Potential new brain stimulation therapies in bipolar illness: transcranial magnetic stimulation and vagus nerve stimulation Mark S. George * , Ziad Nahas, Xiangbao Li, F. Andrew Kozel, Berry Anderson, Kaori Yamanaka MUSC, IOP, Psychiatry Department, 502 North 67 President St., Charleston, SC, 29425 USA Abstract The advances in understanding the functional and structural anatomy of bipolar affective disorder (BPAD) outlined in the rest of this volume provide the background and rationale for attempting to manipulate these regions as potential antidepressant and anti-manic therapies. The idea of using circuit and device based approaches to regulating mood follows in the tradition of electroconvulsive therapy (ECT). In marked contrast to ECT, however, these new stimulation techniques represent an important new paradigm shift, with treatments that neither produce seizures nor require general anesthesia. The new techniques are safer, with fewer side effects, and are more focal than ECT in their entry into the brain. Transcranial magnetic stimulation (TMS) produces direct cortical brain stimulation by creating a powerful transient magnetic field. Five published randomized controlled trials suggest it has clinically significant acute antidepressant effects. One controlled study suggests that it may have antimanic effects as well. Vagus nerve stimulation (VNS) involves direct electrical stimulation of the vagus nerve in the neck, with propagation of the signal to the brainstem. One controlled and one open study in epilepsy patients with depression found antidepressant effects of VNS. An open study of VNS in treatment resistant unipolar and bipolar depression found acute antidepressant effects. These two device-based approaches to stimulating the brain offer promise as potential acute and even long-term treatments. Imaging studies suggest that TMS likely causes changes in mood regulating regions by stimulating limbic regions from the cortex down, while VNS influences this same circuit from the brainstem up. These two approaches are not yet approved by the Food and Drug Administration (FDA) for use in the US, although pivotal trials geared for eventual FDA approval are underway. Finally, the research determining whether and how these devices work to influence mood also promises to help unravel the pathophysiology of BPAD. q 2002 Published by Elsevier Science B.V. Keywords: Transcramial magnetic stimulation; Vagus nerve stimulation; Brain imaging 1. Introduction There is much new interest in this emerging class of brain stimulation antidepressant therapies. In part this interest is spurred on by the knowledge provided by functional brain imaging about the specific brain regions involved in depres- sion, mania, normal mood regulation and emotion proces- sing. The ability to stimulate the brain in awake alert adults without neurosurgery is a significant advance that has long been a dream of clinicians and neuroscientists. Fundamentally, oral pills are inefficient delivery systems that have to pass through the whole body and whole brain before they can reach their intended targets in specific brain regions. The stimulation-based approaches offer the promise of more neuroanatomically specific applications, with fewer side effects because of the precise application of the therapy. Finally, new treatments are needed, because the current generation of treatments is clearly inadequate for many bipolar affective disorder (BPAD) patients, especially in the depressed phase of the illness. 2. Consensus about the functional neuroanatomy of depression? Although the functional anatomy of mood regulation is not nearly as well understood as the circuitry of the visual or motor systems, most scientists agree that certain brain regions are consistently affected in depression, and to a lesser extent, mania (see Drevets et al., this volume). Although there is controversy, and much more work is needed, certain regions have consistently been implicated in the pathogenesis of depression and mood regulation [1– 10]. These include the medial and lateral prefrontal cortex, the cingulate gyrus, and other regions commonly referred to as limbic (amygdala, hippocampus, parahippocampus, septum, hypothalamus, limbic thalamus, insula) and para- limbic (anterior temporal pole, orbitofrontal cortex). These Clinical Neuroscience Research 2 (2002) 256–265 1566-2772/02/$ - see front matter q 2002 Published by Elsevier Science B.V. PII: S1566-2772(02)00049-X www.elsevier.com/locate/clires * Corresponding author. Tel.: 11-843-876-5142; fax: 11-843-792-5702. E-mail address: georgem@musc.edu (M.S. George).