Neuroplasticity Research Articles

Abstract The association of genetic variants in the Human Leukocyte Antigen (HLA) locus with late-onset Alzheimer’s disease has been stringently replicated across several, powerful genome-wide association studies. However, no clear picture has yet emerged of the mechanistic relationship between Alzheimer’s disease and this top genetic hit, despite the fact that the HLA locus is one of the most influential gene loci of the immune system, known to influence antigen presentation, T cell responses and brain plasticity. In this review, we explore this association by outlining five research questions, namely: (i) the association of HLA Class I and Class II genes with Alzheimer’s disease at the allelic and haplotypic levels, (ii) the unconventional role of HLA Class I in the brain, (iii) the infection hypothesis of Alzheimer’s disease in the context of the known role HLA proteins play in immunity, (iv) the possible antigen presentation of Alzheimer’s disease relevant self-antigens and in turn (v) the possibility of T cells existing that are specific for these antigens. Identifying the functional mechanisms underlying this important genetic association with Alzheimer’s disease may hold the key to unravelling new avenues of Alzheimer’s disease immunotherapeutics.

Abstract Background Outcomes for adult patients with high-grade glioma (HGG) remain poor, necessitating new treatment strategies. Key challenges include poor drug penetration in the brain and malignant cell state plasticity. Phase 0 studies identify agents that achieve target modulation through pharmacologically relevant brain concentrations. Methods A Phase 0/1 clinical trial combined the two targeted inhibitors ribociclib (CDK4/6 inhibitor) and everolimus (mTOR inhibitor) in recurrent HGG patients, aiming to identify brain-penetrant combinations and assess their impact on malignant cell states. We enrolled 24 patients with recurrent HGG, characterized by CDKN2A/B deletion or CDK4/6 amplification, PTEN loss or PIK3CA mutations, and wildtype retinoblastoma protein (Rb). Tumors were evaluated for pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics. Results Median unbound ribociclib concentrations in Gadolinium non-enhancing tumor regions were significantly above the biochemical IC50 for CDK4/6 inhibition at 400 and 600 mg QD doses. Unbound everolimus concentrations were undetectable (< 0.1 nM) in tumor regions across all dose levels. Ribociclib treatment was associated with significantly decreased Ki-67 positive cells. Single nucleus RNA sequencing of 17 on-trial IDH-wildtype recurrences and 88 standard-of-care treated recurrences showed a significantly lower fraction of cycling and neural progenitor-like malignant cell populations in ribociclib-everolimus treated tumors. CDK4/6 inhibitor-directed malignant cell state shifts were validated using three patient-derived cell lines. Conclusions This trial underscores the value of integrating pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics in Phase 0/1 surgical studies to assess treatment effects, including malignant cell state shifts. ClinicalTrials.gov identifier: NCT03834740.

Freezing of gait (FOG) in Parkinson's disease (PD) is a disabling motor symptom with unclear pathophysiology. Beyond known basal ganglia dysfunction and cognitive impairment, sensory integration deficits are increasingly key, though their cortical network mechanisms during walking remain poorly understood. This study used functional near-infrared spectroscopy (fNIRS) during sensory-contextual walking to clarify FOG-related cortical networkdynamics, aiming to: (1) Characterize FOG-specific cortical responses to sensory challenges; (2) Distinguish PD-specific versus FOG-associated corticalnetwork dysfunction; (3) Explore dopaminergic modulation of these mechanisms. 40 PD patients [20 with FOG (PD-FOG), 20 without FOG (PD-nFOG)] and 23 healthy-controls (HC) completed four walking tasks [routine Walking-on-Ground (WG), Walking-on-Foam with proprioceptive challenge (WF), Walking-through-Narrow-gate with visuospatial challenge (WN), and Walking-through-Slope with combined proprioceptive/visuospatial challenges (WS)] under OFF and ON dopaminergic medications. Cortical hemodynamics in the Supplementary Motor Area (SMA), Primary Motor Cortex (M1), Primary Somatosensory Cortex (S1), Somatosensory Association Cortex (SAC), Prefrontal Cortex (PFC), and Frontal Eye Field (FEF), as well as walking performance were recorded. Group and medication-state differences were analyzed using ANOVA models. (1) PD-FOG lacked adaptive cortical plasticity (activation/connectivity response) to increasing sensory demands compared to PD-nFOG/HC; (2) PD-FOG exhibited cognitive-sensory/motor hyperconnectivity versus PD-nFOG during WF. PD patients showed widespread sensory-mediated hyperconnectivity and focal sensorimotor hyperactivation during WG/WN versus HC, but FEF hypoactivation during WS; (3) Medication improved gait but suppressed sensorimotor activation and reduced frontoparietal connectivity in PD-FOG; (4) Elevated M1-SMA connectivity predicted OFF-medication FOG, while elevated S1-FEF connectivity predicted ON-medication FOG. Daily FOG severity correlated with distinct OFF-/ON-medication connectivity patterns. This study reveals a medication-dependent, biphasic cortical dysfunction in PD-FOG. The OFF-medication state shows compensatory hyperconnectivity that fails under sensory challenges, indicating deficient plasticity, whereas the ON-medication state exhibits a paradoxical suppression of sensorimotor and integrative networks despite gait improvement. This reconceptualizes FOG as a dynamic network adaptation failure and points to state-specific therapeutic strategies. Registration number ChiCTR2300072744.

Prairie voles (Microtus ochrogaster) are monogamous rodents that establish life-long pair-bonds and display characteristic social and biparental care behaviors. Since social and sexual experiences modulate brain plasticity, the present study aimed to elucidate in female voles if social exposure to a male or social cohabitation with mating, which leads to pair-bonding, modulates spinogenesis processes in the medium spiny neurons (MSNs) in the nucleus accumbens (NAc). Females were randomly assigned to one of the following groups: 1) control (C), voles that cohabited with a familiar female in a clean cage; 2) social exposure (SE), voles housed in a cage divided into two equal compartments by an acrylic screen with small holes. The experimental female was placed in one of the compartments, and a male in the opposite one. Therefore, females were exposed to sensory cues from an adult male. Still, physical contact and copulation were not allowed, and 3) social cohabitation with mating (SCM) females were allowed to mate to induce pair-bonds. The NAc core and shell were processed for Golgi-Cox staining. Our results showed that MSN from SE and SCM groups had higher spine density than C females and a differential density of spine subtypes in the core and shell. Furthermore, only the SE condition induced an increment in MSN dendritic length and arborization in the core and shell regions. These findings demonstrate that males’ sexual cues and mating that promote pair-bonding modulate spinogenesis in the NAc and contribute to understanding the neuronal plasticity mechanism involved in pair-bonding in prairie voles.

Multisensory assessment for hearing phenotypes.

Transcranial ultrasound stimulation modulates neuronal membrane potentials across broad timescales in the awake mammalian brain.

Investigational transcranial magnetic stimulation measures as predictors of aggression in schizophrenia: A cross-sectional study.

Acute carbamoylated erythropoietin reduces social stress-induced anxiety and depression-related behaviors.

Rehabilitation, neuroplasticity, and machine learning: Approaching artificial intelligence for equitable health systems.

Functional neural plasticity after compassion-based interventions: A scoping review of longitudinal neuroimaging studies.

Spinal cord injury (SCI) damages neural circuits and triggers pro-inflammatory responses, resulting in locomotor impairment. The carbohydrate sulfotransferases GlcNAc6ST1 and GlcNAc6ST4 modulate the function of blood monocytes and microglia. However, their specific roles and enzymatic relationships in neuroinflammation and functional recovery after SCI remain unclear. In this study, we demonstrate that mice deficient in both GlcNAc6ST1 and GlcNAc6ST4 (DKO) exhibit improved locomotor recovery compared with mice with a single deficiency. DKO mice exhibit reduced levels of monocytes and activated macrophages/microglia at the injury site alongside increased serotonergic neural fibers, indicating enhanced neural plasticity. RNA sequencing reveals down-regulation of collagen I genes and up-regulation of genes encoding synaptic membrane components in the injured DKO spinal cord. In addition, GALAXY glycomic analysis shows an absence of GlcNAc-6-sulfated N-glycans in the DKO spinal cord. These results suggest that GlcNAc6ST1 and GlcNAc6ST4 play complementary roles in promoting detrimental inflammatory responses post-SCI. Targeting these sulfotransferases could offer a novel therapeutic strategy to improve locomotor recovery after SCI.

This study aimed to map swallowing exercise protocols for healthy older adults based on the principles of neural plasticity and motor learning. The search strategy was run in MEDLINE, CINAHL, Cochrane CENTRAL, Embase, and Web of Science from inception to 6 May 2025. Two researchers independently screened for interventional studies involving swallowing exercises targeting the oropharyngeal, upper oesophageal, and respiratory structures relevant to swallowing in healthy older adults. The reviewers then mapped the eligible studies for adherence to the 10 principles of neural plasticity and principles of motor learning using validated operational definitions. Twenty studies were included for mapping. Studies showed good adherence to principles of neural plasticity like 'use it or lose it', 'repetition matters', and 'salience matters'. However, no study addressed the interference and gaps identified in the application of 'intensity', 'specificity', and 'transference' concepts. Furthermore, gaps were also observed for recommended guidelines across five practice conditions of principles of motor learning, except 'target complexity'. Lastly, gaps were also noted for all the four feedback conditions of principles of motor learning. This mapping review identified common trends and gaps in how principles of neural plasticity and principles of motor learning are integrated into swallowing exercise protocols of healthy older adults, offering valuable insights into concepts that meet or fall short of established guidelines.

Diurnal modulation of optogenetically evoked neural signals.

ABSTRACTRationaleOver 55 million people worldwide suffer from dementia, with 10 million new cases diagnosed annually. Due to the limited efficacy of drug therapies, alternative approaches like repetitive transcranial magnetic stimulation (rTMS) have gained popularity as a non‐invasive, safe method leveraging neural plasticity and brain connectivity. However, its high cost and time commitment highlight the need for biomarkers to predict treatment response.AimsThis pilot study aims to identify a quantitative electroencephalography (QEEG) biomarker to predict which mild cognitive impairment patients will respond to rTMS. By targeting responders early, clinicians can make rTMS more cost‐effective and time‐efficient, reducing wasted treatment on non‐responders.DesignThis multi‐center, assessor‐blinded clinical trial will examine QEEG biomarkers as predictors of rTMS treatment responsiveness in 25 patients with mild cognitive impairment (MCI). Adults aged 60 years or older will undergo cognitive assessments using the Montreal Cognitive Assessment (MoCA) or mini‐mental state examination (MMSE) and have an electroencephalography (EEG) recording. Participants will complete 10 rTMS sessions targeting the left DLPFC over 2 weeks, with 2000 pulses per session at 20 Hz. Cognitive tests will be repeated post‐treatment, and participants will be classified as responders or non‐responders based on cognitive changes, then baseline QEEG parameters will be compared between the two groups. The primary endpoint is the proportion of responders at ten sessions after rTMS (score post‐intervention > score pre‐intervention = responder, according to the minimal clinically important difference (MCID) threshold (i.e., an increase of at least 3 points or 10% on the MMSE, or an increase of at least 1 point on the MoCA); score post‐intervention ≤ score pre‐intervention = non‐responder). The secondary endpoints are the differences in baseline QEEG features between responders and non‐responders.OutcomeBy identifying responders prior to treatment, we can optimize resource allocation, minimize the time and cost associated with ineffective treatments, and ultimately improve the quality of care for individuals with MCI.Trial RegistrationIRCT registration number: IRCT20240218061042N1 (version updated September 7, 2024)

Bridging social isolation, loneliness, and brain aging: A narrative review of mechanisms and translational interventions.

Background: A finely tuned balance between excitation and inhibition is essential for proper brain function. Disruptions in the GABAergic system, which alter this equilibrium, are a common feature in various types of neurological disorders. Understanding GABAergic neuron maturation processes is thus currently a major challenge in basic neuroscience. Thyroid hormones (THs) are required for the proper maturation of parvalbumin (PV)-expressing GABAergic interneurons in the mouse neocortex. However, the timeline of this TH action has yet to be elucidated. The aim of the present study was to define better the time window during which THs promote the postnatal maturation of PV neurons in the mouse neocortex. Methods: We used genetically engineered mouse models expressing dominant-negative mutations of the TH nuclear receptor α1 (TRα1). The consequences of blocking TH signaling at different times in development were assessed in PV neurons of the somatosensory cortex, in terms of histology and gene expression. Results: Histological observations in mice revealed that the action of THs during the first three postnatal weeks was necessary to initiate the expression of PV and the elaboration of a specialized extracellular matrix called the perineuronal net (PNN). By contrast, after the third postnatal week, TH action on PV neuron maturation appeared to be somewhat dispensable. Transcriptome analysis of neocortical GABAergic neurons two weeks after birth identified a small set of putative target genes for TRα1. Several of these genes are involved in the postnatal remodeling of the repertoire of ion channels within PV neurons and in the elaboration of PNNs. Conclusions: These data suggest that THs act as a timer to define the temporal boundaries of the critical period of heightened cortical plasticity, which plays a fundamental role in the development of neuronal circuits. Unveiling the molecular underpinnings of TH action in PV neurons may help understand better neurological disorders associated with alterations of TH signaling, such as hypothyroidism, resistance to THs, or Allan-Herndon-Dudley syndrome, but also more widely, neurological disorders associated with an imbalance in the excitation/inhibition ratio in the brain, including attention-deficit/hyperactivity disorder, autism, and epilepsy.

Sexual behavior induces brain plastic changes such as neurogenesis, but few studies have evaluated possible changes in synaptic plasticity produced by sexual experience. In the present study, we assessed whether two aspects of sexual behavior in male rats, sexual incentive motivation and sexual execution in a partner preference test, could induce micro and macrostructural changes in brain regions involved in controlling sexual behavior belonging to the socio-sexual behavior network and the mesolimbic reward circuit. The microstructural changes were evaluated by synaptophysin immunofluorescence expression. We assessed the macrostructural changes using manganese-enhanced magnetic resonance imaging and volume changes by magnetic resonance imaging. Our results indicate that the mesolimbic reward circuit underwent plastic changes at the level of synaptophysin expression, mainly in the partner preference test group. In the socio-sexual behavior network circuit, an increase in brain activation was observed primarily in the sexual incentive motivation group. When analyzing the activation of the whole brain, the statistical map showed a significant increase in weeks 5 and 10 compared to week 1 in the sexual incentive motivation group. The results confirm that different neuroplastic changes, including synaptophysin expression, brain activation, and volume changes, occur during the acquisition of sexual experience.

Chondroitinase ABC (ChABC) is a bacterial enzyme that can potentially address the inhibitory effects of Chondroitin Sulfate Proteoglycans (CSPGs) in various neurological disorders and injuries. CSPGs are key components of the extracellular matrix that, when accumulated after Central Nervous System (CNS) injury or neurodegenerative diseases, inhibit axonal growth and tissue repair. This review explores the therapeutic potential of ChABC in Spinal Cord Injury (SCI), Traumatic Brain Injury (TBI), stroke, Parkinson's Disease (PD), Alzheimer's Disease (AD), and peripheral nerve regeneration. ChABC's mechanism of action involves the degradation of CSPGs, promoting neural plasticity, axonal regeneration, and functional recovery in SCI and other CNS injuries. In stroke and TBI, ChABC treatment has been shown to enhance neurogenesis, reduce glial scar formation, and support neuronal survival. In neurodegenerative conditions like PD and AD, ChABC's ability to modify the inhibitory extracellular environment offers novel strategies for promoting neuronal repair and cognitive function. Additionally, ChABC has been explored in cancer therapy, where its ability to degrade the tumor extracellular matrix facilitates improved drug delivery and tumor infiltration. While ChABC holds promise, challenges remain in its clinical application, particularly regarding stability, targeted delivery, and long-term effects. This review discusses the mechanism of action of ChABC and various delivery strategies, including viral vectors and localized infusion, and emphasizes the need for further research to optimize ChABC's potential. The future of ChABC in regenerative medicine depends on overcoming these barriers, improving delivery methods, and exploring synergistic treatments for enhanced recovery outcomes.

Abstract The Society for Maternal‐Fetal Medicine 2024 President's Workshop on maternal mental health, cosponsored by the American College of Obstetricians and Gynecologists, will be comprehensively described in this article. Workshop leaders and speakers represented the fields of obstetrics and gynecology (OBGYN), maternal‐fetal medicine (MFM), complex family planning, psychology, psychiatry, and pediatric neuroscience. In addition to clinical expertise, participants had experience in research, policy and advocacy, workforce development, medical education, and community‐based programming. Medical societies, government agencies, nonprofit organizations, and philanthropic foundations were represented. The goals of the workshop were as follows: (1) Expand OBGYN and MFM mental health treatment capacity through discussion of perinatal psychiatric disorders and identification of pertinent educational resources. (2) Leverage two‐generation prenatal brain plasticity science for clinical and research opportunities. (3) Promote access to mental health treatment and prevention during pregnancy and postpartum through identification of effective, scalable health services, interventions, and community‐based programs.

Cross-education (CE), the phenomenon whereby unilateral strength training induces neuromuscular adaptations in the contralateral limb, is underpinned by distributed cortical and subcortical plasticity. This study evaluated acute neural responses to a single bout of metronome-paced unilateral strength training in younger (n = 17; 27 ± 6years) and older adults (n = 18; 67 ± 5years). Neurophysiological assessments included corticospinal excitability and inhibition via transcranial magnetic stimulation (TMS), intracortical inhibition through short-interval intracortical inhibition (SICI), and reticulospinal drive using the StartReact paradigm. Following training, younger adults exhibited a significant reduction in the responsiveness of intracortical inhibitory interneurons, reflected as a release of SICI (pre: 58.05, 95% CI 48.83-67.27; post: 68.88, 95% CI 59.69-78.06; p < 0.01), consistent with diminished GABA-A -mediated synaptic efficacy. In contrast, older adults showed no changes (pre: 65.73, 98% CI 57.00-74.46; post: 60.71, 95% CI 52.03-69.39; p = 0.13), indicating no significant modulation of GABA-A-mediated inhibitory circuits with ageing. No changes in corticospinal excitability were observed in either group. StartReact responses remained stable across timepoints, implying insufficient acute engagement of the reticulospinal tract. Notably, younger adults exhibited a decline in rate of force development (RFD; pre: 912.70, 95% CI 821.97-1003.44 N/s; post: 791.02, 95% CI 700.29-881.75 N/s; p < 0.05), potentially reflecting central fatigue, while older adults displayed no significant change. These findings reveal age-dependent asymmetries in the neural mechanisms underpinning CE, with older adults exhibiting a lack of adaptive modulation in intracortical and subcortical systems. The absence of reticulospinal adaptation underscores the need for sustained or higher-intensity training stimuli to elicit subcortical plasticity. These results inform the development of targeted, age-sensitive neuromuscular rehabilitation strategies.