Nagy et al.

Middle East Current Psychiatry (2022) 29:55 Middle East Current

https://doi.org/10.1186/s43045-022-00210-3
Psychiatry

RESEARCH Open Access

The therapeutic role of repetitive

transcranial magnetic stimulation in children
with attention deficit/hyperactivity disorder
in Egypt a randomized sham controlled clinical
trial
Nahla Al Sayed Nagy1, Ghada Refaat Amin1, Sherine Ahmed Khalil1, Dalia Abdel Moneim Mahmoud1,
Hussien Elkholy1 and Mostafa Shohdy2*   

Abstract
Background: Repetitive transcranial magnetic stimulation showed some evidence for improving symptoms of
ADHD along with its relative safety, thus could serve as a treatment strategy or an alternative to stimulant medica-
tion. Accordingly, 60 children with ADHD were assessed, and 30 participants were allocated to the rTMS group and
received 15 sessions of rTMS over the right dorsolateral prefrontal cortex combined with Atomoxetine 1.2 mg/kg/day.
The other 30 participants were allocated to the Sham group and received 15 sessions of sham rTMS and atomoxetine
1.2 mg/kg/day. Clinical assessments of ADHD symptoms and severity were done and compared at 3 points, before
treatment, after receiving 15 sessions of rTMS and follow-up 1 month after the last rTMS session, using Conner’s Parent
Rating Scale-Revised-Long form, Children’s Global Assessment Scale, and Clinical Global Impression.
Results: The two groups show significant improvement in the T scores of all CPRS subscales, CGI and CGAS. However,
the rTMS group had a significantly more improvement than the sham group in inattention, total ADHD severity, CGI,
and CGAS after rTMS and continued to the follow-up after 1 month.
Conclusions: rTMS is an efficacious intervention for treating ADHD, and combined rTMS and atomoxetine is superior
to atomoxetine alone in improving attention deficit symptoms and total ADHD symptoms severity.
Trial registration: PACTR, PACTR​20211​05584​51583. Registered 25 June 2021. Approved 29 October 2021- Retrospec-
tively registered, https://​pactr.​samrc.​ac.​za/​Trial​Displ​ay.​aspx?​Trial​ID=​15968.
Keywords: ADHD, Attention deficit hyperactivity disorder repetitive transcranial magnetic stimulation, rTMS, Sham
controlled clinical trial

Background
Attention-deficit hyperactivity disorder (ADHD) is a
common neurodevelopmental disorder presented by
inattention and/or hyperactivity/impulsivity causing
*Correspondence: dr.shohdyy@gmail.com; Mostafa.shohdy@ngu.edu.eg
impairment in the child’s academic performance and
2
social functioning [1]. The worldwide ADHD prevalence
Mental Health Department, School of Medicine, Newgiza University, Giza,
Egypt
is estimated to be 7.1% in children and adolescents and
Full list of author information is available at the end of the article 7.2% in the USA [2]; however, the incidence is much

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Nagy et al. Middle East Current Psychiatry (2022) 29:55 Page 2 of 11

higher, reaching 9.4–21.8% in Egypt [3]. Most children on relatively small samples, used few rTMS sessions, and
with ADHD will have attention problems in adulthood, some studies did not include a sham condition [16]. Most
and many have comorbidities and occupational and TMS study’s findings also concluded that increasing the
social difficulties [2]. excitability of the right DLPFC through high-frequency
Studies of MRI in ADHD have found evidence of rTMS can improve ADHD symptoms [17].
brain structural abnormalities in the form of reduc- Given the high prevalence of ADHD in school-aged
tion in the gray matter, reduction in cortical thickness children in Egypt, and the absence of sufficient studies
and the surface area in the frontal, parietal and tempo- on the effect of the combined rTMS and atomoxetine in
ral areas, and reduction in the basal ganglia and insula the treatment of children with ADHD [16], further Sham
as well [4]. These areas are interconnected by func- controlled randomized clinical trials (RCT), applying
tional neurocircuits that regulate attention, thoughts, more numbers of rTMS sessions in a larger sample size in
emotions, and behavior [5]. In addition, fronto-striatal, children with ADHD are needed.
fronto-cerebellar, and interhemispheric white matter Accordingly, the current study is conducted to assess
tracts are proven to be affected [6], and dysregulation the therapeutic role of rTMS combined with Atom-
of these circuits is considered the underlying cause of oxetine in children with ADHD and further to assess
symptoms of inattention and hyperactivity. The fronto- whether the combined therapy is superior to Atomoxe-
striatal circuit is known to mediate executive cogni- tine alone in treating children with ADHD.
tive functions, and its dysregulation causes deficits in
sustained attention, organization, planning, working Methods
memory, and motor response inhibition. Moreover, dys- This study is a double-blind, randomized sham con-
regulation of the fronto-limbic circuits is associated with trolled clinical trial and was conducted at the Institute
symptoms of hyperactivity-impulsivity, delay aversion, of Psychiatry Ain Shams University, between August
aggression, demotivation, and emotional dysregulation. 2019 and August 2021, on 60 children with ADHD with
The fronto-cerebellar circuits are associated with motor ages ranging from 6 to 12 years. The trial protocol was
coordination deficits and problems with the timing and approved by the Research Ethics Committee (REC) at the
timeliness of behavior [7]. Noteworthy that whole-brain Ain Shams University Faculty of Medicine (FMASU REC
voxel-based morphometry (VBM) and functional MRI FWA00017585) retrospectively registered, https://​pactr.​
(fMRI) studies found evidence of right dorsolateral pre- samrc.​ac.​za/​Trial​Displ​ay.​aspx?​Trial​ID=​15968.
frontal cortex (DLPFC) hypoactivity in ADHD during The sample size was calculated by a statistician using
inhibitory control and attentional tasks [8, 9]. Epi info, setting the type-1 error (α) at 0.05 and power
Even while considering psychostimulants as the first- at 80%. Results from a previous study [18], the initial
line treatment for ADHD and their adverse effects are mean was 30 ± 6.86 and dropped to 21 after 10 sessions
typically non-serious and can be transient, they are con- of rTMS at 10 Hz. Accordingly, the sample size was cal-
troversial due to their potential of abuse and that only culated to be 18 subjects. Gómez et al. [19] showed that
50% can tolerate them sufficiently, also their adverse the mean of symptoms checklist (SCL) for ADHD from
effects, on sleep, nausea/vomiting, abdominal pain, appe- DSM-IV was 18.1 ± 11.63 after a daily session of rTMS,
tite, irritability, headaches, labile mood, and growth sup- for 5 consecutive days, making a total of 5 rTMS sessions,
pression [10]. Moreover, a long-term efficacy has not compared to the initial mean 32.4 ± 14.89. Calculations
been proven by research [11], and alternative treatments, according to these values produced a sample size of 28
like behavioral therapies, cognitive training, or dietary subjects, divided into 14 per group. The number was
interventions, have shown limited efficacy [12]. rounded up to include 30 subjects per group for a total
Repetitive transcranial magnetic stimulation (rTMS) number of 60 subjects.
can modulate cortical excitability and brain network As shown in Fig. 1, a flow diagram showing how the
activity. TMS can be used diagnostically to study corti- study sample was recruited and handled during the study.
cal neurophysiology, and the daily use of repetitive TMS Sixty children with ADHD of both sexes and ages ranging
can induce long-lasting changes [13]. Accordingly, they between 6 and 12 years old were included in the study.
are promising therapeutic tool as it can stimulate brain Children with a comorbid diagnosis of autism spectrum
dysregulated neurocircuits that have been implicated disorder, bipolar disorder, obsessive-compulsive disorder,
in ADHD [6]. Furthermore, they are relatively safe [14], conduct disorder, Tourette disorder or other tic disor-
with minimal side effects, cheaper than long-term drug ders, schizophrenia, schizoaffective disorder, any other
treatments and can induce neuroplasticity [15]. psychotic disorder, or other neurological disorders were
Only a few studies have investigated the role of rTMS excluded from the study. Furthermore, participants who
on children with ADHD, most of the studies were applied have specific contraindications to magnetic stimulation
Nagy et al. Middle East Current Psychiatry (2022) 29:55 Page 3 of 11

Fig. 1 A flow diagram showing how the study sample was recruited and handled during the study. Schulz KF, Altman DG, Moher D, for the
CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. Ann Int Med 2010;152. Epub 24
March [20]

such as any metallic object implanted in the skull (with then assessed using the Structured Clinical Interview
the exception of oral dental devices), an implanted medi- for DSM-IV (SCID I) diagnostic tool to diagnose ADHD
cation pump or cochlear implant, implanted intra-car- and to exclude other Axis I diagnoses according to DSM
diac lines or pacemaker, also factors that might increase IV classification, which took place in the first interview
the risk of seizure with TMS such as a history of a sei- with the participants before the start of the study. An
zure disorder, febrile seizures during childhood, known informed written consent was offered for the parents of
brain lesions, or a history of major head trauma involving the patients participating in the study. The consent con-
loss of consciousness for more than 5 min were excluded tained the name of the study and its aim. It included a
from the study. detailed description of the procedure, the expected ben-
Randomization was conducted and ensured via a com- efits, and the side effects that may result from it. While
puter-based random generation. The sets were generated keeping participants’ identity anonymously, they agreed
by the principal investigator. Participants were allocated to use their data for scientific publication. They were
to the study arms, and they were not aware of which type informed about their right to withdraw from the study at
of rTMS they are going to take, also the outcome asses- any time without revealing the reason.
sors were blinded to the allocation of the participants to All participants were drug naïve for stimulants and
the study groups and to the type of rTMS used, as alloca- non-stimulants, and all other medications were stopped
tion of the participants was done without the knowledge 2 weeks before the beginning of the study. Atomoxetine
of the outcome assessors. was started at 0.5mg/kg/day and was titrated to 1.2 mg/
The official sheet of the Okasha Institute of Psychiatry kg/day after 3 days. Thirty participants were allocated to
was used for the assessment and interview. This included the rTMS group who received 15 sessions of rTMS over
demographic data, personal and family history, medical the right DLPC, in conjunction with Atomoxetine 1.2
history, and mental state examination. All subjects were mg/kg/day. The other 30 participants were allocated to
Nagy et al. Middle East Current Psychiatry (2022) 29:55 Page 4 of 11

the Sham control group who received 15 sessions of sham Children’s Global Assessment Scale (CGAS)
rTMS and atomoxetine 1.2 mg/kg/day. All participants It is a unidimensional assessment of social and psychi-
underwent assessments of the severity of ADHD symp- atric functioning for children aged 4–16. The CGAS’s
toms done at 3 points, before the beginning of treatment score ranges from 1 to 100, with 10-point intervals, that
(pre), after receiving 15 sessions of rTMS/Sham rTMS include descriptors of functioning and psychopathology
(post), and on follow-up 1 month after treatment (FU), for each interval. The single numerical score representing
using the Arabic version of revised-conner’s parent rating the severity of disturbance ranges from 1 (most impaired)
scale long version, Children’s Global Assessment Scale to 100 (healthiest) [23].
and Clinical Global Impression. The scores pre, post, and
follow-up were compared to evaluate the improvement
of clinical symptoms, and the therapeutic effects among Clinical Global Impression CGI
the 2 groups were also compared. The primary outcome Clinical Global Impression Scale is designed to assess the
is defined as an improvement in the severity of ADHD effectiveness of a particular treatment: CGI-S assessing
in the rTMS group more than sham group post rTMS. Illness Severity and CGI-C assessing Global Improve-
The secondary outcome is defined as the improvement ment or Change. Efficacy Index or Therapeutic Response.
of the severity of ADHD in the rTMS group more than CGI—Severity scale (CGI-S): measures illness sever-
the sham group on follow-up 1 month after that rTMS ity at baseline and after treatment on a scale of seven
session. points. CGI—Improvement scale (CGI-I): measures the
Magventure R 30 stimulator was used for rTMS. The improvement in the patient’s condition on treatment
used coil was a 75-mm figure-eight coil and the stimula- from a specific point in time on a scale of 7-point rang-
tion is administered at 10 Hz directed to the right dor- ing from 1 (very much improved) to 7 (very much worse)
solateral prefrontal cortex, located at the F4 location [24].
from the EEG 10-20 system. The pulse intensity was set
at 90% of the observed motor threshold, 4 s on-train, 26 s
off inter-train interval with 2000 pulses per session for 5 Statistical analysis
sessions per week, for 15 sessions total (i.e., 30,000 pulses The statistical package for Social Science (SPSS 25) was
total in treatment course) in the active TMS condition. used to review, code, and arrange the data, as well as
For the sham rTMS, the coil was tilted over the right dor- introduce it to a PC. Data was presented and suitable
solateral pre-frontal cortex without touching the scalp. analysis was done according to the type of data obtained
Participants who received less than 75% of the number of for each parameter. Mixed design ANOVA test was used
sessions (12 sessions) were considered dropouts. to assess the statistical significance of the difference
between the two-study group means at different times.
Mean, standard deviation (± SD), and range for paramet-
Clinical assessments ric numerical data as the studied groups were normally
Clinical assessments and follow-ups were done in the distributed and were justified after assessment of normal-
outpatient clinics of Okasha Institute of Psychiatry Ain ity using the Kolmogorov-Smirnov test, while the median
Shams University. In every clinical assessment, parents and interquartile range (IQR) for non-parametric numer-
of the subjects completed the Arabic version of the Con- ical data. Frequency and percentage of non-numerical
ners’ Parent Rating Scale – Revised Long form (CPRS- data. Student’s T test was used to assess the statistical sig-
R-L), Children’s Global Assessment Scale and Clinical nificance of the difference between the two study group
Global Impression means. Pairwise comparisons were used for comparisons
of all possible pairs of group means. Chi-square test was
used to examine the relationship between two qualitative
Arabic version Conners’ Parent Rating Scale – Revised Long variables. P-value: level of significance, P>0.05: nonsig-
Form nificant (NS) and P< 0.05: significant (S).
CPRS-R The Long Form contains 80 items and was con-
ducted by parents and is reliable for use with children
and adolescents. The form is made of a four-point scale Results
where the parents’ rate how often the child engages in the Participant characteristics
behaviors from 0 (Never) to 3 Very Often. It can be used Table 1 illustrates participant characteristics enrolled
to calculate seven subscales, an ADHD Index, three Con- in the study. Insignificant differences were found
ners’ Global Indices (CGI), and three DSM-IV Symptom between the characteristics of both study groups on all
Indices [21, 22]. parameters.
Nagy et al. Middle East Current Psychiatry (2022) 29:55 Page 5 of 11

Table 1 Participant characteristics

Group Test of significance

Sham (n=30) rTMS (n=30)

N (%) Mean ± SD N (%) Mean ± SD Value p-value Sig.

Sex
Male 22 (73.33%) 24 (80%) X2= 0.373 0.542 NS
Female 8 (26.67%) 6 (20%)
Diagnosis
ADHD hyperactive 5 (16.67%) 5 (16.67%) X2= 1.049 0.592 NS
ADHD inattentive 4 (13.33%) 7 (23.33%)
ADHD combined 21 (70%) 18 (60%)
Age 8.47 ± 1.7 8.7 ± 1.76 t= -0.522 0.604 NS
Student’s t test of significance (t= Student’s t test value)
Chi-square test of significance (X2= chi-square test value)

Baseline clinical assessment with atomoxetine) had a significantly improved ADHD

Table 2 shows the baseline ADHD symptoms severity symptoms from baseline to post rTMS/sham and on
in the 2 groups measured using CPRS-R-L, CGAS, and follow-up. There was a significant main effect of time
CGI, which revealed the presence of significant problems on CGI-S, CGI-I, and CGAS as well as on all CPRS sub
but with no significant difference between the 2 groups. scores, Oppositional, Cognitive, Hyperactive, Anxious
Shy, Psychosomatic, and Social Problems, perfectionism
Comparative results as well as the three Conners’ Global Indices (CGI) and
Comparison of the reduction in severity in ADHD three DSM-IV Symptom Indices.
symptoms and improvement before and after treat- Regarding CPRS-R:L, the rTMS group showed statisti-
ment and between the 2 groups by using mixed-design cally significant improvement more than the Sham rTMS
ANOVA tests, revealed that both groups (rTMS com- group in attention deficit symptoms, measured by cogni-
bined with atomoxetine and Sham rTMS combined tive subscale, DSM IV inattentive, conner ADHD Index

Table 2 Severity of ADHD symptoms measured by CPRS-R-L, CGAS, and CGI-severity

T score rTMS group Mean ± SE Sham group Mean Mean difference P value
score± SE

Oppositional 61.13 ± 0.97 60.8 ± 0.97 0.333 0.808

Cognitive 74.77 ± 1.21 73.77 ± 1.21 1.000 0.562
Hyperactivity 74.13 ± 1.22 73.77 ± 1.22 0.367 0.833
Anxious shy 53.97 ± 0.75 54.57 ± 0.75 −0.600 0.575
Perfectionism 51.93 ± 0.83 52.83 ± 0.83 −0.900 0.446
Social problems 71.9 ± 1.18 70.87 ± 1.18 1.033 0.537
Psychosomatic 60.07 ± 0.85 59.6 ± 0.85 0.467 0.699
DSM Inattentive 74.77 ± 1.21 73.77 ± 1.21 1.000 0.562
DSM hyperactive-Impulsive 74.13 ± 1.22 73.77 ± 1.22 0.367 0.833
DSM Total 75.23 ± 0.74 73.87 ± 0.74 1.367 0.195
Conner’s ADHD Index 74.77 ± 1.21 73.77 ± 1.21 1.000 0.562
Conner’s ADHD global index: restless 74.13 ± 1.23 74.07 ± 1.23 0.067 0.970
impulsive
Global index emotional lability 58.8 ± 0.74 60.1 ± 0.74 1.300 0.216
Conner’s global Index Total 74.53 ± 0.74 73.87 ± 0.74 0.667 0.528
CGAS 42.9 ± 1.04 43.87 ± 1.04 0.033 0.982
CGI-S 5.43 ± 0.12 5.27 ± 0.12 0.17 ± 0.17 0.332
Nagy et al. Middle East Current Psychiatry (2022) 29:55 Page 6 of 11

subscales, and total ADHD symptoms severity, meas- score, F = 550.73, P<0.001, a significant main effect
ured by ADHD IV Total and Conner’s Global Index, Post of group on DSM IV TR inattentive score, F = 5.72,
rTMS, and on follow-up after 1 month. P<0.001.02 and a significant interaction between time
Table 3 and Fig. 2 show a statistically significant lower and group as regards their effect on DSM IV TR inatten-
DSM IV inattentive T scores in the rTMS group than in tive score, F = 62.2, P<0.001.
the Sham group, post rTMS, and on follow-up. There is a Table 4 and Fig. 3 show a statistically significant lower
significant main effect of time on DSM IV TR inattentive DSM IV total T score in the rTMS group than in the

Table 3 Comparing mean DSM IV inattentive T score between the 2 groups at different times
DSM IV TR inattentive pre post FU Pairwise comparisons
Mean ± SE Mean ± SE Mean ± SE Pre vs post Pre vs FU Post vs FU

Sham group, N= 30 73.77 ± 1.21 69.07 ± 0.79 63.2 ± 0.74 −4.7 (<0.001) −10.57 (<0.001) −5.87 (<0.001)
rTMS group, N=30 74.77 ± 1.21 61.57 ± 0.79 60.73 ± 0.74 −13.2 (<0.001) −14.03 (<0.001) −0.83 (0.02)
Pairwise comparisons
Mean difference 1.000 −7.500 −2.467
p value 0.562 <0.001 0.021

Fig. 2 Comparing mean DSM IV inattentive T score between the 2 groups at different times

Table 4 Comparing mean total DSM IV T score between the 2 groups at different times
DSM IV TR total Pre Post FU Pairwise comparisons
Mean ± SE Mean ± SE Mean ± SE Pre vs post Pre vs fu post vs fu

Sham N= 30 73.87 ± 0.74 68.93 ± 0.66 63 ± 0.75 −4.93 (<0.001) −10.87 (<0.001) −5.93 (<0.001)
rTMS N= 30 75.23 ± 0.74 61.83 ± 0.66 61.47 ± 0.65 −13.4 (<0.001) −13.77 (<0.001) −0.37 (0.26)
Pairwise comparisons
Mean difference 1.367 −7.100 −1.53
P value 0.195 <0.001 < 0.001
Nagy et al. Middle East Current Psychiatry (2022) 29:55 Page 7 of 11

Fig. 3 Comparing mean total DSM IV T score between the 2 groups at different times

Sham group, post rTMS, and on follow-up. It shows the between time and group as regards their effect on social
significant main effect of time on DSM IV TR total score, problems score (F = 32.61, P<0.001).
F = 1366.4, P<0.001, the significant main effect of group On the other hand, our results revealed that there is no
on DSM IV TR total score, F = 4.86, P<0.001.031, and a statistically significant difference between rTMS com-
significant interaction between time and group as regards bined with Atomoxetine and Sham rTMS combined with
their effect on DSM IV TR total score, F = 155.19, atomoxetine in oppositional, perfectionism, Anxious Shy,
P<0.001. and psychosomatic symptoms.
Table 5 and Fig. 4 show a statistically significant more Table 6 and Fig. 5 represent a statistically significant
improvement in the rTMS group than sham post rTMS, more improvement in the mean CGAS score in the
but an insignificant difference between the 2 groups on rTMS group than in the Sham group, post rTMS, and on
follow-up after 1 month. There is a significant main effect follow-up. The significant main effect of time on CGAS
of time on DSM IV TR hyperactive-impulsive score (F = score was (F = 381.79, P<0.001), the significant main
515.38, P<0.001), a non-significant main effect of group effect of group was (F = 14.45, P<0.001), and the signifi-
on DSM IV TR hyperactive-impulsive score (F = 3.11, cant interaction between time and group was (F = 41.34,
P<0.001.083) and a significant interaction between time P<0.001).
and group as regards their effect on DSM IV TR hyperac- Regarding CGI-Severity score, there is a significant
tive impulsive score (F = 46.62, P<0.001). main effect of time on CGI-S (F = 744.32, P = <0.001),
Regarding the social problem T score, it showed a simi- a significant main effect of group on CGIS (F = 10.71, P
lar outcome, there was a significant main effect of time on = 0.002), and a significant interaction between time and
social problems score (F = 303.14, P<0.001), a non-signif- group as regards their effect on CGI-S (F = 76.91, P =
icant main effect of group on social problems score (F = <0.001). There is a statistically significant lower sever-
1.22, P<0.001.275), but there is a significant interaction ity score in the rTMS group than the sham group after

Table 5 Comparing mean DSM IV hyperactive-impulsive T score between the 2 groups at different times
DSM IV TR hyperactive Pre Post FU Pairwise comparisons
impulsive
Mean ± SE Mean ± SE Mean ± SE Pre vs post Pre vs FU Post vs FU

Sham N= 30 73.77 ± 1.22 68.5 ± 0.85 62.83 ± 0.77 −5.27 (<0.001) −10.93 (<0.001) −5.67 (<0.001)
rTMS N= 30 74.13 ± 1.22 62.1 ± 0.85 62 ± 0.77 −12.03 (<0.001) −12.13 (<0.001) −0.1 (0.802)
Pairwise comparisons
Mean difference 0.367 −6.400 −0.833
P value 0.833 <0.001 0.445
Nagy et al. Middle East Current Psychiatry (2022) 29:55 Page 8 of 11

Fig. 4 Comparing mean DSM IV hyperactive impulsive T score between the 2 groups at different times

Table 6 Comparing mean Children Global Assessment score between the 2 groups at different times
CGAS Pre Post FU Pairwise comparisons
Mean ± SE Mean ± SE Mean ± SE Pre vs post Pre vs fu Post vs fu

Sham group N= 30 43.87 ± 1.04 49.67 ± 1.57 55.83 ± 1.63 8.8 (<0.001) 19.97 (<0.001) 11.17 (<0.001)
rTMS group N= 30 42.9 ± 1.04 59.8 ± 1.57 63.07 ± 1.63 23.9 (<0.001) 25.17 (<0.001) 1.27 (0.337)
Pairwise comparisons
Mean difference 0.033 15.133 5.233
P value 0.982 <0.001 0.027

treatment and on follow-up. Moreover, the rTMS group symptoms (inattention), total ADHD symptoms sever-
had a statistically significant more improvement in CGI ity, and improving the global functioning of children
improv than the sham group, post rTMS, and on follow- with ADHD.
up. It showed a significant main effect of time on CGII (F To date, there are only six studies on the therapeutic
= 12.72, P = 0.001) and group (F = 39.45, P=<0.001) and effect of rTMS on ADHD that were carried out. Four of
showed a significant interaction between time and group the six studies were undertaken on adults and adoles-
as regards their effect on CGII (F = 41.21, P = <0.001). cents with ADHD, and only 2 studies were conducted on
After comparing the 2 studied groups, the effect size children [16].
post rTMS was P=<0.001, η2 = 0.436 with a power of 1.0; Results of this work are consistent with findings of a
however, this effect size is reduced on follow-up 1 month study conducted on randomized 60 children with ADHD
after last rTMS session to be P=0.021, η2 = 0.088 and into either 30 daily 25-min sessions of 10Hz rTMS over
power 0.65. right DLPFC, Atomoxetine (1.2mg/kg), or combined
treatment over 6 weeks and results showed that rTMS,
Discussion ATX, or rTMS combined with ATX can effectively alle-
The present study revealed that 5 daily sessions/week viate attention deficit, hyperactivity impulse, and oppo-
for 3 weeks of high frequency rTMS over the right sitional defiance in ADHD children and the combined
DLPFC combined with Atomoxetine is an effective therapy showed significant advantages in attention deficit
treatment strategy for children with ADHD. Moreo- and hyperactivity impulse [25].
ver, rTMS combined with atomoxetine is more effec- Cao et al. [17] conducted another study and applied
tive than Atomoxetine alone in improving cognitive rTMS in children with ADHD to measure the changes
Nagy et al. Middle East Current Psychiatry (2022) 29:55 Page 9 of 11

Fig. 5 Comparing mean Children Global Assessment score between the 2 groups at different times

in serum miRNA-let-7 level, after being treated by rTMS as the effect size was reduced on follow-up 1 month after
or atomoxetine, which validated the results of this work. the last rTMS session.
A stimulation protocol similar to our work, but with a Another study proved our results, in which 15 dTMS
higher total number of sessions, was used. Instead of sessions over 3 weeks to the right PFC, left PFC, and
conducting five sessions per week for 3 weeks, this study the sham group was conducted. The study found that
ranged from 6 weeks. High frequency 10 Hz rTMS was increased rDLPFC activation was associated with more
directed to the right DLPFC against sham. The findings symptom improvement in the right stimulation group.
of the mentioned study found a statistically significant This study concluded that dTMS is an effective and fea-
improvement in attention deficit, hyperactivity/impulsiv- sible technique that may improve attention symptoms in
ity, and oppositional defiance symptoms, as measured by adults with ADHD [27].
the SNAP-IV scale. Sham rTMS failed to show improve- Also, the results are in concordance with a case study
ment in ADHD children. on the effects of repetitive transcranial magnetic stimu-
The current study findings are also consistent with lation in the treatment of ADHD, of a 22-year-old male
another open-label tolerability and safety trial in 10 chil- diagnosed with ADHD. The protocol applied was 2 weeks
dren with ADHD. Despite using different rTMS param- of daily rTMS sessions to the right dorsomedial prefron-
eters and without using the sham group showed fewer tal cortex (10 Hz, 3000 pulses, 120% motor threshold) to
teacher-rated inattention and parent-rated hyperactivity/ treat attention deficit, hyperactivity, and impulsivity. One
impulsivity symptoms 1 week after five daily sessions of and 3 months after, assessments at baseline showed an
1Hz-rTMS over left DLPFC compared to baseline [19]. overall improvement, steadily over this follow-up period
Alyagon et al. conducted a randomized sham con- [28]. Furthermore, a significant improvement of ADHD
trolled and active study of 43 young adults with ADHD. symptoms after 4 weeks of treatment was present in Nie-
The results thereof proved the results of this work. They derhofer’s study that consisted of five sessions per week,
tested 15 sessions of 18 Hz-rTMS over 3 weeks, with in which low frequency rTMS (1 Hz) was used, to stimu-
1-month follow-up and maintenance sessions over the late the motor area, using 1200 pulses per session [29].
right prefrontal cortex, targeting DLPFC, and inferior Moreover, another two sham-controlled, double-blind
frontal cortex (IFC), validated the findings of the present crossover studies validated the results of this work.
study. Prior to and after the simulation, a short cognitive In 13 ADHD adults, one session of rTMS delivered at
training session, targeting the right prefrontal cortex. 20Hz directed right DLPFC significantly improved over-
They found improvement of adults’ ADHD symptoms, all ADHD symptoms and inattention compared to the
compared to control groups. The treatment effect size sham group [30]. Weaver et al. also observed a significant
was diminished after 1 month of follow-up [26], and this reduction and improvement in the ADHD IV scale after
was in concordance with the results of the present study delivering 10 sessions of high-frequency rTMS (10 Hz)
directed to the right DLPFC [18].
Nagy et al. Middle East Current Psychiatry (2022) 29:55 Page 10 of 11

Our results were inconsistent with the results of Paz Interquartile range; MRI: Magnetic resonance imaging; NS: Nonsignificant; RCT​
: Randomized clinical trials; rTMS: Repetitive transcranial magnetic stimulation;
et al. [31] in their study of deep rTMS on 26 adults with SCID: Structured Clinical Interview for DSM IV; SD: Standard deviation; VBM:
ADHD. Conducting 20 daily sessions of deep TMS using Voxel-based morphometry.
the bilateral H5 coil directed to the prefrontal at high fre-
Acknowledgements
quency failed to show any significant clinical outcome The staff of the child psychiatry clinic and EEG and rTMS unit in the Institute
between active and sham groups. The inconsistency in of Psychiatry – Ain Shams University Hospitals were cooperative with the
the results between the 2 studies may be due to the differ- research team, and therefore contributed to these findings. The authors would
like to voice their sincere gratitude and utmost appreciation.
ent stimulation protocols, while Paz et al., used bilateral
high-frequency deep TMS stimulation to PFC, our study Authors’ contributions
applied high frequency rTMS stimulation to the right NN proposed the research idea and design. GR contributed to developing the
research idea, study methodology, and editing of the manuscript. SK helped
dorsolateral prefrontal cortex. in developing the study methodology and editing of the manuscript. DA
helped in developing the study methodology, revising the data analysis, and
helped in the interpretation and editing of the manuscript. HE contributed to
Limitations
the design of the study methodology and editing of the manuscript. The data
This study aimed to explore the possible therapeutic role collection and analysis were conducted by Mostafa Shohdy, who wrote the
of repetitive transcranial magnetic stimulation and the final manuscript, that was read and approved by all authors.
effectiveness of combining Atomoxetine and rTMS in
Funding
children with ADHD. However, this work has several lim- This research did not receive any specific grant from funding agencies in any
itations, firstly, the sample size is relatively small, so fur- sector. Even though it had no role in any aspect of the study (design, conduct,
data collection and management, analysis and interpretation), Okasha Insti-
ther studies should be conducted on the larger sample in
tute of Psychiatry provided rTMS with no operating fees. Any other expenses
order to ensure the results; moreover, the study included were borne by the authors.
only unmedicated ADHD without comorbidities which
is not representative to the broad spectrum of presenta- Availability of data and materials
The principal investigator, Mostafa Shohdy, has full access to all data used in
tions of ADHD. Secondly, the absence of guidelines for the study, and can furnish data upon request. The integrity of the data and the
combination therapy including the dose of tests atomox- accuracy of its analysis are the responsibility of M. Shohdy.
etine and the stimulation protocol of rTMS. Thirdly, the
absence of tests to assess executive functions to validate Declarations
our results of clinical improvement of inattention, Finally,
Ethics approval and consent to participate
the follow-up period was relatively short, longer follow- The trial protocol was approved by the Research Ethics Committee (REC) at
up periods up to 6 months to track the long-term effect the Ain Shams University Faculty of Medicine (FMASU REC FWA00017585).
of rTMS. The legal guardians of the patients participating in the study signed a consent
form, after the aim, procedure and expected benefits, possible side effects, as
well as the right to abort the participation in the study at any point, without
Conclusions stating reasons, were clearly explained and outlined to them orally and in writ-
ing. They also approved the use and publishing of their data, anonymously, for
Our results showed that five sessions per week, for 3 scientific publications.
weeks (a total of 15 sessions), of high frequency (10 Hz)
repetitive transcranial magnetic stimulation directed to Competing interests
There is no conflict of interest to the best of the authors’ knowledge.
the right DLPFC combined with atomoxetine is an effica-
cious treatment strategy for children with ADHD. Also, Author details
1
the combined treatment is more effective than using Ato- Neurology and Psychiatry Department, Faculty of Medicine, Okasha Institute
of Psychiatry, Ain Shams University, P.O. box 11657, Cairo, Egypt. 2 Mental
moxetine. The optimum combination of treatment pro- Health Department, School of Medicine, Newgiza University, Giza, Egypt.
tocol and validation of our findings shall be furnished
through further research. This study among others Received: 17 March 2022 Accepted: 27 April 2022

proved the clinical effect of rTMS in ADHD giving hope

for further clinical trials to be conducted in order to pave
the way for the approval of rTMS as a relatively safe tool
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