Accelerated transcranial direct current stimulation (acctDCS) compresses more than 2 sessions in a day relative to conventional once-or twice daily tDCS protocols. Although conventional tDCS has an established safety record, it is unclear whether the same level of safety applies to accelerated protocols. This review aims to address the safety and tolerability of acctDCS across healthy and neuropsychiatric populations. Many studies have demonstrated the efficacy of acctDCS protocols, with some characterising and reporting adverse effects. However, there is no study that has systematically reviewed its safety and tolerability for aiding clinicians in optimising treatment decisions. AcctDCS was found to be well tolerated, with either no adverse events (AEs) or treatment discontinuations due to intolerability. AEs were predominantly mild to transient. Systemic symptoms were observed only under the highest cumulative dosing schedules. In future, adequately powered, sham-controlled studies are warranted to assess standardised AE scales.
Transcranial magnetic stimulation (TMS) is a promising non-invasive neuromodulation tool in various psychiatric disorders. By virtue of its deeper penetration and broader volume of influence, deep TMS (dTMS) may engage widespread neural circuits, affording more elaborate neuromodulatory influences over remote but functionally connected brain regions. This narrative review explores the emerging therapeutic aspects of dTMS in psychiatric disorders in the light of contemporary neurobiological understanding. Through this review, we aim to synthesise the current and emerging evidence on dTMS, thereby supporting clinicians in making informed decisions concerning its translational application. The development of H-coils has enabled stimulation of deeper and broader brain regions than possible with repetitive TMS (rTMS). Evidence on safety and efficacy has resulted in FDA clearances for dTMS in treating major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and smoking cessation. Recent advancements include evidence in dual disorders and the clearance of accelerated protocols, with preliminary research on dTMS in neurodevelopmental disorders like ADHD and ASD also showing promise. By extending stimulation beyond superficial cortical targets, dTMS provides an approach to circuit-level neuromodulation that can affect deeper and distributed neural networks. As treatment efforts move towards personalized, circuit-based interventions, the integration of advanced neuroimaging techniques may help in optimising treatment protocols.
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.
