Brain Sciences

11 pages, 928 KB

Open AccessCase Report

Dominant Orbitofrontal Pial Supply in Anterior Cranial Fossa Dural Arteriovenous Fistula: Angiographic Differentiation from Mixed Pial-Dural Arteriovenous Malformation and Anatomy-Based Treatment Selection

by Kosei Goto, Nobuo Kutsuna, Takuto Nishihara and Kotaro Makita

Brain Sci. 2026, 16(5), 534; https://doi.org/10.3390/brainsci16050534 (registering DOI) - 19 May 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Cerebrovascular Disease: Update on Diagnosis and Treatment)

23 pages, 1365 KB

Open AccessArticle

Sparse Multivariate Analysis Reveals Dissociable White Matter Networks for Cognitive and Motor Processing Speed

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

Brain Sci. 2026, 16(5), 533; https://doi.org/10.3390/brainsci16050533 (registering DOI) - 19 May 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Section Neuropsychology)

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21 pages, 643 KB

Open AccessSystematic Review

Functional Near-Infrared Spectroscopy in Hearing Loss: A Systematic Review of Cortical Responses in Distinct Clinical Populations

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

Brain Sci. 2026, 16(5), 532; https://doi.org/10.3390/brainsci16050532 (registering DOI) - 18 May 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Section Sensory and Motor Neuroscience)

43 pages, 2048 KB

Open AccessReview

Organoids to Model Tumor Microenvironment in Progression of Pathogenesis and Treatment Resistance in Glioblastoma Multiforme

by Pranav Kalaga and Swapan K. Ray

Brain Sci. 2026, 16(5), 531; https://doi.org/10.3390/brainsci16050531 (registering DOI) - 18 May 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Section Molecular and Cellular Neuroscience)

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14 pages, 733 KB

Open AccessArticle

Transcranial Magnetic Stimulation over the Left Inferior Parietal Lobule Facilitates Early-Stage Processing During Natural Chinese–English Bilingual Reading

by Junjie Wu, Ruoling Hang, Pingping Xin, Guoli Yan, Chanyuan Gu and Luyao Chen

Brain Sci. 2026, 16(5), 530; https://doi.org/10.3390/brainsci16050530 (registering DOI) - 17 May 2026

Abstract

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 [...] Read more.

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. Full article

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16 pages, 2035 KB

Open AccessArticle

White Matter Infarct Detection with Transformer and Auto-ML-Derived Models

by Vitaly Dobromyslin and Wenjin Zhou

Brain Sci. 2026, 16(5), 529; https://doi.org/10.3390/brainsci16050529 (registering DOI) - 15 May 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Applications of fMRI (Functional Magnetic Resonance Imaging) in Neuropsychiatry and Neurological Disease)

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19 pages, 987 KB

Open AccessSystematic Review

External Ventricular Drains and Infection Risk: Duration as the Dominant Predictor—A Systematic Review and Meta-Analysis

by Thamer H. Alsharif, Badr E. Hafiz, Lamair Albakri, Abdularhman D. Alofi, Ziad Alzahrani, Yazid Maghrabi and Moajeb Alzahrani

Brain Sci. 2026, 16(5), 528; https://doi.org/10.3390/brainsci16050528 (registering DOI) - 15 May 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Cerebrovascular Disease: Update on Diagnosis and Treatment)

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39 pages, 812 KB

Open AccessSystematic Review

Noninvasive Brain Stimulation Techniques and Their Efficacy in Treating Cognition and Memory in Mild Cognitive Impairment and Alzheimer’s Disease—A Systematic Review

by Hector P. Valverde, Benjamin J. Clark, Jeremy Hogeveen and Vincent P. Clark

Brain Sci. 2026, 16(5), 527; https://doi.org/10.3390/brainsci16050527 (registering DOI) - 15 May 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Advanced Applications of Non-Invasive Stimulation for Therapeutics)

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10 pages, 368 KB

Open AccessArticle

Mechanical Thrombectomy in Patients with Malignancy: Comparable Procedural Success but Less Favorable Long-Term Outcomes

by Sena Aksoy, Arsida Bajrami, Songül Şenadım and Serdar Geyik

Brain Sci. 2026, 16(5), 526; https://doi.org/10.3390/brainsci16050526 (registering DOI) - 14 May 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Section Neuro-oncology)

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20 pages, 659 KB

Open AccessReview

Axonal Transport Deficits in Parkinson’s Disease: Insights from Neurotoxin, Genetic, and Sporadic Models

by Xiaobo Wang, Zhaohui Liu and Wanli W. Smith

Brain Sci. 2026, 16(5), 525; https://doi.org/10.3390/brainsci16050525 (registering DOI) - 14 May 2026

Abstract

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, [...] Read more.

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. Full article

(This article belongs to the Special Issue Molecular and Cellular Research in Neurodegenerative Diseases)

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15 pages, 1822 KB

Open AccessArticle

Spasticity in Prolonged Disorders of Consciousness: A Prospective Cohort Study

by Nathalie Draulans, Cecile Utens, Danielle Driessen, Willemijn van Erp, Gerard Ribbers, Jörg Wissel and Aurore Thibaut

Brain Sci. 2026, 16(5), 524; https://doi.org/10.3390/brainsci16050524 (registering DOI) - 14 May 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Clinical Translation in Disorders of Consciousness: New Pathways and Challenges)

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17 pages, 352 KB

Open AccessReview

Human-Derived Cellular Models in Psychiatry: A Focus on the Olfactory Neuroepithelium

by Tommaso Toffanin, Mario Angelo Pagano, Carlo Idotta, Luigi Grassi and Anna Maria Brunati

Brain Sci. 2026, 16(5), 523; https://doi.org/10.3390/brainsci16050523 (registering DOI) - 14 May 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue The Olfactory System in Health and Disease)

21 pages, 865 KB

Open AccessReview

When the Clock Shifts: A Comprehensive Review of Daylight-Saving Time (DST), Circadian Disruption, and Neuropsychological Risk in Chronic Mental Illness

by Liahm Blank, Joshua Khorsandi, Elizabeth England-Kennedy, Srikanta Banerjee, Karen Kopera-Frye, Roberto Sagaribay, Jagdish Khubchandani and Kavita Batra

Brain Sci. 2026, 16(5), 522; https://doi.org/10.3390/brainsci16050522 (registering DOI) - 14 May 2026

Abstract

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, [...] Read more.

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. Full article

(This article belongs to the Section Neuropsychology)

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15 pages, 793 KB

Open AccessArticle

Genomic Profiling of Adults with Pharmacoresistant Genetic Generalized Epilepsy

by Benjamin L. Kidder, Jian Xu, Rui Geng, Hunter Dlugas, Anusha Vavilikolanu, Wei Chen and Vibhangini S. Wasade

Brain Sci. 2026, 16(5), 521; https://doi.org/10.3390/brainsci16050521 (registering DOI) - 14 May 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Section Molecular and Cellular Neuroscience)

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19 pages, 762 KB

Open AccessArticle

Modifiable Barriers to Assessment and Rehabilitation in Justice-Involved Individuals with Self-Reported TBI: The Role of Subjective Sleepiness and Mood

by Sarka Turecka Brown, Maddy Pontius, Jennifer Gallagher, Kim A. Gorgens, Gina Signoracci and Marybeth Lehto

Brain Sci. 2026, 16(5), 520; https://doi.org/10.3390/brainsci16050520 (registering DOI) - 13 May 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Accessing Treatment and Rehabilitation for Underserved Survivors of Brain Injury)

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17 pages, 544 KB

Open AccessArticle

Multivariate Associations Between R-PAS Variables and Suicidal Ideation and Behaviors in Help-Seeking Adolescents

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

Brain Sci. 2026, 16(5), 519; https://doi.org/10.3390/brainsci16050519 (registering DOI) - 13 May 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Advances in Child and Adolescent Psychiatry: Developmental Perspectives, Psychopathology, and Clinical Care)

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24 pages, 3060 KB

Open AccessArticle

Mapping the Human Performance Envelope Through Multivariate Information Transfer

by 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 and Fabio Babiloni

Brain Sci. 2026, 16(5), 518; https://doi.org/10.3390/brainsci16050518 (registering DOI) - 13 May 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Computational Intelligence and Brain Plasticity—2nd Edition)

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1 pages, 127 KB

Open AccessRetraction

RETRACTED: Tsatali et al. Normative Data for the D-KEFS Tower Test in Greek Adult Population Between 20 and 85 Years Old. Brain Sci. 2025, 15, 278

by Marianna Tsatali, Despina Eleftheriadou, Nikoleta Palla, Magda Tsolaki and Despina Moraitou

Brain Sci. 2026, 16(5), 517; https://doi.org/10.3390/brainsci16050517 (registering DOI) - 13 May 2026

Abstract

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” [...] Full article

15 pages, 1092 KB

Open AccessArticle

Is There Still a Role for Twist Drill Craniostomy in Contemporary Management of Chronic Subdural Hematoma?

by Hussam Hamou, Hani Ridwan, Anna Mausberg, Roel Haeren, Hans Clusmann, Anke Hoellig and Michael Veldeman

Brain Sci. 2026, 16(5), 516; https://doi.org/10.3390/brainsci16050516 (registering DOI) - 12 May 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Section Neurosurgery and Neuroanatomy)

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