Transcranial Magnetic Stimulation as Neuroplasticity Modulation Tool in Rehabilitation

Abstract

Since the study of the neuroplastic processes of the brain, it was understood that these processes could be modulated and used in the neurorehabilitation of patients with brain damage. The optimal method of neuromodulation of plasticity is noninvasive transcranial magnetic stimulation (TMS), which can also be used to induce nerve impulses in the parameters we need. This technique allows for measuring the functional state of the central nervous system (CNS) using neurophysiological methods, measuring the effectiveness of rehabilitation, and predicting the restoration of lost functions. We measured the effectiveness of TMS in modulating neuroplasticity using clinical-neurophysiological data and scores of rating scales in rehabilitation. The main studies were provided on the rehabilitation of stroke, but these data can be used in the rehabilitation of other brain injuries.

1. Introduction

Rehabilitation in the broadest sense of this concept is a set of general measures aimed at returning to life, returning lost functions, improving damaged functions, adapting to lost functions as much as possible, modifying life to improve the quality of life, and reintegration into society.

As you can see, a small and short-term damage may be just sufficient to disrupt the functioning of the brain, and years and quite a lot of work can be spent on recovery.

Rehabilitation methods are increasing with the progress and growth of the world economy, along with a deep study of the brain and its untapped potential. If earlier rehabilitation used only methods for recovery only in specialized institutions and the approaches were standard, now the approaches have become individualized and rehabilitation activities continue at the patient’s home, robotics and telemedicine are used, and ideas from science fiction films are being implemented, for example, using a medical avatar for rehabilitation [1].

It is not for nothing that the World Health Organization (WHO) developed the Rehabilitation 2030 initiative, which aims to draw attention to the acute unmet need for rehabilitation worldwide and highlights the importance of strengthening health systems to ensure rehabilitation [2]. This document emphasizes that rehabilitation must be made accessible to all members of society throughout life, and that rehabilitation is a critical component of health care and plays a critical role in ensuring comprehensive health coverage.

2. The role of TMS in brain neuroplasticity

Transcranial magnetic stimulation (TMS) is a noninvasive method of stimulating nerve cells in the brain by applying a pulsed magnetic field to the skull. Now, despite the name transcranial, TMS is also used to stimulate the spinal cord. By influencing brain activity, TMS can influence neuroplasticity, which is the ability of the brain to modulate its structure and function in response to experience and learning.

With the help of TMS, it is possible to induce an increase in the activity of neurons, which can increase the activity of certain areas of the brain, contribute to their strengthening to improve the functions associated with these areas, and stimulate neurogenesis. This property is widely used to enhance the activity of motor cortical areas in the rehabilitation of stroke patients. TMS can affect the balance between excitation and inhibition in the brain, it can increase or decrease synaptic connections depending on stimulation parameters, and this property is used as a treatment for some mental disorders such as depression.

With all this, the TMS method is very convenient for both studying neuroplasticity and modulating neuroplasticity for therapeutic purposes, and TMS equipment is constantly being updated and improved.

Studies show that TMS may have an effect on the stimulation of neurogenesis, which is the formation of new neurons in certain areas of the brain [3, 4]. The effects of TMS may depend on the intensity of the magnetic field, the frequency of stimulation, the duration and frequency of repetition of stimulations, as well as the specific characteristics of brain tissues and their response to stimulation. Thus, it has been shown that high-frequency TMS causes a stimulating effect, and low-frequency TMS, on the contrary, has an inhibitory effect on neuronal connections.

3. How does TMS work?

The TMS method is based on the impact of pulsed magnetic field (MF) using an electromagnetic coil on the brain and the subsequent induction of an electric current in it. The stimulating coil can be located either directly on the scalp or at some distance from the head (for example, at a different angle), depending on which it changes the zone and depth of propagation of the magnetic pulse (MP) and the focus of the stimulus. In modern devices, a magnetic pulse can propagate to a depth of more than 2–6 cm, that is, mainly to the cortical and subcortical structures. An electric current arises in the nerve fibers entering this MP, which leads to depolarization of neurons in the cerebral cortex, and the subsequent propagation of the impulse along nerve structures that are functionally dependent on the area of influence. In this case, either suppression or enhancement of the activity of a number of enzyme and mediator systems occurs. In response to stimulation of the visual cortex, phosphenes appear, and in the motor cortex, movement of the corresponding limbs (according to Penfield’s motor “homunculus”), i.e., motor-evoked potential (MEP), takes place.

The effect of TMS on increasing neuronal activity occurs by using magnetic fields to induce electrical currents in the brain, which can excite neurons and help increase their activity. The TMS process can be broken down into the following steps (see Figure 1) [5].

Figure 1.

The steps of TMS’s influence processes.

Researchers offer several TMS methods to study brain function (see Figure 2).

Figure 2.

Transcranial magnetic stimulation methods.

The effects of TMS may depend on various parameters, such as the intensity of the magnetic field, the frequency of stimulation, the duration and repetition rate of stimulation, as well as the specific characteristics of brain tissue and its response to stimulation. Single-pulse TMS involves the delivery of single magnetic pulses to a specific area of the brain; this technique is used to diagnose and study brain reactions. Electroencephalography (EEG) and electromyography (EMG) can record TMS-evoked potentials (TEPs), which provide insight into cortical reactivity [5]. Paired-Pulse TMS are applied one after the next to assess connectivity between cortical areas. The type of effect depends on their intensity and the interval between them. Triple-Pulse combines TMS with electrical stimulation to study the integrity of the corticospinal tract and measures the percentage of excited fibers. Quadripulse is a unique form of repetitive TMS (rTMS) that allows inducing neuroplasticity with short pulse intervals (facilitation) or long ones (depression). Repetitive TMS—A series of pulses are used for prolonged exposure to the cortex. Low-frequency rTMS (≤1 Hz) suppresses cortical activity, while high-frequency rTMS (>1 Hz) increases it and may cause long-term changes. Navigated transcranial magnetic stimulation (nTMS) is designed to map the corresponding stimulated projection areas when TMS is applied to the cerebral cortex [6]. Unlike the alternative to traditional methods, repetitive TMS (rTMS), theta burst stimulation (TBS) has the advantage of faster stimulation. Intermittent TBS (iTBS) has excitatory effects similar to long-term potentiation (LTP), whereas continuous TBS (cTBS) has inhibitory effects similar to long-term depression (LTD) [7].

Transcranial magnetic stimulation can have both short-term and long-term effects on neuronal activity and its use can be employed for therapeutic purposes, in addition, it has local and long-term effects (see Figure 3).

Figure 3.

The effects of TMS directly on the distribution zone and on brain structures remote from the impact zone [8].

Neuroimaging studies have shown that TMS is biologically active both in tissues directly under the coil and in distant areas, probably due to transsynaptic connections. Local changes in brain activity include the appearance of phosphenes and motor effects that occur during TMS as a result of depolarization of neuron membranes in the area of stimulus propagation and the subsequent appearance of an electrical impulse in the cortical axon neurons. Moreover, depending on the parameters of the impulse delivery, stimulation of one hemisphere can inhibit or facilitate the response received from the other hemisphere, which indicates interhemispheric modulatory effects, reflecting the effect of TMS on brain structures remote from the stimulation zone [9]. An example of such an effect is TMS with paired pulses. So, the motor-evoked potential in response to a TMS pulse preceded by a subthreshold “preparing” pulse is weakened when the interstimulus interval is 1 to 4 milliseconds, and strengthened when the interstimulus interval is 1 to 4 milliseconds, but when this interval is between 5 and 30 milliseconds, it reflects intracortical inhibition or facilitation of conduction, respectively [10]. Based on pharmacological effects, it has been shown that activation or inhibition at GABAergic (GABA, gamma-aminobutyric acid) or dopaminergic synapses causes an intracortical inhibitory effect of paired impulses, while the facilitating effect of paired pulses takes place due to excitation in synapses, the mediator of which is N-methyl-D-aspartate, and changes in the motor threshold depend on the conductivity of ion channels. The identified patterns open up new opportunities for studying local damage in neurochemical systems [11].

A number of studies show that during TMS, changes in blood flow occur not only in the zone of impulse propagation but also in brain structures remote from the stimulation zone [10, 12]. Thus, it was shown, for example, that the intensity of rTMS positively correlated with the level of regional cerebral blood flow in the anterior cingulate cortex ipsilaterally, cerebellum, insula contralaterally, primary auditory cortex, and somatosensory cortex (facial projection). According to some authors, rTMS of the left dorsolateral prefrontal cortex (DLPFC) causes changes in blood flow in both the prefrontal cortex and paralimbic structures [13]. According to other authors, exactly the same effect was demonstrated with rTMS of the prefrontal cortex in the blood flow of limbic structures [14]. In human studies, Szuba et al., in subjects with major depression in response to a single session of rTMS of the left DLPFC with a frequency of 10 Hz, compared with sessions of sham rTMS at the same site of action, at the same pulse frequency and session duration, observed an increase in the production of thyroid-stimulating hormone (TSH) [15]. Activation of hypothalamic-pituitary system with this method is similar to the relief of symptoms of depression after a session of electric shock. Finally, normalization of the dexamethasone suppression test with rTMS has been reported [16].

The effect of reducing the excitability of the human brain with low-frequency rTMS is used as therapy for phantom pain in paralyzed patients, as well as for amputations, for inhibition and reorganization of the motor representation of a nonfunctioning limb. One study showed the inhibitory effects of repetitive transcranial magnetic stimulation (rTMS) on the primary motor cortex (M1) and premotor cortex (PMC) using low-frequency rTMS (0.2–1 Hz) 1200 pulses (20 min) rTMS at 1 Hz and intensity 80-90% of the resting motor threshold and measures of short intracortical inhibition (SICI), intracortical facilitation (ICF) and cortical silent period (CSP), where SICI is a measure of inhibition reflecting intracortical activation of gamma-aminobutyric acid-A receptors ( GABA A), ICF is a measure of facilitation, which is mediated by N-methyl-D-aspartate (NMDA) and GABA A receptors, and CSP is a measure of inhibition, reflecting processes mediated by GABA B. This ability to non-invasively induce an inhibitory effect on a specific brain region allows the use of low-frequency rTMS as a therapeutic tool for patients with neurological disorders accompanied by low or excessive cortical inhibition [17].

4. TMS in rehabilitation

Transcranial magnetic stimulation (TMS) has many applications in the field of rehabilitation.

Recovery after a stroke: After a stroke, many patients experience impaired motor and speech functions. TMS can be used to stimulate the brain and promote functional recovery, improving motor skills, coordination, and speech. This helps patients to improve their independence and quality of life. The mechanism of therapeutic action of TMS is based on the restoration of destroyed or creation of new functional systems within the damaged hemisphere, inclusion in the implementation of motor programs of unused neural networks of the damaged hemisphere, activation of uncrossed pyramidal pathways of the intact hemisphere, creation of collateral pathways around damaged structures, and inclusion in already functioning connections of the damaged hemisphere through crossed pathways. In other words, the method of high-intensity rhythmic TMS, being a powerful neuromodulatory factor, includes a mechanism of plastic reorganization of the motor cortex.

Transcranial magnetic stimulation acts directly on the initial segment of the central motor neuron and transsynaptically within the cortex causing an outgoing volley of impulses affecting the spinal cord motoneurons with the subsequent appearance of a motor-evoked potential (MEP). During voluntary muscle contraction, TMS causes a motor-evoked potential (MEP) and after that—a temporary suppression of muscle potentials—a period of silence. The silent period arises mainly due to a synchronous volley of inhibitory postsynaptic potentials produced by an electromagnetic stimulus at the cortical level. These effects of TMS were decisive for the choice as an auxiliary method of rehabilitation of patients with ischemic stroke in the recovery period. Rhythmic TMS is a noninvasive, painless, and safe method for obtaining controlled activation of the human cortex with a potentiation effect. When stimulating the motor areas of the hemisphere with a pulsed magnetic field, not only contralateral but also ipsilateral descending pathways can be activated, since with TMS it is possible to focus the magnetic stimulus and influence the uncrossed pyramidal tract. The activating effect of TMS on the reticular formation and dopaminergic structures of the brain, which contributes to the activation of compensatory and restorative processes in the central nervous system, improvement in cognitive functions, restoration of praxis, and gnosis, has also been shown.

A group of European experts has revised recommendations on the therapeutic effectiveness of repetitive (or rhythmic) TMS (rTMS), previously published in 2014 [18]. These updated recommendations take into account all rTMS publications, including data up to 2014, as well as literature currently reviewed up to the end of 2018. Level A evidence (definite effectiveness) was achieved for low-frequency rTMS (LF-rTMS) contralateral primary motor cerebral cortex (M1) to restore hand motor skills in the subacute stage of stroke. Level B evidence (probably effective) was achieved for: HF-rTMS of ipsilateral M1 to accelerate motor recovery in subacute stroke and LF-rTMS of the right inferior frontal gyrus in chronic motor aphasia after stroke. Level A/B evidence regarding the effectiveness of rTMS for any other conditions has not been achieved. Current recommendations are based on the differences achieved in the therapeutic efficacy of real and sham (sham TMS) rTMS protocols, replicated in a sufficient number of independent studies. An extensive PubMed review identified 213 articles, including 25 original placebo/sham-controlled TMS studies with at least 10 poststroke patients receiving rTMS over multiple daily sessions compared to the affected contra- and/or ipsilateral hemisphere. Among these studies, a number of studies dealt with limb motor rehabilitation in the subacute stage using low-frequency rTMS (LF-rTMS) with contralateral M1 and/or high-frequency rTMS (HF-rTMS) with ipsilateral M1. Some of them dealt with limb motor rehabilitation in the subacute stage with contralateral intermittent theta stimulation-theta burst stimulation (TBS) or ipsilateral intermittent theta burst stimulation (iTBS). Intermittent theta burst stimulation (iTBS) is a more acceptable protocol, administered at lower intensities and shorter intervals, than conventional rTMS protocols. In addition, studies have been conducted on limb motor rehabilitation in the chronic stage, as well as low-frequency rTMS or iTBS of the cerebellum and restoration of swallowing function [19].

We used rTMS according to the method we developed in the rehabilitation program for patients after stroke, which included multilevel magnetic stimulation using a high-intensity pulsed magnetic field (2–2.2 T): Level I – rhythmic TMS of projections of the motor zones of the cortex of the affected hemisphere with a pulse intensity magnetic field of 70–90% of the maximum output of the stimulator, supply frequency stimulus 30–40 Hz, and pulse duration 0.1 ms; Level II – rhythmic TMS of segmental reflex zones (cervical and lumbar) with a pulsed magnetic field intensity of 40–60% of the maximum output of the stimulator, supply frequency stimulus 40–50 Hz, and pulse duration 0.1 ms; Level III – rhythmic TMS of the peripheral neuromotor apparatus with a pulse intensity magnetic field of 70–100% of the maximum output of the stimulator, supply frequency stimulus 30–40 Hz, and pulse duration 0.1 ms (see Figure 4). The duration of the procedure was 20–25 min (10 procedures per course).

Figure 4.

Multilevel magnetic stimulation technique [20].

The use of therapeutic techniques of transcranial and multilevel magnetic stimulation in poststroke patients helps to improve the clinical course of the disease and reduce the degree of cognitive impairment—impairment of memory, attention, orientation, speech, reading, reducing maladaptation and thereby helping to increase the level of daily household activity and improve motor functions. Our results allow us to conclude that the effect of transcranial and multilevel magnetic stimulation on brain structures responsible for the cognitive sphere occurs at all stages of recovery after stroke, apparently even residual. Multilevel rhythmic magnetic stimulation is a pathogenetically justified and therapeutically effective method of rehabilitation of poststroke patients, which, acting noninvasively on all levels of the neuromotor apparatus (central, segmental, and peripheral), stimulates afferent and efferent impulses, causes plastic reorganization of the projections of motor zones of paretic limbs in the cortex and, due to a multilevel effect on the activation of fine and gross motor skills, accelerates the restoration of cognitive functions [20].

Transcranial magnetic stimulation can help restore damaged neural connections and improve cognitive function, memory, attention, and learning after traumatic brain injury.

For Parkinson’s disease, TMS may help reduce symptoms of movement disorders, and muscle stiffness, and improve motor control.

In the rehabilitation of patients with Alzheimer‘s disease, TMS can be used to improve cognitive function and slow down the progression of the disease.

For musculoskeletal disorders, paralysis, and spasticity, to relieve pain and speed up the process of physical recovery after surgery or injury, TMS helps to strengthen muscles and improve motor skills, reduce pain and inflammation, and helps to speed up the process of physical and tissue recovery.

The results of a systematic review identified the potential benefits of the combined use of virtual reality (VR) and noninvasive brain stimulation (NIBS) as a new approach to rehabilitation. Most of the studies reviewed in five pathologies: stroke, neuropathic pain, cerebral palsy, phobia, posttraumatic stress disorder, and multiple sclerosis rehabilitation reported positive effects from the use of VR-NIBS, but studies are ongoing [21].

The use of TMS in rehabilitation requires a privatized approach and supervision by qualified neurologists, physiotherapists, and occupational therapists, who must develop treatment plans and adjust stimulation parameters according to the needs of each patient. TMS continues to develop as a noninvasive, effective method of rehabilitation and provides the prerequisites for improving the quality of life of patients.

Acknowledgments

I would like to thank my supervisor Professor, Doctor of Medicine Alishir Musayev (posthumously), my second supervisor Professor, Doctor of Medicine Sadagat Huseynova, and my permanent consultant and reviewer, coauthor of many joint works, Professor, Doctor of Medicine Farkhanda Balakishiyeva, for their great contribution and support in carrying out my work, and for my formation as a scientist and competitor.

Conflict of interest

The author declares no conflict of interest.