After spinal cord injury,impairment of the sensorimotor circuit can lead to dysfunction in the motor,sensory,proprioceptive,and autonomic nervous systems.Functional recovery is often hindered by constraints on the tim...After spinal cord injury,impairment of the sensorimotor circuit can lead to dysfunction in the motor,sensory,proprioceptive,and autonomic nervous systems.Functional recovery is often hindered by constraints on the timing of interventions,combined with the limitations of current methods.To address these challenges,various techniques have been developed to aid in the repair and reconstruction of neural circuits at different stages of injury.Notably,neuromodulation has garnered considerable attention for its potential to enhance nerve regeneration,provide neuroprotection,restore neurons,and regulate the neural reorganization of circuits within the cerebral cortex and corticospinal tract.To improve the effectiveness of these interventions,the implementation of multitarget early interventional neuromodulation strategies,such as electrical and magnetic stimulation,is recommended to enhance functional recovery across different phases of nerve injury.This review concisely outlines the challenges encountered following spinal cord injury,synthesizes existing neurostimulation techniques while emphasizing neuroprotection,repair,and regeneration of impaired connections,and advocates for multi-targeted,task-oriented,and timely interventions.展开更多
Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as ...Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as deep brain stimulation and transcranial magnetic stimulation,show limitations such as invasiveness,restricted cortical targeting,and irreversible tissue effects.In this context,low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity.This review comprehensively assesses the therapeutic mechanisms,efficacy,and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases,with emphasis on its role in promoting neuronal regeneration,modulating neuroinflammation,and enhancing functional recovery.We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms,enhancing neural repair and regeneration,and alleviating symptoms associated with neurodegenerative diseases.Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors(e.g.,brain-derived neurotrophic factor),promote autophagy to clear protein aggregates,modulate microglial activation,and temporarily open the blood-brain barrier to facilitate targeted drug delivery.Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-βplaques,improve motor and cognitive deficits,and promote remyelination in various disease models.Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer’s disease and alleviate motor symptoms in Parkinson’s disease,all while demonstrating a favorable safety profile.Past studies support the notion that by integrating safety,precision,and reversibility,low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease.However,more advancements are necessary for future clinical application of low-intensity transcranial ultrasound,including optimizing parameters such as frequency,intensity,and duty cycle;considering individual anatomical differences;and confirming long-term efficacy.We believe establishing standardized protocols,conducting larger trials,and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard.Future research should focus on translating preclinical findings into clinical practice,addressing technical challenges,and exploring combination therapies with pharmacological or gene interventions.展开更多
Machado-Joseph disease,or spinocerebellar ataxia type 3(SCA3),represents the most common autosomal dominant cerebellar ataxia worldwide.Despite its progressive and debilitating nature,disease-modifying therapies remai...Machado-Joseph disease,or spinocerebellar ataxia type 3(SCA3),represents the most common autosomal dominant cerebellar ataxia worldwide.Despite its progressive and debilitating nature,disease-modifying therapies remain elusive.Repetitive transcranial magnetic stimulation(rTMS)has emerged as a promising non-invasive intervention;however,its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding.A recent landmark study published in Brain Stimulation by Chen et al.addressed these challenges by combining a high-dose intermittent theta-burst stimulation(iTBS)protocol with concurrent transcranial magnetic stimulation-electroencephalography(TMS-EEG).This commentary provides an in-depth analysis of their findings,highlighting the restoration of cerebello-cortical inhibition(CBI)as a key therapeutic mechanism.Furthermore,we discuss the broader implications of this work,proposing that future translational research should integrate accelerated iTBS(aiTBS)paradigms,cortical response measurements(CRM),and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.展开更多
Gynandromorphs,rare in vertebrates,exhibit distinct sex-determining gene expression on each side of the body despite sharing a uniform hormonal environment.This provides a unique opportunity to investigate the respect...Gynandromorphs,rare in vertebrates,exhibit distinct sex-determining gene expression on each side of the body despite sharing a uniform hormonal environment.This provides a unique opportunity to investigate the respective roles of genes and hormones in sex determination.We accidently obtained a gynandromorphic Zebra Finch with a male-female chimeric appearance but only with an ovary-like gonad.Its plasma estradiol was significantly higher than that of age-matched females,and its sexual partner preference was also feminine.Although it did not sing like males,its calls showed masculinization.In the brain on one side of the body with male plumage,the area of song motor nucleus,the robust nucleus of the arcopallium(RA),and the excitatory synaptic transmission of RA projection neurons showed masculinization.Transcriptome analysis revealed that genes related to cholinergic neuron function were significantly upregulated in the masculinized side of brain.Moreover,there were extensive and consistent expression differences of neuroactive substance receptor genes in both sides of body,indicating that cell-autonomous determination plays a key role in sex dimorphism of neuromodulation.展开更多
Ultrasound neuromodulation shows promise for treating neurological disorders,but the underlying mechanisms remain unclear.Here,we developed an integrated surface acoustic wave(SAW)ultrasound chip enabling simultaneous...Ultrasound neuromodulation shows promise for treating neurological disorders,but the underlying mechanisms remain unclear.Here,we developed an integrated surface acoustic wave(SAW)ultrasound chip enabling simultaneous electrophysiological recording and Ca^(2+) imaging of cultured hippocampal neurons to investigate neuronal excitability and synaptic transmission during ultrasound stimulation.This study revealed,for the first time,three distinct neuronal response patterns induced by SAW ultrasound:an immediate response showing rapid activation,a delayed response exhibiting facilitation after several minutes,and a non-response maintaining baseline activity.Ultrasound stimulation increased action potential firing,enhanced excitatory postsynaptic currents,and elevated intracellular Ca^(2+) levels.These effects were dependent on extracellular Ca^(2+) influx and primarily dominated by L-type Ca^(2+) channels.Our findings suggest that individual neurons exhibit heterogeneous responses to SAW ultrasound stimulation based on their intracellular Ca^(2+) levels and L-type Ca^(2+) channel activity.This integrated approach provides new insights into the cellular mechanisms of ultrasound neuromodulation while highlighting the potential of SAW technology for precise,cell-type-specific neural control.展开更多
Spinal cord injury is a severe neurological disorder;however,current treatment methods often fail to restore nerve function effectively.Spinal cord stimulation via electrical signals is a promising therapeutic modalit...Spinal cord injury is a severe neurological disorder;however,current treatment methods often fail to restore nerve function effectively.Spinal cord stimulation via electrical signals is a promising therapeutic modality for spinal cord injury.Based on similar principles,this review aims to explore the potential of optical and acoustic neuromodulation techniques,emphasizing their benefits in the context of spinal cord injury.Photoacoustic imaging,renowned for its noninvasive nature,high-resolution capabilities,and cost-effectiveness,is well recognized for its role in early diagnosis,dynamic monitoring,and surgical guidance in stem cell therapies for spinal cord injury.Moreover,photoacoustodynamic therapy offers multiple pathways for tissue regeneration.Optogenetics and sonogenetics use genetic engineering to achieve precise neuronal activation,while photoacoustoelectric therapy leverages photovoltaic materials for electrical modulation of the nervous system,introducing an innovative paradigm for nerve system disorder management.Collectively,these advancements represent a transformative shift in the diagnosis and treatment of spinal cord injury,with the potential to significantly enhance nerve function remodeling and improve patient outcomes.展开更多
Ultrasound neuromodulation offers a non-invasive approach to modulate neural activity in the central nervous system.Precise,minimally invasive devices capable of targeted stimulation remain limited.A 200μm diameter f...Ultrasound neuromodulation offers a non-invasive approach to modulate neural activity in the central nervous system.Precise,minimally invasive devices capable of targeted stimulation remain limited.A 200μm diameter fiber-optic photoacoustic emitter(FPE)was developed,coated with a MXene(Ti3C2Tx)and polydimethylsiloxane composite to generate controllable,broadband ultrasonic waves with high spatial precision.Using this FPE to stimulate the medial prefrontal cortex in mice,it was observed marked alleviation of acute social defeat stress-induced emotional stress,evidenced by reduced anxiety-like behavior and increased social interaction.This approach enables near-field,broadband,and tunable ultrasound neuromodulation with potential applications in treating neuropsychiatric disorders involving emotional regulation.展开更多
Spontaneous recovery frequently proves maladaptive or insufficient because the plasticity of the injured adult mammalian central nervous system is limited.This limited plasticity serves as a primary barrier to functio...Spontaneous recovery frequently proves maladaptive or insufficient because the plasticity of the injured adult mammalian central nervous system is limited.This limited plasticity serves as a primary barrier to functional recovery after brain injury.Neuromodulation technologies represent one of the fastest-growing fields in medicine.These techniques utilize electricity,magnetism,sound,and light to restore or optimize brain functions by promoting reorganization or long-term changes that support functional recovery in patients with brain injury.Therefore,this review aims to provide a comprehensive overview of the effects and underlying mechanisms of neuromodulation technologies in supporting motor function recovery after brain injury.Many of these technologies are widely used in clinical practice and show significant improvements in motor function across various types of brain injury.However,studies report negative findings,potentially due to variations in stimulation protocols,differences in observation periods,and the severity of functional impairments among participants across different clinical trials.Additionally,we observed that different neuromodulation techniques share remarkably similar mechanisms,including promoting neuroplasticity,enhancing neurotrophic factor release,improving cerebral blood flow,suppressing neuroinflammation,and providing neuroprotection.Finally,considering the advantages and disadvantages of various neuromodulation techniques,we propose that future development should focus on closed-loop neural circuit stimulation,personalized treatment,interdisciplinary collaboration,and precision stimulation.展开更多
Current pharmacotherapy for neurodegenerative diseases is limited to providing symptomatic relief,instead of slowing or reversing disease progression.As a form of neuromodulation surgery,deep brain stimulation deliver...Current pharmacotherapy for neurodegenerative diseases is limited to providing symptomatic relief,instead of slowing or reversing disease progression.As a form of neuromodulation surgery,deep brain stimulation delivers electrical pulses thro ugh implanted electrodes in targeted brain regions and has been used to alleviate symptoms in neurodegenerative diseases.Depending on the precise targeting of neural modulation,deep brain stimulation is being explo red for its potential to manage symptoms and improve overall quality of life in neurodegenerative diseases associated with cognitive impairment,such as Alzheimer's disease and dementia in Parkinson's disease.The nucleus basalis of Meynert,a critical component of the cerebral cholinergic system and the Papez circuit,is considered as a promising target for treating cognitive dysfunction in neurodegenerative diseases due to its essential role in regulating cognition,memory,and attention.However,the comprehensive mechanisms by which deep brain stimulation of nucleus basalis of Meynert affects neurodegenerative diseases with cognitive impairment remain largely unchara cterized.Nonetheless,various hypotheses and evidence from animal and clinical studies suggest mechanisms such as the modeulation of the choline rgic system,increased glucose metabolism and regional cerebral blood flow,neuroprotective effects,and the modulation of neural networks.In this review,we update the advances in research rega rding the therapeutic effects and potential mechanisms of deep brain stimulation of nucleus basalis of Meynert on cognitive impairment in neurodegenerative diseases.Additionally,we examine the anatomy,connectivity,and physiological functions of the nucleus basalis of M eynert.Deep brain stimulation of nucleus basalis of Meynert may improve cognitive impairment in neurodegenerative diseases through multiple mechanisms;howeve r,further larger-scale,multi-center clinical trials conducted at earlier disease stages are necessary to fully confirm its efficacy and safety.展开更多
Deep brain sti mulation(DBS)is a neuromodulation tool that involves the delivery of electrical impulses to specific brain regions through implanted electrodes.The principle behind DBS is to modulate dysfunctional neur...Deep brain sti mulation(DBS)is a neuromodulation tool that involves the delivery of electrical impulses to specific brain regions through implanted electrodes.The principle behind DBS is to modulate dysfunctional neural circuits without the need for permanent structural alterations to the brain.Initially developed as a treatment for movement disorders such as Parkinson's disease(PD),DBS has expanded to encompass various neurological and psychiatric disorders.展开更多
Gastroparesis is a severe diabetic complication,caused by a progressive multifactorial enteric neuropathy.To make an early diagnosis in patients at risk of diabetic gastroparesis is crucial for slow down its progressi...Gastroparesis is a severe diabetic complication,caused by a progressive multifactorial enteric neuropathy.To make an early diagnosis in patients at risk of diabetic gastroparesis is crucial for slow down its progression towards full-blown disease source of further complications and requesting effective,but unsafe,drugs as well as invasive surgical treatments.This aim can be achieved by detecting its first signal represented by the gastric emptying(GE)delay,by using,among the tests to measure GE,the simple,safe,reliable,and easily available one,that is realtime ultrasonography,possibly done annually.Once the GE delay has been identified,it is necessary to evaluate with endoluminal functional lumen imaging probe or manometry whether it depends on pylorospasm,which should be treated by means of non-surgical endoscopic therapies.If,instead,it depends on initial gastropathy,detected by electrogastrograhic body surface gastric mapping,it should be treated with the safest prokinetic drugs and with the newly emerging treatments,thus distancing heavy medical and surgical treatments,while waiting for future solutions.展开更多
Neuromodulation for diabetic peripheral neuropathy represents a significant area of interest in the management of chronic pain associated with this condition.Diabetic peripheral neuropathy,a common complication of dia...Neuromodulation for diabetic peripheral neuropathy represents a significant area of interest in the management of chronic pain associated with this condition.Diabetic peripheral neuropathy,a common complication of diabetes,is characterized by nerve damage due to high blood sugar levels that lead to symptoms,such as pain,tingling,and numbness,primarily in the hands and feet.The aim of this systematic review was to evaluate the efficacy of neuromodulatory techniques as potential therapeutic interventions for patients with diabetic peripheral neuropathy,while also examining recent developments in this domain.The investigation encompassed an array of neuromodulation methods,including frequency rhythmic electrical modulated systems,dorsal root ganglion stimulation,and spinal cord stimulation.This systematic review suggests that neuromodulatory techniques may be useful in the treatment of diabetic peripheral neuropathy.Understanding the advantages of these treatments will enable physicians and other healthcare providers to offer additional options for patients with symptoms refractory to standard pharmacologic treatments.Through these efforts,we may improve quality of life and increase functional capacity in patients suffering from complications related to diabetic neuropathy.展开更多
Fecal incontinence is a common condition that can significantly impact patients’quality of life.Obstetric anal sphincter injury and anorectal surgeries are common etiologies.Endoanal ultrasound and anorectal manometr...Fecal incontinence is a common condition that can significantly impact patients’quality of life.Obstetric anal sphincter injury and anorectal surgeries are common etiologies.Endoanal ultrasound and anorectal manometry are important diagnostic tools for evaluating patients.There are various treatment options,including diet,lifestyle modifications,drugs,biofeedback therapy,tibial and sacral nerve neuromodulation therapy,and surgery.In this editorial,we will discuss current controversies and novel approaches to fecal incontinence.Screening for asymptomatic anal sphincter defects after obstetric anal sphincter injury and in patients with inflammatory bowel disease is not generally recommended,but may be helpful in selected patients.The Garg incontinence score is a new score that includes the assessment of solid,liquid,flatus,mucous,stress and urge fecal incontinence.Novel tests such as translumbosacral anorectal magnetic stimulation and novel therapies such as translumbosacral neuromodulation therapy are promising diagnostic and treatment options,for both fecal incontinence and neuropathy.Home biofeedback therapy can overcome some limitations of the office-based therapy.Skeletal muscle-derived cell implantation of the external anal sphincter has been further studied as a possible treatment option.Sacral neuromodulation may be useful in scleroderma,congenital fecal incontinence and inflammatory bowel disease but merits further study.展开更多
Retinal aging has been recognized as a significant risk factor for various retinal disorders,including diabetic retinopathy,age-related macular degeneration,and glaucoma,following a growing understanding of the molecu...Retinal aging has been recognized as a significant risk factor for various retinal disorders,including diabetic retinopathy,age-related macular degeneration,and glaucoma,following a growing understanding of the molecular underpinnings of their development.This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches,focusing on the activation of transcription factor EB.Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies,such as exercise,calorie restriction,rapamycin,and metformin,in patients and animal models of these common retinal diseases.The review critically assesses the role of transcription factor EB in retinal biology during aging,its neuroprotective effects,and its therapeutic potential for retinal disorders.The impact of transcription factor EB on retinal aging is cell-specific,influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways.In vascular endothelial cells,transcription factor EB controls important processes,including endothelial cell proliferation,endothelial tube formation,and nitric oxide levels,thereby influencing the inner blood-retinal barrier,angiogenesis,and retinal microvasculature.Additionally,transcription factor EB affects vascular smooth muscle cells,inhibiting vascular calcification and atherogenesis.In retinal pigment epithelial cells,transcription factor EB modulates functions such as autophagy,lysosomal dynamics,and clearance of the aging pigment lipofuscin,thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization.These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis,neuronal synapse plasticity,energy metabolism,microvasculature,and inflammation,ultimately offering protection against retinal aging and diseases.The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases.Therefore,it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.展开更多
Neurite outgrowth and synapse formation constitute the cellular basis for the establishment and plasticity of neural networks,crucially involved in cognitive functions.However,the techniques currently available to eff...Neurite outgrowth and synapse formation constitute the cellular basis for the establishment and plasticity of neural networks,crucially involved in cognitive functions.However,the techniques currently available to effectively and specifically modulate these processes remain limited.In this work,we propose a non-drug and non-thermal terahertz(THz)photon modulation approach that enhances neuronal growth and synaptogenesis.Frequency screening experiments show that 34.5 THz photon stimulation could effectively promote neurite elongation and postsynaptic density protein 95(PSD95)expression by 26.0%in rat hippocampal neurons.Subsequent cellular experiments reveal an upregulation of the cyclic adenosine monophosphate(cAMP)signaling pathway and adenylyl cyclase type 1(AC1)activity after 34.5 THz photon irradiation.Molecular dynamics simulations suggest that 34.5 THz photons promote the binding between AC1 and ligand,accelerating cAMP generation.In vivo experiments further confirm an increase in hippocampal cAMP levels and dendritic spine density after THz photon stimulation,accompanied by a significant improvement in cognitive performance.Overall,our results suggest THz photon stimulation as an effective and specific method for neuromodulation,promising for future applications in the treatment of cognitive dysfunction.展开更多
Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Cu...Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.展开更多
Zhang et al delivered a paradigm-shifting understanding of electroacupuncture(EA)’s action in diabetic gastroparesis through a well-defined vagal pathway.Their work bridged traditional acupuncture and modern neurogas...Zhang et al delivered a paradigm-shifting understanding of electroacupuncture(EA)’s action in diabetic gastroparesis through a well-defined vagal pathway.Their work bridged traditional acupuncture and modern neurogastroenterology,highlighting EA as a viable strategy for refractory diabetic gastroparesis.The study integrated electrophysiology(gastric slow-wave recordings),functional assays(phenol red gastric emptying,and intestinal propulsion),dynamic positron emission tomography/computed tomography imaging,histopathology,and molecular biology(Western blot,immunofluorescence,and enzyme-linked immunosorbent assay).This comprehensive approach robustly confirmed EA’s efficacy in restoring gastric motility,interstitial cells of Cajal function,and neuropeptide balance.Future studies should prioritize clinical translation and explore synergies with pharmacological agents.展开更多
Depression is a multifaceted disorder with a largely unresolved etiology influenced by a complex interplay of pathogenic factors.Despite decades of research,it remains a major condition that significantly diminishes p...Depression is a multifaceted disorder with a largely unresolved etiology influenced by a complex interplay of pathogenic factors.Despite decades of research,it remains a major condition that significantly diminishes patients’quality of life.Advances in optogenetics have introduced a powerful tool for exploring the neural mechanisms underlying depression.By selectively expressing optogenes in specific cell types in mice,researchers can study the roles of these cells through targeted light stimulation,offering new insights into central nervous system disorders.The use of viral vectors to express opsins in distinct neuronal subtypes enables precise activation or inhibition of these neurons via light.When combined with behavioral,morphological,and electrophysiological analyses,optogenetics provides an invaluable approach to investigating the neural mechanisms of psychiatric conditions.This review synthesizes current research on the application of optogenetics to understand the mechanisms of depression.This study aims to enhance our knowledge of optogenetic strategies for regulating depression and advancing antidepressant research.展开更多
Dysfunction of the interoceptive system is recognized as an important component of clinical symptoms,including anxiety,depression,psychosis,and other mental disorders.Non-invasive neuromodulation is an emerging clinic...Dysfunction of the interoceptive system is recognized as an important component of clinical symptoms,including anxiety,depression,psychosis,and other mental disorders.Non-invasive neuromodulation is an emerging clinical intervention approach,and over the past decade,research on non-invasive neuromodulation aimed at regulating interoception has rapidly developed.This review first outlines the pathways of interoceptive signals and assessment methods,then summarizes the interoceptive abnormalities in psychiatric disorders and current studies for non-invasive neuromodulation targeting interoception,including intervention modes,target sites,interoceptive measures,and potential neurobiological mechanisms.Finally,we discuss significant research challenges and future directions.展开更多
Stroke remains a leading cause of long-term disability worldwide.There is an unmet need for neuromodulatory therapies that can mitigate against neurovascular injury and potentially promote neurological recovery.Transc...Stroke remains a leading cause of long-term disability worldwide.There is an unmet need for neuromodulatory therapies that can mitigate against neurovascular injury and potentially promote neurological recovery.Transcutaneous vagus nerve stimulation has been demonstrated to show potential therapeutic effects in both acute and chronic stroke.However,previously published research has only investigated a narrow range of stimulation settings and indications.In this review,we detail the ongoing studies of transcutaneous vagus nerve stimulation in stroke through systematic searches of registered clinical trials.We summarize the upcoming clinical trials of transcutaneous vagus nerve stimulation in stroke,highlighting their indications,parameter settings,scope,and limitations.We further explore the challenges and barriers associated with the implementation of transcutaneous vagus nerve stimulation in acute stroke and stroke rehabilitation,focusing on critical aspects such as stimulation settings,target groups,biomarkers,and integration with rehabilitation interventions.展开更多
基金supported by the National Key Research and Development Program of China,No.2023YFC3603705(to DX)the National Natural Science Foundation of China,No.82302866(to YZ).
文摘After spinal cord injury,impairment of the sensorimotor circuit can lead to dysfunction in the motor,sensory,proprioceptive,and autonomic nervous systems.Functional recovery is often hindered by constraints on the timing of interventions,combined with the limitations of current methods.To address these challenges,various techniques have been developed to aid in the repair and reconstruction of neural circuits at different stages of injury.Notably,neuromodulation has garnered considerable attention for its potential to enhance nerve regeneration,provide neuroprotection,restore neurons,and regulate the neural reorganization of circuits within the cerebral cortex and corticospinal tract.To improve the effectiveness of these interventions,the implementation of multitarget early interventional neuromodulation strategies,such as electrical and magnetic stimulation,is recommended to enhance functional recovery across different phases of nerve injury.This review concisely outlines the challenges encountered following spinal cord injury,synthesizes existing neurostimulation techniques while emphasizing neuroprotection,repair,and regeneration of impaired connections,and advocates for multi-targeted,task-oriented,and timely interventions.
基金supported by STI2030-Major Project,No,2021ZD0204200(to LX).
文摘Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as deep brain stimulation and transcranial magnetic stimulation,show limitations such as invasiveness,restricted cortical targeting,and irreversible tissue effects.In this context,low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity.This review comprehensively assesses the therapeutic mechanisms,efficacy,and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases,with emphasis on its role in promoting neuronal regeneration,modulating neuroinflammation,and enhancing functional recovery.We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms,enhancing neural repair and regeneration,and alleviating symptoms associated with neurodegenerative diseases.Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors(e.g.,brain-derived neurotrophic factor),promote autophagy to clear protein aggregates,modulate microglial activation,and temporarily open the blood-brain barrier to facilitate targeted drug delivery.Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-βplaques,improve motor and cognitive deficits,and promote remyelination in various disease models.Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer’s disease and alleviate motor symptoms in Parkinson’s disease,all while demonstrating a favorable safety profile.Past studies support the notion that by integrating safety,precision,and reversibility,low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease.However,more advancements are necessary for future clinical application of low-intensity transcranial ultrasound,including optimizing parameters such as frequency,intensity,and duty cycle;considering individual anatomical differences;and confirming long-term efficacy.We believe establishing standardized protocols,conducting larger trials,and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard.Future research should focus on translating preclinical findings into clinical practice,addressing technical challenges,and exploring combination therapies with pharmacological or gene interventions.
基金supported by grants from the Open Research Fund of the Zhejiang Key Laboratory of Precision Psychiatry(2025A2)the Natural Science Foundation of Zhejiang Province(LY23C090002)。
文摘Machado-Joseph disease,or spinocerebellar ataxia type 3(SCA3),represents the most common autosomal dominant cerebellar ataxia worldwide.Despite its progressive and debilitating nature,disease-modifying therapies remain elusive.Repetitive transcranial magnetic stimulation(rTMS)has emerged as a promising non-invasive intervention;however,its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding.A recent landmark study published in Brain Stimulation by Chen et al.addressed these challenges by combining a high-dose intermittent theta-burst stimulation(iTBS)protocol with concurrent transcranial magnetic stimulation-electroencephalography(TMS-EEG).This commentary provides an in-depth analysis of their findings,highlighting the restoration of cerebello-cortical inhibition(CBI)as a key therapeutic mechanism.Furthermore,we discuss the broader implications of this work,proposing that future translational research should integrate accelerated iTBS(aiTBS)paradigms,cortical response measurements(CRM),and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.
基金funded by the National Natural Science Foundation of China(32160123 and 32170974)Jiangxi Provincial Key Project of Natural Science Foundation(20212ACB205002)Jiangxi Provincial Key Laboratory of Organic Functional Molecules(2024SSY05141)。
文摘Gynandromorphs,rare in vertebrates,exhibit distinct sex-determining gene expression on each side of the body despite sharing a uniform hormonal environment.This provides a unique opportunity to investigate the respective roles of genes and hormones in sex determination.We accidently obtained a gynandromorphic Zebra Finch with a male-female chimeric appearance but only with an ovary-like gonad.Its plasma estradiol was significantly higher than that of age-matched females,and its sexual partner preference was also feminine.Although it did not sing like males,its calls showed masculinization.In the brain on one side of the body with male plumage,the area of song motor nucleus,the robust nucleus of the arcopallium(RA),and the excitatory synaptic transmission of RA projection neurons showed masculinization.Transcriptome analysis revealed that genes related to cholinergic neuron function were significantly upregulated in the masculinized side of brain.Moreover,there were extensive and consistent expression differences of neuroactive substance receptor genes in both sides of body,indicating that cell-autonomous determination plays a key role in sex dimorphism of neuromodulation.
基金supported by the National Key Research&Development Program of China(2022YFC3602700,2022YFC3602702)the Science and Technology Innovation 2030-Brain Science and Brain-Inspired Intelligence Project(2021ZD0201301)+2 种基金the National Natural Science Foundation of China(12034015,62088101,32170688,323B1004)Program of Shanghai Academic Research Leader(21XD1403600)Shanghai Municipal Science and Technology Major Project(2021SHZDZX0100,2018SHZDZX01).
文摘Ultrasound neuromodulation shows promise for treating neurological disorders,but the underlying mechanisms remain unclear.Here,we developed an integrated surface acoustic wave(SAW)ultrasound chip enabling simultaneous electrophysiological recording and Ca^(2+) imaging of cultured hippocampal neurons to investigate neuronal excitability and synaptic transmission during ultrasound stimulation.This study revealed,for the first time,three distinct neuronal response patterns induced by SAW ultrasound:an immediate response showing rapid activation,a delayed response exhibiting facilitation after several minutes,and a non-response maintaining baseline activity.Ultrasound stimulation increased action potential firing,enhanced excitatory postsynaptic currents,and elevated intracellular Ca^(2+) levels.These effects were dependent on extracellular Ca^(2+) influx and primarily dominated by L-type Ca^(2+) channels.Our findings suggest that individual neurons exhibit heterogeneous responses to SAW ultrasound stimulation based on their intracellular Ca^(2+) levels and L-type Ca^(2+) channel activity.This integrated approach provides new insights into the cellular mechanisms of ultrasound neuromodulation while highlighting the potential of SAW technology for precise,cell-type-specific neural control.
基金supported by the National Key R&D Program of China,No.2023YFC2509700the Beijing Natural Science Foundation-Haidian Original Innovation Joint Fund,No.L232141the Research and Application of Clinical Characteristic Diagnosis and Treatment Program,No.Z221100007422019(all to WD)。
文摘Spinal cord injury is a severe neurological disorder;however,current treatment methods often fail to restore nerve function effectively.Spinal cord stimulation via electrical signals is a promising therapeutic modality for spinal cord injury.Based on similar principles,this review aims to explore the potential of optical and acoustic neuromodulation techniques,emphasizing their benefits in the context of spinal cord injury.Photoacoustic imaging,renowned for its noninvasive nature,high-resolution capabilities,and cost-effectiveness,is well recognized for its role in early diagnosis,dynamic monitoring,and surgical guidance in stem cell therapies for spinal cord injury.Moreover,photoacoustodynamic therapy offers multiple pathways for tissue regeneration.Optogenetics and sonogenetics use genetic engineering to achieve precise neuronal activation,while photoacoustoelectric therapy leverages photovoltaic materials for electrical modulation of the nervous system,introducing an innovative paradigm for nerve system disorder management.Collectively,these advancements represent a transformative shift in the diagnosis and treatment of spinal cord injury,with the potential to significantly enhance nerve function remodeling and improve patient outcomes.
文摘Ultrasound neuromodulation offers a non-invasive approach to modulate neural activity in the central nervous system.Precise,minimally invasive devices capable of targeted stimulation remain limited.A 200μm diameter fiber-optic photoacoustic emitter(FPE)was developed,coated with a MXene(Ti3C2Tx)and polydimethylsiloxane composite to generate controllable,broadband ultrasonic waves with high spatial precision.Using this FPE to stimulate the medial prefrontal cortex in mice,it was observed marked alleviation of acute social defeat stress-induced emotional stress,evidenced by reduced anxiety-like behavior and increased social interaction.This approach enables near-field,broadband,and tunable ultrasound neuromodulation with potential applications in treating neuropsychiatric disorders involving emotional regulation.
基金supported by the National Natural Science Foundation of China,No.82371399(to YY)the Natural Science Foundation of Jiangsu Province,No.BK20221206(to YY)+1 种基金the Young Elite Scientists Sponsorship Program of Jiangsu Province,No.TJ-2022-028(to YY)the Scientific Research Program of Wuxi Health Commission,No.Z202302(to LY)。
文摘Spontaneous recovery frequently proves maladaptive or insufficient because the plasticity of the injured adult mammalian central nervous system is limited.This limited plasticity serves as a primary barrier to functional recovery after brain injury.Neuromodulation technologies represent one of the fastest-growing fields in medicine.These techniques utilize electricity,magnetism,sound,and light to restore or optimize brain functions by promoting reorganization or long-term changes that support functional recovery in patients with brain injury.Therefore,this review aims to provide a comprehensive overview of the effects and underlying mechanisms of neuromodulation technologies in supporting motor function recovery after brain injury.Many of these technologies are widely used in clinical practice and show significant improvements in motor function across various types of brain injury.However,studies report negative findings,potentially due to variations in stimulation protocols,differences in observation periods,and the severity of functional impairments among participants across different clinical trials.Additionally,we observed that different neuromodulation techniques share remarkably similar mechanisms,including promoting neuroplasticity,enhancing neurotrophic factor release,improving cerebral blood flow,suppressing neuroinflammation,and providing neuroprotection.Finally,considering the advantages and disadvantages of various neuromodulation techniques,we propose that future development should focus on closed-loop neural circuit stimulation,personalized treatment,interdisciplinary collaboration,and precision stimulation.
基金National Key Project of Common and Frequently Occurring Diseases,No.2022YFC25038001the National Natural Science Foundation of China,Nos.82472100,81974279the Natural Science Foundation of Hubei Province,No.2022CFB279(all to HK)。
文摘Current pharmacotherapy for neurodegenerative diseases is limited to providing symptomatic relief,instead of slowing or reversing disease progression.As a form of neuromodulation surgery,deep brain stimulation delivers electrical pulses thro ugh implanted electrodes in targeted brain regions and has been used to alleviate symptoms in neurodegenerative diseases.Depending on the precise targeting of neural modulation,deep brain stimulation is being explo red for its potential to manage symptoms and improve overall quality of life in neurodegenerative diseases associated with cognitive impairment,such as Alzheimer's disease and dementia in Parkinson's disease.The nucleus basalis of Meynert,a critical component of the cerebral cholinergic system and the Papez circuit,is considered as a promising target for treating cognitive dysfunction in neurodegenerative diseases due to its essential role in regulating cognition,memory,and attention.However,the comprehensive mechanisms by which deep brain stimulation of nucleus basalis of Meynert affects neurodegenerative diseases with cognitive impairment remain largely unchara cterized.Nonetheless,various hypotheses and evidence from animal and clinical studies suggest mechanisms such as the modeulation of the choline rgic system,increased glucose metabolism and regional cerebral blood flow,neuroprotective effects,and the modulation of neural networks.In this review,we update the advances in research rega rding the therapeutic effects and potential mechanisms of deep brain stimulation of nucleus basalis of Meynert on cognitive impairment in neurodegenerative diseases.Additionally,we examine the anatomy,connectivity,and physiological functions of the nucleus basalis of M eynert.Deep brain stimulation of nucleus basalis of Meynert may improve cognitive impairment in neurodegenerative diseases through multiple mechanisms;howeve r,further larger-scale,multi-center clinical trials conducted at earlier disease stages are necessary to fully confirm its efficacy and safety.
文摘Deep brain sti mulation(DBS)is a neuromodulation tool that involves the delivery of electrical impulses to specific brain regions through implanted electrodes.The principle behind DBS is to modulate dysfunctional neural circuits without the need for permanent structural alterations to the brain.Initially developed as a treatment for movement disorders such as Parkinson's disease(PD),DBS has expanded to encompass various neurological and psychiatric disorders.
文摘Gastroparesis is a severe diabetic complication,caused by a progressive multifactorial enteric neuropathy.To make an early diagnosis in patients at risk of diabetic gastroparesis is crucial for slow down its progression towards full-blown disease source of further complications and requesting effective,but unsafe,drugs as well as invasive surgical treatments.This aim can be achieved by detecting its first signal represented by the gastric emptying(GE)delay,by using,among the tests to measure GE,the simple,safe,reliable,and easily available one,that is realtime ultrasonography,possibly done annually.Once the GE delay has been identified,it is necessary to evaluate with endoluminal functional lumen imaging probe or manometry whether it depends on pylorospasm,which should be treated by means of non-surgical endoscopic therapies.If,instead,it depends on initial gastropathy,detected by electrogastrograhic body surface gastric mapping,it should be treated with the safest prokinetic drugs and with the newly emerging treatments,thus distancing heavy medical and surgical treatments,while waiting for future solutions.
文摘Neuromodulation for diabetic peripheral neuropathy represents a significant area of interest in the management of chronic pain associated with this condition.Diabetic peripheral neuropathy,a common complication of diabetes,is characterized by nerve damage due to high blood sugar levels that lead to symptoms,such as pain,tingling,and numbness,primarily in the hands and feet.The aim of this systematic review was to evaluate the efficacy of neuromodulatory techniques as potential therapeutic interventions for patients with diabetic peripheral neuropathy,while also examining recent developments in this domain.The investigation encompassed an array of neuromodulation methods,including frequency rhythmic electrical modulated systems,dorsal root ganglion stimulation,and spinal cord stimulation.This systematic review suggests that neuromodulatory techniques may be useful in the treatment of diabetic peripheral neuropathy.Understanding the advantages of these treatments will enable physicians and other healthcare providers to offer additional options for patients with symptoms refractory to standard pharmacologic treatments.Through these efforts,we may improve quality of life and increase functional capacity in patients suffering from complications related to diabetic neuropathy.
文摘Fecal incontinence is a common condition that can significantly impact patients’quality of life.Obstetric anal sphincter injury and anorectal surgeries are common etiologies.Endoanal ultrasound and anorectal manometry are important diagnostic tools for evaluating patients.There are various treatment options,including diet,lifestyle modifications,drugs,biofeedback therapy,tibial and sacral nerve neuromodulation therapy,and surgery.In this editorial,we will discuss current controversies and novel approaches to fecal incontinence.Screening for asymptomatic anal sphincter defects after obstetric anal sphincter injury and in patients with inflammatory bowel disease is not generally recommended,but may be helpful in selected patients.The Garg incontinence score is a new score that includes the assessment of solid,liquid,flatus,mucous,stress and urge fecal incontinence.Novel tests such as translumbosacral anorectal magnetic stimulation and novel therapies such as translumbosacral neuromodulation therapy are promising diagnostic and treatment options,for both fecal incontinence and neuropathy.Home biofeedback therapy can overcome some limitations of the office-based therapy.Skeletal muscle-derived cell implantation of the external anal sphincter has been further studied as a possible treatment option.Sacral neuromodulation may be useful in scleroderma,congenital fecal incontinence and inflammatory bowel disease but merits further study.
基金supported by the Start-up Fund for new faculty from the Hong Kong Polytechnic University(PolyU)(A0043215)(to SA)the General Research Fund and Research Impact Fund from the Hong Kong Research Grants Council(15106018,R5032-18)(to DYT)+1 种基金the Research Center for SHARP Vision in PolyU(P0045843)(to SA)the InnoHK scheme from the Hong Kong Special Administrative Region Government(to DYT).
文摘Retinal aging has been recognized as a significant risk factor for various retinal disorders,including diabetic retinopathy,age-related macular degeneration,and glaucoma,following a growing understanding of the molecular underpinnings of their development.This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches,focusing on the activation of transcription factor EB.Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies,such as exercise,calorie restriction,rapamycin,and metformin,in patients and animal models of these common retinal diseases.The review critically assesses the role of transcription factor EB in retinal biology during aging,its neuroprotective effects,and its therapeutic potential for retinal disorders.The impact of transcription factor EB on retinal aging is cell-specific,influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways.In vascular endothelial cells,transcription factor EB controls important processes,including endothelial cell proliferation,endothelial tube formation,and nitric oxide levels,thereby influencing the inner blood-retinal barrier,angiogenesis,and retinal microvasculature.Additionally,transcription factor EB affects vascular smooth muscle cells,inhibiting vascular calcification and atherogenesis.In retinal pigment epithelial cells,transcription factor EB modulates functions such as autophagy,lysosomal dynamics,and clearance of the aging pigment lipofuscin,thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization.These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis,neuronal synapse plasticity,energy metabolism,microvasculature,and inflammation,ultimately offering protection against retinal aging and diseases.The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases.Therefore,it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.
基金financially supported by National Natural Science Foundation of China Major Program No.T2241002National Science Fund for Distinguished Young Scholars No.12225511New Cornerstone Science Foundation through the Xplore Prize No.2020–1023.
文摘Neurite outgrowth and synapse formation constitute the cellular basis for the establishment and plasticity of neural networks,crucially involved in cognitive functions.However,the techniques currently available to effectively and specifically modulate these processes remain limited.In this work,we propose a non-drug and non-thermal terahertz(THz)photon modulation approach that enhances neuronal growth and synaptogenesis.Frequency screening experiments show that 34.5 THz photon stimulation could effectively promote neurite elongation and postsynaptic density protein 95(PSD95)expression by 26.0%in rat hippocampal neurons.Subsequent cellular experiments reveal an upregulation of the cyclic adenosine monophosphate(cAMP)signaling pathway and adenylyl cyclase type 1(AC1)activity after 34.5 THz photon irradiation.Molecular dynamics simulations suggest that 34.5 THz photons promote the binding between AC1 and ligand,accelerating cAMP generation.In vivo experiments further confirm an increase in hippocampal cAMP levels and dendritic spine density after THz photon stimulation,accompanied by a significant improvement in cognitive performance.Overall,our results suggest THz photon stimulation as an effective and specific method for neuromodulation,promising for future applications in the treatment of cognitive dysfunction.
基金supported by the National Natural Science Foundation of China,No.82071254(to WZ).
文摘Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.
文摘Zhang et al delivered a paradigm-shifting understanding of electroacupuncture(EA)’s action in diabetic gastroparesis through a well-defined vagal pathway.Their work bridged traditional acupuncture and modern neurogastroenterology,highlighting EA as a viable strategy for refractory diabetic gastroparesis.The study integrated electrophysiology(gastric slow-wave recordings),functional assays(phenol red gastric emptying,and intestinal propulsion),dynamic positron emission tomography/computed tomography imaging,histopathology,and molecular biology(Western blot,immunofluorescence,and enzyme-linked immunosorbent assay).This comprehensive approach robustly confirmed EA’s efficacy in restoring gastric motility,interstitial cells of Cajal function,and neuropeptide balance.Future studies should prioritize clinical translation and explore synergies with pharmacological agents.
基金funded by the Natural Science Foundation of China(No.82305049).
文摘Depression is a multifaceted disorder with a largely unresolved etiology influenced by a complex interplay of pathogenic factors.Despite decades of research,it remains a major condition that significantly diminishes patients’quality of life.Advances in optogenetics have introduced a powerful tool for exploring the neural mechanisms underlying depression.By selectively expressing optogenes in specific cell types in mice,researchers can study the roles of these cells through targeted light stimulation,offering new insights into central nervous system disorders.The use of viral vectors to express opsins in distinct neuronal subtypes enables precise activation or inhibition of these neurons via light.When combined with behavioral,morphological,and electrophysiological analyses,optogenetics provides an invaluable approach to investigating the neural mechanisms of psychiatric conditions.This review synthesizes current research on the application of optogenetics to understand the mechanisms of depression.This study aims to enhance our knowledge of optogenetic strategies for regulating depression and advancing antidepressant research.
基金supported by grants from the National Natural Science Foundation of China(82101582)the Shanghai Science and Technology Committee(22Y11903600 and 23Y11906000)the Shanghai Municipal Health Commission(202240266).
文摘Dysfunction of the interoceptive system is recognized as an important component of clinical symptoms,including anxiety,depression,psychosis,and other mental disorders.Non-invasive neuromodulation is an emerging clinical intervention approach,and over the past decade,research on non-invasive neuromodulation aimed at regulating interoception has rapidly developed.This review first outlines the pathways of interoceptive signals and assessment methods,then summarizes the interoceptive abnormalities in psychiatric disorders and current studies for non-invasive neuromodulation targeting interoception,including intervention modes,target sites,interoceptive measures,and potential neurobiological mechanisms.Finally,we discuss significant research challenges and future directions.
基金an Association of British Neurologists Doctoral Research Fellowship co-funded by the Berkeley Foundation and the Stroke Associationsupported by a NIHR Academic Clinical Lectureship in Neurology CL-2020-04-004 NIHR+3 种基金supported by the NIHR Sheffield Biomedical Research Centre(BRC)NIHR Sheffield Clinical Research Facility(CRF)supported by NIHR EME Project Grant NIHR133169funded by Alzheimer’s Research UK Senior Research Fellowship(ARUK-SRF2017B-1)。
文摘Stroke remains a leading cause of long-term disability worldwide.There is an unmet need for neuromodulatory therapies that can mitigate against neurovascular injury and potentially promote neurological recovery.Transcutaneous vagus nerve stimulation has been demonstrated to show potential therapeutic effects in both acute and chronic stroke.However,previously published research has only investigated a narrow range of stimulation settings and indications.In this review,we detail the ongoing studies of transcutaneous vagus nerve stimulation in stroke through systematic searches of registered clinical trials.We summarize the upcoming clinical trials of transcutaneous vagus nerve stimulation in stroke,highlighting their indications,parameter settings,scope,and limitations.We further explore the challenges and barriers associated with the implementation of transcutaneous vagus nerve stimulation in acute stroke and stroke rehabilitation,focusing on critical aspects such as stimulation settings,target groups,biomarkers,and integration with rehabilitation interventions.
