tES Stimulation as a Tool to Investigate Cognitive Processes in Healthy Individuals
Abstract
Abstract. This paper is aimed at providing an introduction to up-to-date noninvasive brain stimulation tools that have been successful in modulating higher-level cognitive functions in healthy individuals. The current review focuses on transcranial electrical stimulation (tES) studies aiming to explore cognitive models from an experimental rather than clinical viewpoint. It focuses primarily on major advances in language, working memory, learning, response inhibition, and other executive functions in healthy individuals, and the use of different methods of electrical brain stimulation such as transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial random noise stimulation (tRNS). The final section summarizes the scientific novelty of the reviewed papers and discusses the possible roles of brain stimulation in future experimental research and clinical applications.
A range of neuroscience tools are used to investigate the human brain during cognitive tasks. Some are based on indirect activation measures (positron emission tomography, PET; functional magnetic resonance imaging, fMRI; near-infrared spectroscopy, NIRS), and others are based on electrical activity recordings (event-related potential, ERP; electroencephalogram, EEG; and magnetoencephalography, MEG). Although these methods provide excellent spatial and temporal resolution (respectively), they can only reveal correlations between brain regions and cognitive tasks but cannot account for causality. An alternative way to explore cognitive functions is to use transcranial magnetic stimulation (TMS), now a standard laboratory tool for investigating perceptual and cognitive functions (Walsh & Cowey, 1999), or more recent transcranial electrical stimulation (tES) techniques (see Paulus, Nitsche, & Antal, 2016) that have old scientific roots but were only recently developed to allow safe uses. The current review will focus on tES in cognitive research in healthy populations.
The interference of tES with brain processes, when coupled with a target cognitive function, can lead to facilitation or impairment of performance, and thus establish a causal link between the stimulated brain region and the cognitive function at hand. The current article discusses how this is done, the ways in which the direction of interference is determined, and presents numerous examples of recent findings obtained with tES methods. The methods can help identify areas that are causally involved in cognitive functions, their interactions, and the specific physiological mechanisms involved (Kuo & Nitsche, 2012).
As opposed to tES studies of the motor cortex, cognitive studies using tES are very heterogeneous as many functions and brain areas are included in cognition. Cognition can be defined as the processes an organism uses to organize information. This includes acquiring information (sensation and perception), selecting (attention), communicating (language), representing (understanding) and retaining (memory) information, and using it to guide behavior (reasoning and coordination of motor outputs). There are already several published reviews on cognitive studies using tES, however they typically include clinical (see a review by Berlim, Van den Eynde, & Daskalakis, 2013) or interventional aspects (see a review by Fregni et al., 2014), or focused on specific domains such as memory (see a review by Manenti, Cotelli, Robertson, & Miniussi, 2012). The current review focuses on tES studies aiming to explore cognitive models from an experimental rather than clinical viewpoint. The reviewed studies cover a representative sample of various cognitive domains, and they were selected based on previously successful applications of brain stimulation exploring cognitive functions in healthy individuals. The current review will mainly focus on major advances in functions such as language, working memory, learning, response inhibition, and other executive functions among healthy individuals by using transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial random noise stimulation (tRNS). Covering all cognitive functions is beyond the scope of the current paper.
Transcranial Direct Current Stimulation (tDCS)
Transcranial direct current stimulation (tDCS) is a noninvasive cortical stimulation technique that applies weak (0.5–2 mA) electrical currents using surface electrodes. The traditional methodology uses two electrodes, a cathode and an anode, placed over regions of interest on the scalp. The electrodes are placed on the scalp using elastic bands or adaptable caps similar to the ones used for EEG (see a review by Wagner, Valero-Cabre, & Pascual-Leone, 2007). The application of weak, continuous electrical current helps facilitate or inhibit particular areas of the brain, and their associated networks.
tDCS induces polarity-dependent cortical activity and excitability enhancements or reductions, which emerge during stimulation, but can persist for 1 hr after stimulation (Nitsche & Paulus, 2000, 2001; Nitsche et al., 2003, 2008). The primary mechanism behind tDCS is thought to be its modulation of the resting membrane potential, which affects spontaneous cortical activity; namely, anodal tDCS causes neural depolarization thus enhancing cortical excitability, and cathodal tDCS causes neural hyperpolarization and hence decreased cortical excitability (Nitsche & Paulus, 2000, 2001). The physiological effects of tDCS were first explored via stimulation of the motor cortex, and have been linked to the neurophysiological mechanisms of long-term potentiation and depression (Liebetanz, 2002; Nitsche et al., 2003; see also Stagg & Nitsche, 2011 for a comprehensive review of the physiological basis of tDCS). In addition, this method affords a highly reliable sham condition (Gandiga, Hummel, & Cohen, 2006).
tDCS studies of cognitive functions started after the first motor studies were published, based on the concept that stimulation effects depend on the polarity of the current flow, with brain excitability being usually increased by anodal tDCS and decreased by cathodal tDCS, as was found and replicated in the motor and visual domains. For cognitive domains, the anodal stimulation was found effective in facilitating cognitive functions, however the cathodal tDCS effects on cognition were challenged in a thorough meta-analysis (Jacobson, Koslowsky, & Lavidor, 2012). While there is much evidence supporting the facilitative effect of the anode (Boggio et al., 2009; Flöel, Rösser, Michka, Knecht, & Breitenstein, 2008; Fregni et al., 2005; Hsu et al., 2011), the cathodal effects are less consistently documented in the cognitive domain (Jacobson, Koslowsky, & Lavidor, 2012). Although there is some support for the classical inhibitory effects of cathodal stimulation (Berryhill, Wencil, Coslett, & Olson, 2010; Hsu et al., 2011; Ladeira et al., 2011; Penolazzi, Stramaccia, Braga, Mondini, & Galfano, 2014), there are some studies that have reported a null effect (Fregni et al., 2005) or even an opposite one (Antal, Kincses, Nitsche, Bartfai, & Paulus, 2004; Dockery, Hueckel-Weng, Birbaumer, & Plewnia, 2009; Pope & Miall, 2012; Weiss & Lavidor, 2012). Below we present and discuss major tDCS studies in language, working memory, learning, response inhibition, and cognitive control that will demonstrate further polarity effects in cognitive studies.
Language
The modern endeavor to understand the basics of language and its neural substrate that began with the seminal work of Broca (1865) and Wernicke (1874) has experienced a recent resurgence with advances in brain stimulation, which provides tools that enable the formulation of strong causal inferences (Silvanto & Pascual-Leone, 2012) in one of the prime brain functions: the language system.
To date, several tDCS studies have explored naming, picture naming, and verbal fluency. Naming is a basic, fundamental capacity of the human brain that requires a number of cognitive processes involving the perception of the visual stimuli, the semantic and lexical processing of their features, the selection and retrieval of relevant information, and finally the articulation of a target concept. Several studies have used tDCS to improve performance by employing anodal tDCS. For example, Iyer and colleagues (2005) provided the first direct evidence of a cognitive enhancement in the context of language production by showing that it is possible to transiently change human verbal fluency capacity by electrical stimulation, and showed that this effect depends on intensity. There were no significant effects on performance with 1-mA tDCS over the prefrontal cortex, however, with 2 mA, verbal fluency improved during anodal stimulation.
In another study, Sparing, Dafotakis, Meister, Thirugnanasambandam, and Fink (2008) explored whether tDCS could enhance visual picture naming. Fifteen healthy participants performed this task before, during, and after tDCS was applied over the posterior perisylvian region (PPR). This position corresponds to the location of Wernicke’s area, including the posterior part of the left superior temporal gyrus (STG), and has been used in a number of stimulation studies (e.g., Mottaghy et al., 1999). Using a double-blind, within-subjects design, participants underwent four different 2 mA stimulation sessions: anodal and cathodal stimulation of left PPR as the main target stimulation and anodal stimulation of the homologous region of the right hemisphere and sham stimulation as control conditions. The results showed that participants responded significantly faster following anodal tDCS to the left PPR. This significant decrease in naming latency was found immediately after the end of anodal tDCS to the left PPR, but was not evident during stimulation. No facilitation effect was observed 5- and 10-min post stimulation. Another successful montage that improved verbal fluency in healthy subjects was employed by Cattaneo, Pisoni, and Papagno (2011), where anodal stimulation of 2 mA was applied for 20 min over Broca’s region (and the reference electrode over the right supraorbitary region).
Another major contribution to the study of naming under tDCS was made by Ross, McCoy, Wolk, Coslett, and Olson (2010) who investigated whether stimulation of the anterior temporal lobes (ATL) would be effective in modulating the memory of the proper names of people the participants knew. The results showed that anodal stimulation to the right ATL significantly improved face naming accuracy for people but not for landmarks’, that were presented as control stimuli. The Ross et al. study (2010) is important because it also incorporated a control condition (the landmarks pictures), and implemented a design that provided a selective and specific effect which significantly enhanced the study’s validity.
Thus, anodal tDCS produced small yet consistent and significant effects in the studies reviewed above. Interestingly, although different regions of interest were targeted (PPR and the dorsolateral prefrontal cortex, DLPFC), naming/verbal fluency performance improved, suggesting that tDCS can directly affect the neural mechanism that underlies the function (e.g., PPR) or a remote terminal that is a part of the network that underlies the function (e.g., DLPFC). This interpretation seems plausible since picture naming and word generation involve a massive activation of the temporal and frontal regions (Indefrey & Levelt, 2004). To affect naming, it is probably better to use high intensity stimulation (1.5–2 mA), considering that 1 mA stimulation did not affect naming (Iyer et al., 2005). This should be done cautiously, as higher intensities generate stronger subjective sensations, hence increasing the difference between real and sham stimulation (O’Connell et al., 2012).
Working Memory
Working memory (WM) is the ability to temporarily hold and manipulate task-relevant information. WM load is considered to be the amount of temporarily stored WM items prior to WM retrieval and is hypothesized to impose higher demands on executive attention as its value increases. Thus, WM tasks that require active maintenance of temporarily stored high-load items are considered to be highly dependent on DLPFC function and executive attention (Kane & Engle, 2002). Most of the transcranial stimulation studies investigating the effects on WM performance stimulated the left DLPFC (Boggio et al., 2006, 2008; Fregni et al., 2005; Mulquiney, Hoy, Daskalakis, & Fitzgerald, 2011; a review by Utz, Dimova, Oppenländer, & Kerkhoff, 2010 and Zaehle, Sandmann, Thorne, Jäncke, & Herrmann, 2011; for other stimulation sites, see Sandrini, Fertonani, Cohen, & Miniussi, 2012).
One of the first studies looking at working memory was performed by Fregni et al. (2005). They were able to show an improvement in performance on the classic n-back (2-back and 3-back) working memory task with a 1-mA, 10-min stimulation session with the anode over left DLPFC and the cathode on the right supraorbital region. These findings were not replicated when the montage was reversed or when anodal stimulation occurred over the left motor region. A similar protocol was adapted by Ohn et al. (2008), this time with 30 min of stimulation. The improvement was noted both during and after the stimulation sessions. A single study then compared varying stimulation intensities (1 mA vs. 2 mA) and found that with 1-mA anodal stimulation there was a faster reaction time on the n-back test as compared with 2 mA, which challenged the notion that higher currents lead to stronger behavioral effects (Hoy et al., 2013).
In a recent study, Andrews, Hoy, Enticott, Daskalakis, and Fitzgerald (2011) reported an interesting result, in which increased digit span (forward, but not backward) was found after anodal tDCS of the left DLPFC, but only when tDCS had been previously delivered concurrently with an n-back working memory test, as compared to tDCS alone or sham tDCS with n-back testing. In other words, using tDCS with a working memory task subsequently increased cognitive control performance as assessed by a different working memory test (the digit span).
Research by Zaehle et al. (2011) characterized the effects of tDCS on working memory performance by measuring EEG responses. Anodal tDCS of the left DLPFC resulted in polarity-dependent changes (anodal increases and cathodal decreases) in EEG alpha and theta frequency over occipitotemporal regions, which are thought to reflect hippocampal-dependent learning processes in the brain (Cashdollar, Duncan, & Duzel, 2011). It should be noted that no behavioral effects of anodal or cathodal tDCS versus sham were seen in the Zaehle et al. study (2011), only effects of anodal versus cathodal stimulation.
In conclusion, we see that tDCS, even with low intensities and single applications, was found useful in improving performance in laboratory tasks of working memory. Stimulation increased WM performance on different storage-and-processing tasks (e.g., n-back speed of performance and accuracy; accuracy in a visual recognition and in a sequential-letter working memory task). The challenge here is to develop stimulation protocols that will generate (safe) long-term modulations (see Park, Seo, Kim, & Ko, 2014) and use ecological memory tasks rather than the artificial n-back.
Learning
Flöel and colleagues (2008) examined tDCS effects on learning and acquisition of novel vocabulary. In their experiment, tDCS stimulation was applied over the posterior part of the left perisylvian area in 19 young right-handed individuals, while participants had to acquire a miniature lexicon of 30 novel object names. This study employed a double-blind sham-controlled within-subjects design. Each participant was given anodal, cathodal (each 20 min of 1 mA), and sham sessions in a randomized, counterbalanced manner. The results indicated that with anodal stimulation, participants showed better associative learning compared to sham and cathodal stimulation. Mood ratings, blood pressure, heart rate, discomfort, RTs, and response styles were similar between stimulation conditions. Importantly, transfer of the vocabulary to the participants’ native language was also significantly better after learning under anodal tDCS than under cathodal tDCS or sham. However, no significant difference between the conditions was found for the lexical knowledge test after one week. This study was the first to show that anodal tDCS, when administered to the left hemisphere, significantly improves the acquisition of novel vocabulary in healthy subjects.
Another study by Liuzzi et al. (2010) tested the hypothesis that language is embodied in neural circuitry connections between perisylvian language areas and the motor cortex. They examined the functional relevance of the left motor cortex for the learning of a novel action word vocabulary by interfering with neural accessibility in the motor cortex by tDCS. The study utilized a between-subjects, double-blind, sham-controlled, randomized design on 30 young healthy, right-handed volunteers. Along with tDCS (anodal, cathodal, or sham), subjects learned a novel vocabulary of 76 concrete, body-related actions through an associative learning paradigm. Compared to the sham stimulation, cathodal tDCS reduced success rates in vocabulary acquisition, as shown by tests of novel action word translation into the native language. The analysis of learning behavior revealed a specific effect of cathodal tDCS on the ability to associatively pair actions with novel words. These effects were not found in the control conditions where tDCS was applied to the prefrontal cortex or when subjects learned object-related words.
This study provided direct evidence that the left motor cortex is causally involved in the acquisition of novel action-related words. In addition, this study stands out thanks to its rigorous methodological design. The inclusion of a target stimulation site alongside a control task clearly addressed the main possible alternative explanation and improved the validity of results. Second, although tDCS is not known for being highly precise in terms of localization, Liuzzi et al. (2010) demonstrated that even when using relatively large electrodes (25 cm2), it is possible to distinguish between close areas, the motor strip, and the frontal cortex. This is in line with recent neuroimaging studies which showed a significant spread of activation following tDCS stimulation at the area underneath the electrode (Holland et al., 2011; Meinzer et al., 2012). Finally, this study demonstrated that cathodal tDCS reduced success rates in vocabulary acquisition, thus providing another venue for tDCS applications in future research.
Response Inhibition
A common feature of human existence is the ability to reverse decisions after they are made but before they are implemented. This cognitive control process, termed response inhibition, allows individuals to recover from potentially harmful situations before it is too late – for example, avoiding touching a hot stove when realizing it is too hot, or not commenting negatively about a coworker who suddenly appears. Cognitive control in general, and response inhibition in particular, are impaired in several neuropsychiatric disorders, such as attention deficit hyperactivity disorder (ADHD; Aron & Poldrack, 2005), and appear to be critically dependent upon intact function of the right Inferior Frontal Gyrus (rIFG; Aron, Robbins, & Poldrack, 2004).
Response inhibition can be evaluated by the Stop-Signal Task (SST; Logan & Cowan, 1984). In the SST there are two types of trials: “go” trials and “stop” trials. In the “go” trials, subjects are required to make a simple discrimination task within a prespecified time window; the “go” trials are more frequent, thus setting up a prepotent response tendency. The “stop” trials are less frequent, and require subjects to refrain from making the response when a stop signal is randomly presented following the go signal (Logan & Cowan, 1984).
Cognitive control processes, in general, are attributed mainly to the prefrontal cortex (PFC). Response inhibition has been localized more specifically to the right inferior frontal gyrus (rIFG), based on both functional brain imaging and lesion-based approaches (Li et al., 2008; Rubia et al., 2001). Studies employing temporary deactivation using magnetic stimulation over the rIFG have indeed found impaired inhibitory control (Chambers et al., 2006), supporting the potential role of the rIFG in response inhibition. However, although magnetic stimulation was successful in establishing an interference stimulation protocol that impaired cognitive control (Figner et al., 2010), its use also involves some practical limitations such as mobility and subjects’ comfort. Therefore in recent years, we can find teams that employ tDCS to affect SST tasks, as described below. In line with the present review aims, we refer to tES studies that tested healthy (adult).
Jacobson, Javitt, and Lavidor (2011) demonstrated that anodal stimulation applied over the rIFG led to significant improvement in the SST performance, but did not modulate response time in the “go” trials (see Figure 1B). In addition, stimulation over rAG, an area which is known not to be involved in the SST (Chambers et al., 2006), did not affect response inhibition (see Figure 1A), demonstrating the regional selectivity of the effect. The Jacobson et al. (2012; see also Stramaccia et al., 2015) results both support theories of brain mechanisms underlying response inhibition, and provide a potential method for behavioral modification.
A different research team targeted a different area. Hsu et al. (2011) conducted a tDCS SST study to investigate the functional role of the pre-SMA in motor inhibition (Li, Huang, Constable, & Sinha, 2006). Three tDCS conditions were employed: Pre-SMA anodal/left cheek cathodal, left cheek anodal/pre-SMA cathodal, and a control group with no tDCS stimulation. Current intensity was set to 1.5 mA for 10 min. Hsu et al. (2011) found that the effects of inhibitory (cathodal) tDCS replicated previous magnetic stimulation findings by impairing performance on the task. The pattern was similar to magnetic stimulation findings in the sense that there was marked failure to inhibit responses when a stop signal was presented (an elevated non-cancelled rate). Additionally, facilitatory effects were observed as a consequence of applying excitatory (anodal) tDCS over the pre-SMA. Decreased non-cancelled rates suggested improvement in inhibiting responses when a stop signal was presented. This improvement or decrement in non-cancelled rates implies that neuronal excitability was modulated by tDCS, as many studies have suggested (Nitsche & Paulus, 2000). These findings also suggest a critical role for pre-SMA in suppressing unwanted actions and facilitating desired ones, as seen in a recent micro-stimulation study (Isoda & Hikosaka, 2007).
Whether dealing with the pre-SMA or the right IFG, SST studies clearly suggest that tDCS has potential clinical applications for individuals exhibiting difficulties with inhibitory control. However, further research is required to understand the nature of the neuronal changes following tDCS that enable modification of response inhibition (here as measured by SST performance). Jacobson, Ezra, Berger, and Lavidor (2012) conducted an EEG-tDCS study that suggested a possible neuronal mechanism for tDCS effects in the SST. They found that the right IFG stimulation protocol applied in their behavioral SST study (Jacobson et al., 2012; see Figures 1A–C) generated a significant and selective diminution of the power of theta band (4–7 Hz). The theta diminution was observed in the rIFG area (represented by the anode electrode), but was not found in the left orbitofrontal cortex (lOFC) area (represented by the cathode electrode). A significant effect was only observed in the theta but not in other bands. Since there is evidence that the electrophysiological activity associated with behavioral inhibition is theta band activity (Lansbergen, Schutter, & Kenemans, 2007; Wienbruch, Paul, Bauer, & Kivelitz, 2005), these results may help in accounting for the improvement in behavioral inhibition following tDCS over the rIFG (see Figure 1D–F).
Other Executive Functions
In addition to working memory (see above), tDCS has been shown to improve higher-order PFC-supported cognitive functions in different domains such as decision-making (Hecht, Walsh, & Lavidor, 2010), risk-taking (Fecteau, Knoch, et al., 2007; Fecteau, Pascual-Leone, et al., 2007), and probabilistic classification (Kincses, Antal, Nitsche, Bartfai, & Paulus, 2004). We will elaborate here on tDCS studies targeting executive control regulation.
Sela, Ivry, and Lavidor (2012) used tDCS to test the hypothesis that a prefrontal cognitive control network is involved in directing semantic decisions required for the comprehension of idioms. A recent conceptualization argues in favor of a broad role of this brain region in figurative language comprehension (Lauro, Tettamanti, Cappa, & Papagno, 2008; Papagno, 2010; see also the meta-analysis by Rapp, Mutschler, & Erb, 2012), and proposed that prefrontal regions are responsible for suppression of alternative interpretations and response monitoring during figurative comprehension.
Sela, Ivry, and Lavidor (2012) used a double-blind, sham-controlled design to explore this “PFC regulation hypothesis.” Participants were randomly allocated to one of two stimulation groups (left DLPFC anodal/right DLPFC cathodal or left DLPFC cathodal/right DLPFC anodal). The stimulation lasted 15 min, with an intensity of 1.5 mA. Over a one-week interval, participants were tested twice on a semantic decision task and a control task (a spoonerism task, which assesses phonological awareness; Romani, Ward, & Olson, 1999) after either receiving active or sham stimulation. The semantic decision task required participants to judge the relatedness of an idiom and a target word where the idiom was either predictable or not (predictability is the ability to complete the idiom based on its first words). Targets were figuratively related, literally related, or unrelated to the idiom. The results showed that after tDCS stimulation, a general deceleration (around 10%) in reaction times to targets was found. In addition, the neural enhancement of a left lateralized prefrontal network (Left DLPFC anodal/Right DLPFC cathodal) improved performance when participants had to make decisions on figurative targets of highly predictable idioms, whereas the neural enhancement of the opposite network (left DLPFC cathodal/Right DLPFC anodal) improved performance on literal targets of unpredictable idioms (see Figure 2). These effects were quite robust, explaining 28% (figurative targets, left DLPFC) and 23% (literal targets, right DLPFC) of the variance, respectively.
The Sela, Ivry, and Lavidor (2012) findings corroborated a hypothesis suggested by Papagno and colleagues (Lauro et al., 2008; Papagno, 2010), and showed how the PFC is involved in selection processes. Sela, Ivry, and Lavidor (2012) posited that the PFC regulates selection processes by implementing a top-down bias based on stimulus characteristics (e.g., idiom predictability).
tDCS was also shown to enhance complex problem-solving by anodal tDCS in the left DLPFC. A study by Cerruti and Schlaug (2009) tested whether prefrontal stimulation can enhance performance on the remote associates test (RAT). Typically, in RAT problems, subjects are presented with three words; for example AGE/MILE/SAND, and must find a common linguistic associate that forms a compound noun or a two-word phrase with each cue word-in this case, STONE (STONE-AGE, MILESTONE, and SANDSTONE). This task requires strong executive function capacities, since lateral associations and internal production of many words are needed until a key decision stage is reached where the subject must select or generate a single answer.
The Cerruti and Schlaug (2009) findings indicated that stimulating the left DLPFC led to increased fluency when it came to the generation of solutions. Their findings prompt interesting questions regarding the influence of tDCS on cognitive control processing and the role of the left DLPFC in supporting the executive control processes needed to solve verbal insight problems. To describe the underlying neurocognitive processes that may modulate verbal problem-solving, Metuki, Sela, and Lavidor (2012) replicated (with a few methodological modifications) the procedure used by Cerruti and Schlaug (2008). The results indicated that anodal tDCS over the left DLPFC enhanced solution recognition, but did not enhance solution generation for difficult problems (see Figure 3). Metuki et al. argued that these findings support the idea that prefrontal left hemisphere (LH) cognitive control mechanisms modulate linguistic processing and defined the conditions where the facilitation effects were effective and substantial. Both the Cerruti and Schlaug (2008) and the Metuki et al. (2012) studies show how physiological and cognitive hypotheses concerning facilitation effects are constrained by site specification (Cerruti & Schlaug, 2008) and experimental conditions (Metuki et al., 2012).
Neural Underpinning of tDCS Effects
Performance measures following tDCS should be considered the prime test to evaluate whether a particular set of stimulation parameters (e.g., electrode positions and size, stimulation intensity and duration) can create a transient change in behavior. Neuroimaging and electroencephalography methods can aid in revealing the nature of the changes that occur after anodal or cathodal stimulation. In spite of the noticeable effects of tDCS on cognitive functions with prefrontal stimulated brain regions, there have been relatively few studies on neural correlates of these effects, compared to stimulation of the motor cortex (Stagg & Nitsche, 2011). In healthy subjects, modulations of brain networks induced by tDCS on the prefrontal cortex were assessed through fMRI at rest (Holland et al., 2011; Keeser et al., 2011; Peña-Gómez et al., 2012).
Holland and colleagues (2011) tested whether tDCS over the left inferior frontal cortex can be used to increase spoken picture-naming performance in healthy participants. For all participants, the anode was placed over the left inferior frontal cortex (IFC) and the cathode was placed over the contralateral frontopolar cortex. The results showed a significant effect of left anodal tDCS on naming latency responses when compared to sham responses. The fMRI measures showed that left anodal tDCS significantly reduced activation in the left frontal cortex, including Broca’s area, compared to sham responses. The imaging data also showed a regionally specific effect. Within the stimulated frontal cortex, not all regions were equally affected; Broca’s area, but not other regions (e.g., precentral or anterior insular cortices) was modulated by anodal tDCS. Holland and colleagues suggested that the reduced activation in Broca’s area might be analogous to the neural priming effects that were seen when utilizing behavioral priming paradigms. A different imaging analysis was applied by Keeser et al. (2011), where healthy subjects underwent real and sham tDCS in random order on separate days. tDCS was applied for 20 min at 2 mA with the anode positioned over the left DLPFC and the cathode over the right supraorbital region. After real tDCS, and compared with sham tDCS, significant changes of regional brain connectivity were found for the default mode network (DMN) and the frontal-parietal networks both close to the primary stimulation site and in connected brain regions. These findings show that prefrontal tDCS modulates resting-state functional connectivity in distinct functional networks of the human brain. Peña-Gómez et al. (2012), in a similar study to Keeser et al. (2011), also scanned brains after active tDCS of the DLPFC and after sham. After active stimulation, functional network connectivity revealed increased synchrony within the focus attention components and reduced synchrony in the DMN components. Exciting results were reported by Stagg et al. (2013) who scanned subjects during application of tDCS to the left DLPFC. They demonstrated increased activation in regions anatomically connected to the DLPFC during anodal tDCS in conjunction with a decreased functional coupling between the left DLPFC and the thalami bilaterally. This finding is interesting because it might provide mechanistic explanations for the behavioral effects of anodal tDCS applied to the left DLPFC in terms of modulating functional connectivity between the DLPFC and thalami.
tACS: Harnessing Oscillatory Brain Activity to Explore and Improve Sensory and Cognitive Functions
Another tES method that can be harnessed to investigate and manipulate brain activity is tACS. tACS provides a potentially powerful approach to establish the functional role of neuronal oscillatory activities in the human brain and exploring the functional role of neural oscillations in cognitive tasks by stimulating the brain with biophysically relevant frequencies during task performance. tACS is thought to interact with ongoing rhythms in the cortex in a frequency-dependent manner, thereby interacting with specific functions of the stimulated region (Kanai, Chaieb, Antal, Walsh, & Paulus, 2008; Kanai, Paulus, & Walsh, 2010; Pogosyan, Gaynor, Eusebio, & Brown, 2009; Thut & Miniussi, 2009; Zaehle, Rach, & Herrmann, 2010). Oscillatory activity is believed to play an important role in linking the crosstalk between brain areas (Thut & Miniussi, 2009), and it has been argued that oscillations are particularly instrumental in top-down processing (see a review by Engel, Fries, & Singer, 2001) or in large-scale integration of bottom-up and top-down processes (Varela, Lachaux, Rodriguez, & Martinerie, 2001).
Although this technique is still largely unexplored and volume conduction effects are not wholly understood (Feurra et al., 2011; Kanai et al., 2010; Schutter & Hortensius, 2011; Zaghi, Acar, Hultgren, Boggio, & Fregni, 2010), recent studies have demonstrated the efficiency of tACS in a variety of domains. For instance, Kanai et al. (2010) showed that cortical excitability of the visual cortex as measured by the thresholds for magnetic pulse evoked phosphenes exhibited frequency dependency, in that 20 Hz tACS over the visual cortex enhanced the sensitivity of the visual cortex. A recent study demonstrated that stimulation in the alpha (7–12 Hz) and gamma bands (30–100 Hz) over the associative sensory cortex induced positive sensory sensations (Feurra et al., 2011).
In a well-cited tACS study, Polanía, Nitsche, Korman, Batsikadze, and Paulus (2012) simultaneously applied tACS at 6 Hz over the left prefrontal and parietal cortices with a relative 0 (“synchronized”) or 180 (“desynchronized”) phase difference or a placebo stimulation condition while healthy subjects performed a delayed letter discrimination task. The results showed that induced frontoparietal theta synchronization significantly improved visual memory-matching reaction times as compared to placebo stimulation. In contrast, exogenously induced frontoparietal theta desynchronization deteriorated performance.
In another study, Sela, Kilim, and Lavidor (2012) used tACS to investigate the effects of oscillatory prefrontal theta (~4–7 Hz) stimulation, a frequency involved in regulatory control during decision-making processes that involves risk-taking (Christie & Tata, 2009). To modulate risk-taking they used a well-established paradigm in the realm of risk-taking known as the Balloon Analog Risk Task (BART; Lejuez et al., 2002). In this task, participants pump a balloon without knowing when it will explode. The more the pump button is pressed, the more points accumulate while at the same time the risk of losing points with a balloon explosion increases. Subjects are thus pressured to decide whether to adopt risky behavior and keep pumping, or use a more conservative strategy and stop. The results showed a significant effect of left PFC stimulation, whereas right PFC and sham stimulations failed to produce any substantial effect on task performance. More specifically, the increase of sequential losses during theta stimulation over the left PFC suggested that subjects lost the ability to adjust their actions based on the negative feedback given to them explicitly during the task (the balloon exploded and they lost all the points they had earned in that round). In addition, it was suggested that left PFC stimulation interfered with a hypostasized “left to right theta dependent switch” that may be obligatory to switch from an explorative “risk-taking mode” to a “risk-averse” mode.
To examine working memory tasks, Jaušovec and Jaušovec (2014) divided 24 healthy young adults into two groups – frontal and parietal – who received theta band tACS with target electrodes placed over left frontal or parietal sites. Each subject was tested on a series of WM tasks (digit span and Corsi block tapping task) under sham and active stimulation in a single-blind design. Parietal tACS significantly increased WM storage capacity, as compared to sham tACS. No such influence was observed for left frontal tACS. Increased WM storage capacity was accompanied by an event-related potential (ERP) P300 latency decrease in the left hemisphere. Jaušovec and Jaušovec (2014) interpreted their results as emphasizing the causal relationship between WM storage capacity and theta frequency oscillations in the left parietal brain area.
Recently, an Italian group demonstrated the potential of tACS to improve fluid intelligence (Santarnecchi et al., 2013). In their study, an imperceptible alternating current delivered through the scalp over the left middle frontal gyrus resulted in a frequency-specific shortening of the time required to find the correct solution in a visuospatial abstract reasoning task classically employed to measure fluid intelligence abilities. Crucially, gamma-band stimulation selectively enhanced performance only on more complex trials involving conditional/logical reasoning.
In summary, while current number of cognitive studies with tACS are not large, the reported successful studies have led Kuo and Nitsche (2012) to predict that in the near future this method will serve to explore basic questions in other domains of cognition by utilizing the huge amount of the electrophysiological data gathered so far.
tRNS – Stochastic Resonance
Transcranial random noise stimulation (tRNS) is a relatively novel tES technique, where a random electrical oscillation spectrum is applied over the cortex. Chaieb et al. (2009), for instance, applied stimulating currents with the 1/f-type power spectrum characteristic of noise measured in the nervous system over the primary motor cortex (M1). The rationale behind this method was the beneficial role played by input noise in sensitizing neuronal systems, which makes it possible to detect weak subthreshold signals. This technique can be used as a sensory prosthesis through a mechanism known as stochastic resonance (Wiesenfeld & Moss, 1995). The fine-tuning of noise in the nervous system may in turn lead to a change in the state of synchrony in oscillating neural networks, affecting local or global processing (e.g., Panagiotaropoulos, Deco, Kapoor, & Logothetis, 2012). In turn, this may provide additional means of cortical stimulation which is not subject to polarity and once optimized, may induce enduring therapeutically relevant aftereffects (Terney, Chaieb, Moliadze, Antal, & Paulus, 2008).
Most current studies have explored the motor cortex; hence, little is known about cognitive functions under tRNS. When applied over M1, it was shown to induce facilitation of motor evoked potentials (MEPs), with an effect outlasting the 10-min stimulation duration, with aftereffects lasting up to 90 min post stimulation (Terney et al., 2008). Chaieb et al. (2009) argued that tRNS possesses many advantages over currently used techniques. In particular, tRNS is an oscillatory current and thus does not have the polarity constraints of tDCS or the perceptible skin sensations when applied.
There have been few cognitive studies with tRNS. Roi Cohen-Kadosh’s group in Oxford reported encouraging findings of improved cognitive training effects when combined with tRNS. In one of their studies, they applied bilateral tRNS over the DLPFC for five consecutive days of tRNS-accompanied arithmetic learning (Snowball et al., 2013). The subjects were healthy young adults with no history of neurological or psychiatric illness, and were randomly divided into a tRNS group (13 subjects) and a sham group (12 subjects). Both the experimenter who assigned participants to the two stimulation groups and the experimenter who administered the stimulation were blinded, and subjects were unaware of the existence of a sham condition. Calculation and drill learning rates were significantly higher for the tRNS group relative to sham controls. Snowball et al. (2013) further tested the groups 6 months after training and reported long-lasting behavioral and physiological modifications in the stimulated group compared to the sham controls for trained and nontrained calculation material. Similar results from the field of numerical cognition were also reported (Cappelletti et al., 2013). In a different cognitive task of face perception, Banissy, Duchaine, Susilo, Rezlescu, and Romanska (2014) reported that 20 min of tRNS of the posterior temporal cortices facilitated facial identity perception compared to the sham condition, but not trustworthiness perception.
However, the mechanism governing tRNS and the consistency of its effects remain unclear. Mulquiney et al. (2011) directly compared tRNS and tDCS effects on working memory using the Sternberg WM task, following stimulation over the DLPFC. Their results replicated previous findings with enhanced memory performance following tDCS, but failed to support the hypothesis that tRNS improves WM. This study had some power limitations in that only 12 subjects were tested; however, it is still important due to the direct comparison of tDCS and tRNS in a cognitive function with healthy subjects. Another study that compared tDCS and tRNS with a convincing sample size (N = 107) was reported by Fertonani, Pirulli, and Miniussi (2011) in perceptual learning with stimulation over the primary visual cortex. They observed an improvement in performance when subjects were stimulated with high frequency (hf-tRNS, 100–640 Hz), and some (not significant) improvement with low-frequency tRNS (0.1–100 Hz), while anodal tDCS reduced performance, and cathodal tDCS did not differ from sham. If we adapt Fertonani et al. (2011) results together with previous similar results with motor cortex stimulation (Terney et al., 2008), the mechanism of action of tRNS might be based on the repeated subthreshold stimulations that prevent homeostasis of the system (Miniussi, Harris, & Ruzzoli, 2013). This effect might potentiate the activity of the neural populations involved in cognitive tasks that facilitate brain plasticity by strengthening synaptic transmission between neurons. Modulation of synaptic transmission efficacy can result in excitability and activity changes in specific cortical networks that are activated by the task’s execution, and these changes correlate with cognitive plasticity at the behavioral level.
Summary
As the current review shows, the utility of using tES methods (tDCS, tACS, and tRNS) over human brains to temporarily modulate cognitive functions in healthy brains, from language to executive functions, was well demonstrated. The variability in the population being studied, the study protocol, stimulation parameters, montages used, timing and method of testing, all may play a role in these discrepancies.
One clear implication of these results is clinical, and the next paragraph considers future developments in this direction. However, the scientific value of tES as tools to explore novel theoretical hypotheses and uncover the neural basis of cognitive functioning should not be underestimated. The cognitive studies described above and others have tackled intriguing questions such as the contribution of the prefrontal cortex and the motor system to language production, learning, and comprehension (e.g., Cerruti & Schlaug, 2009; Iyer et al., 2005; Liuzzi et al., 2010), as well as issues of connectivity (Meinzer et al., 2012), and transcallosal disinhibition (Thiel et al., 2006) using relatively safe, noninvasive methods.
Berryhill, Peterson, Jones, and Stephens (2014) published recently several well-supported points that should be considered when designing a tES study with healthy subjects, pointing to the importance of using challenging tasks to keep the subjects sufficiently engaged and motivated. They also argued that the individual differences might modulate stimulation effects (e.g., working memory capacity, or motivational differences, see Sela, Kilim, & Lavidor 2012). Another reservation worth consideration is that effect sizes in tES studies of cognitive functions in healthy adults are relatively modest (between 0.2 and 0.6, see the review by Jacobson et al., 2012). However, considering the complexity and variety of cognitive functions and their neural correlates, it is rather impressive that a short application of weak electrical currents generates consistent changes in cognitive behaviors.
The review demonstrated the potential contribution of tDCS to basic cognitive science, where good experimental design with precise control conditions and tasks is required. The review also highlighted the efficiency of tDCS as a cognitive enhancement method, however here we still miss studies that explore higher dose protocols and longer term effects.
Future Directions – tES Use in Clinical Contexts and With Training
We saw here that studies with healthy subjects have shown that tES can promote changes in cognitive function after only one session (Kuo & Nitsche, 2012). This area of study may contribute in the future to the investigation of tES applications as an important noninvasive tool for the rehabilitation of cognitive functions. However, the studies so far suggest that the changes in cognitive performance observed after tES stimulation are short lived; this warrants more studies to better explore the development of the application of tES in patients with neurocognitive disorders.
Cognitive training has recently become the preferred method to affect brain plasticity. In the last 20 years, controlled cognitive training studies have demonstrated that learning of new cognitive skills and improving existing skills is possible across different populations and ages (see a review by Green & Bavelier, 2008). Successful training has been documented in clinical populations (Schizophrenia: McGurk, Twamley, Sitzer, McHugo, & Mueser, 2007; ADHD: Shalev, Tsal, & Mevorach, 2007). Several brain-imaging studies have recently revealed training-induced plasticity in the healthy human brain (i.e., Erickson et al., 2007; McNab et al., 2009). Facilitation effects of the integration of tDCS with cognitive training are only beginning to be explored (Cohen Kadosh, Soskic, Iuculano, Kanai, & Walsh, 2010; Ditye, Jacobson, Walsh, & Lavidor, 2012; Reis et al., 2009; Snowball et al., 2013). Combining tES protocols with cognitive training holds great promise for future research. It may be used as a tool for enhancing cognitive functions such as memory, language and attention in healthy individuals and in patients.
We hereby presented an overview of tES use in cognitive research with healthy subjects. The interest, both academic as of the lay public and the media around the tES, will probably continue to increase, given the promising results that the technique has presented in clinical studies as well (Convento et al., 2016). With the promising results found in various cognitive stimulation studies, further studies, with robust methodologies, should strive to replicate, expand, and optimize the findings, perhaps testing larger, different samples and varying tES parameters such as electrode size, dosage, reference electrode, length of sessions, number of days of application, and more. Such studies are still warranted in order to provide a definite picture regarding tES clinical efficacy.
This article presents studies that were supported by the Israel Academy of Sciences Grant No. 367/14, and the Israeli Center of Research Excellence (I-CORE) in Cognition (I-CORE Program 51/11).
Prof. Michal Lavidor is a professor of Psychology in the Department of Psychology at Bar Ilan University (Israel) and the head of the Cognitive Neuroscience laboratory at the Gonda Brain Research Center at this university. Research in her laboratory focuses on the neural basis of language and includes work on hemisphere-based language processes, visual word recognition, gestures, prosody, and the involvement of executive functions in semantic processing. Lavidor and her team develop noninvasive brain stimulation protocols to enhance interhemispheric cooperation and ultimately improve cognitive functions involved in word and emotion recognition.
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