Brain Sciences

31 pages, 8935 KB

Open AccessArticle

Dopaminergic Degeneration Differentially Modulates Primary Motor Cortex Activity and Motor Behavior in Hemiparkinsonian Rats

by Suelen L. Boschen, Julian Seethaler, Shaohua Wang, Wendy D. Lujan, Jodi L. Silvernail, Launia J. White, Michael G. Heckman, Rickey E. Carter, Su-Youne Chang and J. Luis Lujan

Brain Sci. 2025, 15(10), 1123; https://doi.org/10.3390/brainsci15101123 (registering DOI) - 18 Oct 2025

Abstract

Background/Goal: Parkinson’s disease (PD) disrupts dopaminergic transmission, leading to motor deficits and altered activity in the primary motor cortex (M1). While M1 modulation is critical for motor control, its response to dopaminergic degeneration and treatment remains unclear. This study aimed to characterize M1 [...] Read more.

Background/Goal: Parkinson’s disease (PD) disrupts dopaminergic transmission, leading to motor deficits and altered activity in the primary motor cortex (M1). While M1 modulation is critical for motor control, its response to dopaminergic degeneration and treatment remains unclear. This study aimed to characterize M1 neuronal activity and motor behavior in hemiparkinsonian rats using in vivo calcium imaging across naïve, lesioned, and levodopa-treated states. Methods: Thirteen Sprague Dawley rats were injected with GCaMP6f in the M1 and implanted with a GRIN lens and guide cannula targeting the medial forebrain bundle. Calcium imaging and motor behavior were assessed longitudinally using a single pellet reaching test (SPRT) before and after unilateral 6-hydroxydopamine (6-OHDA) lesioning and subsequent levodopa/carbidopa treatment. Dopaminergic lesion severity was quantified via tyrosine hydroxylase immunohistochemistry. Calcium event frequency and influx were analyzed with CNMF-E and statistical modeling. Results: Levodopa treatment improved fine motor performance as shown by a significant reduction in grasp errors (mean difference: −8.91, 95% CI: −16.66 to −1.16, p = 0.031) and increased reaching duration (mean difference: 4.13, 95% CI: 0.94 to 7.32, p = 0.019) compared to the lesioned state. M1 calcium activity showed modulation dependent on lesion severity: low-lesion rats exhibited reduced event frequency (mean difference: 0.04 Hz, 95% CI: 0.001 to 0.08, p = 0.045) and increased influx post-lesion (mean difference: −0.20 z·s, 95% CI: −0.38 to −0.02, p = 0.038), while high-lesion rats showed increased influx only after levodopa treatment (mean difference: −0.34 z·s, 95% CI: −0.52 to −0.16, p = 0.003). Correlation analyses revealed that calcium influx, but not frequency, was negatively correlated with lesion severity during levodopa treatment (Spearman r = −0.857, p = 0.024). Conclusion: M1 neuronal activity appears to be differentially modulated by dopaminergic degeneration and levodopa treatment in a lesion-dependent manner. These preliminary findings suggest dynamic cortical responses in PD and support the utility of calcium imaging for monitoring circuit-level changes in disease and therapy. Further research with larger cohorts and complementary methodologies will be necessary to validate and extend these observations. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases, 2nd Edition)

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14 pages, 449 KB

Open AccessArticle

Disability and Non-Motor Symptoms in Multiple Sclerosis: Exploring Associations and Predictive Factors

by Ana Jerković, Ivona Stipica Safić, Sanda Pavelin, Nikolina Pleić, Klaudia Duka Glavor, Igor Vujović, Joško Šoda, Jasna Duranović and Maja Rogić Vidaković

Brain Sci. 2025, 15(10), 1122; https://doi.org/10.3390/brainsci15101122 (registering DOI) - 18 Oct 2025

Abstract

Background/Objectives: The relationship between multiple sclerosis (MS) disability and co-occurring non-motor symptomatology is not well understood. This study examined the association between disability status and non-motor symptoms—sleep quality, depression, anxiety, and fatigue—in people with multiple sclerosis (MS), as well as the contribution of [...] Read more.

Background/Objectives: The relationship between multiple sclerosis (MS) disability and co-occurring non-motor symptomatology is not well understood. This study examined the association between disability status and non-motor symptoms—sleep quality, depression, anxiety, and fatigue—in people with multiple sclerosis (MS), as well as the contribution of sleep quality to the prediction of fatigue, depression, and anxiety in MS. Methods: A cross-sectional study included 469 MS and 369 control subjects. Disability status of MS subjects was assessed with the Expanded Disability Status Scale (EDSS), while fatigue, depression, anxiety, and sleep quality were evaluated with the Fatigue Severity Scale (FSS), the Hospital Anxiety and Depression Scale (HADS), and the Pittsburgh Sleep Quality Index (PSQI), respectively. Statistical analyses encompassed group comparisons, Pearson correlations, and hierarchical regression models adjusted for age, sex, and EDSS. Results: The results show that MS subjects exhibited higher FSS, HADS-D, and PSQI scores than controls, with intercorrelations and only weak associations with EDSS severity (r = 0.15–0.29). Moreover, PSQI global and HADS-D scores increased with higher EDSS severity, while FSS scores peaked in the moderate EDSS range (4.5–6.5). Global PSQI score independently predicted FSS, HADS-D, and HADS-A. Daytime dysfunction, sleep disturbances, and sleep medication use significantly predicted FSS, HADS-D, and HADS-A scores. Conclusions: Study findings highlight the role of sleep quality in exacerbating depression, anxiety, and fatigue in MS. Full article

(This article belongs to the Special Issue From Diagnosis to Care: Cognitive Challenges and Innovations in Multiple Sclerosis)

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65 pages, 1600 KB

Open AccessReview

How Swimming Modulates Inflammatory Pathways in Pain, Neurodegenerative, and Metabolic Disorders

by Mahdiyeh Kooshki, Rozhin Rezeai-Farimani, Amirmohammad Moradpour, Vafa Baradaran Rahimi and Vahid Reza Askari

Brain Sci. 2025, 15(10), 1121; https://doi.org/10.3390/brainsci15101121 (registering DOI) - 18 Oct 2025

Abstract

Background: As a non-weight-bearing full-body exercise, swimming may reduce inflammation and boost anti-inflammatory agents to decrease the risk of cardiovascular, neurological, and rheumatological disorders. This systematic review examines the current evidence on the role of swimming exercise in modulating immune responses through inflammatory [...] Read more.

Background: As a non-weight-bearing full-body exercise, swimming may reduce inflammation and boost anti-inflammatory agents to decrease the risk of cardiovascular, neurological, and rheumatological disorders. This systematic review examines the current evidence on the role of swimming exercise in modulating immune responses through inflammatory pathways. Methods: First, the PubMed and Scopus databases were searched through December 2024 for studies on swimming and inflammation. The initial search using keywords yielded 509 articles; 102 met the inclusion criteria after screening for relevance, language, and full-text availability. Results: This study suggests that regular swimming reduces neuroinflammation by enhancing BDNF, CREB, and PI3K/Akt signaling while suppressing both mRNA and protein levels of NF-κB, TNF-α, and IL-6 in the brain. In metabolic tissues, it activates SIRT1 and PGC-1α, improving mitochondrial biogenesis and antioxidant defense. Swimming also upregulates PPAR-α and eNOS while downregulating iNOS, leading to reduced vascular inflammation, oxidative stress, and fibrosis in renal and cardiac tissues. Moreover, the enhanced production of IL-10 and the decreasing levels of IL-1β and CRP contribute to systemic anti-inflammatory effects. Conclusions: Consequently, the available evidence suggests that swimming can be a low-impact, full-body exercise with potential therapeutic options in managing inflammation-related conditions such as cardiovascular disease, diabetes, and obesity. Future studies should focus on human clinical trials, investigate mechanisms, and assess longer time frames. Full article

(This article belongs to the Section Neuropharmacology and Neuropathology)

21 pages, 1236 KB

Open AccessArticle

Aging, Cognitive Efficiency, and Lifelong Learning: Impacts on Simple and Complex Sentence Production During Storytelling

by Silvia D’Ortenzio, Francesco Petriglia, Giulia Gasparotto, Sara Andreetta, Marika Gobbo and Andrea Marini

Brain Sci. 2025, 15(10), 1120; https://doi.org/10.3390/brainsci15101120 (registering DOI) - 18 Oct 2025

Abstract

Objectives: This study investigated the effects of healthy aging on sentence production in narrative discourse and examined the role of cognitive abilities and Lifelong Learning (LLL) in mitigating age-related decline. Methods: Three hundred and seven Italian-speaking adults (26–89 years) completed a narrative task [...] Read more.

Objectives: This study investigated the effects of healthy aging on sentence production in narrative discourse and examined the role of cognitive abilities and Lifelong Learning (LLL) in mitigating age-related decline. Methods: Three hundred and seven Italian-speaking adults (26–89 years) completed a narrative task elicited from five picture stimuli, alongside assessments of verbal working memory, sustained attention, and inhibitory control. Morphological and morphosyntactic measures (morphological errors and omissions of content and function words) and syntactic variables (complete sentences, subordinate clauses, and passive sentences) were analyzed. Results: Aging was associated with increased morphological and morphosyntactic errors and reduced syntactic complexity. These effects were non-linear for the % of morphological errors, the % of omission of content words, and the % of complete sentences and were more pronounced after age 70. LLL was negatively associated with morphological and morphosyntactic errors and positively associated with sentence production. Verbal working memory and sustained attention explained additional variance only for omissions of function words, whereas the passive component of verbal working memory only explained additional variance for complete sentence production. Conclusions: These findings suggest that aging affects both simple and complex sentence production, with declines related to morphological errors and omissions. LLL appears to buffer against some grammatical declines, suggesting a role for educational engagement in maintaining syntactic abilities. Clinically, assessing complex sentence production and considering LLL may improve diagnosis and intervention for language disorders in older adults. Full article

(This article belongs to the Special Issue New Perspectives on Language Processing in Aging)

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12 pages, 237 KB

Open AccessReview

FDA-Regulated Clinical Trials vs. Real-World Data: How to Bridge the Gap in Pain Research

by Anthony Reyes, Mohummed Malik, Malik Sahouri and Nebojsa Nick Knezevic

Brain Sci. 2025, 15(10), 1119; https://doi.org/10.3390/brainsci15101119 (registering DOI) - 18 Oct 2025

Abstract

Randomized controlled trials (RCTs) have been regarded as the gold standard for evaluating the efficacy of treatments for chronic pain and are the foundation for regulatory approval and guideline development. However, their restrictive design and dependence on idealized populations can limit their applicability [...] Read more.

Randomized controlled trials (RCTs) have been regarded as the gold standard for evaluating the efficacy of treatments for chronic pain and are the foundation for regulatory approval and guideline development. However, their restrictive design and dependence on idealized populations can limit their applicability to the diverse patients seen in routine chronic pain management. Real-world data (RWD), collected from electronic medical records, registries, claims databases, and digital health platforms, can offer a more comprehensive view of treatment adherence and safety that RCTs often overlook. A key issue in pain medicine is the efficacy–effectiveness gap, where discrepancies exist between the outcomes of therapies and interventions in RCTs versus in real-world practice due to variations in patient populations and adherence. Bridging this gap ensures that observed improvements align with patients’ preferred outcomes and functional goals. Integrating the strengths of RCTs and RWD provides a more comprehensive evidence base to guide clinical decision-making, influence reimbursement policies, and develop equitable guidelines. The primary aim of this paper is to identify factors used in FDA-regulated RCTs and RWD that could be implemented or enhanced in everyday practice to deliver more holistic and patient-centered care in the management of chronic pain. Full article

(This article belongs to the Special Issue Clinical Research on Pain: Advances and Challenges)

17 pages, 1503 KB

Open AccessSystematic Review

Withdrawal-Induced Delirium in Opioid Dependence: A Systematic Review

by Nikodem Świderski, Patryk Rodek and Krzysztof Kucia

Brain Sci. 2025, 15(10), 1118; https://doi.org/10.3390/brainsci15101118 - 17 Oct 2025

Abstract

Background: Delirium is a rare but clinically significant complication of opioid withdrawal that remains poorly characterized in the literature. While classical withdrawal symptoms are well recognized, atypical presentations such as delirium are less frequently reported and often challenging to diagnose due to symptom [...] Read more.

Background: Delirium is a rare but clinically significant complication of opioid withdrawal that remains poorly characterized in the literature. While classical withdrawal symptoms are well recognized, atypical presentations such as delirium are less frequently reported and often challenging to diagnose due to symptom overlap and heterogeneity of withdrawal syndromes. Methods: In this systematic review, we systematically analyzed available case reports and case series describing delirium precipitated by spontaneous opioid withdrawal, tapering, or antagonist-induced withdrawal. Twelve papers met inclusion criteria, comprising a total of fifteen case reports. Results: Most patients (n = 15) developed delirium within hours to days of withdrawal onset, often with fluctuating consciousness, disorientation, perceptual disturbances, and psychomotor changes. Reported risk factors included psychiatric comorbidity (major depressive disorder, anxiety disorder), concomitant use of psychotropic medication, rapid detoxification protocols, and potential exposure to adulterated substances. Management strategies varied but generally involved supportive care, benzodiazepines, antipsychotics, or reinstatement of opioid agonists. Conclusions: The findings highlight the need for heightened clinical awareness, careful differentiation from other withdrawal-related neuropsychiatric states, and systematic exclusion of organic etiologies. Despite the increasing number of patients affected by OWS, the knowledge available to date is based on case reports and a small case series, making it impossible to critically assess the prevalence or identify risk factors. Future research should aim to identify risk factors, optimize treatment, and explore novel diagnostic approaches, including AI-driven monitoring and connectomic analyses, to improve early detection and therapeutic outcomes in opioid withdrawal-associated delirium. Full article

(This article belongs to the Topic New Advances in Addiction Behavior)

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19 pages, 4508 KB

Open AccessArticle

Aging, Rather than Genotype, Is the Principal Contributor to Differential Gene Expression Within Targeted Replacement APOE2, APOE3, and APOE4 Mouse Brain

by Amanda Labuza, Harshitha Pidikiti, Melissa J. Alldred, Kyrillos W. Ibrahim, Katherine Y. Peng, Jonathan Pasato, Adriana Heguy, Paul M. Mathews and Stephen D. Ginsberg

Brain Sci. 2025, 15(10), 1117; https://doi.org/10.3390/brainsci15101117 - 17 Oct 2025

Abstract

Background: Apolipoprotein E (APOE) is the strongest genetic risk determinant for late-onset Alzheimer’s disease (AD). The APOE3 allele is risk-neutral, the APOE4 allele increases the risk of developing AD, and the APOE2 allele is neuroprotective. Methods: We utilized RNA sequencing of hemi-brains [...] Read more.

Background: Apolipoprotein E (APOE) is the strongest genetic risk determinant for late-onset Alzheimer’s disease (AD). The APOE3 allele is risk-neutral, the APOE4 allele increases the risk of developing AD, and the APOE2 allele is neuroprotective. Methods: We utilized RNA sequencing of hemi-brains from a mouse model homozygous for each of these humanized APOE alleles to study gene expression profiles between mice aged 12 months of age (MO) and 18 MO, independent of β-amyloid and tau pathology. Results: More than half of the differentially expressed genes (DEGs) within each genotype were shared with at least one other APOE allele, including 1610 DEGs that were shared across the three genotypes. These DEGs represent changes driven by aging rather than APOE genotype. Aging induced DEGs and biological pathways involving metabolism, synaptic function, and protein synthesis, among others. Alterations in these pathways were also identified by DEGs unique to APOE4, suggesting that the APOE4 allele drives the aging phenotype. In contrast, fewer pathways were identified from DEGs unique to APOE2 or APOE3. Conclusions: Transcriptomic results suggest that the most significant impact on brain-level expression changes in humanized APOE mice is aging and that APOE4 exacerbates this process. These in vivo findings within an established model system are consistent with brain aging being the greatest risk factor for AD and suggest that APOE4 expression promotes an aging phenotype in the brain that interacts with, and contributes to, aging-driven AD risk. Results reinforce the impact age and APOE allele contribute to AD and age-related neurodegeneration, and foster greater mechanistic understanding as well as inform therapeutic intervention. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Regulating Neuronal Function, Homeostasis, and Disease)

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12 pages, 657 KB

Open AccessArticle

Virtual Reality in the Neurorehabilitation of Patients with Idiopathic Parkinson’s Disease: Pilot Study

by Diana Alejandra Delgado-Anguiano, Ulises Rodríguez-Ortiz, Mireya Chávez-Oliveros and Francisco Paz-Rodríguez

Brain Sci. 2025, 15(10), 1116; https://doi.org/10.3390/brainsci15101116 - 16 Oct 2025

Abstract

Background: Parkinson’s disease (PD) is a neurodegenerative condition that affects quality of life due to motor (gait, balance) and cognitive alterations, raising the risk of falling. Virtual reality (RV) and dancing have shown benefits for speed of walking, balance, and postural stability, as [...] Read more.

Background: Parkinson’s disease (PD) is a neurodegenerative condition that affects quality of life due to motor (gait, balance) and cognitive alterations, raising the risk of falling. Virtual reality (RV) and dancing have shown benefits for speed of walking, balance, and postural stability, as well as decreased risk of falls. Objective: The goal of this study was to analyze the effectiveness of RV and dancing using a Kinect Xbox 360 video game to improve walking speed and motor performance and reduce the risk of falls in patients with PD. Method: This is a pre-experimental study with a simple pre-post design, involving a single group of 14 patients diagnosed with PD in stages 1 to 4 of the Hoehn and Yahr (H and Y) scale, from the National Institute of Neurology (INNN). Before and after the intervention, motor tests, the Unified Parkinson’s Disease Rating Scale (UPDRS-III), the Timed Up and Go (TUG) test, and the Tinetti were applied. The intervention consisted of 16 bi-weekly sessions, which included warm-up, coordination exercises, 10 songs, and cool-down. Results: Effects of the RV intervention were observed on improvements in motor tests (z = −2.640, p = 0.008), gait (z = −3.316, p = 0.001), balance (TUG) (z = −2.966, p = 0.001), and on the UPDRS-III scale (total index) (z = −3.048, p = 0.002). An increase in the difficulty level of dancing was also observed (X² = 144.13, p < 0.01). Conclusions: The virtual reality intervention with dancing improved motor performance, including increased walking speed, enhanced postural stability, reduced stiffness and bradykinesia, and a decreased risk of falls Full article

(This article belongs to the Special Issue Advances in the Relationship Among Brain, Physical Function, and Exercise Performance)

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15 pages, 930 KB

Open AccessSystematic Review

Attentional Deficits Following Preterm Birth: A Systematic Review and Meta-Analysis

by Kathrin Kollndorfer, Darlene Alicia Hörle and Florian Ph. S. Fischmeister

Brain Sci. 2025, 15(10), 1115; https://doi.org/10.3390/brainsci15101115 - 16 Oct 2025

Abstract

Objective: Preterm birth has been associated with an elevated risk of a broad range of neurodevelopmental impairments, including attentional deficits. This systematic review and meta-analysis aimed to synthesize the existing evidence on sustained and selective attention in school-aged children born preterm. Methods: Following [...] Read more.

Objective: Preterm birth has been associated with an elevated risk of a broad range of neurodevelopmental impairments, including attentional deficits. This systematic review and meta-analysis aimed to synthesize the existing evidence on sustained and selective attention in school-aged children born preterm. Methods: Following PRISMA guidelines, a comprehensive literature search was conducted across PubMed, Ovid MEDLINE, EMBASE, and Web of Science. Eligible studies included assessments of sustained and/or selective attention in children aged 5–12 years born before 37 weeks of gestation. Data from 15 studies (sustained attention) and 12 studies (selective attention) were analyzed using random-effects meta-analyses. Additionally, subgroup analyses were performed based on gestational age. Results: Preterm-born children showed significantly poorer performance in sustained (Hedges’ g = −0.31, p < 0.001) and selective attention (Hedges’ g = −0.27, p < 0.001) compared to term-born controls. While sustained attention deficits were consistent across all gestational age subgroups, selective attention deficits were more pronounced in very early and extremely early preterm-born children. Moderate to late preterm-born children showed less impairment in selective attention tasks. Conclusions: Preterm birth is associated with measurable and persistent deficits in both sustained and selective attention, with greater vulnerability in children born before 32 weeks of gestation. These findings underscore the importance of implementing early monitoring and intervention strategies specifically designed to support attentional development in this high-risk population. Full article

(This article belongs to the Collection Collection on Developmental Neuroscience)

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25 pages, 1822 KB

Open AccessArticle

Relationships Among Bullying Experiences, Mood Symptoms and Suicidality in Subjects with and Without Autism Spectrum Conditions

by Liliana Dell’Osso, Benedetta Nardi, Stefano Pini, Gabriele Massimetti, Lucrezia Castellani, Francesca Parri, Filippo Del Grande, Chiara Bonelli, Carmen Concerto, Matteo Di Vincenzo, Bianca Della Rocca, Maria Salvina Signorelli, Laura Fusar-Poli, Camilla Figini, Pierluigi Politi, Eugenio Aguglia, Mario Luciano and Barbara Carpita

Brain Sci. 2025, 15(10), 1114; https://doi.org/10.3390/brainsci15101114 - 16 Oct 2025

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Abstract

Background: Bullying is a major public health issue with long-term psychological consequences, particularly for individuals with Autism Spectrum Disorder (ASD) or subthreshold autistic traits, known as “broad autistic phenotype” (BAP). Prior studies have suggested increased vulnerability to victimization and mood disorders in [...] Read more.

Background: Bullying is a major public health issue with long-term psychological consequences, particularly for individuals with Autism Spectrum Disorder (ASD) or subthreshold autistic traits, known as “broad autistic phenotype” (BAP). Prior studies have suggested increased vulnerability to victimization and mood disorders in these populations, but the association between bullying, autistic traits, and affective symptoms remains underexplored. Methods: A total of 98 individuals with at least one ASD symptom (BAP group) and 159 healthy controls (HCs) were recruited. Participants were classified into four groups based on ASD symptoms and bullying history. Standardized self-report instruments (AdAS Spectrum, AQ, MOODS-SR) assessed autistic traits, mood symptoms, and suicidality. Group comparisons, correlation analyses, and multiple regression models were conducted to evaluate the relationships between bullying, autistic traits, and mood disturbances. Results: BAP individuals, particularly those with ASD, reported significantly higher rates of bullying than HCs. Bullied BAP participants exhibited the highest burden of mood symptoms and suicidality. Regression analyses identified both autistic traits and bullying history as significant predictors of suicidal ideation and overall suicidality, though only autistic traits predicted suicidal behaviors. AQ and MOODS-SR scores were positively correlated, especially in depressive and rhythmicity domains. Conclusions: Autistic traits and bullying experiences independently and interactively contribute to increased mood symptomatology and suicidality. These findings underscore the importance of early identification and targeted support for at-risk individuals with ASD or BAP, particularly those with a history of victimization. Full article

(This article belongs to the Special Issue Burnout, Adjustment Disorder and Post-Traumatic Stress Disorder: Risk Factors, Impact, Preventive Strategies and Treatment Options)

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30 pages, 1297 KB

Open AccessSystematic Review

A Systematic Review of Inter-Brain Synchrony and Psychological Conditions: Stress, Anxiety, Depression, Autism and Other Disorders

by Atiqah Azhari, Ashvina Rai and Y. H. Victoria Chua

Brain Sci. 2025, 15(10), 1113; https://doi.org/10.3390/brainsci15101113 - 16 Oct 2025

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Abstract

Background: Inter-brain synchrony (IBS)—the temporal alignment of neural activity between individuals during social interactions—has emerged as a key construct in social neuroscience, reflecting shared attention, emotional attunement, and coordinated behavior. Enabled by hyperscanning techniques, IBS has been observed across a range of dyadic [...] Read more.

Background: Inter-brain synchrony (IBS)—the temporal alignment of neural activity between individuals during social interactions—has emerged as a key construct in social neuroscience, reflecting shared attention, emotional attunement, and coordinated behavior. Enabled by hyperscanning techniques, IBS has been observed across a range of dyadic contexts, including cooperation, empathy, and communication. This systematic review synthesizes recent empirical findings on inter-brain synchrony (IBS)—the temporal alignment of neural activity between individuals—across psychological and neurodevelopmental conditions, including stress, anxiety, depression, and autism spectrum disorder (ASD). Methods: Drawing on 30 studies employing hyperscanning methodologies (EEG, fNIRS, fMRI), we examined how IBS patterns vary by clinical condition, dyad type, and brain region. Results: Findings indicate that IBS is generally reduced in anxiety, depression, and ASD, particularly in key social brain regions such as the dorsolateral and medial prefrontal cortices (dlPFC, mPFC, vmPFC), temporoparietal junction (TPJ), and inferior frontal gyrus (IFG), suggesting impaired emotional resonance and social cognition. In contrast, stress elicited both increases and decreases in IBS, modulated by context, emotional proximity, and cooperative strategies. Parent–child, therapist–client, and romantic dyads exhibited distinct synchrony profiles, with gender and relational dynamics further shaping neural coupling. Conclusions: Collectively, the findings support IBS as a potentially dynamic, condition-sensitive, and contextually modulated neurophysiological indicator of interpersonal functioning, with implications for diagnostics, intervention design, and the advancement of social neuroscience in clinical settings. Full article

(This article belongs to the Special Issue Neural Mechanisms Underlying Social Cognition and Emotional Processing)

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17 pages, 2694 KB

Open AccessArticle

Analysis of the Correlation Between Depression-like Behaviors and Lipid Peroxidation in the Prefrontal Cortex of Mice: The Impact of Early Life Stress

by Xue Mi, Zi-Ling Ye, Xu-Jun Zhang, Xiao-Man Dai and Zhou-Song Luo

Brain Sci. 2025, 15(10), 1112; https://doi.org/10.3390/brainsci15101112 - 15 Oct 2025

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Abstract

Objectives: This study attempted to investigate whether early life stress (ELS) induces lipid peroxidation in the prefrontal cortex (PFC) of mice and its correlation with depression-like behavioral changes. Methods: A mouse ELS model was established via maternal separation. Depressive and anxiety-like [...] Read more.

Objectives: This study attempted to investigate whether early life stress (ELS) induces lipid peroxidation in the prefrontal cortex (PFC) of mice and its correlation with depression-like behavioral changes. Methods: A mouse ELS model was established via maternal separation. Depressive and anxiety-like behaviors were assessed using the forced swim test, sucrose preference test, tail suspension test, and open field test. The expression levels of GPX4, SLC3A2, SLC7A11, TFR1, and lipid peroxidation markers in the PFC of mice were measured and correlated with depression-like behavioral changes. Results: ELS induced depressive and anxiety-like behaviors in mice. The mRNA and protein expressions of GPX4, SLC3A2, and SLC7A11 were downregulated in the PFC of ELS mice; the mRNA level of TFR1 was upregulated but its protein level remained unchanged. In the PFC of ELS mice, the product of lipid peroxidation, malondialdehyde, was significantly increased, while the antioxidants, glutathione and superoxide dismutase, were significantly decreased. These markers were significantly correlated with sucrose preference or immobility time of the ELS mice. Conclusions: The study evidences that early life stress can induce lipid peroxidation in the PFC of mice and that the latter is closely associated with depression-like behaviors, hinting that ELS may induce depression via lipid peroxidation in the PFC. These findings may suggest a potential strategy for the treatment of early-stage stress-related depression. Full article

(This article belongs to the Special Issue Anxiety, Depression and Stress)

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23 pages, 993 KB

Open AccessReview

Multimodal Neuroprotection in Ischemic Stroke: Emerging Non-Pharmacological Interventions from Bench to Bedside

by Junzhao Cui, Jingyi Yang, Luji Liu, Xiaoyun Liu and Xunming Ji

Brain Sci. 2025, 15(10), 1111; https://doi.org/10.3390/brainsci15101111 - 15 Oct 2025

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Abstract

Currently, the effective therapeutic strategies for acute ischemic stroke (AIS) remain revascularization therapies, including intravenous thrombolysis and endovascular thrombectomy. However, the narrow time window and reperfusion injury associated with reperfusion therapy limit favorable outcomes in some patients. As adjuncts to revascularization, certain neuroprotective [...] Read more.

Currently, the effective therapeutic strategies for acute ischemic stroke (AIS) remain revascularization therapies, including intravenous thrombolysis and endovascular thrombectomy. However, the narrow time window and reperfusion injury associated with reperfusion therapy limit favorable outcomes in some patients. As adjuncts to revascularization, certain neuroprotective agents have demonstrated robust preclinical results, but only a few have achieved successful clinical translation due to challenges in dosing and safety concerns. In recent years, convenient and relatively safe non-pharmacological neuroprotective interventions—such as hypothermia, remote ischemic conditioning (RIC), and normobaric hyperoxia (NBO)—have gained increasing research attention. These approaches offer advantages including high safety profiles, excellent tolerability, low cost, and the potential to synergize with reperfusion therapy, underscoring their broad clinical applicability. Numerous clinical trials have validated their potential to improve neurological functional outcomes, and this review explores the mechanisms and clinical applications of non-pharmacological neuroprotective therapies in ischemic stroke. Full article

(This article belongs to the Section Neuropharmacology and Neuropathology)

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13 pages, 3708 KB

Open AccessArticle

Panax notoginseng Flower Extract Attenuates Pentylenetetrazole-Induced Epilepsy by Restoring Glutamate Homeostasis

by Yang Zhao, Feiya Zhu, Jiayu Xie, Yiting Wang, Motlalepula Matsabisa and Minke Tang

Brain Sci. 2025, 15(10), 1110; https://doi.org/10.3390/brainsci15101110 - 15 Oct 2025

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Abstract

Objectives: One-third of patients experience inadequate seizure control with antiseizure medications. Therefore, safer and more effective therapeutic strategies remain urgently needed. Research evidence indicates that Panax notoginseng flower may exhibit potential antiepileptic properties. The study aimed to investigate the neuroprotective and antiepileptic effects [...] Read more.

Objectives: One-third of patients experience inadequate seizure control with antiseizure medications. Therefore, safer and more effective therapeutic strategies remain urgently needed. Research evidence indicates that Panax notoginseng flower may exhibit potential antiepileptic properties. The study aimed to investigate the neuroprotective and antiepileptic effects of Panax notoginseng flower (PNF) extract in a chronic pentylenetetrazole (PTZ)-kindled mouse model and explore its potential mechanisms, focusing on glutamate homeostasis. Methods: Chronic epilepsy was induced in ICR mice via repeated subconvulsive PTZ intraperitoneal injections. Following successful kindling, mice were orally treated with PNF (1.5 g/kg or 3 g/kg) for 30 days. Seizure behaviors were scored using Racines scale. Neuronal survival, systemic and cerebral cytokines, hippocampal glutamate levels (in vivo microdialysis with LC-MS/MS analysis), glutamate homeostasis related proteins glutamate transporter-2 (GLT-1), glutamate-aspartate transporter-1 (GLAST), and glutamine synthetase (GS) were investigated. Results: PNF treatment significantly reduced seizure severity and restored neuronal nuclei (NeuN+) cell neurons in the cortex and hippocampal CA1 region of PTZ kindled mice. PNF attenuated systemic and neuroinflammation by lowering interleukin-1ß (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-α) levels and increasing interleukin-10 (IL-10) in serum and brain of PTZ mice. PNF reduced hippocampal glutamate accumulation and upregulated GLT-1, GLAST, and GS expression, which were altered by PTZ stimulation. Conclusions: The PNF extract exhibits significant neuroprotective and antiepileptic effects in PTZ-kindled mice, likely through restoring glutamate homeostasis, and suppressing inflammation. These findings, with further clinical development, support the therapeutic potential of PNF as a complementary approach for epilepsy management. Full article

(This article belongs to the Collection Collection on Molecular and Cellular Neuroscience)

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16 pages, 462 KB

Open AccessArticle

Integration of Gestalt Therapy with Evidence-Based Interventions for Borderline Personality Disorder—Theoretical Framework and Clinical Model

by Enrico Moretto, Roberta Stanzione, Chiara Scognamiglio, Valeria Cioffi, Lucia Luciana Mosca, Francesco Marino, Ottavio Ragozzino, Enrica Tortora and Raffaele Sperandeo

Brain Sci. 2025, 15(10), 1109; https://doi.org/10.3390/brainsci15101109 - 15 Oct 2025

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Abstract

Background/Objectives: Gestalt therapy traditionally opposes categorical diagnostic labelling due to its fundamental inconsistency with phenomenological and process-oriented ontology. However, this epistemological rigour can limit integration with structured evidence-based interventions for complex personality organizations such as Borderline Personality Disorder (BPD). Despite the evidence base [...] Read more.

Background/Objectives: Gestalt therapy traditionally opposes categorical diagnostic labelling due to its fundamental inconsistency with phenomenological and process-oriented ontology. However, this epistemological rigour can limit integration with structured evidence-based interventions for complex personality organizations such as Borderline Personality Disorder (BPD). Despite the evidence base for DBT and Schema Therapy in treating BPD, these approaches may inadvertently minimize the lived phenomenological experience and organismic wisdom central to recovery. Meanwhile, Gestalt therapy’s anti-diagnostic stance limits its integration with structured evidence-based protocols. This paper proposes a hybrid theoretical model that addresses this gap by integrating the clinical epistemology of Gestalt therapy with Linehan’s biosocial theory of Dialectical Behaviour Therapy (DBT) and schema-focused interventions, while preserving the core principles of Gestalt. Methods: we present a model of theoretical integration that draws on Gestalt contact theory, the four modules of DBT (mindfulness, distress tolerance, emotional regulation, interpersonal effectiveness) and the experiential techniques of Schema Therapy. The integration focuses on the dialectic of acceptance and change, which mirrors Gestalt’s paradoxical theory of change. The proposed framework preserves the non-protocol dimension of Gestalt therapy while incorporating the pragmatic utility of DBT and Schema Therapy. Results: key conceptual contributions we propose include: (1) theorizing the “Draft Self” as the object and subject of therapeutic work, (2) integrating mindfulness and grounding as embodied processes within live Gestalt experiments, (3) activation techniques to explore the identity fragmentation endemic to BPD. Conclusions:his integration offers a coherent, embodied, and process-oriented framework for understanding and treating BPD that validates patients’ lived experience, mobilizes evidence-based interventions, and opens up meaningful intertheoretical dialogue. Full article

(This article belongs to the Special Issue Beyond the Brain: Merging Embodied Mind and AI in the Clinical Neuroscience of Psychotherapy)

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11 pages, 851 KB

Open AccessArticle

Distinguishing Among Variants of Primary Progressive Aphasia with a Brief Multimodal Test of Nouns and Verbs

by Marco A. Lambert, Melissa D. Stockbridge, Lindsey Kelly, Isidora Diaz-Carr, Voss Neal and Argye E. Hillis

Brain Sci. 2025, 15(10), 1108; https://doi.org/10.3390/brainsci15101108 - 15 Oct 2025

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Abstract

Background: Primary Progressive Aphasia (PPA) variants include the non-fluent agrammatic (nfvPPA), logopenic (lvPPA), and semantic (svPPA), which differ in their effects on speech production. However, their impact on modality (oral vs. written) and grammatical word class (nouns vs. verbs) remains controversial. A significant [...] Read more.

Background: Primary Progressive Aphasia (PPA) variants include the non-fluent agrammatic (nfvPPA), logopenic (lvPPA), and semantic (svPPA), which differ in their effects on speech production. However, their impact on modality (oral vs. written) and grammatical word class (nouns vs. verbs) remains controversial. A significant effect of these variables might assist in classification. Materials and Methods: This study used first-visit data from 300 participants with PPA who completed oral and written noun and verb naming (matched in surface word frequency across word class) to test the hypothesis that the three variants show differential impairment on word class or modality. Group differences were evaluated with rank-transformed repeated measures ANOVA. Within individual differences between nouns and verbs and between oral and written modalities were tested with Fisher’s exact tests. Results: A significant modality × variant interaction (p = 0.017) was observed. Participants with lvPPA and nfvPPA demonstrated greater oral than written naming, with nfvPPA also performing better on nouns than verbs. Those with svPPA showed no modality or word class effects but had an overall low accuracy. Three participants with svPPA (but no individuals with the other variants) demonstrated significantly (p = 0.003) more accurate verb than noun naming. Conclusions: Differing modality and word class patterns characterize PPA variants, with nfvPPA more accurate in nouns than verbs on average. Within individuals, only those with svPPA occasionally showed significantly more proficient verb than noun naming. Grammatical word class effects likely arise at distinct levels of cognitive processing underlying naming. Full article

(This article belongs to the Special Issue Primary Progressive Aphasia: What Happens to Speech and Language? What Can We Do to Help?)

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17 pages, 4020 KB

Open AccessArticle

Medication vs. Movement in ADHD: Interaction Between Medication and Physical Activity on Neurocognitive Functioning

by Beverly-Ann Hoy, Michelle Bi, Matthew Lam, Androu Abdalmalak and Barbara Fenesi

Brain Sci. 2025, 15(10), 1107; https://doi.org/10.3390/brainsci15101107 - 15 Oct 2025

Viewed by 247

Abstract

Background/Objectives: Movement during attention-demanding tasks may help compensate for cortical under-arousal in pediatric ADHD patients. However, the influence of medication during movement is unknown. This study assessed the impact of concurrent movement during executive functioning tasks on dorsolateral prefrontal cortex (DLPFC) activation [...] Read more.

Background/Objectives: Movement during attention-demanding tasks may help compensate for cortical under-arousal in pediatric ADHD patients. However, the influence of medication during movement is unknown. This study assessed the impact of concurrent movement during executive functioning tasks on dorsolateral prefrontal cortex (DLPFC) activation and inhibitory control, with a particular focus on the influence of medication status. Methods: Twenty-six children with ADHD (15 medicated; 11 unmedicated) and 24 children without ADHD performed a Stroop task under two conditions: while remaining seated (Stationary condition) and while pedalling on a desk cycle (Movement condition). Functional near-infrared spectroscopy (fNIRS) was used to measure changes in oxygenated and deoxygenated hemoglobin levels in the left DLPFC. Results: Sixty-four percent of unmedicated children with ADHD showed greater left DLPFC activity while desk-cycling compared to remaining stationary. Only 37% of medicated children with ADHD showed the same pattern, with 63% showing greater left DLPFC activation when remaining stationary during executive functioning. Children without ADHD had similar DLPFC patterns as unmedicated ADHD children, with 65% showing increased activation during movement. Unmedicated ADHD children who were able to desk-cycle during the Stroop task had higher overall and incongruent accuracy scores; no Stroop differences were found between conditions for children with ADHD who were medicated or for controls. Conclusions: Medicated ADHD children did not benefit from physical activity during tasks requiring executive control, yet unmedicated ADHD children showed significantly greater DLPFC activation and inhibitory control when engaging in movement. If medication is not suitable for children with ADHD due to adverse side effects, movement during executive functioning may help mimic the benefit of medications and similarly support attention. Full article

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

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32 pages, 5306 KB

Open AccessReview

Neuroimaging and Machine Learning in OCD: Advances in Diagnostic and Therapeutic Insights

by Norah A. Alturaiqi, Wijdan S. Aljebreen, Wedad Alawad, Shuaa S. Alharbi and Haifa F. Alhasson

Brain Sci. 2025, 15(10), 1106; https://doi.org/10.3390/brainsci15101106 - 14 Oct 2025

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Abstract

Background/Objectives: Obsessive–Compulsive Disorder (OCD) is a chronic mental health condition characterized by intrusive thoughts and repetitive behaviors. Traditional diagnostic methods rely on subjective clinical assessments, delaying effective intervention. This review examines how advanced neuroimaging techniques, such as Magnetic Resonance Imaging (MRI) and Diffusion [...] Read more.

Background/Objectives: Obsessive–Compulsive Disorder (OCD) is a chronic mental health condition characterized by intrusive thoughts and repetitive behaviors. Traditional diagnostic methods rely on subjective clinical assessments, delaying effective intervention. This review examines how advanced neuroimaging techniques, such as Magnetic Resonance Imaging (MRI) and Diffusion Tensor Imaging (DTI), integrated with machine learning (ML), can improve OCD diagnostics by identifying structural and functional brain abnormalities, particularly in the cortico-striato-thalamo-cortical (CSTC) circuit. Methods: Findings from studies using MRI and DTI to identify OCD-related neurobiological markers are synthesized. Machine learning algorithms like Convolutional Neural Networks (CNNs) and Support Vector Machines (SVMs) are evaluated for their ability to analyze neuroimaging data. The role of transfer learning in overcoming dataset limitations and heterogeneity is also explored. Results: ML algorithms have achieved diagnostic accuracies exceeding 80%, revealing subtle neurobiological markers linked to OCD. Abnormalities in the CSTC circuit are consistently identified. Transfer learning shows promise in enhancing predictive modeling and enabling personalized treatment strategies, especially in resource-constrained settings. Conclusions: The integration of neuroimaging and ML represents a transformative approach to OCD diagnostics, offering improved accuracy and biologically informed insights. Future research should focus on optimizing multimodal imaging techniques, increasing data generalizability, and addressing interpretability challenges to enhance clinical applicability. These innovations have the potential to advance precision diagnostics and support more targeted therapeutic interventions, ultimately improving outcomes for individuals with OCD. Full article

(This article belongs to the Section Computational Neuroscience, Neuroinformatics, and Neurocomputing)

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30 pages, 2250 KB

Open AccessReview

The Orexin System in Addiction: Neuromodulatory Interactions and Therapeutic Potential

by Toni Capó, Jaume Lillo, Joan Biel Rebassa, Pau Badia, Iu Raïch, Erik Cubeles-Juberias, Irene Reyes-Resina and Gemma Navarro

Brain Sci. 2025, 15(10), 1105; https://doi.org/10.3390/brainsci15101105 - 14 Oct 2025

Viewed by 431

Abstract

According to the World Drug Report, there are nearly 300 million drug users globally. Drug addiction is a chronic, relapsing brain disease that leads to medical, psychological, and social complications. This neuropsychiatric disorder is characterized by a compulsive drug-seeking behavior, continued use despite [...] Read more.

According to the World Drug Report, there are nearly 300 million drug users globally. Drug addiction is a chronic, relapsing brain disease that leads to medical, psychological, and social complications. This neuropsychiatric disorder is characterized by a compulsive drug-seeking behavior, continued use despite harmful consequence, and long-lasting changes in the brain. The reward system, which involves dopaminergic circuits, plays a key role in addiction. Dopamine levels have been described to fluctuate throughout the day, in a circadian fashion, and the effects of drugs have been shown to depend on the time when they are used. Hence, due to its important role in the control of circadian rhythms, the orexinergic system seems to have a role in the regulation of addiction. This system is composed by the orexin receptors 1 and 2 (OX₁R and OX₂R), the ligands orexin A (OXA) and orexin B (OXB) and their respective enzymes for degradation or synthesis. Here, we explore how orexin receptors and orexin peptides are involved in addiction. For instance, OX₁R has been shown to be strongly involved in specific behaviors such as drug-seeking for stimulants, alcohol and other addiction problems, whereas OX₂R appears to be linked with arousal and stress responses. We also investigate how the orexinergic system may regulate drug-seeking behavior by interaction with other brain systems such as the dopaminergic, cannabinoid or opioid systems. Finally, the potential of receptor complexes as new therapeutic targets to treat drug addiction is explored. Full article

(This article belongs to the Special Issue Editorial Board Collection Series: Innovative Research in Molecular and Cellular Neuroscience for Regulation of Cell Death Mechanisms for Functional Neuroprotection)

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17 pages, 976 KB

Open AccessReview

Current State-of-the-Art Animal Models of Pediatric Brain Tumors

by Tanusri Gudavalli, Fred C. Lam, Santosh Guru, Deyaldeen AbuReesh, Yusuke S. Hori, Susan Hiniker, David J. Park and Steven D. Chang

Brain Sci. 2025, 15(10), 1104; https://doi.org/10.3390/brainsci15101104 - 14 Oct 2025

Viewed by 312

Abstract

Brain tumors are unfortunately the most common types of solid tumors in the pediatric population, superseded only by leukemias, and largely bode a poor prognosis. Despite advances in our ability to diagnose and treat pediatric brain tumors, there remains a large unmet need [...] Read more.

Brain tumors are unfortunately the most common types of solid tumors in the pediatric population, superseded only by leukemias, and largely bode a poor prognosis. Despite advances in our ability to diagnose and treat pediatric brain tumors, there remains a large unmet need to develop novel therapies to improve patient outcomes. The recent understanding of the molecular drivers of oncogenesis for many of these tumors has led to the engineering of preclinical small animal models which serve as valuable tools for scientists to study the mechanisms of tumor biology, to understand interactions with the tumor microenvironment, and allow for translatable novel therapeutic discovery. This review focuses on the state-of-the art development of preclinical models of two difficult-to-treat pediatric brain tumors: (1) diffuse midline gliomas, the most lethal form of pediatric brain cancer; (2) medulloblastoma, the most common embryonal tumor of the central nervous system. We will then round off this review with a discussion on the emerging use of multi-omics and AI approaches to complement the testing of novel therapies using these in vivo animal models. Full article

(This article belongs to the Section Neuro-oncology)

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14 pages, 5156 KB

Open AccessArticle

Detection of EEG Activity in Response to the Surrounding Environment: A Neuro-Architecture Study

by Jesús S. García-Salinas, Anna Wróblewska and Michal T. Kucewicz

Brain Sci. 2025, 15(10), 1103; https://doi.org/10.3390/brainsci15101103 - 14 Oct 2025

Viewed by 379

Abstract

Background: The external environment continuously shapes human perception, often without conscious awareness. This influence can be objectively studied using non-invasive recordings of brain activity in controlled virtual reality (VR) settings. We hypothesized that brief presentations of natural features would elicit distinct neural [...] Read more.

Background: The external environment continuously shapes human perception, often without conscious awareness. This influence can be objectively studied using non-invasive recordings of brain activity in controlled virtual reality (VR) settings. We hypothesized that brief presentations of natural features would elicit distinct neural oscillatory patterns detectable through changes in the spectral power of resting-state electroencephalogram (EEG) activity in specific brain regions. Methods: To test this, participants passively viewed three minimalist VR environments—with and without biophilic elements—while their EEG was recorded. Results: Our results revealed consistent changes in spectral power, particularly suppression in the alpha band and an increase in the theta band in the occipital cortex. Conclusions: These findings support the use of resting-state EEGs in immersive VR as a promising and objective method for evaluating how specific design elements influence neural activity, offering valuable insights into the field of neuro-architecture. Full article

(This article belongs to the Section Neurotechnology and Neuroimaging)

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16 pages, 682 KB

Open AccessArticle

Confusion Assessment Protocol: Italian Cross-Cultural Adaptation and Validation

by Giulia Ferri, Anna Carannante, Manuela Iannetti, Sara Schiattone, Paola Ciurli, Fabiana Mogavero, Valentina Massimi, Marta Aloisi, Rita Formisano and Marco Giustini

Brain Sci. 2025, 15(10), 1102; https://doi.org/10.3390/brainsci15101102 - 13 Oct 2025

Viewed by 227

Abstract

Background: This study validated the Italian version of the Confusion Assessment Protocol (CAP), a tool designed to assess Post-Traumatic Confusional State (PTCS) in patients with severe acquired brain injury (sABI) who are not evaluable with standard neuropsychological evaluations. Objectives: The primary aim [...] Read more.

Background: This study validated the Italian version of the Confusion Assessment Protocol (CAP), a tool designed to assess Post-Traumatic Confusional State (PTCS) in patients with severe acquired brain injury (sABI) who are not evaluable with standard neuropsychological evaluations. Objectives: The primary aim of this study was to promote the CAP as a tool for assessing patients who are not still eligible for standard neuropsychological evaluation and to adapt it to Italian-speaking sABI patients by translating it into Italian and conducting a cross-cultural adaptation and evaluating its psychometric properties. The secondary objective was to correlate the CAP scores with broader functional scales, such as the Levels of Cognitive Functioning Assessment Scale (LCF) and Disability Rating Scale (DRS). Methods: A total of 42 sABI patients were enrolled at IRCCS Fondazione Santa Lucia. The CAP was translated and culturally adapted using international back-translation guidelines. Cross-cultural validity was assessed in 20 patients. The final version was administered by three trained raters over two days to evaluate inter- and intra-rater reliability. Results: The Italian version of the CAP demonstrated high internal consistency and substantial inter-rater reliability for key symptoms, including night-time sleep disturbances, decreased daytime arousal, and psychotic-type symptoms. Cognitive impairment showed moderate inter-rater agreement, likely due to symptom fluctuations typical of this recovery phase. The convergent validity of the CAP was confirmed through its correlations with the Levels of Cognitive Functioning (LCF) and the Disability Rating Scale (DRS), demonstrating its clinical utility in integrating cognitive and behavioral symptom assessments. Conclusions: The Italian version of the CAP is a reliable and valid tool for assessing PTCS in sABI. Future developments should address limitations related to symptom intensity, behavioral domains, and differential symptom weighting. Full article

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

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25 pages, 1071 KB

Open AccessReview

Therapeutic Advances in Targeting the Amyloid-β Pathway for Alzheimer’s Disease

by Beiyu Zhang, Yunan Li, Huan Li, Xinai Shen and Zheying Zhu

Brain Sci. 2025, 15(10), 1101; https://doi.org/10.3390/brainsci15101101 - 13 Oct 2025

Viewed by 262

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline and neuropathological hallmarks, including amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), and neurodegeneration. Since the amyloid cascade hypothesis was proposed, Aβ has remained a central therapeutic target, with interventions [...] Read more.

Alzheimer’s disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline and neuropathological hallmarks, including amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), and neurodegeneration. Since the amyloid cascade hypothesis was proposed, Aβ has remained a central therapeutic target, with interventions aiming to reduce Aβ production, aggregation, or downstream toxicity. This review first outlines the historical development of the Aβ hypothesis and the two major APP processing pathways (α-cleavage and β-cleavage), highlighting the role of biomarkers in early diagnosis, patient stratification, and regulatory approval. We then summarize the development and clinical outcomes of anti-Aβ small-molecule drugs, including β-secretase inhibitors, γ-secretase modulators, Aβ aggregation inhibitors, receptor/synapse modulators, and metabolic or antioxidant modalities. We further review the progression of biologic therapies, with a particular focus on monoclonal antibodies, vaccines, and emerging gene-silencing strategies, such as small interfering RNA (siRNA) and antisense oligonucleotides. Finally, we discuss future perspectives, including next-generation biologics, multi-target approaches, optimized delivery platforms, and early-prevention strategies. Collectively, these efforts underscore both the challenges and opportunities in translating anti-Aβ therapies into meaningful clinical benefits for patients with AD. Full article

(This article belongs to the Section Neurodegenerative Diseases)

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12 pages, 556 KB

Open AccessArticle

Difficulty in Attention Switching and Its Neural Basis in Problematic Smartphone Use

by Nanase Kobayashi, Daisuke Jitoku, Toshitaka Hamamura, Masaru Honjo, Yusei Yamaguchi, Masaaki Shimizu, Shunsuke Takagi, Junya Fujino, Genichi Sugihara and Hidehiko Takahashi

Brain Sci. 2025, 15(10), 1100; https://doi.org/10.3390/brainsci15101100 - 13 Oct 2025

Viewed by 322

Abstract

Background: Problematic smartphone use (PSU) involves excessive smartphone engagement that disrupts daily functioning and is linked to attentional control deficits and altered reward processing. The nucleus accumbens (NAcc), a key structure in the reward system, may contribute to difficulty disengaging from rewarding [...] Read more.

Background: Problematic smartphone use (PSU) involves excessive smartphone engagement that disrupts daily functioning and is linked to attentional control deficits and altered reward processing. The nucleus accumbens (NAcc), a key structure in the reward system, may contribute to difficulty disengaging from rewarding digital content. This study examined relationships between NAcc volume, attentional switching, and objectively measured nighttime screen time in individuals with PSU. Methods: Fifty-three participants (aged ≥ 13 years) from an outpatient internet dependency clinic completed psychological assessments, brain MRI, and smartphone logging. PSU was diagnosed by two psychiatrists. Attentional switching was measured via the Autism Spectrum Quotient subscale. Nighttime screen time (00:00–06:00) was recorded via smartphone. MRI-derived NAcc volumes were normalized to total gray matter volume. Correlations, multiple regression (controlling for ASD and ADHD), and mediation analyses were conducted. Results: Difficulty in attention switching correlated with larger right NAcc volume (r = 0.45, p = 0.012) and increased nighttime screen time (r = 0.44, p = 0.014). Right NAcc volume also correlated with nighttime screen time (r = 0.46, p = 0.012). Regression showed right NAcc volume predicted nighttime screen time (β = 0.33, p = 0.022), whereas attentional switching was not significant. Mediation was unsupported. Sensitivity analyses confirmed associations. Conclusions: Larger right NAcc volume independently predicts prolonged nighttime smartphone use and is associated with impaired attentional switching in PSU. Structural variations in reward-related regions may underlie difficulty disengaging from digital content. Integrating neurobiological, cognitive, and behavioral measures offers a framework for understanding PSU. Full article

(This article belongs to the Special Issue The Latest Exploration of Gaming Disorders and Related Mental Health Issues)

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11 pages, 1875 KB

Open AccessArticle

When Time Equals Vision: The Neuro-Ophthalmic Outcomes of Patients with Fulminant Idiopathic Intracranial Hypertension Undergoing Emergent Cerebral Transverse Venous Stenting

by Assaf Kratz, Eyal Walter, Asaf Honig, Alexander Chorny, Gal Ben-Arie, Erez Tsumi, Tamir Regev and Anat Horev

Brain Sci. 2025, 15(10), 1099; https://doi.org/10.3390/brainsci15101099 - 13 Oct 2025

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Abstract

Background: Fulminant idiopathic intracranial hypertension (IIH) is a rare and vision-threatening variant of IIH, characterized by rapid visual deterioration and a high risk of irreversible blindness. Urgent intervention is required to prevent permanent optic nerve damage. Cerebral transverse venous stenting (CTVS) has emerged [...] Read more.

Background: Fulminant idiopathic intracranial hypertension (IIH) is a rare and vision-threatening variant of IIH, characterized by rapid visual deterioration and a high risk of irreversible blindness. Urgent intervention is required to prevent permanent optic nerve damage. Cerebral transverse venous stenting (CTVS) has emerged as an effective treatment for medically refractory IIH, but data on its use in fulminant cases remain limited. Methods: A retrospective consecutive cohort study was conducted at a tertiary center and included all patients with fulminant IIH diagnosed by modified Dandy criteria, with bilateral transverse sinus stenosis > 50% and a trans-stenotic pressure gradient ≥ 8 mmHg on venography. Before stenting, patients received high-dose acetazolamide (up to 3000 mg/day) and IV methylprednisolone (1000 mg/day × 3). Neuro-ophthalmic assessment included BCVA, Ishihara color vision, pupillary exam, disc edema grading, Humphrey visual fields, and optical coherence tomography (OCT). Follow-up occurred at baseline (admission), 1 week, 1 month, 3 months, and 12 months. Results: Five young female patients underwent successful CTVS without peri- or post-procedural complications. Significant improvement in headache and stabilization or recovery of visual function were observed in all patients. OCT revealed early retinal nerve fiber layer thinning within one week, preceding clinical resolution of papilledema. Conclusions: Emergent CTVS appears to be a safe and effective vision-preserving procedure in fulminant IIH, offering rapid intracranial pressure reduction and early neuro-ophthalmologic improvement. OCT may serve as a useful early predictor of treatment success, supporting its role in post-procedural monitoring. Larger prospective studies are warranted. 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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1 pages, 129 KB

Open AccessCorrection

Correction: Marchant et al. Ankle Somatosensation and Lower-Limb Neuromuscular Function on a Lunar Gravity Analogue. Brain Sci. 2025, 15, 443

by Ashleigh Marchant, Nick Ball, Jeremy Witchalls, Sarah B. Wallwork and Gordon Waddington

Brain Sci. 2025, 15(10), 1098; https://doi.org/10.3390/brainsci15101098 - 13 Oct 2025

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Abstract

This update pertains to the article previously published by Marchant et al [...] Full article

32 pages, 532 KB

Open AccessReview

by Elena Barbuti, Claudia Piervincenzi, Serena Ruggieri and Maria Petracca

Brain Sci. 2025, 15(10), 1097; https://doi.org/10.3390/brainsci15101097 - 11 Oct 2025

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Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that affects women more frequently than men. This sex gap has widened over the past century, and appears to be shaped by lifestyle factors more than biological factors. This narrative [...] Read more.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that affects women more frequently than men. This sex gap has widened over the past century, and appears to be shaped by lifestyle factors more than biological factors. This narrative review examines the evidence for sex-specific differences in lifestyle risk factors and their impact on both MS susceptibility and disease progression, with implications for diagnosis, monitoring, and treatment. Smoking, obesity, vitamin D deficiency, ultraviolet radiation exposure, and Epstein–Barr virus infection all interact with sex-related biological pathways to influence MS risk. Women appear to be more vulnerable to the pathogenic effects of smoking and obesity, both independently and in synergy with genetic risk alleles, while vitamin D and UV exposure confer stronger protective effects in females than in males. EBV infection also exhibits sex-dependent immune responses, shaped by hormonal regulation and host–virus genetic interactions. Sex-related lifestyle factors also modulate MS progression. Women experience more inflammatory activity and relapses, whereas men more often develop a progressive phenotype with greater neurodegeneration. Hormonal changes during female reproductive phases, such as pregnancy, breastfeeding, menopause, and hormone-based therapies, critically influence disease activity and progression in MS. Obesity, smoking, vitamin D status, diet, and gut microbiota further interact with sex hormones and genetic background, contributing to variable disease trajectories, also modulated by social determinants such as education level. These findings underscore the need to integrate into clinical practice the evaluation of lifestyle factors in a sex-specific way for diagnosis, monitoring, and treatment of MS. Full article

(This article belongs to the Special Issue Lifestyle and Risk Factors for Multiple Sclerosis)

20 pages, 3090 KB

Open AccessArticle

Regional Brain Volume Changes Across Adulthood: A Multi-Cohort Study Using MRI Data

by Jae Hyuk Shim, Hyeon-Man Baek and Jung Hoon

Brain Sci. 2025, 15(10), 1096; https://doi.org/10.3390/brainsci15101096 - 11 Oct 2025

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Abstract

Background/Objectives: Age-related structural changes in the human brain provide essential insights into cognitive aging and the onset of neurodegenerative diseases. This study aimed to comprehensively characterize age-related volumetric changes across multiple brain regions in a large, diverse, cognitively healthy cohort spanning adulthood (ages [...] Read more.

Background/Objectives: Age-related structural changes in the human brain provide essential insights into cognitive aging and the onset of neurodegenerative diseases. This study aimed to comprehensively characterize age-related volumetric changes across multiple brain regions in a large, diverse, cognitively healthy cohort spanning adulthood (ages 21–90), integrating Korean, Information eXtraction from Images (IXI), and Alzheimer’s Disease Neuroimaging Initiative (ADNI) MRI datasets of cognitively healthy participants to characterize normative volumetric changes across adulthood using demographically diverse datasets. Methods: High resolution 3T T1-weighted MRI images from three distinct cohorts (totaling 1833 subjects) were processed through an optimized neuroimaging pipeline, combining advanced preprocessing with neural network-based segmentation. Volumetric data for 95 brain structures were segmented and analyzed across seven age bins (21–30 through 81–90). Pipeline reliability was validated against FreeSurfer using intraclass correlation coefficients (ICC) and coefficients of variation (CoV). Regression-based correction was used to correct for sex and cohort effects on brain region volume. Then, percentage change in each mean bilateral volumes of regions across the lifespan were computed to describe volumetric changes across life spans. Results: The segmentation pipeline demonstrated excellent agreement with FreeSurfer (mean ICC: 0.9965). Drastic volumetric expansions were observed in white matter hypointensities (122.6%), lateral ventricles (115.9%), and inferior lateral ventricles (116.8%). Moderate-to-notable shrinkage was found predominantly in the frontal lobe (pars triangularis: 21.5%), parietal lobe (inferior parietal: 20.4%), temporal lobe (transverse temporal: 21.6%), and cingulate cortex (caudal anterior cingulate: 16.1%). Minimal volume changes occurred in regions such as the insula (3.7%) and pallidum (2.6%). Conclusions: This study presents a comprehensive reference of normative regional brain volume changes across adulthood, highlighting substantial inter-regional variability. The findings can provide an essential foundation for differentiating normal aging patterns from early pathological alterations. Full article

(This article belongs to the Section Developmental Neuroscience)

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6 pages, 151 KB

Open AccessEditorial

Recent Advances in Assessment and Rehabilitation of Individuals with Communication and Language Disorders

by Dionysios Tafiadis, Angelos Papadopoulos, Louiza Voniati and Nafsika Ziavra

Brain Sci. 2025, 15(10), 1095; https://doi.org/10.3390/brainsci15101095 - 11 Oct 2025

Viewed by 227

Abstract

Currently, in the field of rehabilitation, there is a need for researchers and clinicians to stay updated on recent knowledge worldwide [...] Full article

(This article belongs to the Special Issue Recent Advances in Assessment and Rehabilitation of Individuals with Communication and Language Disorders)

23 pages, 961 KB

Open AccessSystematic Review

Driving Performance in Schizophrenia: The Role of Neurocognitive Correlates—A Systematic Review

by Georgia Karakitsiou, Spyridon Plakias, Aikaterini Arvaniti, Magdalini Katsikidou, Katerina Kedraka and Maria Samakouri

Brain Sci. 2025, 15(10), 1094; https://doi.org/10.3390/brainsci15101094 - 10 Oct 2025

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Abstract

Background/Objectives: Schizophrenia is associated with cognitive deficits that may compromise everyday functioning, including driving. This review systematically examined recent original research (2015–2025) on driving performance in individuals with schizophrenia with a focus on neuropsychological factors, applying a narrative synthesis given the heterogeneity [...] Read more.

Background/Objectives: Schizophrenia is associated with cognitive deficits that may compromise everyday functioning, including driving. This review systematically examined recent original research (2015–2025) on driving performance in individuals with schizophrenia with a focus on neuropsychological factors, applying a narrative synthesis given the heterogeneity of designs and outcomes, while no quantitative meta-analysis was feasible. Methods: Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a structured search of PubMed and Scopus was conducted on 4 May 2025. The inclusion criteria were original studies involving individuals diagnosed with schizophrenia, published between 2015 and 2025. Studies on animals, other psychiatric or neurological conditions, and healthy populations were also excluded. Critical appraisal was performed using the Joanna Briggs Institute (JBI) tools. Extracted data included sample demographics, cognitive deficits, neuropsychological assessments, brain imaging, and the main findings. A narrative synthesis was then performed. Results: Six high-quality studies met the inclusion criteria. Findings were grouped into three categories: (1) driving behavior: fitness to drive varied widely across individuals, (2) cognitive deficits and brain activity: poorer driving-related performance was consistently associated with specific impairments in cognition and brain structure, and (3) medication effects: individuals taking certain atypical antipsychotics demonstrated better driving performance compared to those on other types of medication, while extrapyramidal symptoms negatively influenced driving fitness. Conclusions: Driving in schizophrenia is shaped by cognitive, clinical, and pharmacological factors. These findings highlight the clinical relevance of individualized evaluations, integration into personalized care and targeted rehabilitation to promote driving autonomy and community inclusion. This area remains under-researched, as only six studies met the inclusion criteria, which restricts the robustness and generalizability of the conclusions. Funding: This review received no funding from any external sources. Registration: The review protocol was submitted to PROSPERO (International Prospective Register of Systematic Reviews) under registration number CRD420251060580. Full article

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

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