Brain Sciences

15 pages, 7209 KB

Open AccessArticle

Resting-State 40 Hz EEG Activity Before and After Single-Session Non-Flickering 40 Hz Light Stimulation in Cognitively Normal Older Adults: An Uncontrolled Pilot Study

by Chia-Hsiung Cheng and Hsinjie Lu

Brain Sci. 2026, 16(9), 976; https://doi.org/10.3390/brainsci16090976 - 15 Sep 2026

Abstract

Background: Forty-hertz sensory stimulation has emerged as a potential approach for modulating neural activity relevant to Alzheimer’s disease. However, electrophysiological changes following non-flickering 40 Hz light stimulation in older adults remain unclear. This study investigated whether a single-session intervention of non-flickering 40 [...] Read more.

Background: Forty-hertz sensory stimulation has emerged as a potential approach for modulating neural activity relevant to Alzheimer’s disease. However, electrophysiological changes following non-flickering 40 Hz light stimulation in older adults remain unclear. This study investigated whether a single-session intervention of non-flickering 40 Hz light stimulation would be associated with increased resting-state 40 Hz oscillations in cognitively normal older adults. Methods: In this uncontrolled single-arm pilot study, 16 cognitively normal older adults underwent a 60 min session of non-flickering 40 Hz light stimulation. Resting-state EEG was recorded immediately before and after stimulation. Relative power within 38–42 Hz was analyzed across six predefined scalp regions and the whole-brain measure using one-tailed Wilcoxon signed-rank tests with Benjamini–Hochberg false discovery rate (FDR) correction. Exploratory real-time EEG recordings during stimulation were available in 10 participants. Results: After FDR correction, resting-state 38–42 Hz relative power was higher post-stimulation in the central (FDR = 0.045, effect size = 0.555) and right temporal (FDR = 0.014, effect size = 0.724) regions. In the absolute-power sensitivity analysis, only the right temporal increase remained significant after FDR correction (FDR = 0.042). Exploratory during-stimulation analysis showed a nominally increased 38–42 Hz signal-to-noise ratio in the right temporal region (p = 0.026). One participant reported very mild fatigue; no other adverse responses were reported. Conclusions: This pilot study suggests regional increases in resting-state 38–42 Hz activity after non-flickering 40 Hz light stimulation, with additional absolute-power support for the right temporal finding. These findings remain preliminary given the uncontrolled design and small sample. Full article

(This article belongs to the Section Behavioral Neuroscience)

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38 pages, 4510 KB

Open AccessArticle

Cognitive Control and Metacognition: The Effect of Interference, Working-Memory Load, and Shifting on Confidence in Response Correctness and Partial Error

by Patryk Guzda, Marta Siedlecka and Aleksandra Gruszka

Brain Sci. 2026, 16(9), 975; https://doi.org/10.3390/brainsci16090975 - 15 Sep 2026

Abstract

Background/Objectives: Confidence is typically studied in simple perceptual decisions, although everyday decisions also require cognitive control and monitoring of action. Across two experiments, we examined whether response conflict, stimulus complexity, and sequence affect task performance and retrospective metacognitive judgments concerning different aspects of [...] Read more.

Background/Objectives: Confidence is typically studied in simple perceptual decisions, although everyday decisions also require cognitive control and monitoring of action. Across two experiments, we examined whether response conflict, stimulus complexity, and sequence affect task performance and retrospective metacognitive judgments concerning different aspects of performance: confidence in response correctness and confidence that a covert partial error occurred. Methods: Participants performed a modified Stroop task in which they responded to word colour and, in compound trials, also reported the position of an accompanying line. In Experiment 1 (N = 66), participants rated confidence in the correctness of their responses. In Experiment 2 (N = 47), electromyography was used to identify covert partial errors, and participants rated confidence that a partial error had occurred. Results: Conflict reduced response accuracy, prolonged response times, and was associated with a small reduction in confidence in correct responses. In Experiment 1, the effect of sequence on confidence depended on stimulus complexity: confidence was higher in simple-repeated than in simple-switched trials, whereas the opposite pattern was observed for compound trials. In Experiment 2, partial errors occurred more frequently under conflict but less frequently in compound trials. Greater incorrect-burst surface and longer correction time were associated with higher partial-error confidence, and both relationships were weaker in compound trials. The association with incorrect-burst surface remained reliable after adjustment for response time. Exploratory analyses also showed lower metacognitive sensitivity under conflict and complexity and lower metacognitive efficiency in compound trials. Conclusions: Cognitive-control demands were associated with retrospective metacognitive judgments concerning both completed response outcomes and partial-error events occurring during response generation. Conflict was associated with a small reduction in confidence in correct responses, whereas partial-error confidence was associated with measurable characteristics of the partial-error event. The weaker relationship between EMG-derived response-process characteristics and confidence during compound processing suggests that current task demands affect how strongly internal response-related information is related to metacognitive judgments. Full article

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

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24 pages, 895 KB

Open AccessArticle

Cognitive and Behavioral Functioning in Female Former Soccer Players: Results from the Head Impact and Trauma Surveillance Study (HITSS)

by Shania C. Mulayi, Anna Aaronson, Kelsey J. Goostrey, Fatima Tuz-Zahra, Yorghos Tripodis, William S. Cole-French, Matthew Roebuck, Greta Schneider, Brittany N. Pine, Joseph N. Palmisano, Brett M. Martin, Kenton H. Zavitz, Douglas I. Katz, Christopher J. Nowinski, Ann C. McKee, Thor D. Stein, R. Scott Mackin, Michael D. McClean, Jennifer Weuve, Jesse Mez, Michael W. Weiner, Rachel L. Nosheny, Michael L. Alosco and Robert A. Stern Show full author list Hide full author list

Brain Sci. 2026, 16(9), 974; https://doi.org/10.3390/brainsci16090974 - 15 Sep 2026

Abstract

Background/Objectives: Repetitive head impacts (RHI) from contact and collision sports have been associated with later-life cognitive and neurobehavioral impairments, as well as neurodegenerative conditions such as chronic traumatic encephalopathy (CTE). RHI-associated clinical sequelae among female former soccer players, specifically, are not well understood. [...] Read more.

Background/Objectives: Repetitive head impacts (RHI) from contact and collision sports have been associated with later-life cognitive and neurobehavioral impairments, as well as neurodegenerative conditions such as chronic traumatic encephalopathy (CTE). RHI-associated clinical sequelae among female former soccer players, specifically, are not well understood. This cross-sectional study aimed to examine the relationship of RHI exposure proxies (e.g., total years of soccer play, concussion history, highest level of play, and estimated cumulative heading frequency) with clinical measures (e.g., subjective cognitive complaints, objective cognitive performance, behavioral dysregulation, and depressive symptoms) among 2732 women, aged 40 years or above, enrolled in the Head Impact and Trauma Surveillance Study (HITSS), all of whom formerly played organized soccer. Methods: HITSS participants completed an online battery that elicited self-reported cognitive and behavioral complaints and depressive symptoms and that assessed cognitive performance via computerized tests. Multivariable linear regression models estimated associations between soccer-related RHI proxies and outcome measures, adjusting for age and education. Results: Among the former soccer players, longer duration of soccer play, higher level of play, greater estimated cumulative heading frequency, and concussion history were significantly associated with worse self-reported cognitive functioning, greater behavioral dysregulation, and elevated depressive symptom severity. Apart from a single association between concussion history and visual learning and episodic memory performance, we found no other associations between RHI proxies and objective cognitive test performance. Conclusions: Among middle-aged women who played organized soccer, cumulative RHI exposure corresponded to a higher degree of subjective cognitive complaints, worse behavioral functioning, and more severe depressive symptoms. Continued monitoring of this large cohort of female former soccer players offers a more comprehensive understanding of long-term health consequences of soccer play. Full article

(This article belongs to the Special Issue Heterogeneity in Cognitive Aging: From Healthy Aging to Neurodegenerative Disease)

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19 pages, 2039 KB

Open AccessArticle

Computational–Experimental Characterization of Transcranial Magneto-Acoustic Stimulation for Dose-Efficient Neural Activation

by Ruxin Tan, Fangxuan Chu, Xin Wang, Xiaoqing Zhou, Ren Ma, Tao Yin, Haojun Fan and Zhipeng Liu

Brain Sci. 2026, 16(9), 973; https://doi.org/10.3390/brainsci16090973 - 14 Sep 2026

Abstract

Background/Objectives: Transcranial magneto-acoustic stimulation (TMAS) is an emerging multiphysics neuromodulation modality that introduces magneto-acoustically induced currents into ultrasound-based neural stimulation. However, how this coupled physical input is converted into neuronal recruitment and measurable biological responses remains insufficiently understood. This study aimed to establish [...] Read more.

Background/Objectives: Transcranial magneto-acoustic stimulation (TMAS) is an emerging multiphysics neuromodulation modality that introduces magneto-acoustically induced currents into ultrasound-based neural stimulation. However, how this coupled physical input is converted into neuronal recruitment and measurable biological responses remains insufficiently understood. This study aimed to establish a computational–experimental framework for quantifying TMAS-induced neural activation across stimulation dose, spike timing, and calcium-related response domains. Methods: The model combined ultrasound-induced membrane mechanics, charge-based neuronal electrophysiology, pressure-dependent calcium-current modulation, and a Lorentz-force-mediated current source for TMAS. Regular-spiking excitatory neurons and low-threshold-spiking inhibitory interneurons were simulated to estimate excitation thresholds, firing latency, and spike-pattern transitions. Two model-informed stimulation conditions were examined using in vitro calcium imaging, in vivo hippocampal fiber photometry, and c-Fos/microtubule-associated protein 2 (MAP2) immunofluorescence. Results: TMAS reduced the half-maximal effective dose relative to transcranial ultrasound stimulation by 71.4–76.3% in regular spiking neurons and 51.5–58.2% in low-threshold spiking interneurons, while shortening firing latency and expanding burst-response domains. Experimentally, near-threshold TMAS produced larger peak calcium responses and greater c-Fos/MAP2 immunoreactivity than TUS. Conclusions: TMAS enhances neuronal responsiveness more efficiently than TUS by reducing excitation thresholds, improving spike-timing responses, and reshaping firing-pattern transitions. Consistent with the overall computational comparison, experimental measurements showed greater neuronal activation under TMAS than under TUS at matched ultrasound parameters. Full article

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

136 pages, 2494 KB

Open AccessSystematic Review

Telerehabilitation for Motor Recovery in Adults with Neurological Disorders: A Systematic Review and Meta-Analysis Across Motor Domains, Delivery Models, and Follow-Up Effects

by Rocco Salvatore Calabrò, Arnold Fredrick D’Souza, Sanaz Pournajaf, Francesca Baglio, Carl Froilan D. Leochico and Alon Kalron

Brain Sci. 2026, 16(9), 972; https://doi.org/10.3390/brainsci16090972 - 14 Sep 2026

Abstract

Background/Objectives: Telerehabilitation may extend neurorehabilitation beyond conventional settings, but comparative effects across neurological diagnoses and motor domains remain uncertain. This systematic review and meta-analysis synthesized motor outcomes while distinguishing International Classification of Functioning, Disability and Health activity domains, delivery models, and comparator questions. [...] Read more.

Background/Objectives: Telerehabilitation may extend neurorehabilitation beyond conventional settings, but comparative effects across neurological diagnoses and motor domains remain uncertain. This systematic review and meta-analysis synthesized motor outcomes while distinguishing International Classification of Functioning, Disability and Health activity domains, delivery models, and comparator questions. Methods: Five databases were searched from inception to 8 June 2026 using two database-specific Boolean search strategies. Comparative studies of adults with neurological disorders receiving active remote, digital, virtual, wearable, or hybrid rehabilitation were eligible. Random-effects models used restricted maximum likelihood estimation; Hartung–Knapp confidence intervals were primary when at least three studies were available, and DerSimonian–Laird models were sensitivity analyses. Results: Eighty-seven studies included stroke, Parkinson’s disease, multiple sclerosis, spinal cord injury, acquired brain injury, or ataxia. For walking and mobility activities versus usual care, no additional therapy, or waitlist, the point estimate favoured telerehabilitation but was imprecise and compatible with no difference (standardized mean difference 1.06, 95% confidence interval −0.23 to 2.35; three studies; 121 participants; I² = 57.6%). Global motor-functional and activities-of-daily-living outcomes showed similar uncertainty (0.83, −0.35 to 2.00; three studies; 304 participants; I² = 73.6%). Both findings had very-low-certainty evidence. No pooled comparison included enough studies to assess publication bias. Two-study datasets for balance-related activity/postural control and upper-limb impairment were highly heterogeneous and interpreted descriptively. Conclusions: Comparative evidence for telerehabilitation across neurological diagnoses and motor domains remains uncertain. Programme characteristics are plausible implementation considerations, not established efficacy modifiers. Small evidence sets, wide intervals, clinical heterogeneity, risk of bias, and inconsistent adverse-event ascertainment preclude conclusions about clinical importance or established safety. Full article

(This article belongs to the Section Neurorehabilitation)

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17 pages, 6660 KB

Open AccessArticle

Lamotrigine Attenuates Lipopolysaccharide-Induced Working-Memory Impairment and Is Associated with Changes in Neuroinflammatory, Oxidative-Stress, and Apoptosis-Related Markers

by Bashair Hamed Alharbi, Abdulaziz Arif A. Alshammari and Vasudevan Mani

Brain Sci. 2026, 16(9), 971; https://doi.org/10.3390/brainsci16090971 - 14 Sep 2026

Abstract

Background/Objectives: Persistent neuroinflammation, oxidative imbalance, and neuronal apoptosis are key mechanisms underlying memory loss and working-memory impairment in many neurodegenerative conditions. LTG, an established anticonvulsant recognized for its glutamate-modulating and immune-dampening actions, has been reported to exert neuroprotective actions beyond seizure control. This [...] Read more.

Background/Objectives: Persistent neuroinflammation, oxidative imbalance, and neuronal apoptosis are key mechanisms underlying memory loss and working-memory impairment in many neurodegenerative conditions. LTG, an established anticonvulsant recognized for its glutamate-modulating and immune-dampening actions, has been reported to exert neuroprotective actions beyond seizure control. This study investigated whether LTG can counteract LPS-induced deficits in cognition and neuroinflammatory responses in rats by modulating oxidative stress- and apoptosis-related markers. Methods: A total of twenty-four rats were allocated into four different groups: Control, LPS, LTG, and LTG + LPS. LTG (30 mg/kg, orally) was administered for 15 days, whereas LPS (1 mg/kg, intraperitoneally) was administered during the final four days to provoke neuroinflammation. Working memory abilities were assessed utilizing the Y-maze spontaneous alternation test. Subsequently, brain tissues were analyzed for inflammatory mediators (COX-2, TNF-α, IL-6), apoptotic markers (Caspase-3, Bcl-2, BAX), and oxidative stress indicators (MDA, GSH, catalase). Results: LPS exposure produced significant memory deterioration, accompanied by elevated COX-2, TNF-α, IL-6, and MDA levels, along with reduced GSH and catalase activity, indicating oxidative and inflammatory stress. BAX and Caspase-3 expression were markedly enhanced, whereas Bcl-2 expression was significantly reduced. Pretreatment with LTG markedly attenuated the LPS-induced decline in Y-maze performance, cytokine elevation, and alterations in redox and apoptotic parameters. Conclusions: LTG effectively attenuated LPS-induced cognitive impairment and neuroinflammatory responses, accompanied by improvements in oxidative stress- and apoptosis-related markers. These findings support further investigation of the potential preventive or neuroprotective effects of LTG against neuroinflammation-associated working-memory impairment. Full article

(This article belongs to the Special Issue Neuroprotection for Neurodegenerative Diseases: Current Status and Future Perspectives)

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11 pages, 625 KB

Open AccessCommunication

Improving Risk Stratification and Surgical Decision-Making for Unruptured Cerebral Aneurysm: A Proof-of-Concept of Novel Morphological Parameters and Computational Hemodynamics

by Giuseppe Roberto Giammalva, Gabriele Costantino, Umberto Emanuele Benigno, Lapo Bonosi, Micol Tantillo, Antonino Cirello, Vito Ricotta, Tommaso Ingrassia, Giuseppe Craparo and Giovanni Tringali

Brain Sci. 2026, 16(9), 970; https://doi.org/10.3390/brainsci16090970 - 14 Sep 2026

Abstract

Background: Unruptured intracranial aneurysms (UIAs) represent a major challenge in neurosurgical practice. Rupture risk assessment traditionally relies on qualitative parameters, such as aneurysm size and shape, combined with surgical judgment and clinical expertise. However, these approaches may fail to account for the complex [...] Read more.

Background: Unruptured intracranial aneurysms (UIAs) represent a major challenge in neurosurgical practice. Rupture risk assessment traditionally relies on qualitative parameters, such as aneurysm size and shape, combined with surgical judgment and clinical expertise. However, these approaches may fail to account for the complex interplay between vascular morphology and hemodynamic forces that leads to aneurysm growth and rupture. Therefore, the development of reliable and quantitative parameters is essential to support neurosurgeons in balancing the risks of intervention against the natural history of the disease, thus optimizing decision-making for surgery. Methods: We developed an integrative framework based on a novel morphological parameter (MP), integrating multiple geometric descriptors into a single quantifiable index. To complement morphological assessment, patient-specific computational fluid dynamics (CFD) simulations were performed to evaluate hemodynamic factors known to influence aneurysm progression, thus analyzing structural and flow-related determinants of rupture risk. Results: In a cohort of 60 consecutive patients with MCA UIAs, MP showed strong concordance with the treatment decision made by an expert neurosurgeon regarding the indication for surgical clipping of aneurysms considered at risk of imminent rupture, providing an indirect, objective measure of UIA rupture risk stratification. CFD analyses confirmed that adverse hemodynamic conditions, including elevated intra-aneurysmal pressures and heterogeneous distribution of wall shear stress, correlated with unfavorable morphological features that were considered to indicate a higher risk of rupture by an expert neurosurgeon. Moreover, the integration of expert clinical judgment with quantitative indices may enhance the discrimination between aneurysms requiring early surgical intervention and those suitable for conservative management. Conclusions: This proof-of-concept study highlights the potential added value of combining morphological modelling and patient-specific hemodynamic analysis to support, rather than replace, expert neurosurgical judgment regarding the surgical management of unruptured MCA aneurysms. The proposed parameter (MP) shows concordance with expert operability decisions and may complement current neurosurgical evaluation as an ancillary decision-support tool, potentially contributing to safer operative strategies, more individualized patient management, and ultimately improved patient outcomes in the treatment of unruptured intracranial aneurysms. Full article

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

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14 pages, 2391 KB

Open AccessReview

Machine Learning and Multimodal Biomarker Discovery in Alzheimer’s Disease

by Tariq Tayebi, Monique A. David and Mourad Tayebi

Brain Sci. 2026, 16(9), 969; https://doi.org/10.3390/brainsci16090969 - 14 Sep 2026

Abstract

Background/Objectives: The accelerating integration of machine learning (ML) with molecular, imaging, and physiological data is transforming Alzheimer’s disease (AD) research. Methods & Results: Recent studies demonstrate that multimodal, AI-assisted platforms can enhance early diagnosis, predict biomarker trajectories, and identify novel therapeutic targets. This [...] Read more.

Background/Objectives: The accelerating integration of machine learning (ML) with molecular, imaging, and physiological data is transforming Alzheimer’s disease (AD) research. Methods & Results: Recent studies demonstrate that multimodal, AI-assisted platforms can enhance early diagnosis, predict biomarker trajectories, and identify novel therapeutic targets. This mini-review covers the evolving AD diagnostic and biomarker frameworks, current therapeutic strategies including recently approved anti-amyloid immunotherapies, and advances from contemporary studies employing ML across diverse data streams, ranging from cerebrospinal fluid (CSF) and plasma proteomics to Raman spectroscopy, neuroimaging, transcriptomics, and microbiome signatures. Conclusions: Collectively, they illustrate how artificial intelligence (AI) has shifted A biomarker discovery from univariate to network-based inference, achieving clinically relevant accuracy while emphasizing model interpretability. We discuss biological insights, translational implications, and persisting challenges related to validation, bias, and regulatory integration. Full article

(This article belongs to the Section Neurodegenerative Diseases)

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15 pages, 893 KB

Open AccessPerspective

Primitive-Reflex Profiling After Sport-Related Concussion: An Athlete-Centered Framework for Testing a Candidate Behavioral State Marker

by Erzsébet Stephens-Sarlós, Patrick Stephens and Attila Szabo

Brain Sci. 2026, 16(9), 968; https://doi.org/10.3390/brainsci16090968 - 14 Sep 2026

Abstract

Direct prospective evidence that primitive-reflex expression changes after sport-related concussion (SRC) is currently very limited. This Perspective therefore proposes a deliberately restricted context of use: standardized primitive-reflex profiling as an experimental, low-cost candidate behavioral state marker to be tested within athletes across recovery, [...] Read more.

Direct prospective evidence that primitive-reflex expression changes after sport-related concussion (SRC) is currently very limited. This Perspective therefore proposes a deliberately restricted context of use: standardized primitive-reflex profiling as an experimental, low-cost candidate behavioral state marker to be tested within athletes across recovery, not as an established diagnostic biomarker or a return-to-sport criterion. The standardized 18-reflex protocol underlying this framework demonstrated excellent inter-rater (κ = 0.912–1.000) and intra-rater (κ = 0.912–0.983) reproducibility in the reported 565-participant validation sample; however, athlete-specific reliability, responsiveness to SRC, construct validity, prognostic utility, and treatment sensitivity remain unestablished. We distinguish three testable candidate mechanisms—fronto-subcortical stopping-network dysfunction, altered sensorimotor/afferent gating, and vestibular–reticulospinal dysregulation—and specify findings that would support or weaken each account. A staged research program begins with sport-specific reliability and feasibility, proceeds to prospective within-athlete change beyond measurement error, and only then evaluates mechanistic convergence, incremental prognostic value, and intervention sensitivity. The full 18-reflex profile (30 bilateral or non-lateralized measurements) should remain the primary level of analysis. A summed primitive-reflex burden is retained only as a descriptive summary and must not substitute for reflex-specific analysis. Palmar grasp and Babkin-related responses provide a focused, falsifiable test case for relating lateralized reflex expression to premotor and supplementary motor hemodynamics during force-matched grasping. Progression between stages requires prespecified success criteria, independent replication, and explicit stopping rules. Until those conditions are met, primitive-reflex profiling should remain an experimental outcome embedded within guideline-concordant concussion care. Full article

(This article belongs to the Special Issue Detection and Treatment of Brain Injury)

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20 pages, 13663 KB

Open AccessReview

Brain Health Research in PubMed/MEDLINE: A Bibliometric Analysis of Thematic Structure and Health-Economic Terminology with a Conceptual Performance-Management Framework

by Ioannis Ch. Lampropoulos and Georgia Xiromerisiou

Brain Sci. 2026, 16(9), 967; https://doi.org/10.3390/brainsci16090967 - 13 Sep 2026

Abstract

Background/Objectives: Brain health is an interdisciplinary field; however, the prominence of health-economic concepts within the PubMed/MEDLINE literature explicitly retrieved using the term ‘brain health’ has not been systematically characterized. The present study aimed to map the scientific landscape of the retrieved brain health [...] Read more.

Background/Objectives: Brain health is an interdisciplinary field; however, the prominence of health-economic concepts within the PubMed/MEDLINE literature explicitly retrieved using the term ‘brain health’ has not been systematically characterized. The present study aimed to map the scientific landscape of the retrieved brain health literature and to examine the representation and network prominence of health-economic concepts within this corpus. Methods: Two separate PubMed/MEDLINE searches were conducted using the exact search expression “brain health”. The overall search was performed on 8 April 2026 and yielded an analytical corpus of 18,306 publications (1993–2026), while a separate search on 9 May 2026, restricted by publication year to 2023–2026, yielded the recent-period analytical corpus (n = 10,908). Bibliometric analyses were performed using VOSviewer (version 1.6.20), including keyword co-occurrence analysis and thesaurus-based term standardization. Results: The overall keyword co-occurrence analysis identified five principal thematic clusters: neurobiological mechanisms (n = 117 items), public health and lifestyle (n = 67), neurodegeneration and biomarkers (n = 54), neuroimaging and vascular factors (n = 37), and neurophysiology and interventions (n = 25). The independently retrieved recent-period corpus showed a seven-cluster thematic structure, with prominent topics including neuroinflammation, blood-based biomarkers, and machine-learning applications. The targeted analysis identified health-economic concepts in the complete dataset, including cost–benefit analysis (n = 37), cost of illness (n = 28), cost-effectiveness (n = 24), and healthcare costs (n = 21), but these concepts showed relatively low frequency and limited prominence in the principal co-occurrence network. These findings indicate that health-economic concepts are present within the analyzed PubMed/MEDLINE corpus but show relatively low frequency and limited prominence in the principal keyword co-occurrence network. Conclusions: Within the PubMed/MEDLINE corpus analyzed, health-economic concepts showed relatively low frequency and limited prominence in the principal keyword co-occurrence network. Because the analysis was restricted to PubMed/MEDLINE and used the exact search expression ‘brain health’, these findings characterize the retrieved corpus and should not be interpreted as evidence of a general disconnect between brain health and health economics across the broader multidisciplinary literature. Informed by the bibliometric findings and the broader literature discussed in the manuscript, a conceptual three-axis framework is subsequently proposed, comprising: (1) disease-cost assessment, (2) economic evaluation and return-on-investment assessment of preventive interventions, and (3) population-level brain health performance indicators. Full article

(This article belongs to the Special Issue Neuroprotection for Neurodegenerative Diseases: Current Status and Future Perspectives)

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22 pages, 3654 KB

Open AccessArticle

Brain Regional Predictors of Surgical Response Are Dynamically Associated with Post-Surgical Pain Relief in Trigeminal Neuralgia

by Emili Adhamidhis, Patcharaporn Srisaikaew, Jerry Li, Timur H. Latypov, Alborz Noorani and Mojgan Hodaie

Brain Sci. 2026, 16(9), 966; https://doi.org/10.3390/brainsci16090966 - 13 Sep 2026

Abstract

Background/Objectives: Trigeminal neuralgia (TN) is a severe chronic neuropathic facial pain condition. Although TN can be amenable to surgical treatments, ~25% of patients may have recurrence of pain. Understanding the role of the central nervous system (CNS) gray matter and its impact on [...] Read more.

Background/Objectives: Trigeminal neuralgia (TN) is a severe chronic neuropathic facial pain condition. Although TN can be amenable to surgical treatments, ~25% of patients may have recurrence of pain. Understanding the role of the central nervous system (CNS) gray matter and its impact on surgical treatment effect remains unclear but is of increasing interest. Previous machine learning models identified 13 neuroanatomical regional predictors of TN surgical response. The implications of these regions and how they might relate to clinical status and surgical outcome are not clear. Here, we attempt to further understand CNS alterations in TN by investigating how these potential regional predictors of surgical response may change following surgical treatment, and whether this is related to the degree of pain relief achieved. Methods: Retrospective imaging was acquired from 115 surgically naïve TN patients who underwent Gamma Knife Radiosurgery at Toronto Western Hospital. Patients obtained magnetic resonance imaging scans and reported pain intensity scores before and 3–12 months after surgery. Patients were categorized as responders (≥75% pain relief), partial responders (50–74% pain relief), and non-responders (<50% pain relief). Results: Eight regions spanning default mode, visual, limbic, and dorsal attention networks had significant changes in cortical thickness. Responders demonstrated post-operative neuroplasticity in a greater number of regions with higher within-group statistical significance than both partial and non-responders. Thickening of the contralateral fusiform gyrus was correlated with the degree of pain reduction. Conclusions: Our findings identify key regions impacted by chronic neuropathic pain, which may be associated with pain relief in TN. Full article

(This article belongs to the Special Issue The Evolving Landscape of Trigeminal Neuralgia: From Bench to Bedside and Beyond)

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19 pages, 326 KB

Open AccessReview

Childhood ADHD and Its Adult Mimics: When First-Time ADHD Diagnoses in Adulthood May Reflect Other Conditions—A Narrative Review

by Alessandro Cuomo, Mario Pinzi and Andrea Fagiolini

Brain Sci. 2026, 16(9), 965; https://doi.org/10.3390/brainsci16090965 - 13 Sep 2026

Abstract

Background/Objectives: Attention-deficit/hyperactivity disorder (ADHD) begins in childhood, but its presentation changes over time. Adult ADHD is increasingly recognized; in the United States, 2023 survey data indicate that approximately 6% of adults reported a current diagnosis. This narrative review examines the developmental course of [...] Read more.

Background/Objectives: Attention-deficit/hyperactivity disorder (ADHD) begins in childhood, but its presentation changes over time. Adult ADHD is increasingly recognized; in the United States, 2023 survey data indicate that approximately 6% of adults reported a current diagnosis. This narrative review examines the developmental course of ADHD from childhood to adulthood and the controversial phenomenon of apparent late-onset presentations. Broadened diagnostic criteria, greater public awareness, and expanded access through telehealth may contribute to the rise in adult diagnoses, but these factors do not establish population-level diagnostic inflation. In some first-time adult assessments, the presenting symptoms may be better explained by an alternative or co-occurring condition; longitudinal studies also document associations between childhood ADHD and later borderline personality disorder or bipolar disorder without showing that diagnostic substitution is common. Methods: This is a narrative, non-systematic review. The primary and secondary literature were identified through targeted searches of PubMed/MEDLINE and Google Scholar (studies published through July 2026) using combinations of the terms “adult ADHD”, “diagnostic inflation”, “late-onset ADHD”, “executive function”, “borderline personality disorder”, “retrospective recall” and “stimulant diversion”, supplemented by hand-searching the reference lists of key reviews, current diagnostic manuals (DSM-5, DSM-5-TR, ICD-11) and consensus statements. All cited empirical claims and figures were verified against the primary source before submission. Results: The clinical presentation of ADHD shifts from overt hyperactive–impulsive behaviour in childhood toward executive dysfunction and subjective restlessness in adulthood. Longitudinal cohorts show both persistence and fluctuating remission, while birth-cohort evidence for apparently late-onset ADHD is substantially reduced when cases undergo repeated, multi-informant reassessment. Evidence for the recent rise in adult diagnoses is most direct for criterial broadening and expanded access, is qualitatively strong but difficult to quantify for correction of historical underrecognition and remains contested for genuinely adult-onset ADHD. Mood, anxiety, substance-use, sleep, stress-related, and personality conditions can overlap with or mimic ADHD-like symptoms. Prospective studies also report associations between childhood ADHD and later borderline personality disorder or bipolar disorder, but do not establish how often adult ADHD is diagnosed instead of either condition. Screening instruments and retrospective childhood recall therefore require interpretation within a full developmental and differential assessment. Conclusions: Adult ADHD is a genuine, historically underrecognized, and treatable condition. Its increased visibility warrants careful assessment, because a later diagnosis based on weakly corroborated retrospective evidence may be overconfident even when it is ultimately correct. Maintaining diagnostic integrity across the lifespan requires developmentally informed assessment, systematic differential diagnosis, cautious use of screening instruments, and explicit separation of clinical conclusions from administrative or medico-legal determinations. Full article

(This article belongs to the Special Issue Addressing ADHD in Children: Contemporary Treatment Strategies)

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29 pages, 880 KB

Open AccessArticle

Towards a Neurocognitive Profile of Post-Acute COVID-19: A Longitudinal Study Integrating Subjective Complaints and Computerized Cognitive Testing

by Miroslava Hristova, Radka Massaldjieva, Penka Atanassova and Daniela Kantareva

Brain Sci. 2026, 16(9), 964; https://doi.org/10.3390/brainsci16090964 - 12 Sep 2026

Abstract

Background/Objectives: The relationship between subjective cognitive complaints and objective performance in post-acute COVID syndrome (PACS), and the persistence of objective impairment over extended follow-up, remain unclear. This prospective longitudinal study characterized the neurocognitive profile of PACS by integrating computerized cognitive testing with structured [...] Read more.

Background/Objectives: The relationship between subjective cognitive complaints and objective performance in post-acute COVID syndrome (PACS), and the persistence of objective impairment over extended follow-up, remain unclear. This prospective longitudinal study characterized the neurocognitive profile of PACS by integrating computerized cognitive testing with structured evaluation of subjective complaints across an extended post-infection interval. Methods: A total of 102 adults with a history of COVID-19 infection (3–35 months post-infection; mean age 40.2 ± 10.95 years; 70.6% female) underwent baseline (V1) CogState Battery testing (seven subtests) and structured assessment of persistent post-COVID complaints; 67 participants (65.7%) constituted the matched longitudinal sample and completed the follow-up (V2) after a mean inter-visit interval of 6.69 ± 1.00 months. Domain-specific composites (Attention/Psychomotor function, Learning/Working memory, and two Global indices) were derived from age-adjusted z-scores, with impairment defined as z ≤ −1.5. Results: Persistent complaints were reported by 63.7% of participants at baseline. In the matched longitudinal sample (n = 67) Attention/Psychomotor impairment was the most prevalent and stable finding in the paired sample (65.7% at V1 and 67.2% at V2; McNemar p = 1.000), whereas ONB-defined working-memory impairment declined nominally in the paired sample (39.4% to 24.2%; p = 0.006), although this change did not remain significant after correction for multiple comparisons (BH-FDR q = 0.063). In the baseline sample persistent complaints were associated with poorer objective performance at V1 across all composite indices with small-to-moderate effect sizes (all BH-FDR-adjusted q = 0.042–0.047). These associations were not observed in the follow-up sample at V2. Age was the most robust demographic correlate of impairment, particularly for visuospatial associative memory (CPAL; β = −0.349, p < 0.001); clinical and demographic predictors explained 9.4–13.9% of the variance (R² = 0.094–0.139) in significant models at Visit 1. Conclusions: Attention/psychomotor dysfunction constituted a persistent objective deficit after COVID-19. Subjective complaints at baseline were associated with objective impairments but did not predict cognitive performance at follow-up. These findings support the use of objective computerized cognitive testing alongside symptom screening in the clinical assessment of post-COVID patients. Interpretation is limited by the absence of pre-COVID cognitive data and of a demographically matched healthy, uninfected control group. Full article

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

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14 pages, 912 KB

Open AccessSystematic Review

Exercise Modulates Working Memory-Related Brain Activation Through Bidirectional Neural Mechanisms: An ALE Meta-Analysis of Longitudinal and Cross-Sectional fMRI Studies

by Jiayu Wang, Jun Wang and Wenshuang Tang

Brain Sci. 2026, 16(9), 963; https://doi.org/10.3390/brainsci16090963 - 12 Sep 2026

Abstract

Background: Physical exercise improves working memory (WM) across the lifespan, yet the neural mechanisms underlying this benefit remain incompletely understood, and it is unclear whether intervention-induced neuroplastic changes and long-term exercise-related differences converge on common neural circuits. Methods: We systematically searched PubMed, Web [...] Read more.

Background: Physical exercise improves working memory (WM) across the lifespan, yet the neural mechanisms underlying this benefit remain incompletely understood, and it is unclear whether intervention-induced neuroplastic changes and long-term exercise-related differences converge on common neural circuits. Methods: We systematically searched PubMed, Web of Science, PsycINFO, and CNKI through June 2026 and included 11 task-based fMRI studies (6 longitudinal interventions and 5 cross-sectional comparisons; 403 participants) reporting whole-brain activation coordinates. Activation likelihood estimation (ALE) meta-analyses were performed separately for activation increases and decreases within each design. Results: Longitudinal studies revealed exercise-induced activation increases in the bilateral cerebellum (posterior lobe, cerebellar tonsil) and decreases in the right thalamus. Cross-sectional studies revealed greater activation in the left middle temporal gyrus (BA 21) and reduced activation in the right cingulate gyrus (BA 24) and left caudate body among long-term exercisers relative to controls. Critically, the two designs yielded spatially non-overlapping patterns. Conclusions: These findings support a dual-mechanism model in which exercise strengthens task-positive network engagement while optimizing the suppression of task-irrelevant processing. They further suggest that exercise shapes working memory circuitry across distinct, timescale-dependent neural circuits. Full article

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

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Graphical abstract

30 pages, 4983 KB

Open AccessArticle

Spatial-Frequency Hypergraph Neural Network for EEG-fNIRS Emotion Recognition

by Haifeng Li, Xueying Zhang, Guijun Chen, Yaru Zhou, Ying Sun and Lixia Huang

Brain Sci. 2026, 16(9), 962; https://doi.org/10.3390/brainsci16090962 - 11 Sep 2026

Abstract

Background/Objectives: Hybrid EEG-fNIRS emotion recognition aims to accurately identify an individual’s emotional state by analyzing neurophysiological signals and constitutes an important research direction in affective brain–computer interfaces and human–computer interaction. In recent years, EEG-fNIRS emotion recognition has advanced from handcrafted feature extraction and [...] Read more.

Background/Objectives: Hybrid EEG-fNIRS emotion recognition aims to accurately identify an individual’s emotional state by analyzing neurophysiological signals and constitutes an important research direction in affective brain–computer interfaces and human–computer interaction. In recent years, EEG-fNIRS emotion recognition has advanced from handcrafted feature extraction and shallow fusion to deep learning and graph-based modeling. However, most existing methods rely on predefined fixed frequency-band partitioning and second-order graph structures that only support pairwise connections, making it difficult to accommodate inter-subject frequency variability and to characterize high-order brain network relationships such as multi-channel synergistic activation within a frequency band and cross-frequency coupling. Methods: To address these issues, this paper proposes an EEG-fNIRS emotion recognition framework based on a Spatial-Frequency Hypergraph Neural Network (SF-HGNN). First, a Dynamic Frequency Band Decomposition module is designed to achieve adaptive optimization of the EEG and fNIRS frequency bands; second, a Multi-scale Temporal Convolution module extracts temporal features at different time scales; third, a Spatial-Frequency Adaptive Hypergraph Convolution module is constructed to model intra-band cross-channel spatial synergy and channel-wise cross-frequency coupling; and finally, a Cross-Modal Attention Fusion mechanism achieves high-order interaction between the complementary information of the two modalities. The proposed method was validated on the public ENTER dataset comprising 50 participants and four emotion categories (sadness, happiness, fear, and calm). Results: Experimental results show that SF-HGNN achieves accuracies of 82.94% and 68.85% in subject-dependent and subject-independent experiments, respectively; ablation studies and visualization analyses further verify the effectiveness of each module and the interpretability of the model. Conclusions: Future work will focus on validation with larger-scale data and improving cross-subject domain generalization. Full article

(This article belongs to the Section Neurotechnology and Neuroimaging)

20 pages, 1817 KB

Open AccessArticle

Real-World Use of Opicapone in Management of Patients with Parkinson’s Disease and Early Motor Fluctuations in Spain: 12-Month Interim Analysis of REONPARK Study

by Lydia López-Manzanares, María Cerdán Sánchez, Berta Solano Vila, Tania Delgado Ballestero, Rocío García-Ramos, Juan García Caldentey, Ana Rodríguez-Sanz, Jesús Olivares Romero, Itziar Gaston, Mar Carmona-Abellán, Marina Mata Álvarez-Santullano, Raquel Vázquez Picón, Marta Rodríguez-De Miguel, Iciar Tegel Ayuela, Diogo Magalhães, Joerg Holenz and on behalf of the REONPARK Study Group

Brain Sci. 2026, 16(9), 961; https://doi.org/10.3390/brainsci16090961 - 11 Sep 2026

Abstract

Objective: To evaluate the sustained real-world effectiveness and safety of catechol-O-methyltransferase (COMT) inhibitors added to levodopa in patients with Parkinson’s disease (PD) presenting early motor fluctuations. Methods: REONPARK is an ongoing, multicenter, prospective observational study conducted in Spain. Adult patients with PD and [...] Read more.

Objective: To evaluate the sustained real-world effectiveness and safety of catechol-O-methyltransferase (COMT) inhibitors added to levodopa in patients with Parkinson’s disease (PD) presenting early motor fluctuations. Methods: REONPARK is an ongoing, multicenter, prospective observational study conducted in Spain. Adult patients with PD and end-of-dose motor fluctuations for <2 years initiating a COMT inhibitor were included. Outcomes assessed at 3, 6, and 12 months included Clinician and Patient Global Impression of Change (CGI-C, PGI-C), Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Wearing-off Questionnaire (WOQ-19), Non-Motor Symptoms Scale (NMSS), Parkinson’s Disease Questionnaire-8 (PDQ-8), and safety. This article presents the 3-, 6-, and 12-month planned interim analysis of the study. Results: A total of 143 patients were included (99.3% treated with opicapone), of whom 138, 131, and 89 patients completed the 3, 6, and 12 months of follow-up, respectively. Levodopa doses remained stable in most patients (73% at 12 months). Significant and sustained improvements were observed in MDS-UPDRS Parts III and IV scores, as well as the total MDS-UPDRS score over 12 months, with greater likelihood of Part IV improvement in patients receiving <4.5 mg/kg/day of levodopa. OFF time decreased by 1.6–2.0 h from baseline. ON-time quality was maintained over time with 97.7% of patients reporting no or minimal functional impact from dyskinesia, while 47.7% of patients had no impact from motor fluctuations and 36.4% of patients no longer experienced OFF periods at 12 months. PDQ-8 scores remained stable and no overall benefit on total non-motor symptoms burden was demonstrated, despite improvements in selected domains among patients with a higher baseline non-motor symptoms burden. WOQ-19 scores improved significantly. Conclusions: In PD patients with early motor fluctuations, opicapone initiation was associated with sustained improvements in motor outcomes and reduced OFF time, and maintained the ON-time quality over 12 months, with stable levodopa dosing. Full article

(This article belongs to the Section Neurodegenerative Diseases)

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4 pages, 160 KB

Open AccessEditorial

Special Issue: Eye-Tracking Monitoring of Neurological and Psychiatric Conditions Across Life Span

by Marco Cavallo

Brain Sci. 2026, 16(9), 960; https://doi.org/10.3390/brainsci16090960 - 11 Sep 2026

Abstract

There is something almost paradoxical about eye movements [...] Full article

(This article belongs to the Special Issue Eye-Tracking Monitoring of Neurological and Psychiatric Conditions Across Life Span)

20 pages, 1261 KB

Open AccessReview

Structured Light Music for Stress Adaptation: The BDNF/TrkB Signaling Axis Mediating Neuroplasticity and HPA Axis Regulation

by Jingqi Le, Xuelan Shu, Pingping Jia and Tao Le

Brain Sci. 2026, 16(9), 959; https://doi.org/10.3390/brainsci16090959 - 10 Sep 2026

Abstract

Background/Objectives: Chronic stress poses a major threat to animal health and welfare, yet current interventions are often invasive, poorly compliant, or lack long-term feasibility. This narrative review synthesizes preclinical mechanistic evidence from mammalian animal models to examine how structured auditory stimulation engages [...] Read more.

Background/Objectives: Chronic stress poses a major threat to animal health and welfare, yet current interventions are often invasive, poorly compliant, or lack long-term feasibility. This narrative review synthesizes preclinical mechanistic evidence from mammalian animal models to examine how structured auditory stimulation engages neurotrophic signaling. Structured light music—an auditory stimulus with defined acoustic parameters (e.g., tempo, intensity, and spectral frequency)—has emerged as a promising non-invasive strategy for promoting stress adaptation. However, the molecular mechanism of its effects remains unclear, and systematic analyses linking acoustic features to signaling pathways are scarce. Brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin receptor kinase B (TrkB) constitute a central signaling axis regulating neuroplasticity and stress adaptation, suggesting that this pathway may serve as a critical molecular interface linking auditory stimulation to stress-regulatory processes. Methods: In this review, we focus on structured light music stimuli with distinct acoustic characteristics and examine the molecular mechanisms by which they regulate neural plasticity through the BDNF/TrkB pathway. Results: Existing studies have shown that light music is associated with reversal of stress-induced down-regulation of BDNF/TrkB signaling in the hippocampus and prefrontal cortex. This effect is accompanied by enhanced neurogenesis, dendritic spine remodeling, and synaptic protein synthesis, which are linked to the coordinated activation of three downstream pathways: PI3K/Akt, MAPK/ERK and PLCγ. This cascade reaction further correlates with restoration of negative feedback inhibition of the hypothalamic–pituitary–adrenal axis in the hippocampus, reduces the level of glucocorticoids, and alleviates oxidative stress and inflammatory damage. Conclusions: This review proposes that the BDNF/TrkB pathway may serve as a key molecular basis for light music to regulate neural plasticity and achieve systemic anti-stress effects, and provides new ideas for animal welfare management and the formulation of standardized acoustic intervention strategies. Full article

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20 pages, 9092 KB

Open AccessArticle

Notoginsenoside R1 Attenuates Oxidative Damage After Intracerebral Hemorrhage by Inhibiting LCN2 and Promoting HO-1 in Astrocytes

by Qingyun Liu, Xiao Chen, Baofeng Wang, Yuhao Sun and Liuguan Bian

Brain Sci. 2026, 16(9), 958; https://doi.org/10.3390/brainsci16090958 - 10 Sep 2026

Abstract

Objectives: Intracerebral hemorrhage (ICH) is a devastating form of stroke characterized by high morbidity and mortality, but effective treatment strategy remains in urgent demand. Notoginsenoside R1 (NGR1), a bioactive component extracted from the traditional herb Panax notoginseng has been widely applied in the [...] Read more.

Objectives: Intracerebral hemorrhage (ICH) is a devastating form of stroke characterized by high morbidity and mortality, but effective treatment strategy remains in urgent demand. Notoginsenoside R1 (NGR1), a bioactive component extracted from the traditional herb Panax notoginseng has been widely applied in the therapy of cardiovascular diseases and neurological disorders. This study aims to investigate the effects of NGR1 on oxidative damage following ICH. Methods: NGR1 was administrated to a collagenase-induced ICH mouse model and hemin-stimulated primary astrocytes in vitro. Hematoma volume, brain water content and neurobehavioral outcomes were assessed in the ICH mice. Cell viability was evaluated using the Cell Counting Kit-8 (CCK-8) assay. In astrocytes pretreated with 25 μM NGR1 for 24 h followed by 30 μM hemin treatment for 24 h, levels of reactive oxygen species (ROS), malondialdehyde (MDA), and the glutathione (GSH)/oxidized glutathione (GSSG) ratio were measured. The expression of lipocalin-2 (LCN2), heme oxygenase-1 (HO-1), and glial fibrillary acidic protein (GFAP) was detected via immunofluorescence staining and Western blotting. Additionally, LCN2 and HO-1 were knocked down in astrocytes, using small interfering RNA (siRNA) transfection. Results: LCN2, HO-1, and GFAP expression was upregulated in the peri-lesional area of the brain following ICH. NGR1 alleviated brain injury and improved neurological function in the collagenase-induced ICH mouse model. Specifically, administration of 20 mg/kg NGR1 suppressed the upregulation of LCN2 and increased HO-1 expression post ICH. NGR1 enhanced cell viability and reversed hemin-induced toxicity in astrocytes in vitro. Treatment with 25 μM NGR1 reduced ROS and MDA levels and upregulated the GSH/GSSG ratio in astrocytes exposed to 30 μM hemin. Furthermore, 25 μM NGR1 inhibited LCN2 and GFAP expression while promoting HO-1 expression in hemin-treated astrocytes. The inhibitory effect of NGR1 on LCN2 was reversed by the Nrf-2/HO-1 inhibitor ML385. Moreover, LCN2 knockdown promoted HO-1 expression and suppressed ROS levels in astrocytes. Conversely, HO-1 knockdown increased LCN2 and GFAP expression, thereby reversing the protective effects of NGR1. Conclusions: This study demonstrates that NGR1 alleviates ICH-induced oxidative damage by promoting HO-1 expression and inhibiting LCN2 expression, thereby maintaining redox homeostasis. Full article

(This article belongs to the Special Issue Translational Omics in Neurodegenerative and Neurodevelopmental Disorders)

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