Evidence demonstrates that left PFC tDCS can modulate training-related performance gains in speeded decision-making (Filmer et al., 2013a; Filmer et al., 2013b; Filmer et al., 2019a, Filmer et al., 2017; Erdhardt et al., 2020). Crucially however, how tDCS alters frontal cortex function is not yet fully understood.
One way in which prefrontal tDCS might alter brain function is by modulating plasticity in the fronto-striatal pathways. Studies in animals have shown that frontal cortex anodal tDCS increases fMRI signal intensities in the nucleus accumbens (Takano et al., 2011), and striatal dopamine levels (Leffa et al., 2016). Lu et al. (2015) showed that anodal tDCS over the frontal cortex not only increased whole-brain dopamine levels but also relieved symptoms in a mouse model of Parkinson’s disease, similar to effects of levodopa, an antiparkisonian drug which is converted to dopamine in the intracellular space of dopaminergic midbrain neurons. Studies in humans have shown that prefrontal tDCS remotely activates the striatum (Chib et al., 2013), alters striatal metabolites (Hone-Blanchet et al., 2016), and alters midbrain dopamine release (Fonteneau et al., 2018; Fukai et al., 2019). Furthermore, improvements in task performance correlates with the extent of striatal activation. For example, one recent study showed that prefrontal tDCS results in a similar pattern of brain activation as Levodopa, the dopamine precursor which stimulates dopamine D1 and D2 receptors (Meyer et al., 2019). In a similar vein, strong modulatory effects of pharmacological manipulations of dopamine on tDCS-induced motor cortex plasticity have been shown. For example, Levodopa combined with 2mA motor cortex tDCS resulted in a 20-fold increase in the persistence of tDCS-induced aftereffects, measured via change in motor-evoked potentials, a marker of corticospinal excitability (Kuo et al., 2008). Conversely, blocking dopamine D2 receptors completely removed tDCS-induced aftereffects (Nitsche et al., 2006). The effect of modulating dopamine on tDCS-induced plasticity has been replicated with different types of dopamine agonists and antagonists (Nitsche et al., 2006; Monte-Silva et al., 2010). Despite these observations suggesting a role for dopamine in the effect of tDCS on brain activity, to the best of our knowledge, only three published studies have aimed to manipulate dopamine to examine how it modifies the effect of tDCS on behaviour (Jongkees et al., 2015; Dennison et al., 2019; Borwick et al., 2020). Using tyrosine to manipulate dopamine, these studies found that tyrosine tended to attenuate the effects of offline prefrontal tDCS on cognitive function (Jongkees et al., 2015; Dennison et al., 2019; Borwick et al., 2020). These results are tricky to interpret due to the following reasons. First, tyrosine is a precursor to the dopamine precursor Levodopa and only subtly increases brain dopamine, because tyrosine’s conversion to Levodopa by the rate-limiting tyrosine-hydroxylase enzyme is limited by competition with other endogenous amino acids. In contrast to moderate 100mg doses of Levodopa which significantly increases blood plasma levels of dopamine (Dingemanse et al., 1995), tyrosine results only in subtle increases in plasma dopamine (Cuche et al., 1985). Small increases in dopamine preferentially stimulates presynaptic dopamine D2-like receptors, which paradoxically reduce dopamine release across the synaptic cleft via synaptic autoinhibition (Benoit-Marand et al., 2001; Schmitz et al., 2003). Thus, similar to tyrosine reducing PFC-tDCS effects on cognitive function (Jongkees et al., 2015; Dennison et al., 2019; Borwick et al., 2020), low doses of dopamine drugs (e.g., 25mg Levodopa) reduces the effect of M1 tDCS on motor-evoked potentials (Monte-Silva et al., 2009; Monte-Silva et al., 2010; Fresnoza et al., 2014). This contrasts with moderate doses of dopamine drugs (e.g., 100mg Levodopa) which increases the effect of M1-tDCS on motor evoked potentials. No published studies thus far have tested whether moderate doses of dopamine might increase prefrontal tDCS effects on behaviour, similar to its effects on motor-evoked potentials. To test the idea that prefrontal tDCS affects behavior partly by altering dopamine function, we will combine left PFC cathodal tDCS with a moderate dose of Levodopa, a dopamine precursor known to boost the persistence of M1 tDCS-induced aftereffects at moderate doses (100mg). We will employ offline cathodal tDCS and examine its effects on the response selection task, as used in previous work (Filmer et al., 2013a; Filmer et al., 2013b; Bender et al., 2017; Filmer et al., 2020). An offline stimulation approach is also in line with studies of dopamine manipulations on tDCS-induced aftereffects on motor-evoked potentials (Nitsche et al., 2006; Kuo et al., 2008; Monte-Silva et al., 2009; Monte-Silva et al., 2010; Fresnoza et al., 2014), as well as findings that PFC tDCS increased dopamine release only after stimulation cessation and not during stimulation itself (Fonteneau et al., 2018).