Pain Affects Visual Orientation: an Eye-Tracking Study

Accepted Manuscript Title: Pain Affects Visual Orientation: an Eye-Tracking Study Author: K. Schmidt, M. Gamer, K. Forkmann, U. Bingel PII: DOI: Reference:

S1526-5900(17)30731-9 https://doi.org/doi:10.1016/j.jpain.2017.09.005 YJPAI 3467

To appear in:

The Journal of Pain

Received date: Revised date: Accepted date:

3-4-2017 4-9-2017 24-9-2017

Please cite this article as: K. Schmidt, M. Gamer, K. Forkmann, U. Bingel, Pain Affects Visual Orientation: an Eye-Tracking Study, The Journal of Pain (2017), https://doi.org/doi:10.1016/j.jpain.2017.09.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Pain affects visual orientation: an eye-tracking study

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Short title: Pain affects visual orientation

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Schmidt, K.1,2*, Gamer, M.3,4*, Forkmann, K.2, Bingel, U.1,2

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* both authors contributed equally

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Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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2

Clinic for Neurology, University Hospital Essen, Essen, Germany

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3

Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg,

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Germany

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Department of Psychology, University of Würzburg, Würzburg, Germany

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Corresponding author:

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Katharina Schmidt

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Department of Neurology

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University Duisburg-Essen

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Hufelandstrasse 55

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45147 Essen, Germany

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Phone: +49 201 / 723-2364

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Email: [email protected]

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http://www.uk-essen.de/?id=2376

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DISCLOSURES:

This work was supported by the German Research Foundation SFB936/A4. The

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authors declare no conflict of interest. There were no previous presentations of the research,

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manuscript, or abstract.

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Highlights

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Abstract

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Due to its unique evolutionary relevance, it is understood that pain automatically attracts attention.

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So far, such attentional bias has mainly been shown for pain-related stimuli whereas little is known

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about shifts in attentional focus following actual painful stimulation. This study investigated

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attentional shifts by assessing eye movements into the direction of painful stimulation. Healthy

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participants were presented either a blank screen or a picture showing a natural scene while painful

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electrical stimuli were applied to the left or right hand. In general, painful stimulation reduced

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exploratory behavior as reflected by less and slower saccades as well as fewer and longer fixations.

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Painful stimulation on the right hand induced a rightward bias, i.e. increased initial saccades, total

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number and duration of fixations to the right hemifield of the screen. Pain applied to the left hand as

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well as no pain induced a leftward bias that was largest for the direction of first saccades. These

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findings are in line with previous observations of attentional biases towards pain-related information

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and highlight eye-tracking as a valuable tool to assess involuntary attentional consequences of pain.

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Future studies are needed to investigate how the observed changes in eye movements relate to pain-

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induced changes in perception and cognition.

Pain affects attentional shifts in terms of eye-movements. Pain reduced exploratory behavior (less saccades and longer fixations). It is unclear so far how this might apply to chronic pain conditions.

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Perspective

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The study investigated pain-induced attentional shifts in terms of reflexive eye movements. This

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attention-capturing quality of pain should be examined in chronic pain conditions since it might

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contribute to the cognitive impairments often observed in chronic pain patients.

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Keywords

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experimental pain, electrical pain, eye-tracking, attentional focus, reflexive eye movements

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Introduction

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Pain is known to impair cognitive functioning in healthy subjects and patients suffering from chronic

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pain

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presumably by shifting attention from the current focus to the source of nociceptive input.

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Attentional shifts can be overt or covert. Overt attentional shifts are selective shifts of attention,

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which are associated with reflexive or controlled eye movements, whereas covert attentional shifts

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can occur without eye movements

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away from pain-related information have mainly used dot-probe tasks and other visual detection

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paradigms 3, 13, 21, 39, 51. For example, spatial cuing tasks 49 revealed faster detection of pain compared

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to control signals. Van Damme, Crombez, Lorenz

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presented on the left or right wrist. Prior to visual stimulation painful electrocutaneous stimuli were

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applied to the same or the opposite wrist. Participants showed faster reaction times for visual

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detection when painful stimuli were applied on the same side, indicating an attentional shift towards

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the source of painful stimulation. Whether this attentional shift was also reflected in eye movements

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towards the painful stimulation cannot be concluded, since eye movements were not recorded. In

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contrast, the tracking of eye movements towards an attention-capturing source is an established

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measure to directly examine overt shifts of attention.

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In the context of attentional shifts and pain, several studies combined eye-tracking and dot-probe

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paradigms to investigate the attentional bias towards pain-related information

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subjects, for instance, showed increased initial fixation of pain faces 32. Chronic pain patients directed

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more attention, i.e. eye movements, to pain-related words 11. Moreover, using the tracking of eye

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movements, pain perception and attentional processing have been addressed in chronic pain

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patients12, 24, 36 and their care takers57 or in term of the predictive capacity of induced pain40, 45, 46. In

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these studies, it has been shown that chronic headache patients exhibited an enhanced initial

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orientation towards painful facial expressions compared to a control group24.

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However, eye movements towards actual painful stimulation have not been investigated so far. Due

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to the archaic biological warning function of pain and conclusive effects on the focus of attention, a

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direct measure to investigate pain’s attentional capacity seems reasonable. The tracking of eye-

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movements can support these investigations as a reflexive and direct outcome measure. Our study

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aimed at testing whether painful stimulation results in eye movements towards a nociceptive

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stimulus. Given the high biological relevance of pain, we hypothesized that nociceptive electrical

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stimulation of the hands induces eye movements towards the site of painful stimulation. As a second

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question, we wanted to investigate potential influences of visual stimulation on this viewing behavior

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(blank screen vs. naturalistic pictures). Possibly, due to an increase in perceptual load

1, 8, 14, 27, 41

. Due to its biological warning function pain disrupts ongoing cognitive processes,

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. Previous studies investigating attentional shifts towards or

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asked participants to detect visual stimuli

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. Healthy

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the 3 Page 3 of 31

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presentation of neutral images could reduce attentional orienting towards pain. Further, we aimed at

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testing the potential influence of pain-related cognition including pain-related fear and pain

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catastrophizing on pain-induced eye movements.

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Methods

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Subjects

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Behavioral and eye movement data were acquired in 28 young healthy subjects (all right-handed, 9

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male; age in years: 27.2 ± 4.7 (M ± SD)). All participants reported normal or corrected to normal

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vision (only contact lenses) and no known history of neurological or psychiatric and pain-related

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diseases. Subjects gave written informed consent to participate and were free to withdraw from the

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study at any time. The study was conducted in accordance with the declaration of Helsinki and had

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been approved by the local ethics committee in Hamburg, Germany. Subjects received monetary

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compensation for their study participation.

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Experimental Paradigm

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Subjects were familiarized with the experimental setting and introduced to the purpose of the study,

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i.e. the evaluation of visual processing during painful stimulation. Subjects underwent the

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assessment of pain thresholds for electrical stimuli on both hands and a calibration procedure in

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order to determine individually calibrated electrical pain stimuli to be applied on both stimulation

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sites. Painful stimulation was adjusted separately to yield comparable pain intensity levels of 70 on a

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0 – 100 visual analogue scale (VAS, anchors 0 = “not painful at all” and 100 = “unbearably painful”).

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Finally, all subjects performed the main experiment that comprised the concurrent presentation of

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visual and nociceptive electrical stimuli to test the influence of pain on eye movements. Within the

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main experiment both hands were covered by boxes and were thus not visible. The hands were

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positioned comfortably with the arms in an angular position on the table left and right next to the

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subject. Hence, the hands were positioned in a 45° angle between body axis and arms next to the

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screen on which the pictures were displayed.

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Experimental Procedures

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Before starting the main experiment, subjects answered self-report questionnaires assessing pain-

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related psychological processing, anxiety and depression (see Self-report measures). We then

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assessed electrical pain thresholds separately for both sites of stimulus application [(1) back of the

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left hand, (2) back of the right hand, approximately 2 cm away from the knuckle of the index finger].

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Thresholds were obtained using single pulse stimuli with 0.5 ms duration and by increasing the

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amperage by 0.01 mA between consecutive stimuli starting at 0 mA (ascending method of limits) 17. 4 Page 4 of 31

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The upper limit was set to 15 mA to avoid tissue damage. Participants verbally indicated the first

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change from a tingling to a painful sensation. This procedure was repeated three times for each

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stimulation site and the mean amperage was defined as the site-specific pain threshold.

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Subsequently, subjects underwent an electrical pain calibration procedure to determine the

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amperage corresponding to a level of 70 on a 0 – 100 VAS. Therefore, subjects were applied train

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stimuli (duration 3 s) of varying amperage levels around their individual pain threshold. Following

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each train of stimulation participants rated their subjective pain intensity on a VAS that was

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presented on a computer screen. The amperage that corresponded to a VAS level of 70 was chosen

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to be applied during the experiment. Pain threshold examination and amperage calibration were

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performed separately for both hands in counterbalanced order.

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Subsequently, subjects performed the main task comprising a 2 x 3 design with the within-subject

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factors visual presentation ([1] picture, [2] blank screen) and painful stimulation ([1] pain left, [2] pain

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right, [3] control (no pain)). Each of the 6 conditions comprised 20 trials resulting in a total number of

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120 trials. Trial structure was as follows: presentation of a white fixation cross (duration 1s), picture

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or blank screen with or without concomitant painful stimulation on one hand (duration 3s), blank

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screen (duration 5s), rating period (variable duration), white fixation cross (variable duration of 1-3 s,

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see Fig. 1). Trial order was pseudo-randomized with no more than three consecutive trials of one

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condition in a row. Pictures were assigned to the condition and presented in a randomized order. To

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ensure visual fixation of the middle of the screen before a trial started, participants were instructed

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to fixate the white cross that was presented at the screen center whenever it was shown. After the

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fixation cross disappeared subjects were instructed to explore the screen freely. Subjects then had to

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rate their perceived pain intensity on a VAS whenever a painful stimulus had been applied. The VAS

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was not presented in the control condition. VAS ratings were recorded as behavioral outcome

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measures. Visual stimuli were presented and the recording of eye movement data was controlled via

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the software Presentation (www.neurobs.com).

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[Please insert Figure 1 here, color]

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Electrical pain stimuli

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Painful stimuli were applied using two electrical stimulators (Digitimer DS7A constant current

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stimulator, Hertfordshire, UK) and surface electrodes (Specialty Developments, Bexley, UK) with a

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diameter of approximately 5 mm that were attached to the skin using medical tape. We applied 98 5 Page 5 of 31

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single pulses of 0.5 ms duration with an inter pulse interval of 30 ms resulting in a train of painful

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stimulation with 3 s duration within each trial. The concurrent application of electrical stimuli and

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images were triggered using Presentation.

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Visual stimuli

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The visual stimuli consisted of pictures showing natural scenes without any salient features or

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characteristics (see Fig. 1 for an example). Sixty pictures were selected from the McGill Calibrated

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Colour Image Database (http://www.netsimilar.net/site/tabby.vision.mcgill.ca) based on their

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uniformity and symmetry (e.g. fallen leaves). Visual stimuli were presented on a dark grey

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background for 3s. Pictures were displayed via Presentation on a 20’’ Samsung SyncMaster 204B

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display (40.64 x 30.48 cm) with a resolution of 1600 x 1200 pixels, a refresh rate of 60 Hz and with a

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size of 768 x 576 pixels (visual angle of 21.7° x 16.3°). Each picture was presented once, either in its

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original orientation or as its mirrored version to control for effects of basic visual properties on

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attentional orienting. Stimulus selection (i.e. original or mirrored version) was determined pseudo-

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randomly across participants.

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Eye-tracking setup

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Eye movements were recorded using a video-based eye-tracking system (EyeLink 1000, SR Research,

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Ontario, Canada) with a spatial resolution of less than 0.01°, a spatial accuracy of 0.25° - 0.40° and a

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sampling rate of 1000 Hz. Participants were seated in front of a computer screen with their head

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fixed using a chin rest and a forehead bar. The distance between the eyes and the screen center

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amounted to approximately 51 cm. After adjusting the eye-tracking camera, a nine-point calibration

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procedure was applied before the start of the main experiment. The experiment took place in a

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sound-attenuated room with constant lighting conditions. Programming and recording equipment

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was located outside this room.

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Self-report measures

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Participants filled in several questionnaires assessing anxiety, depression and pain-related

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psychological processing. Specifically, participants completed the German version of the following

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questionnaires: (1) Pain Anxiety Symptom Scale: PASS-D

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questionnaire consisting of 48 items separated into four subscales which measure [i] fearful appraisal

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of pain, [ii] cognitive anxiety, [iii] physiological anxiety and [iv] escape and avoidance behavior. There

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is no cut-off score. (2) Pain Catastrophizing Scale: PCS 43, German version 21: The PCS consist of 13

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items with no divisions into subscales and no cut-off score. (3) Center for Epidemiological Studies–

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Depression Scale 33, German version: ADS-K 18: The ADS-K questionnaire is a short-version instrument

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, German version

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: The PASS is a

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to investigate depression symptoms over the last week. It consists of 15 items and values above 17

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might indicate a current depressive disorder. (4) State Trait Anxiety Inventory: STAI

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version 22. The state and trait version of this questionnaire each consist of 20 items. There are no cut-

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off scores. All questionnaires were analyzed following the respective manuals and internal

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consistencies were calculated for the present sample.

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Statistical analyses

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Eye tracking data were processed and statistical analyses were performed using the statistical

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programming language R 3.2.3 (www.r-project.org). An a priori significance level of α = 0.05 was

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applied and two-tailed testing was used. For repeated measures analyses of variance (rm-ANOVA),

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we used a multivariate approach and in case of significant effects, post-hoc pairwise comparisons

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with p-values adjusted according to Tukey’s honest significant difference method were performed.

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For rm-ANOVAs, we report η2 as effect size estimate along with 95% confidence intervals. All

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residuals of the dependent variables were normally distributed (tested using Kolmogorov-Smirnov-

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Test) and therefore parametric tests were used throughout.

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Behavioral data

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To compare VAS ratings between pain conditions a 2 x 2 rm-ANOVA with the within-subject factors

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painful stimulation ([1] pain left or [2] pain right) and visual presentation ([1] blank screen or [2]

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picture) was performed.

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Eye-tracking data

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Valid eye-tracking data could be obtained from all 28 subjects. Using EyeLink's standard parser

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configuration, eye blinks were detected and eye movement data were parsed into saccades and

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fixations. By standard configuration, a saccade is defined as an eye movement exceeding 30°/s

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velocity or 8000°/s² acceleration. Time intervals between saccades were defined as fixation. All

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fixations were drift corrected with reference to a baseline period of 300 ms preceding stimulus onset

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using the procedure described in the following: First, trials with blinks or saccades during this period

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were excluded from further analyses. Second, x- and y-coordinates of fixations during the baseline

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period were calculated. To ensure accurate fixation on the centrally presented fixation cross, an

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outlier detection method was applied separately for x- and y-coordinates of the baseline values. This

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procedure that was also used in previous eye-tracking studies

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response time data (e.g., McCormick 25) and followed a recursive approach: For each participant, the

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lowest and highest baseline coordinates were temporarily removed, and the mean (M) and standard

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deviation (SD) for the remaining data were calculated. If either of the two removed values fell

10

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, German

was adopted from analyses of

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outside the interval M +/- 3*SD, it was removed permanently. If one or both data points fell within

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the interval, they were returned to the data set. This procedure continued until no more data points

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were discarded permanently. A baseline was defined as valid when neither its x- nor its y-coordinate

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was found to be an outlier. Trials with invalid baseline values were discarded from the data set. The

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final analyses were conducted on the data of 107.4 ± 9.1 (M ± SD) of all 120 trials. Detection of first

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saccades was accomplished within a time window of 100 ms to 1000 ms to specifically emphasize on

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reflexive gaze shifts that occurred early after stimulus onset. In total, participants made saccades

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within this time window in 73.5 ± 17.3 (M ± SD) of all valid trials.

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We analyzed the data on four levels. First, in order to analyze how visual presentation and painful

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stimulation affected basic properties of visual exploration, we calculated a series of rm-ANOVAs with

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the within-subject factors visual presentation ([1] blank screen or [2] picture) and painful stimulation

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([1] pain left, [2] pain right, [3] no pain) on the frequency and latency of first saccades as well as on

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the number and duration of fixations. Furthermore, we calculated a measure of center bias following

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the procedure of Tseng and colleagues

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fixations from the center of the display within each experimental condition. The first fixation was

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discarded when it overlapped from the baseline period. These values were then normalized such that

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0 represents the average distance of a uniform distribution of fixations within the stimulation area of

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768 x 576 pixels to the center of the screen and 100 represents a maximal center bias (i.e., all

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fixations fall on the center of the screen). To examine the influence of the experimental manipulation

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on this center bias, we conducted an rm-ANOVA using the same within-subject factors as for the

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analyses describes above.

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Second, we examined whether the direction of the first saccade was modulated by the experimental

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conditions by calculating a 2 x 3 rm-ANOVAs with the within-subject factors visual presentation ([1]

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blank screen or [2] picture) and painful stimulation ([1] pain left, [2] pain right, [3] no pain) on the

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proportion of leftward gaze directions among all initial saccades. Please note that the proportion of

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rightward saccade directions is complementary to this value (i.e. 1-leftward gaze directions).

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Third, in order to examine whether attentional biases are maintained throughout the whole

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stimulation duration, we calculated the relative proportion of the cumulative number and duration

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of fixations on the left hemifield across the whole stimulation period and subtracted 50% from these

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values. Thus, positive values indicate a leftward bias and negative values a rightward bias. The first

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fixation was discarded when it overlapped from the baseline period. Two separate 2 x 3 rm-ANOVAs

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with the within-subject factors visual presentation ([1] blank screen or [2] picture) and painful

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stimulation ([1] pain left, [2] pain right, [3] no pain) were conducted on the relative number and the

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relative duration of fixations, respectively, to examine how the experimental manipulations 8

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. In detail, we determined the average distance of all

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modulated horizontal eye movements. Similar analyses were also carried out to examine vertical

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biases in viewing behavior (see Supplementary Material).

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Fourth, we examined to what degree attentional shifts during pain stimulation were associated with

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anxiety, depression and pain-related trait variables. To this end, we calculated an average attentional

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bias for the direction of the first saccade as well as the cumulative number and duration of fixations

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during the whole stimulation period as the difference in leftward orienting between left- and

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rightward pain stimulation. The more participants shifted their attention towards the stimulated

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hemifield, the larger this bias score. Positive values indicate a leftward bias for left compared to right

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pain stimulation. Negative values indicate a rightward bias for left compared to right pain

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stimulation. Since results were comparable between blank screen and picture presentation (see

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below), bias scores were averaged across conditions and correlated with the questionnaire data

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using Pearson’s correlation coefficient.

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To illustrate the distribution of fixations, we calculated fixation density maps for the first fixation

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after stimulus onset as well as for all fixations of a given experimental condition. Overlapping

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fixations from the baseline period were not taken into account. Fixation density maps were

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smoothed with a circular Gaussian convolution kernel (full width at half maximum, FWHM = 1°).

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Since most saccades remained within the central region of the screen (see Figure S1), fixation density

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maps were restricted to an area of 10° x 8° around the screen’s center and we plotted them on a

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logarithmic scale. To illustrate the temporal progression of horizontal fixations, spatiotemporal

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fixation maps were generated and smoothed with a Gaussian convolution kernel of FWHM = 1° in the

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spatial and FWHM = 20 ms in the temporal domain. Differential biases as a function of pain location

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were depicted as difference maps of left - right-sided stimulation separately for both visual

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stimulation conditions (blank screen vs. picture, Figure 3).

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Results

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Amperage and pain intensity ratings

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Applied amperage levels were higher for the right hand than the left hand (right: 1.35 ± 2.16 mA; left:

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1.12 ± 1.81 mA, t(27) = 2.38, p = .02, Cohen’s d = 0.45). The rm-ANOVA for pain intensity ratings

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however revealed no statistically significant main effects or interaction, indicating no significant

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differences in subjective pain intensity between the left and the right hand (F(1,27) = 0.09, p = .77, η2

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< .01 [0, .18]), between blank screen and picture presentation (F(1,27) = 0.45, p = .51, η2 = .02 [0,

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.23]) and no significant interaction between both factors (F(1,27) = 0.05, p = .82, η2 < .01 [0, .17]).

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Pain intensity ratings are given in Table 1. 9 Page 9 of 31

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[Please insert Table 1 here]

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General saccade and fixation characteristics

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Descriptive statistics for saccade and fixation characteristics and estimates of the center bias are

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depicted in Table 2. On average, first saccades within a time window of 100 ms to 1000 ms after

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stimulus onset occurred in 68% of all valid trials. Saccades were more likely and occurred earlier

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when a picture was shown as compared to the blank screen (main effect of visual presentation:

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F(1,27) = 43.78, p < .001, η2 = .62 [.34, .80] for saccade frequency and F(1,27) = 17.72, p < .001, η2 =

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.40 [.11, .66] for saccade latency). Painful stimulation reduced the number of saccades and increased

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their latency (main effect of painful stimulation: F(2,26) = 6.09, p = .007, η2 = .32 [.06, .60] for saccade

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frequency and F(2,26) = 5.33, p = .01, η2 = .29 [.04, .58] for saccade latency). For saccade frequency,

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the post-hoc tests for left or right pain vs. no pain were significant (p = .008 and p = .006,

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respectively), for saccade latency, a significant difference was only obtained when contrasting right

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pain stimulation vs. no pain (p = .03). The interaction effect was not significant, neither for saccade

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frequency (F(2,26) = 0.45, p = .64, η2 = .03 [0, .27]) nor for saccade latency (F(2,26) = 1.71, p = .20, η2

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= .12 [0, .40]). Histograms of saccade latencies are shown in Figure S2.

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The pattern of results was comparable for fixation characteristics. More and shorter fixations

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occurred for picture presentation than for the blank screen (main effect of visual presentation:

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F(1,27) = 29.72, p < .001, η2 = .52 [.23, .75] for fixation number and F(1,27) = 7.55, p = .01, η2 = .22

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[.01, .51] for fixation duration). Moreover, pain stimulation reduced the number of fixations and

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increased their duration (main effect of painful stimulation: F(2,26) = 12.10, p < .001, η2 = .48 [.19,

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.72] for fixation number and F(2,26) = 5.81, p = .008, η2 = .31 [.05, .59] for fixation duration). Post-hoc

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tests for left or right pain stimulation as compared to no pain were significant for fixation number (p

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< .001) as well as fixation duration (p = .01 and p = .004, respectively). For both variables, the

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interaction of visual presentation and pain stimulation failed to reach statistical significance (F(2,26)

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= 3.07, p = .06, η2 = .19 [.01, .48] for fixation number and F(2,26) = 1.27, p = .30, η2 = .09 [0, .36] for

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fixation duration).

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For the center bias, we did not obtain main effects of visual presentation (F(1,27) = 1.82, p = .19, η2 =

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.06 [0, .33]) or painful stimulation (F(2,26) = 1.44, p = .26, η2 = .10 [0, .38]) but a significant interaction

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effect of both factors (F(2,26) = 11.51, p < .001, η2 = .47 [.18, .71]). Separate post-hoc tests within

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both stimulation conditions only revealed a significantly lower center bias for right pain as compared 10 Page 10 of 31

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to the no pain condition when a blank screen was shown (p < .001). No further significant differences

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were obtained for the other pairwise comparisons.

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[Please insert Table 2 here]

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Direction of the first saccades

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The direction of first saccades differed between pain conditions as indicated by a significant main

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effect of the factor painful stimulation (F(2,26) = 10.22, p < .001, η2 = .44 [.15, .69]). This effect was

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driven by significant differences in the proportion of leftward saccades for pain applied to the right

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hand compared to pain applied to the left hand (p < .001) and compared to no pain (p < .001, see

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Figure 2A and 3A). There was no statistically significant effect of the factor visual presentation,

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indicating no significant differences in first saccades between blank and picture screens (F(1,27) =

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0.13, p = .72, η2 < .01 [0, .19]) and no significant interaction of both factors (F(2,26) = 0.32, p = .73, η2

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= .02 [0, .25]).

331 332

[Please insert Figure 2 here, color]

333 334

Attentional biases for the whole stimulation duration as indexed by the distribution of fixations

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Fixation density maps indicate that participants mainly fixated the center of the screen during the

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whole viewing duration and showed more exploration when pictures were shown as compared to

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the blank screen (see Figure 2B). Analyses of the number of fixations during the entire trial (3 s) as

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well as the cumulative fixation duration revealed significant main effects of the factor painful

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stimulation (F(2,26) = 5.38, p = .01, η2 = .29 [.04, .58] and F(2,26) = 9.53, p < .001, η2 = .42 [.13, .68],

340

respectively). For both measures, post-hoc tests revealed significant differences between pain right

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and no pain (p = .003 and p < .001, respectively) as well as pain right and pain left (p = .016 and p =

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.005, respectively, see Figure 3B and 3C). The main effects of the factor visual presentation were not

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significant for both measures, indicating no significant differences in the number and the cumulative

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duration of fixations between blank and picture screens (F(1,27) = 0.29, p = .59, η2 = .01 [0, .21] and

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F(1,27) = 0.29, p = .60, η2 = .01 [0, .21], respectively). Similarly, we did not find interaction effects

346

between both factors on the number of fixations or the cumulative duration of fixations (F(2,26) =

347

0.14, p = .87, η2 = .01 [0, .21] and F(2,26) = 0.01, p = .99, η2 < .01 [0, .16], respectively). Confirming 11 Page 11 of 31

348

these findings, spatiotemporal fixation maps depicted in Figure 3D show a relatively stable

349

attentional bias towards the painfully stimulated hemifield throughout the whole stimulation period

350

irrespective of the visual input (blank screen vs. picture). Participants additionally showed a vertical

351

bias in their viewing behavior. However, this increased downward bias for painful stimulation was

352

only evident in the blank screen condition and was absent when pictures were presented

353

concurrently to the pain stimulation (see Supplementary Material).

354 355

[Please insert Figure 3 here, color]

356 357

Self-report measures results

358

Pain- and personality-related questionnaire results are displayed in Table 2. Internal consistency

359

values obtained in our sample indicated good to excellent reliability. Cronbach alphas ranged

360

between 0.78 and 0.92 (PASS-1: 0.87, PASS-2: 0.78, PASS-3: 0.79, PASS-4: 0.86; PCS: 0.87; ADS 0.79;

361

STAI State: 0.92; STAI Trait: 0.81). Although we observed a substantial variability in bias scores (see

362

boxplots in Figure 3), there were no statistically significant correlations between questionnaire scores

363

and attentional biases derived from the eye-tracking data.

364 365

[Please insert Table 3 here]

366 367

Discussion

368

This study investigated whether nociceptive electrical stimulation applied to the hands modulates

369

eye movements during free visual exploration in healthy subjects. In general, comparing pain to the

370

control condition, we observed an increased latency, reduced number of saccades and reduced

371

number of and longer fixations. The center bias did not reflect this pattern but was only reduced for

372

right pain stimulation in the blank screen condition. The discrepancy of this finding to the marked

373

difference in exploratory behavior as a function of visual stimulation (see Figure 2) is mainly due to

374

the reduced number of fixations in the blank screen condition. Thus, although substantially less

375

fixations were observed in this condition, they seemed to be similarly spread across the display. The

376

general pattern of visuomotor behavior regarding saccade and fixation characteristics supports the

377

hypothesis of a pain-related attentional disruption reported in the literature1,

378

painful stimulation induced a shift of attention to the hemifield of the screen ipsilateral to painful

8, 14

. As expected,

12 Page 12 of 31

379

stimulation. Pain applied to the right hand increased initial saccades, total number and duration of

380

fixations to the right hemifield as compared to pain applied to the left hand or the control condition.

381

Interestingly, pain applied to the left hand resulted in no difference with the control condition. Both

382

induced a leftward bias for the initial saccades and no clear hemifield bias for the number and

383

duration of fixations. Visual input did not modulate this horizontal bias. The pattern of results was

384

slightly different for vertical biases in viewing behavior. Participants tended to look downward when

385

experiencing pain, but this effect was restricted to the blank screen condition. Although the sample

386

size was rather small, this study provides interesting insights into the modulation of attentional

387

orienting by pain that will be discussed in more detail in the following.

388 389

Pain captures attention in terms of eye movements

390

We showed that pain captures attention as it induced eye movements towards the direction of its

391

source. This attentional shift likely serves to sharpen perception and reduce reaction times to

392

estimate and prevent further harm. Although our study did not assess behavioral consequences

393

directly, this interpretation is in line with previous research. Van Damme, Crombez, Lorenz

394

reported that subjects detected targets faster when preceded by a painful stimulus. The same may

395

apply to the anticipation of pain. It has been shown that tactile and visual stimuli were detected

396

faster when applied to a location where pain was expected54-56. Whether previously observed shifts

397

of attention included eye movements has not been investigated directly. Our study results indicate

398

an eye-movement-related shift of attention for actual painful stimulation.

399

Previous studies have demonstrated an attentional bias towards pain-related stimuli11-13, 61 or actual

400

painful stimulation50. While most of these studies used experimental paradigms that assess and

401

quantify attentional biases towards pain indirectly, we directly measured reflexive eye movements.

402

Our findings are in line with recent results reporting eye movements towards the site of tactile, non-

403

painful stimulation29. These results demonstrated that visual and tactile stimulation seem to be

404

integrated into an external reference frame since eye movements were biased towards the direction

405

of the stimulated hand, irrespective of a crossed or uncrossed position. Similar mechanisms might

406

also account for painful stimulation5, 16, 35. However, it has not yet been tested whether these shifts of

407

attention involve eye movements.

408

Our observed results of pain-related reductions of saccades and fixations, increased saccade latency

409

and fixation duration might even be amplified in chronic pain. Due to the attention-capturing

410

capacity of pain, chronic pain patients might show attentional restrictions and therefore engage

411

more in pain processing. This idea is supported by studies on chronic pain patients who show 13

50

Page 13 of 31

412

increased attentional shifts (i.e. eye movements) towards pain-related information24,

413

Schoth, Godwin, Liversedge

414

the attentional bias towards pain-related facial expressions compared to healthy subjects. Here,

415

patients suffering from chronic headache showed enhanced initial orientation towards painful facial

416

expressions.

417

In contrast to a consistent rightward bias for pain applied to the right hand, pain applied to the left

418

hand resulted in a leftward bias in the direction of first saccades, which was also observable in the

419

control condition. Since pain left and control condition were comparable, this leftward bias can be

420

interpreted as no demonstrable bias for the left pain condition. However, such leftward bias already

421

evident in the control condition is a phenomenon well described in the literature6, 15, 30. Ossandon,

422

Onat, Konig

423

exploration and without tactile stimulation, initially explored the left side of images before shifting

424

right. Interestingly, this effect only occurred in right-handers. In our study, pain on the right hand

425

might have disrupted this free viewing behavior by inducing reflexive eye movements to the right

426

hemifield. However, the natural leftward bias might have precluded a significant difference between

427

the control and the pain left condition – at least in our right-handed participants.

428

Interestingly, participants’ eye movements did only rarely leave the central area of the images in the

429

current study. Such central bias has been described in the literature44,

430

fostered by the use of uniform and symmetric pictures. Moreover, participants knew that the visual

431

stimuli were irrelevant to the task at hand (i.e., only the pain had to be rated) and might have

432

concentrated on the screen’s center in the anticipation of the VAS or the fixation cross signaling the

433

upcoming trial. Thus, subjects did not look directly at their painfully stimulated but covered hands.

434

Attentional shifts to the side of painful stimulation might even be stronger with visible hands,

435

potentially due to a higher threat value. Moreover, our results show that pain not only induces a

436

spatial bias in its direction but also a measurable change in terms of the general visual exploration

437

pattern.

438

Visual presentation and perceptual load

439

Another factor that might determine the magnitude of pain-induced attentional shifts is perceptual

440

load. Analyzing general saccades and fixations independent of their direction and screen hemifield,

441

we found an increased number and reduced latency of saccades and increased number and shorter

442

fixations with picture presentation compared to a blank screen. This result is expected since subjects

443

looked at the presented pictures. Regarding the direction of first saccades or the distribution of

444

fixation laterality we did not find any differences in attentional biases between picture presentation

30

24

36

. Liossi,

recorded eye movements in chronic headache patients to investigate

and Ossandon, Konig, Heed

29

showed that participants, when free in visual

47

and might have been

14 Page 14 of 31

445

and blank screen, suggesting no influence of visual perceptual load on reflexive horizontal eye

446

movements induced by pain. For vertical eye movements, pictures successfully inhibited downward

447

biases when pain was applied to the hands. This situation might differ for visual stimuli that are task-

448

relevant. Romero, Straube, Nitsch, Miltner, Weiss

449

target stimuli during high compared to low pain in a high but not in a low perceptual load condition,

450

indicating an influence of perceptual load on attentional effects of pain. Pain perception and the

451

interruptive capacity of pain have been shown to depend on the load in cognitive tasks2, 23, 28, 52, 59.

452

However, it should be noted that our used visual conditions might not only differ in perceptual load

453

since, during picture presentation, subjects might look at different aspects of the pictures. Therefore,

454

future studies should use pictures with different levels of complexity instead of blank screen versus

455

picture presentation.

456

No influence of pain-related cognitions

457

Pain-induced changes in eye movements were not associated with pain-related cognitions. Previous

458

studies revealed increased performance impairments and less disengagement from pain in subjects

459

with high pain catastrophizing scores14, 48, 53, indicating enhanced attentional allocation towards pain.

460

Subjects with high compared to low fear of pain showed increased attentional biases towards pain-

461

related stimuli19. Conscious control to reorient away from pain-related stimuli was only present in

462

low fear of pain subjects20. In contrast, the pain-induced attentional shift in our healthy subjects did

463

not correlate with individual fear of pain or pain catastrophizing. This warrants further investigation

464

in chronic pain since maladaptive pain-related cognitions such as pain catastrophizing, hypervigilance

465

and fear of pain are enhanced in clinical populations4, 9. Studies investigating chronic pain conditions

466

reported altered attentional biases towards pain-related stimuli38 that have been associated with the

467

maintenance of chronic pain37, 39. We did not investigate pain-related state variables such as state

468

pain catastrophizing. Since these measures might have greater predictive validity7 they should be

469

added to future studies.

470

Conclusion

471

This study showed that painful stimulation induced a shift of attention in terms of eye movements

472

towards the source of painful stimulation in healthy subjects. Tracking reflexive eye movements

473

seems to be a valuable additional technique to investigate pain-induced changes in attention.

474

Acknowledgements

475

This work was supported by the German Research Foundation SFB936/A4. There is no conflict of

476

interest.

34

reported longer reaction times to detect visual

15 Page 15 of 31

477

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Figure 1: Trial structure. After the presentation of a white fixation cross for 1 s either a natural scene (neutral valence) or a black screen was presented for 3 s. Image or black screen presentation was either paired with electrical painful stimulation on the left hand, electrical painful stimulation on the right hand or no concurrent stimulation. Next, a black/blank screen appeared for 5 s followed by a fixation cross of variable duration of 1 – 3 s. In trials in which pain was applied, a VAS was presented before that second fixation cross.

626 627 628 629 630 631 632 633

Figure 2: Smoothed fixation density maps (visual angle: 10° x 8°) illustrating the distribution of first (A) and all (B) fixations as a function of painful stimulation (pain left, no pain, pain right) and visual presentation (blank screen, picture). Percentage values indicate the relative frequency of fixations in the left visual hemifield (> 50% = leftward bias; < 50% = rightward bias). P-values indicate probabilities associated with that fraction k assuming a binomial distribution f(k; n, p) with parameters n equal to the amount of fixations and p = 0.5. Histograms below each density map depict the data aggregated across the vertical dimension. Fixation density maps as well as histograms are displayed on a logarithmic scale.

634 635 636 637 638 639 640 641 642 643 644 645

Figure 3: Aggregated eye-tracking data for the different experimental conditions. Relative proportion of initial leftward saccades (A), cumulative fixation numbers (B) and cumulative fixation durations (C) as a function of painful stimulation (pain left, no pain, pain right) and visual presentation (blank screen, picture). Error bars indicate SEM. * p < .05, ** p < .01, *** p < .001 for pairwise comparisons with p-values adjusted according to Tukey’s honest significant difference method. Boxplots show the distribution of horizontal bias scores reflecting the difference in leftward orienting between left- and rightward pain stimulation. Smoothed spatiotemporal difference maps for left-sided vs. right-sided pain stimulation during the entire trial (3 s) are depicted in panel (D) with histograms at the bottom showing aggregated data across the temporal domain. Warmer colors indicate enhanced attentional orienting for left-sided vs. right-sided pain stimulation. Colder colors indicate the reversed pattern. Differences from 0 mainly emerged within the central area of the screen (-5 to 5°) but remained stable throughout the whole stimulation period.

646 647

19 Page 19 of 31

648

Table 1: Mean pain intensity ratings (M±SD) separately for the experimental conditions.

Pain left

Pain right

Blank Screen

60.62 (15.02)

60.06 (13.60)

Picture

60.06 (13.60)

59.14 (12.35)

649 650 651

Table 2. General fixation and saccade characteristics and estimates of a central bias.

Proportion of

Blank Screen Pain left No Pain Pain right 0.55 0.65 0.54

Pain left 0.75

Picture No Pain 0.81

Pain right 0.75

first saccades

(0.23)

(0.16)

(0.23)

(0.17)

(0.14)

(0.15)

Latency of first

558.44

528.25

587.29

489.60

445.79

478.53

saccades (ms)

(157.35)

(109.61)

(140.07)

(109.24)

(115.92)

(108.44)

Number of

3.86

4.63

3.90

5.95

7.15

5.88

fixations

(1.61)

(1.60)

(1.74)

(2.39)

(2.01)

(2.47)

Duration of

614.47

527.19

614.49

492.41

351.16

529.87

fixations (ms)

(263.07)

(219.05)

(276.63)

(251.80)

(111.02)

(377.61)

Central bias

43.84

51.30

36.57

36.45

29.18

36.41

(normalized

(34.18)

(28.45)

(47.24)

(19.09)

(20.47)

(20.14)

score) 652 653 654

20 Page 20 of 31

655

Table 3. Questionnaire results and correlations with attentional biases.

Correlations with attentional bias Questionnaire

Mean (SD)

First saccade

All fixation numbers

All fixation durations

ADS-K

7.32 (5.35)

-0.12

0.12

0.09

STAI State

34.64 (7.15)

-0.19

0.13

0.06

STAI Trait

33.32 (6.92)

0.01

0.28

0.26

PCS

17.43 (8.99)

-0.16

-0.02

0.03

1

19.21 (7.40)

0.06

0.19

0.17

2

20.75 (3.91)

0.03

0.19

0.11

3

12.39 (6.37)

-0.11

-0.14

-0.13

4

11.21 (7.63)

0.16

0.21

0.17

PASS

656 657

ADS-K: Center for Epidemiological Studies–Depression Scale; STAI: State Trait Anxiety Inventory; PCS; Pain Catastrophizing Scale; PASS: Pain Anxiety Symptom Scale (subscales 1-4).

658 659 660

21 Page 21 of 31

661

Supplementary Material

662 663

Instructions for the experimental task

664

Participants were instructed for the experimental procedure using the following wording:

665 666 667 668 669 670 671

In the following task, you will repeatedly see a white cross on the screen. Whenever the white cross appears, please fixate it. Between the appearances of the white crosses, you will either see a blank screen or a picture. During blank screen or picture presentation, you are free in your viewing behavior / visual exploration. In addition to the blank screen or picture, you will either feel a painful stimulus on the left hand, or a painful stimulus on the right hand, or no painful stimulus. There will never be painful stimulations on both hands at the same time. After the painful stimulus ends please rate your sensation on the visual analogue scale.

672 673

Distribution of fixations

674 675 676 677 678

Figure S1: Fixation data of all participants depicted separately for all combinations of painful stimulation (pain left, no pain, pain right) and visual presentation (blank screen, picture). The diameter of the dots is proportional to the fixation duration. The size of the depicted area corresponds to the size of the pictures that were used in the experiment (768 x 576 pixels, 21.7° x 16.3° visual angle).

679

22 Page 22 of 31

680

Latency of saccades

681 682 683 684 685 686

Figure S2: Histograms of saccadic latencies in a time window of 100 ms to 1000 ms after stimulus onset as a function of painful stimulation (pain left, no pain, pain right) and visual presentation (blank screen, picture). The blue diamond indicates the mean latency with error bars reflecting standard errors of the mean. In each plot, the average number of saccades per participant as well as the mean latency are noted together with their standard deviations.

687 688 689

23 Page 23 of 31

690

Vertical biases in viewing behavior

691 692 693 694 695

Our main hypotheses were related to horizontal biases in viewing behavior since we manipulated the laterality of pain stimulation. However, since we stimulated at the hands that were placed below the screen, it might be possible that also vertical biases occurred when pain was applied to the left or right hand. To reduce such effects, both hands were covered by boxes and were thus not visible during the experiment.

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Nevertheless, we also analyzed the vertical gaze position using comparable procedures as for the main analyses. In detail, we first calculated the proportion of upward gaze directions among all initial saccades. In order to examine longer-lasting effects, we calculated the relative proportion of the cumulative number and duration of fixations on the upper hemifield across the whole stimulation period. The first fixation was discarded when it overlapped from the baseline period. After subtracting 50% from these measures, positive values indicate an upward bias and negative values a downward bias. Three separate 2 x 3 repeated measures analyses of variance (rm-ANOVA) with the within-subject factors visual presentation ([1] blank screen or [2] picture) and painful stimulation ([1] pain left, [2] pain right, [3] no pain) were conducted on the proportion of initial saccades as well as the relative number and the relative duration of fixations, respectively, to examine how the experimental manipulations modulated vertical eye movements.

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All these analyses were performed using the statistical programming language R 3.2.3 (www.rproject.org). An a priori significance level of α = 0.05 was applied and we used a multivariate approach for the rm-ANOVA. Significant effects were followed by post-hoc pairwise comparisons with p-values adjusted according to Tukey’s honest significant difference method. For rm-ANOVAs, we report η2 as effect size estimate along with 95% confidence intervals.

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The rm-ANOVA on the direction of first saccades revealed a significant interaction effect of the factors painful stimulation and visual presentation (F(2,26) = 3.86, p = .03, η2 = .23 [.02, .52]). This effect was driven by a significantly higher proportion of downward saccades for the right pain as compared to the no pain condition when a blank screen was shown (p = .01). No such differences were observed when a picture was displayed (see Figure S3A). There were no statistically significant main effects of painful stimulation (F(2,26) = 2.19, p = .13, η2 = .14 [0, .43]) or visual presentation (F(1,27) = 3.95, p = .06, η2 = .13 [0, .42]).

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The rm-ANOVAs on the number of fixations during the entire trial (3 s) as well as the cumulative fixation duration revealed significant main effects of the factors painful stimulation (F(2,26) = 6.35, p = .006, η2 = .33 [.06, .61] and F(2,26) = 8.75, p = .001, η2 = .40 [.12, .66], respectively) and visual presentation (F(1,27) = 5.37, p = .03, η2 = .17 [0, .46] and F(1,27) = 8.92, p = .006, η2 = .25 [.02, .54], respectively). These effects were further qualified by a significant interaction of both factors (F(2,26) = 6.59, p = .005, η2 = .34 [.07, .61] and F(2,26) = 6.96, p = .004, η2 = .35 [.08, .62], respectively). As shown in Figure S3B and S3C, a picture presentation generally induced an upward bias in the number and duration of fixations. The same was true for a blank screen presentation but only when no pain was concurrently applied. Post-hoc tests within the blank screen condition revealed significant differences between left pain and no pain (p < .001) as well as between right pain and no pain (p < .001). Thus, when pain was applied to the left or right hand and no further visual input was provided, participants tended to show a downward bias in their exploration pattern. 24 Page 24 of 31

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Figure S3: Aggregated eye-tracking data for the different experimental conditions. Relative proportion of initial upward saccades (A), cumulative fixation numbers (B) and cumulative fixation durations (C) as a function of stimulation (pain left, no pain, pain right) and visual presentation (blank screen, picture). Error bars indicate SEM. * p < .05, *** p < .001 for pairwise comparisons with p-values adjusted according to Tukey’s honest significant difference method.

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