Review article
Spontaneous eye blink rate as predictor of dopamine-related cognitive function—A review

https://doi.org/10.1016/j.neubiorev.2016.08.020Get rights and content

Highlights

  • Eye blink rate (EBR) predicts resting-state dopamine (DA) activity.

  • Receptor subtypes D1 and D2 can both modulate EBR.

  • EBR predicts abnormal DA activity in clinical disorders.

  • EBR is a useful predictor of individual differences in DA-related performance.

Abstract

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.

Introduction

Decades of research show the spontaneous eye blink rate (EBR) is closely associated with central dopamine (DA) function, particularly in the striatum. Specifically, EBR tends to correlate positively with DA activity at rest, illustrated by the fact that reduced and increased activity due to drugs or disorders is associated with low and high EBR, respectively. As a non-invasive and easily-accessible measure, EBR can serve as a reliable albeit non-distinctive method of assessing DA function in humans and might be preferable to invasive and expensive techniques such as positron emission tomography (PET). Indeed, ever since its relation to DA was postulated (Stevens, 1978a), EBR has become a popular method of investigating DA in a variety of contexts. For example, EBR has been used to evaluate effects of dopaminergic drugs on DA function, explore the role of DA in psychiatric disorders, and investigate the effects of individual differences in DA function on cognitive performance. In the present summary review, we provide a comprehensive overview of the literature on EBR as predictor of DA function, focusing on pharmacological studies of EBR, baseline EBR in atypical and healthy populations, and, lastly, whether EBR predicts cognitive performance thought to depend on DA. Lastly, we discuss the different methodologies for EBR assessment and provide recommendations for future research. We hope this review informs future studies of the applicability of EBR to a variety of paradigms and its utility in clarifying cognitive research findings by distinguishing results of low, intermediate, and high blinkers.

To understand the relation between EBR and DA-driven cognition, and to allow theory-driven predictions to be made for results with EBR, it is necessary to first consider the role of DA in neurophysiology and how this translates to cognition. DA exerts widespread, non-linear modulatory influences on both prefrontal cortex and striatum, allowing it to affect a wide range of processes (Nieoullon, 2002, Seamans and Yang, 2004). One characteristic role of DA is that its phasic (stimulus-driven) release in striatum codes a reward prediction error (Hollerman and Schultz, 1998, Schultz et al., 1997), with bursts indicating an outcome better than expected (i.e. a positive error) and dips and pauses indicating an outcome worse than expected (i.e. a negative error) (Maia and Frank, 2011). On the other hand, tonic (background) DA level enhances signal-to-noise ratio of neural activity by suppressing spontaneous firing in neurons with low membrane potentials but enhancing task-dependent firing in neurons with high membrane potentials (Frank, 2005, Hernández-López et al., 1997).

When considering the effects of DA on cognition it is important to distinguish between two of its receptor subtypes that can serve opposite functions, D1 and D2, although more exist. D1 and D2 receptors in prefrontal cortex have been proposed to drive a ‘closed’ vs. ‘open’ processing state that facilitates robust online maintenance and flexible updating (gating) of cognitive representations, respectively (Durstewitz and Seamans, 2008). Particularly relevant for the present review, other models have highlighted a role for D1 and D2 in the basal ganglia, where these receptor systems interact to form a DA-modulated decision threshold for selecting responses and updating representations in the cortex (Bahuguna et al., 2015, Frank and O’Reilly, 2006, Maia and Frank, 2011). Specifically, a D1-rich direct pathway in the basal ganglia provides a ‘Go’ signal that facilitates updating of representations and selection of the response under consideration in the cortex, while a D2-rich indirect pathway provides a ‘NoGo’ signal that suppresses competing responses and representations. Importantly, whereas DA has excitatory effects on D1-driven Go signals, it is inhibitory on D2-driven NoGo signals (Maia and Frank, 2011). As such, higher levels of DA (e.g. due to positive prediction errors) lower the decision threshold and promote gating by facilitating D1-driven Go signals and inhibiting the D2-driven NoGo pathway, whereas at lower levels (e.g. due to negative prediction errors) it reduces inhibition of D2-driven NoGo signals and thus facilitates response suppression and stability of cortical representations.

These models of dopaminergic modulation of the stability and flexibility of cortical representations offer an explanation of why DA tends to follow an inverted-u-shaped association with performance on tasks requiring cognitive control rather than following a more-is-better principle (Cools and D’Esposito, 2011). Cognitive control is popularly defined as achieving a balance between the opposing demands of stable maintenance of task goals in the face of distractors and their flexible updating when situational demands have changed (Cools and D’Esposito, 2011). This suggests that too high levels of DA can facilitate gating up to a point where it becomes dysfunctional, resulting in heightened distractibility and impaired response inhibition because the decision threshold is set too low. Conversely, too little DA might raise the threshold to a point of inducing inflexibility and perseveration. Hence, a moderate DA level would be associated with an optimal compromise between stability and flexibility, although lower or higher DA, e.g. due to genotypic variation, may confer benefits in situations that require more of the former or latter (Cools and D’Esposito, 2011).

The association between DA, its receptor subtypes and cognitive functions allows us to form predictions on how EBR could relate to DA-driven cognition and behavior. Although studies reviewed below suggest EBR can reflect both drug-induced D1 and D2 activity, there is evidence that resting EBR is more strongly related to the D2 receptor system (Groman et al., 2014), perhaps due to increased sensitivity of D2 receptors to DA as compared to D1 (Frank and O’Reilly, 2006). Given that D2 receptors are reportedly up to 11 times as prevalent in the striatum than frontal cortex (Camps et al., 1989) and D2 may have stronger effects on the decision threshold in basal ganglia than D1 (Bahuguna et al., 2015), it is possible EBR primarily relates to cognitive function via D2-driven modulation of the decision threshold in the basal ganglia. A higher EBR, indicative of higher DA activity, should then be related to increased inhibition of the basal ganglia NoGo pathway and a consequently reduced decision threshold and facilitated gating. Indeed, studies on EBR and cognitive flexibility reviewed below support the idea that a higher EBR is associated with increased flexibility, albeit at the potential cost of increased distractibility.

One question remaining is why EBR reflects DA activity. Although the neural circuitry through which DA modulates EBR remains open to further investigation, one prime candidate is the spinal trigeminal complex, which has been proposed to play a direct role in the spontaneous blink generator circuit (Kaminer et al., 2015, Kaminer et al., 2011). Crucially, there is evidence that the basal ganglia, via the superior colliculus and nucleus raphe magnus, can modulate input to and excitability of the trigeminal complex, thus providing a pathway through which DA could affect the trigeminal complex and, in turn, blinking (Basso and Evinger, 1996, Basso et al., 1996, Basso et al., 1993, Evinger et al., 1993, Evinger et al., 1988, Gnadt et al., 1997, Harper et al., 1979, Kimura, 1973, Labuszewski and Lidsky, 1979, Napolitano et al., 1997, Schicatano et al., 2000). In particular, Kaminer et al. (2011) proposed that DA inhibits the trigeminal complex, via effects on the nucleus raphe magnus, which results in increased spontaneous blinking, thus offering a potential account for the relation between DA and EBR.

The present review will be structured as follows. First, to provide insight in the dopaminergic underpinnings of the spontaneous EBR, we summarize studies examining the effects of dopaminergic manipulations on EBR in non-human primates, rats, and humans. Second, to illustrate EBR’s relation to and utility in distinguishing between varying levels of baseline DA function, we review studies that measured EBR in different human populations such as individuals with neurological or psychiatric disorders or history of drug use, different age groups, and gender. Third, to demonstrate the applicability to and usefulness in a variety of paradigms of cognitive research, we provide an overview of studies relating EBR of healthy humans in rest to their performance on cognitive tasks. Lastly, we discuss the different methodologies used to assess EBR and offer recommendations for future research.

We performed an electronic search for articles using the PubMed and Web of Science databases, using the following search terms: (eye blink OR eye-blink OR eyeblink OR blink) AND rate. After selecting articles based on the title and abstract’s relevance to DA function, we performed a forward and backward citation search for additional articles. We included only articles written in English.

Section snippets

Effects of dopaminergic manipulations on eye blink rate

In this section we review studies on the effects of dopaminergic manipulations on EBR in non-human primates, rats, and healthy humans. In Table 1, Table 2 an overview of the following studies is provided, listing all drug and dose combinations, the associated EBR change, sample size, and methodology for EBR assessment. Note that many studies do not report the statistical significance of the change in EBR for every drug and dose combination. To avoid reporting inaccurate information, we list the

Baseline eye blink rate in human populations

Whereas the studies reviewed so far demonstrated pharmacological manipulations of DA can affect EBR, the following studies suggest endogenous differences, that is inter-individual variability in DA can also be of influence. For example, individuals with a history of neurological or psychiatric disorders or chronic/recreational drug use (hereafter referred to as ‘atypical populations’) can exhibit altered EBR. Indeed, Boutros and Hatch (1988) argued increased EBR might be a general marker of

Eye blink rate and cognitive performance in healthy humans

Consistent with the idea spontaneous EBR reflects striatal DA activity, many studies find EBR predicts DA-related cognitive performance. In the following section we review these studies to illustrate the applicability and usefulness of EBR in cognitive research. Most of the available research can be grouped in two broad categories, which are (i) reinforcement learning and motivation, that is learning from positive or negative outcomes of actions and the effort put in and vigor of actions, and

Discussion

This review provided an overview of research on spontaneous EBR as indicator of DA function. Here we summarize the most important conclusions, consider the different methodologies used to assess EBR, and give suggestions for future research.

The reviewed literature indicates, first of all, pharmacological activation of either D1 or D2 receptors can affect EBR, although baseline EBR seems positively related to availability of striatal D2 but not D1 receptors. As such, resting EBR might primarily

Role of the funding source

The funding source had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgements

This work was supported by a research grant from the Netherlands Organization for Scientific Research (NWO) awarded to Lorenza S. Colzato (Vidi grant: #452-12-001). The authors would like to thank Heleen Slagter and an anonymous reviewer for their insightful ideas and constructive criticism.

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