Brain Sciences doi: 10.3390/brainsci16101123

Authors: William Mendez Alejandra Bohórquez Ximena Bohórquez Oscar Bohórquez William J. Shelton Edgar G. Ordóñez-Rubiano

Background: Diffusion MRI tractography can support patient-specific neurosurgical planning, but implementation may be limited by workflow complexity, software requirements, and resource constraints. We describe Tractometric®, a diffusion tractography software engine developed for integration with the Surgimetric® neuronavigation planning environment. Methods: Tractometric® was developed through a multidisciplinary, iterative co-design process involving neurosurgeons and neuroimaging specialists. The software uses a modular Model–View–Controller architecture implemented in Python (version 3.11) and supports multiple diffusion reconstruction models, deterministic and probabilistic tracking, patient-specific and atlas-derived regions of interest (ROIs), visualization, and interoperable export. The present study was designed as a technical development and preliminary clinical feasibility report. Technical workflow characteristics were described retrospectively across 30 cases, while preliminary clinical feasibility was explored in 8 patients undergoing tractography-assisted surgical planning. Intraoperative direct cortical and subcortical electrical stimulation was used as a qualitative clinical reference rather than as a formal diagnostic-accuracy test. Results: Tractometric® implemented a complete workflow from diffusion data loading and preprocessing to tract reconstruction, filtering, visualization, and export to Surgimetric®. The 30-case technical series illustrated variation in processing time and user interaction according to operator experience, reconstruction model, registration, ROI strategy, and manual cleaning. In 8 preliminary clinical cases, reconstructed motor and language pathways were qualitatively concordant with positive intraoperative stimulation findings. No formal sensitivity, specificity, spatial agreement, or test–retest reproducibility estimates were calculated. Conclusions: Tractometric® provides an integrated technical workflow for diffusion tractography and neuronavigation planning and was feasible to implement in a preliminary clinical series. The current data support technical feasibility and workflow integration, but do not establish anatomical accuracy, reproducibility, clinical efficacy, or cost-effectiveness. Independent, prospective validation using standardized acquisitions, predefined tractography parameters, quantitative spatial metrics, and systematic intraoperative mapping is warranted.

Brain Sciences doi: 10.3390/brainsci16101122

Authors: Mehmet Celal Kefeli Mehmet Hamamcı

Background/Objectives: Obsessive–compulsive disorder (OCD) severely impacts both patients and their families. This study aimed to compare sleep quality, insomnia severity, and daytime sleepiness in partners of individuals with OCD against a healthy control group. Additionally, it investigated how patient OCD severity and partner depression and anxiety symptoms relate to these sleep outcomes. Methods: This cross-sectional case–control study included 104 spouses of OCD patients (46 females, 58 males; mean age 37.92 ± 8.22 years) and 100 healthy control spouses (48 females, 52 males; mean age 38.40 ± 7.93 years), all married for at least one year. Spouses completed the Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and Insomnia Severity Index (ISI). Patient OCD severity was assessed using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Results: OCD spouses exhibited significantly higher anxiety and depression scores than controls. Poor sleep quality was reported by 57.7% of OCD spouses versus 32% of controls. After adjusting for confounders (age, body mass index, education, sex, marriage duration), OCD spouses demonstrated significantly worse sleep quality and higher daytime sleepiness. Female spouses experienced a significantly more severe burden of insomnia and sleep disturbances than males. Independent of group, higher depression scores correlated with poorer sleep parameters. Furthermore, patient OCD severity positively correlated with all partner sleep scale scores. Conclusions: We conclude that partners of individuals with OCD are particularly vulnerable to complex sleep difficulties, including poor sleep quality and daytime fatigue. By broadening our clinical focus to address these hidden sleep issues and psychological needs, we may help mitigate secondary health risks and improve the overall well-being of affected families.

Brain Sciences doi: 10.3390/brainsci16101121

Authors: Ahmed Najjar Yasir Hassan Elhassan

Background/Objectives: Trigeminal neuralgia (TN) disproportionately affects older adults, in whom medication intolerance, drug interactions, comorbidities, and limited physiological reserve may complicate management. This structured narrative review examines the evidence concerning the selection, effectiveness, durability, and complications of neurosurgical treatments for medication-refractory TN in older adults. Methods: PubMed was searched from database inception through 1 July 2026 using terms related to TN, older age, and neurosurgical treatment. Eligible publications evaluated microvascular decompression (MVD), radiofrequency lesioning, percutaneous balloon compression (PBC), glycerol rhizotomy, or stereotactic radiosurgery (SRS). Titles and abstracts were screened using predefined eligibility criteria, followed by further assessment of potentially eligible publications and standardized data extraction. Studies reporting separately extractable outcomes for defined older populations were classified as direct evidence; mixed-age studies without age-stratified outcomes were treated as indirect evidence and used primarily for procedural and comparative context. Results: The principal search identified 1324 unique records, and 22 publications were included: six provided direct older-adult evidence and 16 provided indirect contextual evidence. Direct evidence was largely limited to MVD and PBC. In selected older adults, MVD was associated with favorable and potentially durable pain outcomes, whereas PBC generally provided rapid initial pain relief. However, differences in outcome definitions, assessment times, follow-up, and patient selection precluded direct comparison. No included study provided separately extractable outcomes for adults aged ≥65 years undergoing radiofrequency lesioning, glycerol rhizotomy, or SRS. GRADE certainty was low or very low for most procedure-specific and comparative conclusions. Conclusions: Favorable observational outcomes in selected older patients suggest that chronological age alone should not automatically exclude an otherwise appropriate patient from consideration for MVD. Treatment should be individualized according to TN subtype, physiological reserve, comorbidity and anesthetic risk, imaging findings, pain urgency, previous interventions, baseline facial sensation, and patient preferences.

Brain Sciences doi: 10.3390/brainsci16101120

Authors: William R. Swindell Aminah Ali Alfredo Iacoangeli Salman Bhai

Background: ALS is characterized by motor neuron failure with potential neurocognitive comorbidity. Cortical neurons, and their support cells, exhibit pathologic features, some of which have been identified in post-mortem transcriptome studies of the cortex from ALS patients and control subjects. These studies, however, have utilized varying technologies with few attempts to reconcile findings. Methods: This study used meta-analysis to evaluate differential gene expression (ALS vs. control) from 16 prior transcriptome studies utilizing multiple technologies (microarray, bulk RNA-seq or snRNA-seq). Normalization with GC content correction was used to mitigate downstream biases impacting differential expression. Results: Approximately one-third of protein-coding genes (5930 of 16,579) exhibited significant between-study effect size heterogeneity (FDR < 0.05), which was frequently associated with variation in average post-mortem interval. Nonetheless, we identified 269 and 273 differentially expressed genes (DEGs) with relatively consistent increased or decreased expression in the ALS cortex, respectively (FDR < 0.05 with SMD ≥ 0.20 or SMD ≤ −0.20). ALS-increased DEGs were associated with transcription (RNA polymerase), cell signaling (TGF-beta, PI3K), interneurons, microglia, endothelial cells, and deep laminar layers (L5, L6). ALS-decreased DEGs were associated with transcription (RNA polymerase), glial cells (astrocytes, oligodendrocytes) and the L1 layer. There was significant overlap between DEGs from the ALS cortex and those previously identified from ALS spinal cord and blood. Conclusions: These findings highlight signaling pathways, cell types and cortical layers associated with robust changes in ALS cortex gene expression. Our results illustrate the importance of meta-analysis as a tool for understanding between-study heterogeneity and identifying repeatable findings across technologies.

Brain Sciences doi: 10.3390/brainsci16101119

Authors: Liangliang Yi Yutong Liu Haibo Zhou Chun Lin Yaru Yang Xinxin Xiang Huiyingzi Li Manling Huang Xinling Wang

In the original publication [...]

Brain Sciences doi: 10.3390/brainsci16101118

Authors: Takeo Nakanishi Mamoru Fukuchi

Background/Objectives: Prostaglandin E2 (PGE2) is a known inflammatory mediator. It is produced by cyclooxygenase (COX)-1/2 during inflammation via four distinct G protein-coupled receptors (EP1–EP4). PGE2 is involved in the development of brain diseases induced by acute and chronic stresses, although the mechanisms regulating PGE2 concentration remain unclear. This review summarizes the mechanisms in relation to the activity of PGE2, focusing on membrane transporters in neuroinflammation and central nervous system (CNS) disorders. Methodology: A literature search was conducted using the PubMed database to evaluate the roles and dynamics of PGE2 in the central nervous system (CNS) under acute and chronic stress conditions. Results: PGE2 produced during inflammation acts via four receptors (EP1–EP4). These receptors mediate diverse and complex pathways in neurons and glial cells (microglia and astrocytes), influencing pathologies involving acute and chronic inflammation such as cerebral ischemia, Alzheimer’s disease, Parkinson’s disease, and neuropathic pain. EP1, EP2, and EP3 generally promote neurotoxicity, inflammation, and blood–brain barrier disruption, whereas EP4 predominantly exerts anti-inflammatory and neuroprotective effects. Furthermore, membrane transporters, particularly SLCO2A1 (also known as PGT) and MRP4 (encoded by ABCC4), regulate local PGE2 concentrations and facilitate its clearance across the blood–brain and blood–cerebrospinal fluid barriers. Understanding these transporters and receptors provides insights into controlling PGE2 dynamics in CNS diseases. Conclusions: Growing evidence indicates that membrane transporters play critical roles in regulating these levels in the brain, and elucidating the expression profiles of functional PG transporters may offer novel therapeutic strategies for refractory inflammation-based CNS diseases.

Brain Sciences doi: 10.3390/brainsci16101117

Authors: Mario Treviño Oscar Arias-Carrión

Background/Objectives: Individual spikes are difficult to track through recurrent cortical circuits, where convergence, divergence, and nonlinear dynamics rapidly transform activity. However, the statistical properties of an input may remain detectable even when individual spike identity does not. We asked whether the spatiotemporal spectral slope of colored noise remained detectable as activity propagated through a simulated cortical network. Methods: We built a biologically inspired, four-layer recurrent spiking network based on mouse primary visual cortex. A drifting grating was embedded in colored noise spanning five spectral conditions (violet, blue, white, pink, and brown), while noise contrast and stimulus drive were varied independently. The network operated in an asynchronous-irregular regime, and population spectra were characterized using their aperiodic component. Results: Population activity changed systematically with the spectral slope of the noise rather than separating into discrete color representations. A continuous decoder recovered the spectral exponent β from population activity. Decoding generalized to new noise images the decoder had never seen. Removing all synaptic connections left L4 decoding unchanged, showing that the spectral signal there did not require recurrent interaction; recurrence instead determined how much of it reached the other layers. A feedforward model that received the same stimulus but lacked cellular dynamics did not support decoding. Decoding was highest in L4, whereas the univariate effect of β on firing rate peaked one stage downstream, in L2/3, and increasing noise contrast improved spectral discriminability. Recruiting feedforward inhibition in L4 did not change decoding accuracy. Conclusions: Recurrent cortical dynamics can transform input activity while retaining information about its statistical structure. This information was distributed across multiple dimensions of population activity and remained recoverable across cortical layers. Tracking population statistics rather than individual spikes provides a tractable framework for studying how recurrent circuits transform and retain input activity.

Brain Sciences doi: 10.3390/brainsci16101116

Authors: Jianxiang Zhao Yang Zhang Kaiyu Wang Feng Chen Han Chen

Background and Objectives: Elevated intracranial pressure (ICP) is common to many encephalopathies, but the evolution of quantitative electroencephalography (qEEG) indices along a pressure gradient—and their relative suitability for early warning—have not been systematically compared. In this exploratory study we established a stepwise, steady-state rabbit model of graded intracranial hypertension and screened candidate early-warning features against prespecified criteria. Materials and Methods: Eight male New Zealand rabbits were studied; two were excluded—one for circulatory failure during catheterization and one for refractory status epilepticus that reached a humane endpoint—leaving six that completed the protocol. Repeated small-volume inflation of a left parenchymal water balloon was used to define five windows: baseline (BL; ICP < 10 mmHg), 15–20, 25–30 and 35–40 mmHg, and an end stage (END). Eight-channel EEG was recorded synchronously, and δ, θ, α and β power, together with the amplitude-integrated EEG (aEEG) upper margin, lower margin and bandwidth, were computed. Seven candidate features and three criteria (evolution timing, individual consistency and strength of association with ICP) were fixed before analysis; selection stability was assessed by leave-one-rabbit-out (LORO) cross-validation. Results: ICP rose in a controlled manner from 5.43 ± 1.09 to 35.93 ± 1.48 mmHg (Kendall W = 0.96), without systematic changes in respiratory mechanics. As ICP increased, absolute θ and α power declined progressively (ρ = −0.77 and −0.53), whereas absolute δ power did not increase and its rising relative share merely reflected redistribution after the loss of faster activity. The three aEEG components changed asynchronously: the lower margin shifted downward early and persistently (ρ = −0.87 with ICP; W = 0.86), whereas the upper margin changed only terminally and bandwidth showed no consistent direction. Concurrently, MAP rose through the Cushing response, with heart-rate slowing, but the rise was insufficient and CPP fell from 64.78 to 41.24 mmHg, approaching the rabbit lower limit of autoregulation (~50 mmHg CPP) only in the later windows. Because ICP and CPP were tightly coupled within animals, their independent effects on the EEG could not be separated. In leave-one-rabbit-out cross-validation, the lower margin was selected in five of six folds, with a median out-of-sample ρ of −1.00 (a discrete value based on four windows per animal). Conclusions: In this exploratory study in a small cohort (n = 6), qEEG indices evolved asynchronously along the ICP gradient; the aEEG lower margin appeared earliest and remained relatively stable across leave-one-rabbit-out folds, making it a candidate early-warning feature worthy of priority validation. However, because rising ICP and falling CPP were tightly coupled and could not be separated in this model, its early decline cannot be uniquely attributed to either ICP elevation or hypoperfusion. Its alarm threshold and early-warning value still require confirmation in larger independent cohorts with simultaneous CPP and cerebral blood flow monitoring.

Brain Sciences doi: 10.3390/brainsci16101115

Authors: Kholoud Ahmad Bokhary Weaam Abdullah Alrashed Fahad Ali Algahtani Mansour Mohammad Almufarrej Murad Omar Almomani Hala Khalid Jamous Abdulrahman Faisal Albloushi Hanan Khalid Mofty

Background/Objectives: The aim of this study was to investigate the effect of different auditory conditions on pattern-reversal visual evoked potential (PVEP) responses among healthy adults. Methods: This repeated-measure design with a fixed baseline and randomized order of the two auditory conditions was conducted at the Retina Clinic, Ophthalmology Department, Tertiary Hospital in Riyadh, Saudi Arabia. Healthy adults with no systemic or ocular diseases aged 20–60 years were included. All participants underwent comprehensive visual and ocular assessment, including best-corrected visual acuity (BCVA), slit-lamp examination, optical coherence tomography (OCT), screening audiometry, and a PVEP test conducted under three auditory conditions: silence, Quran recitation, and music exposure. P100 latency and amplitude were recorded using 1° and 0.25° stimulation sizes. Statistical analysis was performed using non-parametric statistics. A p-value of less than 0.05 was considered statistically significant. Results: Significant differences in PVEP amplitude responses were observed across auditory conditions, particularly at the 1° stimulation size. The Friedman test demonstrated significant amplitude differences at the 1° stimulation size (χ2 = 16.379, p < 0.001), with silence producing adjusted significantly higher amplitudes compared with Quran recitation and music exposure (p = 0.001 and p = 0.003), respectively. Significant positive correlations were identified between BCVA and P100 amplitude at Quran exposure (r = 0.178, p < 0.05) only at the 0.25° stimulation size. Conclusions: The stimulus size can be sensitive in revealing auditory-related changes in different retinal areas of functional visual pathway alterations. In comparison to baseline (silence), which generally produces the highest amplitudes, both auditory conditions (Quran recitation and music) were associated with lower P100 amplitude, while no significant difference was observed between Quran recitation and music.

Brain Sciences doi: 10.3390/brainsci16101114

Authors: Francesco Monaco Annarita Vignapiano Ernesta Panarello Stefania Landi Felice Spista Rossella Bonifacio Daniela Falchetta Alessandra Marenna Maria Laura Mignone Luca Steardo Gennaro Sosto Giulio Corrivetti

Background: We investigated, in an exploratory cross-sectional design, whether EDS-R score at admission showed adjusted cross-sectional associations with FT3, LDH, and ALT in patients with anorexia nervosa (AN) in residential treatment. Methods: A total of 164 patients with AN (first admission per patient) (AN-R: n = 122; AN-BP: n = 42; mean BMI 15.7 ± 1.7 kg/m2; 98.2% female) admitted consecutively to a specialist residential unit were included. Biochemical parameters were assessed within 48 h of admission using fully automated, internationally standardised analytical methods. FT3 was measured by electrochemiluminescence immunoassay (ECLIA) on automated immunoassay platforms, in accordance with standard immunometric procedures. ALT and LDH were measured by kinetic enzymatic (UV) methods following IFCC recommendations, using high-throughput clinical chemistry analysers. All analyses were performed in the core laboratory (Corelab) of the ASL Salerno hospital network, with internal and external quality control programmes in place. Exercise dependence severity was measured using the EDS-R Multivariable OLS and logistic regression analyses were conducted, adjusting for age, BMI, disease duration, and AN subtype. Results: Among 16 biochemical parameters examined, FT3 and LDH showed the largest Spearman correlations with EDS-R score, though neither survived Bonferroni correction for 16 simultaneous tests (threshold: p < 0.0031) (FT3: ρ = −0.224, p = 0.007; LDH: ρ = +0.244, p = 0.006). In multivariable regression, EDS-R score was independently associated with lower FT3 (β = −0.040, 95% CI [−0.072, −0.008], p = 0.016, n = 144) and higher LDH (β = +14.56, 95% CI [3.78, 25.35], p = 0.009, n = 124), while BMI was not significant in either model. By contrast, BMI was the sole significant predictor of ALT (β = −0.078, 95% CI [−0.136, −0.021], p = 0.008, n = 154), with the EDS-R score being non-significant (β = 0.019, p = 0.604). Binary logistic regression confirmed an association between EDS-R score and low-T3 syndrome (FT3 < 2.30 pg/mL): OR = 1.290 (95% CI [1.043–1.596], p = 0.019). Conclusions: In this exploratory cross-sectional study, EDS-R score showed adjusted associations with lower FT3 and higher LDH, but not ALT, at residential admission in AN, independent of BMI, age, AN subtype, and illness duration. These hypothesis-generating, cross-sectional findings cannot be interpreted as establishing prediction, causation, biomarker validity, or clinical utility. Prospective replication is required before any clinical implications can be considered.

Brain Sciences doi: 10.3390/brainsci16101113

Authors: Andrea Di Piero Alessia Bonavita Laura Piccardi Maria Casagrande Cecilia Guariglia

Background/Objectives: episodic memory refers to the ability to place events within a specific spatial and temporal context, making its association with navigation unsurprising. Incidental episodic memory involves encoding and retrieving information without explicit instruction, a common process in everyday life whose sensitivity to emotional valence warrants further investigation. Methods: sixty-three college students (mean age = 25 years; 28 females) completed two versions of the same task, differing only in the instructions given: one directed attention to emotionally charged images encountered along a route through a city environment; the other directed attention to the route itself. Results: Mann–Whitney tests on uncontaminated first-session conditions and linear mixed models all indicated an advantage of intentional over incidental encoding for the spatial localization of emotional images. The advantage was valence-selective, present for negative and neutral stimuli but absent for positive ones. Signal detection analyses indicated that intentional instructions selectively increased sensitivity (d′). The response criterion also shifted, but in opposite directions for negative and neutral stimuli, so the sensitivity gain cannot be attributed to a uniform change in response bias. The effect was domain-specific: sensitivity for the spatial localization of emotional images increased, whereas sensitivity to navigational route did not improve. Conclusions: positive material thus appears to be encoded spontaneously, with potential implications for rehabilitation and clinical assessment.

Brain Sciences doi: 10.3390/brainsci16101112

Authors: Nicola Montemurro Marina Carbone Rosanna Maria Viglialoro Francesco Simi Giulia Zari Sara Condino Francesco Acerbi

Background: Augmented reality (AR) may support neuronavigation by displaying patient-specific anatomical information and surgical plans directly within the surgeon’s view of the operative field. Reliable registration between virtual content and patient anatomy remains a critical requirement. Patient-specific templates offer a non-invasive registration strategy, but positioning errors at the facial support may propagate to the surgical target. Methods: We performed a preclinical feasibility evaluation of the Video and Optical See-Through Augmented Reality Surgical System (VOSTARS), a head-mounted AR platform for surgical navigation, using patient-specific template-based registration. Six craniotomies were planned using CT datasets from two fresh-frozen human cadaver heads and two corresponding cranial phantoms were generated from the same datasets. Visualization accuracy, reported as target visualization error (TVE3D), and trajectory-tracing performance were first assessed on the phantoms. The complete AR-guided planning-to-execution workflow was subsequently evaluated on the corresponding cadaveric specimens by assessing containment of the AR-traced craniotomy trajectories within patient-specific inspection windows corresponding to a tolerance of ±1.5 mm. Results: In the phantom experiments, the mean TVE3D calculated across five of the six planned craniotomies was 1.64 mm, with individual mean values ranging from 1.33 to 1.91 mm. Craniotomy 1 had a mean TVE3D of 6.92 mm; the higher error was attributed to incorrect phantom assembly. Four of the six craniotomy trajectories traced on the phantoms under AR guidance showed complete overlap with the corresponding virtual trajectories. For the other two, trajectory overlap was 62.5% and 67.0%, with a mean deviation from the planned trajectory of 0.79 mm in both cases. In the cadaveric experiments, the complete AR-guided planning-to-execution workflow was completed for all six planned craniotomies. Two of the six AR-traced craniotomy trajectories were completely contained within the inspection windows corresponding to the predefined ±1.5-mm tolerance. Of the remaining four trajectories, two were partially contained, one was minimally contained and one was not contained within the inspection window. Conclusions: This study supports the technical feasibility of a patient-specific AR workflow for craniotomy guidance across anatomically different cranial approaches. In this exploratory preclinical study, VOSTARS enabled the translation of patient-specific preoperative planning directly to the operative field and provided AR guidance during the initial stages of cranial surgery. The cadaveric findings also highlight template fit and positioning as important determinants of workflow performance. Further quantitative and comparative validation is required before clinical implementation.

Brain Sciences doi: 10.3390/brainsci16101111

Authors: Estefania Espitia-Bautista Cinthia García-Luna Paulina Soberanes-Chávez Javier Berjón Elena Álvarez-Salas Patricia de Gortari

Background: The high worldwide prevalence of obesity, with palatable food hyperphagia as its main etiological factor, justifies studying neural circuit alterations under conditions such as chronic stress and exposure to high-energy diets, which elevate palatable food preference and body weight. Short-term intake of palatable food, acting as a satiety stimulus, activates melanocortin-4 receptor-expressing neurons in the paraventricular hypothalamic nucleus (PVNMC4R) and those from the caudo-lateral region of the parabrachial nucleus (PBN). It remains unclear whether stress targets this circuit, reducing satiety, or whether 2-week palatable diet exposure alters anorexigenic cells’ responsiveness to stress, such as MC4R, pro-thyrotropin-releasing hormone (pro-TRH), vesicular glutamate transporter 2 (vGlut2), and corticotropin-releasing factor (CRF)-expressing neurons. Methods: Male adult Wistar rats subjected to isolation stress or group-housed and fed with chow or palatable food for 2 weeks were fasted and then re-fed for 2 h with chow or chocolate milk. Using immunohistochemical analyses, we determined the circuit responsiveness to stimuli, identifying the cFos-indicated activation of anterior and medial PVN-MC4R, PVN-pro-TRH, PBN-vGlut2, and PBN-CRF-expressing cells. We also analyzed VTA tyrosine hydroxylase and accumbal type-2 dopamine receptor expression, where PBN neurons’ activity impacts and modulates the food-rewarding properties of DAergic circuit responses. Results: PVNMC4R+cFos cells responded differently depending on food type, diet duration, combination, and nature of stimuli (homeostatic/hedonic); their responsiveness pattern was similar to PBNvGlut2+cFos and different from anterior PVNpro-TRH+cFos cells. Conclusions: The results suggest that 2-week palatable diet exposure changes satiety-circuit cells’ responsiveness, showing enhanced activity when stress and palatable food are combined, which seemed associated with their higher food intake.

Brain Sciences doi: 10.3390/brainsci16101110

Authors: Waad Hasan Alkathiri Saeed Ali Alqahtani Abdlatif Ahmed Alghaiheb Bandar Nasser Aljafen Bander Balkhi

Background: This study aimed to estimate treatment retention rates for levetiracetam monotherapy in patients with epilepsy and to characterize treatment failure in this population. Methods: A retrospective cohort study included 769 adult patients with epilepsy between 2015 and 2024 at a tertiary hospital in Saudi Arabia who initiated levetiracetam monotherapy. The date of levetiracetam initiation was designated as the index date, and patients were followed from that point until treatment failure or censoring. Treatment failure was defined as either discontinuation of levetiracetam because of adverse events or the addition of another antiseizure medication due to insufficient seizure control. Kaplan–Meier survival analysis was used to estimate the probability of remaining on levetiracetam monotherapy over the follow-up period. Differences in patient characteristics were assessed between the treatment-failure and success groups using Student’s t-test for continuous variables and either the chi-square test or Fisher’s exact test for categorical variables. Results: Of the 769 patients who initiated levetiracetam monotherapy, 143 (18.55%) experienced treatment failure during the 10-year follow-up period. The overall mean time to levetiracetam treatment failure was 93.58 months. The 25th percentile time to treatment failure was 95 months (95% CI: 60.167–103.133). The median time to treatment failure was not reached. Females comprised 50.3% of the cohort, with no significant difference in sex distribution between groups (p = 0.136). Patients in the treatment-failure group were younger (39.85 ± 16.88 vs. 45.76 ± 19.48, p = 0.0003), had higher estimated Creatinine clearance (CrCl) (132.19 ± 57.83 vs. 118.50 ± 61.15, p = 0.0150), and had predominantly generalized seizure onset (40.56% vs. 33.71%, p = 0.0182) compared with the treatment-success group. Conclusions: Levetiracetam monotherapy demonstrated sustained long-term treatment retention when used as first-line therapy in adults with epilepsy.

Brain Sciences doi: 10.3390/brainsci16101109

Authors: Justyna Krzepota Krzysztof Wrześniewski Joanna Basiaga-Pasternak Marek Cieśluk Aneta Łuć Tomasz Sacewicz Dorota Sadowska

Objectives: The aim of this study was to analyse cognitive functioning and temperamental traits among young adults differing in their level of engagement in video gaming. Methods: The analysis included 67 male students from the Józef Piłsudski University of Physical Education in Warsaw, Branch Campus in Biała Podlaska. Based on average daily gaming time, participants were classified as frequent players (n = 22; mean age 22.45 ± 2.40 years; 6.29 ± 6.07 h/day) or casual players (n = 45; mean age 21.60 ± 1.96 years; 0.94 ± 0.95 h/day). Cognitive functioning was assessed using the Reaction Test (RT), Signal Test (ST), and Determination Test (DT) from the Vienna Test System. Temperament was measured with the Formal Characteristics of Behaviour–Temperament Inventory. Results: Frequent players showed a trend toward shorter reaction time in RT/S3 (U = 356; p = 0.064). In the Signal Test, they demonstrated significantly fewer omitted reactions, more correct responses, higher focused attention, and better total results (all p < 0.01). Regarding temperament, frequent players scored significantly lower on briskness (p = 0.034) and rhythmicity (p = 0.021) than casual players. Conclusions: The present exploratory study suggests a nuanced relationship between media engagement, specific cognitive performance, and temperamental traits. Frequent players demonstrated a robust advantage in parameters of sustained attention, alongside a marginal descriptive trend toward faster psychomotor responses compared to casual players. Regarding temperament, frequent players were characterised by significantly lower self-reported briskness and rhythmicity, while no statistically significant between-group differences were detected for endurance, activity, or emotional reactivity. Crucially, because our data are cross-sectional and the frequent players group comprised exclusively esports students, these differences cannot be interpreted as definitive causal effects or direct consequences of gaming intensity alone.

Brain Sciences doi: 10.3390/brainsci16101108

Authors: Xiaoqin Lian Peiyi Wang Chao Gao Yelan Wu

Background: Automatic sleep staging is fundamental to sleep architecture analysis and the diagnosis of sleep disorders. Sleep staging requires jointly modeling complementary information across modalities, multi-scale physiological features, and temporal relationships across consecutive epochs. In target epoch prediction from consecutive epochs, non-target epochs primarily provide contextual information, but their ground-truth labels remain underused as auxiliary supervision. Methods: We propose CSPT-SleepNet, an automatic sleep staging framework integrating center-driven sequence supervision with multimodal pyramid token encoding. A Multimodal Pyramid Token Encoder extracts hierarchical multi-scale features from electroencephalogram, electrooculogram, and electromyogram signals, followed by intra-modal, cross-modal, and inter-epoch modeling for center-epoch classification. During training, the center epoch receives primary classification supervision, while non-center epochs receive weaker auxiliary supervision based on their ground-truth labels, providing stage-informed contextual support for the prediction target. Results: In subject-independent cross-validation on Sleep-EDF-20, Sleep-EDF-78, and ISRUC-S3, CSPT-SleepNet achieved accuracy (ACC)/macro F1 (MF1) scores of 87.93%/83.53%, 85.81%/80.87%, and 84.06%/82.86%, respectively. In a separate controlled comparison on Sleep-EDF-20, center-driven sequence supervision improved ACC and MF1 by 0.60 and 0.91 percentage points, respectively, over equal-weight sequence supervision. The full model has 3.418 million trainable parameters and requires 397.10 million floating-point operations for an input sequence of nine 30-s epochs. Conclusions: CSPT-SleepNet provides an effective framework for center-epoch sleep staging from consecutive multimodal inputs. Nevertheless, N1 recognition remains challenging, with F1 scores ranging from 55.3% to 62.7% across the three datasets.

Brain Sciences doi: 10.3390/brainsci16101107

Authors: Adi Ahmetspahic Razim Mahmutagic Bekir Rovcanin Ibrahim Omerhodzic Edina Dozic Deniz Bulja Mirza Pojskic Kenan I. Arnautović

Objectives: Adult posterior cervical spinal dysraphism, including meningocele (MC), myelomeningocele (MMC), and myelocystocele (MyCC) is exceptionally rare and remains insufficiently characterised. This study aimed to conduct the first systematic review of the literature on adult cases and report an additional illustrative case. Methods: A PRISMA 2020 systematic review of PubMed/MEDLINE, Web of Science and Scopus was conducted (PROSPERO CRD420261426944). Data were extracted at case level, grouped by the lesion label used by the original authors, and synthesised narratively. Results: Nineteen studies (18 case reports and one case series) described 23 adults (median age 24 years; 19 male): 16 MC, one MyCC and six MMC. An objective neurological abnormality was documented in 14 of 21 examined patients. Nineteen patients were operated on; among 17 with a classified outcome, ten improved, five were intact and two were stable, and none were reported worse (median follow-up 12 months). The additional case was a 62-year-old man with a radiologically diagnosed C4–C5 lesion most consistent with MMC and no objective neurological deficit, managed by observation (3 months of follow-up). Conclusions: The evidence is sparse, heterogeneous and prone to publication bias, and it is insufficient to establish natural history, optimal management or the relative merits of surgery and observation. Standardised terminology, multicentre registries and long-term follow-up are needed.

Brain Sciences doi: 10.3390/brainsci16101106

Authors: Patrick Quercia Steeve Morin

Objectives: Developmental dyslexia is a heterogeneous neurodevelopmental condition in which motor, perceptual, attentional, respiratory, and sleep-related differences have been reported alongside reading difficulties. This Perspective proposes a proprioception-centered sensorimotor coherence framework to consider potential interactions among these domains across the day–night cycle. Methods: This hypothesis-generating narrative Perspective traces the progressive development of the proposed framework from clinical observations to experimental investigations and subsequent refinement of a clinical examination based on functional responses to sensory modulation. No systematic review or new cohort analysis was undertaken. The examination explores three principal domains—tonic-motor regulation, spatial localization, and multisensory integration—together with respiratory and sleep-related factors. Sensorimotor modulation includes ocular, oral, plantar, respiratory, manual, and ergonomic approaches selected according to their observed functional effects across domains. A clinical case illustrates the application of this approach. Results: Experimental studies conducted over nearly two decades in our INSERM laboratory objectively investigated postural regulation, proprioceptive acuity, spatial localization, multisensory processing, and action representation in developmental dyslexia. More recent exploratory clinical studies extended the investigation to respiration and sleep. Taken together, these observations suggest that proprioception-centered sensorimotor coherence may represent one functional level through which motor, perceptual, respiratory, attentional, and learning-related processes interact across the day–night cycle as learning develops and continues. Conclusions: The proposed framework is a working hypothesis rather than an established causal model or a validated treatment for developmental dyslexia. It provides a complementary embodied perspective and identifies clinically observable and experimentally testable relationships that warrant further investigation, including through controlled studies examining the contributions of individual sensory and functional components.

Brain Sciences doi: 10.3390/brainsci16101105

Authors: Susan Allen Fiona Knott Amanda Branson Shelly J. Lane

Background/Objectives: To address the needs of mothers of children with sensory integration differences, we need a greater understanding of their experience and what they find helpful. This study aimed to explore the impact of child sensory integration differences on daily activities and relationships and to identify the relationships, media, and parent interventions mothers regard as helpful and further support that is desired. It compared perceptions of mothers of autistic and non-autistic children. Methods: A single cohort descriptive observational survey study. Questions were generated from previous in-depth interviews. Results: Mothers of autistic children versus non-autistic children both with sensory integration differences reported greater impact on school and community activities and on some relationships. No differences were observed in factors mothers identified as helpful, such as media resources and relationships. Most mothers in the full cohort reported that child sensory integration differences had a pervasive impact on everyday activities and relationships for both mother and child. Supportive relationships, media, social media, and direct interventions to mothers were helpful. Mothers wanted more practical and emotional support for themselves, education of others, and specialist support for their child. Conclusions: Mothers of children with sensory integration differences identified social and professional relationships, media, and parent intervention as helpful, supporting a variety of intervention strategies.

Brain Sciences doi: 10.3390/brainsci16101104

Authors: Claudio Lucchiari Maria Elide Vanutelli

A quarter-century of neuroaesthetics and cultural epidemiology has established that engagement with art is broadly and durably health-bearing, yet the finding sits awkwardly within the paradigm through which it is usually read: a tacit exposure model, in which art is beneficial input, the person is its recipient, and benefit is modelled on the dose received. Translated into practice as social prescribing, now expanding on an evidence base that the field’s own systematic reviews describe as weak, this model inherits the grammar of the receptor and the individual patient, and leaves an anomaly it cannot explain. The epidemiological signature of cultural engagement is that of a cultivated capacity distributed across a coupled system rather than of an administered agent; it survives adjustment for socioeconomic position, health status, health behaviours, and social connectedness, though not the residual confounding we treat as its most serious rival explanation. We advance the hypothesis that aesthetic reception and creative production are two directions of a single generative regime of brain function: neurally instantiated but neither neurally nor individually bounded, scaling from a transient individual state to dyadic and group-level creativity and to the enactive coupling of organism and environment. Cultural vitality thereby becomes a candidate infrastructural determinant of health, adjudicated by three stated criteria and tested through seven falsifiable predictions. Whether the reclassification holds is an empirical question, and one that neuroscience is morally compelled to help resolve before policy commitments harden.

Brain Sciences doi: 10.3390/brainsci16101103

Authors: Mateusz Bargielski Edyta Adamska-Patruno Adam Krętowski Jan Kochanowicz Alina Kułakowska Monika Chorąży

Background: Drug-resistant epilepsy (DRE) is frequently accompanied by cognitive impairment across multiple neuropsychological domains. Objectives: We aimed to synthesize contemporary evidence on cognitive impairment, neurobiological correlates, potentially modifiable clinical factors, and treatment-related cognitive outcomes in predominantly adult populations with DRE. Methods: PubMed/MEDLINE and Web of Science were searched for studies published between January 2017 and September 2026, supplemented by citation searching. Twenty-two studies comprising 2359 participants were included, of whom 1616 (68.5%) had confirmed DRE. Eligibility was independently verified by a second reviewer, and risk of bias was assessed independently by two reviewers using design-specific Joanna Briggs Institute tools. Owing to substantial clinical and methodological heterogeneity, a structured qualitative synthesis was performed. Results: Cognitive impairment involved memory, executive function, attention, language, and processing- or psychomotor-speed-related performance. Cognitive performance was associated with distributed neurobiological abnormalities and with clinical factors including sleep quality, antiseizure medication exposure, and seizure burden. Treatment- and surgery-related cognitive outcomes varied across studies. The predominantly observational evidence and substantial heterogeneity limited causal inference. Conclusions: Cognitive impairment in DRE is heterogeneous and extends beyond memory dysfunction. Current evidence supports multidomain neuropsychological assessment and is compatible with a distributed network framework, although causal mechanisms remain uncertain.

Brain Sciences doi: 10.3390/brainsci16101102

Authors: Michela Barichella Antonio Natale Elena Contaldi Luca Magistrelli Emanuele Cereda Carlotta Bolliri Maria Carmela Macchione Federica Invernizzi Daniela Calandrella Ioannis Ugo Isaias Gianni Pezzoli

Background/Objectives: Twins discordant for Parkinson’s disease (PD) share genetic background and early-life exposures, offering a model for non-genetic determinants of disease. We aimed to evaluate longitudinally the mortality, clinical and lifestyle features, nutritional status and dietary habits of a cohort of PD-discordant twins, with specific attention to the monozygotic (MZ) subgroup. Methods: One hundred and eight subjects from 54 PD-discordant twin pairs (26 MZ, 28 dizygotic [DZ]), with genetically confirmed zygosity, were assessed at baseline (T0) and after 10 years by telephone interview (T1; 33 pairs), using Kaplan–Meier/Cox survival analyses, a clinical and lifestyle history questionnaire, body mass index (BMI), and a food frequency questionnaire (FFQ). Results: Ten-year mortality was markedly higher in PD (31.5% vs. 5.6%; HR 6.83), with all MZ deaths occurring in the affected twin. Constipation was more frequent in PD at both time points (T0 p = 0.004; T1 p = 0.011). Comorbidities, smoking, weight and BMI did not differ within pairs. Preserved-fish intake was stably lower in PD (T0 p = 0.021; T1 p = 0.004); fruit intake was lower in PD at baseline (MZ, p = 0.001) but higher at follow-up (p = 0.029). Conclusions: The mortality difference persisted despite no detected within-pair differences in BMI and comorbidities, consistent with a major contribution of PD itself. Preserved-fish intake remained stably lower in affected twins, whereas increased fruit intake at follow-up may reflect adaptation to constipation; these exploratory dietary findings warrant confirmation.

Brain Sciences doi: 10.3390/brainsci16101101

Authors: Abdulkadir Kankılıç İbrahim Başar Ferhat Kurtoğlu Ali Fahir Özer

Background/Objectives: Third-ventricle colloid cysts are benign but can cause obstructive hydrocephalus and sudden deterioration, and the role of microsurgical transcallosal resection in the endoscopic era remains debated. We evaluated clinical, radiological, and functional outcomes of microscope-assisted interhemispheric transcallosal resection and the effect of preoperative hydrocephalus on recovery. Methods: This retrospective, observational, single-center study analyzed 30 patients with symptomatic, histopathologically confirmed colloid cysts operated on between June 2015 and February 2021, divided into hydrocephalus (n = 16) and non-hydrocephalus (n = 14) groups. Functional outcomes were assessed using the Karnofsky Performance Status (KPS) scale. Results: Mean KPS improved from 65.3 ± 21.0 to 92.0 ± 11.0 (p < 0.001). Patients with hydrocephalus had lower preoperative Glasgow Coma Scale (GCS; p = 0.022) and KPS (p = 0.048) scores, comparable postoperative KPS (p = 0.208), and greater KPS improvement (p = 0.012). Four patients (13.3%) needed external ventricular drainage; none required a permanent shunt. Four patients (13.3%) developed new persistent neurological events (seizures, n = 3; memory impairment, n = 1). No recurrence occurred over a median follow-up of 7.0 years. Conclusions: Microscope-assisted interhemispheric transcallosal microsurgical resection was associated with significant KPS improvement, no permanent shunt requirement, and no recurrence. Despite the increasing use of endoscopic techniques, microsurgical approaches remain valuable due to direct visualization, bimanual dissection, and the potential for durable gross-total resection; however, neurocognitive outcomes were not assessed, and prospective studies are needed.

Brain Sciences doi: 10.3390/brainsci16101100

Authors: Ayşe Kurtulmuş Beyzanur Ereğli Betül Nas Dönmez Aynur Görmez

Background: Immune dysregulation has been implicated in the pathophysiology of autism spectrum disorder (ASD). Soluble urokinase plasminogen activator receptor (suPAR) is a stable biomarker of chronic immune activation that has not previously been investigated in ASD. We compared circulating suPAR and C-reactive protein (CRP) concentrations in adults with high-functioning ASD and healthy controls. Methods: In this cross-sectional case–control study, 38 adults with high-functioning ASD and 37 healthy controls were included. Plasma suPAR and CRP concentrations were measured using enzyme-linked immunosorbent assays. Group differences were examined using hierarchical multiple linear regression analyses adjusting for age, sex, body mass index (BMI), and current smoking status. The Autism Spectrum Quotient (AQ) was administered to all participants, and associations between inflammatory biomarkers and autistic traits were assessed using Spearman’s rank correlation analyses. Sensitivity analyses were performed after excluding participants with CRP concentrations > 10 mg/L to minimise the potential influence of acute inflammatory conditions. Results: In unadjusted analyses, CRP concentrations were significantly higher in the ASD group (p = 0.006), whereas suPAR concentrations did not differ (p = 0.163). After adjustment for age, sex, BMI, and smoking status, the association between ASD and CRP was no longer significant (p = 0.181), with BMI emerging as the strongest independent predictor of CRP (p < 0.001). No association was observed between ASD and circulating suPAR concentrations in either unadjusted or adjusted analyses (p = 0.612). CRP, but not suPAR, was positively correlated with AQ total scores (p = 0.026). Sensitivity analyses excluding participants with high CRP concentrations yielded findings consistent with the primary analyses. Conclusions: Adults with high-functioning ASD showed no evidence of elevated circulating suPAR concentrations. The attenuation of CRP group differences after adjustment for BMI and smoking status highlights the importance of accounting for metabolic factors when interpreting peripheral inflammatory biomarkers in ASD. These findings do not support elevated suPAR levels in adults with high-functioning ASD.

Brain Sciences doi: 10.3390/brainsci16101099

Authors: Jiajun Wei Zhiyang Li Wenju Wang Qiang Cai

Background: Chronic subdural hematoma (CSDH) is the most common bleeding disorder in the nervous system and has a high recurrence rate, posing a serious threat to the lives of elderly individuals. Early identification and adjustment of the treatment regimen in the perioperative period is crucial. The aim of this study was to create a perioperative predictive nomogram for the early prediction of recurrent CSDH (R-CSDH). Methods: A predictive model was developed including 632 patients with CSDH hospitalized between 1 January 2021 and 31 December 2025 from Wuhan University People’s Hospital. The 206 patients from the First People’s Hospital of Xiantao City who were hospitalized between 1 January 2022 and 31 December 2025 formed an external validation cohort. Minimum absolute shrinkage was used to optimize feature selection, and logistic regression analysis was applied to further select features and construct a risk prediction model for recurrent CSDH. The calibration, discrimination, and clinical utility of the predictive models were assessed using calibration plots, the C-index, the area under the curve (AUC), and decision curve analysis. External validation was performed by an external validation cohort. Findings: Age, CT hematoma size, hematoma location, atrophy, density, surgical procedure and D-dimer were the predictors for constructing the predictive nomogram, and the results showed that a logistic regression model based on the above seven factors had good calibration and discriminative ability (C-index: 0.925; 95% confidence interval: 0.893–0.957). The AUC of this predictive model was 0.92487. The calibration curve of the nomogram was close to the ideal diagonal. In addition, the decision curve analysis showed that the net benefit of the model was significantly better. External validation demonstrated the reliability of the predictive nomogram. Interpretation: D-dimer was found to be a novel factor for recurrent chronic subdural hematoma. Our study provides clinicians with an accurate tool for identification and early intervention and therapy to reduce the incidence of R-CSDH.

Brain Sciences doi: 10.3390/brainsci16101098

Authors: Tingting Di Kai Zhang Qian Ru Wenxuan Yin Yilin Jin Ling Chen Hualing Li

Objective: This study investigated how dopaminergic (DAergic) depletion-induced ventral hippocampal neurogenesis triggers hypothalamic–pituitary–adrenal (HPA) axis hyperactivity. Methods: Three-month-old male C57BL/6 mice were subjected to systemic 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or ventral tegmental area (VTA) injections of 1-methyl-4-phenylpyridinium ion (MPP+). We observed tyrosine hydroxylase (TH)-positive cells in the midbrain VTA and hippocampal DA content. We examined BrdU-positive cells in the ventral hippocampal dentate gyrus (vDG) on day 7 (D7) and day 28 (D28) after the BrdU injection. The expression of GAD67 and c-Fos-positive cells reflected the activation of GABAergic neurons. We assessed HPA-axis activity based on the levels of CORT, ACTH, and CRH mRNA. Results: TH immunoreactivity in VTA DAergic neurons and hippocampal DA were markedly reduced on D7 post-MPTP/MPP+ and recovered on D28. The numbers of BrdU-positive cells on D7 and D28 in the vDG were drastically reduced and were remedied by SKF38393 rather than quinpirole. MPTP significantly elevated levels of CORT, ACTH, and CRH mRNA on D28. A SKF38393 injection in the vDG, an AMPA injection in the amBNST, or a muscimol injection in the PVN effectively reversed HPA-axis hyperactivity. Conclusions: These results indicate that VTA DAergic depletion reduces the number of BrdU-labeled newborn cells within the vDG in a D1R-dependent manner. Given our previous work demonstrating unchanged progenitor cell proliferation but impaired survival of vDG newborn neurons under MPTP insult, we propose that disrupted D1R-dependent maintenance of newborn cell populations impairs vHPC-originated glutamatergic input to the amBNST, with associated alterations in the HPA-axis activity.

Brain Sciences doi: 10.3390/brainsci16101097

Authors: Xinhao Li Wanxuan Xiao Mobai Hu Li Li Li Lin

With the accelerating process of global aging, Alzheimer’s disease (AD) has become an enormous public health burden worldwide. However, its pathogenesis is still not fully understood beyond the classic amyloid-β (Aβ) and tau hypotheses. This review aims to fill this critical knowledge gap by proposing the “Iron-Mitochondria-Oligodendrocyte Axis (IMOA)” as a novel metabolic paradigm for deciphering the complex biological mechanisms underlying AD. Specifically, we explicitly aim to address whether this axis functions as a causal, permissive, or modulatory pathway during the early and progressive stages of the disease. We systematically summarize the reciprocal regulatory interactions within this axis, with a focus on how brain iron dyshomeostasis preferentially impacts mitochondria in oligodendrocytes, which are characterized by high metabolic demand. Notably, the IMOA framework highlights disordered iron metabolism as a potential modulatory factor of neurodegeneration by linking iron imbalance to impaired energy metabolism. Excessive intracellular iron induces mitochondrial dysfunction, insufficient energy supply, and reactive oxygen species (ROS) overproduction, thereby triggering oligodendrocyte ferroptosis and myelin degeneration. These events further aggravate neuronal energy depletion, forming a potentially self-sustaining pathological cascade that may operate synergistically with or upstream of Aβ and tau pathologies. This framework not only bridges the logical disconnect between protein accumulation and neuronal degeneration in the Aβ and tau hypothesis but also provides promising targets for multi-target therapeutic strategies. The IMOA offers valuable insights for improving the temporal and spatial precision of AD diagnosis and intervention. Collectively, targeting the IMOA may represent a transformative strategy for developing precision diagnostics and combination therapies to halt or delay the progression of AD.

Brain Sciences doi: 10.3390/brainsci16101096

Authors: Ilaria Riboldi Giuseppe Carrà

Mental disorders among children, adolescents, and young adults represent a major and growing public health concern [...]

Brain Sciences doi: 10.3390/brainsci16101095

Authors: Justyna Zielińska-Turek Jan Gajewski Małgorzata Dorobek

Background/Objectives: Patients with acute ischemic stroke (AIS) and coexisting malignancy have worse outcomes, but it is unclear how much of this reflects malignancy itself rather than pre-stroke function, stroke severity and systemic inflammation. Methods: We retrospectively studied consecutive adults with MRI-confirmed AIS admitted to a neurology department in Warsaw, Poland (2020–2024): 130 with documented malignancy and 100 without. Because every patient with a pre-stroke modified Rankin Scale (mRS) score above 2 had a poor outcome by definition, the primary analysis was restricted to patients with pre-stroke mRS 0–2 (n = 161; 80 versus 81). Logistic models were adjusted sequentially for age, sex, admission NIHSS, pre-stroke mRS and log-transformed C-reactive protein (CRP). Results: Groups were comparable in age and vascular comorbidities. Good 90-day outcome was less frequent with malignancy (40.0% versus 58.0%; p = 0.028), but the association was no longer significant after adjustment for age, sex and admission NIHSS (odds ratio [OR] 1.55, 95% CI 0.69–3.51) and was null after adding pre-stroke mRS and log-CRP (OR 0.67, 0.25–1.81). Admission NIHSS and log-CRP were the consistent independent predictors. Return to within one mRS point of baseline was achieved by 41.5% versus 59.0% (p = 0.011). Among patients with pre-stroke mRS ≤ 2, intravenous thrombolysis rates were similar (22.5% versus 22.2%) and hemorrhagic transformation did not differ (17.4% versus 18.9%). Conclusions: Malignancy added little prognostic information beyond baseline function, stroke severity and systemic inflammation, although a clinically meaningful residual effect cannot be excluded. Among eligible patients, reperfusion appeared equally safe.

Brain Sciences doi: 10.3390/brainsci16101094

Authors: Luke L. Jouppi Clifford A. Pierre Matias Luis Costa Radwan I. Takroni Nicholas Caffes Stepan Capek Aaron J. Gustin Majid Aljoghaiman Zane A. Tymchak Akshal S. Patel Stephen J. Monteith

Objectives: Lesion localization, associated vascular structures, and corticotomy selection pose key challenges when planning cerebral cavernous malformation (CCM) resections in eloquent areas. Head-mounted augmented reality (HMAR) may improve visualization without the gaze disruptions imposed by conventional neuronavigation. This study investigated the preoperative feasibility of HMAR in surgical plan modifications and educational value. Methods: We performed a single-center retrospective review of all CCM patients with HMAR-assisted preoperative planning from 1 September, 2022, to 31 August, 2024. Three-dimensional reconstructions of patients’ magnetic resonance imaging were viewed preoperatively using HMAR. Registration accuracy was confirmed against conventional neuronavigation. Surgical plan modifications entailed alterations of the operative goal, trajectory, or steps. Educational value of HMAR was appraised by trainees as “not helpful” when only confirming existing plans, “helpful” when facilitating a greater understanding of the lesion, and “very helpful” when spurring additional positioning or plan modifications. Results: Of 19 patients with CCM resections, 14 patients with HMAR-assisted preoperative planning were included. The average age was 38.6 ± 14.5 years, with 6 males and 8 females. Three of 14 (21%) surgical approaches were modified following HMAR use: two to minimize cortical disruption and one to avoid injuring an associated developmental venous anomaly. Registration was accurate in all cases. Between registration and utilization, HMAR added an average of 2.7 ± 1.0 min in the operating room. The mean appraisal of the educational value of HMAR was “helpful.” Conclusions: Preoperative planning with HMAR prompted surgical plan modifications and often improved trainees’ understanding without introducing significant workflow disruptions. Three-dimensional visualization offered dynamic spatial details beyond traditional two-dimensional multiplanar MRI.

Brain Sciences doi: 10.3390/brainsci16101093

Authors: Alfonso Alfaro-Rodríguez José Luis Cortes-Altamirano Samuel Reyes-Long Herlinda Bonilla-Jaime Francisco Jacob Avila-Camacho Leonardo Miguel Moreno-Villalba María Elizabeth Herrera-López Angelica González-Maciel Beatríz Pérez-Guille Rosa Eugenia Soriano-Rosales David Calderon-Guzman Hugo Juaréz-Olguín

Background/Objectives: Pain is a common and disabling non-motor manifestation of neurodegenerative disorders, but the contribution of glial cells to nociceptive processing remains incompletely understood. This systematic review evaluated evidence from preclinical models of neurodegenerative diseases linking microglial and astrocytic activity to pain. Methods: The protocol was prospectively registered in PROSPERO (CRD420251084310), and reporting followed PRISMA 2020. We conducted the original electronic search in PubMed/MEDLINE; during major revision, we conducted supplementary searches in Scopus and Web of Science Core Collection. Across the three sources, we identified 2248 records. After hierarchical deduplication by DOI, PMID, and normalized title, 1567 unique records were screened. Eligible in vivo studies assessed microglial and/or astrocytic alterations together with pain- or nociception-related outcomes. Risk of bias was independently evaluated by two investigators using the SYRCLE tool, and findings were synthesized qualitatively. Results: Twenty-six studies met the eligibility criteria: sixteen examined multiple sclerosis/experimental autoimmune encephalomyelitis (61.5%), seven Parkinson’s disease (26.9%), two Alzheimer’s disease-related models (7.7%), and one Huntington’s disease model (3.8%); no eligible amyotrophic lateral sclerosis study was identified. Pain-related alterations involved inflammatory, neuroimmune, synaptic, and astrocyte-associated pathways, but the evidence was strongly model-dependent. Findings based on individual studies, including early astrocytic contributions in experimental autoimmune encephalomyelitis and altered inflammatory allodynia in an Alzheimer’s disease model, are interpreted as study-specific observations requiring replication. Conclusions: The available evidence supports context-dependent associations between glial responses and nociceptive processing; however, marker specificity, EAE predominance, sex and age imbalance, and incomplete reporting of bias control procedures limit causal and cross-disease generalization.

Brain Sciences doi: 10.3390/brainsci16101092

Authors: Thomas Heinbockel Gursimran Virdi Lexington Shannon Sayan Nandi

Stroke is the second leading cause of death after ischemic heart disease, accounting for 10% of all deaths worldwide. Stroke is also a major cause of long-term neurological disability, yet olfactory dysfunction remains an underrecognized consequence of cerebrovascular injury. Smell is rarely evaluated in stroke patients despite its central role in appetite, hedonia, hazard detection, memory, emotional processing, and quality of life. The olfactory system extends from the olfactory epithelium and olfactory bulb to primary olfactory cortex, limbic regions, orbitofrontal cortex, insula, thalamus, hippocampus, broader fronto-limbic networks and cerebellum. The broad anatomical organization of the olfactory system subjects it to frequent perturbation due to stroke or other lesions. Post-stroke olfactory deficits may result from direct injury to olfactory structures, disruption of higher-order olfactory networks, diaschisis, altered sniffing and sensorimotor control, or secondary degeneration. Clinically, these deficits are manifested as hyposmia, anosmia, impaired odor identification, discrimination and memory, altered odor pleasantness, reduced flavor perception, loss of appetite, or reduced odor-guided behavior. Current evidence indicates that olfactory dysfunction can persist into the chronic phase of stroke, although a single prevalence estimate cannot be established because populations, timing, testing methods, and reporting differ substantially across studies. This narrative review provides an overview of stroke-related olfactory dysfunction, emphasizing olfactory pathway anatomy, lesion-relevant mechanisms, clinical consequences, measurement limitations, rehabilitation approaches, and future research priorities. We argue that post-stroke olfactory dysfunction should be understood as a multidimensional network-based disorder rather than a simple binary loss of smell.

Brain Sciences doi: 10.3390/brainsci16101091

Authors: Erdem Baran

Background: Acute kidney injury (AKI) requiring renal replacement therapy (RRT) is common in critically ill patients and is frequently accompanied by delirium. Intradialytic hemodynamic instability, particularly hypotension, may impair cerebral perfusion; however, its quantitative relationship with delirium remains unclear. This study investigated the association between intradialytic hemodynamic instability and Confusion Assessment Method for the Intensive Care Unit (CAM-ICU)-defined delirium in critically ill patients receiving RRT. Methods: This single-center retrospective study included 87 adult intensive care unit (ICU) patients undergoing RRT between September 2025 and May 2026. Delirium was assessed using the CAM-ICU. Intradialytic hemodynamic burden was quantified by the cumulative duration of mean arterial pressure (MAP) < 65 mmHg and the number of hypotensive episodes during RRT. Multivariable logistic regression analyses adjusted for age, sex, and admission SOFA score were performed to evaluate the associations between hemodynamic parameters and delirium, while receiver operating characteristic (ROC) analyses were used to assess their discriminative ability. Results: Of 87 patients, 46 (52.9%) were classified as CAM-ICU-positive for delirium. Patients with delirium had a longer cumulative duration of MAP < 65 mmHg (median, 36.0 vs. 5.0 min; p = 0.048) and more hypotensive episodes (median, 3.0 vs. 1.0; p = 0.032). These differences were no longer significant after normalization to the number of RRT sessions (p = 0.153 and p = 0.249). In addition, neither parameter showed a statistically significant association with delirium after adjustment for age, sex, and admission SOFA score. ROC analysis demonstrated limited discriminative ability (AUC, 0.62 and 0.63, respectively). Mechanical ventilation duration, ICU length of stay or ICU mortality did not show a statistically significant association with CAM-ICU positivity in the adjusted models. Sensitivity analyses using alternative functional forms for cumulative MAP < 65 mmHg duration, including log-transformed, categorical, and natural cubic spline models, did not show statistically significant associations with CAM-ICU positivity. Conclusions: Critically ill patients with delirium had greater cumulative intradialytic hypotensive burden; however, these differences were attenuated after accounting for the number of RRT sessions, and the hemodynamic parameters did not show statistically significant associations with delirium in the adjusted regression models. These findings suggest a potential relationship between intradialytic hemodynamic burden and delirium but do not establish an independent or causal association.

Brain Sciences doi: 10.3390/brainsci16101090

Authors: Milena Raffi Aurelio Trofè Alessandra Laffi Andrea Meoni Alessandro Piras

Background/Objectives: Optic-flow velocity is known to influence postural sway, whereas corresponding electromyographic (EMG) effects may be difficult to detect when muscle activity is averaged over long stimulation periods. We therefore investigated the early temporal organisation of muscle activity following optic-flow onset and examined whether this response was modulated by stimulus velocity, retinal stimulation location, and laterality. Methods: Surface EMG recordings from the tibialis anterior (TA), soleus (SOL), trapezius descendens (TD), and paraspinal C4 muscles were reanalysed from a previously published dataset of 18 healthy adults exposed to radial optic flow at five velocities and three retinal stimulation configurations. RMS activity was quantified in two consecutive post-stimulus windows, 0–200 ms and 200–400 ms, and analysed using repeated-measures ANCOVA with baseline activity entered as a covariate. Results: All four muscles showed greater activation during the 200–400 ms window than during the 0–200 ms window, indicating a consistent temporal increase in EMG activity shortly after optic-flow onset. Additional effects were muscle-specific. In TA, the temporal increase was greater during large-field than peripheral stimulation. In SOL, temporal modulation varied with velocity and body side. TD showed a significant effect of velocity. C4 activity was greater on the right than on the left side. Conclusions: Early postural muscle activity shows a common temporal increase during the first 400 ms after optic-flow onset, together with significant stimulus modulation and laterality. These findings suggest that time-resolved bilateral EMG can reveal aspects of the early postural response that may be hidden when muscle activity is averaged over longer periods.

Brain Sciences doi: 10.3390/brainsci16101089

Authors: Mariana A. M. Misawa Aljeena Rahat Qureshi Ghaliah Nsour Tina Felfeli Jack E. Teplitsky Samuel N. Markowitz Monica Daibert Nido

Purpose: To describe short- and long-term visual outcomes after MAIA microperimetry biofeedback training (BT) in a low-vision rehabilitation cohort. Methods: Retrospective study of patients who completed BT between 2017 and 2023 (4.1 ± 0.6 sessions). The MAIA device recorded P1 and P2 parameters, defined as the percentage of fundus-tracked fixation points falling within device-defined circular windows centered on the trained retinal locus (TRL). Outcomes: baseline, short-term follow-up (<6 months), and long-term follow-up (≥6 months): P1, P2, best-corrected distance visual acuity (BCVA), near visual acuity, fixation stability (BCEA), mean retinal sensitivity (dB), and reading speed (wpm) MNRead app. Results: A total of 346 participants were included. Median P1 increased from 21.5% at Session 1 to 32.0% at Session 5, and P2 increased from 66.0% to 81.5%. Distance and near visual acuity improved significantly at short-term follow-up but were not significantly different from baseline in the overall cohort at long-term follow-up. Reading speed, BCEA, and mean retinal sensitivity did not show significant longitudinal changes. In an exploratory secondary analysis excluding eyes with worsening BCVA, distance and near visual acuity remained significantly improved at long-term follow-up. Conclusions: MAIA-guided BT was associated with improved within-training fixation performance and short-term visual acuity in this heterogeneous retrospective cohort. Long-term improvement was not demonstrated in the overall cohort; exploratory analyses suggest that underlying disease progression may influence long-term outcomes. Prospective controlled studies are required to determine durability and efficacy.

Brain Sciences doi: 10.3390/brainsci16101088

Authors: Ping-Hong Yeh Chen-Haur Yeh Terrence R. Oakes John Ollinger Gerard Riedy

Background: Conventional structural CT and MRI may be normal after mild traumatic brain injury (mTBI), while magnetic resonance spectroscopic imaging (1H-MRSI) can provide regional measures of brain metabolites. We examined supracallosal fronto-parietal metabolite ratios in active-duty service members with military-related TBI and non-TBI military controls, including comparisons by injury mechanism and exploratory clinical associations. Methods: The study used a retrospective cross-sectional cohort. Participants underwent 3T 2D multivoxel 1H-MRSI covering a 6 × 8 × 1 cm3 supracallosal fronto-parietal PRESS/CSI volume of interest. Regional N-acetylaspartate (NAA), choline-containing compounds (Cho), and creatine/phosphocreatine (Cr) measures were processed with SIVIC and summarized as NAA/Cr and Cho/Cr ratios. Linear mixed-effects models were adjusted for age and sex, with Bonferroni correction for regional group comparisons. Male-only analyses were performed as a sensitivity analysis. Associations with clinical and neurocognitive measures were exploratory. Results: The final analytic cohort reported in the manuscript comprised 741 service members with TBI (34.3 ± 8.1 years old; M/F = 711/30; mean 327.4 ± 226.8 days post-injury) and 75 non-TBI controls (M/F = 53/22; mean age: 33.1 ± 10.0 years). TBI participants showed lower Cho/Cr area ratios in multiple fronto-parietal regions, including right precuneus (estimate = −0.0781, SE = 0.0176, t = −4.43, pBonf < 0.0001, Cohen’s d = −0.36, 95% CI [−0.1127, −0.0435]), left superior frontal gyrus (estimate = −0.0715, SE = 0.0163, t = −4.38, pBonf < 0.0001, Cohen’s d = −0.36, 95% CI [−0.1035, −0.0394], and bilateral fronto-parietal WM (right: estimate = −0.0741, SE = 0.0169, t = −4.39, pBonf < 0.0001, Cohen’s d = −0.35, 95% CI [−0.1072, −0.0410]; left: estimate = −0.0656, SE = 0.0161, t = −4.08, Cohen’s d = −0.33, pBonf = 0.0011, 95% CI [−0.0971, −0.0340]). Injury mechanism stratification revealed a widespread reduction in Cho/Cr area in individuals with blast-related TBI relative to unexposed non-TBI controls over the left superior frontal gyrus (estimate = −0.0941, SE = 0.0176, t = −5.35, pBonf < 0.0001, Cohen’s d = −0.44, 95% CI [−0.1287, −0.0596]), right precuneus (estimate = −0.0900, SE = 0.0193, t = −4.66, Cohen’s d = −0.38, pBonf = 0.0010, 95% CI [−0.1279, −0.0521]), and right fronto-parietal WM (estimate = −0.0895, SE = 0.0182, t = −4.91, Cohen’s d = −0.39, pBonf < 0.0001, 95% CI [−0.1253, −0.0537]). Twelve regional differences remained significant in the primary analysis, and the principal pattern was substantially preserved in the male-only sensitivity analysis. Blast-related and multiple-blast comparisons also showed regional Cho/Cr differences; individuals with multiple blast exposures mainly drove Cho/Cr reduction. Exploratory clinical analyses found inverse associations between Cho/Cr and Post-Traumatic Stress Checklist–Civilian version (PCL-C) and Neurobehavioral Symptom Inventory (NSI) scores, and positive associations between selected NAA/Cr measures and cognitive performance. Specifically, higher NAA/Cr area over the left caudal anterior cingulate correlates positively with verbal fluency performance (r = 0.358, p < 0.0001). Higher NAA/Cr peak heights in the left caudal middle frontal cortex correlated with better response inhibition accuracy (r = 0.278, p = 0.0003). Concurrently, lower Cho/Cr values over default mode network hubs—specifically the left caudal anterior cingulate gyrus (estimate = −0.00144, t = −4.02, uncorrected p < 0.0001, 95% CI [−0.00215, −0.00074]), left posterior cingulate gyrus (estimate = −0.00115, t = −3.76, uncorrected p = 0.00019, 95% CI [−0.00175, −0.00055], and the left precuneus gyrus (estimate = −0.00120, t = −3.62, p = 0.00033, 95% CI [−0.00186, −0.00055])—associated significantly with greater self-reported post-traumatic stress severity on the PCL-C. In addition, Cho/Cr in the left fronto-parietal WM was inversely associated with PCL-C (estimate = −0.00115, t = −3.87, p = 0.00012, 95% CI [−0.00174, −0.00057]) and NSI (estimate = −0.00117, SE = 0.00030, t = −3.92, p < 0.0001, 95% CI [−0.00176, −0.00058]). Injury chronicity did not correlate with metabolic alterations. Conclusions: 1H-MRSI identified regional metabolite-ratio differences in this military TBI cohort. The findings support further investigation of regional Cho/Cr and NAA/Cr measures as correlates of clinical heterogeneity after TBI. The widespread depression of Cho/Cr suggests persistent membrane depletion and/or chronic axonal degeneration, particularly in TBI individuals with multiple blast exposures. Although the cross-sectional design does not establish causality, diagnostic sensitivity, biomechanical strain patterns, or longitudinal recovery, the results imply the utility of MRSI as a robust translational tool for phenotyping chronic military brain injury and objectively monitoring long-term neural recovery.

Brain Sciences doi: 10.3390/brainsci16101087

Authors: Maria Svet Arosh S. Perera Molligoda Arachchige

Adversarial testing has strengthened the empirical standards of consciousness science, but recent results also expose a measurement problem: competing theories frequently make predictions about the same neural quantities and can therefore be challenged without being decisively discriminated. This evaluative review incorporates a purposive structured audit of contemporary theories and theory-relevant experiments rather than a systematic census. The audit separates trial-level from origin-level frameworks, explicit from interpreted commitments, and positive from stated-null predictions. Policy count and incompatibility remain sparsely occupied coordinates, whereas organism-wide cortical-autonomic coherence is not explicitly formulated as an access criterion by the trial-level accounts and is therefore treated as a sensitivity-dependent gap rather than an unqualified absence. Importantly, an unoccupied coordinate is not itself a discriminating prediction: direct theoretical adjudication requires opposed commitments. In the baseline theory-addressed content-bearing sample, valenced content is absent; under the most permissive sensitivity rule, it rises to 6 of 57 experiment rows (4 of 30 publications). The crossed conflict-by-valence experiment specified here can be run now, but it does not discriminate among theories that are silent on those coordinates; the autonomic-only condition that would generate a genuinely opposed test cannot yet be run because a validated report-independent measure of interoceptive access is lacking.

Brain Sciences doi: 10.3390/brainsci16101086

Authors: Shelby Chase Loftis Morgan McClellan Anna Lise Sheridan Cynthia Rando Reginald B. O’Hara

Background/Objectives: Parkinson’s disease with mild cognitive impairment (PD-MCI) represents a critical early-intervention window before progression to dementia. However, non-pharmacological cognitive treatment options are poorly characterized. This scoping review maps noninvasive neuromodulation interventions evaluated for cognitive outcomes in PD-MCI and in broader PD populations. Methods: Following JBI scoping review methodology and PRISMA-ScR guidelines, PubMed, Scopus and Google Scholar were searched for empirical studies published between May 2006 and September 2026 that applied noninvasive neuromodulation in adults with PD-MCI or broader PD populations and reported cognitive outcomes. Studies were classified as direct PD-MCI evidence (diagnosis confirmed using Movement Disorder Society Task Force criteria) or adjacent PD cognitive evidence. Results: Eleven studies across five modalities were included: tDCS (n = 6), iTBS (n = 2), TPS (n = 1), tcVNS (n = 1), and taVNS (n = 1). Only four studies (two tDCS and two iTBS) enrolled participants with confirmed PD-MCI; the remaining seven enrolled broader PD populations. Favorable findings came mainly from small samples, and protocols, outcome measures, and populations were heterogeneous. Conclusions: Evidence specific to PD-MCI is limited and mixed. Several studies pairing stimulation with cognitive training reported favorable outcomes, but this pattern was inconsistent and does not establish superiority over stimulation alone. No VNS trial enrolled participants with confirmed PD-MCI or used cognition as a primary endpoint.

Brain Sciences doi: 10.3390/brainsci16101085

Authors: Pier Paolo Berti Alessandro Spimpolo Leda Lorenzon Davide Drusiani Matteo Presa Luca Zavatto Paolo Cipriano Cecchi Davide Costazza Vania Pirillo Matteo Bonatti Francesco Erdini Nadia Oberhofer Giuseppe Maria Della Pepa Francesco Doglietto Andreas Schwarz Mohsen Farsad

Background/Objectives: Differentiating tumour recurrence from treatment-related changes (TRC) after multimodal treatment of high-grade gliomas (HGGs) remains challenging because of the overlap in imaging findings on conventional magnetic resonance. This study compared the diagnostic performance of the main static semiquantitative O-(2-[18F]fluoroethyl)-L-tyrosine positron emission tomography ([18F]FET-PET) parameters and assessed the diagnostic contribution of qualitative tracer uptake. Methods: This retrospective single-centre study included 77 scans from 61 adult patients with previously resected and chemoradiotherapy-treated HGGs undergoing [18F]FET-PET for suspected recurrence. Standardised uptake values (SUVs), tumour-to-background ratios (TBRs), and metabolic tumour volume (MTV) were analysed. Recurrence was determined using a composite histopathological and clinical–radiological reference standard. Diagnostic performance was assessed using receiver operating characteristic analysis, Youden-derived cut-offs and DeLong comparisons. Internal validation was performed by using patient-grouped five-fold cross-validation, in which cut-offs were re-derived within each training partition and applied to the held-out partition. Results: Forty-nine scans were classified as recurrence and 28 as TRC. All semiquantitative parameters except MTV were significantly higher in recurrent disease after false-discovery-rate correction. TBR mean ratio showed the highest accuracy (AUC, 0.80; cut-off, 1.85; sensitivity, 77.6%; specificity, 75.0%), followed by SUV max (AUC, 0.793). Neither prespecified comparison among TBR parameters was significant. The presence of pathological uptake achieved 100% sensitivity, 42.9% specificity, 100% NPV, and 79.2% accuracy. MTV was non-discriminative (AUC, 0.499). SUV max differed significantly between scanners (p = 0.008). Conclusions: Static semiquantitative [18F]FET-PET parameters, except MTV, showed comparable moderate-to-good performance for distinguishing recurrence from TRC. TBRmean may represent a pragmatic primary marker due to its background normalisation reduction of scanner-related variability. Guideline-recommended thresholds should be regarded as reference values requiring local validation and, when appropriate, centre- and protocol-specific calibration.

Brain Sciences doi: 10.3390/brainsci16101084

Authors: Noah B. Drewes Lara Koutah Rishi Jain Hannah E. Johnson Jack Carnduff Khizar R. Nandoliya Kayla Chin Ava Hoeft Savannah Kidd Alexander C. Kowalski Kevin Lu Hannah Roberts Yixuan Ma Guadalupe Ruiz Kyle Struck Jessica Sheelam Dylan J. Thompson Faris Shaikh Krish Patel Kristin R. Delfino Bruce M. Frankel

Background/Objectives: Preoperative antithrombotic therapy is common among patients undergoing subdural hematoma (SDH) evacuation. However, the association with postoperative outcomes remains uncertain. We evaluated this potential association using a multicenter electronic health record cohort and a single-center cohort. Methods: We performed a retrospective cohort study using TriNetX, a multicenter electronic health record (EHR) database, and a single-center cohort. TriNetX was used to identify adults undergoing evacuation of nontraumatic subdural hematoma between 2005 and 2025. The exposed cohort was defined as documented oral anticoagulant or antiplatelet exposure within 7 days before surgery, after which patients were propensity-score matched 1:1. The single-center cohort included surgically treated subdural hematoma patients with clinical, radiographic, laboratory, and operative data. Postoperative outcomes included 30-day mortality, short-term thrombotic complications, and 90-day repeat subdural hematoma surgery. Results: In TriNetX, 15,651 eligible patients were identified. Matched cohorts included 1455 exposed and 1455 unexposed patients. Preoperative antithrombotic exposure was associated with higher 90-day repeat surgery (9.7% vs. 6.5%; hazard ratio [HR] 1.52; p = 0.001), whereas 30-day mortality and 14-day thrombotic complications did not differ significantly. The single-center cohort included 164 surgically treated patients, including 103 exposed and 61 unexposed patients. The reoperation association was not reproduced. However, exposed patients had higher unadjusted 30-day and overall mortality that attenuated after multivariable Cox adjustment. Conclusions: Preoperative antithrombotic exposure was associated with repeat surgery in the TriNetX cohort but not in the single-center cohort. Together, these findings suggest that antithrombotic exposure may identify a medically complex surgical SDH population requiring individualized postoperative surveillance.

Brain Sciences doi: 10.3390/brainsci16101083

Authors: Rafał Gerymski

Technology-mediated sexual behaviours, including cybersex and technosex, are becoming increasingly prevalent as digital technologies, virtual reality, artificial intelligence, and interactive devices continue to develop. Although these behaviours may offer numerous benefits, such as facilitating sexual exploration, supporting individuals with disabilities, and enabling long-distance intimacy, they may also contribute to problematic patterns of use in some individuals. This review synthesises current knowledge on the psychological and neurobiological mechanisms underlying cybersex and technosexual behaviour. The article discusses conceptual and definitional issues, epidemiological data, and theoretical frameworks, including the Triple A model and the “quasi-necrophilia” framework, to explain the characteristics and motivations behind technology-mediated sexual activities. Furthermore, it summarises psychological factors associated with both adaptive and maladaptive use, emphasising the role of emotion regulation, personality traits, neurodevelopmental conditions, mental health, and sexual motivations. The review also presents current evidence on the neurobiology of cybersex and technosex, highlighting the involvement of dopaminergic reward pathways and similarities to other reward-related behaviours. Finally, available approaches to the treatment of problematic technology-mediated sexual behaviour are discussed, including pharmacotherapy, as well as psychoeducation and psychotherapy, with particular attention to the importance of addressing underlying psychological conditions. The article argues that cybersex and technosex should not be inherently pathologised—instead, they should be understood within a biopsychosocial framework that distinguishes between healthy sexual expression and clinically significant impairment.

Brain Sciences doi: 10.3390/brainsci16101082

Authors: Michael J. Shoemaker Kaitlyn R. Batchelor Jozlyn A. Gilman Rachel S. Miller Tarah F. Nicholson

Background/Objectives: The feasibility of high-intensity gait training (HIGT) in the acute care setting has only been demonstrated in two studies and its impact on functional status and length of stay (LOS) is not clear. The purpose of the present study was to further examine the impact of HIGT on acute care LOS and change in Activity Measurement for post-acute care (AM-PAC 6-Clicks). Methods: This was a retrospective medical record review of a cohort of patients in the acute care setting who received HIGT following implementation of a quality improvement project. Historical conventional care patients were identified and matched to the HIGT group using propensity score matching. Linear mixed models were used to examine the effect of group on acute care LOS and change in AM-PAC 6-Clicks. Results: 36 HIGT patients with one matched control and 22 with two matched controls were analyzed. After controlling for unbalanced covariates using a linear mixed model, acute care LOS was 1.2 days shorter in the HIGT group compared to the conventional care control group (p = 0.031, 95% CI 0.11, 2.29). There was no difference in change in AM-PAC 6-Clicks (p = 0.575, 95% CI −1.36, 0.76). Conclusions: Receiving HIGT in the acute care setting was associated with a 1.2-day-shorter LOS compared to conventional care in this study cohort; however, exposure to HIGT does not appear to improve the functional status during acute hospitalization post-stroke in this cohort. The mechanism underlying the association with the shorter LOS remains unclear and may reflect increased confidence in the patient’s readiness for discharge, unmeasured differences between cohorts, or changes in a variety of factors that influence discharge disposition given the cohorts were from two different time periods.

Brain Sciences doi: 10.3390/brainsci16101081

Authors: Ji Hyun Park

Manic and hypomanic states are precipitated by pharmacologically diverse agents, including corticosteroids and antidepressants, and carry serious clinical consequences. Since the last cross-class review in 1995, the literature has fragmented into class-specific reviews lacking a shared mechanistic account. I hypothesize that chemically unrelated drugs perturb a few proximal systems—dopaminergic gain, glutamatergic synaptic potentiation, sleep and circadian timing, glucocorticoid signaling, and neuroimmune signaling—that converge on ventral prefrontal–amygdala–striatal circuitry implicated in secondary mania. Inverting the classical lesion-convergence logic, I treat pharmacological exposures as reversible, dose-graded probes of this network, accommodating withdrawal reversibility, dose dependence, and the affected minority. Evidence is appraised by study design rather than drug class, distinguishing experimentally supported associations from case series lacking exposure denominators. Across 15.4 million post-marketing reports containing 11,698 manic or hypomanic events, which cannot establish incidence or causality, median reported latency ranged from one day (glutamatergic agents) to three to four weeks (antidepressants), a contrast preserved at the drug level. A descriptive temporal-concentration flag identified signals warranting cautious interpretation. Rather than a universal pathway, this untested framework links proximal mechanism to phenotype and time course, generating testable predictions for studies combining exposure measurement, actigraphic sleep monitoring, and repeated activation ratings.

Brain Sciences doi: 10.3390/brainsci16101079

Authors: Marialuisa Zedde Giovanni Merlino Piergiorgio Lochner Francesca Romana Pezzella Stefania Miniello Vincenzo Andreone Celeste Tucci Takahiro Ota Giuseppe Catapano Vincenzo D’Agostino Daniele Giuseppe Romano Luigi Cirillo Mario Muto Leonardo Pantoni Paola Santalucia Rosario Pascarella

The management of suspected ischemic stroke has evolved significantly, largely due to advancements in imaging technologies such as Computed Tomography Perfusion (CTP). This narrative review aims to delineate the practical applications and limitations of CTP in acute stroke evaluation, particularly in challenging scenarios. It is organized around illustrative clinical and imaging cases regarding small subcortical infarctions, posterior fossa ischemia, abnormal reference hemispheres, chronic steno-occlusive disease, the simultaneous involvement of multiple vascular territories, luxury perfusion, diaschisis, and systemic hemodynamic abnormalities. We discuss the core–penumbra paradigm, emphasizing the need for accurate interpretation of perfusion maps to guide therapeutic decisions. While automated CTP analyses enhance diagnostic efficiency, they can overlook critical patient-specific factors and exhibit variability in performance across different software platforms. Limitations in detecting small infarcts, particularly in lacunar strokes, highlight the necessity for qualitative visual assessments alongside quantitative data. Individualized case evaluations are crucial, as discrepancies between automated readings and qualitative interpretations can influence the management of single cases. Furthermore, we propose an integrated approach that combines automated assessments with human expertise to improve diagnostic precision and treatment efficacy. Future research should focus on refining CTP methodologies and enhancing their applicability in diverse clinical contexts to optimize patient management in acute ischemic stroke situations.

Brain Sciences doi: 10.3390/brainsci16101080

Authors: Dan Gu Yu Lei Jiayi Lu Wenmin Yi Qinbin Zhang Yuxuan He Chuanling Wang Zhiyou Cai

Background: With the aging of the global population and the increasing prevalence of cognitive dysfunction worldwide, early identification of cognitive impairment has become an important public health issue. This study aims to investigate the correlation between peripheral serum neurodegenerative biomarkers and age, as well as the discriminative efficacy of cognitive impairment across different age cohorts. Notably, subjects were grouped by clinical cognitive assessment without pathological confirmation via amyloid/tau PET or cerebrospinal fluid testing to define Alzheimer’s disease pathology. Methods: A cross-sectional study enrolled 425 inpatients from the neurology department. Nonparametric tests were used to explore the correlation between age and peripheral serum biomarkers, as well as intergroup differences in biomarker levels among different cognitive statuses. Age-stratified logistic regression models were constructed to evaluate the association between biomarkers and cognitive impairment, with odds ratios (OR) and 95% confidence intervals (CI) calculated. Receiver operating characteristic (ROC) curves and corresponding area under the curve (AUC) were adopted to assess the discriminative performance of each indicator. In this study, cognitive impairment was defined clinically based on MoCA and clinical assessment, not biomarker-confirmed Alzheimer’s disease pathology. Results: Except for glial fibrillary acidic protein (GFAP) (r = 0.062, p = 0.207), all detected biomarkers were significantly correlated with age. Among them, p-Tau181 (r = 0.288, p < 0.001), p-Tau217 (r = 0.275, p < 0.001), Aβ1-42 (r = 0.132, p = 0.007), Aβ1-40 (r = 0.254, p < 0.001), and NfL (r = 0.200, p < 0.001) were positively associated with age, while Aβ42/40 ratio was negatively correlated with age (r = −0.253, p < 0.001). After age-based grouping, phosphorylated tau protein (p-Tau)181 showed relatively better discriminative performance in the <65 years group (AUC = 0.6212, 95% CI: 0.537–0.705); GFAP (AUC = 0.7776, 95% CI: 0.718–0.837) and NfL (AUC = 0.7329, 95% CI: 0.670–0.796) showed higher AUC values among participants aged ≥65 years. Conclusions: The correlation and discriminative efficacy of peripheral serum biomarkers for clinically defined cognitive impairment showed differences across age groups in this exploratory analysis. Within this inpatient cohort, p-Tau181 showed relatively better discriminative performance in the <65 years group, while GFAP and NfL showed numerically higher AUC values in the ≥65 years group. These exploratory findings suggest age-related differences in biomarker performance patterns that warrant further investigation in independent cohorts. The modest AUC (0.6212) for p-Tau181 in the younger group suggests that while it offers a statistical advantage, its clinical utility as a standalone screening tool remains limited, reinforcing the need for comprehensive clinical evaluation. Our results provide exploratory evidence for age-stratified minimally invasive serum-based assessment of clinically defined cognitive impairment in neurological inpatients, and cannot be directly generalized to community populations or used for definite Alzheimer’s disease pathological screening; rather, our results serve as a reference for age-stratified screening in clinical inpatient settings rather than standalone diagnostic criteria.

Brain Sciences doi: 10.3390/brainsci16101078

Authors: Sooyoung Kim Eun Kyoung Lee Youngkwon Ko Hyun-Wook Nah Hye Seon Jeong Seong-Hae Jeong Ae Young Lee Eunhee Sohn

Background/Objectives: Central neuropathic pain (CNP) is difficult to manage, and comparative evidence for non-invasive brain stimulation is limited. We explored the short-term efficacy and safety of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) in CNP. Methods: In this randomized, sham-controlled crossover trial, 26 patients were allocated to active or sham stimulation and received high-frequency rTMS (10 Hz, 2000 pulses/session) and anodal tDCS (2 mA, 30 min) over the primary motor cortex for five days each, separated by a 4-week washout. The primary outcome was change in Numerical Rating Scale (NRS) pain intensity at 1 and 4 weeks, analysed using factorial linear mixed-effects models with and without age adjustment. Results: At 1 week, the difference between active and sham rTMS was 0.76 points (95% CI −0.005 to 1.53; p = 0.051) and 0.42 points after age adjustment (95% CI −0.37 to 1.21; p = 0.30). Active tDCS did not differ from sham tDCS, and active rTMS did not differ from active tDCS. No significant differences were found at 4 weeks or in responder analyses. No serious adverse events occurred. Conclusions: In this small exploratory trial, neither rTMS nor tDCS showed statistically significant superiority over modality-matched sham, and no difference between modalities was demonstrated. Adequately powered trials are needed.

Brain Sciences doi: 10.3390/brainsci16101077

Authors: Edward Jacek Gorzelańczyk Aleksandra Kawala-Sterniuk Ewa Laskowska Piotr Kamiński Piotr Walecki

Background/Objectives: Decision-making differences have been reported in substance-related and behavioral addictions, but Iowa Gambling Task (IGT) performance patterns may differ. We compared IGT performance in gambling disorder, opioid use disorder (OUD) before and approximately 90 min after methadone dosing, and healthy controls. Methods: The study enrolled 103 adult men: 33 with gambling disorder, 30 with opioid use disorder (OUD) receiving methadone maintenance, and 40 healthy controls. One control participant discontinued the IGT before completion, leaving 39 complete control outcome records. Between-cohort inference therefore used 39 controls, 33 participants with gambling disorder, and 30 OUD pre-methadone observations; pre-/post-dose inference used 27 complete OUD pairs as repeated measurements. Results: Net Total differed across the three independent baseline cohorts, F(2,99) = 8.73, p < 0.001, and η2 = 0.150. Controls had higher scores than the gambling-disorder cohort (Holm-adjusted p = 0.032) and the OUD pre-methadone cohort (p < 0.001); gambling disorder versus OUD pre-methadone was not significant (p = 0.083). In OUD, the within-subject condition effect was not significant, F(1,26) = 1.55, p = 0.224. Block-wise profiles are presented descriptively; gambling disorder showed a 2.79-point Block 3-to-4 decrease. Conclusions: The recruited male gambling-disorder and OUD baseline cohorts showed lower mean IGT performance than healthy controls. Block-wise trajectories differed descriptively; the late decline in gambling disorder is exploratory and requires replication with prespecified contrasts or mixed-effects models.

Brain Sciences doi: 10.3390/brainsci16101076

Authors: Yanxue Li Hongjian Gao Lan Lin Min Xiong

Background: White matter (WM) aging is commonly characterized as a largely unitary process of progressive microstructural decline, yet substantial interindividual variation suggests that this view may obscure distinct biological dimensions. Whether WM aging retains a multidimensional organization after minimizing variation attributable to overt clinical pathology remains unknown. Methods: We constructed a clinically defined aging reference cohort (CDAR; n = 17,310) from the UK Biobank (UKB) by excluding overt clinical pathology and analyzed 144 skeleton-based WM microstructural metrics. An additional 10,272 participants with overt clinical diagnoses were included for downstream association analyses, yielding a total analytic sample of 27,582. Surreal-GAN was applied to disentangle latent dimensions of WM aging, with reproducibility-based model selection and cross-sample and cross-sex validation. The biological relevance of the identified dimensions was evaluated through associations with cognitive, lifestyle, peripheral, and disease-related outcomes. Results: Three reproducible and coexisting dimensions of WM aging emerged, comprising distinct spatial configurations rather than a single diffuse aging axis. R1 displayed an anterior-vulnerable/posterior-preserved gradient, R2 reflected a widespread diffuse aging load, and R3 showed a dissociation between the limbic–frontal system and sensorimotor pathways. The three patterns exhibited good cross-sample (r = 0.887–0.935) and cross-sex (r = 0.891–0.937) reproducibility, with strong bilateral hemispheric correspondence (r > 0.86). All three patterns were associated with age but exhibited partially shared and partially independent associations with cognition, lifestyle factors, peripheral phenotypes, and disease risk. Conclusions: WM aging is not adequately captured by a single neuroanatomical process. Even after minimizing overt clinical pathology, it retains a reproducible multidimensional organization, with partially shared and partially independent phenotypic profiles across aging dimensions. These findings suggest that individual differences in WM aging reflect partially separable biological processes rather than variation along a single aging axis.

Brain Sciences doi: 10.3390/brainsci16101075

Authors: Liqing Liu Jiale Wu Zhihui Zhao Qing Liu Xuejun Bai

Background/Objectives: Healthy aging is associated with declines in bimanual coordination, particularly under more demanding coordination modes. However, the electrophysiological changes accompanying these behavioral differences and their relevance to performance remain unclear. This study examined age-group differences in behavioral performance, ERP responses, and beta-band dynamics during in-phase and anti-phase bimanual coordination. Methods: Forty-two right-handed adults were included in the primary analyses of a bimanual coordination task in both in-phase and anti-phase coordination modes. Behavioral outcomes included accuracy, reaction time, and inverse efficiency scores. EEG measures included P1, N1, and P3 responses, prestimulus beta power, fixed-window relative beta power, baseline-adjusted absolute beta power, and individualized cumulative event-related desynchronization burden. Results: The older group was slower and less efficient overall, with disproportionate accuracy and efficiency costs during anti-phase coordination. Electrophysiologically, aging was associated with larger early P1 responses, a sensor-level redistribution of P3 amplitude and latency, and higher prestimulus beta activity. Fixed-window relative beta and baseline-adjusted absolute beta showed age-group differences without corrected coordination effects, whereas individualized cumulative ERD burden showed age-group, coordination, and interaction effects. Conclusions: Healthy aging was associated with poorer discrete bimanual coordination performance, altered early visual and late positive ERP responses, and stronger cumulative beta suppression under demanding anti-phase coordination.

Brain Sciences doi: 10.3390/brainsci16101074

Authors: Alessandro Zampogna Luigi Borzì Domiziana Rinaldi Gabriele Imbalzano Martina Patera Marco Falletti Carlo Alberto Artusi Caterina Pauletti Edoardo Bianchini Leonardo Lopiano Gabriella Olmo Antonio Suppa

Background/Objectives: Parkinson’s disease (PD) is clinically heterogeneous, and motor complications are often inadequately captured during routine outpatient assessments. In this cross-sectional observational study, we investigated whether prolonged home-based wearable monitoring could enable digital motor profiling by identifying clinically meaningful patient subgroups through an unsupervised analytical approach. Methods: Seventy-six patients with PD underwent standardized clinical evaluation followed by prolonged home-based monitoring using a single waist-worn inertial sensor. Wearable-derived measures of gait, mobility, and complex motor manifestations, including dyskinesia and freezing of gait (FOG), were analyzed using an unsupervised clustering approach based exclusively on sensor-derived variables. The resulting subgroups were subsequently characterized using clinical and digital outcomes, and cluster stability and interpretability were examined through bootstrap and complementary machine-learning analyses. Results: Unsupervised clustering identified two distinct digital motor profiles that differed primarily in the burden of motor complications rather than overall disease severity. Although disease duration, Hoehn and Yahr stage, and clinical motor phenotype did not differ significantly, patients in one subgroup exhibited significantly greater dyskinesia, motor fluctuations, and dopaminergic treatment requirements, accompanied by a distinct sensor-derived motor profile during daily life. Dyskinesia-related metrics emerged as the strongest contributors to profile discrimination, and the identified clusters were reproduced with high cross-validated agreement by the surrogate classification model. Conclusions: Prolonged home-based wearable monitoring may support clinically meaningful digital motor profiling in PD. Beyond conventional clinical staging, this approach can identify patients with different burdens of motor complications under real-world conditions. Following appropriate validation, objective digital biomarkers could support patient stratification, longitudinal monitoring, and treatment optimization.

Brain Sciences doi: 10.3390/brainsci16101073

Authors: Zafer Bilgin Erdem Uylas Muhammed Yerlikaya Nurten Dinç Erkan Günay Murat Taş

Background: How exercise intensity affects working memory during concurrent motor-cognitive tasks remains unclear. This study examined working memory during dual-task cycling at the first and second ventilatory thresholds (VT1, VT2). Methods: Eleven trained male endurance athletes (VO2max 49.38 ± 5.69 mL/kg/min) completed a graded exercise test and two randomized crossover sessions of cycling at VT1 or VT2 with a concurrent 2-back task, with 2-back assessments before and after exercise. Hits, false alarms, reaction times and signal detection indices (d′, c) were analyzed using repeated-measures ANOVA and Holm-corrected planned contrasts. Results: At both intensities, hits and d′ decreased during the dual-task (phase effects, p < 0.001), whereas the response criterion did not change. For hits, the primary outcome, the Condition × Phase interaction was significant [F(2, 20) = 4.90, p = 0.019, η2p = 0.329]: hits decreased substantially during the dual-task at VT2 (d = 1.21, pHolm = 0.010) but not significantly at VT1 (p = 0.074), and the VT1-VT2 difference during the dual-task was itself significant (d = 0.98, pHolm = 0.036). A planned contrast directly comparing the pre-to-dual-task change in hits between conditions supported this pattern (p = 0.022), although it did not survive the stricter Holm correction applied within that specific contrast family (pHolm = 0.089). Immediately after exercise, d′ remained below pre-task values after VT2 (pHolm = 0.008) but not after VT1. Conclusions: Concurrent cycling at VT2 was associated with a significantly larger acute decline in working memory than cycling at VT1, directly supporting the study’s primary hypothesis. This intensity-dependent pattern, observed in a modest sample, should be confirmed in larger, adequately powered studies.

Brain Sciences doi: 10.3390/brainsci16101072

Authors: Samuel López-Rodríguez Barbara Postigo-Alonso Myrtha O’Valle-Rodríguez Marta Gómez-Herranz María Dolores Navarro-Pérez Joan Ferri-Campos Enrique Noé-Sebastián Alejandro Galvao-Carmona

Background/Objectives: Auricular Vagal Neuromodulation Therapy (AVNT) constitutes a promising non-invasive therapeutic approach for Disorders of Consciousness (DoCs). However, evidence regarding its effectiveness remains limited. In this context, although the Mismatch Negativity (MMN) is a well-established neurophysiological index associated with recovery in DoCs, its modulation by AVNT has not yet been investigated. This study aimed to evaluate the effect of AVNT on MMN in DoCs. Methods: Forty-four participants with DoCs were evenly assigned to either an experimental or a control group, alongside twenty-two healthy participants used to establish normative data in neurotypical conditions. The latency, peak and peak-to-peak MMN amplitude were assessed as a complement to the Coma Recovery Scale Revised (CRS-R). Subsequently, only the experimental group received AVNT, followed by a second assessment across all groups. Results: The control group showed extensive changes across sessions in both peak and peak-to-peak amplitudes. In contrast, the experimental group exhibited a significant change only in peak amplitude for the fronto-central region, with no changes in peak-to-peak amplitude. Between-session changes in peak and peak-to-peak amplitudes differed between the control and healthy groups in the parieto-occipital region. After adjustment for the inter-session interval, the ANCOVA showed an overall group effect on peak-to-peak amplitude changes in the parieto-occipital and right regions. No differences were detected between the control and experimental groups or between the experimental and healthy groups. Finally, no significant effects were found for MMN latency. Conclusions: These findings could be compatible with a possible effect of AVNT, although the evidence remained insufficient to demonstrate a direct effect of the intervention.

Brain Sciences doi: 10.3390/brainsci16101071

Authors: Lijo Andrews Yasmin El Khaldi Tracy George Tala Abuhamdah Nebojsa Nick Knezevic

Cancer-related cognitive impairment (CRCI) is often attributed to chemotherapy, yet cognitive deficits are detectable in some patients before systemic treatment begins. This review examines a proposed two-hit framework in which cancer-related psychological and physiological stress contributes to pretreatment neural vulnerability, followed by superimposed chemotherapy-associated neurotoxicity. The review focuses on adults with non-central nervous system cancers. This narrative review synthesizes epidemiologic, neuroendocrine, neuroimaging, neuroimmune, autonomic, preclinical, and clinical evidence addressing chronic stress biology, pretreatment cognitive and brain changes, chemotherapy-related neurotoxicity, hypothalamic–pituitary–adrenal (HPA) axis interactions, and potential interventions. Pretreatment cognitive impairment has been reported in approximately one-quarter of patients, accompanied by elevated inflammatory cytokines, altered neurotrophic signaling, and changes in amygdala–hippocampal connectivity. The first hit may reflect interacting cancer- and host-related factors, including systemic inflammation, distress, sleep disruption, fatigue, pain, and HPA-axis/circadian dysregulation. The second hit occurs when chemotherapy inflicts superimposed neurotoxic injury, including white matter degradation, suppressed hippocampal neurogenesis, and blood–brain barrier disruption. The relationship may also be bidirectional: chemotherapy can perturb HPA-axis function, while glucocorticoid signaling may influence treatment response and antitumor immunity. Behavioral, autonomic, and circadian interventions are mechanistically promising, although neuroprotective efficacy remains uncertain. CRCI is likely multifactorial and may begin before chemotherapy. The two-hit framework integrates pretreatment stress-related vulnerability with treatment-associated neurotoxicity but remains hypothesis-generating rather than causally established. Prospective studies beginning at diagnosis and incorporating serial cognitive, psychological, endocrine, inflammatory, autonomic, and neuroimaging measures are needed to test this model and identify patients at greatest risk.

Brain Sciences doi: 10.3390/brainsci16101070

Authors: Francisco Nieto-Escamez

Rehabilitation in neurological disorders has long been framed as a technical endeavor: restoring gait, improving balance, enhancing cognitive performance, and optimizing daily functioning [...]

Brain Sciences doi: 10.3390/brainsci16101069

Authors: Martina Bodria Eleonora Daini Stefano Pioli Monica Piemontese Eleonora Vandini Alessandra Ottani Michele Zoli Daniela Giuliani Antonietta Vilella

Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments. Hydrogen sulfide (H2S) is an endogenous gasotransmitter that exerts pleiotropic neuromodulatory, anti-inflammatory, cytoprotective, and trophic effects within the central nervous system.

Brain Sciences doi: 10.3390/brainsci16101068

Authors: Alexandre Merí-Vived Pedro Víctor López Plaza Antoni Morral Manuel Llusà-Pérez Marcel García-Cuesta Aroa Casado Rodríguez

Background/Objectives: Classical descriptions of median nerve motor anatomy often emphasize muscle-specific destinations, although a single muscular branch may divide to supply several muscles. This can obscure the hierarchical relationship between branch origin and downstream ramification. We therefore quantified the two-dimensional topography of muscular branches arising directly from the median nerve and analyzed each branch origin as a single spatial event linked to its subsequent muscular destinations. Methods: Sixteen fresh, non-frozen right upper limbs from 16 independent adult body donors (8 male and 8 female; mean age, 82.2 ± 9.6 years) underwent standardized dissection. Cartesian coordinates were assigned only to the origin of each first-order muscular branch from the median nerve. Branches were ordered proximodistally and linked to downstream subbranch count and target muscles. Coordinates were normalized to bistyloid distance (RPX) and forearm length (RPY). Donor-clustered bootstrap confidence intervals and mixed-effects models with donor-specific random intercepts summarized spatial variation across branch rank, with the longitudinal association interpreted descriptively because rank was defined proximodistally. Results: Seventy muscular branches generated 274 recorded downstream subbranches and 146 unique branch–muscle associations. Limbs contained a median of 4 muscular branches (range, 2–6), and 32/70 branches (45.7%) supplied two or more target muscles; this proportion includes the anterior interosseous nerve when its origin met the study’s branch-centered definition. The first branch participated in pronator teres innervation in all 16 limbs and was exclusive to that muscle in 11 (68.8%); all five sixth-ranked branches observed in this sample supplied flexor digitorum superficialis. As expected from the ranking definition, increasing branch order was descriptively associated with a more distal origin (β = 0.084; 95% CI, 0.063–0.104) and was associated with a higher normalized transverse coordinate (β = 0.077; 95% CI, 0.050–0.103; p < 0.001). Branch order explained substantially more longitudinal than transverse variance (marginal R2, 0.444 vs. 0.183). Conclusions: Proximodistally ranked median nerve branch origins were associated with frequent and variable downstream multi-muscle pathways. The rank–longitudinal coordinate association does not independently establish anatomical reproducibility. Treating the muscular-branch origin as the coordinate-level unit preserves the anatomical hierarchy, prevents pseudoreplication of shared coordinates, and provides an anatomical framework with potential relevance to peripheral nerve surgery; clinical benefits remain untested.

Brain Sciences doi: 10.3390/brainsci16101067

Authors: Joël Macoir

Background/Objectives: Numerical cognition comprises multiple processes supporting the representation, comprehension, production, and manipulation of numerical information. Although numerical impairments have been described in neurodegenerative diseases, findings remain fragmented across disorders and numerical domains. This systematic review aimed to characterize patterns of preserved and impaired core numerical abilities across neurodegenerative disorders and to examine their implications for cognitive models and clinical assessment. Methods: PubMed, Web of Science, and PsycINFO were systematically searched for original empirical studies in English or French examining core numerical cognition in adults with neurodegenerative disorders or mild cognitive impairment. Reference lists were additionally screened. Methodological quality was appraised using design-specific Joanna Briggs Institute critical appraisal tools. Forty-seven studies published between 1989 and 2026 met the eligibility criteria. Findings were synthesized qualitatively because of substantial heterogeneity in study designs, clinical populations, and numerical measures. Results: Numerical profiles varied considerably across disorders, individuals, and disease stages, but several broad patterns emerged. Basic number comprehension and magnitude processing were often relatively preserved, whereas greater vulnerability was observed for processes requiring transformation, retrieval, or manipulation of numerical information. Arithmetic fact knowledge showed variable preservation, including dissociations between stored knowledge and its retrieval. Calculation procedures and complex calculation were among the most consistently affected abilities. Evidence was strongest for Alzheimer’s disease and semantic variant primary progressive aphasia and remained limited for several other neurodegenerative disorders. Conclusions: Numerical cognition is differentially affected across neurodegenerative diseases, supporting its multicomponent organization. These findings suggest the potential value of multidomain assessment rather than reliance on isolated calculation tasks. However, methodological heterogeneity, variation in methodological strength across studies, and the limited evidence available for several disorders reduce confidence in the generalizability of these patterns and currently preclude defining reliable disease-specific numerical signatures. Registration: OSF, 10.17605/OSF.IO/DU2Y9. Funding: None.

Brain Sciences doi: 10.3390/brainsci16101066

Authors: Liu Yan Tianwen Li Lei Zhao Anmin Gong Hao Fang Wuheng Zuo Yunfa Fu

The large-scale, real-world deployment of brain–computer interface (BCI) is confronted with human factors bottlenecks, including reliability and usability. While modern human factors engineering has encompassed domains such as cognitive ergonomics, workload, adaptive automation, and human-in-the-loop systems, its theories and methodologies have historically placed their main emphasis on overt behavior and peripheral physiological measures, rather than on central neural activity as a primary control input. For the emerging interaction paradigm that takes central nervous activity as direct input and emphasizes long-term brain–computer co-adaptation, there remains a shortage of targeted conceptual and methodological frameworks. As a conceptual review, this paper discusses the necessity and disciplinary foundations for developing Human Factors Engineering for BCIs as an emerging interdisciplinary research direction. First, grounded in the defining features of BCI interaction—such as the implicit nature of input and brain–computer co-adaptation—it delineates the research boundaries and summarizes the core research objects as user neurocognitive characteristics, brain–computer collaborative adaptation mechanisms, multimodal feedback regulation, and contextual adaptation patterns. Second, it identifies three core scientific questions: individual differences and dynamic adaptation, human factors optimization and fault tolerance, and contextual generalizability principles, with ethics, privacy, and user rights and interests as an overarching dimension. Furthermore, it constructs a methodological system consisting of multimodal measurement and modeling, closed-loop validation, and multidimensional evaluation, and examines the supporting role of artificial intelligence approaches within this framework. Centered on the collaborative adaptation across neural, cognitive, and system levels, Human Factors Engineering for BCIs represents a deepening of the human-centered design philosophy. It provides theoretical reference for user-friendly BCI design and extends the research boundaries of human factors engineering.

Brain Sciences doi: 10.3390/brainsci16101065

Authors: José Luis Cortes-Altamirano Alfonso Alfaro-Rodríguez Samuel Reyes-Long Francisco Ulises Ortiz-Moreno Herlinda Bonilla-Jaime Angelica González-Maciel Beatriz Pérez-Guille Rosa Eugenia Soriano-Rosales Rafael Reynoso-Robles David Calderon-Guzman Hugo Juaréz-Olguín

Background: Pain is a frequent and debilitating non-motor symptom of Parkinson’s disease; however, its central neurochemical mechanisms remain incompletely understood. Serotonin modulates nociceptive processing, and the 5-HT3A receptor has been implicated in excitatory signaling and central sensitization. However, thalamic Htr3a transcript regulation during persistent pain associated with dopaminergic injury remains unclear. Objective: To evaluate thalamic Htr3a mRNA expression in 6-OHDA hemi-Parkinsonian rats subjected to formalin-induced persistent pain. Methods: Male Wistar rats were assigned to six groups (n = 6/group): Saline, Formalin, SHAM + Saline, SHAM + Formalin, 6-OHDA + Saline, and 6-OHDA + Formalin. 6-OHDA lesions were validated via apomorphine-induced rotations (>7 turns/min). Nociceptive behavior (flinches) was recorded over 60 min post-formalin injection. Bilateral thalamic Htr3a mRNA expression was quantified by RT-qPCR using Rpl27 as a validated reference gene. Results: 6-OHDA + Formalin rats exhibited a significant increase in persistent-phase nociceptive behavior compared to controls (p < 0.05). Htr3a mRNA expression showed a significant bilateral reduction in 6-OHDA-lesioned rats compared to controls (p < 0.05), with the decrease being significantly more severe in the ipsilateral thalamus (p < 0.001). Conclusions: Unilateral 6-OHDA lesion is associated with a region-dependent reduction in thalamic Htr3a mRNA expression during persistent pain. These results demonstrate transcriptional adaptations of the thalamic serotonergic system in experimental parkinsonian persistent pain.

Brain Sciences doi: 10.3390/brainsci16101064

Authors: Pavan Kumar

Alzheimer’s disease is a progressive neurodegenerative disease in the elderly population [...]

Brain Sciences doi: 10.3390/brainsci16101063

Authors: Ratree Wayland

When I proposed this Special Issue, I used the term language processing broadly to encompass not only the perception and processing of speech sounds but also the use of syntactic, semantic, and contextual information during language comprehension [...]

Brain Sciences doi: 10.3390/brainsci16101062

Authors: Ioannis Chatzistefanou Sophia Tsokkou Alexandros C. Liatsos Panagiotis Tsolkas Kyriaki Papadopoulou Maria Florou Martha Pyraki Theodora Papamitsou

Background: Craniofacial and skull base procedures place cranial nerves at risk of injury, with consequences for movement, sensation, hearing, swallowing, vision, and quality of life. Methods: This narrative review integrates 46 original publications with six targeted references added during revision, addressing injury mechanisms, prevention, postoperative assessment, reconstruction, and rehabilitation across neurosurgery, otolaryngology, and maxillofacial surgery. Results: Recurring mechanisms include traction, compression, ischemia, thermal injury, direct trauma, and transection. Neuromonitoring contributes to localization, functional surveillance, and prognosis when paired with reproducible baseline recordings, appropriate modality selection, technical troubleshooting, and a predefined surgical response to alerts. Preoperative and postoperative electrophysiological testing complements but does not replace intraoperative monitoring. Recognized transection favors immediate tension-free reconstruction when feasible; an anatomically continuous nerve with an unfavorable electrical response requires contextual interpretation rather than automatic sacrifice. Rehabilitation combines target-organ protection, selective motor or sensory retraining, symptom control, and patient-reported assessment. Conclusions: The practical distinction is between a potentially reversible functional disturbance and confirmed structural discontinuity. Management should link monitoring changes to corrective action, preserve viable nerves, and coordinate timely reconstruction with rehabilitation. Heterogeneous, predominantly observational evidence does not support universal alert thresholds, a single reconstruction deadline, or guaranteed functional recovery.

Brain Sciences doi: 10.3390/brainsci16101061

Authors: Luis Real Peña Morena Sallabanda Marta Quirós Martí Kita Sallabanda

Background: Stereotactic radiosurgery (SRS) is an established treatment option for medically refractory trigeminal neuralgia (TN). However, clinical evidence regarding dedicated gyroscopic radiosurgery systems remains limited. This study aimed to evaluate the efficacy, latency of response, safety, retreatment rate, and potential clinical and dosimetric predictors of outcome following ZAP-X gyroscopic radiosurgery for TN. Methods: A consecutive series of patients with pharmacologically refractory TN treated with ZAP-X gyroscopic radiosurgery between February 2023 and September 2025 was analyzed. Treatment consisted of a single isocenter targeting approximately 5 mm of the cisternal-retrogasserian trigeminal nerve, with a maximum dose of 90 Gy and a V70 Gy coverage objective ≥ 50%, using 4 or 5 mm collimators. Pain outcome was assessed using the Barrow Neurological Institute Pain Intensity Scale (BNI), and sensory toxicity was evaluated using the BNI Facial Numbness Scale. Clinical and treatment-related predictors of failure and retreatment were explored using binary logistic regression. Results: Following radiosurgery, 87.5% of patients achieved satisfactory pain control (BNI I–IIIb; 95% CI, 78.8–96.2%), with a significant overall improvement in BNI score compared with baseline (p < 0.001) at the 12 months of follow-up. Half of the patients experienced clinical improvement within the first 15 days. Treatment-related toxicity occurred in 8.9% of patients, while 26.8% required repeat radiosurgery during follow-up. The decision to perform retreatment is made when the patient has shown no improvement in the BNI score at 6 months after the initial treatment. Baseline BNI grade V was the only statistically significant predictor of treatment failure, conferring a more than ninefold higher odds of non-response compared with BNI grade IV (OR 9.33; 95% CI, 1.66–52.3; p = 0.011). Female sex showed a nonsignificant trend toward a lower risk of failure (OR 0.65; 95% CI, 0.13–3.24; p = 0.596). Neither multiple sclerosis-associated TN nor other etiological or dosimetric variables significantly predicted treatment failure. A greater number of beams showed a trend toward an increased probability of retreatment (OR 1.01; p = 0.091), although statistical significance was not reached. Conclusions: Gyroscopic radiosurgery with ZAP-X provides high rates of pain control, rapid clinical response, and a favorable safety profile in patients with refractory TN. Greater baseline pain severity appears to be associated with poorer treatment response. These findings support ZAP-X as an effective frameless radiosurgical alternative for TN, although larger prospective studies are required to identify robust clinical, dosimetric, and radiobiological predictors of long-term outcome.

Brain Sciences doi: 10.3390/brainsci16101060

Authors: Julie Damgaard Rosgaard Jakobsen Estrid Thougaard Lejla Vahl Becirovic Victoria Phuong Amalie Forsberg Jensen Tim Wellinghof Pernille Vinther Nielsen Stefano Raffaele Marta Fumagalli Åsa Fex Svenningsen Bente Finsen Agnieszka Wlodarczyk Flemming Nielsen Kate Lykke Lambertsen Helle Hvilsted Nielsen

Background: Siponimod is a selective modulator of sphingosine-1-phosphate receptors 1 and 5, approved for the treatment of secondary progressive multiple sclerosis. Apart from its immunomodulatory effects, it has been proposed to exert pro-regenerative and pro-myelinating effects. However, it is unclear whether the reported neuroprotective and pro-regenerative effects of siponimod reflect direct engagement on glial cells or arise secondary to reduced neuroinflammation. Methods: We investigated the systemic and central effects of siponimod in naïve mice treated orally with 3 mg/kg for 19 consecutive days. Peripheral immune cell populations were analyzed by flow cytometry, drug exposure was quantified by liquid chromatography and high-resolution mass spectrometry, glial cell populations were assessed by immunohistochemistry, and functional outcomes were evaluated using behavioral tests. Results: Siponimod treatment induced pronounced T cell lymphopenia, characterized by reduced CD8+ T cells and increased proportions of double-negative T cells and CD4+CD25+ T cells. Lymphocyte distribution was compartment-specific, with increased splenic T cell and reduced thymic T cell counts, while lymph nodes were largely unaffected. Siponimod penetrated the CNS, with hippocampal concentrations exceeding plasma levels. Despite robust brain exposure, siponimod did not affect oligodendrocyte lineage cell density, proliferation, microglial cell density, or morphology, nor did it affect behavior in mice. Conclusions: Taken together, these findings demonstrate that under physiological conditions, the actions of siponimod lie primarily in its immunomodulatory effects, while direct effects on glial cells and behavior are absent. Furthermore, this study paves the way for studies of siponimod’s effect on glial cells and neurons in models with minimal or no blood–brain barrier damage.

Brain Sciences doi: 10.3390/brainsci16101059

Authors: Yazmín M. Amador-Segovia Daniel F. Ramos-Rosales Víctor M. Ayala-García Norma Urtiz-Estrada Maribel Cervantes-Flores Luz I. Valenzuela-García Sandra I. Torres-Herrera José M. Salas-Pacheco Miguel A. Leyva López Marcelo Barraza-Salas

Background: The glucocorticoid receptor gene (NR3C1) regulates hypothalamic–pituitary–adrenal (HPA) axis feedback. Evidence of its epigenetic and transcriptional alterations in suicide remains limited and inconsistent, particularly in underrepresented populations. Methods: We measured regional methylation within the assayed NR3C1 exon 1F promoter region and total NR3C1 mRNA expression in dorsolateral prefrontal cortex (BA9) from 13 suicide cases and 13 non-psychiatric controls from northern Mexico. Groups were frequency-matched by age, sex, and post-mortem interval. Methylation was assessed by methylation-sensitive restriction enzyme (MSRE) qPCR and expression by RT-qPCR. Group differences were tested using two-sided exact Mann–Whitney U tests; effect sizes were probability of superiority (PS) and Cliff’s δ. Correlation and male-only analyses were exploratory. All p-values were nominal. Results: Cases showed higher total NR3C1 mRNA expression (U = 45, p = 0.04412; PS = 0.734; δ = 0.467) and regional exon 1F methylation (U = 29, p = 0.00349; PS = 0.828; δ = 0.657). The measures showed a non-significant positive correlation (ρ = 0.27, p = 0.179). In males, methylation remained higher in cases (p = 0.0147), whereas expression remained directionally higher but non-significant (p = 0.165). Conclusions: Individuals who died by suicide showed higher regional exon 1F methylation and NR3C1 mRNA expression in BA9. The measures were not significantly correlated and should be interpreted as separate group-level differences, not evidence of direct methylation–expression coupling. The expression finding is preliminary. Given the small sample, limited clinical information, and comparison with non-psychiatric controls, the differences cannot be attributed specifically to suicide and require replication.

Brain Sciences doi: 10.3390/brainsci16101058

Authors: Sisi Peng Bingqian Lv Wenyan Zhou Linna Ji Junjian Zhang

Background: Individuals with vascular risk factors (VRFs) often experience underrecognized emotional symptoms. This study examined the association of vascular risk factor burden (VRF burden) with anxiety, depression and their symptom co-occurrence. Methods: A total of 381 participants were classified by HAMA and HAMD-17 scores into control, anxiety, depression, and anxiety–depression symptom co-occurrence groups. VRF burden was defined as the number of eight prespecified VRFs. Multivariable linear and logistic regression analyses were performed. Results: Anxiety–depression symptom co-occurrence was the most common symptom pattern (40.9%). Greater VRF burden was associated with higher HAMA (B = 2.549, 95% CI: 2.028–3.070) and HAMD-17 scores (B = 1.802, 95% CI: 1.258–2.346; both p < 0.001). Greater VRF burden was also associated with higher odds of symptom co-occurrence after multivariable adjustment (adjusted OR = 1.944, 95% CI: 1.548–2.441, p < 0.001). Conclusions: VRF burden was associated with more severe emotional symptoms and higher odds of anxiety–depression symptom co-occurrence. Prospective studies are needed to clarify temporal relationships.

Brain Sciences doi: 10.3390/brainsci16101057

Authors: Maria Y. Y. Shiu Melissa Cote Nigel McLeish Jun Han Bae Shawn G. Rhind

Proteins released after brain injury can be measured in blood, but a blood result does not directly measure the concentration at the site of injury. Between brain tissue and a peripheral sample, proteins may enter brain interstitial fluid (ISF), exchange with cerebrospinal fluid (CSF), leave through several drainage or barrier pathways, and undergo dilution and clearance. This narrative review examines those steps for glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament light chain (NfL), S100B, neuron-specific enolase (NSE), tau proteoforms, and amyloid-beta. It also evaluates whether microneedle sampling of dermal ISF (dISF) could support repeated, low-burden measurement. The evidence indicates that gradients and time lags differ by analyte; a single blood-to-skin conversion is unlikely to work. Human dISF studies demonstrate broad molecular overlap with plasma, including similar N-glycan profiles despite lower total protein, and a human aptamer-patch trial demonstrates frequent drug monitoring. These findings do not yet validate a neurological protein assay in skin: no paired clinical study has established quantitative dISF concordance for GFAP, UCH-L1, NfL, tau, or amyloid-beta. The immediate priorities are analyte-specific recovery testing, paired blood–dISF time courses, paired CSF measurements where clinically feasible, and careful accounting for local skin and device effects.

Brain Sciences doi: 10.3390/brainsci16101056

Authors: Feng Li Chi Zhang Weiwei Jiang Bo Song Yingxin Wang Lu Tang Shanshan Chen Xiangyi Liu Jingping Shi

Background: Persistent postural-perceptual dizziness (PPPD) is a chronic functional neuro-otologic disorder marked by persistent dizziness, unsteadiness, and visual dependence. Its electrophysiological mechanisms remain unclear. This study examined resting-state EEG spectral power and functional connectivity in PPPD and their associations with postural stability and clinical symptoms. Methods: Forty patients with PPPD and 40 age- and sex-matched healthy controls were studied with an eyes-closed resting-state EEG recording. Static postural stability was measured with the Pro-Kin system. Spectral power was calculated for delta, theta, alpha, beta, and gamma bands. Functional connectivity was assessed using the weighted phase lag index. Results: Static posturography showed impaired postural stability in patients with PPPD compared with healthy controls. Spectral power analysis showed increased theta-band relative power over the frontal and left parieto–occipital regions. Connectivity analysis showed increased prefrontal–temporal and decreased temporal–occipital connectivity in the theta band, increased fronto–parieto–occipital and decreased parietal–temporal connectivity in the alpha band, and decreased cerebellar and temporal, central connectivity in the gamma band. Conclusions: PPPD was associated with frequency-specific alterations in resting-state cortical oscillations and functional connectivity involving cognitive–affective, visual, and sensorimotor networks. Resting-state EEG may help characterize network-level abnormalities in PPPD.

Brain Sciences doi: 10.3390/brainsci16101055

Authors: Bernadette Murphy

The leading review articles for 2025 are clustered [...]

Brain Sciences doi: 10.3390/brainsci16101054

Authors: Junhao Huang Jinglin Huang Ziqing Liu Xinyue Yang

Background/Objectives: To compare the acute effects of high-intensity interval exercise (HIIE) and moderate-intensity continuous exercise (MICE) on executive-function performance, prefrontal oxyhaemoglobin (Oxy-Hb) signals, brain-derived neurotrophic factor (BDNF), and lactate in sedentary young adults. Methods: Fifteen participants (10 men, 5 women; 22 ± 2 years; BMI 23.07 ± 4.12 kg/m2) completed HIIE, MICE, and seated control sessions in randomized order with 7-day washouts. Stroop, N-back, and Switching tasks; prefrontal fNIRS; plasma BDNF; and blood lactate were assessed before and after each condition. Correlation and indirect-effect analyses were exploratory. Results: Both HIIE and MICE significantly improved inhibitory control, working memory, and cognitive flexibility relative to baseline. For inhibitory control, both exercise modes reduced reaction times in congruent and incongruent Stroop tasks, but only HIIE improved Stroop interference performance. Both HIIE and MICE improved inhibitory control, working memory, and cognitive flexibility relative to baseline. Both reduced reaction times in the congruent and incongruent Stroop, 3-back, and Switching trials, whereas only HIIE improved Stroop interference. Both exercise modes increased Oxy-Hb in the OFA during Stroop and in the FPA and R-DLPFC during Switching. HIIE additionally increased Oxy-Hb in the FPA during Stroop, PTR during Switching, and R-DLPFC during N-back. Both exercise modes increased circulating BDNF and lactate, with a greater lactate response after HIIE. Improvements in executive function were associated with changes in Oxy-Hb, BDNF, and lactate. Conclusions: Both exercise sessions were followed by faster reaction times on selected tasks. The small sample, multiple analyses, and potential systemic contributions to fNIRS signals preclude firm conclusions about exercise-mode superiority or biological mediation.

Brain Sciences doi: 10.3390/brainsci16101053

Authors: Katsuhiro Adachi Satoshi Tanaka Naoto Sakai

Background: Persistent postural–perceptual dizziness (PPPD) is a chronic functional vestibular disorder characterized by persistent dizziness and unsteadiness. Resting-state functional magnetic resonance imaging (rs-fMRI) has identified dysfunction in vestibular, visual, somatosensory, spatial cognitive, and emotional networks in PPPD. Although vestibular rehabilitation has demonstrated efficacy in PPPD, its effects on these dysfunctional neural networks remain unclear. Case: A 37-year-old woman with PPPD had experienced recurrent rotational vertigo approximately every 6 months followed by persistent non-spinning dizziness. Assessment: Baseline assessment showed severe dizziness-related disability (Dizziness Handicap Inventory (DHI) score: 66) and depressive symptoms (Self-Rating Depression Scale (SDS): 40). Posturography demonstrated increased sway with eyes closed, whereas video head impulse testing revealed no significant abnormalities. Rs-fMRI was also performed, and functional connectivity was analyzed using SPM12 and the CONN toolbox with a region-of-interest-to-region-of-interest approach. Outcome: During the 8-week period of vestibular rehabilitation, including continued pharmacotherapy, the DHI score decreased from 66 to 16 and the SDS score from 40 to 27. Among the nine prespecified ROI-to-ROI connections, the largest longitudinal connectivity difference was observed between the right hippocampus and left frontal pole, decreasing from z = 0.110 at baseline to z = −0.277 at follow-up (Δz = −0.387). At the uncorrected exploratory level, connectivity decreased between the right anterior parahippocampal cortex and right angular gyrus but increased between the right parieto-insular vestibular cortex and right lingual gyrus. Conclusion: Clinical improvement following vestibular rehabilitation coincided with changes in PPPD-related functional connectivity, particularly reduced connectivity between the right hippocampus and left frontal pole. Although this single-patient case report had no control condition, included only one rs-fMRI scan at each time point, and involved concurrent pharmacotherapy, this finding may reflect anxiety-related mood changes in spatial cognitive processing.

Brain Sciences doi: 10.3390/brainsci16101052

Authors: Rafael Pereira Azevedo Teixeira Vanessa Teixeira Müller Daniel Rodrigues Lopes Marcson Love Maquiné de Freitas Maycon da Cunha Herzog Dany Alexis Sobarzo Soto Ciro José Brito Bianca Miarka

Background: Non-invasive brain stimulation (NIBS), including transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS), has emerged as a potential ergogenic strategy for modulating neural activity and enhancing cognitive and physical performance in sports. However, evidence regarding its application in combat sports remains limited, heterogeneous, and fragmented. This study aimed to systematically synthesize the effects of NIBS on neuromodulation and cognitive, physical, and psychophysiological performance-related outcomes in combat sport athletes. Although NIBS encompasses several stimulation techniques, the evidence identified in combat sport athletes in this review predominantly involved tDCS. Methods: A systematic review was conducted in accordance with the PRISMA 2020 guidelines and registered in PROSPERO (CRD420251150915). Searches were performed in CAPES, PubMed, Scopus, and SPORTDiscus using predefined keywords related to combat sports and brain stimulation techniques. Studies were included if they involved combat sport athletes and investigated the effects of NIBS on performance-related outcomes. Data extraction included study design, sample characteristics, stimulation protocols, and main findings. Methodological quality was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool for randomized studies and ROBINS-I for non-randomized studies, while certainty of evidence was evaluated using the GRADE framework. Results: Nine studies were included in the final synthesis (eight identified through database searching and one through other methods/manual reference screening), encompassing athletes from taekwondo, judo, boxing, mixed martial arts, fencing, and Brazilian jiu-jitsu. Most studies applied tDCS protocols targeting the primary motor cortex (M1) or the dorsolateral prefrontal cortex (DLPFC), with intensities ranging from 1 to 2 mA and stimulation durations between 10 and 20 min. tDCS demonstrated potential benefits in reaction time, selective attention, memory, and resistance to fatigue, as reflected by increased time to task failure. Additionally, enhancements in neuromuscular activation and reductions in anxiety were observed. However, results were heterogeneous, and some studies reported no significant effects on performance-related variables. Risk-of-bias assessment revealed methodological limitations across studies, and GRADE indicated low-to-very-low certainty of evidence for most outcomes. Conclusions: tDCS may influence selected cognitive, neuromuscular, and fatigue-related outcomes in combat sport athletes; however, the direction and magnitude of these effects are inconsistent across studies. Given the substantial methodological heterogeneity and the low-to-very-low certainty of evidence, no definitive conclusions regarding efficacy or routine practical application can currently be drawn. Further large-scale, standardized, high-quality randomized controlled trials are needed.

Brain Sciences doi: 10.3390/brainsci16101051

Authors: Wei Zhao Jianing Dai Yitong Pan Shixiao Xiao Tongle Xie Yao Li Yongkang Yu

Background/Objectives: Motor imagery electroencephalography (MI-EEG) contains weak, non-stationary patterns that evolve across channels and time. Effective decoding requires local sensorimotor structure, trial-wide context, and ordered temporal evolution to be represented without discarding information from earlier processing stages. Methods: We propose STDR-Net, a Spatio-Temporal Dependency Refinement Network that recalibrates convolutional tokens, models their global interactions, restores the original local representation through a cross-stage residual bridge, and refines the fused sequence with a bidirectional long short-term memory network. STDR-Net was evaluated on BCI Competition IV-2a, BCI Competition IV-2b, and the PhysioNet EEG Motor Movement/Imagery dataset against nine reproduced baselines. The PhysioNet experiment used a pooled mixed-participant trial-level split rather than an unseen-participant evaluation. Results: STDR-Net obtained accuracies of 82.69%, 86.99%, and 59.76% and Cohen’s kappa values of 0.7692, 0.7398, and 0.46, respectively. It achieved the highest observed mean accuracy on IV-2a and competitive performance on IV-2b and PhysioNet. Bridge-specific, ordering, module, and augmentation ablations supported the proposed pathway on IV-2a, whereas the differences on IV-2b were small and not significant after multiplicity correction. Conclusions: The results support information-preserving dependency refinement as a competitive design for MI-EEG decoding, while also showing that its benefit depends on the dataset and evaluation setting.

Brain Sciences doi: 10.3390/brainsci16101050

Authors: Anna Kannonier Sandria Stornig Karl Koschutnig Human-Friedrich Unterrainer Patrick Klepits Andreas Fink

Objectives: The present study examined the effects of a three-week dance intervention on diffusion MRI-based white matter metrics in a sample of individuals diagnosed with substance use disorder (SUD; F19.2). Methods: The intervention was carried out in an inpatient rehabilitation facility twice a week. Participants were partly randomized into two groups, one intervention group and one treatment-as-usual group, which did not differ in terms of substitution or other psychiatric medications. Both groups underwent an MRI assessment at baseline and after the intervention, using diffusion-weighted imaging. Results: Analysis of MRI diffusion data revealed significant effects in the intervention group relative to the treatment-as-usual group, particularly within white matter networks associated with sensorimotor functions, with the most pronounced changes in the cerebellum. Conclusions: These findings suggest that learning a new motor skill may induce white matter changes in the brain in individuals with SUDs.

Brain Sciences doi: 10.3390/brainsci16101049

Authors: Flavio Donnini Cristiana Bellan Sergio Antonio Tripodi Lucia Mundo Paolo Tini

Background/Objectives: Experimental work has implicated TMEM164 in glioblastoma radioresistance through post-translational inhibition of FASN and suppression of radiation-induced necroptosis, supported clinically by a dichotomised single-database survival analysis. We tested whether the previously reported transcript-level clinical association of TMEM164 is reproducible across independent human glioblastoma cohorts and characterised its relationship with tumour status, necroptosis-related transcripts and recurrence. Methods: Secondary analysis of four public resources: TCGA (n = 153), CGGA-693 (n = 104), CGGA-325 (n = 73), and 104 matched primary-recurrence pairs from GLASS. Overall survival was modelled by continuous Cox regression, pooled by Hartung–Knapp random-effects meta-analysis. Results: TMEM164 occupied a higher within-sample percentile in tumour than in non-tumour brains in all three cohorts (Cliff’s δ 0.68–0.85; all p ≤ 1.3 × 10−3), was co-expressed with RIPK1 (ρ 0.25–0.44; all q < 0.05), ranking 43rd of 19,985 genes, and was unchanged by adjustment for tumour composition. No association with overall survival replicated across cohorts, in the pooled analysis (HR 1.11, 95% CI 0.77–1.61; I2 = 49.9%), among irradiated patients or in confirmed IDH-wildtype cases; isolated nominally significant positive estimates arose in exploratory strata and were not reproduced elsewhere. With 277 events, the pooled interval excludes hazard ratios above approximately 1.6 per standard deviation, while smaller effects remain compatible. An optimal cutpoint generated HR 1.83 (p = 0.004) that did not survive correction for selection. TMEM164 protein was quantified in 0 of 99 CPTAC glioblastomas. Conclusions: Baseline bulk-tumour TMEM164 mRNA carries no reproducible prognostic information in adult glioblastoma. The proposed mechanism is post-translational and must be tested at the protein and activity level, on treatment-related tissue sampling.

Brain Sciences doi: 10.3390/brainsci16101048

Authors: Hua Zhang Zhengxu Cai

Objectives: Temporal lobe epilepsy (TLE) causes spontaneous seizures, hippocampal neuronal loss, and cognitive impairment. This study investigated whether miR-206 inhibition attenuates seizures and cognitive dysfunction by activating the BDNF/TrkB cascade in mice with pilocarpine-induced TLE. Methods: Fifty TLE-model C57BL/6N mice were divided into five groups. MiR-206 antagomir or a negative control was stereotaxically injected into the hippocampus. ANA-12, a TrkB inhibitor, was given intraperitoneally. We detected miR-206 with RT-qPCR. EEG was used to assess seizure activity. Spatial cognition was measured via the Morris water maze. Neuronal injury was evaluated using HE and Nissl staining. Target protein levels were quantified by Western blotting. Hippocampal miR-206 was elevated in TLE mice. Results: MiR-206 antagomir lowered miR-206 expression. It prolonged seizure latency. It reduced seizure frequency and duration. It restored spatial learning and memory function. It relieved CA3 neuronal loss and up-regulated BDNF/TrkB, SYP, and PSD95. ANA-12 abolished these protective phenotypes. Conclusions: MiR-206 inhibition confers anti-seizure, neuroprotective, and cognition-improving effects. These benefits depend on functional BDNF/TrkB signalling. miR-206 is a potential therapeutic target for TLE.

Brain Sciences doi: 10.3390/brainsci16101047

Authors: Tatiana Gerasimova Ekaterina Novosadova Ekaterina Stepanenko Lyudmila Novosadova Elena Arsenyeva Artem Eremeev Valentina Nenasheva

Background: Neuroinflammation and neurodegeneration are closely linked in Parkinson’s disease (PD). Specialized pro-resolving mediators (SPMs) are of interest as potential therapeutic agents for PD because they promote the resolution of inflammation. Methods: We investigated whether PARK2 mutations are associated with cell-type-specific patterns of SPM receptor expression by comparing neuronal and glial cultures derived from induced pluripotent stem cells (iPSCs) of PD patients carrying different PARK2 mutations with corresponding cultures from healthy donors (HDs), using real-time PCR and Western blotting. Results: The resolvin E1 receptors, BLT1 and CHEMR23, and the resolvin D1 (RvD1) receptors, GPR32 and FPR2, were detected at both the mRNA and protein levels in PARK2-mutant neurons and glia. Compared with HD cultures, mutant neurons had significantly higher CHEMR23 protein levels despite similar CHEMR23 mRNA levels, whereas no statistically detectable differences in the expression of any of the four receptors were found in glia. Receptor profiles also appeared to differ between cells carrying PARK2 mutations and those carrying mutations in other genes (GBA1, LRRK2). PARK2-mutant neurons showed lower levels of several inflammatory markers than HD neurons, in contrast to the pro-inflammatory profile previously reported in PARK2-mutant glia. A pilot experiment with glial cultures derived from one cell line per group suggested that in the presence of TNFα, RvD1 may reduce IL-6 secretion and increase cellular metabolic activity in PARK2-mutant glia, with responses that appeared to differ from those observed in HD glia. Discussion: The presence of resolvin receptors in PARK2-mutant neurons and glia, together with elevated CHEMR23 protein levels in mutant neurons compared with HD neurons, provides a basis for further investigation of resolvin signaling in PARK2-associated PD. However, the relationship between receptor expression and functional responses to resolvins remains to be established. The contrasting inflammatory profiles of neurons and glia suggest that PARK2-mutant glial cultures may be particularly relevant for investigating the anti-inflammatory effects of resolvins. Conclusions: Cell-type- and genetic-background-associated differences in receptor expression should be considered when developing resolvin-based therapeutic approaches for PD. Further studies are needed to assess the potential anti-inflammatory effects of RvD1 on glial cells in genetic forms of the disease.

Brain Sciences doi: 10.3390/brainsci16101046

Authors: Edicer Ramírez-Rivera Alexandra N. Burgos-Vélez

Background: Late-onset psychosis (onset after age 60) in a patient with no prior psychiatric history is uncommon and frequently signals an underlying neurocognitive or structural brain disorder rather than a primary psychiatric illness. Erotomania, the delusional belief that an inaccessible or higher-status person is in love with the patient, has rarely been described together with cognitive impairment and ventriculomegaly. We describe a case in which these three features occurred together and set out the competing explanations for their co-occurrence. Methods: We report a single retrospective case, drawing on inpatient psychiatric and neurology consultation records, cognitive screening with the Montreal Cognitive Assessment (MoCA), head computed tomography, brain magnetic resonance imaging, and one-month outpatient follow-up. Written informed consent for publication was obtained from the patient during the hospitalization, and his capacity for that specific decision was assessed by the treating team. Results: A 75-year-old man with no psychiatric history developed subacute, fixed erotomanic delusions involving a public figure, with an illogical and circumstantial thought process, intermittent disorientation, and severely impaired judgment. Acting on these beliefs, he sold his home and transferred approximately $200,000 to individuals impersonating the celebrity online. Neuroimaging showed ventriculomegaly disproportionate to cortical sulcal prominence together with chronic small-vessel ischemic change. Neurology characterized the picture as borderline or early normal pressure hydrocephalus versus hydrocephalus ex vacuo with a superimposed neurocognitive disorder. The recommended diagnostic large-volume lumbar puncture was not performed, and no quantitative morphometric measurements were obtained, so normal pressure hydrocephalus remained unconfirmed. MoCA performance worsened from 23/30 at admission to 17/30 one month later, although both assessments were obtained during active psychosis and antipsychotic treatment. He was treated with low-dose antipsychotic medication and discharged with outpatient psychiatric and neurosurgical follow-up, and delusions and cognitive impairment persisted at short-term follow-up. Conclusions: New-onset erotomanic delusions in an older adult should prompt evaluation for an underlying neurocognitive or neurological disorder, including structural imaging for potentially reversible causes. This single case cannot establish the direction of the relationship among the erotomanic syndrome, the cognitive impairment, and the ventriculomegaly. Because impaired judgment in this setting can produce catastrophic financial harm, clinicians should pair neuropsychiatric evaluation with formal decisional capacity assessment.

Brain Sciences doi: 10.3390/brainsci16101045

Authors: Sahil Bajaj Christopher Chad Quarles Katherine Gilmore Ying Qiao Chinmay Mokashi Max Wintermark Jeffrey S. Wefel Kyle R. Noll Michelle Zalles Michael Roth

Background: Diffusion MRI (dMRI) provides sensitive markers of brain microstructure and glymphatic function. The interplay between brain microstructure and glymphatic function in shaping long-term survivorship outcomes remains unclear. We examined associations of dMRI markers with survival and symptom interference in long-term head and neck (HN) cancer survivors and tested whether glymphatic function modified these associations. Methods: dMRI data from 135 long-term HN cancer survivors were analyzed. Radial diffusivity (RD) and fractional anisotropy (FA) were quantified across 76 gray matter regions and 45 white matter tracts. Glymphatic function was indirectly estimated using diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index. Survival status was determined through clinical follow-up, and symptom interference was assessed using the MD Anderson Symptom Inventory. Stepwise regression identified microstructural measures associated with survival and symptom interference, followed by moderation analyses testing the role of DTI-ALPS. Results: Reduced RD in the left medial orbitofrontal cortex (MOFC), higher FA in the left and lower FA in the right entorhinal cortex, and higher FA in the right extreme capsule were associated with longer survival (p < 0.0006, corrected for multiple comparisons). Lower RD in the left uncinate fasciculus (UF) and superior temporal cortex (STC) and lower FA in the right caudal anterior cingulate cortex (CACC) were associated with lower symptom interference (p < 0.0006, corrected for multiple comparisons). Higher DTI-ALPS strengthened the association between preserved MOFC microstructure and longer survival (β = −1.95, p < 0.001) and moderated the associations of microstructure in the UF (βs > 4.08, p < 0.001), STC (β = 5.82, p < 0.001), and CACC (β = 16.47, p < 0.001) with symptom interference. Conclusions: dMRI markers of brain microstructure and glymphatic function are associated with long-term outcomes in HN cancer survivors. These findings support a region-specific resilience framework and highlight the potential of dMRI-based biomarkers for characterizing brain health in cancer survivorship.

Brain Sciences doi: 10.3390/brainsci16101043

Authors: Anna Makarewicz Remigiusz Recław Anna Grzywacz Krzysztof Chmielowiec Łukasz Jaworski Marta Kuczak-Wójtowicz Jolanta Chmielowiec

Addiction neuroscience has advanced the identification of vulnerability and mechanisms involving reward learning, salience, cognitive control, interoception, cue reactivity, and stress regulation. Yet a key translational question remains unresolved: when does an evolving post-perturbation brain–behavior trajectory become relevant to treatment benefit? Prediction models can estimate future craving, lapse, or deterioration, and adaptive-intervention systems can deliver support using prespecified tailoring variables, but neither dynamic treatment regimes, just-in-time adaptive interventions, nor causal machine learning specifies what evidence a temporal quantity must satisfy before it may serve as the tailoring variable itself. This Perspective asks whether prospective recovery position modifies the benefit of the same intervention, and introduces BRAIN-TIME as a falsifiable episode-level architecture for answering that question. It begins with a defined cue, stress, affective, or sleep-related perturbation, follows one prespecified recovery domain relative to an individualized reference, and separates retrospectively adjudicated sustained re-entry from a prospective estimate of incomplete recovery computed only from information available at the decision point, with no use of later observations. Its decisive Stage 1 test is treatment-effect moderation: at a common locked landmark, the benefit of the same intervention and dose must vary across prospectively estimated recovery positions by a prespecified, practically meaningful amount. A minimal proof of concept combines a standardized low-intensity challenge, repeated craving or autonomic sampling, an independent outward-function criterion, negative controls, and randomized fixed-content intervention. No original data are reported, and every quantity specified here is a proposed construct, estimand, or falsification criterion rather than an observed result. BRAIN-TIME is therefore neither a relapse classifier nor an autonomous treatment rule. Its central claim is deliberately narrow: temporal recovery information becomes relevant to treatment timing only when prospective episode position is shown to modify the benefit of the same intervention.

Brain Sciences doi: 10.3390/brainsci16101044

Authors: Gonzalo Márquez David Colomer-Poveda Cristina Benavente Paulino Padial Rafael Timón Blanca de la Fuente Belén Feriche

Background: This study compared the effects of 8 weeks of hypertrophy-oriented resistance training (RT) under normoxia (N), moderate hypobaric hypoxia (HH), and moderate normobaric hypoxia (NH) on functional, neuromuscular and structural adaptations of the quadriceps. Methods: Twenty-nine resistance-trained males (22.5 ± 3.4 years) were assigned to N (n = 10), HH at 2320 m (n = 8), or equivalent NH (FiO2 = 15.9%; ~2320 m; n = 11). Participants completed 22 supervised RT sessions across 8 weeks. Primary outcomes were corticospinal excitability (CSE), assessed via transcranial magnetic stimulation (TMS), and neuromuscular activation, assessed with femoral nerve stimulation and surface electromyography. Secondary measures included back squat one-repetition maximum (1RM_SQ) and vastus lateralis (VL) muscle thickness (MTh) via ultrasound. Results: All groups improved maximal squat performance (p < 0.001; NH Δ29.10 kg, d = −1.72; HH Δ22.61 kg, d = −1.34; N Δ16.82 kg, d = −0.99), VL MTh (p < 0.001; HH Δ0.25 cm, d = −0.66; N Δ0.24 cm, d = −0.63; NH Δ0.10 cm, d = −0.25), and VL maximal compound muscle action potential (Mmax) (p = 0.035; HH Δ1.13 mV, d = −0.65; NH Δ1.07 mV, d = −0.61; N Δ0.61 mV, d = −0.35), regardless of environmental condition. Conversely, the maximum motor-evoked potential obtained from the recruitment curve (RC_MEPmax) decreased following RT (p < 0.001; NH Δ−0.16, d = 1.39; HH Δ−0.08, d = 0.73; N Δ−0.04, d = 0.36). Other CSE markers remained unchanged. Conclusions: Eight weeks of RT under moderate hypoxia induced increases in Mmax and reductions in RC_MEPmax, suggesting training-related neuromuscular adjustments enhancing motor efficiency under hypoxic stress. These adaptations were accompanied by meaningful strength gains, although the mechanisms underlying their relationship remain to be fully elucidated.

Brain Sciences doi: 10.3390/brainsci16101042

Authors: Tehreem Iman Humaira Muzaffar Muhammad Zubair Ghulam Hussain

Background: Peripheral nerve injury causes substantial functional impairment and represents a major health concern worldwide. Peripheral nerve injuries are sequelae of iatrogenic injuries, occupational trauma, and motor vehicle crashes. The available therapeutic approaches, including pharmacological treatment, surgical repair, and rehabilitation, are mostly management therapies rather than curative treatments. Consequently, functional recovery is never achieved. There is a dire need for new therapeutic approaches to facilitate functional restoration. Kaempferol-3-O-rutinoside (K3R) is a plant-derived flavonoid glycoside known for its potent anti-inflammatory and antioxidant properties. Flavonoids may promote tissue recovery following injury by modulating inflammatory responses and reducing oxidative stress. However, the effect of K3R on functional recovery following peripheral nerve injury has not yet been investigated. Therefore, this study aimed to evaluate the effects of K3R on early functional recovery following sciatic nerve crush injury in mice. Methods: Twenty-four BALB/c mice were equally allocated to three groups (n = 8): (1) Sham, (2) Ctrl (Control), and (3) K3R treatment group. K3R (2.5 mg/kg) was dissolved in DMSO and administered intraperitoneally once a day from the time of sciatic nerve injury until the conclusion of the experiment. The Ctrl and sham groups received an equal volume of DMSO according to the same dosing schedule. Sensorimotor function recovery was assessed using behavioral tests, including grip strength, pinprick, sciatic functional index (SFI), and hot plate tests. Hematological and biochemical assays were performed to assess total blood count and oxidative stress markers. Muscle fiber morphology was evaluated by morphometric analysis. Proinflammatory cytokines (TNF-α and IL-6) were measured as indicators of the systemic inflammatory response, whereas S100β protein levels were measured as a marker associated with neural injury and glial responses following sciatic nerve injury. Results: K3R treatment significantly enhanced early sensorimotor function recovery compared with the Ctrl group (p < 0.001). Significant differences in oxidative stress markers TAC (p < 0.001), TOS (p < 0.001), MDA (p = 0.003), and CAT (p = 0.007) were observed among the experimental groups. When comparing the K3R-treated group to the Ctrl group, morphometric analysis revealed an increase in the diameter of muscle fibers (p = 0.011). The levels of IL-6 (p = 0.042) and TNF-α (p = 0.005) indicated attenuation of the systemic inflammatory response, while reduced S100β levels (p = 0.002) were observed in the K3R-treated group, consistent with reduced injury-associated changes. Conclusions: Our findings suggest that K3R may facilitate early functional recovery following sciatic nerve injury, potentially by attenuating oxidative stress and systemic inflammatory responses. However, the precise mechanisms underlying this remain to be elucidated. Future studies should therefore focus on identifying the molecular pathways involved in K3R-mediated recovery, as well as axonal regeneration, Schwann cell activity, and remyelination. Long-term investigations incorporating structural, morphometric, and molecular assessments will be essential to understand its regenerative efficacy and translational potential.

Brain Sciences doi: 10.3390/brainsci16101041

Authors: Dirk W. Eilert Philipp Mensah

Background/Objectives: The relationship between expressive flexibility—the capacity to enhance and suppress visible emotional responses according to situational demands—and mental health has not been systematically synthesized. This systematic review examined associations across psychopathology, psychological well-being, resilience and adaptive functioning, and social functioning. Methods: Following preregistration on the Open Science Framework (10.17605/OSF.IO/BA5HD), PsycINFO, PsycArticles, and PubMed were searched on 23 June 2026, supplemented by citation searching and expert consultation. English-language, peer-reviewed studies of participants aged at least 12 years assessing expressive flexibility and mental health were eligible. Two reviewers independently selected studies and assessed methodological quality using design-specific JBI critical appraisal tools. Narrative synthesis, random-effects meta-analyses, and a structured narrative appraisal of the evidence for each outcome were conducted. Results: Twenty-nine studies were included (cumulative analytic sample: N = 8357). Appraisals identified limitations in confounding control, handling of incomplete follow-up, and methodological reporting. Greater overall expressive flexibility was generally associated with lower psychopathological symptom burden, greater psychological well-being, greater resilience and adaptive functioning, and better social functioning. Component findings varied. Pooled associations were inverse for depressive symptoms (k = 9, N = 3622, r = −0.14, 95% CI [−0.26, −0.01]) and, exploratorily, anxiety (k = 7, N = 3134, r = −0.13, 95% CI [−0.23, −0.03]). The positive association with life satisfaction was preliminary (k = 4, N = 1910, r = 0.27, 95% CI [0.02, 0.49]). Leave-one-out analyses indicated uncertainty across all three syntheses. Heterogeneity was substantial to very high and all prediction intervals included zero. Conclusions: Findings suggest that expressive flexibility is an emotion-expression capacity associated with several dimensions of mental health, primarily in non-clinical samples. Its potential transdiagnostic relevance warrants further investigation, but limited robustness, substantial heterogeneity, and predominantly cross-sectional evidence preclude firm conclusions about generalizability and causal effects.

Brain Sciences doi: 10.3390/brainsci16101040

Authors: Piero Barbanti Jesuély Spieckert de Souza Giulia Fiorentini Francesca Pistoia Cecilia Camarda Alberto Doretti Gabriella Egeo Florindo d’Onofrio Cinzia Aurilia Marco Bartolini Simone Braca Antonio Carnevale Rosario Grugno Massimo Autunno Maurizio Zucco Marco Russo Simone Quintana Stefano Caproni Alfonsina Di Summa Paola Scatena Massimo Filippi Monica Laura Bandettini Di Poggio Cinzia Finocchi Alessandra Cherchi Paolo Solla Riccardo Altavilla Barbara Petolicchio Annalisa Gai Mattia Sansone Rossana Terlizzi Francesco Bono Gennaro Saporito Stefano Messina Elisabetta Iannaccone Roberto De Simone Valentina Favoni Martina Guarinoni Giovanna Viticchi Domenico Cosenza Ludovica Ferraù Laura Di Clemente Prabha Cristina Ranchicchio Steno Rinalduzzi Ilaria Cetta Sara Cazzulo Francesco Tazza Tommaso Ercoli Carla Zanferrari Francesca Gragnani Pietro Antonio Bruno Renata Rao Fabio Valguarnera Maria Albanese Licia Grazzi Fabrizio Vernieri Alfonso Coppola Carlo Colosimo Francesca Cortese Fabrizio Di Stani Frederico Friedrich Vanise Grassi Carlo Tomino Stefano Bonassi Annamaria Porreca Paola Torelli Sabina Cevoli Italian Migraine Registry (I-GRAINE) Study Group Italian Migraine Registry (I-GRAINE) Study Group

What are the main findings?Migraine care in Italy is characterized by a mismatch between healthcare resource utilization and clinical needs, with limited primary-care involvement, repeated specialist consultations, and healthcare nomadism.Healthcare resource utilization is substantial, including extensive diagnostic testing—predominantly brain imaging—as well as emergency department visits, detoxification cycles, and repeated access to headache centers.

Brain Sciences doi: 10.3390/brainsci16101039

Authors: Eleonora Grande Andrea Bartolo Chiara Rita Masotti Alice Esposito Vincenzo Esposito Marco Ciavarro

Objective: Intraoperative direct electrical stimulation (DES) remains the gold standard for mapping motor and cognitive cortical functions during awake brain surgery. However, a reproducible method to relocate these stimulation sites on the common brain template is still lacking, hindering reproducibility and data integration. Here, we propose our tested corticotopography method, as a reliable technique for mapping cortical DES sites onto brain atlases. Methods: Corticotopography was applied by matching the intraoperative image of the exposed cortex with the preoperative 3D MRI-based brain reconstruction using anatomical landmarks (i.e., sulci, gyri, and cortical vessels). Coordinates of the stimulation sites were then extracted using FSLeyes and mapped to MNI152 space. The method’s reliability was then evaluated through an inter-rater comparison. Lesion volume, tumor relapse status, and extent of craniotomy were tested for their potential bias on localization reliability. Results: Ninety eloquent cortical sites were identified in 19 patients undergoing awake surgery for glioma resection. Inter-rater analysis showed high concordance with 87% of stimulated sites presenting a spatial discrepancy below 2.5 mm. No significant differences in localization agreement were observed between newly diagnosed or relapsing tumors or as a function of lesion volume or craniotomy size. Conclusions: We introduce a standardized and reproducible corticotopography technique to localize intraoperative cortical stimulation sites on preoperative anatomical MRI. By formalizing the procedure used to map cortical functions, this method reduces inter-study variability, enabling DES to serve as a cumulative and interoperable resource for functional brain mapping. This allows cortical DES-derived information to be integrated with other neuroimaging modalities and leveraged across neuroscientific domains, including large-scale brain mapping and connectomics.

Brain Sciences doi: 10.3390/brainsci16101038

Authors: Gianpiero Greco Domenico Desantis Stefania Cataldi Francesco Fischetti

Background/Objectives: Playing a musical instrument requires precisely timed movements, bimanual or interlimb coordination, visuomotor mapping, auditory and somatosensory feedback, sequence learning, prediction, and executive regulation. This narrative review synthesizes motor, cognitive, and neuroplastic adaptations associated with active instrumental practice in predominantly healthy adults aged 60 years or older, interpreting practice as a complex sensorimotor and motor–cognitive skill activity. Methods: English-language literature from January 2016 through August 2026 was searched in PubMed/MEDLINE, Scopus, and Web of Science Core Collection, supplemented by Google Scholar and citation chasing. Randomized and controlled interventions were prioritized, with longitudinal and observational evidence used contextually; earlier studies were included selectively for seminal or mechanistic context. Results: Direct motor evidence was less abundant than cognitive evidence. Both piano and mallet-percussion programs improved task-proximal bimanual synchronization, and one large active-control trial found greater improvement in untrained unimanual fine-motor control after one year of piano practice. Selective near transfer to continuation timing was also reported, whereas evidence for generalized dexterity, gait, balance, lower-limb coordination, and everyday motor function remained limited or mixed. Cognitive effects were selective, particularly for processing speed, verbal fluency or switching, and some working-memory measures. Neuroplastic findings included cortical-thickness increase, relative structural preservation, altered auditory–motor connectivity, reduced task activation, and oscillatory modulation. Conclusions: Instrumental practice may provide an engaging and adaptable form of sensorimotor and motor–cognitive skill practice in healthy aging, but broad transfer and neuroprotection are not established. Future trials should quantify skill acquisition, dose, retention, and transfer and compare instrument-specific demands.

Brain Sciences doi: 10.3390/brainsci16101037

Authors: Tawanda Machingura Carly Hudson Lauren Waters

Background/Objectives: Atypical sensory processing in adults experiencing mental illness has been widely studied. The purpose of this review is to systematically map and synthesise literature examining the relationship between atypical sensory processing and participation-related outcomes in adults experiencing mental illness. Methods: A scoping review was conducted in accordance with the Joanna Briggs Institute methodology and the PRISMA-ScR reporting guidelines. Six electronic databases (MEDLINE via PubMed, Embase, Web of Science, CINAHL, Scopus, and the Cochrane Library) were searched from inception to March 2026. Additional grey literature sources were searched via ProQuest. Eligible studies recruited adults experiencing mental illness, reported on sensory processing, and included outcomes relating broadly to participation. Results: Eighteen studies met the inclusion criteria; most focused on schizophrenia spectrum disorders (n = 10). Across diagnoses, participants demonstrated higher rates of atypical sensory processing than normative or control populations. Studies using the Adult/Adolescent Sensory Profile indicated that low registration, sensory sensitivity, and sensory avoidance were associated with reduced participation-related outcomes. Studies using objective measures to identify atypical sensory processing similarly found associations with poorer functioning and quality of life, although relationships were often mediated by other variables. Qualitative studies described the influence of sensory experiences on participation and the use of self-management strategies to support occupational engagement. Evidence for sensory modulation interventions was limited but suggested potential improvements in participation. Conclusions: Atypical sensory processing may negatively impact participation in adults experiencing mental illness. Sensory processing represents a potentially modifiable contributor to participation-related outcomes. Further research is required to clarify causal relationships, establish intervention effectiveness, and develop greater conceptual and terminological consistency across disciplines.

Brain Sciences doi: 10.3390/brainsci16101036

Authors: Yasushi Shibata

Background: Triptans and lasmiditan are considered specific acute medications for migraine attacks. Despite the efficacy of these treatments, continuation of these medications is limited because some patients experience adverse effects. A previous study reported a close association between migraine and neurodevelopmental disorders. The present study investigated triptans and lasmiditan in the treatment of consecutive patients with migraine attacks accompanied by neurodevelopmental disorders. Methods: The enrolled patients were diagnosed with migraine by a certified headache specialist. Neurodevelopmental disorders were diagnosed by multiple specialists. Triptan and/or lasmiditan tablets were prescribed for all patients. Results: Triptans were effective in these patients, providing pain relief within 2 h in all patients, and twelve patients (80%) were pain-free at 2 h. However, throat discomfort was detected in two patients, and it was regarded as a minor adverse event. Lasmiditan (50 mg) was prescribed to 12 patients, and it provided pain relief in 11 patients (92%) at 2 h and rendered 7 patients pain-free (58%) at 2 h. Conversely, mild somnolence and mild dizziness were recorded in two and one patient, respectively (25%). Conclusions: In this study, triptans and lasmiditan were effective and safe in the treatment of migraine attacks accompanied by neurodevelopmental disorders. In this study, several different acute treatments were evaluated non-randomly in a small number of patients, making direct comparisons between treatments difficult. The results of our case series should be clarified in future clinical studies with larger patient populations.

Brain Sciences doi: 10.3390/brainsci16101035

Authors: Malak Albedawe Julian Paul Keenan

Ireland has elevated rates of obesity; Eurostat EU-SILC data indicate Ireland ranks approximately 12th in the EU for combined overweight and obesity among adults, and the usual explanations including diet, inactivity, and socioeconomic conditions do not fully account for the burden of metabolic disease. Here we argue that part of the answer may originate in The Great Hunger (An Gorta Mór) which took place in Ireland from 1845 to 1852. The blighting of the potato crop by Phytophthora infestans and seven years of malnutrition left most of the rural Irish population without their only meaningful source of tryptophan and vitamin B6, the two nutrients the body needs to synthesize serotonin. Fetuses developing during those years may therefore have formed hypothalamic appetite circuits under reduced serotonin availability, potentially resulting in reduced expression of the receptor that signals satiety in the brain. Evidence from the Dutch Hunger Winter, the Great Chinese Famine, Finland, Ghana, and the Holodomor indicates that this type of prenatal nutritional disruption is consistently associated with elevated obesity and metabolic disease risk in adulthood, and that some of the associated epigenetic differences are detectable in subsequent generations, although germline transmission has not been established in humans. Here we explore potential neural epigenetic mechanisms that may have originated in the Great Hunger and in subsequent generations.

Brain Sciences doi: 10.3390/brainsci16101033

Authors: Diana Chira Olivia Verișezan-Roșu Ștefan Strilciuc Nicoleta Jemna Ana-Maria Buruiană Emanuel Ștefănescu Răzvan Marian Melinte Sorin Claudiu Man Dafin Fior Mureșanu

Background: Subjective cognitive complaints (SCCs) in middle-aged and older adults are recognized as early warning signs of future cognitive decline. While biological risk factors have been studied extensively, less is known about how modifiable lifestyle factors, stress, mood and sleep relate to actual performance on cognitive tests. Objective: To examine associations between lifestyle (physical activity, alcohol consumption), psychosocial factors (perceived stress, mood, sleep) and standardized cognitive performance in adults with SCCs. Methods: We conducted a cross-sectional analysis using baseline data from 276 adults aged 50–75 years enrolled in the N-HANCE study. Participants completed the Test of Attentional Performance (TAP) and Digit Span (Forward and Backward). Lifestyle and psychosocial variables were assessed using structured questions and validated self-report scales. Associations were examined using Spearman correlations and Mann–Whitney U tests, with Benjamini–Hochberg correction applied across the full family of 132 predictor–outcome comparisons, followed by linear regression models adjusted for age, sex and educational attainment. Results: Educational attainment showed the strongest and most consistent associations, relating to better performance across attention and memory measures assessed (ρ = 0.21 to 0.44, all q < 0.01). Older age was associated with poorer memory span and less consistent alertness. A history of depression was associated with reduced alertness and this association was essentially unchanged after adjustment (β = −0.19, p < 0.001). Higher BMI was associated with poorer memory span (ρ = −0.18; adjusted β = −0.16, p = 0.005) and higher perceived stress with poorer working memory (Digit Span Backward ρ = −0.21; adjusted β = −0.11, p = 0.046; p = 0.062 under robust standard errors). Associations involving mood and sleep quality attenuated to non-significance after adjustment, while physical activity retained only a marginal association with divided attention. Nineteen of 132 associations survived correction for multiple comparisons. Conclusions: In adults with SCCs, educational attainment and age, a proxy of cognitive reserve and an index of aging respectively, rather than modifiable targets, accounted for the strongest associations with objective cognitive performance. Among potentially modifiable factors, a history of depression and higher BMI showed the most robust independent associations, while associations with mood and sleep did not persist after adjustment and physical activity retained only a marginal association. These cross-sectional findings identify candidate risk and resilience markers that require confirmation in longitudinal follow-up.

Brain Sciences doi: 10.3390/brainsci16101034

Authors: Wojciech Styk Ewa Wojtowicz Ewa Humeniuk

Background: Close relationships may support goal-directed behavior not only through direct interpersonal contact but also through the activation of mental representations of supportive others. However, relatively little is known about whether imagining a supportive close person is associated with sustained behavioral engagement during a cognitive task. Objective: This study examined whether supportive-close-person imagery is associated with higher behavioral indicators of sustained task engagement compared with a non-social control condition and a socially neutral familiar-person imagery condition. Methods: Eighty adults participated in a within-subject repeated-measures study. Each participant completed The Maze Test in three counterbalanced conditions: observation of a neutral object, imagery of a socially neutral familiar person, and imagery of a supportive close person. The primary behavioral indicators were total task time and the number of completed mazes. Average time per maze was treated as an auxiliary indicator of task pace or efficiency. The DASS-42 was administered after each session as a symptom-stability screening measure. Results: Experimental condition had a significant effect on all behavioral outcomes. Participants showed the longest total task time and completed the highest number of mazes in the supportive-close-person condition, intermediate values in the socially neutral familiar-person condition, and the lowest values in the control condition. DASS-42 scores, session number, and condition order did not account for the observed pattern. A censoring-aware Cox model also confirmed the robustness of the condition effect on total task time despite the automatic 1500 s task limit. Conclusions: Imagining a supportive close person was associated with greater sustained engagement in a cognitive task. The findings are consistent with the possibility that close-relationship representations may support goal-directed behavior, although the psychological mechanisms underlying this effect require direct examination in future studies.

Brain Sciences doi: 10.3390/brainsci16101032

Authors: Ziyuan Shen Jingshu Hong Zhongxiong Yao Xiaoxiao Wang Ming Liu Yang Zhou Taotao Liu Xiangyang Guo Zhengqian Li

Background/Objectives: Carotid artery stenosis is a well-established risk factor for vascular cognitive impairment. Although carotid endarterectomy (CEA) reduces the risk of ischemic stroke, its effect on cognitive function remains uncertain. Most previous studies have relied on mean changes in cognitive scores and have not defined postoperative cognitive decline using patient-level thresholds for the Montreal Cognitive Assessment (MoCA). Moreover, few studies have integrated perioperative variables across baseline, intraoperative, and postoperative domains to examine heterogeneity in cognitive outcomes. We therefore defined postoperative cognitive decline using threshold-based MoCA changes and prospectively evaluated perioperative factors associated with distinct cognitive outcomes after CEA. Methods: We prospectively enrolled older patients undergoing elective CEA under general anesthesia. Of 183 patients screened, 162 were ultimately enrolled and analyzed. All patients were managed according to standardized anesthetic and surgical protocols. Preoperative clinical, laboratory, and imaging variables, intraoperative hemodynamic parameters, and postoperative clinical indicators were collected. The primary outcome was cognitive decline at discharge, defined as a decrease of ≥2 points from baseline in the MoCA score. The secondary outcome was cognitive decline at 30 days, defined as a ≥3-point decrease in the telephone MoCA (t-MoCA) score relative to the corresponding baseline domains. Results: Among the 162 enrolled patients, preoperative triglyceride level, preoperative cerebral hypoperfusion volume, surgical laterality, intraoperative mean arterial pressure (MAP) decline, and visual analogue scale (VAS) on postoperative day 1 were independently associated with early postoperative cognitive decline. A prediction model incorporating these five factors achieved an area under the curve (AUC) of 0.752 (95% CI: 0.670–0.835) for cognitive decline before discharge. For 30-day cognitive decline, the model demonstrated an AUC of 0.717 (95% CI: 0.606–0.828). All patients with complete 30-day follow-up were stratified into four cognitive trajectory subtypes, and their longitudinal cognitive changes were visualized using a Sankey diagram. Conclusions: A perioperative model incorporating metabolic, cerebral perfusion, surgical, hemodynamic, and pain-related variables may help identify patients at increased risk of cognitive decline after CEA. The trajectory analysis further reveals heterogeneous postoperative cognitive patterns, including transient, delayed, and persistent decline. These findings support individualized perioperative risk assessment and structured cognitive follow-up. However, no internal or external validation was performed, and further testing is required in larger multicenter cohorts.

Brain Sciences doi: 10.3390/brainsci16101031

Authors: Martina Rizzuti Erica Berretta Valeria Gosti Chiara Baglioni Laura Serra Francesca Gelfo

Background/Objectives: The concept of Cognitive Reserve (CR) has assumed a central role in research on the prevention of cognitive decline. The term refers to the brain’s capacity to manage age-related changes or pathologies by enhancing neural efficiency and utilizing alternative networks or more efficient cognitive strategies. In human subjects, CR is commonly estimated through indicators such as educational attainment, occupational complexity, and involvement in leisure activities. Leisure activities have been identified as a significant behavioral indicator and can be classified into three main subcomponents: cognitive, physical, and social activities. This narrative review aims to summarize how leisure activities provide cognitive and/or emotional benefits and how these activities help build CR and brain resilience. Methods: Given the conceptual and methodological heterogeneity of this literature, a narrative review design was adopted for an integrative synthesis across cognitive, social, and physical domains in healthy individuals aged 18 and older. Selected studies’ primary outcomes were cognitive and/or emotional effects, with neurophysiological effects as secondary outcomes, a prerequisite for inclusion. Results: Across adulthood, participation in cognitive, social, and physical leisure activities was consistently associated with better cognitive performance and emotional well-being, with cognitive activities more closely linked to cognitive gains and social and physical activities more closely linked to combined benefits; however, evidence is observational or short-term, limiting causal inference. Conclusions: Leisure activities are consistently associated with cognitive and emotional well-being in healthy adults and may support CR development, although longitudinal and intervention research is needed to clarify causal pathways and confounders such as education and socioeconomic status.

Brain Sciences doi: 10.3390/brainsci16101030

Authors: Qinyi Qiao Jiahao Du Fanfu Fang Ping Shi

Background: Expectation is a powerful cognitive modulator of pain, but how different types of emotion regulation approaches interact with expectancy to influence pain processing remains unclear. The present study compared self-selected habitual strategies (cognitive reappraisal or deep breathing) with an assigned non-habitual imagery-based strategy. Methods: Twenty-four right-handed healthy participants (11 in the self-selected group, 13 in the assigned strategy group) completed a pain expectancy task under two conditions: Attend (passive observation without regulation) and Regulate (active application of the assigned or self-selected strategy). Electrical stimuli were delivered to the left or right forearm. Functional near-infrared spectroscopy (fNIRS) was used to record prefrontal and sensorimotor cortical activation, and subjective pain ratings were collected using a 0–10 Visual Analogue Scale (VAS). Behavioral ratings, cortical activation (β-values in four regions of interest, ROIs), and neural–behavioral correlations were examined. Results: In Attend trials, negative expectancy (high cue followed by medium pain, HM) enhanced pain compared with the no-bias condition (medium cue followed by medium pain, MM), while positive expectancy (low cue followed by medium pain, LM) reduced pain. In Regulate trials, the self-selected group showed a significant LM–MM difference under both left- and right-side stimulation, whereas the assigned strategy group showed a significant LM–MM difference only under left-side stimulation. At the neural level, the Stimulating Location × Group interaction in the left primary somatosensory cortex (L-S1) and right premotor cortex/supplementary motor area (R-PMC/SMA) showed moderate effect sizes (ηp2 = 0.177 and 0.165), but none survived false discovery rate (FDR) correction. In neural–behavioral correlation analyses, one significant correlation was observed in the Attend condition (R-PMC/SMA), along with one marginal trend (L-S1); no significant correlations were found in the Regulate condition after FDR correction. Conclusions: Self-selected habitual strategies and assigned non-habitual imagery-based strategies modulate pain expectancy through different behavioral patterns. Habitual self-selected approaches produced more consistent pain reduction under positive expectancy, whereas the assigned imagery-based approach showed weaker and less consistent regulatory effects. However, the neural findings were exploratory and did not survive FDR correction. The advantage of self-selected habitual approaches may lie in self-selection and automaticity rather than in activating specific brain regions. Because stimulation side was not counterbalanced, laterality inferences cannot be drawn.

Brain Sciences doi: 10.3390/brainsci16101029

Authors: Peter J. Whorwell

The most common gastrointestinal disorders encountered in secondary care are the functional gastrointestinal disorders, now known as disorders of gut brain interaction (DGBI) of which irritable bowel syndrome (IBS) is the most prevalent example. The pathophysiology of these conditions is beginning to be better understood although they are likely to have a multifactorial basis rather than there being a single ‘cause’. The biopsychosocial treatment model recommends that rather than just relying on pharmacology, everything about an individual’s situation should be considered in their management including psychological and social factors. Gut directed hypnotherapy (GDH) has been shown to reduce symptoms, decrease psychological distress, improve quality of life and normalise the physiology of the gut in patients with IBS. It can also be used to explore the psychosocial issues affecting an individual and provides an opportunity to enhance a biopsychosocial approach to treating a range of gastrointestinal disorders. We have been researching GDH for IBS and related disorders for many years and some of the emerging evidence has now reached a point where, for instance, it is now endorsed for the treatment of IBS in a number of national and international guidelines.

Brain Sciences doi: 10.3390/brainsci16101028

Authors: Paolo Palmisciano Branden J. Cord

The clinical management of intracranial aneurysms is undergoing a transformative shift from traditional luminal evaluation to advanced vessel wall characterization. Conventional “lumenography,” including DSA, CTA, and MRA, provides essential morphological data but fails to capture the biological processes, such as inflammation and wall remodeling, that drive aneurysm instability and rupture. This review evaluates the development of high-resolution vessel wall MRI (VW-MRI) and emerging modalities like photon-counting detector CT (PCD-CT) and 4D-Flow MRI. VW-MRI, particularly at 3T and 7T field strengths, utilizing “black-blood” sequences, has introduced Aneurysm Wall Enhancement (AWE) as a promising adjunctive imaging biomarker. AWE correlates with macrophage infiltration and neovascularization, offering a non-invasive means to identify “vulnerable” lesions that may be more prone to rupture. Furthermore, PCD-CT provides unprecedented spatial resolution and metal artifact reduction, while 4D-Flow MRI enables the quantification of hemodynamic stressors like wall shear stress. The integration of artificial intelligence and radiomics further enhances diagnostic precision through automated detection and quantitative risk scoring. By synthesizing technical principles with clinical applications, this review illustrates how these advanced modalities are moving neurovascular care toward a more personalized, biology-based approach to stroke prevention and aneurysm management.

Brain Sciences doi: 10.3390/brainsci16101027

Authors: Osmar Pinto Neto Tatiana Okubo Rocha Pinho

Background/Objectives: Machine learning (ML) is frequently proposed for Parkinson’s disease (PD) diagnosis, but reported accuracy may not reflect methodological quality, generalizability, or clinical feasibility. We compared diagnostic performance, risk of bias, external validation, and deployment burden across biomarker modalities. Methods: We searched PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE, Web of Science, and Institute of Electrical and Electronics Engineers (IEEE) Xplore for studies from January 2020 through March 2026 using a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020-compliant protocol registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY). AI-assisted screening was audited in 147 records (Cohen’s κ = 0.862). Reviewers verified extracted data and Risk Of Bias ASsessment Tool (PROBAST) judgments. Deployment burden was rated across five acquisition domains. Full-text assessment used a modality-stratified sample of retained records; we audited those not selected. Results: Of 8135 deduplicated records, 2046 were retained after screening and 377 reports were sampled for full-text assessment; the final synthesis included 264 studies across nine modalities. Among 252 studies reporting accuracy, median best-model accuracy was 95.3% (range 64.9–100%). However, under our adapted PROBAST rules, 259 studies (98.1%) were at high overall risk of bias; 215 (81.4%) remained at high overall risk when the external-validation item was excluded, and only 20 (7.6%) met the external-validation definition. In ten within-study comparisons, external performance fell in eight. Median deployment burden ranged from 1.0 (voice/speech) to 4.2 (neuroimaging). Conclusions: Reported performance has advanced faster than evidence of generalizability and clinical implementation. Clinical translation will require subject-independent evaluation, external multisite validation, and transparent reporting of performance and deployment requirements. These proportions describe the sample assessed, not the entire PD machine learning literature.

Brain Sciences doi: 10.3390/brainsci16101026

Authors: Ioannis Mavroudis Oindrila Das Foivos Petridis Dimitrios Kazis

Background: Memory problems are amongst the most troublesome and least understood of the symptoms in functional cognitive disorder (FCD) and in persistent post-concussion symptoms (PPCS). Standard neuropsychological testing typically shows only minor objective deficits, which results in a clear mismatch between the level of subjective distress and the actual degree of impairment. Current explanations of this discrepancy either attribute it to undetected hippocampal storage failure or regard it as a non-specific functional overlay; we believe that both of these explanations are incomplete. Methods: This is a narrative review incorporating an integrative hypothesis, not a systematic review. The literature was found using searches of databases and by tracing citations, and the sources were chosen on the basis of their conceptual relevance rather than according to a comprehensive protocolMethods of Literature Selection. The following three types of claims are distinguished throughout: those findings which have been established empirically in humans, those which are based on animal studies, and the hypotheses put forward in this paper. Results: Current evidence shows that episodic memory is spread out over a hippocampal–entorhinal–prefrontal–anteromedial thalamic–cortical control system, with the anteromedial thalamus being responsible for deciding which traces are stabilised and the prefrontal areas providing support for retrieval and for metacognitive evaluation. We suggest that the memory symptoms in both cases are due to a malfunction of this control system rather than to a failure of storage. In the case of FCD, entry is thought to occur in a top-down manner via abnormally precise priors of cognitive failure, impaired global metacognition, hypervigilant self-monitoring and overfitting of the self-model. With regard to PPCS, entry is believed to take place in a bottom-up way as a result of a real neurometabolic and network injury, after which fatigue, sleep disruption and hypermonitoring keep the symptoms going; in susceptible individuals, a concussion may serve as a gateway to FCD. Maladaptive, use-dependent plasticity is proposed as the common underlying mechanism. Conclusions: A unified framework incorporating metacognitive and systems consolidation processes is able to explain the discrepancy and makes eight predictions that can be tested together with provisional criteria for the transition from a primary-FCD to an organic-PPCS. The framework is put forward for future testing rather than being presented as a fully established explanation.

Brain Sciences doi: 10.3390/brainsci16101025

Authors: Andreas G. Prentakis Christos I. Fragoulis Christos G. Theleritis Michelle M. Mielke Nikos P. Smyrnis Konstantinos P. Tsioufis Antonios M. Politis

Background/Objectives: Cardiovascular diseases (CVDs) share common risk factors with cognitive decline. The scope of this cross-sectional study was to evaluate sex-based differences in cognitive capacity in patients with CVDs. Methods: We evaluated cognitive performance in 246 patients with CVDs using the Montreal Cognitive Assessment (MoCA). Other risk factors, comorbidity with depression and anxiety disorders, and frailty score were evaluated, and patients were stratified by sex and age. Results: Age and hypertension were associated with lower MoCA scores for both sexes. However, diagnosis of depression, dyslipidemia, higher Body Mass Index (BMI), and fewer years of education were associated with a lower MoCA score only in female participants. No statistically significant difference was found in mean MoCA scores between male and female subjects of the same age groups. Conclusions: Sex-based differences and shared risk factors may be taken into account when evaluating cognitive performance, especially in patients with CVD.

Brain Sciences doi: 10.3390/brainsci16101024

Authors: Kaixin Huang Lei Zhao Fan Wang Zhengshuang Li Jingao Gao Lixiang Ren Yuhui Chen Yunfa Fu Tianwen Li

Background: Visual imagery (VI) is a cognitive process that generates visual representations in the absence of external visual input; however, the spatiotemporal organization of its neural representations remains poorly understood. Methods: In this study, we combined electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) with representational similarity analysis (RSA) and the Schaefer 2018 functional parcellation atlas to compare the correspondence between brain network representations and CORnet-S model representations during visual perception (VP) and VI. We further examined the cross-modal associations between EEG time–frequency representations and fMRI network representations during VI. Results: Significant model–brain representational correspondence was detected in the visual network during VP, and no significant correspondence was detected in any network during VI, yielding different descriptive significance profiles across the two tasks. Cross-modal EEG–fMRI RSA further revealed frequency- and time-dependent representational correspondence involving the frontoparietal, default mode, ventral attention, visual, and limbic networks. Significant cross-modal correspondence was observed across the alpha, beta, and gamma bands, with descriptive variation in the networks and temporal clusters involved in each frequency band. Conclusions: Collectively, these findings suggest that VI is not merely a reinstatement of VP but is associated with distributed representational patterns involving multiple functional networks. This study provides multimodal evidence for understanding the neural mechanisms underlying VI.