Brain Sciences

17 pages, 1173 KB

Open AccessArticle

Sleep State Misperception in Insomnia: The Role of Sleep Instability and Emotional Dysregulation

by Elettra Cini, Francesca Bolengo, Elisabetta Fasiello, Francesca Berra, Maurizio Gorgoni, Marco Sforza, Francesca Casoni, Paola Proserpio, Vincenza Castronovo, Luigi De Gennaro, Luigi Ferini-Strambi and Andrea Galbiati

Brain Sci. 2025, 15(10), 1078; https://doi.org/10.3390/brainsci15101078 (registering DOI) - 4 Oct 2025

Abstract

Background/Objectives: Sleep state misperception (SSM) is a common phenomenon in insomnia disorder (ID), characterized by a discrepancy between subjective and objective sleep metrics. Recent studies have revealed microstructural EEG alterations specifically in misperceiving ID patients, yet clinically accessible SSM markers remain limited. This [...] Read more.

Background/Objectives: Sleep state misperception (SSM) is a common phenomenon in insomnia disorder (ID), characterized by a discrepancy between subjective and objective sleep metrics. Recent studies have revealed microstructural EEG alterations specifically in misperceiving ID patients, yet clinically accessible SSM markers remain limited. This study aimed to characterize SSM within ID by integrating standard polysomnography (PSG) features and cognitive-affective traits, focusing on accessible clinical tools. Methods: Twenty patients with ID and twenty healthy controls (HC) underwent a night of PSG recording and completed both sleep diaries and a comprehensive psychological assessment. SSM was quantified using the Total Sleep Time misperception index (TSTm), analyzed both dimensionally and categorically Results: IDs reported significantly altered sleep parameters compared to HCs, both subjectively and objectively. Within the ID sample, although underestimators and normoestimators had similar objective TST, underestimators showed significantly more cortical arousal density (CAd), a higher percentage of sleep stage 1 and higher non-acceptance of emotions. Notably, none of the HC reached the threshold for being classified as underestimators. Regression analyses identified CAd, latency to sleep stage 3 and to REM, percentage of REM sleep and lack of emotional clarity, as key predictors of TSTm. Conclusions: SSM in insomnia reflects a dimensional vulnerability grounded in subtle sleep fragmentation and emotional dysregulation. Recognizing SSM as a clinically meaningful phenomenon may guide more targeted, emotion-focused, interventions for insomnia. Full article

(This article belongs to the Special Issue Behavioural, Emotional and Cognitive Processes Linked to Healthy Sleep and Insomnia)

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13 pages, 3253 KB

Open AccessCase Report

Delayed Intracerebral Hemorrhage 15 Years After Indirect Revascularization in Moyamoya Disease: A Case Report and Review of the Literature

by Merih C. Yilmaz and Keramettin Aydin

Brain Sci. 2025, 15(10), 1077; https://doi.org/10.3390/brainsci15101077 (registering DOI) - 4 Oct 2025

Abstract

Background and Clinical Significance: Moyamoya disease (MMD) is a progressive intracranial vasculopathy characterized by stenosis or occlusion of the terminal internal carotid arteries and the development of fragile collateral networks. It predisposes patients to ischemic and hemorrhagic strokes. Although both direct and [...] Read more.

Background and Clinical Significance: Moyamoya disease (MMD) is a progressive intracranial vasculopathy characterized by stenosis or occlusion of the terminal internal carotid arteries and the development of fragile collateral networks. It predisposes patients to ischemic and hemorrhagic strokes. Although both direct and indirect revascularization procedures are recommended to restore cerebral blood flow, recurrent cerebrovascular events may still occur, and delayed hemorrhage following revascularization is particularly uncommon. Case Description: We report the case of a 42-year-old woman who presented with seizure, syncope, and aphasia. Cranial computed tomography (CT) revealed a large left temporal–insular intraparenchymal hematoma with a midline shift. Computed tomography angiography (CTA) demonstrated bilateral internal carotid artery narrowing and collateral vessel proliferation, without aneurysm. Her history indicated a hemorrhagic stroke 15 years earlier, at which time MMD was diagnosed by magnetic resonance angiography (MRA) and managed with multiple burr hole surgeries. She remained free of cerebrovascular events until the current presentation. The patient underwent emergent hematoma evacuation, followed by intensive care management. Postoperatively, she demonstrated neurological improvement, though with residual motor aphasia and right-sided weakness, and was discharged for rehabilitation. Conclusions: This case underscores the rare occurrence of delayed intracerebral hemorrhage 15 years after indirect revascularization in MMD. Although revascularization surgery remains the standard therapeutic approach, this report highlights the importance of sustained long-term surveillance, strict risk factor management, and careful postoperative follow-up. The key point is that late hemorrhagic complications, though uncommon, must be considered in the long-term care of MMD patients following revascularization. Full article

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

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19 pages, 2450 KB

Open AccessReview

Acupuncture Modulation of the Lung–Brain Axis in Alzheimer’s Disease: Mechanisms and Therapeutic Perspectives

by Jiaxing Zou, Ruiwei Liao, Wen Zhang and Zaoyuan Kuang

Brain Sci. 2025, 15(10), 1076; https://doi.org/10.3390/brainsci15101076 - 3 Oct 2025

Abstract

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline and an impaired quality of life, for which no curative treatment is currently available. Recent research indicates that chronic pulmonary conditions—including chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea [...] Read more.

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline and an impaired quality of life, for which no curative treatment is currently available. Recent research indicates that chronic pulmonary conditions—including chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA)—exhibit significant epidemiological associations with AD pathogenesis, suggesting that the lung–brain axis may contribute to AD development. Acupuncture, a core TCM intervention, shows promise for modulating multisystem functions and enhancing cognitive performance. This review synthesizes the current evidence regarding pulmonary diseases influencing AD through the lung–brain axis, elucidates potential mechanisms by which acupuncture may modulate pulmonary function and mitigate AD pathology, and explores future directions for lung–brain axis-targeted acupuncture interventions. Our overarching aim is to propose integrative, evidence-based strategies that combine Chinese and Western medicine for the prevention and management of AD. Full article

(This article belongs to the Section Neurodegenerative Diseases)

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14 pages, 1400 KB

Open AccessArticle

Role of Glyoxalase in Astrocytes’ Supportive Function Under Hyperglycemic Conditions: Aminoguanidine and Kir4.1 Channel Recovery

by Jadier Colón-Vázquez, Nathaly M. Rosado-Rivera, Joshua J. Navedo-Jackson, Arelys A. Angueira-Laureano, Yanitza Hernandez-Santiago, Geronimo Maldonado-Martinez, Miguel P. Méndez-González, Misty J. Eaton, Serguei N. Skatchkov and David E. Rivera-Aponte

Brain Sci. 2025, 15(10), 1075; https://doi.org/10.3390/brainsci15101075 - 3 Oct 2025

Abstract

Background/Objectives: Diabetes mellitus is a metabolic disorder, and hyperglycemia results in abnormal brain function. Since glycolysis is the main energy pathway in glial cells, astrocytes possess a more developed glyoxalase (Glo) system than neurons and exhibit better survival. Glycolysis helps to protect glia [...] Read more.

Background/Objectives: Diabetes mellitus is a metabolic disorder, and hyperglycemia results in abnormal brain function. Since glycolysis is the main energy pathway in glial cells, astrocytes possess a more developed glyoxalase (Glo) system than neurons and exhibit better survival. Glycolysis helps to protect glia from (i) dicarbonyl stress and (ii) formation of advanced glycation end products (AGEs). Since aminoguanidine (AG) is an inhibitor of AGE production, the purpose of this study was to determine the role of AG in crucial astrocytic proteins, such as Kir4.1, Glo1, and Glo2, in hyperglycemic conditions. Methods: We cultured astrocytes in normal (5 mM)- and high (25 mM)-glucose conditions. After two weeks, we seeded the cells in six-well plates, with 300,000 cells/well, and then treated them with 9 mM of AG for 24 h. Results: Expression of the glyoxalases Glo1 and Glo2, and of Kir4.1, is decreased in hyperglycemic conditions; however, treatment with AG recovers the expression of the Kir4.1 protein as well as the inward currents of hyperglycemic astrocytes. Conclusion: We demonstrated that regulation of the glyoxalase system via AG or another scavenger of carbonyl and aldehydes containing polyamine groups can contribute to the recovery of astrocyte function in diabetic patients. Full article

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

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13 pages, 1029 KB

Open AccessArticle

Topography of Cortical Activation with Mirror Visual Feedback and Electromyography-Triggered Electrical Stimulation: A Functional Near-Infrared Spectroscopy Study in Healthy Older Adults

by Yuji Inagaki, Miku Nakatsuka, Yumene Naito and Daisuke Sawamura

Brain Sci. 2025, 15(10), 1074; https://doi.org/10.3390/brainsci15101074 - 2 Oct 2025

Abstract

Background/Objectives: Stroke often results in lasting upper limb deficits. Mirror visual feedback (MVF) supports motor recovery, and electromyography-triggered electrical stimulation (ES) could enhance engagement. However, the effects in healthy older adults, age-matched to typical patient cohorts, remain insufficiently understood. We tested MVF and [...] Read more.

Background/Objectives: Stroke often results in lasting upper limb deficits. Mirror visual feedback (MVF) supports motor recovery, and electromyography-triggered electrical stimulation (ES) could enhance engagement. However, the effects in healthy older adults, age-matched to typical patient cohorts, remain insufficiently understood. We tested MVF and MVF + ES using functional near-infrared spectroscopy. Methods: Seventeen right-handed older adults performed left-wrist flexion under three visual conditions: circle fixation, viewing the right hand at rest, and mirror viewing, with/without electrical stimulation to the right-wrist flexors time-locked to left-forearm electromyography. Oxygenated hemoglobin (oxy-Hb) was recorded over the bilateral inferior frontal gyrus (IFG), precentral gyrus (PrG), postcentral gyrus (PoG), supramarginal gyrus (SMG), superior parietal lobule (SPL), and supplementary motor area. Effects were assessed with linear mixed-effects models (stimulation × visual condition); pairwise comparisons of estimated marginal means used Fisher’s least significant difference. Left-forearm electromyography verified comparable effort across conditions. Results: Linear mixed-effects models revealed left-lateralized increases in oxy-Hb, most prominently under mirror viewing with stimulation. Post hoc tests showed high oxy-Hb in the left IFG, PrG, PoG, SMG, and SMA. The left EMG did not differ. Conclusions: In healthy older adults, MVF paired with EMG-triggered ES enhances frontoparietal–motor engagement beyond MVF alone, with recruitment shaped by visuo–proprioceptive congruence. These findings support mechanistic plausibility and motivate dose–response optimization and patient-focused trials testing behavioral transfer in stroke. Full article

(This article belongs to the Section Neurorehabilitation)

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26 pages, 6503 KB

Open AccessArticle

Acai Berry Extracts Can Mitigate the L-Glutamate-Induced Neurotoxicity Mediated by N-Methyl-D-Aspartate Receptors

by Maryam N. ALNasser, Nirmal Malik, Abrar Ahmed, Amy Newman, Ian R. Mellor and Wayne G. Carter

Brain Sci. 2025, 15(10), 1073; https://doi.org/10.3390/brainsci15101073 - 1 Oct 2025

Abstract

Background/Objectives: Stroke is the second leading cause of death worldwide. There is an unmet need to manage stroke pathophysiology, including L-glutamate (L-Glu)-mediated neurotoxicity. The acai berry (Euterpe sp.) contains phytochemicals with potentially nutraceutical content. The aim of this study was to assess [...] Read more.

Background/Objectives: Stroke is the second leading cause of death worldwide. There is an unmet need to manage stroke pathophysiology, including L-glutamate (L-Glu)-mediated neurotoxicity. The acai berry (Euterpe sp.) contains phytochemicals with potentially nutraceutical content. The aim of this study was to assess the ability of acai berry extracts to counter L-Glu neurotoxicity using human differentiated TE671 cells. Methods: The cytotoxicity of L-Glu and acai berry extracts was quantified using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Mitochondrial function was examined by a quantitation of cellular ATP levels, the maintenance of the mitochondrial membrane potential (MMP), and the production of reactive oxygen species (ROS). Whole-cell patch-clamp recordings monitored the activation of N-methyl-D-aspartate receptors (NMDARs). Candidate phytochemicals from acai berry extracts were modeled in silico for NMDAR binding. Results: L-Glu significantly reduced cell viability, ATP levels, the MMP, and increased cellular ROS. Generally, acai berry extracts alone were not cytotoxic, although high concentrations were detrimental to ATP production, maintenance of the MMP, and elevated ROS levels. Whole-cell patch-clamp recordings revealed that the combined addition of 300 µM L-Glu and 10 µM glycine activated currents in differentiated TE671 cells, consistent with triggering NMDAR activity. Acai berry extracts ameliorated the L-Glu-induced cytotoxicity, mitochondrial dysfunction, elevated ROS levels, and limited the NMDAR-mediated excitotoxicity (p < 0.001–0.0001). Several virtual ligands from acai berry extracts exhibited high-affinity NMDAR binding (arginine, 2,5-dihydroxybenzoic acid, threonine, protocatechuic acid, and histidine) as possible candidate receptor antagonists. Conclusions: Acai berry phytochemicals could be exploited to reduce the L-Glu-induced neurotoxicity often observed in stroke and other neurodegenerative diseases. Full article

(This article belongs to the Section Neuropharmacology and Neuropathology)

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19 pages, 1111 KB

Open AccessArticle

Exploring Face Perception Efficiency in Patients with Lacunar Stroke: A Study with Familiar and Unfamiliar Face Recognition

by Chi-Yu Lin, Mary Wen-Reng Ho and Sarina Hui-Lin Chien

Brain Sci. 2025, 15(10), 1072; https://doi.org/10.3390/brainsci15101072 - 30 Sep 2025

Abstract

Background/Objectives: Stroke is a major cause of disability worldwide, with ischemic stroke being the most common type. This study investigated face perception in patients with lacunar strokes, specifically examining the ability to distinguish and recognize familiar and unfamiliar faces. Methods: We [...] Read more.

Background/Objectives: Stroke is a major cause of disability worldwide, with ischemic stroke being the most common type. This study investigated face perception in patients with lacunar strokes, specifically examining the ability to distinguish and recognize familiar and unfamiliar faces. Methods: We tested 52 patients with lacunar stroke (mean age = 65.97 ± 9.96) and 28 age-matched healthy controls (HC) (mean age = 66.24 ± 10.15). The participants received three face perception tasks: Name that Celebrity, Identity Sorting Task, and Face & Object Solitaire, and were also given the MMSE and mRS clinical assessments. Results: For the Name that Celebrity task, the stroke group had a lower efficiency score than the control group (i.e., they needed 2–3 extra slides of cues to recognize famous persons). For the Face Identity Sorting task, both groups were more accurate when sorting familiar faces; however, the stroke group performed significantly worse than the healthy group when sorting unfamiliar faces. For the Face/Object Solitaire task, the control group performed better than the stroke group on the face solitaire, but there were no differences in the object solitaire condition. Conclusions: Our findings suggest that despite having a normal mean MMSE score (HC: 28.22, Stroke: 27.96), patients with lacunar stroke had difficulties recognizing famous faces and discriminating among unfamiliar faces. This may reveal an overlooked deficit in face perception, highlighting the importance of future interventions that specifically focus on face recognition skills to enhance patients’ daily social interactions and the overall effectiveness of post-stroke rehabilitation programs. Full article

(This article belongs to the Special Issue Advances in Face Perception and How Disorders Affect Face Perception)

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22 pages, 1783 KB

Open AccessReview

Effects of Virtual Reality on Motor Function and Balance in Incomplete Spinal Cord Injury: A Systematic Review and Meta-Analysis of Controlled Trials

by Yamil Liscano, Florencio Arias Coronel and Darly Martínez

Brain Sci. 2025, 15(10), 1071; https://doi.org/10.3390/brainsci15101071 - 30 Sep 2025

Abstract

Background/Objectives: Incomplete spinal cord injury (iSCI) represents a significant challenge in neurorehabilitation, with conventional limitations including recovery plateaus and declining patient motivation. Virtual reality (VR) and augmented reality (AR) have emerged as promising technologies to supplement traditional therapy through gamification and multisensory [...] Read more.

Background/Objectives: Incomplete spinal cord injury (iSCI) represents a significant challenge in neurorehabilitation, with conventional limitations including recovery plateaus and declining patient motivation. Virtual reality (VR) and augmented reality (AR) have emerged as promising technologies to supplement traditional therapy through gamification and multisensory feedback. This systematic review and meta-analysis evaluates the effectiveness of VR and AR interventions for improving balance and locomotor function in patients with incomplete spinal cord injury. Methods: A systematic review was conducted following PRISMA guidelines, with searches in PubMed, Scopus, Web of Science, Science Direct, and Google Scholar. Randomized controlled trials and high-quality controlled studies evaluating VR/AR interventions in patients with iSCI (American Spinal Injury Association Impairment Scale [AIS] classifications B, C, or D) for a minimum of 3 weeks were included. A random-effects meta-analysis (Standardized Mean Difference, SMD; 95% Confidence Interval, CI) was conducted for the balance outcome. Results: Eight studies were included (n = 142 participants). The meta-analysis for balance (k = 5 studies) revealed a statistically significant improvement with a large effect size (SMD = 1.21, 95% CI: 0.04–2.38, p = 0.046). For locomotor function, a quantitative meta-analysis was not feasible due to a limited number of methodologically homogeneous studies; a qualitative synthesis of this evidence remained inconclusive. Substantial heterogeneity was observed in the balance analysis (I² = 81.5%). No serious adverse events related to VR/AR interventions were reported. Conclusions: VR/AR interventions show potential as an effective adjunctive therapy for improving balance in patients with iSCI, though the benefit should be interpreted with caution due to considerable variability between studies. The current evidence for locomotor function improvements is insufficient to draw conclusions, highlighting a critical need for more focused research. Substantial heterogeneity indicates that effectiveness may vary according to specific intervention characteristics, populations, and methodologies. Larger multicenter studies with standardized protocols are required to establish evidence-based clinical guidelines. Full article

(This article belongs to the Topic Applications of Virtual Reality Technology in Rehabilitation)

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26 pages, 811 KB

Open AccessReview

Audio-Visual Entrainment Neuromodulation: A Review of Technical and Functional Aspects

by Masoud Rahmani, Leonor Josefina Romero Lauro and Alberto Pisoni

Brain Sci. 2025, 15(10), 1070; https://doi.org/10.3390/brainsci15101070 - 30 Sep 2025

Abstract

Audiovisual Entrainment (AVE) is a non-invasive, non-pharmacological neuromodulation approach that aims to align brain activity with externally delivered auditory and visual rhythms. This review surveys AVE’s historical development, technical parameters (e.g., frequency, phase, waveform, color, intensity, presentation mode), components and delivery methods, reported [...] Read more.

Audiovisual Entrainment (AVE) is a non-invasive, non-pharmacological neuromodulation approach that aims to align brain activity with externally delivered auditory and visual rhythms. This review surveys AVE’s historical development, technical parameters (e.g., frequency, phase, waveform, color, intensity, presentation mode), components and delivery methods, reported clinical applications, and safety considerations. Given the heterogeneity of AVE protocols and terminology, we conducted a structured narrative review (PubMed, Scopus, Google Scholar; earliest records to July 2025), including human and animal studies that met an operational definition of regulated AVE and consistent administration of specified auditory and visual frequencies, with critical methodological details reported. We highlight AVE’s accessibility and versatility, outline a stepwise parameter reporting framework to support standardization, and discuss putative mechanisms via sensory and oscillatory pathways. However, current findings are heterogeneous and include null or limited effects. Mechanistic understanding and parameter optimization remain insufficiently developed, and premature claims of efficacy are not warranted. Rigorous, standardized, and adequately controlled studies are needed before AVE can be considered a reliable therapeutic tool. Full article

(This article belongs to the Section Neuropsychology)

10 pages, 469 KB

Open AccessArticle

Neurological Emergencies in Incarcerated Patients: Clinical Characteristics, Severity, and Outcomes in an Emergency Department with an Embedded Neuro-Emergency Expert Model

by Byung Joon Choi, Jin Hyouk Kim, Won Soek Yang, Young Sun Park and Sang Ook Ha

Brain Sci. 2025, 15(10), 1069; https://doi.org/10.3390/brainsci15101069 - 30 Sep 2025

Abstract

Background: Incarcerated patients with neurological complaints present substantial diagnostic and care-delivery challenges in emergency departments (EDs). We delineate the clinical spectrum, severity, and outcomes among incarcerated patients managed in an ED with an embedded neuro-emergency expert model. Methods: A retrospective observational [...] Read more.

Background: Incarcerated patients with neurological complaints present substantial diagnostic and care-delivery challenges in emergency departments (EDs). We delineate the clinical spectrum, severity, and outcomes among incarcerated patients managed in an ED with an embedded neuro-emergency expert model. Methods: A retrospective observational study of adult ED visits for neurological symptoms was conducted from September 2018 to June 2025 at a government-designated regional emergency center serving multiple correctional facilities. Incarceration was confirmed in the electronic medical record. Extracted variables included demographics, chief complaint, comorbidities, triage and acuity scale, Glasgow Coma Scale (GCS), neuroimaging, ED diagnoses, and outcomes (hospital admission, ICU care, ED/in-hospital mortality). Results: Sixty-five patients were included (median age 57.0 years [IQR 47.0–64.5]; 95% male). Chief complaints were altered mental status (36.9%), hemiparesis (21.5%), and seizures (13.8%). On arrival, 40.0% had GCS ≤ 12, including 23.1% with severe impairment (GCS 3–8). Non-contrast head CT was obtained in 95.4% and diffusion-weighted MRI in 38.5%. Frequent diagnoses were psychiatric/functional neurological disorder (16.9%), metabolic encephalopathy (15.4%), and acute ischemic stroke (12.3%). Serious conditions (stroke, hypoxic brain injury, central nervous system infection, status epilepticus, and neuroleptic malignant syndrome) were diagnosed in 41.5%. Hospital admission occurred in 63.1% (ICU care in 47.7%); in-hospital mortality was 10.8%. Conclusions: ED visits by incarcerated individuals with neurological complaints were often linked to serious diagnoses, ICU use, and mortality, challenging assumptions of exaggeration. Over two in five had stroke, hypoxic brain injury, central nervous system infection, or status epilepticus. The findings support rapid, systematic, bias-aware evaluation with early neurological involvement, clear imaging triggers, safety protocol, and expedited transfers from correctional facilities. Full article

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16 pages, 4297 KB

Open AccessCommunication

Clomipramine Induced Oxidative Stress and Morphological Alterations in the Prefrontal Cortex and Limbic System of Neonatal Rats

by Norma Angélica Labra-Ruíz, Julieta Griselda Mendoza-Torreblanca, Norma Osnaya-Brizuela, Armando Valenzuela-Peraza, Maribel Ortiz-Herrera, Gerardo Barragán-Mejía, Noemí Cárdenas-Rodríguez and Daniel Santamaría-Del Ángel

Brain Sci. 2025, 15(10), 1068; https://doi.org/10.3390/brainsci15101068 - 30 Sep 2025

Abstract

Although clomipramine (CLO) is widely used as a serotonin reuptake inhibitor, its subchronic administration during the early stages of brain development leads to depressive-like behaviors in adulthood. High doses of CLO have been linked to mitochondrial impairment and increased reactive oxygen species in [...] Read more.

Although clomipramine (CLO) is widely used as a serotonin reuptake inhibitor, its subchronic administration during the early stages of brain development leads to depressive-like behaviors in adulthood. High doses of CLO have been linked to mitochondrial impairment and increased reactive oxygen species in cells and adult animals. It is unknown whether subchronic administration of this drug at early ages can induce oxidative stress (OS) in adulthood. The objective of this study was to evaluate OS and cellular damage in the prefrontal cortex and limbic system (hippocampus and amygdala) of rats exposed to CLO neonatally. Methods: Forty male Wistar rats were divided into experimental (EXP) and control (CTRL) groups. The EXP animals received CLO (15 mg/kg, twice daily, subcutaneously, postnatal days 5–35); the CTRL animals received saline. At 55 and 85 days of age, the brains were collected for biochemical assays and histological analysis. Results: Rats exposed to neonatal CLO presented significant reductions in reduced glutathione (GSH) and increases in oxidized glutathione (GSSG) and malondialdehyde in both studied regions, especially on day 85. The GSH/GSSG ratio decreased, indicating persistent OS. Histology revealed neuronal degeneration, pyknotic nuclei, cell shrinkage, and disorganized tissue, which progressed from days 55 to 85. Conclusions: Early exposure to CLO can cause long-lasting neurochemical and structural alterations in the brain regions associated with the regulation of emotions and some behavioral responses that can persist over time and affect behavior in adulthood. Full article

(This article belongs to the Special Issue Toxic Mechanisms and Emerging Therapeutic Strategies in Brain Disorders)

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22 pages, 5077 KB

Open AccessArticle

Restoration of Enzymatic Activity of Energy-Related Proteins in Rats with Traumatic Brain Injury Following Administration of Gamma-Glutamylcysteine Ethyl Ester

by Brittany Rice, Jonathan Overbay, Andrea Sebastian, Patrick G. Sullivan and Tanea T. Reed

Brain Sci. 2025, 15(10), 1067; https://doi.org/10.3390/brainsci15101067 - 30 Sep 2025

Abstract

Background/Objectives: Biochemical processes such as the glycolytic pathway and Kreb’s cycle are important in producing ATP for the brain. Without a sufficient supply of glucose for energy metabolism, the brain cannot efficiently regulate or coordinate the actions and reactions of the body. It [...] Read more.

Background/Objectives: Biochemical processes such as the glycolytic pathway and Kreb’s cycle are important in producing ATP for the brain. Without a sufficient supply of glucose for energy metabolism, the brain cannot efficiently regulate or coordinate the actions and reactions of the body. It is well documented that traumatic brain injury (TBI) is associated with reduced energy metabolism through the production of reactive oxygen/nitrogen species. Antioxidants, such as glutathione (GSH), have been shown to combat the deleterious effects of oxidation by scavenging ROS/RNS, inhibiting propagation, and removing neurotoxic byproducts. Gamma-glutamylcysteine ethyl ester (GCEE), an ethyl ester moiety of gamma-glutamylcysteine, exhibits antioxidant activity by increasing GSH production. This therapeutic has protective effects against oxidative stress through the elevation of glutathione. Methods: This study investigates the enzymatic activities of several key energy-related proteins that have been identified as nitrated in treated Wistar rats with moderate TBI. To test the hypothesis that the elevation of GSH production upon administration of GCEE will normalize enzymatic activity post-TBI, adult male Wistar rats were equally divided into three groups: sham, saline, and GCEE. Rats were treated with 150 mg/kg saline or GCEE at 30 and 60 min post-TBI. Upon sacrifice, brains were harvested and enzymatic activity was measured spectrophotometrically. Results: An increase in enzymatic activity upon GSH elevation via GCEE administration in several key enzymes was observed. Conclusions: GCEE is a potential therapeutic strategy to restore energy-related proteins in the brain post-TBI via GSH elevation. Full article

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

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26 pages, 842 KB

Open AccessArticle

Speech Production Intelligibility Is Associated with Speech Recognition in Adult Cochlear Implant Users

by Victoria A. Sevich, Davia J. Williams, Aaron C. Moberly and Terrin N. Tamati

Brain Sci. 2025, 15(10), 1066; https://doi.org/10.3390/brainsci15101066 - 30 Sep 2025

Abstract

Background/Objectives: Adult cochlear implant (CI) users exhibit broad variability in speech perception and production outcomes. Cochlear implantation improves the intelligibility (comprehensibility) of CI users’ speech, but the degraded auditory signal delivered by the CI may attenuate this benefit. Among other effects, degraded [...] Read more.

Background/Objectives: Adult cochlear implant (CI) users exhibit broad variability in speech perception and production outcomes. Cochlear implantation improves the intelligibility (comprehensibility) of CI users’ speech, but the degraded auditory signal delivered by the CI may attenuate this benefit. Among other effects, degraded auditory feedback can lead to compression of the acoustic–phonetic vowel space, which makes vowel productions confusable, decreasing intelligibility. Sustained exposure to degraded auditory feedback may also weaken phonological representations. The current study examined the relationship between subjective ratings and acoustic measures of speech production, speech recognition accuracy, and phonological processing (cognitive processing of speech sounds) in adult CI users. Methods: Fifteen adult CI users read aloud a series of short words, which were analyzed in two ways. First, acoustic measures of vowel distinctiveness (i.e., vowel dispersion) were calculated. Second, thirty-seven normal-hearing (NH) participants listened to the words produced by the CI users and rated the subjective intelligibility of each word from 1 (least understandable) to 100 (most understandable). CI users also completed an auditory sentence recognition task and a nonauditory cognitive test of phonological processing. Results: CI users rated as having more understandable speech demonstrated more accurate sentence recognition than those rated as having less understandable speech, but intelligibility ratings were only marginally related to phonological processing. Further, vowel distinctiveness was marginally associated with sentence recognition but not related to phonological processing or subjective ratings of intelligibility. Conclusions: The results suggest that speech intelligibility ratings are related to speech recognition accuracy in adult CI users, and future investigation is needed to identify the extent to which this relationship is mediated by individual differences in phonological processing. Full article

(This article belongs to the Special Issue Language, Communication and the Brain—2nd Edition)

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1 pages, 129 KB

Open AccessCorrection

Correction: Waid-Ebbs et al. Response to Training in Emotion Recognition Function for Mild TBI/PTSD Survivors: Pilot Study. Brain Sci. 2025, 15, 728

by J. Kay Waid-Ebbs, Kristen Lewandowski, Yi Zhang, Samantha Graham and Janis J. Daly

Brain Sci. 2025, 15(10), 1063; https://doi.org/10.3390/brainsci15101063 - 30 Sep 2025

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue At the Frontiers of Neurorehabilitation: 3rd Edition)

24 pages, 1075 KB

Open AccessArticle

Adult Dyslexia Traits as Predictors of Hot/Cool Executive Function and Prospective Memory Abilities

by Christina Protopapa, Rachael L. Elward and James H. Smith-Spark

Brain Sci. 2025, 15(10), 1065; https://doi.org/10.3390/brainsci15101065 - 29 Sep 2025

Abstract

Background/Objectives: Executive functioning (EF) and prospective memory (PM) difficulties have been documented in adults with developmental dyslexia. However, research has tended to focus on university students with a formal diagnosis, overlooking adults who may experience symptoms of dyslexia without ever being formally [...] Read more.

Background/Objectives: Executive functioning (EF) and prospective memory (PM) difficulties have been documented in adults with developmental dyslexia. However, research has tended to focus on university students with a formal diagnosis, overlooking adults who may experience symptoms of dyslexia without ever being formally diagnosed. The present online study aimed to investigate the effects of dyslexia traits on EF and PM in a larger, community-based sample by prioritising the use of self-report measures that include and differentiate between underexplored aspects of EF and PM in the dyslexia literature. Methods: One hundred and eighty adult volunteers of a wide range of ages were included in the final analysis. Participants completed four self-report questionnaires with good pedigrees assessing dyslexia traits and ADHD symptomatology, as well as everyday experiences of five distinct EFs, PM and PM strategies. Results: Hierarchical regression analyses revealed that, after controlling for age and ADHD symptomatology, more self-reported dyslexia traits were associated with more frequent EF problems overall and lower confidence in PM Abilities. Elevated dyslexia traits were significantly associated with self-reports of more difficulties with time-management, organisation and self-restraint, but not with more difficulties with motivation and regulation of emotion. No significant associations were found between dyslexia traits and the self-reported use of PM-enhancing strategies. Conclusions: The findings are considered in the light of potential metacognition deficits and theoretical and practical implications are discussed. Full article

(This article belongs to the Special Issue Beyond Boundaries: Current Advances in Developmental Learning Disorders)

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35 pages, 424 KB

Open AccessReview

Idiopathic Intracranial Hypertension Animal Models and Venous Sinus Stenting: Status of Disease and Device-Focused Evidence

by Julien Ognard, Gerard El Hajj, Sevda Alipour Khabir, Esref A. Bayraktar, Sherief Ghozy, Ramanathan Kadirvel, David F. Kallmes and Waleed Brinjikji

Brain Sci. 2025, 15(10), 1064; https://doi.org/10.3390/brainsci15101064 - 29 Sep 2025

Abstract

Background/Objectives: Idiopathic intracranial hypertension (IIH) often features dural venous sinus stenosis; venous sinus stenting (VSS) improves venous outflow and intracranial pressure, but most stents are off-label, and few are engineered for intracranial venous anatomy. The aim was to synthesize animal models relevant to [...] Read more.

Background/Objectives: Idiopathic intracranial hypertension (IIH) often features dural venous sinus stenosis; venous sinus stenting (VSS) improves venous outflow and intracranial pressure, but most stents are off-label, and few are engineered for intracranial venous anatomy. The aim was to synthesize animal models relevant to IIH/VSS, catalogue stents used clinically for VSS and summarize corresponding animal data, appraise current preclinical VSS research, and propose a pragmatic preclinical evaluation framework. Methods: We performed a targeted search (PubMed, Web of Science, Scopus; through to May 2025), dual-screened the records in Nested Knowledge, and extracted the model/device characteristics and outcomes as per the predefined criteria. Results: We identified 65 clinical VSS studies; most were retrospective and used off-label carotid/peripheral/biliary stents (Precise, Zilver, and Wallstent were the most frequent). Recent dedicated systems (River, BosStent) have limited animal evidence; VIVA has GLP porcine venous peripheral data demonstrating its patency, structural integrity, and benign healing outcomes. Rodent models reproduce obesity/androgen drivers with modest, sustained ICP elevation; large animal models show the technical feasibility of in sinus implantation, but no chronic focal venous stenosis model fully mirrors the IIH condition. Conclusions: Despite broad clinical uptake, the translational underpinnings of VSS in IIH remain incomplete: most devices lack intracranial venous-specific preclinical validation, and there is no existing animal model that recapitulates both IIH biology and focal sinus stenosis. Full article

(This article belongs to the Section Neurosurgery and Neuroanatomy)

16 pages, 1512 KB

Open AccessArticle

The Effect of Intraocular Haloperidol on Motor Function in Models of Two Neuropsychiatric Disorders: Implications for the Origin and Treatment of Parkinson’s Disease, Psychosis and Drug Addiction

by Gregory L. Willis

Brain Sci. 2025, 15(10), 1062; https://doi.org/10.3390/brainsci15101062 - 29 Sep 2025

Abstract

Background: It has recently been proposed that the retina plays an important modulatory role in the control of motor function that is usually attributed exclusively to the function of the nigro-striatal dopamine (NSD) system. Indeed, it has been proposed further that Parkinson’s disease [...] Read more.

Background: It has recently been proposed that the retina plays an important modulatory role in the control of motor function that is usually attributed exclusively to the function of the nigro-striatal dopamine (NSD) system. Indeed, it has been proposed further that Parkinson’s disease (PD) begins in and progresses from the retina and may be effectively treated from there. While previous intraocular work has employed intravitreal (IVIT) administration of toxins to induce experimental PD, the first study series reported here examines the effect of IVIT haloperidol on motor performance while the second study examines the effect of IVIT haloperidol on the unilateral rotation model of PD, both in a circadian context. Methods: Motor tests included open field performance and the latency to perform three motor tests after the IVIT injection of haloperidol with and without amphetamine pretreatment. In a second study, IVIT injections of the melatonin antagonist ML-23 or L-dopa were made after unilateral lesions of the NSD in rats that were placed in a rotometer examining spontaneous ipsilateral and contralateral turning. Results: IVIT haloperidol produced robust changes in several motor parameters during the light and dark phase of the LD cycle which were enhanced by amphetamine pretreatment. In the second study, while IVIT L-dopa had only a minor effect on spontaneous rotation during the light phase, IVIT haloperidol produced a robust effect upon ipsilateral turning. The reduction in spontaneous ipsilateral turning was seen after IVIT injections into the eye ipsilateral or contralateral to the hemisphere in which NSD destruction occurred. Reduced turning was seen during both the light and dark phases of the L/D cycle. Conclusions: These results illustrate that IVIT injections of DA and melatonin receptor antagonists can differentially alter motor function via the retina. This suggests that the retina may be a treatment target not only for PD but also for other DA- and melatonin-mediated disorders such as drug addiction, psychosis and schizophrenia. Full article

(This article belongs to the Special Issue The Retina, Visual Function and Circadian Involvement in Parkinson’s Disease)

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14 pages, 755 KB

Open AccessArticle

Comparative Analysis of AI Models in Predicting Treatment Strategies for Unruptured Intracranial Aneurysms

by Manou Overstijns, Sameer Nazeeruddin, Pierre Scheffler, Roland Roelz, Jürgen Beck and Amir El Rahal

Brain Sci. 2025, 15(10), 1061; https://doi.org/10.3390/brainsci15101061 - 29 Sep 2025

Abstract

Objectives: The increasing incidence of unruptured intracranial aneurysms (UIAs) has led to significant demands on neurovascular boards. Large language models (LLMs), such as ChatGPT-4, ChatGPT-3.5, Claude, and Atlas GPT, have emerged as tools to support clinical decision-making. This study compares treatment recommendations from [...] Read more.

Objectives: The increasing incidence of unruptured intracranial aneurysms (UIAs) has led to significant demands on neurovascular boards. Large language models (LLMs), such as ChatGPT-4, ChatGPT-3.5, Claude, and Atlas GPT, have emerged as tools to support clinical decision-making. This study compares treatment recommendations from these AI models with those of an interdisciplinary neurovascular board to evaluate their accuracy and alignment. Methods: We retrospectively included all 57 patients with UIAs discussed by the neurovascular board in 2023. The board’s consensus decision served as the reference standard. Key clinical and radiographic data, including PHASES, ELAPSS, and UIATS scores, were provided to the AI models. Each model was tasked with recommending either conservative or operative management and specifying the treatment modality (clipping, coiling, flow diverter, or WEB device/flow diverter) where appropriate. AI model recommendations were compared with the board’s decisions for management and the specific treatment modality of the UIA. Results: ChatGPT-4 achieved the highest accuracy in correctly predicting conservative or operative management (89%) and specific treatment types (73%), followed by Atlas GPT (74% accuracy in conservative/operative decisions and 55% accuracy in specific treatment types), Claude (70% accuracy in conservative/operative decisions and 50% accuracy in specific treatment types), and ChatGPT-3.5 (82% accuracy in conservative/operative decisions and 27% accuracy in specific treatment types). ChatGPT-3.5 displayed a strong preference for clipping (94.3%). ELAPSS scores significantly influenced AI recommendations and decision-making, particularly for ChatGPT-4 and ChatGPT-3.5. Follow-up recommendations for conservative management were shorter among AI models, with Claude suggesting the shortest interval (7.72 months) compared to the neurovascular board’s 13.36 months. Conclusions: AI models, particularly ChatGPT-4, align closely with expert neurovascular board decisions and offer promising support for initial clinical decision-making, particularly in resource-limited settings. However, interdisciplinary neurovascular boards remain unreplaceable for UIA management, and AI should be viewed as a complementary tool. The observed improvement from ChatGPT-3.5 to ChatGPT-4 underscores the rapid evolution of AI technology, and further advancements are expected to enhance both performance and accuracy in the future. Full article

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

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11 pages, 568 KB

Open AccessArticle

Craniotomy Complexity and Outcomes in Exoscope-Assisted Cranial Surgery: A Single-Center Retrospective Analysis

by Salvatore Cardali, Alfredo Conti, Domenicantonio Collufio, Domenico Matalone, Antonio Morabito, Francesco Messineo, Giuseppe Ricciardo, Giovanni Raffa and Giada Garufi

Brain Sci. 2025, 15(10), 1060; https://doi.org/10.3390/brainsci15101060 - 29 Sep 2025

Abstract

Objective: The exoscope is an emerging digital visualization technology in neurosurgery that provides high-definition 3D 4k magnified views of the surgical field on external monitors, promoting improved ergonomics and enhanced team involvement. This study presents a single center experience of 26 patients undergoing [...] Read more.

Objective: The exoscope is an emerging digital visualization technology in neurosurgery that provides high-definition 3D 4k magnified views of the surgical field on external monitors, promoting improved ergonomics and enhanced team involvement. This study presents a single center experience of 26 patients undergoing brain tumor resection using the Olympus Orbeye exoscope with surgical approaches of different complexities and provides a review of the current literature on exoscopic adoption in neurosurgical oncology. Methods: We retrospectively reviewed clinical, surgical, and outcome data from a consecutive series of 26 patients who underwent brain tumor resection with the ORBEYE exoscope. Metrics analyzed included extent of resection, surgical technique, and complications in two different complex scenarios: superficial and deep lesions. Results: In our institutional case series, use of the exoscope enabled gross total or subtotal resection in all the patients, with a surgical complication rate comparable to that reported for operative microscopes (14.3–23.1%), which was stated to be non-significant and independently correlated to the use of the exoscope. No device-related adverse events were observed, and postoperative neurological outcomes were in line with the overall survival pathological examination of the lesion treated. Conclusions: In this cohort, the exoscope enabled the safe and effective resection of superficial and deep lesions with outcomes comparable to those historically reported with operating microscopes. Gross total resection rates were high in the superficial cohort and substantially higher than in the deep cohort, while complication rates did not differ significantly between groups. Future prospective studies with long-term follow-up are needed to assess oncological outcomes and define the optimal role of exoscopic technology in neurosurgical oncology. Full article

(This article belongs to the Section Neuro-oncology)

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