Clinical research with transcranial direct current stimulation (tDCS): Challenges and future directions

Abstract

Background Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity, direct current to cortical areas facilitating or inhibiting spontaneous neuronal activity. In the past ten years, tDCS physiological mechanisms of action have been intensively investigated giving support for the investigation of its applications in clinical neuropsychiatry and rehabilitation. However, new methodological, ethical, and regulatory issues emerge when translating the findings of preclinical and phase I studies into phase II and III clinical studies. The aim of this comprehensive review is to discuss the key challenges of this process and possible methods to address them. Methods We convened a workgroup of researchers in the field to review, discuss and provide updates and key challenges of neuromodulation use for clinical research. Main Findings/Discussion We reviewed several basic and clinical studies in the field and identified potential limitations, taking into account the particularities of the technique. We review and discuss the findings into four topics: (i) mechanisms of action of tDCS, parameters of use and computer-based human brain modeling investigating electric current fields and magnitude induced by tDCS; (ii) methodological aspects related to the clinical research of tDCS as divided according to study phase (i.e., preclinical, phase I, phase II and phase III studies); (iii) ethical and regulatory concerns; (iv) future directions regarding novel approaches, novel devices, and future studies involving tDCS. Finally, we propose some alternative methods to facilitate clinical research on tDCS.

Effects of tDCS on motor learning and memory formation: A consensus and critical position paper

“…Systematic determination of the optimal timing of stimulation for inducing long-lasting effects, and how this varies across individuals, is another avenue where more research is needed (Manenti, Sandrini, Brambilla, & Cotelli, 2016;Martin, Liu, Alonzo, Green, & Loo, 2014). Indeed, a more coordinated effort where experimental parameters and modeling assumptions are iteratively refined is required (Bestmann, 2015;Brunoni et al, 2012).…”

“…Noninvasive brain stimulation (NIBS), most commonly repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), have been used to modulate motor and cognitive functions in human subjects (Brunoni et al, 2012;Bütefisch, Khurana, Kopylev, & Cohen, 2004;Duque et al, 2007;Jahanshahi & Rothwell, 2000;Marshall, Helgadottir, Molle, & Born, 2006;Perceval, Floel, & Meinzer, 2016;Wassermann, Tormos, & Pascual-Leone, 1998) (Figure 1) a . It has been argued that rTMS and tDCS can either enhance or decrease excitability in targeted cortical regions depending on the parameters of stimulation employed (Chen et al, 1997;Galea, Jayaram, Ajagbe, & Celnik, 2009;Labruna et al, 2016;Woods et al, 2016) and the underlying intrinsic state of the stimulated brain networks (Dayan, Censor, Buch, Sandrini, & Cohen, 2013;Sandrini, Umilta, & Rusconi, 2011).…”

Excitability modulation of the motor system induced by transcranial direct current stimulation: A multimodal approach

“…Specifically, when tDCS is applied over M1, the main effect observed is an increase in the amplitude of the motor evoked potential (MEP) in the contralateral hand muscles after anodal stimulation, and a decrease after the cathodal one (Nitsche and Paulus, 2000;Nitsche and Paulus, 2001). To overcome the limitations of this indirect approach, several studies have focused their attention on other neurophysiologic measurements as surrogate markers of tDCS-induced cortical neuromodulatory effects (Brunoni et al, 2011). In this framework, the use of neuroimaging methods, such as functional magnetic resonance (Baudewig et al, 2001;Jang et al, 2009;Kwon et al, 2008;Polania et al, 2012;Stagg et al, 2009a), positron emission tomography Paquette et al, 2011), laser doppler flowmetry (Wachter et al, 2011) and electroencephalography (EEG) (Ardolino et al, 2005;Polania et al, 2010a), have provided further evidence of changes in neural activity induced by tDCS.…”

Effects of acute transcranial direct current stimulation in hot and cold working memory tasks in healthy and depressed subjects

“…Certified psychiatrists screened the participants using the Portuguesetranslated version of the MINI [23] and assessed depression severity with the Portugueseversion of the 17-items HDRS [13]. (Table 1) ( Table 1) The depressed subjects were recruited from an ongoing non-inferiority, triple-arm, Depressed subjects fulfilled the main eligibility criteria: (1) were antidepressant-free for at least 3 weeks (5 weeks for fluoxetine); (2) presented score of at least 17 on the HDRS-17; (3) aged between 18 and 40 years-old; (4) at least 12 years of schooling; (5) absence of other medical and psychiatric diagnoses (except for anxiety disorders whether in comorbidity with MDD). Healthy controls were matched according to gender and years of schooling, and were recruited among students and civil servants from the study site, in the University of São Paulo (São Paulo, Brazil).…”

“…In this context, tDCS is a useful tool to induce prefrontal cortex activation. TDCS is a non-invasive neuromodulatory technique that employs weak direct currents (0.5-2 mA) to modulate brain activity [4] by regulating the frequency of action potentials triggered in the neuronal network [3]. Previous reports demonstrated that anodal tDCS over the DLPFC exerts beneficial effects in cognitive tasks [5], although most of them were methodologically limited [7,16,24,28].…”