Noninvasive Spinal Cord Stimulation: Technical Aspects and Therapeutic Applications Raffaele Nardone, MD, PhD* †‡ ; Yvonne Höller, PhD* ‡ ; Alexandra Taylor, MSc* ‡ ; Aljoscha Thomschewski, BSc* ‡ ; Andrea Orioli, PhD † ; Vanessa Frey, MSc* ‡ ; Eugen Trinka, MD* ‡ ; Francesco Brigo, MD †§ Background: Electrical and magnetic trans-spinal stimulation can be used to increase the motor output of multiple spinal segments and modulate cortico-spinal excitability. The application of direct current through the scalp as well as repetitive transcranial magnetic stimulation are known to influence brain excitability, and hence can also modulate other central nervous system structures, including spinal cord. Objective: This study aimed to evaluate the effects and the therapeutic usefulness of these noninvasive neuromodulatory techniques in healthy subjects and in the neurorehabilitation of patients with spinal cord disorders, as well as to discuss the possible mechanisms of action. A comprehensive review that summarizes previous studies using noninvasive spinal cord stimu- lation is lacking. Methods: PubMed (MEDLINE) and EMBASE were systematically searched to identify the most relevant published studies. We performed here an extensive review in this field. Results: By decreasing the spinal reflex excitability, electrical and magnetic trans-spinal stimulation could be helpful in normal- izing reflex hyperexcitability and treating hypertonia in subjects with lesions to upper motor neurons. Transcutaneous spinal direct current stimulation, based on applying direct current through the skin, influences the ascending and descending spinal pathways as well as spinal reflex excitability, and there is increasing evidence that it also can induce prolonged functional neuroplastic changes. When delivered repetitively, magnetic stimulation could also modulate spinal cord functions; however, at present only a few studies have documented spastic-reducing effects induced by repetitive spinal magnetic stimulation. Moreover, paired peripheral and transcranial stimulation can be used to target the spinal cord and may have potential for neuromodulation in spinal cord-injured subjects. Conclusions: Noninvasive electrical and magnetic spinal stimulation may provide reliable means to characterize important neurophysiologic and pathophysiologic aspects of spinal cord function. Moreover, transcutaneous direct current stimulation and repetitive magnetic stimulation may hold therapeutic promise in patients with spinal cord disorders, although future well- controlled studies are needed to corroborate and extend the preliminary findings. Keywords: Electrical trans-spinal stimulation, magnetic trans-spinal stimulation, repetitive magnetic stimulation, spinal cord disorder, transcutaneous direct current stimulation Conflict of Interest: The authors reported no conflict of interest. INTRODUCTION Noninvasive transcutaneous electric stimulation of the spine (tsESS) and transcutaneous magnetic stimulation of the spine (tsMSS) of the spine over cervicothoracic or thoracolumbar regions in healthy humans at rest produce multisegmental compound muscle action potentials. These compound muscle action poten- tials, also termed transpinal evoked potentials, are evoked in distal and proximal muscles of upper and lower limbs in animals and humans (1,2). Both tsESS and tsMSS of the spine over the cervicothoracic or thoracolumbar region significantly reduce the amplitude of the Hoffmann (H)-reflexes. Furthermore, the transpinal evoked poten- tials recorded from arm or leg muscles are not susceptible to homosynaptic depression, have nearly half the latency of the H-reflex, and are increased upon excitation of group I afferents (1–3). Address correspondence to: Raffaele Nardone, MD, PhD, Department of Neurol- ogy, Franz Tappeiner Hospital, Merano, Via Rossini, 5, 39012 Merano (BZ), Italy. Email: raffaele.nardone@asbmeran-o.it * Department of Neurology, Christian Doppler Klinik, Paracelsus Medical Univer- sity and Centre for Cognitive Neuroscience, Salzburg, Austria; † Department of Neurology, Franz Tappeiner Hospital, Merano, Italy; ‡ Spinal Cord Injury and Tissue Regeneration Center, Paracelsus Medical Univer- sity, Salzburg, Austria; and § Department of Neurological and Movement Sciences. Section of Clinical Neu- rology, University of Verona, Verona, Italy For more information on author guidelines, an explanation of our peer review process, and conflict of interest informed consent policies, please go to http:// www.wiley.com/WileyCDA/Section/id-301854.html Neuromodulation: Technology at the Neural Interface Received: February 21, 2015 Revised: May 23, 2015 Accepted: June 3, 2015 (onlinelibrary.wiley.com) DOI: 10.1111/ner.12332 1 www.neuromodulationjournal.com Neuromodulation 2015; ••: ••–•• © 2015 International Neuromodulation Society