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.

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.

Caliper-based precise positioning of the target(CALIPPOT)for transcranial magnetic stimulation without neuronavigation system

To the editor:Transcranial magnetic stimulation(TMS)is a non-invasive brain modulation technique.One important usage of TMS is the transient interruption of cognitive brain function(also named virtual lesion)for investigating precisely where and when a specific cortical region contributes to a specific cognitive function.1 A more important usage of TMS is the treatment of brain disorders by repetitive TMS(rTMS).

The role of temperature‐enhanced fault closure in promoting postinjection pressure diffusion and seismicity in enhanced geothermal systems

Post shut‐in seismic events in enhanced geothermal systems(EGSs)occur predominantly at the outer rim of the co‐injection seismic cloud.The concept of postinjection fracture and fault closure near the injection well has been proposed and validated as a mechanism for enhancing post shut‐in pressure diffusion that promotes seismic hazard.This phenomenon is primarily attributed to the poro‐elastic closure of fractures resulting from the reduction of wellbore pressure after injection termination.However,the thermal effects in EGSs,mainly including heat transfer and thermal stress,may not be trivial and their role in postinjection fault closure and pressure evolution needs to be explored.In this study,we performed numerical simulations to analyze the relative importance of poro‐elasticity,heat transfer,and thermo‐elasticity in promoting postinjection fault closure and pressure diffusion.The numerical model wasfirst validated against analytical solutions in terms offluid pressure diffusion and against heatedflow‐through experiments in terms of thermal processes.We then quantified and distinguished the contribution of each individual mechanism by comparing four different shut‐in scenarios simulated under different coupled conditions.Our results highlight the importance of poro‐elastic fault closure in promoting postinjection pressure buildup and seismicity,and suggest that heat transfer can further augment the fault closure‐induced pressure increase and thus potentially intensify the postinjection seismic hazard,with minimal contribution from thermo‐elasticity.

Advances of Research on Auricular Vagus Nerve Stimulation for Treatment of Nervous System Diseases

As a new type of nerve regulation technology, Vagus Nerve Stimulation is currently used in the treatment of nervous system diseases. Auricular Vagus Nerve Stimulation has become one of the research hotspots in this field, because there is no implantation risk. However, there is no unified standard for the treatment parameters of aVNS for nervous system diseases. In this paper, the research progress of the anatomical structure and parameters of the vagus nerve and its role in nervous system diseases are reviewed to provide basis for further research.

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.

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.

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.

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.

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.

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。

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.

Suppression of stimulated Brillouin and Raman scatterings using an alternating frequency laser and transverse magnetic fields

A novel scheme to suppress both stimulated Brillouin scattering(SBS) and stimulated Raman scattering(SRS) by combining an alternating frequency(AF) laser and a transverse magnetic field is proposed. The AF laser allows the laser frequency to change discretely and alternately over time. The suppression of SBS is significant as long as the AF difference is greater than the linear growth rate of SBS or the alternating time of the laser frequency is shorter than the linear growth time of SBS. However, the AF laser proves ineffective in suppressing SRS, which usually has a much higher linear growth rate than SBS. To remedy that, a transverse magnetic field is included to suppress the SRS instability. The electrons trapped in the electron plasma waves(EPWs) of SRS can be accelerated by the surfatron mechanism in a transverse magnetic field and eventually detrapped. While continuously extracting energy from EPWs, the EPWs are dissipated and the kinetic inflation of SRS is suppressed. The one-dimensional particle-in-cell simulation results show that both SBS and SRS can be effectively suppressed by combining the AF laser with a transverse magnetic field with tens of Tesla. The total reflectivity can be dramatically reduced by more than one order of magnitude. These results provide a potential reference for controlling SBS and SRS under the related parameters of inertial confinement fusion.

Broadband bidirectional Brillouin–Raman random fiber laser with ultra-narrow linewidth

We present a Brillouin–Raman random fiber laser(BRRFL)with full-open linear cavity structure to generate broadband Brillouin frequency comb(BFC)with double Brillouin-frequency-shift spacing.The incorporation of a regeneration portion consisting of an erbium-doped fiber and a single-mode fiber enables the generation of broadband BFC.The dynamics of broadband BFC generation changing with the pump power(EDF and Raman)and Brillouin pump(BP)wavelength are investigated in detail,respectively.Under suitable conditions,the bidirectional BRRFL proposed can produce a flatamplitude BFC with 40.7-nm bandwidth ranging from 1531 nm to 1571.7 nm,and built-in 242-order Brillouin Stokes lines(BSLs)with double Brillouin-frequency-shift spacing.Moreover,the linewidth of single BSL is experimentally measured to be about 2.5 kHz.The broadband bidirectional narrow-linewidth BRRFL has great potential applications in optical communication,optical sensing,spectral measurement,and so on.

Treadmill exercise in combination with acousto-optic and olfactory stimulation improves cognitive function in APP/PS1 mice through the brain-derived neurotrophic factor-and Cygb-associated signaling pathways

A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease.Consequently,enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression.Nonetheless,nonpharmacological interventions aimed at inducing adult neurogenesis are currently limited.Although individual non-pharmacological interventions,such as aerobic exercise,acousto-optic stimulation,and olfactory stimulation,have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease,the therapeutic effect of a strategy that combines these interventions has not been fully explored.In this study,we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months.Amyloid deposition became evident at 4 months,while neurogenesis declined by 6 months,further deteriorating as the disease progressed.However,following a 4-week multifactor stimulation protocol,which encompassed treadmill running(46 min/d,10 m/min,6 days per week),40 Hz acousto-optic stimulation(1 hour/day,6 days/week),and olfactory stimulation(1 hour/day,6 days/week),we found a significant increase in the number of newborn cells(5'-bromo-2'-deoxyuridine-positive cells),immature neurons(doublecortin-positive cells),newborn immature neurons(5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells),and newborn astrocytes(5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells).Additionally,the amyloid-beta load in the hippocampus decreased.These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice.Furthermore,cognitive abilities were improved,and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation,as evidenced by Morris water maze,novel object recognition,forced swimming test,and tail suspension test results.Notably,the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2weeks after treatment cessation.At the molecular level,multifactor stimulation upregulated the expression of neuron-related proteins(NeuN,doublecortin,postsynaptic density protein-95,and synaptophysin),anti-apoptosis-related proteins(Bcl-2 and PARP),and an autophagyassociated protein(LC3B),while decreasing the expression of apoptosis-related proteins(BAX and caspase-9),in the hippocampus of amyloid precursor protein/presenilin 1 mice.These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways.Furthermore,serum metabolomics analysis indicated that multifactor stimulation regulated differentially expressed metabolites associated with cell apoptosis,oxidative damage,and cognition.Collectively,these findings suggest that multifactor stimulation is a novel non-invasive approach for the prevention and treatment of Alzheimer's disease.

Transcranial photobiomodulation for the brain: a wide range of clinical applications

Photobiomodulation therapy(PBMT)is a rapidly growing approach to the healing,stimulation,protection,and regeneration of many human organs and tissue types.PBMT started in the 1960s as low-level laser therapy for wound healing,but since then the introduction of light-emitting diodes(LEDs)has dramatically increased the number of applications and reports of positive results.PBMT generally uses red(620-700 nm)and/or near-infrared(780-1270 nm)wavelengths of light at an intensity that causes no tissue heating,and its activity is based on well-established biological and cellular mechanisms(de Freitas and Hamblin,2016).While laser therapists continue to use various types of laser in their office practice,LEDs are ideally suited for home use devices because they are completely safe and without any known significant adverse effects.Among the various body parts on which PBMT has been shown to exert beneficial effects,the brain stands out as perhaps the most promising overall.PBMT has been shown to reduce neuroinflammation,while increasing mitochondrial function,oxygen consumption,and blood flow within the brain(Hamblin,2016).Moreover,PBMT can stimulate the processes of synaptogenesis,neurogenesis,and neuroplasticity thus helping the brain to heal itself.