Neural Correlates Differ in High and Low Fear-Avoidant Chronic Low Back Pain Patients When Imagining Back-Straining Movements

Accepted Manuscript Neural correlates differ in high and low fear-avoidant chronic low back pain patients when imagining back-straining movements Antonia Barke, Mira A. Preis, Carsten Schmidt-Samoa, Jürgen Baudewig, Birgit Kröner-Herwig, Peter Dechent PII:

S1526-5900(16)30066-9

DOI:

10.1016/j.jpain.2016.05.005

Reference:

YJPAI 3255

To appear in:

Journal of Pain

Received Date: 7 October 2015 Revised Date:

20 April 2016

Accepted Date: 6 May 2016

Please cite this article as: Barke A, Preis MA, Schmidt-Samoa C, Baudewig J, Kröner-Herwig B, Dechent P, Neural correlates differ in high and low fear-avoidant chronic low back pain patients when imagining back-straining movements, Journal of Pain (2016), doi: 10.1016/j.jpain.2016.05.005. 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.

ACCEPTED MANUSCRIPT Neural correlates differ in high and low fear-avoidant chronic low back pain patients when imagining back-straining movements

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Philipps University Marburg, Department of Psychology, Marburg, Germany

Georg-Elias-Müller-Institute for Psychology, Department of Clinical Psychology and

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Antonia Barke1, Mira A. Preis2, Carsten Schmidt-Samoa3, Jürgen Baudewig4, Birgit KrönerHerwig2, Peter Dechent3

Psychotherapy, University of Göttingen, Göttingen, Germany 3

Department of Cognitive Neurology, University Medical Center Göttingen, Göttingen, 4

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Germany

German Primate Center, Göttingen, Germany

Disclosures: The Stiftung der Georg-August-Universität (Stiftung des privaten Rechts)

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contributed to the reimbursements for the participants. There are no conflicts of interest.

Keywords: fear avoidance; chronic low back pain; fMRI; fear of movement; kinesiophobia

Address editorial correspondence to: Dr. Antonia Barke Fachbereich Psychologie AG Klinische Psychologie und Psychotherapie Philipps-Universität Marburg Gutenbergstraße 18 D-35032 Marburg Email: [email protected]

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ACCEPTED MANUSCRIPT Abstract The fear-avoidance model postulates that in an initial acute phase chronic low back pain (CLBP) patients acquire a fear of movement that results in avoidance of physical activity and contributes to the pain becoming chronic. The current fMRI study investigated the neural

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correlates of imagining back-straining and neutral movements in CLBP patients with high (HFA) and low fear avoidance (LFA) and healthy pain-free participants. Ninety-three persons (62 CLBP patients, 31 healthy controls; age 49.7 ± 9.2 years) participated. The CLBP patients

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were divided into an HFA and an LFA group using the Tampa Scale of Kinesiophobia. The participants viewed pictures of back-straining and neutral movements and were instructed to

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imagine that they themselves were executing the activity shown. When imagining backstraining movements, HFA patients as well as healthy controls showed stronger anterior hippocampus activity than LFA patients. The neural activations of HFA patients did not differ from those of healthy controls. This may indicate that imagining back-straining movements

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triggered pain-related evaluations in healthy controls and HFA participants, but not in LFA participants. Although heightened pain expectancy in HFA compared to LFA patients fits well with the fear-avoidance model, the difference between healthy controls and LFA patients was

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unexpected and contrary to the fear-avoidance model. Possibly, negative evaluations of the back-straining movements are common but the LFA patients employ some kind of strategy

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enabling them to react differently to the back-straining events. Perspective

It appears that low fear-avoidant back pain patients utilise some kind of strategy or underlying mechanism which enables them to react with less fear in the face of potentially painful movements. This warrants further investigation since countering fear and avoidance provide an important advantage with respect to disability.

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ACCEPTED MANUSCRIPT 1. Introduction The fear-avoidance model (FA model) is the leading explanation for the transition from acute low back pain to chronic back pain9, 34, 67. According to the FA model, in the acute phase, the person acquires a fear of movement69 or ‘kinesiophobia’26 and as a consequence

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begins to avoid physical activity. In the long-term, the reduced activity results in musculoskeletal deconditioning1, 34, 67, 69 and may culminate in a vicious circle characterised by pain
catastrophising
fear of movement/hypervigilance
avoidance of movement


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pain sensitisation
pain9. This behavioural pattern may lead to increasing disability and, if the avoidance is extended to various areas of life, can give rise to generalised withdrawal and

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abet the development of a depressive syndrome35, 67. The FA model also received support for other musculoskeletal conditions, such as knee pain14, 49, neck pain30, 33, 43 and fibromyalgia44, 63

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In the last decade, the FA model has generated a large amount of research activity,

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accruing evidence that supports the model with regard to chronic low back pain (CLBP)9: persons with a strong fear of movement expected more pain10,

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and showed distinct

physiological patterns19 when they anticipated back-stressing movements, they performed less

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well in movement tasks than patients with low fear-avoidance11, 18, 39, 65 and reported more disability11, 47, 65, 66. However, it has also been recognised that not all CLBP patients show a

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fear of movement, but that there may be a subgroup of patients who react with endurance rather than avoidance when faced with pain21, 22, 63. In addition, the disuse/deconditioning for CLBP patients was not unequivocally confirmed57, 64. Despite the FA model’s pervasiveness, little is known about the neural correlates of the postulated fear. In an earlier study we investigated the neural correlates of viewing backstraining movements with an event-related fMRI study3 and expected to find neural activities in structures related to fear processing, such as the amygdalae, insulae, cingulate gyrus, fusiform gyrus and the substantia nigra15. However, we failed to find any neural correlates of 3

ACCEPTED MANUSCRIPT fearful processing of such pictures of back-straining movements in high fear-avoidant CLBP participants, despite the fact that their fear processing in general was unimpaired. One major limitation of our previous study was that the participants only passively viewed the photographs of the movements and thus it could not be excluded that they may

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have focused on other aspects of the pictures and failed to relate the movement to themselves. To address this limitation, the present study specifically instructed the participants to imagine that they themselves were performing the movements shown in the pictures. Moreover, we

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tested a much larger sample (n = 93) and included men.

We used an fMRI block design to compare CLBP patients with high and low fear-

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avoidance and healthy pain-free participants when they imagined executing back-straining and neutral movements. We hypothesised that when patients with high fear-avoidance imagined back-straining movements as opposed to neutral movements, they would show activations in regions related to fear processing. We also hypothesised that these activations

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would be more pronounced for patients with high fear-avoidance than for patients with low

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fear-avoidance or controls.

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ACCEPTED MANUSCRIPT 2. Materials and method 2.1 Participants 2.1.1 Recruitment Patients with CLBP were recruited via local rehabilitation centres and newspaper

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advertisements. Patients were included if the location of their back pain was the lower back, the pain had persisted for at least six months and they reported an average pain intensity of at least 5 on a numerical rating scale from 0 to 10 (with 0 being ‘no pain’ and 10 being the

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‘worst imaginable pain’) over the previous four weeks. Specific causes of their back pain had been ruled out by their physicians. Healthy controls were recruited via newspaper

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advertisements. All of the participants were screened for further pain conditions, neurological disorders and standard MRI counterindications, such as metal objects in the body. In addition, the German version of the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID

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I) 70 was conducted with each participant in order to exclude any mental disorders.

2.1.2 Sample characteristics

Ninety-three persons (mean age 49.7 ± 9.2 years) participated in the study. Of these

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participants, 62 suffered from unspecific CLBP and 31 were pain-free controls matched for age and sex (HC). The participants with CLBP were divided by means of a median split

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performed on the basis of their scores in the German version of the Tampa Scale of Kinesiophobia (TSK)26, 55 into persons with high fear-avoidance (HFA: TSK > 34.5; n = 31) and low fear-avoidance (LFA: TSK < 34.5; n = 31). For a full characterisation of the groups, including pain duration, pain intensity and age see Table 1.

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ACCEPTED MANUSCRIPT 2.2. Design A 3 × 2 repeated measures design with the between-factor group (HFA, LFA and HC)

2.3. Psychometric instruments

2.3.1. Pain characteristics and fear of movement

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and the within-factor movement type (back-straining and neutral) was used.

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Pain duration, location and intensity as well as other pain characteristics were assessed using the pain questionnaire of the German chapter of the International Association for the

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Study of Pain (Deutscher Schmerzfragebogen, DSF)12. The participants rated the average, maximum and minimum pain intensity they had experienced in the previous four weeks on a numerical rating scale from 0 to 10 (with 0 being ‘no pain’ and 10 representing the ‘worst imaginable pain’). Pain-related disability was assessed using the German version of the Pain Disability Index (PDI)13, 51. The PDI measures subjective disability, i.e. the extent to which

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the chronic pain interferes with the person’s ability to engage in everyday activities. The instrument consists of seven items to be rated from 0 to 10 (with 0 being ‘no disability’ and

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10 being ‘total disability’), which cover the following areas: family/home responsibilities; recreation; social activities; occupation; sexual behaviour; self-care and life-support activities.

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Catastrophising cognitions were assessed using the German version of the Pain Catastrophising Scale (PCS)41,

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. Pain catastrophising denotes the tendency to experience

pain as very threatening and to exaggerate its seriousness. The PCS consists of 13 statements regarding what the person may think or feel when they are in pain (example item: ‘It's terrible and I think it's never going to get any better’) and the participants have to judge their agreement with each statement on a five-point rating scale (0 = ‘not at all’ to 4 = ‘all the time’).

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ACCEPTED MANUSCRIPT The fear of movement was assessed with the TSK26,

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. The TSK is a reliable

instrument for the assessment of fear of movement in CLBP patients, with satisfactory internal consistency (Cronbach’s α = .76 - .84)17 and consists of 17 statements expressing fear of physical activity (e.g. ‘I’m afraid that I might injure myself if I exercise’), which have to be

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rated on a four-point rating scale from 1 = ‘strongly disagree’ to 4 = ‘strongly agree’. Items 4, 8, 12 and 16 are inverted.

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2.3.2. Depression and anxiety

Manifest depression was excluded through the SCID I interview. In order to measure

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depression as a dimensional construct, we used the Centre for Epidemiologic Studies Depression Scale (CES-D)23, 53. The CES-D is well-suited to assessing depression in clinical and non-clinical populations and consists of 20 items pertaining to various possible symptoms of depression (example item: ‘I felt depressed’). For each item, the participants had to rate on

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a four-point scale the number of days during the previous week that he or she had experienced the symptom being described (0 = ‘rarely’ [less than one day], 1 = ‘sometimes’ [one to two days], 2 = ‘often’ [three to four days], 3 = ‘most of the time’ [five to seven days]). The items

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4, 8, 12 and 16 are scored inversely.

Trait and state anxiety were measured with the German version of the State–Trait–

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Anxiety Inventory (STAI)32, 58. The state version consists of 20 items describing thoughts or feelings related to fearful worried states (example item: ‘I feel tense’), for which the person has to rate on a scale from 1 = ‘not at all’ to 4 = ‘very much so’ how much the statement describes how they presently feel. Half the items (1, 2, 5, 8, 10, 11, 15, 16, 19, 20) are scored inversely. The trait version also consists of 20 items describing a fearful and worried disposition (example item: ‘I worry too much over something that really does not matter’). The person has to rate on a scale from 1 = ‘almost never’ to 4 ‘almost always’ whether these

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ACCEPTED MANUSCRIPT statements describe how they feel in general. The items (1, 6, 7, 10, 13, 16, 19) are scored inversely.

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2.4. Stimulus material

A total of 48 colour photographs of movements and postures served as stimulus material. The pictures are identical to the movement pictures we used in our previous study3. The majority of pictures were taken from the Photograph Series of Daily Activities

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(PHODA)27, supplemented by pictures produced by one of the authors (AB). The photographs

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were selected from a larger pool of 138 pictures on the basis of a pilot study with 21 CLPB patients and 20 controls. For more detail of the picture selection process see Barke et al. (2012)3. Twenty-four photographs each depicted either back-straining or neutral movements and postures (Figure 1). The back-straining movements showed activities that CLBP patients normally avoid, such as bending down or lifting heavy boxes (numbers of the PHODA

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pictures used: 1, 2, 3, 4, 20, 22, 29, 31, 46, 57, 64, 65, 68, 76, 82, 83, 85, 87, 88, 91, 99). The neutral movements showed less strenuous activities, such as sitting, standing or walking (they

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also included a few PHODA pictures: 8, 60, 61, 69, 84, 92).

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2.5 Procedure

The study protocol was approved by the Ethics Committee of the University Medical

Center, Göttingen. Prior to their participation, the participants received full written information about the study and signed an informed consent form. The participants received a small amount of financial compensation for their participation in the study and a CD with the anatomical pictures of their brains.

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ACCEPTED MANUSCRIPT All participants attended two separate appointments. During the first appointment, the SCID I interview was carried out and the participants received the questionnaires, which they filled in at home and brought with them for the second appointment. During the second appointment, the MRI scanning took place. Immediately before the MRI session, the

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participants filled in the state version of the STAI in order to assess their anxiety prior to the scan. The participants were then placed in the MRI scanner in a supine position, wearing foam earplugs for noise protection and headphones for communication with the experimenter and

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additional noise protection. After the anatomical reference scans, the functional imaging commenced and the pictures were presented to the participants using MR-compatible LCD-

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goggles with a resolution of 800 × 600 (Resonance Technology, Northridge, CA, USA). If a participant required glasses, corrective lenses were combined with the goggles in order to ensure corrected-to-normal vision.

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2.5.1. Stimulation paradigm

The pictures were presented in alternating (back-straining / neutral) blocks. Each block lasted 24 seconds and contained four pictures, presented for six seconds each, either of back-

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straining movements (back-straining) or neutral movements (neutral). Twelve back-straining and twelve neutral blocks were shown, resulting in a total duration of 9.6 minutes. Each

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picture was presented twice. The picture order was randomised except for the block structure. The participants were instructed to look at the pictures and to imagine that they themselves were executing the activity shown in the picture.

2.5.2. Image acquisition The MRI scans were acquired at 3 Tesla (Siemens Magnetom TIM Trio, Siemens Healthcare, Erlangen, Germany) with an 8-channel phased-array head coil. For anatomical reference, a 3D T1-weighted dataset was acquired (turbo fast low angle shot (FLASH); echo 9

ACCEPTED MANUSCRIPT time (TE): 3.26 ms; repetition time (TR): 2250 ms; inversion time: 900 ms, flip angle 12°; isotropic resolution of 1 × 1 × 1 mm³). The functional datasets were acquired using T2*weighted gradient-echo echo-planar imaging (TE: 36 ms, TR: 2000 ms, flip angle 70°, 22 slices of 4 mm thickness at an in-plane resolution of 2 × 2 mm²). A total of 288 whole-brain

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volumes were recorded within the functional run. In order to reach magnetic saturation, four preparatory scans were acquired and subsequently discarded from the analyses.

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2.5.3. Stimulus ratings

After the scanning session, the participants were asked to view the pictures again, this

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time on a computer screen, and to rate each movement in terms of valence and arousal on a 9point scale using the computerised version of the self-assessment manikin6. For valence the instruction was: ‘Please rate: how positive/negative is the depicted movement for you personally?’; for arousal it was: ‘Please rate: how strong is the arousal you feel with respect to

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the depicted movement?’ The end points of the valence scale were marked as ‘very negative’ and ‘very positive’, while the end points of the arousal scale were ‘none’ and ‘very strong’. Each picture was presented separately and the order of presentation was randomised. The

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picture remained visible until the participant had rated it and pressed the button labelled ‘next’. The ratings of two participants were not recorded due to a technical problem. The

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imagining was not measured directly, because doing so would have disturbed the act of imagining the actions. However, at the end of the experiment we interviewed the participants whether they found it hard to imagine the movements in the timeframe and whether they had succeeded in doing so. The answers indicated that the participants had indeed imagined the depicted actions and postures (and nearly all participants recalled spontaneously some of the movements telling us how they went about it).

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ACCEPTED MANUSCRIPT 2.6. Data analysis 2.6.1 Functional data The functional data were analysed using Brain Voyager QX Software version 2.1.2 (Brain Innovation, Maastricht, the Netherlands). Standard preprocessing steps included 3D

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motion correction, slice scan time correction, temporal filtering (linear trend removal and high-pass filtering) and spatial smoothing with a Gaussian kernel (full width at half maximum 8 × 8 × 8 mm3). For high pass filtering and linear trend removal, the presence of low

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frequencies was estimated and removed using a GLM containing sines and cosines (up to 2 cycles/run, 0.0034 Hz). The filtering was performed in the time domain by using the GLM to

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estimate and remove the contributions of low frequencies in each voxel's time course. The functional datasets were co-registered to the anatomical reference scans and transformed into Talairach space. A brain mask was generated based on the Talairach-transformed anatomical images. Subsequent functional analyses were restricted to the voxels in this mask. Group

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analysis was performed using the multisubject (random effects) approach of the general linear model. In a first step, the 24s duration of each block (boxcar) was convolved with the canonical haemodynamic response function resulting in two predictors (back-straining

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movements, neutral movements) for the types of movement. On the basis of these predictors, beta values were estimated for each voxel, which express the strength of the predictor for that

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voxel. This step included a % normalization of the raw BOLD signal time-courses to account for differences in mean BOLD signal levels across voxels or subjects. In a first step, betamaps for the contrast (back-straining > neutral) were generated for each participant. In the secondlevel analysis, the betamaps were used to examine the effect of movement type across all participants, regardless of group-membership, and for each group individually. For these analyses, the Bonferroni-corrected results are reported. In a second step, the groups were compared in planned contrasts and the contrasts between HFA > LFA, HFA > HC and LFA > HC are reported. For the group comparisons, the uncorrected cluster threshold was set at p = 11

ACCEPTED MANUSCRIPT .001. On the basis of the number of activated voxels and the estimated smoothness of the map, Monte-Carlo simulations (1000 iterations) were performed in order to determine the minimum cluster size required to yield an error rate of no more than p < .05 at the cluster level. Activations were assigned to anatomical locations according to the nearest co-ordinates in the

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Talairach Daemon database28, 29. Often, clusters span several structures. For these, we report the cluster maxima in the text. In addition, further activated structures are included in the tables whenever a local maximum of the t-score was located in the structure. A local

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maximum is defined as a maximum at least 10 mm apart from the next maximum. If two local maxima are closer together, only the maximum with the higher statistical value is reported

statistical value is reported.

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and the other one is suppressed. For each structure, only the maximum with the highest

For a correlation analysis, CLBP patients with high and low fear-avoidance were pooled and voxelwise correlations with the TSK score were calculated. The uncorrected

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threshold was set at p = .001 and cluster level corrections applied.

All clusters quoted in this study are numbered consecutively.

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2.6.2 Questionnaire data and stimulus ratings Questionnaire data pertaining to the participants of all three groups (CES-D and STAI)

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as well as age were compared between the groups using one-way ANOVAs, employing Tukey post hoc tests, when appropriate. For measures applicable to the participants with back pain only (TSK-DE, PDI, PCS-D, pain duration, pain intensity) independent t-tests (twotailed) were used in order to compare the high and low fear-avoidant participants. As measures of effect size, Cohen’s d and η2 were calculated. With regard to the valence and arousal ratings collected after the scanning session, we calculated two 3 × 2 repeated measures ANOVAs for valence and arousal of the movements with the between-subject factor group (HFA, LFA, HC) and the within-subject factor 12

ACCEPTED MANUSCRIPT movement type (back-straining, neutral). In cases where Mauchly’s test indicated that the sphericity assumption had been violated, Greenhouse-Geisser corrections were performed and

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the resulting values reported. Tukey’s post hoc tests were used for further analyses.

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ACCEPTED MANUSCRIPT 3. Results 3.1. Stimulus ratings 3.1.1. Valence and arousal ratings for the neutral and back-straining movements Valence. The 3 × 2 repeated measures ANOVA for the valence ratings of the

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movements with the between-factor group and the within-factor movement type showed no main effect for group (P > .10), but revealed a main effect for movement type (F(1, 88) = 368.06, P < .001, η2 = .629) and an interaction group × movement type (F(2, 88) = 5.16, P <

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.005, η2 = .018). Tukey’s post hoc test showed that, within each group, the back-straining movements were rated more negatively than the neutral movements (all Ps < .001). Tukey’s

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test found no significant differences between the neutral movements between the groups. For the back-straining movements, both the HFA and the LFA CLBP patients rated the pictures as more negative than the HC (all Ps < .01), but did not differ from each other (P > .10) (see Figure 2 for more detail).

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Arousal. The 3 × 2 repeated measures ANOVA for the arousal ratings showed main effects for Group (F(2, 88) = 5.95, P < .005, η2 = .070) and movement type (F(1, 88) = 106.61, P < .001, η2 = .213), and an interaction group × movement (F(2, 88) = 5.29, P < .01, η2 = .021.

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Tukey’s post hoc test showed that, within each group, the back-straining movements were rated as more arousing than the neutral movements (all Ps < .005). Tukey’s post hoc tests for

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group showed that HFA pain patients rated the movements as more arousing than HC (P < .01) and so did LFA patients (P < .01); however, no difference was observed between HFA and LFA. Post hoc tests for group x movement showed that the HFA as well as the LFA rated the back-straining movements as more arousing than the HC (HFA: P < .001; LFA: P < .05), but did not differ from each other. The neutral pictures were rated equally non-arousing by all groups (see Figure 2 for more detail).

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ACCEPTED MANUSCRIPT 3.2. Imaging results 3.2.1. Back-straining movements > neutral movements 3.2.1.1 All participants

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Across all groups imagining back-straining movements evoked stronger activations than imagining neutral movements in the right middle temporal gyrus (cluster numbers in parentheses: (1)), the right inferior parietal lobule (3), the bilateral superior parietal lobules (2,

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4), the left middle frontal gyrus (6) and the left precentral gyrus (5). These structures were the locations of the clusters’ peak voxels. However, the clusters extended to adjacent structures

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(see Table 2 for a complete list). The inverse contrast (neutral movements > back-straining movements) activated the left posterior cingulate cortex (8) and the right cuneus (7).

3.2.1.2 CLBP participants with high fear-avoidance (HFA) When HFA participants imagined executing back-straining movements as opposed to neutral

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movements, the right middle occipital gyrus (9, 10), the left inferior temporal gyrus (15), the bilateral superior parietal lobuli (11, 14), the left cuneus (13) and areas in the right cerebellum

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(12) were activated (see Table 3 for a complete list and Figure 3 middle column). The inverse

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contrast evoked activations in the right cuneus (16).

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3.2.1.3 CLBP participants with low fear-avoidance (LFA) In the LFA, imagining executing back-straining movements activated the right

fusiform gyrus (17) and the left inferior temporal gyrus (18). The inverse contrast evoked activations in the bilateral posterior cingulate (19, 21) and the right cuneus (20) (see Table 4 for a complete list and Figure 3 right column).

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3.2.1.4 Pain-free control participants When HC imagined carrying out back-straining movements as opposed to neutral movements, the bilateral occipital gyri (22, 25), the right inferior and superior parietal lobule

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(23, 24), the left precuneus (27) and cuneus (26), the left inferior temporal gyrus (29) and the declive (cerebellum) (28) were activated, whereas the inverse contrast evoked activations in

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the right cuneus (30) (see Table 5 for a complete list and Figure 3 left column).

3.2.2.1 HFA > LFA

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3.2.2. Group comparisons

Comparing HFA patients imagining back-straining movements as opposed to neutral movements with LFA patients, we found that the HFA showed stronger activations in the

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right hippocampus (32), the right parahippoccampal gyrus (31) and the left middle temporal gyrus (33). The inverse contrast (LFA > HFA) was empty (Table 6 and Figure 4 left column). For the clusters identified by the contrast HFA > LFA we calculated the beta differences

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(see Figure 5).

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back-straining movements > neutral movements for all groups, including the control group

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3.2.2.2 HFA > HC No differences were found between the back pain participants with high fearavoidance and the pain-free control participants.

3.2.2.3 LFA > HC 16

ACCEPTED MANUSCRIPT For the contrast LFA > HC, no activations were found. Inversely, pain-free controls showed stronger activations in the right hippocampus (34) and the right lingual gyrus (35) than LFA (see Table 6 and Figure 4 right column).

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3.2.3 Correlations with the TSK

Combining the back pain patients into one group (HFA and LFA: n = 62) and calculating the correlation of the contrast back-straining movements > neutral movements

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with the TSK score showed no regions above the threshold of P < .001.

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ACCEPTED MANUSCRIPT 4. Discussion We investigated the neural correlates of imagining back-straining movements in high and low fear-avoidant CLBP patients by means of fMRI and compared them to those of painfree controls. Patients with low fear-avoidance differed from patients with high fear-

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avoidance and pain-free controls, but contrary to expectations, patients with high fearavoidance and control participants did not show any differences in their neural correlates. On a behavioural level, back pain patients rated the back-straining movements as more negative

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and more arousing than pain-free control participants.

The main effect for movement type, imagining back-straining movements relative to

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neutral movements, evoked activations in areas that Caspers and colleagues identified in their meta-analysis8 as consistently involved in action observation and imitation (e.g. middle occipital gyrus, fusiform gyrus, superior parietal lobule, precentral gyrus). Imagined actions are represented similarly to overtly performed and observed actions45. Given that back-

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straining movements (e.g. lifting a heavy-looking box) were more complex activities than neutral movements (e.g. standing, sitting) this seems to indicate that the participants indeed followed the instructions and observed and imagined the presented movements.

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When they imagined back-straining movements in contrast to neutral movements, patients with high fear-avoidance showed stronger activations in the right anterior (ventral)

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hippocampus, the right parahippocampal gyrus and the left middle temporal gyrus than the low fear-avoidant patients. The hippocampus receives afferents from the septum and the area entorhinalis; its efferents reach the thalamus and the gyrus cingulum and it is reciprocally connected with the basal amygdala60,

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. Chronic pain has been demonstrated to affect

hippocampus size and connectivity2, 24, 42, 56. Evidence of anatomical and functional variability along the hippocampal long axis has inspired different proposals of long-axis functional specialization52. The dorsal hippocampus is primarily associated with cognitive functions, e.g. spatial navigation37, 38, whereas the anterior hippocampus is involved in emotion, stress and 18

ACCEPTED MANUSCRIPT affect16. In particular, the anterior hippocampus was shown to play an important role in anxiety: in animal studies, lesions in the ventral hippocampus were consistently associated with reduced anxiety in a number of standard anxiety paradigms4. In humans, the anterior hippocampus is involved in the modulation of pain through anxiety20, 50, 73. Activation in the

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right hippocampus was positively correlated (r = .74) with high pain expectancy sensitivity during the expectancy of a painful thermal stimulation73, and the hippocampus found to be differentially activated in response to identical noxious stimuli, depending on whether the

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perceived pain was enhanced by pain-related anxiety. In the context of the present study, anterior hippocampus activation may indicate that imagining back-straining movements in

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contrast to neutral movements triggered pain-related representations to arise in high fearavoidant participants, but not in low fear-avoidant participants. This is in accordance with the predictions of the fear-avoidance model. The findings can be interpreted as the neural correlates of anxiety induced by imagining back-straining movements. The anxiety in turn

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may lead to the extensive avoidance behaviour shown by the high fear-avoidant patients71. Apart from the anterior hippocampus, another part of the hippocampal formation, the right parahippocampal gyrus, was also more strongly activated in high fear-avoidant than in

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low fear-avoidant CLBP patients. The parahippocampal gyrus has been associated with the reactivation of pain memories25 and pain sensitivity48. The reported peak coordinates differ

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considerably between the studies; the coordinates resembling most closely those found in the present study were associated by Roy and colleagues54 with the cerebral modulation of pain by emotions.

The high fear-avoidant CLBP patients also showed a stronger activation in the middle temporal gyrus than the low fear-avoidant patients. According to Palermo and colleagues’46 ALE meta-analysis of fMRI studies, the middle temporal gyrus is associated with pain anticipation, perhaps indicating that high fear-avoidance leads to pain anticipation when confronted with back-straining movements. 19

ACCEPTED MANUSCRIPT Healthy controls also revealed stronger activations in the anterior hippocampus, and in addition in the lingual gyrus, than low fear-avoidant participants. Both hippocampal clusters (differentiating the low fear-avoidant participants from the high fear-avoidant participants and from healthy controls) overlapped extensively. This is unexpected, since the healthy controls

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did not suffer from chronic pain and the classical fear-avoidance model postulates that the movement–pain connections are learned in the acute phase of the back pain. However, even if a person does not suffer from chronic back pain, he or she may distinguish between back-

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straining movements and neutral movements on an affective level. After all, back-straining movements are generally more strenuous and even pain-free persons estimated them as

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potentially more harmful7. In our study, this is borne out by the fact that all participants, including the pain-free controls, rated the back-straining movements as more negative and arousing than the neutral ones. In healthy persons this may not influence daily living; however, when confronted with chronic pain, such fear-avoidance has a major impact on

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disability outcomes71.

Remarkably, a direct comparison of healthy controls and high fear-avoidant patients showed no differences in neural correlates at all. The absence of a difference between healthy

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controls and high fear-avoidant back pain patients – even though at odds with the fearavoidance model – is in line with our first study3. In that study, the participants only passively

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viewed the pictures. Therefore the question remained open as to whether the absence of differences between high fear-avoidant patients and pain-free participants could be attributed to the fact that the participants failed to relate the presented movements to their own person. In the present study, we can now rule out this explanation. In addition, Lloyd and colleagues who compared neural responses to intense (non-painful) tactile stimulation to the lower back between healthy controls and chronic low back pain patients with poor adjustment did not find any differences between the two groups.36 There are some important differences between Lloyd and colleagues and the present study: They did not investigate fear-avoidance directly 20

ACCEPTED MANUSCRIPT and used tactile lower back stimulation. However, despite these differences it is remarkable that in both studies no differences in neural responses were found between healthy controls and pain patients with low adjustment and yet both groups differed in their reaction from patients who adjust well to their chronic pain.

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To analyse this unexpected similarity between high fear-avoidant participants and healthy controls further, we also showed the beta differences (back-straining movements neutral movements) for the healthy controls in the regions that differed between high fear-

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avoidant and low fear-avoidant patients for all three groups; here it also becomes apparent that for all structures for which a difference between high and low fear-avoidance was found,

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the similarities between high fear-avoidant participants and controls are high, with the low fear-avoidant participants showing the diverging pattern of activation. Instead of concentrating on the participants with high fear-avoidance, perhaps we should examine more closely the participants who have experienced back pain, but report low

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fear avoidance. As is well known, they generally do better than persons with high fearavoidance in that they expect less pain when anticipating movements10,

61, 62

and perform

better in physical tasks11, 65. We suspect that the low fear-avoidant participants may use some

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kind of coping which enables them not to react with fear to potentially painful events, but to focus on other aspects. Perhaps they concentrate on the desired outcome and the benefit of the

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actions and activities, rather than any pain that might accompany it. This process may be adaptive or it may represent endurance behaviour as hypothesized by Hasenbring21,

22

. A

similar interpretation was offered by Lloyd who proposed that well-adjusted patients use topdown processes to achieve adjustment to the pain, for instance by distracting themselves from signals arising from the lower back.36 The lingual gyrus also showed stronger activation in healthy controls relative to low fear-avoidant participants. To date, little is known about the functions of the lingual gyrus, especially with respect to pain research. As part of a visuo-spatial neural network it codes and 21

ACCEPTED MANUSCRIPT stores environmental information5, and is implicated in the early visual processing of threatrelated information31,

40

. Regarding its role in the present context one can only speculate:

Perhaps it translates into a more intensive processing of the details of the possible threatening character of the back-straining movement scenes by the healthy controls as compared to the

However, this should be addressed in future research.

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Strength and limitations

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low fear-avoidant participants, who may employ strategies of avoiding such processing.

The picture stimuli were carefully selected on the basis of pilot studies with back pain

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patients and healthy participants. The CLBP patients in our sample were severely affected: they had been suffering from moderate to strong pain (mean pain rating of 6) for a long time (over 12 years). The high fear-avoidant patients’ average TSK-scores was 39 points, which is well within the range of being commonly regarded as highly fear-avoidant65, 66, 68. However,

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limitations of the study were that the fear-avoidance of the healthy sample was not assessed and that the stimulus ratings were collected retrospectively after the scanning. Continuing the investigations of our previous study3, in which the participants may

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have passively viewed the back-straining movements, this time they were instructed to imagine that they themselves were carrying out the movement in order to engage their

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personal representations of the movements shown. However, even though the participants have related the feared movements to themselves, the pictures may not have posed a threat to them as they knew that they would not have to perform the feared movements in reality.

Conclusion Based on the fear-avoidance model we expected to find fear-related neural activation in high fear-avoidant CLBP patients compared to low fear-avoidant CLBP patients and healthy controls when imagining back-straining movements. Indeed, high fear-avoidant 22

ACCEPTED MANUSCRIPT patients showed stronger anterior hippocampus and middle temporal gyrus activation when imagining back-straining movements compared to low fear-avoidant patients, supporting the conclusion that fear-avoidance may have triggered representations related to pain-expectancy to occur. However, healthy controls also had stronger hippocampus activation when

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contrasted with low fear-avoidant patients, contradicting an aspect of the fear-avoidance model, which postulates that the movement–pain connections are learned in the acute phase of the back pain. We speculated that negative evaluations of the movement may have also been

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activated in healthy controls when they were confronted with back-straining movements. By contrast, the low fear-avoidant patients may have developed some kind of coping mechanism

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that enables them not to react with fear to back-straining movements.

Research to date has concentrated mainly on high fear-avoidant patients because they were so adversely affected. Perhaps future research should place a stronger focus on low fearavoidant patients and investigate what may enable them to not react with fear when faced with

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potentially painful movements.

23

ACCEPTED MANUSCRIPT Acknowledgements We gratefully acknowledge the help of the following persons: Ilona Pfahlert and Britta Perl conducted the MRI scans, Julia Glombiewski and Jens Tersek helped with the data collection in the pilot study for the selection of the movement stimuli. Elisabeth Vögtle and Johanna

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König carried out SCID I interviews.

24

ACCEPTED MANUSCRIPT Figure captions Figure 1. Example pictures of back-straining movement (left) and a neutral movement (right). The left picture is part of the PHODA26, the right picture was taken by the first author. Figure 2. Valence and arousal ratings for the stimuli as a function of group and movement

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type. Note: error bars show standard deviations. For the valence ratings, low numbers indicate negative valence (1 = very negative to 9 = very positive). For the arousal ratings, low numbers indicate low levels of arousal (1 = no arousal to 9 = extreme arousal). HFA: high fear-

patients; HC: healthy pain-free participants.

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avoidant chronic low back pain patients; LFA: low fear-avoidant chronic low back pain

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Figure 3. Bonferroni-corrected activation maps for the within-group contrast back-straining movements > neutral movements. Left column: healthy pain-free participants; middle column: high fear-avoidant chronic low back pain patients; right column: low fear-avoidant chronic low back pain patients. The statistical maps are shown overlaid on the averaged T1-

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weighted dataset of all subjects.

Figure 4. Second-level comparisons (between-group) of the contrast back-straining movements > neutral movements. The statistical maps were cluster-level corrected and are

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shown overlaid on the averaged T1-weighted dataset of all subjects. HFA: high fear-avoidant chronic low back pain patients; LFA: low fear-avoidant chronic low back pain patients; HC:

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healthy pain-free participants. Figure 5. Beta-values of the predictors for the clusters 31–33 (a–c). Please note that the clusters were extracted on the basis of the contrast HFA > LFA (shown in black) and the values for HC (shown in grey) are only provided for purposes of comparison. HFA: high fearavoidant chronic low back pain patients; LFA: low fear-avoidant chronic low back pain patients; HC: healthy pain-free participants.

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ACCEPTED MANUSCRIPT Table Legends Table 1. Participants’ characteristics Table 2. Structures activated for the contrast back-straining movements > neutral movements and the reverse contrast across all groups (n=93) (Bonferroni corrected). Total area activated: 104557 mm3

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Table 3. Structures activated for the contrast back-straining movements > neutral movements and the reverse contrast within the HFA (Bonferroni corrected). Total area activated 13884 mm3

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Table 4. Structures activated for the contrast back-straining movements > neutral movements and the reverse contrast within the LFA (Bonferroni corrected). Total area activated 6739 mm3

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Table 5. Structures activated for the contrast back-straining movements > neutral movements and the reverse contrast within the HC (Bonferroni corrected). Total area activated 25269 mm3

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Table 6. Structures activated for the group comparisons HFA > LFA and HC > LFA (p < .001, cluster level corrected). All other group comparisons were empty.

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Table 1. Participants’ characteristics

29.3 12.3 6.0 3.0 7.6 2.7 15.5

39.1 12.0 7.0 4.4 7.9 3.6 18.4

3.8 10.0 1.5 2.5 1.7 2.1 9.9

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3.6 8.8 1.2 2.1 1.0 1.7 11.5

F(2,90) 1.46 3.87* 2.23 8.63***

η2 0.082 0.164

t(60) 10.38*** 0.15 2.88** 2.37* 1.01 1.75 1.03

d 2.64 0.73 0.60 -

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TSK Pain duration (years) Average painb Min. painb Max. painb PDI mean PCS

HC (n = 31) 18 female/13 male M SD 49.3 8.2 30.2 6.7 34.9 9.6 7.7 5.2

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HFA (n = 31) 16 female/15 male M SD 51.8 9.9 36.0 9.0 40.2 12.0 14.1 8.2

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Age STAI-trait STAI-state CES-D

LFA (n = 31) 17 female/14 malea M SD 47.9 9.2 34.5 8.3 39.1 8.9 15.0 8.4

* P < 0.05; ** P < 0.01; *** P < 0.001.

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Notes – LFA: Chronic low back pain patients with high r fear-avoidance; HFA: Chronic low back pain patients with high fear-avoidance; HC: healthy pain-free control participants; STAI: State–Trait–Anxiety Inventory; CES-D: Centre of Epidemiological Studies Depression Scale; TSK: Tampa Scale of Kinesiophobia; PDI: Pain Disability Index; PCS: Pain Catastrophizing Scale. a A χ2 test showed no difference for sex between the groups (χ2 = 0.26, df = 2, P > 0.05). b Pain ratings on a numerical rating scale ranging from 1 (‘no pain’) to 10 (‘worst pain imaginable’) over the previous four weeks.

CES-D Tukey’s post hoc test: HC lower than both CLBP groups, all P < 0.01. STAI-trait Tukey’s post hoc test: CLBP high fear-avoidance higher than healthy participants P < 0.05.

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Table 2. Structures activated for the contrast back-straining movements > neutral movements and the reverse contrast across all groups (n=93) (Bonferroni corrected). Total area activated: 104557 mm3

Anatomical Description

L

x

y

z

t

57

-68

-6

7.15

Cluster

RI PT

R BA

x

y

z

t

18,19

-59

-71

-6

6.51

1

19

17,18

-7

-68

-3

7.97

1

18

18

-25

-92

3

11.09

1

18

-37

-71

-12

8.40

1

19

-49

-68

-3

11.59

1

37

-34

-44

42

8.18

4

40

-28

-53

54

9.60

4b

7

-19

-8

57

5.57

5

6

b

Back-straining > Neutral 1 b

44

-62

0

11.85

1

Lingual Gyrus

14

-80

-9

10.28

1

Cuneus

14

-102

3

5.76

1

Fusiform Gyrus Inferior Temporal Gyrus

Superior Parietal Lobule

35

-50

57

32

-35

39

5.74

26

-53

48

9.18

Middle Frontal Gyrus

23

-68

Neutral > Back-straining Posterior Cingulate

14

-12

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Cerebellum, Culmen

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Precentral Gyrus Cerebellum, Declive

6.93

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Inferior Parietal Lobule

-56

12

10.35

7.56

2

40

b

3

40

2b

7

1

7

BA

37 (V5)

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Middle Temporal Gyrus

SC

Middle Occipital Gyrus

Cluster

-

30

-40

37

21

6.12

6

46

-25

-14

51

6.98

5b

6

-25

-71

-15

8.30

1

-

-31

-56

-21

7.26

1

-

-16

-59

12

7.21

8b

30

Cuneus 2 -80 18 12.55 7b 18 3 Cluster sizes (mm ) – 1: 72142; 2: 5071; 3: 145; 4: 16349; 5: 750; 6: 236; 7: 9061; 8: 803. Cluster maxima are marked with a superscript b.

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Table 3. Structures activated for the contrast back-straining movements > neutral movements and the reverse contrast within the HFA (Bonferroni corrected). Total area activated 13884 mm3

Anatomical Description

L

x

y

z

t

50

-65

-6

7.12

Cluster

x

y

z

t

18

RI PT

R

17

-25

-92

3

8.02

13b

7.01

b

7

b

37

BA

Back-straining > Neutral

Superior Parietal Lobule

29

-80

6

8.14

10

20

-92

6

7.25

10

6.14

b

26

-53

48

Inferior Temporal Gyrus 11 26 Neutral > Back-straining

-80 -65

-12

6.77

-21

6.45

TE D

Cerebellum, Declive

b

11

37

SC

Cuneus

9b

7

M AN U

Middle Occipital Gyrus

10

-

b

-

12

-31 -49

-56 -68

54 -3

6.62

AC C

EP

Cuneus 2 -80 18 6.97 16b 18 3 Cluster sizes (mm ) – 9: 2296; 10: 4937; 11: 228; 12: 1416; 13: 1171; 14: 1179; 15: 1146; 16: 1511. Cluster maxima are marked with a superscript b.

Cluster

14

15

BA

18

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Table 4. Structures activated for the contrast back-straining movements > neutral movements and the reverse contrast within the LFA (Bonferroni corrected). Total area activated 6739 mm3

Anatomical Description

L

x

y

z

t

38

-56

-3

5.68

Cluster

BA

RI PT

R x

y

z

t

-49

-71

-3

5.92

18b

19

14 -56 15 6.21 19b 30 -16 -56 Posterior Cingulate Cuneus 2 -77 18 9.10 20b 18 3 Cluster sizes (mm ) – 17: 239; 18: 194; 19: 1006; 20: 4892; 21: 408. Cluster maxima are marked with a superscript b.

12

-6.01

21b

30

Back-straining > Neutral Fusiform Gyrus

17b

SC

Inferior Temporal Gyrus

37

AC C

EP

TE D

M AN U

Neutral > Back-straining

Cluster

BA

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Table 5. Structures activated for the contrast back-straining movements > neutral movements and the reverse contrast within the HC (Bonferroni corrected). Total area activated 25269 mm3

Anatomical Description

L

x

y

z

t

Cluster

Middle Occipital Gyrus Cuneus

44

-65

3

9.37

26

-77

15

7.52

22

Lingual Gyrus

20

-86

3

8.60

22

5.98

b

BA

x

y

z

t

37

-25

-92

6

6.93

25b

18

b

Back-straining > Neutral

Superior Parietal Lobule Fusiform Gyrus

26

-47 -53

54 48

5.60

Precuneus Inferior Temporal Gyrus 23

-68

-12

2

-83

21

Cuneus 3

40

24

-25

-83

24

5.94

26

19

-37

-47

48

6.19

27

40

-37

-71

-12

5.48

28

19

6.45

b

-

5.99

30b

18

-25

-56

54

27

b

-46

-71

0

8.06

29

-19

-65

-12

6.359

28b

Cluster sizes (mm ) – 22: 15575; 23: 183; 24: 531; 25: 1541; 26: 172; 27: 1627; 28: 1650; 29: 3397; 30: 593. Cluster maxima are marked with a superscript b.

AC C

BA

7

22

EP

Neutral > Back-straining

b

Cluster

17

7.34

TE D

Cerebellum, Declive

23

SC

35

18

M AN U

Inferior Parietal Lobule

22b

RI PT

R

7

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Table 6. Structures activated for the group comparisons HFA > LFA and HC > LFA (p < .001, cluster level corrected). All other group comparisons were empty.

Anatomical Description

L

x

y

z

t

Cluster

BA

32

-56

9

4.43

31b

30

5.16

b

28

Hippocampus

23

-20

-15

32

HC > LFA Hippocampus

26

-17

-15

4.89

M AN U

Middle Temporal Gyrus

SC

HFA > LFA Parahippocampal Gyrus

RI PT

R

34b b

x

y

z

t

-31

-59

15

5.03

28

AC C

EP

TE D

19 29 -59 6 4.31 35 Lingual Gyrus 3 Cluster sizes (mm ) – HFA > LFA: 31: 574; 32: 967; 33: 897; HC > LFA: 34: 604; 35: 560. Cluster maxima are marked with a superscript b.

Cluster

33b

BA

19

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

EP

TE D

M AN U

SC

RI PT

High and low fear-avoidant chronic low back pain (CLBP) patients were examined. The CLBP patients imagined executing back-straining activities during fMRI. High vs. low fear-avoidant CLBP patients showed stronger hippocampus activations. High fear-avoidant CLPB patients vs. pain-free controls did not differ.

AC C

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