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.

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.

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.

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.

Exploring the synergy of the eyebrain connection:neuromodulation approaches for neurodegenerative disorders through transcorneal electrical stimulation

The connection and interaction between the eye and the brain are crucial to understanding brain disorders(Marchesi et al.,2021).Both the eye and the brain have a limited regenerative capacity as there are few progenitor cells,and nerve cells do not replicate.Hence,neurodegeneration implicates irreversible damage to the central nervous system,as observed in several neurodegenerative diseases(Marchesi et al.,2021).

Effect of transcranial direct current stimulation on postoperative sleep disturbance in older patients undergoing lower limb major arthroplasty:a prospective,double-blind,pilot,randomised controlled trial

Background Postoperative sleep disturbance(PSD)is a common and serious postoperative complication and is associated with poor postoperative outcomes.Aims This study aimed to investigate the effect of transcranial direct current stimulation(tDCS)on PSD in older patients undergoing lower limb major arthroplasty.Methods In this prospective,double-blind,pilot,randomised,sham-controlled trial,patients 65 years and over undergoing lower limb major arthroplasty were randomly assigned to receive active tDCS(a-tDCS)or sham tDCS(s-tDCS).The primary outcomes were the objective sleep measures on postoperative nights(N)1 and N2.Results 116 inpatients were assessed for eligibility,and a total of 92 patients were enrolled;47 received a-tDCS and 45 received s-tDCS.tDCS improved PSD by altering the following sleep measures in the a-tDCS and s-tDCS groups;the respective comparisons were as follows:the promotion of rapid eye movement(REM)sleep time on N1(64.5(33.5-105.5)vs 19.0(0.0,45.0)min,F=20.10,p<0.001)and N2(75.0(36.0-120.8)vs 30.0(1.3-59.3)min,F=12.55,p<0.001);the total sleep time on N1(506.0(408.0-561.0)vs 392.0(243.0-483.5)min,F=14.13,p<0.001)and N2(488.5(455.5-548.5)vs 346.0(286.5-517.5)min,F=7.36,p=0.007);the deep sleep time on N1(130.0(103.3-177.0)vs 42.5(9.8-100.8)min,F=24.4,p<0.001)and N2(103.5(46.0-154.8)vs 57.5(23.3-106.5)min,F=8.4,p=0.004);and the percentages of light sleep and REM sleep on N1 and N2(p<0.05 for each).The postoperative depression and anxiety scores did not differ significantly between the two groups.No significant adverse events were reported.Conclusion In older patients undergoing lower limb major arthroplasty,a single session of anodal tDCS over the left dorsolateral prefrontal cortex showed a potentially prophylactic effect in improving postoperative short-term objective sleep measures.However,this benefit was temporary and was not maintained over time.

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.

Comparisons of transcranial alternating current stimulation and repetitive transcranial magnetic stimulation treatment therapy for insomnia:a pilot study

To the editor:Insomnia disorder has a serious and widespread detrimental effect on humans with comorbidity with other mental or physical health problems.In recent years,noninvasive brain stimulation(NIBS)techniques,especially transcranial magnetic stimulation(TMS)and transcranial electrical stimulation,have been increasingly used for the treatment of brain diseases,including insomnia disorder.

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).

Effect of novel accelerated intermittent theta burst stimulation on suicidal ideation in adolescent patients with major depressive episode:a randomised clinical trial

To the editor:Affective disorders,including major depressive disorder(MDD)and bipolar disorder,have emerged as the primary cause of adolescent suicide.Moreover,suicide mostly occurs in the major depressive episode(MDE)of affective disorders.Suicidal ideation(SI)has been identified as an immediate precursor to suicide,such that reducing its severity is conducive to suicide prevention in adolescents.

Effects of a periodic intermittent theta burst stimulation in Alzheimer's disease

Background Previous studies havedemonstrated that excitatory repetitive transcranial magnetic stimulation(rTMS)can improve the cognitive function of patients with Alzheimer's disease(AD).Intermittent theta burst stimulation(iTBS)is a novel excitatory rTMS protocol for brain activity stimulation with the ability to induce long-term potentiation-like plasticity and represents a promising treatment for AD.However,the long-term effects of iTBS on cognitive decline and brain structure in patients with AD areunknown.Aims We aimed to explore whether repeating accelerated iTBS every three months could slow down the cognitive decline in patients with AD.Methods In this randomised,assessor-blinded,controlled trial,iTBS was administered to the left dorsolateral prefrontal cortex(DLPFC)of 42 patients with AD for 14days every 13weeks.Measurements included the Montreal Cognitive Assessment(MoCA),a comprehensive neuropsychological battery,and the grey matter volume(GMV)of the hippocampus.Patients were evaluated at baseline and after follow-up.The longitudinal pipeline of the Computational Anatomy Toolbox for SPM was used to detect significant treatment-related changes over time.Results The iTBS group maintained MoCA scores relative to the control group(t=3.26,p=0.013)and reduced hippocampal atrophy,which was significantly correlated with global degeneration scale changes.The baseline Mini-Mental State Examination(MMSE)score,apolipoprotein E genotype and Clinical Dementia Rating were indicative of MoCA scores at follow-up.Moreover,the GMV of the left(t=0.08,p=0.996)and right(t=0.19,p=0.977)hippocampus were maintained in the active group but significantly declined in the control group(left:t=4.13,p<0.001;right:t=5.31,p<0.001).GMV change in the left(r=0.35,p=0.023)and right(r=0.36,p=0.021)hippocampus across the intervention positively correlated with MoCA changes;left hippocampal GMV change was negatively correlated with global degeneration scale(r=-0.32,p=0.041)changes.Conclusions DLPFC-iTBS maybe a feasible and easy-to-implement non-pharmacological intervention to slow down the progressive decline of overall cognition and quality of life in patients with AD,providing a new AD treatment option.Trial registration number NCT04754152.

Methodological considerations of priming repetitive transcranial magnetic stimulation protocols in clinical populations

INTRODUCTION Repetitive transcranial magnetic stimulation(rTMS)is a neuroplasticity-enhancing technique that modifies brain responsiveness to various therapeutic modalities in clinical psychiatric and neurological applications. Furthermore,its effect can be attributed to long-term potentiation(LTP)or longterm depression(LTD)-like neuroplasticity.However,responsiveness to rTMS is largely variable in healthy and pathological brains and is mediated by complex biological mechanisms.Metaplasticity refers to a higher-order plasticity mechanism in which the direction and magnitude of synaptic plasticity are modified by prior neuronal activity and is believed to be a significant factor leading to the response variability of rTMs.

Presurgical structural imaging and clinical outcome in combined bed nucleus of the stria terminalis-nucleus accumbens deep brain stimulation for treatment-resistant depression

Background Structural imaging holds great potential for precise targeting and stimulation for deep brain stimulation(DBS).The anatomical information it provides may serve as potential biomarkers for predicting the efficacy of DBS in treatment-resistant depression(TRD).Aims The primary aim is to identify preoperative imaging biomarkers that correlate with the efficacy of DBS in patients with TRD.Methods Preoperative imaging parameters were estimated and correlated with the 6-month clinical outcome of patients with TRD receiving combined bed nucleus of the stria terminalis(BNST)-nucleus accumbens(NAc)DBS.White matter(WM)properties were extracted and compared between the response/non-response and remission/non-remission groups.Structural connectome was constructed and analysed using graph theory.Distances of the volume of activated tissue(VAT)to the main modulating tracts were also estimated to evaluate the correlations.Results Differences in fibre bundle properties of tracts,including superior thalamic radiation and reticulospinal tract,were observed between the remission and nonremission groups.Distance of the centre of the VAT to tracts connecting the ventral tegmental area and the anterior limb of internal capsule on the left side varied between the remission and non-remission groups(p=0.010,t=3.07).The normalised clustering coefficient(γ)and the small-world property(σ)in graph analysis correlated with the symptom improvement after the correction of age.Conclusions Presurgical structural alterations in WM tracts connecting the frontal area with subcortical regions,as well as the distance of the VAT to the modulating tracts,may influence the clinical outcome of BNST-NAc DBS.These findings provide potential imaging biomarkers for the DBS treatment for patients with TRD.

Dual roles of the amygdala-hippocampus circuit in the regulation of rapid eye movement sleep and depression symptoms by repetitive transcranial magnetic stimulation in patients with insomnia

To the editor:It is commonly reported that people with insomnia often experience comorbid emotional disorders,such as mood and anxiety disorders.12 A study found that fragmented rapid eye movement(REM)sleep in individuals with insomnia is associated with higher Beck Depression Inventory(BDI)scores.3 REM sleep architecture disruption is a typical symptom of insomnia.

The Effect of Umami Stimulation on Salivary Secretion Rate and Duration

Purpose: Umami reportedly promotes salivation. We aimed to investigate the effects of taste stimuli on slow and fast salivary secretion in humans using umami, sweet, and sour stimuli. Methods: Eight healthy women participated between 14:00 and 15:00, taking the circadian rhythm of salivary secretion into account. The types and concentrations of the taste solutions were glutamic acid (1.7 × 10−3 M), inosinic acid (9.8 × 10−3 M), and guanylic acid (9.8 × 10−3 M) for umami stimulation, citric acid (6.5 × 10−3 M) for acidity stimulation, and sucrose (1.6 × 10−2 M) for sweetness stimulation. First, the unstimulated salivary flow rate was measured. Then, 3 ml of a flavor solution was dropped under the tongue using a syringe. The saliva was expelled into an aluminum cup every minute and weighed. The first minute’s value minus 3 ml flavor solution was the stimulated salivary secretion rate produced by each flavor. The time-to-return to the initial unstimulated salivary flow rate was the duration of the stimulated saliva secretion rate. Results: The mean unstimulated salivary flow rate across participants was 0.64 ± 0.25 ml/min (range: 0.23 - 1.03 ml/min). The highest amount of saliva was induced by citric acid. There were significant differences between citric acid and the other flavor solutions (p < 0.05 for glutamic acid, inosinic acid, and sucrose;p < 0.01 for guanylic acid). There were no significant differences in duration of salivation between the flavor solutions. When the participants were divided into slow (0.45 ± 0.16 ml/min) and fast groups (0.83 ± 0.15 ml/min) based on their median resting salivary secretion rate, there were no significant differences between the two groups in the amount of saliva secreted at 1 minute after stimulation and the duration of the salivary secretion rate. Conclusion: Umami stimulation was effective in slowing salivary secretion and sustaining salivary secretion after stimulation.

A robust viscoelastic surfactant tolerating 20% HCl up to 150℃ for oil well stimulation

Viscoelastic surfactants(VES)are often used as viscous diverters in acidizing stimulation to prolong the acid consumption time and maximize zonal coverage of the acid for improving well productivity.However,the ceiling temperature of commercial VES cannot exceed 120℃in practical use because of the poor thermal stability and fragile molecular structure,hindering their implementation in hightemperature oil reservoirs,i.e.,≥150℃.Here we synthesized a novel C22-tailed diamine,N-erucaminopropyl-N,N-dimethylamine(EDPA),and examined comparatively its rheological behavior,assemblies morphology and molecular stability in 20 wt%HCl with a commercial VES,erucyl dimethyl amidopropyl betaine(EDAB).The feasibility of EDPA for acidizing stimulation was assessed by acid etching of carbonate rock with its HCl solution at 150℃.Rheological results showed that the 2.5 wt%EDPA—20 wt%HCl solution maintains stable viscosity of 90 m Pa s at 150℃for 60 min,while that of 2.0 wt%EDAB HCl solution is just 1 m Pa s under identical conditions.1H NMR spectra and cryo-TEM observations revealed that the chemical structure and self-assembled architectures of EDPA remained intact in such context,but the EDAB suffered from degradation due to the hydrolysis of the amide group,accounting for the poor heat-resistance and acid-tolerance.The reaction rate of 2.5 wt%EDPA HCl solution with carbonate rock was one order of magnitude lower than that of 20 wt%HCl solution at 150℃,underpinning the potential of EDPA to be used in the high-temperature reservoirs acidizing.This work improved the thermal tolerance of VES in highly concentrated HCl solution,paving a feasible way for the acidization of high-temperature reservoir environments(~150℃).

“Flow” Transcranial Direct Current Stimulation (tDCS) for Depression Treatment in a Primary Healthcare General Practice—An Open-Label Cohort Study Measuring Montgomery-Åsberg Depression Rating Scale (MADRS-S) Outcomes

Background: Flow FL-100 is a transcranial direct current stimulation (tDCS) device self-administered by a patient at home in combination with a software application delivered wellbeing behaviour therapy training. tDCS has evidence of effectiveness in treating symptoms of depression. Purpose/Aim: This post marketing study evaluated the effect of Flow on depression for primary care general practice patients with depression symptoms. Methods: Open-label patient cohort design with no control group. Inclusion criteria were aged 18 years or over and reporting depression symptoms. Participants self-administered five 30 minute tDCS sessions per week for the first three weeks, and then 3 sessions per week following this. Three, six and ten week assessment with participant self-report measure: Montgomery- Åsberg Depression Rating Scale (MADRS-S). Results: MADRS-S remission rates were between 29% - 30% at three weeks, 33% - 34% at six-weeks and 50% at 10-weeks treatment. There was a significant improvement in MADRS-S with large effect sizes at all time points. Conclusions: Flow tDCS can be delivered through a primary healthcare general practice service and patients will choose to use. Flow tDCS provides an effective depression treatment in addition and as an alternative to antidepressants and psychotherapy. tDCS has evidence as an effective depression treatment, and the widespread availability of tDCS in primary care general practice should be considered.

Prolonged intermittent theta burst stimulation restores the balance between A_(2A)R-and A_(1)R-mediated adenosine signaling in the 6-hydroxidopamine model of Parkinson's disease

An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease progression,demonstrating the need for novel approaches in PD.Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson's disease.However,the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown.The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling.Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test.Immunoblot,quantitative reverse transcription polymerase chain reaction,immunohistochemistry,and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen.Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals.A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen.Treatment with intermittent theta burst stimulation began 7 days after the lesion,coinciding with the onset of motor symptoms.After treatment with prolonged intermittent theta burst stimulation,complete motor recovery was observed.This improvement was accompanied by downregulation of the e N/CD73-A_(2A)R pathway and a return to physiological levels of A_(1)R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation.Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A_(1)R and elevated the expression of A_(2A)R.Intermittent theta burst stimulation reversed these effects by restoring the abundances of A_(1)R and A_(2A)R to control levels.The shift in ARs expression likely restored the balance between dopamine-adenosine signaling,ultimately leading to the recovery of motor control.