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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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S.-B. Wang et al.
9.2 rTMS
9.2.1 Unilateral rTMS
9.2.1.1 Efficacy
Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that employs rapidly changing extracranial magnetic elds to induce
local intracranial currents, which are sufciently strong to depolarize a small group
of neurons and thereby manipulate the electrophysiological activity of the cortex [1,
2]. Since 2008, high-frequency rTMS has been approved by the FDA for treating
patients with treatment-resistant depression, as its efcacy and effectiveness have
been demonstrated. Consequently, rTMS has been widely utilized as a therapeutic
intervention for various psychiatric and neurological disorders [3–6].
Moreover, in recent years, an increasing number of studies have suggested
that rTMS could be benecial for treating the core symptoms of ASD [3, 7–9].
Studies have shown that the application of high-frequency rTMS to the left parietal cortex can improve social and language decits in children with low-functioning ASD by enhancing remote brain connectivity and reorganization in these
individuals [9]. Studies have also found that low-frequency rTMS targeting the
dorsolateral prefrontal cortex (DLPFC) can improve repetitive and stereotyped
behavior in individuals with autism [8]. Additionally, a study employing rTMS
on the left dorsolateral prefrontal cortex to treat comorbid depression in autistic
patients revealed that depressive symptoms ameliorated with treatment, and
family members’ evaluations of autism symptoms also showed improvement
[3]. Although the optimal parameters for rTMS therapy have yet to be established, there remains signicant potential for unilateral rTMS in treating the
core symptoms of ASD.
9.2.1.2 Safety
In addition to efcacy, numerous clinical trials and meta-analyses have evaluated
the safety of rTMS in both clinical practice and research, indicating that the incidence of adverse events is low across various populations and devices [1, 10, 11].
The International Federation of Clinical Neurophysiology has released safety
guidelines. However, in comparison to the literature on adults, there is a relative
scarcity of safety data for rTMS in the pediatric population. Available data suggest
that children and adolescents have a safety prole similar to that of adults, with
adverse event rates ranging from 3.4% to 10.11%. The incidence of adverse events
varies depending on the patient population, the form of TMS, and the number of
treatments. Consistent with the adult literature, the most commonly reported side
effects in the pediatric literature are transient headache and neck pain [10]. However,
due to the frequent use of psychotropic medications in individuals with ASD, and
the increased prevalence of epilepsy within this population, individuals with ASD
may have additional concerns regarding the relative risk of seizures [1]. This suggests that TMS should be administered with caution, with continuous monitoring
for potential adverse effects and further investigation into the safety of TMS.
9 Autism Spectrum Disorder
245
9.2.1.3 Treatment Regimen
Regarding research on unilateral rTMS therapy for ASD, most studies are categorized into two major stimulation frequency camps. The rst camp aims to improve
ASD symptoms by applying high-frequency rTMS to the temporoparietal cortex or
the dorsolateral prefrontal cortex. Panerai et al. applied high-frequency (8 Hz)
rTMS to the left anterior motor cortex of children with intellectual disability and
ASD.The authors reported a signicant improvement in eye-hand coordination,
which was further enhanced when combined with behavioral eye-hand integration
training [12]. A study employing 10Hz high-frequency rTMS on the left dorsolateral prefrontal cortex demonstrated that both depressive symptoms and core symptoms of ASD improved with treatment [3].
The second camp aims to alleviate ASD symptoms using low-frequency
rTMS.The earliest research on rTMS for ASD involved applying low-frequency
stimulation to the dorsolateral prefrontal cortex (either on the left side or bilaterally
in sequence) to decrease excitability in individuals with ASD.Following the protocol, behavioral assessments conducted after 18 sessions of transcranial magnetic
stimulation indicated lower scores for irritability, hyperactivity, stereotypic behavior, and compulsions. Additionally, autonomic measures revealed a signicant
increase in cardiac septal variability, suggesting that 18 sessions of low-frequency
rTMS for ASD enhanced cardiac vagal control and diminished sympathetic arousal
[1, 13]. However, these experimental designs are all open-label (with a waiting list
control group), so the results may be confounded by placebo effects or adaptation to
the environment and protocol.
9.2.1.4 Clinical Recommendations
The application of unilateral rTMS, whether low-frequency or high-frequency, to
stimulate the temporal parietal cortex or dorsolateral prefrontal cortex, may be
effective. However, due to the relative scarcity of safety data for rTMS in pediatric
populations, transcranial magnetic stimulation should be carefully considered in
clinical practice and closely monitored for potential adverse reactions.
9.2.1.5 Bilateral rTMS
Efficacy
Regarding bilateral repetitive transcranial magnetic stimulation (rTMS), previous
reports primarily involve direct stimulation of the bilateral dorsolateral prefrontal cortex,
as well as separate stimulation of the left and right sides, followed by simultaneous
stimulation of the bilateral prefrontal cortex. Wang etal. examined the impact of 12 sessions of rTMS on the autonomic activity of children with ASD in the dorsolateral prefrontal cortex (DLPFC). They observed a signicant increase in the variability index of
the patients’ cardiac intervals, suggesting enhanced vagal nerve control and reduced
sympathetic nerve excitability. Behavioral assessments indicated that the children’s
scores for irritability, hyperactivity, stereotyped behavior, and compulsive behavior
decreased [14, 15]. Studies on rTMS have applied left-sided, right-sided, and bilateral
stimulation sequentially. These studies have found that rTMS therapy targeting the
246
S.-B. Wang et al.
prefrontal cortex can enhance brain function and social skills in individuals with autism
[16–18]. At the same time, studies have found that this approach can improve executive
function in patients with ASD, including enhancements in behavioral performance for
visual attention tasks and reductions in omission error rates [19]. However, Manuel F
etal. found no signicant difference in the impact of the rMTS group and the sham
stimulation group on executive function [20]. Therefore, the effectiveness of rTMS in
treating executive function deciencies associated with ASD in the DLPFC warrants
further investigation.
Safety
The safety of bilateral rTMS treatment for ASD is comparable to that of unilateral
rTMS stimulation. Existing studies have demonstrated that it has comparable and
favorable safety proles to those observed in other psychiatric populations. The
most frequently reported side effects are transient headaches and neck pain [10],
and the most severe side effect is an increased risk of epileptic seizures [1]. The
incidence of adverse events varies depending on the patient population, the form of
transcranial magnetic stimulation, and the frequency of treatment; therefore, close
monitoring of possible adverse reactions is necessary.
Treatment Regimen
Studies on bilateral rTMS treatment for ASD can also be categorized into two camps
based on the frequency of stimulation: those using low frequency and those using
high frequency. The rst camp advocates for low-frequency rTMS stimulation,
which is also the frequency reported in most studies. These studies stimulated the
dorsolateral prefrontal cortex using 0.5-1Hz low-frequency rTMS, either simultaneously or alternately on the left and right sides, to explore changes in brain function and improvements in social and executive abilities [15, 16, 18, 19]. Another
study utilized the second largest camp, employing high-frequency rTMS stimulation, to investigate its effects on executive function in individuals with ASD.Although
no signicant difference was found between the effects of active and sham stimulation rTMS on executive function, the study conrmed that repeated high-frequency
rTMS targeting the DLPFC in young and middle-aged ASD patients has comparable safety proles to those observed in other psychiatric populations [10].
Clinical Recommendations
The application of bilateral rTMS, whether low frequency or high frequency, to
stimulate the DLPFC may be effective. The most noticeable effect, however, was
the decrease in OCD-like (obsessive-compulsive disorder, OCD) symptoms at the
end of the treatment, as measured by the Y-BOCS scale.
9.2.1.6 Accelerated rTMS
Accelerated TMS is an emerging treatment approach within the TMS eld that can
achieve similar, or even better, efcacy levels by reducing treatment time and
enhancing response rates. Nonetheless, research into accelerated TMS remains in
its infancy. While it may hold the promise of reducing treatment duration and
9 Autism Spectrum Disorder
quickly alleviating depressive symptoms in patients with depression, there are currently no established treatment protocols, and no studies have been conducted on its
application in ASD. Consequently, further research is essential to elucidate its
potential in treating ASD.
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9.2.2 Deep TMS
9.2.2.1 Efficacy
Deep TMS employs H-Coils, which are exible and come in various congurations
to stimulate different brain regions associated with various neuropsychiatric disorders [21].
Only a few studies have reported on the effects of deep TMS in adults with
ASD.The ndings of these studies suggest that deep TMS applied to the mPFC may
be benecial for high-functioning ASD patients experiencing OCD or anxiety
symptoms. A case report indicated that two weeks of daily excitatory stimulation
(5Hz) applied to the mPFC enhanced social functioning in a 20-year-old woman
with high-functioning ASD [22]. A later research by the same study group discovered that stimulating the mPFC enhanced social relations and decreased socially
related anxiety [23]. Another case report suggests that deep TMS may have modulated networks associated with mentalizing abilities and self-referential processes in
two young patients diagnosed with high-functioning autism [24].
9.2.2.2 Safety
9.2.2.3 Treatment Regimen
The mPFC serves as a critical node within functional networks that are essential for
mentalizing abilities, which are vital for social interactions and have been found to
be impaired in adults with ASD.
One study examined the changes in emotional and cognitive processing following daily sessions of 5Hz deep TMS H7 Coil over 5weeks in two high-functioning
ASD patients, and both patients exhibited improvement in various cognitive functions, with a global improvement of 20% for P1 and 30% for P2in the neuropsychological battery [24]. Another study indicates that 28 adults with high-functioning
ASD or Asperger’s disorder completed two weeks of weekday treatment sessions
(5Hz, 10-second trains, 20-second inter-train intervals, and 1500 pulses per session). Participants in the deep TMS group, compared to those in the sham group,
demonstrated a signicant reduction in social-related symptoms posttreatment and
at follow-up. Furthermore, a decrease in self-oriented (socially related) anxiety during challenging and emotional social situations was observed only in the deep TMS
group from baseline to follow-up [23].
9.2.2.4 Clinical Recommendations
Deep TMS is increasingly being utilized in the treatment of both core and associated symptoms of ASD.Drawing from previous reports, we have noted alterations
248
in the emotional, cognitive, and social domains among adult ASD patients, along
with a signicant reduction in symptoms akin to OCD.However, clinical recommendations remain unclear. Therefore, further research is necessary to determine if
these positive outcomes can be sustained in the long term, and there is a pressing
need for larger-scale, randomized controlled trials.
S.-B. Wang et al.
9.2.3 Priming TMS
Priming TMS is an innovative approach in rTMS, which involves preconditioning
low-frequency (LF) stimulation trains with subthreshold stimulation at a high frequency (HF) [25], and there is a lack of research on the eld of ASD.
9.2.4 Synchronized TMS
Synchronized TMS (sTMS) represents an innovative approach to noninvasive brain
stimulation. Utilizing a trio of rotating neodymium magnets, sTMS can deliver
extremely low-energy, sinusoidal magnetic elds that synchronize with an individual’s intrinsic alpha frequency (IAF). However, scholarly investigations into its use
for ASD are lacking.
9.2.5 TBS
9.2.5.1 iTBS
Efficacy
Theta burst stimulation (TBS) is a modied form of rTMS.Intermittent TBS (iTBS),
which delivers bursts of TBS pulses for 2seconds every 10seconds, can enhance
cortical excitability, yet it features a shorter stimulation duration (3min) and a lower
total number of TMS pulses and intensity [26]. Recent studies have investigated the
efcacy of iTBS in ASD and support its effects on certain domains of ASDassociated decits. Ni and colleagues applied iTBS over the bilateral posterior superior temporal sulcus (pSTS) or DLPFC to explore its impact in adults with ASD.The
study demonstrated that a single session of active iTBS to the DLPFC led to immediate improvements on executive functioning tasks, while there were no signicant
differences in neuropsychological function following a single pSTS session [27]. Ni
and colleagues also conducted a clinical trial on a group of intellectually capable
children with autism and found that 8-week iTBS over the bilateral pSTS improved
social relating and reduced repetitive behaviors in children with ASD.Higher IQ,
better baseline social cognitive performance, and less attention-decit hyperactivity
disorder (ADHD) severity predicted a better response to pSTS stimulation for social
relating [28]. Another study investigated the effects of iTBS on the pSTS in
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249
intellectually capable adults with ASD, revealing signicant immediate impacts on
parent-rated autistic symptoms among the participants. The outcomes of multisession iTBS on cognitive exibility and clinical symptoms were inuenced by baseline social-communicative impairment, baseline cognitive performance, concurrent
psychotropic medication use, and baseline autistic symptoms [29]. Individuals with
autism-like traits (ALT) are part of a subclinical group that shares social decits
with those diagnosed with ASD.Research has indicated that iTBS of the right pSTS
can enhance the emotion perception abilities of ALT individuals by modulating the
associated neural networks [30].
A case-control study investigated the use of iTBS to measure motor cortex (M1)
plasticity in youth with ASD compared with typically developing children (TDC).
It was found that both groups experienced a mean increase in excitability after
30min of iTBS; however, the time course of excitability changes varied. Post-hoc
testing revealed a signicant decrease in amplitude in the ASD group at 20 min
post-iTBS compared to the TDC, after correcting for multiple comparisons [31].
Abujadi and colleagues reported that iTBS in the right DLPFC could improve target
executive function decits and restricted, repetitive behaviors in male children and
adolescents with ASD [32]. Oberman and coworkers observed an increased duration of response to the TBS paradigm among high-functioning adults with ASD,
which may be associated with hyperplasticity [33].
Safety
The safety of iTBS in individuals with ASD has been investigated in previous studies. Meta-analysis has shown that iTBS is feasible and tolerable in capable youth
and young adults with ASD [34]. A case-control study supported the nding that
iTBS was well tolerated by all youths with ASD aged 11–18years [31]. Self-reports
indicated that iTBS was well tolerated. However, transient discomfort during stimulations due to muscle twitches around the eyes was reported by ve participants in
a study [30]. No other serious adverse effects, such as headaches or seizures, were
reported in previous studies [32].
Treatment Regimen
The iTBS protocol includes 190 seconds of stimulation in a 2-second on and
8- second off pattern. Most studies have explored the effects of iTBS on the neuroplasticity of the pSTS, DLPFC, and M1, as well as the improvement in clinical
symptoms. The stimulation camps include unilateral and bilateral stimulation. The
study by Ni and colleagues shows promise for improvement in social symptoms and
autistic symptoms through targeted iTBS pulses to the bilateral pSTS [28, 29].
Stimulation of the right pSTS could enhance emotion perception in individuals with
ASD by signicantly decreasing resting-state functional connectivity between the
rpSTS and the left cerebellum [30]. Stimulation of the right DLPFC may enhance
cognitive function and reduce repetitive behaviors in male children and adolescents
with ASD [32]. These results suggest that further controlled interventional studies
of iTBS for ASD are warranted.
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S.-B. Wang et al.
Clinical Recommendations
Considering the improvement effect of iTBS on neuropsychological function, social
symptoms, and autistic symptoms in ASD, iTBS could be a vital therapeutic strategy for the treatment of ASD.It is worth noting that individual factors modulating
the response to iTBS should be explicitly considered. The level of clinical recommendation for iTBS was unclear.
9.2.5.2 Accelerated iTBS
Previous research has demonstrated that accelerated intermittent TBS has been
shown to be an effective antidepressant treatment. The conclusions indicate that this
treatment has demonstrated safety and excellent tolerability. The results encourage
further research into the use of accelerated iTBS for the treatment of ASD patients
with comorbid depression.
9.2.5.3 Continuation TBS
Efficacy
The continuous theta-burst stimulation (cTBS) protocol consists of 40seconds of
continuous stimulation. Various studies have examined the effectiveness of cTBS in
individuals with ASD.Adults with ASD have shown a greater and more enduring
inhibitory response to cTBS, which is likely attributed to abnormalities in cortical
plasticity mechanisms associated with ASD [35]. A study investigated the mechanisms of plasticity and metaplasticity in humans with ASD and fragile X syndrome
(FXS) following cTBS over the primary motor cortex (M1). It found that after a
40-second cTBS train, individuals with ASD exhibited a signicantly longer duration of suppression in motor-evoked potentials (MEPs) amplitude compared to
healthy controls, whereas individuals with FXS demonstrated a signicantly shorter
duration [36]. Jannati etal. found that motor-evoked potential (MEP) at T15 postcTBS is a signicant biomarker for adults with ASD, and its utility is modulated by
brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) polymorphisms [35].
However, Yeh etal. did not nd a signicant impact of cTBS over the left
DLPFC on white matter macrostructure and microstructure, as well as on connections, in children and emerging adults with autism [37]. Furthermore, an
8-week randomized, double-blind, sham-controlled trial was conducted to
investigate the efcacy of inhibitory cTBS over the left DLPFC in individuals
with ASD.The ndings do not support the notion that cTBS over the left DLPFC
is more effective than sham stimulation for children, adolescents, and adults
with ASD [38]. An additional study, where TBS was applied to children with
ASD, demonstrated an increase in the duration of response across childhood and
revealed a subgroup of children who showed paradoxical facilitation to the typically suppressive cTBS paradigm. The authors suggested that their ndings may
reect abnormalities in GABAergic inhibitory control in those individuals who
showed paradoxical facilitation [39].
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251
Safety
The safety of cTBS has been evaluated in a previous study, which indicated that all
participants tolerated cTBS procedures without complications or unexpected side
effects [35].
Treatment Regimen
Previous studies have explored the impact of cTBS over the DLPFC on core
symptoms in ASD and found no signicant effects [37]. In another study, the
variations in symptoms and executive function were explored using cTBS over
the left DLPFC in individuals with ASD.The active group did not demonstrate
superiority over the Sham group in any clinical or neuropsychological metrics
at Week 8 or Week 12 [38]. Oberman etal. explored M1 plasticity and metaplasticity using cTBS in individuals with ASD and found that these individuals
exhibited a signicantly longer duration of suppression in motor-evoked potentials (MEPs) amplitude [36].
Clinical Recommendations
Previous studies have found that cTBS has greater and more enduring effects on
motor cortical excitability in children with ASD, with aberrant responses becoming
more pronounced as they age [40, 41]. It is suggested that cTBS induces inhibitory
neuromodulation at the stimulated site. However, some ndings indicate that earlier
positive open-label trial results may be attributable to generalized placebo effects
[38]. The clinical recommendation level for iTBS was unclear.
9.2.5.4 Bilateral TBS
Efficacy
Studies have found that iTBS applied to the bilateral DLPFC and bilateral posterior
superior temporal sulcus (pSTS) is associated with improvements in autistic symptoms, executive functioning, social interaction, and reductions in repetitive behaviors among individuals with ASD [27–29].
Safety
Previous studies have demonstrated that a course of at least 1month of regular and
repeated bilateral iTBS is feasible and acceptable for intellectually capable children
and adolescents with ASD [28].
Treatment Regimen
Studies have investigated the therapeutic effect of iTBS on the bilateral pSTS using
various designs, such as single-session [27] and multisession [29]. Multisession
iTBS over the bilateral pSTS could improve parent-rated autistic symptoms in ASD,
while there were no signicant differences in neuropsychological function following a single pSTS session.
252
Table 9.1 TMS in ASD
Clinical recommendations
Duration
TMS
Unilateral rTMS unclear unclear unclear unclear unclear
Bilateral rTMS unclear unclear unclear unclear unclear
Accelerated
rTMS
Deep TMS unclear unclear unclear unclear unclear
Priming TMS unclear unclear unclear unclear unclear
Synchronized
TMS
iTBS unclear unclear unclear unclear unclear
Accelerated iTBS unclear unclear unclear unclear unclear
cTBS unclear unclear unclear unclear unclear
Bilateral TBS unclear unclear unclear unclear unclear
MST unclear unclear unclear unclear unclear
unclear unclear unclear unclear unclear
unclear unclear unclear unclear unclear
a
(sessions)
S.-B. Wang et al.
Levels +
ReferencesTarget Frequency Length (min)
Clinical Recommendations
It has been demonstrated that iTBS over the pSTS is practicable and safe in individuals with ASD, and it may favorably increase patient compliance and accessibility [28]. The clinical recommendation level for iTBS was unclear.
9.2.6 MST
Magnetic seizure therapy (MST) employs HF magnetic stimulation to induce generalized seizures [42] and alleviates adverse neurocognitive effects by specically
targeting localized brain regions and inducing seizures in supercial cortical areas
[43]. MST results in shorter recovery times and lower levels of cognitive impairments in individuals with major depressive disorder compared to ECT [44].
Consequently, MST has been proposed as a potential alternative to ECT [45].
Emerging evidence supports the clinical efcacy of MST in treating depression
[46], bipolar depression [44], schizophrenia [42], and OCD [47], but its effectiveness for ASD remains unclear (Table9.1).
9.3 tDCS
Transcranial direct current stimulation (tDCS) is a type of transcranial electrical stimulation (tES) that operates on the principle of stimulating the cerebral cortex using a weak,
constant electrical current. Unlike transcranial magnetic stimulation (TMS), the current
in tDCS is not strong enough to induce action potentials; instead, it modulates the likelihood of neuronal ring in the affected area [48]. The basic structure of tDCS comprises
a stimulator, electrodes (an anode and a cathode), cables, conductive gel, and software.
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253
The current intensity remains constant during brief ramping up and down phases, typically ranging from 0.5 to 2mA, with a treatment session lasting between 5 and 30min
[48]. Research into tDCS intervention for autism has been steadily growing in recent
years, with the majority using conventional tDCS to assess its efcacy, while fewer studies have explored HD-tDCS (High-denition tDCS).
9.3.1 Conventional tDCS
9.3.1.1 Efficacy
Most studies have reported that conventional tDCS is effective in alleviating symptoms in autism. In terms of its mechanism, conventional tDCS may modify local
and global brain network dynamics through processes such as the regulation of
neural synapses [48, 49]. Thus, targeting various sites can result in different effects.
The most frequently targeted area is the left DLPFC.This region is closely associated with executive function, and certain neuropsychological studies have found
that stimulating this area can enhance attention, working memory, and cognitive
exibility [50–52]. Results from randomized controlled trials have shown that stimulating this area effectively reduces scores on symptom assessment tools (CARS,
ATEC, SRS-2, etc.) for individuals with autism [53–56] and even demonstrates a
cumulative efcacy over time [57]. The stimulation of the right temporoparietal
junction (rTPJ) may enhance social functioning and empathy in individuals with
autism [58]. Additionally, the activation of the ventromedial prefrontal cortex
(vmPFC) has been shown to improve emotion recognition [59], and the cerebellum
has been associated with increased brain complexity [60].
9.3.1.2 Safety
Conventional tDCS has not typically exhibited adverse effects in individuals with
autism in most studies. During the treatment period, the most commonly reported
effect was itchiness [56, 61]. Posttreatment, the predominantly reported effects
were mood changes, particularly irritability [57]. Mood changes (42.9%), irritability (35.7%), tingling (28.6%), and itching (28.6%) were the most commonly
observed effects in a recent review [62]. Clinically, a review has indicated that children may exhibit greater scalp sensitivity, which could be mitigated by employing a
lower concentration of NaCl solution (15–140mmol/L) to minimize the likelihood
of side effects [63].
9.3.1.3 Treatment Regimen
There are two types of stimulation: anodal stimulation, which facilitates activity in
targeted brain regions, and cathodal stimulation, which suppresses it. As previously
mentioned, stimulation targets for autism typically include the DLPFC, rTPJ,
vmPFC, and cerebellum. Among various stimulation strategies, the most common
plan for autism involves placing the anodal electrode over the left DLPFC and the
cathodal electrode on the right shoulder. The stimulation current is usually kept at a
stable level between 1 and 2mA, with 30-second ramp-up and ramp-down phases.