Editorial

Brain stimulation refers to neural modulation of specific brain regions or networks, typically by electric or electromagnetic fields. Brain stimulation technologies have emerged as both tools to probe brain function and as therapeutic options for patients with neuropsychiatric disease who fail to respond to medications or can’t tolerate them. Interest amongst clinicians and researchers in the field has risen dramatically in the last 20 years, as evidenced by publications on the subject. For example, a search on PubMed using the term ‘Brain Stimulation’ revealed 76 articles published in 1996, 609 in 2006, and 1786 in 2016. Accordingly, a review of pertinent applications of these technologies for the treatment of psychiatric disease is quite timely.

The burden of psychiatric disease is increasing rapidly and worldwide. According to the World Health Organization, depression is now the leading cause of disability in the world, and four of the six leading causes of years lived with disability are due to psychiatric disorders, namely depression, alcohol-use disorders, schizophrenia, and bipolar disorder. It is estimated that the cost of mental health conditions in developed countries is between 3–4% of gross domestic product. Unfortunately, medication is ineffective or insufficient for many patients with psychiatric disease. For example, ∼30% of patients with major depression don’t respond to currently available medications or experience intolerable side-effects (Rush et al., 2006). Accordingly, there is increased focus on alternative treatment modalities such as brain stimulation, as evidenced by the steep rise in research interest in the field, recent clinical trials, and regulatory approval of several brain stimulating technologies in the last two decades, for example deep brain stimulation (DBS) for Parkinson’s disease, vagus nerve stimulation for epilepsy and depression, and transcranial magnetic stimulation (TMS) for depression.

Although brain stimulation is an evolving field, the ‘gold standard’ brain stimulating treatment for depression, electroconvulsive therapy (ECT), dates back more than 70 years. Weiner and Reti (2017) begin this collection of reviews with key updates in the clinical application of ECT, including optimizing clinical response whilst minimizing cognitive side-effects. Despite advances in ECT administration, such as the introduction of ultra-brief pulses, which are thought to reduce the volume of neural tissue being stimulated, resulting in fewer cognitive side-effects (Sackeim et al., 2008), the fear of memory loss remains a major concern for patients. Radman and Lisanby (2017) review innovations in the design of novel seizure therapies that seek to improve the risk benefit ratio of convulsive therapy through enhanced control of the focality of stimulation. The design of seizure therapies with spatial precision in their targeting is intended to avoid stimulation of deep brain structures implicated in memory formation and retention, such as the hippocampus. They provide detail on the development of two innovations in seizure therapy, namely individualized low-amplitude seizure therapy and magnetic seizure therapy.

Subsequent to the introduction of ECT in the 1930s and 1940s, pharmacologic treatments for psychiatric diseases dominated. Most novel brain stimulation methodologies have emerged only in recent years for several reasons: advances in technology, improved understanding of brain circuitry sub-serving psychiatric disease and treatment response, and as a response to medication ineffectiveness or intolerance. Some of these brain stimulation technologies—for example TMS—began as research tools for scientists trying to non-invasively probe brain function, and were later co-opted by psychiatrists and neurologists as potential treatments. On the other hand, DBS is an example of a treatment modality that has emerged out of our increasing knowledge about brain circuitry sub-serving neuropsychiatric disease.

As treatment, brain stimulation is most often considered when other treatments fail or when medications elicit unpleasant or dangerous side-effects. Clearly, taking medication has the advantages of convenience and typically being cheaper. However, novel brain stimulating techniques can target key brain regions directly, focally, and quickly, facilitating accelerated responses and greater efficacy compared with pharmaceuticals that need to cross the blood–brain barrier, and can produce unwanted systemic side-effects. When conventional treatments for depression are ineffective, patients with depression are increasingly turning to TMS for treatment, especially because it is devoid of the cognitive side-effects associated with ECT. There are now two devices with distinct coil designs, the conventional figure-of-8 coil and the H-coil, that have regulatory approval for the treatment of depression in adults (Levkovitz et al., 2015; O’Reardon et al., 2007). As well as an expansion in available coils, TMS is also being used increasingly off-label, including for indications other than major depressive disorder and for medication-resistant depression in children, which is reviewed in Magavi, Reti, and Vasa (2017) in this Special Edition.

Although TMS may be more effective than simply another medication trial in a treatment resistant depressive patient, it is, nonetheless, time-consuming and costly, and not as effective as ECT. Therefore, a major challenge for the field is learning more about clinical predictors or biomarkers of response as well as improving its efficacy. The observation of hypoactivity in the prefrontal cortex of depressed patients led George et al. (2015) to evaluate the effectiveness of focal stimulation by TMS for enhancing activity in this region and combatting depression. Our understanding of the neural circuitry engaged by TMS has come a long way since then. To this end, Dubin (2017) reviews advances in neuroimaging and its application for optimizing TMS for depression. He suggests candidate imaging biomarkers which may be predictive of response to TMS. In contrast, Kobayashi et al. (2017) review the evidence that electrophysiologic measures of cortical excitability could be used as biomarkers for screening different TMS treatment paradigms. Finally, Goetz and Deng (2017) review major developments in TMS technology, including coils, stimulators, and waveforms. They then review biophysical models of electromagnetic stimulation that have become a major driver for technological development and the understanding of TMS mechanisms of action.

There are other limitations of TMS that will not be solved by optimizing coil design and stimulation parameters, such as the high cost of devices. Another limitation is a trade-off between depth of stimulation and focality, demonstrated by mathematical modelling. In other words, focal stimulation is only possible at a relatively shallow depth, whereas coils with deeper spread are less focal (Peterchev, Deng, & Goetz, 2015). Accordingly, there is interest in other non-invasive, non-convulsive technologies that might be cheaper and more focal at depth. Transcranial direct current stimulation (tDCS) is a simple and inexpensive form of brain stimulation that utilizes weak direct current applied to the scalp to modulate cortical excitability, resulting in plasticity that outlasts the stimulation. Kuo, Chen, and Nitsche (2017) give an overview of pathological alterations of plasticity in psychiatric diseases, gather clinical studies involving tDCS to ameliorate symptoms, and discuss future directions of applications, with an emphasis on optimizing stimulation effects. Another promising technology on the horizon that has the potential to overcome the difficulty of stimulating both focally and deeply is transcranial focused ultrasound that has been demonstrated in the intact mouse brain (Tufail et al., 2010). Fini and Tyler (2017) highlight scientific breakthroughs and observations that have driven the development of the field of ultrasonic neuromodulation. They also discuss the future outlook for ultrasonic neuromodulation specifically in the context of applications employing transcranial focused ultrasound for the investigation, diagnosis, and treatment of neuropsychiatric disorders.

Although DBS is typically considered a last resort treatment when other interventions have failed, it does offer the distinct advantage of high spatial accuracy and is not accompanied by cognitive side-effects nor requires repeated anaesthesia as for convulsive therapies. Stimulation can either be chronic, intermittent, or, as described below, precisely synchronized with electrophysiological or behavioural feedback signals. Graat, Figee, and Nitsche (2017) review the progress of DBS in psychiatry, including for obsessive-compulsive disorder, for which the clinical trial data is strongest. DBS is also under consideration for numerous other psychiatric disorders, which is also reviewed. A major drawback of conventional chronic DBS is accelerated habituation and rebound symptoms, which were initially observed in the treatment of neurological disorders such as Parkinson’s Disease and essential tremor. Accordingly, there is considerable interest in improving DBS technologies by dynamically adapting stimulation parameters to patient status. Lo and Widge (2017) review closed-loop neuromodulation platforms and the ongoing challenges and limitations in their development, including identifying meaningful biomarkers for titration.

We trust the review articles in this volume will be of interest to clinical and research psychiatrists. Brain stimulation is an expanding field that will continue to benefit from timely updates, which we believe are presented in this issue.

Disclosure statement

Dr Reti has received supplies at no cost from Neuronetics, Inc. Dr Reti was and is site principal investigator on multi-site TMS trials sponsored by Brainsway, Inc. and the US Department of Defense.