Brain Sciences最新文献

{"title":"Auricular Ultrasonic Vagus Nerve Stimulation: Effectiveness of Blinding and Occurrence of Adverse Effects in Healthy Volunteers.","authors":"Bas Labree, Marcus Kaiser, Mohamad A Pourhoseingholi, Derek J Hoare, Magdalena Sereda","doi":"10.3390/brainsci15090986","DOIUrl":"10.3390/brainsci15090986","url":null,"abstract":"<p><strong>Background/objectives: </strong>Both invasive and non-invasive electrical stimulation of the vagus nerve have been studied as potential treatments for neurological conditions, with mixed results. Ultrasonic Vagus Nerve Stimulation (U-VNS), which non-invasively stimulates the auricular branch of the vagus nerve using ultrasound, may offer a more targeted and effective approach than electric currents. To facilitate future clinical trials of U-VNS, this study aimed to (1) investigate the effectiveness of blinding of a U-VNS device versus a sham device and (2) record the type, onset, and duration of any adverse effects resulting from U-VNS.</p><p><strong>Methods: </strong>In this single-blind randomised controlled study, twenty healthy volunteers were randomly assigned to receive either a 30 min session of true U-VNS and a 30 min session of sham stimulation 1 week later, or vice versa. The effectiveness of blinding and the occurrence of adverse effects were measured using self-report questionnaires.</p><p><strong>Results: </strong>James' Blinding Index showed that blinding using the sham device was highly effective in both the real U-VNS condition, BI = 0.9 (95% CI: 0.7-1.0), and the sham condition, BI = 1.0 (95% CI: 1.0-1.0). The adverse effects reported were mild, transient, and mostly related to sensations on the skin immediately under the transducer of the device.</p><p><strong>Conclusions: </strong>A high level of blinding effectiveness can be achieved for U-VNS by using a sham device. Adverse effects are generally mild and transient. These findings will inform the design of future clinical trials of U-VNS.</p>","PeriodicalId":9095,"journal":{"name":"Brain Sciences","volume":"15 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NRGAMTE: Neurophysiological Residual Gated Attention Multimodal Transformer Encoder for Sleep Disorder Detection.","authors":"Jayapoorani Subramaniam, Aruna Mogarala Guruvaya, Anupama Vijaykumar, Puttamadappa Chaluve Gowda","doi":"10.3390/brainsci15090985","DOIUrl":"10.3390/brainsci15090985","url":null,"abstract":"<p><strong>Background/objective: </strong>Sleep is significant for human mental and physical health. Sleep disorders represent a crucial risk to human health, and a large portion of the world population suffers from them. The efficient identification of sleep disorders is significant for effective treatment. However, the precise and automatic detection of sleep disorders remains challenging due to the inter-subject variability, overlapping symptoms, and reliance on single-modality physiological signals.</p><p><strong>Methods: </strong>To address these challenges, a Neurophysiological Residual Gated Attention Multimodal Transformer Encoder (NRGAMTE) model was developed for robust sleep disorder detection using multimodal physiological signals, including Electroencephalogram (EEG), Electromyogram (EMG), and Electrooculogram (EOG). Initially, raw signals are segmented into 30-s windows and processed to capture the significant time- and frequency-domain features. Every modality is independently embedded by a One-Dimensional Convolutional Neural Network (1D-CNN), which preserves signal-specific characteristics. A Modality-wise Residual Gated Cross-Attention Fusion (MRGCAF) mechanism is introduced to select significant cross-modal interactions, while the learnable residual path ensures that the most relevant features are retained during the gating process.</p><p><strong>Results: </strong>The developed NRGAMTE model achieved an accuracy of 94.51% on the Sleep-EDF expanded dataset and 99.64% on the Cyclic Alternating Pattern (CAP Sleep database), significantly outperforming the existing single- and multimodal algorithms in terms of robustness and computational efficiency.</p><p><strong>Conclusions: </strong>The results shows that NRGAMTE obtains high performance across multiple datasets, significantly improving detection accuracy. This demonstrated their potential as a reliable tool for clinical sleep disorder detection.</p>","PeriodicalId":9095,"journal":{"name":"Brain Sciences","volume":"15 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dopaminergic Inhibition of the Inwardly Rectifying Potassium Current in Direct Pathway Medium Spiny Neurons in Normal and Parkinsonian Striatum.","authors":"Qian Wang, Yuhan Wang, Francesca-Fang Liao, Fu-Ming Zhou","doi":"10.3390/brainsci15090979","DOIUrl":"10.3390/brainsci15090979","url":null,"abstract":"<p><p><b>Background:</b> Despite the profound behavioral effects of the striatal dopamine (DA) activity and the inwardly rectifying potassium channel (Kir) being a key determinant of striatal medium spiny neuron (MSN) activity that strongly affects behavior, previously reported DA regulations of Kir are conflicting and incompatible with MSN function in behavior. <b>Methods and Results:</b> Here, we used DA depletion mouse models that have hyperfunctional DA receptors such that potential DA regulation of Kir may be enhanced and relatively large and thus detected reliably. We show that in striatal brain slices from normal mice with an intact striatal DA system, the predominant effect of DA activation of D1Rs in D1-MSNs is to cause a modest depolarization and an increase in input resistance by inhibiting Kir, thus moderately increasing the spike outputs from behavior-promoting D1-MSNs. In brain slices from parkinsonian (DA-depleted) striatum, DA increases D1-MSN intrinsic excitability more strongly than in normal striatum, consequently more strongly increasing D1-MSN spike firing that is behavior-promoting. This DA inhibition of Kir is occluded by the Kir blocker barium chloride (BaCl₂). In behaving parkinsonian mice, BaCl₂ microinjection into the dorsal striatum stimulates movement and also occludes the motor stimulation of D1R agonism. <b>Conclusions:</b> Taken together, our results resolve the long-standing question about what D1R agonism does to D1-MSN excitability in normal and parkinsonian striatum and strongly indicate that D1R inhibition of Kir is a key ion channel mechanism that mediates the profound motoric and behavioral stimulation of striatal D1R activation in normal and parkinsonian animals.</p>","PeriodicalId":9095,"journal":{"name":"Brain Sciences","volume":"15 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging Interventions in Behavioral Addictions: A Narrative Review of Psychedelics and Neuromodulation.","authors":"Krista Ulisse, Jehad Albitar, Jourdan T Aromin, James Berry","doi":"10.3390/brainsci15090980","DOIUrl":"10.3390/brainsci15090980","url":null,"abstract":"<p><p>Addiction remains a persistent public health crisis, marked by poor treatment retention and limited pharmacotherapy options. Emerging treatments, such as psychedelic-assisted psychotherapy and neuromodulation, offer promising avenues for circuit-level interventions in behavioral addictions. This narrative review synthesizes the current landscape of psychedelic compounds and neuromodulation techniques with a focus on their mechanisms of action, applications in specific behavioral addictions, and translational potential. By targeting disrupted reward, executive control, and stress regulation networks, these interventions may facilitate meaningful recovery and long-term remission in otherwise treatment refractory cases. We highlight key findings, current research limitations, and future directions in integrating these novel therapies into the treatment of gambling disorder; internet gaming disorder/gaming disorder, predominantly online; internet use disorder; and compulsive sexual behavior disorder.</p>","PeriodicalId":9095,"journal":{"name":"Brain Sciences","volume":"15 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12467898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain Cortical Area Characterization and Machine Learning-Based Measure of Rasmussen's S-R-K Model.","authors":"Daniele Amore, Daniele Germano, Gianluca Di Flumeri, Pietro Aricò, Vincenzo Ronca, Andrea Giorgi, Alessia Vozzi, Rossella Capotorto, Stefano Bonelli, Fabrice Drogoul, Jean-Paul Imbert, Géraud Granger, Fabio Babiloni, Gianluca Borghini","doi":"10.3390/brainsci15090981","DOIUrl":"10.3390/brainsci15090981","url":null,"abstract":"<p><strong>Background: </strong>the Skill, Rule, and Knowledge (S-R-K) model is a framework used to describe and analyze human behaviour and decision-making in complex environments based on the nature of the task and kind of cognitive control required. The S-R-K model is particularly useful in fields like human factor engineering, system design, and safety-critical industries because it helps to understand human errors and how they relate to different levels of cognitive control. However, the S-R-K model is still qualitative and lacks specific and quantifiable metrics for determining what kind of cognitive control a person is using at any given time. This aspect makes difficult to directly measure and compare performance across the three levels. This study aimed therefore to characterize the S-R-K model from a neurophysiological perspective by analyzing the operator's cerebral cortical activity.</p><p><strong>Methods: </strong>in this study, participants carried out experimental tasks able to replicate the Skill (tracking task), Rule (rule-based navigation) and Knowledge conditions (unfamiliar situations).</p><p><strong>Results: </strong>participants' Electroencephalogram (EEG) was recorded during tasks execution and then Global Field Power (GFP) was estimated in the different EEG frequency bands. Brodmann areas (BAs) and EEG features were then used to characterize the S-R-K pattern over the cerebral cortex and as inputs to build up the machine learning-based model to estimate participants' cognitive control behaviours while dealing with tasks.</p><p><strong>Conclusions: </strong>the results demonstrate the possibility of objectively measuring the different S, R and K levels in terms of brain activations. Furthermore, such evidence is consistent with the scientific literature in terms of cognitive functions corresponding to the different levels of cognitive control.</p>","PeriodicalId":9095,"journal":{"name":"Brain Sciences","volume":"15 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12467830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-Invasive Cervical Spinal Stimulation and Respiratory Recovery After Spinal Cord Injury: A Randomized Controlled Trial with a Partial Crossover Design.","authors":"Hatice Kumru, Agustin Hernandez-Navarro, Sergiu Albu, Loreto García-Alén","doi":"10.3390/brainsci15090982","DOIUrl":"10.3390/brainsci15090982","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Respiratory impairment is the leading cause of morbidity and mortality in participants with spinal cord injury (SCI). Cervical SCI (cSCI) severely compromises respiratory function due to paralysis and weakness of the respiratory muscles. Recent evidence suggests that transcutaneous electrical spinal cord stimulation (tSCS) may enhance motor strength and promote functional recovery. Therefore, cervical tSCS, applied at cervical segments, holds potential as a therapeutic strategy to improve respiratory function in participants with cervical SCI. <b>Methods</b>: This randomized controlled trial with a partial crossover design included participants with both complete and incomplete cSCI. Neurological assessments were used, as well as tests to evaluate pulmonary function maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), and spirometric measurements. These assessments were conducted at baseline and after the last session. The experimental group received tSCS at the C3-C4 and C6-C7 cervical spinal levels, delivered at a frequency of 30 Hz during occupational therapy. The control group underwent identical occupational therapy sessions without stimulation. Each session lasted 30 min and was conducted over eight days. <b>Results</b>: Fifteen participants with cSCI received tSCS, while 11 cSCI participants were included in the control group. Seven participants took part in both groups. Only the tSCS group showed significant improvements in MIP, MEP, and forced vital capacity (<i>p</i> < 0.05), while no significant changes were observed in the control group. <b>Conclusions</b>: tSCS applied at the cervical segments can promote respiratory function following cervical SCI. This approach may support neuroplasticity and help reduce long-term respiratory complications in participants with cervical SCI. However, to confirm these effects, long-term stimulation protocols and follow-up studies in larger SCI populations are required.</p>","PeriodicalId":9095,"journal":{"name":"Brain Sciences","volume":"15 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12469035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electroacupuncture Attenuates Fibromyalgia Pain Through Increased PD-1 Expression in Female Mice.","authors":"I-Han Hsiao, Wei-Hung Chen, Ming-Chia Lin, Hsin-Cheng Hsu, Hsien-Yin Liao, Yi-Wen Lin","doi":"10.3390/brainsci15090976","DOIUrl":"10.3390/brainsci15090976","url":null,"abstract":"<p><strong>Background/objectives: </strong>Fibromyalgia causes chronic long-term pain, with symptoms lasting for months to years. Given the lack of evidence-based methods for diagnosing and assessing fibromyalgia, it ranks among the most difficult chronic pain conditions to treat. Programmed cell death ligand 1 (PD-L1) can inhibit acute and chronic pain transmission by inhibiting neuronal ion channels.</p><p><strong>Methods: </strong>Here, we aimed to explore the analgesic efficacy and mechanism of PD-L1/PD1 in an intermittent cold stress-induced fibromyalgia pain mouse model.</p><p><strong>Results: </strong>Von Frey and Hargreaves tests were performed, showing that the mouse model exhibited mechanical (day 4: 2.08 ± 0.13 g, <i>n</i> = 9) and thermal hyperalgesia (day 4: 3.93 ± 0.45 s, <i>n</i> = 9). Electroacupuncture (EA) or intraventricular PD-L1 injection effectively alleviated the nociceptive response and led to low PD-1 levels in the mouse dorsal root ganglia, spinal cord, thalamus, somatosensory cortex, and cerebellum, as measured through Western blots. In contrast, the pain-related kinase levels increased after fibromyalgia induction; these effects were reversed by EA and PD-L1 via the inhibition of microglia/astrocytes and Toll-like receptor 4.</p><p><strong>Conclusions: </strong>Our results show that EA can treat fibromyalgia pain in mice through effects on the PD-L1/PD1 pathway, indicating its potential as a therapeutic target in fibromyalgia.</p>","PeriodicalId":9095,"journal":{"name":"Brain Sciences","volume":"15 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12467811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting Depression Therapy Outcomes Using EEG-Derived Amplitude Polar Maps.","authors":"Hesam Akbari, Wael Korani, Sadiq Muhammad, Reza Rostami, Reza Kazemi, Muhammad Tariq Sadiq","doi":"10.3390/brainsci15090977","DOIUrl":"10.3390/brainsci15090977","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Depression is a mental disorder that can lead to self-harm or suicidal thoughts if left untreated. Psychiatrists often face challenges in identifying the most effective courses of treatment for patients with depression. Two widely recommended depression-related therapies are selective serotonin reuptake inhibitors (SSRIs) and repetitive transcranial magnetic stimulation (rTMS). However, their response rates are approximately 50%, which is relatively low. This study introduces a computer-aided decision (CAD) system designed to determine the effectiveness of depression therapies and recommends the most appropriate treatments for patients. <b>Methods</b>: Each channel of the EEG is plotted in two-dimensional (2D) space via a novel technique called the amplitude polar map (APM). In each channel, the 2D plot of APM is utilized to extract distinctive features via the binary pattern of five successive lines method. The extracted features from each channel are fused to generalize the pattern of EEG signals. The most relevant features are selected via the neighborhood component analysis algorithm. The chosen features are input into a simple feed-forward neural network architecture to classify the EEG signal of a depressed patient into either a respondent to depression therapies or not. The 10-fold cross-validation strategy is employed to ensure unbiased results. <b>Results</b>: The results of our proposed CAD system show accuracy rates of 98.06% and 97.19% for predicting the outcomes of SSRI and rTMS therapies, respectively. In SSRI predictions, prefrontal and parietal channels such as F7, Fz, Fp2, P4, and Pz were the most informative, reflecting brain regions involved in emotional regulation and executive function. In contrast, rTMS prediction relied more on frontal, temporal, and occipital channels such as F4, O2, T5, T3, Cz, and T6, indicating broader network modulation via neuromodulation. <b>Conclusions</b>: The proposed CAD framework holds considerable promise as a clinical decision-support tool, assisting mental health professionals in identifying the most suitable therapeutic interventions for individuals with depression.</p>","PeriodicalId":9095,"journal":{"name":"Brain Sciences","volume":"15 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunological Targets in Generalized Myasthenia Gravis Treatment: Where Are We Going Now?","authors":"Elena Rossini, Luca Leonardi, Stefania Morino, Giovanni Antonini, Laura Fionda","doi":"10.3390/brainsci15090978","DOIUrl":"10.3390/brainsci15090978","url":null,"abstract":"<p><strong>Background: </strong>Generalized myasthenia gravis (gMG) is a heterogeneous autoimmune disorder marked by antibody-mediated disruption of neuromuscular transmission. Despite advancements in immunosuppressive therapies and biologics, a subset of patients remains refractory, necessitating more targeted and personalized treatment strategies.</p><p><strong>Objective: </strong>This review aims to synthesize current knowledge of the immunopathological mechanisms across gMG subtypes and to explore emerging therapeutic targets tailored to these diverse disease phenotypes.</p><p><strong>Methods: </strong>A narrative review was conducted, integrating recent findings from clinical trials, immunogenetic studies, and preclinical research to describe subtype-specific immune mechanisms and corresponding therapeutic innovations.</p><p><strong>Results: </strong>gMG subtypes-characterized by autoantibody profiles (AChR, MuSK, LRP4, or seronegative), thymic histopathology, and age of onset-demonstrate distinct immunological pathways. Early-onset MG is associated with thymic hyperplasia and Th17-driven inflammation; thymoma-associated MG involves central tolerance breakdown; late-onset MG shows immune senescence and altered T-cell regulation. MuSK- and LRP4-positive MG exhibit unique cytokine and antibody signatures. Novel therapeutic strategies include B cell- and T cell-targeted therapies (e.g., anti-CD19, anti-CD38, JAK inhibitors), cytokine inhibitors (IL-6, IL-17, IL-23), FcRn antagonists, complement inhibitors, and gene- or cell-based therapies such as CAR-T and CAAR-T cells.</p><p><strong>Conclusion: </strong>The evolving landscape of gMG treatment reflects a shift toward immunopathology-based precision medicine. Better characterization of subtype-specific molecular signatures and immune dysfunctions is essential to guide clinical decision-making and improve outcomes for treatment-refractory patients.</p>","PeriodicalId":9095,"journal":{"name":"Brain Sciences","volume":"15 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Botulinum Toxin: An Unconventional Tool for the Treatment of Depression?","authors":"Matteo Gambini, Riccardo Gurrieri, Gerardo Russomanno, Gianmatteo Cecchini, Federico Mucci, Manuel Glauco Carbone, Donatella Marazziti","doi":"10.3390/brainsci15090971","DOIUrl":"10.3390/brainsci15090971","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Major depressive disorder (MDD) represents a leading cause of global disability, with approximately one-third of patients exhibiting treatment resistance (TRD) despite adequate pharmacological interventions. This treatment gap underscores the urgent need for novel therapeutic strategies. Recently, a series of data suggests that botulinum neurotoxin of type A (BoNT-A), traditionally used for neuromuscular and cosmetic indications, could constitute a potential antidepressant tool. This narrative review critically examines the current preclinical and clinical findings of BoNT-A in MDD. <b>Methods:</b> A comprehensive search of PubMed, Scopus, and Web of Science was conducted up to June 2025, including randomized controlled trials, observational studies, animal models, and mechanistic investigations. Search terms included \"Botulinum Toxin,\" \"BoNT type A\", \"Depression\", \"Major Depressive Disorder\", \"Facial Feedback\", and \"Neurobiology\". <b>Results:</b> Some randomized and observational studies would indicate that glabellar BoNT-A injections might lead to significant reductions in depressive symptoms in patients with MDD and TRD. Proposed mechanisms include both peripheral modulation of emotional expression and brain effects, such as reduced amygdala hyperactivity, increased BDNF expression, and enhanced monoaminergic transmission. Preclinical studies confirm that BoNT-A modulates limbic and brainstem circuits, possibly implicated in affective regulation. The few comparative studies suggest therapeutic efficacy comparable to that of SSRIs, with a more rapid onset. Preliminary data also support its application in bipolar depression and comorbid anxiety disorders. <b>Conclusions</b>: The available literature would indicate that BoNT-A might constitute a promising candidate at least as an adjunctive treatment in MDD, although the impact of current findings is limited due to the methodological heterogeneity and the small sample sizes of patients examined. Further large-scale, placebo-controlled trials are warranted to elucidate the mode of action of BoNT-A and to validate or not its clinical effectiveness.</p>","PeriodicalId":9095,"journal":{"name":"Brain Sciences","volume":"15 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}