Bryant J. Jongkees

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.

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.

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.

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.

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 DAs 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 Tyrs 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.

People are different: tyrosine's modulating effect on cognitive control in healthy humans may depend on individual differences related to dopamine function.

The amino-acid tyrosine (TYR) is thought to modulate cognitive functions that are driven by dopamine (DA), as consumption of TYR enhances DA levels in the brain (Gibson and Wurtman, 1977; Cuche et al., 1985). It could therefore reverse decreases in DA level that are detrimental for cognitive performance (Muly et al., 1998; Goldman-Rakic et al., 2000; Nieoullon, 2002). So far, TYR has been considered not so much as an enhancer of healthy cognitive functioning but rather as a means to reduce the negative side-effects of dopamine-related pathologies, such as Parkinsons disease (Growdon et al., 1982; Lemoine et al., 1989), phenylketonuria (van Spronsen et al., 1996), depression (Gelenberg and Gibson, 1984), and attention deficit hyperactivity disorder (Wood et al., 1985). However, the outcomes were mixed: some patients reported significant improvements, while other did not. In clinical samples some variation in response may be explained by impaired processes such as DA synthesis, which would lessen or even completely prevent an effect of TYR. But even healthy samples differ in response to TYR supplementation, which suggests that clinically impaired DA function is not the only source of variation. The focus of the present opinion article is not on clinical populations but on TYR effects on cognitive control in healthy humans. In healthy individuals, TYR has often been used to reduce the negative effects of conditions that deplete the brains dopaminergic resources, such as extreme stress. The supply of TYR was found to reduce stress-induced impairments of working memory and attentional tasks, but more so in individuals who were particularly sensitive to the stressors (Deijen and Orlebeke, 1994; Shurtleff et al., 1994; Mahoney et al., 2007). Even without exposure to stress, administration of TYR has been shown to have an acute beneficial effect on task-performance thought to be related to DA, e.g., simultaneously performing multiple tasks (Thomas et al., 1999), the updating and monitoring of working memory (Colzato et al., 2013a), and inhibitory control (Colzato et al., 2014a). Taken together, in healthy humans TYR seems to work against what has been coined “ego-depletion”—the exhaustion of limited cognitive control (CC) resources (Baumeister et al., 1998). Demanding tasks may deplete the available control resources more, especially in individuals having fewer resources and/or those that suffer more from the situational demands, and TYR may be able to replete the missing resources to some degree. This possibility should not be surprising given that CC relies on DA (Cools, 2006). The hypotheses that DA is one of the depleted resources and TYR reverses its depletion are consistent with the idea that there is an optimal level of DA at which cognitive performance peaks while it suffers at lower levels (Muly et al., 1998; Goldman-Rakic et al., 2000; Nieoullon, 2002). Given that TYR raises the DA level, we argue that TYR can enhance cognitive performance in healthy individuals whenever one has a lower than optimal DA level. Besides individual differences in the response to task-induced depletion, DA level also seems to vary between healthy individuals in a more stable and enduring fashion (Cools, 2006; Cools et al., 2008, 2009). This suggests that individuals differ in how far away they are from their optimum, i.e., some individuals have a lot of room for improvement, while others may already have an optimal, or even a higher-than-optimal DA level. We expect that individuals with an optimal baseline have little left of the enzyme called tyrosine-hydroxylase, which converts TYR into DA (Daubner et al., 2011). This means that they have little risk of overdosing from TYR supplementation, instead they should experience hardly any change in performance. Given that individuals can vary in their response to TYR supplementation, it is necessary that future studies on TYR take into account individual differences, so to ensure that samples are comparable and results are generalizable. To this end we discuss a number of DA-related measures and factors that could predict or modulate the effect of TYR supplementation. This is by no means an exhaustive list; the aim of this opinion article is rather to point out and highlight some accessible predictors of DA function that may help to improve designing future TYR studies and making the analyses of their outcomes more informative. To this date, the individual differences discussed below have not yet been investigated in combination with TYR. However, based on literature that details their relation to DA function we argue that these individual differences will prove fruitful for future research.

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.

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.