation between overall quality of life and general health perception (r = 0.793, p < 0.001). Fatigue and MSIS scores showed no association with treatment. Conclusions: Cognitive impairment is common in RRMS and can be detected using brief assessment tools, such as the BICAMS. Incorporating cognitive screening and PROs into clinical practice is essential to guide comprehensive management. Full article

Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron failure and poor prognosis. This study performed a meta-analysis of gene expression datasets that compared bulk-processed post-mortem spinal cord from ALS and control (CTL) patients. The analysis included 569 samples (454 ALS, 115 CTL) from 348 individuals (262 ALS, 86 CTL). Patterns of differential expression bias, related to mRNA abundance, gene length and GC content, were discernable from individual studies but attenuated by meta-analysis. A total of 213 differentially expressed genes (DEGs) were identified (144 ALS-increased, 69 ALS-decreased). ALS-increased DEGs were most highly expressed by microglia and associated with MHC class II, immune response and leukocyte activation. ALS-decreased DEGs were abundantly expressed by mature oligodendrocytes (e.g., the MOL5 phenotype) and associated with myelin production, plasma membrane and sterol metabolism. Comparison to spatial transcriptomics data showed that DEGs were prominently expressed in white matter, with increased DEG expression strongest in the ventral/lateral white matter. These results highlight white matter as the spinal cord region most strongly associated with the shifts in mRNA abundance observed in bulk-processed tissues. These shifts can be explained by attrition of mature oligodendrocytes and an ALS-emergent microglia phenotype that is partly shared among neurodegenerative conditions. Full article

Cognitive impairment is a prevalent and disabling feature of multiple sclerosis (MS), significantly impacting patients’ quality of life (QoL) and psychological well-being. Despite its clinical relevance, there are currently no approved pharmacological treatments for cognitive deficits in MS, highlighting the need for effective non-pharmacological interventions. This narrative review explores evidence from studies evaluating the efficacy of cognitive re-education (CR) approaches (including traditional, group-based, computer-assisted, virtual reality, and innovative methods such as music therapy) on cognitive and QoL outcomes in people with MS. The findings demonstrate that while CR consistently influences cognitive domains such as memory, attention, and executive function, its effects on QoL are more variable and often depend on intervention type, duration, and individual patient characteristics. Notably, integrative approaches like virtual reality and music therapy show promising results in enhancing both cognitive performance and psychosocial well-being. Several studies report that cognitive gains are accompanied by improvements in mental health and functional QoL, particularly when interventions are tailored to individual needs and delivered within multidisciplinary frameworks. However, some interventions yield only limited or transient QoL benefits, underlining the importance of personalized, goal-oriented strategies that address both cognitive and psychosocial dimensions. Further research is needed to optimize intervention strategies and clarify the mechanisms linking cognitive and QoL outcomes. Full article

Background: Combined cognitive and exercise training improves exercise endurance, including submaximal muscular endurance. Its effects on maximal muscular strength have yet to be determined. Accordingly, we tested the effects of combined training on muscular strength (one repetition maximum, 1RM) and endurance (as many repetitions as possible, AMRAP). Methods: Resistance-trained adults (five males, three females) completed ten sessions (four testing, six training) over 4 weeks. In each testing session, they were assessed for bench press 1RM before they completed AMRAP at 50% of initial 1RM. In each training session, they performed five bench press sets (five repetitions at 80% current 1RM), with each set followed by a hard 5 min cognitive task (Time-Load Dual-Back or Color Multi-Source Interference). Ratings of perceived exertion (RPE) were averaged to provide a session RPE. At the end of each session, participants completed a Psychomotor Fatigue Threshold Test and rated mental fatigue. Results: ANOVAs (four testing sessions) showed that combined training increased 1RM (p < 0.001; averaging 8.0 kg or 11% from sessions 1–4) and AMRAP (p < 0.01; 5.1 repetitions or 22%). Moreover, training increased RPE (p < 0.05; 0.3 or 5%) and decreased mental fatigue ratings (p < 0.001; −1.2 or −49%) but did not affect Psychomotor Fatigue Threshold Test reaction times (p > 0.05; 2 ms or 0%). Conclusions: A 4-week training program that combined high-intensity cognitive and resistance exercise tasks improved maximal and submaximal resistance exercise performance. This pilot study provides preliminary evidence that high-intensity combined training can enhance muscular strength and endurance. Full article

Background: Chronic pain is closely associated with dysregulation of the autonomic nervous system, often reflected by reduced heart rate variability (HRV). While observational studies have demonstrated this association, the extent to which pain interventions modulate HRV and the impact of individual factors on HRV changes remain unclear. Objective: To evaluate the impact of pain interventions on HRV parameters through meta-analysis of randomized controlled trials (RCTs), and to examine whether intervention type and individual factors such as body mass index (BMI) moderate HRV responses. Methods: We conducted a systematic review of 23 RCTs and a meta-analysis of 21 RCTs (1262 subjects) involving patients with acute and chronic pain. HRV outcomes were extracted pre- and post-intervention. Both between-group (active vs. sham/control) and one-group (pre-post within active group) analyses were performed for time-domain indices—standard deviation of normal-to-normal intervals (SDNN), root mean square of successive differences (RMSSD), and percentage of successive normal-to-normal intervals > 50 ms (pNN50)—and frequency-domain indices—high-frequency (HF) and low-frequency (LF) components. Meta-regressions tested moderators including BMI, age, and pain phenotype. The protocol was registered in PROSPERO (CRD42023448264). Results: Twenty-three RCTs involving 1262 participants with a wide range of pain conditions were included. Meta-analysis of time-domain HRV parameters showed a trend toward improvement: SDNN (g = 0.435, p = 0.059) approached significance, while RMSSD (g = 0.361, p = 0.099) and pNN50 (g = 0.222, p = 0.548) showed smaller, non-significant effects. Frequency-domain analysis revealed a significant moderate reduction in the LF/HF ratio (g = −0.378, p = 0.003), suggesting a shift toward parasympathetic dominance. HF and LF showed small, non-significant changes. One-group meta-analysis confirmed significant improvements in vagally mediated HRV, with large effects for RMSSD (g = 1.084, p < 0.001) and HF (g = 0.622, p < 0.001), and a moderate effect for SDNN (g = 0.455, p = 0.004). Meta-regression identified BMI as a significant moderator: higher BMI was associated with attenuated improvements in HF and RMSSD and a slight shift toward sympathetic predominance. Conclusions: Pain interventions can significantly modulate autonomic function, as reflected in HRV improvements, particularly in vagally mediated indices. These effects are influenced by patient characteristics such as BMI. HRV may serve as a valuable biomarker for both treatment efficacy and autonomic recovery in pain management. In this context, HRV highlights its role as a biomarker for pain dysregulation and compensatory failure, reflecting shared top-down modulation between nociception and autonomic regulation. Full article

Glutamate and dopamine receptors play a crucial role in regulating synaptic plasticity throughout the sleep–wake cycle. These receptors form various heterocomplexes in synaptic areas; however, the role of this protein interactome in sleep–wake cycles remains unclear. Co-immunoprecipitation experiments were conducted to observe the complexation of the NMDA glutamate receptor (NMDAR) subunits GluN2A and GluN2B, metabotropic glutamate receptors mGluR1/5, and dopamine receptors (D1R and D2R) with the scaffold protein Homer in the synaptic membranes of the hippocampus after six hours of sleep deprivation (SD) in rats. Our findings indicate that the level of Homer in the GluN2A/mGluR1/D1R interactome decreased during SD, while the content of Homer remained unchanged in the GluN2B/mGluR1/D2R heterocomplex. Moreover, Homer immunoprecipitated a reduced amount of inositol trisphosphate receptor (IP3R) in the microsomal and synaptic fractions, confirming the dissociation of the ternary supercomplex Homer/mGluR1/IP3R during SD. Additionally, our findings indicate that SD increases the synaptic content of the AMPA receptor (AMPAR) subunit GluA1. Unlike AMPAR, NMDAR subunits in synaptic membranes do not undergo significant changes. Furthermore, the G-to-F actin ratio decreases during SD. Changes in the assembly of actin filaments occur due to the dephosphorylation of cofilin. These results suggest that SD causes the dissociation of the GluN2A/mGluR1/D1R/Homer/IP3R heterocomplex in synaptic and endoplasmic membranes. Full article

Prognostication of neurodevelopmental outcomes for neonates with hypoxic–ischemic encephalopathy (HIE) is primarily reliant on structural assessment using conventional brain magnetic resonance imaging in the clinical setting. Diffuse optical tomography (DOT) can provide complementary information on brain function at the bedside, further enhancing prognostic accuracy. The predictive accuracy and generalizability of DOT-based neuroimaging markers are unknown. This study aims to test the feasibility of prospectively recruiting and retaining neonates for 12 months in a larger study that investigates the prognostic utility of DOT-based biomarkers of HIE. The study will recruit 25 neonates with HIE over one year and follow them beyond NICU discharge at 6 and 12 months of age. Study subjects will undergo resting-state DOT measurement within 7 days of life for a 30–45-min period without sedation. A customized neonatal cap with 10 sources and eight detectors per side will be used to quantify cortical functional connectivity and to generate brain networks using MATLAB-based software (version 24.2). The Ages and Stages Questionnaires—3rd edition will be used for standardized developmental assessments at follow-up. This feasibility study will help refine the design and sample-size calculation for an adequately powered larger study that determines the clinical utility of DOT-based neuroimaging in perinatal brain injury. Full article

Peripheral nerve injury initiates a complex cascade of events coordinating immune responses, extracellular matrix (ECM) remodeling, and neuronal repair. While β2-microglobulin (B2M) is well known for its role in MHC class I-mediated antigen presentation and CD8⁺ T-cell differentiation, its potential contributions to non-immune processes remain underexplored. In this study, we investigated the role of B2M in peripheral nerve regeneration using a chronic constriction injury (CCI) model in wild-type and B2M-deficient (B2M-KO) mice. Flow cytometry, RNA sequencing (RNA-seq), and quantitative PCR (qPCR) were performed to assess T-cell subset dynamics and gene expression following injury. Flow cytometric analysis showed that CD3⁺CD4⁺ and CD3⁺CD8⁺ T-cell populations increased by day 7 post-injury. While CD3⁺CD4⁺ T-cell expansion occurred in both groups, a significant increase in CD3⁺CD8⁺ T cells was observed only in wild-type mice. RNA-seq analysis at 3 days post-injury—prior to substantial T-cell accumulation—revealed marked downregulation of ECM-related genes in B2M-KO mice, including collagens, matrix-associated proteins, and other key ECM components. KEGG analysis identified suppression of ECM–receptor interaction, PI3K-Akt, and TGF-β signaling pathways. qPCR confirmed reduced expression of Thbs1 in B2M-KO mice. These findings suggest that B2M plays a critical, CD8⁺ T-cell-independent role in regulating ECM dynamics and regenerative signaling during early nerve repair, expanding the conceptual framework of B2M’s function beyond classical immune roles. Full article

Background: We aimed to determine the utility of different electrodiagnostic (EDx) methods in diagnosing meralgia paresthetica (MP). Methods: Twenty-nine MP patients and 26 controls were included. Sensory nerve action potential (SNAP) and somatosensory evoked potential (SEP) of the lateral femoral cutaneous nerve (LFCN) and tibial SEPs were measured bilaterally. Results: At least one LFCN SNAP was unobtainable in 18 patients (62%) and two controls (8%). In all remaining 11 patients, SNAPs were abnormal at least unilaterally. By contrast, LFCN SEPs were recorded bilaterally in all subjects and were abnormal in 16 patients (sensitivity 48%). Patients’ tibial SEP latency was significantly larger than that of controls (p < 0.001). Conclusions: LFCN NCSs are superior to SEP in the evaluation of MP. However, SEP studies may be useful in old (>60 years) and obese subjects with unobtainable LFCN SNAP. Longer tibial SEP points to subclinical neuropathy in MP patients predisposed to LFCN entrapment. Full article

At the 14th Panhellenic Conference on Alzheimer’s Disease and 6th Mediterranean Conference on neurodegenerative diseases, we experienced an exciting journey, following the patient through the stages of their neurodegenerative disease: onset, diagnosis, progression, and eventual outcome. Fighting alongside him are researchers, doctors, psychologists, biologists, chemists, pharmacists, nurses, trainers, physiotherapists, speech therapists, occupational therapists, electrical engineers, architects, and other scientists, even actors and musicians, who aim to prevent and cure the disease, limit its progression, and improve the quality of life of those affected by it. Among them, their caregivers stand out as the most dedicated companions. In a collection of abstracts that reflects the work of all of the above, we capture the results of our biennial scientific meeting, which, thanks to them, is constantly evolving in a promising way. Full article