Brain Sciences doi: 10.3390/brainsci16050536

Authors: Elvira Anna Carbone Matteo Aloi Renato de Filippis Marianna Rania Alessia Scordo Claudia Procopio Lavinia Rotella Daria Quirino Ettore D’Onofrio Pasquale De Fazio Cristina Segura-Garcia

Background/Objectives: Sleep disturbances are highly prevalent in young individuals with eating disorders (EDs) and are associated with increased psychopathology and poorer clinical outcomes. However, sleep alterations in ED populations are heterogeneous and may reflect distinct underlying clinical profiles. The study aimed to identify sleep quality profiles and examine their clinical correlates in youth with EDs. Methods: A total of 288 youth outpatients with EDs completed the Pittsburgh Sleep Quality Index (PSQI), along with measures of eating and general psychopathology. Latent Profile Analysis (LPA) was conducted using PSQI scores to identify distinct sleep profiles. Multinomial logistic regression models were performed to assess clinical variables of profile membership. Results: A four-profile solution was identified: (1) less impaired sleepers, (2) medication-using sleepers, (3) global poor sleepers, and (4) sleep-initiation-difficulty sleepers. Profiles differed significantly in ED severity, affective symptoms, emotion regulation difficulties, and sleep-related eating behaviors. Profiles characterized by greater sleep impairment exhibited higher levels of binge eating, night eating, and psychological distress. Multinomial logistic regression analyses indicated that night eating was the largest contributor to latent profile membership across all comparisons, significantly increasing the likelihood of belonging to more impaired sleep profiles. Conclusions: Sleep in individuals with EDs is characterized by distinct and clinically meaningful profiles rather than a uniform pattern of impairment. These findings support the clinical utility of person-centered approaches to better characterize sleep disturbances in ED populations.

Brain Sciences doi: 10.3390/brainsci16050535

Authors: Devon Pacheco Major Emily Cary Erin Matsuba Natalie Russo Beth Prieve

Background: Neural stability, defined as trial-by-trial fluctuations in neural responses to the repetitive sensory input, is an indicator of neural processing stability. The auditory brainstem response (ABR) can provide an electrophysiological measure of neural stability. Findings on neural stability differences between autistic and neurotypical individuals are inconsistent, potentially due to methodological differences and sample heterogeneity. This study aimed to investigate the relationship between neural stability in the brainstem and autistic traits in a group of children with and without a diagnosis of autism. We examined whether the degree of neural stability differs based on the evoking stimulus and response component analyzed, and whether neural stability relates to parent-reported autistic traits, as measured by the Autism Spectrum Quotient (AQ) and social responsiveness scale-2 (SRS-2). Methods: In total, 41 participants had usable click ABRs and 34 had usable sABRs. Neural stability was quantified using Pearson correlation analyses between binaurally evoked subaverage ABR waveforms. Parent-reported measures of autistic traits were collected. Results: Neural stability differed across ABR components, with the click ABR being significantly more stable than sABR components. Decreased neural stability is significantly related to autistic traits measured by the AQ but not the SRS-2. There was no significant response component by AQ interaction. Conclusions: Neural stability in the auditory brainstem pathway is linked to individual differences in autistic traits measured by the AQ but not the SRS, implying that early sensory processing neural stability may be related to broader features of autistic traits rather than social communication alone.

Brain Sciences doi: 10.3390/brainsci16050534

Authors: Kosei Goto Nobuo Kutsuna Takuto Nishihara Kotaro Makita

Background: Anterior cranial fossa dural arteriovenous fistulas (ACF DAVFs) usually receive ethmoidal dural supply. Pial arterial supply has been described in intracranial DAVFs, including ACF DAVFs, but a dominant orbitofrontal pial feeder can create diagnostic overlap with mixed pial-dural arteriovenous malformation and make endovascular treatment hazardous. Case Presentation: A 75-year-old man with atrial fibrillation presented with right middle cerebral artery occlusion and underwent intravenous thrombolysis followed by mechanical thrombectomy. During right internal carotid angiography, transient arterial-phase opacification of a contralateral frontal draining vein through the anterior communicating artery prompted post-recanalization angiography. A high-grade left ACF DAVF was diagnosed, with dominant supply from the left orbitofrontal artery, minor anterior ethmoidal supply, two venous drainage routes, cortical venous reflux, and a varix. Although the DAVF was incidental to the ischemic presentation, it was considered to require treatment because of high-risk angioarchitecture, including Borden type III/Cognard type IV drainage, cortical venous reflux, and venous ectasia. No intraparenchymal nidus or normal venous-phase use of the refluxing veins was identified. Because pial transarterial access and complete transvenous closure were considered unsafe or uncertain, microsurgical draining-vein disconnection was performed. Postoperative angiography confirmed complete obliteration. Conclusions: In this case, microsurgical disconnection achieved angiographic cure, and the patient was transferred for rehabilitation with a modified Rankin Scale score of 1. The central diagnostic and therapeutic issue in pial-feeder-dominant ACF DAVF is not rarity alone, but angiographic differentiation from mixed pial-dural arteriovenous malformation and assessment of whether the shunt can be closed without compromising normal pial arteries or venous outflow. The thrombectomy angiogram provided the route to diagnosis, whereas pial arterial dominance and divided venous drainage determined the curative strategy.

Brain Sciences doi: 10.3390/brainsci16050533

Authors: Shahwar Yasir Nzamukiza Fidele Eduardo Martinez-Montes Lidice Galan-Garcia Cheng Luo Maria Luisa Bringas Vega Pedro A. Valdes-Sosa

Background: Reaction time (RT) is a fundamental measure of information processing speed in cognitive neuroscience and is influenced by both structural and functional brain properties. While prior studies have independently linked white matter microstructure and EEG alpha oscillations to cognitive performance, their joint contribution to distinct aspects of RT remains unclear. This study aims to investigate whether multimodal data can dissociate neural systems underlying cognitive and motor components of processing speed. Methods: We analyzed diffusion tensor imaging, resting-state individual EEG alpha peak frequency (IAF), demographic variables, and behavioral RT measures from a GO/NO-GO paradigm in 24 healthy adults from the Cuban Human Brain Mapping Project. Behavioral metrics included the mean, standard deviation and skewness of reaction times for simple and complex tasks. Sparse multiple canonical correlation analysis was applied to identify multivariate associations across modalities. Results: Two significant latent dimensions were identified. The first dimension linked bilateral fronto-temporal association tracts (SLF, IFOF, UNC) with complex RT performance, reflecting higher-order cognitive processing. The second dimension associated motor and interhemispheric tracts (CGC, CST, ILF, forceps major and minor) with intra-individual asymmetric variability (skewness) across tasks, indicating a motor-execution consistency system. IAF did not significantly contribute to either dimension. Sex showed strong associations with both components. Conclusions: Distinct white matter networks were associated with separable cognitive and motor aspects of processing speed, while resting-state alpha frequency did not show stable contributions with behavioral variability in this sample. IAF showed minimal contribution within the identified sparse multivariate dimensions. These findings highlight the importance of multimodal and multivariate approaches for understanding and potentially disentangling complex brain–behavior relationships.

Brain Sciences doi: 10.3390/brainsci16050532

Authors: Valeria Del Vecchio Giovanni Freda Andrea de Bartolomeis Nicola Serra Domenico D’Errico Salvatore Allosso Elena Cantone Davide Brotto Judit Gervain Patrizia Trevisi Anna Rita Fetoni

Background/Objectives: Functional near-infrared spectroscopy (fNIRS) has emerged as a non-invasive, implant-compatible imaging modality capable of capturing cortical hemodynamics during ecologically valid auditory and linguistic tasks. Its silent operation and tolerance to electrical artifacts make it particularly well suited to the study of hearing-impaired individuals, including cochlear implant (CI) users. However, evidence on the application of fNIRS to investigate speech perception, cognitive performance, and proxy of cortical activation patterns in patients with hearing loss (HL) remains fragmented. This systematic review aims to provide a structured, population-stratified description of current fNIRS literature on auditory and cognitive processing in adults with age-related hearing loss (ARHL) and CI users. Methods: A systematic search on PubMed Central, Web of Science and Scopus, based on PRISMA (2020) guidelines, was conducted to identify original studies that evaluate speech perception by means of fNIRS to assess auditory and cognitive process in hearing-impaired populations. Results: Across studies, fNIRS consistently detected activation of superior temporal and frontal cortices during speech-related tasks. In ARHL, increased dorsolateral prefrontal cortex (DLPFC) recruitment during speech-in-noise indicated compensatory yet inefficient processing. Longitudinal auditory training led to reduced prefrontal overactivation and enhanced temporal–frontal connectivity. In CI users, cortical responses to phonological and comprehension tasks show partially overlapping activation patterns with normal hearing (NH) peers, although arising within different neurobiological contexts, and are modulated by device experience and residual hearing (AV) speech, and stimulus-level effects further shape cortical responses. When interpreted in light of developmental evidence, these findings may be contextualized as reflecting distinct trajectories of cortical reorganization, rather than a common mechanism. Conclusions: fNIRS provides a tool to investigate auditory and cognitive responses in distinct hearing-impaired populations under ecologically valid conditions. It detects maladaptive frontal inefficiency in ARHL, tracks neuroplastic changes after rehabilitation, and captures population-specific cortical recruitment patterns in CI users. These findings are descriptive and context-dependent, and do not support cross-population mechanistic generalizations. Standardized protocols and longitudinal pediatric studies are needed to clarify the potential clinical relevance of fNIRS-derived cortical measures.

Brain Sciences doi: 10.3390/brainsci16050531

Authors: Pranav Kalaga Swapan K. Ray

Glioblastoma multiforme (GBM) remains the most aggressive and therapeutically intractable primary brain tumor, with many patients experiencing rapid relapse despite maximal surgical resection followed by standard chemoradiation. This persistent failure reflects the convergence of profound tumor-intrinsic genetic heterogeneity and a highly dynamic, spatially structured, and immunosuppressive tumor microenvironment (TME). Together, these forces create strong selective pressures that fuel tumor evolution, intratumoral diversity, phenotype plasticity, diffuse invasion, and robust resistance to therapy. The TME of GBM is orchestrated through a complex interplay between diverse cellular constituents, including tumor-associated macrophages, reactive astrocytes, endothelial cells, pericytes, and GBM stem cells, and non-cellular components such as extracellular matrix remodeling, hypoxia, metabolic and nutrient gradients, and spatially patterned cytokine and chemokine signaling networks. Additionally, heterogeneity in blood–brain barrier (BBB) and blood–tumor barrier (BTB) complicates drug delivery and immune surveillance, reinforcing therapeutic resistance and regional tumor adaptation. Conventional two-dimensional cell cultures and animal models fail to sufficiently capture these multiscale, patient-specific interactions, limiting their translational predictive power. In this narrative review, we synthesize recent advances in GBM organoid technologies as physiologically relevant, three-dimensional platforms that more faithfully recapitulate TME for driving tumor evolution and treatment resistance. We compare complementary organoid strategies, including patient-derived GBM organoids that preserve native cytoarchitecture, cerebral organoid co-culture systems that reconstruct tumor–brain interactions, and advanced platforms incorporating immune and vascular features such as air–liquid interface cultures, microglia-enriched systems, and BBB/BTB-integrated models. Finally, we highlight emerging innovations such as spatial transcriptomics, organoid-on-a-chip systems, live imaging coupled with lineage tracing, genome engineering, and artificial intelligence integration that collectively position GBM organoids at the forefront of precision neuro-oncology, reproducing TME, enabling dynamic mapping of tumor evolution, and accelerating patient-specific therapeutic discovery.

Brain Sciences doi: 10.3390/brainsci16050530

Authors: Junjie Wu Ruoling Hang Pingping Xin Guoli Yan Chanyuan Gu Luyao Chen

Background: Proficient second language (L2) reading relies on complex neurocognitive processes. Neuroimaging studies have identified key brain regions recruited during L2 reading, including the left inferior parietal lobule (LIPL) and the calcarine cortex (CAL). The LIPL has been suggested to be involved in phonological decoding during L2 reading, whereas the CAL has been implicated in early-stage visual processing. However, given the correlational nature of neuroimaging techniques, it remains unclear whether these regions play causal roles in L2 reading or are merely epiphenomenal. Methods: To address this issue, the present study used transcranial magnetic stimulation (TMS) to modulate neural activity in these regions and eye-tracking technology to assess subsequent reading performance in Chinese–English bilinguals. Specifically, ninety-seven participants were randomly assigned to one of three offline TMS conditions: LIPL, CAL or vertex (as a control site) stimulation, after which they performed a natural sentence reading task in English. Results: The results showed that, compared to the control condition, TMS over the LIPL significantly reduced first fixation duration, whereas no significant effects emerged on gaze duration, regression path reading time, or total reading time. TMS over the CAL produced no significant effects on any eye-movement measures. Conclusions: These findings suggest that the LIPL plays a causal role in L2 reading for early-stage lexical processing through phonological decoding. Overall, this study is the first to employ TMS and eye-tracking to investigate the neural mechanisms underlying natural L2 reading.

Brain Sciences doi: 10.3390/brainsci16050529

Authors: Vitaly Dobromyslin Wenjin Zhou

Background: The past decade has seen a reversal in the U.S long-term decline in age-adjusted mortality rate from stroke. Timely stroke detection can boost the patient’s chances for recovery by enabling life-saving treatment and informing the patient of their increased risk of successive infarcts. Since no single imaging modality can currently provide accurate and safe stroke detection at both acute and chronic stages, there is a need to develop novel imaging biomarkers with both diagnostic and prognostic value. Methods: We trained a U-shaped, nested hierarchical transformer model (UNesT) for T1-w white matter infarct segmentation using the ATLAS R2 dataset. Model reproducibility was independently evaluated on the Washington University (WU) stroke dataset. To boost T1-w UNesT stroke detection performance, automated machine learning techniques were used to extract 77 novel resting state fMRI (rs-fMRI) stroke biomarkers. Results: Stroke detection performance of the T1-w UNesT model degraded from Dice indices of 0.611 to 0.24 and 0.41 for the subacute and chronic timepoints respectively in the WU dataset. After UNesT re-optimization with the training portion of the WU dataset, the test set Dice index improved to 0.41–0.50. The spectral peak amplitude at the subacute timepoint increased the T1-w UNesT Dice index from 0.41 to 0.50 (p < 0.01) and correlated with language recovery. Conclusions: By training a UNesT model on the T1-w stroke data from one dataset and evaluating it on an independent dataset, we highlight the dataset drift concerns. Spectral peak amplitude is proposed as a novel rs-fMRI biomarker for improving stroke detection and predicting stroke recovery trajectory.

Brain Sciences doi: 10.3390/brainsci16050528

Authors: Thamer H. Alsharif Badr E. Hafiz Lamair Albakri Abdularhman D. Alofi Ziad Alzahrani Yazid Maghrabi Moajeb Alzahrani

Background/Objectives: External ventricular drains (EVDs) are widely used in the management of intracranial hemorrhage and hydrocephalus; however, they carry a significant risk of device-related central nervous system infections, including ventriculitis and meningitis, which are associated with increased morbidity, mortality, and prolonged intensive care stays. We conducted a systematic review and meta-analysis to evaluate whether prolonged EVD duration (>10 days) is associated with an increased risk of ventriculostomy-related infection compared with shorter duration (≤10 days), and to explore the association with cerebrospinal fluid (CSF) leak where data were available. Methods: A comprehensive literature search of PubMed, Google Scholar, Web of Science, and Cochrane CENTRAL was performed from database inception through September 2025, including English-language clinical trials, cohort studies, and case–control studies reporting infection outcomes related to EVD management factors. Two reviewers independently screened studies and extracted data. A random-effects meta-analysis was conducted to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs). Results: Sixteen studies comprising approximately 5500 patients met the inclusion criteria. Shorter EVD duration (≤10 days) was associated with a significantly lower risk of infection (pooled OR 0.45, 95% CI 0.30–0.68; p = 0.0002), corresponding to a 55% reduction in the odds of ventriculostomy-related infection. Prolonged EVD duration was consistently associated with increased infection risk across studies. Conclusions:These findings suggest that minimizing EVD duration may reduce infection risk and support early removal when clinically feasible. However, given the observational nature of the included studies, the results should be interpreted with caution. Further research is warranted to evaluate additional modifiable risk factors, including CSF leakage and sampling practices.

Brain Sciences doi: 10.3390/brainsci16050527

Authors: Hector P. Valverde Benjamin J. Clark Jeremy Hogeveen Vincent P. Clark

Background/Objectives: The growing aging population is susceptible to cognitive and memory impairment, most commonly due to Alzheimer’s disease, with no cures currently available. Noninvasive brain stimulation (NIBS) techniques may serve to improve cognition and delay catastrophic memory loss. Methods: A systematic review of NIBS research on cognitive impairment was carried out using PubMed, with additional backward citation searching. A total of 81 studies using NIBS were included. Conclusions: The reviewed studies show that NIBS holds promise in improving memory deficits in patients with cognitive impairment. While the longevity of benefits from transcranial electrical stimulation appears limited, its short-term effects may provide benefits when used consistently. Transcranial magnetic stimulation appears to provide longer-lasting benefits. Transcranial focused ultrasound stimulation may also provide further benefits through more precise targeting of deeper brain structures compared to other NIBS techniques. Together, these results suggest that NIBS shows promise for the treatment of symptoms related to cognitive and memory impairment, and may help to alleviate some of the growing issues associated with the increasing level of Alzheimer’s disease in an aging population.

Brain Sciences doi: 10.3390/brainsci16050526

Authors: Sena Aksoy Arsida Bajrami Songül Şenadım Serdar Geyik

Background and Aims: Patients with malignancy are frequently excluded from randomized thrombectomy trials, and evidence regarding the safety and efficacy of mechanical thrombectomy (MT) in this population remains incompletely defined. We aimed to compare procedural success, functional outcomes, and mortality between acute ischemic stroke (AIS) patients with and without malignancy undergoing MT. Methods: We retrospectively analyzed 110 patients treated with MT. Patients were stratified into two groups: those with malignancy (n = 48) and those without malignancy (n = 62). Baseline demographics, vascular risk factors, procedural metrics, angiographic outcomes, and clinical outcomes including functional independence (modified Rankin Scale [mRS] 0–2), 90-day mortality and intracranial hemorrhage were compared. Results: Baseline demographics and admission stroke severity were similar between groups. Smoking was significantly more frequent in the malignancy group (25% vs. 11.3%, p < 0.001). Successful reperfusion (TICI 2b-3) was achieved in 95.8% of malignancy patients and 98.4% of controls (p = 0.51). Functional independence at 90 days was lower in the malignancy group (42.6% vs. 61.3%, p = 0.04), whereas 90-day mortality was significantly higher (44.7% vs. 19.4%, p = 0.004); this increase in mortality remained significant after multivariate analysis. There were no significant differences in rates of intracranial hemorrhage between groups (p = 0.53). Conclusions: Mechanical thrombectomy is technically effective and safe in patients with malignancy; however, long-term functional recovery and survival are significantly worse, likely reflecting the effect of cancer itself rather than procedural factors. Careful patient selection and multidisciplinary decision-making are essential in this population.

Brain Sciences doi: 10.3390/brainsci16050525

Authors: Xiaobo Wang Zhaohui Liu Wanli W. Smith

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies. Over recent decades, various cellular mechanisms underlying PD have been elucidated, including autophagy, mitochondrial dysfunction, neuroinflammation, and axonal transport. Among them, axonal transport plays a critical role in maintaining the dynamic homeostasis of proteins, membrane-bound organelles, and cellular metabolism within neurons. Unfortunately, a comprehensive overview of axonal transport in PD remains absent. In this review, we synthesized the current literature on axonal transport in PD, leveraging neurotoxic and genetic models to explore the causes and consequences of axonal transport alterations in PD. Through this summary, we aim to deepen our understanding of PD pathogenesis and provide potential therapeutic targets for intervention.

Brain Sciences doi: 10.3390/brainsci16050524

Authors: Nathalie Draulans Cecile Utens Danielle Driessen Willemijn van Erp Gerard Ribbers Jörg Wissel Aurore Thibaut

Background: Spasticity is a frequent and disabling complication in patients with prolonged disorders of consciousness (PDOC), yet its prevalence, distribution, evolution, and relationship with recovery of consciousness remain poorly characterized. The aim was to investigate the prevalence, severity, distribution, and evolution of spasticity in PDOC patients undergoing early intensive neurorehabilitation (EIN), and to explore clinical factors associated with spasticity and its relationship with level of consciousness (LOC). Methods: This study was embedded in the nationwide prospective DOCTOR cohort and included 126 PDOC patients admitted for EIN in the Netherlands between 2019 and 2023. Spasticity was assessed at admission and discharge using the Ashworth Scale (AS) across seven bilateral muscle groups. Associations between spasticity, demographic and clinical variables, medication use, nociception, and recovery of consciousness were analyzed. Results: Spasticity was highly prevalent at EIN admission (88%) and discharge (90%), with mostly bilateral and widespread involvement. Elbow flexors, wrist flexors, hip adductors, and knee flexors were most frequently affected. Severe spasticity was present in 19% at admission and 30% at discharge. Spasticity severity correlated positively with pain scores and use of spasmolytics, but not with LOC. No association was found between spasticity at admission and recovery of consciousness. Conclusions: Spasticity is nearly ubiquitous and often progressive in PDOC, even during specialized neurorehabilitation. Its evolution appears independent of recovery of consciousness, underscoring the need to assess and manage spasticity as a distinct clinical entity. Prospective interventional studies are warranted to optimize spasticity treatment in this population.

Brain Sciences doi: 10.3390/brainsci16050523

Authors: Tommaso Toffanin Mario Angelo Pagano Carlo Idotta Luigi Grassi Anna Maria Brunati

Severe mental disorders, including schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD), are leading causes of global disability, yet current treatments remain largely symptomatic and fail to alter disease trajectories. Converging evidence from genetics, longitudinal studies, and systems neuroscience supports a dimensional and transdiagnostic architecture of psychopathology, involving shared polygenic risk and overlapping neurodevelopmental and circuit-level alterations. Traditional approaches—such as post-mortem brain analysis, neuroimaging, and animal models—have delineated core molecular perturbations (e.g., dopaminergic, glutamatergic, and GABAergic dysfunction), as well as informed translational frameworks for mechanistic investigation, but remain constrained by restricted access to dynamic processes and incomplete recapitulation of human-specific biology. The advent of human-derived cellular models, particularly human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), has partially addressed these limitations, enabling the study of patient-specific neurodevelopment and synaptic function in vitro. Within this evolving landscape, the olfactory neuroepithelium (ONE) has emerged as an accessible source of neural progenitors, obtainable through minimally invasive procedures, providing a window into living human neurobiology. ONE-derived cells retain donor-specific genetic and epigenetic signatures while recapitulating disease-relevant phenotypes across major psychiatric disorders, including altered neurodevelopmental dynamics, synaptic gene expression, and inflammatory profiles. Here, we present a narrative review of the principal cellular and tissue models used in biological psychiatry, examining their respective strengths, limitations, and translational relevance across experimental contexts. By situating these approaches within a unified framework, we aim to clarify their complementarity, identify current gaps, and outline future directions, highlighting the emerging potential of ONE-based models to bridge genetic risk, cellular dysfunction, and clinical phenotype, thereby advancing precision psychiatry.

Brain Sciences doi: 10.3390/brainsci16050522

Authors: Liahm Blank Joshua Khorsandi Elizabeth England-Kennedy Srikanta Banerjee Karen Kopera-Frye Roberto Sagaribay Jagdish Khubchandani Kavita Batra

Daylight Saving Time (DST) creates abrupt, externally imposed circadian disruptions that can impair sleep regulation, hormonal balance, cognitive performance, and emotional stability. Although these effects are known in the general population, individuals with chronic mental illness, whose circadian systems are often intrinsically dysregulated, may face increased neuropsychological consequences. This comprehensive review synthesizes evidence from chronobiology, psychiatry, neuroscience, and population health to examine how DST-related circadian misalignment impacts cognitive functioning, mood regulation, suicidality risk, and symptom exacerbation across psychological disorders such as depression, anxiety disorders, bipolar disorder, post-traumatic stress disorder, attention-deficit/hyperactivity disorder, and psychotic disorders. Following the Scale for the Assessment of Narrative Review Articles (SANRA) guidelines, a search of PubMed, PsycINFO, Scopus, and Google Scholar was conducted to identify studies published from 2000–2026 examining DST, circadian rhythm disruption, neuropsychological outcomes, and chronic mental illness. Empirical, theoretical, and mechanistic studies were included to ensure comprehensive synthesis. Across conditions, DST, particularly spring forward transitions, is associated with increased sleep disturbance, impaired executive functioning, reduced attention and working memory, heightened emotional reactivity, increased depressive symptoms, elevated risk of manic episodes, and short-term increases in suicidality. Neurobiological mechanisms include altered melatonin secretion, cortisol dysregulation, Hypothalamus Pituitary Axis (HPA-axis) activation, and clock-gene desynchrony. DST may function as a modifiable negative environmental influence capable of affecting neuropsychological functioning in vulnerable populations. These findings underscore the need for clinical awareness, preventive strategies, and policy reconsiderations, including calls to eliminate seasonal time changes. Standardizing DST-related research outcomes and expanding longitudinal, multi-site studies will be essential for advancing this emerging field.

Brain Sciences doi: 10.3390/brainsci16050521

Authors: Benjamin L. Kidder Jian Xu Rui Geng Hunter Dlugas Anusha Vavilikolanu Wei Chen Vibhangini S. Wasade

Background/Objectives: Genetic generalized epilepsies (GGE) often remit in childhood, yet a subset of adults remain pharmacoresistant with substantial morbidity. The genetic basis of adult pharmacoresistant GGE is poorly defined. This descriptive study used whole-genome sequencing (WGS) to identify recurrent coding variants and pathways associated with pharmacoresistant adult GGE. Methods: WGS was performed in ten racially diverse adults (mean age 37.2 years; range 20–52) with electroencephalographically confirmed, pharmacoresistant GGE (mean onset 13.7 years). Analysis prioritized variants present in at least 80% of participants and which were either (i) missense variants predicted deleterious with ANNOVAR or (ii) loss-of-function variants predicted high-impact from snpEff. Pathway enrichment and overlap with a commercial clinical epilepsy gene panel were assessed. Results: Filtering identified 133 unique, deleterious coding variants across 69 genes shared by at least eight participants. Four genes (APOL4, KMT2C, SON, VDR) overlapped a clinical epilepsy panel, supporting the capacity of WGS to recover clinically relevant loci. Prioritized loci implicated gastrointestinal and metabolic regulators (e.g., MUC6, PNLIPRP2), chemosensory receptors (OR10D3, OR8U1, TAS2R19), neuroimmune mediators (LILRA2, SIGLEC12, OAS2), and ion transporters (KCNJ12, P2RX5, RHBG), consistent with multifactorial mechanisms of pharmacoresistance. Conclusions: This exploratory WGS study focused exclusively on adults with pharmacoresistant GGE, revealing shared high-impact variants and convergent pathways spanning absorption/metabolism, vitamin D signaling, immunity, and ion transport. Findings broaden the genetic landscape of pharmacoresistant GGE while motivating validation in larger, multiethnic cohorts.

Brain Sciences doi: 10.3390/brainsci16050520

Authors: Sarka Turecka Brown Maddy Pontius Jennifer Gallagher Kim A. Gorgens Gina Signoracci Marybeth Lehto

Background/Objectives: Sleep problems, cognitive deficits, and mood disorders are prevalent in justice-involved populations, especially among individuals with a history of traumatic brain injury (TBI), though the association between these variables remains understudied. This retrospective study examined the relationship between subjective sleepiness and mood state on neuropsychological functioning in a forensic population with self-reported TBI. Methods: Data were obtained from 419 inmates and probationers with a self-reported history of TBI using the Ohio State University Traumatic Brain Injury Identification Method and Automated Neuropsychological Assessment Metrics (ANAM). Multiple linear regression models examined associations between cognitive performance across domains (i.e., reaction time, learning, attention, processing speed, working memory, delayed memory, and inhibition) and subjective sleepiness and mood states (i.e., depression, anxiety, fatigue, restlessness, anger, happiness, and vigor) measured by self-report scales embedded in the ANAM. Results: Negative mood state was most associated with impaired performance on tests of learning, delayed memory, spatial working memory, and reaction time, as well as global neurocognitive test performance. Subjective sleepiness was predictive of poorer performance on reaction time tasks, while positive mood states were related to better performance on the same task. Regression models were statistically significant (p < 0.05), with subjective sleepiness and mood accounting for approximately 1–5% of the variance in cognitive performance. Conclusions: Subjective sleepiness and mood symptoms are significantly related to cognitive performance among justice-involved individuals with self-reported TBI. While these factors can contribute to the need for rehabilitation, they may also reduce the likelihood of successful engagement. Importantly, both sleepiness and mood are modifiable treatment targets, and adapting interventions to accommodate cognitive inefficiencies can improve engagement and overall treatment benefit.

Brain Sciences doi: 10.3390/brainsci16050518

Authors: Gianluca Borghini Khadija Latrach Gianluca Di Flumeri Pietro Aricò Vincenzo Ronca Andrea Giorgi Rossella Capotorto Alessia Ricci Stefano Bonelli Vanessa Arrigoni Paola Tomasello Fabrice Drogoul Jean Paul Imbert Géraud Granger Fabio Babiloni

Background/Objectives: The human performance envelope (HPE) is a multidimensional model that represents the range in which an individual operator’s performance is acceptable or begins to become dangerous. Although several alternative models have been proposed, HPE currently remains primarily a theoretical concept. The goal of the study was therefore to translate this theoretical concept into practical applications, seeking to characterize and measure how HPE manifests itself in real-world contexts. Methods: Multivariate Autoregressive (MVAR) models and conditional transfer entropy (cTE) have been used in the analysis of complex systems in which processes are interdependent and mutually influence their dynamics over time. Professional Air Traffic Controllers were involved in the study and asked to deal with realistic traffic scenarios while their behavioural, subjective and neurophysiological data were collected. MVAR–cTE models were then employed to estimate the interactions among controller human factors and to identify the most appropriate characterization of the HPE. Results: The results showed high and significant correlations among each controller’s performance and the corresponding neurophysiological-based HPE values. Furthermore, high-performance conditions (best) were characterized by significantly higher HPE values and higher inter-human factor connections compared to the low-performance (worst) status. This evidence suggested that a densely interconnected network of Human Factors is a prerequisite for operational resilience. Conclusions: The study provided the first application of a neurophysiological framework to model the directed interactions between human factors, translating the theoretical HPE into a quantifiable model validated against operator performance.

Brain Sciences doi: 10.3390/brainsci16050519

Authors: Marzia Di Girolamo Roberta Invernizzi Paola Galli Irene Orlandi Luciano Giromini Donald J. Viglione Renato Borgatti Martina Maria Mensi Marika Orlandi

Background/Objectives: Suicidal ideation and behavior in adolescence remain difficult to assess due to their multifactorial and fluctuating nature. Performance-based measures may provide additional information on psychological correlates associated with suicidality beyond self-report and interview data. Methods: This study examined multivariate associations between RorschachPerformance Assessment System (R-PAS) variables and suicidality in a clinical sample of 153 help-seeking adolescents. Elastic net penalized regression models were estimated to evaluate joint patterns of R-PAS variables derived from the Suicide Concern Composite (SC-Comp) and selected developmentally relevant indices, controlling for age, sex at birth, sociodemographic and clinical factors. Suicidal ideation severity and lifetime suicidal behavior were assessed using the Columbia–Suicide Severity Rating Scale (C-SSRS). Results: For both outcomes, morbid content (MOR) and Location, Space, and Object Qualities-Complexity (LSO-Cmplx) emerged as consistent multivariate correlates, with vigilance–avoidance (VFD) contributing only in the model for suicidal ideation severity. Model performance was modest (R2 = 0.09), indicating limited explanatory power. The findings do not support clinical or predictive use of R-PAS variables for suicidal ideation and behaviors, but indicate a small set of reproducible multivariate associations within this sample. Conclusions: The results suggest that certain R-PAS variables show weak but consistent associations with suicidality in a help-seeking adolescent sample. Given the cross-sectional design and modest explanatory power, the findings should be interpreted as exploratory and hypothesis-generating, and further studies are needed to clarify the robustness and meaning of these associations.

Brain Sciences doi: 10.3390/brainsci16050517

Authors: Marianna Tsatali Despina Eleftheriadou Nikoleta Palla Magda Tsolaki Despina Moraitou

The journal retracts and removes the article, “Normative Data for the D-KEFS Tower Test in Greek Adult Population Between 20 and 85 Years Old” [...]

Brain Sciences doi: 10.3390/brainsci16050516

Authors: Hussam Hamou Hani Ridwan Anna Mausberg Roel Haeren Hans Clusmann Anke Hoellig Michael Veldeman

Background/Objectives: Chronic subdural hematoma (cSDH) is an increasingly prevalent neurosurgical condition in the aging population. Burr hole craniotomy (BHC) with irrigation and postoperative drainage represents the evidence-based standard of care, yet recurrence rates remain substantial. Twist drill craniostomy (TDC), a minimally invasive bedside procedure performed under local anesthesia, offers theoretical advantages for frail patients but has been largely abandoned due to concerns regarding incomplete evacuation and recurrence. This study aimed to identify the predictors of a successful TDC outcome and to compare the recurrence rates between TDC and BHC. Methods: We performed a retrospective cohort study of consecutive patients undergoing surgical treatment for radiologically confirmed cSDH at RWTH Aachen University Hospital between 2015 and 2023. Hematoma morphology was classified using an extended CT-based architecture system and grouped into homogeneous, organized, sedimented, or subacute categories. The primary endpoint was recurrence requiring surgical reintervention. Multivariable logistic regression was used to identify independent predictors of recurrence among patients discharged after definitive TDC. Propensity score matching was performed to compare recurrence rates between TDC and BHC while adjusting for baseline demographic, clinical, and radiographic differences. Results: Among 178 patients initially treated with TDC, 56 (31.5%) were discharged without conversion to BHC. Late recurrence occurred in 26 of 56 patients (46.4%) treated definitively with TDC. In multivariable analysis, homogeneous hematoma architecture was the only independent predictor of recurrence (adjusted OR 4.48, 95% CI 1.10–22.07, p = 0.037). Propensity score matching yielded 48 well-balanced pairs of TDC and BHC patients. Recurrence rates remained significantly higher after TDC compared with BHC (42.6% vs. 17.0%, p = 0.012), as confirmed by conditional logistic regression (adjusted OR 3.20, 95% CI 1.17–8.73). Conclusions: Twist drill craniostomy may provide definitive treatment in carefully selected patients but is associated with substantially higher recurrence rates than burr hole craniotomy, particularly in homogeneous hematomas. Burr hole evacuation remains the preferred standard approach, while optimized drainage protocols and architecture-guided selection may define a limited role for TDC in high-risk patients.

Brain Sciences doi: 10.3390/brainsci16050515

Authors: Frederik Have Dornonville de la Cour Sun-Hee Skovgaard Christensen Stine Flensburg Hansen Anne Norup

Background/Objectives: Fatigue is a common symptom in adults with cerebral palsy (CP), characterized by fluctuations across the day. This pilot study aimed to evaluate the feasibility, reliability, and validity of ecological momentary assessment (EMA) for capturing these temporal dynamics in adults with CP. Methods: Ten adults with CP (60% female, mean age = 44 years, Gross Motor Function Classification System levels I–III) and eight typically developed controls (62% female, mean age = 39 years) completed a 20-item EMA survey ten times daily for seven days using the SEMA3 smartphone application. Feasibility was evaluated through retention rates, response rates, and qualitative interviews. Intraindividual variability, within-person reliability, measurement reactivity, and convergent validity with the Fatigue Severity Scale (FSS) were examined using mixed-effects regression and multilevel measurement error autoregressive (MEAR) models. Results: No participants dropped out. Average response rates were 76% (CP) and 75% (control). The protocol was perceived as acceptable overall, though demanding by some participants. In the CP group, 61% of total variability in momentary fatigue was attributable to within-person fluctuations, and within-person reliability was 0.73 (SEM = 1.13). No evidence of reactivity to self-monitoring was found in fatigue ratings or qualitative interviews. FSS scores were positively associated with person-level average momentary fatigue, β = 0.51, p = 0.048. Conclusions: EMA is feasible in adults with CP and reveals substantial within-person fluctuations in fatigue. These findings provide initial proof-of-concept and inform methodological amendments for a future large-scale study of fatigue dynamics aiming to advance symptom management in this population.

Brain Sciences doi: 10.3390/brainsci16050514

Authors: Hiwa Rahmani Hamid Amoozi Ibrahim Saif Allah Ahmed Refai Kevin E. Power

Purpose: This study investigated whether an acute bout of submaximal unilateral arm cycling elicits sustained changes in corticospinal excitability (CSE) and short-interval intracortical inhibition (SICI) in the homologous muscles of the non-exercised, resting limb. A secondary aim was to determine whether prior exercise induces a preconditioning effect on subsequent motor output. Methods: Transcranial magnetic stimulation was used to assess motor evoked potential (MEP) amplitude (single-pulse) and SICI (paired-pulse) in the resting non-dominant flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles of healthy participants. Measures were obtained at rest, during a 10 min bout of unilateral arm cycling (30 W, 60 rpm), and throughout a 20 min recovery period. To assess potential preconditioning effects, measurements were repeated during a second 2 min cycling bout following a 20 min recovery. Rest and exercise conditions were analyzed separately due to differences in stimulation intensity (RMT vs. AMT). Results: Unilateral arm cycling did not produce sustained changes in CSE or SICI in the resting limb when both arms were at rest. Furthermore, unilateral arm cycling followed by a 20 min recovery period did not result in a preconditioning effect, as CSE in the resting limb was not enhanced during a subsequent unilateral arm cycling bout. Conclusions: Submaximal unilateral arm cycling induces a transient, state-dependent increase in CSE to the non-exercised limb without altering SICI. The absence of SICI modulation suggests that this facilitation is not mediated by GABAA-dependent intracortical mechanisms, and may instead reflect modulation arising from spinal and interlimb locomotor circuitry. The lack of sustained post-exercise effects indicates that low-intensity arm cycling does not induce a plasticity-permissive cortical state, highlighting a distinction between transient, movement-dependent facilitation and longer-lasting exercise-induced neuroplasticity.

Brain Sciences doi: 10.3390/brainsci16050513

Authors: Ana Filipa Sobral Daniel José Barbosa

The brain is an extremely complex organ whose function depends on the precise coordination of molecular, cellular, and network processes [...]

Brain Sciences doi: 10.3390/brainsci16050512

Authors: Peter Walla

The scientific pursuit of understanding human “emotion” has historically been plagued by a fundamental lack of conceptual consensus. Researchers, clinicians, and the lay public frequently utilize terms such as “emotion,” “feeling,” “affect,” and “mood” as interchangeable synonyms, creating a linguistic ambiguity that hampers both experimental precision and diagnostic validity. In response to this “umbrella term” crisis, the Walla Emotion Model (WEM), also referred to as the ESCAPE Model (Emotions Convey Affective Processing Effects), introduces a redefined and distinct terminology designed to disentangle the neurophysiological, experiential, and behavioral components of affective phenomena. The essence of this new model is the removal of the umbrella aspect from the term emotion and defining “emotion” strictly as behavioral output, and “feeling” as the conscious perception of released neurochemicals, both resulting from non-conscious affective processing. By doing so, the WEM provides a logical, clear, and easy-to-apply terminological lens for diagnosing, communicating, and treating clinical conditions that include what has previously been termed “emotion” dysregulation. When “emotion” is used as an umbrella term, it depends on the school one follows how one would explain such clinical conditions. The most critical argument for introducing the WEM is that each prior school has had its focus on another set of phenomena that generate an “emotion”. The WEM terminology provides a clear separation of brain activity, subjective experience, and expression regarding affective phenomena. Various clinical conditions that include “emotion” dysregulation exist; however, to highlight the potential benefits of the WEM, the current essay has its focus on two of the most frequent conditions, namely Borderline Personality Disorder (BPD) and Major Depressive Disorder (MDD). The goal is to provide an analysis of the WEM architecture, evaluating its utility in clinical neuropsychology, and delineating its theoretical advantages when combined with traditional categorical and dimensional models. However, it is important to emphasize that this essay is only theoretical. It does not include any direct empirical support, but it suggests the replacing of existing terminology with WEM terminology.

Brain Sciences doi: 10.3390/brainsci16050511

Authors: Renate Delucchi Danhier Barbara Mertins

Background/Objectives: Visuospatial impairments are among the earliest cognitive symptoms in Alzheimer’s disease (AD) and related dementias (ADRD), yet standard assessments often lack ecological validity and focus on isolated domains. This study examines whether integrating linguistic, behavioral, and eye-tracking measures provides a more comprehensive characterization of cognitive deficits within a multimodal, exploratory framework. Methods: Twenty older adults (10 with mild to moderate dementia, including AD/ADRD, and 10 age-matched controls) completed three tasks: (1) oral narrative production, (2) visuospatial behavioral tasks (manipulation, recognition, reproduction), and (3) free-viewing eye-tracking. Linguistic, behavioral (time, errors), and fixation-based measures were analyzed using non-parametric statistics, with emphasis on effect sizes and cross-domain patterns. Results: The clinical group differed consistently from controls across domains. Linguistic measures showed increased output but reduced quality, including lower syntactic complexity, more grammatical errors, greater pragmatic deviations, and reduced gist comprehension. Behavioral tasks revealed slower performance and more frequent failures. Eye-tracking differences were less pronounced, showing a tendency toward longer fixations and less efficient visual exploration. A composite multimodal index showed clear separation between groups, indicating a consistent pattern of impairment across measures. Conclusions: Cognitive differences in dementia are expressed across multiple domains, with the strongest effects in linguistic and behavioral measures. These findings highlight the value of multimodal profiles for capturing multidimensional impairment. Results should be interpreted as exploratory and require confirmation in larger, confirmatory studies.

Brain Sciences doi: 10.3390/brainsci16050510

Authors: Toshiya Nezu Yuji Fujino Hinayo Kaneko Tadamitsu Matsuda Tsubasa Kawasaki Toshiyuki Fujiwara

Sense of agency (SoA) refers to the experience or belief that one’s own actions directly lead to a particular event in the body or external world. SoA does not arise from a single mechanism; rather, evidence suggests the integration of predictive, sensory, and contextual cues whose relative weighting may vary across tasks and individuals. Since this process requires the maintenance, comparison, and updating of action-related information, working memory-related processes have been proposed as a candidate contributor to selected components of agency. At the same time, aging is associated with alterations in temporal processing, sensory precision, executive control, and other functions that may change the use of agency-related cues. However, the extent to which age-related differences in SoA can be explained by working memory-related processes remains undefined. This narrative review examines the theoretical and empirical basis for considering working memory as a candidate mechanism linking aging and SoA. Specifically, it discusses major theoretical frameworks of agency, measurement approaches, evidence on aging-related differences in SoA, and studies suggesting that cognitive load- and working memory-related factors may modulate agency-related processing. Current evidence is suggestive, although it remains indirect, highlighting key methodological limitations and outlining priorities for future research to clarify how aging- and working-memory-related processes may shape different components of agency.

Brain Sciences doi: 10.3390/brainsci16050509

Authors: Marc Teichmann Kimihiro Nakamura

The nonfluent/agrammatic variant of primary progressive aphasia (nfav-PPA) and primary progressive apraxia of speech (PPAOS) are neurodegenerative syndromes that raise diagnostic challenges related to several issues. First, there are two divergent conceptions, one stipulating that (i) nfav-APP and PPAOS are distinct entities, and the other (ii) that PPAOS has to be integrated into the nfav-APP spectrum. A second related issue concerns the consideration of phonological dimensions, lying at the language interface with speech, which could potentially help overcome the nfva-PPA/PPAOS controversy. Third, there is a lack of internationally validated clinical tests assessing apraxia of speech and syntactic abilities with sufficient specificity and sensitivity. This narrative review discusses these issues taking into account clinical, neurocognitive and neurobiological dimensions. It proposes a conceptual-integrative framework conciliating competing nfav-APP/PPAOS accounts while suggesting a graded continuum with subdivisions, related to neurodegenerative expansion throughout language/speech production systems, ranging from syntactic to phonological to phonetic-articulatory impairments. A second controversy in the field of PPA arises from divergent conceptions of semantic PPA (sv-PPA), defined by primary damage to verbal semantics, and of semantic dementia (SD) characterized by multimodal semantic impairments. The current consensus criteria of PPA have deconstructed the initial SD conception by absorbing it into sv-PPA, hence leaving mixed and some non-verbal semantic phenotypes nosologically orphaned. Again, the article proposes a conceptual and integrative model, built on findings from clinical research and cognitive neuroscience, suggesting a graded continuum with subdivisions spanning from verbal to different non-verbal semantic impairments including social-semantic/behavioral phenotypes.

Brain Sciences doi: 10.3390/brainsci16050508

Authors: Feiyang Zhang Dequan Fang Shiji Yuan Huaizhi Tang Xiao Liang Shuai Wang Kang Ma Dezhi Zheng Shangchun Fan

Background/Objectives: Mental fatigue during driving can arise under different task conditions and typically progresses from mild to severe states. Active fatigue is usually linked to cognitively demanding driving, whereas passive fatigue is associated with prolonged monotonous driving. However, studies on multilevel mental fatigue remain scarce, and direct comparisons of prefrontal multimodal physiological responses to active and passive fatigue are still limited. The objective of this study is to characterize and compare the prefrontal multimodal physiological signatures across three fatigue levels under two simulated driving paradigms designed to induce active and passive fatigue. Methods: Eleven healthy participants completed two simulated driving tasks designed to induce active and passive fatigue. Physiological data were recorded using a self-developed prefrontal EEG-fNIRS system, and pulse-related signals were derived from the hemodynamic measurements. Based on subjective and objective indicators, fatigue was classified into non-fatigue (NonF), moderate fatigue (ModF), and severe fatigue (SevF). Results: In the active-fatigue-inducing paradigm, significant changes in prefrontal EEG and hemodynamic already emerged from NonF to ModF; for example, the EEG β/(θ + α) power ratio increased from 0.973 to 1.157 (p < 0.001) and the normalized mean deoxyhemoglobin feature increased from −0.06 to 0.09 (p < 0.001). In the passive-fatigue-inducing paradigm, EEG changes became prominent mainly from ModF to SevF, with β/(θ + α) power ratio decreasing from 0.806 to 0.761 (p < 0.05). Pulse rate variability showed increasing trends in both paradigms. Conclusions: These findings suggest that the two simulated driving paradigms were associated with distinct prefrontal electrophysiological, hemodynamic, and autonomic evolution patterns across three fatigue levels, supporting graded fatigue assessment and multimodal fatigue monitoring in driving.

Brain Sciences doi: 10.3390/brainsci16050507

Authors: Yuqi Chen Ming Meng

Background/Objectives: Adversarial domain adaptation methods are widely used in EEG-based emotion recognition to reduce the influence of individual differences and the non-stationary characteristics of electroencephalogram (EEG) signals. Most existing methods employ binary domain discriminators to align source and target domains at the global distribution level. However, such strategies often neglect the potential multimodal structure of emotional EEG data and the asymmetric emotional processing characteristics of the left and right hemispheres. To address these issues, this study proposes a Bi-Hemispheric Adversarial Domain Adaptation Neural Network (BiHADA) for EEG-based emotion recognition. Methods: In the proposed BiHADA framework, the conventional binary domain discriminator is extended into a multimodal discriminator by incorporating the label structure information of source-domain data into the domain discrimination process. This design encourages features belonging to the same emotional category to be aligned across domains and promotes positive knowledge transfer. In addition, dual adversarial domain adaptation branches are constructed to model the left and right hemispheres separately, enabling the network to capture hemisphere-specific emotional representations. Furthermore, discriminator-derived perplexity is introduced to evaluate the distribution alignment quality of target samples and to adaptively determine the weights of the corresponding hemisphere classifiers, thereby reducing the influence of poorly aligned samples during the final decision stage. Results: Experiments on the SEED dataset show that BiHADA achieves classification accuracies of 86.82% and 92.71% in cross-subject and cross-session tasks, respectively. These results demonstrate that the proposed method can effectively improve the transferability and discriminability of EEG emotional features under different domain adaptation scenarios. Conclusions: The proposed BiHADA method enhances EEG-based emotion recognition by jointly considering class-structure-guided domain alignment, hemispheric functional asymmetry, and branch-wise adaptation quality. The results suggest that incorporating source-domain label structure and hemisphere-specific adaptation can improve cross-domain EEG emotion recognition performance.

Brain Sciences doi: 10.3390/brainsci16050506

Authors: Saketh Amasa Parsa Radfar Aiyana Adams Asha Collier Justin Buendia

Background: Subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality despite advances in neurocritical care. Vitamin D plays a role in immune modulation, endothelial function, and neuroprotection; however, its impact on outcomes following SAH remains poorly defined. We evaluated the association between low vitamin D status and clinical outcomes in patients with nontraumatic SAH. Methods: We conducted a retrospective propensity score-matched cohort study using the TriNetX Research Network database. Adult patients with nontraumatic SAH and at least one recorded serum 25-hydroxyvitamin D level obtained within 3 months on or before diagnosis were included. The low vitamin D cohort was defined as 0–20 ng/mL, and the comparator cohort as 20–40 ng/mL. Cohorts were matched 1:1 using propensity scores adjusted for demographic and clinical covariates, including chronic kidney disease, liver disease, osteoporosis, and intestinal malabsorption. The primary outcome was 30-day all-cause mortality. Secondary outcomes included seizures, hydrocephalus, cerebral edema, and external ventricular drain placement. Results: After matching, 2314 patients were included in each cohort. Thirty-day mortality occurred in 9.3% of patients in the low vitamin D cohort and 7.6% of patients in the comparator cohort (hazard ratio [HR] 1.229; 95% CI, 1.006–1.503; p = 0.043). Seizures were more frequent in the low vitamin D cohort (8.6% vs. 6.9%; odds ratio [OR] 1.274; 95% CI, 1.026–1.581; p = 0.028). Hydrocephalus was also more common among patients with low vitamin D (5.1% vs. 3.9%; OR 1.328; 95% CI, 1.003–1.758; p = 0.047). No significant differences were observed in cerebral edema or external ventricular drain placement. Conclusions: Low vitamin D status was associated with increased short-term mortality, seizure incidence, and hydrocephalus following nontraumatic SAH. These findings suggest that vitamin D status may represent a potential prognostic biomarker warranting prospective investigation.

Brain Sciences doi: 10.3390/brainsci16050505

Authors: Wen Dai Qun Zhang Jing Tian Shouyan Wang Rongrong Lu

Background/Objectives: Upper-limb motor dysfunction is common after stroke, and patients often have limited recovery during rehabilitation. In this study, we aimed to investigate the relationship between contralesional neurophysiological parameters and the effects of rehabilitation on upper-limb motor function in stroke patients with corticospinal tract damage. Methods: Forty patients with subacute stroke with an absent MEP response on the ipsilesional side before admission were included. Contralesional neurophysiological parameters, including resting motor threshold, contralesional MEP, contralesional short-interval intracortical inhibition (short-ICI), and contralesional long-interval intracortical inhibition (long-ICI), were assessed via transcranial magnetic stimulation (TMS) pre-admission. The coefficients of variation for MEP, short-ICI, and long-ICI were calculated to assess cortical stability. Rehabilitation effect was measured using changes in the Fugl–Meyer assessment score after 21 days of rehabilitation. Results: No single contralesional parameter significantly predicted rehabilitation effect. Further exploratory analysis revealed that a model combining contralesional neurophysiological parameters was associated with proximal limb motor function recovery. Short-ICI played a prominent role in this exploratory model. Conclusions: Contralesional neurophysiological markers demonstrated limited predictive value in patients with stroke with moderate-to-severe motor dysfunction and damaged corticospinal tract function on the ipsilesional side. However, a model combining multimodal contralesional TMS measures, particularly short-ICI, may offer incremental value in predicting proximal limb motor improvement following 21-day rehabilitation. Although this mechanism was not directly measured, the findings suggest a compensatory role of the cortico-reticulo-spinal pathway. These exploratory results should be interpreted with caution regarding their clinical applicability and are premature as a predictive tool, pending rigorous external validation.

Brain Sciences doi: 10.3390/brainsci16050504

Authors: Giulia Paparella Adriana Martini Anna Sofia Grandolfo Matteo Panfili Luca Angelini Martina De Riggi Simone Aloisio Daniele Birreci Annalisa Maraone Francesco Saverio Bersani Matteo Bologna

Background: Essential tremor (ET) is a clinically heterogeneous disorder involving motor and non-motor features. Voluntary movement abnormalities, including movement slowness (bradykinesia), have been frequently described in ET. Among non-motor symptoms, insomnia is also frequently reported, raising the possibility of shared underlying mechanisms with bradykinesia (e.g., brainstem noradrenergic dysfunction involving the locus coeruleus due to Lewy body pathology). We investigated the relationship between movement abnormalities, as objectively quantified using finger-tapping kinematic analysis, and sleep disturbances in ET. Methods: A subsample of 29 ET patients included in a previous study underwent kinematic analysis of finger-tapping. Insomnia was evaluated using the Insomnia Severity Index (ISI). Patients were stratified according to the presence of bradykinesia (e.g, movement slowness during finger-tapping) and insomnia (ISI ≥ 8). Group comparisons and correlational analyses were performed to assess the association between kinematic measures of bradykinesia, insomnia severity and other clinical features. Results: Fourteen subjects (48.3%) exhibited bradykinesia on kinematic analysis, and eleven patients (37.9%) met the criteria for insomnia. The prevalence of insomnia was similar between patients with and without bradykinesia. Likewise, no significant differences in finger-tapping kinematics were observed between ET patients with and without insomnia. Kinematic measures of bradykinesia did not correlate with ISI scores (all p > 0.05), whereas ISI scores were significantly positively correlated with clinical tremor severity. Conclusions: The current kinematic analysis suggests no relationship between movement abnormalities and sleep disturbances in ET. While bradykinesia in ET possibly relies on the dysfunction of cerebellar–basal ganglia circuits, insomnia in ET may reflect prominent brainstem dysfunction. Larger studies integrating kinematic assessments, neuroimaging, and longitudinal designs are needed to clarify the relationship between movement and sleep disturbances in ET

Brain Sciences doi: 10.3390/brainsci16050503

Authors: Dariusz Krok Ewa Telka Sebastian Binyamin Skalski-Bednarz Mariusz G. Kuźniar

Background/Objectives: Mindfulness has been identified as a protective factor in promoting adaptive psychological outcomes among cancer patients, yet the mechanisms linking mindfulness to fundamental existential beliefs, such as basic hope, remain underexplored. In addition, mediational processes underlying these relationships remain understudied. Building on the theoretical framework of Acceptance and Commitment Therapy, we tested a serial multiple mediation model in which illness acceptance and fear of recurrence sequentially mediated the association between mindfulness and basic hope. Methods: Adult patients diagnosed with pelvic cancer (N = 273) who were undergoing oncological treatment completed questionnaires measuring mindfulness, illness acceptance, fear of recurrence, and basic hope. Mediation analysis was used to examine multiple mediation effects. Results: Illness acceptance also functioned as a single mediator between mindfulness and basic hope. In contrast, fear of recurrence was not a mediator between mindfulness and basic hope. The main finding was the serial mediation pathway through illness acceptance and fear of recurrence. The indirect effects showed that mindfulness was positively associated with illness acceptance dimensions—life satisfaction during illness, reconciliation with the disease, and self-distancing from the disease—which, in turn, were negatively associated with fear of recurrence, ultimately relating to higher levels of basic hope. Conclusions: The findings highlight the critical role of acceptance- and fear-related processes in sustaining basic hope among cancer patients and suggest that mindfulness-based interventions may foster adaptive adjustment to illness. Implications for clinical practice include integrating mindfulness and acceptance-focused strategies to enhance hope and support emotional well-being in patients coping with cancer.

Brain Sciences doi: 10.3390/brainsci16050502

Authors: José Miguel Sánchez-Nieto Beatriz Hernández-Monjaraz Víctor Manuel Mendoza-Núñez

Cognition in older adults may be influenced by environmental factors; however, the pathways linking environmental exposures and cognition remain unclear. The aim of this narrative review is to synthesize evidence on the association between the environment and cognition in older adults, integrating biological, environmental, and behavioral elements. Systematic reviews and original studies addressing this topic were identified in Web of Science, PubMed, and Scopus. The primary neural processes associated with maintaining cognition during aging are neuronal plasticity and compensatory scaffolding. Participation in intellectually stimulating activities, physical exercise, and a healthy diet; mitigation of chronic stress; reduction in the severity of depressive symptoms; and buffering against the adverse effects of air pollution are proposed as plausible pathways that may mediate the relationship between neural processes and the environment. In this context, environmental factors that affect cognition can be classified at three levels: (i) micro-level (family and home): social interaction with family members and indoor pollution; (ii) meso-level (community and services): social interaction, land-use diversity, transportation systems, environmental design, and urban green spaces; and (iii) macro-level (society in general and public policies): social representations of old age and aging (positive aging vs. ageism) and public policies aimed at improving pathways related to cognitive maintenance. Overall, the environment may influence cognition in older adults; however, the available studies show methodological and conceptual heterogeneity, inconsistent findings, and important gaps in knowledge.

Brain Sciences doi: 10.3390/brainsci16050501

Authors: Francesca Romana Barbieri Massimo Marano Daniele Marruzzo Alessandra Ricci Brunetto De Sanctis Alessandro Riario Sforza Riccardo Paracino Stefano Toro Serena Pagano Fabrizio Mancini Carolina Noya Davide Luglietto Riccardo Antonio Ricciuti

Background/Objectives: Preservation of critical white matter (WM) pathways is essential for maximizing surgical safety in neuro-oncology and functional neurosurgery. Constrained spherical deconvolution (CSD) offers superior modeling of complex fiber architecture compared to diffusion tensor imaging (DTI). This case series evaluates the clinical utility of CSD in surgical planning and intraoperative navigation. Methods: A retrospective review of 20 patients (15 brain tumors, 5 functional disorders) treated between September 2022, and September 2024 was performed. All patients underwent preoperative MRI with CSD-based reconstruction of eloquent WM tracts. Clinical presentation, tract involvement, surgical strategy, and postoperative outcomes were analyzed. Results: CSD reliably reconstructed CST, AF, IFOF, OT, and DRTT depending on tumor location or DBS target. Compared with standard DTI, CSD provided improved delineation of tract extent and tumor–tract interfaces. Gross total resection (GTR) was achieved in all tumor patients without new neurological deficits. DBS cases showed precise correlation between stimulation thresholds, side effects, and CSD-predicted distances to critical WM tracts. DRTT targeting resulted in marked clinical improvement in Holmes tremor. Conclusions: CSD enhances anatomical accuracy in WM tract visualization, supporting safer resections in eloquent areas and improving DBS targeting. Its integration into routine workflow may optimize neurosurgical outcomes.

Brain Sciences doi: 10.3390/brainsci16050500

Authors: Carlotta Marrangone Alessio Mosca Manuel Marzola Francesca Martella Martina Di Bartolomeo Vittore Verratti Giovanni Martinotti Claudio D’Addario

Background/Objectives: High-altitude exposure represents a complex psychophysiological stressor involving hypoxia, physical effort, sleep disruption and psychological strain. The endocannabinoid system (ECS) plays a key role in stress regulation, yet its epigenetic modulation under extreme environmental conditions remains poorly characterized. This pilot and exploratory study investigated DNA methylation and descriptive microRNA (miRNA) expression patterns of CNR1 and FAAH genes, and their associations with mood and anxiety outcomes, in trekkers exposed to Himalayan high altitude. Methods: Twenty-one healthy lowlanders completed a longitudinal expedition from 2860 m to 5050 m. Psychometric measures (SVARAD, BDI, SAS, SHAPS) and saliva samples were collected at baseline (T0) and at high altitude (T1). DNA methylation of CNR1 and FAAH regulatory regions was quantified by pyrosequencing. Exosomal miRNAs targeting these genes were profiled using qRT-PCR, on pooled samples; results are presented descriptively. Results: DNA methylation analysis revealed heterogeneous, sex-specific epigenetic patterns following high-altitude exposure. A significant increase in CNR1 promoter methylation at CpG4 was observed in males at T1, whereas methylation remained largely stable in females. Descriptive miRNA expression data showed bidirectional differences between groups, consistent with context-dependent stress regulation. Convergent directional patterns between miR-23b-3p expression and CNR1 methylation in males were observed. However, given the descriptive nature of the miRNA data, this observation is purely exploratory and requires replication before any mechanistic conclusions can be drawn. Psychometrically, participants showed a mild mood decline without overt clinical symptoms. Sex-specific differences in the relationship between CNR1 methylation and psychometric outcomes were observed and warrant further investigation in adequately powered cohorts. Conclusions: These preliminary findings suggest that CNR1 epigenetic regulation warrants further investigation as a potential indicator of stress adaptation and psychological responses and underscore the need to consider sex differences when evaluating resilience and vulnerability to extreme environments.

Brain Sciences doi: 10.3390/brainsci16050499

Authors: Diana Sarahi De la Merced-García Rocío Valle-Bautista Rebeca Hernández-García Néstor Fabián Díaz Anayansi Molina-Hernández

Intracellular calcium (Ca2+) signaling is a central regulator of corticogenesis, governing haveneural stem cell behavior, fate transitions, neuronal migration, and circuit assembly. Beyond its canonical role as a second messenger, Ca2+ shapes cytoskeletal organization by modulating microtubule dynamics essential for mitotic spindle function, radial glial scaffold, nucleokinesis, and neurite extension. This review synthesizes evidence from in vivo, ex vivo, and in vitro studies to delineate Ca2+-dependent pathways and Ca2+-binding proteins that couple, within restricted Ca2+ microdomains in space and time, to microtubule regulation during mammalian cortical development. We highlight mechanistic nodes involving calmodulin, Ca2+/calmodulin-dependent kinases (CaMKs), S100 proteins, cadherins/protocadherins, centrins (CENs), and Ca2+ sensors such as STIM1 and calneurons, which collectively coordinate spindle orientation, progenitor division modes, radial migration, and neurite outgrowth. Finally, we discuss how perturbations in Ca2+-controlled cytoskeletal programs may contribute to abnormal cortical cytoarchitecture and neurodevelopmental disease. By integrating Ca2+ microdomain transients with microtubule control modules, this review provides a unified framework for understanding how Ca2+ orchestrates key cellular events during mammalian corticogenesis and propose that Ca2+ oscillatory codes are translated into direct or indirect microtubule/cytoskeletal remodeling transitions that determine neural stem cell fate, migration, and maturation, to accurately establish cortical architecture and function.

Brain Sciences doi: 10.3390/brainsci16050498

Authors: Giovanni Stanghellini

This review explores the hypothesis that schizophrenic symptoms may be understood not as isolated deficits, but as interconnected manifestations of a structural reorganization of consciousness. The premises of this work are grounded in a comparative matrix that suggests an underlying “consanguinity” between the philosopher’s voluntary epoché—the suspension of the natural attitude performed to study the inner workings of consciousness—and the involuntary “unworlding” passively experienced in schizophrenia. By exploring this shared ontological ground, the text suggests how specific phenomenological shifts, such as the collapse of the “vital drive,” may manifest as clinical markers; this process may eventually lead to an involuntary “transcendental reduction” where the mind’s internal machinery becomes an object of forced awareness. Building on these premises, the review tentatively outlines several key achievements. It addresses the substrate-subjectivity gap by linking biological sensory-binding failures to the onset of involuntary hyper-reflexivity. Regarding structural loss and gain of function, it suggests that the psychotic transition involves a simultaneous erosion of common-sense coherence and an intensified receptivity to unfiltered perceptual fragments, which may trigger a search for metaphysical meanings. In terms of a therapeutic synthesis, it proposes exploring the conversion of “artless decentering” into a manageable, strategic distance through mindfulness and person-centered position-taking. Finally, it discusses a potential nosographic evolution, advocating for future diagnostic classifications that prioritize the experiencing self and qualitative insights to support a more translational and empathetic approach to psychiatry.

Brain Sciences doi: 10.3390/brainsci16050497

Authors: Paolo Palmisciano Mario Zuccarello

Intracranial aneurysms are common vascular lesions with a highly variable natural history. While most unruptured intracranial aneurysms remain stable throughout life, a biologically aggressive subset progresses to growth and rupture, resulting in aneurysmal subarachnoid hemorrhage with substantial morbidity and mortality. Contemporary evidence demonstrates that aneurysm behavior is dynamic rather than static and reflects the interaction of hemodynamic forces, inflammatory vascular remodeling, genetic susceptibility, and environmental risk factors. Rupture risk is not constant over time and may be highest early after aneurysm formation, followed by a period of relative quiescence in selected lesions. Traditional population-based risk estimates have therefore evolved toward individualized risk stratification incorporating aneurysm size, location, morphology, growth, patient-specific factors, and emerging imaging and computational biomarkers. This chapter reviews the epidemiology, pathobiology, growth patterns, and rupture risk of intracranial aneurysms, integrating foundational observational studies with recent advances in genetics, vessel wall imaging, and predictive modeling. Understanding the natural history of brain aneurysms is essential for balancing the risks of observation against intervention and for guiding future innovations in aneurysm management.

Brain Sciences doi: 10.3390/brainsci16050495

Authors: Lauren M. Friedman Gabrielle Fabrikant-Abzug Lindsay C. Chromik

Behavioral parent training (BPT) is a front-line psychosocial treatment for childhood ADHD, yet its real-world effectiveness is often constrained by parents’ ability to consistently implement learned strategies. Parental ADHD is a prevalent and mechanistically important factor shaping both parenting behavior and child treatment response. Among parents with ADHD, deficits in executive functioning and emotion regulation, abilities essential for consistent and effective BPT implementation, often interfere with parents’ ability to apply learned strategies. Consequently, parental ADHD predicts reduced in-home skill use and attenuated child treatment gains, positioning it as a potentially critical, treatment-relevant risk factor. This narrative review synthesizes evidence on the intergenerational transmission of ADHD-related impairments, the impact of parental ADHD on parenting practices, and the role of parental ADHD as a moderator of BPT outcomes. We also examine existing approaches to addressing parental ADHD within the context of child BPT, including both pharmacological and psychosocial strategies, and evaluate their implications for parenting and child response. Building on this, we propose an intergenerational reconceptualization of psychosocial care for childhood ADHD in which parental functioning is routinely assessed and supported within BPT. Promising directions include integrating CBT-informed strategies to scaffold parents’ cognitive and regulatory processes, incorporating digital health tools that provide just-in-time guidance at the point of parenting performance, and tailoring BPT emphasis for families affected by multigenerational ADHD. Ultimately, embedding parent-focused supports within BPT may be essential for strengthening treatment impact, durability, and real-world effectiveness for many children and families.

Brain Sciences doi: 10.3390/brainsci16050496

Authors: Nathan R. Luzum Marcia H. McCall Charlotte Talley Boyd Heather Columbano Edward Ip Santiago Saldana Alison H. Oliveto Merideth Addicott

Background/Objectives: A sub-anesthetic dose of ketamine has shown promise in reducing craving, withdrawal symptoms, and use of drugs such as alcohol, cocaine, and opioids among individuals with substance use disorders. Ketamine’s therapeutic potential for tobacco use is unknown. Here, we investigated a single sub-anesthetic dose among adults with tobacco use disorder who were not interested in changing their smoking behavior. Methods: Utilizing a randomized, within-subject crossover, double-blinded, counter-balanced, midazolam-controlled design, participants (n = 18) received a 0.71 mg/kg infusion of ketamine and a 0.025 mg/kg infusion of midazolam (i.e., active placebo) at least two weeks apart. Participants were asked to abstain from smoking after the infusions until the post-infusion sessions, 1 day following infusion, where participants completed measures of smoking behavior, craving, and withdrawal symptoms. Participants continued to record their smoking behavior over the 7 days following infusion. Participants also completed a semi-structured qualitative interview regarding their experiences. Results: Compared to midazolam, ketamine infusion led to a non-significant reduction (p = 0.10, ηp2 = 0.153) in the number of cigarettes smoked during the requested abstinence period. Following this period, there were no significant differences in ad lib smoking. Ketamine showed no effect on craving or withdrawal symptoms. Participants reported more intense psychological experiences following ketamine infusion (p < 0.001, ηp2 = 0.830) and about half reported it felt easier to abstain from smoking after the ketamine infusion. Conclusions: While well tolerated, these findings suggest ketamine has little to no direct effect on quantitative measures of cigarette smoking, craving, or withdrawal. However, the qualitative measures suggest ketamine improves mood and reduces craving in some individuals for several days. Future studies should investigate whether ketamine can indirectly support smoking cessation among individuals with comorbid psychiatric indications for ketamine treatment.

Brain Sciences doi: 10.3390/brainsci16050494

Authors: Tomi-Ann Roberts James W. Pennebaker Benita Jackson

Much of the interoception literature assumes that people can accurately detect their heart rate, stomach contractility, muscle tension, and other biological cues. This is not true. Instead, interoception is an active integrative psychological process where the feeling of one’s internal state emerges from physiological signals, contextual cues, and the social and cultural experiences of living in a body. Thinking of interoception this way shifts the focus from measuring accuracy at detecting biological signaling to studying lived experience. One such experience is the widespread objectification of women’s bodies. Living in a body that is chronically evaluated creates a particular form of self-consciousness. Here, we propose that self-objectification redirects attention toward the body, potentially reshaping both the allocation of attention to internal sensations and their interpretation and thereby offering a theoretical account of paradoxes in the interoception literature, such as women’s lower detection accuracy but higher symptom reporting, and mismatches between subjective and physiological reports of menopausal hot flashes. We consider implications for women’s health, including reproductive health, ACL injury risk, and chronic pain. Our framework suggests that “feeling like a woman” reflects an interoceptive experience shaped significantly by objectification, with important consequences for well-being.

Brain Sciences doi: 10.3390/brainsci16050492

Authors: Isabel Tissieres Stephanie Clarke Sonia Crottaz-Herbette

Background: Firefighters search for survivors in low-visibility environments and have documented expertise in spatial orientation and wayfinding. No studies so far have investigated their ability to make use of auditory spatial cues. Methods: The performance of 41 professional firefighters and 24 control subjects to localise sounds played in a dark environment at 9 azimuthal positions was assessed using (i) meaningless single sounds and (ii) meaningful sounds presented with two simultaneous distractors. Localisation errors were analysed with a 3-way ANOVA Task × Position × Group. Results: The analysis yielded significant main effects of Task, Position and Group. The localisation errors tended to be smaller when localising meaningless single sounds (main effect Task), for items presented at central as compared to peripheral positions (main effect Position), and by firefighters rather than controls (main effect Group). The interactions Position × Group and Task × Position were significant; firefighters performed more accurately at peripheral positions than controls, and meaningless single sounds yielded fewer localisation errors at the periphery than meaningful sounds presented with distractors. Conclusions: Professional firefighters perform better than controls at explicit localisation of sounds, including in conditions where sound objects need to be segregated from distractors by spatial cues. These results suggest that firefighters have acquired expertise in the explicit and implicit use of auditory spatial cues. The proficiency of firefighters needs to be taken into consideration when planning and carrying out interventions.

Brain Sciences doi: 10.3390/brainsci16050493

Authors: Tracy Milane Edoardo Bianchini Lanfranco De Carolis Antonio Suppa Marco Salvetti Clint Hansen Massimo Marano Domiziana Rinaldi Nicolas Vuillerme

Background/Objectives: Freezing of gait (FOG) and sleep disturbances are common in people with Parkinson’s disease (PwPD). A bidirectional association between them has been suggested, but quantitative evaluations are scarce. This study aimed to compare sleep disturbances in mild-to-moderate PwPD with (PD+FOG) and without FOG (PD−FOG), and to assess the association between FOG severity and sleep parameters. Methods: Data from 54 PwPD with disease stage <4 and no severe cognitive decline were included (27 PD+FOG and 27 propensity score-matched for age, sex, and disease duration PD−FOG). Demographics and clinical variables were collected. Clinical assessment included the new freezing of gait questionnaire (NFOG-Q), Parkinson’s Disease Sleep Scale (PDSS-2), Epworth Sleepiness Scale (ESS) and Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). Mann–Whitney U, Fisher’s exact and Spearman’s tests were used for group comparisons and correlations, respectively. Results: Significant differences were observed between PD+FOG and PD−FOG groups in MDS-UPDRS part II (p = 0.011) and part IV (p = 0.011), with higher scores in PD+FOG participants. No significant differences were found in PDSS-2 or ESS between the two groups. A significant moderate positive correlation was found between NFOG-Q score and PDSS-2 (ρ = 0.416; p = 0.044) in PD+FOG participants. Conclusions: FOG severity was positively associated with sleep disturbances within the PD+FOG group. However, no significant difference in sleep quality or excessive daytime sleepiness was found between PD+FOG and PD−FOG after propensity score matching. PD+FOG participants experienced more severe motor complications and greater impairment in daily activities compared to PD−FOG.

Brain Sciences doi: 10.3390/brainsci16050491

Authors: Mao-Yang Zhou Jin-Shan Li Zhao-Xin Sun Jie Yin Yun Zhao Fang Xie Xue Wang Sheng-Hui Zhang Zhao-Wei Sun Ling-Jia Qian

Background: Chronic stress is a major risk factor for cognitive decline and blood–brain barrier (BBB) disruption, yet the underlying molecular mechanisms remain elusive. This study aimed to investigate the specific role of the metabolic intermediate homocysteine (Hcy) in chronic stress-induced BBB dysfunction and cognitive impairment. Methods: We utilized a male Sprague-Dawley rat model of chronic unpredictable mild stress (CUMS) and administered vitamin B complex to lower Hcy levels in vivo. Regional Hcy accumulation, BBB permeability, and cognitive behaviors were assessed. In vitro, primary rat brain microvascular endothelial cells (BMECs) were exposed to Hcy to evaluate barrier-forming function, transcriptomic alterations, DNA methylation patterns, Cav1.2 expression, and reactive oxygen species (ROS) production. Results: CUMS selectively induced BBB hyperpermeability and significant Hcy accumulation predominantly within the rat hippocampus, which correlated intimately with cognitive deficits. Lowering Hcy levels via vitamin B supplementation successfully restored hippocampal BBB integrity and alleviated cognitive impairment. In addition, elevated Hcy severely impaired the barrier function of BMECs. Mechanistically, Hcy reduced global DNA methylation in BMECs and specifically induced targeted DNA hypomethylation at the intro region of Cacna1c. This epigenetic shift caused the transcriptional derepression and overexpression of the Cav1.2 calcium channel. Upregulated Cav1.2 subsequently triggered a robust ROS burst, leading to tight junction degradation. Conclusions: Our findings unveil a novel metabolic–epigenetic axis where Hcy-driven Cacna1c hypomethylation directly disrupts BMECs function to dismantle the hippocampal BBB. Lowering Hcy or targeting this Hcy-Cav1.2 pathway establishes a promising therapeutic strategy for mitigating stress-related neurovascular damage and cognitive disorders.

Brain Sciences doi: 10.3390/brainsci16050490

Authors: Aysegul Esen Aydin Mehmet Emin Akdeniz Orhun Mete Cevik

Background/Objectives: The posterior commissure (PC) and habenular commissure (HC) are fine-caliber midline fiber bundles located within the epithalamic roof of the third ventricle. Their small size and deep anatomical position render them vulnerable during fiber dissection, and it is difficult to delineate reliably with conventional diffusion MRI. To define a reproducible microsurgical strategy for three-dimensional exposure of the PC and HC, and to evaluate their tractographic representation using high-resolution diffusion template data. Methods: Four formalin-fixed adult cadaveric brains were prepared using a modified Klingler technique and underwent systematic microsurgical fiber dissection focused on preservation of the epithalamic roof and midline commissures. Diffusion MRI data from the Human Connectome Project (HCP-1065) were reconstructed in MNI space using q-space diffeomorphic reconstruction in DSI Studio to attempt deterministic tractographic reconstruction of the PC and HC. Results: In all specimens, the PC was identified as a compact transverse bundle superior to the rostral cerebral aqueduct within the inferior pineal lamina. The HC appeared as a thinner band superior to the pineal recess, interconnecting the bilateral habenular nuclei and separated from the PC by the hypothalamic sulcus. A midline-prioritized dissection sequence facilitated preservation of commissural continuity. Deterministic tractography reproduced adjacent peduncular trajectories but failed to consistently reconstruct discrete HC or PC streamlines. Conclusions: Cadaveric fiber dissection remains the most reliable method for studying the fine commissural anatomy of the epithalamus. A midline-first, roof-preserving strategy enhances visualization of the PC and HC and may have implications for posterior third ventricular surgery and stereotactic targeting.

Brain Sciences doi: 10.3390/brainsci16050486

Authors: Junpei Nagasawa Tatsuhiro Yokoyama Ryuichi Okamoto Junya Ebina Mari Shibukawa Takehisa Hirayama Osamu Kano

Background: The Circle of Willis (CoW) is a key collateral pathway that enables communication between the anterior and posterior cerebral circulations. However, anatomical variations in the A1 segment of the anterior cerebral artery, such as hypoplasia or aplasia, can alter hemodynamics and may compromise this collateral function. While incomplete CoW configurations have been linked to aneurysm formation and altered patterns of hemorrhage, their role in the distribution of cerebral infarctions remains controversial. We aimed to explore the association between A1 segment hypoplasia/aplasia and infarct laterality across different etiological subtypes. Methods: We retrospectively analyzed patients with unilateral anterior circulation infarction admitted between April 2017 and March 2023. The CoW was assessed by magnetic resonance angiography (MRA). A1 segment hypoplasia was defined as a segment diameter <1 mm, and A1 aplasia was defined as non-visualization on MRA. The side with hypoplasia or aplasia was defined as the minor side, and the contralateral side as dominant. We assessed whether infarction occurred on the minor or dominant side. Results: Among 198 patients with unilateral anterior circulation infarction classified as lacunar, cardioembolic stroke (CES), or embolic stroke of undetermined source (ESUS), 30% had A1 hypoplasia or aplasia, with similar prevalence across subtypes. Infarcts occurred on the A1 dominant side in 53% of lacunar, 55% of ESUS, and 75% of CES cases. Although this difference did not reach statistical significance (p = 0.43), it should be interpreted with caution given the limited sample size. Conclusions: The rates of A1 hypoplasia and aplasia were similar across stroke types. No statistically significant association was identified. The findings remain inconclusive given the limited sample size. These results should be considered exploratory and hypothesis-generating.

Brain Sciences doi: 10.3390/brainsci16050485

Authors: Tamotsu Tsukahara Hisao Haniu Yoshikazu Matsuda

Synucleinopathies, including Parkinson’s disease and dementia with Lewy bodies, are characterized by progressive α-synuclein (α-Syn) aggregation accompanied by chronic neuroinflammatory changes. However, the mechanistic relationship between disrupted proteostasis and inflammatory signaling remains incompletely defined and may vary across disease stages and clinical subtypes. Lysophospholipids (LPLs) are bioactive lipids derived from membrane phospholipids that participate in diverse cellular processes. These functions are primarily mediated through G protein-coupled receptor (GPCR) signaling, but may also involve direct effects on membrane organization and biophysical properties. In addition to receptor-mediated pathways, the surrounding lipid environment may influence protein behavior, although its role in neurodegenerative processes remains to be fully elucidated. Within this framework, LPLs can be considered not only as signaling molecules but also as modulators of the cellular environment in which proteostasis and inflammatory responses occur. In this review, we adopt a lipid-centered perspective in which LPLs occupy an interface between lipid signaling, protein aggregation, and neuroinflammation. Rather than acting as a single initiating factor, altered lipid metabolism is likely to contribute through multiple interconnected pathways. Although current evidence is largely derived from preclinical studies, it supports a role for lipid-related mechanisms, particularly in early stages of synucleinopathy.

Brain Sciences doi: 10.3390/brainsci16050489

Authors: Xue Weng Yang Lu Xinyue Zhao Haoran Jiang Lin Li Xiuyan Guo

Background: Rhythmic knowledge enables the precise timing of actions in dynamic environments. Although rhythm learning has been extensively studied, it remains debated whether such learning arises primarily from the perceptual encoding of rhythmic inputs or from the repetitive execution of periodic actions. Methods: To address this question, we developed a temporal-rhythm serial reaction time (TR-SRT) paradigm that dissociates rhythmic structures in perceptual inputs from the timing of motor responses. Across three experiments, participants learned rhythms under visuomotor (Experiment 1, N = 27), visual-only (Experiment 2, N = 26), or motor-only (Experiment 3, N = 26) conditions while electroencephalography was recorded. Results: Behavioral learning slopes revealed robust rhythm learning in both the visuomotor and visual-only conditions, whereas no learning emerged when rhythmic structure was confined to motor timing alone. Post-learning awareness tests further indicated that the acquired rhythmic knowledge was predominantly implicit. Consistently, global (whole-brain) theta-band magnitude (4.8–5.2 Hz) was enhanced only in the conditions that supported rhythm learning. Conclusions: These findings indicate that rhythm learning depends primarily on perceptual temporal structure rather than the repetition of rhythmic actions and identify increased global theta oscillations as a neural signature of this perceptually driven and largely implicit learning process.

Brain Sciences doi: 10.3390/brainsci16050488

Authors: Yue Huang Xiaogen Liao Chuanbin Ni

Background/Objectives: Sensory experiences and emotional information contribute to conceptual knowledge. Compared to exteroceptive modality (e.g., visual, auditory), interoceptive modality predominates in the representation of emotional concepts. However, few studies have examined the interoceptive modality-specific effects on emotional word processing. Additionally, questions remain about when emotional valence interacts with sensory experiences during the processing of emotional words, and to what extent these words are grounded in different sensory experiences. Methods: To address these gaps, the present ERP study investigated how sensory information (interoception and vision) influences emotional word processing in a lexical decision task. Results: Behavioral results showed significant differences between interoceptive and visual words, as well as between positive and negative valence. A trend toward an interaction between sensory modality and emotional valence was also observed. ERP results indicated that negative words elicited a more positive-going P2 than positive words. Significantly smaller N400 amplitudes were observed for interoceptive words than visual words in the positive condition. Negative visual words evoked enhanced LPC amplitudes compared with both negative interoceptive words and positive visual words. Conclusions: The present findings suggest a dynamic pattern of valence effects in emotional word processing, characterized by a negativity bias and a positivity bias at different stages. Furthermore, our findings highlight that interoception promotes the semantic retrieval and integration of emotional words. This study provides empirical support for the modality-specific hypothesis within the framework of interoceptive embodied cognition and offers novel implications for future research on emotional word processing.

Brain Sciences doi: 10.3390/brainsci16050487

Authors: Nirupama A. Sabnis Luke C. Cooksey Hareesh Jayakumar Mariana Moguel Mendez Ezek Mathew Roland Max Petty Amalendu Ranjan Luis Colon-Perez Rob Dickerman Porunelloor A. Mathew Bruce A. Bunnell

Glioblastoma (GB) remains the most aggressive primary brain malignancy, with the Stupp regimen persisting as the standard of care for nearly two decades despite poor survival outcomes. This review was synthesized by extensively reviewing and analyzing the literature from PubMed, Scopus, and Web of Science to evaluate the emerging promising therapeutic and diagnostic strategies for combating GB. Results indicate significant progress in molecularly targeted therapies, biomimetic nanocarriers, and advanced radiotherapy. While immunotherapeutic approaches, such as checkpoint inhibitors and vaccines, show variable clinical success, the integration of bioinformatics and machine learning has significantly enhanced treatment response prediction. Furthermore, advances in radiomics and molecular imaging have improved the differentiation between true tumor progression and pseudoprogression, potentially reducing invasive diagnostic requirements. Additionally, other emerging and investigational adjuvant therapeutic approaches have shown promise. We conclude that, while multimodal strategies integrating molecular and computational approaches offer a path toward personalized GB management, significant barriers—namely tumor heterogeneity and the blood–brain barrier—persist. Future research must prioritize precision-based combinatorial models to successfully translate these preclinical advancements into improved clinical outcomes for patients.

Brain Sciences doi: 10.3390/brainsci16050484

Authors: Louis Versweyveld Greet Vanderlinden Wim Vandenberghe Aline Delva Koen Van Laere

Background/Objectives: Imaging of both cardiac sympathetic denervation and nigrostriatal dopaminergic degeneration can support the diagnosis of Parkinson’s disease (PD). However, their temporal relationship and combined diagnostic value remain unclear. This review addresses (1) whether nigrostriatal degeneration and cardiac sympathetic denervation are correlated in PD and (2) the comparative and combined diagnostic accuracy of striatal dopaminergic and cardiac sympathetic imaging in PD. Methods: We searched PubMed (October 2025) for studies assessing both a striatal dopaminergic and a cardiac sympathetic imaging biomarker in the same PD cohort, supplemented by citation chaining. Diagnostic accuracy studies were evaluated using QUADAS-2. Results: Nineteen studies met the inclusion criteria. Ten studies examined within-subject associations; six reported significant correlations ranging from weak to strong (ρ ~0.2–0.8). Two studies observed a significant correlation for the akinetic-rigid subtype but not for the tremor-dominant subtype of PD. Ten studies compared diagnostic accuracies, five of which used pre-defined thresholds and consistently found higher sensitivity for [123I]FP-CIT SPECT (78–100%) compared to [123I]MIBG scintigraphy (65–82%), but higher specificity for [123I]MIBG (range 75–100%) than for [123I]FP-CIT (range 11–73%). Adding [123I]MIBG scintigraphy to [123I]FP-CIT SPECT generally increased specificity but had inconsistent effects on overall accuracy. QUADAS-2 revealed substantial risks of patient selection bias, data-driven thresholds, and limited blinding. Conclusions: Reported correlations between nigrostriatal dopaminergic degeneration and cardiac sympathetic denervation in PD are inconsistent, likely reflecting both methodological heterogeneity and real variation between phenotypes. There may be a stronger correlation in the akinetic-rigid phenotype. Dopaminergic imaging is more sensitive in early PD, while cardiac sympathetic imaging is more specific for differentiating PD from atypical Parkinsonian syndromes. However, study designs greatly restrict the generalizability of reported diagnostic accuracies.

Brain Sciences doi: 10.3390/brainsci16050483

Authors: Colin Rafter Erika McCarthy Curt Stilp Jason Brumitt

Background/Objectives: Mindfulness-based interventions (MBIs) have been linked to psychological and cognitive benefits, yet evidence for their impact on brain structure remains sparse. Neuroimaging suggests MBIs may alter gray matter volume (GMV), density (GMD), and cortical thickness (CT). The purpose of this scoping review was to investigate structural neuroplasticity following MBIs. Methods: Following PRISMA-ScR guidelines, databases were searched for studies published between 2010 and 2023 that used structural MRI to assess structural brain changes in subjects after receiving MBIs. Nine studies met inclusion criteria, including five randomized controlled trials. Results: Mindfulness interventions ranged from 10 h of training to long-term practice spanning decades. Structural changes were most consistently observed in the insula, prefrontal cortex, hippocampus, posterior cingulate, and temporoparietal junction, regions tied to interoception, executive control, and self-referential processing. The greatest structural changes were reported in studies implementing multi-month interventions or long-term meditative practice. Conclusions: MBIs are associated with structural brain changes across a limited and heterogeneous body of literature, but current evidence is insufficient to draw firm conclusions regarding causality or consistency of effect. Larger, diverse, and more methodologically rigorous trials with extended follow-up are needed to clarify the durability and significance of observed changes.

Brain Sciences doi: 10.3390/brainsci16050482

Authors: Flavia Primosa Serena Cazzato Lucia Gotri Romano Marchini Orejeta Diamanti Laura Iacorossi Andreina Saba

Background/Objectives: Severe brain injuries generate complex, long-term needs requiring intensive physical, cognitive and relational care. These conditions also profoundly affect families, who often experience emotional distress, uncertainty and a heavy caregiving burden. Although neuro-palliative care is increasingly recognised, the early integration of palliative care for this population remains limited. This study aimed to explore healthcare professionals’ perceptions of the palliative care needs of patients with severe brain injuries and their caregivers and to identify factors that hinder or facilitate early palliative care implementation in specialised settings. Methods: An interpretive qualitative study was conducted using Reflexive Thematic Analysis. Fifteen semi-structured narrative interviews were carried out with healthcare professionals working in specialised hospital units in Northern Italy. Data were analysed inductively through an iterative and reflexive process following Braun and Clarke’s six phases. Methodological rigour and transparency were ensured using the COREQ checklist. Results: Five themes were identified: (1) intensive, individualised patient care needs with complex communication issues; (2) palliative needs centred on dignity, quality of life and early integrated management; (3) caregivers’ involvement and expectation-related difficulties; (4) continuous or anticipatory grief requiring structured psychological support; (5) facilitators and barriers influencing care pathways. Conclusions: Healthcare professionals identify intertwined and evolving palliative care needs in both patients with severe brain injuries and their families. The findings highlight the perceived importance of early, integrated and multidisciplinary neuro-palliative care models focused on dignity, symptom relief and sustained emotional support.

Brain Sciences doi: 10.3390/brainsci16050480

Authors: Wilson Alexander Zambrano Vélez Johanna Lilibeth Alcívar Ponce Walter Gonzalo Bailón Bailón Harol Marcial Castillo del Valle Rocisela Adriana Baquerizo Quirumbay

Background/Objectives: Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with working memory deficits linked to frontoparietal alterations. Non-invasive brain stimulation (NIBS) is a potential intervention to modulate neuroplasticity and improve this executive function. In this study, we aimed to evaluate the clinical efficacy of non-invasive brain stimulation techniques (tDCS/rTMS) for strengthening working memory in children and adolescents with ADHD. Methods: This systematic review adhered to the PRISMA 2020 guidelines, with a search of Scopus and Web of Science conducted to identify relevant studies published between 2011 and 2026. Eligibility criteria, defined a priori, included original empirical studies (RCTs and quasi-experimental designs) focusing on pediatric populations (≤18 years) diagnosed with ADHD. Eligible interventions involved tDCS or rTMS with explicit working memory outcomes. Only peer-reviewed articles published in English or Spanish were included. Reviews, case reports, and studies exclusive to adults were excluded. Data on application parameters, durability, and safety were extracted for narrative synthesis. Results: Six studies met the criteria. Both tDCS and rTMS targeting the left dorsolateral prefrontal cortex showed improvements in working memory, particularly in executive components measured using digit span backward and N-back tasks. High-frequency rTMS (10 Hz) with repeated sessions showed more consistent effects, while tDCS showed modest and variable improvements. Evidence regarding long-term effects was limited. Both techniques were well-tolerated, with mild and transient adverse events. Conclusions: NIBS shows promise as a complementary intervention to improve working memory in pediatric ADHD; however, current evidence is limited. Larger, standardized, longitudinal trials are required to confirm its efficacy and clinical utility.

Brain Sciences doi: 10.3390/brainsci16050481

Authors: Barbara Rizzi Maria Chiara Gandini Andreina Saba Giada Lonati Angela Recchia

Background/Objectives: In Palliative Care (PC), the communication is an essential aspect of care becoming particularly significant at the end-of-life. In neurodegenerative diseases, communication involves additional complexity due to prolonged disease trajectories, early cognitive decline, and frequent loss of decision-making capacity. The aim of this study was to explore PC healthcare professionals’ experiences with communication process and relational dynamics involving families of patients with advanced and terminal neurogenerative disease. Methods: The study design was qualitative, using semi-structured interviews and reflexive thematic analysis. Participants were healthcare professionals directly involved in communication with the family. Results: Twenty PC professionals were interviewed, generating 792 coded excerpts. Four themes emerged: (1) Navigating PC in neurodegenerative diseases, highlighting shift from oncology-centred palliative models toward neuropalliative care, with distinctive relational challenges; (2) Navigating conversations between professionals and families, describing multidisciplinary communication, core clinical and emotional topics, and goal-oriented decision-making in contexts of impaired patient capacity; (3) Facing challenges in health care professional–family communication, including conspiracy of silence, absence of Advance Treatment Directives (ATD) or Shared Care Planning (SCP), and limited collaboration with neurologists; and (4) Envisioning methods for improvement, emphasizing the need for disease-specific competencies, advanced relational skills, interprofessional coordination, and support for professionals’ emotional wellbeing. Conclusions: Communication in neurodegenerative palliative care is an ongoing relational and interpretative process requiring professionals to mediate uncertainty, surrogate decision-making, and caregiver burden. Strengthening disease-specific communication skills, early integrated PC, and structured interprofessional collaboration may enhance shared decision-making, caregiver support, and care continuity.

Brain Sciences doi: 10.3390/brainsci16050478

Authors: Jiwon Jeong Seung Hyeon Lee Dongsun Park

Background/Objectives: Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition currently diagnosed through subjective behavioral assessments. Objective blood-based biomarkers are needed to enable earlier and more accurate identification. In this study, we aimed to identify synapse-related biomarkers associated with ASD and evaluate their potential as serum-based indicators. Methods: RNA sequencing was performed on the cerebellum, hippocampus, and cerebral cortex of a valproic acid-induced rat model of ASD to identify differentially expressed genes (DEGs). Functional enrichment analyses, including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, were conducted to explore associated pathways. Synapse-related hub genes were selected by comparison with the SFARI autism gene database, and the serum expression of candidate proteins was assessed using Western blotting. Results: A total of 692, 813, and 1059 DEGs were identified in the cerebellum, hippocampus, and cortex, respectively. Enrichment analyses highlighted dendrite development, postsynaptic density, and glutamatergic synapse pathways as significantly affected. Six synaptic hub genes were prioritized, among which serum MAP1A expression was significantly elevated in the ASD rats. Conclusions: These findings suggest that serum MAP1A may represent a potential biomarker reflecting synaptic abnormalities in ASD. Further validation in human cohorts and integration into a multi-marker framework are warranted to account for the heterogeneity of ASD.

Brain Sciences doi: 10.3390/brainsci16050479

Authors: Chunsheng Wang Baojing Zhang Jun Ren

Background: Optimism bias is the tendency to expect more positive and fewer negative events for themselves versus for others. However, it remains unclear whether the valence focus of this bias depends on how events unfold (i.e., through autonomous choice vs. external imposition). This study used behavioral and ERP measures to investigate how the event source modulates the valence focus of optimism bias. Methods: Thirty participants completed a 2 (event source: autonomous choice vs. external imposition) × 2 (valence: positive events vs. negative events) × 2 (target: self vs. other) task while an EEG was recorded. The late positive potential (LPP) was analyzed as a neural index of self-relevance. Results: Behaviorally, autonomous choice preserved optimism bias for positive events (self > other, p = 0.023), whereas external imposition induced it for negative events (self < other, p = 0.006). Under autonomous choice, the LPP mirrored this pattern (enhanced for self-positive events, p = 0.038). Under external imposition, the LPP showed only a valence-general self-bias (main effect of target, p = 0.014). Conclusions: These preliminary findings suggest that event sources may influence the valence focus of optimism bias. Under autonomous choice, the bias is positive-focused. Under external imposition, it shifts to negative-focused. This dissociation between behavioral and neural patterns is consistent with dual patterns in optimism bias expression, though further research is needed.

Brain Sciences doi: 10.3390/brainsci16050477

Authors: Azadeh Hassannejad Nazir Jeanette Hellgren Kotaleski Hans Liljenström

As social beings, humans make decisions partly based on social interaction. Observing the behavior of others can lead to learning from and about them, potentially increasing trust and prompting trust-based behavioral changes. Observation-based decision making involves different neural structures. The orbitofrontal cortex (OFC) and lateral prefrontal cortex (LPFC) are known as neural structures mainly involved in processing emotional and cognitive decision values, respectively, while the anterior cingulate cortex (ACC) plays a pivotal role as a social hub, integrating the afferent expectancy signals from the OFC and LPFC. This paper presents a neurocomputational model of the interplay between observational learning and trust, as well as their role in individual decision making. Hence, our model provides a framework for investigating how emotional and rational responses may change when individuals observe the action–outcome associations of an alleged expert. We have modeled the neurodynamics of three cortical structures (OFC, LPFC, and ACC) and their interactions, where the neural oscillatory properties, modeled with Dynamic Bayesian Probability, represent the observer’s attitude towards the expert and the decision options. As an example of an everyday behavioral situation related to climate change, we use the choice of transportation between home and work. The model generates EEG-like signals that show how patterns of neural activity change during observation-based decision making. The simulations suggest that higher levels of trust influence both emotional and rational evaluations when individuals observe the actions and outcomes of an expert. Overall, the proposed framework provides insight into how observational learning and trust work together to shape decision making. It highlights the dynamic interplay between emotional and cognitive processes and offers a mechanistic understanding of how social information can influence behavior.

Brain Sciences doi: 10.3390/brainsci16050475

Authors: Terry Lichtor

A dramatic increase in knowledge regarding the molecular biology of brain has been established over the past few years [...]

Brain Sciences doi: 10.3390/brainsci16050476

Authors: Wende Li Xiaoyu Xia

Spinal cord stimulation (SCS) has expanded beyond pain treatment, becoming a neuromodulatory method capable of recruiting spinal and supraspinal circuits involved in motor recovery. This review summarises mechanistic knowledge, supports engineering developments, and describes the changing clinical translation of SCS in rehabilitation. Mounting scientific data shows that SCS’s effects go beyond dorsal column modulation and may involve segmental networks that promote activity-dependent plasticity and sensorimotor pathway restoration, probably due to a combination of Hebbian and non-Hebbian mechanisms (synaptic potentiation, interneuronal reorganisation, and altered afferent–efferent coupling). More recent advances, such as bursts and the high-frequency paradigm, closed-loop control, and data-driven parameter optimisation methods, improve the precision, stability, and calibration of stimulation for each individual. By combining SCS with non-invasive forms of neuromodulation (TMS, tDCS, and peripheral nerve stimulation), one can potentially further intensify corticospinal plasticity and maintain improvements in functions. Spinal cord stimulation remains an established treatment for chronic neuropathic pain, including failed back surgery syndrome and complex regional pain syndrome. In recent years, however, increasing attention has been directed toward its potential role in motor recovery after spinal cord injury and stroke. Progress in this area is limited by patient heterogeneity, variability in outcome measures, the complexity of multimodal rehabilitation protocols, and regulatory and logistical constraints—particularly when adaptive or closed-loop systems are used. Current evidence suggests that motor-restorative applications of SCS should be interpreted cautiously and integrated within carefully designed rehabilitation programmes, with attention to patient selection and realistic expectations regarding the durability of the benefit.

Brain Sciences doi: 10.3390/brainsci16050474

Authors: Hanbo Yang Yi Wang Yicheng Sun

Background: This study examined condition-dependent electroencephalography (EEG) changes under progressive degradation of visual and tactile information. Methods: Using a controlled visual–tactile paradigm, we systematically manipulated visual degradation and tactile impairment at multiple levels and analyzed time–frequency activity and P300 responses. Results: The results showed condition-dependent changes in oscillatory activity and P300 amplitude across graded visual–tactile degradation conditions. In several conditions, degradation in one modality was accompanied by increased neural responses in the other modality. However, this pattern was not monotonic: stronger responses were observed under some moderate degradation combinations, whereas responses were reduced under severe dual-modal degradation. Conclusions: In addition, the relative balance between visual-task and tactile-task responses varied across conditions, suggesting flexible but condition-dependent changes in modality weighting rather than a fixed hierarchy between modalities. Overall, these findings are consistent with graded neural adaptation under visual–tactile uncertainty, but they do not by themselves establish a specific causal mechanism of sensory reallocation.

Brain Sciences doi: 10.3390/brainsci16050473

Authors: Narcisa Carmen Mladin Dana Rad Dumitru Ștefan Coman Miron Gavril Popescu Maria Iulia Felea Radiana Marcu Gavril Rad

Background/Objectives: As artificial intelligence systems become increasingly embedded in everyday cognitive tasks, human–AI interaction is no longer limited to tool use but evolves into a dynamic process of mutual adaptation. While extensive research has examined algorithmic learning, far less attention has been given to how users progressively adapt to AI systems. This paper introduces the concept of algorithmic habituation, defined as the gradual accommodation of users to the regularities and predictive patterns of AI systems. The objective is to provide a neurocognitive and systems-based framework that explains this phenomenon. Methods: The study develops a conceptual and integrative framework grounded in classical theories of habituation, neuroplasticity, predictive processing, and systems theory. Building on these foundations, we propose a mechanistic model of human–AI co-adaptation, conceptualized as a recursive feedback loop involving repeated interaction, pattern recognition, expectation stabilization, and cognitive economy. In addition, a typology of algorithmic habituation is advanced, alongside proposed empirical pathways for future validation, including scale development, experimental paradigms, and longitudinal designs. Results: The proposed framework suggests that repeated interaction with AI systems leads to stabilization of cognitive expectations, reduced cognitive effort, and increased behavioral standardization. This process extends beyond perceptual habituation into higher-order domains, including decision-making, creativity, and moral judgment. The typology identifies four primary forms of algorithmic habituation: cognitive, decisional, creative, and moral. The model predicts both adaptive outcomes (efficiency, reduced cognitive load) and maladaptive consequences (reduced reflexivity, automation bias, and potential erosion of critical thinking). Conclusions: Algorithmic habituation represents a novel construct at the intersection of neuroscience, cognitive psychology, and human–AI interaction. By framing user adaptation as a form of neurocognitively grounded habituation within recursive systems, this paper contributes a new perspective to understanding AI integration in human cognition. The framework has implications for digital wellbeing, education, and AI ethics, and opens multiple avenues for empirical research.

Brain Sciences doi: 10.3390/brainsci16050472

Authors: Yumi Ju Jihye Kim Sura Kang HyunJu Park

Background: Traditional diagnosis-based classifications often fail to capture neurocognitive heterogeneity among children with developmental disabilities (DD). Establishing function-based subtyping is essential for developing individualized education frameworks that move beyond categorical labels. Methods: This pilot study employed a data-driven clustering approach integrating neurophysiological and cognitive indices to identify functional subtypes in 18 school-aged children (8 typically developing; 10 with DD). Input features included EEG-derived theta/beta ratio (TBR) and cognitive variables from the CANTAB Multitasking Test (MTT). Ecological validity was evaluated using the Virtual Kitchen Errand Task for Children (VKET-C). Results: K-means clustering revealed three distinct groups. In terms of MTT performance, Cluster 1 exhibited high accuracy and short response latencies. Cluster 2 demonstrated a “Slow but Accurate” pattern, with prolonged reaction times irrespective of diagnosis. Cluster 3 presented a “Fast but Error-prone” profile, showing significantly higher TBR values and increased error rates, indicative of cognitive impulsivity. Notably, clusters did not align with diagnostic boundaries. The three identified clusters significantly differentiated commission errors on the VKET-C task and showed greater explanatory power for VR task performance than diagnosis-based classifications. Conclusions: Cluster-based classification better differentiated VR task performance, particularly commission errors, than traditional diagnosis-based grouping. Integrating diagnosis with neurocognitive deep phenotyping approaches may enable more individualized intervention and educational support for children.

Brain Sciences doi: 10.3390/brainsci16050471

Authors: Manuele Cesare Augusto Fusco Gianfranco Damiani Antonello Cocchieri

Background/Objectives: Ischemic stroke, hemorrhagic stroke, and transient ischemic attack (TIA) differ in terms of medical severity and prognosis; however, it remains unclear whether these differences are reflected in nursing complexity and nursing intensity when assessed using standardized nursing language. Methods: This retrospective study analyzed routinely collected nursing and administrative data from an acute care hospital. Hospitalizations were classified as ischemic stroke, hemorrhagic stroke, or TIA using ICD-9-CM codes. Nursing complexity was measured as the number of nursing diagnoses (NDs) documented within 24 h of admission, while nursing intensity was measured as the number of nursing actions (NAs) recorded during hospitalization. Group differences were tested using ANOVA and Kruskal–Wallis tests, as appropriate. Results: A total of 728 hospitalizations were included: 429 ischemic strokes, 236 hemorrhagic strokes, and 63 TIAs. Overall, 4136 NDs and 27,528 NAs were recorded. Distinct patterns emerged across stroke categories. ND counts differed significantly (F = 5.81, p = 0.003), with TIA showing lower counts than both ischemic and hemorrhagic stroke, while no significant difference was observed between ischemic and hemorrhagic stroke. NA counts also differed significantly (H = 16.73, p < 0.001), with the highest counts in hemorrhagic stroke, intermediate counts in ischemic stroke, and the lowest counts in TIA. In a sensitivity analysis standardized by length of stay, nursing intensity also differed significantly across stroke categories (H = 12.999, p = 0.002), although the pattern differed from that observed for cumulative counts. Conclusions: Nursing complexity and nursing intensity showed distinct patterns across stroke categories. While complexity was comparable between ischemic and hemorrhagic stroke and lower in TIA, intensity followed a clear gradient, highest in hemorrhagic stroke, intermediate in ischemic stroke, and lowest in TIA. Standardized nursing data may complement medical indicators by capturing additional dimensions of patient needs and care delivery in people with stroke.

Brain Sciences doi: 10.3390/brainsci16050470

Authors: Zheng Zhang Shen Wu Kegao Liu Jingxue Zhang Qian Liu Ningli Wang Hai Xue

Background: Recent studies strongly suggest that low intracranial pressure (ICP) may be involved in the pathogenesis of glaucomatous optic neuropathy. As retinal ganglion cells (RGCs) are highly susceptible to mitochondrial dysfunction, mitochondrial injury may be associated with optic neuropathy related to reduced ICP. In this study, aquaporin-1 (AQP1)-null mice were used to investigate whether reduced ICP is associated with alterations in mitochondrial structure and the release of optic atrophy type 1 (OPA1) and cytochrome c from mitochondria. Methods: Intraocular pressure (IOP) and ICP were measured in AQP1-null mice, and mitochondrial structural changes were examined using transmission electron microscopy (TEM). Total OPA1 and cytochrome c protein levels were evaluated using immunocytochemistry and Western blotting. Cytosolic and mitochondrial fractions were extracted from retinal tissues, and the subcellular distribution of OPA1 and cytochrome c was further analyzed by Western blotting. Bax and Bcl-2 expression levels were also detected. Results: TEM revealed mitochondrial fission, matrix swelling, and abnormal cristae depletion in the retinas of 1-, 3-, and 6-month-old AQP1-null mice. Morphometric quantification further confirmed significantly reduced mitochondrial length across all age groups and increased mitochondrial width at 1 and 6 months in AQP1-null mice compared with wild-type controls. Decreased retinal OPA1 immunoreactivity and protein expression were observed across all age groups of AQP1-null mice compared with age-matched C57BL/6 control mice. Subcellular fractionation showed increased mitochondrial release of OPA1 (at 3 and 6 months) and cytochrome c (at 1, 3, and 6 months) in the retinas of AQP1-null mice. Altered Bax expression was also detected in the retinas of AQP1-null mice with reduced ICP at all examined ages. Conclusions: Mitochondrial ultrastructural abnormalities, including fission and cristae depletion, altered OPA1 distribution, increased mitochondrial release of OPA1 and cytochrome c, and upregulated Bax expression were observed in the retinas of AQP1-null mice with reduced ICP. These concurrent changes indicate a close association between reduced ICP and retinal mitochondrial dysfunction. Maintaining mitochondrial integrity may therefore serve as a potential protective strategy against optic nerve degeneration in patients with chronic low ICP.

Brain Sciences doi: 10.3390/brainsci16050469

Authors: Suqin Guo Rui Liu Si Cheng Xia Liu Jianping Wu

Ischemic stroke remains a leading cause of death and disability worldwide. While thrombolysis and endovascular thrombectomy are current mainstays of treatment, their clinical efficacy is often undermined by ischemia–reperfusion injury (I/R). This injury induces secondary brain damage, primarily via disruption of the blood–brain barrier (BBB). No approved therapies directly target BBB protection. This review reinterprets the pathophysiological mechanism of BBB disruption after stroke through a dynamic spatiotemporal framework. The pathological cascade reaction is clearly divided into two core stages: the ischemic phase is mainly driven by energy failure and calcium overload; the reperfusion phase is further divided into four consecutive and progressive sub-stages, namely, oxidative stress burst, amplification of inflammatory response, matrix metalloproteinase 9 (MMP-9)-mediated barrier degradation and programmed cell death. This review critically assesses current therapies and identifies major clinical translation gaps, including a temporal mismatch between preclinical and clinical windows, unacceptable toxicity, lack of durable efficacy and biphasic effects. Matching specific interventions to the different pathophysiological stages of blood–brain barrier disruption is essential for optimizing clinical outcomes.

Brain Sciences doi: 10.3390/brainsci16050468

Authors: Simona Aresta Cinzia Palmirotta Muhammad Asim Petronilla Battista Gaia C. Santi Gianvito Lagravinese Claudia Cava Pietro Fiore Andrea Santamato Paolo Vitali Isabella Castiglioni Gennaro D’Anna Leonardo Rundo Christian Salvatore

Background/Objectives: Brain tumors are highly lethal cancers, with gliomas representing the most complex subtype. Magnetic resonance imaging (MRI) is the main non-invasive imaging modality. This review evaluates deep learning (DL) and artificial intelligence methods for brain tumor segmentation and classification. Methods: In this systematic review, PubMed and Scopus were searched for articles published from 2022 to March 2025. Authors independently identified eligible studies based on predefined inclusion criteria and extracted data. The study quality and risk of bias were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist. Results: Thirty-one studies met the inclusion criteria from 310 records, with eight addressing both segmentation and classification. Most segmentation studies used publicly available multiparametric MRI datasets. Performance varied by architecture and tumor region, with whole-tumor segmentation achieving the highest Dice Similarity Coefficient (DSC). Classical U-Nets reported DSC values ranging 80–87%, while models with residual or attention mechanisms exceeded 90%. Classification focused on tumor type and glioma grading, using features learned from multiparametric MRI. Reported accuracy ranged from 91.3% to 99.4%, with sensitivity and specificity often above 95%. However, variability across tumor subregions, limited external validation, reliance on public datasets, and heterogeneous preprocessing raise concerns about robustness and real-world generalizability. Evidence on the use of explainability methods for both tasks remains limited. Conclusions: DL models for glioma segmentation and classification demonstrate promising performance. However, standardized validation protocols, multi-center datasets, and the integration of explainable artificial intelligence techniques are needed to improve transparency, robustness, and clinical applicability.

Brain Sciences doi: 10.3390/brainsci16050467

Authors: Danjela Ibrahimi José R. García-Martínez

Amblyopia is increasingly conceptualized as a neurodevelopmental visual disorder that often arises from discordant binocular visual experience during early life and is associated with abnormal binocular interactions, interocular suppression, orientation-dependent developmental abnormalities in selected refractive phenotypes, and experience-dependent plasticity, consistent with a distributed-network perspective rather than a purely monocular acuity deficit. We performed a structured state-of-the-art narrative synthesis of peer-reviewed reviews, randomized controlled trials, and key mechanistic human studies indexed in PubMed/MEDLINE, Web of Science, and Scopus (1 January 2016–28 February 2026; last search 28 February 2026), prioritizing recent evidence from 2021–2026. Literature supports consideration of clinically trackable constructs beyond best-corrected visual acuity (BCVA), including quantified suppression/imbalance, binocular function, and functionally meaningful outcomes such as reading-related limitation and broader functional impact. Across established and emerging intervention classes, treatment effects are heterogeneous across ages and etiologies. Evidence is strongest for conventional penalization and selected active training-based approaches, whereas newer protocol-standardized approaches remain investigational and require prospective evaluation with transparent exposure/dose reporting. Based on these findings, we outline a clinically oriented, core outcome set for amblyopia and strabismus (COSAMS)-aligned framework that combines quantified binocular imbalance with multidimensional phenotyping and a hypothesis-driven, prospectively testable therapeutic model intended to structure (not replace) clinical decision-making. Priorities for precision-oriented amblyopia care include standardization of suppression metrics, adoption of core outcome sets, transparent reporting of ‘not measurable’ outcomes and missingness, and prospective validation of phenotype-driven, prediction-ready frameworks.

Brain Sciences doi: 10.3390/brainsci16050466

Authors: Mazen Almethen

Background/Objectives: This study aimed to investigate school-based speech–language pathologists’ (SLPs) perceptions of their ability and needs to identify and remediate students with dyslexia. Methods: A qualitative approach was employed, utilizing semi-structured interviews with school-based SLPs. The findings were thematically analyzed by following six steps; (a) familiarization with the data; (b) initial code generation; (c) theme identification; (d) theme review; (e) defining and naming themes; and (f) report writing. Results: The findings revealed that participants had a very limited knowledge of dyslexia, and most did not consider reading difficulties within their scope of practice. Professional development opportunities, collaboration with teachers, and administrative support were identified as crucial factors to enhance SLPs’ practice supporting dyslexic cases in school settings. Conclusions: The study showed that school-based SLPs lack the necessary knowledge to work with students with dyslexia, which aligns with results observed in other countries. This finding highlights the importance of empowering their abilities to effectively support students with dyslexia.

Brain Sciences doi: 10.3390/brainsci16050465

Authors: Eleazar Ramírez Hernández Citlalli Netzahualcoyotzi Gabriela Hurtado-Alvarado José Luis Sánchez Ali Pereyra Morales David Arredondo-Zamarripa Luis Fernando Hernández-Zimbrón Dulce Papy-Garcia Jorge Guevara Natalia Gutiérrez Ponce Wilton Gomez-Henao Yonathan Garfias Gustavo Ortiz Chavez Edgar Zenteno

Epidemiological and clinical research on neurodegenerative diseases has shown that metabolic dysregulations increase the risk of developing Alzheimer’s Disease (AD). Many metabolic changes can be grouped into metabolic syndrome (MetS), which is defined as the presence of three or more risk factors, including insulin resistance, hyperglycemia, hypertension, central obesity, and dyslipidemia. These changes cause systemic effects that are crucial in triggering neuroinflammation and neurodegeneration, key factors in AD development. All these factors impair energy metabolism in peripheral tissues and the brain by decreasing glucose utilization, leading to alterations in O-GlcNAcylation, glycosylation, mitochondrial function, oxidative stress, chronic inflammation, synaptic dysfunction, autophagy impairment, and blood–brain barrier (BBB) dysfunction. However, these factors are modified and largely influenced by lifestyle choices. A newer perspective emphasizes that regular exercise is vital for maintaining brain metabolism as we age. Current evidence suggests that engaging in physical activity for individuals with metabolic syndrome reduces their risk of Alzheimer’s disease, enhances prognosis, and improves cognitive abilities. This review explores how metabolic syndrome relates to Alzheimer’s and highlights possible strategies for prevention and treatment.

Brain Sciences doi: 10.3390/brainsci16050464

Authors: Junhui Wang

The field of neuroimmunology has changed dramatically over the last ten years [...]

Brain Sciences doi: 10.3390/brainsci16050463

Authors: Qixin Zhu Zhen Zhang Leiming Zhang Qian Li Ting Zhang Fei Yang

Background: Neuroinflammation is recognized as a key contributor to Parkinson’s disease (PD), but the relationships between inflammatory signaling, immune-state alterations, and cell-type-specific transcriptional programs remain unclear. Methods: Public transcriptomic datasets, including GSE20141 (discovery cohort) and the substantia nigra subset of GSE114517 (external validation cohort), were analyzed. Genes identified by exploratory differential-expression screening in the discovery cohort were intersected with predefined inflammation- and chemokine-related gene sets to define a candidate space for downstream prioritization. Protein–protein interaction, Gene Ontology, KEGG, and immune-signature analyses were performed, followed by machine learning-based feature prioritization using Elastic Net, support vector machine-recursive feature elimination, and random forest. Prioritized candidates were further evaluated by cross-platform validation, single-nucleus transcriptomic mapping, and a hypothesis-generating in silico perturbation analysis in PD astrocytes. Results: Seventeen genes were retained at the intersection of PD-related differentially expressed genes and inflammation-/chemokine-associated gene sets. These candidates formed a response module enriched in mitochondrial organization, oxidative phosphorylation, and mitophagy pathways. Immune-signature analysis suggested an altered transcriptome-derived immune landscape in PD, with changes in NK cell-related signatures and significant correlations between immune-state scores and the candidate genes. Machine learning-based prioritization yielded five shared candidates, of which only CCL2 and PAK6 showed same-direction support with nominal significance in the external validation cohort. Single-nucleus transcriptomic analysis localized CCL2 predominantly to astrocytes, whereas PAK6 was more strongly associated with neuronal populations, particularly OTX2-positive ventral midbrain neurons. In silico perturbation analysis further predicted that CCL2 suppression in PD astrocytes may be associated with translational- and ribosome-related regulatory programs. Conclusions: CCL2 and PAK6 emerged as prioritized candidate biomarkers associated with PD-related inflammatory and chemokine-linked transcriptional alterations in the substantia nigra. More broadly, this study provides a multi-layered framework for candidate prioritization, cross-platform validation, and cell-type-level contextualization in PD neuroinflammation. Because the study is computational and the perturbation analysis is predictive, orthogonal experimental validation will be required to determine whether CCL2 and PAK6 are biomarkers of disease-associated transcriptional states, functional contributors to PD pathogenesis, or both.

Brain Sciences doi: 10.3390/brainsci16050462

Authors: Naoki Hamada Shiho Fukuda Han Gao Hitoshi Oda Hiroshi Kunimura Taku Kawasaki Koichi Hiraoka

Background/Objectives: Bimanual movements with a 90° relative phase are typically unstable but can be facilitated by Lissajous visual feedback, which integrates the movements of the two hands into a single visual representation. We examined whether such visual integration leads to a unified sensorimotor representation by testing whether unilateral tactile stimulation suppresses motor output bilaterally during bimanual force production. Methods: Fifteen healthy participants produced rhythmic bimanual index finger flexion with a 90° relative phase under two feedback conditions: Lissajous feedback and individual visual feedback. In each trial, vibrotactile stimulation was applied to either hand or not applied at one of four phases of the force cycle. Force trajectory error and post-stimulus electromyographic (EMG) activity of the first dorsal interosseous muscle were analyzed. Results and Discussion: Lissajous feedback reduced force trajectory error compared with individual feedback. Tactile stimulation did not produce bilateral suppression of motor output. This indicates that visual integration of bimanual movements does not lead to global bilateral suppression of motor output induced by unilateral tactile stimulation. A significant reduction in post-stimulus EMG amplitude was observed only when the right hand was stimulated during one phase of the Lissajous feedback task. This suppression may reflect the unmasking of the tactile stimulus-induced inhibition within sensorimotor processes in the left hemisphere when visual feedback of the two hands is merged into a single representation.

Brain Sciences doi: 10.3390/brainsci16050461

Authors: Ahmed I. Anwar Alaa Abd-Elsayed Alan D. Kaye

Spinal cord injuries disrupt the motor, sensory, and autonomic functions routinely carried out by the spinal cord, with injury progressing from primary mechanical damage from the initial trauma to a secondary phase driven by inflammation and cellular cascades. This disruption significantly impacts the patient’s ability to perform basic physiological and voluntary functions seen in a normal spinal cord, which often results in long-term disability and dependence on supportive care. Stem cell therapies, including mesenchymal stem cells, neural stem cells, and induced pluripotent stem cells, have been investigated as potential regenerative approaches that may promote repair through neuroprotection, remyelination, and axonal regeneration. Preclinical studies have demonstrated encouraging results in motor and sensory recovery following injury; however, clinical evidence remains limited and variable. Some studies report improvements in motor and sensory function post-injury, with improvements in bladder and bowel management, tissue repair, and other functions. Overall, the outcomes vary based on cell type, delivery method, and the stage of spinal cord injury. The key challenges of stem cell therapy include safety concerns and the limited number of small-scale studies currently available. Additionally, understanding the variability in therapeutic outcomes and identifying optimal treatment conditions are critical steps toward advancing stem cell therapies in spinal cord injury repair. This review aims to characterize and summarize the stem cell approach to the treatment of spinal cord injuries, while also critically highlighting the limitations of current preclinical and clinical evidence, as well as the importance of continued investigation into the long-term and functional recovery processes and possibilities, as well as the patient’s quality of life following treatment with stem cells for spinal cord injury.

Brain Sciences doi: 10.3390/brainsci16050460

Authors: Maria Comas

Sleep is a fundamental biological process with broad implications for physical recovery, emotional regulation, and cognitive functioning [...]

Brain Sciences doi: 10.3390/brainsci16050459

Authors: Sevval Soylu Ersan Arslan Bulent Kilit Yusuf Soylu

Background/Objective: Mental fatigue (MF) significantly impairs psychomotor performance in dynamic sports; however, its specific impact on closed-skill precision-demanding tasks remains underexplored. This study investigated the acute effects of experimentally induced MF exposure on psychophysiological responses, mood states, and archery shooting performance. Methods: Fifteen well-trained male compound-bow archers participated in a randomized crossover study. Participants completed an MF condition (30 min modified Stroop task) and a control condition (CON; passive viewing of a neutral documentary), separated by a 72 h washout period. Continuous heart rate (HR), archery shooting accuracy, ratings of perceived exertion (RPE), rating scale of mental effort (RSME), state anxiety (VAS-A), mood states, and exercise enjoyment scale (EES) were assessed. Results: The Stroop task successfully induced subjective MF. Consequently, shooting accuracy significantly deteriorated in the MF condition compared to that in the CON condition (p < 0.001; g = 0.731). While HR and VAS-A remained consistent across conditions, the MF condition elicited a significant increase in RPE (p = 0.007; g = 0.836) and RSME (p = 0.010; g = 0.794). Furthermore, MF significantly increased feelings of anger and fatigue while drastically reducing PACES (p < 0.001; g = 1.530). Conclusions: Acute MF significantly degrades fine motor accuracy in precision sports. The pronounced dissociation between elevated RPE and stable peripheral physiological strain suggests that performance decline is driven by top-down cognitive burden rather than physiological limitations. Therefore, systematic monitoring of cognitive load is crucial for optimizing performance in precision sports.

Brain Sciences doi: 10.3390/brainsci16050458

Authors: Flavio Donnini Giuseppe Minniti Salvatore Chibbaro Giulio Bagnacci Armando Perrella Giuseppe Battaglia Giovanni Rubino Pierpaolo Pastina Tommaso Carfagno Marta Vannini Maria Antonietta Mazzei Alfonso Cerase Paolo Tini

Background: Clinical target volume (CTV) delineation in glioblastoma remains debated, particularly in the era of modern chemoradiation and image-guided radiotherapy. Whether reduced CTV margins can preserve oncological outcomes without increasing marginal or out-of-field failures remains uncertain. We evaluated the association of the gross tumor volume (GTV)-to-CTV margin with survival, patterns of failure, and its interaction with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Materials and Methods: We retrospectively analyzed a single-center cohort of patients with glioblastoma treated with conventionally fractionated chemoradiation (58–60 Gy in 29–33 fractions). Patients were categorized into two predefined margin groups: <1.5 cm and 1.5 cm. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and patterns of failure. Survival was assessed using Kaplan–Meier estimates and Cox regression, including an interaction term with MGMT status. Results: Among 102 eligible patients, 95 were included in the margin-based OS analysis. Reduced margins (<1.5 cm; applied range 1.0–1.4 cm) were not associated with worse OS, either overall or within MGMT subgroups. No significant differences were observed in PFS or recurrence patterns, with overlapping distributions and no increase in marginal or out-of-field recurrences. MGMT methylation and gross total resection were independently associated with improved survival, while no statistically significant interaction between margin and MGMT status was detected. Conclusions: In this retrospective exploratory cohort, reduced GTV-to-CTV margins were not associated with a clear signal of worse survival or less favorable recurrence patterns. These findings are consistent with the oncological adequacy of margins around 15 mm and justify cautious prospective evaluation of whether further reduction can be achieved safely, including formal assessment of toxicity, neurocognitive outcomes, and quality of life.

Brain Sciences doi: 10.3390/brainsci16050457

Authors: Feifei Wu Raffaella Buonanno Valentina Baro Vincenzo Levi Giulia Melinda Furlanis Mariasole Gagliano Andrea Guerra Alberto D’Amico Carlo Giorgio Giussani Roberto Eleopra Luca Denaro Angelo Antonini Andrea Landi

Objective: Deep Brain Stimulation (DBS) has been consolidated as a valid therapeutic option for advanced Parkinson’s disease (PD). The identification of specific targets can be achieved through different methods, including conventional direct and indirect methods. The aim of our multicentric study is to provide a comparison between these traditional methods and artificial intelligence (AI) in the ascertainment of the ideal targets. Materials and Methods: A total of eight patients, who received bilateral STN (subthalamic nucleus) DBS implantation between 2022 and 2023 were analyzed. Target coordinates were calculated based on the Schaltenbrand and Wahren atlases and the AI using the RebrAIn system during the planning phase; intraoperatively, the targets were either confirmed or adjusted according to microelectrode recordings (MERs). The differences in the three Cartesian axes of stereotactic coordinates (X, Y, and Z) according to these methods were evaluated and compared through non-parametric ANOVA Friedman test. Results: The results revealed significant agreement in the lateral–lateral coordinates (X, X′, X″), indicating stability in target determination along this axis across the methods. However, more substantial discrepancies were observed in the antero-posterior and cranio-caudal coordinates, suggesting lower consistency between the examined methodologies. Conclusions: Our preliminary study results suggest that, despite the challenges posed by interindividual anatomical variability and the limitations of imaging techniques, artificial intelligence has shown comparable values on the lateral–lateral X coordinates. The accuracy of predictive targeting using machine learning models needs to be validated by further studies, but the preliminary results appear to indicate a potential promising role for artificial intelligence in integrating the preoperative workflow.

Brain Sciences doi: 10.3390/brainsci16050456

Authors: Carmela Rifici Rosaria De Luca Francesco Corallo Sabrina Miceli Santina Caliri Andrea Calderone Rosalia Calapai Alessio Mirabile Maria Pagano Angelo Quartarone Rocco Salvatore Calabrò

Background/Objectives: Spatial neglect after stroke may be difficult to characterize in patients with severe motor, cognitive, and communication impairment. Augmentative and alternative communication interfaces require visual scanning and intentional selection and may therefore provide an ecological context in which lateralized visuospatial behavior becomes clinically observable. Methods: A 58-year-old man with a unilateral right-hemisphere hemorrhagic stroke underwent serial assessment at baseline before training, at the end of 24 AAC sessions delivered over 2 months in addition to standard neurorehabilitation, and at 1-month follow-up. Measures included cognitive functioning, behavioral responsiveness, global disability, bedside communication status, and P300 latency. The AAC/eye-tracking intervention also generated process data across 21 analyzable sessions, including calibration quality, free-exploration heatmaps, and performance in the Stars and Bow-Target tasks. Results: Global measures showed modest early improvement followed by stabilization. Cognitive functioning improved from 2 to 3 and remained stable, behavioral responsiveness increased from 7 to 10 and then to 11, bedside communication increased from 7 to 9 and remained stable, and P300 latency decreased from 393 to 350 and then to 351 ms, whereas global disability remained unchanged at 25 throughout. Calibration was at least good in all quadrants and never scored 0. Performance was lower and more unstable in Stars than in Bow-Target. Heatmaps showed rightward clustering, reduced left-sided exploration, and limited whole-screen scanning. Conclusions: AAC/eye-tracking did not provide formal diagnostic proof of neglect, but it supported ecological recognition of a neglect-like lateralized exploratory pattern under less guided conditions.

Brain Sciences doi: 10.3390/brainsci16050455

Authors: Sihang Peng Qi Xu

Background: Multi-center resting-state functional magnetic resonance imaging (rs-fMRI) is important for neurodevelopmental disorder diagnosis, but cross-site differences in repetition time (TR) can cause temporal feature misalignment. In addition, blood-oxygenlevel-dependent (BOLD) signals are non-stationary, so disease-related information may be distributed across multiple time scales. Existing methods usually do not explicitly model physical sampling intervals or coordinate temporal and spectral information across scales, which may limit cross-site generalization in heterogeneous multi-center settings. Methods: We propose Spec-RWKV, a spectrum-guided linear recurrent framework for multi-site rs-fMRI diagnosis. It includes three components: PrismTimeMix, which models temporal dynamics using decay rates derived from physical half-lives and converts them adaptively across TRs; a TR-adaptive continuous wavelet transform, which aligns spectral representations across sites by adjusting frequency coverage; and spectrum-guided adaptive temporal aggregation, which uses spectral context to weight temporal features. Results: On ABIDE-I and ADHD-200, Spec-RWKV achieved AUCs of 75.86% and 76.31%, respectively. Under leave-one-site-out validation, it achieved the best mean AUC on ABIDE-I and the best mean accuracy and AUC on ADHD-200. Conclusions: Spec-RWKV explicitly models sampling-rate differences and multi-scale spectral structure, with results supporting strong cross-site generalizability.

Brain Sciences doi: 10.3390/brainsci16050453

Authors: Kamila Saramak Anna Dunalska Katarzyna Śmiłowska Wiktor Śliwiński Ali Abusrair Sanja Gluščević Simon Schmitt Kirsten R. Müller-Vahl Natalia Szejko

Background: Behavioural therapy (BT), including Comprehensive Behavioural Intervention for Tics (CBIT), is an evidence-based first-line treatment for patients with tic disorders. However, access remains limited due to a shortage of trained providers, geographical barriers, costs, and high treatment burden for patients and families. Rapid advances in digital health technologies including telemedicine, web-based treatment platforms, and mobile applications offer new opportunities to expand access to BT for individuals with tic disorders across the lifespan. Methods: For the purpose of this narrative review, we conducted a literature search in PubMed, Europe PMC, and the Cochrane Library to identify relevant studies investigating the effectiveness of digital health treatment approaches in tic disorders. Results: A total of 16 original studies were included. Although the available evidence remains limited and heterogeneous, existing studies suggest that emerging technologies for delivering behavioural interventions for tic disorders, including telehealth-based CBIT, digital therapy platforms, and app-supported habit reversal training (HRT), are feasible, cost-effective, user-friendly, flexible, and safe. These approaches also appear effective for symptom monitoring and personalized treatment support in both pediatric and adult populations. Conclusions: Recent technological advances have the potential to reduce the treatment gap in tic disorders, provided that these approaches are implemented within rigorous, evidence-based, and ethically grounded frameworks.

Brain Sciences doi: 10.3390/brainsci16050454

Authors: Quan Zhang Dewen Ru Jiang Fang Jun Zeng Qiang Yuan Zhuoying Du Gang Wu Jianhong Zhu Jin Hu

Background: Intracerebral hemorrhage (ICH) is a devastating subtype of stroke, in which neuroinflammation and blood–brain barrier (BBB) disruption are secondary pathophysiological events that drive progressive brain injury. Histone lysine demethylase JMJD3 (Jumonji C domain-containing protein 3) is a master epigenetic switch governing inflammatory signaling; however, its participation in ICH-induced vascular disruption and its possible mechanism remain elusive. Objective: To examine the expression patterns of JMJD3 in the context of ICH and to evaluate the therapeutic potential of its specific inhibitor, GSK-J4, in attenuating neuroinflammation and BBB disruption in a murine ICH model. Methods: Hemin treatment of a mouse C8-D1A astrocytic cell line was used to develop an in vitro ICH model. The transcript level of the Jmjd3 gene and its correlation with pro-inflammatory signaling were analyzed with or without GSK-J4 pretreatment. ICH in vivo was created experimentally in adult male C57BL/6 mice through stereotactic striatal injection of collagenase IV, and the mice were randomly assigned to sham, ICH + vehicle, and ICH + GSK-J4 (30 mg/kg intraperitoneally (i.p.), every other day starting three days before ICH) groups. At three days post-ICH, ipsilateral brain tissues were collected to detect JMJD3 cellular localization, pro-inflammatory mediator levels, tight junction protein expression, BBB ultrastructure, and hematoma volume. White matter integrity and neuronal recovery were assessed on day 7, and sensorimotor function was assessed longitudinally on days 1, 3, 5, 7, and 14. Results: Jmjd3 gene transcription was upregulated in hemin-treated astrocytes and correlated positively with IL-6 pro-inflammatory signaling activation. In vivo, the co-localization of JMJD3 with the astrocytic identifier glial fibrillary acidic protein (GFAP) was markedly increased in the area adjacent to the hematoma at three days post-ICH. GSK-J4 administration significantly suppressed the pro-inflammatory signaling cascade by decreasing the levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase-9 (MMP-9), enhanced brain vascular structural and functional integrity by upregulating tight junction proteins zonula occludens protein-1 (ZO-1) and claudin-5, improved BBB ultrastructural integrity, and decreased hematoma volume at three days post-ICH. Furthermore, GSK-J4 administration promoted white matter integrity (increased myelin basic protein [MBP] expression) and neuronal recovery (increased neuron-specific nuclear protein [NeuN] expression) at seven days post-ICH and significantly improved the performance of ICH mice in sensorimotor behavioral tests. Conclusions: Astrocytic JMJD3 is upregulated following ICH and promotes neuroinflammation, which in turn mediates BBB disruption. Pharmacological inhibition of JMJD3 by GSK-J4 attenuates neuroinflammation and subsequent BBB damage, accelerates hematoma resolution, and promotes histological and functional recovery after ICH, likely by downregulating MMP-9 expression. These findings identify astrocytic JMJD3 as a novel epigenetic therapeutic target for acute ICH.

Brain Sciences doi: 10.3390/brainsci16050451

Authors: Xuejie Zhang Jisheng Xu Xulin Zhou Yan Yang Guosi Ying Xue Li

Background: Long-term methamphetamine use disrupts brain function and impairs cognition. Currently, there is a lack of effective treatments for cognitive dysfunction in this population. This study aimed to investigate the effects of different exercise interventions on cognitive function and brain activation in methamphetamine-dependent individuals and to explore the potential neural mechanisms underlying cognitive improvement. Methods: In this randomized, assessor-blind, controlled study, 162 male methamphetamine-dependent individuals in compulsory isolation were randomly assigned to one of four groups: traditional regimen training (TR, n = 41), aerobic exercise (AE, n = 40), multimodal cognitive exercise training (MC, n = 40), and a control group (MA, n = 41). All participants completed an 8-week intervention. Cognitive function was assessed before and after the intervention using the Stroop task, while fNIRS was used to measure task-related hemodynamic responses. In addition, the Memory and Executive Screening (MES) and choice reaction time tests were used to evaluate cognitive and psychomotor performance. Results: After 8 weeks, traditional regimen training (p = 0.006), aerobic exercise (p = 0.024), and multimodal cognitive exercise training (p < 0.001) all significantly improved Stroop task accuracy. Aerobic exercise significantly increased activation in L-DLPFC (p = 0.044), R-DLPFC (p = 0.036), and L-FPA (p = 0.038), improved MES-T scores (p < 0.001) and shortened choice reaction time (p < 0.001). Traditional regimen training increased L-DLPFC activation (p = 0.026), improved MES-T scores (p < 0.001), and shortened choice reaction time (p < 0.001). Multimodal cognitive exercise training increased activation in L-DLPFC (p = 0.006), R-DLPFC (p = 0.014), and L-FPA (p = 0.002), improved MES-T scores (p < 0.001) and shortened choice reaction time (p < 0.001). Conclusions: Cognitive impairment in methamphetamine-dependent individuals may be associated with reduced prefrontal functional activity. Different exercise modalities produced different patterns of cognitive improvement and brain activation, with multimodal cognitive exercise training showing the largest overall benefit.

Brain Sciences doi: 10.3390/brainsci16050452

Authors: Błażej Pilarski Szymon Florek Alexander Suchodolski Mariola Szulik Robert Pudlo

Heart failure (HF) is a leading cause of morbidity and mortality worldwide, and its co-occurrence with psychiatric disorders poses significant therapeutic challenges. This narrative review examines the safe use of psychopharmacological agents in patients with HF, focusing on mood stabilizers (particularly lithium) and antipsychotics. We summarize clinically relevant pharmacokinetic and pharmacodynamic interactions between these agents and guideline-directed HF therapies, including ACEIs, ARBs, ARNIs, beta-blockers, MRAs, SGLT2 inhibitors, and diuretics. Lithium is particularly prone to interactions due to its narrow therapeutic index and dependence on renal sodium handling, with RAAS inhibitors, thiazide diuretics, and SGLT2 inhibitors increasing the risk of toxicity. Antipsychotics are associated with QT prolongation, orthostatic hypotension, and electrolyte disturbances, with substantial variability between agents. This review highlights key clinical risks, provides a practical summary of drug interactions, and outlines principles for individualized, multidisciplinary management. Care requires coordinated cardiology–psychiatry collaboration, careful drug selection, and assessment of renal function, electrolytes, drug levels, and ECG parameters. Further studies and improved guideline integration are needed.

Brain Sciences doi: 10.3390/brainsci16050450

Authors: Hashir Aazh Vinay Parameshwarappa Arnaud Noreña Kelly N. Jahn Stefan Fink Stephan Wolpert Rodrigo Donoso-San Martín Lukas Rüttiger Marlies Knipper Wei Sun Richard Salvi

Pharmacological approaches to tinnitus have remained peripheral within research, despite persistent patient demand and advances in auditory neuroscience. There is increasing consideration of whether these developments now justify renewed focus on pharmacological research in tinnitus and hyperacusis. This paper presents a narrative synthesis of perspectives arising from an international scientific meeting, based on invited contributions from speakers who expanded on themes related to their presentations, integrating insights from systems neuroscience, cellular and molecular mechanisms, animal and human models of auditory hypersensitivity, and patient-reported experience. Rather than summarising individual presentations, the analysis focuses on converging mechanistic explanations, biological heterogeneity, emerging therapeutic targets, and advances in objective measurement. Particular attention is given to how evolving mechanistic frameworks can support patient education and clinical communication, even in the absence of disease-modifying treatments. Taken together, these discussions reflect renewed examination of pharmacological approaches to tinnitus and hyperacusis, with attention to both emerging mechanistic rationales and the substantial challenges that remain. Integrating mechanistic insights, phenotype-informed care, and responsible communication may help clarify research priorities and support informed clinical and patient-facing discussions.

Brain Sciences doi: 10.3390/brainsci16050449

Authors: Philipp Geiger Christian Preuss-Hernandez Daniel Pinggera Claudius Thomé Ondra Petr

Background: Temporary arterial occlusion (TAO) is a key adjunct in microsurgical clipping of middle cerebral artery (MCA) aneurysms, but its safe duration and impact on perioperative ischemia—particularly in subarachnoid hemorrhage (SAH)—remain uncertain. Methods: A retrospective cohort of 245 patients undergoing microsurgical clipping of MCA aneurysms (154 incidental, 91 SAH) at a tertiary neurovascular center (2010–2020) was analyzed. TAO use, cumulative duration (>5, >8, >10, >15 min), number of applications, and occlusion site were extracted alongside clinical, radiographic, and outcome data. The primary endpoint was perioperative ischemia within 48 h; secondary endpoints included clinically relevant cerebral vasospasm (CVS), intraoperative rupture, and functional outcome (mRS) at discharge and 6 months. Multivariable logistic and ordinal regression models adjusted for demographic, aneurysmal, and treatment covariates. Results: TAO was used in 134 cases (54.7%; mean total duration 10.4 ± 8.7 min). In the overall cohort, TAO (presence or duration) was not independently associated with perioperative ischemia or CVS. In the SAH subgroup, cumulative TAO > 5 min conferred an approximately sixfold higher odds of ischemia (p = 0.012; OR 6.33), whereas no threshold was significant in incidental aneurysms. Female sex, M2 location, SAH at admission, and initial GCS < 9 independently predicted ischemia; female sex, higher ASA grade, larger size, irregular morphology, and SAH predicted CVS. SAH and aneurysm wall calcification were associated with worse 6-month mRS. Conclusions: TAO appears safe in elective clipping of incidental MCA aneurysms when applied judiciously, but cumulative durations beyond 5 min substantially increase ischemia risk in SAH patients. TAO management should therefore be individualized by rupture status, neurological grade, and aneurysm morphology rather than a single universal time limit.

Brain Sciences doi: 10.3390/brainsci16050447

Authors: Eugenio Cavalli Giuseppe Rosario Pietro Nicoletti Ferdinando Nicoletti

Background/Objectives: Schizophrenia is one of the most extensively studied yet conceptually unstable disorders in the history of medicine and brain sciences. Since its formalization at the turn of the twentieth century, the disorder has been repeatedly redefined, reflecting changes in clinical observation, diagnostic philosophy, and neuroscientific models of brain function. The objective of this review is to critically examine the historical evolution of schizophrenia as a medical construct and to analyze how shifts in diagnostic systems have shaped the search for biological and molecular biomarkers. Methods: A narrative-historical review of the literature was conducted, integrating classical psychiatric texts, diagnostic manuals, and contemporary neuroscientific studies. Key milestones in the conceptualization of schizophrenia were analyzed alongside the development of biological hypotheses, including neurochemical, electrophysiological, neuroimaging, genetic, immunological, omics-based, and digital approaches. Emphasis was placed on identifying conceptual continuities, ruptures, and methodological limitations across historical periods. Results: The analysis reveals that the evolution of schizophrenia has been characterized by increasing diagnostic standardization accompanied by growing biological heterogeneity. While successive biological models have provided valuable insights into specific aspects of the disorder, none have yielded single, robust diagnostic biomarkers. Instead, findings consistently reflect partial overlaps between clinical phenotypes and biological signals, strongly influenced by historically derived diagnostic categories. Conclusions: The persistent absence of definitive diagnostic biomarkers for schizophrenia reflects not only technical limitations but also the historical construction of the disorder as a heterogeneous clinical category. Understanding this historical context is essential for interpreting current findings in brain sciences. Future research is likely to benefit from stratification-based, dimensional, and integrative frameworks that move beyond categorical diagnosis while preserving clinical relevance.

Brain Sciences doi: 10.3390/brainsci16050448

Authors: Sabrina Turker Natalia Kartushina Narly Golestani

Background: Dyslexia is a reading disorder that is associated with phonological processing and awareness difficulties. However, little is known about phonetic production in dyslexia. Whereas individual differences in speech sound perception were linked to native and foreign speech sound production in typical readers, this remains to be explored in dyslexia. Given the phonetic processing deficits frequently encountered in dyslexia, we aimed to pinpoint potential differences in the acoustic realization of native phonemic production in adults with dyslexia. Methods: Ten adults with dyslexia and ten age-matched typical readers produced 24 native-language minimal voiced–voiceless word pairs across three places of articulation (labial, dental, velar) in a reading task. Acoustic analyses addressed phonemic category size, between-category distance, and voice onset time (VOT). Pseudoword reading performance served as an index of phonological decoding ability. Results: For category size, we observed a trend-level group-by-type interaction (p = 0.059, η2 = 0.04): both groups showed larger category sizes for voiced than voiceless consonants, but this difference was numerically larger in typical readers. Between-category distance showed a marginal group effect (p = 0.089, η2 = 0.14), with larger differences between categories in dyslexia. VOT showed the expected effect of voicing, but no group differences. Conclusions: Our results indicate broadly preserved speech production in dyslexia, alongside subtle differences in category separation and size in dyslexia, marked by considerable inter-individual variability.

Brain Sciences doi: 10.3390/brainsci16050446

Authors: Cecilia Carapelli Marzio Gerbella Francesca Tambuscio Giuseppe Di Cesare

When people interact, their actions reflect mood, attitude, and intention. Stern termed the affective qualities conveyed by actions, such as gentleness or rudeness, Vitality Forms (VFs). Previous research shows that children with autism spectrum disorder (ASD) differ from neurotypical (NT) peers in both perceiving and expressing these fundamental aspects of communication. It remains unclear whether these differences arise from structural or connectivity alterations in brain regions involved in VF processing. This study investigated structural and microstructural brain differences between children with ASD and NT peers, focusing on the VF-related network, which includes the dorso-central insula (DCI), premotor cortex (PM), middle cingulate cortex (MCC), and dorsolateral prefrontal cortex (DLPFC). Structural MRI data were collected from 60 right-handed boys aged 6–10 years (30 ASD, 30 NT), with diffusion MRI data available for a subset (20 ASD, 20 NT). A multimodal approach combined voxel-based morphometry (VBM), tract-based spatial statistics (TBSS), and probabilistic tractography. VBM revealed increased grey-matter volume in the PM, DLPFC, and MCC in the ASD group, with no differences in the DCI. TBSS showed white-matter microstructural alterations in premotor-related pathways. Probabilistic tractography further indicated atypical organization of tracts connecting the PM with the DLPFC, MCC, and DCI in children with ASD. Overall, the findings suggest atypical development of the premotor cortex and its associated white-matter connections in ASD, supporting theoretical accounts that link this network to altered processing of affective action dynamics during social interaction.

Brain Sciences doi: 10.3390/brainsci16050445

Authors: Panhui Wang Kewei Sun Shengdong Ye Di Wu Shengli Li Xiaodong Zhao Wei Xiao

Objective: This study developed the Uncertain Drop Stress Test (UDST), an uncertain stress induction paradigm based on the high survival-relevant threat of fear of falling, wherein neither the occurrence nor the timing of the fall is predictable. The aim was to compare its stress induction efficacy and neural oscillatory changes with those of the Socially Evaluated Cold Pressor Test (SECPT), a certain stress paradigm, and to examine gender differences. Methods: Forty-eight participants (24 males; 24 females) were recruited. Psychological indicators (subjective stress, negative affect, and state anxiety) and physiological indicators (heart rate, heart rate variability, galvanic skin response, and salivary cortisol) were measured before and after stress to compare induction efficacy. Resting-state EEG was collected for frequency domain analysis to explore neural oscillatory changes. Results: UDST induced more pronounced psychophysiological changes. Notably, only UDST significantly decreased heart rate variability and increased galvanic skin response. UDST triggered an “exogenous vigilance mode” characterized by enhanced high-frequency (Beta/Gamma) activity, whereas SECPT elicited an “interoceptive focusing mode” characterized by suppressed low-frequency (Theta/Alpha) activity. Females exhibited higher heart rate and Beta activity than males under both stress conditions. Conclusions: UDST elicits stronger psychophysiological responses and distinct neural oscillatory patterns, with females showing greater stress reactivity.

Brain Sciences doi: 10.3390/brainsci16050444

Authors: Sara Hirsch Karel Kostev Ali Hammed Bert Bosche Marek Molcanyi Christian Tanislav

Background: New therapies like intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) for acute ischemic stroke (AIS) can significantly impact outcomes and complication rates. This study examines the nationwide impact of MT implementation on decompressive hemicraniectomy (DH) in Germany, accounting for the effects of the COVID-19 pandemic. Methods: Annual treatment numbers (2015 to 2023) for IVT, MT, DH, cranioplasty (CP), and Computer-Aided Design CP (CAD CP) were extracted using the Operation and Procedure Codes (OPS). Age and sex distributions were analysed in four age groups (0–39, 40–59, 60–79, ≥80 years). Hospitalizations for AIS, subarachnoid haemorrhage (SAH), and intracranial haemorrhage (ICH) were included. Annual treatment rates were calculated. Results: In 2015 250,802 patients with AIS, 11,082 patients with SAH and 47,336 patients with ICH were documented. Overall, AIS hospitalizations declined slightly by 1.1%, whereas SAH and ICH decreased more markedly by 15.6% and 14.3%, respectively, with the most pronounced reductions observed during the COVID-19 pandemic. Among AIS patients, intravenous thrombolysis increased from 16% to 20%, while mechanical thrombectomy rates increased from 3% to 9%. Both reperfusion therapies showed increasing use particularly among patients aged ≥80 years (IVT: +35%; MT: +42%). DH remained overall stable (+2.82%), with a predominance in men (60%). In contrast, CP procedures declined by 25.3%, whereas CAD CP increased by 35% during the observation period. Conclusions: Long-term increasing trends in reperfusion therapies, especially mechanical thrombectomy, were largely unaffected by the COVID-19 pandemic and—contrary to expectation—obviously had no influence on the emergence of decompressive hemicraniectomy in our descriptive analysis.

Brain Sciences doi: 10.3390/brainsci16050443

Authors: Shuyao Tang Gangying Fu Wenjing Yu Mengfen Zhou Ting Chen Zhenyan Song Shaowu Cheng Ping Li

Background/Objectives: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and chronic neuroinflammation. Increasing evidence suggests that the imbalance between pro-inflammatory Th17 cells and anti-inflammatory regulatory T (Treg) cells plays a critical role in AD pathogenesis. However, a comprehensive synthesis of how natural compounds modulate Th17/Treg balance in AD remains lacking. This review aims to summarize current preclinical evidence on Th17/Treg dysregulation and evaluate the immunomodulatory potential of natural compounds in AD. Methods: This review focuses on preclinical evidence derived from experimental AD models and related inflammatory models to evaluate how natural compounds modulate Th17/Treg balance, neuroinflammation, and cognitive function, with an emphasis on underlying molecular and immunometabolic mechanisms. Results: Th17/Treg imbalance contributes significantly to AD-associated neuroinflammation and disease progression. Representative natural compounds, including paeoniflorin, quercetin, and ganoderic acid A, have demonstrated the ability to rebalance Th17/Treg responses, suppress neuroinflammation, and improve neuronal survival in experimental models. These compounds are highlighted due to their relatively stronger evidence in AD-related models and more clearly defined immunomodulatory mechanisms. These effects are partially mediated through modulation of key signaling pathways and immunometabolic reprogramming. Conclusions: Targeting Th17/Treg balance with natural compounds represents a promising multi-target immunomodulatory strategy for AD. However, most current evidence is derived from preclinical or non-AD models, and clinical validation remains limited. Future studies should prioritize AD-specific models and translational research to evaluate therapeutic potential in humans.

Brain Sciences doi: 10.3390/brainsci16050442

Authors: Inmaculada Méndez-Freije Débora Areces Celestino Rodríguez

Background: Reading is a fundamental skill for children’s cognitive, social, and academic development which relies on the integration of multiple linguistic and cognitive abilities. Longitudinal studies consistently show that oral language skills predict reading development both in typically developing children and in those at risk for reading difficulties (RD). Despite strong empirical evidence, a gap remains between research and educational practice. Objective: The present study aims to compare linguistic variables, including vocabulary, oral text comprehension, oral morphological awareness (OMA), and morphological skills between diagnostic group (control vs. at-risk), study grade, and sex. Method: The study included 93 Spanish-speaking children aged 6 to 12 years (M = 8.7, SD = 1.9; 50 boys, 43 girls). Two diagnostic groups were established: 44 children at risk of reading difficulties (including ADHD or DLD) and 49 typically developing controls. Participants were also classified by academic cycle: 55 in the first cycle (1st–2nd grade) and 38 in the second cycle or higher (3rd–6th grade). Linguistic variables were measured through tests administered individually, with data collected during one-on-one assessment sessions. Results: Among the variables analysed, significant differences were observed only in morphological skills and OMA. No significant differences were found based on sex, whereas both academic cycle and diagnostic group showed significant effects. Conclusions: The most relevant and novel finding is that the type and frequency of errors in the OMA task could serve as an early indicator of students at risk of RD. OMA assessment could therefore be a promising method of early screening and targeted interventions.

Brain Sciences doi: 10.3390/brainsci16050440

Authors: Oscar Arias-Carrión

Restless legs syndrome (RLS) is traditionally conceptualized as a dopamine-responsive sensorimotor disorder; however, new evidence suggests a more complex and heterogeneous neurobiological basis. Findings from neuroimaging, genetic studies, circadian biology, and clinical research indicate that dopaminergic dysfunction occurs within a broader context of neuromodulatory imbalance involving iron metabolism, adenosinergic signalling, glutamatergic excitability, and, potentially, noradrenergic pathways. In parallel, quantitative susceptibility mapping and related approaches have provided indirect evidence of altered brain iron distribution, although results remain variable across studies. Clinically, RLS extends beyond nocturnal discomfort and is associated with sleep fragmentation, impaired quality of life, and neuropsychiatric comorbidity, as well as treatment-related complications such as augmentation. However, current diagnostic frameworks remain predominantly phenomenological, and available biomarkers lack sufficient validation for routine clinical use. In this narrative review, the available clinical, genetic, and neuroimaging evidence is synthesized to propose an integrative, network-based model in which iron-dependent neuromodulatory processes influence excitability across cortico–striatal–thalamo–limbic circuits. This framework is intended as a hypothesis-generating model rather than a definitive explanation of disease mechanisms. Substantial heterogeneity across studies, together with variability in clinical presentation and limited reproducibility of candidate biomarkers, underscores the need for standardized methodologies and longitudinal, multimodal investigations. Future work should aim to test this model empirically, refine biological stratification, and determine whether network-informed approaches can improve diagnosis and therapeutic targeting in RLS.

Brain Sciences doi: 10.3390/brainsci16050441

Authors: Michela Balconi Benedetta Vignati Flavia Ciminaghi Laura Angioletti

Background/Objectives: Goal-directed praxis actions (GOPAs) integrate perception, motor planning, and executive control. While neural correlates of single actions are known, less is understood about how complexity conditions and their hierarchical organization into elementary tasks shape neural dynamics during ecologically manual assembly tasks. This study tested how electrophysiological (EEG) activity reflects global complexity and selective engagement of executive and sensorimotor systems across GOPAs. Methods: 38 healthy young adults completed two assembly conditions differing in complexity (basic and advanced) decomposed into four elementary tasks: identification, handling, alignment, and joining. EEG was recorded across five frequency bands (delta, theta, alpha, beta, and gamma) and four regions of interest (ROI): frontal, fronto-central, temporo-central, and parieto-occipital. Results: Neural activity varied significantly depending on different complexity, elementary task, and ROI. The advanced-complexity condition elicited stronger neural responses compared to the basic-complexity condition, reflecting greater cognitive, and sensorimotor demands. A task-related gradient emerged, with joining showing the highest activity, followed by alignment, while identification and handling showed lower activation. Frontal regions, particularly in theta activity, were more involved under higher complexity, suggesting increased executive control. In contrast, beta and gamma activity predominated in temporo-central and parieto-occipital regions, supporting visuomotor and sensorimotor integration. Conclusions: EEG oscillatory dynamics during ecological GOPAs are selectively modulated by complexity condition and hierarchical task organization. Neural activity tracks functional demands of specific action phases rather than general arousal, highlighting dynamic coordination between executive and sensorimotor systems during complex manual behavior.

Brain Sciences doi: 10.3390/brainsci16050439

Authors: Krystsina Liaukovich Olga Martynova

Background/Objectives: Temporal predictability may sharpen our ability to distinguish similar sounds, but whether this relies on attention is unclear. This study examined how temporal structure influences frequency discrimination. Methods: Thirty-six adults completed active (attend) and passive (ignore) listening tasks across three paradigms that varied in temporal structure: oddball (isolated deviants), two-tone frequency discrimination paradigm (pairs comparison), and local irregularity of the local/global paradigm (five-tone sequences, bundles). Stimuli varied in difficulty via small or large frequency deviations. Behavioral responses and subjective ratings were collected during active and passive listening. EEG was recorded to assess mismatch negativity (MMN) (either early MMN (eMMN) or mismatch response (MMR)) and P300 event-related potentials. Results: Under active listening, temporal predictability significantly improved performance, but only for difficult discriminations. The local-irregularity condition yielded higher hit rates and greater perceptual sensitivity (d’) than the other paradigms. This benefit was accompanied by enhanced P300, yet participants rated the conditions as equally difficult, indicating no metacognitive awareness. Under passive listening, predictability helped only for easy stimuli, marked by a larger MMR. No reliable change-detection response occurred for difficult sounds when attention was diverted. Conclusions: These findings suggest that the combination of temporal predictability and repeated standard presentation in the local irregularity paradigm can improve frequency discrimination under challenging, attended conditions, with some evidence for partial dissociation between objective performance and subjective awareness. However, substantial individual variability and cross-paradigm confounds caution against strong causal claims. These results are broadly consistent with predictive coding frameworks but require replication with counterbalanced designs and larger deviant trial counts.

Brain Sciences doi: 10.3390/brainsci16050438

Authors: Katarzyna Chyl-Tanaś Marcin Szczerbiński Artur Pokropek

Background/Objectives. Low functional literacy in adulthood is a growing issue, yet the cognitive profiles of struggling adult readers in transparent orthographies remain under-researched. This study investigated the cognitive and reading-related predictors of reading comprehension in Polish adults using the Simple View of Reading framework. Methods. We analyzed data from 158 adults recruited as typical readers (TRs, n = 76) and low readers (LRs, n = 82) based on functional reading comprehension scores. Participants completed comprehensive behavioral assessments measuring decoding, listening comprehension, phonological awareness and memory (PA&M), rapid automatized naming (RAN), and language abilities. Results. Path analysis indicated that both decoding and listening comprehension independently and significantly distinguished TRs from LRs (McKelvey-Zavoina R2 = 43.6%). However, multigroup analysis revealed differing mechanisms between the two groups: reading comprehension in TRs was driven primarily by listening comprehension, whereas comprehension in LRs was constrained by decoding, which was heavily influenced by RAN and PA. Furthermore, latent profile analysis uncovered significant heterogeneity among the struggling readers, identifying three distinct subgroups: a language-deficit profile (53.8%), a cognitively typical profile (37.5%), and a dyslexic profile (8.8%). These distinct subprofiles aligned with varied background factors, including self-reported dyslexia and early home literacy environment. Conclusions. This study demonstrates that functional reading difficulties in Polish adults are not homogeneous. The identification of three distinct profiles among low readers - language deficit, cognitively typical, and dyslexic - highlights that interventions must be tailored to specific cognitive needs. These findings underscore the necessity for specialized adult-literacy support in Poland to address the growing challenge of low functional literacy and its associated social and economic risks.

Brain Sciences doi: 10.3390/brainsci16050437

Authors: Juan José Mengual Carmen Montalvo Sandra Boned Carla Avellaneda-Gómez Manuel Gómez-Choco

Background/Objectives: Early neurological deterioration (END) is a frequent and clinically relevant complication in patients with a single small subcortical infarction (SSI), including lacunar infarction and branch atheromatous disease (BAD). Despite initially mild symptoms, END occurs in approximately 20–25% of cases and is strongly associated with poor functional outcomes. However, definitions, mechanisms, predictors, and therapeutic strategies remain heterogeneous. This review aims to synthesize current evidence regarding the incidence, pathophysiology, predictors, and management of END in SSI. Methods: We performed a narrative review of published studies addressing END in patients with lacunar stroke or SSI. We analyzed data on END definitions and incidence, imaging and clinical predictors, proposed pathophysiological mechanisms, and preventive and rescue therapeutic strategies. Results: END definitions vary across studies, most commonly defined as a ≥2-point increase in the National Institutes of Health Stroke Scale within 48–72 h. Hemodynamic compromise due to proximal perforator pathology, particularly in BAD, appears central to END development. Advanced imaging studies demonstrate perfusion abnormalities beyond the infarct core, supporting the concept of a “lacunar penumbra.” Lesion topology, proximal infarct patterns, parent artery plaques, larger infarct size, and vertical extension are consistent imaging predictors. Clinical factors such as diabetes mellitus, higher baseline severity, systemic inflammation, and increased arterial stiffness further modulate risk. Preventive strategies, including early dual antiplatelet therapy and intensified antithrombotic regimens, show promising signals, while induced hypertension may benefit selected patients as a rescue therapy. However, evidence remains largely observational or derived from subgroup analyses. Conclusions: END in SSI is a multifactorial and potentially modifiable process driven by interactions between proximal vascular pathology, hemodynamic failure, and tissue vulnerability. Standardized definitions, MRI-based phenotyping, and mechanism-driven trials are needed to optimize risk stratification and develop targeted preventive and rescue strategies.