Brain Res. [JOURNAL]
Sun
200 papers
Differential modulation of EEG microstate spatiotemporal dynamics by rTMS and iTBS correlates with clinical improvement in Alzheimer's disease.
Xu G, Gao J, Wang T … +5 more , Wu H, Liu S, Ji Y, Wang P, Guo M
Brain Res · 2026 Aug · PMID 41990984 · Publisher ↗
BACKGROUND: Transcranial magnetic stimulation (TMS) is an effective therapy for patients with Alzheimer's Disease (AD), potentially modulating aberrant functional connectivity. Electroencephalography (EEG) microstates re...
BACKGROUND: Transcranial magnetic stimulation (TMS) is an effective therapy for patients with Alzheimer's Disease (AD), potentially modulating aberrant functional connectivity. Electroencephalography (EEG) microstates represent transient large-scale resting networks and have emerged as candidate markers for AD. However, their modulation by repetitive TMS (rTMS) and intermittent theta burst stimulation (iTBS) protocols remains to be elucidated. METHODS: Resting-state EEG was recorded from 28 AD patients at baseline and following the 1st, 7th, and 14th sessions of rTMS or iTBS treatment. Polarity-insensitive modified k-means clustering was used to segment EEGs into constituent microstates, which were then subjected to source localization to identify their corresponding cortical regions. Longitudinal changes within subjects in clinical status and microstate parameters (duration, occurrence, coverage, transition probability) were evaluated with one-way repeated-measures analysis of variance, and differences between rTMS and iTBS groups were assessed using t-tests. RESULTS: Four microstates (MS A-D) were identified from EEG data. rTMS predominantly induced sustained suppression of MS-B, whereas iTBS elicited early-phase increases in MS-C activity. Clinical symptoms improvement following TMS correlated with increased MS-C and decreased MS-B activity. Source localization revealed rTMS predominantly modulated MS-B generators in the occipital cortex (impacting visual and dorsal attention networks), while iTBS preferentially engaged MS-C generators in the parietal cortex (affecting sensorimotor and frontoparietal networks). CONCLUSIONS: We identified distinct EEG microstates and their underlying cortical generators associated with clinical improvement in AD following treatment with rTMS and iTBS protocols. The results demonstrate protocol-specific spatiotemporal modulation profiles and temporal dynamics, highlighting differential neural mechanisms of rTMS and iTBS.
DJ-1 deficiency in SH-SY5Y cells reveals dysregulated networks of genes and pathways involved in neuronal function and disease.
Gock N, Kim G, Morin T … +5 more , Young MA, Mahal A, Kostka J, Beischlag TV, Lee FJS
Brain Res · 2026 Aug · PMID 41990983 · Publisher ↗
Parkinson's disease (PD) is the second most common neurodegenerative disorder. Although the etiology of idiopathic PD is unclear, recessive loss-of-function mutations in PARK7/DJ-1 cause familial early-onset PD, which mi...
Parkinson's disease (PD) is the second most common neurodegenerative disorder. Although the etiology of idiopathic PD is unclear, recessive loss-of-function mutations in PARK7/DJ-1 cause familial early-onset PD, which mirrors key features of the idiopathic form. In this study, we ablate PARK7/DJ-1 via CRISPR-Cas9 from the human neuronal cell line, SH-SY5Y. Subsequently, RNA sequencing and the DESeq2 toolkit were utilized to identify 5468 differentially expressed genes (DEG) between PARK7/DJ-1 knockouts and control SH-SY5Y cells. Three genes from each of the top 10 upregulated and downregulated gene lists were selected and confirmed via RT-PCR. Differentially expressed gene lists were run through the WebGestalt functional enrichment analysis toolkit to identify enriched gene ontology (GO) terms. Among the top significantly enriched GO biological process terms include terms related to synaptic transmission (downrgulated DEG) and development (upregulated DEG). Differentially expressed genes were run through the STRING database to predict protein-protein interactions (PPI). A highly significant PPI enrichment was observed (p < 1.0e-16). To gain insight into what could potentially be driving the observed expression changes, we performed an iRegulon analysis within Cytoscape to identify potential upstream transcription factors. The top transcriptional factors identified for driving downregulated genes was REST, while EP300 was identified as the top candidate driving upregulated genes. Our results indicate that loss of DJ-1 in human neuronal cells leads to dysregulation of networks of connected genes and pathways that are implicated in neurodegenerative disease as well as neuronal function.
Exercise preconditioning attenuates ischemic neurological deficits without modulating motor learning in a rodent model of focal cortical ischemia.
Silva-García J, Eurolo I, Fuentes-Flores R … +1 more , Valdés JL
Brain Res · 2026 Aug · PMID 41974320 · Publisher ↗
Ischemic stroke is a leading cause of death and disability worldwide. Among survivors, one-third live with permanent impairments, and two-thirds experience upper limb dysfunction. Despite advances in acute care, no unive...
Ischemic stroke is a leading cause of death and disability worldwide. Among survivors, one-third live with permanent impairments, and two-thirds experience upper limb dysfunction. Despite advances in acute care, no universally effective rehabilitation strategies are available. Physical exercise improves cardiovascular health and promotes neuroplasticity, acting as a potential preconditioning factor against ischemic injury. While most preclinical studies use extensive lesion models, the effects of physical exercise preconditioning (PEP) on focal stroke and post-stroke motor learning remain underexplored. This study aims to assess the effects of PEP on neurological deficits, motor learning capacities, and plasticity markers, following focal ischemia induced by endothelin-1 in the caudal forelimb area of the primary motor cortex (M1) in rats. Twenty-four Sprague-Dawley male rats were randomized into 4 groups; two of them underwent 4 weeks of voluntary wheel running, and two were sedentary, before sham or stroke surgery, followed by neurological function evaluation, training in a skilled reaching task (SRT), and immunohistochemistry to assess plasticity markers (p-CREB and Arc) in M1. PEP significantly reduced neurological impairment but did not improve motor learning. However, PEP promotes compensatory strategies to solve the task, such as utilizing ipsilesional forelimbs and mitigating motivational deficits. PEP significantly increased p-CREB and Arc expression, suggesting the activation of plasticity-related pathways, despite these markers not correlating with motor learning outcomes. In conclusion, PEP modulated both behavioral and plasticity responses to focal stroke. These findings support exercise as a low-cost, accessible strategy to enhance neuroplasticity, highlighting its role as a foundation for stroke rehabilitation.
METTL3 attenuated bupivacaine-induced neurotoxicity by enhancing m6A-modified BDNF expression.
Xiong Q, Peng L, Song X … +1 more , Fu W
Brain Res · 2026 Aug · PMID 41966347 · Publisher ↗
Bupivacaine (BUP), a widely used amide-type local anesthetic, exhibits neurotoxic effects. This study aimed to explore the functions of brain-derived neurotrophic factor (BDNF) and methyltransferase Like 3 (METTL3) in BU...
Bupivacaine (BUP), a widely used amide-type local anesthetic, exhibits neurotoxic effects. This study aimed to explore the functions of brain-derived neurotrophic factor (BDNF) and methyltransferase Like 3 (METTL3) in BUP-induced hippocampal neuronal damage. HT22 cells and SH-SY5Y cells were treated with various concentrations of BUP. METTL3 and BDNF were manipulated using either overexpression or knockdown approaches to assess their functional roles. Cell viability, apoptosis, mitochondrial membrane potential and oxidative stress markers (Lactate Dehydrogenase (LDH), Reactive Oxygen Species (ROS), Superoxide Dismutase (SOD), Malondialdehyde (MDA)) were evaluated using Cell Counting Kit-8 (CCK-8), flow cytometry, JC-1 staining and commercial kits. The expression of BDNF, METTL3, Caspase-9, Bax and Bcl-2 was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. The N6-methyladenosine (m6A) modification of BDNF mRNA was assessed using Methylated RNA Immunoprecipitation (Me-RIP) and commercial kits. BUP treatment dose-dependently reduced viability, while increasing oxidative stress and apoptosis in our cellular model. BDNF expression was down-regulated in BUP-induced cells. Additionally, BUP stimulation suppressed both total m6A levels and METTL3 expression in cell models. Overexpression of BDNF ameliorated BUP-induced cell damage. METTL3 stabilized BDNF through m6A modification, and the depletion BDNF reversed the protective effect of overexpressing METTL3 on BUP-induced neurotoxicity. Together, our results indicated that METTL3 attenuated BUP-induced neurotoxicity by enhancing BDNF expression via m6A modification.
BET protein inhibitor JQ1 reduces inflammationand hippocampal amyloid-β level without altering Tau phosphorylation in LPS-challenged adult wild-type mice.
Matuszewska M, Cieślik M, Sulejczak D … +2 more , Wilkaniec A, Czapski GA
Brain Res · 2026 Aug · PMID 41966346 · Publisher ↗
A growing body of evidence highlights the role of infection and inflammation in the progression of Alzheimer's disease (AD). In this study, we aimed to analyze the impact of JQ1, an inhibitor of bromodomain and extraterm...
A growing body of evidence highlights the role of infection and inflammation in the progression of Alzheimer's disease (AD). In this study, we aimed to analyze the impact of JQ1, an inhibitor of bromodomain and extraterminal domain (BET) proteins, which are key readers of the epigenetic acetylation code, on AD-related gene expression changes and biochemical alterations in the hippocampus during a lipopolysaccharide (LPS)-induced systemic inflammatory response in mice. JQ1 and LPS were administered intraperitoneally to adult male wild-type C57BL/6J mice. Changes in selected general and brain-specific parameters were measured for up to 12 h. Our results demonstrated that inhibition of BET proteins reduced LPS-induced sickness behavior and time-dependent elevation of proinflammatory signaling. LPS did not significantly alter amyloid-β (Aβ) levels; however, a significant reduction in Aβ load was observed in JQ1-treated animals overall, suggesting that BET proteins play a crucial role in regulating Aβ levels in the brain. At the same time, JQ1 treatment did not affect LPS-induced increases in phospho-Tau levels. Our results suggest that inhibiting BET proteins, in addition to their anti-inflammatory action, may be an effective strategy for reducing Aβ levels in the brain. However, a mechanistic explanation of this phenomenon requires further investigation.
Altered AMPA receptor subunit configuration contributes to dysfunctional excitatory synaptic activity in BCNU rat-model of focal cortical dysplasia (FCD).
Kumar AJ, Nambiar S, Sharma A … +5 more , Tripathi M, Sarat Chandra P, Dixit AB, Siraj F, Banerjee J
Brain Res · 2026 Aug · PMID 41956280 · Publisher ↗
Focal Cortical Dysplasia (FCD) is a leading cause of drug-resistant epilepsy, yet its molecular drivers remain unclear. AMPA receptor subunit composition plays a key role in synaptic excitability and may be altered in FC...
Focal Cortical Dysplasia (FCD) is a leading cause of drug-resistant epilepsy, yet its molecular drivers remain unclear. AMPA receptor subunit composition plays a key role in synaptic excitability and may be altered in FCD. To investigate whether dysregulated expression of AMPAR subunits, specifically GluA1 and GluA4, contributes to the enhanced excitatory synaptic activity in FCD rat-model, BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) was administered in-utero to induce FCD in rats. At postnatal-day 30 (P30), somatosensory cortex samples were analysed using qPCR and immunohistochemistry for GluA1, GluA4, and GluN2B. Whole-cell patch clamp recordings of spontaneous excitatory postsynaptic currents (sEPSCs) were performed, with APV and CNQX used for pharmacological dissection. GluA1 expression was significantly reduced in FCD tissue at both mRNA and protein levels (p < 0.05), while GluA4 showed significant upregulation (p < 0.01). GluN2B levels remained unchanged. Functionally, FCD neurons displayed increased sEPSC amplitude (p = 0.0022) and frequency (p = 0.045), with a leftward shift in interevent intervals (p = 0.0002). Power spectrum analysis further supported a distinct glutamatergic signature and increased channel activity in FCD. A near-suppression of events after CNQX + APV application confirmed the glutamatergic nature of currents. Significant reduction of sEPSC amplitude and increase in rise-time in control group on APV application with no change in FCD group suggests AMPA receptor predominance in excitatory synaptic activity in FCD. Our findings reveal alterations in subunit configuration of AMPARs in FCD, driving hyperexcitable synaptic transmission through faster, less desensitizing glutamatergic currents. These molecular and functional changes suggest pathological reprogramming of excitatory synapses in FCD and AMPARs as potential therapeutic targets.
Perspective reasoning and the real-time comprehension of spoken narrative: Insights from eye movements.
Mozuraitis M, Daneman M, Chambers CG
Brain Res · 2026 Aug · PMID 41956279 · Publisher ↗
Various aspects of communicative meaning hinge on issues of perspective, and key components of perspective reasoning are known to accompany real-time language comprehension. Drawing on the Visual World Paradigm, past stu...
Various aspects of communicative meaning hinge on issues of perspective, and key components of perspective reasoning are known to accompany real-time language comprehension. Drawing on the Visual World Paradigm, past studies have shown that listeners' ability to manage privileged knowledge about objects' existence or presence in a context is more effective than the ability to manage privileged knowledge about objects' identity. The present study tests the generalizability of these findings in a situation where listeners are processing spoken narratives. The central question is how effectively listeners manage privileged narrative- level information that should not be attributed to story characters. For example, when a character utters a referring expression, listeners' interpretation should not draw on information unknown to the character. Experiment 1 (off-line comprehension measures) demonstrates that listeners reliably encode and recall story characters' knowledge states. In contrast, Experiment 2 (real-time gaze measures) shows that, although listeners effectively manage privileged narrative knowledge about characters' existence during real-time comprehension, they are less effective when this privileged knowledge concerns characters' identity. Together the results validate and extend past findings and highlight connections to broader phenomena including referential opacity and qualitatively distinct forms of perspective-taking.
A local-field potentials of the midbrain of humans associated with the onset of sound and alterations in frequency within the sound: event-driven study.
Kantserova A, Pitskhelauri D, Podlepich V … +1 more , Oknina L
Brain Res · 2026 Jul · PMID 41951092 · Publisher ↗
The study recorded and analyzed local field potentials (LFPs) from the human inferior colliculi of 6 patients during surgery. LFPs were recorded in response to onset of simple tones with frequencies 600, 800, 1000, 2000,...
The study recorded and analyzed local field potentials (LFPs) from the human inferior colliculi of 6 patients during surgery. LFPs were recorded in response to onset of simple tones with frequencies 600, 800, 1000, 2000, and 4000 Hz and "complex" sound. "Complex" sound included 7 fragments of different frequencies: 600, 800, 1000, 1500, 2000, and 4000 Hz. In the case of the "complex" sound, the LFPs were recorded in response both to its onset and frequency alterations within the stimulus. We identified distinct peak groups related to the onset of tones and frequency changes. Peaks Vs-VIs-S1s are related to the sound onset and frequency modulations within the sound. The group of peaks S2s (Vs2-VIs2)-S3s seems to be related to the sound's volume. We hypothesize that two functional types of neuron populations in the inferior colliculi exist: one that responds to sound onset and frequency alterations within a sound, and another that is triggered by increases in sound volume. The hypothesis offers a new perspective on the functional division of midbrain neural ensembles involved in auditory perception. Nevertheless, given the small number of observations and limitation of the LFPs method, the proposed hypothesis requires further experimental verification.
Intrinsic neural timescale abnormalities reveal molecular and neuromodulatory basis of concomitant exotropia.
Yu FL, He YZ, Hu ZX … +2 more , Zheng ZL, Huang X
Brain Res · 2026 Jul · PMID 41951091 · Publisher ↗
BACKGROUND: Concomitant exotropia (CE) is a prevalent strabismic disorder characterized by outward ocular deviation and impaired binocular vision. While structural and functional brain abnormalities have been reported in...
BACKGROUND: Concomitant exotropia (CE) is a prevalent strabismic disorder characterized by outward ocular deviation and impaired binocular vision. While structural and functional brain abnormalities have been reported in CE, the temporal dynamics of intrinsic neural timescale remain largely unexplored. METHODS: This study employed a multimodal framework combining resting-state functional MRI (rs-fMRI), transcriptomic data from the Allen Human Brain Atlas (AHBA), and neurotransmitter receptor density maps to investigate alterations in intrinsic neural timescales (INT) in CE. A total of 87 participants (43 CE patients, 44 matched controls) underwent rs-fMRI scanning. Voxel-wise and network-level INT were computed, followed by partial least squares (PLS) regression linking INT alterations with regional gene expression. Functional enrichment, cell-type specificity, and spatial correlations with PET-based receptor maps were also analyzed. RESULTS: Compared to controls, CE patients exhibited significantly reduced INT in the right middle frontal gyrus and basal ganglia network, indicating impaired temporal integration in oculomotor and executive control circuits. Transcriptomic analyses revealed that INT-related genes were enriched for immune-inflammatory and neurodevelopmental pathways. Excitatory and inhibitory neurons were the dominant contributors to the altered transcriptional profiles, implicating excitation-inhibition imbalance as a core mechanism. Furthermore, INT alterations showed significant negative correlations with glutamatergic, GABAergic, and opioid receptor distributions, suggesting neuromodulatory dysregulation in CE. CONCLUSIONS: This study provides the first evidence of altered INT in CE and uncovers their molecular and neurochemical substrates. The findings highlight INT as a sensitive biomarker for temporal dysfunction in CE and emphasize the utility of integrative imaging-genomic approaches in elucidating its pathophysiology.
Are the eyes the window to the soul? The importance of the eyes in facial expression recognition.
Billetdeaux KA, Herzmann G
Brain Res · 2026 Aug · PMID 41951090 · Publisher ↗
Facial expressions convey important information about emotional states to others. The eyes are utilized for this type of nonverbal communication depending on how much they are open, presence or number of creases at the e...
Facial expressions convey important information about emotional states to others. The eyes are utilized for this type of nonverbal communication depending on how much they are open, presence or number of creases at the edges of the eyes, and whether or not the eyebrows are raised or furrowed. This study investigated how important the eyes are for facial expression recognition. Participants were shown a series of faces that expressed anger, fear, happiness, or sadness. Stimuli were shown either with diminished information of the eye region or no alteration, and the eyes were shown in either isolation or in the context of the face. Participants were asked to identify the expression of the stimulus shown while the N170 peak amplitude and latency, P300, and late positive potential (LPP) were recorded. Participants were more accurate and showed lower amplitudes when recognizing expressions in context of the face than from the eyes only, indicating the importance of configural and contextual information of the face in addition to the eyes. Similar results were found when information from the eyes was not diminished than when it was diminished, demonstrating the importance of the information contained in the eyes during facial expression recognition. Perceptual analysis and stimulus evaluation were differently impacted by the combination of the experimental manipulations, showing differences in the importance of configural and contextual information for early and later recognition processes. Lastly, differences in these effects across the various expressions were demonstrated through both neural and behavioral data.
Neural and behavioral markers of mental fatigue and fatigability in athletes: an EEG study using single and mixed cognitive tasks.
Dirik HB, Özpolat S
Brain Res · 2026 Jul · PMID 41935558 · Publisher ↗
This study examined time-dependent neural correlates and behavioral markers of mental fatigue and fatigability in athletes using single and mixed cognitive task paradigms with electroencephalography (EEG). Forty athletes...
This study examined time-dependent neural correlates and behavioral markers of mental fatigue and fatigability in athletes using single and mixed cognitive task paradigms with electroencephalography (EEG). Forty athletes completed Stroop, Flanker, Arithmetic, or mixed-task paradigms. EEG data were analyzed using power spectral density (PSD) in the theta, alpha, and beta frequency bands and event-related potential (ERP) analysis focusing on P300 amplitude and latency. Behavioral measures included reaction time, error rate, and subjective fatigue assessed using a Visual Analog Scale. The results showed that subjective fatigue increased significantly over time across all task conditions (p < 0.001). Behavioral performance differed across tasks, with higher error rates and longer reaction times in the Arithmetic and mixed-task conditions compared to the Stroop and Flanker tasks (p < 0.001). PSD analyses revealed significant task-related differences (p < 0.05), including higher frontal theta power during the Arithmetic task and lower posterior theta power during the mixed-task condition. Alpha power increased significantly over time in posterior regions (p < 0.05). P300 amplitude decreased across time blocks in central, centroparietal, and parietal locations (p < 0.001), while P300 latency differed across tasks (p < 0.01). In conclusion, increased subjective fatigue and time-dependent changes in posterior EEG activity occurred without behavioral performance decline, supporting a distinction between mental fatigue and fatigability.
Neural correlates of handgrip strength asymmetry in normal aging and older adults with mild cognitive impairment.
Younis M, Vints WAJ, Kušleikienė S … +6 more , Helsper S, Himmelreich U, Česnaitienė VJ, Masiulis N, Levin O, Bautmans I
Brain Res · 2026 Jul · PMID 41933684 · Publisher ↗
BACKGROUND: Handgrip strength asymmetry (HGS-A) has emerged as a potential non-invasive biomarker reflecting cognitive and neural vulnerability in older adults, yet the neural mechanisms linking asymmetry with cognitive...
BACKGROUND: Handgrip strength asymmetry (HGS-A) has emerged as a potential non-invasive biomarker reflecting cognitive and neural vulnerability in older adults, yet the neural mechanisms linking asymmetry with cognitive decline remain incompletely characterized. This study aimed to determine the relationships between HGS-A, cognitive function, and regional cortical thickness in healthy older adults and individuals with mild cognitive impairment (MCI). METHODS: Sixty-eight community-dwelling adults aged 60-85 (42 cognitively healthy, 26 MCI) underwent bilateral handgrip strength assessment using Jamar dynamometry. Cognitive evaluations included global cognition (MoCA) and domain-specific functions (ANAM4 battery). Structural MRI was performed, and cortical thickness was quantified from T1-weighted images within regions affected in MCI and Alzheimer's disease. Associations between HGS-A, cognitive performance, and cortical thickness were examined using partial correlation analyses adjusted for age and sex. RESULTS: In cognitively healthy participants, greater handgrip strength asymmetry within normal limits (<15%) significantly correlated with higher global cognitive scores (MoCA; r = 0.32, p = 0.043) and increased cortical thickness in the left postcentral gyrus (r = 0.52, p < 0.001; FDR-corrected). Conversely, these relationships were absent in participants with MCI and in those exhibiting high asymmetry levels (≥15%). Domain-specific cognitive tasks showed no significant associations with HGS-A in either group. Exploratory analyses suggested an inverted U-shaped relationship, where both minimal and excessive asymmetry reflect worse cognitive function. CONCLUSIONS: Handgrip strength asymmetry within normal limits (<15%) is linked to better cognition and cortical integrity, whereas both minimal and excessive asymmetry may reflect reduced cognitive function in older adults.
APOE genotype and astrocyte activity collectively influence AD biomarkers and Aβ burden.
Chen W, Su F, Kong H … +9 more , Wang Y, Yi C, Zheng Y, Fang Y, Shi X, Lin Y, Zhou J, Zhang X, Pei Z
Brain Res · 2026 Jul · PMID 41933683 · Publisher ↗
BACKGROUND: The apolipoprotein E ε4 (APOE ε4), a well-established genetic risk factor for Alzheimer's disease (AD), is deeply involved in amyloid-β (Aβ) and tau pathology. Blood-based biomarkers (BBMs), including Aβ42/40...
BACKGROUND: The apolipoprotein E ε4 (APOE ε4), a well-established genetic risk factor for Alzheimer's disease (AD), is deeply involved in amyloid-β (Aβ) and tau pathology. Blood-based biomarkers (BBMs), including Aβ42/40, phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL), offer accessible proxies of AD pathology. Reactive astrocytes, indicated by elevated GFAP, are increasingly recognized as key players in AD progression. However, how astrocyte reactivity interacts with APOE genotype to shape BBMs and Aβ deposition remains unclear. METHODS: We included 283 participants across the cognitive spectrum including cognitively unimpaired (CU), mild cognitive impairment (MCI), and all-cause dementia (ACD) from Guangzhou health aging and dementia cohort. Primary outcome measures were plasma biomarkers (Aβ42/40 ratio, p-tau181, GFAP, and NfL) and amyloid PET standardized uptake value ratio (SUVR). Participants were stratified by APOE ε4 carrier status and astrocyte activation. Group comparisons, correlation analyses, and sensitivity analyses were performed. RESULTS: Stage-dependent APOE effects were observed: while modulating Aβ42/40 ratios in both CU and MCI, APOE influenced p-Tau181 only in MCI, exclusively under Ast-. SUVR was significantly higher in APOE ε4 + group at MCI stage, particularly in Ast- cases. Intriguingly, p-Tau/Aβ42 showed strong SUVR correlations across all subgroups except APOE ε4- Ast- group. DISCUSSION: Our findings indicate that astrocyte reactivity is associated with differences in how APOE ε4 relates to both peripheral BBMs and central Aβ deposition, supporting an interplay between genetic risk and neuroinflammatory states in AD pathogenesis.
Mechanical properties of the developing brain in a model of fetal alcohol spectrum disorders and relationships to perineuronal net integrity.
Williams LT, Milbocker KA, Smith E … +6 more , Bodner CP, Caban-Rivera DA, McGarry MDJ, Van Houten EEW, Klintsova AY, Johnson CL
Brain Res · 2026 Jul · PMID 41933682 · Full text
Neuroimaging is a useful tool for examining altered neurodevelopmental trajectories in fetal alcohol spectrum disorders (FASD). FASD affects 1 in 20 infants in the United States with higher prevalence in specific regions...
Neuroimaging is a useful tool for examining altered neurodevelopmental trajectories in fetal alcohol spectrum disorders (FASD). FASD affects 1 in 20 infants in the United States with higher prevalence in specific regions across the globe. Advanced neuroimaging methods, such as volumetric morphometry and diffusion-weighted imaging, are critical for determining the effectiveness of interventions that support neurodevelopment in FASD. In this study, we introduce the use of magnetic resonance elastography (MRE), a cutting-edge neuroimaging technique used to measure the mechanical properties of brain tissue, to assess the impact of alcohol exposure and combined exercise and environmental complexity intervention on neurodevelopment in a rat model of FASD. Our results indicate that brain stiffness is reduced in juvenile alcohol-exposed rats which is recovered to baseline by adulthood, and damping ratio increases in all rats with age. Additionally, we quantified cortical perineuronal net (PNN) density which follows similar trends to shear stiffness and damping ratio, suggesting MRE may be an effective method for noninvasively monitoring FASD progression related to extracellular matrix integrity.
Stem cells as emerging regenerative approaches for post-traumatic stress disorder: Mechanisms and translational challenges.
Thong CN, Yap YH
Brain Res · 2026 Jul · PMID 41932671 · Publisher ↗
Post-traumatic stress disorder (PTSD) is a debilitating neuropsychiatric condition triggered by severe trauma, characterised by dysregulated fear circuitry, hippocampal atrophy with impaired neurogenesis, chronic neuroin...
Post-traumatic stress disorder (PTSD) is a debilitating neuropsychiatric condition triggered by severe trauma, characterised by dysregulated fear circuitry, hippocampal atrophy with impaired neurogenesis, chronic neuroinflammation, neuroendocrine dysregulation, and disrupted prefrontal-limbic connectivity. Existing treatments are largely symptomatic, failing to address underlying neurobiological deficits. Emerging regenerative approaches using human stem cells, particularly induced pluripotent stem cell-derived neural progenitor cells (iPSC-NPCs), human embryonic stem cells (hESCs), mesenchymal stem cells (MSCs), and their extracellular vesicles (EVs), offer mechanistic plausibility for neural repair via direct neuronal replacement, paracrine neurotrophic support (e.g., BDNF, GDNF, VEGF), immunomodulation (e.g., shifting microglia to anti-inflammatory phenotypes), and promotion of synaptic plasticity and epigenetic reprogramming. Preclinical evidence remains limited and largely indirect, with sparse PTSD-specific studies (e.g., one report of iPSC-NPC transplantation reducing fear behaviour and enhancing hippocampal BDNF/neuronal density in a rat model) supplemented by convergent data from adjacent CNS injury paradigms. MSC- and iPSC-derived EVs, enriched with regulatory miRNAs (e.g., miR-124, miR-21, miR-146a), emerge as a safer, cell-free alternative with strong immunomodulatory potential and greater translational feasibility. However, reproducibility is constrained by model variability, lack of independent replication, and absence of PTSD-focused clinical trials. Major challenges include tumorigenicity risks (especially for pluripotent-derived cells), immune rejection, epigenetic/genomic instability, manufacturing scalability, stringent regulatory requirements, and elevated ethical thresholds for invasive therapies in a non-lethal psychiatric disorder. This review examines how stem cell actions align with PTSD brain changes, critically assesses the limited evidence, and suggests a careful translational plan.
Upregulation of synapse-associated protein 97 in the spinal dorsal horn exacerbates inflammatory pain through mediating GluA1-containing AMPARs membrane trafficking.
Yv L, Qiao Y, Wang X … +4 more , Yuan H, Wei S, Li L, Xu JT
Brain Res · 2026 Jul · PMID 41916464 · Publisher ↗
Molecules involved in trafficking and organization of glutamate receptors at the synapses between primary afferents and spinal dorsal horn neurons play an important role in the regulation of pain-related synaptic transmi...
Molecules involved in trafficking and organization of glutamate receptors at the synapses between primary afferents and spinal dorsal horn neurons play an important role in the regulation of pain-related synaptic transmission. Synapse-associated protein 97 (SAP97) interacts directly with the AMPARs subunit GluA1 and drives GluA1-containing AMPARs trafficking from the Golgi network to the plasma membrane. However, the role of SAP97 in inflammatory pain remains unclear. In this study we found that intraplantar injection of complete Freund's adjuvant (CFA) in male and female rats led to increase in the production of SAP97 protein in the ipsilateral spinal dorsal horn neurons. Knockdown of SAP97 expression with microinjection of AAV-EGFP-SAP97 shRNA into lumbar 5 spinal dorsal horn alleviated mechanical allodynia and thermal hyperalgesia after CFA injection. Moreover, the association of SAP97 with GluA1 and the membrane insertion of GluA1-containing AMPARs in postsynaptic density (PSD) were also inhibited by the treatment. In addition, overexpression of SAP97 by microinjection of AAV-EGFP-SAP97 into lumbar 5 spinal dorsal horn in naïve rats resulted in abnormal pain, and caused enhanced-interaction of SAP97 with GluA1 and increased-membrane trafficking of GluA1-containing AMPARs in PSD fraction. The established inflammatory pain was partially attenuated by intrathecal injection of NASPM, an antagonist of GluA1-containing AMPARs, on day 7 after CFA injection. Collectively, our results indicate that the CFA-induced upregulation of SAP97 contributes to the pathogenesis of inflammatory pain via promoting GluA1-containing AMPARs membrane trafficking in the spinal dorsal horn. Targeting spinal SAP97 might be a promising therapeutic strategy to treat inflammatory pain.
Anodal transcranial direct current stimulation (tDCS) over premotor and parietal cortex improves upper limb proprioception.
Allahverdloo E, Abdollahi I, Quessy S … +2 more , Neva J, Dancause N
Brain Res · 2026 Jul · PMID 41905603 · Publisher ↗
Proprioception plays a critical role in motor control and is often impaired following orthopedic or neurological damage. Non-invasive brain stimulation methods, such as transcranial direct current stimulation (tDCS), cou...
Proprioception plays a critical role in motor control and is often impaired following orthopedic or neurological damage. Non-invasive brain stimulation methods, such as transcranial direct current stimulation (tDCS), could potentially be used to modulate proprioceptive processing and help recovery. Among cortical areas, the premotor cortex (PMC) and posterior parietal cortex (PPC) are key regions involved in proprioceptive processing. We investigated the effects of tDCS delivered with the anode positioned over the right PMC and PPC on active joint position sense (AJPS) in healthy adults. Forty-five right-handed participants were randomly assigned to receive anodal tDCS targeting either PMC, PPC, or a SHAM tDCS protocol. Stimulation was applied for 20 min per day, over five consecutive days. AJPS of the elbow flexion and shoulder internal and external rotation, both with the arm ipsilateral and contralateral to the stimulation, were assessed before and after the 5 days protocol. Anodal tDCS stimulation of both PMC and PPC induced significant reductions in angular error compared to SHAM. We found no significant differences between the ipsilateral and contralateral arms or across movements, supporting that tDCS can have a broad, positive impact on proprioceptive accuracy in healthy individuals. Our results suggest that PMC and PPC could provide promising targets for neuromodulatory interventions aiming at enhancing proprioceptive sense.
Netrin-1 derived from BMSC-exosomes promotes axonal regeneration and functional recovery after spinal cord injury via inhibition of the RhoA/ROCK pathway.
He B, Yang W, Yang J … +1 more , Zhang J
Brain Res · 2026 Jul · PMID 41905602 · Publisher ↗
OBJECTIVE: Spinal cord injury (SCI) leads to severe neurological dysfunction. This study investigated the role of exosome-derived netrin-1 (NTN1) in axonal repair after SCI. METHODS: BMSC-Exos were isolated and character...
OBJECTIVE: Spinal cord injury (SCI) leads to severe neurological dysfunction. This study investigated the role of exosome-derived netrin-1 (NTN1) in axonal repair after SCI. METHODS: BMSC-Exos were isolated and characterized, and their uptake by neural stem cells (NSCs) was confirmed. An in vitro axonal injury model was established using microfluidic chambers, and NSCs were treated with BMSC-Exos with or without an NTN1-neutralizing antibody or the ROCK inhibitor Y-27632. Axonal outgrowth and RhoA/ROCK-related signaling were assessed by immunofluorescence and Western blot. In vivo, a rat contusion SCI model received intrathecal BMSC-Exos with or without NTN1 neutralization. Locomotor recovery was evaluated using Basso-Beattie-Bresnahan (BBB) scoring, and spinal cord tissues were analyzed histologically. RESULTS: NTN1 was enriched in BMSC-Exos and increased in NSCs after exosome treatment. In vitro, BMSC-Exos promoted axonal outgrowth after injury, and this effect was partially attenuated by NTN1 neutralization, accompanied by changes in RhoA/ROCK-related signaling. In vivo, BMSC-Exos improved locomotor recovery and reduced spinal cord tissue damage, whereas NTN1 neutralization weakened these effects. CONCLUSION: BMSC-Exos promote axonal repair and functional recovery after SCI, at least in part through exosome-derived NTN1 associated with modulation of RhoA/ROCK signaling.
Gene expression of the HCN family in rats with pilocarpine-induced epilepsy and in human hippocampal and cortical tissue.
Dos Santos RS, Dos Santos MFC, da Costa JC … +5 more , Machado DC, Antocheviez GN, Lima NL, Mezzari MHDS, Isolan GR
Brain Res · 2026 Jul · PMID 41903877 · Publisher ↗
BACKGROUND: Epilepsy is a chronic pathophysiological syndrome defined by excessive and recurrent neuronal electrical discharges in the brain, affecting approximately 0.8% of the global population. The concept of channelo...
BACKGROUND: Epilepsy is a chronic pathophysiological syndrome defined by excessive and recurrent neuronal electrical discharges in the brain, affecting approximately 0.8% of the global population. The concept of channelopathy emerges as a fundamental basis for this dysfunction, involving failures in voltage-gated ion channels. Among these, hyperpolarization-activated cation channels (HCN), encoded by the HCN1-4 genes, are unique due to their pacemaker function and sensitivity to abnormal electrical activity, regulating resting membrane potential and neuronal excitability. METHODS: The expression of HCN1-HCN4 genes was analyzed in experimental and human models of epilepsy. Male Wistar rats were assigned to control and pilocarpine-induced epilepsy groups, representing the acute and chronic phases of the disease. Following the induction of status epilepticus, regions of the central nervous system, including hippocampal subfields, temporal cortex, and cerebellum, were collected for molecular analysis. Human hippocampal tissue was obtained from patients with pharmacoresistant temporal lobe epilepsy undergoing surgery, while samples from patients with traumatic brain injury were used as controls. Gene expression was quantified by real-time PCR using specific primers, and data were analyzed using the 2ΔΔCT method, normalized to β-actin, with statistical significance set at P < 0.05. RESULTS: HCN1-4 transcripts were detected in all analyzed regions of the rat and human central nervous system. In control rats, HCN1 was the predominant subtype across hippocampal, cortical, and cerebellar regions. Acute pilocarpine-induced epilepsy was associated with minimal changes in HCN expression patterns. In contrast, chronic epilepsy resulted in a marked, region-specific downregulation of HCN1 and HCN2, particularly in hippocampal and neocortical areas. Human hippocampal and cortical tissues exhibited a similar expression profile, with HCN1 predominance in controls and altered relative expression in epileptic samples, supporting conserved epilepsy-related remodeling of HCN channel expression. CONCLUSIONS: Our results support previous finding and further suggest unexpected actions of CHCNs in the brain and indicate that HCN isoforms is dynamically regulated in human as well as in experimental models of hippocampal epilepsy, suggesting also that transcriptional dysregulation of HCN might contribute to the epileptogenic process and that certain mechanisms for the altered expression of HCN channels may be involved in the epileptogenic mechanisms.
Synergistic effect of carboxymethyl chitosan and phloroglucinol against rotenone induced Parkinson's disease in zebrafish model.
Parthiban A, Thippeswamy NP, Jayanthi PA … +2 more , Palaniselvam S, Ramachandran S
Brain Res · 2026 Jul · PMID 41895390 · Publisher ↗
Parkinson's disease (PD) is a prevalent neurodegenerative disorder that impairs motor function in humans. This research explores the combined neuroprotective effects of carboxymethyl chitosan (CMC) and phloroglucinol (PG...
Parkinson's disease (PD) is a prevalent neurodegenerative disorder that impairs motor function in humans. This research explores the combined neuroprotective effects of carboxymethyl chitosan (CMC) and phloroglucinol (PGL) in a zebrafish (ZF) model of PD induced by rotenone (ROT). The structural features of the CMC-PGL conjugate were analysed using UV-visible, Fourier Transform Infrared (FT-IR), and fluorescence spectroscopy. The phenolic content of conjugated sample was estimated and confirmed the conjugation of CMC with PGL. The LD of CMC-PGL was determined as 8 μg/mL in ZF embryo (ZFE). In vivo experiments revealed that ROT exposure decreased locomotor activity, while CMC-PGL 4 mg/L treated ZF exhibits improved was confirmed by the ToxTrac analysis. Behavioural parameters improvements were also seen in Novel tank test (NTT) and light/dark tests with CMC-PGL 4 mg/L (LD) and CMC-PGL 8 mg/L (HD) treated ZF. RP- HPLC showed the significant (P < 0.0001) restoration of dopamine (DA) levels post-treatment. Histological analysis showed ROT-induced brain damage in ZF, including necrosis, cytoplasmic vacuolisation, and neuronal degeneration, whereas in the CMC-PGL 4 mg/L showed a decrease in neuronal loss and vacuolisation. These findings suggest that CMC-PGL conjugates may hold promise as therapeutic agents for managing neurodegeneration (ND) associated with PD.
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