Neuromodulator interactions and spinal cord injury in lamprey

Neuromodulation is mediated by neurotransmitters that typically act on G-protein-coupled receptors.It can confer behavioural flexibility by modifying the functional properties of anatomically hard-wired neural circuits.Single neuromodulators generally have divergent cellular and synaptic effects（Harris-Warrick and Johnson,2010）,and different modulators,

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.

Transcranial Direct Current Stimulation: Effects on Motor and Non-Motor Symptoms of Parkinson’s Disease

Introduction: In the last thirty years, brain neuromodulation techniques have been used as an alternative to pharmacological treatment of neurological disorders. Parkinson’s disease (PD) is a neurodegenerative disorder leading to bradykinesia, rest tremor, postural changes, and non-motor symptoms such as depression, anxiety, sleep disorders, pain, and cognitive decline that compromises executive functions (EFs), responsible for the orderly execution of behaviors and tasks of daily life and intentional and directed actions. To this date, a few studies with transcranial direct current stimulation (tDCS) have shown beneficial effects in PD patients concerning specific motor and non-motor symptoms, targeting the motor cortex and/or prefrontal regions. Objective: The main objective of this study was to evaluate the effects of left prefrontal tDCS across a broad spectrum of motor and non-motor symptoms of PD using established validated scales. Method: Single-blind randomized clinical trial with 18 volunteers with PD, aged between 45 and 80 years (66.1 ± 9.65), who met inclusion and exclusion criteria. Participants were submitted to assessments of motor and non-motor functions employing psychometric scales and tests to evaluate EFs and were randomly divided into two groups: control (sham stimulation) and experimental (active stimulation). All participants were involved in three separate tDCS sessions. The anode was positioned over the left dorsolateral prefrontal cortex and the cathode over the right supraorbital region, with a direct current intensity of 2 mA, lasting 20 minutes. At the end of the three sessions, all participants were reassessed. Results: Significant effects of tDCS on non-motor functions were observed for cognition (verbal fluency of actions, clock copy test, appointment by visual confrontation, and verbal memory with immediate free recall) and subjective assessment of sleep quality (overall restlessness and discomfort in the arms and legs at night, leg and arm cramps at night and distressing dreams). There was also an improvement in the rate of errors and successes for congruent and incongruent stimuli of the Stroop Test. The beneficial effects on motor function were decreased rigidity, improved gait, and greater agility in the finger-tapping test. Conclusion: Three tDCS sessions showed positive results for participants with PD, producing significant improvements in various motor and non-motor functions, including sleep quality, cognition, and EFs. Additionally, the present results indicate that tDCS neuromodulation of the left dorsolateral prefrontal cortex region is feasible, safe, and provides significant objective benefits for PD patients.

Current Status of Neuromodulatory Therapies for Disorders of Consciousness

Treatment for disorders of consciousness （DOCs） is still a Gordian knot. Evidence-based guidelines on the treatment of DOC patients are not currently available, while neuromodulation techniques are seen as a potential treatment. Multiple neuromodulation therapies have been applied. This article reviews the most relevant studies in the literature in order to describe a clear picture of the current state of neuromodulation therapies that could be used to treat DOC patients. Both invasive and noninvasive brain stimulation is discussed. Significant behavioral improvements in prolonged DOCs under neuromodulation therapies are rare. The efficacy of various such therapies remains a matter of debate. Further clinical investigations of existing techniques in larger samples properly controlling for spontaneous recovery are needed, and new approaches are awaited.

Neuromodulatory therapies for patients with prolonged disorders of consciousness

Background:Reviving patients with prolonged disorders of consciousness(DOCs)has always been focused and challenging in medical research.Owing to the limited effectiveness of available medicine,recent research has increasingly turned towards neuromodulatory therapies,involving the stimulation of neural circuits.We summarised the progression of research regarding neuromodulatory therapies in the field of DOCs,compared the differences among different studies,in an attempt to explore optimal stimulation patterns and parameters,and analyzed the major limitations of the relevant studies to facilitate future research.Methods:We performed a search in the PubMed database,using the concepts of DOCs and neuromodulation.Inclusion criteria were:articles in English,published after 2002,and reporting clinical trials of neuromodulatory therapies in human patients with DOCs.Results:Overall,187 published articles met the search criteria,and 60 articles met the inclusion criteria.There are differences among these studies regarding the clinical efficacies of neurostimulation techniques for patients with DOCs,and large-sample studies are still lacking.Conclusions:Neuromodulatory techniques were used as trial therapies for DOCs wherein their curative effects were controversial.The difficulties in detecting residual consciousness,the confounding effect between the natural course of the disease and therapeutic effect,and the heterogeneity across patients are the major limitations.Large-sample,well-designed studies,and innovations for both treatment and assessment are anticipated in future research.

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.

Intestinal flora and depressive disorders:exploration and prospect of microbial-gut-brain axis

This paper examines the correlation between depressive disorders and intestinal flora.Depression is a common affective disorder characterized by low mood,loss of interest,anhedonia,high incidence,high recurrence rate,high disability rate,and high medical costs.The incidence and harmfulness of depressive disorder are gradually increasing,and its etiology is complex and diverse,among which the abnormal intestinal flora is considered to be one of the causes of depressive disorder.This article reviews the results of several studies that found intestinal flora imbalance in depressed patients,including changes in the type and quantity of flora and changes in metabolic pathways.In addition,antibiotic and probiotic treatments have also been shown to be effective in alleviating depressive symptoms,further indicating the importance of intestinal flora disturbances in the pathogenesis of depression.We also explored the relationship between intestinal flora and the pathogenesis of depressive disorders.Through neuro-immuno-endo-crine-metabolic pathways,intestinal flora can affect the function of the central nervous system,cause changes in the host’s mental behavior,and lead to or aggravate depressive symptoms.Overall,this study not only found differences in the intestinal flora of patients with depressive disorders but also revealed the potential role of intestinal flora in the pathogenesis.Importantly,this provides a new theoretical basis for further clarifying the pathogenesis of depressive disorders and formulating diagnosis and treatment strategies.

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.

Median arcuate ligamentum syndrome:Four case reports

BACKGROUND Median arcuate ligamentum syndrome(MALS)is a disease entity with unclear pathogenesis.If it is not considered in advance,the clinical diagnosis of the disease is very difficult because patients complain of digestive discomfort including pain.However,this characteristic is not specific to MALS.There have been no studies to assist in making a quick diagnosis.The aim of this case series was to recognize that MALS must be considered as a differential factor in the cause of abdominal pain.CASE SUMMARY We described cases in which four patients complained of abdominal pain over a long period but in whom a diagnosis of MALS could not be made.If the gastroenterologist does not take into account abdominal pain in advance,the patient is considered an asymptomatic gallstone patient and has their gallbladder removed despite imaging evaluation.The patient may also be considered a psychiatric patient and may be administered psychiatric drugs over a long period.In all four cases in this report,the patients experienced abdominal pain.In three cases,the diagnosis was possible by the clinician’s judgment considering both clinical symptoms and imaging techniques shortly after the onset of symptoms.However,in one case that lasted over 20 years,a clear diagnosis was not possible.Even after complaining of colicky pain and performing a cholecystectomy,the diagnosis was made only after the symptoms persisted.In all four cases,the symptoms were relieved by neuromodulators.CONCLUSION MALS is a rare disease and it is easy to miss because it is not malignant,but patients can suffer from pain over a long period.For the accurate diagnosis of a patient complaining of abdominal pain,the diagnosis must be differentiated.In addition,as there are asymptomatic patients,patients who need treatment should be carefully selected,and improvement with medical treatment can be expected.Large-scale studies are also needed.

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.