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.

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.

Age-related driving mechanisms of retinal diseases and neuroprotection by transcription factor EB-targeted therapy

Retinal aging has been recognized as a significant risk factor for various retinal disorders,including diabetic retinopathy,age-related macular degeneration,and glaucoma,following a growing understanding of the molecular underpinnings of their development.This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches,focusing on the activation of transcription factor EB.Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies,such as exercise,calorie restriction,rapamycin,and metformin,in patients and animal models of these common retinal diseases.The review critically assesses the role of transcription factor EB in retinal biology during aging,its neuroprotective effects,and its therapeutic potential for retinal disorders.The impact of transcription factor EB on retinal aging is cell-specific,influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways.In vascular endothelial cells,transcription factor EB controls important processes,including endothelial cell proliferation,endothelial tube formation,and nitric oxide levels,thereby influencing the inner blood-retinal barrier,angiogenesis,and retinal microvasculature.Additionally,transcription factor EB affects vascular smooth muscle cells,inhibiting vascular calcification and atherogenesis.In retinal pigment epithelial cells,transcription factor EB modulates functions such as autophagy,lysosomal dynamics,and clearance of the aging pigment lipofuscin,thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization.These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis,neuronal synapse plasticity,energy metabolism,microvasculature,and inflammation,ultimately offering protection against retinal aging and diseases.The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases.Therefore,it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.

Progress in neurorehabilitation research and the support by the National Natural Science Foundation of China from 2010 to 2022

The National Natural Science Foundation of China is one of the major funding agencies for neuro rehabilitation research in China.This study reviews the frontier directions and achievements in the field of neurorehabilitation in China and wo rldwide.We used data from the Web of Science Core Collection(WoSCC) database to analyze the publications and data provided by the National Natural Science Foundation of China to analyze funding information.In addition,the prospects for neurorehabilitation research in China are discussed.From 2010 to 2022,a total of 74,220 publications in neurorehabilitation were identified,with there being an overall upward tendency.During this period,the National Natural Science Foundation of China has funded 476 research projects with a total funding of 192.38 million RMB to support neuro rehabilitation research in China.With the support of the National Natural Science Foundation of China,China has made some achievements in neurorehabilitation research.Research related to neurorehabilitation is believed to be making steady and significant progress in China.

Cortico-striatal gamma oscillations are modulated by dopamine D3 receptors in dyskinetic rats

Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.

Transcranial direct current stimulation efficacy in trigeminal neuralgia

Trigeminal neuralgia is a severe,disabling pain and its deafferentation remains a challenge for health providers.Transcranial direct current stimulation is a non-invasive stimulation technique which finds new utility in managing pain.There-fore,the introduction of alternative,non-invasive,safe,and effective methods should be considered in treating patients with trigeminal neuralgia unresponsive to conventional treatment.

Effect of transcranial direct current stimulation on supernumerary phantom limb pain in spinal cord injured patient:A case report

BACKGROUND Supernumerary phantom limb(SPL)sensation is the experience of additional limbs,either single or a pair of limbs.Unique to traumatic spinal cord injuries,we report effect of transcranial direct current stimulation(tDCS)on SPL pain in a patient with cervical cord injury.CASE SUMMARY The subject was a 57-year-old man who was diagnosed with complete spinal cord injury(C6/C5,motor level;C5/C5,sensory level;AIS-A)approximately three months ago.After a period of 2 wk,we administered anodal tDCS over the motor cortex for 15 minutes at an intensity of 1.5 mA.Following that treatment,the patient experienced a decrease of SPL pain intensity and frequency,which lasted for 1 week after the end of treatment.CONCLUSION Targeting the motor cortex through neuromodulation appears to be a promising option for the management of SPL pain.

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.

Double-target neural circuit-magnetic stimulation improves motor function in spinal cord injury by attenuating astrocyte activation

Multi-target neural circuit-magnetic stimulation has been clinically shown to improve rehabilitation of lower limb motor function after spinal cord injury. However, the precise underlying mechanism remains unclear. In this study, we performed double-target neural circuit-magnetic stimulation on the left motor cortex and bilateral L5 nerve root for 3 successive weeks in a rat model of incomplete spinal cord injury caused by compression at T10. Results showed that in the injured spinal cord, the expression of the astrocyte marker glial fibrillary acidic protein and inflammatory factors interleukin 1β, interleukin-6, and tumor necrosis factor-α had decreased, whereas that of neuronal survival marker microtubule-associated protein 2 and synaptic plasticity markers postsynaptic densification protein 95 and synaptophysin protein had increased. Additionally, neural signaling of the descending corticospinal tract was markedly improved and rat locomotor function recovered significantly. These findings suggest that double-target neural circuit-magnetic stimulation improves rat motor function by attenuating astrocyte activation, thus providing a theoretical basis for application of double-target neural circuit-magnetic stimulation in the clinical treatment of spinal cord injury.

Transcranial Direct Current Stimulation Combined with Peripheral Neuromuscular Stimulation Improves Quality of Life, Fatigue, and Pain in a Patient with Rheumatoid Arthritis and Refractory Radicular Pain Related to Spinal Stenosis

Background: Transcranial direct current stimulation (tDCS) has emerged as an adjuvant noninvasive neuromodulation tool to control fatigue and pain. To date, no studies have assessed the safety and efficiency of tDCS in patients with rheumatoid arthritis and with fatigue, poor quality of life, and refractory radicular pain associated with spinal stenosis. Case Presentation: An 85-year-old woman patient presented with rheumatoid arthritis in remission, refractory radicular pain-associated spinal stenosis, fatigue, and impaired quality of life. The patient underwent 16 daily sessions of tDCS intervention (2 mA, 20 min, positively and negatively charged electrodes were positioned at C1 and Fp2, respectively), in addition to simultaneous peripheral neuromuscular electrical stimulation (frequency of 100 Hz and amplitude of 500 μs). After the intervention, neither disease relapse nor clinical intercurrence occurred. Moreover, there was a significant and sustained improvement in her health-related quality of life, with a reduction in the level of pain and chronic fatigue. Conclusion: The present case report shows that tDCS is safe and may be an adjuvant tool for the treatment of pain and fatigue in patients with systemic autoimmune disease, as well as for improving quality of life. Further studies are required to corroborate this case report.

Transcranial direct current electrical stimulation in combination with aerobic exercise:A pilot study in post-COVID-19 systemic autoimmune rheumatic patients

BACKGROUND Systemic autoimmune rheumatic diseases(SARDs)are a group of diseases with multiorgan involvement and a high prevalence of chronic pain and fatigue.Patients with SARDs and post-coronavirus disease 2019(COVID-19)syndrome experience aggravation of symptoms.In this context,it is essential to establish strategies to reduce chronic pain and fatigue and improve quality of life.AIM To assess the efficacy of transcranial direct current stimulation(tDCS)for the treatment of fatigue and pain-associated post-COVID-19 syndrome in patients with SARDs.METHODS This study included nine patients with different types of SARDs.All patients had reverse transcription-polymerase chain reaction(RT-PCR)test confirmed COVID-19 as well as significant,persistent fatigue and pain that began to worsen after infection.Anodal tDCS was administered in five daily sessions(2mA,20 min).Concomitantly,patients were involved in aerobic exercise program.All participants were evaluated using specific questionnaires and strength assessment by handgrip and physical function by timed-up-and-go test and sit-to-stand test at baseline(within one week before tDCS protocol),and one week after tDCS protocol.During all procedures,the patients’treatments remained unchanged.RESULTS The sample comprised eight women and one man with a mean age of 48.7±9.6 years.After the tDCS protocol,pain and fatigue significantly improved on the visual analog scale(P<0.05).The physical function also improved 9.5±2.7 vs 6.8±0.8(P=0.001)for timed-up-go-test and 10.3±3.7 vs 15.1±4.0(P=0.037)for sit-to-stand test.None of the patients experienced any adverse events.CONCLUSION The present study showed that tDCS in combination with aerobic exercise was effective in improving physical function,and reducing fatigue/pain in SARDs patients with post-COVID-19 syndrome.

Clinical Trial Demonstrates Efficacy of Transcranial Direct Current Stimulation (tDCS) in Improving Pain Management from Post-Laminectomy Syndrome

Chronic pain, a multidimensional experience affecting individuals’ sensory, cognitive, and emotional aspects, significantly impacts their quality of life. Post-laminectomy syndrome, a condition characterized by persistent back pain following spinal surgery, often leads to disability and increased healthcare utilization. Methods: This randomized, controlled, blind clinical trial aimed to investigate the efficacy of Transcranial Direct Current Stimulation (tDCS) in managing pain from post-laminectomy syndrome in patients. Twenty-four participants were assigned to three groups: sham stimulation, active stimulation over primary motor cortex (M1), or stimulation over dorsolateral prefrontal cortex (DLPFC). Stimulation was administered for five consecutive days, 20 minutes per session, using a current of 1.5 mA through 25 cm2 electrodes. Pain intensity was assessed using Visual Analog Scale (VAS) before, during, and after intervention. Results: An ANOVA model demonstrates significant reduction in pain intensity compared to baseline in VAS, (F(7, 285) = 12.292;p 0.001;Power = 1.000;η2p = 0.534), in tDCS applied to M1, after five days of intervention. After stimulation, a significant improvement was observed in WHOQoL-Bref Quality of life item 1 (p = 0.04), considering statistical significant difference p 0.05. Correlation between the variables: quality of life, depression, anxiety and pain also demonstrates reduction in depression and anxiety according to Beck’s Depression and Anxiety Inventories (BDI and BAI), p 0.05. This effect was not observed in DLPFC stimulation group. Patients who believed they received active stimulation, in sham group, demonstrated potential for effective blinding. Conclusion: The tDCS applied to primary motor cortex effectively improved pain management and psychiatry symptoms in post-laminectomy syndrome patients. The technique’s low cost, ease of use, and high tolerability make it a promising adjuvant therapy for chronic pain conditions like post-laminectomy syndrome.

Personalized medicine in functional gastrointestinal disorders:Understanding pathogenesis to increase diagnostic and treatment efficacy

There is overwhelming evidence that functional gastrointestinal disorders(FGIDs) are associated with specific mechanisms that constitute important targets for personalized treatment. There are specific mechanisms in patients presenting with functional upper gastrointestinal symptoms(UGI Sx). Among patients with UGI Sx, approximately equal proportions(25%) of patients have delayed gastric emptying(GE), reduced gastric accommodation(GA), both impaired GE and GA,or neither, presumably due to increased gastric or duodenal sensitivity.Treatments targeted to the underlying pathophysiology utilize prokinetics,gastric relaxants, or central neuromodulators. Similarly, specific mechanisms in patients presenting with functional lower gastrointestinal symptoms, especially with diarrhea or constipation, are recognized, including at least 30% of patients with functional constipation pelvic floor dyssynergia and 5% has colonic inertia(with neural or interstitial cells of Cajal loss in myenteric plexus); 25% of patients with diarrhea-predominant irritable bowel syndrome(IBSD) has evidence of bile acid diarrhea; and, depending on ethnicity, a varying proportion of patients has disaccharidase deficiency, and less often sucrose-isomaltase deficiency. Among patients with predominant pain or bloating, the role of fermentable oligosaccharides, disaccharides, monosaccharides and polyols should be considered. Personalization is applied through pharmacogenomics related to drug pharmacokinetics, specifically the role of CYP2 D6, 2 C19 and 3 A4 in the use of drugs for treatment of patients with FGIDs. Single mutations or multiple genetic variants are relatively rare, with limited impact to date on the understanding or treatment of FGIDs. The role of mucosal gene expression in FGIDs, particularly in IBS-D, is the subject of ongoing research. In summary, the time for personalization of FGIDs, based on deep phenotyping, is here;pharmacogenomics is relevant in the use of central neuromodulators. There is still unclear impact of the role of genetics in the management of FGIDs.

Cerebral ischemia and neuroregeneration

Cerebral ischemia is one of the leading causes of morbidity and mortality worldwide. Although stroke （a form of cerebral ischemia）-related costs are expected to reach 240.67 billion dollars by 2030, options for treatment against cerebral ischemia/stroke are limited. All therapies except anti-thrombolytics （i.e., tissue plasminogen activator） and hypothermia have failed to reduce neuronal injury, neurological deficits, and mortality rates following cerebral ischemia, which suggests that development of novel therapies again st stroke/cerebral ischemia are urgently needed. Here, we discuss the possible mechanism（s） underlying cerebral ischemia-induced brain injury, as well as current and future novel therapies （i.e., growth factors, nicotinamide adenine dinucleotide, melatonin, resveratrol, protein kinase C isozymes, pifithrin, hypothermia, fatty acids, sympathoplegic drugs, and stem cells） as it relates to cerebral ischemia.

Multimodal treatment for spinal cord injury: a sword of neuroregeneration upon neuromodulation

Spinal cord injury is linked to the interruption of neural pathways,which results in irreversible neural dysfunction.Neural repair and neuroregeneration are critical goals and issues for rehabilitation in spinal cord injury,which require neural stem cell repair and multimodal neuromodulation techniques involving personalized rehabilitation strategies.Besides the involvement of endogenous stem cells in neurogenesis and neural repair,exogenous neural stem cell transplantation is an emerging effective method for repairing and replacing damaged tissues in central nervous system diseases.However,to ensure that endogenous or exogenous neural stem cells truly participate in neural repair following spinal cord injury,appropriate interventional measures(e.g.,neuromodulation)should be adopted.Neuromodulation techniques,such as noninvasive magnetic stimulation and electrical stimulation,have been safely applied in many neuropsychiatric diseases.There is increasing evidence to suggest that neuromagnetic/electrical modulation promotes neuroregeneration and neural repair by affecting signaling in the nervous system;namely,by exciting,inhibiting,or regulating neuronal and neural network activities to improve motor function and motor learning following spinal cord injury.Several studies have indicated that fine motor skill rehabilitation training makes use of residual nerve fibers for collateral growth,encourages the formation of new synaptic connections to promote neural plasticity,and improves motor function recovery in patients with spinal cord injury.With the development of biomaterial technology and biomechanical engineering,several emerging treatments have been developed,such as robots,brain-computer interfaces,and nanomaterials.These treatments have the potential to help millions of patients suffering from motor dysfunction caused by spinal cord injury.However,large-scale clinical trials need to be conducted to validate their efficacy.This review evaluated the efficacy of neural stem cells and magnetic or electrical stimulation combined with rehabilitation training and intelligent therapies for spinal cord injury according to existing evidence,to build up a multimodal treatment strategy of spinal cord injury to enhance nerve repair and regeneration.

Locus coeruleus-norepinephrine: basic functions and insights into Parkinson’s disease

The locus coeruleus is a pontine nucleus that produces much of the brain's norepinephrine.Despite its small size,the locus coeruleus is critical for a myriad of functions and is involved in many neurodegenerative and neuropsychiatric disorders.In this review,we discuss the physiology and anatomy of the locus coeruleus system and focus on norepinephrine's role in synaptic plasticity.We highlight Parkinson's disease as a disorder with motor and neuropsychiatric symptoms that may be understood as aberrations in the normal functions of locus coeruleus.

Epidural electrical stimulation for spinal cord injury

A long-standing goal of spinal cord injury research is to develop effective repair strategies,which can restore motor and sensory functions to near-normal levels.Recent advances in clinical management of spinal cord injury have significantly improved the prognosis,survival rate and quality of life in patients with spinal cord injury.In addition,a significant progress in basic science research has unraveled the underlying cellular and molecular events of spinal cord injury.Such efforts enabled the development of pharmacologic agents,biomaterials and stem-cell based therapy.Despite these efforts,there is still no standard care to regenerate axons or restore function of silent axons in the injured spinal cord.These challenges led to an increased focus on another therapeutic approach,namely neuromodulation.In multiple animal models of spinal cord injury,epidural electrical stimulation of the spinal cord has demonstrated a recovery of motor function.Emerging evidence regarding the efficacy of epidural electrical stimulation has further expanded the potential of epidural electrical stimulation for treating patients with spinal cord injury.However,most clinical studies were conducted on a very small number of patients with a wide range of spinal cord injury.Thus,subsequent studies are essential to evaluate the therapeutic potential of epidural electrical stimulation for spinal cord injury and to optimize stimulation parameters.Here,we discuss cellular and molecular events that continue to damage the injured spinal cord and impede neurological recovery following spinal cord injury.We also discuss and summarize the animal and human studies that evaluated epidural electrical stimulation in spinal cord injury.

A new brain stimulation method: Noninvasive transcranial magneto–acoustical stimulation

We investigate transcranial magneto–acoustical stimulation（TMAS） for noninvasive brain neuromodulation in vivo.TMAS as a novel technique uses an ultrasound wave to induce an electric current in the brain tissue in the static magnetic field. It has the advantage of high spatial resolution and penetration depth. The mechanism of TMAS onto a neuron is analyzed by combining the TMAS principle and Hodgkin–Huxley neuron model. The anesthetized rats are stimulated by TMAS, resulting in the local field potentials which are recorded and analyzed. The simulation results show that TMAS can induce neuronal action potential. The experimental results indicate that TMAS can not only increase the amplitude of local field potentials but also enhance the effect of focused ultrasound stimulation on the neuromodulation. In summary, TMAS can accomplish brain neuromodulation, suggesting a potentially powerful noninvasive stimulation method to interfere with brain rhythms for diagnostic and therapeutic purposes.

Transcranial magnetic stimulation for geriatric depression: Promises and pitfalls

As the global population gets older, depression in the elderly is emerging as an important health issue. A major challenge in treating geriatric depression is the lack of robust efficacy for many treatments that are of significant benefit to depressed working age adults. Repetitive transcranial magnetic stimulation(r TMS) is a novel physical treatment approach used mostly in working age adults with depression. Many TMS trials and clinics continue to exclude the elderly from treatment citing lack of evidence in this age group. In this review, we appraise the evidence regarding the safety and efficacy of rT MS in the elderly. A consistent observation supporting a high degree of tolerability and safety among the elderly patients emerged across the Randomised Controlled Trials and the uncontrolled trials. Further, there is no reliable evidence negating the utility of rT MS in the elderly with depression. We also identified several factors other than age that moderate the observed variations in the efficacy of rT MS in the elderly. These factors include but not limited to:(1) brain atrophy;(2) intensity and number of pulses(dose-response relationship); and(3) clinical profile of patients. On the basis of the current evidence, the practice of excluding elderly patients from TMS clinics and trials cannot be supported.

Central nervous system stimulation therapies in phantom limb pain:a systematic review of clinical trials

Phantom limb pain is a chronic pain syndrome that is difficult to cope with.Despite neurostimulation treatment is indicated for refractory neuropathic pain,there is scant evidence from randomized controlled trials to recommend it as the treatment choice.Thus,a systematic review was performed to analyze the efficacy of central nervous system stimulation therapies as a strategy for pain management in patients with phantom limb pain.A literature search for studies conducted between 1970 and September 2020 was carried out using the MEDLINE and Embase databases.Principles of The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline were followed.There were a total of 10 full-text articles retrieved and included in this review.Deep brain stimulation,repetitive transcranial magnetic stimulation,transcranial direct current stimulation,and motor cortex stimulation were the treatment strategies used in the selected clinical trials.Repetitive transcranial magnetic stimulation and transcranial direct current stimulation were effective therapies to reduce pain perception,as well as to relieve anxiety and depression symptoms in phantom limb pain patients.Conversely,invasive approaches were considered the last treatment option as evidence in deep brain stimulation and motor cortex stimulation suggests that the value of phantom limb pain treatment remains controversial.However,the findings on use of these treatment strategies in other forms of neuropathic pain suggest that these invasive approaches could be a potential option for phantom limb pain patients.