Self-prioritization in working memory gating.

Working memory (WM) involves a dynamic interplay between temporary maintenance and updating of goal-relevant information. The balance between maintenance and updating is regulated by an input-gating mechanism that determines which information should enter WM (gate opening) and which should be kept out (gate closing). We investigated whether updating and gate opening/closing are differentially sensitive to the kind of information to be encoded and maintained in WM. Specifically, since the social salience of a stimulus is known to affect cognitive performance, we investigated if self-relevant information differentially impacts maintenance, updating, or gate opening/closing. Participants first learned to associate two neutral shapes with two social labels (i.e., "you" vs. "stranger"), respectively. Subsequently they performed the reference-back paradigm, a well-established WM task that disentangles WM updating, gate opening, and gate closing. Crucially, the shapes previously associated with the self or a stranger served as target stimuli in the reference-back task. We replicated the typical finding of a repetition benefit when consecutive trials require opening the gate to WM. In Study 1 (N = 45) this advantage disappeared when self-associated stimuli were recently gated into WM and immediately needed to be replaced by stranger-associated stimuli. However, this was not replicated in a larger sample (Study 2; N = 90), where a repetition benefit always occurred on consecutive gate-opening trials. Overall, our results do not provide evidence that the self-relevance of stimuli modulates component processes of WM. We discuss possible reasons for this null finding, including the importance of continuous reinstatement and task-relevance of the shape-label associations.

Baseline-dependent effect of dopamine's precursor L-tyrosine on working memory gating but not updating.

Adaptive goal-directed behavior requires a dynamic balance between maintenance and updating within working memory (WM). This balance is controlled by an input-gating mechanism implemented by dopamine in the basal ganglia. Given that dopaminergic manipulations can modulate performance on WM-related tasks, it is important to gain mechanistic insight into whether such manipulations differentially affect updating (i.e., encoding and removal) and the closely-related gate opening/closing processes that respectively enable/prevent updating. To clarify this issue, 2.0 g of dopamine's precursor L-tyrosine was administered to healthy young adults (N = 45) in a double-blind, placebo-controlled, within-subjects study. WM processes were empirically distinguished using the reference-back paradigm, which isolates performance related to updating, gate opening, and gate closing. L-tyrosine had a selective, baseline-dependent effect only on gate opening, which was evidenced by markedly reduced variance across subjects in gate opening performance in the L-tyrosine compared with the placebo condition, whereas the whole-sample average performance did not differ between conditions. This indicates a pattern of results whereby low-performing subjects improved, whereas high-performing subjects were impaired on L-tyrosine. Importantly, this inverted U-shaped pattern was not explained by regression to the mean. These results are consistent with an inverted-U relationship between dopamine and WM, and they indicate that updating and gating are differentially affected by a dopaminergic manipulation. This highlights the importance of distinguishing these processes when studying WM, for example, in the context of WM deficits in disorders with a dopaminergic pathophysiology.

The Effect of Cerebellar tDCS on Sequential Motor Response Selection.

Transcranial direct current stimulation (tDCS) transiently alters cortical excitability and synaptic plasticity. So far, few studies have investigated the behavioral effects of applying tDCS to the cerebellum. Given the cerebellum's inhibitory effects on cortical motor areas as well as its role in fine motor control and motor coordination, we investigated whether cerebellar tDCS can modulate response selection processes and motor sequence learning. Seventy-two participants received either cerebellar anodal (excitatory), cathodal (inhibitory), or sham (placebo) tDCS while performing a serial reaction time task (SRTT). To compare acute and long-term effects of stimulation on behavioral performance, participants came back for follow-up testing at 24 h after stimulation. Results indicated no group differences in performance prior to tDCS. During stimulation, tDCS did not affect sequence-specific learning, but anodal as compared to cathodal and sham stimulations did modulate response selection processes. Specifically, anodal tDCS increased response latencies independent of whether a trained or transfer sequence was being performed, although this effect became smaller throughout training. At the 24-h follow-up, the group that previously received anodal tDCS again demonstrated increased response latencies, but only when the previously trained sequence and a transfer sequence had to be performed in the same experimental block. This increased behavioral interference tentatively points to a detrimental effect of anodal cerebellar tDCS on sequence consolidation/retention. These results are consistent with the notion that the cerebellum exerts an inhibitory effect on cortical motor areas, which can impair sequential response selection when this inhibition is strengthened by tDCS.

The COMT Val158 Met polymorphism does not modulate the after-effect of tDCS on working memory.

Transcranial direct current stimulation (tDCS) can alter cortical excitability, neural plasticity, and cognitive-behavioral performance; however, its effects are known to vary across studies. A partial account of this variability relates to individual differences in dopamine function. Indeed, dopaminergic manipulations alter the physiological and cognitive-behavioral effects of tDCS, and gene polymorphisms related to dopamine have predicted individual response to online tDCS (i.e., stimulation overlapping with the critical task). Notably, the role of individual differences in dopamine has not yet been properly assessed in the effect of offline tDCS (i.e., stimulation prior to the critical task). We investigated if and how the COMT Val158 Met polymorphism (rs4680) modulates the after-effect of prefrontal tDCS on verbal working memory (WM). One hundred and thirty-nine participants were genotyped for the COMT Val158 Met polymorphism and received anodal-over-left, cathodal-over-right (AL-CR), cathodal-over-left, anodal-over-right (CL-AR), or sham stimulation over the dorsolateral prefrontal cortex in a between-subjects, pretest-posttest study design. WM was assessed using the N-back task. The results provide no evidence that the COMT polymorphism impacts the after-effect of prefrontal tDCS on WM. Taken together with previous findings on dopamine and tDCS interactions, the results of the present study suggest that (a) indirect markers of dopamine (such as COMT) are differently related to online and offline effects of tDCS, and (b) findings from studies involving pharmacological manipulation should be generalized with caution to findings of inter-individual differences. In sum, we argue that state (i.e., a manipulation of) and trait (i.e., baseline) differences in dopamine may exert different effects on online and offline tDCS.

Transcutaneous Vagus Nerve Stimulation (tVNS) Enhances Response Selection During Sequential Action.

Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive and safe technique that transiently enhances brain GABA and noradrenaline levels. Although tVNS has been used mainly to treat clinical disorders such as epilepsy, recent studies indicate it is also an effective tool to investigate and potentially enhance the neuromodulation of action control. Given the key roles of GABA and noradrenaline in neural plasticity and cortical excitability, we investigated whether tVNS, through a presumed increase in level of these neurotransmitters, modulates sequential behavior in terms of response selection and sequence learning components. To this end we assessed the effect of single-session tVNS in healthy young adults (N = 40) on performance on a serial reaction time task, using a single-blind, sham-controlled between-subject design. Active as compared to sham tVNS did not differ in terms of acquisition of an embedded response sequence and in terms of performance under randomized response schedules. However, active tVNS did enhance response selection processes. Specifically, the group receiving active tVNS did not exhibit inhibition of return during response reversals (i.e., when trial N requires the same response as trial N-2, e.g., 1-2-1) on trials with an embedded response sequence. This finding indicates that tVNS enhances response selection processes when selection demands are particularly high. More generally, these results add to converging evidence that tVNS enhances action control performance.

Variable heart rate and a flexible mind: Higher resting-state heart rate variability predicts better task-switching.

The neurovisceral integration model proposes that heart rate variability (HRV) is linked to prefrontal cortex activity via the vagus nerve, which connects the heart and the brain. HRV, an index of cardiac vagal tone, has been found to predict performance on several cognitive control tasks that rely on the prefrontal cortex. However, the link between HRV and the core cognitive control function "shifting" between tasks and mental sets is under-investigated. Therefore, the present study tested the neurovisceral integration model by examining, in 90 participants, the relationship between vagally mediated resting-state HRV and performance in a task-switching paradigm that provides a relatively process-pure measure of cognitive flexibility. As predicted, participants with higher resting-state HRV (indexed both by time domain and frequency domain measures) showed smaller switch costs (i.e., greater flexibility) than individuals with lower resting-state HRV. Our findings support the neurovisceral integration model and indicate that higher levels of vagally mediated resting-state HRV promote cognitive flexibility.

Color vision predicts processing modes of goal activation during action cascading.

One of the most important functions of cognitive control is action cascading: the ability to cope with multiple response options when confronted with various task goals. A recent study implicates a key role for dopamine (DA) in this process, suggesting higher D1 efficiency shifts the action cascading strategy toward a more serial processing mode, whereas higher D2 efficiency promotes a shift in the opposite direction by inducing a more parallel processing mode (Stock, Arning, Epplen, & Beste, 2014). Given that DA is found in high concentration in the retina and modulation of retinal DA release displays characteristics of D2-receptors (Peters, Schweibold, Przuntek, & Müller, 2000), color vision discrimination might serve as an index of D2 efficiency. We used color discrimination, assessed with the Lanthony Desaturated Panel D-15 test, to predict individual differences (N = 85) in a stop-change paradigm that provides a well-established measure of action cascading. In this task it is possible to calculate an individual slope value for each participant that estimates the degree of overlap in task goal activation. When the stopping process of a previous task goal has not finished at the time the change process toward a new task goal is initiated (parallel processing), the slope value becomes steeper. In case of less overlap (more serial processing), the slope value becomes flatter. As expected, participants showing better color vision were more prone to activate goals in a parallel manner as indicated by a steeper slope. Our findings suggest that color vision might represent a predictor of D2 efficiency and the predisposed processing mode of goal activation during action cascading.

Influences of glutamine administration on response selection and sequence learning: a randomized-controlled trial.

Precursors of neurotransmitters are increasingly often investigated as potential, easily-accessible methods of neuromodulation. However, the amino-acid glutamine, precursor to the brain's main excitatory and inhibitory neurotransmitters glutamate and GABA, remains notably little investigated. The current double-blind, randomized, placebo-controlled study provides first evidence 2.0 g glutamine administration in healthy adults affects response selection but not motor sequence learning in a serial reaction time task. Specifically, glutamine increased response selection errors when the current target response required a different hand than the directly preceding target response, which might indicate enhanced cortical excitability via a presumed increase in glutamate levels. These results suggest glutamine can alter cortical excitability but, despite the critical roles of glutamate and GABA in motor learning, at its current dose glutamine does not affect sequence learning.

l-Tyrosine administration modulates the effect of transcranial direct current stimulation on working memory in healthy humans.

BACKGROUND: Transcranial direct current stimulation (tDCS) is an increasingly popular method of modulating cognitive functions in humans. However, some doubt its efficacy as findings are inconsistent or remain unreplicated. It is speculated dopamine (DA) might play an important role in this inconsistency, by determining the direction and strength of the cognitive-behavioral effects of tDCS. However, so far evidence for this hypothesis has been correlational in nature, precluding definitive conclusions. OBJECTIVE: The present proof-of-principle study aimed at investigating a potentially causal role for DA in the effect of tDCS on cognition in healthy humans. METHODS: In Experiment 1 we aimed to replicate previous findings showing administration of DA's precursor l-Tyrosine (Tyr), presumably by inducing a modest increase in DA level, can enhance working memory (WM) performance as assessed with a verbal N-back task. In Experiment 2 we investigated the effect of Tyr administration on bilateral tDCS over dorsolateral prefrontal cortex (DLPFC) and WM. RESULTS: Experiment 1 showed Tyr administration enhances performance in a verbal N-back task. Experiment 2 showed Tyr modulates the effect of bilateral tDCS over DLPFC on WM. Specifically, tDCS had opposite effects on performance depending on current direction through the brain and Tyr administration. CONCLUSIONS: The present study provides two major findings. First, we replicate Tyr's beneficial effect on verbal WM. Second, our results indicate a causal role for DA in the effect of tDCS on cognition. For this reason, we encourage future studies to consider the modulating effect of DA, as a step towards more consistent and replicable results regarding the efficacy of tDCS.

Spontaneous eye blink rate as predictor of dopamine-related cognitive function-A review.

An extensive body of research suggests the spontaneous eye blink rate (EBR) is a non-invasive indirect marker of central dopamine (DA) function, with higher EBR predicting higher DA function. In the present review we provide a comprehensive overview of this literature. We broadly divide the available research in studies that aim to disentangle the dopaminergic underpinnings of EBR, investigate its utility in diagnosis of DA-related disorders and responsivity to drug treatment, and, lastly, investigate EBR as predictor of individual differences in DA-related cognitive performance. We conclude (i) EBR can reflect both DA receptor subtype D1 and D2 activity, although baseline EBR might be most strongly related to the latter, (ii) EBR can predict hypo- and hyperdopaminergic activity as well as normalization of this activity following treatment, and (iii) EBR can reliably predict individual differences in performance on many cognitive tasks, in particular those related to reward-driven behavior and cognitive flexibility. In sum, this review establishes EBR as a useful predictor of DA in a wide variety of contexts.

Tryptophan supplementation modulates social behavior: A review.

Tryptophan (TRP), the precursor of serotonin (5-HT), is one of the most investigated amino-acids. TRP supplementation can increase 5-HT levels in the brain and for this reason numerous studies have investigated whether administration of TRP can positively influence social behavior that relies on serotonergic function. Here we review the available studies on TRP, to clarify if and under what circumstances TRP supplementation might modulate social behavior. TRP supplementation seems to improve control over social behavior in patients and individuals suffering from disorders or behaviors associated with dysfunctions in serotonergic functioning. In contrast, in healthy humans TRP supplementation seems to promote social behavior. Although more research is needed to disentangle and understand the relations between individual differences, TRP effectivity, 5-HT functioning, social interactions, and context, we conclude TRP can be a promising tool for modulating social behavior.

Effect of tyrosine supplementation on clinical and healthy populations under stress or cognitive demands--A review.

Consuming the amino-acid tyrosine (TYR), the precursor of dopamine (DA) and norepinephrine (NE), may counteract decrements in neurotransmitter function and cognitive performance. However, reports on the effectiveness of TYR supplementation vary considerably, with some studies finding beneficial effects, whereas others do not. Here we review the available cognitive/behavioral studies on TYR, to elucidate whether and when TYR supplementation can be beneficial for performance. The potential of using TYR supplementation to treat clinical disorders seems limited and its benefits are likely determined by the presence and extent of impaired neurotransmitter function and synthesis. Likewise, the potential of TYR supplementation for enhancing physical exercise seems minimal as well, perhaps because the link between physical exercise and catecholamine function is mediated by many other factors. In contrast, TYR does seem to effectively enhance cognitive performance, particularly in short-term stressful and/or cognitively demanding situations. We conclude that TYR is an effective enhancer of cognition, but only when neurotransmitter function is intact and DA and/or NE is temporarily depleted.

Eating to stop: tyrosine supplementation enhances inhibitory control but not response execution.

Animal studies and research in humans have shown that the supplementation of tyrosine, or tyrosine-containing diets, increase the plasma tyrosine and enhance brain dopamine (DA). However, the strategy of administering tyrosine (and the role of DA therein) to enhance cognition is unclear and heavily debated. We studied, in a healthy population, whether tyrosine supplementation improves stopping overt responses, a core cognitive-control function. In a double-blind, placebo-controlled, within-subject design, one hour following the administration of tyrosine (corresponding to the beginning of the 1h-peak of the plasma concentration) or placebo, participants performed a stop-signal task-which taps into response inhibition and response execution speed. Participants in the Tyrosine condition were more efficient in inhibiting unwanted action tendencies but not in reacting to go signals. This is the first demonstration that the supplementation of tyrosine selectively targets, and reliably improves the ability to stop overt responses.

Working memory reloaded: tyrosine repletes updating in the N-back task.

In this study we tested the idea that the food supplement l-Tyrosine (TYR) repletes resources required for cognitive-control operations. We investigated whether the "updating" (and monitoring) of working memory (WM) representations, a key cognitive-control function, can be promoted by administering TYR, the biochemical precursor of dopamine. Participants performed an N-back task where we compared the WM-demanding 2-back condition with the WM-undemanding 1-back condition. As expected, TYR promoted performance in the more demanding (2-back) but not in the easier (1-back) condition, suggesting that TYR selectively targets cognitive-control operations. This result suggests that TYR can replete cognitive resources when more control is needed and, more generally, that food can act as a cognitive enhancer.