Noninvasive Brain Stimulation for Neurorehabilitation in Post-Stroke Patients: Comparison
Please note this is a comparison between Version 1 by Jianguang Xu and Version 5 by Catherine Yang.

Noninvasive brain stimulation (NIBS) is a popular neuromodulatory technology of rehabilitation focusing on the local cerebral cortex, which can improve clinical functions by regulating the excitability of corresponding neurons. Increasing evidence has been obtained from the clinical application of NIBS in post-stroke Through this approach, neurons or nerve signal transduction in adjacent or distant parts of the stimulation site are excited, inhibited, or regulated, thereby changing nerve function and improving the quality of life of patients, especially repetitive . The principle and research situation of NIBS techniques including transcranial magnetic stimulation (rTMS) and TMS), transcranial direct current stimulation (tDCS). With advances in neuronavigation technologies, functional near-infrared spectroscopy, and functional MRI, specific brain regions can be precisely located for, transcranial focused ultrasound stimulation (tFUS), and transcutaneous vagus nerve stimulation, which also (tVNS) were introduced in detail in the presents the possibility that neuromodulation in post-stroke rehabilitation evolving from a single target to multiple targets, circuit study. Due to the specific advantages of being noninvasive, painless, safe, and cheap, in addition to having different parameters and even networks. It is essential to review the findings of current research, discusstreatment modes, NIBS shows broad prospects for development. Application and future directions of NIBS application, and finallythem in Post-Stroke Rehabilitation were discussed to promote the use of NIBS in post-stroke rehabilitation.

  • noninvasive brain stimulation
  • repetitive transcranial magnetic stimulation
  • transcranial direct current stimulation
  • transcranial focused ultrasound stimulation
  • transcutaneous vagus nervestimulation
  • post-stroke

1. Introduction

Stroke, is the second-leading cause of death and the third-leading cause of disability in the world, and patients with stroke often suffer from functional impairmentscharacterized by high morbidity, mortality, and deficits [1]. Motor weisakness, sensory dysfunctbion, speech disturbances, dysphagia, unilateral neglect, cognitive dysfunction, and emotional impairment in post-stroke patients will need long-term rehabilitation [2][3][4]. The pathologlity, usually of stroke involves both the focal neurologic deficits and the impairment of the neural circuit or brain networks [5][6]. As a uses symptomeans of physical factor therapy, noninvasive brain stimulation (NIBS) is a physical therapy that can regulate specific regions in brain by electrical, magnetic, or ultrasound stimulation in vivo, thereby modulating the excitability of neurons and multiple cerebral hypoxia due to a sudden blockage or rupture of brain functions [7][8][9][10].

Thvesse effectls of NIBS on physical functions in post-stroke patients have been reported by extensive clinical research [11][12]. However, . It seriously threatens human life andue to the small sample size (less than 30 individuals) and unstandardized stimulhealth. Rehabilitation parameters of clinical studies [13][14][15], NIBS hais an ess enot yet been included in the standardized tretial treatment protocols for post-stroke rehabilitation.

2. Overview of Neuromodulation and NIBS

Npatieuromodulation technology refers to the use of implantable or non-implantable techniques (e.g., electrical, magnetic, or ultrasonic methods) to obtain therapeutic effects by changing the fts suffering from function or state of the nervous system. Through this approach, neurons or nerve signal transduction in adjacent or distant parts of the stimulation site are excited, inhibited, or regulated, thereby changing nerve function and improving the quality of life of patients [10][11][12]. Noninvasive neual impairments, through which hemiparomodulation techniques mainly include transcranial magnetic stimulation (TMS), transcranial electrical stimulation (tES), transcranial focused ultrasound stimulation (tFUS), transcranial unfocused ultrasound stimulation (tUUS), and transcutaneous vagus nerve stimulation (tVNS), among which repetitive transcranial magnetic stimulation (rTMS) and tDCS have proven effective in treating sis, aphasia, dysphagia, unilateral neglect, depression and pain [16][17][18]. Due to, and the specific advantages of being noninvasive, painless, safe, and cheap, in addition to having different parameters and treatment modes, NIBS shows broad prospects for development.

3. Technology and Research Situation of NIBS

3.1 TMS

TMS induces electricognitive dysfunction can be restored to val currents in the brain through electromagnetic induction caused by an energized coil placed on the scalp that is a highly effective, painless, and nious degrees.

Noninvasive brain stimulation procedure,(NIBS) causing changes in excitability and plasticity of the targeted cortical neuronal populations. Magnetic fields can penetrate the scalp and skull and generate subthreshold- or suprathreshold-induced currents in the cerebral cortex concurrently, which depolarize neurons to generate action potentials to modulate and stimulate neuronal activity in target areas, and then can mostly affect the cortex function by synchronizing activity in related brain regions [15]. The reis a popular neuromodulatory technologulatory effect of TMS on the cerebral cortex is influenced by factors such as coil shape, stimulation site, frequency, intensity, dosage (number of pulses, time, and duration) and other parameters.

3.2 tES

tES reof rehabilitation fers to physical therapy cusing electrical current to stimulate the brain, and it has gained popularity as a long-term therapy for patients with neurological disorders due to its convenience and potential effects on the brain network [19]. tES is an NIBS ton local cerebral cortechnique in experimental and clinical fields, including transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcranial pulsed current stimulation (tPCS), and transcranial random noise stimulation (tRNS). Unlike tACS and tDCS, tPCS can intrigue randomly generated quadratic pulses, which may in turn increase endogenously generated brain oscillations, thereby facilitating the synchronization of deep brain structures with cortical activity [20]. A, which can improve clinical functions by regulatinother promising alternative, tRNS, is a noisy electrical stimulation that increases cortical the excitability through a random “noise” resonance [21]. Bof coth of them are currently lacking in research, herein, the two most widely used tES techniques, tDCS and tACS, are summarized in the following section.

3.2.1 tDCS

tDCS mainly dresponding nelivers low direct current to brain tissue trons. Through electrodes placed on the scalp. A constant electric field can impact thethis approach, neurons in the cerebral cortex, thereby activating sodium-potassium pumps, calcium-dependent channels, and NMDA receptor activity to depolarize or hyperpolarize neuronal membrane potential [22][23], thuor nerve s regulating neuronal activity and cortical excitability. However, unlike TMS, tDCS does not induce action potentials directly, whereby stimulation sites are more scattered. Its effects are thought to be achieved by altering the polaritygnal transduction in adjacent or distant parts of the membrane to change their probability of triggering action potentials, thus modulating the activation of neurons in the stimulated area. The parameters of tDCS have a decisive effect on its biological effects [24], including electrode shape, size, number, placement, polarity, stimulation intensity, duration, and stimulation waveform [24][25][26], in wstimulation site are excited, inhibited, or regulated, thich slight changes will produce distinctly different effects [27].

3.2.2 tACS

tACS selectively enreby chances synaptic connectivity in neuronal circuits and synaptic plasticity by modulating the brain’s intrinsic endogenous neural oscillatory patterns and altering neurotransmitter levelsing nerve [28]. Then, tACS fultimately improves the coordinated activity between local brain areas and brain regions [19][29]. Unlike TMS and tDCS, tACS coction and impletely avoids skin irritations [19]. It stimulates cortovical neurons with sinusoidal or biphasic alternating current, modulates endogenous brain oscillations, and induces changes in synaptic plasticity to improve long-term brain function and depressive symptoms [30][31][32]. tACS uses difg the quality of life oferent parameter stimulation electrodes, alternating current to stimulate specific targeatients.

There are no acknowledged parameters, including stimulation frequency, intensity, phase, and duration, which may influence the effects of tACS.

3.3 tFUS

Ultrasound is an acoustic wavprinciple and rese with a frequency greater than the hearing detection level of the human ear (>20 kHz); it is a mechanical wave generated by the vibratirch situation of a sound source and propagated through a compressed and expanded medium. tFUS, especially MR-guided focused ultrasound (MRgFUS) [8], combfour NIBS techniques includines the properties of deep focus targeting with high spatial resolution. It can stimulate deep and relatively superficial brain tissue in a precise, stable, focused, and noninvasive manner [33], and transcranial magnetit has become one of the hot spots in basic and clinical research. The neuromodulatory effect of tFUS is mainly produced by the mechanical, thermal, and cavitation effects of ultrasound. By changing the frequency, intensity, pulse repetition frequency, pulse width, and duration of the ultrasound, the neurons at the stimulation (TMS), transcranial direct current stimulation site are activated or inhibited, thus regulating the neural function [9].

3.4 tVNS

tVNS involve(tDCS), trans applying electrical stimulation to peripheral vagus nerves. It transmits signals to the brain, causing changes in brain electrical activity and neurotransmitters, thereby modulating the functional activity of neurons [34]. tVNS can be mainly classifieranial focused ultrasound into two types: one is transcutaneous auricular vagus nerve stistimulation (taVNS), which consists of electrically stimulating the auricular branch of the vagus nerve [35] (especially the auricular vessels); anFUS), and the other is transcutaneous cervical vavagus nerve stimulation (tcVNS), which consists of electrically stimulating the vagus nerve in the carotid sheath of the anterolateral neck [36]. tVNS VNS) were introducexertsd neuromodulatory effects, mainly by transmitting electrical stimulation to the brain, as well as increasing the plasticity of neural activity idetailedly in the left prefrontal cortex, motor cortex, sensory cortexpresent [37], righst caudate nucleus, middle cingulate gyrus, and cerebellum [38]. It alsy. Due to enhances the plasticity of corticospinal motor pathways by activating widely projected neuromodulatory systems [39], ultimately increasinspecific advantag synaptic connections to muscle tissue and enhancing motor functions of [40].

4. Application of NIBS in Post-Stroke Rehabilitation

The usbe of NIBS in clinical practice is continuously developing, and its role and position in neurological rehabilitation have become increasingly prominent. Combined with adjunctive exercises, the application of NIBS has been extrapolated from the treatment of post-stroke motor dysfunction to sensory disorders, aphasia, dysphagia, unilateral neglect, cognitive dysfunction, depressiong noninvasive, painless, safe, and even disorders of consciousness in the acute phasecheap, [41].

5. Current Status and Prospects

5.1 Effectiveness and Sustainability

Due to the heterogeneity of stroke injury location and the differences in the site, frequency, and duration of NIBS stimulation, it is difficult to use uniform criteria to judge the effectiveness and long-term efficacy of NIBS. However, there is a time-dependent effect of NIBS. In particular, cognitive function is significantly correlated with the number and duration of stimulation [42], which has b addition to having different parameters and treatmeen well-validated by recent studies. The session of commonly used treatments for NIBS reported in studies generally ranges from 5 to 20 (1–4 weeks), with follow-up usually after the end of treatment; the longest reported effective duration is 1 year [43].

5.2 Limitations and Future Trends

5.2.1. Small Samples, and Insufficient and Short Follow-Up Studies

Firstly, most studies on the apt modes, NIBS shows broad plication of NIBS in stroke only included small sample sizes, usually fewer than 30 individuals in each group [44][45][46]. Secondly, mosspect of the current studies focused on motor function, speech, and cognitive function after stroke, mainly using rTMS and tDCS for intervention, while there are fewer studies investigating other functional impairments or using alternate NIBS techniques. Lastly, the follow-up duration after NIBS intervention in stroke patients was relatively short. Most studies assessed outcome indicators at the end of the intervention course, with the longest follow-up duration being 1 year [47].

5.2.2. Variety of Therapeutic Options and Prospects

In previous stu for development. Application andies, M1 and DLPFC were most frequently used as single stimulation targets, while other brain regions such as supplementary motor areas, S1, dACC, thalamus, and hippocampus have been rarely reported. Some recent studies found that functional connections are damaged in post-stroke patients [48]. Stimulating one or two targets ofuture directions of the same neural circuit can modulate the whole circuit and achieve better functional recovery. PAS protocols [49] incl fouding within-system, cross-system, and cortico–cortical, which are composed of rTMS or peripheral stimulation, provide the concept and feasibility of bi-targeted neuromodulation, especially cortico–cortical PA common NIBS [50][51]. On the basis of the understanding of brain network doctrine and the summary analysis of existing studies, we believe that neuromodulation can go from single-target stimulation to two-target stimulation, and then to multi-target stimulation of the same circuit, eventually achieving stimulchniques in Post-Stroke Rehabilitation of the whole brain network, which will be a future development direction. Animal experiments have reported similar approaches, such as modulation of touch being able to improve dexterous motor function [52].

Swere discussed to promotecondly, the protocols of these neuromodulation techniques in NIBS applied in stuse of NIBS. 

Moroke patients still need further optimization and can be combined into exponentially increasing stimulation programs depending on the choice of stimulation location, intensity, frequency, total time, and whether the stimulation is continuous or not [53], awell-designed high-quality randomong which the treatment parameters that may lead to adverse effects need further modification [54]. The opzed contimal parameters for TMS, tES, tFUS, and tVNS need to be more clearly defined and harmonized, and more comprehensive well-designed high-quality studieolled clinical trials on the selection of optimal parameters are expected to provide evidence for the early development of standardized therapeutic protocols forof various techniques of NIBS.

Lastly,NIBS most of the available studies focused on examining the therapeutic effects and neuromodulatory mechanisms of a particular technique in stroke, but the possibility of combining difechniques. Different NIBS techniques in stroke is often ignored. The main reasons for this may be the difficulty in assessing the effects of combining various techniques and the difficulty in explaining the interactions between the combinations. Given the differences in the mechanisms of various NIBS, the integration of different techniques may enhance the neuromodulatory effect, and different NIBS combination models have been reported in the literature for application in stroke patients, such as rTMS-tDCS and TMS-tACS [55]. There are also many studies comcombination on multi-target of the brain network will bining NIBS with fMRI or EEG [51] techniques, for example, TMS-EEG, and TMS-fMRI can be used in combination to better individualize and synchronize neuromodulation in stroke patients, revealing possible remote top-down effect at the neural population level [56]. Furthera future developmore, the combination of cathodal cerebellar tDCS and visual feedback was reported to improve balance control in a healthy population [57] ant direction in nd these findings should also be considered to deeply elaborate the mechanism of NIBS techniques in post-stroke dysfunction, which will be a future directiuromodulation of development.

6. Conclusions

NIBS can be used as a therapeutic measure in post-stroke neurorrehabilitation to promote recovery of functional impairment in patients when combined with movement training or other rehabilitation treatments. Overcoming the current limitations, NIBS can provide better and more precise modulation of neural circuits and neural networks, reduce adverse effects, and improve therapeutic effectiveness.

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