Difficulties maintaining prolonged fixation and attention-deficit/hyperactivity symptoms share genetic influences in childhood

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Psychiatry Research

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Short communication

Di fficulties maintaining prolonged fixation and attention-deficit/

hyperactivity symptoms share genetic in fluences in childhood

Terje Falck-Ytter ^a,b,c,⁎ , Erik Pettersson ^d , Sven Bölte ^b,e,f , Brian D'Onofrio ^g , Paul Lichtenstein ^d , Daniel P. Kennedy ^g

a

Department of Psychology, Uppsala University, Uppsala, Sweden

b

Center of Neurodevelopmental Disorders at Karolinska Institutet (KIND), Dept of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden

c

Swedish Collegium for Advanced Study (SCAS), Uppsala, Sweden

d

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

e

Child Psychiatry Stockholm, Center for Psychiatry Research, Stockholm County Council, Sweden

f

Curtin Autism Research Group, School of Occupational Therapy, Social Work and Speech Pathology, Curtin University, Perth, WA, Australia

g

Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA

A R T I C L E I N F O

Keywords:

Neurodevelopmental disorder Intermediate phenotype Etiology

A B S T R A C T

This study investigated the association between the ability to maintain prolonged (2-minute) fixation on a visual target and ADHD traits in a sample consisting of 120 monozygotic and 120 dizygotic twin pairs, aged 9 to 14 years. More intrusive saccades during the task was associated with higher level of parent-reported ADHD traits.

Both intrusive saccades and ADHD symptoms had high heritability estimates, and there was a moderate genetic correlation between number of intrusive saccades and ADHD. This study suggests that inability to maintain ocular fixation for longer times is etiologically linked to ADHD traits in the general population.

1. Introduction

Current definitions of psychiatric diagnoses such as Attention- Deficit/Hyperactivity Disorder (ADHD) suffer from weak connection to basic behavioral and brain sciences (Carpenter Jr, 2016; Cuthbert and Insel, 2013). In order to improve upon this situation, it is critical to study quantifiable psychological constructs, preferably with known neural bases, and to understand how these constructs are related to psychiatric conditions (Gottesman and Gould, 2003; Kendler and Neale, 2010).

Eye tracking provides precise measurement of eye movement be- haviors, many of which have been studied extensively in humans as well as animals (Holmqvist et al., 2011). In addition, some eye tracking tasks are quick and easy to administer, and thus eye tracking has a huge translational potential (e.g., risk assessment, monitoring treatment outcome in clinical trials).

To control ones eye movements is a prerequisite for optimal cog- nitive and behavioral performance in a wide range of everyday tasks, and reduced eye movement control has previously been linked to ADHD. For example, previous research has demonstrated that children with ADHD have problems maintaining visual fixation during goal-di- rected behavior (Gould et al., 2001; Munoz et al., 2003). Both the core

symptoms of ADHD (inattention, impulsivity, hyperactivity) and sac- cade suppression are linked to fronto-striatal networks; hence atypi- calities in these brain areas might explain the link between eye move- ment control and ADHD (Munoz et al., 2003). Short fixations during exploration of visual scenes in infancy predict poor attentional and behavioral control in toddlerhood (Papageorgiou et al., 2014), sug- gesting that altered control of visual fixation could represent a pre- cursor to ADHD.

These lines of evidence suggest that ADHD and problems main- taining fixation during goal directed action could be etiologically linked. In line with this view, Siqueiros Sanchez et al. (2020, based on data from the same sample as we report on here) recently found that ADHD traits were specifically linked to the tendency to produce “pre- mature” gaze shifts during an anti-saccade task and that this association was mediated in part by genetic factors. In the anti-saccade task, these errors occur on a very short timescale, and performance is aggregated across many trials in the experiment. In the current study, we employed a conceptually related task, but which speci fically assesses the ability to maintain prolonged fixation on a target without looking away (ocular fixation task; Gould et al., 2001). Notably, there are no distractors in this task.

We expected to find a phenotypic positive correlation between

https://doi.org/10.1016/j.psychres.2020.113384

Received 19 May 2020; Received in revised form 28 July 2020; Accepted 12 August 2020

⁎

Corresponding author at: Department of Psychology, Uppsala University, Uppsala, Sweden.

E-mail address: terje.falck-ytter@psyk.uu.se (T. Falck-Ytter).

Psychiatry Research 293 (2020) 113384

Available online 18 August 2020

0165-1781/ © 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

T

failure on the task and ADHD traits, and that this association would be driven primarily by genetic factors. We assessed performance on the ocular fixation task ( Gould et al., 2001) and traits of ADHD in a sample of twins, aged 9 to 14 years. ADHD is likely to represent the extreme end of a phenotypic and etiological continuum (Larsson et al., 2012;

Papageorgiou et al., 2014; see also Robinson et al., 2016; Siqueiros Sanchez et al., 2020), suggesting that studying traits in the general population is relevant for our understanding of more severe, clinically impairing manifestations.

2. Methods

A total of 240 same sex twin pairs ( final sample after exclusion; age (M/SD) 11.44/1.27 years; monozygotic 50.0%; 44.2% boys) were re- cruited from a population-based twin study in Sweden (CATSS (Anckarsäter et al., 2011)) targeting 100% of the (twin) population of which approximately 70% choose to participate. The sample size was determined based on the availability of twins in the area, and is com- parable to previous twin studies (Ronald et al., 2010). As we have re- ported earlier (Siqueiros Sanchez et al., 2019), the present study sample is largely representative of the larger CATSS sample on terms of sex and parental education level. Opposite- sex twins, individuals with severe uncorrected hearing or vision impairment, known presence of a genetic syndrome, presence of known significant medical condition likely to a ffect brain development or the child's ability to participate in the study (e.g. Cerebral Palsy, Down's syndrome, cystic fibrosis) were excluded.

Further, to be included in the study, the participants’ parents had to be fluent in Swedish.

In addition to the pairs included in the final sample, 28 additional pairs were tested, of which 8 pairs were excluded due to experimental failure (predominantly sound disturbances) in either of the twins, and 20 pairs due to not ful filling the specific eye tracking criteria listed below in either of the twins.

We assessed ADHD symptoms using the average of the raw scores from the Inattention and the Hyperactivity/Impulsivity subscale of the Conners 3 (Parent ratings; M/SD = 4.00/4.84, Skewness = 2.26) (Conners, 2008), and overall IQ using the average of the scaled scores from the subscales Digit span, Matrices, Coding and Vocabulary from the Wechsler Intelligence Scale for Children (4 Ed) (Wechsler, 2003);

see (López Pérez et al., 2019) for further information about and ana- lyses of the IQ measures used in this study.

The study was approved by the ethics review board in Stockholm, parents provided written informed consent, and gift vouchers were provided as incentive for participation (~$35 /child).

In the ocular fixation task, the child was instructed to look at a fixation cross at the center of a computer screen for two minutes without looking away (no distractors; Gould et al., 2001). The number of saccades exiting an Area of Interest (AOI) covering the fixation cross plus ~2 visual degrees (Munoz et al., 2003) served as the dependent variable (M/SD = 2.46/4.59, Skewness = 3.01). To ensure that we had su fficient data and that the data was reasonably distributed given the nature of the task (with essentially only one thing to look at), we further required that the total looking time in the fixation cross AOI was more than 30 s and that at least 75% of all fixations were on the fixation cross AOI. These relatively liberal criteria were used because we wanted to include as much variability in the data (i.e. children with attentional problems) and in order to include children with temporal gaps in the gaze data (this can occur, for example, if the fixation filter has diffi- culties classifying fixations, or because the tracker itself did not record data during certain periods, due to technical difficulties, or because the child actually looked away from the screen). The average recorded looking duration on the fixation cross AOI after applying these filters was 101,21 s (SD = 19.26) and 1.49 s outside the fixation cross AOI (SD = 3.26), showing that, as expected, participants spent the absolute majority of time looking at the fixation cross. Eye movements were measured using Tobii T120 (120 Hz, Tobii AB, Danderyd Sweden) and

saccades were identified using the Tobii I-VT filter.

We decomposed the variation in each variable into genetic, shared environmental, and non-shared environmental effects. Sex and IQ were included as covariates. Because an initial ACE-model indicated no in- fluence of the shared environment (Supplementary Table S1), the uni- variate and bivariate twin modeling results below are based on an AE- decomposition.

3. Results

Across the full sample, the Spearman correlation between intrusive saccades and parent-reported ADHD symptoms was r = 0.26, p < 0.001. We obtained high heritability estimates for intrusive sac- cades (0.72; 95% CI, 0.60–0.84) and ADHD symptoms (0.86; 95% CI, 0.82–0.90; Supplementary Table S1) and a moderate genetic correla- tion between the two (genetic r = 0.52; Fig. 1 and Supplementary Table S2). In terms of the covariates, higher IQ was associated with having less ADHD symptoms. Moreover, girls tended to have less ADHD symptoms than boys. Both higher IQ and higher age was associated with having fewer intrusive saccades, and girls tended to have fewer intrusive saccades than boys (statistics in Supplementary Table S2).

4. Discussion

We showed that in childhood, the rate of intrusive saccades during a 2-min ocular fixation task is highly heritable and associated with parent-reported ADHD traits in the general population. Further, as hypothesized, we found a significant genetic correlation between in- trusive saccades and ADHD, suggesting that some of the genetic factors a ffecting eye movement control needed to maintain prolonged fixation are also affecting ADHD traits. These results demonstrate that the two constructs are etiologically linked, a result that is in line with the view that ADHD symptoms and voluntary saccadic suppression involve overlapping brain areas linked to top down attentional control (Munoz et al., 2003). Shared environmental factors were negligible for intrusive saccades as well as for ADHD traits.

In addition to shining light on the etiology of a speci fic psycholo- gical mechanism associated with ADHD, the current study also Fig. 1. Results from the bivariate twin analysis (correlated factors model) showing a genetic correlation (0.52) between ADHD symptoms and intrusive saccades. We excluded the shared environment parameter because AIC/BIC comparisons indicated that it did not contribute to model fit (supplementary Table S1). The links between the observed variables and the latent A and E factors are Poisson regression paths. A = Heritability; E = Non-shared en- vironment. Values in parentheses are standard errors.

T. Falck-Ytter, et al.

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illustrates how eye tracking can bridge gaps between various levels of understanding of complex psychiatric constructs. More specifically, the study hints that studies of eye movements in twins might accelerate the search for endophenotypes linked to neurodevelopmental disorders (Gottesman and Gould, 2003; Kendler and Neale, 2010). Independent assessment of the two main constructs (eye tracking for eye movement control and parent report for ADHD traits) is a clear strength of the current study. A limitation of the study is the relatively small sample size (for a twin study), rendering large con fidence intervals.

The results are in line with a previous report that was based on the same sample, which suggested that the tendency to produce too early saccades during the anti-saccade task was positively correlated with ADHD traits, phenotypically and genetically (Siqueiros Sanchez et al., 2020). Together, the two studies provide strong support for the view that a failure to maintain stable fixation on targets during tasks re- quiring sustained attention is etiological linked to ADHD traits in childhood. Notably, difficulties maintaining ocular fixation have been found in patients with a clinical ADHD diagnosis (Gould et al., 2001.) These findings, together with the fact that shorter fixation duration has been found in infants who later develop impairments in attention and effortful control (Papageorgiou et al., 2014), suggest that problems with ocular fixation could be an endophenotype for ADHD. It should be noted however, that the design of this study (cross sectional, correla- tional) cannot speak to causality or to potential developmental pro- cesses linking eye movements and ADHD traits.

Author contributions

TFY and DPK developed the study concept and study design with support from the co-authors. TFY supervised the data collection and analyzed the eye tracking data. EP performed twin modeling analyses.

TFY drafted the manuscript with support from EP. All authors revised the manuscript critically and approved the final version. TFY and EP had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Supplemental Material: Additional supporting information ac- companies this article (Supplementary Table S1 and Supplementary Table S2).

Declaration of Competing Interest

The authors declared have no conflicts of interest with respect to their authorship or the publication of this article.

Acknowledgements

This study was supported by grants to TFY from Stiftelsen Riksbankens Jubileumsfond (NHS14-1802:1; Pro Futura Grant in col- laboration with the Swedish Collegium for Advanced Study) the Swedish Research Council (SRC; 2018-06232), to SB from SRC (523- 2009-7054) and to PL from FORTE (2012-1678) and from SRC (2011- 2492). We thank Viktor Persson, Fanny Engman, Clara Holmberg, Anna

Sahlström, Sigrid Elfström, Ida Hensler, Anton Gezelius, Helena Nizic, Ronja Runnström Brandt, Mathilda Eriksson, Lotta Sjöberg and Linnea Adolfsson for help with the data collection.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.psychres.2020.113384.

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