NeuroSci, Volume 6, Issue 3 (September 2025) – 9 articles

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