ABSTRACT Postural‐locomotor disorders, particularly freezing of gait and postural instability, are among the most disabling symptoms of advanced Parkinson's disease (PD) and respond only partially to dopaminergic therapy. Evidence for virtual reality (VR) approaches in moderate to severe PD remains limited. This prospective randomized controlled open‐label exploratory trial evaluated the addition of multisensory passive immersive VR with synchronized plantar tactile stimulation to conventional rehabilitation for gait, balance, and freezing disorders in moderate‐to‐severe PD (Hoehn and Yahr Stages 2–4). In the study, 80 PD patients were randomized into an experimental group (EXP, n = 40) receiving standard pharmacotherapy and conventional rehabilitation plus 10 sessions of passive immersive VR with synchronized plantar tactile stimulation and a comparison group (COM, n = 40) receiving standard pharmacotherapy and conventional rehabilitation only. Because the VR sessions were added to an otherwise identical program, the trial evaluates the effect of adding this intervention rather than a VR‐ or tactile‐specific effect. Outcomes were assessed at baseline and after 10 days using the Unified Parkinson's Disease Rating Scale (UPDRS), Berg Balance Scale (BBS), and Freezing of Gait Questionnaire (FoG‐Q). The EXP group showed significant improvements in the UPDRS “Gait” cluster (an eight‐item composite of UPDRS items 2.11, 2.12, 2.13, 3.9, 3.10, 3.11, 3.12, and 3.13, range 0–32; median from 12.5 to 8.0 points, p < 0.001), BBS (from 38.0 to 43.5 points, p < 0.001), and FoG‐Q (from 9.0 to 6.5 points, p < 0.001). A formal group × time analysis confirmed a differential treatment effect for every outcome. For the main outcome, the UPDRS “Gait” cluster, the baseline‐adjusted between‐group difference was −2.48 points (95% CI −3.37 to −1.59; p < 0.001; Hedges' g = 1.16). Large effects also favored the EXP group for the FoG‐Q (−2.14 points, 95% CI −2.62 to −1.66; g = 1.65), the BBS (+2.20 points, 95% CI 1.31 to 3.10; g = 1.06), the UPDRS freezing subscore (items 2.13 + 3.11; −0.89 points, 95% CI −1.13 to −0.66; g = 1.32), and the UPDRS postural subscore (items 3.12 + 3.13; −0.74 points, 95% CI −1.08 to −0.41; g = 0.93). Secondary outcome p ‐values were adjusted for multiple comparisons using the Holm and Benjamini–Hochberg procedures. By contrast, in the COM group, no significant change was observed for freezing of gait ( p = 0.083), and improvements in other outcomes were smaller than in the EXP group. No serious adverse events were recorded. The trial was exploratory, so the effect estimates require confirmation rather than supporting robustness in themselves. Overall, multisensory passive immersive VR with synchronized plantar tactile stimulation was well tolerated and shows preliminary promise as an adjunct to conventional rehabilitation for gait and balance disorders in moderate‐to‐severe PD. Wider clinical implementation requires long‐term multicenter studies with standardized assessment criteria and analysis of long‐term sustainability. These findings support integrating passive VR technologies into personalized neurorehabilitation programs.
ABSTRACT Alzheimer's disease (AD) is a progressive neurological condition marked by cognitive decline, memory impairment, extracellular amyloid‐β (Aβ) accumulation, and intracellular neurofibrillary tangles (NFTs). Among the multiple molecular pathways involved in AD pathogenesis, glycogen synthase kinase‐3β (GSK‐3β) has emerged as a crucial signaling regulator due to its extensive contribution to neuronal survival, synaptic plasticity, metabolism, and cellular stress responses. Growing evidence suggests that abnormal activation of GSK‐3β contributes not merely to classical AD hallmarks, including tau hyperphosphorylation and amyloidogenesis, but is also linked to mitochondrial dysfunction, neuroinflammation, autophagic impairment, ferroptosis, insulin resistance, and oxidative stress through modulation of the Nrf2 pathway. These findings place GSK‐3β as a crucial molecular hub linking different pathogenic pathways in AD. This review outlines the structural attributes along with regulatory mechanisms of GSK‐3β and extensively explores its involvement in AD pathophysiology. Specific emphasis is given to evolving mechanisms, such as metabolic dysregulation, ferroptosis, and antioxidant signaling pathways. Additionally, current breakthroughs in therapeutic targeting techniques such as ATP‐competitive inhibitors, non–ATP‐competitive inhibitors, allosteric modulators, natural chemicals, and clinically studied medicines are emphasized. The translational difficulties linked to selectivity, blood–brain barrier permeability, and clinical efficacies are also explored. Collectively, this review reinforces the therapeutic relevance of GSK‐3β and indicates potential opportunities for creating effective disease‐modifying therapies in AD.
ABSTRACT Chronic stress induces strong alteration of hippocampal synaptic plasticity, impairing long‐term potentiation and facilitating long‐term depression, processes thought to be involved in the pathophysiology of depression. Ketamine, a noncompetitive antagonist of the N ‐methyl‐D‐aspartate receptor, has emerged as a fast‐acting antidepressant whose action is believed to involve restoring impaired plasticity, though its sustained effects are elusive. Here, we investigated how chronic mild stress and subsequent acute and chronic ketamine treatments modulate synaptic plasticity in the Schaffer collateral pathway in the dorsal hippocampus of stress‐vulnerable Wistar‐Kyoto rats. Adult male rats were subjected to 4 weeks of chronic mild stress and vulnerability was determined through behavioral performance in the forced swim and elevated plus maze tests. Stress‐vulnerable rats received saline or either an acute or chronic subanesthetic dose of ketamine (10 mg/kg), and hippocampal slices were harvested for synaptic plasticity investigation. Conversely to what occurred in nonstressed rats, in stress‐vulnerable rats treated with saline, neither long‐term potentiation (LTP) nor long‐term depression (LTD) could be induced following high‐frequency and low‐frequency stimulation, respectively. Acute ketamine restored normal LTP but not LTD, while chronic ketamine restored LTD but not LTP. These findings highlight complex temporal dynamics in the modulation of hippocampal synaptic plasticity by ketamine following chronic stress and demonstrate that acute and chronic treatment regimens differentially affect the induction of LTP and LTD.
Organization and specification of the nervous system start in the embryo and are largely controlled by a cluster of transcription factors known as HOX genes, which control body patterning and morphogenesis at the transcriptional level. However, this entire process requires the influence of multiple pathways, including cell signalling, genomic and post-genomic pathways. These include the Wnt (wingless) pathway, which controls neuronal development and polarity, and the small miRNA pathway, which regulates genes post-transcriptionally. In this study, we investigated mir-57, the homolog of human miR-10 in Caenorhabditis elegans and its role in influencing motor neuron function. mir-57 is expressed posteriorly throughout development and enriched in motor neurons. Absence of mir-57 results in decreased movement and abnormal axonal projections of posterior motor neurons. Moreover, the Wnt pathway genes cam-1 and mom-5 are mir-57 targets and show elevated expression at the post-transcriptional level in mir-57 deletion mutants. Taken together this study suggests that mir-57 influences Wnt receptor expression to maintain posterior motor neuron axon morphology.
ABSTRACT The objective of this study was to determine how structural and EEG‐based functional connectivity jointly distinguish levels of motor impairment after stroke. We estimated patient‐specific (1) structural connectivity using MRI‐derived lesion models and (2) functional connectivity using source‐localized EEG, guided by each patient's structural connectome. Analyses focused on the brainstem and three motor‐related cortical regions bilaterally: primary motor cortex (M1), dorsal premotor cortex (PMd), and supplementary motor cortex (SMA). Network analysis metrics (degree centrality, average efficiency, betweenness centrality) were applied to structural and functional data, contrasting motor networks between patients with high (H) and low (L) upper extremity motor function. Structural disconnection of the brainstem from M1 and PMd carried the highest probability of low motor status. All network measures were elevated in the H group compared to the L group across motor‐related regions, indicating a globally strengthened motor network organization associated with better motor function. Functional connectivity revealed convergent but distinct patterns. In the delta band (1–3 Hz), ipsilesional motor regions showed stronger connectivity in the H group. In the beta band (14–29 Hz), contralesional motor regions demonstrated enhanced connectivity in H patients, consistent with prior evidence that contralesional motor regions may contribute to motor function after ipsilesional injury. We also introduced a novel metric, motor betweenness centrality, to quantify the role of nonmotor regions in rerouting motor‐related communication. Almost all new hubs identified structurally were associated with lower motor status, suggesting less efficient network organization in more impaired patients. Thus, preservation of direct motor pathways supports better motor status, while reliance on alternative, less efficient routes correlates with worse outcomes. By contrast, EEG routing revealed that H patients recruited proximal cortical hubs, while L patients relied on distant, inefficient ones, highlighting functional network organization not evident in the structural analysis. These patterns suggest that more local network organization, rather than more distributed rerouting, is associated with better motor status within the motor system. In summary, multimodal network properties reliably identified key motor ROIs predictive of motor status. This concordance suggests that EEG‐based metrics, particularly delta‐ and beta‐band connectivity, are associated with lesion‐derived structural disruption and complementary features of motor‐network organization. Structural connectivity damage within motor circuits defines the extent of network disruption associated with motor impairment, while EEG functional connectivity provides complementary information about network organization measured at the time of assessment. Together, these measures characterize different aspects of motor network integrity after stroke.
