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Effects of non-invasive brain stimulation in children and young people with psychiatric disorders: a protocol for a systematic review

Abstract

Background

Most psychiatric disorders have their onset in childhood or adolescence, and if not fully treated have the potential for causing life-long psycho-social and physical sequelae. Effective psychotherapeutic and medication treatments exist, but a significant proportion of children and young people do not make a full recovery. Thus, novel, safe, brain-based alternatives or adjuncts to conventional treatments are needed. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are non-invasive brain stimulation (NIBS) techniques which have shown clinical benefits in adult psychiatric conditions. However, in children and young people their efficacy is not well established. The objective of this study will be to systematically evaluate the evidence on clinical effects of NIBS in children and young people with psychiatric disorders, assessing disorder-specific symptoms, mood and neurocognitive functions.

Methods

We designed and registered a study protocol for a systematic review. We will include randomised and non-randomised controlled trials and observational studies (e.g. cohort, case-control, case series) assessing the effects of NIBS in children and young people (aged ≤ 24 years old) for psychiatric disorders. The primary outcome will be reduction of disorder-specific symptoms. Secondary outcomes will include effects on mood and cognition. A comprehensive search from database inception onwards will be conducted in MEDLINE, EMBASE and PsycINFO. Grey literature will be identified through searching multiple clinical trial registries. Two reviewers will independently screen all citations, full-text articles and abstract data. The methodological quality of the studies will be appraised using appropriate tools. We will provide a narrative synthesis of the evidence and according to heterogeneity will conduct an appropriate meta-analysis. Additional analyses will be conducted to explore the potential sources of heterogeneity.

Discussion

This systematic review will provide a broad and comprehensive evaluation of the evidence on clinical effects of NIBS in children and young people with psychiatric disorders. Our findings will be reported according to the PRISMA guidelines and will be of interest to multiple audiences (including patients, researchers, healthcare professionals and policy-makers). Results will be published in a peer-reviewed journal.

Systematic review registration

PROSPERO CRD42019158957

Peer Review reports

Background

Mental health disorders affect 10–20% of the child and adolescent population [1]. In a recent population-based survey, one in eight (12.8%) 5- to 19-year olds in England was found to have at least one mental disorder [2]. In a large multi-national self-report survey initiated by the World Health Organisation (WHO), a third of first-year university students screened positive for one of the major anxiety, mood or substance disorders [3]. Importantly, 50% of all adult mental health disorders emerge before 14 years of age and 75% by 25 years [4]. Thus, the disease burden of such disorders, starting from childhood into emerging adulthood, is considerable in earlier as well as later decades of life, with protracted adverse outcomes in educational attainment, employment, physical health and social functioning [1, 5, 6].

The appearance of psychiatric disorders during childhood/adolescence coincides with significant neurodevelopmental processes identified by longitudinal neuroimaging studies [7]. These include a general decrease in grey matter volume from a childhood peak an increase in white matter volume, alongside a reported imbalance between the dominant limbic and reward systems which develop first, and the executive prefrontal system which matures later [8,9,10]. These processes continue until the early-mid 20s [11, 12], in accordance with the more extensive and psychosocially based definitions of adolescence and emerging adulthood [13, 14]. Neurobiological dynamics, and the limbic-executive maturation gap in particular, have been proposed to contribute to the vulnerability to psychopathology [15], although further study is warranted [16].

The importance of early detection and intervention is supported by the evident neuroplasticity of the adolescent brain (which provides a window for impacting development [17]) and by clinical studies showing that early intervention improves outcome, e.g. in psychosis [18] and in eating disorders [19, 20]. Treatment guidelines for psychiatric disorders in children and young people focus on psycho-social interventions (including psychotherapies) and psychopharmacological treatments [21]. However, outcomes are variable, and only partially meet existing needs. While psychotherapy for children and young people has shown significant benefits in research trials [22], effects are considerably diminished in routine clinical settings [23]. Pharmacotherapy for children and young people is not well-established for many disorders [24], and adult-approved pharmacological treatments are often given “off-label” with little supportive evidence [25]. There are also significant unresolved concerns over the safety of pharmacotherapy in children and young people [26]. Given the limitations of current treatment modalities for psychiatric disorders in children and young people, researchers are highlighting the need for novel biotherapies that can be used safely, as additions or alternatives to established, conventional interventions in youth mental health [27].

Transcranial magnetic stimulation (TMS) is a non-invasive procedure used to modulate cortical excitability in target brain regions: it is generally considered to be safe [28]. In TMS, an electromagnetic coil is used to generate a magnetic field that passes through the skull and induces a current in the underlying neural tissue, which depolarises neurones [29]. Single- and paired-pulse TMS can temporarily affect motor, sensory or cognitive behaviour [30] and repetitive TMS (rTMS) can induce changes in neural activity that outlast the rTMS train [31] with more durable changes reported when rTMS is given daily for 1–6 weeks [32].

A widely accepted mechanism for rTMS- and theta burst stimulation (TBS)-induced changes in synaptic efficacy is the long-term potentiation/depression (LTP/LTD) of excitatory synaptic transmission [33]. Indeed, findings have shown that rTMS and TBS in adults can be effective in improving symptoms in neuropsychiatric disorders associated with cerebral hyper- or hypo-excitability, including schizophrenia [34,35,36], eating disorders [37] and obsessive-compulsive disorder [38, 39]. Evidence in major depressive disorder (MDD) is the most established [40, 41] and has been incorporated into clinical guidelines [42, 43]. Pooled analyses of rTMS trials identified young age as a predictor for higher efficacy of rTMS in depression [44] and for auditory hallucinations in schizophrenia [45].

In children and young people, preliminary results indicate benefits of rTMS in treatment-resistant depression [46,47,48], attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) [49, 50]. For example, Hett et al. [48] found that all 14 studies included in the review reported that rTMS had some effect at reducing symptoms of depression in adolescents. Additionally, Masuda et al. [49], suggested that rTMS may ameliorate ASD symptoms (e.g. lethargy) that conventional treatments have failed to address. However, the absence of sham-controlled randomised trials and lack of rigorous treatment protocols is consistently noted in systematic reviews. Systematic reviews suggest that the safety profile of rTMS is comparable to that found in adults, with most adverse events being mild and overall uncommon [51, 52].

Transcranial direct current stimulation (tDCS) is another well-established non-invasive neuromodulation technique. It involves application of a constant weak direct current via electrodes placed on the scalp [53]. The current applied is subthreshold and unlike rTMS, it cannot induce neuronal firing, but rather modulates existing neuronal activity by changing excitability and discharge, i.e. it is affected by brain activity at the time of the stimulation [54]. Generally, cathodal stimulation results in decreased cortical excitability whereas anodal stimulation increases it [55]. Due to the relative ease of use and its safety, it has been studied extensively as a means of cognitive enhancement and behavioural modulation [53], as well for clinical therapeutic effects across psychiatric/neurological disorders [56].

Previous reviews have looked at the application of tDCS across psychiatric disorders in adults [57,58,59]: beneficial effects have been demonstrated in depression and schizophrenia in particular, as well as the absence of serious adverse events. An evidence-based analysis of clinical trials until 2016 by the European Chapter of the International Federation of Clinical Neurophysiology, found ‘probable efficacy’ in fibromyalgia, non-resistant depression and craving/addiction [56].

With regard to paediatric populations, a systematic review by Buchanan et al. [60], found that overall the safety evidence appears to be strong and consistent for 10- to 20-min tDCS sessions ranging from 0.5 to 2 mA in ages 5–18. These findings are in keeping with previous reviews, including Muszkat et al. [61] who identified six studies of tDCS in children and adolescents with psychiatric disorders. The authors concluded that the technique may be well tolerated and safe but that efficacy could not be established. A later more comprehensive review by Palm et al. [62] included studies on neurological and psychiatric disorders and found positive clinical effects in ADHD and ASD. They also emphasised the dearth of data for tDCS treatment of other psychiatric disorders in children and adolescents, particularly for depression and schizophrenia. More recent narrative reviews [63, 64] have reported similar conclusions, emphasising the rapid expansion of research, with over a dozen registered trials in ClinicalTrials.gov and several completed unpublished trial, but without giving further details on these. Thus, emerging study data are anticipated.

In summary, systematic reviews are available that have examined the safety profile of rTMS and tDCS in children and adolescents [51, 52]. Other reviews have summarised clinical efficacy in psychiatric conditions but have not followed rigorous methodology for systematic reviews [64, 65], require updating [61] or have focused exclusively on a specific condition [47, 49]. Furthermore, available reviews have not included unpublished data. As this is a rapidly developing field, relevant to clinicians and researchers, a broad, up-to-date systematic review encompassing published and unpublished data is required. Our primary aim is to examine the disorder-specific effects of rTMS and tDCS as therapeutic interventions in the treatment of different psychiatric disorders in children and young people. Our secondary aim is to assess broader effects of these interventions on mood and cognitive functioning in children and young people with mental health problems. Lastly, we will review application methods for both techniques such as coil modalities and stimulation parameters, in order to synthesise data on available efficacious and safe rTMS and tDCS protocols.

Objectives

This study will systematically review available data on past, ongoing and upcoming studies using rTMS or tDCS as a therapeutic intervention in children and young people (age ≤ 24 years), with psychiatric disorders. The age range is extended to 24 years as continued neurodevelopment occurs until the mid-20s, particularly in fronto-limbic systems [66, 67]. This review will address the following questions:

  1. 1.

    What are the effects of rTMS and tDCS on disorder-specific symptoms in children and young people with different psychiatric disorders?

  2. 2.

    In children and young people with disorders other than mood disorders, what are the effects of rTMS and tDCS on mood?

  3. 3.

    What are the effects of rTMS and tDCS on neurocognition in this population?

  4. 4.

    What stimulation parameters have been used in rTMS and tDCS administration and how have these affected results?

  5. 5.

    What populations and stimulation parameters methods are being used in ongoing studies?

Methods

The present study protocol is being reported in accordance with the reporting guidance provided in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement [68] (see PRISMA-P checklist in Additional file 1). This protocol has been registered within the International Prospective Register of Systematic Reviews (PROSPERO) database (registration ID CRD42019158957). Any amendments made to this protocol when conducting the study will be outlined in PROSPERO and reported in the final manuscript. The proposed systematic review and meta-analysis will be reported in accordance with the reporting guidance provided in the PRISMA statement [69].

Eligibility criteria

Studies will be included according to the following criteria: participants, interventions and comparators, outcome(s) of interest and study design.

Participants

We will include studies involving children and young people (aged ≤ 24 years old) with all major psychiatric disorders typically affecting this age group. Eligible psychiatric disorders (ICD-10 code) will be autism spectrum disorder (F84), attention deficit hyperactivity disorder (F90), conduct disorders (F91), impulse control disorders (F63), schizophrenia (F20), bipolar disorder (F31), depression (F32 and F33), anxiety disorders (F40 and F41), obsessive-compulsive disorder (F42), tic disorders (F95), posttraumatic stress disorder (F43), substance abuse disorder (F10–F19), somatoform disorders (F45), eating disorders (F50) and personality disorders (F60). We will exclude studies in non-clinical populations.

Interventions

Multiple session (sessions ≥ 2) studies using tDCS and rTMS for a clinical purpose will be included. For rTMS studies, we will include all variants of rTMS administered, including low-frequency rTMS (LF-rTMS), high-frequency rTMS (HF-rTMS), intermittent theta burst stimulation (iTBS), continuous theta burst stimulation (cTBS), paired associative stimulation (PAS), repetitive paired-pulse stimulation (PPS) or quadripulse stimulation (QPS).

Comparators

Sham stimulation or treatment as usual. For some reports there may be no comparison (open-label trials, case reports, case series).

Outcomes of interest

The primary outcome will be disorder-specific clinical outcomes, as measured by a standardised assessment tool pre-and post-intervention, e.g., the Positive and Negative Syndrome Scale (PANNS) for schizophrenia or described narratively. Secondary outcomes will be (1) change in mood as measured by a standardised assessment tool pre- and post-intervention, e.g., Hamilton Depression Rating Scale (HDRS); (2) change in neurocognitive functioning, e.g., Iowa Gambling Task (IGT); and (3) reported adverse outcomes including side effects.

Study design

We will consider randomised controlled trials, non-randomised control trials, open-label trials, crossover trials, cohort, case-control, case series and case reports.

Only studies published in English will be included. No limitations will be imposed on publication status (unpublished studies will be eligible for inclusion) or study conduct period.

Information sources and search strategy

The primary source of literature will be a structured search of electronic databases (from their inception onwards): MEDLINE, EMBASE and PsycINFO. The secondary source of potentially relevant material will be a search of clinical trial registries including the WHO International Clinical Trials Registry Platform (ICTRP) registry, ClinicalTrials.gov, the National Institute of Health (NIH) registry, the European Union Clinical Trials Register and the International Standard Randomised Controlled Trials Number (ISRCTN) registry. We will perform hand-searching of the reference lists of included studies and relevant reviews. The literature searches will be designed and conducted by the review team with the assistance of an experienced health information specialist. Our main literature search will be peer-reviewed by a senior health information specialist using the Peer Review of Electronic Search Strategies (PRESS) checklist [70]. The search will include a broad range of terms and keywords related to children and young people, psychiatric disorders and non-invasive brain stimulation (NIBS). A draft search strategy for MEDLINE is provided in Additional file 2.

Study selection

All articles yielded by the searches will be uploaded on to Rayyan QCRI web application which will be used for the selection process [71]. Two authors will independently screen all titles and abstracts for inclusion criteria. If eligibility cannot be ascertained from the title or abstract, the full text will be examined. Any disagreement regarding the included articles will be resolved through discussion, and if necessary, a third reviewer from the team will be consulted. After the initial screening, duplicates will be removed and the remaining articles will be reviewed in full-text form for inclusion and data extraction. Documentation regarding the source of article (database/trial registry/manual reference check), its inclusion or exclusion and the reasoning will be recorded and presented in the PRISMA flowchart.

Data extraction

Two authors will extract data independently and in duplicate from the included articles, using a purpose-developed form adapted from the Cochrane data collection form for intervention reviews [72] (see Additional file 3). This form was piloted on several papers obtained from a preliminary search. The extracted data will be recorded in spreadsheets using Excel software. Extracted data will include the following items:

  • Study characteristics. Title, reference citation, publication type, language of publication, study design and a priori sample size calculation

  • Participants/population. Number of participants, age, gender, ethnicity, inclusion/exclusion criteria, main disorder, treatment setting, severity of illness, co-morbidities and subgroup division (e.g., according to age or disorder subtype like attention deficit disorder with and without hyperactivity)

  • Intervention. Concomitant treatments participants received during intervention, e.g. medication or psychotherapy, brain-manipulation during stimulation, e.g. cognitive or other task which may have been completed during stimulation

  • rTMS. Type of rTMS used, coil type, site of stimulation, neuro-navigation use, stimulation intensity, session duration and frequency, total number of sessions and compliance with rTMS regimen

  • tDCS. Stimulation electrode location, current intensity and duration, session number and frequency and total number of sessions

  • Comparators. Sham, treatment as usual, waitlist and no comparison

  • Outcomes. Dropout, main disorder-specific assessment tool and results, mood assessment tool and outcome, cognitive assessment tool and outcomes and adverse effects reported

Risk of bias in individual studies

Risk of bias will be evaluated using the Cochrane risk of bias 2.0 tool (RoB 2.0) in randomised controlled trials [73], the Cochrane tool for risk of bias in non-randomised studies of interventions (ROBINS-I) in non-randomised studies [74] and the Newcastle-Ottawa Scale (NOS) to assess the quality of cohort and case-control studies [75]. Two reviewers will complete assessments independently for our primary and secondary outcomes of interest across studies. Disagreements will be resolved by discussion and the assessment of a third reviewer, if consensus is not reached. The results from these quality assessments will be detailed in the summary of findings table.

Data synthesis

A narrative synthesis method will first be used to describe the results of the systematic review. All eligible trials will be summarised in narrative form, and summary of findings tables will be organised according to (a) type of intervention used (i.e. rTMS or tDCS) and (b) disorder. These tables will include key study characteristics (study design, population and intervention parameters, disorder-specific symptoms, mood and neurocognition outcomes). Population and stimulation parameter details for ongoing treatment trials will be detailed in a separate table according to (a) type of intervention being used (i.e. rTMS or tDCS) and (b) disorder.

Then, where possible, meta-analysis methods will be applied. We will use Revman 5.3 software to synthesise and analyse all outcome data. We will use tau-squared and the I2 test to quantify the statistical heterogeneity between studies examining our outcomes of interest, with I2 values of 25%, 50% and 75% representing low, medium and high heterogeneity, respectively [76]. If feasible and appropriate, outcome data will be used to perform random effects meta-analyses because of heterogeneity is expected a priori. The random effects model assumes the study level effect estimates follow a normal distribution, considering both within-study and between-study variation.

Subgroup analyses

We will carry out subgroup analyses to test the sources of heterogeneity based on disorder type, intervention type (rTMS or tDCS), study design (e.g., randomised controlled trial or non-randomised controlled trial), intervention duration (number of sessions), illness duration and concomitant treatment (that is, medication, psychological treatment, behavioural treatment or cognitive training).

Sensitivity analyses

Potential reasons for heterogeneity will be explored in sensitivity analyses; the pre-specified subgroup analyses, if feasible, will be examined to determine potential reasons for any observed statistical heterogeneity.

Meta-bias and strength of evidence

In order to assess for publication bias, we will use our clinical trials registry search to identify trial protocols which have not published their results and compare published results to their protocols where available. The overall quality of evidence for all outcomes will be evaluated using the Grading, Recommendations, Assessment, Development and Evaluation (GRADE) framework [77], estimating individual risk of bias, meta-bias, precision, consistency, directedness and the magnitude of effect. These indicators will determine the certainty of the estimated effect, which will be rated as either very low, low, high or very high.

Discussion

In this review, we aim to synthesise the findings of studies addressing the effects of rTMS and tDCS on clinical outcomes in children and young people with psychiatric disorders. It will be based on eligible published studies from inception to present and will allow us to assess study quality and analyse outcome data. It will also provide information on ongoing trials and relevant unpublished studies. Anticipated limitations include the paucity of high-quality trials and insufficient homogeneity of data to perform quantitative analysis. The findings may have valuable implications for multiple stakeholders including patients, health care professionals, health system decision-makers and researchers working in non-invasive brain stimulation. The use of our expected findings by healthcare professionals could contribute to making informed decisions about the choice of therapy. For the research implications, our expected findings could generate relevant research questions related to using NIBS in children and young people with psychiatric disorders.

We plan to disseminate our findings to different audiences including young people and parents of young people with psychiatric disorders, healthcare professionals, researchers and health system decision-makers working in Children and Adolescent Mental Health Services. As we are a clinical academic research group, we have close contact with patient advocacy groups who will be engaged in every step of the dissemination process. The dissemination of our work will consist of publishing our review papers in a peer-reviewed journal, presenting at national and international conferences in the domain of non-invasive brain stimulation and youth mental health and circulating our findings (in plain English) on media networks (e.g. LinkedIn and Twitter).

Availability of data and materials

Not applicable.

Abbreviations

rTMS:

Repetitive transcranial magnetic stimulation

tDCS:

Transcranial direct current stimulation

NIBS:

Non-invasive brain stimulation

PRISMA:

Preferred reporting items for systematic review and meta-analysis

WHO:

World Health Organisation

TMS:

Transcranial magnetic stimulation

LTP:

Long-term potentiation

LTD:

Long-term depression

TBS:

Intermittent theta burst stimulation

MDD:

Major depressive disorder

ADHD:

Attention deficit hyperactivity disorder

ASD:

Autism spectrum disorder

LF-rTMS:

Low-frequency repetitive transcranial magnetic stimulation

HF-rTMS:

High-frequency repetitive transcranial magnetic stimulation

iTBS:

Intermittent theta burst stimulation

cTBS:

Continuous theta burst stimulation

PAS:

Paired associative stimulation

PPS:

Paired-pulse stimulation

QPS:

Quadripulse stimulation

PANNS:

Positive and Negative Syndrome Scale

HDRS:

Hamilton Depression Rating Scale

IGT:

Iowa Gambling Test

ICTRP:

International Clinical Trials Registry Platform

NIH:

National Institute of Health

ISRCTN:

International Standard Randomised Controlled Trials Number

PRESS:

Peer Review of Electronic Search Strategies

RoB 2.0:

Risk of Bias 2.0

ROBINS-I:

Risk of Bias in Non-randomised Studies of Interventions

NOS:

Newcastle-Ottawa Scale

GRADE:

Grading, Recommendations, Assessment, Development and Evaluation

References

  1. 1.

    Kieling C, Baker-Henningham H, Belfer M, Conti G, Ertem I, Omigbodun O, et al. Child and adolescent mental health worldwide: evidence for action. Lancet. 2011;378(9801):1515–25 Available from: https://doi.org/10.1016/S0140-6736(11)60827-1.

    Article  Google Scholar 

  2. 2.

    Sadler K, Vizard T, Ford T, Marcheselli F, Pearce N, Mandalia D, et al. Mental health of children and young people in England, 2017: summary of key findings. Community. 2018.

  3. 3.

    Auerbach RP, Mortier P, Bruffaerts R, Alonso J, Benjet C, Cuijpers P, Demyttenaere K, Ebert DD, Green JG, Hasking P, Murray E, Nock MK, Pinder-Amaker S, Sampson NA, Stein DJ, Vilagut G, Zaslavsky AM, Kessler RC, WHO WMH-ICS Collaborators. WHO world mental health surveys international college student project: prevalence and distribution of mental disorders. J Abnorm Psychol. 2018;127(7):623–38. https://doi.org/10.1037/abn0000362.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Kessler RC, Adler L, Ames M, Demler O, Faraone S, Hiripi E, et al. The World Health Organization Adult ADHD Self-Report Scale (ASRS): a short screening scale for use in the general population. Psychol Med. 2005;35(2):245–56. https://doi.org/10.1017/S0033291704002892.

    Article  PubMed  Google Scholar 

  5. 5.

    Costello EJ, Egger H, Angold A. 10-Year research update review: The epidemiology of child and adolescent psychiatric disorders: I. Methods and public health burden. J Am Acad Child Adolesc Psychiatry. 2005;44(10):972–86 Available from: https://doi.org/10.1097/01.chi.0000172552.41596.6f.

    Article  Google Scholar 

  6. 6.

    Costello EJ, Maughan B. Annual research review: optimal outcomes of child and adolescent mental illness. J Child Psychol Psychiatry Allied Discip. 2015;56(3):324–41. https://doi.org/10.1111/jcpp.12371.

    Article  Google Scholar 

  7. 7.

    Paus T, Keshavan M, Giedd JN. Why do many psychiatric disorders emerge during adolescence? Nat Rev Neurosci. 2008;9(12):947–57. https://doi.org/10.1038/nrn2513.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Giedd JN. The teen brain: insights from neuroimaging. J Adolesc Health. 2008;42(4):335–43. https://doi.org/10.1016/j.jadohealth.2008.01.007.

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Giedd JN, Lalonde FM, Celano MJ, White SL, Wallace GL, Lee NR, et al. Anatomical brain magnetic resonance imaging of typically developing children and adolescents. J Am Acad Child Adolesc Psychiatry. 2009;48(5):465–70 Available from: https://doi.org/10.1097/CHI.0b013e31819f2715.

    Article  Google Scholar 

  10. 10.

    Konrad K, Firk C, Uhlhaas PJ. Brain development during adolescence: neuroscientific insights into this developmental period. Dtsch Arztebl Int. 2013;110(25):425–31. https://doi.org/10.3238/arztebl.2013.0425.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Tamnes C, Ostby Y, Fjell A, Westlye L, Due-Tonnessen P, Walhovd K. Brain maturation in adolescence and young adulthood: regional age-related changes in cortical thickness and white matter volume and microstructure. Cereb Cortex. 2009;20(3):534–48. https://doi.org/10.1093/cercor/bhp118.

    Article  PubMed  Google Scholar 

  12. 12.

    Mills KL, Goddings AL, Herting MM, Meuwese R, Blakemore SJ, Crone EA, Dahl RE, Güroğlu B, Raznahan A, Sowell ER, Tamnes CK. Structural brain development between childhood and adulthood: convergence across four longitudinal samples. Neuroimage. 2016;141:273–81. https://doi.org/10.1016/j.neuroimage.2016.07.044.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Curtis AC. Journal of Adolescent and Family Health: defining adolescence. J Adolesc Fam Heal. 2015;7(2):1–39. Available from: http://scholar.utc.edu/jafh%5Cn. http://scholar.utc.edu/jafh/vol7/iss2/2.

  14. 14.

    Arnett JJ. Emerging adulthood: a theory of development from the late teens through the twenties. Am Psychol. 2000;55(5):469–80. https://doi.org/10.1037/0003-066X.55.5.469.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Jones PB. Adult mental health disorders and their age at onset. Br J Psychiatry. 2013;202(SUPPL. 54):5–11.

    Article  Google Scholar 

  16. 16.

    McAnarney ER. Adolescent brain development: forging new links? J Adolesc Health. 2008;42(4):321–3. https://doi.org/10.1016/j.jadohealth.2007.10.012.

    Article  PubMed  Google Scholar 

  17. 17.

    Patel V, Saxena S, Lund C, Thornicroft G, Baingana F, Bolton P, Chisholm D, Collins PY, Cooper JL, Eaton J, Herrman H, Herzallah MM, Huang Y, Jordans MJD, Kleinman A, Medina-Mora ME, Morgan E, Niaz U, Omigbodun O, Prince M, Rahman A, Saraceno B, Sarkar BK, de Silva M, Singh I, Stein DJ, Sunkel C, UnÜtzer JÜ. The Lancet Commission on global mental health and sustainable development. Lancet. 2018;392(10157):1553–98. https://doi.org/10.1016/S0140-6736(18)31612-X.

    Article  PubMed  Google Scholar 

  18. 18.

    McGorry PD. Early intervention in psychosis: obvious, effective, overdue. J Nerv Ment Dis. 2015;203(5):310–8. https://doi.org/10.1097/NMD.0000000000000284.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Schmidt U, Adan R, Böhm I, Campbell IC, Dingemans A, Ehrlich S, Elzakkers I, Favaro A, Giel K, Harrison A, Himmerich H, Hoek HW, Herpertz-Dahlmann B, Kas MJ, Seitz J, Smeets P, Sternheim L, Tenconi E, van Elburg A, van Furth E, Zipfel S. Eating disorders: the big issue. Lancet Psychiatry. 2016;3(4):313–5. Available from: http://www.sciencedirect.com/science/article/pii/S221503661600081X. https://doi.org/10.1016/S2215-0366(16)00081-X.

    Article  PubMed  Google Scholar 

  20. 20.

    Treasure J, Stein D, Maguire S. Has the time come for a staging model to map the course of eating disorders from high risk to severe enduring illness? An examination of the evidence. Early Interv Psychiatry. 2015;9(3):173–84. https://doi.org/10.1111/eip.12170.

    Article  PubMed  Google Scholar 

  21. 21.

    NICE. NICE clinical guidelines [Internet]. NICE Guidance. Available from: https://www.nice.org.uk/guidance/conditions-and-diseases/mental-health-and-behavioural-conditions. Accessed 10 July 2020.

  22. 22.

    Weisz JR, Sandler IN, Durlak JA, Anton BS. Promoting and protecting youth mental health through evidence-based prevention and treatment. Am Psychol. 2005;60(6):628–48. https://doi.org/10.1037/0003-066X.60.6.628.

    Article  PubMed  Google Scholar 

  23. 23.

    Weisz JR, Ugueto AM, Cheron DM, Herren J. Evidence-based youth psychotherapy in the mental health ecosystem. J Clin Child Adolesc Psychol. 2013;42(2):274–86. https://doi.org/10.1080/15374416.2013.764824.

    Article  PubMed  Google Scholar 

  24. 24.

    Kölch M, Plener PL. Pharmacotherapy in psychiatric disorders of children: current evidence and trends. Pharmacopsychiatry. 2016;49(6):219–25. https://doi.org/10.1055/s-0042-117644.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Richey RH, Hughes C, Craig JV, Shah UU, Ford JL, Barker CE, et al. A systematic review of the use of dosage form manipulation to obtain required doses to inform use of manipulation in paediatric practice. Int J Pharm. 2017;518(1–2):155–66 Available from: https://doi.org/10.1016/j.ijpharm.2016.12.032.

    CAS  Article  Google Scholar 

  26. 26.

    Cipriani A, Zhou X, Del Giovane C, Hetrick SE, Qin B, Whittington C, et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. Lancet. 2016;388(10047):881–90 Available from: https://doi.org/10.1016/S0140-6736(16)30385-3.

    CAS  Article  Google Scholar 

  27. 27.

    Paul Amminger G, Berger M, Rice SM, Davey CG, Schäfer MR, McGorry PD. Novel biotherapies are needed in youth mental health. Australas Psychiatry. 2017;25(2):117–20. https://doi.org/10.1177/1039856217698237.

    Article  PubMed  Google Scholar 

  28. 28.

    Rossi S, Hallett M, Rossini PM, Pascual-Leone A, Avanzini G, Bestmann S, et al. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009.

  29. 29.

    Hallett M. Transcranial magnetic stimulation and the human brain. Nature. 2000;406(6792):147–50. https://doi.org/10.1038/35018000.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Hanakawa T, Mima T, Matsumoto R, Abe M, Inouchi M, Urayama SI, et al. Stimulus-response profile during single-pulse transcranial magnetic stimulation to the primary motor cortex. Cereb Cortex. 2009.

  31. 31.

    Hoogendam JM, Ramakers GMJ, Di Lazzaro V. Physiology of repetitive transcranial magnetic stimulation of the human brain. Brain Stimul. 2010.

  32. 32.

    Schlaepfer TE, Kosel M, Nemeroff CB. Efficacy of repetitive transcranial magnetic stimulation (rTMS) in the treatment of affective disorders. Neuropsychopharmacology. 2003;28(2):201–5. https://doi.org/10.1038/sj.npp.1300038.

    Article  PubMed  Google Scholar 

  33. 33.

    Ma J, Zhang Z, Kang L, Geng D, Wang Y, Wang M, Cui H. Repetitive transcranial magnetic stimulation (rTMS) influences spatial cognition and modulates hippocampal structural synaptic plasticity in aging mice. Exp Gerontol. 2014;58:256–68. https://doi.org/10.1016/j.exger.2014.08.011.

    Article  PubMed  Google Scholar 

  34. 34.

    Kennedy NI, Lee WH, Frangou S. Efficacy of non-invasive brain stimulation on the symptom dimensions of schizophrenia a meta analysis of randomized controlled trials. Eur Psychiatry. 2018;49:69–77. https://doi.org/10.1016/j.eurpsy.2017.12.025.

    Article  PubMed  Google Scholar 

  35. 35.

    Li Z, Yin M, Lyu XL, Zhang LL, Du XD, Hung GCL. Delayed effect of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms of schizophrenia: findings from a randomized controlled trial. Psychiatry Res. 2016;240:333–5. https://doi.org/10.1016/j.psychres.2016.04.046.

    Article  PubMed  Google Scholar 

  36. 36.

    Plewnia C, Zwissler B, Wasserka B, Fallgatter AJ, Klingberg S. Treatment of auditory hallucinations with bilateral theta burst stimulation: a randomized controlled pilot trial. Brain Stimul. 2014;7(2):340–1. https://doi.org/10.1016/j.brs.2014.01.001.

    Article  PubMed  Google Scholar 

  37. 37.

    Dalton B, Bartholdy S, McClelland J, Kekic M, Rennalls SJ, Werthmann J, et al. Randomised controlled feasibility trial of real versus sham repetitive transcranial magnetic stimulation treatment in adults with severe and enduring anorexia nervosa: the TIARA study. BMJ Open. 2018;8(7):1–11.

    Article  Google Scholar 

  38. 38.

    Dunlop K, Woodside B, Olmsted M, Colton P, Giacobbe P, Downar J. Reductions in cortico-striatal hyperconnectivity accompany successful treatment of obsessive-compulsive disorder with dorsomedial prefrontal rTMS. Neuropsychopharmacology. 2016.

  39. 39.

    Trevizol AP, Shiozawa P, Cook IA, Sato IA, Kaku CB, Guimarães FB, et al. Transcranial magnetic stimulation for obsessive-compulsive disorder: an updated systematic review and meta-analysis. J ECT. 2016;32(4):262–6. https://doi.org/10.1097/YCT.0000000000000335.

    Article  PubMed  Google Scholar 

  40. 40.

    Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, Knyahnytska Y, Kennedy SH, Lam RW, Daskalakis ZJ, Downar J. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018;391(10131):1683–92. https://doi.org/10.1016/S0140-6736(18)30295-2.

    Article  PubMed  Google Scholar 

  41. 41.

    Fitzgerald PB, Daskalakis ZJ. The effects of repetitive transcranial magnetic stimulation in the treatment of depression. Expert Rev Med Devices. 2011.

  42. 42.

    Milev RV, Giacobbe P, Kennedy SH, Blumberger DM, Daskalakis ZJ, Downar J, Modirrousta M, Patry S, Vila-Rodriguez F, Lam RW, MacQueen GM, Parikh SV, Ravindran AV, the CANMAT Depression Work Group. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. Neurostimulation treatments. Can J Psychiatr. 2016;61(9):561–75. https://doi.org/10.1177/0706743716660033.

    Article  Google Scholar 

  43. 43.

    NICE. Repetitive transcranial magnetic stimulation for depression. 2015. Available from: https://www.nice.org.uk/guidance/ipg542

    Google Scholar 

  44. 44.

    Fregni F, Marcolin MA, Myczkowski M, Amiaz R, Hasey G, Rumi DO, Rosa M, Rigonatti SP, Camprodon J, Walpoth M, Heaslip J, Grunhaus L, Hausmann A, Pascual-Leone A. Predictors of antidepressant response in clinical trials of transcranial magnetic stimulation. Int J Neuropsychopharmacol. 2006;9(6):641–54. https://doi.org/10.1017/S1461145705006280.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Koops S, Slotema CW, Kos C, Bais L, Aleman A, Blom JD, et al. Predicting response to rTMS for auditory hallucinations: younger patients and females do better. Schizophr Res. 2018;195:583–4 Available from: https://doi.org/10.1016/j.schres.2017.08.060.

    Article  Google Scholar 

  46. 46.

    Donaldson AE, Gordon MS, Melvin GA, Barton DA, Fitzgerald PB. Addressing the needs of adolescents with treatment resistant depressive disorders: a systematic review of rTMS. Brain Stimul. 2014;7(1):7–12. https://doi.org/10.1016/j.brs.2013.09.012.

    Article  PubMed  Google Scholar 

  47. 47.

    Magavi LR, Reti IM, Vasa RA. A review of repetitive transcranial magnetic stimulation for adolescents with treatment-resistant depression. Int Rev Psychiatry. 2017;29(2):79–88. https://doi.org/10.1080/09540261.2017.1300574.

    Article  PubMed  Google Scholar 

  48. 48.

    Hett D, Rogers J, Humpston C, Marwaha S. Repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression in adolescence: a systematic review. J Affect Disord. 2021;278(September 2020):460–9 Available from: https://doi.org/10.1016/j.jad.2020.09.058.

    Article  Google Scholar 

  49. 49.

    Masuda F, Nakajima S, Miyazaki T, Tarumi R, Ogyu K, Wada M, Tsugawa S, Croarkin PE, Mimura M, Noda Y. Clinical effectiveness of repetitive transcranial magnetic stimulation treatment in children and adolescents with neurodevelopmental disorders: a systematic review. Autism. 2019;23(7):1614–29. https://doi.org/10.1177/1362361318822502.

    Article  PubMed  Google Scholar 

  50. 50.

    Gomez L, Vidal B, Morales L, Baez M, Maragoto C, Galvizu R, et al. Low frequency repetitive transcranial magnetic stimulation in children with attention deficit hyperactivity disorder Preliminary results. Brain Stimul. 2014;7:757–69.

    Article  Google Scholar 

  51. 51.

    Allen CH, Kluger BM, Buard I. Safety of transcranial magnetic stimulation in children: a systematic review of the literature. Pediatr Neurol. 2017;68:3–17 Available from: https://www.sciencedirect.com/science/article/pii/S0887899416305045?via%3Dihub. [cited 2019 Sep 19].

    Article  Google Scholar 

  52. 52.

    Krishnan C, Santos L, Peterson MD, Ehinger M. Safety of noninvasive brain stimulation in children and adolescents. Brain Stimul. 2015.

  53. 53.

    Woods AJ, Antal A, Bikson M, Boggio PS, Brunoni AR, Celnik P, Cohen LG, Fregni F, Herrmann CS, Kappenman ES, Knotkova H, Liebetanz D, Miniussi C, Miranda PC, Paulus W, Priori A, Reato D, Stagg C, Wenderoth N, Nitsche MA. A technical guide to tDCS, and related non-invasive brain stimulation tools. Clin Neurophysiol. 2016;127(2):1031–48 Available from: https://doi.org/10.1016/j.clinph.2015.11.012.

    CAS  Article  Google Scholar 

  54. 54.

    Stagg CJ, Antal A, Nitsche MA. Physiology of transcranial direct current stimulation. J ECT. 2018.

  55. 55.

    Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol. 2000;527(3):633–9. https://doi.org/10.1111/j.1469-7793.2000.t01-1-00633.x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Lefaucheur J, Antal A, Ayache SS, Benninger DH, Brunelin J, Cogiamanian F, et al. Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation ( tDCS ). Clin Neurophysiol. 2017;128(1):56–92 Available from: https://doi.org/10.1016/j.clinph.2016.10.087.

    Article  Google Scholar 

  57. 57.

    Kuo M, Chen P, Nitsche MA. The application of tDCS for the treatment of psychiatric diseases. Int Rev Psychiatry. 2017;29(2):146–67. https://doi.org/10.1080/09540261.2017.1286299.

    Article  PubMed  Google Scholar 

  58. 58.

    Meron D, Hedger N, Garner M, Baldwin DS. Neuroscience and Biobehavioral Reviews. Transcranial direct current stimulation (tDCS) in the treatment of depression: systematic review and meta-analysis of efficacy and tolerability. Neurosci Biobehav Rev. 2015;57:46–62 Available from: https://doi.org/10.1016/j.neubiorev.2015.07.012.

    Article  Google Scholar 

  59. 59.

    Palm U, Hasan A, Strube W, Padberg F. tDCS for the treatment of depression: a comprehensive review. Eur Arch Psychiatry Clin Neurosci. 2016;266(8):681–94. https://doi.org/10.1007/s00406-016-0674-9.

    Article  PubMed  Google Scholar 

  60. 60.

    Buchanan DM, Bogdanowicz T, Khanna N, Lockman-dufour G, Robaey P, Angiulli AD. Brain sciences. Systematic review on the safety and tolerability of transcranial direct current stimulation in children and adolescents; 2021.

    Google Scholar 

  61. 61.

    Muszkat D, Polanczyk GV, Dias TGC, Brunoni AR. Transcranial direct current stimulation in child and adolescent psychiatry. J Child Adolesc Psychopharmacol. 2016;26(7):590–7. https://doi.org/10.1089/cap.2015.0172.

    Article  PubMed  Google Scholar 

  62. 62.

    Palm U, Segmiller FM, Natascha A, Freisleder EF. Transcranial direct current stimulation in children and adolescents: a comprehensive review; 2016. p. 1219–34.

    Google Scholar 

  63. 63.

    Hameed MQ, Dhamne SC, Gersner R, Kaye HL, Oberman LM, Pascual-Leone A, et al. Transcranial magnetic and direct current stimulation in children. Curr Neurol Neurosci Rep. 2017;17(2).

  64. 64.

    Lee JC, Kenny-Jung DL, Blaker CJ, Cmasari DD, Lewis CP. Transcranial direct current stimulation in child and adolescent psychiatric disorders. Child Adolesc Psychiatr Clin N Am. 2019;28(1):61–78. https://doi.org/10.1016/j.chc.2018.07.009.

    Article  PubMed  Google Scholar 

  65. 65.

    Becker JE, Shultz EKB, Maley CT. Transcranial magnetic stimulation in conditions other than major depressive disorder. Child Adolesc Psychiatry Clin NA. 2019;28(1):45–52 Available from: https://doi.org/10.1016/j.chc.2018.08.001.

    Article  Google Scholar 

  66. 66.

    Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC, et al. Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci U S A. 2004.

  67. 67.

    Sowell ER, Thompson PM, Holmes CJ, Jernigan TL, Toga AW. In vivo evidence for post-adolescent brain maturation in frontal and striatal regions [1]. Nat Neurosci. 1999;2(10):859–61. https://doi.org/10.1038/13154.

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: Elaboration and explanation. BMJ. 2015.

  69. 69.

    Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62(10):1006–12. https://doi.org/10.1016/j.jclinepi.2009.06.005.

    Article  PubMed  PubMed Central  Google Scholar 

  70. 70.

    McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V, Lefebvre C. PRESS peer eeview of electronic search strategies: 2015 guideline statement. J Clin Epidemiol. 2016;75:40–6. https://doi.org/10.1016/j.jclinepi.2016.01.021.

    Article  PubMed  Google Scholar 

  71. 71.

    Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev. 2016.

  72. 72.

    Li T, Higgins JPT, Deeks JJ. Collecting data. In: Cochrane handbook for systematic reviews of interventions; 2019. p. 109–41.

    Chapter  Google Scholar 

  73. 73.

    Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:1–8.

    Google Scholar 

  74. 74.

    Sterne JAC, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:4–10.

    Google Scholar 

  75. 75.

    Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. 2012. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp

    Google Scholar 

  76. 76.

    Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011.

  77. 77.

    Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction - GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011.

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Acknowledgements

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Funding

YDL is supported by the Daniel Turnberg Royal College of Physicians travel fellowship. LG is supported by a PhD studentship from the National Institute of Health Research (NIHR) Mental Health Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) and King’s College London (KCL). ICC and US receive salary support from the NIHR Mental Health BRC at SLaM and KCL. US is supported by an NIHR Senior Investigator Award. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

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US initiated the project and is the guarantor of the review. The review team developed the review protocol in meetings and discussions. YDL and LG wrote the protocol and all team members commented and approved it before submission. The authors read and approved the final manuscript.

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Correspondence to Ulrike Schmidt.

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Supplementary Information

Additional file 1.

PRISMA-P 2015 Checklist.

Additional file 2.

Search strategy draft for Medline (via OVID platform).

Additional file 3.

Extraction data form.

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Lewis, Y.D., Gallop, L., Campbell, I.C. et al. Effects of non-invasive brain stimulation in children and young people with psychiatric disorders: a protocol for a systematic review. Syst Rev 10, 76 (2021). https://doi.org/10.1186/s13643-021-01627-3

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Keywords

  • Neuromodulation
  • Non-invasive brain stimulation (NIBS)
  • Repetitive transcranial magnetic stimulation (rTMS)
  • Transcranial direct current stimulation (tDCS)
  • Children and adolescents
  • Young people