Fahad A. Somaa
Tom A. de Graaf
Alexander T. Sack- 1Department of Occupational Therapy, Faculty of Medical Rehabilitation, King Abdulaziz University, Jeddah, Saudi Arabia
- 2Section Brain Stimulation and Cognition, Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands
- 3Center of Integrative Neuroscience, Maastricht University, Maastricht, Netherlands
- 4Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Brain + Nerve Centre, Maastricht University Medical Centre+, Maastricht, Netherlands
Transcranial Magnetic Stimulation (TMS) has widespread use in research and clinical application. For psychiatric applications, such as depression or OCD, repetitive TMS protocols (rTMS) are an established and globally applied treatment option. While promising, rTMS is not yet as common in treating neurological diseases, except for neurorehabilitation after (motor) stroke and neuropathic pain treatment. This may soon change. New clinical studies testing the potential of rTMS in various other neurological conditions appear at a rapid pace. This can prove challenging for both practitioners and clinical researchers. Although most of these neurological applications have not yet received the same level of scientific/empirical scrutiny as motor stroke and neuropathic pain, the results are encouraging, opening new doors for TMS in neurology. We here review the latest clinical evidence for rTMS in pioneering neurological applications including movement disorders, Alzheimer's disease/mild cognitive impairment, epilepsy, multiple sclerosis, and disorders of consciousness.
Introduction
Transcranial magnetic stimulation (TMS) is a non-invasive, safe and painless procedure to activate or modulate cortical targets in the central nervous system (CNS) (1, 2). TMS is based on Faraday's law of electromagnetic induction, whereby an electrical current is discharged into a TMS coil, generating a perpendicular magnetic field that transcranially and thus noninvasively reaches the brain where it, due to its time-varying characterstics, generates an electric field and electrical currents in the targeted brain tissue (3, 4). If sufficiently strong, such induced electrical currents depolarize the neurons and result in TMS-induced action potentials (neural firing) measurable with electroencephalogram (EEG) (5) and/or with motor evoked potentials(MEPs) (2, 6), or also indirectly with functional magnetic resonance imaging (fMRI) (7).
The effects of rTMS on cortical excitability depend on the precise parameters selected in the so-called rTMS protocols (Table 1) as well as coil geometry (Table 2) (8). As a rule of thumb, low frequency [LF ≤ 1 hertz (Hz)] rTMS decreases cortical excitability and high frequency rTMS (HF ≥ 5–20 Hz) increases excitability (6). For example, when applied to the motor cortex, LF-TMS reduces MEP amplitudes and increases the duration of the cortical silent period, while HF-rTMS leads to opposite effects.
TMS helps to study the neural pathways in various CNS pathologies. Single pulse TMS (sTMS) evokes immediate sensory or motor responses and can therefore help assess the efficacy or speed of conduction of a particular neural pathway (1). Repetitive TMS (rTMS) modulates brain function in such a way that effects last beyond the period of stimulation. The magnetic and electrical fields generated by rTMS bring about many changes in the human brain that may confer therapeutic benefit (2). For instance, since rTMS can have lasting effects on cortical excitability through induced synaptic plasticity mechanisms, it is likely to help in the treatment of various psychiatric and CNS disorders where cortical excitability is one of the primary underlying pathologies (1, 2, 6, 8, 13).
The therapeutic potential and applications of rTMS have received much attention in recent years. Especially in the field of psychiatry, rTMS is now a widely recognized and applied treatment option for the therapy of major depressive disorder (14, 15) or obsessive compulsive disorder (16, 17) and shown to be clinically effective and reimbursed by health insurances (18, 19).
The clinical applications of TMS seem to be less successfully applied in neurology, which is somehow surprising and not necessarily straightforward, as TMS is deeply rooted as a diagnostic technique in neurology and clinical neurophysiology (20–23). It is therefore encouraging to see that in the recent update of the evidence-based guidelines by Lefaucheur (24) on the therapeutic use of rTMS, two neurological applications (neurorehabilitation after motor stroke and the treatment of neuropathic pain) received the highest level of evidence rating, namely “level A evidence” (definite efficacy). This rating was on par with the rating used for TMS application in depression treatment.
There are other currently applied rTMS treatments in neurology, for instance in the acute treatment of migraine and migraine prevention, non-motor stroke, other CNS pain syndromes, and H-coil deep TMS for poststroke aphasia (6, 25, 26). But beyond motor stroke and neuropathic pain, few rTMS protocols and applications have yet received the same level of scientific/emperical scrutiny. For some potential applications, there is no recommendation, or classification of efficacy, based on evidence from randomized controlled trials, systematic reviews and meta-analyses (27). However, it is important to realize that the lack of a formal recommendation, or classification of efficacy, does not necessarily mean that an rTMS application has no promise. Sometimes, the lack of such a recommendation is due to underpowered, or inconsistent, evidence from clinical studies. However, other times, the evidence that exists is in fact very promising, but not yet of sufficient size or scope that recommendations are warranted. It is therefore crucial to continue monitoring the state of evidence for these less investigated yet pioneering rTMS applications. Here, we focus on those “other” or “underinvestigated” neurological disorders, by reviewing the latest clinical evidence for the potential of rTMS in the treatment of movement disorders, Alzheimer's disease/mild cognitive impairment (MCI), epilepsy, multiple sclerosis (MS), and disorders of consciousness.
Literature Search Strategy
General literature search, Google Scholar and MEDLINE search was carried out until December 25, 2020, by using the following search terms in various combinations: “transcranial magnetic stimulation,” “treatment,” “neurological diseases,” “Alzheimer's disease,” “Parkinson's disease,” “post stroke,” “multiple sclerosis,” “epilepsy,” “dystonia,” “Tourette syndrome,” “chronic tic disorders,” “Huntington's disease,” “choreas.” Only English language publications covering therapeutic benefits and challenges of TMS in neurological conditions of the CNS were considered. Literature covering pathophysiological and diagnostics aspects of TMS were excluded. Similarly studies looking at therapeutic benefits and challenges in neurobehavioral, psychiatric and chronic pain conditions were not included in the narrative review.
TMS in Movement Disorders
rTMS has been shown to bring about some level of improvement in movement disorders, such as Parkinson's disease (PD), dystonia, Huntington's disease, and Tourette syndrome (Table 3) (8).
Table 3. TMS in Movement disorders.
Parkinson's Disease
It has been suggested by experimental research that changes in neurotransmitter release, transsynaptic efficiency, signaling pathways and gene transcription are induced by rTMS (58–62). Additionally, current research suggests that repetitive transcranial magnetic stimulation (rTMS) stimulates neurogenesis, neuronal survival, and the release of neuroprotective chemicals in Parkinson's disease patients (58, 63–65). One possible mechanism of action may relate to high-frequency rTMS-enhanced activity in the caudate nucleus as well as a relief of dopamine deficiency in nigrostriatal-thalamo-cortical circuitry (66–68). For instance, rTMS over M1 seems to affect dopamine release in nigrostriatal regions (24, 69).
Literature shows that rTMS could potentially be used as an important adjunctive treatment for PD (Table 3) (8, 34, 35, 70). Bradykinesia and tremor are two of the most debilitating motor symptoms in PD and thought to be related to abnormal oscillations in the subthalamic nucleus (STN) (71). Literature suggests that rTMS, especially the bilateral delivery over motor cortical regions, helps in improving motor symptoms (8, 13, 24, 27, 70). In these patients, favorable targets for high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) include primary motor cortex (M1), less focal motor cortex (MC) stimulation such as to leg or bilateral hand MC, and dorsolateral prefrontal cortex (DLPFC), while supplementary motor area (SMA) was found to be the most favorable low-frequency repetitive transcranial magnetic stimulation (LF-rTMS target) (8, 13, 70). rTMS to these targets has also been found effective for levodopa-induced dyskinesia (LID) (37). However, Lefaucheur (24) felt that these benefits were sometimes the results of a single session, and the prolonged clinical benefit needs to be investigated. Additionally, literature reporting the beneficial effect of HF-rTMS of the left DLPFC in treating non-motor depressive symptoms in PD has been covered in many review articles (8, 13, 70). However, a randomized trial failed to show any significant benefit in mood upliftment (24, 72).
In their evidence based guidelines on the therapeutic use of rTMS, Lefaucheur (24) suggest that of the various targets studied, M1 stimulation may be recommended for treating motor symptoms in PD with repeated HF-rTMS. A large double-cone coil applied to M1 leg area may help improve freezing-of-gait. However, specific recommendations for the use of rTMS in PD could not be made without further research.
Repetitive transcranial magnetic stimulation (rTMS) has been suggested as a potential treatment for cognitive impairment in Parkinson's disease (PD), with effects that appear to be additive to dopaminergic medicines (73). While it is difficult to pinpoint the exact role of pathological neural oscillations in certain aspects of motor and cognitive function, current research clearly suggests that these pathological oscillations interact and contribute to the motor and cognitive deficits seen in Parkinson's disease (74). Another study found that repetitive transcranial magnetic stimulation (rTMS) over (motor region) M1 is beneficial for motor function and may have a slight favorable effect on cognition (73). The efficacy of TMS on depression and cognition in Parkinson's disease has yielded promising preliminary results. Although it is unknown if these effects are transient, what the underlying processes are, and if such neuromodulation might transfer to real-world settings, a small study found that TMS can improve working memory in PD patients (75).
Dystonia
The exact mechanisms of action of rTMS in alleviating dystonia remain unknown (76–80). Although motor cortex hyperexcitability appears to be the cause of aberrant co-contraction and overflow to adjacent muscles, several studies have shown that plasticity processes and integrated sensorimotor processing are also likely to be involved (76, 78, 81, 82).
Cortical hyperexcitability in dystonia is thought to be caused by two abnormalities in the sensorimotor system (83). The inhibitory systems are less excited and there is an increase in the plasticity of neural connections. Hence, rTMS may be a useful therapeutic tool for dystonia if it can increase intracortical inhibition and reduce excessive cortical plasticity. LF-rTMS and cTBS protocols (continuous theta burst stimulation; a patterned inhibitory rTMS protocol thought to have analogous effects to LF-rTMS) have been investigated in dystonia by targeting M1, PMC, SMA, primary somatosensory cortex, and cerebellum. Different protocols were used for writer's cramp and craniocervical dystonia (Table 3) (84). A literature review by Erro et al. (84) found mixed evidence of benefit. While some studies reported short-lasting objective or subjective improvement in dystonia, others did not (Table 3).
Huntington's Disease
The dopaminergic system, particularly in the frontal brain, can be affected by rTMS. TMS can cause an increase in the flow of dopamine to numerous parts of the brain, including the nucleus accumbens and the dorsal striatum, due to the connection between dopaminergic pathways in the cortex and those sub cortical structures (85–88). These dopaminergic pathways are the likely mediators in the beneficial effects of rTMS in Huntington disease patients (85, 87, 88).
There are currently only very limited, very small, studies (<10 patients in a study) (Table 3) reporting inconclusive evidence of the beneficial effect of TMS in ameliorating motor symptoms in Huntington's Disease (51–53). SMA is believed to play a key role in maintaining the executive aspects of motor control in Huntington's Disease (89). A small study did report a benefit in uplifting mood (non-motor symptom) (53).
Tourette Syndrome
Very little is known about mechanisms of action of rTMS in Tourette syndrome (90, 91). It was suggested that low frequency rTMS may help with tics and obsessive behaviors by resetting a hyperactive motor cortex (90, 92). But there are currently a limited number of rTMS studies in adult Tourette syndrome, overall showing mixed results (Table 3). Some LF-rTMS (1 Hz) and HF-rTMS (15 Hz) studies targeting motor and premotor cortical sites demonstrated no success or a limited benefit in severe Tourette syndrome (54, 55, 93). On the other hand, several open-label studies targeting SMA with LF-rTMS (1 Hz) demonstrated a decrease in the frequency and intensity of tics (56, 94–97).
Essential Tremor
rTMS can regulate brain functions through plasticity effects and it has been targeted to the tremor network to achieve therapeutic effects (93, 98–101). One rTMS protocol that has been tested in clinical trials is LF-rTMS of the cerebellum (99, 102, 103). However, this protocol did not show any improvement in tremor variables in essential tremor (103) or in resting tremor in PD (104). Other researchers tried stimulating the left M1 or premotor cortical targets but did not find any appreciable benefit in tremor reduction (105, 106).
However, a double-blind sham controlled study (N = 10; five essential tremor, five sham) investigating LF-rTMS of the pre-SMA found significant reduction in tremors after 15 daily sessions. Though tremor reductions were also seen in the sham group (26% in essential tremor and 19% of patients in sham), sustained effects at 4 and 8 week follow-up were only seen in the essential tremor group (107).
Gaps and Challenges
Of the various movement disorders discussed, rTMS may currently be considered an emerging strategy in ameliorating certain motor symptoms in Parkinson's disease, with moreover an effect in uplifting mood. There remains a need to increase the effectiveness of rTMS in Parkinson's disease by finding optimal stimulation strategies. When it comes to the other movement disorders covered here, the few studies showing therapeutic benefit of rTMS in dystonia seem too small to yield conclusive evidence. Though SMA has shown some promise as an effective target in Huntington's disease, also there, rTMS trials have been small and results inconclusive. The rTMS trials in Tourette syndrome show a lack of significant effects, raising doubt about the possible efficacy of rTMS. In tremor, though LF-rTMS to cerebellum and pre-SMA has shown some benefit in essential tremor, overall, the available data from small samples remains inconclusive. Larger, well- designed trials assessing rTMS efficacy in treating each of these disorders are required. Also, there is a need to reduce variability in the TMS protocols evaluated for any particular movement disorder. Another issue is that the same TMS protocol may give different results in different individuals (inter-individual variability) and also in the same individual at different times (intra-individual variability). In a recent article, our group has described the possible determinants causing these intra- and inter-subject variability, hindering its reliability, and efficacy. Among differences in general TMS reactivity due to differnces in, e.g., scalp-cortex distances or cortical excitability, recent findings suggest a systematic state-dependence of rTMS in which the cognitive but also spontaneous oscillatory brain state can modulate the size and direction of rTMS effects in the brain (108). Hopefully, the overview of currently available evidence provided here can help inform further clinical work.
TMS in Alzheimer's Disease
Protocols of rTMS are based on persistently enhancing cortical excitability by repetitive high-frequency stimulation (109, 110). Long-term potentiation (LTP)-like changes in synaptic strength, which are commonly assumed to be a major cellular mechanism of learning and memory, are thought to be involved in such facilitation (109–111). The expression of plasticity-related neurotrophins like brain-derived neurotrophic factor (BDNF) which diminishes in the hippocampus of Alzheimer's disease patients, is regulated by neuronal activity and LTP (109, 112). Hence rTMS can considerably increase BDNF levels. By the correction or blunting of impaired LTP-like plasticity and associated signaling defects seen in AD, rTMS may provide clinical benefit (109, 113, 114). rTMS has also shown to be an inhibitory neuron function modifier as the studies show that GABAergic synaptic strength on principal neurons is reduced by 10 Hz stimulation, confirming a concept in which GABAergic synapses influence overall inhibitory/excitatory balance (109, 115, 116).
Two recent meta-analyses showed that rTMS may be an effective therapy to improve cognitive ability in patients with mild to moderate AD including MCI. In the first meta-analysis (15 RCTs; N = 240), rTMS was found to be an effective therapy to improve cognitive impairment in AD (117). rTMS significantly improved cognition in AD compared to sham (P = 0.0006). A subgroup analysis suggested that rTMS on multiple sites and multiple sessions (>10) provided more significant cognitive enhancement than rTMS on single site for ≤ 10 sessions. 20 Hz was more effective than 10 or 1 Hz frequencies. Concurrent cognitive training and/or patients with higher education seemed to confer higher benefit than single therapy, or in patients with lower education or severe dementia (117).
The other meta-analysis (12 studies including 8 RCTs; N = 231) also suggested that rTMS significantly improved cognition in AD compared to sham (P < 0.0001) (118). The sub-analysis moreover showed that multiple targets had better effects than single (0.86 vs. 0.13) and ≥5 sessions had better effect than ≤ 3 sessions (2.77 vs. 0.29). However, this meta-analysis did not find any benefit of concurrent cognitive training (118).
Thus, the meta-analyses showed that rTMS to multiple sites [Broca, right/left DLPFC, Wernicke, right/ left parietal somatosensory association cortex (pSAC), inferior frontal gyrus] and long-term treatment yields better cognitive performance than single site or short duration rTMS (109, 117, 118). However, while encouraging, this cannot be considered as a conclusive evidence as the studies included in both meta-analyses (Table 4) had small sample size, and some were not sham-controlled.
Table 4. TMS in Alzheimer's disease.
Gaps and Challenges
There is no recommendation yet for therapeutic use of TMS in AD and MCI (109). There are limited studies showing long-term efficacy. The clinical trials reporting positive effects on cognitive outcome measures in AD are very small and there are no clear neurobiological mechanisms to explain the benefit of rTMS in AD (109). In their evidence based guidelines, Lefaucheur (24) note that multisite rTMS with concurrent cognitive training in AD may possibly improve cognition, memory, apathy, and language in mild and early stage AD (including MCI). However, they do not recommend its clinical use until long-term observational studies show that multisite rTMS with cognitive training is more beneficial than single-site focused rTMS with cognitive training. They also stress the need for neurophysiological and imaging studies to improve the understanding of the neural mechanisms of action. Additionally, a TMS strategy that may show positive effects in young adults may have detrimental effects in older adults or in patients with brain affected by AD pathology, so one should proceed with caution.
TMS in Multiple Sclerosis
MS is usually treated with disease-modifying therapies. However, despite treatment, patients develop relapsing/remitting MS (RRMS) and secondary progressing MS (SPMS). Since TMS has no known interaction with MS drugs, it can be used as an adjunctive treatment for management of motor and sensory symptoms of MS (8). It is believed that some of the MS symptoms are related to neuronal transmissionin the brain (6). LF-rTMS of a single neuron can cause prolonged inhibition of neuronal transmission while HF-rTMS can improve neuronal transmission (132) Thus trains of rTMS pulses modify activity in the targeted region of brain lasting for minutes or even hours (132). Thus, TMS may alleviate debilitating MS symptoms such as fatigue, spasticity, and gait abnormalities and manual dexterity, which affect quality of life (QoL), especially in patients with RRMS and SPMS (Table 5) (2, 62).
Table 5. TMS in multiple sclerosis.
Agüera et al. (141) reported a case of RRMS (33 years, female) not responding to medications prescribed over 9 years and rapidly progressing disease. The patient benefited from rTMS which was prescribed as a compassionate treatment as no other treatment was producing any benefit. Post rTMS, there was improvement in her neuropsychological functions and blood tests showed a reduction in oxidative stress after 4 months of treatment (141).
There is mixed evidence of benefit in fatigue. In 34 patients with secondary progressive MS, HF-rTMS (20 Hz) and intermittent TBS (iTBS), a patterned excitatory protocol with after-effects analogous to HF-rTMS was used for spasticity management. HF-rTMS and iTBS significantly showed significant reduction in spasticity on the Modified Ashworth Scale compared to sham stimulation (142). Intermittent theta burst stimulation (iTBS) had longer-lasting effect on the Subjective Evaluating Spasticity Scale (SESS) and when given after HF-rTMS resulted in reduction in pain and fatigue. However, a systematic review and meta-analysis comparing transcranial direct current stimulation (tDCS), TMS, and transcranial random noise stimulation (tRNS) did not find TMS to be beneficial in fatigue (143). The analysis included 207 patients from 14 studies (11 for tDCS, 2 for TMS, and 1 for tRNS). The analysis reported that tDCS had significant short-term and long-term treatment effects compared to sham stimulation but TMS and tRNS were not found to be superior to sham stimulation (143). However, Gaede et al. (144) reported some benefit of H-coil HF-rTMS deep brain stimulation to motor cortex in 37 patients with MS related fatigue. There was significant sustained median Fatigue Severity Scale (FSS) decrease of 1.0 point (95%CI, 0.45, 1.65). However, some participants discontinued treatment due to minor side effects and the study size was too small to make any conclusive suggestion.
Gaps and Challenges
There is no conclusive recommendation yet for therapeutic use of TMS in MS. In their evidence based guidelines, Lefaucheur (24) suggests that iTBS targeted to the leg motor cortex may be recommended to treat lower limb spasticity in MS. However, they do not recommend using iTBS to the hand motor cortex for improving manual dexterity. Nor do they recommend using H-coil HF-rTMS deep brain stimulation to motor cortex to improve fatigue. Since iTBS and H-coil HF-rTMS has shown some benefit in MS, large studies with set iTBS and H-coil HF-rTMS protocols in MS will be required to identify how TMS can be effectively, therapeutically and routinely used in MS.
TMS in Epilepsy
Though antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment, one third of patients on AEDs develop drug resistance. Of these, many patients are not suitable candidates for surgical ablation. This patient group, which is at increased risk of morbidity, may respond to LF-TMS (8). rTMS could reduce likelihood of seizures in this patient population probably due to its ability to cause prolonged inhibitory effect on synaptic potential and focal cortical excitability (6). TMS has also been used to study the effects of AEDs on the brain (145). In patients who are candidates for surgical ablation, TMS helps identify the brain areas which are more seizure prone. Alternatively, TMS helps identify areas of cortical excitability in various epilepsy syndromes (145).
A Cochrane review of seven pilot studies from different regions of the world showed that, in all studies, TMS was used in patients with drug-resistant epilepsy (146). However, the definition of drug resistance differed between studies and ranged from ≤ 1 complex partial/secondarily generalized seizure per month to ≥3 seizures per month. Additionally patient should have had ≤ 2 unchanging AEDs. All studies used figure 8 coil though the sham TMS methods varied (146).
A meta-analysis of 11 studies (n = 164) evaluating the efficacy of LF-rTMS in medically intractable epilepsy found a significant effect size in seizure frequency [effect size: 0.34, 95% confidence interval (CI) 0.10-0.57] (147). Seizure reduction was significantly higher in patients with neocortical epilepsy or cortical dysplasia than those with other epileptic disorders (effect size of 0.71 vs. 0.22) (147).
In their systematic review, Cooper et al. (132) included 12 studies in patients with drug-resistant epilepsy being treated with LF-rTMS. Meta-analysis of the five studies with individual participant data (IPD) (n = 34) showed that patients with temporal seizure focus had significantly more favorable response than patients with extratemporal epilepsy (50 vs. 14%, p = 0.045). Stimulation with a figure-8 coil resulted in significantly more favorable response than stimulation with other types of coils (47 vs. 0%, p = 0.01). Meta-analysis of seven studies without IPD (n = 212) showed that seizure reduction rates were significantly higher in patients with mean age ≤ 21 years than those older than 21 years (69 vs. 18%) and in patients treated with targeted stimulation vs. those treated without targeted stimulation (47 vs. 14–20%). The pooled rate of 50% seizure reduction with LF-rTMS was 30% (95% CI 12–57%) (132).
Gaps and Challenges
There is no recommendation yet for therapeutic use of TMS in epilepsy. Though the Cochrane review found rTMS to be safe and effective in reducing epileptiform discharges, the review could not find clear evidence of the efficacy of rTMS in reducing seizure frequency (146). There is currently too much variability in the TMS techniques used in studies, in the outcomes reported and in the definition of drug-resistant epilepsy (147, 148).
TMS in Disorders of Consciousness
Disorders of consciousness (DOC) mainly include minimally conscious state (MCS) and the “vegetative state,” clinically known as the unresponsive wakefulness syndrome (UWS). The clinical efficacy of rTMS has been studied in these patients using different HF-rTMS protocols, mainly targeting the left M1 (149–151) and the right and left DLPFC (152–154) or iTBS to left DLPFC (155). Cincotta et al. (149) (N = 11 patients with UWS) and Liu et al. (150) (N-7 patients with DOC and 11 healthy controls) tested 20 Hz rTMS of the M1 but found no evidence of therapeutic effect. He et al. (151) posted results of a randomized sham controlled study of six patients with DOC treated with 20 Hz rTMS of the M1 for five consecutive days. rTMS resulted in long-lasting behavioral and neurophysiological modifications in one patient with traumatic brain injury while five other patients showed localized brain reactivity at several electrodes, but no significant electroencephalography changes. This was a very small study with inconclusive evidence of efficacy of HF-rTMS pf M1 in DOC.
Similarly, targeting DLPFC did not provide any conclusive evidence of effect in DOC. Naro et al. (152) (N = 10 postanoxic UWS and 10 healthy controls) did not find any significant clinical change after a single session of 10 Hz rTMS to the right DLPFC. However, three patients showed short-lasting clinical improvement caused by a significant transient effect induced by rTMS (152). On the contrary, Xia et al. (153), found clinically significant benefit of 10-Hz rTMS to the left DLPFC for 20 consecutive sessions in 16 patients (5 MCS and 11 UWS). In another 2017 study, Xia et al. reported reduced EEG signal power in low-frequency and increased signal power in the high-frequency bands (154).
A study using iTBS (600 pulses per session at 80% of active motor threshold) to the left DLPFC for 5 consecutive days in eight patients with MCS or UWS reported some clinical benefit after rTMS but the benefit was statistically significant only after a week. This was a small study with no sham control.
Gaps and Challenges
There is no recommendation yet for therapeutic use of TMS in DOC. Though some clinical benefit in consciousness level was seen using HF-rTMS of the left M1 or after HF-rTMS or iTBS of the left DLPFC, the small sample size of these studies limits the generalization of the results. Also, contrary results from other studies raise a level of doubt regarding efficacy in DOC. Further studies testing the efficacy of TMS protocols to left M1 or DLPFC are required to determine whether TMS has any efficacy in DOC.
Safety of TMS in Neurological Conditions
TMS is a relatively safe procedure. A systematic review of 93 RCTs found the TMS group had 2.60 times higher (95% CI 1.75 3.86) odds of experiencing an adverse event (AE) than placebo (p < 0.00001). Headache and dizziness were the most common AEs. However, the overall pooled estimate of treatment discontinuation due to an AE was 2.5% (95% CI 1.9-3.2%) with TMS and 2.7% (95% CI 2.0-3.5%) with placebo (156).
A meta-analytic utility prediction study including 35 studies investigating treatment of focal epilepsy (N = 6,398; 28 AEDs and 7 rTMS studies; AEDs n = 4,919; rTMS n = 136 and placebo n = 1,343) found that adjunctive rTMS provided superior QoL as compared to AEDs (148). However, there was no difference in seizure reductions between AEDs and rTMS (p = 0.94). Reduction of seizure frequency from baseline to final treatment follow-up with AED, rTMS and placebo was 36.1 ± 15.2%, 36.2 ± 7.2% and 19.6 ± 8.5%, respectively. The superior QoL was due to fewer side effects, most of which were considered mild (148). There was no difference in adverse effects between rTMS and sham TMS groups. This suggests that adjustments in the treatment environment may have mitigated the TMS related adverse effects. On the other hand, adverse effects were the main reason for treatment discontinuations in the AEDs arms of the studies (148).
A Cochrane review of seven studies analyzing the effect of TMS in epilepsy found that adverse effects were uncommon; most reported adverse effects were headache, dizziness, and tinnitus and did not lead to a significant change in medications (146). A meta-analysis of 17 RCTs evaluating rTMS to left DLPFC (10 Hz) at 60-110% resting motor threshold (rMT) reported a significant incidence of headache in the treatment group.
TMS use in epilepsy may induce seizures in patients with a known neurological disorder and clinicians should be aware and alert about this complication (6, 157). However, the risk is very low, most incidences are transient and self-limiting and do not have any long-term sequelae (157).
Clinical Effects of rtms in Cerebellar Ataxias
Cerebellar low frequency TMS works by lowering the inhibitory regulation of the cerebellar cortex over the dentate nucleus, hence potentiating some of the impaired functionality of dentate nucleus. Furthermore, a reduced inhibitory signal from Purkinje cells may boost the activation of the vestibular nuclei, resulting in improved balance in patients with cerebellar ataxias (158–162).
Spinocerebellar Ataxia
Dysfunction of the cerebellum and its connected neural networks causes a neurodegenerative disorder known as spinocerebellar ataxia (SCA). In a randomized, double-blinded and sham-controlled study significant improvement in clinical and kinematic outcomes of postural control in standing were observed in patients who completed a 4-week rTMS intervention with 1-month follow up as compared to the patients receiving sham intervention (159).
Hereditary Ataxias
The role of TMS in diagnosis, pathophysiology and treatment interventions of genetically confirmed hereditary ataxias was studied in a critical review (23). Hereditary ataxias are a heterogeneous group of neurodegenerative disorders affecting motor cortex and the corticospinal tract. Early involvement of the corticospinal tract and motor cortex circuitry was shown by the available data and the effectiveness of cerebellar repetitive TMS (rTMS) as treatment approach was observed (23).
Truncal Ataxia
The efficacy of TMS over the cerebellum for inherited spinocerebellar degeneration was reported in a placebo-controlled trial (107). Patients treated with active TMS showed a significant reduction in truncal ataxia. The contraction of nuchal and shoulder muscles was evoked by active stimulation. Sham stimulation, on the other hand, generated the same noise as active stimulation, as well as some scalp sensation. The study's findings revealed that the disease type had an impact on TMS's effectiveness (163).
A study of Ihara et al. (164) compared pre and post severity of ataxia, cerebellar hemispheric blood flow (CHBF), ascorbate free radical (AFR), superoxide dismutase protein, superoxide scavenging activity, and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in cerebrospinal fluid (CSF) during an 8-week course of repetitive transcranial magnetic stimulation (rTMS) in 20 individuals with spinocerebellar degenerations (SCD). After applying rTMS, AFR and ataxia severity decreased in SCD patients and CHBF increased.
Neurodegenerative Ataxia
A review of Alberto et al. (165) concluded that non-invasive brain stimulation has made substantial advances in developing particular protocols of stimulation to regulate cerebellar excitability with the aim to restore the cerebellar physiological activity in ataxia patients. Literature showed that rTMS or tDCS may be useful tools for patients suffering from neurodegenerative ataxia.
Placebo Effects
In rTMS, there are substantial placebo effects. This means that efficacy of rTMS (response rates, remission rates, etc.) should be evaluated not just in isolation, but in comparison to placebo groups. Therefore, clinical studies without good blinding and placebo control provide limited information on the extent to which clinical outcomes are attributable to direct neuromodulation effects or to indirect placebo effects. This is not only highly relevant in psychiatric applications, but also in neurology as, e.g., very evident in essential tremor. Most of the studies included in this review are placebo controlled. But it remains the case that some literature on neurological disorders lacks proper controls/blinding.
Limitations and Strengths of the Review
This review is limited by its narrative structure. There is a high possibility of study selection bias. However, it is a comprehensive review of literature and its judicious interpretation that covers all aspects of TMS that a clinician would require for selecting the right patient population and TMS strategy for either investigating or treating a particular neurological disorder.
Future Prospects and Summary
Several animal studies are being conducted and cerebellar stimulation is being explored to treat movement disorders (166). However, in general, TMS therapy for a particular neurological condition needs more directional exploration by standardizing study designs, end points, TMS frequency, target, coil, location of stimulus and other such variables.
This review shows that though TMS is not the first line treatment in the discussed neurological conditions, it has an important place in ameliorating symptoms and improving QoL of patients with debilitating disease not responding to drug therapy. With right patient, target and strategy selection, as summarized in Table 6, the required efficacy may be seen. However, it is too early to unambiguously recommend TMS as a therapeutic clinical option in many of these neurological conditions. To reach that stage, more clinical studies are necessary. By providing the current overview, hopefully we could contribute to informing those studies.
Table 6. The patient population and TMS strategy that may provide benefit and needs to investigated further in larger trials.
Author Contributions
FS primarily did the literature review and wrote first draft. TG and AS contributed further insights and co-authored with FS the final manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AS is Chief Scientific Advisor for PlatoScience and Alphasys; as well as Director of the International Clinical TMS Certification Course (www.tmscourse.eu).
The remaining 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.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Keywords: transcranial magnetic stimulation (TMS), Alzheimer, Parkinson, movement disorder, epilepsy, migraine, stroke
Citation: Somaa FA, de Graaf TA and Sack AT (2022) Transcranial Magnetic Stimulation in the Treatment of Neurological Diseases. Front. Neurol. 13:793253. doi: 10.3389/fneur.2022.793253
Received: 11 October 2021; Accepted: 25 February 2022;
Published: 20 May 2022.
Edited by:
Sergio Machado, Federal University of Santa Maria, BrazilReviewed by:
Roberto Rodríguez-Labrada, Cuban Neuroscience Center, CubaEman M. Khedr, Assiut University, Egypt
Copyright © 2022 Somaa, de Graaf and Sack. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Alexander T. Sack, YS5zYWNrJiN4MDAwNDA7bWFhc3RyaWNodHVuaXZlcnNpdHkubmw=