TMS is a neuromodulation technique that uses large transient magnetic fields to induce focal electrical fields in a specific brain area, and the availability of sophisticated equipment has made it possible to employ repetitive TMS (rTMS). The effects of rTMS vary depending on the shape of the coil (figure of eight, H coil, double cone coil),2 pacing pattern (high frequency, low frequency, theta-burst), and stimulation site. In fact, TMS is considered as a tool with great therapeutic potential because it is safe and the risk of severe negative side effects upon application is very low.

2.1.1 Mechanism of action

TMS induces short pulses of intracranial electrical current and is applied in several ways: as single pulse, as paired pulse to the same or different brain areas, or as rTMS. Single-pulse stimulus depolarizes neurons3; however, rTMS can induce changes in excitability of the cerebral cortex, locally as well as in neurons at areas far from the stimulation site, along functional anatomical connections.3, 4 Although underlying mechanisms of the therapeutic outcomes of rTMS application have not been fully elucidated, rTMS can induce changes in cerebral blood flow,5 oxygen consumption, cortical activity,6 and release of neurotransmitters.7, 8 Therefore, it has been argued that these functional changes might be associated with positive clinical results.

2.1.2 TMS application to alleviate the symptoms of neurological disorders

For effective rTMS application, adjustments in both spatial and temporal parameters are essential. In literature, for the determination of spatial location of a target in brain, 52% of the studies have used magnetic resonance imaging, 27% scalp measurement, 15% functional magnetic resonance imaging, and 6% hotspot targeting.9 Similarly, temporal parameters, which include stimulation frequency, number of pulses per trial, and interval duration between each stimulus, are also diverse. For stimulation frequency, few studies have used low-frequency stimulation of 1 Hz and most studies have applied a high-frequency stimulation ranging from 5 Hz (in 14%), 10–19 Hz (in 67%), to more than 20 Hz (in 20%). The stimulus interval time varied from 300 ms to 37,400 ms, and the number of pulses administered in each trial was <10; however, some studies applied more than 20 pulses. Additionally, combining rTMS with concurrent behavioral interventions in some neurological disorders has turned out to be more effective.10 Therapeutic benefits of rTMS are summarized in Table 1.

TABLE 1. Therapeutic benefits of application of rTMS in neurological disorders Disorder Participant size Stimulation site Stimulus frequency Outcome of treatment

Effect size or SMD

and p-value

References

and comment

Parkinson´s disease 646 M1 High frequency (10–50 Hz) Long-term motor function improvement

0.97

(p < 0.01)

Yang et al., 201814 (Meta-analysis of 23 studies) Alzheimer´s disease 293 DLPFC Low frequency (1 Hz) Improvement in memory functions 1.53 (p < 0.005) Chou et al., 201925 (Meta-analysis of 13 studies) High frequency (5–20 Hz) 0.77 (p < 0.005) 94 DLPFC High frequency (>1 Hz) Improvement in cognitive functions 1.00 (p = 0.0008) Liao et al., 201526 (Meta-analysis of 7 studies) Attention deficit hyperactivity disorder 43 PFC High frequency (18 Hz) Improvement in ADHD symptoms 0.96 (p = 0.0009) Alyagon et al., 202033 (Clinical trial) 7 PFC High frequency (10 Hz) Improvement in ADHD symptoms 0.48 (p < 0.05) Weaver et al., 201232 (Pilot study) Dyslexia 10 IPL and STG High frequency (5 Hz) Improvement in reading performance 0.54 (p < 0.001)

Costanzo et al., 201335

(Pilot study)

Autism spectrum disorder 317

DLPFC (16 studies)

PFC (3 studies)

SMA (3 studies)

PMC (1 study)

Multiple sites (1 study)

Low to high frequency (0.5–50 Hz) Significant improvement in repetitive behavior, sociability, and cognitive and executive functions ND Khaleghi et al., 202042 (Review of 24 studies) 339

DLPFC (15 studies)

PFC (3 studies)

PMC (3 studies)

Multiple sites (2 study)

Low to high frequency (>0.5) Improvement in repetitive and stereotyped behaviors, social behavior, and executive functions

0.29–0.53

(p < 0.008)

Barahona-Correa et al., 201841 (Meta-analysis of 23 studies) Chronic pain 682

M1

High frequency (5–20 Hz) Significant reduction in pain intensity (up to 32%) ND Gatzinsky et al., 202050 (Systematic review of 24 studies) 250 M1 High frequency (5–20 Hz) Significant pain relief and long-lasting analgesic effect ND Hamid et al., 201948 (Systematic review of 7 clinical trials) 727 M1 High frequency (5–20 Hz) Significant pain relief (>30%) ND Galhardoni et al., 201549 (Review of 27 clinical trials) Abbreviations: DLPFC, dorsolateral prefrontal cortex; IPL, inferior parietal lobe; M1, primary motor cortex; ND, not determined; PFC, prefrontal cortex; PMC, premotor cortex; SMA, supplementary motor area; SMD, standardized mean difference; STG, superior temporal gyrus. Parkinson's disease

A progressive degeneration of dopaminergic neurons in the basal ganglia leads to severe impairment in motor functions of patients with Parkinson´s disease (PD). The application of rTMS by several clinical groups found that PD patients improved motor functions upon application of high-frequency (10 Hz) rTMS in M1 area of motor cortex and most patients showed improvements in bradykinesia.11-15 The motor improvements in PD patients were associated with changes in neuronal activity.16 Furthermore, a meta-analysis of 23 studies with total of 646 patients found that the application of rTMS to the motor cortex area of brain produces a significant long-term improvement in motor functions.14

Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease that causes cognitive deficits and is the most common form of dementia. The application of rTMS in AD patients has been shown to improve motor17, 18 and cognitive functions.19, 20 The cognitive improvement was observed immediately and one month after the treatment but not after 6 months.21, 22 Furthermore, the application of high-frequency (10 Hz) TMS significantly improved cognitive performance in AD patients with mild deterioration,23, 24 and similarly, meta-analysis studies found that rTMS is effective in treating cognitive dysfunctions in AD patients.25, 26

Vascular dementia

Vascular dementia is the second most common form of dementia after AD, and it accounts for at least 20% of dementia cases. A study in rats with vascular dementia showed that application of TMS was able to improve spatial learning and memory,27 protect pyramidal cells from apoptosis, and promote synaptic plasticity in the CA1 area of the hippocampus.28, 29 However, the studies in humans are scarce. Nevertheless, a randomized controlled pilot study in 7 patients with vascular disease and mild cognitive deficits without vascular dementia showed that one session of high-frequency rTMS applied to the left DLPFC improved executive functioning, whereas no effects on any other cognitive functions were observed.30 Another study in patients with vascular disease and vascular cognitive impairments but without dementia found that the stimulation of left DLPFC and not left M1 area with 4 sessions of rTMS significantly improved the cognitive ability.31

Attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is primarily associated with deficits in attention and executive functions. A pilot study in 9 adolescents and young adults with ADHD found significant improvement after the treatment with high-frequency (10 Hz) rTMS.32 Another pilot study in 43 adult ADHD patients showed that the application of high-frequency (18 Hz) rTMS for 3 weeks caused significant improvement in ADHD symptoms.33 In contrast, a study in adult ADHD patients reported no effect after application of deep TMS (dTMS).34 The effect of standard rTMS is more focal and reaches a depth of 0.7 cm, while the effect of dTMS is broader and reaches a significant depth of 3.2 cm. Therefore, it seems that a focal treatment with rTMS is more effective in the treatment of ADHD.

Dyslexia

Dyslexia affects at least 5% of school-aged children and is characterized by difficulty in learning to read and spelling of written texts. Most dyslexics have difficulties in relating alphabet letters to the sounds they symbolize. So far, there is no study with larger number of dyslexia patients. In a study with 10 dyslexics, treatment with high-frequency (5 Hz) rTMS to areas that are not very active in dyslexics during reading, such as the left superior temporal gyrus and the left inferior parietal lobe, improved both precision and reading speed of the dyslexic adults.35

Autism spectrum disorder

Autism spectrum disorder (ASD) is a developmental disorder and is characterized by the difficulty in social interaction and emotional recognition, repetitive behaviors, and lack of interest. The prevalence of ASD is estimated at 1 every 110 births with a higher incidence in children.36-38 In a study, application of low-frequency (1 Hz) rTMS on DLPFC area of autistic patients caused significant improvements in the process of goal recognition, reduction of motor errors to specific stimuli, and reduction of repetitive and stereotactic behaviors.39 Another study showed that autistic youths as well as adults improved their executive functions after the application of high-frequency (20 Hz) rTMS on the DLPFC.40 In the same line, a review of 24 studies with 317 ASD patients and a meta-analysis of 23 studies with 339 ASD patients found that the application of rTMS improved the ASD symptoms in patients.41, 42

Down syndrome

Down syndrome is a genetic disorder; however, patients with Down syndrome show various neurological symptoms, such as neuromotor abnormalities, reduced learning capacity, cognitive and language alterations, and hampered reading skills.43-45 The first study with TMS on the motor cortex showed that young people with Down syndrome have normal cortical excitability, but altered cortical synaptic plasticity.46 So far, there is no study of TMS application to improve the language and cognitive alterations in Down syndrome.

Chronic pain

Chronic pain is a disorder associated with various pathologies and is thought to develop from CNS nerves damage. It has been shown that a single stimulation with high-frequency TMS produced small (12%) but short-term reduction in pain intensity, which was not considered as clinically meaningful.47 However, a systematic review of 12 randomized clinical trials involving 350 patients with focal or generalized chronic pain found that low-frequency rTMS stimulation produced no effect, whereas high-frequency stimulation induced long-lasting analgesic effect and meaningful relief from chronic pain.48 Similarly, other systematic reviews and meta-analysis have identified that rTMS49, 50 as well as rTMS combined with exercise51 has beneficial effect on relieving patients from chronic pain.