Exploiting fly models to investigate rare human neurological disorders

Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted therapies.To investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary time.Genetic tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological diseases.Drosophila boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug candidates.Researchers can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical trials.In this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic implications.We discuss rare diseases associated with both neuron-expressed and glial-expressed genes.Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal movements.And we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell syndrome.Loss-of-function mutations in ACOX1 result in ACOX1 deficiency,characterized by very-long-chain fatty acid accumulation and glial degeneration.Notably,this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology,offering a platform for the rapid identification of potential therapeutic interventions.Rare neurological diseases involve a wide range of expression systems,and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia.Furthermore,mutations within the same gene may result in varying functional outcomes,such as complete loss of function,partial loss of function,or gain-of-function mutations.The phenotypes observed in patients can differ significantly,underscoring the complexity of these conditions.In conclusion,Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases.By facilitating the modeling of these conditions,Drosophila contributes to a deeper understanding of their genetic basis,pathophysiology,and potential therapies.This approach accelerates the discovery of promising drug candidates,ultimately benefiting patients affected by these complex and understudied diseases.

Potassium and calcium channels in different nerve cells act as therapeutic targets in neurological disorders

The central nervous system, information integration center of the body, is mainly composed of neurons and glial cells. The neuron is one of the most basic and important structural and functional units of the central nervous system, with sensory stimulation and excitation conduction functions. Astrocytes and microglia belong to the glial cell family, which is the main source of cytokines and represents the main defense system of the central nervous system. Nerve cells undergo neurotransmission or gliotransmission, which regulates neuronal activity via the ion channels, receptors, or transporters expressed on nerve cell membranes. Ion channels, composed of large transmembrane proteins, play crucial roles in maintaining nerve cell homeostasis. These channels are also important for control of the membrane potential and in the secretion of neurotransmitters. A variety of cellular functions and life activities, including functional regulation of the central nervous system, the generation and conduction of nerve excitation, the occurrence of receptor potential, heart pulsation, smooth muscle peristalsis, skeletal muscle contraction, and hormone secretion, are closely related to ion channels associated with passive transmembrane transport. Two types of ion channels in the central nervous system, potassium channels and calcium channels, are closely related to various neurological disorders, including Alzheimer's disease, Parkinson's disease, and epilepsy. Accordingly, various drugs that can affect these ion channels have been explored deeply to provide new directions for the treatment of these neurological disorders. In this review, we focus on the functions of potassium and calcium ion channels in different nerve cells and their involvement in neurological disorders such as Parkinson's disease, Alzheimer's disease, depression, epilepsy, autism, and rare disorders. We also describe several clinical drugs that target potassium or calcium channels in nerve cells and could be used to treat these disorders. We concluded that there are few clinical drugs that can improve the pathology these diseases by acting on potassium or calcium ions. Although a few novel ion-channelspecific modulators have been discovered, meaningful therapies have largely not yet been realized. The lack of target-specific drugs, their requirement to cross the blood–brain barrier, and their exact underlying mechanisms all need further attention. This review aims to explain the urgent problems that need research progress and provide comprehensive information aiming to arouse the research community's interest in the development of ion channel-targeting drugs and the identification of new therapeutic targets for that can increase the cure rate of nervous system diseases and reduce the occurrence of adverse reactions in other systems.

Neuroprotective potential of traditional Ayurvedic Kadha:age-related neurological disorders:a comprehensive literature review

Despite modern medicine’s advancements,age-related neurological diseases like Alzheimer’s disease and Parkinson’s disease remain challenging due to high costs,side effects,and limited accessibility.Ayurveda,a traditional Indian medicine system,offers Kadha tea as a potential herbal option.This review explores Kadha’s components(basil(Ocimum basilicum L.),black pepper(Piper nigrum L.),Cinnamon(Cinnamomum verum J.Presl),ginger(Zingiber officinale Roscoe),and raisin(Vitis vinifera L.))and their interaction with various neurological disorders.Studies suggest Kadha exhibits anti-inflammatory,antioxidant,and antiviral properties,potentially impacting Alzheimer’s disease,Parkinson’s disease,neurotoxicity,neuroinflammation,and brain trauma.By focusing on specific disease mechanisms and Kadha’s intergrade effects,this review aims to elucidate its potential role in managing age-related neurological disorders.

Neurological Disorders Caused by Structural Dysfunction of VANGL2

Background: VANGL2 plays a variety of roles in various cellular processes, including tissue morphogenesis, asymmetric cell division, and nervous system development. There is currently a lack of systematic organization in the development and disease of the nervous system. Purpose: To explore the role of VANGL2 in the development of the nervous system and related diseases. Methods: Literature review and analysis of the role of VANGL2 in the development and disease of the nervous system. Results: VANGL2 defects lead to the development of the nervous system through the misconfiguration of various cells, which affects the development of the cochlea, the conduction of neural signals, and the development of nervous system-related diseases such as Alzheimer’s disease, GBM, Bohling-Opitz syndrome, and hydrocephalus. Conclusions: The VANGL2 gene is essential for nervous system development and its deficiency is linked to severe congenital conditions and various disorders, highlighting the need for more research on treatments for related gene defects.

Liposomes as versatile agents for the management of traumatic and nontraumatic central nervous system disorders:drug stability,targeting efficiency,and safety

Various nanoparticle-based drug delivery systems for the treatment of neurological disorders have been widely studied.However,their inability to cross the blood–brain barrier hampers the clinical translation of these therapeutic strategies.Liposomes are nanoparticles composed of lipid bilayers,which can effectively encapsulate drugs and improve drug delivery across the blood–brain barrier and into brain tissue through their targeting and permeability.Therefore,they can potentially treat traumatic and nontraumatic central nervous system diseases.In this review,we outlined the common properties and preparation methods of liposomes,including thin-film hydration,reverse-phase evaporation,solvent injection techniques,detergent removal methods,and microfluidics techniques.Afterwards,we comprehensively discussed the current applications of liposomes in central nervous system diseases,such as Alzheimer's disease,Parkinson's disease,Huntington's disease,amyotrophic lateral sclerosis,traumatic brain injury,spinal cord injury,and brain tumors.Most studies related to liposomes are still in the laboratory stage and have not yet entered clinical trials.Additionally,their application as drug delivery systems in clinical practice faces challenges such as drug stability,targeting efficiency,and safety.Therefore,we proposed development strategies related to liposomes to further promote their development in neurological disease research.

Neurological disorders and inflammatory bowel diseases

Extraintestinal manifestations occur in about one-third of patients living with inflammatory bowel disease(IBD) and may precede the onset of gastrointestinal symptoms by many years. Neurologic disorders associated with IBD are not frequent, being reported in 3% of patients, but they often represent an important cause of morbidity and a relevant diagnostic issue. In addition, the increasing use of immunosuppressant and biological therapies for IBD may also play a pivotal role in the development of neurological disorders of different type and pathogenesis. Hence, we provide a complete and profound review of the main features of neurological complications associated with IBD, with particular reference to those related to drugs and with a specific focus on their clinical presentation and possible pathophysiological mechanisms.

Potential effects of mesenchymal stem cell derived extracellular vesicles and exosomal miRNAs in neurological disorders

Mesenchymal stem cells are multipotent cells that possess anti-inflammatory,antiapoptotic and immunomodulatory properties.The effects of existing drugs for neurodegenerative disorders such as Alzheimer’s disease are limited,thus mesenchymal stem cell therapy has been anticipated as a means of ameliorating neuronal dysfunction.Since mesenchymal stem cells are known to scarcely differentiate into neuronal cells in damaged brain after transplantation,paracrine factors secreted from mesenchymal stem cells have been suggested to exert therapeutic effects.Extracellular vesicles and exosomes are small vesicles released from mesenchymal stem cells that contain various molecules,including proteins,mRNAs and microRNAs.In recent years,administration of exosomes/extracellular vesicles in models of neurological disorders has been shown to improve neuronal dysfunctions,via exosomal transfer into damaged cells.In addition,various microRNAs derived from mesenchymal stem cells that regulate various genes and reduce neuropathological changes in various neurological disorders have been identified.This review summarizes the effects of exosomes/extracellular vesicles and exosomal microRNAs derived from mesenchymal stem cells on models of stroke,subarachnoid and intracerebral hemorrhage,traumatic brain injury,and cognitive impairments,including Alzheimer’s disease.

Targeting Gut Microbiota Dysbiosis: Potential Intervention Strategies for Neurological Disorders

It is well known that the gut microbiota plays an extremely important role in modulating host physiological functions such as immunity and metabolic homeostasis.In recent years,accumulated evidence has revealed that the gut microbiota can regulate the functions of the central nervous system(CNS)through the gut-brain axis,which provides a novel insight into the interactions between the gut and brain.This review focuses on the molecular mechanism of the crosstalk between the gut microbiota and the brain via the gut-brain axis,and on the onset and development of neurological disorders triggered by gut microbiota dysbiosis.These topics are followed by a critical analysis of potential intervention strategies targeting gut microbiota dysbiosis,including the use of probiotics,prebiotics,synbiotics,and diets.While research on the microbiota-gut-brain axis is still in its relative infancy,clarifying the molecular mechanism that underlies how the gut microbiota regulates neurological functions not only holds the promise of revealing potentially novel pathogeneses of neurological disorders,but also may lead to the development of potential diagnosis biomarkers and intervention strategies targeting microbiota dysbiosis for neurological disorders.

Stem cells:a promising candidate to treat neurological disorders

Neurologic impairments are usually irreversible as a result of limited regeneration in the central nervous system.Therefore,based on the regenerative capacity of stem cells,transplantation therapies of various stem cells have been tested in basic research and preclinical trials,and some have shown great prospects.This manuscript overviews the cellular and molecular characteristics of embryonic stem cells,induced pluripotent stem cells,neural stem cells,retinal stem/progenitor cells,mesenchymal stem/stromal cells,and their derivatives in vivo and in vitro as sources for regenerative therapy.These cells have all been considered as candidates to treat several major neurological disorders and diseases,owing to their self-renewal capacity,multi-directional differentiation,neurotrophic properties,and immune modulation effects.We also review representative basic research and recent clinical trials using stem cells for neurodegenerative diseases,including Parkinson＇s disease,Alzheimer＇s disease,and age-related macular degeneration,as well as traumatic brain injury and glioblastoma.In spite of a few unsuccessful cases,risks of tumorigenicity,and ethical concerns,most results of animal experiments and clinical trials demonstrate efficacious therapeutic effects of stem cells in the treatment of nervous system disease.In summary,these emerging findings in regenerative medicine are likely to contribute to breakthroughs in the treatment of neurological disorders.Thus,stem cells are a promising candidate for the treatment of nervous system diseases.

What have we learned about the kallikrein-kinin and renin-angiotensin systems in neurological disorders?

The kallikrein-kinin system(KKS) is an intricate endogenous pathway involved in several physiological and pathological cascades in the brain. Due to the pathological effects of kinins in blood vessels and tissues, their formation and degradation are tightly controlled. Their components have been related to several central nervous system diseases such as stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy and others. Bradykinin and its receptors(B1R and B2R) may have a role in the pathophysiology of certain central nervous system diseases. It has been suggested that kinin B1R is up-regulated in pathological conditions and has a neurodegenerative pattern, while kinin B2R is constitutive and can act as a neuroprotective factor in many neurological conditions. The renin angiotensin system(RAS) is an important blood pressure regulator and controls both sodium and water intake. AngⅡ is a potent vasoconstrictor molecule and angiotensin converting enzyme is the major enzyme responsible for its release. AngⅡ acts mainly on the AT1 receptor, with involvement in several systemic and neurological disorders. Brain RAS has been associated with physiological pathways, but is also associated with brain disorders. This review describes topics relating to the involvement of both systems in several forms of brain dysfunction and indicates components of the KKS and RAS that have been used as targets in several pharmacological approaches.

nNOS-mediated protein-protein interactions:promising targets for treating neurological and neuropsychiatric disorders

Neurological and neuropsychiatric disorders are one of the leading causes of disability worldwide and affect the health of billions of people.Nitric oxide(NO),a free gas with multitudinous bioactivities,is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase(nNOS)in the brain.Inhibiting nNOS benefits a variety of neurological and neuropsychiatric disorders,including stroke,depression and anxiety disorders,posttraumatic stress disorder,Parkinson’s disease,Alzheimer’s disease,chronic pain,and drug addiction.Due to critical roles of nNOS in learning and memory and synaptic plasticity,direct inhibition of nNOS may cause severe side effects.Importantly,interactions of several proteins,including post-synaptic density 95(PSD-95),carboxyterminal PDZ ligand of nNOS(CAPON)and serotonin transporter(SERT),with the PSD/Disc-large/ZO-1 homologous(PDZ)domain of nNOS have been demonstrated to influence the subcellular distribution and activity of the enzyme in the brain.Therefore,it will be a preferable means to interfere with nNOS-mediated proteinprotein interactions(PPIs),which do not lead to undesirable effects.Herein,we summarize the current literatures on nNOS-mediated PPIs involved in neurological and neuropsychiatric disorders,and the discovery of drugs targeting the PPIs,which is expected to provide potential targets for developing novel drugs and new strategy for the treatment of neurological and neuropsychiatric disorders.

Current sustained delivery strategies for the design of local neurotrophic factors in treatment of neurological disorders

Although therapeutic potential of neurotrophic factors(NTFs)has been well recognized for over two decades,attempts to translate that potential to the clinic have been disappointing,largely due to significant obstacles in delivery,including inadequate protein dose/kinetics released at target sites.Considerable efforts have been made to improve the therapeutic performance of NTFs.This articles reviews recent developments in localized delivery systems of NTFs for the neurological disorders treatments with a main focus on sustained delivery strategies.Different non-covalent binding approaches have been employed to immobilize proteins in hydrogels,microspheres,electrospun nanofibers,and their combined systems,which serve as depots for sustained local release of NTFs.The challenges associated with current NTFs delivery systems and how these systems can be applied to neurological diseases and disorders have been discussed in the review.In conclusion,optimal delivery systems for NTFs will be needed for reliable and meaningful clinical benefits;ideally,delivering a time and dose-controlled release of bioactive multiNTFs at different individual optimal kinetics to achieve multi-functions in target tissues is significant preferred.

Past,present,and future of deep transcranial magnetic stimulation:A review in psychiatric and neurological disorders

Deep transcranial magnetic stimulation(DTMS)is a new non-invasive neuromodulation technique based on repetitive transcranial magnetic stimulation technology.The new H-coil has significant advantages in the treatment and mechanism research of psychiatric and neurological disorders.This is due to its deep stimulation site and wide range of action.This paper reviews the clinical progress of DTMS in psychiatric and neurological disorders such as Parkinson’s disease,Alzheimer’s disease,post-stroke motor dysfunction,aphasia,and other neurological disorders,as well as anxiety,depression,and schizophrenia.

Drug utilization evaluation of medications used in the management of neurological disorders

Background and object:The burden of neurological disorders in India is expected to increase due to the rapid demographic and epidemiological transition,with irrational drug use,which is also a global concern.Thus,drug utilization evaluation is designed to ensure appropriate medicine use within the healthcare settings.The aim of the study was to assess the rate and pattern of drug utilization in the management of neurological disorders.Materials and methods:A hospital-based cross-sectional drug utilization evaluation study on neurological drugs was carried out at the Department of Neurology over a span of six months.All legible prescriptions consisting neurological medications irrespective of patient's gender,aged≥18 years were included for the study.The World Health Organization(WHO)core drug use indicators were used to assess the drug prescribing and utilization patterns.Results:A total of 310 prescriptions were reviewed,where male predominance was found to be 56.45%.Out of 310 prescriptions,drugs belonging to 26 neurological classes were prescribed for the management of various neurological disorders.The majority of patients were diagnosed with epilepsy and the most prescribed drugs per patient were phenytoin(14.8%)and valproic acid(6.45%).By following the WHO core drug prescribing indicators,65.47%of drugs prescribed from the India National List of Essential Medicines,2022,followed by 29.83%of drugs prescribed in generic name and 10.86%of prescriptions including injections.Conclusion:The study findings showed that the prescribing pattern in the Department of Neurology was in accordance with the WHO core prescribing indicators.But,the extent of polypharmacy prescriptions was very high.Therefore,interventions are very necessary to promote rational drug prescribing patterns and thus clinical pharmacists can contribute to assess and review the drug utilization pattern to optimize the drug therapy and improvement in patient safety.

Tongue dysfunction in neurological and neuromuscular disorders: A narrative literature review

Evaluation of oral function is useful for tracking longitudinal changes in swallowing function. Using videofluoroscopic(VF) images, we can evaluate swallowing function, but it is extremely difficult to quantitatively evaluate the oral phase. Recently, several studies have tried to quantitatively assess tongue function by analyzing tongue movement on VF images, to measure tongue thickness by ultrasonography, and to measure tongue pressure as surrogate for tongue strength. In this review article,the current state of quantitative assessments of tongue function for identification and management of dysphagia in patients with neuromuscular and other neurological disorders(NNMD) has been outlined. Disturbed bolus transport in patients with NNMD has been quantitatively measured on VF images by analyzing tongue base movement and bolus transport from the mouth to the pharynx. Enlarged tongue in Duchenne muscular dystrophy patients were observed by measuring the transverse width of the tongue on ultrasound. Tongue pressures that were measured using a handheld probe in NNMD patients were less than half of those in healthy subjects. More studies are needed to develop guidelines what types of tongue dysfunction give an indication of adjusting diet and introducing tube feeding to NNMD patients.

Induced pluripotent stem cells for modeling neurological disorders

Several diseases have been successfully modeled since the development of induced pluripotent stem cell(i PSC) technology in 2006. Since then, methods for increased reprogramming efficiency and cell culture maintenance have been optimized and many protocols for differentiating stem cell lines have been successfully developed, allowing the generation of several cellular subtypes in vitro. Gene editing technologies have also greatly advanced lately, enhancing disease-specific phenotypes by creating isogenic cell lines, allowing mutations to be corrected in affected samples or inserted in control lines. Neurological disorders have benefited the most from i PSC-disease modeling for its capability for generating disease-relevant cell types in vitro from the central nervous system, such as neurons and glial cells, otherwise only available from post-mortem samples. Patient-specific i PSC-derived neural cells can recapitulate the phenotypes of these diseases and therefore, considerably enrich our understanding of pathogenesis, disease mechanism and facilitate the development of drug screening platforms for novel therapeutic targets. Here, we review the accomplishments and the current progress in human neurological disorders by using i PSC modeling for Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy, amyotrophic lateral sclerosis, duchenne muscular dystrophy, schizophrenia and autism spectrum disorders, which include Timothy syndrome, Fragile X syndrome, Angelman syndrome, Prader-Willi syndrome, PhelanMc Dermid, Rett syndrome as well as Nonsyndromic Autism.

Type-B monoamine oxidase inhibitors in neurological diseases:clinical applications based on preclinical findings

Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.

Studying neurological disorders using induced pluripotent stem cells and optogenetics

Neurological disorders are amongst the most widely studied human aliments.Yet,they are also one of the most poorly understood.Although most of these disorders are polygenic,genotype still plays an important role in their etiologies.For example,in schizophrenia and autism spectrum disorders,there is a 40-60%concordance rate in monozygotic twins,with 60-90%heritability（Burmeister et al.,2008）.However,the mechanisms by which multiple genes and their genomic variations influence the phenotypes of the disorders remain to be understood. The complexities of the disorders are tur- ther compounded by the individual rarity of the genomic variations and their variable penetrance （Cook and Scherer, 2008）. Thus, conventional disease modeling, such as gene knockout in cells or in animals, to attain the desired disease genotype may not be the most suitable platform for tackling most neurological disorders.

The importance of fasciculation and elongation protein zeta-1 in neural circuit establishment and neurological disorders

The human brain contains an estimated 100 billion neurons that must be systematically organized into functional neural circuits for it to function properly.These circuits range from short-range local signaling networks between neighboring neurons to long-range networks formed between various brain regions.Compelling converging evidence indicates that alterations in neural circuits arising from abnormalities during early neuronal development or neurodegeneration contribute significantly to the etiology of neurological disorders.Supporting this notion,efforts to identify genetic causes of these disorders have uncovered an over-representation of genes encoding proteins involved in the processes of neuronal differentiation,maturation,synaptogenesis and synaptic function.Fasciculation and elongation protein zeta-1,a Kinesin-1 adapter,has emerged as a key central player involved in many of these processes.Fasciculation and elongation protein zeta-1-dependent transport of synaptic cargoes and mitochondria is essential for neuronal development and synapse establishment.Furthermore,it acts downstream of guidance cue pathways to regulate axo-dendritic development.Significantly,perturbing its function causes abnormalities in neuronal development and synapse formation both in the brain as well as the peripheral nervous system.Mutations and deletions of the fasciculation and elongation protein zeta-1 gene are linked to neurodevelopmental disorders.Moreover,altered phosphorylation of the protein contributes to neurodegenerative disorders.Together,these findings strongly implicate the importance of fasciculation and elongation protein zeta-1 in the establishment of neuronal circuits and its maintenance.

Random noise stimulation in the treatment of patients with neurological disorders

Random noise stimulation technique involves applying any form of energy(for instance,light,mechanical,electrical,sound)with unpredictable intensities through time to the brain or sensory receptors to enhance sensory,motor,or cognitive functions.Random noise stimulation initially employed mechanical noise in auditory and cutaneous stimuli,but electrical energies applied to the brain or the skin are becoming more frequent,with a series of clinical applications.Indeed,recent evidence shows that transcranial random noise stimulation can increase corticospinal excitability,improve cognitive/motor performance,and produce beneficial aftereffects at the behavioral and psychological levels.Here,we present a narrative review about the potential uses of random noise stimulation to treat neurological disorders,including attention deficit hyperactivity disorder,schizophrenia,amblyopia,myopia,tinnitus,multiple sclerosis,post-stroke,vestibular-postural disorders,and sensitivity loss.Many of the reviewed studies reveal that the optimal way to deliver random noise stimulation-based therapies is with the concomitant use of neurological and neuropsychological assessments to validate the beneficial aftereffects.In addition,we highlight the requirement of more randomized controlled trials and more physiological studies of random noise stimulation to discover another optimal way to perform the random noise stimulation interventions.