Brain Sciences

24 pages, 6230 KB

Open AccessArticle

Genetic Loss of VGLUT1 Alters Histogenesis of Retinal Glutamatergic Cells and Reveals Dynamic Expression of VGLUT2 in Cones

by Sriparna Majumdar and Vincent Wu

Brain Sci. 2025, 15(9), 1024; https://doi.org/10.3390/brainsci15091024 - 22 Sep 2025

Viewed by 525

Abstract

Background/Objectives: Glutamatergic neurotransmission is essential for the normal functioning of the retina. Photoreceptor to bipolar and bipolar to ganglion cell signaling is mediated by L-glutamate, which is stored in and released from vesicular glutamate transporter 1 (VGLUT1) containing synaptic vesicles. VGLUT1 is [...] Read more.

Background/Objectives: Glutamatergic neurotransmission is essential for the normal functioning of the retina. Photoreceptor to bipolar and bipolar to ganglion cell signaling is mediated by L-glutamate, which is stored in and released from vesicular glutamate transporter 1 (VGLUT1) containing synaptic vesicles. VGLUT1 is expressed postnatally, P2 onwards, and is required for the glutamatergic retinal wave observed between P10 and P12 in the developing mouse retina. P9–P13 postnatal age is critical for retinal development as VGLUT1 expressing ribbon synapses activate in the outer and inner plexiform layers, and rod/cone mediated visual signaling commences in that period. Although it has been hypothesized that glutamatergic extrinsic signaling drives cell cycle exit and initiates cellular differentiation in the developing retina, it is not clear whether intracellular, synaptic, or extrasynaptic vesicular glutamate release contributes to this process. Recent studies have attempted to decipher VGLUT’s role in retinal development. Here, we investigate the potential effect of genetic loss of VGLUT1 on early postnatal histogenesis and development of retinal neural circuitry. Methods: We employed immunohistochemistry and electrophysiology to ascertain the density of glutamatergic, cholinergic, and dopaminergic cells, spontaneous retinal activity, and light responses in VGLUT1 null retina, and contrasted them with wildtype (WT) and melanopsin null retina. Results: We have demonstrated here that VGLUT1 null retina shows signs of age dependent retinal degeneration, similar to other transgenic mice models with dysfunctional photoreceptor to bipolar cell synapses. The loss of VGLUT1 specifically alters glutamatergic cell density and morphological maturation of retinal ganglion cells. Moreover, VGLUT2 expression is lost in the majority of VGLUT2 cones in the absence of VGLUT1 coexpression, except when VGLUT2 coexpresses transiently with VGLUT3 in these cones, or when VGLUT1 null mice are dark reared. Conclusions: We present the first evidence that synaptic or extrasynaptic postnatal glutamate release from VGLUT1 containing vesicles impacts histogenesis of glutamatergic cells, pruning of retinal ganglion cell dendrites and VGLUT2 expression in cones. Full article

(This article belongs to the Special Issue The Eye as the Window to Brain Science: Fields of Neuroscience Created from Eye Research)

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16 pages, 545 KB

Open AccessArticle

A Lumped Parameter Modelling Study of Leukoaraiosis Suggests Its Vascular Pathophysiology May Be Similar to Normal-Pressure Hydrocephalus

by Grant A. Bateman and Alexander R. Bateman

Brain Sci. 2025, 15(9), 1023; https://doi.org/10.3390/brainsci15091023 - 22 Sep 2025

Viewed by 418

Abstract

Introduction: Leukoaraiosis (LA) or white matter disease is a significant component of vascular dementia. There is a large overlap noted between normal-pressure hydrocephalus (NPH) and LA. A previously reported lumped parameter modelling study of NPH led to novel findings in this disease. Given [...] Read more.

Introduction: Leukoaraiosis (LA) or white matter disease is a significant component of vascular dementia. There is a large overlap noted between normal-pressure hydrocephalus (NPH) and LA. A previously reported lumped parameter modelling study of NPH led to novel findings in this disease. Given the overlap between LA and NPH, the purpose of the current study is to perform a lumped parameter study into LA to see if the vascular pathophysiology is similar to NPH. Methods: A lumped parameter model originally developed to study normal-pressure hydrocephalus was extended to investigate LA. The model was constrained by the known cerebral blood flow and cerebral blood volumes found in LA, as derived from the literature. Results: Similar to NPH, in LA, the model predicted a balanced increase in arterial and venous outflow resistance, with the resulting ischemia affecting the white matter rather than the grey matter. However, unlike NPH, in LA, the findings are irreversible, most likely due to structural venous wall changes. Conclusions: The model suggests that the vascular physiology of LA maybe similar to NPH. A common pathophysiology is discussed based on a pulsation-induced increase in the venous outflow resistance. Full article

(This article belongs to the Special Issue The Latest Exploration of Cerebrovascular Diseases: From Preclinical Research to Treatment)

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33 pages, 598 KB

Open AccessReview

Idea Density and Grammatical Complexity as Neurocognitive Markers

by Diego Iacono and Gloria C. Feltis

Brain Sci. 2025, 15(9), 1022; https://doi.org/10.3390/brainsci15091022 - 22 Sep 2025

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Abstract

Language, a uniquely human cognitive faculty, is fundamentally characterized by its capacity for complex thoughts and structured expressions. This review examines two critical measures of linguistic performance: idea density (ID) and grammatical complexity (GC). ID quantifies the richness of information conveyed per unit [...] Read more.

Language, a uniquely human cognitive faculty, is fundamentally characterized by its capacity for complex thoughts and structured expressions. This review examines two critical measures of linguistic performance: idea density (ID) and grammatical complexity (GC). ID quantifies the richness of information conveyed per unit of language, reflecting semantic efficiency and conceptual processing. GC, conversely, measures the structural sophistication of syntax, indicative of hierarchical organization and rule-based operations. We explore the neurobiological underpinnings of these measures, identifying key brain regions and white matter pathways involved in their generation and comprehension. This includes linking ID to a distributed network of semantic hubs, like the anterior temporal lobe and temporoparietal junction, and GC to a fronto-striatal procedural network encompassing Broca’s area and the basal ganglia. Moreover, a central theme is the integration of Chomsky’s theories of Universal Grammar (UG), which posits an innate human linguistic endowment, with their neurobiological correlates. This integration analysis bridges foundational models that first mapped syntax (Friederici’s work) to distinct neural pathways with contemporary network-based theories that view grammar as an emergent property of dynamic, inter-regional neural oscillations. Furthermore, we examine the genetic factors influencing ID and GC, including genes implicated in neurodevelopmental and neurodegenerative disorders. A comparative anatomical perspective across human and non-human primates illuminates the evolutionary trajectory of the language-ready brain. Also, we emphasize that, clinically, ID and GC serve as sensitive neurocognitive markers whose power lies in their often-dissociable profiles. For instance, the primary decline of ID in Alzheimer’s disease contrasts with the severe grammatical impairment in nonfluent aphasia, aiding in differential diagnosis. Importantly, as non-invasive and scalable metrics, ID and GC also provide a critical complement to gold-standard but costly biomarkers like CSF and PET. Finally, the review considers the emerging role of AI and Natural Language Processing (NLP) in automating these linguistic analyses, concluding with a necessary discussion of the critical challenges in validation, ethics, and implementation that must be addressed for these technologies to be responsibly integrated into clinical practice. Full article

(This article belongs to the Section Neurolinguistics)

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14 pages, 593 KB

Open AccessStudy Protocol

Accelerated Optimized Protocol of Intermittent Theta-Burst Stimulation for Negative Symptoms in Schizophrenia (ACTh-NS): A Randomized, Double-Blind, Sham-Controlled Study Design

by Ivan Taiar, July Silveira Gomes, Lucas Jorge, Carolina Ziebold, André Fernandes, Renan Biokino, Pedro Lorencetti, André Brunoni and Ary Gadelha

Brain Sci. 2025, 15(9), 1021; https://doi.org/10.3390/brainsci15091021 - 22 Sep 2025

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Abstract

Introduction: Intermittent theta burst stimulation (iTBS) has been associated with improvements in the negative symptoms (NSs) of schizophrenia. However, optimizing by shorter protocols remains necessary. Furthermore, understanding their impact on other clinical symptoms, sleep, and autonomic regulation is important to underlying therapeutic effects. [...] Read more.

Introduction: Intermittent theta burst stimulation (iTBS) has been associated with improvements in the negative symptoms (NSs) of schizophrenia. However, optimizing by shorter protocols remains necessary. Furthermore, understanding their impact on other clinical symptoms, sleep, and autonomic regulation is important to underlying therapeutic effects. Objectives: Evaluate the efficacy of an accelerated iTBS protocol on reducing NSs in patients with schizophrenia. We hypothesize a 20% reduction in BNSS scores in the active group, as well as improvements in disorder-related aspects, including sleep patterns, symptoms severity, and cognition. Methods: A double-blind, randomized, sham-controlled clinical trial design will be conducted to test the effects of the accelerated iTBS protocol in 60 participants with schizophrenia (30 active and 30 sham) with moderate NSs. iTBS protocol will consist of four daily sessions, with 600 pulses per session for five consecutive days. Patients will be assessed at three time points (baseline, after intervention and 30 days follow up) for clinical symptoms, cognition and heart rate variability. The primary outcome will be negative symptoms using the Brief Negative Symptom Scale (BNSS). Study register: Brazilian Registry of Clinical Trials (CAEE: 71102823.4.0000.5505). Conclusions: The accelerated iTBS protocol has demonstrated promising effects on NSs. However, it is still necessary to establish an effective and feasible high-dosage protocol. This study will contribute to optimizing therapeutic protocols for schizophrenia, with a particular focus on clinical applicability. Additionally, it will provide an opportunity to deepen the understanding of the physiological effects of neuromodulation, contributing to the understanding of its underlying mechanisms. Full article

(This article belongs to the Special Issue Non-Invasive Brain Stimulation for Brain Disorders)

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4 pages, 150 KB

Open AccessEditorial

Bridging Neurobiology, Heterogeneity, and Comorbidity in Mood Disorders

by Balwinder Singh

Brain Sci. 2025, 15(9), 1020; https://doi.org/10.3390/brainsci15091020 - 22 Sep 2025

Viewed by 552

Abstract

Mood disorders are among the most disabling and complex psychiatric conditions, affecting millions worldwide and contributing substantially to morbidity, mortality, and healthcare utilization [...] Full article

(This article belongs to the Special Issue Clinical Research on Mood Disorders: Opportunities and Challenges)

18 pages, 3752 KB

Open AccessCase Report

Nyctalopia Due to Vitamin A Deficiency Secondary to Short Bowel Syndrome: When the Electroretinogram Is the Diagnostic Key

by Moisés León-Ruiz, Julián Benito-León and Carlos Castañeda-Cabrero

Brain Sci. 2025, 15(9), 1019; https://doi.org/10.3390/brainsci15091019 - 20 Sep 2025

Viewed by 420

Abstract

Background: Vitamin A deficiency (VAD) can occur due to malnutrition or reduced intestinal absorption, such as in short bowel syndrome (SBS). The main causes of SBS in adults include post-radiotherapy and surgery (e.g., repeated bowel resections). VAD mostly involves rods producing nyctalopia and [...] Read more.

Background: Vitamin A deficiency (VAD) can occur due to malnutrition or reduced intestinal absorption, such as in short bowel syndrome (SBS). The main causes of SBS in adults include post-radiotherapy and surgery (e.g., repeated bowel resections). VAD mostly involves rods producing nyctalopia and reduced amplitudes of the electroretinogram (ERG) in scotopic conditions, with a characteristic negative ERG pattern (b/a < 1). Case Report: We report a 67-year-old woman with a history of gastric adenocarcinoma and several surgeries, who developed a progressive 3-month clinical picture of night blindness. Results: Urgent blood tests, biomicroscopy, intraocular pressure measurements, fundoscopy, and a cranial MRI were all normal. Visual evoked potentials showed increased latencies in both eyes, and full-field ERG showed a significant alteration in responses under scotopic conditions, and, to a lesser extent, under photopic conditions. Laboratory tests confirmed VAD, probably due to post-surgery and radiotherapy SBS. After parenteral vitamin replacement, VAD was clinically, analytically, and electroretinographically resolved. Discussion: VAD diagnosis is based on history, neuro-ophthalmological examination, and serum levels of retinol (<0.3 µg/mL) and/or retinol/retinol-binding protein (<0.8). In cases of a history of SBS, acquired nyctalopia, negative ERG, and clinical, analytical, and electroretinographic improvement with restoration of vitamin A levels, VAD should be suspected. ERG is crucial for early and appropriate management. Conclusions: As far as we know, this is the first reported VAD case secondary to SBS following surgical resections and radiotherapy of gastric adenocarcinoma with neuro-ophthalmological, laboratory, and electroretinographic monitoring of VAD recovery. Full article

(This article belongs to the Special Issue The Eye as the Window to Brain Science: Fields of Neuroscience Created from Eye Research)

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12 pages, 3251 KB

Open AccessArticle

CT-Based Quantitative Analysis of Ossification Centres in the C7 Vertebra of Human Fetuses

by Magdalena Grzonkowska, Michał Kułakowski, Karol Elster, Bartłomiej Hankiewicz, Michał Janiak, Agnieszka Rogalska, Milena Świtońska, Andrzej Żytkowski and Mariusz Baumgart

Brain Sci. 2025, 15(9), 1018; https://doi.org/10.3390/brainsci15091018 - 20 Sep 2025

Viewed by 358

Abstract

Objectives: The present study aimed to analyze the growth dynamics of the ossification centers of the seventh cervical (C7) vertebra in the human fetus, focusing on linear, planar, and volumetric parameters of both the vertebral body and neural processes. Methods: The [...] Read more.

Objectives: The present study aimed to analyze the growth dynamics of the ossification centers of the seventh cervical (C7) vertebra in the human fetus, focusing on linear, planar, and volumetric parameters of both the vertebral body and neural processes. Methods: The study was conducted on 55 human fetuses of both sexes (27 males and 28 females), aged 17–30 weeks’ gestation. High-resolution computed tomography, three-dimensional reconstruction, digital image analysis, and appropriate statistical modeling were used to obtain detailed morphometric measurements of the C7 ossification centers. Results: All morphometric parameters—length, cross-sectional area, and volume—of the vertebral body ossification center increased linearly with gestational age, except for the sagittal diameter, which followed a logarithmic growth pattern. Linear growth was likewise observed in all diameters of the neural process ossification centers, including length, width, cross-sectional area, and volume. No statistically significant sex-related or side-related differences were detected. Conclusions: The CT-based morphometric data and growth models for the ossification centers of C7 presented in this study offer preliminary reference values for the vertebra prominens during fetal development. Although limited by sample size, these results establish a baseline that may assist anatomists, radiologists, obstetricians, pediatricians, and spinal surgeons in assessing cervical-spine maturation and in detecting congenital anomalies prenatally. Further studies involving larger and more diverse fetal cohorts are warranted to validate and extend these observations. Full article

(This article belongs to the Special Issue Translational Neuroanatomy: Recent Updates and Future Perspectives—2nd Edition)

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16 pages, 421 KB

Open AccessReview

Navigating a Misty Road: Novel Ways to Study the Impact of Cognition on Driving Performance in Multiple Sclerosis

by Ioannis Nikolakakis, Panagiotis Grigoriadis, Nefeli Dimitriou, Dimitrios Parisis, Grigorios Nasios, Lambros Messinis and Christos Bakirtzis

Brain Sci. 2025, 15(9), 1017; https://doi.org/10.3390/brainsci15091017 - 20 Sep 2025

Viewed by 473

Abstract

Background/Objectives: The ability to drive is closely linked to participation in daily activities and quality of life in people living with neurological disorders. Cognitive deficits in people with multiple sclerosis (pwMS) are known to hinder this ability, yet concrete fitness-to-drive criteria remain [...] Read more.

Background/Objectives: The ability to drive is closely linked to participation in daily activities and quality of life in people living with neurological disorders. Cognitive deficits in people with multiple sclerosis (pwMS) are known to hinder this ability, yet concrete fitness-to-drive criteria remain elusive and assessment guidelines lack uniformity. A plethora of cognitive tests have provided associations with various aspects of driving performance and on-road behavior; however, several studies reveal limitations and inconsistencies in most tests’ sensitivity and predictive effect. Novel and resurfaced modalities for cognitive assessment, in the form of advanced imaging techniques and electrophysiological studies, may offer improved sensitivity in driving-related abilities in earlier and milder stages. Their application in addition to evaluations in driving simulators may aid future research and enhance the quality of evidence to inform decision-making. Methods: We searched for the relevant literature in the PubMed database and synthesized the available findings for the applications of currently clinically used cognitive tests, markers derived from functional magnetic resonance imaging (fMRI) and diffuse tensor imaging (DTI), as well as event-related potentials (ERP). Results: Advanced imaging modalities and ERP studies may better capture neurobiological changes that lead to driving impairment in pwMS, and they may also be applied to detect cognitive alterations earlier and with greater precision, helping to predict driving difficulties in this population. Conclusions: Novel tools and driving simulator settings could improve our understanding of the relation between cognition and driving in pwMS, enhance protocol homogeneity in driving studies, and aid in the formation of guidelines. The evidence in this review supports an increase in their application in future studies. Full article

(This article belongs to the Special Issue Optimizing Driving Safety: Neurocognitive Insights, Health-Promoting Strategies, and Policy Innovation)

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13 pages, 14788 KB

Open AccessArticle

Long-Term Preservation of Human Head and Neck Specimens for Neurosurgical Training: A Technical Note

by Francesco Signorelli, Valid Rastegar, Matteo Palermo, Domenico Laino, Fabio Zeoli and Massimiliano Visocchi

Brain Sci. 2025, 15(9), 1016; https://doi.org/10.3390/brainsci15091016 - 20 Sep 2025

Viewed by 503

Abstract

Purpose: Cadaveric dissection is a cornerstone of neurosurgical education, providing trainees with a realistic 3D understanding of anatomy and a safe environment to practice surgical approaches. A preservation technique was developed that merges the advantages of fresh-frozen and embalmed cadavers, maintaining tissue realism [...] Read more.

Purpose: Cadaveric dissection is a cornerstone of neurosurgical education, providing trainees with a realistic 3D understanding of anatomy and a safe environment to practice surgical approaches. A preservation technique was developed that merges the advantages of fresh-frozen and embalmed cadavers, maintaining tissue realism while enhancing durability. This approach preserves flexibility and natural color, improves anatomical detail, and creates a safe, long-lasting model ideal for neurosurgical training. Methods: Four specimens were thawed, cannulated, and irrigated before implementing a protocol consisting of low concentration formaldehyde with glycerol and ethanol for extended preservation. The specimens were prepared for both neurosurgery training and educational purposes, and their condition was evaluated with a semi-quantitative scale. Each specimen was evaluated independently by two raters, blinded to the time-point, using a semi-quantitative scale anchored to predefined criteria (0–3 per domain). Inter-rater reliability was calculated using the intraclass correlation coefficient (ICC [2,k]) for continuous scores and Cohen’s κ for categorical agreement. Results: Over nine years of intermittent use, the specimens remained in good condition: tissues retained sufficient softness for dissection, injected vessels stayed vivid in color, and no foul odor or microbial growth was observed. The evaluation employed a semi-quantitative scale, with results ranging from 11/14 to 14/14. The mean values demonstrate stable tissue quality over time, with only minor variations in color and perfusion. The inter-rater reliability was high (ICC = 0.91; κ = 0.88). Conclusions: The preservation method leverages the strengths of both fresh-frozen and embalmed models. The results suggest feasibility of long-term reuse, although further quantitative validation is needed. Full article

(This article belongs to the Section Neurosurgery and Neuroanatomy)

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15 pages, 661 KB

Open AccessArticle

A BIO-EEG Hyperscanning Study of Moral Dyadic Negotiation

by Angelica Daffinà, Laura Angioletti and Michela Balconi

Brain Sci. 2025, 15(9), 1015; https://doi.org/10.3390/brainsci15091015 - 19 Sep 2025

Viewed by 555

Abstract

Background/Objectives: Recent social neuroscience research has increasingly shifted from individual moral decision-making to the study of how people negotiate moral dilemmas in interpersonal contexts. This multimethod hyperscanning study investigated whether initial differences in moral decision-making orientation within a dyad influence neural and autonomic [...] Read more.

Background/Objectives: Recent social neuroscience research has increasingly shifted from individual moral decision-making to the study of how people negotiate moral dilemmas in interpersonal contexts. This multimethod hyperscanning study investigated whether initial differences in moral decision-making orientation within a dyad influence neural and autonomic synchronization during a joint moral negotiation. Methods: Fourteen dyads were classified as homologous or heterologous based on the similarity or dissimilarity of their individual decision-making orientations. Each dyad was asked to negotiate and reach a shared decision on a moral dilemma involving a realistic health emergency scenario. Electroencephalography (EEG) and autonomic signals were recorded simultaneously. Dissimilarity indices were computed to assess inter-brain and autonomic synchronization. Results: EEG analyses revealed a significant effect only in the delta frequency band: all dyads, regardless of orientation, showed greater dissimilarity in the left frontal region compared to the left temporo-central and right parieto-occipital regions. In addition, autonomic data indicated greater heart rate variability (HRV) dissimilarity in homologous dyads than in heterologous ones. However, these results did not confirm our initial hypotheses, indicating the opposite pattern. Conclusions: Left frontal delta dissimilarity emerged as an exploratory candidate marker of moral negotiation across dyads. Greater HRV dissimilarity in homologous dyads suggests that, in these dyads, successful negotiation may be supported by complementary rather than synchronized autonomic responses. This multimethod hyperscanning approach highlights the complex and partially dissociable contributions of neural and autonomic processes to the regulation of shared moral decision-making. Full article

(This article belongs to the Section Cognitive, Social and Affective Neuroscience)

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12 pages, 1252 KB

Open AccessArticle

Potential Predictors of Mortality in Adults with Severe Traumatic Brain Injury

by Rachel Marta, Yaroslavska Svitlana, Kreniov Konstiantyn, Mamonowa Maryna, Dobrorodniy Andriy and Oliynyk Oleksandr

Brain Sci. 2025, 15(9), 1014; https://doi.org/10.3390/brainsci15091014 - 19 Sep 2025

Viewed by 476

Abstract

Background: Severe traumatic brain injury (sTBI) in adults remains a leading cause of mortality and disability worldwide. Early identification of reliable predictors of outcome is crucial for risk stratification and ICU management. Disturbances of hemostasis and metabolic factors such as body mass index [...] Read more.

Background: Severe traumatic brain injury (sTBI) in adults remains a leading cause of mortality and disability worldwide. Early identification of reliable predictors of outcome is crucial for risk stratification and ICU management. Disturbances of hemostasis and metabolic factors such as body mass index (BMI) have been proposed as potential prognostic markers, but evidence remains limited. Methods: We conducted a retrospective, multicenter study including 307 adult patients with sTBI (Glasgow Coma Scale ≤ 8) admitted to three tertiary intensive care units in Ukraine between September 2023 and July 2024. All patients underwent surgical evacuation of hematomas and decompressive craniotomy. Laboratory parameters (APTT, INR, fibrinogen, platelets, D-dimer) were collected within 12 h of admission. BMI was calculated from measured height and weight. Predictive modeling was performed using L1-regularized logistic regression and Random Forest algorithms. Class imbalance was addressed with SMOTE. Model performance was assessed by AUC, accuracy, calibration, and feature importance. Results: The 28-day all-cause mortality was 32.9%. Compared with survivors, non-survivors had significantly lower GCS scores and higher INR, D-dimer, and APTT values. Very high VIF values indicated severe multicollinearity between predictors. Classical logistic regression was not estimable due to perfect separation; therefore, regularized logistic regression and Random Forest were applied. Random Forest demonstrated higher performance (AUC 0.95, accuracy ≈ 90%) than logistic regression (AUC 0.77, accuracy 70.1%), although results must be interpreted cautiously given the small sample size and potential overfitting. Feature importance analysis identified increased BMI, prolonged APTT, and elevated D-dimer as leading predictors of mortality. Sensitivity analysis excluding BMI still yielded strong performance (AUC 0.91), confirming the prognostic value of coagulation markers and GCS. Conclusions: Mortality in adult sTBI patients was strongly associated with impaired hemostasis, obesity, and low neurological status at admission. Machine learning-based modeling demonstrated promising predictive accuracy but is exploratory in nature. Findings should be interpreted with caution due to retrospective design, severe multicollinearity, potential overfitting, and absence of external validation. Larger, prospective, multicenter studies are needed to confirm these results and improve early risk stratification in severe TBI. Full article

(This article belongs to the Section Neurosurgery and Neuroanatomy)

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18 pages, 711 KB

Open AccessReview

Exploring Imagined Movement for Brain–Computer Interface Control: An fNIRS and EEG Review

by Robert Finnis, Adeel Mehmood, Henning Holle and Jamshed Iqbal

Brain Sci. 2025, 15(9), 1013; https://doi.org/10.3390/brainsci15091013 - 19 Sep 2025

Viewed by 949

Abstract

Brain–Computer Interfaces (BCIs) offer a non-invasive pathway for restoring motor function, particularly for individuals with limb loss. This review explored the effectiveness of Electroencephalography (EEG) and function Near-Infrared Spectroscopy (fNIRS) in decoding Motor Imagery (MI) movements for both offline and online BCI systems. [...] Read more.

Brain–Computer Interfaces (BCIs) offer a non-invasive pathway for restoring motor function, particularly for individuals with limb loss. This review explored the effectiveness of Electroencephalography (EEG) and function Near-Infrared Spectroscopy (fNIRS) in decoding Motor Imagery (MI) movements for both offline and online BCI systems. EEG has been the dominant non-invasive neuroimaging modality due to its high temporal resolution and accessibility; however, it is limited by high susceptibility to electrical noise and motion artifacts, particularly in real-world settings. fNIRS offers improved robustness to electrical and motion noise, making it increasingly viable in prosthetic control tasks; however, it has an inherent physiological delay. The review categorizes experimental approaches based on modality, paradigm, and study type, highlighting the methods used for signal acquisition, feature extraction, and classification. Results show that while offline studies achieve higher classification accuracy due to fewer time constraints and richer data processing, recent advancements in machine learning—particularly deep learning—have improved the feasibility of online MI decoding. Hybrid EEG–fNIRS systems further enhance performance by combining the temporal precision of EEG with the spatial specificity of fNIRS. Overall, the review finds that predicting online imagined movement is feasible, though still less reliable than motor execution, and continued improvements in neuroimaging integration and classification methods are essential for real-world BCI applications. Broader dissemination of recent advancements in MI-based BCI research is expected to stimulate further interdisciplinary collaboration among roboticists, neuroscientists, and clinicians, accelerating progress toward practical and transformative neuroprosthetic technologies. Full article

(This article belongs to the Special Issue Exploring the Neurobiology of the Sensory-Motor System)

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19 pages, 1247 KB

Open AccessArticle

Longitudinal and Cross-Sectional Relations Between Early Rise Time Discrimination Abilities and Pre-School Pre-Reading Assessments: The Seeds of Literacy Are Sown in Infancy

by Marina Kalashnikova, Denis Burnham and Usha Goswami

Brain Sci. 2025, 15(9), 1012; https://doi.org/10.3390/brainsci15091012 - 19 Sep 2025

Viewed by 380

Abstract

Background/Objectives: The Seeds of Literacy project has followed infants at family risk for dyslexia (FR group) and infants not at family risk (NFR group) since the age of 5 months, exploring whether infant measures of auditory sensitivity and phonological skills are related to [...] Read more.

Background/Objectives: The Seeds of Literacy project has followed infants at family risk for dyslexia (FR group) and infants not at family risk (NFR group) since the age of 5 months, exploring whether infant measures of auditory sensitivity and phonological skills are related to later reading achievement. Here, we retrospectively assessed relations between infant performance on a rise time discrimination task with new pre-reading behavioural measures administered at 60 months. In addition, we re-classified dyslexia risk at 60 months and again assessed relations to rise time sensitivity. Participants were re-grouped using the pre-reading behavioural measures as either dyslexia risk at 60 months (60mDR) or no dyslexia risk (60mNDR). Methods: FR and NFR children (44 English-learning children) completed assessments of rise time discrimination at 10 and/or 60 months, phonological awareness, phonological memory, rapid automatised naming (RAN), letter knowledge, and language skills (receptive vocabulary and grammatical awareness). Results: Longitudinal analyses showed significant time-lagged correlations between rise time sensitivity at 10 months and both RAN and letter knowledge at 60 months. Rise time sensitivity at 60 months was significantly poorer in those children re-grouped as 60mDR, and rise time sensitivity was significantly related to concurrent phonological awareness, RAN, letter knowledge, and receptive vocabulary, but not to tests of grammatical awareness. Conclusions: The data support the view that children’s rise time sensitivity is significantly related to their pre-reading phonological abilities. These findings are discussed in terms of Temporal Sampling theory. Full article

(This article belongs to the Topic Language: From Hearing to Speech and Writing)

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9 pages, 1098 KB

Open AccessArticle

Heatstroke Is Associated with an Increased Risk of Chronic Headache: A Retrospective Cohort Study

by Karel Kostev, Ira Rodemer, Marcel Konrad and Jens Bohlken

Brain Sci. 2025, 15(9), 1011; https://doi.org/10.3390/brainsci15091011 - 19 Sep 2025

Viewed by 500

Abstract

Background: Heatstroke is the most severe form of heat-related illness. It is characterized by an elevated core body temperature and central nervous system dysfunction. The aim of this study was to investigate the association between heatstroke and subsequent migraine development. Methods: This retrospective [...] Read more.

Background: Heatstroke is the most severe form of heat-related illness. It is characterized by an elevated core body temperature and central nervous system dysfunction. The aim of this study was to investigate the association between heatstroke and subsequent migraine development. Methods: This retrospective cohort study used data from the Disease Analyzer database (IQVIA) and included individuals diagnosed with heatstroke, as well as propensity score-matched individuals without heatstroke. Data about these individuals was recorded in 1216 general practices in Germany between January 2005 and December 2023. Five-year cumulative migraine incidence was assessed using Kaplan–Meiercurves, and univariable Cox regression analysis was performed to evaluate the association between heatstroke and migraine. Results: The study included 5794 individuals with heatstroke and 28,970 matched controls without heatstroke (median age: 30 years, 31–32% female). Most heatstroke cases were documented in June (32–34%), followed by July (30%), August (15–17%), and May (13%). Within five years of follow-up, 8.8% of patients with heatstroke and 4.0% of controls were diagnosed with migraine. The regression analysis revealed that heatstroke was significantly associated with an increased risk of migraine in the total population (HR: 2.26; 95% CI: 2.00–2.57), as well as in women (HR: 2.33; 95% CI: 1.96–2.79) and men (HR: 2.26; 95% CI: 1.89–2.70). Conclusion: This study highlights an important, yet previously underrecognized, association between heatstroke and an increased risk of migraine. As global temperatures continue to rise, public health strategies should focus not only on the acute prevention and management of heat-related illnesses, but also on their potential long-term neurological consequences. Full article

(This article belongs to the Special Issue Climate-Related Neurological Problems and Diseases)

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30 pages, 515 KB

Open AccessReview

Autism Spectrum Disorder: What Do We Know and Where Do We Go?

by Gerry Leisman and Robert Melillo

Brain Sci. 2025, 15(9), 1010; https://doi.org/10.3390/brainsci15091010 - 18 Sep 2025

Viewed by 2532

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that manifests in early childhood and persists throughout an individual’s life. Characterized by a range of symptoms affecting social interaction, communication, and behavior, ASD presents a spectrum of varying degrees of severity and presentation. [...] Read more.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that manifests in early childhood and persists throughout an individual’s life. Characterized by a range of symptoms affecting social interaction, communication, and behavior, ASD presents a spectrum of varying degrees of severity and presentation. Recent research emphasizes the importance of understanding the diverse manifestations of ASD across different populations. Core features include social communication differences and restricted and repetitive behaviors (RRBs), often linked to co-occurring conditions such as anxiety and ADHD. The study of ASD has evolved significantly, highlighting the need for individualized approaches to diagnosis and intervention. This paper explores current knowledge on ASD, examining the latest research findings and discussing future directions for improving the lives of those affected by the disorder. The purpose is to present a map of the field and an evidence-strength framing of what is known and unknown, and where the evidence is equivocal. Key areas of focus include behavioral, psychological, genetic, metabolic, immunological, and neurological features, as well as developmental and maturational factors. The aim is to provide a comprehensive overview of what is known, what remains unclear, and where future research should be directed. Full article

(This article belongs to the Section Neuropsychiatry)

13 pages, 718 KB

Open AccessArticle

Quantitative Analysis of Intracranial Atherosclerosis and Its Correlation with Ischemic Cerebrovascular Disease and Prognosis

by Jingjing Cai, Sizhan Chen, Shiyu Hu, Lijie Ren and Gelin Xu

Brain Sci. 2025, 15(9), 1009; https://doi.org/10.3390/brainsci15091009 - 18 Sep 2025

Viewed by 521

Abstract

Background: Intracranial atherosclerosis disease (ICAD) represents a significant etiology of stroke. This study aimed to evaluate correlations between intracranial atherosclerotic burden and risk of ischemic events. Methods: In this prospective observational study, all enrolled patients underwent High-Resolution Magnetic Resonance vessel wall Imaging [...] Read more.

Background: Intracranial atherosclerosis disease (ICAD) represents a significant etiology of stroke. This study aimed to evaluate correlations between intracranial atherosclerotic burden and risk of ischemic events. Methods: In this prospective observational study, all enrolled patients underwent High-Resolution Magnetic Resonance vessel wall Imaging (HR MR-VMI) within two weeks of onset, or of enrollment. Baseline assessments included modified American Heart Association plaque type, stenosis degree, intra-plaque hemorrhage (IPH), plaque thickness, plaque length, and vessel wall enhancement. Modified Rankin Scale (mRS) was followed with one-year treatment in adherence to the guidelines. Comparative analyses were conducted between symptomatic and asymptomatic groups, culprit versus non-culprit plaques, and favorable versus poor prognosis groups. Results: The study included 129 symptomatic and 42 asymptomatic patients. Hypertension, diabetes, and smoking were more prevalent in patients in the symptomatic group. Vulnerable plaque (97.7% vs. 64.3%, p = 0.003), IPH (17.8% vs. 4.8%, p = 0.022) and higher stenosis degree (χ² = 2.675, p = 0.008) were significantly more prevalent in the symptomatic group. Culprit plaques were predominantly located in the superior wall of the middle cerebral artery (MCA) (χ² = 15.561, p = 0.001) and the left wall of the basilar artery (χ² = 34.138, p = 0.008). Factors associated with poor prognosis included older age (63.63 ± 8.19 vs. 55.63 ± 13.15, p = 0.001), presence of IPH (31.82% vs. 14.29%, p = 0.037), and elevated D-dimer levels (0.77 ± 0.60 vs. 0.40 ± 0.36, p = 0.022). Conclusions: Vulnerable plaque, specific lesion locations, and higher stenosis degree are significantly associated with ischemic events in ICAD. While plaque enhancement and stenosis correlate with stroke occurrence, they show no clear association with prognosis. Neither the length nor the thickness of plaques manifests a significant correlation with either stroke events or the prognostic outcomes. Full article

(This article belongs to the Special Issue Application of MRI in Brain Diseases)

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12 pages, 262 KB

Open AccessArticle

Sex-Specific Association Between XPC rs2228001 Polymorphism and Parkinson’s Disease Risk in a Mexican Population: A Case–Control Study Exploring Gene–Environment Interactions

by Karla Mariana Alvarado-Retana, Daniel Francisco Ramos-Rosales, Elizabeth Irasema Antuna-Salcido, Sergio Manuel Salas-Pacheco, Francisco Xavier Castellanos-Juárez, Edna Madai Méndez-Hernández, Alma Cristina Salas-Leal, Osmel La Llave-León, Gerardo Quiñones-Canales, Oscar Arias-Carrión, Ada Sandoval-Carrillo and José Manuel Salas-Pacheco

Brain Sci. 2025, 15(9), 1008; https://doi.org/10.3390/brainsci15091008 - 18 Sep 2025

Viewed by 446

Abstract

Background/Objectives: Emerging evidence implicates impaired DNA repair mechanisms in the pathogenesis of Parkinson’s disease (PD), particularly in the context of oxidative stress and environmental exposures. This study investigated the association between five polymorphisms in nucleotide excision repair (NER) pathway genes and PD susceptibility [...] Read more.

Background/Objectives: Emerging evidence implicates impaired DNA repair mechanisms in the pathogenesis of Parkinson’s disease (PD), particularly in the context of oxidative stress and environmental exposures. This study investigated the association between five polymorphisms in nucleotide excision repair (NER) pathway genes and PD susceptibility in a northern Mexican mestizo population. Methods: We conducted a case–control study including 137 patients with clinically diagnosed PD and 137 age- and sex-matched controls. Genomic DNA was isolated from peripheral blood, and genotyping of ERCC1 (rs11615), ERCC2 (rs13181), XPA (rs1800975), XPC (rs2228001), and XPF (rs1799801) was performed using TaqMan real-time PCR assays. Associations between genotype frequencies and PD were evaluated using logistic regression models adjusted for age, sex, and pesticide exposure. Results: A significantly higher prevalence of pesticide exposure was observed in PD patients than in controls (OR 2.08, 95% CI 1.18–3.68; p = 0.01). The XPC rs2228001 C/C genotype was independently associated with increased PD risk in males (OR 3.25, 95% CI 1.07–9.85; p = 0.042), even after adjusting for uric acid, pesticide exposure, and cognitive status (MMSE score). No significant associations were found for other NER-related polymorphisms. Male PD patients also exhibited significantly lower serum uric acid levels than controls (p = 0.046), supporting a link between oxidative stress and disease vulnerability. Conclusions: Our findings suggest a sex-specific genetic contribution to PD susceptibility involving the XPC rs2228001 variant, particularly in the context of pesticide exposure. These results underscore the relevance of DNA repair pathways in PD pathogenesis and highlight the importance of integrated models incorporating genetic and environmental risk factors. Full article

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

20 pages, 966 KB

Open AccessSystematic Review

Effectiveness of AI-Assisted Digital Therapies for Post-Stroke Aphasia Rehabilitation: A Systematic Review

by Yamil Liscano, Lina Marcela Bernal and Jhony Alejandro Díaz Vallejo

Brain Sci. 2025, 15(9), 1007; https://doi.org/10.3390/brainsci15091007 - 18 Sep 2025

Viewed by 1225

Abstract

Background: Traditional aphasia therapy is often limited by insufficient dosage, a barrier that AI-assisted digital therapies are poised to overcome. However, it remains unclear whether gains on specific tasks translate to functional, real-world communication. This systematic review evaluates the effectiveness of these novel [...] Read more.

Background: Traditional aphasia therapy is often limited by insufficient dosage, a barrier that AI-assisted digital therapies are poised to overcome. However, it remains unclear whether gains on specific tasks translate to functional, real-world communication. This systematic review evaluates the effectiveness of these novel interventions and investigates the potential for a “generalization gap” when compared to conventional treatments for post-stroke aphasia rehabilitation. Methods: Following PRISMA guidelines, we systematically reviewed randomized controlled trials (2010–2024) from six databases. We included studies examining AI-powered digital platforms for adults with chronic post-stroke apha-sia that reported standardized language outcomes. Results: Our analysis of five trials (n = 366) shows that AI-assisted therapies successfully deliver high-dose interventions, leading to significant improvements in trained language skills, including word retrieval (up to 16.4% gain) and auditory comprehension. However, a critical “generalization gap” was consistently identified: these impairment-level gains rarely transferred to functional, real-world communication. Conclusions: AI-assisted digital therapies effectively solve the dosage problem in aphasia care and improve specific linguistic deficits. Their primary limitation is the failure to generalize skills to everyday use. Future platforms must therefore be strategically redesigned to incorporate therapeutic principles that explicitly target the transfer of skills, bridging the gap between clinical improvement and functional communication. Full article

(This article belongs to the Special Issue Clinical Research on Neurological Rehabilitation After Stroke)

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33 pages, 1053 KB

Open AccessSystematic Review

Clinical Management of Synthetic-Cannabinoid-Induced Psychosis: A Systematic Review of Treatment Strategies and Outcomes

by Alessio Mosca, Stefania Chiappini, Andrea Miuli, Clara Cavallotto, Mauro Pettorruso, Giovanni Martinotti and Fabrizio Schifano

Brain Sci. 2025, 15(9), 1006; https://doi.org/10.3390/brainsci15091006 - 17 Sep 2025

Viewed by 1395

Abstract

Background: Synthetic cannabinoid receptor agonists (SCRAs, commercially known as “Spice”) have become a leading cause of substance-induced psychosis worldwide. These compounds show strong associations not only with acute psychotic episodes but also, in a subset of patients, with persistent or relapsing psychotic disorders, [...] Read more.

Background: Synthetic cannabinoid receptor agonists (SCRAs, commercially known as “Spice”) have become a leading cause of substance-induced psychosis worldwide. These compounds show strong associations not only with acute psychotic episodes but also, in a subset of patients, with persistent or relapsing psychotic disorders, patterns that raise concern about progression to schizophrenia. Yet clinicians still lack clear, evidence-based guidance, and the optimal management of SCRA-induced psychosis remains inadequately defined. Methods: We carried out a systematic search of PubMed, Scopus, and Web of Science on 2 April 2025, identifying 35 primary studies that together describe roughly 4600 clinical presentations (≈77% male; mean age: 24.7 years). Results: Across diverse settings a convergent three-step pharmacological strategy emerged. First, rapid tranquillization with parenteral benzodiazepines consistently controlled severe agitation and autonomic instability. Second, when florid psychosis persisted beyond 30–60 min, clinicians introduced a second-generation antipsychotic—most commonly olanzapine, risperidone, or aripiprazole—often at doses exceeding those used for primary psychoses. Third, for the minority of refractory or relapse-prone cases, escalation to long-acting injectable formulations or low-dose clozapine achieved symptom control, even at plasma levels below those required in treatment-resistant schizophrenia. Although the evidence base consists largely of uncontrolled clinical descriptions, across studies, a recurrent clinical pattern was observed: initial benzodiazepines for agitation, followed by antipsychotics when psychosis persisted and escalation to clozapine or long-acting injectables in refractory cases. This approach appears to be associated with symptom improvement, although the certainty of the evidence is low to very low. Conclusions. Prospective, comparative studies are urgently needed to refine dosing, directly compare antipsychotic classes, and evaluate emerging cannabinoid-modulating interventions. Full article

(This article belongs to the Special Issue Drug Development for Schizophrenia)

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11 pages, 1656 KB

Open AccessArticle

Spinal Cord Injury in Real Time: Intra-Operative Ultrasound for Acute Phase Examination in Non-Human Primates

by Eleni Sinopoulou, Michelle W. Chow, Numaira Obaid, Emily Chong, Yvette S. Nout-Lomas, Rachele Wurr, Ryan Macon, J. Russell Huie, Adam R. Ferguson, Mark H. Tuszynski, Michael S. Beattie, Jacqueline C. Bresnahan and Carolyn J. Sparrey

Brain Sci. 2025, 15(9), 1005; https://doi.org/10.3390/brainsci15091005 - 17 Sep 2025

Viewed by 527

Abstract

Background: A spinal cord contusion injury is among the most clinically relevant models for studying pathophysiology and for developing potential therapeutic interventions for spinal cord injuries (SCI). Methods: In this study, we implemented an intra-operative ultrasound (IOU) approach to precisely locate and examine [...] Read more.

Background: A spinal cord contusion injury is among the most clinically relevant models for studying pathophysiology and for developing potential therapeutic interventions for spinal cord injuries (SCI). Methods: In this study, we implemented an intra-operative ultrasound (IOU) approach to precisely locate and examine the lesion site at 5 and 10 min post-injury after a cervical hemi-contusion injury in a non-human primate (NHP) model. We assessed acute lesion progression from 5 to 10 min and then compared that to the lesion extent as measured by MRI 3 weeks later. Results: We observed a small increase in the rostrocaudal and mediolateral lesion area (mm²) from 5 to 10 min and a further 26% increase in the mediolateral lesion extent when comparing 5 and 10 min to 3 weeks post-injury. Conclusions: By enabling high-resolution ultrasound visualization of the hemicontusion lesion in vivo, this approach can provide critical insights into the early progression of SCI. It can help with further refining this preclinical SCI model and provide significant predictive value for the animals’ recovery post-injury. Full article

(This article belongs to the Special Issue Spinal Cord Injury)

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23 pages, 2647 KB

Open AccessReview

Primary Cilia and Cardiovascular Risk Factors in Alzheimer’s Disease

by Clare L. Sunderman, Kathleen V. Forero, Qasim Alorjani, Raghad Buqaileh, Gillian M. Gallagher, Sestina M. Ventresca, William S. Messer, Jr. and Wissam A. AbouAlaiwi

Brain Sci. 2025, 15(9), 1004; https://doi.org/10.3390/brainsci15091004 - 17 Sep 2025

Viewed by 633

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia worldwide due to an aging population. AD is characterized as a progressive neurodegenerative disease that leads to atrophy of brain tissue, causing cognitive deficits. Amyloid beta plaques and neurofibrillary tangles are pathological hallmarks [...] Read more.

Alzheimer’s disease (AD) is the most common cause of dementia worldwide due to an aging population. AD is characterized as a progressive neurodegenerative disease that leads to atrophy of brain tissue, causing cognitive deficits. Amyloid beta plaques and neurofibrillary tangles are pathological hallmarks of AD, yet the cause is still highly debated. Many other cardiovascular diseases and vascular manifestations share the same symptoms as patients with AD. In this review, the current understanding of AD is summarized with a brief discussion on how primary cilia dysfunction and impaired nitric oxide (NO) signaling contribute to cardiovascular risk factors, vascular pathology, and cognitive decline in AD. Finally, we highlight primary cilia as a possible therapeutic target and any future directions for treating AD. Full article

(This article belongs to the Section Neurodegenerative Diseases)

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23 pages, 1586 KB

Open AccessReview

Statistical Parametric Mapping and Voxel-Based Specific Regional Analysis System for Alzheimer’s Disease (VSRAD): Principles and Clinical Applications

by Shinji Yamamoto, Nobukiyo Yoshida, Noriko Sakurai, Yukinori Okada, Norikazu Ohno, Masayuki Satoh, Koji Takeshita, Masanori Ishida and Kazuhiro Saito

Brain Sci. 2025, 15(9), 999; https://doi.org/10.3390/brainsci15090999 - 16 Sep 2025

Viewed by 664

Abstract

Background: The voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) allows quantitative evaluation of the degree of an individual’s brain atrophy through statistical comparison of brain magnetic resonance imaging (MRI) of their brain to a normative database of healthy Japanese individuals. [...] Read more.

Background: The voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) allows quantitative evaluation of the degree of an individual’s brain atrophy through statistical comparison of brain magnetic resonance imaging (MRI) of their brain to a normative database of healthy Japanese individuals. Currently, the VSRAD is used in routine clinical practice in the diagnosis of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Recent studies using VSRAD have explored its utility in the assessment of brain atrophy associated with various conditions, including diabetes, oral health status, and olfactory dysfunction. This review summarizes the principles of the VSRAD and its foundational method, voxel-based morphometry (VBM), and their clinical and research applications. Methods: This narrative review was conducted by performing a literature search of PubMed to identify articles regarding VBM and the VSRAD that were published between 2005 and 2025. Results: VSRAD yields four indices for quantifying the severity and extent of gray matter atrophy, especially in the medial temporal lobe. Studies have demonstrated its high diagnostic accuracy in distinguishing among AD, mild cognitive impairment (MCI), and DLB. Furthermore, it is correlated with neuropsychological test scores and has been applied to evaluate brain changes associated with diabetes, olfactory dysfunction, and physical inactivity. Motion-corrected MR images, which utilize AI techniques, have also been validated using VSRAD-derived metrics. Conclusions: Quantifying brain atrophy using the VSRAD allows objective evaluation and facilitates the investigation of its association with various diseases. Specifically, VSRAD can be considered a useful adjunctive tool for diagnosing AD and DLB. Full article

(This article belongs to the Section Neurodegenerative Diseases)

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19 pages, 1875 KB

Open AccessArticle

Boosting Working Memory in ADHD: Adaptive Dual N-Back Training Enhances WAIS-IV Performance, but Yields Mixed Corsi Outcomes

by Alessandra Lintas, Michel Bader and Alessandro E. P. Villa

Brain Sci. 2025, 15(9), 998; https://doi.org/10.3390/brainsci15090998 - 16 Sep 2025

Viewed by 6146

Abstract

Background/Objectives: This study investigates the efficacy of working memory training (WMT) using the dual N-back (DNB) task on cognitive performance in young adults with Attention-Deficit/Hyperactivity Disorder (ADHD). Methods: Over the course of at least 18 daily sessions conducted within one month, 106 participants [...] Read more.

Background/Objectives: This study investigates the efficacy of working memory training (WMT) using the dual N-back (DNB) task on cognitive performance in young adults with Attention-Deficit/Hyperactivity Disorder (ADHD). Methods: Over the course of at least 18 daily sessions conducted within one month, 106 participants (33 non-medicated ADHD, 42 medicated ADHD, and 45 controls) were randomly assigned to either a fixed dual 1-back (FD1B) training condition or an adaptive DNB condition, wherein the N-back level increased following successful completion of each trial block. Cognitive performance was assessed pre- and post-intervention using the Wechsler Adult Intelligence Scale–Fourth Edition (WAIS-IV) Working Memory Index (WMI) and the Corsi Block-Tapping Task. Results: A mixed-design ANOVA revealed significant improvements in DNB performance across all groups, with the adaptive training condition producing larger gains (e.g., a 204.6% improvement in controls, Cohen’s

d = 1.85

). WAIS-IV WMI scores—particularly the Digit Span Backward subtest—also improved significantly post-training, with greater effect sizes in the adaptive condition (

d = 0.46

) than in FD1B (

d = 0.27

). Corsi performance showed very modest gains, showing a surprising tendency to be more associated with the FD1B condition than the adaptive condition. Control participants outperformed the medicated ADHD group on WAIS-IV subtests, although no significant differences emerged between medicated and non-medicated ADHD participants. Correlational analyses indicated task-specific training effects, with adaptive training enhancing associations between DNB and Corsi performance in both controls (

r = 0.60

) and medicated ADHD participants (

r = 0.51

). Conclusions: This study demonstrates that dual N-back training improves verbal working memory in young adults with ADHD, specifically in a sample without psychiatric comorbidities. Transfer benefit to visuospatial domains appears limited and may not generalize to adolescents, older adults, or individuals with complex clinical profiles. The results underscore the importance of tailoring training protocols to maximize cognitive outcomes across different domains. Full article

(This article belongs to the Section Neurorehabilitation)

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18 pages, 687 KB

Open AccessReview

Positive Clinical Signs in Functional Neurological Disorders: A Narrative Review and Development of a Clinical Decision Tool

by Ioannis Mavroudis, Katerina Franekova, Foivos Petridis, Alin Ciobica, Sotirios Papagiannopoulos and Dimitrios Kazis

Brain Sci. 2025, 15(9), 997; https://doi.org/10.3390/brainsci15090997 - 16 Sep 2025

Viewed by 1046

Abstract

Background: Functional Neurological Disorders (FNDs) encompass a spectrum of disabling conditions, including functional limb weakness, tremor, gait disorders, seizures, and cognitive impairments. While previously diagnosed by exclusion, a growing consensus now supports the use of positive clinical signs as a basis for [...] Read more.

Background: Functional Neurological Disorders (FNDs) encompass a spectrum of disabling conditions, including functional limb weakness, tremor, gait disorders, seizures, and cognitive impairments. While previously diagnosed by exclusion, a growing consensus now supports the use of positive clinical signs as a basis for diagnosis. Despite this paradigm shift, frontline clinicians lack an integrated, accessible clinical tool for guiding diagnostic reasoning across FND subtypes. Objectives: This study aims to (1) synthesize the contemporary evidence on positive clinical signs across major FND subtypes and (2) develop a structured Clinical Decision Tool to support early and confident diagnosis in routine clinical settings. Methods: A focused narrative review was conducted using peer-reviewed publications and neurology reference texts, identifying reproducible positive clinical signs relevant to FND diagnosis. Signs were extracted, tabulated by subtype, and integrated into a modular decision-making framework designed for usability across outpatient, emergency, and specialist contexts. Results: The review identified 60+ positive signs across seven FND subtypes. These include Hoover’s sign for limb weakness, entrainment for tremor, variable responsiveness in NESs, and paradoxical memory performance in Functional Cognitive Disorder. A Clinical Decision Tool was developed, featuring subtype-specific checklists, diagnostic confidence indicators, and red flag alerts, and it is currently available in printable format. Conclusions: This study offers a novel, evidence-based decision tool to facilitate the positive diagnosis of FND. By consolidating observable signs into a practical format, it aims to reduce diagnostic delays, avoid unnecessary investigations, and enhance patient–clinician communication. Future efforts will focus on clinical validation and digital implementation. Full article

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14 pages, 464 KB

Open AccessArticle

Does Music Experience Impact the Vascular Endothelial Response to Singing?

by Mehri Bagherimohamadipour, Muhammad Hammad, Alexis Visotcky, Rodney Sparapani and Jacquelyn Kulinski

Brain Sci. 2025, 15(9), 996; https://doi.org/10.3390/brainsci15090996 - 16 Sep 2025

Viewed by 562

Abstract

Background: Vascular endothelial function is closely related to brain health, especially in individuals with cardiovascular risk factors. In a randomized, crossover clinical trial (NCT04121741), we have previously shown that 30 min of singing improves microvascular endothelial function in older adults with coronary artery [...] Read more.

Background: Vascular endothelial function is closely related to brain health, especially in individuals with cardiovascular risk factors. In a randomized, crossover clinical trial (NCT04121741), we have previously shown that 30 min of singing improves microvascular endothelial function in older adults with coronary artery disease. Here, we report on secondary and exploratory analyses, including (1) changes in cortisol and cytokine levels and their impact on vascular endothelial function, and (2) the impact of personal music experience on vascular function. Methods: Participants had three study visits separated by 2–7 days, according to a randomized, researcher-blinded, crossover, controlled design: (1) a 30-min period of live singing with an in-person music therapist, (2) a 30-min period of singing along to an instructional video and (3) a 30-min rest (control). Primary outcomes included macrovascular endothelial function assessed by brachial artery flow-mediated dilation (BA FMD%) and microvascular function assessed by peripheral arterial tonometry [Framingham reactive hyperemia index (fRHI) and reactive hyperemia index (RHI)]. Exploratory outcomes included (log) changes in salivary cortisol and cytokine (IL-6, TNF-α, IL-1β, IL-8) levels. Participants were asked to complete the Brief Music Experience Questionnaire (BMEQ), a 53-item validated self-report questionnaire designed to measure an individual’s overall experience with music. The BMEQ assesses how people perceive, react to, and engage with music in various aspects of their lives. Results: Sixty-five subjects (mean age 67.7 ± 6.6 years, 40% female) completed the study. Compared to those subjects completing the BMEQ (n = 31), there were no significant differences in age, sex, race, or presence of diabetes mellitus, hypertension, high cholesterol, heart failure, chronic kidney disease, or chronic respiratory disease in subjects who did not complete the BMEQ (n = 34). Total BMEQ score did not impact changes in BA FMD% (−3.49 ± 2.00, p = 0.086), changes in fRHI (0.58 ± 0.93, p = 0.535), or changes in RHI (0.73 ± 0.65, p = 0.262). When we decompose the sum of squares based on intervention, sex, race, and age, the BMEQ score does not predict changes in vascular function measures. In cross-over analyses, there were no acute changes in salivary cortisol or cytokine levels with 30 min of singing compared to control. Changes in IL-8 were directly related to changes in microvascular endothelial function (0.470 ± 0.184, p = 0.012 for RHI and 0.780 ± 0.248, p = 0.002 for fRHI). Changes in TNF-α were inversely related to changes in fRHI (−0.547 ± 0.263, p = 0.040). Changes in cortisol concentrations were not related to measures of vascular function. Conclusions: The beneficial changes in microvascular endothelial function are not modified by personal music experience in older subjects with known coronary artery disease. There were no changes in salivary cortisol or cytokine levels after 30 min of singing compared to control. Full article

(This article belongs to the Special Issue Rethinking the Role of Applied Auditory and Music Neuroscience to Neurorehabilitation)

20 pages, 1125 KB

Open AccessReview

Beyond Hot Flashes: The Role of Estrogen Receptors in Menopausal Mental Health and Cognitive Decline

by Jung Min Cho, Jihye Lee, Eun-Mi Ahn and Jaehoon Bae

Brain Sci. 2025, 15(9), 1003; https://doi.org/10.3390/brainsci15091003 - 16 Sep 2025

Viewed by 2195

Abstract

Menopause is a natural phase in a woman’s life marked by the cessation of menstruation, typically accompanied by hormonal fluctuations that have significant impacts on physical and mental health. While much attention has been given to the physical symptoms of menopause, such as [...] Read more.

Menopause is a natural phase in a woman’s life marked by the cessation of menstruation, typically accompanied by hormonal fluctuations that have significant impacts on physical and mental health. While much attention has been given to the physical symptoms of menopause, such as hot flashes and osteoporosis, the neurocognitive consequences of hormonal fluctuations during the menopausal transition and the subsequent sustained estrogen loss after menopause have received less focus. Estrogen receptors (ERs), specifically ERα and ERβ, play a critical role in maintaining brain health, influencing mood, memory, and cognition. This review explores the connection between estrogen receptor signaling and mental health during menopause, focusing on mood disorders such as depression and anxiety, as well as cognitive decline and dementia. We discuss the molecular mechanisms by which ERs modulate brain function, including their effects on neuroplasticity, neurotransmitter systems, and gene expression. The review also examines current clinical approaches to managing menopausal cognitive and mental health issues, including hormone replacement therapy and selective ER modulators, while emphasizing the need for further research into alternative therapies and individualized treatments. The importance of estrogen receptors in the menopausal brain and their potential as therapeutic targets is critically evaluated, aiming to shed light on this often-overlooked aspect of menopause and aging. Full article

(This article belongs to the Section Neuropsychology)

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12 pages, 1361 KB

Open AccessArticle

Age and Self-Expansion Behaviors Correlate with Spatial Navigation in Healthy Adults

by Melissa Ansara, MaKayla Duggan, Alana Schafer, Karina Villalobos, Alexis N. Chargo, Ana M. Daugherty, Taylor N. Takla and Nora E. Fritz

Brain Sci. 2025, 15(9), 1002; https://doi.org/10.3390/brainsci15091002 - 16 Sep 2025

Viewed by 466

Abstract

Background: Spatial navigation is one’s ability to travel through their environment to reach a goal location. Self-expansion is the motivation to increase one’s self-perception through engaging in novel activities. Our objective was to examine the relations among self-expansion, age, and navigation ability and [...] Read more.

Background: Spatial navigation is one’s ability to travel through their environment to reach a goal location. Self-expansion is the motivation to increase one’s self-perception through engaging in novel activities. Our objective was to examine the relations among self-expansion, age, and navigation ability and investigate how one’s internal motivation may influence navigation performance across paradigms. Methods: In total, 33 younger adults (YAs; 19F, 14M, mean age = 25.0 ± 1.6) and 74 older adults (OAs; 52F, 22M, mean age = 69.5 ± 8.0) completed the following: Self-Expansion Preference Scale (SEPS), Wayfinding Questionnaire (WQ), Virtual Supermarket Task, Virtual Morris Water Maze (vMWM), and a Floor Maze Task (FMT). Mann–Whitney U tests and Spearman ρ correlations were used to examine differences in navigation performance between YAs vs. OAs and self-expanders vs. self-conservers, and relations among the measures, respectively. Results: YAs had lower vMWM completion times compared to OAs (p < 0.001). Self-expanders had better recall of the vMWM environment compared to self-conservers (p = 0.049), independent of age. Greater self-expansion in YAs was correlated with lower spatial anxiety (ρ = −0.356, p = 0.042) and faster completion of the FMT (ρ = −0.36, p = 0.042). Discussion: Our results build on established age-related deficits in navigation abilities to identify correlations of self-expansion and better performance in various navigation tasks. Independent of age, individuals with greater inclination towards self-expansion exhibit superior navigation abilities. Future research should explore underlying mechanisms driving these associations and investigate intervention strategies aimed at improving navigation skills in aging populations through increasing self-expansion. Full article

(This article belongs to the Special Issue Neuropsychological Exploration of Spatial Cognition and Navigation)

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20 pages, 3208 KB

Open AccessArticle

Analysis of Neurophysiological Correlates of Mental Fatigue in Both Monotonous and Demanding Driving Conditions

by Francesca Dello Iacono, Luca Guinti, Marianna Cecchetti, Andrea Giorgi, Dario Rossi, Vincenzo Ronca, Alessia Vozzi, Rossella Capotorto, Fabio Babiloni, Pietro Aricò, Gianluca Borghini, Marteyn Van Gasteren, Javier Melus, Manuel Picardi and Gianluca Di Flumeri

Brain Sci. 2025, 15(9), 1001; https://doi.org/10.3390/brainsci15091001 - 16 Sep 2025

Viewed by 608

Abstract

Background/Objectives: Mental fatigue during driving, whether passive (arising from monotony) or active (caused by cognitive overload), is a critical factor for road safety. Despite the growing interest in monitoring techniques based on neurophysiological signals, current biomarkers are primarily validated only for detecting [...] Read more.

Background/Objectives: Mental fatigue during driving, whether passive (arising from monotony) or active (caused by cognitive overload), is a critical factor for road safety. Despite the growing interest in monitoring techniques based on neurophysiological signals, current biomarkers are primarily validated only for detecting passive mental fatigue under monotonous conditions. The objective of this study is to evaluate the sensitivity of the MDrow index, which is based on EEG Alpha band activity, previously validated for detecting passive mental fatigue, with respect to active mental fatigue, i.e., the mental fatigue occurring in cognitively demanding driving scenarios. Methods: A simulated experimental protocol was developed featuring three driving scenarios with increasing complexity: monotonous, urban, and urban with dual tasks. Nineteen participants took part in the experiment, during which electroencephalogram (EEG), photoplethysmogram (PPG), and electrodermal activity (EDA) data were collected in addition to subjective assessments, namely the Karolinska Sleepiness Scale (KSS) and the Driving Activity Load Index (DALI) questionnaires. Results:The findings indicate that MDrow shows sensitivity to both passive and active mental fatigue (p < 0.001), thereby demonstrating stability even in the presence of additional cognitive demands. Furthermore, Heart Rate (HR) and Heart Rate Variability (HRV) increased significantly during the execution of more complex tasks, thereby suggesting a heightened response to mental workload in comparison to mental fatigue alone. Conversely, electrodermal measures evidenced no sensitivity to mental fatigue-related changes. Conclusions: These findings confirm the MDrow index’s validity as an objective and continuous marker of mental fatigue, even under cognitively demanding conditions. Full article

(This article belongs to the Section Cognitive, Social and Affective Neuroscience)

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19 pages, 1603 KB

Open AccessArticle

Cross-Linguistic Influences on L2 Prosody Perception: Evidence from English Interrogative Focus Perception by Mandarin Listeners

by Xing Liu, Xiaoxiang Chen, Chen Kuang and Fei Chen

Brain Sci. 2025, 15(9), 1000; https://doi.org/10.3390/brainsci15091000 - 16 Sep 2025

Viewed by 599

Abstract

Background/Objectives: This study sets out to explore how L1 Mandarin speakers with varying lengths of L2 experience perceived English focus interrogative tune, L*H-H%, within the framework of the autosegmental–metrical model. Methods: Eighteen Mandarin speakers with varying lengths of residence in the United States [...] Read more.

Background/Objectives: This study sets out to explore how L1 Mandarin speakers with varying lengths of L2 experience perceived English focus interrogative tune, L*H-H%, within the framework of the autosegmental–metrical model. Methods: Eighteen Mandarin speakers with varying lengths of residence in the United States and eighteen English native speakers were invited to perceive prosodic prominence and judge the naturalness of focus prosody tunes. Results: For the perception of on-focus pitch accent L*, Mandarin speakers performed well in the prominence detection task but not in the focus identification task. For post-focus edge tones, we found that phrase accents were more susceptible to L1 influences than boundary tones due to the varying degrees of cross-linguistic similarity between these intonational categories. The results also show that even listeners with extended L2 experience were not proficient in their perception of L2 interrogative focus tunes. Conclusions: This study reveals the advantage of considering the degree of L1-L2 similarity and the necessity to examine cross-linguistic influences on L2 perception of prosody separately in phonological and phonetic dimensions. Full article

(This article belongs to the Special Issue Language Perception and Processing)

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20 pages, 1600 KB

Open AccessReview

Acute Vertigo, Dizziness and Imbalance in the Emergency Department—Beyond Stroke and Acute Unilateral Vestibulopathy—A Narrative Review

by Sun-Uk Lee, Jonathan A. Edlow and Alexander A. Tarnutzer

Brain Sci. 2025, 15(9), 995; https://doi.org/10.3390/brainsci15090995 - 15 Sep 2025

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Abstract

New-onset vertigo, dizziness and gait imbalance are amongst the most common symptoms presenting to the emergency department, accounting for 2.1–4.4% of all patients. The broad spectrum of underlying causes in these patients cuts across many specialties, which often results in diagnostic challenges. For [...] Read more.

New-onset vertigo, dizziness and gait imbalance are amongst the most common symptoms presenting to the emergency department, accounting for 2.1–4.4% of all patients. The broad spectrum of underlying causes in these patients cuts across many specialties, which often results in diagnostic challenges. For patients meeting the diagnostic criteria for acute vestibular syndrome (AVS, i.e., presenting with acute-onset prolonged vertigo/dizziness with accompanying gait imbalance, motion intolerance, nausea/vomiting, with or without nystagmus), the typical differential diagnosis is vertebrobasilar stroke and acute unilateral vestibulopathy. However, other disorders may also present with AVS. These include non-neurological causes such as drug side-effects or intoxication, electrolyte disturbances, cardiac disease, severe anemia, carbon monoxide poisoning, endocrine disorders and others. Other non-stroke neurological disorders may also present with AVS or episodic vertigo/dizziness, including demyelinating CNS diseases, posterior fossa mass lesions, acute thiamine deficiency and vestibular migraine. Furthermore, acute physiological abnormalities (e.g., hypotension, fever, severe anemia) may unmask previous vestibular impairments that had been well-compensated. Here, we review the diagnostic approach to patients with acute-onset dizziness in the emergency room and discuss the most important differential diagnoses beyond stroke and acute unilateral vestibulopathy. Full article

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

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Brain Sci., Volume 15, Issue 9 (September 2025) – 128 articles

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