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BDNF Val66Met is associated with performance in a

computerized visual-motor tracking test in healthy adults

Yeimy Gonzlez-Giraldo, BSc 1,7; Johana Rojas, BSc 2,7; Shane T. Mueller, PhD 3;
Brian J. Piper, PhD 4; Ana Adan, PhD 5,6; Diego A. Forero, MD, PhD 1,*

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Laboratory of NeuroPsychiatric Genetics, Biomedical Sciences Research Group, School of Medicine, Universidad

Antonio Nario. Bogot, Colombia.

School of Health Sciences, Universidad Colegio Mayor de Cundinamarca. Bogot, Colombia.

Department of Cognitive and Learning Sciences, Michigan Technological University, Houghton, Michigan, USA.

School of Pharmacy, Husson University, Bangor, Maine, USA.

Department of Psychiatry and Clinical Psychobiology, University of Barcelona, Barcelona, Spain.

Institute for Brain, Cognition and Behavior (IR3C), Barcelona, Spain

These authors contributed equally to this work

Correspondence: Prof. Dr. Diego Forero, MD, PhD. Laboratory of NeuroPsychiatric Genetics, Biomedical Sciences

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Research Group, School of Medicine, Universidad Antonio Nario. Bogot, Colombia. Phone: + 57 313 2610427.

Word Count in Body of Manuscript: 2514

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Word Count in Abstract: 120

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Email: diego.forero@uan.edu.co

Tables: 2, Figures: 1, Supplementary Files: 1

Keywords: Neurogenetics, Endophenotypes, Latin America, Motor Learning, Candidate

Genes, Brain Derived Neurotrophic Factor.

Running Title: BDNF gene and visual-motor tracking performance

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Abstract
Brain derived neurotrophic factor (BDNF) is known to play an important role in
neuroplasticity and cognitive processes. We explored the association of BDNF Val66Met
polymorphism with performance in a visual-motor tracking test. One hundred and sixty
seven young healthy Colombian adults completed a computerized version of the Pursuit
Rotor Task, using the Psychology Experiment Building Language (PEBL) platform. DNA

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genotyping was performed by allele-specific PCR. We found that BDNF Val/Met and
Met/Met subjects had a better performance in the pursuit rotor task (p value: 0.03). Our

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findings suggest that BDNF gene is key to understand differences in motor performance
in healthy participants in different populations. This approach could be useful for future

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fine mapping of genetic modifiers for neuropsychiatric diseases.

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Introduction
Adequate functioning of the mechanisms underlying motor learning and performance
are important for daily activities in normal subjects and for pathophysiological
mechanisms of neuropsychiatric diseases and related processes for rehabilitation
(Chang, 2014; Dayan & Cohen, 2011). Neural plasticity in a number of brain regions and
neurophysiological networks (such as the primary motor cortex, premotor cortex and the
supplementary motor area) is known to be correlated with these processes (Dayan &

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Cohen, 2011). Several experimental paradigms, such as finger tapping, have been used
for an initial exploration of the basis of motor learning and performance in humans

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(Dayan & Cohen, 2011).

In recent years, explorations of genetic factors have started to provide evidence of

specific molecular mechanisms associated with motor learning and performance in

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healthy subjects (Kleim et al., 2006; Smolders, Rijpkema, Franke, & Fernandez, 2012).

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Given the important role of proteins involved in synaptic plasticity, the brain derived

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neurotrophic factor (BDNF) gene has been a key candidate (Kleim et al., 2006).

BDNF is a commonly studied neurotrophin that plays an important role in several basic
neural processes such as synaptic plasticity and long-term potentiation and cognitive
phenomena, such as learning and memory processes (Forero, Benitez, et al., 2006).
This protein of 267 amino acids is encoded by the BDNF gene, which is located on
chromosome 11 and has 8 exons (gene size: 65 kb) (Liu et al., 2005). A change of
Valine to Methionine in codon 66 (Val66Met) constitutes a functional Single Nucleotide
Polymorphism (SNP) in BDNF (dbSNP ID: rs6265); this variation affects intracellular

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traffic and activity-dependent release of BDNF in an allele-specific manner (Egan et al.,

2003).

BDNF Val66Met polymorphism has been studied as a genetic candidate for differences
in performance in cognitive tests in healthy subjects, showing that Val/Val carriers had
better declarative memory and hippocampal activation (Kambeitz et al., 2012). Previous
studies have used relatively simple behavioral paradigms, such as finger tapping, to

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study the possible association of BDNF gene and motor learning and performance
(Kleim et al., 2006; Lee et al., 2013; McHughen et al., 2010) (Table 1, for further

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details). In general, the tasks requiring placing and moving manual skills (Piper, 2011)
show no associations with BNDF genotype; with a few cases using visual-motor tracking

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tasks in which Val/Met subject exhibited poorer performance after relatively long-term
learning.

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The aim of this study was to test the hypothesis that healthy carriers of the BDNF Met

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allele could show differences in performance in a computerized visual motor tracking

task, using the Pursuit Rotor Test (PRT) of the Psychology Experiment Building
Language battery. The PRT has long been used as a measure of both perceptual-motor
skill, and of motor adaptation and learning (R. Ammons, 1955; R. B. Ammons, 1947).
More recent research has suggested that such motor learning is governed by two
complementary processes (Smith, Ghazizadeh, & Shadmehr, 2006; Trewartha, Garcia,
Wolpert, & Flanagan, 2014): a fast process linked to declarative memory that adapts
and decays quickly (Keisler & Shadmehr, 2010) and a slower process that adapts and
decays more gradually. We hypothesized that our results could differ from these

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previous results for two reasons. First, the majority of null results in Table 1 involved fine
motor movement and placing, whose motor control differs from smooth pursuit (Wolpert,
Diedrichsen, & Flanagan, 2011). Second, we tested participants from a South American
population (whereas previous studies were carried out in samples of European and
Asian descent) and our sample size is several times larger than previous studies
(median sample for previous studies was 38 participants). Environmental or epigenetic
factors (Forero, Velez-van-Meerbeke, Deshpande, Nicolini, & Perry, 2014) could lead to

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this population having different performance advantages. We thus expected that a test
as such as the PEBL PRT, that hypothetically requires fast learning and adaptation

motor learning.

Materials and methods

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Subjects

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linked to declarative memory systems, could identify allele-specific effects of BDNF on

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One hundred and sixty eight unrelated subjects were recruited at a University in Bogot,

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Colombia. The population living in Bogot is composed of a European genetic

background with some historical admixture with Amerindians (Forero, Arboleda, Yunis,
Pardo, & Arboleda, 2006; Ojeda et al., 2013). Participants were only included if they
were young university students whose four grandparents were born in Colombia.
Participants were excluded if they had personal history of neuropsychiatric diseases,
were taking medications acting on nervous system, or if they have incomplete
phenotypic or genotypic data. All participants provided written informed consent
(Beskow et al., 2001) and the study was approved by the institutional ethics committee.

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Phenotypic Evaluations
All participants completed a self-administered questionnaire. The questionnaire was
used to collect socio-demographic variables (age, sex, personal and familial history of
neuropsychiatric disorders). We applied to all participants a computerized task, the
PEBL Pursuit Rotor Test, for analyzing quantitative and objective measures of motor
performance, using the Psychology Experiment Building Language (PEBL) platform,
which is freely available at http://pebl.sourceforge.net/ and has been described

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previously (Mueller & Piper, 2014). Pursuit rotor test consists on following, with the
mouse pointer, a small red circle that rotates clockwise at a constant speed around a

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larger circle (Piper, 2011) (Figure 1). Subjects received verbal and visual instructions
before the start of the testing phase, where they had 30 seconds to complete two rounds

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of the test (each one with a duration of 15 seconds) Source code was modified to allow
its application in the Spanish language, using a laptop (Hewlett-Packard Company, Palo

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Alto, CA, USA) running a Windows 7 operating system. Performance scores were given

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by the total time on target for each individual. The PEBL Pursuit Rotor task has been

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shown to be sensitive to a number of neurologically and genetic factors, including

development, gender, and handedness (Piper, 2011), tremor (Walecki, Laso, Kunc, &
Gorzelaczyk, 2013), synaptic plasticity deficits related to Tourrette's Syndrome (Brandt
et al., 2014), and relatively unimpacted by time of day (which nevertheless did impact an
attention task) or extensive practice (which did improve performance a dynamic
compensatory tracking task), see (Ahonen, Dunham, Getty, & Kosmowski, 2012).
Neuroimaging studies have identified a possible role of circuits in the prefrontal cortex
and the presupplementary motor area related to the pursuit rotor task (Hatakenaka,
Miyai, Mihara, Sakoda, & Kubota, 2007).

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Genotyping
A sample of peripheral blood from each participant was taken for genomic DNA
extraction, using a salting out method (Miller, Dykes, & Polesky, 1988; Morales et al.,
2009). Genotyping of BDNF Val66Met was performed by tetra-primer allele specific
Polymerase Chain Reaction (PCR) in a Labnet MultiGene 96-well thermal cycler (Labnet
International Inc, Edison, NJ, USA). PCR products were separated in a 2% agarose gel

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at 140V and visualized with ultraviolet light after SYBR-safe staining (Invitrogen,
Carlsbad, CA, USA). We used 4 primers: (P1: CCT ACA GTT CCA CCA GGT GAG

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AAG AGT G, P2: TCA TGG ACA TGT TTG CAG CAT CTA GGT A, P3: CTG GTC CTC
ATC CAA CAG CTC TTC TAT AAC and P4: ATC ATT GGC TGA CAC TTT

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CGA ACC CA) (Sheikh, Hayden, Kryski, Smith, & Singh, 2010). The PCR reactions
included 2 l of genomic DNA (~50 ng), 1.5 mM MgCl 2, 10X reaction buffer, 1 M of

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each primers, 1 mM of dNTPs, Betaine 1 M and 0.75 U of Taq polymerase (Bioline,

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London, United Kingdom) in a final volume of 20 l. PCR program consisted of

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a 3 -min denaturation step at 94C (1 cycle), 94C for 20s, 63C for 25s, 72C for 40s
(30 cycles), and 72C for 5 minutes (1 cycle). Alleles and genotypes were scored as
follows: An allele as 401 and 204 bp bands and G allele as 401 and 253 bp bands. A
random subsample (10% of subjects) was reanalyzed for both polymorphisms to assure
consistency in the genotyping results. All genotypes were checked by two different
investigators in order to confirm and validate the results (Benitez et al., 2010; Ojeda,
Nino, et al., 2014). Additionally, genotyping data were validated by a method based in
qPCR, which combines high resolution melting and allele-specific PCR (Ojeda, Lopez-

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Leon, & Forero, 2014), in a CFX96 Touch Real-Time PCR Detection System (BioRad,
Hercules, California).

Statistical analyses
X2 test was used for calculation of HardyWeinberg equilibrium and estimation of
genotype and allele frequencies was carried out with the SNPStats program (Perea et
al., 2014; Sole, Guino, Valls, Iniesta, & Moreno, 2006). Performance scores were given

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by the total time on target (values from 0 to 15.000 milliseconds) for the second round of
the test: Higher values for time on target corresponded to better performances. A linear

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regression model was used to analyze the association of BDNF genotypes with
quantitative measures of motor learning, correcting for sex and age (Piper, 2011). A p

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value < 0.05 was considered as statistically significant.

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Results

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In total 167 subjects participated in this study, 118 were women and 49 men, with ages

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from 18 to 34 years (mean: 21.2, SD: 2.9). Scores for pursuit rotor task ranged from
1344 to 14058 time-on-target (in milliseconds) with a theoretical maximum of 15000
milliseconds (average time-on-target of 8599 milliseconds; SE: 220.9). There were no
significant differences in mean scores between female and male subjects (p value:
0.37).

Minor allele frequency for the Val66Met polymorphism in BDNF was 0.13 (A/Met allele),
the distribution of genotypes was: Val/Val (G/G) n=128 (77%), Met/Val (A/G) n=34 (20
%) and Met/Met (A/A) n= 5 (3%). Observed genotypes were in Hardy-Weinberg

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equilibrium (p value: 0.17). Mean performance scores (time-on-target in milliseconds) for

the G/G, A/G and A/A subjects were 8342.7, 9657.0 and 7956.6, respectively (Figure
S1).

A linear regression model was used to assess the association between BDNF Val66Met
genotypes and pursuit rotor task scores, correcting by sex and age. We found a
significant association, under a dominant model, where Met carrier subjects (Val/Met

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and Met/Met) had a better performance in comparison with Val/Val homozygous

subjects (p value 0.03) (Table 2).

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Discussion

Previous studies on BDNF and motor learning in healthy subjects have been carried out
with a variety of tests, such as finger tapping, mainly in populations of European descent

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(Table 1) (Cirillo, Hughes, Ridding, Thomas, & Semmler, 2012; Freundlieb et al., 2012;

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Joundi et al., 2012; Kleim et al., 2006; Lee et al., 2013; Li Voti et al., 2011; McHughen &

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Cramer, 2013; McHughen et al., 2010; Smolders et al., 2012; Witte et al., 2012). It is
important to highlight that, in comparison with previous studies, our work is the largest
(in terms of sample size) in this field and that our study is the first work that uses the
computerized PEBL PRT as a quantitative endophenotype of fine motor function, an
automated brief visuomotor tracking test, for exploration of genetic correlates. As shown
in Table 1, most previous studies of the impact of BDNF Val66Met on performance of
manual tasks have involved tasks requiring tapping and manipulating and longer-term
visuomotor learning, whereas the Pursuit Rotor test is a very brief assessment of
visuomotor tracking. Research has indicated that pursuit motor control behaves as a

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series of ballistic (Craik, 1948) Fitts-law movements (Zhang & Hornof, 2012), with
corrective movements involving a tight perceptual-motor cycle. This type of motor control
is fundamentally different from simple keypress motor responses whose motor control
and decision properties obey the Hick-Hyman law (Seow, 2005). Furthermore,
adaptation on the PRT may primarily involve a fast motor learning process linked to
declarative memory, which (Kambeitz et al., 2012) showed was associated with BNDF
genotype). In addition, other works have used tests that are possibly more demanding

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cognitively or involve a slower motor learning process (Cirillo et al., 2012; Joundi et al.,
2012; McHughen & Cramer, 2013; Smolders et al., 2012); and although one used a

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visuomotor tracking task (Cirillo et al., 2012) it is different from the task we used in this
work (lines that moved down the screen while making left and right movements that

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were unpredictable). It is possible that its small sample size (only 29 subjects in total, 17
Met carriers vs 12 non Met carriers) and differences in genetic background could also

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explain the differences in findings. Joundi et al (Joundi et al., 2012) used a task that

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was oriented to test visuomotor adaptation (a 60 degree deviation) and Smolders et al

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(Smolders et al., 2012) used a task oriented to assess bimanual motor control.

In this study, we found that the subjects that are carriers of the Met allele (Val/Met and
Met/Met genotypes) showed a better performance on the pursuit rotor task. Our current
findings are in agreement with previous neurophysiological and imaging studies that
found differences in brain activation and functioning in key areas between BDNF
genotypes (evidence of motor cortex plasticity), following experimental paradigms that
used motor training or external stimuli (Kleim et al., 2006; Lee et al., 2013; McHughen et
al., 2010). Our findings of a positive association of BDNF and the PEBL pursuit rotor test

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11

is compatible with current theories of motor learning that suggest that the initial stage of
motor learning (fast stage) is related to the function of brain circuits involved in superior
cognitive functions, such as the dorsolateral prefrontal cortex (Dayan & Cohen, 2011;
Wolpert et al., 2011), considering the role of BDNF dependent plasticity on those neural
circuits (Hong, Liou, & Tsai, 2011). A recent animal model of chronic stroke showed that
Met/Met genotype carriers showed a better motor and neurophysiological functioning
(Qin et al., 2014). There is evidence from previous studies that the alleles associated

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with better cognitive performance in other ethnicities are different from those found in
samples of European descent (Gonzalez-Giraldo et al., 2014; Solis-Ortiz, Perez-Luque,

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Morado-Crespo, & Gutierrez-Munoz, 2010; Wang et al., 2013).

Analysis of different populations is a key factor in genetic analysis of human brain

endophenotypes (Forero et al., 2014). Frequencies of risk alleles, patterns of linkage

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disequilibrium and interactions with environmental factors are known to vary between

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populations (Gatt, Burton, Williams, & Schofield, 2015). Limitations of the current study

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includes: Use of a single task for the analysis of motor function and study of a single
functional SNP in BDNF gene. Analysis of genetic and epigenetic variants in other
candidate molecules involved in synaptic plasticity mechanisms will be fundamental for
a better understanding of motor learning and performance in healthy subjects (Forero,
Arboleda, Vasquez, & Arboleda, 2009; Hernandez, Tse, Pang, Arboleda, & Forero,
2013; Strazisar et al., 2014).

In the context of molecular genetics of cognitive endophenotypes, the use of an

automated neuropsychological battery (such as PEBL), has several advantages,

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allowing a quantitative assessment (in real time) of multiple cognitive domains for a
large number of participants (Gonzalez-Giraldo et al., 2014; Ness et al., 2011; Tumkaya
et al., 2013). In addition, as PEBL is freely available, it facilitates testing in different
economic backgrounds, leading to the possibility of sampling a greater genetic diversity
in different countries and ethnicities (Mueller & Piper, 2014). Our analysis of genetic
factors associated with motor learning endophenotypes could be also useful in the
context of the fine mapping of genetic modifiers for neurological and psychiatric

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diseases in patients (Alaerts et al., 2009; Castro et al., 2013; Galvez et al., 2014; He,
Zhang, Yung, Zhu, & Wang, 2013).

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Acknowledgements

This study was supported by grants from Universidad Antonio Nario (VCTI-UAN,
Project # 20131079). YGG was supported by a fellowship from VCTI-UAN (Young

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Scientists Program).

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Table 1. Overview of published studies on allele-specific effects of BDNF Val66Met

and performance in fine-motor tasks

Country

Sample size

Age

Kleim, 2006

USA

26 (14 males)

18-29

McHughen,
2010a

USA

24 (14 males)

18-30

Finger tapping,
Pegboard, Pinch grip

No significant differences

McHughen,
2010b

USA

29 (18 males)

18-30

Driving-Based Motor
Learning Task

Val/Met subjects showed more

driving errors and poorer retention
over 4 days

Li Voti, 2011

Italy

38 (22 males)

28 +/- 5.6

No significant differences

Smolders,
2012

Netherlands

69 (35 males)

18-35

Digital versin of
Preilowskis Task

Joundi, 2012

Spain

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Index Finger movements

42 (32 males)

20.6

Joystick-controlled
visuomotor adaptation
task

Cirillo, 2012

Australia

29 (17 males)

18-39

Freundlieb,
2012

Germany

38 (12 males)

22-27

Serial Reaction Time

Task

No significant differences

Witte, 2012

Germany

32 (0 males)

20-49

Serial Reaction Time

Task

No significant differences

73.3

Peg board, Finger

tapping, Pinch grip,
Speed of reaction time,
Driving-based motor
learning task

No significant differences in elderly

subjects

Finger tapping

No significant basal differences.

Met/Met subjects did not show
increase in performance after
intermittent theta burst stimulation

Association
No significant differences

Women that were Met carriers

showed a poorer performance on
difficult angles
Val/Met subjects showed slower
rates of adaptation to a visuomotor
deviation during initial learning and
for 24-h retention
No significant differences in motor
performance or motor learning

20-40

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Korea

38 (14 males)

Index finger abduction

acceleration,
Visuomotor tracking task

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Lee, 2013

USA

Tests
Finger tapping,
Pegboard, Pinch grip

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2013

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Table 2. Association between BDNF Val66Met polymorphism and performance on

PEBL pursuit rotor task.

Time on Target a

p value b

Val/Val (G/G)
Val/Met and Met/Met (A/G and A/A)

128
39

8342.7 (260.4)
9439.0 (380.1)

0.03

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Genotype Groups

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a. Time on target (in milliseconds), presented as means (SE).

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b. Linear regression test, correcting by sex and age, performed in SNPstats.

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Figure 1. Overview of the PEBL Pursuit Rotor Test

Pursuit rotor test consists on following, with the mouse pointer of the computer, a small
red circle that rotates clockwise at a constant speed around a larger circle presented on
the computer screen. Performance scores for each individual were given by the total

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time on target (in milliseconds).

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81x81mm (150 x 150 DPI)

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Figure S1. Scatter plot showing the distribution scores for the PEBL pursuit rotor task
(Time-on-target, in milliseconds) according to the BDNF Val66Met genotypes.

Human Kinetics, 1607 N Market St, Champaign, IL 61825