Research reportTDCS increases cortical excitability: Direct evidence from TMS–EEG
Introduction
Transcranial direct current stimulation (tDCS) is offering new perspectives in cognitive neuroscience and neuropsychology in both research and therapeutic settings. Several studies have successfully employed tDCS to modulate cortical excitability, in turn affecting a wide range of sensorimotor and cognitive functions in healthy and pathological human brains (see Antal et al., 2011, Jacobson et al., 2012, Nitsche and Paulus, 2011, Utz et al., 2010, Vallar and Bolognini, 2011 for reviews). This evidence has fostered the application of this technique in rehabilitation settings (e.g., Brunoni et al., 2011), based on results showing that tDCS may induce not only on-line effects on spontaneous neuronal activity, but also long-lasting after-effects likely mediated by mechanisms of synaptic long-term potentiation and depression (i.e., LTP and Long-term Depression, LTD, respectively), which affect neuroplasticity (Liebetanz et al., 2002, Nitsche, Fricke et al., 2003, Nitsche et al., 2008, Stagg et al., 2009).
tDCS is effective in the rehabilitation of patients with neuropsychiatric and neurological disorders such as epilepsy (Fregni, Thome-Souza et al., 2006, Nitsche and Paulus, 2009), Parkinson's (Fregni et al., 2006) and Alzheimer's disease (Ferrucci et al., 2008), chronic pain (O'Connell et al., 2011, Bolognini et al., 2013), migraine (Antal et al., 2008, Dasilva et al., 2012), major depression (Boggio et al., 2008, Ferrucci et al., 2009, Brunoni et al., 2011, Nitsche et al., 2009), as well as cognitive and motor disorders of patients with cerebrovascular diseases (Bolognini, Pascual-Leone, & Fregni, 2009; Gomez et al., 2013; Kandel, Beis, Le Chapelain, Guesdon, & Paysant, 2012; Monti et al., 2012; Mylius et al., 2012).
tDCS offers several advantages that render this tool so attractive for neuro-rehabilitation, as compared with other brain stimulation techniques: it is safer than invasive brain stimulation, which is usually associated to higher surgical risks and costs; in comparison to Transcranial Magnetic Stimulation (i.e., TMS), it is less uncomfortable, easier to handle and less expensive.
Despite being increasingly used, the precise neurophysiologic mechanisms underlying tDCS effects remain to be fully elucidated. At a neuronal level, tDCS modulates cortical excitability by shifting the resting membrane potential in a polarity-dependent way: anodal stimulation increases the spontaneous firing rate, by slightly depolarizing the membranes, whereas cathodal stimulation decreases cortical excitability by hyperpolarizing neurons' membranes. This mechanism of action was first illustrated by pioneering in vivo animal studies (Bindman et al., 1962, Creutzfeldt et al., 1962, Purpura and McMurtry, 1965), showing that cortical excitability shifts depend on current polarity, stimulation intensity, as well as on the type and spatial orientation of the targeted neurons.
Long-lasting and polarity-dependent effects of tDCS were first explored in humans by stimulating the motor cortex and measuring the level of cortical excitability by means of motor evoked potentials (MEPs) by TMS (Nitsche and Paulus, 2001, Nitsche et al., 2005, Priori et al., 1998). The coupling of anodal-excitatory and cathodal-inhibitory effects are well established in the sensory and motor domains, both at physiological and behavioral levels, while evidence is more controversial for higher-level mental activity (Jacobson et al., 2012). Indeed, studies involving cognitive tasks show that while the anodal stimulation typically facilitates behavioral performance, the inhibitory effects of the cathodal stimulation are less consistent (Jacobson et al., 2012, Vallar and Bolognini, 2011).
On-line effects brought about by tDCS may be traced back to cellular mechanisms including membrane polarization. Conversely, longer-term after-effects may depend on LTP and LTD mechanisms, likely mediated by N-methyl-d-aspartate (NMDA) receptors and altering GABAergic activity and intracellular CA2+ concentration (Liebetanz et al., 2002, Nitsche, Fricke et al., 2003, Stagg et al., 2009). Indeed, the anodal after-effects are prolonged by the NMDA agonist d-Cycloserine (Nitsche, Jaussi et al., 2004), reduced by NMDA antagonist such as beta-adrenergic protanol (Nitsche et al., 2004), and abolished, irrespective of polarity, by NMDA-receptor-antagonist dextromethorphane. In addition to NMDA mechanisms, in a slice preparation of mouse motor cortex, anodal stimulation induced synaptic potentiation, depending on both brain-derived neurotrophic factor (BDNF) secretion, and tropomyosin-related kinase B (TrkB) activation (Fritsch et al., 2010). The long-term effects of tDCS also involve non-synaptic mechanisms arising from changes in pH and transmembrane proteins, which may alter neurons' membrane function (Ardolino, Bossi, Barbieri, & Priori, 2005).
Beyond shifting cortical excitability of the target area under the electrodes, tDCS may also affect cortical connectivity by modulating activity of distant brain regions, functionally or structurally connected to the stimulated area. For instance, Kirimoto et al., (2011) explored whether tDCS over the supplementary motor cortex modifies the excitability of ipsilateral primary motor (M1) and somatosensory (S1) cortices via neuronal connectivity, by measuring somatosensory evoked potentials (SEPs) and MEPs. Results showed that anodal tDCS decreased MEPs and increased SEPs amplitude, while cathodal stimulation yielded opposite effects.
Several studies recorded resting state electroencephalographic (EEG) and functional magnetic resonance imaging (fMRI) activity in neurologically unimpaired participants, during or immediately after tDCS, in order to gather evidence concerning tDCS-induced regional cerebral activations or deactivations. For instance, a modulation of Visual Evoked Potentials (VEPs) amplitude was found both during and after tDCS, with effects dependent on the stimulation polarity and duration (Accornero et al., 2007, Antal et al., 2004). In the language domain, Wirth and coauthors (2011) traced the neurophysiological underpinnings of the behavioral effects induced by anodal tDCS over left prefrontal cortex during a overt picture naming. Both behavioral and neurophysiological variables were tested during and after the end of the stimulation. An on-line enhancement of a language ERP component and an offline reduction of delta activity were reported, indicating that anodal tDCS induced an excitatory effect on frontally mediated neural processes and related language functions.
Lang et al., (2005) by means of PET, assessed the magnitude, duration and regional distribution of changes in regional Cerebral Blood Flow (rCBF), after tDCS stimulation over M1. When compared to sham tDCS, anodal and cathodal tDCS induced respectively widespread increases and decreases of rCBF in cortical and subcortical areas. Accordingly anodal tDCS over M1 increased rCBF, not only under the electrode, but also in a more widespread network, involving contralateral motor-related cortical areas (Zheng, Alsop, & Schlaug, 2011, using the arterial spin labeling technique).
Widespread activations induced by tDCS are in line with the observations made by computational models of current flow indicating that strong electric fields occur not only underneath and near the stimulating electrodes but also in the regions between them (Miranda, Mekonnen, Salvador, & Ruffini, 2013).
So far, our understanding of the precise electrophysiological effects of tDCS and how they spread across cortical networks is still far from being exhaustive (Brunoni et al., 2011). The combined use of neuroimaging techniques and tDCS can be crucial to improve our knowledge. In this perspective, we used an integrated TMS–Electroencephalography (TMS-EEG) system to explore the effects of anodal tDCS of the posterior parietal cortex (PPC). Global and local cortical excitability was assessed both on-line (i.e., during tDCS), and off-line (i.e., after 15 min from the end of the stimulation). The main advantage of this approach is to provide real-time and direct information on cortical reactivity, through TMS-evoked potentials (TEPs) recording and analysis. The PPC was chosen as TMS hotspot for two main reasons. First, we wanted to take advantage of the TMS-EEG technique, which allows exploring cortical reactivity of areas, such as the PPC, otherwise not functionally measurable, since they cannot produce a direct TMS output such as MEPs for M1 and phosphenes for the primary visual cortex (V1). Second, from a theoretical perspective, the PPC plays a key role in different sensorimotor and cognitive functions (Andersen and Cui, 2009, Critchley, 1953, Fogassi and Luppino, 2005, Ikkai and Curtis, 2011, Shomstein, 2012) and tDCS has been successfully applied to this area for modulating sensory (e.g., Bolognini et al., 2010, Bolognini, Olgiati et al., 2010, Bolognini et al., 2013, Convento et al., 2013, Mancini et al., 2012) and cognitive (Berryhill, Wencil, Branch Coslett, & Olson, 2010; Sparing et al., 2009; Stone & Tesche, 2009) processing in healthy participants.
Section snippets
Participants
Fourteen healthy, right-handed volunteers (four males, mean age 27 years, SD 5.9, range 22–38) participated in the study. Participants did not have any contraindication to noninvasive brain stimulation (Poreisz et al., 2007, Rossi et al., 2009), namely no history of medical disorders, no substance abuse or dependence, no use of central nervous system-effective medication, and, particularly, no psychiatric and neurological disorders, including brain surgery, tumor, or intracranial metal
Results
Fig. 1A shows the experimental set-up and the NBS positioning system, and Fig. 1B the EEG responses, recorded at the 60 electrodes (black traces), when TMS was applied over the PPC in one representative participant. The TEPs recorded at the electrode under the stimulator is shown in red trace. As already found in previous studies (Rosanova et al. 2009, Ferrarelli et al. 2012), TEPs waveform following PPC stimulation are characterized by two negative components within the first 100 msec. This
Discussion
To the best of our knowledge, this is the first study in which TMS and compatible continuous EEG recording is used to investigate on-line and after-effects of tDCS on a region outside the motor system. Our results show that, at a global level (i.e., GMFP), anodal tDCS of the right PPC increases cortical excitability in a temporal window of 0–100 msec both during and 15 min after the end of the stimulation. At the local level, anodal tDCS of the right PPC induces off-line widespread enhancements
Acknowledgments
We thank Simone Sarasso for his insightful suggestions.
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