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2 Transcranial Direct Current Stimulation
29
between stimulation sessions has been demonstrated to be a crucial determinant of the
outcomes during the second period of stimulation. For instance, Monte-Silva and colleagues reported that cathodal tDCS exhibited enhanced lasting inhibitory effects (measured 1–2 h after the second stimulation period) when there was a 24-h separation
between the two periods of stimulation, whereas no such enhancement was observed
with a 3-h interval. Angelo Alonzo and colleagues investigated the impact of daily or
alternate-day tDCS sessions on motor cortical excitability. Their ndings revealed that
administering tDCS on a daily basis resulted in signicantly greater increases in motor
evoked potential (MEP) amplitude compared to an alternate-day schedule over a xed
5-day period. These results suggest that a time interval of 1day falls within the critical
window for consolidative and cumulative excitatory effects, while a 2-day interval lies
outside this crucial period [2].
2.5 Summary and Outlook
In conclusion, tDCS demonstrates immense potential in both basic and clinical
applications as a noninvasive neuromodulation technique and promising therapeutic
tool due to its user-friendly nature, cost-effectiveness, high tolerability, and minimal
disruption to subjects [1]. By modulating membrane potential, cortical excitability,
synaptic plasticity, and cortical functional connectivity, tDCS exerts a signicant
impact on brain function. Moreover, the regulatory effects of tDCS on nonneuronal
cells have further enhanced our understanding of its mechanisms of action within
the brain.
When applying tDCS, it is crucial to consider the impact of stimulation polarity,
duration, and current intensity, as well as electrode placement, in order to meticulously design studies, optimize the efcacy of tDCS applications, and accurately
predict potential responses of clinical populations to this treatment modality.
Additionally, careful consideration must be given to the poststimulation effects of
tDCS when utilizing it.
The future research can prioritize the following two aspects for conducting longterm studies:
1. Personalized tDCS treatments: Variations in brain anatomy and genetic poly-
morphisms have an impact on the efcacy of tDCS treatments [39]. MRI-based
head models offer a limited means to investigate how individual anatomical factors affect the neurophysiological outcomes of tDCS [59].
2. tDCS treatment at home: The therapeutic effects of tDCS necessitate consecutive
daily applications in order to achieve clinically signicant outcomes. To address
the practical challenge of patients having to make repeated visits for treatment, the
exploration of home-based tDCS represents a crucial avenue for future research.
The provision of tDCS treatment at home obviates the necessity for patients to
travel to medical or research facilities for each treatment session [6]. Moreover,
tDCS treatment at home can enhance treatment compliance and facilitate access to
tDCS for patients residing in geographically remote areas [60, 61].
30
Acknowledgments H.S. and X.Z. conceived of the project. J.F., L.Z., and H.S. drafted the manu-
script. All authors approved the nal version of the manuscript for submission.
Disclosure/Conicts of Interest The authors declare no competing interests.
Financial Support This work was supported by grants from the National Natural Science
Foundation of China (Grant Nos. 71942003, 32171080, 32100886, 32161143022, and 32200914);
the Chinese National Programs for Brain Science and Brain-like Intelligence Technology (Grant
No. 2021ZD0202101); the Institute of Health and Medicine, HefeiComprehensive National
Science Center, Global Select Project (Grant No. DJK-LX-2022008); the Open Foundation of the
Institute of Linguistics and Applied Linguistics, Anhui Jianzhu University (YYX2024KF01); the
Open Fund of Key Laboratory of Philosophy and Social Science of Anhui Province on Adolescent
Mental Health and Crisis Intelligence Intervention (SYS2024B01); and also supported by Shanghai
Key Laboratory of Brain-Machine Intelligence for Information Behavior.
J. Fu et al.
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J. Fu et al.
Major Depressive Disorder
TianHongZhang, ZhanMingShi, LingYunZeng,
andJiJunWang
Abstract
Major depressive disorder (MDD) presents a signicant challenge due to its severity
and the limited effectiveness of conventional pharmacological treatments and psychotherapies for many patients. This underscores the need for alternative therapeutic
approaches. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have emerged as promising noninvasive brain stimulation
techniques that address these needs. This chapter systematically reviews the applications of various TMS and tDCS paradigms, including bilateral repeat TMS
(rTMS), accelerated rTMS, deep TMS, priming rTMS, synchronized rTMS, intermittent theta-burst stimulation (iTBS), accelerated iTBS, continuous theta-burst
stimulation (cTBS), bilateral TBS, magnetic seizure therapy, high-denition tDCS,
and a comparison between rTMS and tDCS.By exploring these physical treatment
modalities, the chapter highlights their potential in effectively managing MDD and
offers insights into their respective roles in enhancing patient care.
3
Keywords
rTMS · Deep TMS · Priming rTMS · Synchronized rTMS · iTBS · Accelerated
iTBS · cTBS · Bilateral TBS · MST · tDCS · HD-tDCS · Depression
T. Zhang (*) · J. Wang
Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai
Engineering Research Center of Intelligent Psychological Evaluation and Intervention,
Shanghai Key Laboratory of Psychotic Disorders, Shanghai, People’s Republic of China
Z. Shi
Chongqing Jiangbei Mental Health Center, Chongqing, People’s Republic of China
L. Zeng
Department of Psychiatric Rehabilitation, Shenzhen Kangning Hospital,
ShenZhen, GuangDong, China
© The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2025
W. Zheng, Y. Ning (eds.), TMS and tDCS for Psychiatric Disorders,
https://doi.org/10.1007/978-981-96-8504-2_3
33
34
T. Zhang et al.
Abbreviations
aMST accelerated MST
aTBS accelerated theta burst stimulation
CBT cognitive behavioral therapy
cTBS continuous theta-burst stimulation
DLPFC dorsolateral prefrontal cortex
ECT electroconvulsive therapy
EEG electroencephalogram
FDA Food and Drug Administration
HAMA Hamilton Rating Scale for Anxiety
HAMD Hamilton Rating Scale for Depression
HD-tDCS high-denition tDCS
HF high frequency
iTBS intermittent theta-burst stimulation
LF low frequency
MADRS Montgomery–Asberg Depression Rating Scale
MDD major depressive disorder
MRI magnetic resonance imaging
MST magnetic seizure therapy
MT motor threshold
NNT number needed to treat
OR odds ratio
QEEG quantitative EEG
RCT randomized controlled trial
rTMS repetitive transcranial magnetic stimulation
SNT Stanford Neuromodulation Therapy
tDCS transcranial direct current stimulation
TMS transcranial magnetic stimulation
TRD treatment-resistant depression
RBANS Repeatable Battery for the Assessment of Neuropsychological Status
RUL right unilateral
WHO World Health Organization
3.1 Introduction
Major depressive disorder (MDD) is a group of mental health conditions characterized by persistent low mood, loss of interest, and impaired daily functioning.
Symptoms may include feelings of sadness, fatigue, sleep disturbances, changes in
appetite, difculty concentrating, and lowered self-esteem. These disorders not only
affect emotional well-being but can also impact cognitive processes, behavior, and
physical health. The prevalence of MDD is relatively high, with approximately
3–8% of the global population experiencing major depression at some point in their
lives [1]. Statistical data show that women are generally at a higher risk than men
3 TMS and tDCS for Major Depressive Disorder
35
[2], and both adolescents and the elderly are particularly vulnerable to these conditions [3–5]. In recent years, the incidence of MDD has been rising, highlighting the
need for increased awareness and intervention. The severity of MDD is signicant
and can lead to serious consequences if left untreated. Individuals often experience
debilitating emotional pain, which can result in social isolation, decreased work and
academic performance, and an increased risk of suicide [6]. According to the World
Health Organization (WHO), depression is a leading cause of disability worldwide,
severely impacting individuals’ daily functioning and social capabilities. Research
indicates that individuals with depression may experience a reduction in work performance [7], and the lost productivity was estimated at approximately 28–30 lost
days per year [8]. This impairment signicantly affects their ability to engage in
daily activities and social interactions.
The effectiveness of conventional pharmacological treatments and psychotherapies for MDD is often limited, with many patients experiencing inadequate
responses. For instance, a systematic review by Cipriani etal. [9] found that only
about 50% of patients achieve remission after the rst course of antidepressant therapy, and many do not respond to multiple treatment attempts. Furthermore, a study
indicated that approximately 30% of patients with MDD remain treatment-resistant,
highlighting the urgent need for alternative therapeutic options [9]. Additionally, a
meta-analysis revealed that cognitive behavioral therapy (CBT), while effective for
some, has a response rate of only about 40–60% in clinical settings, suggesting that
a signicant proportion of patients may not benet from standard psychological
interventions [10]. These limitations underscore the necessity for innovative treatments such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) to address the unmet needs of individuals suffering
from MDD.
Repetitive TMS (rTMS) is a technique approved by the U.S.Food and Drug
Administration (FDA) for the treatment-resistant depression (TRD). Conventional
rTMS involves high frequency (HF) to the left dorsolateral prefrontal cortex
(DLPFC) and low frequency (LF) to the right DLPFC.However, not all depressed
patients could benet from standard rTMS protocols. A meta-analysis showed that
patients who received HF rTMS to the left DLPFC had an average response rate of
29.3% [11]. LF rTMS to the right DLPFC had similar therapeutic effects to HF
DLPFC [12]. Therefore, newer forms of rTMS paradigms are warranted to improve
antidepressant response and remission rates in patients with depression, especially
those who are refractory to adequate antidepressant trials. In this chapter, we review
the efcacy and safety of conventional and newer forms of rTMS and tDCS paradigms, including bilateral rTMS, accelerated rTMS, deep TMS, priming TMS, synchronized TMS, intermittent theta burst stimulation (iTBS), accelerated iTBS,
continuation TBS, bilateral TBS, magnetic seizure therapy (MST), high-denition
tDCS (HD-tDCS), and a comparison between rTMS and tDCS.Bilateral rTMS is
dened as LF stimulation of the right DLPFC in addition to HF stimulation of the
left DLPFC.Accelerated rTMS and accelerated iTBS is dened as more than one
rTMS or iTBS session per day. Deep TMS is dened as a specialized (H) coil that
is more precise and allows deeper stimulation through brief magnetic pulses that
36
induce targeted neuronal depolarization in the cerebral cortex. Priming rTMS is
dened as a specic protocol in which a brief period of low-intensity high-frequency
TMS (“priming stimulation”) is performed rst, followed by the main treatment of
low-frequency right DLPFC rTMS.Synchronized rTMS is dened as the use of
rotating spherical neodymium magnets placed along the midline of the scalp to
deliver low-eld sinusoidal waveform stimulation that is synchronized to an individual’s alpha electroencephalogram (EEG) frequency. Continuous TBS (cTBS) is
dened as a 40-s train of uninterrupted TBS.Bilateral TBS was administered with
right-side continuation followed by FDA-approved left-side iTBS.MST is dened
as the use of magnetic elds to induce a generalized seizure. HD-tDCS was delivered using the 1×1 tDCS low-intensity stimulator with a 4×1 adapter. In the context of depression treatment, several studies have aimed to replace LF-rTMS with
continuous TBS delivered to the right DLPFC or HF-rTMS with iTBS delivered to
the left DLPFC [13]. Currently, the FDA has approved the deep rTMS and iTBS
device for the treatment of TRD patients.
T. Zhang et al.
3.2 TMS
3.2.1 rTMS
3.2.1.1 Unilateral rTMS
Efficacy
MDD presents a complex landscape of symptoms and treatment responses, making
it a challenging condition to manage. A signicant portion of patients, estimated at
30–50%, fail to achieve sufcient relief from rst-line treatments, which typically
include a combination of antidepressant medications and CBT [14]. Conventional
antidepressants primarily target neurotransmitter systems such as serotonin, norepinephrine, and dopamine, but their effectiveness can vary greatly among individuals.
While large-scale meta-analyses indicate that these medications are generally more
effective than placebos, the overall impact is relatively modest, with an effect size
around 0.3 [9].
TRD, characterized by a lack of response to at least two consecutive antidepressant trials at appropriate doses over a period of 4–6weeks, poses a signicant public
health challenge. Patients with TRD often experience greater functional impairments and an elevated risk of suicide. Although recent FDA approvals of treatments
like esketamine provide new options for TRD, there remains a pressing need for
effective treatments that act quickly. TMS offers a noninvasive alternative that has
shown promise in addressing these gaps, providing a viable option for patients who
have not responded to traditional therapies.
Conventional rTMS therapy, particularly at 10 and 1Hz, has demonstrated signicant efcacy in treating depression. HF (10Hz) stimulation is applied to the left
DLPFC, enhancing neural activity and improving mood states. Numerous studies
indicate that patients often experience marked reductions in depressive symptoms
3 TMS and tDCS for Major Depressive Disorder
37
and improvements in overall functioning following treatment. Conversely, LF
(1 Hz) stimulation targets the right prefrontal cortex to inhibit excessive neural
activity, making it suitable for certain TRD cases.
The effectiveness of conventional rTMS for treating MDD has been thoroughly
investigated, particularly regarding its acute antidepressant effects when applied to
the DLPFC.A systematic review and meta-analysis [11] encompassing 29 randomized controlled trials (RCTs) with 1371 participants demonstrated a signicant
pooled odds ratio (OR) of 3.3 for treatment response. Additionally, the analysis
revealed an OR of 3.3 for remission, indicating a robust efcacy of rTMS in alleviating depressive symptoms.
Further validation comes from another meta-analysis of 16 double-Blind parallel-design RCTs [15], which compared HF rTMS to sham treatments, yielding a
signicant effect size (Cohen’s d) of −0.55 (95% CI, −0.75 to −0.35) for its antidepressant effects. These ndings underscore the potential of rTMS as an effective
intervention for patients with depression, particularly those who have not responded
adequately to antidepressants.
Two multicenter RCTs have specically focused on rTMS treatment in patients
with MDD who were not on antidepressant medications. The rst study, sponsored
by industry, reported a 24% response rate and a 17% remission rate with active
rTMS, compared to 15% and 8%, respectively, for sham rTMS [16]. The second
study, funded by the National Institute of Mental Health, found a 15% response rate
and 14% remission rate with active treatment, contrasting with a mere 5% response
and remission rate for the sham group [17].
The recent systematic review and network meta-analysis [18] provides compelling evidence for the efcacy of HF-rTMS in treating TRD.Their analysis,
which encompasses numerous prospective RCTs, found that HF-rTMS signicantly increases the odds of response compared to sham treatments, with an OR
of 3.07 (95% CI: 2.24–4.21). This substantial effect size indicates that the benets of HF-rTMS are unlikely to be inuenced by confounding factors or biases.
Several critical aspects of this meta-analysis counter the criticisms regarding
HF-rTMS’s efcacy. First, the studies included were all prospective RCTs,
which typically ensure a balanced representation of both observed and unobserved covariates. Second, the narrow condence intervals around the OR indicate a high level of precision in the estimated treatment effect. Additionally,
multiple sensitivity analyses conducted within the review consistently supported the primary ndings, reinforcing the robustness of the results. Although
not every rTMS trial demonstrated statistically signicant superiority over sham
treatments, this may be attributed to the complexities of treating highly comorbid populations or instances of Type II error. Overall, these ndings advocate
for the consideration of HF-rTMS as a viable and effective option for individuals suffering from TRD.
Overall, while rTMS demonstrates medium-range efcacy, there is ongoing
research into optimizing treatment parameters and combining rTMS with other
therapeutic approaches to enhance its effectiveness further. However, individual
variability in treatment response is noteworthy, as some patients may not achieve
38
T. Zhang et al.
the desired improvements. This underscores the need for personalized treatment
plans and ongoing research to optimize the application of rTMS in depression
management.
Our previous study involved a naturalistic approach to assess the efcacy of addon rTMS in treating depressive and anxiety symptoms, focusing on a sample of 117
patients, including 42 adolescents and 75 adults [19]. All participants had mood or
anxiety disorders and received at least 10 sessions of rTMS targeting the left DLPFC
at a frequency of 10Hz. The outcomes were measured using the Hamilton Rating
Scale for Depression (HAMD) and the Hamilton Rating Scale for Anxiety (HAMA)
at baseline, after 10 sessions, and during follow-up at 2 and 4weeks. The results
demonstrated a signicantly higher response rate in adolescents, with a notable percentage of patients achieving remission compared to their adult counterparts.
This study highlights the signicant efcacy of add-on rTMS in treating depressive and anxiety symptoms specically in adolescents, suggesting that this population experiences greater clinical improvement compared to adults. This underscores
the potential of rTMS as a valuable therapeutic option for young patients, particularly when conventional pharmacological treatments may be less effective or carry
greater risks. The results support the notion that rTMS could serve as a promising
alternative or adjunctive treatment for adolescents facing mood and anxiety disorders. Given the limitations of current pharmacological approaches, including low
remission rates and concerns about adverse effects, rTMS offers a safe and effective
option that can be integrated into treatment plans for young patients. The demonstrated benets in symptom reduction and overall improvement in mental health
underscore the importance of considering rTMS as a viable treatment strategy in
clinical practice for this vulnerable population.
Another study investigated the efcacy of adjunct rTMS in elderly patients with
acute depressive episodes. A total of 114 inpatients were included, with 54in the
elderly group (aged ≥60) and 60in the adult group (aged 18–59) [20, 21]. All participants had a baseline HAMD score of ≥14 and were drug-free for at least 2weeks
prior to enrollment. After 4weeks of rTMS treatment, the remission rate in the
elderly group was 36%, compared to 68% in the adult group. Although the remission rate was lower in the elderly, the response rates were similar, at 77% for the
elderly and 91% for adults. These ndings suggest that rTMS is effective in improving depressive symptoms in elderly patients.
The results highlight the potential value of rTMS for treating depression in older
adults, particularly given the increased risk of adverse effects and drug interactions
associated with traditional pharmacotherapy in this population. As a noninvasive
treatment option, rTMS demonstrated good tolerability and signicantly reduced
depressive symptoms without increasing the risk of serious adverse events. This
suggests that rTMS could serve as a valuable adjunctive treatment for elderly
patients experiencing acute depressive episodes, offering a promising alternative for
rapid intervention. Future research should further explore its long-term effectiveness and adaptability across diverse patient backgrounds.