Search Results (989)

N-acetylcysteine (NAC) has garnered increasing interest for its neurotherapeutic capabilities beyond its recognized functions as a mucolytic agent and an antidote for acetaminophen toxicity. This review consolidates findings from both preclinical and clinical studies to investigate NAC’s diverse modulatory effects on the central nervous system (CNS). NAC primarily functions as an antioxidant by replenishing glutathione and mitigating oxidative stress; however, it produces glutathione-independent effects through the modulation of mitochondrial redox systems, ferroptosis, and the Nrf2-ARE signaling pathway. It plays a significant role in neuroinflammatory processes by inhibiting the production of cytokines, the expression of iNOS, and the activation of microglia. Furthermore, NAC affects various neurotransmitter systems—including glutamatergic, dopaminergic, GABAergic, serotonergic, cholinergic, and adrenergic pathways—by modulating synaptic transmission, receptor activity, and transporter functionality. It promotes neuroprotection through the enhancement of neurotrophic factors, the preservation of mitochondrial integrity, and the upregulation of survival signaling pathways. Recent evidence also emphasizes NAC’s role in gene expression and the regulation of cortisol levels. The extensive range of NAC’s neurobiological effects highlights its therapeutic potential in treating neurodegenerative and neuropsychiatric disorders. Nevertheless, the variability in clinical outcomes indicates a pressing need for more focused, mechanism-based research. Full article

Alcohol use disorder (AUD) is a widespread, multifaceted disorder involving overproduction of pro-inflammatory cytokines, oxidative liver injury, and dysfunction of the brain’s dopaminergic reward circuits. Korean red ginseng (KRG), an herbal supplement derived from Panax ginseng, has demonstrated qualities potentially useful to the treatment of AUD, including antioxidative, anti-inflammatory, neuroprotective, and anxiolytic effects. This review examines active constituents of KRG, their pharmacological actions, and evidence supporting KRG’s therapeutic potential in the context of AUD, while also assessing its safety profile, adverse effects, and potential drug interactions. KRG’s main bioactive constituents, ginsenosides, appear to have roles in modulating alcohol-metabolizing enzymes, ethanol-activated inflammatory cytokine cascades, and neurological systems disrupted by AUD, including GABAergic and dopaminergic pathways. Evidence from animal models and limited small-scale human trials suggests KRG may alleviate symptoms of alcohol withdrawal, enhance cognitive performance, and attenuate anxiety through these pathways. While generally safe for consumption, several case reports and animal studies have indicated KRG’s potential to pose a variety of risks in vulnerable populations at high, prolonged doses, including hepatotoxicity, cardiovascular changes, mood disturbances, and hormonal effects. Furthermore, KRG’s neuromodulating role and influence on cytochrome P450 enzymes make it liable to interact with several medications, including warfarin, midazolam, selegiline, and serotonergic agents. Overall, KRG shows promise as a complementary supplement in managing aspects of AUD, though current evidence is limited by low sample sizes, inconsistent reports regarding nuances of ginsenosides’ mechanisms, and a low number of human trials. Further human-focused research is needed to elucidate its safety, efficacy, and mechanism. Full article

Acute transverse myelitis (ATM) is a rare, immune-mediated disorder of the spinal cord characterized by sensory, motor, and autonomic dysfunction. Although the human papillomavirus (HPV) vaccine is widely regarded as safe, isolated reports have suggested a potential temporal association with autoimmune neurological events, including ATM. We present a case of a 21-year-old woman who developed ATM two weeks following administration of the first dose of the HPV vaccine (Cervarix). The clinical presentation included rapid-onset paraparesis, sensory deficits, and sphincter dysfunction. An MRI revealed a T2-hyperintense lesion at the Th10–Th12 level. A cerebrospinal fluid analysis showed elevated protein levels. The patient underwent corticosteroid therapy, plasmapheresis, and IVIG, followed by a comprehensive, individualized rehabilitation program. This included balance and stability training, Redcord-based neuromuscular activation, electrostimulation, and pelvic floor therapy. Although no causal link between HPV vaccination and ATM has been established, this case emphasizes the importance of considering post-vaccinal autoimmune phenomena. More importantly, it illustrates the critical role of early, targeted rehabilitation—particularly pelvic floor re-education and neuromodulation—in improving outcomes in patients with significant motor and autonomic deficits. Full article

Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) are marked by progressive network dysfunction that challenges conventional, protocol-based neurorehabilitation. In parallel, neuromodulation, encompassing deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), and artificial intelligence (AI), has matured rapidly, offering complementary levers to tailor therapy in real time. This narrative review synthesizes current evidence at the intersection of AI and neuromodulation in neurorehabilitation, focusing on how data-driven models can personalize stimulation and improve functional outcomes. We conducted a targeted literature synthesis of peer-reviewed studies identified via PubMed, Embase, Scopus, and reference chaining, prioritizing recent clinical and translational reports on adaptive/closed-loop systems, predictive modeling, and biomarker-guided protocols. Across indications, convergent findings show that AI can optimize device programming, enable state-dependent stimulation, and support clinician decision-making through multimodal biomarkers derived from neural, kinematic, and behavioral signals. Key barriers include data quality and interoperability, model interpretability and safety, and ethical and regulatory oversight. Here we argue that AI-enhanced neuromodulation reframes neurorehabilitation from static dosing to adaptive, patient-specific care. Advancing this paradigm will require rigorous external validation, standardized reporting of control policies and artifacts, clinician-in-the-loop governance, and privacy-preserving analytics. Full article

Background/Objectives: Epilepsy is a neurological disorder that severely impacts patients’ quality of life. In clinical practice, specific pharmacological and surgical interventions are tailored to distinct seizure types. The identification of the epileptogenic zone enables the implementation of surgical procedures and neuromodulation therapies. Consequently, accurate classification of seizure types and precise determination of focal epileptic signals are critical to provide clinicians with essential diagnostic insights for optimizing therapeutic strategies. Traditional machine learning approaches are constrained in their efficacy due to limited capability in autonomously extracting features. Methods: This study proposes a novel deep learning framework integrating temporal and spatial information extraction to address this limitation. Multivariate variational mode decomposition (MVMD) is employed to maintain inter-channel mode alignment during the decomposition of multi-channel epileptic signals, ensuring the synchronization of time–frequency characteristics across channels and effectively mitigating mode mixing and mode mismatch issues. Results: The Bern–Barcelona database is employed to classify focal epileptic signals, with the proposed framework achieving an accuracy of 98.85%, a sensitivity of 98.75%, and a specificity of 98.95%. For multi-class seizure type classification, the TUSZ database is utilized. Subject-dependent experiments yield an accuracy of 96.17% with a weighted F1-score of 0.962. Meanwhile, subject-independent experiments attain an accuracy of 87.97% and a weighted F1-score of 0.884. Conclusions: The proposed framework effectively integrates temporal and spatial domain information derived from multi-channel epileptic signals, thereby significantly enhancing the algorithm’s classification performance. The performance on unseen patients demonstrates robust generalization capability, indicating the potential clinical applicability in assisting neurologists with epileptic signal classification. Full article

Transcutaneous auricular vagus nerve stimulation (taVNS), an emerging noninvasive neuromodulation technique, has shown promise for improving memory. A better understanding of the epigenetic mechanisms underlying the effects of taVNS would inform the molecular outcomes essential for memory and cognition. In this review, we synthesize the current literature on the neurophysiological and biochemical basis of taVNS. Next, we explore how DNA methylation regulators (e.g., DNA methyltransferase 3a) and readers (e.g., methyl-CpG binding protein 2) differentially regulate memory, and how their activity and expression can be regulated by neuronal activity. Finally, we describe the potential involvement of DNA methylation in mediating the memory regulatory effects of taVNS and discuss possible directions for future studies. Full article

Alzheimer’s disease (AD) is considered to be one of the most common types of dementia, threatening the health of elderly individuals. Enhancing the brain’s cholinergic activity is currently the primary therapeutic strategy for treating AD patients. Acetylcholine and butyrylcholine are key targets in this approach, as they function as neuromodulators within the cerebrum—particularly in its various cholinergic regions responsible for essential functions like memory, thought, inspiration, and excitement. Oxidative stress and free radicals are considered to play a crucial role in the pathogenesis of AD and may be key factors in its etiology. Additionally, oxidants and oxidative stress-induced products can upregulate amyloid precursor protein (APP) expression, promoting Aβ aggregation. Another major factor in the pathogenesis of AD is the imbalance of metal homeostasis in the brain. Notably, the mammalian brain contains significantly higher concentrations of Cu, Zn, and Fe ions compared to other tissues. The present review focuses on novel bifunctional metal chelators with potential antioxidant activity for the treatment of AD. Full article

Major depressive disorder (MDD) is a prevalent and disabling psychiatric condition with limited treatment options for patients who are resistant to conventional pharmacological and psychotherapeutic interventions. Stem cell (SC)-based therapies have emerged as a promising experimental approach, offering multifaceted mechanisms of action including neurogenesis, immunomodulation, antioxidative protection, and neuromodulation. This narrative review synthesizes current evidence from preclinical studies and early-phase clinical trials on the efficacy of mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs) in alleviating depressive-like behaviors. Mechanistic insights include enhanced hippocampal neurogenesis, modulation of the brain-derived neurotrophic factor (BDNF)–TrkB pathway, attenuation of neuroinflammation through microglial polarization, and restoration of serotonergic signaling via peripheral-to-central pathways such as via the vagus nerve. In addition, the therapeutic potential of extracellular vesicles (EVs) and intranasal administration as non-invasive delivery strategies is discussed. While animal and first preclinical studies suggest potential benefit, significant translational barriers remain, including issues of scalability, long-term safety, and ethical considerations. Further rigorous studies are needed to validate stem-cell-based therapies as viable treatments for MDD. Full article

Chronic pain is a complex and persistent condition involving sustained nociceptive input, maladaptive neuroplastic changes, and neuroimmune interactions. Central to its pathophysiology is the dysregulation of neuromodulatory signaling pathways, including neurotransmitters (e.g., dopamine, serotonin, norepinephrine), neuropeptides (e.g., substance P, CGRP), and neurotrophic factors (e.g., BDNF), which modulate both central and peripheral sensitization mechanisms. In disorders such as fibromyalgia, altered monoaminergic transmission has been implicated in the attenuation of descending inhibitory control, thereby enhancing pain perception and reducing responsiveness to conventional therapies. Concurrently, neuroinflammation, driven by glial cell activation and cytokine release, further exacerbates neuronal excitability and reinforces maladaptive signaling loops. Recent technological advances, including transcriptomic profiling, functional neuroimaging, and single-cell RNA sequencing, have provided new insights into patient-specific patterns of neuromodulatory dysfunction, highlighting potential biomarkers for disease stratification and therapeutic targeting. These developments support the hypothesis that dysregulated neuromodulatory circuits not only underlie diverse chronic pain phenotypes but may also serve as intervention points for precision medicine. This narrative review synthesizes current evidence on the roles of neuromodulatory systems in chronic pain, focusing on synaptic plasticity, nociceptor sensitization, and neuroimmune crosstalk. By integrating preclinical findings with clinical observations, we propose a mechanistic framework for understanding pain chronification and guiding future therapeutic strategies. Harnessing neuromodulatory targets, whether pharmacologically or via neuromodulation technologies, could offer more personalized and effective approaches to chronic pain management. Full article

Nuclear factor erythroid 2-related factor 2 (NRF2) serves as a master transcriptional regulator of cellular antioxidant responses through orchestration of cytoprotective gene expression, establishing its significance as a therapeutic target in cerebral pathophysiology. Classical electrophilic NRF2 activators, despite potent activation potential, exhibit paradoxically reduced therapeutic efficacy relative to single antioxidants, attributable to concurrent oxidative stress generation, glutathione depletion, mitochondrial impairment, and systemic toxicity. Although emerging non-electrophilic pharmacological activators offer therapeutic potential, their utility remains limited by bioavailability and suboptimal potency, underscoring the imperative for innovative therapeutic strategies to harness this cytoprotective pathway. Non-pharmacological interventions, including neuromodulation, physical exercise, and lifestyle modifications, activate NRF2 through non-canonical, non-electrophilic pathways involving protein–protein interaction inhibition, KEAP1 degradation, post-translational and transcriptional modulation, and protein stabilization, though mechanistic characterization remains incomplete. Such interventions utilize multi-mechanistic approaches that synergistically integrate multiple non-electrophilic NRF2 pathways or judiciously combine electrophilic and non-electrophilic mechanisms while mitigating electrophile-induced toxicity. This strategy confers neuroprotective effects without the contraindications characteristic of classical electrophilic activators. This review comprehensively examines the mechanistic underpinnings of non-pharmacological NRF2 modulation, highlighting non-electrophilic activation pathways that bypass the limitations inherent to electrophilic activators. The evidence presented herein positions non-pharmacological interventions as viable therapeutic approaches for achieving non-electrophilic NRF2 activation in the treatment of cerebrovascular and neurodegenerative pathologies. Full article

In this perspective article, we introduce Ecocebo as a novel concept describing the modulatory effects of physical environments, whether natural or built, on drug effect. Positioned as a spatial component of the placebo effect, Ecocebo is grounded in evidence-based design principles and proposes that environmental features such as natural light, greenery, spatial geometry, and calming esthetics can significantly influence sensory, emotional, and cognitive processes. These environmental factors may enhance or modify pharmacological responses, especially for analgesics, anxiolytics, and antidepressants. We highlighted how exposure to restorative spaces can reduce pain perception, stress, and the need for medication, paralleling findings in placebo research where contextual and sensory cues influence brain regions linked to emotion and pain regulation. We propose virtual reality (VR) as the most suitable methodological tool to study Ecocebo in controlled and ecologically valid settings. VR allows for the precise manipulation of spatial features and real-time monitoring of physiological and psychological responses. We also propose integrating VR with neuromodulation techniques to investigate brain–environment–drug interactions. Finally, we addressed key methodological challenges such as defining control conditions and standardizing the measurement of presence. This perspective opens new directions for the integration of non-pharmacological and pharmacological interventions and personalized therapeutic environments to optimize clinical outcomes. Full article

Chronic pain management is constantly evolving, and our literature review aims to describe the general innovations happening within the field. The need for advancements in chronic pain is a necessity, as debilitating back pain and other forms of chronic pain are significant issues in the United States. Traditionally, medications have been the initial treatment options in cases of chronic pain; however, the advancement in pharmacogenetics has led to an increased ability to create more personalized medication plans. Additionally, neuromodulation in spinal cord stimulation, transcranial magnetic stimulation, transcranial direct-current stimulation, and dorsal root ganglion stimulation continue to see increased usage in mainstream chronic pain management. These techniques have continued to prove successful in many chronic pain management cases. They are allowing practicing physicians more confidence in the variety of treatment options. Lastly, great strides have also been made in stem cell and regenerative therapies, such as platelet-rich plasma injections, and artificial intelligence, further advancing the various treatment options and overall efficiency of pain management. This review aims to critically analyze and review the most up-to-date literature within each section mentioned and comprehensively discuss the future of innovation in chronic pain management. Full article

Chronic pain is a dynamic, brain-wide condition that eludes effective management by conventional, static treatment approaches. Transcutaneous Electrical Nerve Stimulation (TENS), traditionally perceived as a simple and generic modality, is on the verge of a significant transformation. Guided by advances in brain-state decoding and adaptive algorithms, TENS can evolve into a precision neuromodulation system tailored to individual needs. By integrating multimodal neuroimaging—including the spatial resolution of functional magnetic resonance imaging (fMRI), the temporal sensitivity of an Electroencephalogram (EEG), and the ecological validity of functional near-infrared spectroscopy (fNIRS)—with real-time machine learning, we envision a paradigm shift from fixed stimulation protocols to personalized, closed-loop modulation. This comprehensive review outlines a translational framework to reengineer TENS from an open-loop device into a responsive, intelligent therapeutic platform. We examine the underlying neurophysiological mechanisms, artificial intelligence (AI)-driven infrastructures, and ethical considerations essential for implementing this vision in clinical practice—not only for chronic pain management but also for broader neuroadaptive healthcare applications. Full article

Background: Emotion regulation (ER) plays a vital role in mental health, spanning mood, anxiety, and personality disorders. Cognitive reappraisal (CR) is one of the most common ER strategies and depends on prefrontal brain areas, but its success varies, and its neural basis is not fully clear. Interest is growing in using transcranial direct current stimulation (tDCS) to support ER, yet most studies have focused only on the dorsolateral prefrontal cortex (dlPFC) and used simple tasks. Objective: This study explored whether tDCS applied to either the dlPFC or the ventromedial prefrontal cortex (vmPFC) could shape autonomic responses during CR while people watched emotionally engaging film clips. Methods: Participants were randomly assigned to receive either active or sham tDCS over the dlPFC or vmPFC. While stimulated, they used CR strategies (positive reappraisal, fictional reappraisal, or distancing) to manage their reactions to negative film scenes. Heart rate (HR), skin conductance (SC), and respiratory rate (RR) were tracked throughout as physiological indicators. Results: Active dlPFC tDCS combined with CR led to significantly greater reductions in HR toward the end of emotional exposure, compared to sham or non-CR conditions. dlPFC stimulation also lowered HR even without explicit CR, pointing to possible effects on automatic regulation. vmPFC effects were inconsistent, and no reliable effects were observed for SC or RR. Conclusions: These results suggest that tDCS effects on autonomic ER depend on the brain region and timing. dlPFC stimulation may strengthen both intentional and automatic emotion regulation, especially when combined with reappraisal, highlighting the value of realistic emotional tasks in neuromodulation studies. Full article

Brain tumors elicit complex neuropsychiatric disturbances that frequently occur prior to radiological detection and hinder differentiation from major psychiatric disorders. These syndromes stem from tumor-dependent metabolic reprogramming, neuroimmune activation, neurotransmitter dysregulation, and large-scale circuit disruption. Dinucleotide hypermethylation (e.g., IDH-mutant gliomas), through the accumulation of 2-hydroxyglutarate (2-HG), execute broad DNA and histone hypermethylation, hypermethylating serotonergic and glutamatergic pathways, and contributing to a treatment-resistant cognitive-affective syndrome. High-grade gliomas promote glutamate excitotoxicity via system Xc⁻ transporter upregulation that contributes to cognitive and affective instability. Cytokine cascades induced by tumors (e.g., IL-6, TNF-α, IFN-γ) lead to the breakdown of the blood–brain barrier (BBB), which is thought to amplify neuroinflammatory processes similar to those seen in schizophrenia spectrum disorders and autoimmune encephalopathies. Frontal gliomas present with apathy and disinhibition, and temporal tumors lead to hallucinations, emotional lability, and episodic memory dysfunction. Tumor-associated neuropsychiatric dysfunction, despite increasing recognition, is underdiagnosed and commonly misdiagnosed. This paper seeks to consolidate the mechanistic understanding of these syndromes, drawing on perspectives from neuroimaging, molecular oncology, neuroimmunology, and computational psychiatry. Novel approaches, including lesion-network mapping, exosomal biomarkers or AI-based predictive modeling, have projected early detection and precision-targeted interventions. In the context of the limitations of conventional psychotropic treatments, mechanistically informed therapies, including neuromodulation, neuroimmune-based interventions, and metabolic reprogramming, are essential to improving psychiatric and oncological outcomes. Paraneoplastic neuropsychiatric syndromes are not due to a secondary effect, rather, they are manifestations integral to the biology of a tumor, so they require a new paradigm in both diagnosis and treatment. And defining their molecular and circuit-level underpinnings will propel the next frontier of precision psychiatry in neuro-oncology, cementing the understanding that psychiatric dysfunction is a core influencer of survival, resilience, and quality of life. Full article