Brief Communication Effects of transcranial direct current stimulation coupled with repetitive electrical stimulation on cortical spreading depression Felipe Fregni a, ⁎ , David Liebetanz b , Katia K. Monte-Silva c , Manuella B. Oliveira c , Angela A. Santos c , Michael A. Nitsche b , Alvaro Pascual-Leone a , Rubem C.A. Guedes c a Center for Noninvasive Brain Stimulation, Harvard Medical School and Beth Israel Deaconess Medical Center, 330 Brookline Ave, KS 452, Boston, MA 02215, USA b Department of Clinical Neurophysiology, Georg-August-University, Goettingen, Germany c Laboratory of Neurophysiology and Nutrition, Department of Nutrition, Federal University of Pernambuco State, Recife, Brazil Received 12 July 2006; revised 28 September 2006; accepted 29 September 2006 Available online 17 November 2006 Abstract We have recently shown that two techniques of brain stimulation – repetitive electrical stimulation (ES) (that mimics transcranial magnetic stimulation) and transcranial direct current stimulation (tDCS) – modify the velocity of cortical spreading depression (CSD) significantly. Herein we aimed to study the effects of these two techniques combined on CSD. Thirty-two Wistar rats were divided into four groups according to the treatment: sham tDCS/sham ES, sham tDCS/1 Hz ES, anodal tDCS/1 Hz ES, cathodal tDCS/1 Hz ES. Our findings show that 1 Hz ES reduced CSD velocity, and this effect was modified by either anodal or cathodal tDCS. Anodal tDCS induced larger effects than cathodal tDCS. Hereby CSD velocity was actually increased significantly after anodal tDCS/1 Hz ES. Our results show that combining two techniques of brain stimulation can modify significantly the effects of ES alone on cortical excitability as measured by the neurophysiological parameter of cortical spreading depression and therefore provide important insights into the effects of this new approach of brain stimulation on cortical activity. © 2006 Elsevier Inc. All rights reserved. Keywords: Cortical spreading depression; Cortical electrical stimulation; Transcranial direct current stimulation; Transcranial magnetic stimulation; Wistar rats; Cortical excitability We have recently shown that cortical stimulation with repetitive electrical stimulation (ES) (a technique that mimics the effects of transcranial magnetic stimulation) and with transcranial direct current stimulation (tDCS) results in a sig- nificant change in the velocity of the phenomenon of cortical spreading depression (Fregni et al., 2005a; Liebetanz et al., 2006). Because the interest in the clinical application of brain stimulation has been increasing and recent studies investigating the use of both techniques in combination in humans subjects (Siebner et al., 2004; Lang et al., 2004) showed that priming rTMS treatment with tDCS modifies the effects of rTMS on motor cortex excitability, the further exploration of the neurophysiological effects of this strategy of brain stimulation is warranted. Therefore we aimed to investigate the effects of preconditioning of cortical electrical stimulation with tDCS on an animal model of cortical spreading depression (CSD), comparing the effects of 1 Hz ES (preconditioned with sham tDCS) vs. 1 Hz ES preconditioned with either anodal or cathodal tDCS on the phenomenon of CSD. In this study, we used CSD as an index of brain function. This phenomenon was first described by Leão (Leao, 1944; Teive et al., 2005) and it is characterized by massive alterations in cerebrocortical ion homeostasis in response to the stimulation of a point of the brain tissue (Somjen, 2005). These alterations result in a wave of neuronal depolarization that propagates at a rate of 2–5 mm min - 1 across the cortical surface, accompanied by reversible electroencephalogram (EEG) suppression and a negative deflection of the direct current potential (Guedes and Cavalheiro, 1997). CSD has been extensively studied in several conditions of brain function alteration, providing important information about brain activity, therefore being a useful index to study brain function experimentally (Guedes, 1984; Guedes, 2005). Finally, we used repetitive electrical stimulation, because the technical limitations of rTMS in rats result in a diffuse Experimental Neurology 204 (2007) 462 – 466 www.elsevier.com/locate/yexnr ⁎ Corresponding author. Fax: +1 617 975 5322. E-mail address: ffregni@bidmc.harvard.edu (F. Fregni). 0014-4886/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2006.09.019