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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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Abbreviations
ADHD Attention Decit Hyperactivity Disorder
ASD Autism Spectrum Disorder
CS Conditioning Stimulus
cTBS Continuous iTBS
DLPFC Dorsolateral Prefrontal Cortex
HF-Rtms High-Frequency rTMS
iTBS Intermittent TBS
LF-rTMS Low-Frequency rTMS
MT Motor Threshold
PPC Posterior Parietal Cortex
ppTMS Paired-pulse TMS
RMT Resting Motor Threshold
SMA Supplementary Motor Area
spTMS Single-pulse TMS
TDC Typically Developing Children
tDCS Transcranial Direct Current Stimulation
TMS Transcranial Magnetic Stimulation
vmPFC Ventromedial Prefrontal Cortex
M. Gu et al.
8.1 ADHD
8.1.1 Definition andIntroduction
Attention-decit/hyperactivity disorder (ADHD) is a common neurodevelopmental
disorder characterized by symptoms of inattention, hyperactivity, and impulsivity.
Typically beginning in childhood, ADHD can persist into adulthood. The global
prevalence of ADHD in children and adolescents is approximately 5.29% [1], while
the prevalence in early adulthood is around 2.5% [2], gradually declining to about
1% with age [3]. Males are more frequently diagnosed than females. The causes of
ADHD are multifactorial, including genetic predispositions, environmental inuences (e.g., maternal smoking during pregnancy, preterm birth), and neurophysiological abnormalities, such as dysfunctions in the prefrontal cortex [4, 5]. ADHD is
associated with a range of cognitive decits, particularly in executive functions [6].
Compared to unaffected control groups, individuals with ADHD show impairments
in behavioral inhibition, working memory, attention, planning, and organizational
skills, which contribute to poor academic performance, interpersonal relationship
issues, and emotional challenges [7].
8 Attention Decit Hyperactivity Disorder
225
8.1.2 Therapeutic Method
The rst-line treatment for ADHD includes central nervous system stimulants such
as methylphenidate and amphetamines. Nonstimulant medications like norepinephrine reuptake inhibitor atomoxetine and α-2 adrenergic agonists guanfacine and
clonidine are also options for children over 7 and adults. Multiple RCTs and metaanalyses have demonstrated signicant short-term improvements in ADHD symptoms [8, 9]. However, in natural cohort studies (without the strict control of RCTs),
long-term medication adherence declines, reducing the expected therapeutic effects
[10]. Additionally, side effects such as delayed growth and the potential for stimulant misuse limit the widespread application of these medications, prompting the
search for alternative treatments.
In recent years, non-pharmacological interventions like transcranial magnetic
stimulation (TMS) and transcranial direct current stimulation (tDCS) have shown
potential in treating ADHD by modulating neuronal activity to improve attention
and impulsivity, especially in patients who cannot tolerate or wish to reduce medication. However, due to differences in treatment parameters, targeted brain regions,
study populations, and treatment duration, results have been inconsistent. This
chapter will focus on analyzing and describing these variations.
8.2 TMS
8.2.1 Single-Pulse TMS (spTMS)
8.2.1.1 Efficacy
TMS is a noninvasive brain stimulation technique, which was rst proposed by
Barker etal. based on the principle of electromagnetic induction [17]. TMS can
enhance or attenuate neuronal activity by applying magnetic elds to specic brain
regions, exploring the control of attention by individual brain regions, and enhancing understanding of potential treatments for ADHD.TMS can be divided into single-pulse TMS, paired-pulse TMS, repetitive TMS, and theta pulse stimulation
modes. Single-pulse transcranial magnetic stimulation (spTMS) is a technique with
a high spatiotemporal resolution [18]. In the late 1980s, Amassian etal. rst proposed that spTMS could be used as a reversible virtual injury that alters and interferes with neural activity, thereby exploring the function of specic brain regions
and accurately detecting the state of brain activity [19]. The therapeutic efcacy of
spTMS is still in the experimental research phase. Research has shown that applying
spTMS with primary somatosensory cortices (SI) and the contralateral posterior
parietal cortex (PPC), both play a sequential and unique role in the neural processes
of cross-modal association and working memory [20]. In addition, modulation of
brain regions associated with attention decits, such as the prefrontal cortex and
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M. Gu et al.
parietal cortex, using spTMS can help the connection of attention neural networks
by improving neuroplasticity and promoting better attention function [21–23].
Existing studies suggest that spTMS can help better understand the occurrence of
ADHD, but its potential as a standalone treatment is still under investigation and
more clinical trials are needed to determine efcacy.
8.2.1.2 Safety
The application of spTMS in children has not caused serious adverse effects. As
early as 20years ago, researchers evaluated the safety of spTMS in children, and the
results showed that the risk of spTMS for children was very small [24, 25]. Common
side effects include headache, scalp pain, numbness/tingling, ringing in ears, and
nausea/vomiting. These side effects are usually transient and mild. Besides, TMS
may increase the risk of seizures, especially in children with a history of epilepsy or
brain injury [26, 27]. Compared with rTMS, spTMS has a lower stimulation frequency and a lower incidence of adverse reactions. Since factors such as age, health
status, and neurodevelopmental status may all affect the safety of TMS, further
studies and long-term follow-up data are still necessary to fully evaluate the safety
of its application in children.
8.2.1.3 Treatment Regimen
The application of spTMS in the treatment of ADHD is in the early stage of research,
and its treatment plan is still being explored. The spTMS protocol consisted of single-pulse discharges typically separated by 4–8s [21]. Common target areas include
the motor cortex, prefrontal cortex, and other regions involved in various cognitive
functions [28]. Current studies mostly calibrate the stimulation intensity based on
the motor threshold (MT), usually using an intensity of 80% to 120% of the Resting
motor threshold (RMT), which is considered safe and affordable for patients, and
50–200 pulses per session can be used [27]. The evidence for the treatment of
ADHD by spTMS is still limited, the optimal stimulation parameters, target area,
and treatment regimen are not yet clear, and more clinical trials are needed to validate further research.
8.2.1.4 Clinical Recommendations
At present, spTMS is not widely used in clinical practice, but its combination with
drug therapy can provide a promising multimodal approach. The combination of the
two may result in a potential synergistic effect. Medications usually target the dopamine and norepinephrine neurotransmitter systems to relieve symptoms such as
inattention and impulsivity. However, TMS can modulate brain activity in specic
brain regions such as the prefrontal cortex to improve neuroplasticity [29, 30]. On
the other hand, neuroimaging techniques, such as fMRI, EEG, and MEG, can not
only identify the specic brain areas and their neural networks related to ADHD but
also ensure the target selection and efcacy evaluation of TMS by accurately locating and detecting the dysfunction areas, so as to provide a comprehensive and personalized treatment plan for clinical treatment [31, 32].
8 Attention Decit Hyperactivity Disorder
227
8.2.2 Paired-Pulse TMS (ppTMS)
8.2.2.1 Efficacy
The current application of ppTMS in the eld of mental illness is mainly in the
assessment of mental illness status, and it has not yet been formalized. Previous
studies have shown that the neural inhibitory motor circuits in children with ADHD
can be disrupted [33]. The measurement of short-interval intracortical inhibition
(SICI) by ppTMS can be used to quantify the core feature of ADHD, which is unrestrained impulsive behavior [34]. Studies have shown that children with ADHD
experience a 30–40% reduction in resting state SICI, which is negatively correlated
with the severity of ADHD symptoms, particularly excessive physical activity [35].
8.2.2.2 Safety
ppTMS has been recognized as a specialized tool for evaluating cortical circuits,
and neurophysiological studies typically use the ppTMS paradigm to detect cortical
excitability and inhibition, which is widely used in TMS research for ADHD [36].
8.2.2.3 Treatment Regimen
ppTMS outputs paired stimulation pulses each time, which are referred to as initial
conditioning stimulus (CS) and subsequent test stimulus (TS), and by setting the
stimulation intensity, frequency, and interval time between two pulses to achieve the
purpose of stimulation, if the interval between CS and TS is 1-5ms, SICI will be
triggered [37].
8.2.2.4 Clinical Recommendations
The study of cortical excitability and inhibition in child and adolescent psychiatry
using ppTMS can help identify new biomarkers and provide information for treatment selection and the characterization of endophenotypes and phronotypes [36].
Currently, several established ppTMS schemes exist for assessing the severity of
ADHD and evaluating the effectiveness of drug therapy, which can aid in the selection of ADHD medications and foster the development of future ADHD treatments
[38]. It is worth mentioning that the disruption of the promotion and inhibition circuits observed in pediatric patients did not manifest in adult ADHD patients [39].
ppTMS with specic intensity, frequency, and pattern can help detect, regulate, and
even restore brain activity [21]. Overall, ppTMS has a promising future in the treatment of ADHD.
8.2.3 rTMS
8.2.3.1 Low-Frequency rTMS (LF-rTMS)
Efficacy
Low-frequency rTMS can normalize the imbalance of excitatory and inhibitory processes in the motor cortex through its inhibitory effect on the motor cortex, thus
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M. Gu et al.
improving the symptoms of hyperactivity in ADHD patients. Some studies have
used low-frequency rTMS to treat children with ADHD, which can effectively
improve the children’s attention decit symptoms at school and hyperactivity/
impulsivity symptoms at home, with a good safety prole [40].
Safety
A single-blind pseudo-stimulation randomized controlled study on 25 children with
ADHD aged 8–14 years, intervening in their rst somatomotor area with 1 Hz
rTMS at an intensity of 80% (resting motor threshold, RMT) RMT for 900 consecutive stimulations, and monitoring their 64-lead EEG with the TMS-induced N100
wave amplitude, which showed a signicant decrease in both N100 and MEP wave
amplitudes after the low-frequency rTMS intervention. rTMS was well tolerated,
with only three children reporting mild transient headaches before, during, or after
rTMS, and EEG recordings showed no signs of epileptic activity.
Treatment Regimen
Niederhofer etal. showed [12] that stimulation of motor areas with low-frequency
rTMS (1Hz), 1200 stimuli per day for 5d per week, resulted in a signicant improvement in ADHD symptoms after 4weeks of treatment; it was also effective in children with ADHD treated with methylphenidate and helped to reduce the dose of the
original medication used. In order to evaluate the safety and efcacy of lowfrequency rTMS in ADHD boys with ADHD who did not respond to conventional
treatment. Gómez etal. conducted [11] an open trial, 10 patients with ADHD aged
7 to 12years were treated with a buttery coil, with stimulation of the left DLPFC,
at a frequency of 1Hz, with 90% RMT, for 5 consecutive days, with 1500 stimulation per day. The treatment was well tolerated and completed. Seven subjects
reported transient mild headache or localized discomfort that lasted only a few minutes and disappeared without medication. Two subjects reported neck pain. Overall,
treatment of the left DLPFC with rTMS at 1Hz was well tolerated safe and reliable
by the children. Moreover, the behavioral problems of the children as rated by parents and teachers improved signicantly after the treatment.
Clinical Recommendations
rTMS, as a kind of physical therapy, basic principle is that electric current stimulates brain tissues to release dopamine and promote cortical excitability, which in
turn affects brain blood ow and metabolism. rTMS adopts different stimulation
sites, stimulation intensity, stimulation frequency, and treatment duration, and its
clinical efcacy on ADHD patients varies. rTMS has a good clinical effect on children with ADHD, and low-frequency transcranial magnetic stimulation therapy has
been shown to be effective in treating children with ADHD.As shown in Table8.1.
8 Attention Decit Hyperactivity Disorder
Table 8.1 TMS in ADHD
Clinical recommendations
Stimulus per day (times)/
TMS
spTMS Not clear
ppTMS Not clear
LF-rTMS L-DLPFC 1Hz 1500 times 5 [11]
Motor area 1Hz 1200 times 5 [12]
HF-rTMS R-DLPFC 20Hz 30s 1 [13]
Bilateral
prefrontal
rPFC 18Hz 20s 15 [15]
rPFC 10Hz 2000 times 10 [16]
iTBS Not clear
cTBS Not clear
Abbreviations: spTMS Single-pulse TMS, ppTMS Paired-pulse TMS, LF-rTMS Low frequency
rTMS, HF-rTMS High frequency rTMS; iTBS Intermittent TBS; cTBS Continuous iTBS, L-DLPFC
Left-Dorsal lateral prefrontal cortex, R-DLPFC Right-Dorsal lateral prefrontal cortex, rPFC Right
prefrontal cortex
18Hz 20s 20 [14]
stimulation interval (s)
Duration
(sessions)
229
ReferencesTarget Frequency
8.2.3.2 High-Frequency rTMS (HF-rTMS)
Efficacy
A meta-analysis of fMRI in ADHD patients suggests that ADHD patients have
underactivation in the right prefrontal cortex [41], and that HF-rTMS can have an
activating effect on stimulated brain regions [42]. HF-rTMS acting on cortical
motor areas or dorsolateral prefrontal cortex induces modulation of endogenous
dopamine release into the caudate nucleus, which increases cortical excitability and
improves frontal brain functioning and arousal levels in frontal regions, thus improving attention decits.
Safety
A randomized, pseudo-stimulation-controlled crossover study of 9 patients with
adult ADHD showed that high-frequency rTMS was safe with no serious adverse
effects [16].
Treatment Regimen
One study was conducted on adult patients with ADHD using rTMS stimulation site
for the right dorsolateral prefrontal cortex, stimulated at a 100% motor threshold
intensity of 20Hz, with a stimulation interval of 30seconds. The results of the study
showed that after a single session of true rTMS to the right prefrontal cortex using
a HF-rTMS, there was a signicant improvement in attention, but no signicant
changes in mood and anxiety [13]. However, in a randomized double-blind placebocontrolled rTMS treatment of adult ADHD patients with deep TMS with bilateral
prefrontal stimulation, 20 daily sessions of transcranial magnetic stimulation for 4
consecutive weeks, with each training session consisting of 55 sets of impulses at a
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M. Gu et al.
frequency of 18Hz, spaced at intervals of 20seconds, and with an intensity of 120%
of the measured motor thresholds, but no bilateral deep rTMS was found to have
benecial effects [14]. We evaluated targeting the rPFC with multiple repetitive
transcranial magnetic stimulation (rTMS) to 43 adult patients with ADHD with
daily high-frequency (18Hz) stimulation for a period of 3weeks, which resulted in
a signicant improvement in clinical symptoms and documented EEG changes
composed of the alpha and low-gamma power that were highly correlated with clinical symptoms [15].
HF-rTMS is widely used not only in adult ADHD patients but also in children
and adolescents with ADHD.
In a randomized, pseudo-stimulation-controlled crossover study of 9 patients
with ADHD aged 15–20years, rTMS stimulation was performed at the site of the
right prefrontal cortex at a frequency of 10Hz (100% motor threshold), with 2000
pulses per session, 5 times per week for 2weeks. The results showed that TMS was
safe with no serious adverse effects, signicant improvements in overall clinical
impression and ADHD-IV scores were observed in both the TMS stimulation and
pseudostimulation groups, but no signicant differences were found between the
two groups, and participants in the group receiving effective transcranial magnetic
stimulation began to show signicant improvement in clinical symptoms early in
the treatment period, noting that a large-sample controlled study is still needed [16].
Clinical Recommendations
HF-rTMS plays an active role in the treatment of adults with ADHD.In addition,
when combined with drug therapy, the dose of drugs can be reduced. A study found
that 6-week rDLPFC HF-rTMS combined with atomoxetine was more effective
than rTMS alone or atomoxetine alone [43], and the results of a recent meta-analysis showed that rTMS not only signicantly improves the core symptoms of ADHD
patients, but also has a signicant effect in cognitive function improvement [44].
However, the limitation of current clinical studies on rTMS for ADHD is the small
sample size, and more clinical studies with larger clinical sample sizes are still
needed to further observe the efcacy of rTMS (as shown in Table8.1).
8.2.4 TBS
8.2.4.1 Intermittent TBS (iTBS)
Efficacy
No independent study of iTBS in ADHD patients was reported. There was only one
case-control study that investigated the use of a low-intensity rTMS protocol to
measure motor cortex (M1) plasticity in youth with autism spectrum disorder (ASD)
compared with typically developing children (TDC). Nine youth with ASD (two of
them had combined ADHD) and nine TDC participated. This study demonstrated
early evidence for a potential physiological biomarker of cortical plasticity in youth
8 Attention Decit Hyperactivity Disorder
231
with ASD using a rapid low-intensity rTMS protocol with a discriminate measure at
20minutes following stimulation [45].
Safety
No moderate or severe adverse events were identied by structured diagnostic interviews and no seizures occurred. One subject reported a mild headache (rated: minimal) following iTBS, which spontaneously resolved.
Treatment Regimen
A modied iTBS protocol consisted of bursts of 3 pulses at 30Hz repeating every
200ms for 2seconds (1 train) with trains repeating every 10seconds apart for a total
of 300 pulses.
Clinical Recommendations
Unable to make clinical recommendations due to lack of clinical evidence, and
more clinical studies are needed to further observe the efcacy and safety of iTBS.
8.2.4.2 Continuous iTBS (cTBS)
Efficacy
Similarly, no independent study of cTBS in ADHD patients was reported. But there
are studies have shown that rTMS to be effective in reducing tics [46, 47]. To determine whether 8 sessions of cTBS over supplementary motor area (SMA) given over
2days may reduce tics and motor cortical network activity in Tourette syndrome/
chronic tic disorders. Steve W. Wu etal. conducted a randomized (1: 1), doubleblind, sham-controlled trial of functional MRI (fMRI)-navigated, 30Hz cTBS at
90% of resting motor threshold (RMT) over SMA in 12 patients ages 10–22years.
Comorbid ADHD (n=8) was permitted. Active, fMRI-navigated cTBS administered in 8 sessions over 2days to the SMA induced signicant inhibition in the
motor network (SMA, bilateral M1). However, both groups on average experienced
tic reduction at 7days [48].
Safety
All 12 patients who received cTBS completed the study without serious adverse
events. Three participants complained of mild adverse events (abdominal pain,
headaches, dry eyes) which resolved without medical intervention.
Treatment Regimen
The cTBS magnetic pulsing pattern consists of 3 pulses per burst (30Hz) with
bursts repeating 5 times per second for a total of 600 pulses per train.
Clinical Recommendations
Unable to make clinical recommendations due to lack of clinical evidence, and
more clinical studies are needed to further observe the efcacy of cTBS.
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M. Gu et al.
8.3 tDCS
8.3.1 Conventional tDCS
8.3.1.1 Efficacy
Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation
technique that has shown potential efcacy in alleviating ADHD symptoms. Studies
indicate that different stimulation sites can positively inuence various executive
functions in ADHD patients. For example, the left dorsolateral prefrontal cortex
(DLPFC) is a common target, and several studies have found that anodal tDCS
stimulation of this area can increase correct response rates in Go/No-Go tasks,
enhance selective attention, and improve inhibitory control functions [49, 54].
Similarly, the right DLPFC has also been found effective in improving attention
decit symptoms in adult ADHD patients [50, 55].
Additionally, stimulation of the ventromedial prefrontal cortex (vmPFC) has
shown potential in regulating emotions and impulse control. For instance, Vöckel
etal. demonstrated that anodal tDCS applied to the vmPFC signicantly improved
effort maintenance in high-effort tasks among children with ADHD [51]. In other
studies, vmPFC stimulation was found to reduce delay discounting behavior,
encouraging children with ADHD to choose larger delayed rewards [56]. However,
while tDCS has shown improvements in several tasks, some studies did not nd
signicant effects, possibly due to individual differences, stimulation parameters,
and treatment designs [57, 58].
8.3.1.2 Safety
Overall, tDCS is considered a safe treatment method, with most studies reporting
mild side effects such as scalp tingling, skin-burning sensations, or transient headaches. For example, Schertz etal. recorded mild scalp tingling and itching sensations
in children with ADHD, but these symptoms typically resolved shortly after treatment [58]. However, certain populations may experience more noticeable adverse
reactions. For instance, Westwood etal. reported negative emotional responses, such
as irritability, sleep difculties, and appetite loss among adolescent ADHD patients,
indicating that tDCS may cause emotional uctuations in specic groups [59]. This
highlights the need for close monitoring during treatment, and adjustments or discontinuation may be necessary depending on the patient’s response.
8.3.1.3 Treatment Regimen
The efcacy of tDCS in the treatment of ADHD is highly dependent on the detailed
design of the treatment protocol, including the stimulation target, intensity, frequency, duration, and total number of sessions. First, the stimulation target usually
involves brain regions associated with executive functions, emotional regulation,
and impulse control, such as the left or right DLPFC and vmPFC.Stimulation of the
left DLPFC is commonly used to improve attention and inhibitory control functions
[49, 54], while the right DLPFC is targeted for attention regulation in adult ADHD
patients [50, 55]. Meanwhile, stimulation of the vmPFC mainly addresses emotional and decision-making adjustments [51, 56].
8 Attention Decit Hyperactivity Disorder
Table 8.2 tDCS in ADHD
Clinical recommendations
Anode
tDCS
Conventional
tDCS
HD-tDCS Right inferior
Abbreviations: tDCS Transcranial direct current stimulation, HD-tDCS High-Denition
Transcranial Direct Current Stimulation
position Cathode position
F3 Fp2 1.5 15 3 [49]
F4 F3 2 30 28 [50]
Fpz F4 2 20 1 [51]
Right inferior
frontal gyrus
Fp2
frontal gyrus
Fpz、Afz、
AF4、AF8
Intensity
(mA)
0.25/0.5 20 5 [52]
1 20 10 [53]
Length
(min)
Duration
(sessions)
References
233
Regarding stimulation intensity, current levels are typically set between 1.0 and
2.0mA.Lower intensities are often applied in studies involving children to minimize discomfort or adverse effects [58, 60], while higher intensities are frequently
used in adults to achieve more signicant therapeutic outcomes [61, 62]. Each tDCS
session generally lasts between 15 and 30minutes; shorter durations are employed
to reduce discomfort, especially in pediatric patients, while longer sessions promote
more signicant neuroplastic changes in adults. The frequency and total number of
sessions also vary according to the treatment goals. Short-term studies often involve
daily sessions over a few days [57], whereas long-term protocols may include multiple sessions per week over four weeks or longer [50, 58], with total sessions reach-
ing 20 to 30 [55].
8.3.1.4 Clinical Recommendations
tDCS can be a supplementary treatment option for ADHD but should be applied
with caution, especially in children and adolescents. Clinicians should prioritize
targeting the left or right DLPFC for improving attention and executive functions
while considering vmPFC for emotional and impulse control. Combining tDCS
with other non-pharmacological therapies, such as cognitive training, may enhance
effectiveness. Treatment protocols should be tailored based on patient age, symptom type, and initial response, with careful monitoring of potential side effects, such
as mood changes. Further optimization of parameters is needed to maximize efcacy and minimize risks (as shown in Table8.2).
8.3.2 High-Definition Transcranial Direct Current Stimulation
(HD-tDCS)
8.3.2.1 Efficacy
Compared to traditional tDCS, the major advantage of HD-tDCS lies in its highdensity electrode conguration, which allows the current to be more focused on the
target area, reducing the impact on peripheral irrelevant areas. Currently, there are
few studies on the use of HD-tDCS in treating ADHD.The initial study showed that
after three treatments on 15 children and adolescents with ADHD (targeting the