Review articleDoes a single neurostimulation session really affect mood in healthy individuals? A systematic review
Introduction
Since the introduction of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) as non-invasive tools for examining motor cortex functioning, the application of neurostimulation has substantially increased over the last several decades. Multiple sessions of neurostimulation are frequently used in the treatment of psychiatric disorders such as depression (e.g., Burt et al., 2002, Mitchell and Loo, 2006, O’Reardon et al., 2007, Boggio et al., 2008, George et al., 2010). These techniques are also used to investigate neural conductions and connections in the human brain, and are of considerable interest for researchers interested in understanding the basic neurophysiology of mood in healthy participants (Paus et al., 2001, Pascual-Leone et al., 2002). Non-invasive neurostimulation techniques have also been used to investigate specific cognitive functions of the prefrontal cortex in healthy participants. The prefrontal cortex (PFC) plays an important role in the neuronal networks involved in emotion processing (which is lateralized in the PFC) and mood regulation (Nitsche et al., 2012). Given that prefrontal regions have been associated extensively with cognitive and emotional regulatory processes (Cerqueira et al., 2008, Damasio, 2000, Davidson et al., 2002), it is crucial to know whether the reported effects of neurostimulation cannot be attributed to mood changes. Therefore, in this review, we offer a systematic overview of studies reporting the effects of a single session of repetitive TMS and tDCS on self-reported mood in healthy participants (for a more elaborate review on the techniques, mechanisms of action, and safety of TMS and tDCS, see George and Aston-Jones (2010)).
TMS involves delivering a brief magnetic pulse to the scalp through a coil. The magnetic field penetrates the brain and induces an electric field in the underlying region of the cerebral cortex (Barker et al., 1985). An electrical field of sufficient intensity will depolarize cortical neurons generating action potentials and can either activate or suppress motor, sensory, or cognitive functions, depending on the brain location and parameters of its delivery (George and Belmaker, 2007). Several studies have shown that rTMS is a safe technique when recommended guidelines are followed (Rossi et al., 2009) and can produce neural and behavioral effects that last for up to 40 min (e.g., Tsuji and Rothwell, 2002, Peinemann et al., 2004). Importantly, it has been suggested that activation of the left DLPFC or deactivation of the right DLPFC might have a positive impact on mood and emotion in clinically depressed individuals (Mitchell and Loo, 2006). Indeed, rTMS has been shown to alter aspects of cortical excitability and cortical inhibition (Chen and Seitz, 2001). Low-frequency (LF)-rTMS (≤1 Hz) is considered to ‘inhibit’ cortical regional activity, while high-frequency (HF)-rTMS (≥1 Hz) ‘activates’ cortical areas (Chen et al., 1997, Maeda et al., 2000a). It should be acknowledged that there is inter-individual variability in these inhibitory/excitatory effects. Although, most research on inter-individual variability has focused on the motor cortex (e.g., Maeda et al., 2000b). Future research should expand their focus on other stimulation target sites. Early research in this area found that HF-rTMS applied to the left prefrontal cortex had a negative effect on mood in healthy volunteers (George et al., 1996, Pascual-Leone et al., 1996, Dearing et al., 1997). However, these studies were often characterized by small sample sizes while the effects obtained were limited and inconsistent, and perhaps most importantly, not sham-controlled. The presence of a sham (placebo) condition is used to try and ensure that changes in performance can be ascribed to TMS effects upon a specific brain area (for a more in depth discussion on the different sham conditions used in neurostimulation research, see Sandrini et al. (2011)). Therefore, a more comprehensive overview is needed to establish whether a single session of rTMS affects mood in healthy participants.
In recent years another neuromodulation tool (transcranial Direct Current Stimulation; tDCS), has received increased interest. tDCS is the application of a weak electrical direct current that flows between two electrodes (i.e. patches placed on the scalp). The current enters the brain from the anode, travels through the brain tissue towards the cathode, which has the ability to modulate spontaneous firing rates of the cortical neurons by depolarizing or hyperpolarizing the neural resting membrane potential. Anodal tDCS enhances while cathodal tDCS reduces cortical excitability (Priori, 2003; Nitsche et al., 2009).
Research has shown that 10 min of stimulation can produce neural and behavioral effects that last for up to 40 min (Lang et al., 2004). Furthermore, tDCS modulates excitability in the motor, visual, and prefrontal cortex and differs from other noninvasive brain stimulation techniques such as TMS, since it does not induce neuronal firing by suprathreshold neuronal membrane depolarization, but rather modulates spontaneous neuronal network activity (Nitsche et al., 2008, Priori et al., 2009). Hence, the term Neuromodulation is often used. For the readability of this paper and given its common use in the literature we will refer to Neurostimulation for both techniques. The effects of tDCS depend on the polarity of the electric current such that anodal stimulation increases brain activity and excitability while cathodal stimulation reduces it. Although tDCS electrical fields are relatively non-focal, electrode positioning is critical. TDCS studies usually use one anode and one cathode electrode placed over the scalp to modulate a particular area of the central nervous system. However, a reference electrode is sometimes positioned on the shoulder, arm or leg. Electrode positioning is usually determined according to the International EEG 10–20 System (for a review of tDCS studies exploring different brain areas see Utz et al. (2010)). In this review, several terms used to describe tDCS placements of the electrodes (i.e., “montages”) need to be discussed: next to the active electrode (which can be anodal or cathodal depending on the study question), researchers in the field also use the terms “reference” electrode to refer to the “neutral” electrode. However, the term “reference” electrode may also be problematic, because the “reference” electrode is not physiologically inert and can contribute to activity modulation as well. This could be a potential confound depending on the research question under investigation. Nonetheless, researchers use the above terms to highlight that they are operating based on the assumption that one electrode is being explored as the “stimulating” whereas the other is the “reference” (for a detailed discussion on the parameters of stimulation see Brunoni et al. (2012)). The most applied montage of the electrodes used in research on depression is bilateral stimulation at frontolateral locations [F3 and F4 of the international EEG 10/20 system (Jasper, 1958)]. In anodal stimulation of the left prefrontal cortex, the anode placed over F3 (left prefrontal) and the cathode/anode over F4 (right prefrontal). This montage is often referred to as bifrontal tDCS or bilateral tDCS. However, this terminology is not always used consistently in the neurostimulation literature. Bifrontal refers to the positioning of two anodal electrodes on frontal regions (F3 & F4) and two cathode electrodes over the left and right mastoids, while bilateral refers to “anode and cathode on the same place contra lateral”. For reasons of clarity, in this review we will describe in detail the specific montages used in tDCS studies (for an overview on electrode placements and subsequent effects see Nitsche et al. (2008)). TDCS is a safe method in humans as shown by neuro-psychological testing (e.g., Iyer et al., 2005, Fregni et al., 2006), electroencephalogram assessment (e.g., Iyer et al., 2005), neuroimaging studies (e.g., Nitsche et al., 2004) and brain metabolites evaluation (e.g. Nitsche and Paulus, 2001) (for a more elaborate review on the techniques, mechanisms of action, and safety, see George and Aston-Jones (2010); or a state of the art overview, see Nitsche et al. (2008)).
Importantly, although rTMS and tDCS are subject to different mechanisms of action – rTMS induces brief pulses of electric current of a relatively high intensity, whereas tDCS induces a continuous electric current of low intensity – stimulation of the PFC with rTMS and tDCS has been shown to produce similar effects in different neural circuitries (Fregni et al., 2008a), neurotransmitter systems (Keck et al., 2002, Nitsche et al., 2006, Strafella et al., 2001), and the treatment of psychiatric diseases (for a review see Miniussi et al., 2008, George et al., 2009, George and Aston-Jones, 2010). However, in patient populations these treatment studies are based on multiple rTMS or tDCS sessions. Nonetheless, investigating the effects of a single session of rTMS and tDCS in experimental research holds important implications. Given that effects on cognition (e.g. information processing) within a study could be (partly) explained by changes in mood it is crucial to scrutinize possible effects of neurostimulation on mood. Since an abundance of research has shown the impact of mood on cognition (e.g., Ashby et al., 1999, Pourtois et al., 2013), knowledge on the effect of neurostimulation on mood is crucial for understanding the effects on cognition in rTMS and tDCS research in healthy participants. Nevertheless, until now no unequivocal answer has been offered on this matter and the last review on this topic was conducted over 15 years ago (Mosimann et al., 2000). Based on the growing interest in and publication of rTMS and tDCS research (in healthy participants) over the last decade, an updated review on this topic seems warranted. Therefore, the aim of the present review is to provide a systematic overview of both rTMS and tDCS studies assessing the impact of one non-invasive stimulation session over the PFC on subjective self-reported mood of healthy participants. Moreover, we outline all possible stimulation sites and sides (left versus right (DL)PFC), as well as the frequency (HF vs LF), electrode placement, stimulation parameters, and mood measurement. Finally, it is important to note that the aim of this review is to not only focus on studies which emphasize the possible impact of neurostimulation on mood as a primary hypothesis, but to also examine studies which reported mood effects as secondary to the main research question. Consequently, we can incorporate more easily null-findings, which otherwise might not have been published, to give a more conclusive overview and allow for a broader discussion on this topic.
Section snippets
Methods
Articles for inclusion were identified by conducting a systematic literature search in the databases PubMed and Web of Science in the period between January 1955 and December 2014. The search criteria were ‘transcranial’, ‘prefrontal’, and ‘healthy’. Based on this combination of terms we identified 627 hits. After careful consideration (title and abstract), we focused on studies with one session of stimulation targeting the prefrontal cortex, healthy participants, including all parameters and
Description of the studies
The identified publications consisted of 30 studies, of which 13 were tDCS and 17 were rTMS studies. The studies comprise 16 papers which focused on mood effects of prefrontal non-invasive stimulation as a primary hypothesis, while in the other 14 studies mood changes were measured as a secondary outcome. Of these latter 14, two studies investigated the effect of HF-rTMS on sleep: Cohrs et al., 1998, Marshall et al., 2004. In two other studies, Fregni et al., 2008a, Fregni et al., 2008b looked
Discussion
In the current review 30 studies were included, of which 24 reported no changes in mood. Based on our extensive review several points are worth noting. First, there is the crucial impact of localization when conducting neurostimulation research. All rTMS studies which reported significant mood changes used the 5 cm rule in combination with the motor cortex site (i.e., motor threshold of the APB and ADM). In early studies this rule was used to place the TMS coil roughly over the prefrontal cortex
Acknowledgements
Preparation of this paper was supported by Grant BOF10/GOA/014 for a Concerted Research Action of Ghent University (awarded to RDR). This work was also supported by the Ghent University Multidisciplinary Research Partnership The integrative neuroscience of behavioral control” (CB). We thank Dr. Sean Hughes for his comments and language proofing of the paper.
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