Non-invasive Brain Stimulation Post Stroke

Abstract

Stroke is the second most common cause of death and dementia and the first most common cause of disability in developed nations. Tissue in the penumbra may be salvaged by reperfusion treatment using recombinant tissue plasminogen activator or thrombectomy with a stent retriever, which improves the ultimate neurological prognosis. However, because of the limited therapeutic window of 6 hours, it is only available to 5–10% of the community. Non-invasive brain stimulation (NIBS) has recently gotten a lot of interest for its potential involvement in stroke recovery. When used correctly, NIBS methods employ electrical and magnetic stimulation to modify the excitability of deep brain tissue without harming it. This may result in long-term neuroplastic modifications. Based on different protocols, stimulation to the cerebral cortex can be either excitatory or inhibitory. This has led to NIBS being used therapeutically to alleviate depression. In recent years, stroke patients have been studied to see whether NIBS has therapeutic benefits on cognitive skills.

1. Introduction

Stroke is the world’s second leading cause of death and the third leading cause of disability [1]. Stroke survivors may experience a variety of disabilities that require temporary or long-term assistance. It has a major impact on the patient, their family, the economy of the country, and the world economy [2]. The burden of stroke-related damage is expected to rise in the following decades as the population ages. Even though the death rate from stroke has reduced, the incidence of stroke has not, increasing the number of stroke survivors [3].

Even if people with this condition survive the acute period of their illness, they may have long-term physical and psychological consequences. After the first stroke, the quality of life and health are significantly reduced due to post-stroke impairment [4]. It is still difficult to regain arm and hand function after a stroke, despite stroke rehabilitation methods showing some promise. Due to the increase in the incidence of strokes in 2030 and inadequate facilities offering reperfusion treatments within the small therapeutic window, novel approaches to promote spontaneous brain plasticity are needed [5]. Post-lesional brain plasticity after stroke may be helpful or “adaptive,” or harmful or “maladaptive,” which hinders neurological rehabilitation [6].

Individuals may have considerable dysfunction due to cognitive impairment after a stroke. Memory loss, attention problems, executive and behaviour issues are the most common symptoms seen. After conducting a nationwide epidemiological cohort study on the population and prevalence of chronic brain damage, researchers found that memory impairment (90%), attention disturbance (82%), and executive function impairments were the most frequent cognitive symptoms (75%). Injury mechanisms, demographics, and social variables all impact the intensity and range of cognitive symptoms. Research suggests that 42–92% of patients in the acute phase have attention deficit disorder, and 24–51% have symptoms after leaving acute care. According to recent research, 23–55% of stroke survivors experience memory problems within 3 months, while 11–31% experience memory impairment a year after their stroke. This percentage is comparable in the traumatic brain injury (TBI) group (25%). When people suffer from Unilateral Spatial Neglect (USN) [7], they have trouble orienting themselves or responding or reporting stimuli that emerge on the side opposite the lesion. Stroke patients are more likely than the average population to develop USN. As a result of these cognitive difficulties, rehabilitation efforts are severely hampered, as is returning to work. Cognitive rehabilitation is primarily concerned with making positive changes in a person’s day-to-day life. Instead, cognitive rehabilitation relies on learning compensatory techniques and strategies that have an impact on cognitive function [8]. Several systematic evaluations have looked at how well people recover cognitively after a stroke or traumatic brain injury [9].

In addition to invasive treatments, there has been an increase in interest in examining the influence of non-invasive cortical stimulation on the rehabilitation process [3]. Neuromodulatory non-invasive brain stimulation (NIBS) approaches are being tested to improve motor function following a stroke. Neuromodulation aims to improve adaptively or reduce maladaptive post-stroke reorganisation processes [10].

The idea behind NIBS came from Faraday’s law of induction when, in the 1980s, some researchers stimulated specific areas of the brain using a pulsed magnetic field and noticed changes in the neuronal firing and impulse conduction. Barker et al. demonstrated the first example of transcranial magnetic stimulation (TMS) [11].

Prior to that, electroconvulsive therapy (ECT) to treat severe depression had already been in use since the 1940s. Further studies led to the knowledge that TMS can change the balance between excitation and inhibition leading to speculation that it might be useful in treating conditions such as Parkinson’s disease. However, it was not until the 1990s that specific stimulators were developed that could deliver repetitive impulses to the brain. This lead to the development of a technique called transcranial direct-current stimulation (tDCS) [12, 13].

Transcranial magnetic stimulation (TMS) and transcranial direct-current stimulation (tDCS) have been studied for their effects on motor, sensory, and cognitive skills in stroke patients [3].

TMS can change function and enhance or reduce activity in cortical areas depending on stimulation frequency, duration, coil form, and magnetic field strength. The effects of repeated transcranial magnetic stimulation (rTMS) on cortical excitability can linger up to 2 hours after the stimulation cycle has ended. From minutes to 1 to 2 hours, tDCS can increase or decrease excitability in the stimulated region. Unlike TMS, tDCS appears to modify the activation of sodium- and calcium-dependent channels, as well as NMDA receptor function, causing LTP and LTD-like alterations (Figure 1) [15, 16].

Figure 1.

Examples of commercial (A) transcranial direct-current stimulation and (B) transcranial magnetic stimulation equipment, (C, D) coil/electrode montage over the motor cortex, and (D, E) maps of electrical fields generated [14].

1.1 Brain plasticity after stroke

Cortical plasticity refers to the brain’s capacity to change how it functions as a consequence of new learning. In other words “plasticity” refers to any changes in brain organisation as a result of repeated exposure to a stimulus. The term “synaptic plasticity” refers to the ability of synapses to change their strength over time. A single synapse houses all of the plasticity’s manifestations. Both short-term synaptic plasticity and long-term synaptic plasticity have been documented, indicating that synaptic transmission may be boosted or decreased in different time periods [17]. A mechanism known as LTP has been extensively explored when it comes to learning and memory. However, brain damage has been linked to plasticity. That is all it says about the processes at work; it does not explain how the brain may modify its functional and structural structure (both histologically and anthropologically) in the wake of injury and make better use of what is left. The excitability of neuronal networks close and far from the affected region is altered by a stroke. There is less or greater positive plasticity in people who do not fully heal from their injuries. Activity-dependent rebuilding and synaptic strengthening are two pathways for plasticity. Brain-derived nerve factor (BDNF) increases glutamate release and synaptic activity over time. According to animal studies, after a stroke, there is a short window of neuroplasticity during which the most significant advances in recovery may be made. Identifying the processes involved in post-stroke healing and optimising their promotion in each person is the problem.

Another problem is that opposite effects occur at the same time. Tonic inhibition through GABA overexpression is seen in the acute phase of the peri-infarct region. Neuroprotective method to prevent excitotoxicity as well as neuronal death has been hypothesised. Increasing behavioural recovery by blocking GABAergic activity for 1 month might be beneficial. TMS may detect this drop-in activity in the acute period in the patient. The idea was developed over two decades ago, works by delivering a high-intensity electric current through a coil to activate the cortex. For a duration of 0.3–1 ms, a magnetic field of 2–2.5 Tesla is generated by a microsecond-long discharge. A coil is positioned on the scalp to reach the cortex, and the coil creates a magnetic current. An electromagnetic field is formed inside the brain, which dissipates after 3 cm, according to the Faraday principle. This electric field depolarizes neurons in the brain beneath the coil, either directly through an axon hillock or indirectly through depolarizing interneurons [18].

The result of using TMS on the motor cortex is an involuntary contralateral muscular contraction. The magnitude of this motor-evoked potential (MEP) is connected to the number of neurons that have responded to the stimulation, and the latency is a technique to determine that how long it takes for inspiration to generate an MEP. Stroke survivors are on a follow-up of up to 1 year using the following prognostic criteria—the persistence of a motor-evoked potential (MEP) after stimulating the affected hemisphere, which is an excellent predictor of recovery. In contrast, hypo excitability showing lack of response is an indicator of poor functional outcome. However, a condition known as “diaschisis” might result from a unilateral brain injury in which brain regions are affected distant from the lesion site. This term was first used in 1914 by von Monakow. The consequences of a localised brain lesion on physically distant but functionally related regions are discussed [19]. It was initially a clinical notion, but several functional imaging modalities that indicate a change in blood flow to the brain in targeted regions make it possible to display cerebellar diaschisis and transcallosal diaschisis on contralateral cortical regions. A deafferentation mechanism in which the wounded cortex prevents the healthy target structure from being activated is the principle at work (or injured subcortical area). According to Roy and Sherrington’s neurovascular coupling hypothesis, this activation may be either excitatory or inhibitory, affecting the metabolism and local blood flow [20].

The existence of a cortico-cerebellar diaschisis during the acute phase of stroke was related to a worse clinical prognosis after 2 months. Through the corpus callosum, the inter-hemispheric route is highly inhibited. Healthy brains have balanced interhemispheric inhibition, meaning that neither hemisphere is a more significant “inhibitor” than another. Neurovascular coupling theory says that after an infarct on one side, increased cerebral blood flow in the contralateral identical region corresponds to greater activity in that region. This was associated with the most severe impairments, which was surprising. As a result, the contralateral hemisphere continues to impose its inhibitory tone on ischemic hypoactivity, adding to the neurological deficit’s rapid progression. As previously stated, the stroke and the overwhelming imbalanced inhibitory impulse from the better and healthier contralateral hemisphere would cause the ipsilateral ischemic cortex to become doubly impaired. As early as the first week following a stroke, there is evidence of an unbalanced interhemispheric inhibition. Two types of intracortical inhibitory circuits may be studied using TMS paired-pulse protocols—those that are mediated by GABA-A and those by GABA-B.TMS was utilised to discover predictive markers in an investigation of 10 stroke patients who were followed up for 6 months. Recovery is linked to the ipsilateral cortico-spinal pathways of the impacted hemisphere’s comparable integrity in the acute period (as measured by MEP and motor threshold). In both hemispheres, however, recovery is connected to the creation of alternative neural networks as measured with short-term and long-term intracortical inhibition [21].

The contralateral hemisphere appeared to be more significant in major infarcts than in mild infarcts in this small sample. However, extrapolating results to all stroke patients is problematic because of the limited sample and various abnormalities (in the anterior and posterior circulation area, cortical or subcortical). The hemiparetic impairment is worsened in animal tests when the lidocaine is applied to the unaffected hemisphere 4 weeks before the injection, and the middle cerebral artery is closed. This is particularly true if significant lesions are created. As a result, whereas an interhemispheric imbalance is harmful during the acute phase, it is helpful throughout the healing period [22].

Physical medicine and rehabilitation facilities increasingly utilise constraint-induced treatment, which is a direct result of these findings. Forcing a person with cerebral palsy to use one limb while forcing the healthy limb to be inactive is the idea. Two things happen—the stroke-related contralateral main motor cortex region is less active, minimising its inhibitory transcallosal and harmful influence on the ischemic hemisphere, while the ipsilateral hemisphere is overactive. For example, in a meta-analysis of controlled trials of “constraint-induced therapy,” researchers found that the paretic limb improved steadily over time [23]. Still, they could not develop an exact treatment plan because of the wide variety of treatment protocols utilised and the limited number of participants. There was a remarkable correlation between the clinical improvement and the two-fold increase in the excitability characteristics of the damaged hemisphere as evaluated by TMS.

2. Nibs

2.1 rTMS

The brain is stimulated by rTMS, also known as repetitive transcranial magnetic stimulation. It includes a continuous sequence of pulses or periodic cycles that alter corticospinal reactivity and processes that might be comparable to LTD or LTP. A further week or two is spent repeating the daily exposure of the exact location for 20 minutes. Pacing has an impact on the outcome. Cortical excitability rises with high-frequency stimulation (i.e., >3 Hz) and decreases with a low-frequency stimulus (i.e., less than 1 Hz) [24].

A conscious patient may quickly and painlessly operate this device. Involuntary contralateral muscle contractions, which may be captured as an MEP, indicate exactly where the coil should be placed over the main motor cortex (M1). A real-time neuronavigation in conjunction with a patient’s own cerebral MRI is indicated as soon as the targeted stimulated region is outside M1. The degree of spatial/temporal resolution through this technique is excellent. However, large and costly equipment is needed, and it cannot be done at the patient’s bedside [25].

Repetitive transcranial magnetic stimulation (rTMS) underwent modifications to create theta-burst stimulation. It uses 50 Hz pulses delivered in three-pulse bursts, separated by a five-pulse gap. Intermittent theta-burst stimulation uses TBS trains lasting 2 s that are repeated every 10 s, increasing excitability. Continuous theta-burst stimulation, on the other hand, uses TBS trains lasting 20–40 seconds to reduce excitability in the cortex (Figure 2).

Figure 2.

Blink reflex recordings in a male patient with spinal cord injury before and after rTMS over the vertex [26].

2.2 tDCS

DCS of the brain in tDCS is more of a neuromodulator than anything else. It is a lot smaller and more portable electrophysiological equipment that may be used at the patient’s bedside. Weak polarising direct current is delivered into the brain by two large electrodes on the head. To modify the threshold of cortical neurons and the intrinsic excitability of the cortex, a direct current source (0.5–2 mA) is used. At the same time, the active electrode is placed over the desired location. Network excitability is polarity-dependent—anodal stimulation raises it, whereas cathodal stimulation lowers it. TDCS is also more convenient to utilise in conjunction with behavioural tasks or during physical and occupational therapy due to its small size (Figures 3 and 4) [29].

Figure 3.

(a) TMS, (b) tACS application of alternating current through an electrode [27].

Figure 4.

TMS induced motor evoked potential [28]. Neurophysiological basis of the motor evoked potential (MEP). (A) TMS-induced activation of the corticospinal neurons with a predominant contribution by late Indirect waves (I waves). and (B) Temporo-spatial summation at the cortico-motoneuronal synapses (C) Motor evoked potential.

2.3 NIBS for stroke patients

More than 1400 papers have been published thus far on NIBS in humans, with 230 of those papers focusing on stroke-related issues. Mostly, they are concerned with assessing upper-limb motor function, with speech impairments coming in second.

When we look at animal studies there are comparatively little preclinical non-human data on NIBS. The reasons for this are (a) the unavailability of small-sized equipment and (b) ethical issues regarding animal safety. The first animal study for NIBS was conducted in 1990 on rats. Thereafter, a number of studies were conducted on animal models to study the effects of NIBS in Alzheimer’s disease, depression, epilepsy, Huntington’s disease, and stroke. These studies demonstrated positive effects of NIBS on neurorepair, particularly improved motor and cognitive performance. The results of these studies have contributed significantly towards the development of NIBS strategies and protocols [30, 31].

NIBS has been linked to post-stroke aphasia, apraxia, attention, gait abnormalities, and coordination deficits. NIBS stroke treatment techniques were created to improve “adaptive” plasticity and combat “maladaptive” plasticity [22].

After a left hemisphere stroke, aphasia is a frequent side effect. In the past 10 to 15 years, advances in neuroimaging have shown two distinct patterns—Patients with minor left hemisphere lesions are more likely to engage perilesional areas, while individuals with larger ones in the left hemisphere are more likely to recruit homotopic areas mostly in the right. By activating the lesional and contralesional regions of the brain, many non-invasive brain stimulation treatments have been utilised to assist patients to recover from a stroke. Most of these brain stimulation investigations focused on blocking homotopic areas in the right posterior IFG (triangular portion) to effect a supposedly disinhibited right inferior frontal gyrus. In other experiments, the contralesional (right) frontotemporal area or sections of the intact left IFG and perilesional areas have also been stimulated with anodal or excitatory tDCS to increase speech-motor output. Since it provides the cornerstone for motor cortex stimulation research, the interhemispheric disinhibition notion also applies to the language system [32].

2.4 Use of combined treatments methods

Whether NIBS combined with rigorous physical therapy, constraint-induced treatment, robot therapy, or EMG-triggered functional neuromuscular stimulation has any added benefits, remains debatable. NIBS can be used with rTMS or tDCS, but there are no data to support it. This failure remains mysterious. To begin with, it is possible that following the initial process there will be a ceiling effect. The other theory is that the adjuvant treatment has an inhibitory impact rather than a priming effect created by the initial surgery. For this to be adequately understood, it must be viewed in conjunction with the concept of metaplasticity—that is, the ability of activity-dependent synaptic plasticity to be influenced by prior activity at synapses, thereby shifting the criterion for LTP and LTD induction—as well as the concept of homeostatic plasticity, which allows neurons as well as circuits to maintain stability despite synaptic instabilities. Therefore, NIBS may have opposing and invalidating effects on the motor task depending on when it is used (prior, during, or just after neurorehabilitation). Motor learning and NIBS may interact differently depending on when it is administered. More profound knowledge of this interaction is needed to determine whether or not it impacts the synaptic state [33].

There is a larger risk of epilepsy during the acute period of recovery. Therefore early research remains focused on whether or not rTMS could be used to assess the inhibition of the contralateral, unaffected main motor region 3–12 months following stroke. One-time (30-minute) or repeated (20–30-minute) treatments were given to patients with acute ischemic stroke for five working days. Chronic stroke patients were treated with 10 Hz excitatory rTMS, and their brain activity was monitored immediately after the treatment. There were just 10–20 patients in each of the first four investigations. According to research, higher frequencies (3 Hz) were shown to be beneficial in the acute phase, 10 days following the start of the stroke. They found no extra advantage to delivering a greater primary cortex excitation (10 vs. 3 Hz) when contrasting two high-frequency impulses. The treated groups had altered MEP and motor thresholds, as well [18].

These investigations were modest (even in the more extensive trials, 20% of patients were lost to follow-up), although the infarcts were clinically and radiographically homogenous, with subcortical infarcts being the most common. Researchers used a randomised control experiment known as a “crossover study” to assign participants to either receive actual or “sham” stimulation, followed by a 1-week washout period or be randomly assigned to get either one or the other.

Throughout most crossover experiments, patients received one rTMS treatment and one sham session separated by 1 week. The sequence of the trials was chosen at random, and most of the time, the assessment focused on measuring handgrip power or pinching power and velocity. When particularly examined, the rTMS effect had vanished after 30 minutes, indicating that it had no impact on the next session’s outcomes.

Because the device is less costly and simpler to use than rTMS, tDCS offers great potential. tDCS has been found to extend the time it takes for patients to recover from motor impairments when used repeatedly. To combat extremely high levels of interhemispheric inhibition via the contralesional M1 and reverse the ipsilesional hypoexcitability, stimulation paradigms such as cathodal stimulation of the undamaged hemisphere and anodal stimulation of the afflicted hemisphere have been proposed. Repetitive transcranial magnetic stimulation (rTMS) has been used mostly in the chronic phase of illness for repeated tDCS sessions. For example, it was found that compared to sham tDCS, cathodal tDCS of the unaffected hemisphere enhanced hand motor performance, which was assessed by a blinded Jebsen Taylor Hand function test. The effects of cathodal tDCS applied 5 days in a row persisted for at least 2 weeks. Lindenberg et al. investigated tDCS stimulation (cathodal stimulation in the unaffected hemisphere and anodal stimulation in the afflicted hemisphere) in 20 chronic stroke patients who were also receiving physical and occupational therapy (with a follow-up of more than 5 months) [34]. When compared to placebo, real stimulation resulted in a greater improvement in motor function (+21% for Fugl-Meyer and 19% for Wolf Motor Function test scores), and this improvement lasted at least 1 week following the treatment. It was shown that in the group that received actual stimulation, the ipsilesional primary and premotor cortexes were more active during timed movements of the afflicted limb [35].

3. Stimulation protocols using reorganisation models as a base

Before now, most NIBS procedures were built on the interhemispheric competitive concept, which holds that the healthy hemisphere suppresses the injured hemisphere excessively. This model-based strategy is widely employed in recent and continuing clinical studies, despite being typically useless at the collective level. The reliability of this concept has been called into doubt, particularly in seriously damaged individuals, and an alternate model, the vicariation model, has been proposed. According to this model [22] when one of the brain’s hemispheres is impaired, the other makes up for it by performing better and resulting in an adaptive system rather than a maladaptive one.

The bimodal-balance recovery model combines these previously disparate theories, allowing us to get closer to personalised treatment. Assume that a patient is best served by the inter-hemispheric competition or vicariation model. It uses a metric known as “structural reserve” in this situation, which is defined as the integrity of white matter motor pathways. Patients with a strong structural reserve have a maladaptive over-activation of the undamaged hemisphere; patients with poor structural reserve have a compensating over-activation [36]. The fact that patients with extensive brain damage, who are thought to have a limited structural reserve, have inferior results when inhibitory NIBS protocols are administered to their undamaged hemispheres supports this approach, stressing the need to change “one-size-fits-all” NIBS protocols. However, whether clinical and imaging parameters may serve as good substitutes for structural reserve has not been answered. Much research has looked at these factors’ capacity to predict stroke outcome, but the strongest evidence comes from those studies [37]. Using diffusion tensor imaging, the fractional anisotropy for white matter tracts is routinely employed to quantify white matter integrity. Although stroke prognosis may be accurately predicted with a strong predictive biomarker, this is not always the case for responding to certain NIBS paradigms. Prognostic biomarkers could be a good place to start, but they must be verified to show their unique function and relative relevance in affecting the outcome of NIBS after a stroke reaction. According to two recent promising studies, behavioural assessments like the Action Research Arm Test and the Fugl-Meyer score, together with imaging-based measures of white matter integrity, are predictive of responsiveness to NIBS. As a result of such studies, the bimodal-balance recovery model is given support, as are future studies that will validate these selection biomarkers using clinical and imaging initiatives related to the structural reserve [38].

Methodologically, significant/extensive trials with many individuals and variables are required to build a framework for customising the treatment for each patient using NIBS. Machine learning algorithms would be best suited for analysing such vast volumes of complicated data. Because of the strong association between imaging-based biomarkers and clinical manifestations of stroke, potential models for guiding NIBS therapy do not need to be particularly complicated. Instead, strongly correlated steps can be whittled down to factors of a lower dimension that describe a significant amount of variability.

4. Connectivity across the entire nervous system

Stroke is a widespread illness that affects people throughout the body. After a stroke, the impact of disrupted networks may be felt far and wide, and the formation of new indirect connections is the fundamental mechanism regulating these effects [39]. Individual stroke recovery is linked to alterations in long-range connections between different brain areas outside of lesions, as well as their regulation throughout time, as studied in resting-state functional MRI in whole-brain. Alterations best describe a single patient in numerous functional networks, which are common in strokes. Since both stroke connectivity and NIBS protocol changes have primarily been examined in the setting of isolated networks, these variables are likely to have contributed to the documented response variability with NIBS. However, this has not been fully explored thus far. It’s hard to assume that a single functional network is being addressed in these patients when administering stimulation because of the impact of NIBS on dispersed networks and the notion of stroke as a dispersed disease. Rs-fMRI whole-brain connectivity is ideal for application in patients since it provides information on the functional connectivity of several brain networks in a single task-free scan. A much more accurate model of spontaneous reorganisation following stroke might be developed using this method, and it could be useful in devising personalised stimulation regimes [10]. Connectivity techniques have a methodological disadvantage in that they depend on a prior determination of relatively arbitrary multiple networks. This issue is solved by reducing the number of dimensions in the brain’s connections. Areas are grouped in a parametric, gradual way based on their connection patterns using the data-driven technique. Reduced dimensionality of whole-brain linkages may offer a fingerprinting of the connectome at the individual level, reflecting a clearer image of stroke spanning several functional domains. When we used this technique to study stroke lesions, we discovered that the degree of rearrangement that occurred in the first week after stroke was linked to the position of the stroke lesions in space for whole-brain neural systems. We believe that constructing whole-brain connection models will help us better understand the long-term consequences of localised lesions [40].

NIBS reaction prediction using electroencephalogram (EEG) connectivity has shown impressive outcomes. Functional integration modifications to prognostic models of stroke output have added value, so we believe connectivity patterns could be a potential biomarker for NIBS responses in future research. As time goes on, establishing a relationship between a connectome fingerprint and sudden retrieval in several functional domains will be critical and the impact of the connectome fingerprint on clinical reactions to NIBS before stimulation.

5. Neuronal oscillations that are ongoing

A variety of variables may influence response to NIBS, both instantaneous (“state”) as well as phenotypic (“trait”). Both may be evaluated using the features of neural oscillations, which indicate the cortex’s receptivity to stimulus. You cannot know in advance how someone will react to a stimulation procedure. Even in the absence of disease, the same NIBS procedure might have excitation, inhibiting, or no impacts on motor elicited potentials in different people. One strategy is to time the stimulation to coincide with the most excitable brain states to limit this unpredictability. The findings that pre-stimulus alpha oscillations correlate with TMS response variability, that the intensity of sensorimotor mu oscillations (8–12 Hz over central-parietal electrodes) correlates with the magnitude of motor evoked potentials, and that the synchrony of mu oscillations in contralateral M1 is related to greater interhemispheric inhibition, all support the importance of these processes [10]. Current research focuses on NIBS that are “state-dependent.”

Subject-specific and highly heritable characteristics of neuronal oscillations characterise immediate cortical responsiveness to NIBS Alpha band (80 Hz) power, and the temporal variation of α- and β-band oscillations are especially relevant here. These findings support the hypothesis that neuronal oscillation features during rest might reflect a phenotypic trait in addition to transitory situations. Healthy people have reasonably good intra-subject reliability for the response to NIBS, which is also strongly heritable. Recently, EEG research found a correlation between healthy people’s reaction to paired-pulse TMS and alpha band temporal dynamics before intervention on an individual basis. These findings demonstrate that cortical plasticity is purely genetic, indicating that the brain can be controlled in a trait-like manner [41].

The critical condition is an equilibrium between inhibitory and excitatory that is best for processing information in neural networks. Additionally, critical states are connected with long-range temporal connections (LRTCs) in neuronal oscillation amplitude dynamics. Following a stroke, and various other neuropsychiatric illnesses, LRTCs—which connect to cortical excitability—are prone to be disrupted, as they are in both cases. This suggests that patterns of disruption are associated with spontaneous recovery since the network eventually achieves a compensating equilibrium. Clinically approachable approaches such as resting EEG may be used to quantify the trait-like features of neural oscillations [33].

6. Approaches to NIBS that are new

Recent advancements in NIBS technology are expected to aid in the formulation of more personalised treatment plans. Through multi-locus TMS, it will be possible to move beyond single-area stimulation to target specific muscle groups with different functions in post-stroke motor therapy. Because the coil does not need to be repositioned, this method stimulates many locations with excellent temporal accuracy. With improved induced electrical field modelling, it is possible to forecast exactly what changes will be caused by NIBS on some kind of sub-regional level (for instance, in particular areas of the motor homunculus). Finally, non-invasive stimulation techniques such as transcranial focused ultrasound or temporal interference could be used to target deep brain areas that are inaccessible with TMS and tDCS yet critical for dexterity deficiencies and pathological synergies in stroke [42]. They may help progress NIBS translation while accepting the unavoidable variability of stroke pathophysiology and the discovery and validation of useful biomarkers related to NIBS.

6.1 Side effects and ethical issues regarding NIBS

Minimal side effects, such as transient headache, neck pain, and transient hearing changes, have been reported with the use of NIBS by researchers. However, most of these results are from studies that involved single burst stimulation and knowledge about potential detrimental side effects of repeated stimulation are minimal [43]. An area that poses ethical questions is making the distinction between enhancement and treatment (Figures 5 and 6).

Figure 5.

Patterns of application of transcranial magnetic stimulation [44]. *convention TMS a. ≤1 Hz stimulation frequency pulses in a continuous train. b. ≥5 Hz stimulation frequency pulses separated by periods of no stimulation (e.g., 1200 pulses at 20 Hz, delivered as 30 trains of 40 pulses (2 s duration) separated by 28 s intertrain intervals. **patterned TMS short bursts of 50 Hz rTMS are repeated at a rate in the theta range (5 Hz).

Figure 6.

Maximum safe train duration (seconds) limits [45].

In view of ongoing efforts to improve the efficacy of TMS as a technique of inducing persistent changes in brain function, assessing the safety of TMS with neuroimaging becomes extremely important. For therapeutic and research purposes, use of TMS the following three requirements must be kept in mind.

1. Informed consent from the subject or their legal representative

2. Potential benefits must outweigh the risks

3. The subjects chosen must not be socially, physically, or economically vulnerable [44]

6.2 Guidelines for NIBS

There are an infinite number of protocol combinations that can be used. However, it is crucial that careful monitoring of motor, sensory, and cognitive functions be done before, during, and after the intervention.

The resulting growing clinical use of NIBS requires careful guidelines both in terms of equipment and training of the medical staff carrying out NIBS.

In the United States (US), the Food and Drug Administration (FDA) has cleared seven devices for therapeutic TMS in patients of treatment-resistant depression, one device for pre-surgical motor and language cortical mapping, and one device for abortive treatment of migraines. To date, there are no FDA-approved applications of tCS. The FDA takes into account details like coil positioning, output waveform, strength and distribution of the magnetic field safety features of the device.

Currently, there are no requirements or certifications governing a provider’s proficiency regarding NIBS before using it. However, it is recommended that all physicians using it undergo training. There are limited programs being offered in some institutes [46].

7. Test results and future trials

Both rTMS and tDCS have been shown to have long-term benefits, with improvements ranging from 10 to 20% based on the literature’s upper limb motor performance assessments. In the acute period (6–29 days) high-frequency stimulation of the ipsilaterally affected hemisphere is more effective than low-frequency stimulation of the non-affected, undamaged hemisphere [47].

Stroke-specific adverse effects include moderate headache (2.4%), anxiousness (0.3%), neuro-cardiogenic syncope (0.6%), worsening of pre-existing sleeplessness (0.3%), and local pain at the stimulation site [6]. Adverse events in children and young adults are very similar to those seen in adults—headaches (11.5%), scalp irritation (2.5%), twitching (1.2%), mood swings (1.2%), tiredness (0.9%), tinnitus (0.6%), tingling (11.5%), itchiness (5.8%), redness (4.7%), and scalp irritation (3.1%) have been reported after tDCS protocols [7].

Seizures are the only possible major side effect [48]. Other than stroke peculiarities, certain relevant aspects have been identified from the overall NIBS experience. Even while 0–3.6% of individuals with epilepsy have an epileptic seizure while receiving NIBS, this does not alter the course of their condition. If the antiepileptic plasma level is insufficient, there is a higher incidence of interictal epileptiform discharges (>10/min) and complex temporal seizures are also common (>4/month). Stimulation is followed by a current epileptic seizure (48 hours), and the risk is increased if the epileptogenic region is specifically excited. If there is a family history of epileptic seizures, if the patients receive regular epileptogenic psychotropes, if there is chronic alcohol or opiate abuse, an underpinning neurological disease, severe heart disease, sleep problems, a younger child, or female sex, there is a higher risk of inducing an epileptic seizure in non-epileptic patients [48].

8. Concluding comments

In the literature, the extent of improvement from upper limb motor functional evaluation using rTMS or tDCS is reported to be around 10% and 20%. Clinical trials’ results do not match those of meta-analyses, but variability in stroke history, personal susceptibility, outcomes, and a lack of basic understanding of where to administer adjuvant medicines-and the impact of concurrent medications confuse interpretation. As the illness progresses, pharmacological, electrophysiological, or physical adjuvant treatment might potentially improve patient care. Considering the disease’s severity, this should favour a patient-tailored strategy more than other techniques.