Background/Objectives: Cognitive stimulation and cognitive training are used as non-pharmacological approaches to support people living with Alzheimer’s disease, but Alzheimer-specific evidence is dispersed across heterogeneous intervention formats. This scoping review mapped structured cognitive stimulation and training interventions evaluated in people with mild-to-moderate Alzheimer’s disease and summarized the cognitive, emotional, functional, and follow-up outcomes reported. Methods: The review was conducted using the Joanna Briggs Institute methodology and reported according to PRISMA-ScR. PubMed, SciELO, PEDro, LILACS, and Google Scholar were searched on 24 February 2025 for studies published between January 2015 and 24 February 2025 in English, Portuguese, or Spanish. Intervention studies were eligible. Two reviewers independently screened records and charted data, with disagreements resolved by a third reviewer. Results: Of 352 records identified, five studies involving 245 participants were included. Interventions comprised virtual-reality cognitive stimulation, conventional cognitive training, group reminiscence therapy, a multicomponent music–reminiscence–reality-orientation intervention, and computerized cognitive training. In the limited technology-assisted evidence, statistically significant changes were reported in global cognition or selected memory, language, attention, and executive outcomes. Conventional cognitive training showed signals of improvement in initiative and temporary stabilization of memory, whereas reminiscence-based interventions primarily reported changes in depressive and neuropsychiatric symptoms. Where longer follow-up was available, benefits diminished over time. Conclusions: The mapped evidence suggests that structured cognitive stimulation and training may produce short-term, outcome-specific benefits in mild-to-moderate Alzheimer’s disease. Given the small and heterogeneous evidence base, these findings represent modality-related patterns within the included studies and should not be interpreted as evidence of comparative effectiveness.
Background: Peripheral nerve injury drives persistent remodeling of the dorsal root ganglion (DRG) microenvironment, but the cellular states and intercellular signaling mechanisms that sustain neuropathic pain remain poorly understood. Methods: Here, we integrated single-cell transcriptomics with histological, behavioral, and electrophysiological approaches to identify an interferon-responsive state in satellite glial cells (SGCs) of the DRG following spared nerve injury (SNI). Results: This state was distinguished by STAT1-associated interferon-responsive genes’ activation and enhanced chemokine signaling, particularly involving CXCL10 and its receptor CXCR3. These molecular alterations were accompanied by remodeling of intercellular communication among SGCs, sensory neurons, and immune cells. Pharmacological inhibition of STAT1 or blockade of CXCR3 not only reduced sensory-neuron hyperexcitability but also attenuated pain hypersensitivity and improved deficits in hindlimb weight bearing and gait after SNI. Conclusions: Collectively, our findings indicate that interferon-responsive SGCs (IFN SGCs) contribute to the maintenance of neuropathic pain by regulating STAT1-dependent chemokine signaling in the DRG. Targeting this signaling pathway may provide a therapeutic strategy for persistent neuropathic pain.
Background/Objectives: Prosopagnosia is characterised by severe difficulties recognising facial identity. While many self-identified developmental cases fail to meet widely used cognitive task-based criteria for inclusion in research, the extent to which this is an issue in acquired prosopagnosia is unknown. We therefore assessed the sensitivity of widely used inclusion cutoffs and face-processing tests in 14 self-identified British acquired prosopagnosia cases. Results: We found the −2 SD cutoff did not detect impairment in 9/11 (82%) individuals on the Cambridge Face Perception Test, 5/11 (45%) of cases on the Cambridge Face Memory Test, and 2/14 (14%) on the Famous Faces Test. Requiring impairments on two memory tasks at −2 SD or −1 SD resulted in at most 8/14 (57%) and 5/14 (36%) of cases not meeting the criteria, respectively. A more liberal approach, which additionally allowed for inclusion using a single test score at −2 SD, performed better by excluding at most 2/14 (14%). Given that the Famous Faces Test alone at the −2 SD level performed identically to our liberal approach, we suggest it could be used if an objective assessment is deemed necessary. Conclusions: We extend the recent suggestions in the literature that self-identified prosopagnosia cases who fail to meet cognitive test criteria warrant further investigation to explain the reasons for their self-reported status. We therefore advocate a more inclusive approach to prosopagnosia research.
Background: Characteristic circuitry in superficial layers of neocortex has been repeatedly shown to carry out lateral inhibition: excitatory–inhibitory interactions within a specific anatomical design. Methods: We provide simulation and formal analyses of the emergent operations of this circuitry. Results: Derived directly from anatomical circuit layout and physiological activation patterns, we show that this circuit carries out two distinct effective procedures on its inputs: categorization, and component analysis; moreover, we show that each procedure’s emergence is dependent on a single biological parameter: the relative strength of local feedback inhibitory cells. We characterize the detailed nature of both the biological activity and the emergent statistical operations and evaluate them in the context of extensive related literature in statistics, machine learning, and computational neuroscience. Conclusions: Very notably, the two emergent operations (clustering and component analysis) have not previously been shown to contain deep mathematical connections to each other, let alone to each be derivable from a single overarching algorithmic precursor that has clustering and component analysis as two special cases. The identification of that deep formal mathematical connection, and its arrival directly from a detailed biological circuit, represents a rare instance of novel mathematical relations arising from biological analyses.
Background/Objectives: Ischemic stroke (IS) induces substantial phenotypic remodeling within the neurovascular unit, and pericytes have been implicated in the cellular responses to ischemic injury. However, the molecular characteristics and regulatory mechanisms underlying pericyte phenotypic remodeling after ischemic stroke remain incompletely understood. Methods: In this study, we used PDGFR-β-CreERT2; ZsGreen lineage-tracing mice and a middle cerebral artery occlusion (MCAO) model to characterize the temporal changes in PDGFR-β-lineage cells following ischemic injury. In vitro, human brain vascular pericytes (HBVPs) exposed to oxygen–glucose deprivation/reperfusion (OGD/R) and subsequently maintained in neurobasal medium to examine ischemia-related phenotypic changes. The involvement of KLF2-associated signaling was further investigated using KLF2 knockdown approaches. Results: We observed increased expression of Nestin in PDGFR-β-lineage cells during the early post-ischemic period, followed by the emergence of subsets co-expressing GFAP or DCX during the subacute stage. These findings indicate the acquisition of neuroglial- and neuronal-associated molecular features, rather than providing definitive evidence of lineage conversion or functional differentiation. The expression of these markers declined at later stages, whereas PDGFR-β-lineage cells were also associated with vascular remodeling during the recovery phase. In vitro, OGD/R-treated HBVPs exhibited increased expression of DCX, MAP2, and NeuN. KLF2 knockdown attenuated these molecular changes. Consistently, OGD/R was associated with increased KLF2, phosphorylated ERK1/2, and MAP2 expression, whereas KLF2 knockdown reduced ERK1/2 phosphorylation and MAP2 expression. These findings suggest that KLF2 is associated with ERK1/2 activation and MAP2 expression during ischemia-related phenotypic remodeling of PDGFR-β-lineage cells. Conclusions: Overall, our results identify transient neuroglial- and neuronal-associated molecular changes in pericytes after ischemic injury and provide evidence for an association between KLF2 and ERK1/2–MAP2 signaling in this process, while further studies are required to determine whether these changes represent stable lineage conversion or functional neuronal differentiation.
Introduction: Obsessive–compulsive disorder (OCD) is clinically heterogeneous, and the neurocognitive characteristics of autogenous and reactive obsessional presentations remain insufficiently understood. This study compared neurocognitive performance and exploratory clinical–cognitive associations in strictly classified autogenous and reactive OCD presentations. Methods: This cross-sectional study included 67 outpatients with OCD classified as having reactive (n = 35) or autogenous (n = 32) presentations based on clinical evaluation and the Yale–Brown Obsessive Compulsive Scale Symptom Checklist. Patients with mixed presentations were excluded. Executive functioning, attentional control, cognitive flexibility, and verbal learning and memory were assessed using the Wisconsin Card Sorting Test, Stroop Test, and Rey Auditory Verbal Learning Test. Depressive symptoms were assessed using the Beck Depression Inventory. Results: The groups were comparable in age, age at OCD onset, illness duration, and overall OCD symptom severity, whereas depressive symptom scores were higher in the autogenous group. Neuropsychological performance was broadly comparable between groups. The autogenous group showed better RAVLT-6 performance, reflecting recall after interference, with a nominally significant unadjusted group difference. This difference remained significant in an exploratory ANCOVA adjusting for depressive symptoms, education, and age at OCD onset, although it did not survive false-discovery-rate correction. Exploratory within-group correlations were observed; however, formal Fisher’s r-to-z comparisons revealed no significant differences between groups. Conclusions: Strictly classified autogenous and reactive OCD presentations showed broadly similar neuropsychological profiles, with a preliminary group difference in recall after interference. Within-group correlations should be interpreted as exploratory and hypothesis-generating rather than as evidence of presentation-specific clinical–cognitive mechanisms. Replication in larger samples is warranted.
Background/Objectives: Schizophrenia causes substantial disability and reduced life expectancy, while symptoms frequently persist despite antipsychotic treatment. Long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) have been proposed as adjunctive therapy because of their anti-inflammatory and neurobiological properties. This systematic review and exploratory meta-analysis evaluated the efficacy and safety of adjunctive n-3 PUFAs in adults with schizophrenia. Methods: The review followed PRISMA 2020 and was prospectively registered in PROSPERO (CRD420251178174). PubMed, Web of Science, Scopus, Ovid, CENTRAL, ClinicalTrials.gov, and ICTRP were searched without language or date restrictions. Randomized controlled trials of n-3 PUFAs added to antipsychotic therapy were included. Risk of bias was assessed using RoB 2. PANSS scores were pooled as mean differences (MDs) using an inverse-variance random-effects model with REML estimation; dichotomous outcomes were pooled as risk ratios (RRs) using an inverse-variance random-effects model with the DerSimonian–Laird estimator or a fixed-effect model with the Mantel–Haenszel method, with a 0.5 continuity correction for zero cells. Results: Of 301 records, 10 randomized controlled trials met the eligibility criteria. Where sufficient comparable data were available, exploratory meta-analyses were conducted. Only one trial provided strict intention-to-treat final PANSS total data. A two-trial sensitivity meta-analysis (116 participants) showed no significant reduction in final PANSS total scores (MD −5.04, 95% CI −14.16 to 4.08; I2 = 55.8%). Results were also nonsignificant for clinical response (RR 1.62, 95% CI 0.27–9.78), all-cause discontinuation (RR 1.32, 95% CI 0.31–5.65), and discontinuation due to adverse events (RR 1.35, 95% CI 0.38–4.81). Extreme sensitivity analyses remained nonsignificant. Subgroup signals involving clozapine or baseline fatty-acid status were not consistently replicated. Evidence was limited by few studies, attrition, and substantial heterogeneity in n-3 PUFA formulation, dose, duration, population, and concomitant antipsychotic therapy. Conclusions: Current evidence does not support routine adjunctive n-3 PUFAs for symptom reduction in adults with schizophrenia. The available data cannot identify an optimal EPA/DHA formulation, dose, or responsive clinical subgroup; larger biomarker-informed trials are needed.
Background/Objectives: Optic nerve injury involves heterogeneous neuronal and microenvironmental responses that may require sequential, state-dependent intervention. BioEdge-RGC was developed as a transcriptomics-informed computational benchmark for transferring a globally planned model-predictive-control policy to compact regional neural models operating with incomplete observations and reduced communication. Methods: Public mouse optic-nerve-crush transcriptomic datasets were summarized into seven retinal ganglion cell modules and eight retinal environment modules and fused into a 15-dimensional temporal reference state for a 16-region, five-step simulator. A candidate-constrained MPC expert was approximated by a central neural teacher and local, neighbour-aware, and coordinated regional students trained using hybrid knowledge distillation or direct MPC supervision. Missing observations, severe simulated injury, INT8 quantization, local parameter perturbations, and an independent GSE229033 transcriptomic plausibility assessment were evaluated. Results: The central teacher retained 99.90% of the MPC objective, and the coordinated distilled student retained 99.69% of teacher performance while reducing modeled communication from 5520 to 1080 bytes per episode. The coordinated-versus-local mean-objective difference was +0.000053 and did not meet the predefined +0.008 threshold; direct MPC supervision performed at least as well as hybrid distillation. The principal objective-based conclusions were preserved across all nine local parameter conditions, whereas the coordinated failure-rate advantage was not parameter-robust. In GSE229033, six of seven modules changed in the predefined favorable direction, but the oriented composite bootstrap interval included zero. Conclusions: Compact regional neural policies reproduced MPC performance with minimal objective loss and substantially lower modeled communication. The external transcriptomic analysis provided limited plausibility support for the RGC state orientation, while neither analysis validated simulator dynamics, controller efficacy, biological treatment effects, or clinical applicability.
Background: Mild traumatic brain injury (mTBI) may rapidly alter neurocognitive function and has been associated with an increased risk for post-traumatic stress disorder (PTSD). However, neuroimaging investigations during the acute post-trauma phase remain sparse. We previously reported greater left anterior insular cortex (aIC) activation during the cognitive appraisal of fearful versus neutral emotional faces in survivors who did and did not exhibit probable PTSD at 3 months, but not at 2 weeks, after a motor vehicle collision (MVC). Given previous studies suggesting that mTBI may lead to increased cortical activation in the early post-trauma period, we hypothesize that aIC activation within 2 weeks post-MVC may be elevated among probable PTSD survivors who sustained an mTBI compared to those who did not sustain mTBI. Methods: In this secondary hypothesis-driven analysis, previously reported task-related activation at both 2 weeks and 3 months after trauma was extracted from the aIC region of interest and compared among groups of survivors diagnosed with probable PTSD at 3 months with (n = 5) and without (n = 11) mTBI in the emergency department. An exploratory analysis of change over time included two time points and additional groups of survivors without probable PTSD with (n = 10) and without (n = 12) mTBI. Results: At 2 weeks, aIC activation was significantly greater in the probable PTSD with mTBI group than in the probable PTSD without mTBI group (mean = 0.125, SD = 0.053 vs. 0.014, SD = 0.111) (Welch’s t (13.86) = 2.71, two-sided p = 0.017). aIC activation in probable PTSD survivors with and without mTBI was not significantly different at 3 months after MVC. The time and time × group interactions were not significant in brain activation and post-traumatic stress symptoms, but within-group tests suggest that decreases in post-traumatic stress symptoms over time were significant in groups without mTBI. Conclusions: These preliminary results are consistent with the hypothesized association between mTBI and greater aIC activation to negative emotional stimuli in the early post-trauma period among survivors with probable PTSD, but do not support post-trauma brain changes in survivors with mTBI, probable PTSD, both conditions, or neither condition. These preliminary findings warrant further investigation into the relationship between mTBI and probable PTSD-related cortical alterations during the acute post-trauma period.
Background: Neuropathic pain (NP) is a debilitating chronic condition driven by maladaptive neuroimmune interactions in the spinal cord, with microglia playing a central pathological role. Electroacupuncture (EA) has shown analgesic effects in clinical and preclinical studies, but the microglia-centered mechanisms underlying these effects remain incompletely integrated. This review aims to provide a comprehensive mechanistic synthesis of how EA modulates microglia-associated neuroinflammatory pathways in neuropathic pain. Methods: This systematic search-narrative review used systematic search and screening procedures to identify English-language animal studies published between 2015 and 2025 in PubMed, CINAHL, Web of Science, and Cochrane Library. Twenty-six animal studies investigating EA effects on microglia-associated signaling pathways in neuropathic pain models met the inclusion criteria. Because of substantial heterogeneity in neuropathic pain models, EA parameters, molecular endpoints, and behavioral outcomes, findings were synthesized narratively, and no meta-analysis was performed. Results: The reviewed evidence revealed four convergent mechanistic categories through which EA modulates microglial activity: (1) attenuation of purinergic microglial activation via downregulation of IRF8, P2X4R, P2X7R; (2) suppression of innate immune sensing and inflammasome pathways, including TLR4/MyD88/NF-κB and NLRP3 signaling; (3) inhibition of downstream inflammatory amplification through p38 MAPK, PI3K/AKT, and COX-2 pathways; and (4) promotion of pro-resolution mechanisms involving IL-10/β-endorphin, PD-L1, GRK2/TREM2/DAP12, α7nAChR, GLP-1R, and GABAergic signaling. Conclusions: The available preclinical evidence suggests that EA modulates multiple microglia-associated pathways, attenuating inflammatory signaling while enhancing selected pro-resolution mechanisms. These findings provide a mechanistic framework for understanding EA-induced analgesia in neuropathic pain and highlight microglial signaling networks as important targets for future experimental and translational investigation.
Chronic pain is a major global health burden and often remains difficult to treat with current therapies, which frequently provide incomplete relief and may cause systemic side effects. As essential organelles in eukaryotic cells, mitochondria facilitate ATP synthesis and serve as key regulators of calcium homeostasis and apoptosis. Evidence points to mitochondrial dysfunction not merely as a result of trauma, but as a fundamental factor in why pain becomes persistent. On the other hand, the endoplasmic reticulum (ER) is more than just a structural component of the cell; it is a multi-functional organelle responsible for protein quality control, including folding and degradation, as well as lipid production and calcium signaling. ER dysfunction is a primary driver of various pathologies, such as cardiovascular disease, cancer, and neurodegenerative disorders. The organelle’s ability to execute its vital functions is strictly dependent on sufficient levels of ATP. Because mitochondrial and ER functions are closely interconnected through calcium exchange, ATP-dependent protein homeostasis, oxidative stress, and mitochondria-associated ER membranes, their dysfunction may act together to amplify nociceptive sensitization and pain chronification. In this review, we summarize current evidence linking mitochondrial dysfunction, ER stress, and ER-mitochondrial crosstalk to the pathogenesis of chronic pain and discuss their potentials as therapeutic targets.
BACKGROUND:Global cerebral ischemia initiates a cascade of pathophysiological changes that progressively impair subsequent perfusion of brain tissue. Some authors have proposed that adequate cerebral perfusion becomes impossible after approximately 10-30 min of global ischemia. However, the extant evidence base for this threshold and its variations across studies has not yet been systematically examined. OBJECTIVE:To synthesize the literature on post-ischemic cerebral perfusion success as a function of ischemia duration. METHODS:We searched PubMed (11 February 2026) for studies of global cerebral ischemia in animal or human models that reported quantitative or categorical measures of perfusion quality. Eligible studies included those assessing perfusion via restoration of blood flow, via external perfusion of non-blood solutions, and/or via tracer injection following reperfusion. Studies of focal ischemia were excluded. Data extracted included species, ischemia duration, temperature during ischemia, ischemia model, perfusate type, and perfusion quality assessment method. The perfusion quality outcome was operationalized as either the average percentage of brain tissue perfused or the percentage of brains in a group that was adequately perfused. Study quality was assessed using a custom domain-specific checklist. RESULTS:We included 60 studies with 192 study arms reporting on the perfusion of the brains of rabbits, rats, pigs, dogs, cats, and humans. Studies differed in the model of ischemia, the perfusate, the perfusion parameters, the quality assessment methods, and other factors. Longer ischemia was associated with lower perfusion quality, but substantial heterogeneity across studies prevented identification of a consistent sharp temporal threshold. Some studies found that at least partial perfusion was possible after longer periods. Within-study dose-response curves were more consistent than the pooled cross-study pattern. CONCLUSIONS:How long the brain remains perfusable after circulatory arrest has not yet been definitively established. On average, perfusion quality clearly declines rapidly as the duration of global cerebral ischemia increases. However, some studies, often using interventions such as hypothermia or vasopressors, have reported at least partial perfusion of the brain even after 30 or 60 min of ischemia. Moreover, at least partial perfusion has been reported in human brain banking studies after postmortem intervals of several hours or days in some donors. Limitations of this review include substantial heterogeneity in study methods and outcome measures, which precluded formal meta-analysis. Future research may benefit from more thorough and precise measures of perfusion quality.
Objective: Depressive symptoms exist on a continuum in the general population, yet the underlying neurobiological mechanisms, particularly the interplay between resting-state networks and task-evoked social cognitive responses, remain elusive. Methods: Leveraging the Human Connectome Project (HCP) dataset, we included 867 participants. With depression scores as the independent variable and age/sex as covariates, we systematically examined associations with sleep quality, negative emotions, sensory scores, gray matter volume (GMV), fractional amplitude of low-frequency fluctuations (fALFF), multi-seed resting-state functional connectivity (rsFC), as well as brain activation and behavioral performance during working memory, emotion recognition, social cognition, relational reasoning, language comprehension, and gambling tasks. The statistical threshold was set at voxel-level p < 0.001 (uncorrected) combined with cluster-level FWE correction at p < 0.05. Results: (1) Depression scores were positively correlated with sleep disturbances, negative emotions (anger/fear), and pain. (2) In resting-state, depression scores negatively correlated with ventral striatum (VS)-cerebellum/parahippocampal gyrus/fusiform rsFC, yet positively correlated with pregenual anterior cingulate cortex (preACC)-supplementary motor area (SMA) rsFC. (3) In task-fMRI, only the social task showed a positive association with task accuracy and regional activation in bilateral pre/postcentral gyri, superior temporal gyri, left middle frontal gyrus, and SMA/paracentral lobule. Conclusions: Elevated depression scores are linked to a pattern that may reflect relative decoupling between reward and perceptual systems, along with enhanced connectivity in cognitive control circuits. Socially, high scorers exhibit a pattern suggestive of compensatory hypervigilance, accompanied by enhanced behavioral performance. This study provides multidimensional evidence for the dimensional neural representation of depressive symptoms.
Background/Objectives: Depression and anxiety disorders exhibit significant clinical heterogeneity, which complicates diagnosis and treatment. This study investigated whether tripartite interactions between biological sex, the serotonin transporter gene promoter region (5-HTTLPR), and brain-derived neurotrophic factor (BDNF) G196A polymorphisms explain specific symptom-level variations. Methods: A community sample of 271 Australian adults was genotyped for common 5-HTTLPR (short/long) and BDNF (G/A) variants. Participants completed self-reported measures of anxiety (SAS), depression subtypes (SDS; clinical content scales), and psychological resilience (CDRISC). Morning salivary cortisol, BMI, and substance use were assessed as potential confounds. Statistical analyses utilised a three-way factorial ANCOVA to test for interactions on raw scores, controlling for age. Significant omnibus interactions were decomposed via planned stratified ANCOVAs within each 5-HTTLPR stratum. Results: The BDNF GA genotype exerted opposite effects on anxiety and anhedonia depending on sex and 5-HTTLPR background. In females, GA was associated with increased symptoms on an ss background, whereas in males, GA was associated with increased symptoms on an ll background. These effects were highly specific to anxiety and anhedonic depression, while depressed mood, cognitive, and somatic subtypes remained unaffected. Findings were independent of cortisol, BMI, smoking, alcohol use, and psychological resilience. Conclusions: The findings reveal a complex, sex-dependent genetic interaction that selectively influences anhedonia and anxiety. They should be interpreted in the context of modest subgroup sizes following genotype stratification and require replication in larger independent cohorts. Nonetheless, this study highlights the value of considering sex-stratified genetic backgrounds and symptom specificity to advance personalised precision medicine in psychiatry.
Background: Acute confusional state, or delirium, is a common neuropsychiatric disorder in older adults, particularly in emergency departments. It is associated with high morbidity and mortality, as well as difficult detection. Its early identification is crucial to prevent complications and improve prognosis. This study aims to identify and analyze available strategies for the early diagnosis of delirium in geriatric patients in emergency departments. Methods: A literature review and meta-analysis were conducted between 2020 and 2026 using the PubMed, Scopus, Web of Science, CINAHL, and Cochrane databases (PRISMA 2020). To estimate the prevalence of patients with delirium in emergency departments, a meta-analysis was performed using Stats Direct statistical software (Version 4). Methodological quality was evaluated according to the Oxford Centre for Evidence-Based Medicine levels of evidence. Results: Eleven studies were included, demonstrating that delirium in emergency departments is highly prevalent among older adults, particularly those with dementia, polypharmacy, or functional impairment. The 4AT scale was the most frequently used screening tool, notable for its strong sensitivity. Hypoactive delirium emerged as the most common subtype and carried the poorest prognosis. Furthermore, its presence was associated with longer hospital stays, increased complications, and higher mortality rates, while a lack of training among healthcare staff continues to limit early detection. The meta-analysis detected no publication bias and revealed a 20.6% prevalence of delirium among patients in emergency departments. Conclusions: One in five patients attending the emergency department presents with delirium. Delirium in geriatric emergency care demands a structured clinical response grounded in prevention, early detection, and professional training. Integrating validated diagnostic tools and reinforcing the role of nursing professionals are key to improving patient outcomes and safety.
Background: Performance estimates in motor-imagery electroencephalography (MI-EEG) can depend strongly on how observations are partitioned for training, model selection, and testing. Random sample- or window-level splitting may place data from the same participant in different folds and therefore does not answer the same question as evaluation on previously unseen participants. Methods: We evaluated a previously developed Gramian angular field-phase-locking value (GAF-PLV) classifier on the retained full cohort (N=105) using binary left-versus-right MI and leave-one-subject-out cross-validation (LOSO). Separately, a predefined, outcome-independent subset (N=30) was used for a matched sensitivity analysis of eight classifiers, binary and four-class tasks, and three validation strategies: random five-fold cross-validation, LOSO, and nested LOSO with subject-grouped inner model selection. Results: In the full-cohort GAF-PLV analysis, mean accuracy was 58.07% ± 8.27% and Macro-F1 was 53.48% ± 11.19%, with substantial between-subject variability. In the predefined matched subset, performance estimates and numerical model rankings changed across validation strategies. For example, the numerically highest binary-accuracy model was ShallowConvNet under random five-fold cross-validation, DeepConvNet under LOSO, and ATCNet under nested LOSO. Conclusions: Random within-cohort classification and generalisation to previously unseen subjects are distinct evaluation targets. MI-EEG reports should state the cohort, partition unit, validation design, and model-selection procedure. Rankings in the multi-model analysis are conditional on the predefined 30-subject subset and common 0.4 s input setting and are not presented as definitive full-cohort or architecture-optimal rankings.
Background/Objectives: Gait impairment and reduced handgrip strength are common in Parkinson’s disease (PD), but their relationship remains unclear. This study examined whether associations between handgrip force and gait reflect PD-specific impairment or broader functional capacity. Methods: In this cross-sectional study, 45 individuals with PD and 51 healthy older adults completed unilateral maximal isometric handgrip testing and overground gait assessment at preferred and maximal speed. Handgrip variables included peak force (PF), rate-of-force development (RFD), and impulse. Gait speed, cadence, and step length were recorded. Results: PF was significantly associated with gait speed and step length in both groups, especially under maximal-speed conditions. RFD and impulse were not significantly associated with gait performance in either group. Compared to controls, participants with PD showed poorer gait performance, with lower preferred walking speed and shorter step length in both gait conditions. Within the PD group, PF was lower on the more-affected side than on the less-affected side, whereas most RFD and impulse variables showed no side differences. Conclusions: Maximal handgrip strength, but not upper-limb RFD or impulse, was associated with key gait outcomes in both PD and healthy older adults. These findings suggest that handgrip strength may reflect general functional capacity rather than a PD-specific neuromuscular mechanism and support its use as a practical clinical indicator of mobility-related function.
BACKGROUND:Falls among older adults are linked to central nervous system deterioration and executive function deficits. OBJECTIVES:This study evaluates the feasibility of a gamified EEG-based neurofeedback intervention combined with adaptive working-memory training, targeting neural processes associated with attentional inhibition and working memory in older adults, and characterises, as exploratory secondary outcomes, the oscillatory and functional measures that change over the training period. METHODS:Twenty healthy older adults (65.0±3.3 years) completed a 24-session longitudinal training programme. The intervention combined real-time alpha-band neurofeedback (NF), targeting left-frontal alpha activity associated with inhibitory control, with an adaptive N-back task engaging theta-band working memory processes. Behavioural outcomes included the Colour Trail Making Test A and B (CTMT-A/B), the Berg Balance Scale short form (BBS-3P), and the four-item Dynamic Gait Index (DGI-4). EEG was recorded at the Early, Middle, and Later stages to characterise training-related neural and behavioural changes. RESULTS:The programme proved highly deliverable: adherence was 100% across all 24 sessions, no session was terminated early, and no severe adverse events occurred. Participants acquired control of the trained signal, with left-frontal alpha power rising across training at the neurofeedback target site, and frontal theta increased bilaterally under adaptive working memory load, consistent with the reduced hemispheric asymmetry characteristic of this age group. Scores changed in the direction of improvement on all four behavioural measures; however, functional changes were small, and cognitive changes cannot be separated from repeated-testing effects. Of sixteen candidate EEG-behaviour associations, four showed moderate-to-large participant-level coefficients and were retained as candidate associations: right-frontal alpha with balance (r=-0.64) and with gait adaptability (r=-0.48), and bilateral frontal theta with processing speed (r=-0.53 and -0.51). Several associations that appeared strong when observations were pooled across stages did not survive participant-level modelling, indicating that repeated-measures methods are needed in this literature. All associations are exploratory, uncorrected for multiplicity, and reported with effect sizes and confidence intervals. CONCLUSIONS:The gamified neurofeedback and working-memory training programme was feasible, well tolerated, and fully adhered to in a supervised experimental setting by community-dwelling older adults and was accompanied by measurable modulation of the targeted frontal rhythms. This study delivers a shortlist of candidate EEG features, with the effect-size estimates needed to power a confirmatory trial. Because the design is single-arm, both functional scales approached ceiling, and the same test forms were repeated at each stage, practice effects cannot be separated from intervention effects, and these associations are hypothesis-generating; a sham-controlled trial in a fall-prone population is the appropriate next step.
A pro-inflammatory state, characterized by elevated levels of pro-inflammatory cytokines, is frequently reported among individuals presenting with primary first-episode psychosis (FEP), particularly those with environmental risk factors such as maternal infections and early childhood traumatic experiences. These findings suggest that immune system disturbances may play a crucial role in the onset of psychotic disorders. Building on this, cytokines may contribute to the risk of FEP from the stage of neurodevelopment, where they can induce aberrant changes in neuronal growth. During early childhood, these cytokine-mediated processes may disrupt normal neuronal maturation and lead to brain alterations that increase vulnerability to primary psychotic disorders. Furthermore, pro-inflammatory cytokines exhibit strong bidirectional modulatory interactions with dopamine, a key neurotransmitter implicated in the pathogenesis and persistence of psychosis. Notably, these cytokines may also influence the clinical presentation and severity of psychosis. In addition, antipsychotic medications can partially modulate cytokine levels, and this modulation has been correlated with the efficacy of antipsychotics in treating various psychotic symptoms. Frequently reported cytokines in this context include interleukins (IL-1β, IL-2, IL-4, IL-6, IL-8, and IL-10), tumour necrosis factor-α (TNF-α), and interferon-gamma (IFN-γ). We conducted a non-systematized literature search on Google Scholar and PubMed for studies looking at cytokines in primary psychotic disorders during FEP. In this narrative review, we provide an overview of the literature on immune dysregulation in FEP, with a particular emphasis on cytokines.
Background/Objectives: This study proposes Diffusion Inverse Filtering (DIF), a spatially informed transformation designed to counteract spatial smoothing in functional-connectivity representations (i.e., functional networks) and thereby enhance their discriminative power for pattern recognition. Spatial smoothing in electroencephalography (EEG) signals and derived features, such as functional connectivity, is largely attributed to volume conduction. Functional connectivity has been increasingly used in brain-computer interface (BCI) studies; however, this spatial smoothing can introduce spurious connections and distort functional-connectivity patterns. Methods: DIF approximates spatial smoothing in functional connectivity, which is potentially associated with volume conduction, as a diffusion-like process and applies a regularized inverse operation to transform the observed functional networks into networks with enhanced discriminative representations. The effectiveness of DIF in enhancing the discriminative power of functional-connectivity representations in pattern recognition was evaluated using emotion recognition as the paradigm task, which is a critical component of BCI systems. Experimental results show that DIF generally improves emotion-recognition performance relative to the originally observed functional networks under electrode-sparsification conditions, with the most consistent improvements observed for Pearson correlation coefficient (PCC) estimation. Both signal-level processing, which operates on EEG signals before functional-connectivity estimation, and function-al-connectivity-level transformations, including graph signal processing (GSP)-based filtering applied after functional-connectivity estimation, were included as comparators. Under this framework, DIF is also considered a functional-connectivity-level transformation, but does not rely on a GSP framework. Results: The performance of DIF demonstrates the potential of functional-connectivity-level transformation as a complement or alternative to signal-level processing for enhancing connectivity-based pattern recognition. Overall, DIF improves classification performance and offers strong compatibility with modern functional-connectivity-based BCI pipelines.
