Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by synaptic dysfunction, neuronal degeneration, and the accumulation of amyloid-β plaques and hyperphosphorylated tau protein aggregates. At the same time, currently available therapies provide only limited symptomatic relief and minimal disease-modifying benefits. Monoamine oxidase-B (MAO-B) has emerged as a relevant therapeutic target due to its role in oxidative stress and neurodegeneration. This review evaluates the therapeutic potential of garcinol, a polyisoprenylated benzophenone derived from Garcinia indica, as a prospective MAO-B inhibitor for AD using an integrated network pharmacology and computational modelling framework. ADMET profiling indicated low gastrointestinal absorption, no blood–brain barrier permeability, and a predicted LD₅₀ of approximately 2300 mg/kg, suggesting a favourable toxicity profile. Network pharmacology analysis identified 477 overlapping targets between garcinol and AD, followed by the construction of a protein–protein interaction network and identification of hub genes. KEGG pathway enrichment highlighted a significant role for the erythropoietin-activated phosphoinositide 3-kinase (PI3K) signalling pathway, associated with neuroprotection, anti-apoptotic mechanisms, and attenuation of amyloid and tau pathology. Quantum chemical analysis revealed a HOMO–LUMO gap of 0.15227 Hartree (Ha), indicating balanced molecular reactivity. Molecular docking demonstrated that garcinol binds favourably to human MAO-B (PDB ID: 2V5Z), with a docking score of -8.2 kcal/mol. Although this affinity was lower than that of the reference inhibitor safinamide (-9.2 kcal/mol), and was therefore selected for further molecular dynamics evaluation. Molecular dynamics simulations over 100 ns confirmed stable and consistent interactions within the MAO-B active site. Collectively, these findings provide compelling computational evidence supporting garcinol as a promising computational lead scaffold for MAO-B inhibition. While experimental validation is required, this integrative in silico approach highlights garcinol’s potential for further preclinical development as an AD therapeutic.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and driven by multifactorial mechanisms, including oxidative stress, mitochondrial dysfunction, and neuroinflammation. Current therapies provide only symptomatic relief, underscoring the need for disease-modifying agents targeting interconnected pathogenic pathways. Hesperidin, a citrus flavanone glycoside, exhibits antioxidant, anti-inflammatory, and anti-apoptotic activities with promising molecular interactions against key PD targets. This review aims to integrate computational, in vitro, and in vivo evidence to evaluate hesperidin’s potential as an anti-Parkinsonian agent. Recent studies indicate that the citrus flavanone hesperidin exerts multimodal neuroprotective effects in PD by targeting oxidative stress, neuroinflammation, and dopaminergic dysfunction. Molecular docking reveals strong binding to dopamine D2 receptors, TNF-α, NF-κB, and GSK-3β, suggesting modulation of neurotransmission, inflammatory signaling, and apoptosis. Experimental evidence further demonstrates that hesperidin enhances neuronal survival, reduces α-synuclein accumulation, restores antioxidant enzymes, and decreases lipid peroxidation and nitric oxide levels. These integrated in silico and experimental findings highlight hesperidin as a promising disease-modifying candidate targeting interconnected pathogenic pathways in dopaminergic neurodegeneration. This study highlights hesperidin’s strong binding to key molecular targets, whereas experimental evidence also confirms its antioxidant, anti-inflammatory, and anti-apoptotic effects, supporting its potential as a disease-modifying candidate in PD therapy. However, further comprehensive preclinical and translational studies are required to explore its efficacy, safety, and therapeutic applicability in clinical settings.
Major Depressive Disorder (MDD) is not only characterized by affective symptoms such as persistent sadness and loss of interest but is also marked by significant cognitive deficits. These impairments span multiple domains including attention, memory, executive function, and information processing speed, often persisting beyond the resolution of mood symptoms and adversely impacting functional recovery and quality of life. This review aims to explore the neurobiological basis of cognitive impairment in MDD, identify key biomarkers associated with these deficits, and discuss their implications for diagnosis, prognosis, and therapeutic intervention. The systematically reviewed literature related to cognitive dysfunction in MDD with a focus on neuroimaging studies, molecular and genetic biomarkers, and longitudinal data. Emphasis was placed on identifying consistent biological correlates and mechanism. Cognitive impairment in MDD is a pervasive, biologically grounded dimension that warrants independent clinical attention. Incorporating cognitive assessments into standard diagnostic protocols and developing pharmacological and non-pharmacological interventions targeting these deficits may significantly improve long-term outcomes in patients with MDD.
Aromachology is the scientific study of the psychological effects of scent, which emerged as a promising non-pharmacological approach to enhancing mental well-being. Unlike aromatherapy, which primarily focuses on therapeutic applications, aromachology emphasizes the sensory, emotional, and psychophysiological responses associated with olfactory exposure. This systematic review aimed to synthesize current human evidence on the psychophysiological and behavioral effects of essential oil inhalation, with particular focus on mood regulation, cognitive performance, stress reduction, emotional responses, and autonomic regulation. Peer-reviewed studies published between 2000 and 2025 were identified through electronic databases such as PubMed, Scopus, Web of Science, etc., using PRISMA guidelines. Eligible studies included human experimental or clinical investigations assessing psychological, behavioral, neurophysiological, or physiological outcomes following inhalation exposure to essential oils. Extracted outcomes included EEG activity, HRV, blood pressure, salivary biomarkers, cognitive performance, mood, anxiety, stress, and sleep-related measures. Essential oils such as Lavender, Jasmine, African stone, Citrus, Peppermint, and Rosemary demonstrated significant effects on mood, anxiety, attention, and memory. These effects were mediated by olfactory-limbic pathways and neurochemical modulation (e.g., serotonin, dopamine, cortisol). Psychophysiological markers confirmed autonomic shifts toward parasympathetic dominance and enhanced cortical activity. Personalized nostalgic scents also evoked vivid autobiographical memories, supporting applications in cognitive rehabilitation. Aromachology offers a scientifically grounded, non-invasive modality for psychological modulation. Its integration into clinical, occupational, and lifestyle settings may support mental wellness, cognitive enhancement, and sensory nutrition strategies.
Patients with or surviving breast cancer suffer from chemotherapy-related cognitive impairment, a multifactorial comorbid condition usually referred to as chemo-brain, that interferes with their daily activities, affects their coping ability, and worsens their quality of life. This narrative review is devoted to reporting the central clinical studies that handle aspects of chemo-brain and related interfering factors in patients with breast cancer and endeavor to help them through various supportive care procedures. Chemo-brain is a complex prognostic comorbidity that is caused by several interrelated factors, including anxiety, depression, fatigue, poor self-perception, and executive dysfunctions. Both objective and subjective screening tests are widely used, and those based on gene polymorphisms and telomeres will play a key role in identifying high-risk patients who require special monitoring. For that purpose, supportive care strategies are often considered, including cognitive training techniques like self-hypnosis, physical exercises (with or without nutritional care), and support group treatments. Cognitive changes in patients having undergone chemotherapy for breast cancer are associated with, and likely aggravated by, physical and neuropsychological issues such as fatigue, pain, anxiety, depression, and sleep disturbance, thus highlighting the urgent need to detect and assess chemo-brain symptomatology to improve treatment programs. Subjective and objective screening tests are, therefore, extensively implemented in the clinical setting, and ensuing assessment scores tend to be accounted for in achieving supportive care interventions parallel to standard anticancer follow-up.
Non-suicidal self-injury (NSSI) represents a major clinical and public health concern in adolescence, yet its mechanisms cannot be fully explained by individual psychopathology or social stress alone. This narrative review synthesizes recent evidence on neurobiological and psychosocial processes implicated in the initiation and maintenance of adolescent NSSI. Particular attention is given to prefrontal–limbic dysregulation, altered reward and pain processing, stress-response abnormalities, neuroimmune changes, epigenetic consequences of early adversity, and developmentally salient interpersonal and online contextual risk factors. Current evidence suggests that adolescent NSSI develops through a cascade in which early adversity and epigenetic embedding shape neurobiological dysregulation and individual psychological vulnerability, thereby lowering the threshold for self-injury in the context of proximal interpersonal, familial, digital, or minority-related stressors. Adverse childhood experiences may contribute to later differences in prefrontal–limbic regulation, hypothalamic–pituitary–adrenal axis activity, inhibitory control, pain perception, and reward responsivity. These alterations may converge with emotion dysregulation, impulsivity, interpersonal sensitivity, and invalidating or stressful social contexts to precipitate NSSI initiation. Once established, NSSI may be maintained through negative reinforcement, pain- and reward-related relief, altered pain thresholds, and neuroadaptive feedback loops. Taken together, the literature supports a developmental cascade diathesis–stress model in which adolescent NSSI is best understood as the product of interacting biological vulnerabilities, psychosocial pressures, and reinforcing behavioral processes. Future work should prioritize longitudinal, multimodal studies capable of clarifying temporal pathways, distinguishing mechanisms of initiation from those of maintenance, and identifying integrative biomarkers. Clinically, these findings highlight the need for mechanism-informed and personalized interventions targeting emotion regulation, stress reactivity, interpersonal context, pain/reward processing, and the reinforcing functions of NSSI.
Sleep disturbances, highly prevalent in addictions, have been shown to trigger relapse to drugs of abuse. Relapse involves a complex dysregulation of brain circuits controlling reward, impulse control, and emotional regulation. On the one hand, basic research has focused on brain mechanisms responsible for connecting sleep deprivation and addiction. Although some papers include evidence on alterations in limbic and cortico-striatal circuits on sleep-deprived- and addicted- animals, the majority of the studies explores pharmacodynamics in different models of addiction. On the other hand, clinical evidence has shown that sleep disturbances are common in patients with a history of drug consumption and that they could be a risk factor to relapse. Substantial heterogeneity in patient populations and in the methodologies to evaluate sleep disturbances and assess drug consumption, makes the results difficult to interpret. However, sleep deprivation shares neurobiological mechanisms with the dopaminergic reward system and is therefore a risk factor for relapse to drugs. Current pharmacological therapies for drug abuse do not reverse sleep disturbances, and this could be an obstacle to recovery and a risk factor to relapse. The purpose of this narrative review is to summarize preclinical and clinical studies supporting the neurobiological links between sleep deprivation and addiction to psychostimulants. Likewise, we explored functional or structural alterations, assessed by neuroimaging, electrophysiology, or neurochemical measures, in limbic- and cortico-striatal- circuits induced by sleep deprivation, in animal models or in patients with a history of drug addiction to psychostimulants. Whereas published papers on sleep deprivation and relapse to psychostimulants are scarce, we discuss how the literature on these topics can help us to understand and to prevent relapse to psychostimulants, and also to design potential interventions for the prevention and the treatment of psychostimulant addiction in humans. A comprehensive review of original research papers, systematic and narrative reviews published in peer-reviewed journals in English was conducted in Pub Med, Science Direct, Scopus, Web of Science. Nearly 200 published papers were included, encompassing animal models of addiction and clinical populations with a history of psychostimulant use. Across studies, sleep disturbances –reduced total sleep time, sleep fragmentation– were consistently associated with increased drug-seeking behavior and higher relapse vulnerability. These findings indicate that sleep disturbances are a robust correlate of relapse risk and support the integration of sleep-focused interventions into treatment protocols for psychostimulant use disorders.
This review synthesizes evidence published between 2010 and 2025 on noise-induced cochlear synaptopathy (hidden hearing loss), with the aim of clarifying its underlying neural mechanisms, summarizing findings from animal and human studies, and outlining current clinical implications and future research priorities. Animal studies consistently demonstrate that moderate noise exposure can induce permanent loss of inner hair cell–auditory nerve synapses, particularly low-SR fibers affecting low-SR fibers, despite full recovery of audiometric thresholds. These synaptic deficits are associated with reduced auditory brainstem response (ABR) wave I amplitudes, disrupted temporal coding, and progressive spiral ganglion neuron degeneration in the absence of outer hair cell loss. Human studies yield more heterogeneous results but frequently report smaller ABR wave I amplitudes, reduced envelope-following responses, altered middle-ear muscle reflexes, and poorer speech-in-noise performance among noise-exposed individuals with clinically normal audiograms. Preventive strategies show consistent benefit, whereas experimental therapeutic approaches—such as neurotrophin delivery and antioxidant interventions—demonstrate promise in animal models but remain limited in human translation. Current evidence supports cochlear synaptopathy as a key mechanism underlying suprathreshold auditory deficits that are not detected by conventional audiometry. A multimodal diagnostic framework incorporating electrophysiological, behavioral, and exposure-history measures is warranted. Future progress will depend on standardized diagnostic criteria, improved exposure characterization, and biomarker-driven clinical trials to guide targeted prevention and treatment strategies for hidden hearing loss.
Neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease, are characterized by progressive neuronal loss, synaptic dysfunction, and cognitive and motor impairments, for which disease-modifying therapies remain limited. Anatabine, a minor alkaloid derived from Solanaceae plants, has recently gained attention due to its antioxidant, anti-inflammatory, and neuromodulatory properties. Although extensively studied in inflammatory and metabolic conditions, its therapeutic relevance in neurodegeneration has not been comprehensively evaluated. This review systematically examines the neuroprotective potential of anatabine in NDs by integrating evidence from in vitro, in vivo, and computational studies to elucidate its mechanistic and translational significance. In vitro studies demonstrate that anatabine reduces reactive oxygen species production, activates Nrf-2/ARE signaling, and suppresses NF-κB and STAT3-mediated neuroinflammation. Anatabine dose-dependently downregulates BACE1 expression and reduces Aβ₁–₄₀/₄₂ accumulation, thereby attenuating Aβ-induced synaptic and mitochondrial dysfunction. Whereas, in vivo studies demonstrate that anatabine decreases cerebral Aβ burden, microglial activation (Iba-1, CD45), and pro-inflammatory mediators including iNOS, COX-2, TNF-α, IL-1β, IL-6, IL-17, and IFN-γ. These molecular effects preserve dopaminergic neuron integrity, stabilize striatal dopamine signaling, and improve behavioral outcomes such as locomotor activity, sociability, working memory, and attention. Molecular docking analyses further reveal high-affinity interactions of anatabine with key neurodegenerative targets, including Aβ (-22.6 kcal/mol), dopamine D2 receptor (-7.2 kcal/mol), TNF-α (-5.9 kcal/mol), NF-κB (-5.2 kcal/mol), and STAT3 (-5.8 kcal/mol), corroborating its multi-target mode of action. By integrating mechanistic insights, molecular docking data, and behavioral outcomes, this review underscores the potential of anatabine as a disease-modifying therapeutic candidate for neurodegenerative disorders. Nonetheless, further preclinical validation and well-designed clinical studies are required to establish its safety, efficacy, and translational applicability in human populations.
Alzheimer’s disease is a neurological condition that is characterised by different lesions, primarily the senile/neuritic plaques and neurofibrillary tangles. Due to the extensive degradation of cholinergic neurons throughout the hippocampus and cortex, the cholinergic transmission is reduced, which ultimately leads to cognitive abnormalities. As they are heavily influenced by the cholinesterases, cholinesterase inhibitors are the verified group of drugs approved for the disease. This review tries to explore and understand the underlying factors for the positive and negative effects of donepezil. Donepezil, being a reversible, selective, and competitive inhibitor of acetylcholinesterase, significantly stimulates the cholinergic transmission. It has improved performance in several pharmacological models of learning and memory impairments. Numerous extensive studies have confirmed the effectiveness of donepezil in treating symptoms in mild, moderate, and even severe stages of AD based on the patient’s behaviour, daily activities, and cognitive performance. Even though it is used to treat an extensive array of patients suffering from AD, there are some side effects, such as vomiting, diarrhoea, insomnia, convulsions, and bradycardia that may occur with the treatment. Therefore, if the patient is cognitively responding to the drug, other factors, including the presence of other concurrent medications, the dose of the drug needs to be investigated as possible reasons for these adverse events. Hence, to have a better understanding of the complex interplay between donepezil and other factors that can cause these effects, further clinical studies are required to appreciate the positive effects while minimizing the negative ones.
The widespread and increasing use of proton pump inhibitors (PPIs), particularly among middle-aged and older adults, has raised concerns regarding potential long-term neurological effects. Given the rising global burden of dementia, this review aims to critically evaluate the current preclinical and clinical evidence examining the association between chronic PPI use and cognitive impairment, including dementia. Experimental studies suggest that PPIs can cross the blood–brain barrier (BBB) and may influence neurobiological pathways implicated in dementia, including amyloid-β (Aβ) metabolism, tau pathology, neuroinflammation, synaptic dysfunction, and oxidative stress. Clinical and observational studies have reported heterogeneous findings, with some suggesting an increased risk of cognitive decline or dementia, particularly in older or genetically susceptible populations, while others report no significant association after adjustment for confounders. Emerging evidence highlights indirect mechanisms linking long-term PPI use to cognitive dysfunction, such as vitamin B12 deficiency, gut microbiota dysbiosis with disruption of the gut–brain axis, and impaired calcium homeostasis. However, most available data are observational and susceptible to confounding by indication, polypharmacy, and reverse causation. Current evidence linking PPI use to cognitive decline and dementia remains inconclusive. While biologically plausible mechanisms exist, clinical findings are inconsistent and do not establish causality. These uncertainties underscore the importance of cautious, evidence-based PPI prescribing, regular medication review, and appropriate monitoring in long-term users, particularly older adults. Well-designed longitudinal, mechanistic, and interventional studies are needed to clarify potential neurocognitive risks and identify vulnerable populations.
Parkinson’s Disease (PD) is a long-term, progressive neurodegenerative disease that primarily impacts the motor system due to the degeneration of dopaminergic neurons in the substantia nigra of the brain. While conventional pharmacological therapies like dopamine replacement provide symptomatic relief, they do not halt or reverse neuronal degeneration. As a result, there is growing interest in complementary approaches, particularly the use of nutraceuticals, for their potential neuroprotective effects. This review aims to explore the role of nutraceuticals in the prevention and management of PD by examining their mechanisms of action and summarizing recent findings from preclinical and clinical studies. Nutraceuticals are naturally occurring compounds derived from dietary sources that offer health or therapeutic benefits, including disease prevention and management. In the context of PD, several nutraceuticals such as polyphenols (e.g., curcumin, resveratrol), vitamins D and E, omega-3 fatty acids, flavonoids, and coenzyme Q10 have been studied for their antioxidant, anti-inflammatory, and mitochondrial-supportive properties. These mechanisms are particularly relevant given that PD pathogenesis involves oxidative stress, mitochondrial dysfunction, and neuroinflammation. Some nutraceuticals also enhance neuroplasticity and reduce alpha-synuclein aggregation, a hallmark of PD pathology. The combination of nutrigenomics and precision nutrition is becoming increasingly popular to deal with the personal genetic predispositions that determine the reaction to nutrients, metabolic processes, and susceptibility to neuroinflammation in PD. Nutrigenomic techniques that use genotype-nutrient interaction profiling, transcriptomic biomarkers, and gut-brain axis modulations can be viewed as the future of going beyond generalized supplementation and towards individual neuro-nutraceutical therapy. Nevertheless, massive longitudinal studies, standardised dosing regimens, and multi-omics confirmation are essential to bridge the current gap of efficacy in the lab and clinical translation in PD. Nutraceuticals show promising potential as adjunctive therapies for PD. Their ability to address multiple pathological mechanisms simultaneously makes them valuable candidates for improving long-term outcomes. However, while current findings are encouraging, more rigorous clinical trials are essential to confirm their efficacy, determine optimal dosages, and assess long-term safety profiles. A multidisciplinary approach that combines standard pharmacological treatment with nutraceutical supplementation, lifestyle adjustments, and dietary modifications may provide a holistic strategy for managing PD.
This review discusses non-motor symptom replication in neurotoxic mouse models of Parkinson’s disease (PD). Non-motor symptoms can begin years prior to the onset of motor symptoms, with the cause of non-motor symptoms remaining widely unknown. This highlights the need for researchers to investigate non-motor symptom pathology, with the aim of earlier diagnosis and identifying potential early and alternative treatment options. Neurotoxic models are the most common Parkinson’s disease models in mice, as they are quick to induce, reproducible, cost-effective and replicate dopaminergic neuron loss and symptoms. The non-motor symptoms of Parkinson’s disease included in this review are olfactory dysfunction, anxiety, depression, sleep and circadian rhythm disorders, cognitive impairments and gastrointestinal dysfunction. We have reviewed the most commonly used behavioural tests for each non-motor symptom in neurotoxic models in mice, and have provided some recommendations and highlighted their limitations. This review provides a comprehensive review of studies in one place for the researcher to make quick and easy decisions on what neurotoxic model to use and what test to use to replicate the required non-motor symptom based on the aims of the researcher. Through the replication of non-motor symptoms and modelling PD in mice, researchers can help uncover the pathogenesis and potential treatments for non-motor symptoms in PD. We hope this review will be useful for the beginners and experienced researchers who wish to embark on behavioural tests in neurotoxin mouse models of Parkinson’s disease to investigate the molecular mechanisms and possible treatments.
Protein aggregation involving misfolded proteins like alpha-synuclein (α-Syn), tau, and amyloid-beta is a key factor in neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s. These aggregates disrupt cellular homeostasis and lead to neurotoxicity. Understanding their formation is crucial for developing disease modifying treatment. A literature review was performed using PubMed, Scopus, and Web of Science to identify studies on protein misfolding, aggregation, and related therapeutic strategies. Keywords related to protein aggregation, neurodegeneration, and interventions were used. Studies were selected based on innovation, relevance, and translational potential. Protein aggregation is influenced by genetic mutations, oxidative stress, proteostasis imbalance, and environmental factors. Promising therapies include molecular chaperones, aggregation inhibitors, autophagy enhancers, and immunotherapies. However, therapeutic translation is limited by issues such as blood-brain barrier permeability, off-target effects, and patient variability. New delivery systems and multi-targeted approaches are under investigation to improve outcomes. Targeting protein aggregation is a promising but challenging approach for treating neurodegenerative diseases. Continued research into molecular mechanisms and therapeutic innovation is essential. Collaborative efforts integrating biology, pharmacology, and technology may lead to effective, clinically translatable therapies.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder driven by multifactorial pathogenic mechanisms, including early oxidative stress and mitochondrial dysfunction, followed by α-synuclein aggregation, neuroinflammation, and impaired neurotrophic support. Given that current therapies are largely symptomatic and non-disease-modifying, there is a need for multitarget therapeutic strategies. Therefore, the present study aims to evaluate the antiparkinsonian potential of apigenin, a naturally occurring flavone, in modulating key pathogenic targets of PD. A comprehensive literature-based mechanistic analysis was conducted to elucidate the molecular pathways underlying apigenin-mediated neuroprotection in PD. Relevant studies were systematically retrieved from PubMed, ScienceDirect, Scopus, Embase, and Google Scholar. In addition, in-silico molecular docking studies were performed to evaluate the binding interactions of apigenin with key pathological targets, including α-synuclein and dopamine receptors (D2, D3, and D4). Furthermore, ADMET analysis was carried out to assess the drug-likeness, pharmacokinetic properties, and safety profile of apigenin. The findings indicate that apigenin exerts robust anti-Parkinson potential through modulation of multiple signaling pathways, including inhibition of NF-κB-mediated pro-inflammatory cytokine production, suppression of pro-apoptotic mediators, and attenuation of MAPK-driven neuroinflammatory responses. Furthermore, apigenin influences critical PD-related mediators such as α-synuclein aggregation, TGF-β, acetylcholinesterase activity, dopaminergic signaling, and ROS. Molecular docking revealed favorable interactions of apigenin with α-synuclein and dopamine receptors, while ADMET profiling suggested acceptable pharmacokinetic and safety characteristics. This study highlights that apigenin possesses significant multitargeted activity against key pathogenic mechanisms of PD, underscoring its potential as a promising candidate for further preclinical and translational research toward disease-modifying therapies.
This narrative review examines neuromodulation as a potential augmentation strategy for cognitive-behaviour therapy (CBT) with exposure and response prevention (ERP) in obsessive-compulsive disorder (OCD). By synthesising behavioural, neurobiological, and clinical literature, we evaluate how circuit-based interventions can enhance extinction learning (EL), the core mechanism of ERP, and improve outcomes. ERP is the gold-standard treatment for OCD, yet a substantial proportion of patients do not respond adequately or drop out. EL, driven by habituation, inhibitory memory formation, and expectancy violation underpins ERP. EL is often impaired in OCD, linked to cortico-limbic dysfunction. Of note, ventromedial prefrontal cortex (vmPFC) plays a central role in extinction memory formation as well as retrieval, and hence, can be considered as the central “extinction locus”. Non-invasive neuromodulation techniques have shown preliminary efficacy in modulating these circuits. Preclinical studies show that stimulation of vmPFC before or during exposure may enhance EL. However, conventional methods may not be adequate to stimulate deeper structures such as the vmPFC. Novel focal and noninvasive neuromodulatory techniques, such as transcranial focused ultrasound or temporal interference stimulation, have to be evaluated. Cognitive domains beyond extinction, including working memory, error monitoring, and distress tolerance, also represent promising neuromodulatory targets. Neuromodulation offers a promising, circuit-based approach to augment ERP in OCD by strengthening EL and related processes. Future progress requires focal, personalised, and mechanistically guided protocols.
Neuroinflammation plays a pivotal role in disrupting synaptic resilience, thereby contributing to the onset and progression of major neurodegenerative and neuropsychiatric disorders. While its molecular mechanisms are well documented, the translational pharmacology linking these immune processes to synaptic recovery remains insufficiently synthesized. This review proposes an integrative framework of translational neuroimmune-synaptology, focusing on how modulation of glial activation, cytokine signaling, oxidative stress, and complement cascades can be strategically leveraged for Restoration of synaptic resilience. Recent primary studies demonstrate that selective microglial and astrocytic modulators, cytokine-targeted biologics, and mitochondrial protectants can reverse inflammation-driven synaptic loss. Nevertheless, clinical translation remains limited by barriers such as inadequate blood–brain barrier (BBB) penetration, off-target immune suppression, and inconsistent biomarker validation. Novel modalities—such as RNA therapeutics, CRISPR-based gene modulation, and AI-assisted drug repurposing—show potential to overcome these translational bottlenecks, provided their safety, delivery, and regulatory challenges are critically addressed. By reframing neuroinflammation as a modifiable and measurable determinant of synaptic function, this review consolidates mechanistic and pharmacological perspectives on neuroinflammation-induced synaptic dysfunction. Within the framework of translational neuroimmune-synaptology, it delineates actionable strategies to restore synaptic resilience and bridges preclinical discoveries with clinical therapeutic translation.
Nicotine dependency is a significant concern in the realm of public health since it has been observed to have adverse consequences on both an individual's physical well-being and socioeconomic status. Nicotine addiction induces neuroadaptive alterations, particularly within the reward and motivation circuits. Nicotine is classified as a sympathomimetic drug, which induces the synthesis of catecholamines, constricts the coronary and cutaneous blood vessels, increases heart rate and cardiac contractility, and transiently raises blood pressure. Nicotine has been found to not only decrease insulin sensitivity but also potentially worsen or induce diabetes, as well as increase endothelial dysfunction. The complicated interaction between neurotransmitters and transcription factors highlights the intricacy of nicotine addiction and offers valuable understanding for future therapeutic approaches. Gaining a comprehensive understanding of these processes is crucial to successfully tackling this worldwide health concern. Further, pharmacological modulation of CREB with different pathways such as the NO-cGMP-PKG pathway, ERK pathway, BDNF signalling pathway, and DARPP pathway is explored in the review article.
This study aimed to identify brain regions associated with specific types of synesthesia and investigate their neuroanatomical correlates and potential associations with co-occurring clinical disorders. The primary goal was to uncover quantitative and categorical relationships among brain regions, synesthetic experiences, and related conditions. Pearson’s correlation test was used to assess the relationship between increased activity in specific brain regions and synesthesia types. The Chi-square test was used to examine the association between the presence of brain region activation and clinical conditions such as autism spectrum disorder (ASD), migraine, anxiety, depression, schizophrenia, post-traumatic stress disorder (PTSD), epilepsy, bipolar disorder, and obsessive-compulsive disorder (OCD). These statistical analyses provided a comprehensive understanding of the interplay between neural activation patterns and synesthesia. Significant correlations were found between brain regions and synesthesia types: a strong positive correlation between the fusiform gyrus and grapheme-color synesthesia (r = 0.72, p < 0.001); a significant relationship between the posterior parietal cortex (PPC) and sound-color synesthesia (r = 0.68, p < 0.001); and a moderate relationship between insular activity and lexical-gustatory synesthesia (r = 0.45, p = 0.01). Clinical associations revealed a moderate correlation between synesthesia and ASD (r = 0.56, p < 0.001), whereas no significant association was observed between synesthesia and PTSD (χ² = 1.36, p = 0.75). This study highlights the significant associations between specific brain regions and types of synesthesia, with the fusiform gyrus, PPC, visual cortex (V4/V8), parieto-occipital cortex, inferior temporal gyrus, and insula playing critical roles in synesthesia development. The high correlation with migraine, anxiety, and depression and the moderate correlation with ASD indicate potentially overlapping neurodevelopmental characteristics and associative patterns of hyperconnectivity, whereas the relationship with schizophrenia requires further investigation.
Addiction is a complex, chronic disorder that affects tens of millions of people around the world. It is characterized by compulsive substance use or engagement in harmful behaviors despite adverse consequences. Recognized as a chronic and relapsing brain disorder, the transition from casual drug use to addiction involves a gradual process of escalated intake underpinned by significant changes in brain function, particularly in neural circuits governing reinforcement, learning, and behavior. This article is based on an assessment of the preclinical and clinical literature, delineating the biphasic nature of the addiction cycle—from use to abuse to addiction. The biphasic model focuses on progressive neurobehavioral adaptations that underlie phase transitions in stimulus reinforcement, motivation, associative learning, tolerance, and inhibitory control. Understanding how drug-induced alterations in brain function affect cognition, emotion, and behavior is essential for developing more effective strategies for addiction detection, recovery, and prevention. Addiction is a complex disorder affecting tens of millions globally. This review is based on a comprehensive assessment of the preclinical and clinical literature to identify converging evidence describing how the brain and behavior are gradually transformed as drug use (or misuse) deteriorates to abuse and, eventually, addiction. The biphasic and maladaptive nature of the accompanying changes are dissected in five categories—reinforcement, motivation, associative learning, tolerance, and inhibitory control. Results support a biphasic trajectory for each of the five categories. Cumulative changes in the neural circuitry responsible for phase transitions—posited to be conceptually dynamic, not static or linear—are linked to various cognitive, emotional, and behavioral outcomes. Early drug use is dominated by positive reinforcement, liking, classical conditioning, physiological tolerance, and impulsive behavior. As substance abuse accelerates, altered brain function fosters compulsive drug intake, governed by negative reinforcement, wanting, craving, instrumental (habitual) responding, and conditioned tolerance. The biphasic model of addiction delivers a systematic framework that illuminates the drug-induced neural adaptations that impel deviations in cognitive processing, emotional reactivity, and behavioral regulation. These objective neurobehavioral markers are expected to inform category- and phase-specific diagnostic and treatment strategies. Empirical validation will be needed to assess the model’s predictive and translational utility, as well as its applicability to non-substance (behavioral) addiction.
