Towards frequency adaptation for delayed feedback deep brain stimulations

In neurodegenerative disorders such as Parkinson＇s disease （PD）, deep brain stimulation （DBS） is a desirable approach when the medication is less effective for treating the symptoms. DBS incorporates transferring electrical pulses to a specific tissue of the central nervous system, obtaining therapeutic results by modulating the neuronal activity of that region. DBS has certain advantages such as reversibility and adjustability features over medication, since the neuronal firing patterns can be recorded and used to alter the parameters of the DBS signal （Benabid et al., 2009）. One of the DBS indications is its ability to suppress the abnormal neuronal activity to treat symptoms like tremor, akinesia and dystonia.

Outcomes in spasticity after repetitive transcranial magnetic and transcranial direct current stimulations

Non-invasive brain stimulations mainly consist of repetitive transcranial magnetic stimulation and transcranial direct current stimulation. Repetitive transcranial magnetic stimulation exhib- its satisfactory outcomes in improving multiple sclerosis, stroke, spinal cord injury and cerebral palsy-induced spasticity. By contrast, transcranial direct current stimulation has only been studied in post-stroke spasticity. To better validate the efficacy of non-invasive brain stimulations in im- proving the spasticity post-stroke, more prospective cohort studies involving large sample sizes are needed.

Effects of Electric Stimulations Applied during Absolute Refractory Period on Cardiac Function of Rabbits with Heart Failure

The effects of electric currents applied during absolute refractory period （ARP） on the cardiac function of rabbits with heart failure due to myocardial infarction （MI）, and the safety of this method were investigated. Thirty rabbits were randomly assigned equally to 3 groups： sham-operated group, LV-anterior wall cardiac contractility modulation （LV-CCM） group, and septum-CCM （S-CCM） group. A thoracotomy was performed on all the rabbits. Electric pulses were delivered during the ARP on the anterior wall of left ventricle in CCM group and in the septum in S-CCM group, respectively. The left ventricular systolic pressure （LVSP） and maximum positive left ventricular pressure change （＋dp/dtmax）, heart rates, ventricular tachycardia, ventricular fibrillation were observed. It was found that, as compared with the baseline, LVSP, and ＋dp/dtmax were significantly increased, on average, by 15.2% and 19.5% in LV-CCM group （P〈0,05）, and by 8.5% and 10.8% in S-CCM group （P〈0.05）. LVEDP was significantly decreased and -dp/dtmx increased both in LV-CCM group and S-CCM group （P〈0.05）. CCM had no effect on heart rate and induced no arrhythmia in short time. It is concluded that electric currents delivered during the ARP could significantly enhance the contractility of myocardium safely, suggesting that CCM stimulation is a novel potent method for contractility modulation.

Extrinsic sound stimulations and development of periphery auditory synapses

The development of auditory synapses is a key process for the maturation of heating function. However, it is still on debate regaralng wnemer the development of auditory synapses is dominated by acquired sound stimulations. In this review, we summarize relevant publications in recent decades to address this issue. Most reported data suggest that extrinsic sound stimulations do affect, but not govern the development of periphery auditory synapses. Overall, periphery auditory synapses develop and mature according to its intrinsic mechanism to build up the synaptic connections between sensory neurons and/or interneurons.

High-Performance Magnetic-core Coils for Targeted Rodent Brain Stimulations

Objective and Impact Statement.There is a need to develop rodent coils capable of targeted brain stimulation for treating neuropsychiatric disorders and understanding brain mechanisms.We describe a novel rodent coil design to improve the focality for targeted stimulations in small rodent brains.Introduction.Transcranial magnetic stimulation(TMS)is becoming increasingly important for treating neuropsychiatric disorders and understanding brain mechanisms.Preclinical studies permit invasive manipulations and are essential for the mechanistic understanding of TMS effects and explorations of therapeutic outcomes in disease models.However,existing TMS tools lack focality for targeted stimulations.Notably,there has been limited fundamental research on developing coils capable of focal stimulation at deep brain regions on small animals like rodents.Methods.In this study,ferromagnetic cores are added to a novel angle-tuned coil design to enhance the coil performance regarding penetration depth and focality.Numerical simulations and experimental electric field measurements were conducted to optimize the coil design.Results.The proposed coil system demonstrated a significantly smaller stimulation spot size and enhanced electric field decay rate in comparison to existing coils.Adding the ferromagnetic core reduces the energy requirements up to 60%for rodent brain stimulation.The simulated results are validated with experimental measurements and demonstration of suprathreshold rodent limb excitation through targeted motor cortex activation.Conclusion.The newly developed coils are suitable tools for focal stimulations of the rodent brain due to their smaller stimulation spot size and improved electric field decay rate.

重复经颅磁刺激对育龄期前庭性偏头痛伴位置性眩晕患者疗效分析

目的探讨重复经颅磁刺激(repetitive transcranial magnetic stimulation,rTMS)对育龄期前庭性偏头痛(vestibular migraine,VM)伴位置性眩晕的疗效。方法收集如皋市人民医院神经内科、耳鼻咽喉科门诊育龄期VM伴位置性眩晕患者57例,进行一般情况、量表评价。采用随机数字法分为rTMS组和对照组,所有患者均予以规范非甾体止痛药物、抗眩晕药物治疗,rTMS组给予低频(1 Hz)rTMS作用于枕叶。分别采用SRM-IV眩晕诊疗系统、眼震电图行位置试验、温度试验评估前庭功能,采用眩晕障碍量表(dizziness handicap inventory,DHI),头痛程度视觉模拟量表(VAS)以及头痛影响测评量表(headache impact test-6,HIT-6)对治疗前、治疗2周、治疗3个月疗效评估。结果育龄期VM伴位置性眩晕患者发病年龄23~49(38.72±7.93)岁,52.63%(30/57)患者以后半规管受累为主,33.33%(19/57)患者温度试验异常。组间比较,治疗2周时对照组情绪(DHI-E)优于rTMS组,治疗3个月时rTMS组VAS、HIT-6评分改善程度显著优于对照组(P<0.05),其余时间段VAS、HIT-6、DHI组间比较无统计学差异。组内比较,治疗2周、治疗3个月与治疗前比较,rTMS组和对照组VAS、HIT-6、DHI评分均有统计学差异;治疗3个月与治疗2周比较时,rTMS组除躯体(DHI-P)外其余各评价指标均有统计学差异,对照组仅HIT-6评分、DHI-P存在统计学差异。结论低频rTMS能有效改善VM伴位置性眩晕患者头痛症状,改善眩晕症状并不优于单纯口服药物,随治疗时间延长,rTMS对头痛及眩晕改善越明显。

Functional near-infrared spectroscopy in non-invasive neuromodulation

Non-invasive cerebral neuromodulation technologies are essential for the reorganization of cerebral neural networks,which have been widely applied in the field of central neurological diseases,such as stroke,Parkinson’s disease,and mental disorders.Although significant advances have been made in neuromodulation technologies,the identification of optimal neurostimulation paramete rs including the co rtical target,duration,and inhibition or excitation pattern is still limited due to the lack of guidance for neural circuits.Moreove r,the neural mechanism unde rlying neuromodulation for improved behavioral performance remains poorly understood.Recently,advancements in neuroimaging have provided insight into neuromodulation techniques.Functional near-infrared spectroscopy,as a novel non-invasive optical brain imaging method,can detect brain activity by measuring cerebral hemodynamics with the advantages of portability,high motion tole rance,and anti-electromagnetic interference.Coupling functional near-infra red spectroscopy with neuromodulation technologies offe rs an opportunity to monitor the cortical response,provide realtime feedbac k,and establish a closed-loop strategy integrating evaluation,feedbac k,and intervention for neurostimulation,which provides a theoretical basis for development of individualized precise neuro rehabilitation.We aimed to summarize the advantages of functional near-infra red spectroscopy and provide an ove rview of the current research on functional near-infrared spectroscopy in transcranial magnetic stimulation,transcranial electrical stimulation,neurofeedback,and braincomputer interfaces.Furthermore,the future perspectives and directions for the application of functional near-infrared spectroscopy in neuromodulation are summarized.In conclusion,functional near-infrared spectroscopy combined with neuromodulation may promote the optimization of central pellral reorganization to achieve better functional recovery form central nervous system diseases.

High-frequency repetitive transcranial magnetic stimulation promotes neural stem cell proliferation after ischemic stroke

Prolife ration of neural stem cells is crucial for promoting neuronal regeneration and repairing cerebral infarction damage.Transcranial magnetic stimulation(TMS)has recently emerged as a tool for inducing endogenous neural stem cell regeneration,but its underlying mechanisms remain unclea r In this study,we found that repetitive TMS effectively promotes the proliferation of oxygen-glucose deprived neural stem cells.Additionally,repetitive TMS reduced the volume of cerebral infa rction in a rat model of ischemic stro ke caused by middle cerebral artery occlusion,im p roved rat cognitive function,and promoted the proliferation of neural stem cells in the ischemic penumbra.RNA-sequencing found that repetitive TMS activated the Wnt signaling pathway in the ischemic penumbra of rats with cerebral ischemia.Furthermore,PCR analysis revealed that repetitive TMS promoted AKT phosphorylation,leading to an increase in mRNA levels of cell cycle-related proteins such as Cdk2 and Cdk4.This effect was also associated with activation of the glycogen synthase kinase 3β/β-catenin signaling pathway,which ultimately promotes the prolife ration of neural stem cells.Subsequently,we validated the effect of repetitive TMS on AKT phosphorylation.We found that repetitive TMS promoted Ca2+influx into neural stem cells by activating the P2 calcium channel/calmodulin pathway,thereby promoting AKT phosphorylation and activating the glycogen synthase kinase 3β/β-catenin pathway.These findings indicate that repetitive TMS can promote the proliferation of endogenous neural stem cells through a Ca2+influx-dependent phosphorylated AKT/glycogen synthase kinase 3β/β-catenin signaling pathway.This study has produced pioneering res ults on the intrinsic mechanism of repetitive TMS to promote neural function recove ry after ischemic stro ke.These results provide a stro ng scientific foundation for the clinical application of repetitive TMS.Moreover,repetitive TMS treatment may not only be an efficient and potential approach to support neurogenesis for further therapeutic applications,but also provide an effective platform for the expansion of neural stem cells.

Vagus nerve stimulation in cerebral stroke:biological mechanisms,therapeutic modalities,clinical applications,and future directions

Stroke is a major disorder of the central nervous system that poses a serious threat to human life and quality of life.Many stro ke victims are left with long-term neurological dysfunction,which adversely affects the well-being of the individual and the broader socioeconomic impact.Currently,poststroke brain dysfunction is a major and difficult area of treatment.Vagus nerve stimulation is a Food and Drug Administration-approved exploratory treatment option for autis m,refractory depression,epilepsy,and Alzheimer’s disease.It is expected to be a novel therapeutic technique for the treatment of stroke owing to its association with multiple mechanisms such as alte ring neurotransmitters and the plasticity of central neuro ns.In animal models of acute ischemic stroke,vagus nerve stimulation has been shown to reduce infarct size,reduce post-stroke neurological damage,and improve learning and memory capacity in rats with stroke by reducing the inflammatory response,regulating bloodbrain barrier permeability,and promoting angiogenesis and neurogenesis.At present,vagus nerve stimulation includes both invasive and non-invasive vagus nerve stimulation.Clinical studies have found that invasive vagus nerve stimulation combined with rehabilitation therapy is effective in im proving upper limb motor and cognitive abilities in stroke patients.Further clinical studies have shown that non-invasive vagus nerve stimulation,including ear/ce rvical vagus nerve stimulation,can stimulate vagal projections to the central nervous system similarly to invasive vagus nerve stimulation and can have the same effect.In this paper,we first describe the multiple effects of vagus nerve stimulation in stroke,and then discuss in depth its neuroprotective mechanisms in ischemic stroke.We go on to outline the res ults of the current major clinical applications of invasive and non-invasive vagus nerve stimulation.Finally,we provide a more comprehensive evaluation of the advantages and disadvantages of different types of vagus nerve stimulation in the treatment of cerebral ischemia and provide an outlook on the developmental trends.We believe that vagus nerve stimulation,as an effective treatment for stroke,will be widely used in clinical practice to promote the recovery of stroke patients and reduce the incidence of disability.

Working toward an integrated plasticity/network framework for repetitive transcranial magnetic stimulation to inform tailored treatments

Non-invasive brain stimulation techniques(NIBS),including repetitive transcranial magnetic stimulation(rTMS) and transcranial electric stim ulation(tES),are increasingly being adopted clinically for treatment of neuropsychiatric and neurological disorders,albeit with varying success.The rationale behind the use of NIBS has historically been that stim ulation techniques modulate neuronal activity in the targeted region and consequently induce plasticity which can lead to therapeutic outcomes.

Contribution of glial cells to the neuroprotective effects triggered by repetitive magnetic stimulation:a systematic review

Repetitive transcranial magnetic stimulation has been increasingly studied in different neurological diseases,and although most studies focus on its effects on neuronal cells,the contribution of nonneuronal cells to the improvement trigge red by repetitive transcranial magnetic stimulation in these diseases has been increasingly suggested.To systematically review the effects of repetitive magnetic stimulation on non-neuronal cells two online databases.Web of Science and PubMed were searched fo r the effects of high-frequency-repetitive transcranial magnetic stimulation,low-frequencyrepetitive transcranial magnetic stimulation,intermittent theta-bu rst stimulation,continuous thetaburst stimulation,or repetitive magnetic stimulation on non-neuronal cells in models of disease and in unlesioned animals or cells.A total of 52 studies were included.The protocol more frequently used was high-frequency-repetitive magnetic stimulation,and in models of disease,most studies report that high-frequency-repetitive magnetic stimulation led to a decrease in astrocyte and mic roglial reactivity,a decrease in the release of pro-inflammatory cyto kines,and an increase of oligodendrocyte proliferation.The trend towards decreased microglial and astrocyte reactivity as well as increased oligodendrocyte proliferation occurred with intermittent theta-burst stimulation and continuous theta-burst stimulation.Few papers analyzed the low-frequency-repetitive transcranial magnetic stimulation protocol,and the parameters evaluated were restricted to the study of astrocyte reactivity and release of pro-inflammatory cytokines,repo rting the absence of effects on these paramete rs.In what concerns the use of magnetic stimulation in unlesioned animals or cells,most articles on all four types of stimulation reported a lack of effects.It is also important to point out that the studies were developed mostly in male rodents,not evaluating possible diffe rential effects of repetitive transcranial magnetic stimulation between sexes.This systematic review supports that thro ugh modulation of glial cells repetitive magnetic stimulation contributes to the neuroprotection or repair in various neurological disease models.Howeve r,it should be noted that there are still few articles focusing on the impact of repetitive magnetic stimulation on non-neuronal cells and most studies did not perform in-depth analyses of the effects,emphasizing the need for more studies in this field.

MicroRNA-146a-loaded magnesium silicate nanospheres promote bone regeneration in an inflammatory microenvironment

Reconstruction of irregular oral-maxillofacial bone defects with an inflammatory microenvironment remains a challenge,as chronic local inflammation can largely impair bone healing.Here,we used magnesium silicate nanospheres(MSNs)to load microRNA-146a-5p(miR-146a)to fabricate a nanobiomaterial,MSN+miR-146a,which showed synergistic promoting effects on the osteogenic differentiation of human dental pulp stem cells(hDPSCs).In addition,miR-146a exhibited an anti-inflammatory effect on mouse bone marrow-derived macrophages(BMMs)under lipopolysaccharide(LPS)stimulation by inhibiting the NF-κB pathway via targeting tumor necrosis factor receptor-associated factor 6(TRAF6),and MSNs could simultaneously promote M2 polarization of BMMs.MiR-146a was also found to inhibit osteoclast formation.Finally,the dual osteogenic-promoting and immunoregulatory effects of MSN+miR-146a were further validated in a stimulated infected mouse mandibular bone defect model via delivery by a photocuring hydrogel.Collectively,the MSN+miR-146a complex revealed good potential in treating inflammatory irregular oralmaxillofacial bone defects.

Safety and effectiveness of neuromuscular electrical stimulation in cardiac surgery:A systematic review

BACKGROUND Lack of mobilization and prolonged stay in the intensive care unit(ICU)are major factors resulting in the development of ICU-acquired muscle weakness(ICUAW).ICUAW is a type of skeletal muscle dysfunction and a common complication of patients after cardiac surgery,and may be a risk factor for prolonged duration of mechanical ventilation,associated with a higher risk of readmission and higher mortality.Early mobilization in the ICU after cardiac surgery has been found to be low with a significant trend to increase over ICU stay and is also associated with a reduced duration of mechanical ventilation and ICU length of stay.Neuromuscular electrical stimulation(NMES)is an alternative modality of exercise in patients with muscle weakness.A major advantage of NMES is that it can be applied even in sedated patients in the ICU,a fact that might enhance early mobilization in these patients.AIM To evaluate safety,feasibility and effectiveness of NMES on functional capacity and muscle strength in patients before and after cardiac surgery.METHODS We performed a search on Pubmed,Physiotherapy Evidence Database(PEDro),Embase and CINAHL databases,selecting papers published between December 2012 and April 2023 and identified published randomized controlled trials(RCTs)that included implementation of NMES in patients before after cardiac surgery.RCTs were assessed for methodological rigor and risk of bias via the PEDro.The primary outcomes were safety and functional capacity and the secondary outcomes were muscle strength and function.RESULTS Ten studies were included in our systematic review,resulting in 703 participants.Almost half of them performed NMES and the other half were included in the control group,treated with usual care.Nine studies investigated patients after cardiac surgery and 1 study before cardiac surgery.Functional capacity was assessed in 8 studies via 6MWT or other indices,and improved only in 1 study before and in 1 after cardiac surgery.Nine studies explored the effects of NMES on muscle strength and function and,most of them,found increase of muscle strength and improvement in muscle function after NMES.NMES was safe in all studies without any significant complication.CONCLUSION NMES is safe,feasible and has beneficial effects on muscle strength and function in patients after cardiac surgery,but has no significant effect on functional capacity.

Brain-wide activation involved in 15 mA transcranial alternating current stimulation in patients with first-episode major depressive disorder

Background Although 15 mA transcranial alternating current stimulation(tACS)has a therapeutic effect on depression,the activations of brain structures in humans accounting for this tACS configuration remain largely unknown.Aims To investigate which intracranial brain structures are engaged in the tACS at 77.5 Hz and 15 mA,delivered via the forehead and the mastoid electrodes in the human brain.Methods Actual human head models were built using the magnetic resonance imagings of eight outpatient volunteers with drug-naïve,first-episode major depressive disorder and then used to perform the electric field distributions with SimNIBS software.Results The electric field distributions of the sagittal,coronal and axial planes showed that the bilateral frontal lobes,bilateral temporal lobes,hippocampus,cingulate,hypothalamus,thalamus,amygdala,cerebellum and brainstem were visibly stimulated by the 15 mA tACS procedure.Conclusions Brain-wide activation,including the cortex,subcortical structures,cerebellum and brainstem,is involved in the 15 mA tACS intervention for first-episode major depressive disorder.Our results indicate that the simultaneous involvement of multiple brain regions is a possible mechanism for its effectiveness in reducing depressive symptoms.

绍兴文理学院刘庆明博士团队介绍

绍兴文理学院刘庆明博士团队在Translational Psychiatry(SCI,IF=5.8,中科院1区top)期刊上发表了题为“Modulation of d1PFC function and decision-making capacity by repetitive transcranial magnetic stimulation in me thamphetamine use disorder”的研究论文。

Outcomes and efficacy of magnetic resonance imaging-compatible sacral nerve stimulator for management of fecal incontinence: A multi-institutional study

BACKGROUND Fecal incontinence(FI)is an involuntary passage of fecal matter which can have a significant impact on a patient’s quality of life.Many modalities of treatment exist for FI.Sacral nerve stimulation is a well-established treatment for FI.Given the increased need of magnetic resonance imaging(MRI)for diagnostics,the In-terStim which was previously used in sacral nerve stimulation was limited by MRI incompatibility.Medtronic MRI-compatible InterStim was approved by the United States Food and Drug Administration in August 2020 and has been widely used.AIM To evaluate the efficacy,outcomes and complications of the MRI-compatible InterStim.METHODS Data of patients who underwent MRI-compatible Medtronic InterStim placement at UPMC Williamsport,University of Minnesota,Advocate Lutheran General Hospital,and University of Wisconsin-Madison was pooled and analyzed.Patient demographics,clinical features,surgical techniques,complications,and outcomes were analyzed.Strengthening the Reporting of Observational studies in Epidemiology(STROBE)cross-sectional reporting guidelines were used.RESULTS Seventy-three patients had the InterStim implanted.The mean age was 63.29±12.2 years.Fifty-seven(78.1%)patients were females and forty-two(57.5%)patients had diabetes.In addition to incontinence,overlapping symptoms included diarrhea(23.3%),fecal urgency(58.9%),and urinary incontinence(28.8%).Fifteen(20.5%)patients underwent Peripheral Nerve Evaluation before proceeding to definite implant placement.Thirty-two(43.8%)patients underwent rechargeable InterStim placement.Three(4.1%)patients needed removal of the implant.Migration of the external lead connection was observed in 7(9.6%)patients after the stage I procedure.The explanation for one patient was due to infection.Seven(9.6%)patients had other complications like nerve pain,hematoma,infection,lead fracture,and bleeding.The mean follow-up was 6.62±3.5 mo.Sixty-eight(93.2%)patients reported significant improvement of symptoms on follow-up evaluation.CONCLUSION This study shows promising results with significant symptom improvement,good efficacy and good patient outcomes with low complication rates while using MRI compatible InterStim for FI.Further long-term follow-up and future studies with a larger patient population is recommended.

肌松监测在临床中的应用

肌松药是全身麻醉手术中重要的辅助用药,肌松药用于全身麻醉后改变了靠加深全麻以获得肌肉松弛满足手术的需求。对于肌松药,要根据不同的药物种类、与其他药物的联合应用以及患者自身的情况等进行应用。虽然现在麻醉医生对于肌松药的应用已经较为熟练,但是仍有很多由于术后残余肌松所造成的不良反应的发生。且有研究发现,适当的深度肌松也可以更有助于手术的进行。因此,我们可以充分的利用肌松监测来达到肌松药的合理应用,并且通过监测来减少甚至避免术后残余肌松的发生。本综述就从对肌松监测的概述出发,总结其用于临床的优劣。

Multiple Mild Stimulations Reduce Membrane Distribution of CX3CR1 Promoted by Annexin al in Microglia to Attenuate Excessive Dendritic Spine Pruning and Cognitive Deficits Caused by a Transient Ischemic Attack in Mice

A transient ischemic attack(TIA)can cause reversible and delayed impairment of cognition,but the specific mechanisms arestill unclear.Annexin al(ANXA1)is a phospholipid-binding protein.Here,we confirmed that cognition and hippocampal synapses were impaired in TIA-treated mice,and this could be rescued by multiple mild stimulations(MMS).TIA promoted the interaction of ANXAl and CX3CR1,increased the membrane distribution of CX3CR1 in microglila,and thus enhanced the CX3CR1 and CX3CL1 interaction.These phenomena induced by TIA could be reversed by MMS.Meanwhile,the CX3CR1 membrane distribution and CX3CR1-CX3CL1 interaction were upregulated in primary cultured microglia overexpressing ANXAl,and the spine density was significantly reduced in co-cultured microglia overexpressing ANXAl and neurons.Moreover,ANXAl overexpression in microglia abolished the protection of MMS after TIA.Collectively,our study provides a potential strategy for treating the delayed synaptic injury caused by TIA.

Millimetric devices for nerve stimulation:a promising path towards miniaturization

Nerve stimulation is a rapidly developing field,demonstrating positive outcomes across several conditions.Despite potential benefits,current nerve stimulation devices are large,complicated,and are powered via implanted pulse generators.These facto rs necessitate invasive surgical implantation and limit potential applications.Reducing nerve stimulation devices to millimetric sizes would make these interventions less invasive and facilitate broader therapeutic applications.However,device miniaturization presents a serious engineering challenge.This review presents significant advancements from several groups that have overcome this challenge and developed millimetricsized nerve stimulation devices.These are based on antennas,mini-coils,magneto-electric and optoelectronic materials,or receive ultrasound power.We highlight key design elements,findings from pilot studies,and present several considerations for future applications of these devices.

Optimal transcorneal electrical stimulation parameters for preserving photoreceptors in a mouse model of retinitis pigmentosa

Retinitis pigmentosa is a hereditary retinal disease that affects rod and cone photoreceptors,leading to progressive photoreceptor loss.Previous research supports the beneficial effect of electrical stimulation on photoreceptor survival.This study aims to identify the most effective electrical stimulation parameters and functional advantages of transcorneal electrical stimulation(tcES)in mice affected by inherited retinal degeneration.Additionally,the study seeked to analyze the electric field that reaches the retina in both eyes in mice and post-mortem humans.In this study,we recorded waveforms and voltages directed to the retina during transcorneal electrical stimulation in C57BL/6J mice using an intraocular needle probe with rectangular,sine,and ramp waveforms.To investigate the functional effects of electrical stimulation on photoreceptors,we used human retinal explant cultures and rhodopsin knockout(Rho^(-/-))mice,demonstrating progressive photoreceptor degeneration with age.Human retinal explants isolated from the donors’eyes were then subjected to electrical stimulation and cultured for 48 hours to simulate the neurodegenerative environment in vitro.Photoreceptor density was evaluated by rhodopsin immunolabeling.In vivo Rho^(-/-)mice were subjected to two 5-day series of daily transcorneal electrical stimulation using rectangular and ramp waveforms.Retinal function and visual perception of mice were evaluated by electroretinography and optomotor response(OMR),respectively.Immunolabeling was used to assess the morphological and biochemical changes of the photoreceptor and bipolar cells in mouse retinas.Oscilloscope recordings indicated effective delivery of rectangular,sine,and ramp waveforms to the retina by transcorneal electrical stimulation,of which the ramp waveform required the lowest voltage.Evaluation of the total conductive resistance of the post-mortem human compared to the mouse eyes indicated higher cornea-to-retina resistance in human eyes.The temperature recordings during and after electrical stimulation indicated no significant temperature change in vivo and only a subtle temperature increase in vitro(~0.5-1.5°C).Electrical stimulation increased photoreceptor survival in human retinal explant cultures,particularly at the ramp waveform.Transcorneal electrical stimulation(rectangular+ramp)waveforms significantly improved the survival and function of S and M-cones and enhanced visual acuity based on the optomotor response results.Histology and immunolabeling demonstrated increased photoreceptor survival,improved outer nuclear layer thickness,and increased bipolar cell sprouting in Rho^(-/-)mice.These results indicate that transcorneal electrical stimulation effectively delivers the electrical field to the retina,improves photoreceptor survival in both human and mouse retinas,and increases visual function in Rho^(-/-)mice.Combined rectangular and ramp waveform stimulation can promote photoreceptor survival in a minimally invasive fashion.