Noninvasive brain stimulation

We are at a time of substantial and growing interest for noninvasive brain stimulation. This is reflected in expanding technological, scientific, and clinical efforts, and paralleled by increasing public curiosity and financial investment. Scientists and clinicians are becoming increasingly aware of the need for new treatments for brain diseases, predicated on novel approaches grounded on a deeper, more detailed understanding of brain function. Large-scale brain mapping initiatives like the Human Connectome Project (http://www.humanconnectomeproject.org), the Human Brain Project (https://www. humanbrainproject.eu/), and president Obama’s highly publicized Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative (http://www.nih.gov/science/brain/) reflect this growing awareness. The human nervous system is complex and there is a crystalizing realization that most aspects human behavior and symptomatic manifestations of brain disease might be best conceptualized as alterations in function of distributed, plastic neural networks. Deeper understanding of the human nervous system promises to enable more targeted, controlled interventions. Brain stimulation offers an opportunity to modulate specific neural networks, and thus affect behavior and address symptoms of disease. At the same time, brain stimulation represents a controllable input that can be well characterized and can help gain novel insights into the integrity and dynamics of neural networks. Thus, brain stimulation can offer help to patients while advancing scientific insights. In this context, noninvasive brain stimulation approaches have the additional appeal of their safety provide and lack of surgical invasiveness. To-date, methods based in electromagnetic and electric stimulation, notably transcranial magnetic stimulation (TMS) and transcranial current stimulation (tCS), are the two most popular and best studied noninvasive brain stimulation tools. However, there is a fast growing array of techniques to query and modulate brain activity without invasive surgical approaches, including methods utilizing light, ultrasound, viral and other vectors. Noninvasive brain stimulation techniques can effectively modify, suppress, augment or disrupt brain function depending on stimulation, individual, context, and environmental characteristics. Applications include investigation into fundamental principles of brain function, translational efforts of insights in animal models into humans, research on brain-behavior relations, and novel therapeutic approaches for neurologic and psychiatric illnesses. The present special issue of the European Journal of Neuroscience brings together all recent published papers on noninvasive brain stimulation to provide a timely and useful overview of the state of the art. TMS, as we still basically apply it, was introduced in 1984/5 by Anthony Barker and colleagues at the University of Sheffield, UK, and has steadily expanded in its realm of potential applications in basic, translational and clinical neuroscience. Repetitive TMS, introduced in the late 1980’s, has also steadily increased in annual number of publications with a major impetus from the interest in its therapeutic potential. tCS witnessed a resurgence in the 1990’s with growing adaption of its potential human applications. As we enter 2014, there are over 10 000 TMS manuscripts catalogued on Pubmed (Source: www.ncbi.nlm.nih.gov/pubmed), at least 2000 of which focus on repetitive TMS, and over 1000 publications on tCS. The number of registered clinical trials (www.clinicaltrials.gov) for both TMS (600+) and tCS (200+) is also extraordinary. While the bulk of the clinical trials focus directly on disorders of cognitive and brain function, what is quite striking is the diversity of applications being formally tested. These applications extend not only outside of the brain, to spinal cord and peripheral nervous system, but beyond what are classically described as nervous system disorders (e.g. bone marrow, autoimmune functions, dyspnea). On the one hand this is exciting, because various body systems ultimately interact with the nervous system, and the ability to be able to treat a host of diseases with varied etiologies by these non-invasive techniques is appealing. Nonetheless, one worries that we are leaping from disease to disease without sufficient consideration of mechanisms of action of these noninvasive brain stimulation interventions in any one of them. This may be risky because failed clinical trials, provide minimal insight into why, and may send the wrong message to the scientific community and the layperson. Thus, this timely special issue of the European Journal of Neuroscience, while highlighting the growing interest in noninvasive brain stimulation, also seeks to emphasize the urgent need for greater insights into mechanisms of action and fundamental investigation that may promote technological improvement and sophistication. As mentioned above, a particularly important appeal of noninvasive brain stimulation methods (and in general of all brain stimulation approaches) is the potential of helping patients while gaining critical insights into fundamental questions of brain function and pathophysiology of nervous system diseases. It is likely that scientific and clinical interest in noninvasive brain stimulation will continue to expand the nearly exhaustive list of possible applications. However, most transformative would be to truly integrate technological, basic and clinical neuroscience with therapeutic efforts. This may lead, for example, to exploration of combined behavioral and brain stimulation interventions that are individually targeted considering genetic and epigenetic factors, and that incorporate improved drug targeting and local tissue and brain network susceptibility considerations. Clearly there is much exciting work to be done. As mentioned, TMS and tCS (particularly transcranial direct current stimulation, tDCS), have been the most broadly used noninvasive brain stimulation methods to-date and are the focus of this special issue of the European Journal of Neuroscience. Thanks to substantial human, preclinical, cellular, and modeling studies, we know that TMS operates by activating cortical inhibitory and excitatory interneurons according to stimulation characteristics (intensity, coil orientation, pulse shape/duration), and biological characteristics