Brain Sciences

21 pages, 1102 KB

Open AccessArticle

Near-Real-Time Epileptic Seizure Detection with Reduced EEG Electrodes: A BiLSTM-Wavelet Approach on the EPILEPSIAE Dataset

by Kiyan Afsari, May El Barachi and Christian Ritz

Brain Sci. 2026, 16(1), 119; https://doi.org/10.3390/brainsci16010119 - 22 Jan 2026

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Abstract

Background and Objectives: Epilepsy is a chronic neurological disorder characterized by recurrent seizures caused by abnormal brain activity. Reliable near-real-time seizure detection is essential for preventing injuries, enabling early interventions, and improving the quality of life for patients with drug-resistant epilepsy. This study [...] Read more.

Background and Objectives: Epilepsy is a chronic neurological disorder characterized by recurrent seizures caused by abnormal brain activity. Reliable near-real-time seizure detection is essential for preventing injuries, enabling early interventions, and improving the quality of life for patients with drug-resistant epilepsy. This study presents a near-real-time epileptic seizure detection framework designed for low-latency operation, focusing on improving both clinical reliability and patient comfort through electrode reduction. Method: The framework integrates bidirectional long short-term memory (BiLSTM) networks with wavelet-based feature extraction using Electroencephalogram (EEG) recordings from the EPILEPSIAE dataset. EEG signals from 161 patients comprising 1032 seizures were analyzed. Wavelet features were combined with raw EEG data to enhance temporal and spectral representation. Furthermore, electrode reduction experiments were conducted to determine the minimum number of strategically positioned electrodes required to maintain performance. Results: The optimized BiLSTM model achieved 86.9% accuracy, 86.1% recall, and an average detection delay of 1.05 s, with a total processing time of 0.065 s per 0.5 s EEG window. Results demonstrated that reliable detection is achievable with as few as six electrodes, maintaining comparable performance to the full configuration. Conclusions: These findings demonstrate that the proposed BiLSTM-wavelet approach provides a clinically viable, computationally efficient, and wearable-friendly solution for near-real-time epileptic seizure detection using reduced EEG channels. Full article

(This article belongs to the Section Neural Engineering, Neuroergonomics and Neurorobotics)

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10 pages, 237 KB

Open AccessArticle

High-Frequency Spinal Cord Stimulation for the Treatment of Spasticity: A Preliminary Case Series

by Alessandro Izzo, Benedetta Burattini, Renata Martinelli, Quintino Giorgio D’Alessandris, Manuela D'Ercole, Maria Filomena Fuggetta and Nicola Montano

Brain Sci. 2026, 16(1), 118; https://doi.org/10.3390/brainsci16010118 - 22 Jan 2026

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Abstract

Background: Spasticity is a complex and multifactorial condition resulting from upper motor neuron injury. It manifests through muscle contractions, pain, limited range of motion, and clonus, which significantly impair daily activities and quality of life. High-frequency spinal cord stimulation (HF SCS) has shown [...] Read more.

Background: Spasticity is a complex and multifactorial condition resulting from upper motor neuron injury. It manifests through muscle contractions, pain, limited range of motion, and clonus, which significantly impair daily activities and quality of life. High-frequency spinal cord stimulation (HF SCS) has shown optimal results in treating chronic neuropathic pain, but its potential role in spasticity remains underexplored. This study aimed to evaluate the efficacy of HF SCS in patients with spasticity. Methods: From April 2021 to July 2024, six patients with spasticity from various etiologies underwent SCS implantation at our institution. Clinical evaluations including the use of the Visual Analog Scale (VAS), Douleur Neuropathique 4 (DN4), and the Ashworth score, as well as ambulation ability and clonus episodes, were performed preoperatively and at a minimum of six months post-surgery. Subjective assessments of motor function, including coordination, movement efficiency, and postural transitions, were also recorded. Results: The mean age of patients was 50.12 ± 9.41 years, with follow-up averaging 24.32 ± 10.83 months. Statistically significant improvements were observed in VAS (p = 0.0412) and DN4 (p = 0.0422) scores, alongside a reduction in clonus episodes. All patients reported subjective improvements in coordination, movement efficiency, and postural transitions. Ambulation remained stable or improved in all cases. No perioperative complications or sensory/motor side effects were noted. Conclusions: HF SCS offers a promising approach to managing spasticity, with improvements in motor function, ambulation, and postural transitions. These findings support further investigation into HF SCS for spasticity, with multicenter trials needed to optimize treatment protocols and identify the most responsive patient populations. Full article

(This article belongs to the Special Issue New Advances in Functional Neurosurgery—2nd Edition)

20 pages, 2476 KB

Open AccessCase Report

Improving Lexicosemantic Impairments in Post-Stroke Aphasia Using rTMS Targeting the Right Anterior Temporal Lobe

by Sophie Arheix-Parras, Sophia R. Moore and Rutvik H. Desai

Brain Sci. 2026, 16(1), 117; https://doi.org/10.3390/brainsci16010117 - 22 Jan 2026

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Abstract

Background/Objectives: Repetitive Transcranial Magnetic Stimulation (rTMS) can enhance post-stroke aphasia recovery. The right Inferior Frontal Gyrus is the most common target in rTMS studies for inhibitory stimulation. However, lexicosemantic processes involve a large brain network including the Anterior Temporal Lobe (ATL). We [...] Read more.

Background/Objectives: Repetitive Transcranial Magnetic Stimulation (rTMS) can enhance post-stroke aphasia recovery. The right Inferior Frontal Gyrus is the most common target in rTMS studies for inhibitory stimulation. However, lexicosemantic processes involve a large brain network including the Anterior Temporal Lobe (ATL). We hypothesize that rTMS targeting the ATL will improve lexicosemantic impairments in people with post-stroke aphasia. Methods: In a Single-Case Experimental Design, three people with post-stroke aphasia with lexicosemantic impairments performed Picture and Auditory Naming and Semantic Decision tasks five times a week for one or two weeks to establish baseline scores. Then, each participant received continuous inhibitory Theta Burst Stimulation targeting the right ATL, five times a week for two weeks. After each rTMS session, participants performed all linguistic tasks. A follow-up measurement was performed one month after the end of the study. Results: All participants showed significant improvement in the Picture Naming task, while only P1 improved in Auditory Naming accuracy. In the Semantic Decision task, only P2 showed improvement in both accuracy and RT, while P1 showed improvement in RT alone and P3 showed no improvement. Conclusions: The results suggest that ATL could be a potential target for future brain stimulation studies in aphasia involving lexicosemantic impairments. RTMS targeting the ATL may modulate the connected ventral semantic stream, leading to improvements in lexical access. This preliminary study highlights the possibility of selecting the cortical target for rTMS based on the clinical profile of the participant, an approach that will need further investigation in larger sham-controlled studies. Full article

(This article belongs to the Special Issue Diagnosis and Treatment of Post-Stroke and Progressive Aphasias)

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45 pages, 1773 KB

Open AccessSystematic Review

Neural Efficiency and Sensorimotor Adaptations in Swimming Athletes: A Systematic Review of Neuroimaging and Cognitive–Behavioral Evidence for Performance and Wellbeing

by Evgenia Gkintoni, Andrew Sortwell and Apostolos Vantarakis

Brain Sci. 2026, 16(1), 116; https://doi.org/10.3390/brainsci16010116 - 22 Jan 2026

Viewed by 270

Abstract

Background/Objectives: Swimming requires precise motor control, sustained attention, and optimal cognitive–motor integration, making it an ideal model for investigating neural efficiency—the phenomenon whereby expert performers achieve optimal outcomes with reduced neural resource expenditure, operationalized as lower activation, sparser connectivity, and enhanced functional integration. [...] Read more.

Background/Objectives: Swimming requires precise motor control, sustained attention, and optimal cognitive–motor integration, making it an ideal model for investigating neural efficiency—the phenomenon whereby expert performers achieve optimal outcomes with reduced neural resource expenditure, operationalized as lower activation, sparser connectivity, and enhanced functional integration. This systematic review examined cognitive performance and neural adaptations in swimming athletes, investigating neuroimaging and behavioral outcomes distinguishing swimmers from non-athletes across performance levels. Methods: Following PRISMA 2020 guidelines, seven databases were searched (1999–2024) for studies examining cognitive/neural outcomes in swimmers using neuroimaging or validated assessments. A total of 24 studies (neuroimaging: n = 9; behavioral: n = 15) met the inclusion criteria. Risk of bias assessment used adapted Cochrane RoB2 and Newcastle–Ottawa Scale criteria. Results: Neuroimaging modalities included EEG (n = 4), fMRI (n = 2), TMS (n = 1), and ERP (n = 2). Key associations identified included the following: (1) Neural Efficiency: elite swimmers showed sparser upper beta connectivity (35% fewer connections, d = 0.76, p = 0.040) and enhanced alpha rhythm intensity (p ≤ 0.01); (2) Cognitive Performance: superior attention, working memory, and executive control correlated with expertise (d = 0.69–1.31), with thalamo-sensorimotor functional connectivity explaining 41% of world ranking variance (r² = 0.41, p < 0.001); (3) Attention: external focus strategies improved performance in intermediate swimmers but showed inconsistent effects in experts; (4) Mental Fatigue: impaired performance in young adult swimmers (1.2% decrement, d = 0.13) but not master swimmers (p = 0.49); (5) Genetics: COMT Val158Met polymorphism associated with performance differences (p = 0.026). Effect sizes ranged from small to large, with Cohen’s d = 0.13–1.31. Conclusions: Swimming expertise is associated with specific neural and cognitive characteristics, including efficient brain connectivity and enhanced cognitive control. However, cross-sectional designs (88% of studies) and small samples (median n = 36; all studies underpowered) preclude causal inference. The lack of spatially quantitative synthesis and visualization of neuroimaging findings represents a methodological limitation of this review and the field. The findings suggest potential applications for talent identification, training optimization, and mental health promotion through swimming but require longitudinal validation and development of standardized swimmer brain atlases before definitive recommendations. Full article

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

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15 pages, 242 KB

Open AccessReview

Real-World Evidence for Psychiatric Disorders from the German Disease Analyzer Database: A Narrative Review

by Karel Kostev, Marcel Konrad and Jens Bohlken

Brain Sci. 2026, 16(1), 115; https://doi.org/10.3390/brainsci16010115 - 21 Jan 2026

Viewed by 319

Abstract

The German IQVIA Disease Analyzer (DA) database has become an increasingly important source of real-world evidence for psychiatric research. Over the past decade, and particularly since 2020, DA-based studies have addressed a broad spectrum of psychiatric outcomes including depression, anxiety disorders, schizophrenia, bipolar [...] Read more.

The German IQVIA Disease Analyzer (DA) database has become an increasingly important source of real-world evidence for psychiatric research. Over the past decade, and particularly since 2020, DA-based studies have addressed a broad spectrum of psychiatric outcomes including depression, anxiety disorders, schizophrenia, bipolar disorder, dementia, sleep disorders, and the mental health consequences of chronic somatic diseases and of contracting COVID-19. Using large, representative outpatient cohorts, these studies have examined factors associated with the incidence of psychiatric disorders, patterns of psychiatric and somatic comorbidity, treatment trajectories, and long-term outcomes under routine care conditions. The DA database’s longitudinal structure, nationwide coverage, and inclusion of multiple medical specialties enable it to capture psychiatric disorders throughout patient lifetimes and across different clinical contexts. This narrative review summarizes psychiatric research using the DA database that has been published since 2020, focusing on study design, main findings, methodological strengths and limitations, and implications for future psychiatric epidemiology and clinical research. Full article

(This article belongs to the Section Neuropsychiatry)

30 pages, 746 KB

Open AccessArticle

From the Visible to the Invisible: On the Phenomenal Gradient of Appearance

by Baingio Pinna, Daniele Porcheddu and Jurģis Šķilters

Brain Sci. 2026, 16(1), 114; https://doi.org/10.3390/brainsci16010114 - 21 Jan 2026

Viewed by 195

Abstract

Background: By exploring the principles of Gestalt psychology, the neural mechanisms of perception, and computational models, scientists aim to unravel the complex processes that enable us to perceive a coherent and organized world. This multidisciplinary approach continues to advance our understanding of [...] Read more.

Background: By exploring the principles of Gestalt psychology, the neural mechanisms of perception, and computational models, scientists aim to unravel the complex processes that enable us to perceive a coherent and organized world. This multidisciplinary approach continues to advance our understanding of how the brain constructs a perceptual world from sensory inputs. Objectives and Methods: This study investigates the nature of visual perception through an experimental paradigm and method based on a comparative analysis of human and artificial intelligence (AI) responses to a series of modified square images. We introduce the concept of a “phenomenal gradient” in human visual perception, where different attributes of an object are organized syntactically and hierarchically in terms of their perceptual salience. Results: Our findings reveal that human visual processing involves complex mechanisms including shape prioritization, causal inference, amodal completion, and the perception of visible invisibles. In contrast, AI responses, while geometrically precise, lack these sophisticated interpretative capabilities. These differences highlight the richness of human visual cognition and the current limitations of model-generated descriptions in capturing causal, completion-based, and context-dependent inferences. The present work introduces the notion of a ‘phenomenal gradient’ as a descriptive framework and provides an initial comparative analysis that motivates testable hypotheses for future behavioral and computational studies, rather than direct claims about improving AI systems. Conclusions: By bridging phenomenology, information theory, and cognitive science, this research challenges existing paradigms and suggests a more integrated approach to studying visual consciousness. Full article

(This article belongs to the Special Issue Broken Mirrors of the Mind: Illusions, Paradoxes, and the Construction of Consciousness)

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35 pages, 1837 KB

Open AccessReview

Beyond Transplantation: Engineering Neural Cell Therapies and Combination Strategies for Spinal Cord Repair

by Lyandysha V. Zholudeva, Dennis Bourbeau, Adam Hall, Victoria Spruance, Victor Ogbolu, Liang Qiang, Shelly Sakiyama-Elbert and Michael A. Lane

Brain Sci. 2026, 16(1), 113; https://doi.org/10.3390/brainsci16010113 - 21 Jan 2026

Viewed by 382

Abstract

Spinal cord injury (SCI) remains one of the most formidable challenges in regenerative medicine, often resulting in permanent loss of motor, sensory, and autonomic function. Cell-based therapies offer a promising path toward repair by providing donor neurons and glia capable of integrating into [...] Read more.

Spinal cord injury (SCI) remains one of the most formidable challenges in regenerative medicine, often resulting in permanent loss of motor, sensory, and autonomic function. Cell-based therapies offer a promising path toward repair by providing donor neurons and glia capable of integrating into host circuits, modulating the injury environment, and restoring function. Early studies employing fetal neural tissue and neural progenitor cells (NPCs) have demonstrated proof-of-principle for survival, differentiation, and synaptic integration. More recently, pluripotent stem cell (PSC)-derived donor populations and engineered constructs have expanded the therapeutic repertoire, enabling precise specification of interneuron subtypes, astrocytes, and oligodendrocytes tailored to the injured spinal cord. Advances in genetic engineering, including CRISPR-based editing, trophic factor overexpression, and immune-evasive modifications, are giving rise to next-generation donor cells with enhanced survival and controllable integration. At the same time, biomaterials, pharmacological agents, activity-based therapies, and neuromodulation strategies are being combined with transplantation to overcome barriers and promote long-term recovery. In this review, we summarize progress in designing and engineering donor cells and tissues for SCI repair, highlight how combination strategies are reshaping the therapeutic landscape, and outline opportunities for next-generation approaches. Together, these advances point toward a future in which tailored, multimodal cell-based therapies achieve consistent and durable restoration of spinal cord function. Full article

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

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31 pages, 784 KB

Open AccessSystematic Review

Structural and Functional Neuroimaging Biomarkers as Predictors of Psychosis Conversion in Ultra-High Risk Individuals: A Systematic Review

by Giovanni Martinotti, Tommaso Piro, Nicola Ciraselli, Luca Persico, Antonio Inserra, Mauro Pettorruso, Giuseppe Maina and Valerio Ricci

Brain Sci. 2026, 16(1), 112; https://doi.org/10.3390/brainsci16010112 - 20 Jan 2026

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Abstract

Background: Approximately 20–30% of ultra-high risk (UHR) individuals transition to psychosis within 2–3 years. Neurobiological markers predicting conversion remain critical for precision prevention strategies. Objective: To systematically identify and evaluate structural and functional neuroimaging biomarkers at UHR baseline that predict subsequent conversion to [...] Read more.

Background: Approximately 20–30% of ultra-high risk (UHR) individuals transition to psychosis within 2–3 years. Neurobiological markers predicting conversion remain critical for precision prevention strategies. Objective: To systematically identify and evaluate structural and functional neuroimaging biomarkers at UHR baseline that predict subsequent conversion to psychosis. Methods: Following PRISMA 2020 guidelines, we searched five databases from January 2000 to February 2025. Two independent reviewers screened studies and assessed quality using the Newcastle–Ottawa Scale. Eligible studies examined baseline neuroimaging measures (structural MRI, functional MRI, diffusion tensor imaging, magnetic resonance spectroscopy) as predictors of psychosis conversion in UHR cohorts. Results: Twenty-five studies comprising 2436 UHR individuals (627 converters, 25.7%) were included (80.0% high quality). Reduced baseline gray matter volume in medial temporal structures (hippocampus: Cohen’s d = −0.45 to −0.68; parahippocampal gyrus: d = −0.52 to −0.71) and prefrontal cortex (d = −0.41 to −0.68) consistently predicted conversion. Progressive gray matter loss in superior temporal gyrus distinguished converters (d = −0.72). Reduced prefrontal–temporal functional connectivity predicted conversion (AUC = 0.73–0.82). Compromised white matter integrity in uncinate fasciculus (fractional anisotropy: d = −0.47 to −0.71) and superior longitudinal fasciculus predicted transition. Elevated striatal glutamate predicted conversion (d = 0.52–0.76). Thalamocortical dysconnectivity showed large effects (Hedges’ g = 0.66–0.88). Multimodal imaging models achieved 78–85% classification accuracy. Conclusions: Neuroimaging biomarkers, particularly medial temporal and prefrontal structural alterations, functional dysconnectivity, and white matter abnormalities, demonstrate moderate-to-large effect sizes in predicting UHR conversion. Multimodal approaches combining structural, functional, and neurochemical measures show promise for individualized risk prediction and early intervention targeting in precision prevention strategies. Full article

(This article belongs to the Section Developmental Neuroscience)

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22 pages, 9556 KB

Open AccessArticle

L-Borneolum Attenuates Ischemic Stroke Through Remodeling BBB Transporter Function via Regulating MFSD2A/Cav-1 Signaling Pathway

by Peiru Wang, Yilun Ma, Dazhong Lu, Li Wen, Fengyu Huang, Jianing Lian, Mengmeng Zhang and Taiwei Dong

Brain Sci. 2026, 16(1), 111; https://doi.org/10.3390/brainsci16010111 - 20 Jan 2026

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Abstract

Objective: This study compares the brain protective effects of L-borneolum and its main components (a combined application of L-borneol and L-camphor) on the rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). It also makes clear the intrinsic regulatory mechanisms that link the neuroprotective [...] Read more.

Objective: This study compares the brain protective effects of L-borneolum and its main components (a combined application of L-borneol and L-camphor) on the rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). It also makes clear the intrinsic regulatory mechanisms that link the neuroprotective effects of these compounds on IS to the blood-brain barrier (BBB), based on network pharmacology predictions. Furthermore, the study investigates the relationship between these compounds and the Major Facilitator Superfamily Domain-containing Protein 2A (MFSD2A)/Caveolin-1 (Cav-1) signaling axis. Methods: The MCAO/R model in rats was established to evaluate the therapeutic effect of L-borneolum (200 mg/kg) and its main components combination of L-borneol and L-camphor (6:4 ratio, 200 mg/kg). Neurological scores, 2,3,5-triphenyl tetrazolium chloride (TTC) staining, hematoxylin-eosin (HE) staining, and Nissl staining were performed to evaluate the neurological damage in the rats. Cerebral blood flow Doppler was applied to monitor the cerebral blood flow changes. Immunofluorescence analysis of albumin leakage and transmission electron microscopy (TEM) were conducted to evaluate blood-brain barrier (BBB) integrity. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine the optimal drug concentration. Trans-epithelial electrical resistance (TEER) and horseradish peroxidase (HRP) assays were employed to confirm the successful establishment of an in vitro BBB co-culture model. Network pharmacology was utilized to predict the biological processes, molecular functions, and cellular components involved in the treatment of ischemic stroke (IS) by the main components of L-borneolum (L-borneol and L-camphor). Finally, immunofluorescence, real-time fluorescent quantitative PCR (RT-qPCR) and western blot analyses were performed to detect the expression of Major Facilitator Superfamily Domain Containing 2A (MFSD2A), caveolin-1 (CAV-1), sterol regulatory element-binding protein 1 (SREBP1) in brain tissue and hCMEC/D3 cells. Results: Network pharmacology prediction indicated that L-borneolum and its main components (L-borneol and L-camphor) in the treatment of IS are likely associated with vesicle transport and neuroprotection. Treatment of IS with L-borneolum and its main components significantly decreased neurological function scores and cerebral infarction area, while alleviating pathological morphological changes and increasing the number of Nissl bodies in the hippocampus. Additionally, it improved cerebral blood flow, reduced albumin leakage, and decreased vesicle counts in the brain. The trans-epithelial electrical resistance (TEER) of the co-culture model stabilized on the fifth day after co-culture, and the permeability to horseradish peroxidase (HRP) in the co-culture model was significantly lower than that of the blank chamber at this time. RT-qPCR and Western blot results demonstrated that, compared to the model group, the expression of SREBP1 and MFSD2A significantly increased, while the expression of Cav-1 decreased. Conclusions: L-borneolum and its main components combination (L-borneol/L-camphor, 6:4 ratio) may exert a protective effect in rats with IS by improving BBB transport function through modulation of the MFSD2A/Cav-1 signaling pathway. Full article

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

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34 pages, 2650 KB

Open AccessConference Report

Neuroimaging and Pathology Biomarkers in Parkinson’s Disease and Parkinsonism

by Roberto Cilia, Dario Arnaldi, Bénédicte Ballanger, Roberto Ceravolo, Rosa De Micco, Angelo Del Sole, Roberto Eleopra, Hironobu Endo, Alfonso Fasano, Merle C. Hoenig, Jacob Horsager, Stéphane Lehéricy, Valentina Leta, Fabio Moda, Maria Nolano, Tiago F. Outeiro, Laura Parkkinen, Nicola Pavese, Andrea Quattrone, Nicola J. Ray, Martin M. Reich, Irena Rektorová, Antonio P. Strafella, Fabrizio Tagliavini, Alessandro Tessitore and Thilo van Eimeren Show full author list Hide full author list

Brain Sci. 2026, 16(1), 110; https://doi.org/10.3390/brainsci16010110 - 19 Jan 2026

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Abstract

The “Neuroimaging and Pathology Biomarkers in Parkinson’s Disease” course held on 12–13 September 2025 in Milan, Italy, convened an international faculty to review state-of-the-art biomarkers spanning neurotransmitter dysfunction, protein pathology and clinical translation. Here, we synthesize the four themed sessions and highlights convergent [...] Read more.

The “Neuroimaging and Pathology Biomarkers in Parkinson’s Disease” course held on 12–13 September 2025 in Milan, Italy, convened an international faculty to review state-of-the-art biomarkers spanning neurotransmitter dysfunction, protein pathology and clinical translation. Here, we synthesize the four themed sessions and highlights convergent messages for diagnosis, stratification and trial design. The first session focused on neuroimaging markers of neurotransmitter dysfunction, highlighting how positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) provided complementary insights into dopaminergic, noradrenergic, cholinergic and serotonergic dysfunction. The second session addressed in vivo imaging of protein pathology, presenting recent advances in PET ligands targeting α-synuclein, progress in four-repeat tau imaging for progressive supranuclear palsy and corticobasal syndromes, and the prognostic relevance of amyloid imaging in the context of mixed pathologies. Imaging of neuroinflammation captures inflammatory processes in vivo and helps study pathophysiological effects. The third session bridged pathology and disease mechanisms, covering the biology of α-synuclein and emerging therapeutic strategies, the clinical potential of seed amplification assays and skin biopsy, the impact of co-pathologies on disease expression, and the “brain-first” versus “body-first” model of pathological spread. Finally, the fourth session addressed disease progression and clinical translation, focusing on imaging predictors of phenoconversion from prodromal to clinically overt stages of synucleinopathies, concepts of neural reserve and compensation, imaging correlates of cognitive impairment, and MRI approaches for atypical parkinsonism. Biomarker-informed pharmacological, infusion-based, and surgical strategies, including network-guided and adaptive deep brain stimulation, were discussed as examples of how multimodal biomarkers may inform personalized management. Across all sessions, the need for harmonization, longitudinal validation, and pathology-confirmed outcome measures was consistently emphasized as essential for advancing biomarker qualification in multicentre research and clinical practice. Full article

(This article belongs to the Section Neurodegenerative Diseases)

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22 pages, 1120 KB

Open AccessReview

Beyond Cognitive Load Theory: Why Learning Needs More than Memory Management

by Andrew Sortwell, Evgenia Gkintoni, Jesús Díaz-García, Peter Ellerton, Ricardo Ferraz and Gregory Hine

Brain Sci. 2026, 16(1), 109; https://doi.org/10.3390/brainsci16010109 - 19 Jan 2026

Cited by 3 | Viewed by 494

Abstract

Background: The role of cognitive load theory (CLT) in understanding effective pedagogy has received increased attention in the fields of education and psychology in recent years. A considerable amount of literature has been published on the CLT construct as foundational guidance for instructional [...] Read more.

Background: The role of cognitive load theory (CLT) in understanding effective pedagogy has received increased attention in the fields of education and psychology in recent years. A considerable amount of literature has been published on the CLT construct as foundational guidance for instructional design by focusing on managing cognitive load in working memory to enhance learning outcomes. However, recent neuroscientific findings and practical critiques suggest that CLT’s emphasis on content-focused instruction and cognitive efficiency may overlook the complexity of human learning. Methods: This conceptual paper synthesises evidence from cognitive science, developmental psychology, neuroscience, health sciences and educational research to examine the scope conditions and limitations of CLT when applied as a general framework for K–12 learning. One of the major theoretical issues identified is the lack of consideration for the broad set of interpersonal and self-management skills, creating potential limitations for real-world educational contexts, where social-emotional and self-regulatory abilities are as crucial as cognitive competencies. Results: As a result of the critique, this paper introduces the Neurodevelopmental Informed Holistic Learning and Development Framework as a neuroscience-informed construct that integrates cognitive, emotional, and interpersonal dimensions essential for effective learning. Conclusions: In recognising the limitations of CLT, the paper offers practitioners contemporary, neurodevelopmentally informed insights that extend beyond cognitive efficiency alone and better reflect the multidimensional nature of real-world learning. Full article

(This article belongs to the Special Issue Neuroeducation: Bridging Cognitive Science and Classroom Practice)

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4 pages, 151 KB

Open AccessEditorial

Advances in Research on Brain Health and Dementia: Prevention and Early Detection of Cognitive Decline and Dementia: Series II

by Takao Yamasaki

Brain Sci. 2026, 16(1), 108; https://doi.org/10.3390/brainsci16010108 - 19 Jan 2026

Viewed by 290

Abstract

Dementia is a rapidly growing global health challenge, underscoring the urgent need for effective strategies aimed at the prevention and early detection of cognitive decline [...] Full article

(This article belongs to the Special Issue Advances in Research on Brain Health and Dementia: Prevention and Early Detection of Cognitive Decline and Dementia: Series II)

18 pages, 800 KB

Open AccessArticle

Gaze-Speech Coordination During Narration in Autism Spectrum Disorder and First-Degree Relatives

by Jiayin Xing, Joseph C. Y. Lau, Kritika Nayar, Emily Landau, Mitra Kumareswaran, Marcia Grabowecky and Molly Losh

Brain Sci. 2026, 16(1), 107; https://doi.org/10.3390/brainsci16010107 - 19 Jan 2026

Viewed by 212

Abstract

Background/Objectives: Narrative differences in autism spectrum disorder (ASD) and subtle and parallel differences among their first-degree relatives suggest potential genetic liability to this critical social-communication skill. Effective social-communication relies on coordinating signals across modalities, which is often disrupted in ASD. Therefore, the current [...] Read more.

Background/Objectives: Narrative differences in autism spectrum disorder (ASD) and subtle and parallel differences among their first-degree relatives suggest potential genetic liability to this critical social-communication skill. Effective social-communication relies on coordinating signals across modalities, which is often disrupted in ASD. Therefore, the current study examined the coordination of fundamental skills—gaze and speech—as a potential mechanism underlying narrative and broader pragmatic differences in ASD and their first-degree relatives. Methods: Participants included 35 autistic individuals, 41 non-autistic individuals, 90 parents of autistic individuals, and 34 parents of non-autistic individuals. Participants narrated a wordless picture book presented on an eye-tracker, with gaze and speech simultaneously recorded and subsequently coded. Time series analyses quantified their temporal coordination (i.e., the temporal lead of gaze to speech) and content coordination (i.e., the amount of gaze-speech content correspondence). These metrics were then compared between autistic and non-autistic groups and between parent groups and examined in relation to narrative quality and conversational pragmatic language skills. Results: Autistic individuals showed reduced temporal coordination but increased content coordination relative to non-autistic individuals with no significant differences found between parent groups. In both autistic individuals, and parent groups combined, increased content coordination and reduced temporal coordination were linked to reduced narrative quality and pragmatic language skills, respectively. Conclusions: Reduced temporal and increased content coordination may reflect a localized strategy of labeling items upon visualization. This pattern may indicate more limited visual, linguistic, and cognitive processing and underlie differences in higher-level social-communicative abilities in ASD. To our knowledge, this study is the first to identify multimodal skill coordination as a potential mechanism contributing to higher-level social-communicative differences in ASD and first-degree relatives, implicating mechanism-based interventions to support pragmatic language skills in ASD. Full article

(This article belongs to the Collection Editorial Board Members’ Collection Series: Autism Spectrum Conditions from Childhood to Adulthood—Current Situation and Prospects)

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14 pages, 700 KB

Open AccessArticle

Positive and Negative Affect and Eating Behavior Among Adults: The Mediating Role of Emotion Regulation

by Despoina Kourtidi, Evangelos Ntouros and Agorastos Agorastos

Brain Sci. 2026, 16(1), 106; https://doi.org/10.3390/brainsci16010106 - 19 Jan 2026

Viewed by 382

Abstract

Background: Emotions substantially influence human eating behavior, but while negative affect has been consistently associated with maladaptive eating patterns, the role of positive affect remains underexplored. Thereby, emotion regulation (ER) is considered a key mechanism through which affective states may influence eating [...] Read more.

Background: Emotions substantially influence human eating behavior, but while negative affect has been consistently associated with maladaptive eating patterns, the role of positive affect remains underexplored. Thereby, emotion regulation (ER) is considered a key mechanism through which affective states may influence eating behavior. However, its mediating role remains unclear, particularly among non-clinical populations. Objectives: This study aimed to investigate the potential mediating role of ER in the relationship between negative and positive affect and maladaptive eating behavior in a non-clinical adult sample. Methods: This cross-sectional online survey was administered to a general-population convenience sample of 189 adults. Participants completed four standardized self-report questionnaires: Eating Attitudes Test (EAT-26), Positive and Negative Affect Schedule (PANAS), Difficulties in Emotion Regulation Scale (DERS-36), and Depression Anxiety Stress Scale (DASS-21). Correlational analyses and multiple regression models were used to examine the relationships between variables and to test the mediating role of ER. Results: Negative affect was significantly associated with both maladaptive eating behavior (r = 0.29, p < 0.01) and ER difficulties (r = 0.51, p < 0.01). Positive affect was only negatively related to emotion dysregulation (r = −0.47, p < 0.01). ER did not mediate the relationship between either positive or negative affect and maladaptive eating behavior. Conclusions: Findings underscore the influence of negative affect in maladaptive eating behavior, independently of ER. Although positive affect did not directly predict disordered eating behavior, its association with reduced ER difficulties warrants further exploration of its potential protective role. Full article

(This article belongs to the Topic The Relationship Between Bodily, Autonomic, and Communicative Behaviors and the Experiential and Cognitive Aspects of Emotion)

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13 pages, 1153 KB

Open AccessArticle

Temporal Modulation of Corticospinal Excitability by Repetitive Peripheral Magnetic Stimulation in Healthy Young Adults

by Rehab Aljuhni, Srinivas Kumar, Christina Sawa and Sangeetha Madhavan

Brain Sci. 2026, 16(1), 105; https://doi.org/10.3390/brainsci16010105 - 19 Jan 2026

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Abstract

Background: Repetitive peripheral magnetic stimulation (rPMS) delivers magnetic pulses to peripheral nerves and muscles, producing afferent input that can modulate corticospinal excitability (CSE). While the effects of rPMS on upper-limb muscles have been explored, its short-term effects on lower-limb CSE remain less [...] Read more.

Background: Repetitive peripheral magnetic stimulation (rPMS) delivers magnetic pulses to peripheral nerves and muscles, producing afferent input that can modulate corticospinal excitability (CSE). While the effects of rPMS on upper-limb muscles have been explored, its short-term effects on lower-limb CSE remain less understood. This study aimed to investigate the short-term effects of rPMS on CSE in the tibialis anterior (TA) muscle among healthy individuals. Methods: Twenty participants completed a repeated- measure, pre-post study. rPMS was applied to the non-dominant TA muscle at 10% above motor threshold for 15 min. CSE was assessed using transcranial magnetic stimulation (TMS), with measurements of motor evoked potential (MEP) amplitude, latency, and duration recorded at baseline, immediately after, 30 min, and 60 min post-stimulation. All analyses were conducted on clean datasets following removal of artifact-related outliers. Results: MEP amplitude showed a significant main effect of Side (p = 0.005), with greater values on the stimulated compared to the non-stimulated side. No significant main effects were found for Time (p = 0.351) or for the Side × Time interaction (p = 0.900). Descriptively, the largest increase in amplitude on the stimulated side was observed at 30 min post-stimulation (12% above baseline). MEP latency and duration showed no significant main or interaction effects. Conclusions: In conclusion, a single rPMS session applied to the TA produced a modest, side-specific increase in CSE lasting up to 60 min, as reflected in MEP amplitude. However, the absence of a significant time effect and perhaps non-optimized stimulation parameters limit the interpretation of sustained neuromodulatory effects. Future studies should examine optimal stimulation parameters and explore underlying mechanisms using measures such as the cortical silent period and interhemispheric inhibition. Full article

(This article belongs to the Section Neurotechnology and Neuroimaging)

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11 pages, 1054 KB

Open AccessReview

Abnormal MRI Features in Children with ADHD: A Narrative Review of Large-Scale Studies

by Chunyang Wang, Shiyun Wang, Li Sun and Jing Sui

Brain Sci. 2026, 16(1), 104; https://doi.org/10.3390/brainsci16010104 - 18 Jan 2026

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Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood, characterized by persistent inattention, hyperactivity, and impulsivity. This narrative review aims to synthesize and critically evaluate recent large-scale magnetic resonance imaging (MRI) studies to clarify the neuroanatomical and functional brain alterations associated with [...] Read more.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood, characterized by persistent inattention, hyperactivity, and impulsivity. This narrative review aims to synthesize and critically evaluate recent large-scale magnetic resonance imaging (MRI) studies to clarify the neuroanatomical and functional brain alterations associated with ADHD in children. By addressing current gaps in understanding, this work seeks to identify reliable neurobiological markers that could improve diagnostic accuracy and guide personalized interventions. The literature reveals that large-scale structural MRI studies consistently report abnormal development in total cortical volume and surface area, prefrontal cortex volume, and basal ganglia volume in children with ADHD. Moreover, gray matter alterations show significant age-dependent effects, with the degree of impairment potentially serving as neurobiological markers. Diffusion magnetic resonance imaging studies reveal disrupted white matter microstructures in regions such as the left uncinate fasciculus, superior and inferior longitudinal fasciculi, corpus callosum, cingulum, and internal capsule. Importantly, these white matter abnormalities often persist into adulthood, highlighting their clinical relevance. Functional MRI findings indicate reduced global connectivity within core hubs of the default mode network in children with ADHD. Furthermore, deficits in inhibitory control identified via fMRI may represent one of the neurofunctional signatures that differentiates ADHD from typically developing controls. By consolidating evidence from large-scale multimodal MRI studies, this review provides a comprehensive understanding of the neurodevelopmental alterations in ADHD and underscores their potential utility for improving diagnosis and treatment. Full article

(This article belongs to the Section Neuropsychiatry)

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Open AccessSystematic Review

Neuropsychological Sequelae and Neuroradiological Correlates of Arachnoid Cysts in Adults: A Systematic Review

by Odysseas Lorentzos, Panayiotis Patrikelis, Giuliana Lucci, Lambros Messinis and Stefanos Korfias

Brain Sci. 2026, 16(1), 103; https://doi.org/10.3390/brainsci16010103 - 18 Jan 2026

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Abstract

Background/Objectives: Intracranial arachnoid cysts (Acs) are congenital, usually benign lesions that are frequently regarded as clinically silent in adulthood. Nonetheless, growing evidence indicates that Acs may be associated with subtle but measurable cognitive dysfunction. This systematic review synthesizes neuropsychological and functional neuroimaging findings [...] Read more.

Background/Objectives: Intracranial arachnoid cysts (Acs) are congenital, usually benign lesions that are frequently regarded as clinically silent in adulthood. Nonetheless, growing evidence indicates that Acs may be associated with subtle but measurable cognitive dysfunction. This systematic review synthesizes neuropsychological and functional neuroimaging findings in adults with intracranial Acs, with a focus on cognitive profiles, functional interactions with the adjacent cortex, and postoperative reversibility. Methods: In accordance with PRISMA 2020 guidelines, MEDLINE/PubMed and Scopus were searched for English-language studies published up to 2023 that reported neuropsychological assessments and/or functional neuroimaging in adult patients with Acs, including single-case reports, case series, and group studies with pre- and post-operative data. Results: Sixty studies met the inclusion criteria. Across anatomical locations, Acs were most consistently associated with impairments in verbal and visual memory and learning, attention, and executive functions, as well as reduced processing or psychomotor speed, whereas language deficits were less consistently observed. Several studies reported postoperative improvement in one or more cognitive domains, suggesting partial reversibility in selected patients. Functional neuroimaging findings revealed altered cortical function in regions adjacent to the cyst, including reduced regional metabolism or cerebral blood flow and task-related activation changes, supporting a functional interaction between Acs and the neighboring cortex. Conclusions: Overall, adults with Acs may exhibit subtle cognitive alterations that vary according to cyst location and appear to be moderated by compensatory mechanisms. These findings underscore the clinical relevance of systematic neuropsychological evaluation and highlight the need for prospective, standardized studies integrating cognitive and neuroimaging outcomes. Full article

(This article belongs to the Special Issue New Insights into Mental Health Research for Neurological and Psychiatric Disorders)

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19 pages, 1208 KB

Open AccessPerspective

A Prefrontal Neuromodulation Route for Post-Traumatic Olfactory Dysfunction: A Perspective Supported by Recovery During Left-DLPFC rTMS

by Chiara Di Fazio and Sara Palermo

Brain Sci. 2026, 16(1), 99; https://doi.org/10.3390/brainsci16010099 - 17 Jan 2026

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Abstract

Post-traumatic olfactory dysfunction (PTOD) is a common and often persistent sequela of mild traumatic brain injury (mTBI), with limited evidence-based treatment options. We propose that high-frequency rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) may support olfactory recovery via top-down modulation of [...] Read more.

Post-traumatic olfactory dysfunction (PTOD) is a common and often persistent sequela of mild traumatic brain injury (mTBI), with limited evidence-based treatment options. We propose that high-frequency rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) may support olfactory recovery via top-down modulation of distributed olfactory, attentional, and reward networks, and we outline key mechanistic and methodological considerations for future studies. We summarize the case of a 70-year-old woman with severe post-traumatic hyposmia persisting for ~5 months, who underwent a 12-week, 10 Hz rTMS course over left DLPFC (36 sessions; 800 pulses/session). Using a structured door diary and repeated ratings across odour categories, she reported stepwise improvement starting around sessions 10–12 (re-emergence of pungent odours) and progressing to broad restoration, including subtle fragrances, by treatment end; no adverse events occurred. While causality cannot be inferred from a single case, this pattern is consistent with a network-level neuromodulatory effect and motivates controlled trials combining standardized olfactory testing with neurophysiology and neuroimaging. Full article

(This article belongs to the Special Issue Review in Neuropsychology: Advances and Future Directions)

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10 pages, 523 KB

Open AccessCase Report

Switching from Oral Cholinesterase Inhibitors to a Transdermal Donepezil Patch Attenuated Gastrointestinal Symptoms and Allowed Treatment Continuation in Three Patients with Alzheimer’s Disease in Clinical Settings

by Yumiko Motoi and Nobuo Sanjo

Brain Sci. 2026, 16(1), 98; https://doi.org/10.3390/brainsci16010098 - 17 Jan 2026

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Abstract

Background: Cholinesterase inhibitors (ChEIs) are commonly prescribed for the treatment of Alzheimer’s disease (AD) and achieve long-term benefits for cognition and survival in real-world settings. However, the discontinuation rate is high due to their side effects, with gastrointestinal (GI) symptoms hampering long-term [...] Read more.

Background: Cholinesterase inhibitors (ChEIs) are commonly prescribed for the treatment of Alzheimer’s disease (AD) and achieve long-term benefits for cognition and survival in real-world settings. However, the discontinuation rate is high due to their side effects, with gastrointestinal (GI) symptoms hampering long-term prescriptions. The risk of side effects associated with rivastigmine was previously shown to be lower with transdermal delivery than with oral capsules; however, this has yet to be examined in detail for donepezil, the most widely used ChEI. The daily application of a donepezil transdermal patch was officially approved in Japan in 2023. The incidence of side effects was lower with the donepezil transdermal patch than with oral donepezil in healthy volunteers, but has not yet been assessed in clinical settings. Results: We herein report three AD patients in two different memory clinics who developed GI symptoms with oral ChEIs that were attenuated by switching to the donepezil transdermal patch. Conclusions: The donepezil transdermal patch may improve tolerability and adherence in patients who develop gastrointestinal adverse effects with oral donepezil. Full article

(This article belongs to the Section Behavioral Neuroscience)

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Open AccessArticle

Use of Laser Speckle Contrast Imaging for Distribution of Animals by Severity of Brain Tissue Damage in a Neonatal Hypoxia-Ischemia Model in Mice

by Vladimir Pokrovskii, Konstantin Lapin, Viktoria Antonova, Mikhail Korokin, Oleg Gudyrev, Vladimir Gureev, Liliya Korokina, Olesya Scheblykina, Arkadii Nesterov, Maria Maslinikova, Ivan Chatsky, Denis Mukhamedov and Mikhail Pokrovskii

Brain Sci. 2026, 16(1), 102; https://doi.org/10.3390/brainsci16010102 - 17 Jan 2026

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Abstract

Background/Objectives: Inter-individual variability in injury severity represents a major barrier to reproducibility in neonatal hypoxia–ischemia (HI) models. Objective early postoperative stratification of animals is therefore essential for standardized group allocation and reliable assessment of experimental outcomes. This study aimed to evaluate whether [...] Read more.

Background/Objectives: Inter-individual variability in injury severity represents a major barrier to reproducibility in neonatal hypoxia–ischemia (HI) models. Objective early postoperative stratification of animals is therefore essential for standardized group allocation and reliable assessment of experimental outcomes. This study aimed to evaluate whether laser speckle contrast imaging (LSCI) can be used as a rapid, noninvasive tool for early post hoc stratification of ischemic brain damage severity in neonatal mice following HI. Methods: Neonatal CD-1 mice (postnatal day 9; n = 60) underwent hypoxia–ischemia using a modified Rice–Vannucci protocol. Cerebral perfusion was assessed by laser speckle contrast imaging at baseline, 3 h, and 7 days after HI. The difference in mean perfusion between ipsilateral and contralateral hemispheres at 3 h (Δ perfusion) was used to stratify animals into severity groups. Brain injury was quantified by 2,3,5-triphenyltetrazolium chloride (TTC) staining at 24 h and 7 days. Survival was monitored for 7 days and analyzed using Kaplan–Meier curves and the log-rank (Mantel–Cox) test. Results: LSCI-derived Δ perfusion at 3 h enabled the formation of distinct injury-severity groups (no visible damage, mild, moderate, and severe) with significant between-group differences (p < 0.0001). TTC-based lesion area increased stepwise across severity groups, and Δ perfusion correlated with lesion size when all animals were analyzed together (r = 0.688, p = 0.0011). No significant correlations were observed within individual severity groups, indicating that the overall association was driven primarily by between-group differences. Survival analysis revealed 75% mortality in the severe injury group (p < 0.0001). Conclusions: LSCI represents a robust and practical approach for early, objective, group-level stratification of neonatal mice by HI injury severity, thereby improving reproducibility and statistical validity in preclinical studies. However, its ability to predict outcomes within individual severity categories is limited, and repeated long-term measurements may pose technical challenges. Full article

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

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37 pages, 1276 KB

Open AccessReview

Versatility of Transcranial Magnetic Stimulation: A Review of Diagnostic and Therapeutic Applications

by Massimo Pascuzzi, Nika Naeini, Adam Dorich, Marco D’Angelo, Jiwon Kim, Jean-Francois Nankoo, Naaz Desai and Robert Chen

Brain Sci. 2026, 16(1), 101; https://doi.org/10.3390/brainsci16010101 - 17 Jan 2026

Viewed by 676

Abstract

Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that utilizes magnetic fields to induce cortical electric currents, enabling both the measurement and modulation of neuronal activity. Initially developed as a diagnostic tool, TMS now serves dual roles in clinical neurology, offering insight [...] Read more.

Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that utilizes magnetic fields to induce cortical electric currents, enabling both the measurement and modulation of neuronal activity. Initially developed as a diagnostic tool, TMS now serves dual roles in clinical neurology, offering insight into neurophysiological dysfunctions and the therapeutic modulation of abnormal cortical excitability. This review examines key TMS outcome measures, including motor thresholds (MT), input–output (I/O) curves, cortical silent periods (CSP), and paired-pulse paradigms such as short-interval intracortical inhibition (SICI), short-interval intracortical facilitation (SICF), intracortical facilitation (ICF), long interval cortical inhibition (LICI), interhemispheric inhibition (IHI), and short-latency afferent inhibition (SAI). These biomarkers reflect underlying neurotransmitter systems and can aid in differentiating neurological conditions. Diagnostic applications of TMS are explored in Parkinson’s disease (PD), dystonia, essential tremor (ET), Alzheimer’s disease (AD), and mild cognitive impairment (MCI). Each condition displays characteristic neurophysiological profiles, highlighting the potential for TMS-derived biomarkers in early or differential diagnosis. Therapeutically, repetitive TMS (rTMS) has shown promise in modulating cortical circuits and improving motor and cognitive symptoms. High- and low-frequency stimulation protocols have demonstrated efficacy in PD, dystonia, ET, AD, and MCI, targeting the specific cortical regions implicated in each disorder. Moreover, the successful application of TMS in differentiating and treating AD and MCI underscores its clinical utility and translational potential across all neurodegenerative conditions. As research advances, increased attention and investment in TMS could facilitate similar diagnostic and therapeutic breakthroughs for other neurological disorders that currently lack robust tools for early detection and effective intervention. Moreover, this review also aims to underscore the importance of maintaining standardized TMS protocols. By highlighting inconsistencies and variability in outcomes across studies, we emphasize that careful methodological design is critical for ensuring the reproducibility, comparability, and reliable interpretation of TMS findings. In summary, this review emphasizes the value of TMS as a distinctive, non-invasive approach to probing brain function and highlights its considerable promise as both a diagnostic and therapeutic modality in neurology—roles that are often considered separately. Full article

(This article belongs to the Special Issue Application of Transcranial Magnetic Stimulation (TMS) in Motor Control and Learning)

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13 pages, 10493 KB

Open AccessArticle

Toward Standardized Protocols: Determining Optimal Stimulation Volumes for 5 Hz Repetitive Peripheral Magnetic Stimulation (rPMS) of the Tibial Nerve—A Controlled Exploratory Study

by Volker R. Zschorlich, Dirk Büsch, Sarah Schulte, Fengxue Qi and Jörg Schorer

Brain Sci. 2026, 16(1), 100; https://doi.org/10.3390/brainsci16010100 - 17 Jan 2026

Viewed by 216

Abstract

Background: Repetitive peripheral magnetic stimulation (rPMS) has emerged as a promising non-invasive treatment modality for reducing muscle hypertonus and spasticity. However, standardized protocols regarding stimulation parameters, particularly the number of stimuli required to achieve therapeutic effects, remain largely undefined. Methods: In [...] Read more.

Background: Repetitive peripheral magnetic stimulation (rPMS) has emerged as a promising non-invasive treatment modality for reducing muscle hypertonus and spasticity. However, standardized protocols regarding stimulation parameters, particularly the number of stimuli required to achieve therapeutic effects, remain largely undefined. Methods: In an exploratory study, seventeen healthy participants (15 male, 2 female) underwent progressive rPMS treatments at 5 Hz frequency with incrementally increasing stimulus counts (105, 210, 315, 420, and 840 stimuli). Seventeen participants served as controls (11 male, 6 female) receiving sham stimulation. Achilles tendon reflexes were elicited using a computer-controlled reflex hammer, and compound muscle action potential (CMAP) peak-to-peak amplitudes were recorded via surface electromyography before and immediately after each stimulation session. Results: The overall repeated-measures ANOVA indicated a significant main effect (F(5, 80) = 4.98, p = 0.001, η²_p = 0.237). All rPMS treatments produced significant reductions in CMAP amplitudes compared to baseline (p < 0.05). No progressive dose-dependent relationship was observed between stimulus count and response magnitude, suggesting a threshold effect rather than progressive inhibition. Control group showed no significant changes (p ≤ 0.56). Conclusions: Low-frequency (5 Hz) rPMS produces rapid inhibitory effects on spinal reflex circuits with onset after as few as 105 stimuli. These findings indicate that treatment effects can be achieved with substantially fewer stimuli than previously assumed. Further research is needed to identify parameters capable of achieving greater reflex suppression. Full article

(This article belongs to the Section Neurorehabilitation)

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13 pages, 3582 KB

Open AccessCase Report

Adult-Onset Diffuse Midline Glioma, H3K27-Altered: A Genomics-Guided, Individualized, Multimodal Treatment Approach

by Abdussamet Çelebi, Bilal Yıldırım, Emine Yıldırım, Selver Işık, Ezgi Çoban, Erhan Bıyıklı, Osman Köstek, İbrahim Vedat Bayoğlu and Murat Sarı

Brain Sci. 2026, 16(1), 97; https://doi.org/10.3390/brainsci16010097 - 16 Jan 2026

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Abstract

Background: H3K27-altered diffuse midline glioma (DMG) is a highly aggressive central nervous system malignancy with limited therapeutic options and poor prognosis. Precision medicine strategies that integrate molecular profiling with individualized treatment selection represent a critical avenue for improving outcomes. Case presentation: [...] Read more.

Background: H3K27-altered diffuse midline glioma (DMG) is a highly aggressive central nervous system malignancy with limited therapeutic options and poor prognosis. Precision medicine strategies that integrate molecular profiling with individualized treatment selection represent a critical avenue for improving outcomes. Case presentation: We describe a 31-year-old woman with H3K27-altered DMG who, after standard chemoradiotherapy, was treated with a personalized, mechanism-guided combination regimen based on her tumor’s molecular profile. Next-generation sequencing identified pathogenic alterations in ATRX, H3F3A, and NF1, with a high NF1 mutation allelic fraction indicating RAS/MAPK pathway activation. Immunohistochemistry demonstrated elevated phosphorylated mTOR consistent with PI3K/AKT/mTOR pathway upregulation. The individualized regimen comprised trametinib and everolimus for dual pathway inhibition, the tissue-agnostic agent dordaviprone (ONC201), metabolic modulation with 2-deoxy-D-glucose, and electric field-based therapy. At seven months, MRI showed approximately a 60% volumetric reduction in the enhancing tumor component, accompanied by marked T2-weighted signal regression. Clinically, the patient remained neurologically intact with a Karnofsky Performance Score of 100%. Conclusions: This case illustrates the potential clinical value of a genomics-guided, multimodal treatment strategy in H3K27-altered DMG. The systematic integration of comprehensive molecular profiling with mechanistically rational treatment selection may contribute to meaningful radiological and clinical benefit in this otherwise uniformly fatal disease. These observations support further investigation of individualized, pathway-targeted approaches in prospective studies and N-of-1 trial frameworks. Full article

(This article belongs to the Special Issue Brain Tumors: From Molecular Basis to Therapy)

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15 pages, 1508 KB

Open AccessArticle

Global and Local Processing of Letters and Faces in Children and Adolescents with Typical and Atypical Development

by Silvia Primativo, Roberta Daini, Jennifer Pavia, Elisa Fucà, Floriana Costanzo, Cristina Caciolo, Paolo Alfieri, Deny Menghini, Stefano Vicari and Lisa S. Arduino

Brain Sci. 2026, 16(1), 96; https://doi.org/10.3390/brainsci16010096 - 16 Jan 2026

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Abstract

Background/Objectives: this paper investigates the local vs. global visual processing preference in typically developing (TD) children, youth with Down syndrome (DS), and youth with Williams syndrome (WS). In particular, the global precedence effect (GPE) and the global interference effect (GI) have recently been [...] Read more.

Background/Objectives: this paper investigates the local vs. global visual processing preference in typically developing (TD) children, youth with Down syndrome (DS), and youth with Williams syndrome (WS). In particular, the global precedence effect (GPE) and the global interference effect (GI) have recently been described as two distinct and at least partially independent effects. Methods: in this study, 50 participants (TD = 25, DS = 13, WS = 12) completed two experiments requiring the identification of either the global or local level of hierarchical stimuli, which consisted of letters and schematic faces. For each stimulus type, two separate blocks were conducted, one with the task to focus on the local elements and the other with the task to focus on the global shape. Results: our results indicate that TD children demonstrate a global precedence effect for letters but not for schematic faces, suggesting a developmental modulation of configural processing. In contrast, both DS and WS groups showed a global processing bias for schematic faces and a significant global interference effect in both conditions, likely reflecting deficits in inhibitory control. Conclusions: these findings challenge the notion that DS and WS individuals can be classified strictly as global or local processors, respectively, emphasizing the influence of stimulus type and cognitive demands. Implications for neurodevelopmental research and clinical interventions are discussed. Full article

(This article belongs to the Section Developmental Neuroscience)

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27 pages, 1112 KB

Open AccessArticle

SleepMFormer: An Efficient Attention Framework with Contrastive Learning for Single-Channel EEG Sleep Staging

by Mingjie Li, Jie Xia, Jiadong Pan, Sha Zhao, Xiaoying Zhang, Hao Jin and Shurong Dong

Brain Sci. 2026, 16(1), 95; https://doi.org/10.3390/brainsci16010095 - 16 Jan 2026

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Abstract

Background/Objectives: Sleep stage classification is crucial for assessing sleep quality and diagnosing related disorders. Electroencephalography (EEG) is currently recognized as a primary method for sleep stage classification. High-performance automatic sleep staging methods based on EEG leverage the powerful contextual modeling capabilities of Transformer [...] Read more.

Background/Objectives: Sleep stage classification is crucial for assessing sleep quality and diagnosing related disorders. Electroencephalography (EEG) is currently recognized as a primary method for sleep stage classification. High-performance automatic sleep staging methods based on EEG leverage the powerful contextual modeling capabilities of Transformer Encoder architectures. However, the global self-attention mechanism in Transformers incurs significant computational overhead, substantially hindering the training and inference efficiency of automatic sleep staging algorithms. Methods: To address these issues, we introduce an end-to-end framework for automatic sleep stage classification using single-channel EEG: SleepMFormer. At the algorithmic level, SleepMFormer adopts a task-driven simplification of the Transformer encoder to improve attention efficiency while preserving sequence modeling capability. At the training level, supervised contrastive learning is incorporated as an auxiliary strategy to enhance representation robustness. From an engineering perspective, these design choices enable efficient training and inference under resource-constrained settings. Results: When integrated with the SleePyCo backbone, the proposed framework achieves competitive performance on three widely used public datasets: Sleep-EDF, PhysioNet, and SHHS. Notably, SleepMFormer reduces training and inference time by up to 33% compared to conventional self-attention-based models. To further validate the generalizability of MaxFormer, we conduct additional experiments using DeepSleepNet and TinySleepNet as alternative feature extractors. Experimental results demonstrate that MaxFormer consistently maintains performance across different model architectures. Conclusions: Overall, SleepMFormer introduces an efficient and practical framework for automatic sleep staging, demonstrating strong potential for related clinical applications. Full article

(This article belongs to the Section Sleep and Circadian Neuroscience)

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11 pages, 409 KB

Open AccessArticle

Detecting Dementia Using Lexical Analysis: Terry Pratchett’s Discworld Tells a More Personal Story

by Melody Pattison, Ahmet Begde and Thomas D. W. Wilcockson

Brain Sci. 2026, 16(1), 94; https://doi.org/10.3390/brainsci16010094 - 16 Jan 2026

Viewed by 8678

Abstract

Background/Objectives: Dementia, characterised by cognitive decline, significantly impacts language abilities. While the risk of dementia increases with age, it often manifests years before clinical diagnosis. Identifying early warning signs is crucial for timely intervention. Previous research has demonstrated that changes in language, [...] Read more.

Background/Objectives: Dementia, characterised by cognitive decline, significantly impacts language abilities. While the risk of dementia increases with age, it often manifests years before clinical diagnosis. Identifying early warning signs is crucial for timely intervention. Previous research has demonstrated that changes in language, such as reduced vocabulary diversity and simpler sentence structures, may be observed in individuals with dementia. This study investigates the potential of linguistic analysis to detect early signs of cognitive decline by examining the writing of Sir Terry Pratchett, a renowned author diagnosed with Posterior Cortical Atrophy (PCA), typically a form of dementia caused by Alzheimer’s disease. Methods: This study analysed 33 Discworld novels by Terry Pratchett, comparing linguistic features before and after a potential turning point identified through analysis of adjective type-token ratios (TTR). Results: A significant decrease in lexical diversity (TTR) was observed for nouns and adjectives in later works. Total wordcount increased, while lexical diversity decreased, suggesting a shift towards simpler language. This shift coincided with a decrease in adjective TTR below a defined threshold, occurring approximately ten years before Pratchett’s formal diagnosis. Conclusions: These findings suggest that subtle changes in linguistic patterns, such as decreased lexical diversity, may precede clinical diagnosis of dementia by a considerable margin. This research highlights the potential of linguistic analysis as a valuable tool for early detection of cognitive decline. Further research is needed to validate these findings in larger cohorts and explore the specific linguistic markers associated with different types of dementia. Full article

(This article belongs to the Special Issue Advances in Speech and Language Research for Cognitive Well-Being in Aging)

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17 pages, 4250 KB

Open AccessSystematic Review

The Contribution of Ethnicity to the Association of MTHFR Variants C677T and A1298C with Autism Spectrum Disorder: A Meta-Analysis

by Yining Pan, Brooklyn McDill and Marie Mooney

Brain Sci. 2026, 16(1), 93; https://doi.org/10.3390/brainsci16010093 - 16 Jan 2026

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Abstract

Background: Common polymorphisms in the MTHFR gene, C677T and A1298C, have been associated with increased risk for psychiatric neurodevelopmental disorders, including autism spectrum disorder (ASD). However, studies provide conflicting evidence for the strength of the association with ASD based on both the [...] Read more.

Background: Common polymorphisms in the MTHFR gene, C677T and A1298C, have been associated with increased risk for psychiatric neurodevelopmental disorders, including autism spectrum disorder (ASD). However, studies provide conflicting evidence for the strength of the association with ASD based on both the allelic variant and population structure of the cohorts studied. Methods: Using systematic literature search and selection criteria, we calculated ASD-associated odds ratios for the two most-reported MTHFR variants. Twenty-two articles reported the association between MTHFR C677T and ASD, including 13913 subjects (4391 cases, 9522 controls). Nine articles, including 3009 subjects (1462 cases, 1547 controls), evaluated the link between MTHFR A1298C and ASD susceptibility. Results: We identified a statistical association between ASD and the MTHFR C677T variant, regardless of race or ethnicity. However, there was no statistical support for an association between ASD and the MTHFR A1298C variant. In both cases, substantial-to-considerable residual heterogeneity remained (I² ~67% and 73%, respectively). Exploring the heterogeneity by meta-regression on race/ethnicity, the African (Egyptian) cohort with MTHFR C677T variants had a higher ASD susceptibility than Asian or European cohorts in most models, though this susceptibility difference was not observed between Africans and Europeans for the homozygous case (TT vs. CC). Similarly, the African (Egyptian) cohort with MTHFR A1298C variants also had a higher ASD susceptibility than Asian or European cohorts in most models, though this susceptibility difference was not observed between Africans and Asians for the homozygous case (CC vs. AA). Conclusions: Our findings support previous analyses that identified a statistical association between ASD and the MTHFR C677T variant but none between ASD and the MTHFR A1298C variant. We also reveal a greater potential for these variants to exacerbate ASD phenotypes in an African (Egyptian) cohort. Future studies should assess the mechanistic contribution of these variants to MTHFR function, especially potential hypomorphic sensitivity in individuals with African (Egyptian) ancestry. Full article

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18 pages, 3332 KB

Open AccessArticle

Calpain-2 Regulates Kinesin and Dynein Dysfunction in Neurotoxin-Induced Motoneuron Injury

by Vandana Zaman, Camille Green, Kayce Sitgreaves, Amy Gathings, Kelsey P. Drasites, Noah Coleman, Jessica Huell, Townsend McDonald, Narendra L. Banik and Azizul Haque

Brain Sci. 2026, 16(1), 92; https://doi.org/10.3390/brainsci16010092 - 16 Jan 2026

Viewed by 449

Abstract

Background/Objectives: Neurodegenerative diseases are driven by multiple interconnected pathological mechanisms involving both intrinsic and extrinsic molecular and cellular processes. Efficient bidirectional intracellular transport is essential for neuronal survival and function, enabling the movement of organelles, proteins, and vesicles between the neuronal soma and [...] Read more.

Background/Objectives: Neurodegenerative diseases are driven by multiple interconnected pathological mechanisms involving both intrinsic and extrinsic molecular and cellular processes. Efficient bidirectional intracellular transport is essential for neuronal survival and function, enabling the movement of organelles, proteins, and vesicles between the neuronal soma and distal compartments. This process is primarily mediated by kinesin-dependent anterograde transport and dynein-dependent retrograde transport. Disruption of either motor protein compromises endosome–lysosome recycling, leading to cellular dysfunction and neurodegeneration. However, the mechanisms underlying motor protein impairment in Parkinson’s disease (PD) remain incompletely understood. Methods: We investigated the involvement of kinesin and dynein in intracellular transport dysfunction using both in vitro and in vivo models of PD. Cultured neuronal cells were exposed to MPP+ (1-methyl-4-phenylpyridinium) to model PD-associated neurotoxicity, and motor protein function, vesicular trafficking, and endosomal recycling were assessed. In parallel, an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model of PD was used to evaluate dynein-positive fiber density in the spinal cord. The role of calpain-2 was examined by co-treatment with the selective calpain-2 inhibitor zLLYCH2F in both experimental systems. Results: MPP+ exposure disrupted kinesin- and dynein-mediated transport in neuronal cytoplasm, resulting in impaired vesicular trafficking and defective endosome–lysosome recycling. These alterations led to abnormal accumulation of vesicles in both perinuclear regions and at the cell periphery. Pharmacological inhibition of calpain-2 with zLLYCH2F restored motor protein function and normalized vesicle distribution in MPP+-treated cells. Consistent with in vitro findings, MPTP-treated mice exhibited a significant reduction in dynein-positive fiber density within the spinal cord, which was prevented by co-treatment with zLLYCH2F. Conclusions: Our findings demonstrate that calpain-2 activation contributes to kinesin and dynein dysfunction following MPP+/MPTP exposure, leading to impaired intracellular transport and vesicle recycling in PD models. Inhibition of calpain-2 preserves motor protein function, maintains cytoskeletal integrity, and supports normal intracellular trafficking. These results identify calpain-2 as a critical regulator of motor protein stability and suggest that targeting calpain-2 may represent a promising therapeutic strategy for mitigating intracellular transport defects in Parkinson’s disease. Full article

(This article belongs to the Special Issue The Neural Processes Underlying Parkinson’s Disease and Related Synucleinopathies)

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22 pages, 3789 KB

Open AccessArticle

Alterations in Multidimensional Functional Connectivity Architecture in Preschool Children with Autism Spectrum Disorder

by Jiannan Kang, Xiangyu Zhang, Zongbing Xiao, Zhiyuan Fan, Xiaoli Li, Tianyi Zhou and He Chen

Brain Sci. 2026, 16(1), 91; https://doi.org/10.3390/brainsci16010091 - 15 Jan 2026

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Abstract

Background: Autism Spectrum Disorder (ASD) is a type of neurodevelopmental disorder, and its exact causes are currently unknown. Neuroimaging research suggests that its clinical features are closely linked to alterations in brain functional network connectivity, yet the specific patterns and mechanisms underlying these [...] Read more.

Background: Autism Spectrum Disorder (ASD) is a type of neurodevelopmental disorder, and its exact causes are currently unknown. Neuroimaging research suggests that its clinical features are closely linked to alterations in brain functional network connectivity, yet the specific patterns and mechanisms underlying these abnormalities require further clarification. Methods: We recruited 36 children with ASD and 36 age- and sex-matched typically developing (TD) controls. Resting-state EEG data were used to construct static and dynamic low- and high-order functional networks across four frequency bands (δ, θ, α, β). Graph-theoretical metrics (clustering coefficient, characteristic path length, global efficiency, local efficiency) and state entropy were applied to characterize network topology and dynamic transitions between integration and segregation. Additionally, between-frequency networks were built for six band pairs (δ-θ, δ-α, δ-β, θ-α, θ-β, α-β), and network global measures quantified cross-frequency interactions. Results: Low-order networks in ASD showed increased δ and β connectivity but decreased θ and α connectivity. High-order networks demonstrated increased δ connectivity, reduced α connectivity, and mixed alterations in θ and β. Graph-theoretical analysis revealed pronounced α-band topological disruptions in ASD, reflected by a lower clustering coefficient and efficiency and higher characteristic path length in both low- and high-order networks. Dynamic analysis showed no significant entropy changes in low-order networks, while high-order networks exhibited time- and frequency-specific abnormalities, particularly in δ and α (0.5 s window) and δ (6 s window). Between-frequency analysis showed enhanced β-related coupling in low-order networks but widespread reductions across all band pairs in high-order networks. Conclusions: Young children with ASD exhibit coexisting hypo- and hyper-connectivity, disrupted network topology, and abnormal temporal dynamics. Integrating hierarchical, dynamic, and cross-frequency analyses offers new insights into ASD neurophysiology and potential biomarkers. Full article

(This article belongs to the Section Neural Engineering, Neuroergonomics and Neurorobotics)

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Open AccessArticle

Relationships Among Functional Status, Global Self-Reported Categorical Measure of Activity Level, Health-Related Quality of Life and Psychological State in Patients with Parkinson’s Disease in Greece

by Anna Christakou, Nektaria Angeliki Komisopoulou, Amalia Panagiota Louka and Vasiliki Sakellari

Brain Sci. 2026, 16(1), 90; https://doi.org/10.3390/brainsci16010090 - 15 Jan 2026

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Abstract

Background/Objectives: Parkinson’s disease is the second most common neurodegenerative disorder, affecting patients’ daily lives in multiple domains, including functional status, health-related quality of life, and psychological well-being. This study examined the relationship between self-reported global activity level, functional status, Health Related QoL [...] Read more.

Background/Objectives: Parkinson’s disease is the second most common neurodegenerative disorder, affecting patients’ daily lives in multiple domains, including functional status, health-related quality of life, and psychological well-being. This study examined the relationship between self-reported global activity level, functional status, Health Related QoL (HRQoL), and psychological state among patients with Parkinson’s disease in Greece. Methods: Thirty volunteers (mean age = 69.07, SD = 11.24), members of the Greek Parkinson’s Patients and Caregivers Association, completed (a) the Parkinson’s Disease Questionnaire to evaluate HRQoL and (b) the Hospital Anxiety and Depression Scale (HADS) to assess psychological state. Participants then performed (a) the Five Times Sit to Stand Test (FTSST) and (b) the Berg Balance Scale (BBS) to evaluate functional status. All questionnaires and the test used in the present study have been validated in Greek. Correlation analysis with Spearman r tests with Bonferroni correction was performed between the above variables. Subsequent linear regression models were used to identify independent predictors of HRQoL and balance using SPSS 29.0.2.0. Results: Participants reported elevated anxiety (M = 9.67, SD = 4.44) and depressive symptoms (M = 8.97, SD = 4.08), alongside relatively high HRQoL scores (M = 40.09, SD = 18.40). Impaired functional performance was observed, with 22 participants failing to complete the FTSST within 16 s and 16 scoring below 40 on the BBS. Functional status was strongly correlated with HRQoL (r = −0.696, p < 0.001) and activity level (r = −0.521, p < 0.008). Depression was also significantly associated with poorer HRQoL (r = 0.618, p < 0.008) and lower activity levels (r = −0.545, p < 0.008). Regression analyses revealed that balance (β = −0.526), disease duration (β = 0.437), anxiety (β = 0.411), and lower limb function (β = −0.351) were significant independent predictors of HRQoL (R² = 0.785; F(9, 20) = 12.69; p < 0.001), while HRQoL (β = −0.738) and lower limb function (β = −0.391) independently predicted balance (R² = 0.699; F(9, 20) = 4.72; p = 0.002), suggesting a bidirectional relationship between physical function and subjective well-being. Conclusions: Activity level, HRQoL, functional status, and psychological state in patients with Parkinson’s disease are interrelated factors. Increased levels of anxiety and depression, as well as reduced HRQoL, were observed. The findings point to a potentially reinforcing cycle between poor balance and diminished quality of life, with anxiety and age playing key roles. Overall, the results illustrate that functional, psychological, and HRQoL measures interact in complex ways, emphasizing the multidimensional profile of patients with Parkinson’s disease. Further studies with larger samples are required to confirm these findings. Full article

(This article belongs to the Section Neurodegenerative Diseases)

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Brain Sci., Volume 16, Issue 1 (January 2026) – 119 articles

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