Bench to Clinical Translational Applications of Noninvasive Brain Stimulation

The field of noninvasive brain stimulation (NIBS) has grown very rapidly in the past two decades (1–3). One of the main driving factors has been the knowledge gained from numerous novel in vitro and in vivo investigational approaches as well as computational modeling efforts aimed at characterizing brain activity in response to stimulation (4). In addition, the safe therapeutic profile of NIBS, its relative ease of implementation, and the contrasting limitations of current pharmacologic approaches also have contributed significantly to the accelerated development of NIBS for therapeutic purposes (5,6). The field of NIBS combines the development of novel techniques such as transcranial magnetic stimulation (TMS) and paired associative stimulation in addition to the modified use of relatively older methods of brain stimulation such as transcranial direct current stimulation (tDCS) and transcranial electrical stimulation. The breadth of methodologies available reflects the diversity of their possible applications and their relative strengths such as distribution of current including focality and penetration (7–9). As such, while the physiologic profile of each technique may differ, in many ways they can be viewed as complementary. The following nine papers, first presented at our meeting, Clinical, Assessment, and Intervention Updates in Neurorehabilitation (November 19 and 20, 2010), focus on brain stimulation modalities as neuromodulatory tools, their potential applications, and important questions that need to be addressed to allow for effective translation to human applications. In the first of two introductory review articles, Volz et al. discuss the application of NIBS in pain and stroke with a particular focus on the development of animal models to assess feasibility and efficacy (10). Along these same lines, Vahabzadeh-Hagh et al. discuss the use of rodent and rodent diseased models in NIBS (specifically TMS) and their potential utility in determining optimal stimulation parameters and safety for preclinical trials and eventual human testing (11). These two articles emphasize that although animal models are useful in understanding mechanisms, optimizing parameters of stimulation, and assessing safety, they have important limitations that need to be considered when translating to human applications. At the interface of animal models and translational clinical applications, basic neuroscience research using NIBS in healthy and brain-damaged human subjects has been critical in developing innovative investigative protocols. This is highlighted by the work of Bagce et al., who present original findings using NIBS in conjunction with virtual reality technology in chronic stroke patients (12). Using TMS to induce motor evoked potentials, these authors found that specific visuomotor discordance alters movement performance associated with changes in the primary motor cortex (9). This article reinforces the notion that TMS also can be a useful neurophysiologic marker, particularly for neuroplasticity protocols related to the primary motor cortex. Continuing on the theme of motor physiology and rehabilitation, Cortes et al. present a review on the uses of TMS in helping to better understand mechanisms implicated in motor dysfunction and recovery (specifically in hemiparesis following stroke) (13). This article also carefully reviews the use of TMS as a neuroplasticity marker for the quantification of the functional state of corticospinal pathways and changes and reorganization following injury and recovery as well as prognostic potential. Within the sensory rehabilitation domain, Plow et al. present a revised analysis of results obtained from a larger study investigating the use of tDCS paired with computer-based visual rehabilitative training to improve visual function in patients with hemianopia (14). They report that this combined training approach enhances the recovery of visual function as compared with training delivered alone and, furthermore, the effect of tDCS appears to differentially affect the magnitude and sequence of visual recovery. This article provides an example of a strategy that has been increasingly investigated in this field: the combination of NIBS with behavioral training to enhance neuroplasticity modulation and rehabilitative outcomes (15,16). The potential utility of NIBS as a therapeutic approach in traumatic brain injury (TBI) also has seen a significant rise in interest. Villamar et al. propose a rationale for the use of NIBS (i.e. TMS and tDCS) based on the pathophysiologic events that typically follow TBI (17). Specifically, the variations in pathophysiologic mechanisms across time suggest the need for differential and targeted intervention strategies for which the differential effects of the NIBS may be well suited. In cases of severe TBI, not only NIBS but also invasive brain stimulation may have therapeutic potential to improve behavioral functioning. Giacino et al. describe the experimental use of central thalamic deep brain stimulation (CT-DBS) to enhance arousal functions in chronic minimally conscious state patients by eliciting action potentials to excite thalamocortical and thalamostriatal pathways (18). The authors present results and discuss ongoing challenges from a case study suggesting that CT-DBS can significantly increase cognitive and motor functional outcomes and in some cases with sustained levels lasting beyond the stimulation period. Although these two articles highlight that neuromodulation techniques may be promising techniques to enhance recovery, there are still limited data to support more firm conclusions on this potential application. Furthermore, the issue of different mechanisms of action and effects when comparing invasive vs. NIBS needs to be considered.