Brain Stimulation Therapies for Clinicians

Brain stimulation in psychiatry used to be synonymous with ECT. The recent publication of Brain Stimulation Therapies for Clinicians reflects the exciting development that clinicians now have more than one brain stimulation technique with which to treat patients who are resistant to pharmacotherapy. While ECT is still a mainstay in the treatment of severe and medication-resistant psychiatric disorders, clinicians now have a growing list of Food and Drug Administration (FDA) approved or investigational interventions that alter brain function via electrical or magnetic fields. These interventions include new modifications of ECT, vagus nerve stimulation, transcranial magnetic stimulation (TMS), magnetic seizure therapy, deep brain stimulation, transcranial direct current stimulation, implanted cortical stimulation, and others on the horizon. Two of these tools, TMS and transcranial direct current stimulation, are noninvasive, which opens the additional possibility of probing brain function in both health and disease and in ways not possible previously. As interventions, noninvasive neuromodulation tools can be used to examine relationships between brain and behavior, moving us from correlation to causation and testing hypotheses generated by functional imaging. They also hold out the possibility of leveraging knowledge about pathophysiology to develop targeted therapeutic interventions.

The face of clinical brain stimulation is changing rapidly. Take, for example, our oldest intervention—ECT. With ECT, we have moved from the original goal of inducing a generalized seizure to the recognition that not all seizures are equally effective. Innovations in electrode placement and parameters of stimulation have dramatically improved the risk-benefit ratio of ECT. It is important to recognize, however, that some of these seemingly new innovations actually have historical roots. For example, ultrabrief pulse ECT, recently reported to improve cognitive outcome (1) , was published by Cronholm and Ottosson as early as the 1960s (2 , 3) . Indeed, the 1959 book Treatment of Mental Disorder chronicles many since forgotten variations in electrical parameters that likewise await rediscovery (4) . Similarly, one of the latest developments, the use of deep brain stimulation in the treatment of depression, had its roots in the classic work of J. Lawrence Pool, who in 1948 used deep brain stimulation in the caudate of a Parkinson’s patient for the treatment of his depressive symptoms.

These tools may have historical roots, but with today’s advanced technology we can achieve forms of brain stimulation not dreamt possible decades ago. For example, new delivery systems for deep brain stimulation include light-emitting diodes that can deliver precisely timed light-driven stimulation to trigger synaptic transmission in cells containing light-sensitive ion channels (5) . These developments open the possibility of selectively targeting specific neuronal populations that overlap in space, thereby improving the functional selectivity of our as yet most focal intervention. In another example, the original TMS devices induced pulses that were shaped like sine waves because these were easier to generate using the electrical components available at the time. However, it has been known for decades that sine wave ECT is less efficient and induced more side effects than brief-pulse square waves. Fortunately, engineering advances have now made it possible to perform TMS with a controllable pulse shape (cTMS) (6) . Developments such as this will enable us to empirically determine the relations between pulse characteristics and physiological outcome and should aid in the refinement of brain stimulation interventions.

Conceptualizations of how brain stimulation works are likewise evolving apace with neuroscience developments. For example, the original conceptualization that deep brain stimulation “shuts down” the stimulated brain region depicted in chapter 7 has recently given way to new theories of altered neural dynamics. This shift in thinking from a static lesion to a dynamic alteration in the functioning of a distributed network reflects an evolution of thought regarding the functional role of neural oscillations. For decades, the field has passively recorded the electrical signals generated by the electrical activity of the brain, but only recently are we beginning to understand whether these rhythms are epiphenomena of neuronal activity or its very substance (7) . Now that we can noninvasively and exogenously evoke oscillations with TMS (8) , we are equipped for the first time to experimentally determine their function and therapeutic potential.

These tools have much to teach us about how the brain works and about the brain basis of psychiatric illness. For example, the distributed network of brain regions hypothesized to be involved in depression can be accessed at a variety of nodes. Lateral cortical regions can be targeted with TMS and implanted cortical stimulation, while deep nodes can be targeted via deep brain stimulation. The clinical impact of intervening in the circuit at these different access points can teach us about the functional role of the circuit and inform treatment development. These tools may also offer new insights into how ECT works. In ECT, the seizure and the electricity that induced it are coupled. With TMS, implanted cortical stimulation, and deep brain stimulation, we can deliver electricity in a regionally specific fashion without inducing a seizure, while with magnetic seizure therapy we can trigger cortically focused seizures without exposing deeper brain structures to electricity. This enables us to examine the relative contributions of the electricity and the seizure to the efficacy and side effects of ECT.

Collectively, brain stimulation tools represent a new family of therapeutic interventions that utilize various forms of electrical fields, either directly applied or indirectly induced via magnetic fields, to treat and study neuropsychiatric disorders. These tools, and the science behind them, define the emerging field of therapeutic neuromodulation. Excitement about therapeutic neuromodulation is great and has rekindled interest in the fundamental principles of how electrical fields change brain function. The authors point out that the brain is an electrical organ. Like the heart, there is a role for both chemical and electrical interventions in the treatment of brain-based disorders. This recognition calls for a greater emphasis on the electrical aspects of brain function in medical education to prepare the next generation of clinicians and researchers to optimally apply these brain stimulation tools.

This book addresses the need for a basic familiarity with the electrical aspects of brain function (i.e., neurophysiology) and the physics and engineering of brain stimulation (i.e., interventional neurophysiology) to help prepare clinicians to understand and use these tools. It provides an excellent introduction for physicians and non-medical professionals, to whom the book will be most useful, as a guide to the brain stimulating modalities available to consider in referring for new or adjunctive treatment. It offers an essential, crisp, and very accessible and easily read review of the different therapeutic modalities and their applications. Highly practical and comprehensive in content, this book nonetheless deserves a complete reading, as it tersely orients the reader to the entire field. This book serves as a useful introduction to the field that will leave the reader wanting more, and it nicely showcases the significant contributions of the authors to the field. After this introductory level text, the reader will be well prepared to consult one of the more comprehensive texts that are now available. All sections of this book are well referenced and give the reader enough papers to follow up with for each specific topic. However, for the specialist seeking to know more about this rapidly expanding field, the papers cited represent a fraction of the literature currently available.

The authors achieve their stated goal of inviting the reader into the world of brain stimulation and offering a starter kit for further exploration. However, the field is rapidly changing, and, in the words of Elbert Hubbard, “The world is moving so fast these days that the man who says it can’t be done is generally interrupted by someone doing it.” Echoing this sentiment, Trimble comments in his foreword to the book, “I predict that a succession of revised versions will follow from this first edition of the book, and that even the authors will look back with surprise that they had not more accurately predicted the future.” Indeed, there are already major new developments since the book’s publication. The most notable of these is the recent FDA approval of TMS for the treatment of depression (October 2008). Furthermore, topics that were dismissed as having little data now have substantial literatures. For example, magnetic seizure therapy has shown evidence of safety and preliminary evidence of antidepressant efficacy, and a large two-center randomized trial is under way. Additionally, follow-up studies of larger samples of depressed patients receiving deep brain stimulation have been published and large-scale sham-controlled multicenter trials are under way.

The authors make their case that the future of brain stimulation as a treatment is very bright. As scientific advances continue at a rapid pace, brain stimulation treatments seem likely to play an enormous role not just in advancing psychiatric research but also for a growing range of clinical indications. The authors boldly suggest that the array of emerging brain stimulation modalities have the potential to revolutionize the practice of psychiatry during the current century. At the very least, brain stimulation—from early devices such as ECT to the newest ones such as deep brain stimulation—offers a new and diverse class of therapeutics that the reader will come to believe can be an alternative to current psychotherapeutic and pharmacological interventions. But to realize this promise, we have much work to do as a field. Whereas biochemistry and molecular biology are the basic sciences of pharmacotherapy, the emerging field of brain stimulation will require a basic-science understanding of how electrical modulation of neuronal populations alters the functioning of distributed networks. Only through a nuanced understanding of this process may we hope to rationally design device-based therapies than can treat the currently untreatable and discover the otherwise unknowable.