Treatment of sleep disorders with repetitive transcranial magnetic stimulation

Overview

The prevalence of sleep disorders in the population is remarkably high, and poor sleep quality can lead to various health problems. Current standard treatments for sleep disorders involve pharmacological and psychotherapeutic approaches. A new potentially effective method that could be introduced is repetitive transcranial magnetic stimulation (rTMS). Repetitive TMS is a modern non-invasive biological treatment method that has been used in the treatment of psychiatric and neurological disorders for many years. The principle of rTMS involves the application of repeated pulses of magnetic field, which subsequently induce electrical activity in the stimulated area of the brain. The advantage of this therapy is its excellent tolerance and minimal side effects. Its role in the treatment of sleep disorders has not yet been sufficiently explored. This paper reviews the potential use of rTMS in the management of different sleep disorders, including a summary of recent studies, the stimulation protocols employed, their effectiveness, and possible underlying biological mechanisms. Strongest evidence for the effectiveness of rTMS has been found for the treatment of primary insomnia, but it has also been effective in addressing restless legs syndrome, sleep disorders in Parkinson‘s disease, and insomnia comorbid with psychiatric disorders. There have even been isolated reports of successful rTMS treatments for sleep-related bruxism, obstructive sleep apnea, and narcolepsy.

Keywords:

Narcolepsy – obstructive sleep apnea – repetitive transcranial magnetic stimulation – major depressive disorder – restless legs syndrome – sleep bruxism – sleep initiation and maintenance disorders

This is an unauthorised machine translation into English made using the DeepL Translate Pro translator. The editors do not guarantee that the content of the article corresponds fully to the original language version.

 

Introduction

The prevalence of sleep disorders in the population is estimated at 32.1-41.7% [1,2]. The presence of a sleep disorder is a risk factor for the development of many comorbidities such as cardiovascular disease, diabetes mellitus, obesity, dementia, substance dependence, chronic pain and depressive disorder [3,4]. The International Classification of Sleep Disorders (ICSD-3) divides sleep disorders into seven basic groups: insomnia, sleep-related breathing disorders, hypersomnia from a central cause, circadian rhythm disorders, parasomnias, sleep-related movement disorders, and other sleep disorders. As conventional pharmacotherapy and psychotherapy offer only limited help in the treatment of sleep disorders, it is necessary to explore new therapeutic approaches. One of these is the use of the stimulatory potential of transcranial magnetic stimulation.

 

The principle of repetitive transcranial magnetic stimulation

Repetitive Transcranial Magnetic Stimulation (rTMS) is a modern non-invasive biological treatment method that has been successfully used in the field of neuropsychiatric disorders to treat mood disorders [5], tinnitus [6], negative symptoms in schizophrenia [7], obsessive-compulsive disorder [8], generalized anxiety disorder, post-traumatic stress disorder [9] and other indications. The principle consists in the application of repetitive pulses of magnetic field, which are induced by discharges of high intensity alternating electric current passing through a coil that is placed near the surface of the head. Each pulse of the magnetic field then induces electrical activity in the stimulated area of the brain. The advantages of rTMS are its excellent tolerability and thus high adherence rate to the therapy, its painlessness, non-invasive design and minimum contraindications and side effects. Headache is the most common adverse effect in up to 23% of patients [10], but it is usually mild and short-lived. They also include neck pain, muscle twitching and itchy skin.

Recently, there has been increasing evidence of the potential of rTMS to influence subjective and objective symptoms associated with sleep disorders. The most frequently studied issues are primary insomnia and insomnia in depressive disorder. Many other studies and case reports demonstrate that rTMS can also have an effect on sleep-related movement disorders, sleep-disordered breathing, hypersomnia and insomnia in other psychiatric and neural disorders.

 

Methods

As of May 13, 2022, a PubMed and Google Scholar database search was performed using the keywords "rTMS", "repetitive transcranial magnetic stimulation", "sleep", "sleep disorders", and "insomnia". The review included studies that dealt with the clinical application of the method in the treatment of sleep disorders and for which the full text in English was available, including a description of the stimulation protocol. A total of 29 such studies were identified, including meta-analyses, randomised control group studies, observational studies and case reports.

 

Stimulation protocols for rTMS in the treatment of sleep disorders

Several protocols have achieved promising results in the experimental treatment of sleep disorders. In insomnia, the use of low-frequency (1 Hz) stimulation in the right dorsolateral prefrontal cortex (DLPFC) is most commonly investigated, but there are also studies using high-frequency stimulation (5-15 Hz) of the parietal cortex, especially in the presence of depressive disorder. In sleep disorders associated with abnormal motor activity (Parkinson's disease, restless legs syndrome, bruxism), stimulation of the relevant motor cortex is applied. Most interventions involve 10-30 applications, but some clinical trials show an effect even after a single stimulation. Another variable in stimulation protocols is the intensity of stimulation, which is derived from the resting motor threshold (MT). MT is the minimum intensity of stimulation required to elicit a motor evoked potential, which is usually monitored by muscle contraction of the fingers of the hand (thenar dominant hand) and is individual for each patient. Most current studies use an intensity of 80-120% of the motor threshold found during stimulation.

 

Effectiveness of rTMS in the treatment of individual sleep disorders

Primary insomnia

Several studies have focused on the treatment of so-called non-organic psychophysiological (primary) insomnia (i.e., insomnia that is not etiologically related to any other disease or medication use) [11-14]. rTMS has been shown to increase sleep quality compared with hypnotic and cognitive-behavioural therapy for insomnia [11], as well as compared with a blinded, placebo-controlled group [13]. The results were supported by objective assessment of the reduction in EEG abnormalities recorded by overnight polysomnographic recording [11,14].

The effect of rTMS in primary insomnia has been confirmed by recent meta-analyses. Jiang et al. [15] analyzed the results of 9 studies with a sham control group in patients suffering from primary insomnia. According to their findings, rTMS caused a significant reduction in subjective sleep difficulties as measured by the Pittsburgh Sleep Quality Index (PSQI; PSQI), with the most significant effect observed with 30 applications. Another meta-analysis conducted by Sun et al [16] evaluated 36 studies, concluding that rTMS has the ability to reduce insomnia symptoms captured by the PSQI. The results of polysomnography, although more variable, suggested a reduction in slow-wave and REM sleep. And the most recent meta-analysis by Ma et al [17] confirmed the effect of rTMS versus sham stimulation in 27 controlled studies, with the effect also demonstrated by objective methods (polysomnography, actigraphy).

 

Insomnia accompanying mental illness

As up to 85% of patients with depressive disorder have concurrent symptoms of insomnia [18], several studies, mostly secondary analyses of data from patients treated for depressive disorder, have investigated the possibility of modifying sleep quality with rTMS treatment. The current results (Table 2) [19-25] are mixed and definitive assessment is complicated by the lack of controlled studies and the variety of stimulation protocols used.

Only one clinical trial included a sham control arm. Rosenquist et al [25] used 10 Hz rTMS on the left DLPFC in 301 patients in monotherapy-resistant depressive disorder. Subjectively assessed sleep quality increased significantly, both in the active and placebo stimulation groups. However, there was no statistically significant difference between the groups, suggesting that the placebo effect may have been involved in alleviating insomnia. The weakness of the study is the low specificity of the chosen questionnaires assessing sleep quality and the secondary analysis of the data.

One reason for the inconsistent results of previous research may be the stimulation parameters used in the treatment of depressive disorder. Different treatment protocols have been shown to have different clinical effects depending on the area stimulated and the frequency of stimulation used [26]. In insomnia, increased cortical excitation has been found in studies [27], and research suggests that high-frequency stimulation has an excitatory effect on neuronal networks and activity, whereas low-frequency stimulation inhibits activity [28]. The most widely used protocol for treating depressive disorder targets the left DLPFC using high-frequency stimulation, and this setting may not be optimal for treating comorbid sleep disorders. It is possible that multiregional and combined protocols, such as excitatory stimulation on one side and inhibitory stimulation contralaterally, may yield more convincing results in the treatment of comorbid depressive disorder and insomnia.

The effect of rTMS in the treatment of insomnia in patients suffering from generalized anxiety disorder was investigated by Huang et al [29]. After the intervention (1 Hz, right parietal region, 10 applications), subjectively perceived severity of insomnia as assessed by the PSQI questionnaire was reduced compared to the control group, which correlated with the degree of reduction in anxiety symptoms as assessed by total Hamilton Anxiety Scale scores.

Repetitive TMS also has a role in the treatment of psychoactive substance dependence syndrome. Lin et al [30] examined mood and sleep quality in 105 heroin or methamphetamine abstinent users. In the active group (10 Hz rTMS, left DLPFC, stimulation for 6 weeks), there was a reduction in subjectively perceived insomnia as measured by the PSQI compared to the sham group. Again, however, it is difficult to determine whether the alleviation of insomnia was due to a demonstrated reduction in anxiolytic and depressive symptoms.

 

Obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is a common condition in which the muscles of the upper airway become excessively relaxed during sleep, leading to constriction and inability to breathe (apnoea). The subsequent activation of the sympathetic nervous system leads to a brief awakening, but this can be repeated hundreds of times per hour. Sleep is of poor quality and leads to excessive daytime sleepiness. The prevalence of OSA in the population is approximately 5% and is associated with an increased risk of cardiovascular complications [31]. However, apart from treatment with a continuous positive airway pressure (CPAP) machine, therapeutic options are limited. The possibility of treating OSA with rTMS was addressed by Melo-Silva et al [32,33], who stimulated the somatotopic representation of the tongue (musculus genioglossus) in the motor cortex of sleeping patients to stimulate upper airway muscle contraction. Their protocol used five to ten nonrepetitive pulses in 14 patients during the NREM-2 (non-rapid-eye-movement) sleep phase at the end of expiration and inspiration initiation. After the intervention, respiratory parameters were adjusted. However, the benefit of the repetitive protocol was not confirmed [34].

 

Hypersomnia and narcolepsy

Data on the effectiveness of rTMS in the treatment of hypersomnia are less numerous. Sonmez et al. [35] found that 30 applications of high-frequency rTMS to the left DLPFC in 17 adolescents produced a statistically significant reduction in hypersomnia symptoms on subjective assessment, but no effect was found in self-reported insomnia.

Narcolepsy is characterised by excessive and willfully irrepressible daytime sleepiness, often accompanied by cataplexy (sudden reduction in muscle tone induced by emotion) and hypnagogic hallucinations. At present, the only treatment for narcolepsy is pharmacological treatment. There is only one case report [36] of the use of rTMS in the treatment of a 14-year-old girl who underwent 25 applications of high-frequency (10 Hz) rTMS in the left DLPFC region. Symptoms of daytime sleepiness and cataplexy were suppressed.

 

Restless legs syndrome

Restless legs syndrome (RLS) is a neurological disorder associated with discomfort in the lower limbs and urge to move, which, as shown (Table 3) [37-41], can also be influenced by rTMS. The effect has been demonstrated in comparison to a control group [37], even after a single application [38]. Positive effects on RLS symptoms and presenting anxiety can persist for up to two months [39], and an objective increase in total sleep time has been reported by overnight polysomnographic recording [40]. The pathophysiology of RLS is related to disruption of the dopaminergic system and there are studies [42,43] demonstrating increased dopaminergic activity following rTMS stimulation of the frontal and parietal cortex in animals and humans. However, in another study, the change in dopaminergic activity in depressed patients was not confirmed [44]; therefore, the explanation for this mechanism is still ambiguous.

 

Sleep-related bruxism

Sleep-related bruxism is the grinding and clicking of teeth against each other during sleep, which leads to waking, poor quality sleep, and often disturbing a fellow sleeper. In addition, it has dental consequences, which tend to be pain in the chewing muscles, jaw joint and head. Apart from mechanical protection of the teeth at night and the administration of benzodiazepines, current treatment is very limited. A pilot study by Zhou et al [45] involved 12 participants suffering from sleep bruxism who participated in 5 consecutive 1 Hz rTMS stimulations of the somatosensory representation of the musculus masseter in the motor cortex bilaterally. Electromyographic measurements showed a statistically significant decrease in masseter activation in sleep after stimulation, including alleviated pain. Thus, rTMS appears to be a promising method in the treatment of bruxism, but further more robust studies with a control group are needed to verify the effect.

 

Sleep disorders in Parkinson's disease

Poor quality and fragmented sleep is often seen in Parkinson's disease. The possibility of influencing sleep quality in this group of patients was investigated by Van Dijk et al. [46] in 13 patients. They found that application of 5 Hz rTMS in the parietal cortex increased the continuity and efficiency of sleep captured by actigraphy, but application in the motor cortex did not have such an effect. Motor symptoms were not affected by treatment. In contrast, 10 applications of 15 Hz rTMS bilaterally in the primary motor cortex region in 11 patients alleviated the subjectively perceived severity of insomnia according to Antczak et al [47]. In polysomnographic findings, there was a reduction in NREM 1 sleep and nocturnal awakenings. However, this result may have been related to the alleviation of motor symptoms that was also noted. The different result from the previous study shows that the effect of rTMS depends on the stimulation parameters used and the localization of the stimulation. In a third study, Arias et al [48] used low-frequency (1 Hz) rTMS in the vertex region for 10 days. However, the effect of rTMS on sleep was not demonstrated, and the subjective perception of sleep quality was comparable to the sham group.

 

Biological basis of rTMS treatment of sleep disorders

The exact mechanism of biological action of rTMS is not entirely clear and it is assumed that the mechanism of action is multifactorial, including changes in cerebral blood flow, induction of neuroplasticity, changes in functional brain connectivity and neurotransmitter synthesis.

Since increased cortical excitability has been shown in insomnia [27], low-frequency rTMS stimulation could lead to its normalization and increase sleep quality by hyperpolarizing neurons. Changes in evoked motor potentials reflecting the degree of cortical activation have been achieved by rTMS intervention [14]. In addition to insomnia, increased excitability has also been found in RLS, but decreased cortical excitability has conversely been observed in OSA syndrome and narcolepsy [27].

In several studies, rTMS has been observed to promote brain-derived neurotrophic factor (BDNF) synthesis [49] and gamma-aminobutyric acid (GABA) release in neurons [50]. There is also evidence that both BDNF and GABA play a role in sleep regulation [52,53], which explains the effect of third-generation hypnotics that are GABA receptor agonists. Increases in plasma concentrations of GABA and BDNF in insomnia following successful rTMS intervention have already been documented [14]. Excessive cortical activation in insomnia may also affect stress axis activation, leading to increased plasma concentrations of cortisol, thyrotropic hormone (TSH), fT4 (free thyroxine), fT3 (free triiodothyronine) and adrenocorticotropic hormone (ACTH). Normalization of plasma concentrations of these hormones after successful rTMS intervention correlated with increased sleep quality [11].

Other theories concern the secretion of neurotransmitters. A possible role of melatonin has been speculated, but high-frequency rTMS applied during nighttime hours had an inhibitory effect on melatonin secretion [53]. The effect of low-frequency stimulation on melatonin secretion is unknown. Transcranial magnetic stimulation also modulates the serotoninergic and noradrenergic systems, which have a role in sleep regulation, including affecting the number of receptors in the frontal cortex [54]. The effect of rTMS in RLS and Parkinson's disease also suggests a possible effect on the activity of the dopaminergic system, but specific studies focusing on this area have not yet provided consistent results [42-44].

An important mechanism of action of rTMS on insomnia may be the influence of inflammatory parameters (e.g., C-reactive protein, tumor necrosis factor alpha [TNF-a ], interleukin 1 and 6, prostaglandins, fibrinogen, and fluctuations in peripheral blood leukocyte numbers and abundance) that are associated with poor quality sleep [55,56]. Sleep regulation and the immune system are interrelated. Components of the immune system, particularly the cytokines interleukin 1, TNF-a and prostaglandin PGD2, are involved in the regulation of physiological sleep and also mediate the increase in the amount of NREM sleep after the body's defenses are challenged by pathogens. Poor quality sleep is also associated with chronic infectious and inflammatory diseases such as AIDS, hepatitis C, African trypanosomiasis, infectious mononucleosis, rheumatoid arthritis, fibromyalgia, chronic inflammatory bowel disease, and atopic eczema [56,57]. Proinflammatory cytokines, among others, activate the enzyme indoleamine-2,3-dioxygenase, which leads to increased degradation of tryptophan, a precursor of serotonin and melatonin [57]. Melatonin deficiency can then lead to poor quality sleep and disruption of circadian rhythms. The involvement of the immune system in disease-related changes in sleep is supported by recent research on the effects of immunotherapy (e.g. anti-TNF therapy) on sleep, which shows that suppressing the activity of certain pro-inflammatory cytokines increases sleep quantity and quality [56].

Some studies suggest that rTMS applied to depressed patients may modulate the inflammatory response of the body [58,59], but the results are inconclusive. In other studies, the effect of rTMS on increasing plasma tryptophan concentration has not been confirmed [60]. Research on the link between the immune system and sleep disorders is complicated by diurnal variations in the concentration of inflammatory markers and the need for repeated and time-specific blood draws.

 

Limitations of the study

The number of studies dealing with the issue of rTMS and sleep is limited, with many limitations and in some cases only case reports. For example, some of them did not specify the specific type of chronic insomnia (14) or did not indicate the criteria used to make the diagnosis (36). Another weakness of some of the studies mentioned is the lack of information on the duration of the therapeutic effect (34).

 

Conclusion

Repetitive TMS represents a promising and emerging method in the treatment of sleep disorders that could find application in the treatment of conditions unresponsive to conventional psychotherapeutic or pharmacological approaches.

Successful interventions have been reported in the treatment of primary insomnia, RLS and sleep disorders in Parkinson's disease. Isolated successes have also been recorded in the treatment of sleep-related bruxism and insomnia in substance dependence and generalized anxiety disorder. However, in the treatment of OSA, the effect has only been seen in a non-repetitive protocol. Successful treatment of narcolepsy with rTMS has so far been described in only one case report. However, the results of studies in the treatment of insomnia in depressed patients are generally inconsistent, probably due to suboptimally applied stimulation parameters. Another limitation is the relatively small sample size of patients. Moreover, in secondary analyses of data in comorbidities, it is difficult to distinguish the intrinsic effect of rTMS from positive changes in sleep quality due to amelioration of the severity of the underlying illness. The possibility of influencing parasomnias and circadian rhythm disorders has not yet been investigated at all.

There are also many unanswered questions. Which stimulation protocol is most appropriate for each disease? How long does the effect of stimulation last? Is there a patient population in which the intervention has a greater effect than in others? Does the time of day of stimulation affect the effect? Future research may answer these questions.

 

Grant support

The work was supported by the Cooperatio programme (Neuroscience) and the project of the Ministry of Health of the Czech Republic - RVO VFN64165.

 

Conflict of interest

The authors declare that they have no conflict of interest in relation to the subject of the study.

 

Tables

Table 1: Comparison of studies of repetitive transcranial magnetic stimulation in the treatment of primary insomnia.

ACHT - let the authors add; BDNF - brain-derived neurotrophic factor; DLPFC - right dorsolateral prefrontal cortex; GABA - gamma-aminobutyric acid; ISI - insomnia severity index; KBTi, cognitive behavioral therapy for insomnia; L, left; MEP, motor evoked potentials; O, objective; P, right; PSG, polysomnography; PSQI, Pittsburgh Sleep Quality Index; S, subjective; TSH, thyrotropin hormone

 

 

Table 2. Comparison of studies of repetitive transcranial magnetic stimulation in the treatment of insomnia in depressive disorder.

Study	Sample size	Protocol	Location	Number of applications	Measurements	Control group	Effect
Li et al., 2013 [19]	30	10 Hz	?	20	PSQI	-	S
Lowe et al., 2013 [20]	139	1-10 Hz	L, P DLPFC	10-45	sBDI, sHAMD	-	S
Pellicciari et al., 2013 [21]	10	1 + 10 Hz	DLPFC bilaterally	10	PSG	-	O
Nishida et al., 2017 [22]	14	10 Hz	DLPFC bilaterally	10	PSQI, actigraphy	-	S
Antczak et al., 2017 [23]	13	10 Hz	L DLPFC	20	AIS, actigraphy	-	NO
Collins et al., 2021 [24]	21	10 Hz	L DLPFC	30	PSQI	-	S
Rosenquist et al., 2013 [25]	301	10 Hz	L DLPFC	30	sHAMD, sIDS-SR	sham	NO

AIS, Athens Insomnia Scale; DLPFC, dorsolateral prefrontal cortex; L, left; O, objective; P, right; PSG, polysomnography; PSQI, Pittsburgh Sleep Quality Index; S, subjective; sBDI, Beck Depression Severity Inventory: Sleep quality items only; sHAMD - Hamilton Depression Rating Scale: sleep quality items only; sIDS-SR - Inventory of Depressive Symptomatology Self Report, a self-report depressive symptomatology scale: sleep quality items only

 

 

Table 3. Comparison of studies of repetitive transcranial magnetic stimulation in the treatment of restless legs syndrome.

Study	Sample size	Protocol	Location	Number of applications	Measurements	Control group	Effect
Altunrende et al., 2014 [37]	19	5 Hz	L motor cortex supplementary	10	IRLS	Sham, double blind	IRLS
Lin et al., 2015 [39]	14	15 Hz	L frontal motor cortex	14	IRLS, PSQI, HAMA, HAMD	-	IRLS, PSQI, HAMA
Sanchez-Escandon et al., 2017 [40]	1	1 Hz	L motor cortex primary	12	PSG	-	SE, TST
Liu et al., 2015 [41]	15	5 Hz	Motor cortex primary, bilaterally	1	IRLS	-	IRLS
Lanza et al., 2018 [38]	23	1 Hz	L motor and somatosensory cortex	1	YOU	Sham	YOU

HAMA - Hamilton Anxiety Rating Scale; HAMD - Hamilton Depression Rating Scale; IRLS - International RLS Rating Scale; L - left; P - right; PSG - polysomnography; PSQI - Pittsburgh Sleep Quality Index; SE - sleep efficiency; TST - total sleep time; VAS - visual analogue scale for subjective assessment of sleep quality