Tyrosine’s Effect on Cognitive Flexibility: Dependent On Dosage

Abstract

Background: Tyrosine is the precursor to dopamine, which has been heavily associated

with cognitive flexibility (CF). Evidence has suggested that tyrosine enhances CF only when

in situations with high cognitive loads (CL), although this has been disputed.

Objective: The current study examines whether tyrosine and changes in CL affect CF as

measured by a simple response time task, digit span test and the Wisconsin Card Sorting

Task (WCST).

Method: Using a double-blind trial, the effects of high and low CLs combined with tyrosine or

placebo on CF was tested in 70 University students.

Results: While no main effect of drug or CL was found for total errors or perseverative errors

on the WCST, a main effect of CL was found for reaction time on the WCST. There was also

only a significant interaction between drug and CL for reaction time. Interestingly, both

tyrosine and a low CL and placebo and a high CL enhanced CF.

Conclusion: The results contradict evidence of tyrosine and a high CL enhancing CF.

Introduction

Tyrosine (TYR) has been one of the most frequently researched amino acids. TYR is

the precursor to the neurotransmitter dopamine (DA), which is believed to have a role in

reward-related learning (Montague, Hyman & Cohen, 2004). Steenbergen et al. have

suggested TYR aids in reducing the negative effects of conditions, like stress, that deplete

DA in the brain (2015). TS has been found to reduce impairments of attentional tasks and

working memory caused by stress, though this was found more so in individuals who were

more sensitive to the stressors (Mahoney et al., 2007). TYR supplementation (TS) has been

shown to increase plasma tyrosine levels in the blood and enhance DA release in the brain

(Steenbergen et al., 2015; Wurtman, 1992). This has led to various studies investigating

whether cognitive performance relying on catecholamine function can be positively

influenced by TS, with results varying greatly (Jongkees et al., 2015).

pg. 1
 Cognitive flexibility (CF) is the notion that the cognitive system can adapt to changing

task demands by modifying cognitive processes such as shifting attention and plan formation

(Deak, 2003). Task-switching performance has been established as a reliable indicator of

cognitive flexibility (Monsell, 2003; Miyake et al., 2000). Steenbergen et al. have stated that

high cognitive flexibility can be indicated from a small amount of time needed to switch

between two different tasks (2015). CF has a neurobiological underpinning specifically

concerned with DA as negative consequences of catecholamine depletion due to high

cognitive loads (CL) can be neutralised by TYR (Jongkees et al., 2015).

Jongkees et al. found that TYR is effective in enhancing cognitive flexibility, though

only when there is no impairment in neurotransmitter function, and DA is temporarily

depleted (2015). Research has found that only tasks with a high CL benefit from TS (Colzato

et al., 2013; Thomas et al., 1999). Furthermore, Colzato et al. found that TS may replenish

catecholamine within the brain when more cognitive control is needed to carry out a task

(2014). However, it has been suggested that the effects of TS only occur in stressful or

cognitively demanding situations (Jongkees et al., 2015). Furthermore, there was found to

be no effect of TS on depressed patients (Gelenberg et al., 1990) or patients with

phenylketonuria (Smith et al., 1998), suggesting that TYR’s effect on CF is only applicable to

‘healthy’ individuals.

The primary goal of the current study was to replicate previous findings of the effect

of TS on CF in the presence of high CL. High and low demands on the cognitive system

have been indicated in previous research by the digit span task and simple response time

task respectively (Colzato et al., 2013). Utilising these differing CLs before undertaking a

measure of cognitive flexibility, this study aims to replicate the consensus within the literature

that TS increases CF by negating the negative consequences of depletion of DA within the

brain after performing the digit span task, but does not when performing the simple reaction

time task. Three hypotheses can, therefore, be generated. It is hypothesised that drug

administration will have a main effect on CF, with TYR increasing CF. A main effect of CL is

also hypothesised, with a high CL increasing CF. The third hypothesis – that an interaction

pg. 2
between CL and drug exists where TYR and a high CL increases CF – predicts an

agreement between previous research and the current study.

Method

Participants

During the lecture in Herbert Wing 1, Collegiate Campus, Sheffield Hallam University

(SHU) on the Thursday afternoon of the week before the study was completed, participants

were presented with the information sheet (appendix 1) which also included the inclusion

criteria and asked to circle whether they thought they would take part, so the correct amount

of apparatus could be ordered. Participation was for a Research Methods Training module

assessment but was voluntary. 70 participants were recruited, consisting of 59 females

(84%) and 11 males (16%). The mean age of the participants was 19.91 (SD=1.64,

range=8). The study was ethically approved by the Department of Psychology, Sociology

and Politics at SHU.

Design

The current study used a double-blind mixed, experimental, factorial 2*2*(2) design

with two between-participant IVs – drug (placebo or TYR) and CL (low or high; lCL and hCL

respectively) – and one within-participants IV – a pre and post drug measure of time taken

on the Wisconsin Card Sorting Test (WCST; Mueller, 2011; Grant, Berg & Heaton, 1981;

Heaton et al., 1993; Berg, 1948). Randomisation was used in order to present an information

pack to participants detailing which conditions they would be in, with the four conditions

being ‘placebo & lCL’, ‘placebo & hCL’, ‘TYR & lCL’ and ‘TYR & hCL’. The two placebo

conditions acted as a control. The DV was the number of perseverative and total errors on

the WCST.

Apparatus

Two grams of TYR (or the placebo contained 2 grams of cellulose) was dissolved in

250ml of orange juice in a plastic cup and had a participant number written on the

underneath. This approach was used by Colzato et al. although they used 400ml of orange

juice (2013). A computer in the IT lab at the Main Building, Collegiate Campus, SHU was

pg. 3
used to run the three tasks in the experiment in the PEBL application (Mueller & Piper, 2014;

Mueller, 2014).

Materials

An instruction pack was given to participants with their participant number at the top,

containing the participant information sheet (appendix 1), TYR safety questionnaire

(appendix 2 which included ticking the appropriate responses to the questions asked),

consent form (appendix 3) and either the lCL (appendix 4) or hCL (appendix 5) instructions.

After this was completed, participants answered the post-experiment TYR question

(appendix 6) and the TYR adverse effects questionnaire (appendix 7 which included a 1-4

Likert response scale to the severity of a list of symptoms and, if the symptoms were

present, the likelihood this was due to TYR consumption).

Stimuli

The cognitive flexibility task (WCST; Mueller, 2011; Grant, Berg & Heaton, 1982;

Heaton et al., 1993; Berg, 1948) was used both before and after drug administration. The

WCST entails numerous stimulus cards being presented to the participant who is required to

match the cards without being told how to do so, only whether the particular match they have

selected is right or wrong. The cards can be matched according to number, colour or shape.

The three DVs of interest from the WCST are the total errors, perseverative errors and

reaction time (RT). Perseveration is the idea of being incapable to switch ideas, evidenced

by repetition of gestures (Grinnell, 2018). This would be reflected through participants

repeatedly matching the cards incorrectly, even when they are told it is incorrect.

The lCL task was a simple response time task (Logan, Cowan & Davis, 1984). The

stimulus (an ‘X’) appears after a delay from the previous response from the participant. The

task was performed in two blocks – the first delay was set to 250ms and the second delay

was set to 2500ms. The DV of interest here was the reaction time.

The hCL task was a digit span task (Croschere et al., 2012). The auditory

presentation of the number strings is muted (Appendix 5) with participants’ response time

pg. 4
and their memory span being the two DVs of interest when presented with the visual number

string.

Procedure

During week 15 of the academic year, various Research Methods workshops ran in

the Main Building at SHU where the data collection took place. Participants entered the IT

lab listed on their timetable and were told by the tutor to sit on the left side of the room at a

computer if they were participating (if not participating, individuals were told to sit on the right

side of the room). Participants were given the instruction pack and asked to read through the

information sheet and fill in the TYR safety questionnaire and consent form. The information

sheet told participants that the study was looking into the effect of TS on cognitive flexibility

when modulated by CL. This took up to 15 minutes. Once all participants had completed the

consent form, they were asked to read and work through the instructions they had been

given – either the lCL or hCL. The exact instructions can be found in appendix 4 and 5.

When told to have the drink containing either TYR or the placebo, participants were required

to step outside the room, take the drink and then return to their computer to watch the

unstimulating YouTube video (“Amazing Wildlife of Alaska(full documentary)HD”, 2015). This

portion of the study took up to an hour and a half for participants to complete. Once the

study was complete, participants were given the debrief sheet (appendix 8). Overall, the

study took approximately 1 hour and a half to complete.

Results

SPSS was used for analysis. New variables were computed in order to separate out

the conditions into drug and placebo. Next, the three DVs of interest from the WCST were

collapsed from the pre and post drug measures (two separate variables) to create a new

single variable for each – the difference between them. This resulted in three DVs to be

analysed to see if TYR had an effect on any of the three – ‘Change in Total Errors’, ‘Change

in Perseverative Errors’ and ‘Change in Reaction Time’. To check the data for normality,

histograms and boxplots were created for these three variables (appendix 9.1-9.6). Multiple

outliers arose from this, so Z-scores were generated to see if there were any extreme

pg. 5
outliers. Following the advice of Field, the cut-off point for an acceptable Z-score is 3.29

(2014). this resulted in participant 15’s score for the Change in Total Errors variable

becoming the extreme outlier. This score was therefore winsorized from ‘41’ to the next

highest non-outlier value+1 making the score ‘31’, as outlined by Field (2014).

Table 1 shows the means and SDs for the change in the three DVs of interest in the

WCST. These suggest that there was a larger reduction in reaction time after drug/CL

administration than in total or perseverative errors.

Table 1. Means (SDs) For The Change In The Three Variables Measured In The WCST.

Variables Mean (SD)

Change in Total Errors 5.84 (10.61)

Change in Perseverative Errors 2.66 (6.64)

Change in Reaction Time 168.33 (159.60)

To obtain the Change in Total Errors variable, a difference in scores from the total

errors at baseline compared to after drug/CL administration was obtained. The effects of

drug and CL on the Change in Total Errors was tested by conducting a univariate ANOVA.

There was no statistically significant main effect of drug, with TYR resulting in a similar

reduction in total errors ( x =5.13, CI: 1.39, 8.88) to placebo ( x =6.58, CI: 3.03, 10.12), F(1,

66)=.31, p=.579. There was also no statistically significant main effect of CL, with a hCL

resulting in a similar reduction ( x =4.86, CI: 1.25, 8.46) to a lCL ( x =6.85, CI: 3.17, 10.54),

F(1, 66)=.60, p=.442. There was no significant interaction between CL and drug on total

errors, F(1, 66)=.11, p=.742. Appendix 9.7 graphically visualises this finding.

To obtain the Change in Perseverative Errors variable, the difference in scores

between the perseverative errors at baseline compared to after drug/CL administration was

obtained. A univariate ANOVA was conducted to test the effects of drug and CL on the

Change in Perseverative Errors. There was no statistically significant main effect of drug,

pg. 6
with TYR resulting in a similar reduction in perseverative errors ( x =1.93, CI: -.38, 4.24) to

placebo ( x =3.37, CI: 1.18, 5.55), F(1, 66)=.81, p=.373. There was also no statistically

significant main effect of CL, with a hCL resulting in a similar reduction ( x =1.48, CI: -.75,

3.70) to a lCL ( x =3.82, CI: 1.55, 6.10), F(1, 66)=2.17, p=.145. There was no significant

interaction between cognitive load and drug on perseverative errors, F(1, 66)=.00, p=.990.

Appendix 9.8 graphically visualises this finding.

To obtain the Change in Reaction Time variable, the difference in scores between

the reaction time at baseline compared to after drug/cognitive load administration was

obtained. A univariate ANOVA was conducted to test the effects of drug and cognitive load

on the Change in Reaction Time. There was no statistically significant main effect of drug,

with TYR resulting in a similar reduction in reaction time ( x =144.55, CI: 92.27, 196.83) to

placebo ( x =187.44, CI: 137.92, 236.95), F(1, 66)=1.41, p=.239. There was a statistically

significant main effect of cognitive load on reaction time, with a lCL resulting in a larger

reduction ( x =209.59, CI: 158.11, 261.07) compared to a hCL ( x =122.40, CI: 72.06, 172.75),

F(1, 66)=5.84, p=.018, η p2=.081 (moderate). There was also a statistically significant

interaction between cognitive load and drug on reaction time, F(1, 66)=5.22, p=.026, η
2
p=.073 (moderate). Appendix 9.9 graphically visualises this finding.

In order to see where the significant interaction lies, 4 a planned priori comparisons

were run. There was no significant difference between cognitive loads in the placebo

condition, t(35)=.12, p=.909, with a lCL resulting in a similar reduction in reaction time

(M=189.82) to a hCL (M=185.05). There was a significant difference between cognitive loads

in the TYR condition, t(31)=2.80, p=.009, with a lCL resulting in a greater reduction in

reaction time (M=229.35) than a hCL (M=59.75).

There was no significant difference between the drugs in the lCL condition,

t(32)=-.81, p=.422, with TYR resulting in a similar reduction in reaction time (M=229.35) to

placebo (M=189.82). There was a significant difference between the drugs in the hCL

pg. 7
condition, t(34)=2.36, p=.024, with placebo resulting in a greater reduction in reaction time

(M=185.05) than TYR (M=59.75).

In order to check that TYR had an effect on CF and not on the tasks that manipulated

the cognitive load, three independent samples t-tests were conducted. There was no

significant effect of TYR on the reaction time in the lCL task, t(32)=1.91, p=.065. No

significant effect of TYR on the memory span in the hCL task was observed, t(34)=-.28,

p=.781. There was also no significant effect of TYR on the response time in the hCL task,

t(34)=-1.68, p=.102. Table 2 shows the means and SDs for the three DVs of the two

cognitive load tasks.

Table 2. Means (SDs) For The Three DVs Of The Two Cognitive Load Tasks.

Name of Cognitive Load Task DV Measured Mean (SD) Tyrosine Mean (SD) Placebo

Simple Response Time Task Reaction Time 345.53 (26.04) 364.94 (32.77)

Digit Span Memory Span 6.81 (1.11) 6.70 (1.26)

Response Time 5973.25 (1935.01) 5016.20 (1485.88)

Finally, in order to assess the relationship between the drug participants consumed

and if they could correctly identify what drug they consumed a Chi-square test was

conducted. There was no significant association between the two variables, X2(1)=1.22,

p=.269, Cramer’s V=.13. The effect was small, with 70.27% of placebo consuming

participants and 57.58% of TYR consuming participants incorrectly identifying the placebo

they consumed.

Discussion

The aim of the current study was to corroborate previous findings that TYR will

enhance CF only under situations of high CL. The analyses showed that reaction time on the

WCST (one measure of CF) was enhanced in the ‘TYR & lCL’ condition, and also that

reaction time on the WCST was enhanced in the ‘placebo & hCL’ condition.

pg. 8
 These findings allow for the first (that TYR will increase CF) and the second (that

high CL will increase CF) to be partially accepted. However, the findings also mean that the

third hypothesis (that an interaction where TYR and high CL would increase CF) must be

rejected.

These findings, therefore, do not corroborate previous literature that suggests TYR

increases CF only in situations with high CL (Colzato et al., 2013; Thomas et al., 1999;

Jongkees et al., 2015). One reason that this may have occurred concerns itself with the

already fragile nature of this previous finding within the literature. Jongkees et al. has

suggested that the plentiful amount of studies investigating TYRs effect on CF vary

dramatically in their findings (2015). The findings of Gelenberg et al. (1990) and Smith et al.

(1998) suggest that the findings of TYR and high CL increasing CF may only apply to

‘healthy’ adults. The current study used university students with a mean age of 19.91.

Justice and Dornan have found that older female students that would be considered adults

reported the highest levels of cognitive monitoring, followed by younger male students who

would be considered adolescents, with male adult students and female adolescent students

reporting the lowest levels of cognitive monitoring (2001). With the current study having 84%

females and the mean age being adolescent, this could be a potential reason why the

converse to previous literature with ‘healthy’ adults was found.

Perhaps the key reason why the current study does not support previous literature is

related to the sample size of the current study. With N=70, post-hoc power calculations were

conducted on the two significant ANOVA findings. The ANOVA suggesting that the lCL

condition resulted in the greater reduction in reaction time did not reach enough statistical

power (1-=0.69), with the ANOVA suggesting a significant interaction between cognitive

load and drug on reaction time not reaching enough power either (1-=0.57). Since the

conventional power rate is 1-=0.8, this could suggest that the current study may be at risk

of type-1 errors (Field, 2014). The power calculation indicated that N=95 was needed for

enough power. A further limitation to the current study is that previous literature

pg. 9
demonstrating protocols for the dosage of TYR indicate that both drugs should be dissolved

in 400ml of orange juice (Dennison et al., 2018). Since the current study used 250ml of

orange juice, this means the standard procedure was not followed which may have an

impact on the results.

Alongside the suggestions of Jongkees et al. (2015), future research needs to

employ more varied doses of TYR in order to indicate two things – an optimal dose of TYR

and if the findings of the current study were due to the reduction in TYR dosage from being

dissolved in 400ml to 250ml of orange juice.

In conclusion, this study has shown that CF was enhanced when consuming TYR

and undertaking a task that is not cognitively demanding, and also when consuming the

placebo and undertaking a cognitively demanding task. However, it was suggested that the

differences emerging in this study compared to previous literature may be due to a differing

dosage of TYR. Future research needs to measure the effect of varied doses of TYR and CL

on CF.

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