A Physiological Marriage Made in Heaven: Treating and Measuring the Brain Through Stimulation.

Abstract

Brain stimulation is emerging as an important treatment for a variety of neurologic and psychiatric disorders—particularly when pharmacological options fail. For example, it is estimated that up to one-third of patients with depression do not respond to conventional pharmacotherapy, and such resistance is associated with extraordinary suffering for the patient and high costs to society. Unfortunately, most patients not responding to pharmacotherapy continue to be offered medications despite limited evidence supporting their use. This is most often due to a lack of widespread availability of these newer approaches. Recently, the National Institutes of Mental Health has dedicated an entire program to brain stimulation, which should make these approaches more accepted and, thus, utilized in a timely manner. This program seeks to further the use of brain stimulation as both a physiological and treatment tool for a variety of neurological and psychiatric disorders. In this special edition of Clinical Pharmacology & Therapeutics, we have curated a series of articles intended to review the current and potential future uses for brain stimulation to enhance therapeutic outcomes for patients with central nervous system disorders. About a third of patients with depression fail to respond to antidepressant treatments.1 In the United States, the population of patients estimated to be experiencing treatment-resistant depression (TRD) is about 8 million per year. TRD has been reported to cost the US taxpayer up to US $60 billion annually, and these patients often suffer with severe symptoms, including suicidality; this may explain why depression is ranked highest in relation to overall global disease burden (Table 1). Of the patients with TRD, only about 1% receive electroconvulsive therapy (ECT), which is widely considered the gold standard treatment for TRD.2 ECT can produce remission of depressive symptoms in 60–75% of patients with depression3 and remission, or near remission, of suicidality in up to 81% of patients at the completion of the acute ECT course.4 However, ECT is complicated by its negative stigma and adverse cognitive effects, including postictal disorientation, and anterograde and retrograde amnesia.5 Numerous patients refuse ECT because of these significant adverse cognitive effects. ECT is also negatively stigmatized, contributing to the previously mentioned fact that only about 1% of patients with TRD receive ECT.2 Nevertheless, ECT was once heralded as a medical breakthrough and has helped the field reorient to the possibility that innovative approaches to brain stimulation may result in therapeutic innovation for neurologic and psychiatric disorders. Repetitive transcranial magnetic stimulation (rTMS) is US Food and Drug Administration (FDA) approved for the treatment of depression, and a large body of evidence supports its safety and antidepressant efficacy.6, 7 The rTMS involves delivery of a series of magnetic pulses over the prefrontal cortex on a daily basis for up to 4–6 weeks. The efficacy of rTMS in depression has been established in numerous randomized controlled trials enrolling thousands of patients over the last 20 years, and affirmed in several large meta-analyses. This explains why, in just over 10 years, rTMS is accepted as a standard of care for patients with TRD. Repetitive transcranial magnetic stimulation has also been shown to be effective in a variety of additional disorders, including Parkinson's disease, which is a progressive neurologic disorder. In this issue, Fitzgerald8 provides a practice article focused on maintenance rTMS for depression, and Trevizol and Blumberger9 and Chen and Chen10 provide comprehensive reviews on the use of rTMS in the treatment of depression and Parkinson's disease, respectively; both articles highlight important potential areas of innovation to existing treatments that may galvanize further research aimed at improving approaches to rTMS treatment delivery. With the introduction of rTMS there were also parallel developments in other key areas related to brain stimulation. The first of these was the use of TMS as a neurophysiological tool. Since the early 1990s, TMS was used to evaluate a number of neurophysiological processes in both healthy and diseased states. TMS can measure both excitatory and inhibitory neurotransmission in the cortex based on evidence suggesting that TMS can stimulate both inhibitory and excitatory interneurons in addition to pyramidal neurons.11, 12 In the motor cortex, TMS can be combined with electromyography using paradigms including short-interval cortical inhibition,13, 14 cortical silent period TMS,15, 16 and intracortical facilitation13 to measure GABAergic and glutamatergic neurotransmission. As such, TMS can directly measure the activity of these key neurophysiological processes in vivo. In the last 2 decades, efforts have also translated these measures from the motor cortex to areas of the brain more closely associated with pathophysiology of psychiatric disorders (e.g., the dorsolateral prefrontal cortex). Similar to the motor cortex, single and paired stimulation protocols can be used to evaluate both GABAergic and glutamatergic inhibitory neurotransmission.17 What is particularly appealing about these methods is that there is clear anatomic convergence between the site of stimulation with rTMS or ECT and the site of neurophysiological investigation through TMS- electroencephalography (EEG). Additionally, as both treatments (rTMS and ECT) and biological targeting (TMS-EEG) affect the same neural processes, a change in the neural circuitry that is induced by the treatment should be reflected as a change in neural circuity changes that is recorded through TMS-EEG biological targeting. Such efforts are currently underway (NCT0319105). In this issue, Hui et al.18 review TMS-EEG as a physiological tool and emphasize its potential for translational research—both in relation to probing treatment-related illness and treatment biomarkers but also in relation to understanding key physiological processes that may be aberrant in a variety of neurologic and psychiatric disorders. Biological target engagement is the next challenge to this important field as we search for ways to improve therapeutic outcomes. Such biological target engagement can take many forms but the most common to date has involved magnetic resonance imaging. Intriguingly, in the field of addictions Hanlon et al.19 evaluates how the neural architecture influences rTMS-induced functional change through both diffusion tensor imaging and functional magnetic resonance imaging that also involved cue-reactivity modulation in alcohol use disorders. The potential to combine these imaging methods to better understand connectivity in alcohol use disorders may lead to an improved understanding of this devastating disease and better ways to redirect treatment that may lead to improved clinical outcomes. Further, in this issue Fidel-Rodriguez et al.20 reviews the literature that interleave TMS with functional magnetic resonance imaging as a further methodological advancement. The combination of these methods can be used for both better target precision through advanced brain stimulation methods and also to better understand mechanisms of brain response in a variety of neurological and psychiatric disorders. Additional engineering innovations in the last 2 decades have led to the development of newer forms of brain stimulation. Transcranial direct current stimulation (tDCS) utilizes low-amplitude direct electrical fields (i.e., between 1 and 2 mA) applied for 20–30 minutes for both therapeutic and neurophysiological purposes. Transcranial direct current stimulation is applied as a direct electrical current. It was initially postulated that anodal tDCS produced regional changes toward excitation (e.g., long-term potentiation) and cathodal tDCS produced regional changes amounting to long-term depression, although the last few years of research indicates that the effects on cortical neurophysiology are much more complex. Transcranial direct current stimulation is lightweight and portable and can be used in multiple settings (e.g., hospital and home). Transcranial direct current stimulation is very well tolerated, and has been used as a treatment for both neurological (e.g., pain) and psychiatric disorders (e.g., depression and schizophrenia). Fitzgibbon et al.21 and Rajji et al.22 provide evidence for the current and potential future use of these devices in relation to treatment for pain disorders and for prevention of, and treatment for, Alzheimer's disease. What is most appealing about tDCS as a treatment option is its safety, portability, ease of use, and the potential to enhance cognition in vulnerable populations to which few if any treatments are available. Deep brain stimulation (DBS) also emerged over 2 decades ago as a potential treatment option in both neurologic and psychiatric disorders. DBS is inserted into deep regions, and its insertion is assisted through both neuroimaging and neurophysiological targeting. DBS is currently used as an effective treatment tool for a variety of neurological disorders (e.g., tremors and Parkinson's disease), and it has been extensively evaluated as a treatment for depression, albeit with less success. This special issue includes point-counterpoint articles by Holtzheimer et al.23 and Downar et al.,24 which weigh the strengths and weaknesses of pursuing ongoing efforts to evaluate DBS as a treatment for depression. Our last treatment is not conventionally regarded as a form of brain stimulation but rather involves the modification of brain circuitry noninvasively through focused ultrasound. Davidson et al.25 describe here the use of this innovative method to deliver lesions to pathophysiological circuitry in the brain. This may have profound consequences both in relation to the ability of focused ultrasound to disrupt pathophysiologic circuitry in the brain but also to alter future drug delivery in brain regions where drug delivery may be compromised. At the rate that manuscripts are being published on brain stimulation in human subjects, no one special edition can reflect the breadth of innovation helping to transform this exciting field. For this special issue of the journal, we have attempted to highlight key areas of brain stimulation research that both reflect the breadth of treatment innovation and also cover key areas through which brain stimulation can help to identify candidate biological targets, which can be engaged to understand brain mechanisms and methods to improve clinical outcomes. Although we remain optimistic for the future of these methods, there is also room for some caution. First, as with all good science, replication is much needed. Second, as we continue to strive for creative and salubrious solutions to the affected brain, we must be certain that our findings—particularly those related to biological target engagement—can be used with high fidelity and easily translated into standard clinical settings. Third, we must be mindful of scalability. That is, although some of these treatments can be effectively deployed in many clinical settings, others may be limited to more select tertiary or quaternary care centers. As such, they must be investigated with these in mind (i.e., highly resistant patients who have failed less-invasive brain stimulation approaches). Finally, we must always be cautious not to generalize too broadly and to continue to investigate these treatments in a variety of different clinical conditions. As an example, whereas rTMS is regarded as an effective treatment for major depressive disorders, its efficacy in disorders where there is another primary diagnosis (e.g., substance use disorders) will need to be fully investigated to avoid unnecessary costs and burden to patients. Despite these limitations, brain stimulation has a propitious future for neurologic and psychiatric disorders, and we fully anticipate novel breakthroughs that will ultimately help to solve some of the most complex, disabling, and costliest disorders of society. In the last 5 years, Z.J.D. has received research and equipment in-kind support for an investigator-initiated study through Brainsway Inc. and Magventure Inc. His work was supported by the Canadian Institutes of Health Research (CIHR), the National Institutes of Mental Health (NIMH), the Temerty Family and Grant Family, through the Centre for Addiction and Mental Health (CAMH) Foundation, and the Campbell Institute. R.F.T.'s work on this issue was supported by funding from a Canada Research Chair in Pharmacogenomics, the Canadian Institutes of Health Research (e.g., Foundation grant FDN-154294), as well as NIDA funding, the Centre for Addiction and Mental Health, and the Campbell Institute. Over the past five years, R.F.T. has consulted for Apotex, Quinn Emanuel, and Ethismos on unrelated topics. R.F.T. is also an associate editor for Clinical Pharmacology & Therapeutics.