Post-Stroke Rehabilitation: Management

## **Chapter 5**

## Role of Yoga and Spirituality in Stroke Rehabilitation

*Pratap Sanchetee*

## **Abstract**

In spite of the best treatment, 30–50% of stroke survivors are left with significant physical and/or psychological disabilities and consequent decline in quality of life (QOL). The silver lining is that up to 80% of stroke survivors can become independent in activities of daily living with adequate rehabilitation. Rehabilitation with physiotherapy, occupational therapy, and speech therapy offers a good opportunity to regain functional abilities. However, there is a shortage of neurorehabilitation (NR) programs across the globe, more so in resource-poor countries. The secular practice of yoga and spirituality is associated with a host of physical, physiological, cognitive, and psychological benefits that can be effectively included in stroke rehabilitation (SR). It has been shown to increase creativity and reduce stress as well as improve muscle power, dexterity, visual perception, and reaction time. These practices promote the positive effects on carotid atherosclerosis, hypertension, diabetes, and coronary artery disease, which are all identified risk factors associated with stroke occurrence or reoccurrence. Yoga and relevant practices are low cost and have good acceptance amongst patients and caregivers. In spite of yoga and meditation as useful tool, it has not been addressed adequately in stroke rehabilitation.

**Keywords:** yoga, spirituality, neurorehabilitation, stroke rehabilitation, neuropsychiatric complications, stress

## **1. Introduction**

Stroke is the leading cause of disability across the globe and with better care, more people are living following stroke with mild to severe neurologic deficits. This has a negative impact on both psychological and physical health and quality of life [1]. The majority of such patients reach the plateau of their recovery within 6 months [2]. It has been observed that a good and sustainable rehabilitation program can result in improvement in muscle power, balance, mobility, risk of fall, and aerobic capacity in up to 70% of the poststroke patients [3]. Rehabilitation in stroke focuses on the recovery of function and cognition to the maximum level achievable and may include a wide range of complementary strategies including yoga [4]. The rehabilitation of stroke is a multidisciplinary process involving physicians or stroke specialists, nurses, physiotherapists, psychologists, nutritionists, occupational therapists, speech therapists, and audiologists [5, 6]. These patients require long-term rehabilitation and because of the high cost and lack of qualified therapists, they are not able to avail

them. Thus, there is a strong need for novel strategies, which are low cost, suitable for home care, particularly in rural areas, and address the physical and mental needs of the patients and caregivers [7]. Yoga and meditation are such tools that are being explored in the last two decades or more. However, it is yet to find widespread acceptance. This review aims to update and synthesized the role of yoga and meditation intervention in stroke rehabilitation (SR).

## **2. Stroke rehabilitation**

The primary purpose of rehabilitation is to maintain or improve an individual's functioning and independence. Neurorehabilitation (NR) services are essential to optimize physical, psychological, and cognitive functioning of patients with compromised neuropsychological functions especially in the initial 3–6 months poststroke [8]. There are marked inconsistencies in quality of care and rehabilitation services across the globe. Such services are needed both during the acute stage and during later phase of disease [9, 10]. NR with conventional physiotherapy, occupational therapy, and speech therapy offers them a good opportunity to regain QOL and activities of daily livings (ADLs). However, it is mostly underutilized and major barriers are limited availability, geographical distance, high cost, and lack of awareness about its benefits [8, 11, 12].

SR is a multidisciplinary process involving doctors, nurses, physiotherapists, occupational therapists, neuropsychologists, linguistic and speech specialists, audiologists, and nutritionists [13]. It is not a "one size fits all" intervention and a combination of interventions suits better to treat motor and sensory impairments, cognitive deficits, and psychological issues. Physical therapy in form of active and passive joint movement, muscle strengthening, and gait training was the cornerstone of SR till the recent past. Newer techniques such as repetitive task training (RTT), constraintinduced movement therapy (CIMT), mirror therapy, use of botulinum toxin to relieve spasticity, advanced gait training with robotic-assisted therapy and virtual reality, electrical stimulation (ES), noninvasive brain stimulation (NIBS), cognitive rehabilitation, and neurofeedback are newer addition to the armamentarium [6].

While use of technology (e.g., virtual medical examination, tele-counseling, robotic-based and exoskeleton interventions, and telerehabilitation) to manage NR has the potential to reach a large number of patients even in remote areas with limited physical contact, they have the disadvantage of complexity and high cost [8]. In this situation, yoga and spirituality as an adjunct to conventional physical and psychosocial aspects of rehabilitation merit a serious consideration [6]. Subsequent discussion in this article will focus on spirituality and yoga as an adjunct in SR.

## **3. Spirituality and yoga**

Ancient spirituality and related practices, not synonyms with religion, are widely used for prevention of diseases, promotion of health, and as possible treatment modality for neurological and psychiatric disorders [14]. These practices include prayer, yoga, meditation, dietary modification, and mental remodeling. Recently, we are discovering their health benefits and are finding a bigger role in the field of rehabilitation [15]. They are cost-effective and self-administered options with advantages of their use in both urban and rural areas with minimal physical interactions. Spirituality and yoga, though interconnected, are different as explained below.

*Role of Yoga and Spirituality in Stroke Rehabilitation DOI: http://dx.doi.org/10.5772/intechopen.106903*

## **3.1 Spirituality**

Spiritual technologies are not new to us and are guiding us through ancient times. There is no agreed definition of the term spirituality. It is a blend of humanistic psychology with an individual relationship with higher powers and the subjective experience of the "deepest values and meanings by which people live" [16–18].

To have wider application, it is necessary to distinguish spirituality from religion. While spirituality refers to a quest in life or a transcendent relationship with a higher power, religion focuses on community-based doctrine, prescribed beliefs, practices, and rituals [6, 17, 18]. Spirituality is generally considered to be a much broader construct than religious faith, although the two concepts may overlap [19]. It must be clarified that being spiritual does not necessarily mean religious, whereas the reverse is true.

As such studies relating to spirituality and rehabilitation for neurological illnesses are limited, much research is needed to evaluate their specific role [1, 17]. Though higher levels of spirituality are known to be associated with a better quality of life (QOL) for people with neurodisability and their caregivers, most of the medical staff are not well equipped to administer it [20, 21].

### **3.2 Yoga and meditation**

Yoga is a way of life and an ancient mind-body practice that originated in India more than 5,000 years ago. It is now recognized worldwide to have spiritual, physical, and mental health benefits [1, 22, 23]. The word "yoga" is derived from Sanskrit verb "*yuj*" meaning to yoke or unite. Commonly, yoga is translated to imply the union of body, mind, and spirit [22, 24]. Meditation in its many forms has been practiced over millions of years by diverse groups of people in many different traditions. In a more modern context, it can be defined as "a systematic practice and implementation of mind and body in the living process of human beings to keep harmony within self, within society, and with nature" [25].

There are many practices of yoga and they include varying combinations of spiritual way of life, different bodily postures (*asanas*), controlled breathing (*pranayam*), physical and mental relaxation, contemplation, control of thoughts and mind (concentration meditation), and open-mindedness or mindfulness [1, 14, 22]. Meditation, the most important component of yoga, aims at giving peace to the mind and increasing awareness of environment and higher consciousness.

The practices of yoga and meditation strengthen willpower and control of mind and body to work in perfect synergy [1, 13]. They are known to promote cardiorespiratory and metabolic health (reduction of carotid atherosclerosis, dyslipidemia, hypertension, diabetes, and coronary artery disease) and as a possible treatment modality for a variety of neurological and psychosomatic disorders [1, 22, 26].

## **4. Mechanism of improvement in stroke with yoga**

Though yoga and spiritual techniques-based practices are becoming increasingly popular in the management of many physical and psychological illnesses, the neurobiological effects of such practices in improvement are not well understood [4, 27, 28]. It must be appreciated that unlike majority of conventional SR techniques aims at deficit recovery (external mechanism), spirituality and yoga work at intrinsic recovery of the brain as well. Neuropsychological studies have shown that mindfulness meditation training improves immunity, cognitive skills (thinking, reasoning,

judgment, and memory), attention-related behavioral responses and emotional liability, and reduction in autonomic arousal [1, 27].

### **4.1 Autonomic nervous system**

There is increasing support for the theory that relates the positive effects of yoga to a close link between the central nervous system and the autonomic nervous system, along with the endocrine and immune systems. It is believed that yoga techniques favor a down-regulation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), leading to a prevalence of the parasympathetic nervous system over the SNS, possibly through direct vagal stimulation [4]. Moreover, breathing control and meditation practices in yoga increase the autonomic control, and reduce blood pressure, heart rate, and breathing. These changes may help in poststroke rehabilitation through restoration of physical and mental health, promotion and coordination of complex movements, balance, strengthening, and breathing.

## **4.2 Hormonal changes**

The stress hormones (such as cortisol) that compromise the immune system can be balanced through practice of yoga [29]. The practice of yoga enhances the activity of many hormones connected with mental health such as melatonin and gamma aminobutyric acid (GABA) [30, 31].

There are pieces of evidence that meditation-based training increases many growth factors such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), glialderived thrombospondin 1 and 2, and growth-inducing proteins (neuromodulin, CAP23, MARCKS) [32]. Higher levels of these growth factors are associated with better neuroplasticity, neuronal morphology (synaptic and dendritic changes), and cortical reorganization improving functional outcomes following neurological illnesses.

### **4.3 Brain structures**

Till recently, it was believed neural tissues do not regenerate. Now, we have learned that it is possible to reconstruct neural circuits with transplanted endogenous neural stem cells or through mental training such as meditation [33, 34]. Long practice with yoga has been associated with changing brain structures with an increase in gray matter density in structures involving memory, attention, self-awareness, compassion, and control of the autonomic nervous system [27, 33]. Functional magnetic resonance imaging (fMRI) studies have shown increased gray matter in the hippocampus, prefrontal cortex, cingulate cortex, and brain networks including the default mode network (DMN) [1, 26, 27, 35]. In contrast to this, there was a decrease in the grey matter in the amygdala, the part of the brain associated with fear and stress.

## **4.4 Epigenetic**

Epigenetic refers to a way to regulate gene activity in real time without modifying the DNA sequence. It allows the body to function in changing environment. Yoga and related practices have been shown to alter gene expression, particularly those related to free radical handling, inflammation processes, mitochondrial energy production and utilization, and apoptosis [1, 36, 37].

## **4.5 Cellular oxygenation and general well being**

As a result of practice of *asanas* (body posture), *pranayam* (control of breathing), and control of thoughts and mind, there is general improvement in well-being and a positive outlook in life. With respiratory practice (*pranayam*), there is improvement in the lung capacity and respiratory health, which in turn improves supply of the oxygenated blood to multiple organs for smooth optimal function [30].

## **4.6 Dietary modifications**

Lifestyle diseases such as obesity, accelerated atherosclerosis, insulin resistance, type 2 diabetes, and cardiovascular disease are major risk factor contributors to occurrence of stroke [38]. They are targets in both primary and secondary preventions of the stroke. Current dietary practice is loaded with a high proportion of refined carbohydrates and saturated fats. Thus, it is logical to build body-mind through diet, exercise, healthy lifestyle choices, and mental remodeling with spirituality. Spirituality and meditation techniques mandate a vegetarian diet rich in fiber content and unsaturated fats with less refined carbohydrates (**Table 1**).


#### **Table 1.**

*Some simple dietary principles with spiritual technologies.*

## **5. Yoga and spirituality for stroke rehabilitation**

Spirituality, meditation, and mind-body exercises are novel therapeutic approaches in improving neurological outcomes and enhancing cognitive capabilities [13, 39, 40]**.** Such practices allow SR in less complex and highly individualized environment. However, yoga and meditation programs should be tailored to deliver personalized interventions according to each person's profile and rehabilitation needs. Being a low-cost model, it improves availability of rehabilitation in low- to middleincome countries. Though it is effective and less labor intensive, there is a lack of evidence-based review to support the claim.

Few specific practices of meditation that have been used for stroke rehabilitation are *Preksha* Meditation (based on perception theory), Qigong (Chinese body-mind exercise), and yoga-based *asanas* or exercises [11, 19, 39, 24, 32, 41–45]. A recent systematic review concluded that yoga can be used as self-administered practice in stroke rehabilitation, due to its effect on relieving the mind and body from stress. Yoga was found to act at both psychological and physical levels, and improvements were noted in self-efficacy and confidence [1, 4].

#### **5.1 Motor and sensory functions**

**Rehabilitation in ICU & During acute phase:** Patients with moderate-to-severe stroke are often subjected to prolonged bed rest and mechanical ventilation [13]. Such patients have a significant deficit of motor functions in form of profound muscle weakness, fatigue, diffuse myalgia, balance deficits, fear of falling (FoF), dysautonomia, orthostatic hypotension, respiratory muscle weakness, deep vein thrombosis, decubitus ulcer, joint contracture, and impaired ADLs. Neuromotor rehabilitation is a key concept of recovery from immobilization syndrome. Modified yoga (a combination of postures, breathing, and meditation) has been shown to improve vital capacity, muscle power, range of movements, walking capacity and speed, self-efficacy, and improved quality of life [11, 22, 41, 43, 46].

**Rehabilitation during subacute and chronic phase:** Several investigators have found improvements in muscle force, balance, aerobic capacity, timed mobility, and aphasia in subjects with chronic poststroke hemiparesis following yogic interventions [24, 39, 42]. Bastille and Gill-Body [41] demonstrated that yoga results in significant improvement in muscle power and range of movements in hemiplegic limbs and some positive effects on the Berg Balance Scale (BBS), Timed Movement Battery (TMB), and quality of life (QOL) as assessed with Stroke Impact Scale (SIS). Schmid et al. [11] in a study of 37 poststroke patients managed with yoga interventions observed significant improvement in balance (Berg Balance Scale, 41.3±11.7 vs. 46.3±9.1; *P*<0.001) and fear of fall (51% vs. 46%; *P* < 0.001). In a study carried out by Singh et al. [43], *Preksha* Meditation training was given to 22 subjects with hemiplegia and was compared with an equal number of controls at 3 months. A significant improvement was observed in muscle power and range of movements in hemiplegic limbs. In another prospective trial, Qigong practice for 16 weeks in stroke subjects was associated with improvement in balance capacity, physical well-being, and psychological well-being [44]. Psychological improvement with reduction in anxiety and depression and better QOL are additional advantages of mediation, which is helpful for patients and their caregivers [21–23, 42, 47]**.** Wang et al. [45] in a systemic analysis of 33 rt-fMRI neurofeedback studies on 651 healthy individuals and 15 stroke patients observed a learned modulation of brain signals, with associated changes at both the neural and the behavioral levels with this intervention.

Thus, meditation and mind-body exercises are a novel therapeutic approaches to enhance cognitive capabilities and are effective in improving poststroke outcomes [11, 21, 22, 26, 39, 40].

#### **5.2 Cognitive rehabilitation**

A large number of patients with stroke suffer from cognitive impairment. There are many types of cognitive deficits in these patients, which include forgetfulness, confusion, disorientation, problems with attention, executive functioning, information processing, etc. [48, 49]. However, cognitive rehabilitation is still far from satisfaction. Meditation and other mind-body interventions are effective in improving cognitive functions in these patients [50, 51]. However, only a small number of stroke patients have been evaluated with yoga-based interventions and Mindfulness-Based Stress Reduction (MBSR) programs in subjects with cognitive impairment. There is a requirement to study a larger number of patients and to design modified yoga program to suit different characteristics of stroke patients.

## **5.3 Stress and psychological**

Apart from motor deficits, stroke patients have a significant cognitive deficit, stress, negative emotions, frustration, boredom, disturbed sleep, anxiety, losing a job, financial problems, depression, and behavior-related problems that hamper their recovery [8, 52]. These emotional stress results not only in *de novo* illnesses but can exacerbate preexisting illnesses as well. Some simple tips are given in **Table 2** and the list can be expanded with personal experience.

It is pertinent for us to identify stressors early and manage them accordingly. Few simple steps are


#### **Table 2.**

*Simple mental remodeling steps.*

Spiritual techniques and yoga provide a good non-pharmacological approach to handling such psychological issues that are common among patients and caregivers [1, 22, 25, 49, 53]. Yoga has been demonstrated to provide relief from stressful psychological states with a reduction in anxiety, depression, and cortisol levels. Immink et al. [42] observed significant improvements in quality of life associated with a perceived motor function (P = .0001), perceived recovery (P = .072), and memory-related quality of life scores (P = .022), with decreases in state and trait anxiety following yoga intervention. In a recent cross-sectional, online survey of clinicians (n >600) regarding coping strategies employed by them to mitigate stress was physical activity/ exercise (59%), psychotherapy (26%), yoga (25%), religious or spiritual practices (23%), meditation (23%), and virtual support groups (16%) [54].

## **5.4 Caregivers**

Developing a caregiver-driven stroke rehabilitation program has been attractive in India to address the scarcity of rehabilitation centers and trained therapists. The physical and mental health of caregivers is an important consideration in long-term SR. Spirituality and resilience needs of caregivers must be strengthened so that they can cope with the burden [8, 19].

## **6. Modification of yoga practices for stroke rehabilitation**

While motor deficit and spasticity management in SR are well organized, the mental health program is not standardized and there is a requirement to develop a holistic module considering all aspects of rehabilitation. Spirituality and yoga are

cost-effective self-administered options for SR and should find a place in the SR schedule [1, 6]. It is recommended that these interventions should be tailored to deliver personalized interventions according to each person's profile and rehabilitation needs (duration of illness and level of impairment, function and mobility, etc.).


**Table 3.**

*Stroke rehabilitation module with spiritual and yoga practices (To be under guidance of a physician & trained yoga teacher).*

*Role of Yoga and Spirituality in Stroke Rehabilitation DOI: http://dx.doi.org/10.5772/intechopen.106903*

Some of the *asanas* suggested are downward-facing dog, tree pose, and child pose, and these can restore balance and significantly reduce the risk of falling for stroke patients. In view of physical limitations, practice of *asanas* should have provision for adequate support such as practice against the wall, use of head gears, etc. A suggested module as designed by the author is given in **Table 3** and should be modified as per patient's need.

## **7. Future**

There is a good potential for spiritual technologies to be included in the NR schedule. Some of the areas that need to be considered for research are as follows:


## **8. Conclusions**

The field of stroke rehabilitation has a bright future. In spite of good potential for recovery, these rehabilitative measures are underutilized and major barriers are limited availability, geographical distance, high cost, and lack of awareness about its benefits. Scientific evidence indicates that yoga may constitute a promising add-on therapy for a number of diseases. It is a simple to learn, adaptable and community-based practice, which could be cost-effective [1, 4]. Studies relating to spirituality and rehabilitation for neurodisability including stroke are limited [16, 17]. They can be employed at a hospital, home, and workplaces alike. Recent experiments have proved its benefit in achieving physical, mental, and spiritual health. Medical and paramedical practitioners involved in SR should be aware of them and educate the patients and caregivers.

Meditation is a body-mind exercise that could be a cost-effective and useful technique for poststroke rehabilitation [21, 23]. Though spiritual techniques are effective and less labor intensive, there is a lack of evidence-based review to support the claim. Such interventions should be considering variables such as duration of illness, type and level of impairment, and functional need. However, large-scale methodologically robust trials are required to study mobility, balance, postural stability, coordination, cognitive changes, and QOL [4]. It is recommended that yoga and meditation interventions should be designed to meet patients' different characteristics (time after stroke, level of impairment, function, and mobility). To maintain the continuum for stroke care and reduce morbidity and mortality with stroke, there is a need for

public health systems in both developed and developing countries to improve stroke awareness and to implement proper strategies of triage, acute treatment, well-defined rehabilitation plans, and teleservices [8].

## **Funding**

Nil.

## **Author contributions**

This review was prepared by the sole author (PS).

## **Conflict of interest**

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## **Abbreviation**



## **Author details**

Pratap Sanchetee Sanchetee Neurology Research Institute, Jodhpur, Rajasthan, India

\*Address all correspondence to: pratap.sanchetee@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Role of Yoga and Spirituality in Stroke Rehabilitation DOI: http://dx.doi.org/10.5772/intechopen.106903*

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## **Chapter 6**

## Microbiome-Based Interventions: A New Prospect in Post-Stroke Rehabilitation

*Mubarak Muhammad, Rabi'u Musa Isah and Abdurrazak Muhammad*

## **Abstract**

Post-stroke rehabilitation remains the preferred therapeutic option for stroke survivors due to its unrestrictive therapeutic window of unlimited lifelong applicability. However, post-stroke rehabilitative interventions are still far from ideal and optimal recovery from lost functions after stroke. This heralds the search for strategies to complement rehabilitative interventions. Expanding the armamentarium of the existing post-stroke rehabilitation strategies will go a long way towards the attainment of optimal functions lost due to stroke. One of the promising emerging trends in stroke is cherished within the microbiome present in the gastrointestinal system. There is bidirectional communication between stroke and gut microbiome via gut-brain axis, and plethora of evidence pointed that modulation of this axis impact on stroke outcome, as well as evidence linking gut microbiome in modulation of brain neuroplasticity. Herein, we explored evidence that will support future research and perspectives into the potentiality of microbiome-based interventions as an integral part of post-stroke rehabilitation. Findings support the premise of the function of gut microbiome in brain neuroplasticity, and this could be fundamental towards translating similar phenomenon in human stroke to promote brain neuroplasticity in complement with post-stroke rehabilitation.

**Keywords:** microbiome, microbiota, microbiota gut-brain axis, stroke, post-stroke rehabilitation, neuroplasticity

## **1. Introduction**

A stroke occurs due to interruptions in blood supply to the brain, and over the years stroke consistently constitutes the second most common cause of mortality after cardiovascular diseases and a foremost root of chronic adult disability [1–3]. Individuals that survive stroke experience a multifaceted range of impairments as a result of loss of brain function due to the infarct, with acute clinical treatment of those impairments tailored towards rescuing the larger component of potentially affected but yet viable neurons in the ischemic penumbra that surround the ischemic core [4]. However, the approved strategy to salvage neurons in the ischemic penumbra using recombinant tissue plasminogen activator (rtPA) and mechanical thrombectomy remains largely unsatisfactory and is only available to an only small fraction of about 5% of stroke patients due to narrow time of applicability within 4.5 h of stroke onset [5]. Moreover, despite advancement in understanding the mechanism of neuronal demise after stroke and the corresponding development of neuroprotective agents, translating findings from bench to bedside has been largely disappointing, as about 70 agents tested in more than 140 clinical trials have all been unsatisfying [6].

Therefore, post-stroke rehabilitation aims at restoring functional impairments as well as promoting better compensation of the resulting defects after stroke remains a favorite therapeutic option against stroke due to its relative advantage of unrestrictive time of applicability [7]. Rehabilitative interventions are principally based on modifying and boosting the neuronal plasticity processes [8, 9]. Neuroplasticity is a general term used to denote the life-long natural capability of the nervous system to act in response to intrinsic or extrinsic stimuli by rearranging itself in terms of structural, functional, and molecular form [10]. There are numerous processes of neuroplasticity that allow for neuronal reorganization, which includes neurogenesis, gliogenesis, angiogenesis, synaptogenesis, dendritic arborization, axonal sprouting, long-term potentiation (LTP), enrollment of other pathways, strengthening of functionally silent synapses. Thus, the categorization into neuronal plasticity (neurogenesis), synaptic plasticity (LTP), and global plasticity is often used to take into account the various organizational level of neuroplasticity. Brain injury, due to stroke, is one of the potent stimuli that lead to the activation of neuroplasticity processes to initiate spontaneous recovery. The rehabilitative interventions take advantage of this endogenous brain capacity to promote it as well as remodel it in the right direction to achieve maximum recovery from functional impairment after stroke [11, 12].

Nevertheless, it was estimated that about 50% of individuals that survived stroke are left with residual functional impairment even with rehabilitative interventions [13]. This prompted the search for strategies that enhance neuroplasticity to complement rehabilitative interventions. Various strategies to achieve that using transcranial direct current stimulation, functional electrical stimulation, deep brain stimulation, brain-derived neurotrophic factor (BDNF) therapy, Statins therapy, erythropoietin (EPO) therapy, phosphodiesterase type 5 inhibitors, and vascular endothelial growth factor (VEGF) therapy have all been under investigation [4]. But considerations for gut microbiomebased interventions to enhance neuroplasticity and supplement neuro-rehabilitation of stroke have not been explored. This is despite the fact that there exists numerous evidence indicating mechanistic link implicating gut microbiome in the pathogenesis of stroke and mediating through gut microbiome to impact on stroke outcome [14–17], as well the role microbiome as a potential modulator of brain neuroplasticity [18].

Gut microbiome is composed of a complex community of trillions of microbes, consisting of bacteria, fungi, viruses, archaea, and protozoa, with bacteria constituting more than 90% of the gastrointestinal ecosystem [19–22]. The mechanism through which the gut microbiome mediates an integral role in the pathogenesis of stroke has been well established [23]. Brain lesion due to stroke together with the effect from stroke-induced immunosuppression caused harmful consequences on gut microbiome via top-down signaling of microbiota gut-brain axis. Such consequences include dysbiosis, imbalance in resident intestinal immune function, and intestinal barrier dysfunction [24]. The bottom-up signaling of microbiota gut-brain axis through microbiome associated effect in up-regulation in pro-inflammatory immune cells and cytokines, as well as an increase in permeability of microbes and their components, lead to compounding effect on stroke injury by escalating

neuro-inflammation and unsettling in integrity of blood–brain barrier (BBB) [25]. In this paper, therefore, we explored evidence that will support future research and perspectives into the potentiality of microbiome-based interventions as an integral part of post-stroke rehabilitation.

## **2. Post-stroke rehabilitation and neuroplasticity**

Post-stroke rehabilitation entails healthcare that manages post-stroke disability and the underline condition that cause or accompany the stroke, with the goal that focuses on reducing the disability and enhancing the performance in activities of daily living (ADL). Because post-stroke rehabilitation objectives are complex and dynamic involving measures to avoid further decline in function, optimize the existing function, and reach for the highest possible level of independence (physically, psychologically, socially, and financially) possible, multidisciplinary interventions from a number of disciplines are employed [26]. Post-stroke rehabilitation guidelines are therefore developed based on evidence-based best data to improve and support the best clinical rehabilitation of stroke [27, 28]. Nevertheless, even with the best clinical practice in post-stroke rehabilitation, certain populations of stroke survivors are still living with residual disabilities. Rehabilitation as a process generally explores the basis for brain recovery from impairments, which are adaptation, restitution, and neuroplasticity [29].

Recovery in function in post-stroke brain depends majorly on neuroplasticity. Neuroplasticity entails the inherent capability of the CNS to change structurally and functionally as a result of new experiences [30]. There exist many techniques to detect neuroplasticity in the human brain. The most frequently used include functional magnetic resonance imaging (fMRI) which assesses changes in activation and recruitment of brain regions and noninvasive brain stimulation which can detect a change in volume, location, and excitability of motor cortical maps [31]. The basic processes in learning-related plasticity include the amplification of existing neuronal connections, as well as the formation of new connections to support learned behaviors [32]. These processes are then followed by synaptic pruning of the connections as skill and preferential pathways develop. For this, one of the current approaches to optimize the functional benefits of post-stroke motor rehabilitation is by focusing on interventions that encourage motor learning-related neuroplasticity [31].

The molecular level of synaptic plasticity has been extensively studied. In synaptic plasticity, there is exocytosis of neurotransmitters to modulate synaptic plasticity either at monosynaptic or multi-synaptic level, thus neurotransmitter-receptor binding is critical to synaptic plasticity [33]. Within the cortex, glutamate receptors play a key role, as glutamate is the most important excitatory neurotransmitter. The arrival of impulses from neighboring neurons leads to the activation of metabotropic glutamate receptors. This allows for calcium influx which consequently engages machinery for protein synthesis and permanently changes postsynaptic neurons [34].

## **3. Microbiota gut brain axis and stroke**

Gut-brain axis has recently been increasingly recognized as one of hallmark biological processes linked with the pathophysiology of stroke [35]. Gut-brain axis primarily refers to the network of biological connections that link the gastrointestinal tract (GIT) and the central nervous system (CNS), allowing for bidirectional

communication between the two [36, 37]. By implication, the bidirectional communication here indicates two-way communication implying that while on hand the brain modulates the regulation of gut activities (top-down signaling); on the other hand, the gut also can regulate the functions of the brain (bottom-up signaling). These regulatory signals between the two are executed through multiple mechanisms, including neural, endocrinal, immunological, and metabolic pathways. The components of the brain that drive gut-brain axis include the hypothalamus, medial prefrontal cortex, nucleus of the solitary tract in the medulla, and amygdala among others [38]. The gastrointestinal components include the intestinal cells and the microbes within the gut termed microbiota. The term gut microbiota refers to complex assembly of microbes residing within the human gastrointestinal tract [39]. The microbes within microbiota community are constituted by extraordinary densities of 100 trillions of microorganisms, including more than 1000 species, of mostly bacteria, but also fungi, archaea, protozoa, and viruses, together with their collective genomes termed microbiome [21, 22]. Because the gut microbiota contributes to the major components involved in gut-brain axis, the term microbiota gut-brain axis is used as an extension to recognize the integral position of gut microbiota in gut-brain axis [40].

Mounting lines of evidence demonstrate that gut microbiota dysbiosis is one of the key causative factors in stroke pathology, and the interaction between stroke and microbiota pathologies is noticeable via microbiota-gut-brain-axis. The term dysbiosis is used to indicate disruption in the balance of composition of gut microbiota towards decreased intestinal biodiversity of beneficial or commensal species and increased pathogenic bacteria species [41]. Under normal circumstances, the composition of intestinal microbiota is in a status of eubiosis, where there's a preponderance of potentially beneficial species such as *Firmicutes* and *Bacteroides* over a very low percentage of potentially pathogenic species such as *Proteobacteria*. This normal balance is critical for health and homeostasis, especially in the brain, and when dysfunctional leads to the development and progression of diseases [42]. For instance, stroke leads to gut microbiota dysbiosis, and this causes dysfunctional gut-brain axis signaling that further amplified neuroinflammation and oxidative stress damage.

Several studies involving human and animal models of stroke have demonstrated gut microbiota dysbiosis involvement in the pathology of stroke. Stanley [43] examined the composition of the mucosal microbiota after stroke in a model of focal cerebral ischemia. This study found that ischemic stroke is associated with microbiota dysbiosis, as well as far-reaching and robust changes to the intestinal mucosal microbiota. Crasper [44] observed the role of bacterial translocation from the gut in post-stroke infection in an animal model of stroke. It was observed from this study that ischemic stroke results in impairment of gut permeability, as well as a marked inducement in gut dysbiosis**.** Stanley [45] studied whether post-stroke infection originated from commensal bacteria that normally reside in the intestinal tracts. Animal models that had post-stroke lung infection microbiota were observed, the microbes were found to originate from small intestinal microbes by more than 60%, and this was attributed to stroke-induced impairment in gut barrier that allows for intestinal microbiota to reach peripheral tissues.

Haak [46] studied the hypothesis of whether patients diagnosed with acute ischemic stroke and manifest with dysbiosis in gut microbiota composition may change the risk development of post-stroke infections following hospitalization in a case–control study. Outcome of this study revealed a drastic reduction in anaerobic gut bacteria in stroke cases, which is closely associated with post-stroke infection. Boaden [47] performed a case–control study involving patients diagnosed and screened with ischemic stroke

### *Microbiome-Based Interventions: A New Prospect in Post-Stroke Rehabilitation DOI: http://dx.doi.org/10.5772/intechopen.103976*

to determine the composition of gut microbiota and its important blood metabolite trimethylamine-N-oxide. Ischemic stroke patients were found to have mark dysbiosis in gut microbiota composition with more preponderance of pathogenic microbiome and fewer commensal or beneficial microbiome. This dysbiosis was found to be correlated with the stroke severity. The blood level of trimethylamine-N-oxide was in contrast found to be significantly lower in patients with ischemic stroke. Tan [48] evaluated the gut microbiome and short-chain fatty acids spectrum, as well as their possible relation with the measure of variability in ischemic stroke severities. A mark change in composition of intestinal microbiota was observed among stroke patients when compared with control, specifically depicting deficiency in short-chain fatty acids producing bacteria which become marked with the increasing severity of stroke.

Wang [49] designed a study that sought to determine intestinal flora diversity in patients diagnosed and screened with ischemic stroke, as well as investigate whether the intestinal microflora can be used as a marker for early diagnosis of cerebral infarction. Intestinal flora composition was found to be significantly different between ischemic stroke patients in relative to the healthy control. Intestinal flora composition could be an important indicator for cerebral infarction, and due to the observed positive correlation between serum level apolipoprotein E and Gamma-proteobacteria, the serum level apolipoprotein E holds potential to predict cerebral infarction. Huang [50] carried out a study that aimed to investigate the variability in characteristics of gut microbiota among patients with acute cerebral infarction. It was revealed from this study that the abundance of three bacterial species that were abnormally higher in patients with acute cerebral ischemia in comparison to healthy controls. Yamashiro [51] observed two parameters of gut microbiota, its constituent composition, and organic acid content if they are related with ischemic stroke, and whether there is a relationship that could result in mediating biological processes such as metabolism and inflammation. Findings showed evidence of microbiota dysbiosis among the patients diagnosed with ischemic stroke, this dysbiosis was found to be associated with biological indicators of host inflammation (such as interleukin-6, high sensitivity C-reactive protein, and with white blood cell counts) and metabolism (such as acetic acid, valeric acid, and low-density lipoprotein cholesterol).

Li [52] set out a study to examine the variation in gut microbiota profile between patients diagnosed and screened with ischemic in comparison with healthy controls, and to study if such variation will be associated with the assessed clinical parameters. Patients with cerebral infarction showed dysbiosis in gut microbiota composition. This dysbiosis is related to clinical measures of stroke severity, as bacterial genera that were found to be reduced among stroke patients were negatively associated with stroke severity. Singh [53] carried out a study to determine the mechanism through which post-stroke dysbiosis links with immune response, especially the intestinal immune cells balance. Ischemic stroke was confirmed to induce dysbiosis of microbiota, and this dysbiosis proved to cause alteration in intestinal immune cells balance.

## **4. The role of gut microbiome in brain plasticity**

**Table 1** below shows evidence about the influence of gut microbiome on brain plasticity through microbiota gut-brain axis.

There exist various modalities through which gut microbiome can be modulated to complement neuroplasticity with stroke rehabilitation. Development and testing of specific interventions such as probiotics, prebiotics, dietary-based intervention, or


#### **Table 1.**

*Role of gut microbiome on brain plasticity through microbiota gut-brain axis.*

*Microbiome-Based Interventions: A New Prospect in Post-Stroke Rehabilitation DOI: http://dx.doi.org/10.5772/intechopen.103976*

any agent that targets particular gut microbiome metabolites will provide a potential novel strategy for gut microbiome-based intervention in stroke rehabilitation.

## **5. Mechanism through which microbiome-based interventions could improve stroke recovery and rehabilitation**

The potentiality of microbiota gut-brain axis in the pathogenesis and therapeutics of stroke has been also promising in human studies. Guo [17] carried out a case–control study involving acute ischemic stroke patients that were treated with traditional Chinese medicine termed tanhuo decoction (THD). It was observed that THD offers neuroprotection via modulation of microbiota gut-brain axis, where it regulates several gut bacteria to lower microbial metabolites such as lipopolysaccharide (LPS) and trimethylamine N-oxide (TMAO). Zhong [63] examined evidence-based literature the effect of probiotics, as one of the specific entities within microbiome-based interventions in the management of patients with stroke. Probiotics were found to possess enormous potential for clinical applicability in promoting stroke recovery. The various mechanisms through which microbiome-based interventions could improve stroke recovery and rehabilitation are illustrated in **Figure 1** below:

#### **Figure 1.**

*Schematic illustration of various mechanisms through which microbiome-based interventions could improve stroke recovery and rehabilitation.*

## **6. Conclusion**

The role of microbiome-based modulation to mediate brain plasticity through microbiota gut-brain axis is highlighted; this could be fundamental towards

translating similar phenomenon in human stroke to promote brain neuroplasticity in complement with post-stroke rehabilitation**.**

## **Conflict of interest**

The authors declare no conflict of interest.

## **Author details**

Mubarak Muhammad1 \*, Rabi'u Musa Isah<sup>2</sup> and Abdurrazak Muhammad3

1 Neurorehabilitation Unit, Department of Physiotherapy, Kazaure General Hospital, Kazaure, Jigawa State, Nigeria

2 Department of Physiotherapy, Murtala Muhammad Specialist Hospital, Kano State, Nigeria

3 Department of Chemical Science, School of Science and Information Technology, Skyline University, Nigeria

\*Address all correspondence to: mubarakmahmad@yahoo.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 7**

## Non-invasive Brain Stimulation Post Stroke

*Fahad Somaa*

## **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.

**Keywords:** stroke, brain stimulation, non-invasive brain stimulation, rehabilitation, plasticity

## **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 strokerelated 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].

*Non-invasive Brain Stimulation Post Stroke DOI: http://dx.doi.org/10.5772/intechopen.102013*

#### **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.

### *Non-invasive Brain Stimulation Post Stroke DOI: http://dx.doi.org/10.5772/intechopen.102013*

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 constraintinduced 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 metaanalysis 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 thetaburst stimulation, on the other hand, uses TBS trains lasting 20–40 seconds to reduce excitability in the cortex (**Figure 2**).

## **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].

## **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 nonhuman 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,

**Figure 2.** *Blink reflex recordings in a male patient with spinal cord injury before and after rTMS over the vertex [26].*

**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.*

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 speechmotor 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

### *Non-invasive Brain Stimulation Post Stroke DOI: http://dx.doi.org/10.5772/intechopen.102013*

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 imagingbased 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

*Non-invasive Brain Stimulation Post Stroke DOI: http://dx.doi.org/10.5772/intechopen.102013*

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 centralparietal 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

#### **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].*

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**).

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.

## **Author details**

Fahad Somaa Department of Occupational Therapy, King Abdulaziz University, Jeddah, Saudi Arabia

\*Address all correspondence to: fsomaa6549@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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*Non-invasive Brain Stimulation Post Stroke DOI: http://dx.doi.org/10.5772/intechopen.102013*

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## **Chapter 8**
