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

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 [8‐10]. 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 [34‐36], 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 [46‐48], 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 [57‐59]: 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.

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].

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).