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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5250_Библиотеки_им_академика_М_И_Перельмана.pdf
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Keywords
J. Deng et al.
Sleep disorders · Insomnia · Transcranial magnetic stimulation · Transcranial
direct current stimulation · Dorsolateral prefrontal cortex
Abbreviations
cTBS Continuous theta-burst stimulation
DLPFC Dorsolateral prefrontal cortex
DMN Default mode network
dTMS Deep transcranial magnetic stimulation
iTBS Intermittent theta-burst stimulation
LF Low-frequency
M1 Primary motor cortex
MST Magnetic seizure therapy
PSQI Pittsburgh sleep quality index
PTSD Post-traumatic stress disorder
rMT Resting motor threshold
rTMS Repetitive transcranial magnetic stimulation
sTMS Synchronized transcranial magnetic stimulation
TBS Theta burst stimulation
tDCS Transcranial direct current stimulation
TMS Transcranial magnetic stimulation
TRD Treatment-resistant depression
12.1 Introduction
Sleep occupies approximately one-third of the human lifespan. Sleep disorders are
a set of common, complex, and recurrent diseases, which seriously impact psychosomatic health and serve as a risk factor for diabetes, obesity, depression, and anxiety [1, 2]. The diagnostic category for sleep disorders encompasses primary
disorders such as insomnia, parasomnias, and obstructive sleep apnea, as well as
secondary syndromes that disrupt sleep architecture through quantitative, qualitative, or cyclical abnormalities. Insomnia represents the most prevalent diagnostic
entity within this spectrum, affecting 10–20% of the general population [3].
Clinical management challenges arise from multifactorial contributors including
polypharmacy, environmental disruptions, sedentary lifestyles, excessive screen
exposure, chronic stress, and comorbid affective disorders.
Pharmacological interventions for insomnia predominantly include benzodiazepines and Z-hypnotics (e.g., zolpidem and zopiclone). However, their clinical
utility remains constrained by adverse effects including excessive sedation,
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327
parasomnias, withdrawal syndromes, and abuse liability [4]. Melatonin receptor
agonists, typied by ramelteon, demonstrate efcacy in circadian rhythm sleep
disorders when administered with precise timing, primarily through reduction of
sleep onset latency [5]. Nevertheless, these agents show limited efcacy in
addressing sleep maintenance impairment [6]. Psychotherapeutic approaches,
particularly cognitive behavioral therapy, have established efcacy for both
insomnia [7] and restless legs syndrome [8], while the insufcient access limits
its utilization [9]. Complementary non-pharmacological interventions, including
music therapy [10], acupuncture [11], essential oils [12], and light therapy [13],
demonstrate variable therapeutic efcacy. These collective ndings underscore
the critical need for developing novel therapeutic modalities with enhanced efcacy and broader accessibility.
Noninvasive brain stimulation (NIBS) has emerged as a promising therapeutic
approach for treating sleep disorders through modulation of neural plasticity and
functional connectivity. The NIBS paradigm comprises two primary modalities—
transcranial magnetic stimulation (TMS) and transcranial direct current stimulation
(tDCS). Each employs multiple stimulation protocols specically designed to
address specic clinical objectives [14]. Compared to pharmacological interventions and psychotherapy, TMS demonstrates cost-efcient superiority in improving
sleep architecture and reducing hyperarousal states, characterized by clinically signicant efcacy, sustained therapeutic benets, and absent risk of pharmacological
dependence [15]. Furthermore, TMS has proven effective in alleviating cognitive
decits consequent to sleep deprivation [16], and emerging evidence suggests its
therapeutic potential for restless legs syndrome management [17]. However, limited
therapeutic efcacy has been observed in OSA patients receiving TMS, [18] with
current evidence base requiring Systematic integration for other sleep disorder indications [19]. Similarly, while tDCS shows promise for sleep quality improvement
across varied clinical contexts [20], suboptimal stimulation parameters may produce inconsistent outcomes in narcolepsy and insomnia patients [21, 22]. This
underscores the critical need for developing standardized stimulation protocols
capable of effectively modulating arousal process and sleep-wake homeostasis [23].
Given the inconsistencies regarding the efcacy and stimulation parameters of
NIBS, further research is necessary to establish the optimal stimulation strategy.
This chapter presents a comprehensive review and clinical recommendations of the
application of TMS and tDCS in the treatment of sleep disorders, especially insomnia disorders. The content will cover standard repetitive transcranial magnetic stimulation (rTMS), accelerated rTMS (aTMS), deep TMS (dTMS), priming TMS
(pTMS), synchronized TMS (sTMS), theta burst stimulation (TBS), magnetic seizure therapy (MST) and tDCS.We further provide evidence-based clinical recommendations while identifying existing research limitations and proposing future
investigative directions to optimize therapeutic outcomes.
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12.2 TMS
12.2.1 rTMS
12.2.1.1 Unilateral rTMS
Efficacy
A systematic review synthesized evidence from 28 clinical trials investigating the
effects of rTMS on sleep quality and sleep disturbances across various neuropsychiatric conditions [24]. Meta-analysis revealed consistent improvements in both
objective polysomnographic metrics (including rapid eye movement sleep latency
and slow-wave sleep duration) and subjective sleep quality. The majority of
included studies targeted the dorsolateral prefrontal cortex (DLPFC), with left
prefrontal predominance, employing low-frequency protocols (≤1Hz) that demonstrated sustained therapeutic efcacy. Notably, rTMS-induced benets persisted for up to 30 days post-intervention, with longitudinal investigations
reporting signicantly reduced relapse rates and symptom recurrence at 3-month
follow-up compared to pharmacotherapy or psychotherapy cohorts. Emerging
evidence further supports dose-dependent therapeutic effects, where higher stimulation intensity (≥110% motor threshold) correlates with enhanced clinical outcomes in insomnia management [25].
While numerous studies consistently report subjective sleep quality improvement following rTMS, objective polysomnographic measures show less consistent
improvements. Only a restricted subset of investigations have implemented shamcontrolled designs to adequately control for placebo effects. Among these rigorously designed trials, signicant placebo responses have been observed in certain
cohorts, whereas negligible effects emerged in others. This methodological heterogeneity may reect variations in stimulation parameters, with most investigations
utilizing low-frequency (LF) rTMS protocols (≤1Hz) directed at either DLPFC or
parietal cortical regions [26].
Emerging evidence underscores the therapeutic potential of rTMS in managing comorbid sleep disorders associated with psychiatric conditions. Two seminal clinical trials specically evaluated divergent rTMS protocols in patients
presenting with insomnia comorbid with generalized anxiety disorder or major
depressive disorder. Both studies reported improvements in all subjective and
objective sleep parameters. However, the reliability of these ndings must be
considered alongside limitations, including an unblinded study design.
Additionally, the results of both studies may be inuenced by the fact that participants with psychiatric conditions were permitted to take variable doses of
short-acting benzodiazepines and agomelatine [27].
Safety
rTMS exhibits an exceptional tolerability prole. The therapeutic prole of rTMS
is characterized by a low incidence of adverse events, with transient cephalalgia
and cervical myalgia representing the most frequently reported minor complaints.
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Moderate-intensity reactions typically involve scalp dysesthesia and periorbital
muscle contractions, while severe neurological complications such as generalized
tonic-clonic seizures or hypomanic episodes remain exceptionally rare. Cardiac
pacemaker recipients and individuals with seizure disorders warrant particular
caution, necessitating rigorous pretreatment screening protocols. Absolute contraindications include intracranial metallic implants (e.g., cochlear prostheses, aneurysm clips) and deep brain stimulation hardware, which may pose signicant
safety risks through electromagnetic interference [28]. These evidence-based
safety parameters enable rTMS implementation across diverse clinical populations, with risk mitigation strategies effectively managing potential treatmentrelated complications.
Treatment Regimen
From a neurophysiological perspective, rTMS protocols are classied into highfrequency (>5Hz) and low-frequency (≤1Hz) stimulation paradigms, with conventional clinical applications favoring high-frequency protocols at approximately
10Hz. A review published in 2021 on the effectiveness of rTMS for the treatment
of insomnia revealed considerable variability in study characteristics and outcomes. The majority of studies employed low-frequency rTMS targeting the
DLPFC or parietal cortex. Other target sites included the vertex, the raphe nuclei,
the medial aspects of the bilateral frontal, occipital, and temporal cortices, as
well as specic acupuncture points [28]. Technical parameters demonstrated
considerable variability: stimulation intensity ranged from 80% to 130% of
motor threshold (MT), with intersession pulse counts varying between 1100 and
2400. Each session lasted from 10 to 90min, with the majority lasting for 20min.
Session duration spanned 10–90min (modal value: 20min), and treatment regimens most commonly involved daily sessions (5days/week) over 2–4weeks.
Outcome assessments were predominantly conducted immediately post-intervention, with only seven studies (21.9%) extending follow-up to 1–22weeks.
Notably, the functional topography of neural networks modulates rTMS effects
across different cortical regions. This neurobiological phenomenon suggests that
identical stimulation frequencies may elicit divergent neurophysiological
responses depending on target localization within cortico-limbic-thalamic circuits [29].
Clinical Recommendations
Clinical Recommendation: Unclear (Table 12.1). The evidence base remains
insufcient to establish standardized treatment protocols for rTMS in sleep disorders. This decit primarily stems from the nascent stage of research in this
domain, compounded by methodological limitations across existing studies.
Critical shortcomings include: the majority lack sham-controlled designs, a considerable number of recent studies have small sample sizes, and inconsistent
objective outcomes despite subjective improvement reports. These discrepancies
underscore the necessity for rigorous, multimodal evaluation frameworks in
future investigations.
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Table 12.1 TMS in sleep disorder
Clinical recommendations
Length
TMS
Unilateral
rTMS
Bilateral rTMS Right DLPFC and
Accelerated
rTMS
Deep TMS / / / / Unclear
Priming TMS / / / / Unclear
Synchronised
TMS
iTBS / / / / Unclear
Accelerated
iTBS
cTBS Right DLPFC cTBS 30 10 [64]
Bilateral TBS / / / / Unclear
MST / / / / Unclear
Right DLPFC LF (1Hz) 20 10–20 [60–62]
LF (1Hz) 30–40 10–15 [31, 59]
left DLPFC
/ / / / Unclear
/ / / / Unclear
Right DLPFC and
left DLPFC
cTBS and
iTBS
(min)
20 10 [57]
Duration
(sessions)
J. Deng et al.
Levels +
referencesTarget Frequency
12.2.1.2 Bilateral rTMS
Efficacy
Current empirical evidence remains scarce regarding bilateral rTMS for applications in sleep disorders, with most investigations omitting sham-controlled or control groups. Notably, a study investigated the effects of sequential bilateral LF
rTMS over DLPFC on patients with primary insomnia [30]. They found that
sequential bilateral LF rTMS over DLPFC alleviated primary insomnia, including
reduced the amplitude of MEP, and elevated the serum concentrations of brainderived neurotrophic factor and gamma-aminobutyric acid. Furthermore, correlations among these effects were demonstrated. Another open-label pilot study
utilizing sequential bifrontal LF-rTMS reported subjective sleep quality enhancements as per PSQI scores [31]. These preliminary ndings highlight the therapeutic potential of bilateral LF-rTMS while underscoring the critical need for
larger-scale, sham-controlled trials to validate these neurophysiological and biochemical correlates.
There was one study that found bilateral rTMS ameliorated sleep disorder and
HPA axis dysfunction in patients with major depression [32]. To date, no randomized controlled trials (RCTs) have directly compared the neuromodulation efcacy
of unilateral versus bilateral TMS modalities in sleep disorders, representing a critical knowledge gap requiring urgent investigation through double-blind RCTs.
Safety
Among the extant limited studies employing bilateral rTMS protocols, sequential
bilateral LF-rTMS demonstrated excellent tolerability proles.
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Treatment Regimen
A study utilized sequential bilateral LF-rTMS (1Hz) with 10-s active-duty cycles
separated by 2-s interstimulus intervals, delivered at 80% resting motor threshold
(rMT). Each 30-min session comprised 15min of left DLPFC stimulation followed
by 15min targeting the right DLPFC, delivering a total of 1500 pulses per session.
This twice-daily protocol (5days/week) was maintained for 14days. In two additional studies mentioned previously, one involved sequential bilateral LF rTMS
stimulation over a 3-week period, with each session lasting 40min. Studies also
revealed two additional treatment paradigms: (1) a 3-week sequential bilateral
LF-rTMS regimen (40-min sessions; left→right DLPFC sequence), and (2) a dualfrequency approach combining 10Hz excitatory left DLPFC stimulation with concurrent 1Hz inhibitory right DLPFC modulation.
Clinical Recommendations
Clinical Recommendation: Unclear (Table12.1). Insufcient evidence to establish
clinical efcacy. While current evidence demonstrates clinically promising outcomes for bilateral LF-rTMS targeting DLPFC, the absence of sham-controlled
comparison substantially limits interpretational validity. This methodological limitation is compounded by the lack of RCT data and small sample sizes in existing
studies. To address these critical gaps, future investigations should prioritize largescale, double-blind sham-controlled RCTs and extended follow-up periods. Such
rigorous evaluation is essential to differentiate true therapeutic effects from nonspecic placebo responses in insomnia management.
12.2.1.3 Accelerated rTMS
Accelerated TMS (aTMS) an emerging therapeutic modality characterized by ≥2
daily treatment sessions, demonstrates signicant potential for optimizing neuromodulation outcomes. This accelerated paradigm demonstrates particular promise
in treating neuropsychiatric disorders, including depression, schizophrenia, and
others. However, critical knowledge gaps persist regarding its therapeutic potential
for primary insomnia and insomnia comorbid with affective disorders.
Clinical Recommendation Unclear (Table 12.1). Current data do not support
denitive conclusions regarding aTMS efcacy in insomnia management.
12.2.2 Deep TMS
Deep TMS (dTMS) an FDA-approved intervention for treatment-resistant depression
(TRD), has received regulatory approval in Europe for a broader spectrum of neuropsychiatric indications. The H1-coil variant is authorized for treating unipolar depression, bipolar depression, negative symptoms of schizophrenia, and post- traumatic
stress disorder (PTSD), while other H-coil congurations (e.g., H7) demonstrate utility in managing Alzheimer’s disease (prevalence: 5.8 million in the United States),
chronic pain syndromes, substance use disorders, obsessive-compulsive disorder,
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autism spectrum disorder, Parkinson’s disease, stroke rehabilitation, and multiple
sclerosis [33]. Emerging evidence suggests dTMS may improve sleep architecture in
comorbid insomnia populations.
There are few studies that examined the improvement of insomnia symptoms by dTMS.One study explored the impact of dTMS on comorbid insomnia
in patients with TRD using a retrospective analysis, which suggested dTMS
alleviated insomnia symptoms in patients with TRD [34]. Further research
incorporating a prospective study design in a multicenter setting is warranted
to replicate these findings. Clinical Recommendation: Unclear (Table 12.1).
Current data do not support definitive clinical adoption pending robust validation studies.
12.2.3 Priming TMS
Emerging evidence from RCTs in diverse clinical populations supports the therapeutic efcacy of priming rTMS (prTMS) across neuropsychiatric and neurological domains, demonstrating enhanced cortical plasticity and network connectivity
compared to conventional protocols. However, no clinical investigations to date
have evaluated prTMS’s efcacy in insomnia, representing a critical gap in translating these neurophysiological advancements to sleep disorders. While prTMS
shows promise for refractory neuropsychiatric conditions, current data insufciently support its clinical adoption for insomnia pending robust validation
through sham- controlled multicenter trials. Clinical Recommendation: Unclear
(Table12.1).
12.2.4 Synchronised TMS
Synchronized Transcranial Magnetic Stimulation (sTMS), an emerging therapeutic noninvasive brain stimulation, employs three-axis rotational neodymium magnet arrays to generate low-energy, sinusoidal magnetic elds synchronized with
endogenous α-band oscillations. Preliminary investigations demonstrate sTMSinduced neurophysiological modulation, including enhanced α-rhythm synchronization and reduced theta power in healthy volunteers. While current evidence
supports sTMS efcacy in major depressive disorder (MDD) and substance use
disorder, its therapeutic potential for sleep disorders remains uninvestigated.
Neurobiological mechanisms underlying sTMS may involve entrainment of thalamocortical rhythms and normalization of functional connectivity, though rigorous
clinical validation is required. Current data is insufcient to recommend sTMS for
sleep disorders. Multicenter RCTs are needed to evaluate therapeutic efcacy.
Clinical Recommendation: Unclear (Table12.1).
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12.2.5 TBS
12.2.5.1 iTBS
TBS, an innovative neuromodulation paradigm, employs theta-frequency (50Hz)
magnetic pulse trains to induce cortical plasticity through frequency-specic synaptic plasticity mechanisms. Intermittent TBS (iTBS) has demonstrated an ability to
enhance motor cortical excitability, whereas continuous TBS (cTBS) induces prolonged cortical inhibition.[35] Emerging evidence positions iTBS as a clinically
viable therapeutic modality for MDD.A prior study has shown that iTBS-induced
reduction of DMN functional connectivity and insular cortex activation, correlating
with improved insomnia severity index scores.[36] These neurophysiological effects
suggest iTBS may target maladaptive thalamocortical rhythms implicated in insomnia pathophysiology. Clinical Recommendation: Unclear (Table12.1). Current evidence is insufcient to recommend routine clinical application pending validation
through large-scale RCTs.
12.2.5.2 Accelerated iTBS
Accelerated iTBS protocols, characterized by multiple daily sessions over consecutive days, demonstrate signicant advantages in treatment efciency by reducing
total treatment duration (≤5days) and cumulative pulse delivery (≤3000 pulses)
compared to conventional schedules. Beyond their established rapid-acting antidepressant effect, these protocols show promise in mitigating acute suicidality in
TRD. Emerging clinical evidence from RCT. Notably, there has been a single
reported instance where accelerated iTBS targeted at the bilateral DLPFC may ameliorate neuropsychiatric sequelae of long-COVID syndrome, including anxiety and
insomnia after 10 daily sessions [37]. Clinical Recommendation: Unclear
(Table12.1). While accelerated iTBS shows compelling antidepressant and neuropsychiatric benets, current evidence insufciently supports routine use for insomnia pending validation through large-scale RCTs.
12.2.5.3 cTBS
Efficacy
The standardized cTBS protocol delivers 200 contiguous burst trains (600 pulses
total) within a 40-s period, inducing LTD-like neuroplastic changes characterized
by sustained cortical excitability reduction [38]. This brief intervention (2–3min
per session) demonstrates enhanced participant tolerability compared to conventional rTMS protocols requiring 20–30 min per session [35], while maintaining
comparable neuromodulatory efcacy. cTBS has garnered attention for its capacity
to suppress corticospinal excitability for up to 60min following brief stimulation
sessions [35, 39, 40]. Recent evidence extends its therapeutic scope, demonstrating
cTBS-mediated enhancement of NREM stage 2 sleep architecture through increased
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J. Deng et al.
slow-wave activity and decreased sleep onset latency in healthy volunteers [41]. A
RCT evaluated 10 daily cTBS sessions (5days/week for 2 weeks) targeting the
DLPFC.The intervention group exhibited signicant insomnia symptom amelioration, evidenced by reduction in ISI scores and improved polysomnographic parameters including increased total sleep time and slow-wave sleep [42]. These ndings
corroborate cTBS’s potential as a time-efcient intervention for sleep disorders.
Safety
Current evidence supports the safety prole of cTBS when targeting the right
DLPFC for insomnia treatment. One study found that targeting the right DLPFC
with cTBS effectively reduced insomnia severity in patients, without any adverse
effects. Participants exhibited excellent tolerability, with no occurrences of seizures, neurological decits, or complaints related to cognitive impairment [42].
Chungetal. reviewed studies on the effects of TBS on clinical symptom improvement in patients with depression. Their ndings revealed that cTBS has signicant
efcacy in alleviating symptoms, with no reported adverse effects [38]. A metaanalysis has reported that seizures associated with TBS have occurred only once to
date, corresponding to a crude seizure risk of 0.02% per session. The overall crude
risk of mild adverse events was estimated to be 1.1%, which is comparable to that
of high-frequency rTMS protocols [43]. Notably, the reported seizure occurred at
an intensity of 100% of the rMT on primary motor cortex (M1), whereas most
studies adhere to the original TBS protocol using 80% of the of the active motor
threshold [44].
Treatment Regimen
TBS protocols exhibit neuroanatomical and temporal specicity across different
sleep disorders, with therapeutic parameters (intervention targets, session frequency,
and treatment duration) tailored to underlying pathophysiology. In patients with
insomnia, a standardized 2-week protocol (10 daily sessions of cTBS targeting the
right DLPFC) demonstrated signicant reductions in insomnia severity. Follow-up
evaluations at 1month and 6months posttreatment also demonstrated markedly
lower insomnia severity compared to the sham stimulation group [38]. cTBS interventions for other sleep disorders should be tailored based on brain regions closely
associated with the condition. For example, targeting the M1 may be a suitable
choice for patients with restless legs syndrome or obstructive sleep apnea. In cases
of sleep deprivation, stimulation of the occipital cortex may be an effective strategy.
However, further scientic research is required to validate these approaches [19].
Clinical Recommendations
Previous studies have suggested that primary insomnia may be associated with
hyperactivity of the DLPFC.Therefore, cTBS intervention targeting this region to
suppress its hyperactivity may be a suitable approach for patients with insomnia.
The standard pattern of cTBS was employed and consisted of bursts of 3 pulses at
50Hz with bursts repeated at a frequency of 5Hz. Each session encompassed a total
of 1800 pulses, delivered in intervals of 15minutes between sets of 600 pulses.
12 Sleep Disorders
Given the current evidence base being limited to an investigation, rigorous validation through multicenter RCTs becomes imperative to establish both the efcacy
and safety proles of these intervention strategies. Clinical Recommendation:
Unclear (Table12.1).
335
12.2.5.4 Bilateral TBS
Two protocols of TBS with opposing effects on cortical excitability have been proposed; iTBS and cTBS with excitatory and inhibitory consequences, respectively.
Bilateral TBS, integrating left prefrontal iTBS (targeting demonstrated hypoactivity
in the left DLPFC) with right prefrontal cTBS (addressing hyperactivity in the right
DLPFC), has emerged as a promising candidate for TRD.No studies have explored
the effect of bilateral TBS intervention on insomnia disorders. Clinical
Recommendation: Unclear (Table12.1).
12.2.6 MST
Magnetic Seizure Therapy (MST), an emerging neuroregulatory technique in psychiatric, employs time-varying magnetic elds to induce therapeutic seizures
through cortical and subcortical network activation. While sharing mechanistic
similarities with electroconvulsive therapy, including glutamate-mediated excitotoxicity and neuroplasticity induction, MST demonstrates reduced cognitive side
effects. Emerging evidence from MST trials reveals promising efcacy in
TRD.Additional research is necessary to ascertain the long-term effects of MST
and to establish its role within the spectrum of psychiatric interventions. Current
data insufciently support routine clinical adoption pending completion of shamcontrolled multicenter trials. Clinical Recommendation: Unclear (Table12.1).
12.3 tDCS
12.3.1 Efficacy
tDCS is a noninvasive technique that employs a constant, low-intensity direct current (ranging from 1 to 2mA) to modulate cortical neuronal activity [45]. Anodal
tDCS is generally believed to enhance the functionality of the underlying cortical
areas, whereas cathodal tDCS exerts a suppressive effect [46]. Emerging clinical
evidence demonstrates tDCS’s therapeutic potential in sleep disorders. They found
that sleep disturbances comorbid with organic lesions can be signicantly improved
after tDCS by increasing slow-wave sleep, sleep quality, and modulating synaptic
connectivity [47]. However, contradictory ndings exist in PTSD-related insomnia.
A trial targeting DLPFC with 1.5mA cathode tDCS for 15 sessions in patients with
insomnia caused by post-traumatic encephalopathy showed no signicant therapeutic effect [48].