Normal manual straight ahead pointing in Complex Regional Pain Syndrome.

There is evidence to suggest that people with Complex Regional Pain Syndrome (CRPS) can have altered body representations and spatial cognition. One way of studying these cognitive functions is through manual straight ahead (MSA) pointing, in which participants are required to point straight ahead of their perceived body midline without visual feedback of the hand. We therefore compared endpoint errors from MSA pointing between people with CRPS (n = 17) and matched controls (n = 18), and examined the effect of the arm used (Side of Body; affected/non-dominant, non-affected/dominant). For all participants, pointing errors were biased towards the hand being used. We found moderate evidence of no difference between Groups on endpoint errors, and moderate evidence of no interaction with Side of Body. The differences in variability between Groups were non-significant/inconclusive. Correlational analyses showed no evidence of a relationship between MSA endpoint errors and clinical parameters (e.g. CRPS severity, duration, pain) or questionnaire measures (e.g. body representation, "neglect-like symptoms", upper limb disability). This study is consistent with earlier findings of no difference between people with CRPS and controls on MSA endpoint errors, and is the first to provide statistical evidence of similar performance of these two groups. Our results do not support a relationship between clinical or self-reported measures (e.g. "neglect-like symptoms") and any directional biases in MSA. Our findings may have implications for understanding neurocognitive changes in CRPS.

Introduction

Complex Regional Pain Syndrome (CRPS) is pathological pain condition characterised by motor deficits, and autonomic symptoms [1, 2]. This condition can also be accompanied by neuropsychological changes [for reviews, see 3, 4], such as changes in spatial perception, which might be considered neglect-like [3, 5], although alternative interpretations exist [6-8]. Recently we showed that people with CRPS do not show a consistent visuospatial attention bias [8, 9]. However, some studies that have suggested biases in the representations of space (i.e. the mental knowledge or model of external space). For example, when asked to indicate when a visual target passes the point in front of the body midline in an otherwise darkened room (“visual straight ahead” judgements; VSA), people with CRPS have shown a bias away from the affected arm [10-14], a leftward bias [15] (i.e. pseudoneglect), or no bias [16, 17]. When performed in the dark, VSA is thought to reflect any lateral shifts in the representations of the body midline and of external space relative to one’s own position (i.e. egocentric spatial representations) [14, 18]. However, when performed in light conditions, the availability of other visual cues makes it possible to recruit allocentric representations (i.e. the representation of objects in space relative to each other). The observation of normal VSA judgments made by people with CRPS in light conditions [14] therefore suggest that only egocentric, and not allocentric, representations of space are biased.

Manual straight ahead (MSA) is related to VSA, and involves pointing straight in front of one’s perceived body midline without visual feedback of the pointing arm’s location (e.g. with the eyes closed). MSA has previously been used to quantify directional biases of the perceived body midline in an egocentric reference frame in healthy controls [e.g. 19–23], and people with post-stroke neglect. Like VSA in dark conditions, MSA is thought to reflect egocentric representations of space [24]. However, unlike VSA, MSA can also provide insights into proprioceptive accuracy (i.e. in the pointing arm), and the ability to align the felt position of the arm with the perceived direction of straight ahead. Two studies found that people with CRPS were more variable than control participants when matching the position of their affected or unaffected arm to externally-defined targets [25, 26], indicating impaired proprioception. Furthermore, a recent study of people with CRPS found that their pointing accuracy depended on the type of sensory information available (visual, proprioceptive, or visual-proprioceptive) [27]. It could therefore be informative to use MSA to gain further insights into both spatial representations and limb proprioception, and to evaluate whether there are also deficits in the way that arm proprioceptive information is combined with egocentric spatial representations.

Even though six of the eight studies to investigate VSA in CRPS have reported evidence for a directional bias, almost none of the studies that have evaluated MSA in CRPS have found any such evidence. Two case studies of a woman with unilateral CRPS found that her MSA was biased toward the affected side when using either hand [10, 11], suggesting hyperattention towards (rather than “neglect” of) the affected limb. By contrast, MSA did not deviate from zero for either hand when averaged across seven people with CRPS [17]. Larger group studies also reported no MSA bias for either hand in people with CRPS compared to pain-free controls [n = 17; 27], or other pain patients and pain-free controls [n = 20; 28]. However, since the pointing errors were measured against external objects that was seen by the participant prior to the task (respectively, a large protractor, and a vertical line marked on the well), these studies might have inadvertently encouraged the use of allocentric reference frames (i.e. if the participant pointed to the remembered location of the 0° mark on the protractor, or the line on the wall, rather than to straight ahead of their body midline). The apparent lack of MSA bias in CRPS despite stronger evidence for VSA bias could indicate that any bias in the representation of egocentric space is overcome when arm proprioception is involved in the task. However, much of the current understanding of MSA in CRPS is limited by potential task confounds, or small sample sizes. Furthermore, most of these studies did not analyse whether there were any differences in the variability of pointing errors made by people with CRPS, which would provide insights into possible deficits in arm proprioception or in aligning felt arm position with the spatial representation of straight ahead. The only exception is the study by Kolb and her colleagues [28] which found no evidence of higher MSA variability in people with CRPS. Finally, the existing studies only allow the conclusion that there is no evidence for a difference in the MSA directional errors and variability of CRPS patients and controls: they do not provide evidence that they are equivalent.

To address these gaps, we used motion capture to sensitively measure MSA in people with upper limb CRPS-I and pain-free controls. We compared differences between Groups (CRPS, controls) and Side of Body (affected/non-dominant, non-affected/dominant) on MSA and its variability. If people with CRPS have a directional bias in their egocentric spatial representations, we would expect to see greater endpoint errors on MSA than for controls. We would also expect people with CRPS to show greater variability on MSA than controls if their proprioception is less precise. If such variability is present to similar extents for pointing with the affected and unaffected limb, this could indicate higher level problems with aligning felt limb position with egocentric spatial representations (rather than, for example, proprioceptive deficits due to peripheral changes). Previous research has found an association between VSA and “neglect-like symptoms” [15], although others do not find evidence for such a relationship [16]. We therefore explored the relationship between MSA, clinical data, and questionnaire measures to see if spatial biases were related to CRPS symptoms, “neglect-like symptoms”, and/or disability. Finally, we complemented our frequentist analyses with Bayesian statistics to allow insights into the weight of evidence for the null hypothesis as well as the alternate hypothesis [29].

Materials and methods

Participants

We recruited 17 people with unilateral upper limb CRPS-I (Mage = 53.53, SD = 11.67; 16 female; 14 right-handed; Table 1); and 18 pain-free controls matched for age, sex, and handedness (Mage = 54.17, SD = 12.22; 17 female; 15 right-handed). We decided on our sample size pragmatically. The target sample size was based on the maximum number of people with CRPS we could feasibly recruit and test given financial and time constraints. The final sample size meant that the study was able to reliably detect a large effect of ƞp2 ≥ .21, with an alpha of .05, and 80% power. Twelve participants met the Budapest research criteria for CRPS [1, 2], three met the clinical criteria, and two met the criteria for CRPS not otherwise specified. After completing the MSA task, all participants also took part in a study that aimed to characterise the process of sensorimotor adaptation [30]. The current study is reported separately because it was focused on assessing the presence of any systematic bias in MSA for people with CRPS, rather than the difference in the transfer of sensorimotor prism adaptation after-effects to spatial representations [e.g. 31]. Exclusion criteria for both groups were a history of brain injury, brain disorders, or psychiatric disorders. For safety reasons, we excluded people with a pacemaker, spinal cord stimulator or similar devices; or who were pregnant or breastfeeding. The study complied with the 2013 declaration of Helsinki and had ethical permission from the UK Health Research Authority (REC reference 12/SC/0557). Informed written consent was obtained.

Table 1

Clinical information for people with upper limb CRPS.

ID	CRPS Severity; Budapest criteria	Duration (months)	Current pain	Pain DETECT	CRPS BPD	DASH	TSK	NBQ	Inciting event	Medication	Comorbidities
UL1	13; R	67	8	24	20	65.9	29	3.2	Soft tissue injury of the hand	Co-codamol, etodolac, omeprazole, amitriptyline, sertraline	TMJ, FMS, IBS, migraine
UL2	5; C	64	4	15	14	29.5	29	1.8	Hand surgery	Aspirin, bisoprolol fumarate, levothyroxine sodium, ramipril, folic acid, methotrexate, statin, paracetamol	Frozen joints, arthrosis
UL3	10; R	32	8	29	43	79.5	39	4.2	None identified	Buprenorphine, gabapentin, naproxen, omeprazole, antihistamine, promethazine	FMS, migraine, PCOS, asthma
UL4	7; NOS	99	2	21	7	31.8	27	1.2	Elbow spiral fracture	Aspirin, felodipine, ramipril, paracetamol, lansoprazole	FMS
UL5	11; R	93	2	11	16	43.2	20	1.6	Soft tissue injury of the hand	Paracetamol, ibuprofen
UL6	12; R	74	9	30	36	77.3	41	3.2	Shoulder surgery	Gabapentin, topiramate, zolmitriptan, paracetamol, ibuprofen, senna glycoside	Migraine, frozen shoulder
UL7	10; C	79	2	22	15	31.8	21	2.0	None identified	None
UL8	6; NOS	91	1	8		11.4	29	2	Wrist fracture	Pregabalin, amitriptyline, calcium carbonate
UL9	11; R	140	8	11	22	52.3	37	3.2	Multiple hand fractures	Bisoprolol
UL10	11; R	39	10	19	29	63.6	41	3.6	Elbow fracture	Amitriptyline, omeprazole
UL11	11; R	148	4	28	33	52.3	31	-	Wrist fracture	Pregabalin, amitriptyline, co-codamol, paracetamol	Low mood
UL12	10; R	16	8	12	22	38.6	40	3.0	Wrist fracture	Amitriptyline	Cartilage damage in knee (Left)
UL13	11; R	43	5	17	21	54.5	26	2.2	Surgery for dislocated shoulder	Morphine sulphate, pregabalin, propranolol	Migraines, PCOS
UL14	9; C	59	6	10	13	36.4	38	1.6	Soft tissue injury of the wrist	Co-codamol, amitriptyline, pregabalin
UL15	14; R	39	5	24	32	77.3	40	3.4		Nortriptyline, paracetamol, aminophylline, budesonide, formoterol fumarate dihydrate, salbutamol sulphate	Asthma
UL16	12; R	14	6	26	33	59.1	52	5.6	Multiple wrist fractures	Pregabalin, paracetamol	Diabetes
UL17	8; R	138	6	16	7	-	-	1.0	Forearm fracture	Amitriptyline, tramadol, amlodipine	FMS
M (SD)	10.06 (2.41)	72.65 (41.62)	5.53 (2.74)	19.00 (7.17)	22.69 (10.66)	50.28 (19.74)	33.75 (8.58)	2.68 (1.22)

BDP = Body perception disturbance score [32]. C = Clinical criteria for CRPS met. DASH = The Disabilities of the Arm, Shoulder and Hand questionnaire [33]. FMS = fibromyalgia syndrome. IBS = Irritable bowel syndrome. NBQ = Neurobehavioral questionnaire (“neglect-like symptoms”) [34, 35]. NOS = CRPS not otherwise specified. PCOS = Polycystic ovary syndrome. TMJ = Temporomandibular joint syndrome. TSK = Tampa scale of kinesiophobia [36]. R = Research criteria for CRPS met.— = not measured.

Procedure

All individuals provided informed written consent prior to participation. People with CRPS then went on to have an assessment of their sensory, vasomotor, sudomotor/oedema, and motor/trophic signs and symptoms of CRPS. The number of reported symptoms and observed signs were used to calculate a CRPS severity score [Table 1; 37]. To assess handedness, all participants completed the Edinburgh handedness inventory [38]. A score < -40 indicates left-handedness, a score > 40 indicates right-handedness, and any other score indicates ambidextrousness. Three people with CRPS were classed as left-handed, four as ambidextrous, and eight as right-handed. Two control participants were classed as left-handed, three as ambidextrous, and 11 as right-handed.

People with CRPS then completed questionnaire measures (neuropathic-type pain, body representation disturbance, “neglect-like symptoms”, upper limb disability, fear of movement [32, 34–36, 39]). Neuropathic type pain was assessed by the painDETECT [39], where a higher score (/38) reflects a greater likelihood of neuropathic pain [39]. Body representation was assessed by the Body perception disturbance Scale [32], where a higher score (/57) indicates greater disturbance. Motor and limb ownership related “neglect-like symptoms” were measured by the Neurobehavioral questionnaire [34, 35], where a higher score (/6) indicates a greater severity of “neglect-like” symptoms. The Disabilities of the Arm, Shoulder and Hand questionnaire was used to measure self-reported upper limb disability, where a higher score (/100) indicates a more severe disability [33]. Fear of movement was assessed by the Tampa scale of kinesiophobia, where a higher score (/17) reflects greater fear of movement [36].

Next, all participants completed the MSA pointing task. Participants were seated and rested their head on a chinrest. With their eyes closed, they performed 10 MSA pointing movements using their non-affected/dominant hand, followed by 10 pointing movements with their affected/non-dominant hand. We used a fixed order so that participants with CRPS could become familiar with the task before completing it with their affected hand.

To start a trial, participants placed their index finger on a raised tactile point (~1cm diameter) that was aligned with their body midline and immediately in front of their trunk (the “start location”). A 200 ms auditory cue (800 Hz) signaled that they should fully extend their arm and point their index finger to what felt like straight ahead of their nose, at a comfortable speed. The next trial commenced once a sensor was detected near (i.e. ±2 cm laterally, ±3 cm distally) the start location.

We recorded kinematic data from a sensor placed on the index finger, using an electromagnetic motion capture system (trakSTAR™, 3D Guidance®, Northern Digital Incorporated). For each trial, we calculated angular errors (°) at movement offset (i.e. once resultant velocity dropped below 50mm/s) from a straight line in the mid-sagittal plane for each trial. Endpoint errors were adjusted to compensate for a calibration error causing a 1.26° leftward bias. Errors made towards the affected/non-dominant side of space were coded as negative. See preregistration (https://osf.io/6jpfg/) for full details about the pre-processing of kinematic data, and the clinical and questionnaire measures (available from https://osf.io/t9j52/) used.

Statistical analyses and inference criteria

We conducted frequentist and Bayesian repeated measures analyses of variance (ANOVAs) to address our hypotheses related to MSA errors and MSA variability. We calculated the mean MSA error and its variability (i.e. SD) from the 10 trials for each participant and for each hand. To address the hypothesis related to the presence of a directional bias in spatial representations, we compared Groups (CRPS, Controls), and Side of Body (affected/non-dominant, non-affected/dominant) on MSA errors. To address the question related to proprioceptive precision, we compared Groups and Side of Body on MSA variability. To see if spatial biases were related to CRPS symptoms and/or disability, we performed correlational analyses of the relationship between MSA, clinical data, and questionnaire measures.

We considered a p-value < 0.05 as statistically significant for frequentist analyses. For Bayesian analyses we report Bayes Factors (BF) expressed in favour of the alternative hypothesis (i.e. BF10), analysed using an uniformed uniform prior. We considered a BF10 of 1–3 as inconclusive/anecdotal evidence for the alternative hypothesis, 3–10 moderate evidence, and 10–30 strong evidence [29]. In contrast, we considered a BF10 of 1/3-1 as inconclusive/anecdotal evidence for the null hypothesis, 1/10-1/3 moderate evidence, and 1/30-1/10 strong evidence. We used JASP v0.13.1 [40] for frequentist and Bayesian analyses (see https://osf.io/t9j52/ for data and analysis script).

Results

Directional errors

MSA was similar between people with CRPS and controls: we found moderate evidence [29] of no main effect of Group on endpoint errors, F(1, 33) = 0.01, p = 0.971, ƞp2 < .01, BF10 = 0.314. We found a main effect of Side of Body, F(1, 33) = 14.11, p < 0.001, ƞp2 = .30, BF10 = 3217.454 (Fig 1), whereby people made errors towards their affected/non-dominant side when pointing with their affected/non-dominant arm (M = -4.16°, SE = 1.26), and errors towards the non-affected/dominant side when using their non-affected/dominant arm (M = 3.21°, SE = 0.96). The interaction between Group and Side of Body was not significant, F(1, 33) = 0.06, p = 0.803, ƞp2 < .01, with moderate evidence of no effect, BF10 = 0.297. The results were broadly similar when we re-expressed endpoint errors in terms of left (negative) and right (positive), when clinical measures were included as covariates, and when we excluded participants with comorbid pain conditions. Furthermore, we visually inspected the data split by different CRPS classifications (i.e. NOS, clinical criteria, research criteria), we did not see any indication that these results were shaped by the inclusion of people in these different diagnostic categories.

Fig 1

Manual straight ahead endpoint errors.

Mean endpoint errors in degrees are presented split by Side of Body (affected/non-dominant, non-affected/dominant), for participants with CRPS (orange dots, n = 17, Maffected = -4.78°, SD = 8.99; Mnon-affected = 3.42°, SD = 5.77), and for control participants (blue dots, n = 18, Mnon-dominant = -4.16°, SD = 5.85, Mdominant = 3.01°, SD = 5.79). Black dots show mean values for each Side of Body, with bootstrapped 95% confidence intervals (error bars). A negative score indicates errors made towards the affected/non-dominant side. *** p < 0.001.

Variability

When comparing the intra-individual standard deviations of endpoint errors, we found no significant main effect of Group, F(1, 33) = 2.96, p = 0.095, ƞp2 = .08, although the Bayesian analysis was inconclusive, BF10 = 1.10. There was moderate evidence for no effect of Side of Body, F(1, 33) = 0.12, p = 0.733, ƞp2< .01, BF10 = 0.255. There was no significant interaction between Group and Side of Body, F(1, 33) = 2.43, p = 0.129, ƞp2 = .07, although the Bayesian analysis was inconclusive, BF10 = 0.858.

Correlations

We explored correlations between MSA outcomes, clinical data [e.g. CRPS severity; 37], and questionnaire measures [32, 34–36, 39] for participants with CRPS (Fig 2). We did not observe any significant correlations between MSA outcomes and clinical measures. Greater MSA errors towards the non-affected side for the non-affected hand correlated with lower painDETECT scores. The questionnaire measures were highly correlated with each other (r = .50 to .86), except for neuropathic-type pain and fear of movement. MSA errors for the affected hand negatively correlated with MSA errors for the non-affected hand, reflecting that individual participants showed similar biomechanical reach behaviour for each hand (i.e. either undershooting or overshooting with each hand). A similar correlation was found for the control participants (r = -.41, p = .091), albeit non-significant.

Fig 2

Correlation matrix for people with upper limb CRPS.

Pearson correlation matrix for people with upper limb CRPS (n = 17). CRPS severity was calculated based on the Budapest criteria [1, 2, 37], where a higher score (/16) indicates more signs and symptoms. Significant correlations (i.e. p < 0.05) are presented in boldface.

Discussion

We found moderate evidence for no difference between people with CRPS and matched controls on directional MSA endpoint errors. This finding is consistent with previous MSA research [10, 11, 17, 27, 28]. Our study is the first to find statistical evidence in favour of no MSA bias in CPRS relative to controls [41, 42]. We did not find evidence of any differences in MSA variability when comparing between groups or the arm used, consistent with previous research [28]. However, our Bayesian analysis did not provide evidence in favour of no difference.

The only other study to test the equivalence of MSA errors of people with CRPS and pain-free controls was Verfaille and her colleagues [27]. They found inconclusive/anecdotal evidence in favour of no difference when coded relative to the CRPS-affected side of space. Their sample was the same size as ours (i.e. 17 people with CRPS). Although largely comparable, the subtle differences in findings could be due to methodological differences. For instance, we recorded endpoint errors using a motion capture system sensitive to ±1.4 mm. In the study by Verfaille and her colleagues [27], the experimenter visually inspected endpoint errors against a protractor that was precise to 1°. This difference could have been sufficient to enable our study to detect evidence for the null hypothesis, whereas the findings of Verfaille and her colleagues were inconclusive/anecdotal. It is, however, noteworthy that our findings are largely compatible considering that our study involved people with more chronic CRPS (M duration = 72.65, SD = 41.62) compared to the sample tested by Verfaille and her colleagues (M duration = 13.09, SD = 9.36).

Our study adds to an emerging pattern that MSA has generally been reported as unbiased in CRPS, whereas the evidence is less consistent for the presence or absence of a VSA bias. Discrepancies in the spatial biases in CRPS could relate to the different reference frames (egocentric, allocentric), regions of space (peripersonal, extrapersonal), and/or qualities (goal-directed, defensive) of the space being tested [3]. For instance, VSA is thought to predominantly rely on egocentric reference frames [14, 18], whereas MSA also involves proprioceptive information [24]. The targets in VSA are typically presented at a distance from participants (e.g. 260 cm away in Verfaille et al. [27]), and thus are in extrapersonal/far space. In MSA, the “target” is a felt position and thus would be considered to be located in personal space and/or imaginary space. These task differences might have given rise to the finding that MSA is unbiased for people with CRPS [17, 27, 28], while some studies suggested that VSA is biased [10-15]. However, it should be noted that the findings of VSA bias in CRPS are not consistent, and that the study that had the largest number of participants did not find any evidence of a bias [n = 53; 16].

Our finding of no difference between the variability of MSA errors of people with CRPS and controls contrasts with reports of bilateral proprioceptive deficits in CRPS on arm position matching tasks [25, 26]. These discrepancies could be due to the reference frames required. MSA is presumed to rely on an egocentric reference frame [24], whereas matching arm position to an external target depends on a combination of egocentric and allocentric reference frames [43]. Recent studies have showed that people with CRPS differ from pain-free controls in how they integrate bodily and visual information [44], and in how they update bodily and spatial representations when interacting with external objects [i.e. tools; 45]. It is possible that this altered integration and/or updating is related to the deficits that are observed on arm matching tasks for people with CRPS. Alternatively, given that our Bayesian analysis was inconclusive about whether the null could be supported, it could be that more subtle differences in MSA variability could be detected in studies involving more participants.

Individual MSA errors did not correlate with clinical variables, or with most questionnaire measures, suggesting that egocentric spatial representations were not related to CRPS symptoms, similar to a recent study of VSA in CRPS [16]. If “neglect-like symptoms” [34, 35] were related to spatial perception biases in CRPS, as in hemispatial neglect, they would correlate with MSA error—we found no such evidence. By contrast, our findings showed that “neglect-like symptoms” were positively correlated with CRPS severity, pain, body representation distortion, upper limb disability, and fear of movement, which is consistent with previous findings [28], and might indicate that neuropsychological changes in CRPS are related to motor-neglect (i.e. underutilisation of a limb/body side that cannot be fully attributed to sensory and/or motor deficits) rather than biased spatial representations [6, 34, 46]. If this were the case, then these findings could inform neuropsychological treatments for CRPS by suggesting that movement/motor-neglect be more effective targets than spatial representations. Therefore, “neglect-like symptoms” are of clinical relevance to CRPS [16], although they appear unrelated to spatial perception biases.

Our study is not without limitations. The sample size meant that our study was only powered to reliably detect large effects, despite having more participants than most previous studies [10, 11, 17] of MSA in CRPS. Although not an aim of the study, this limitation meant that we were not able to explore the direct contribution of factors such as CRPS classification (i.e. not otherwise specified, clinical criteria, research criteria), the presence/absence of painful comorbid conditions, or handedness. The limited power also means that our exploratory correlational analyses should be interpreted with a degree of caution.

Conclusions

In contrast to potential biases in VSA pointing [10-15], our study corroborates past research showing no directional bias in MSA pointing in CRPS [17, 27, 28]. This finding complements recent findings that show no visuospatial attention bias in people with CRPS [8, 9, 47] by showing that egocentric spatial representations are also unaffected. The inconsistent findings of spatial biases in CRPS could relate to the different reference frames, regions of space, and/or qualities of the space being tested [3]. We did not find any evidence of impaired proprioception for people with CRPS, which, although consistent with previous MSA findings [28], contrasts findings from position matching task [25, 26]. Therefore, reconciling these discrepant findings is needed to further our understanding of neurocognitive changes in CRPS.

17 May 2021

PONE-D-21-14359

Normal manual straight ahead pointing in Complex Regional Pain Syndrome

PLOS ONE

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18 Jun 2021

We would like to thank the editor for his helpful comments on our manuscript. We have revised it following his suggestions, and we believe that the paper is stronger as a result.

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27 Sep 2021

PONE-D-21-14359R1Normal manual straight ahead pointing in Complex Regional Pain SyndromePLOS ONE

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Please make sure to address - by revisions or explanation - the major concerns of Reviewer #1.

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Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

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The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Review Vitterso et al. Normal manual straight ahead pointing in Complex Regional Pain Syndrome.

Dear authors,

sorry that this took a while to do this review.

In the paper you present a case series of 17 patients with CRPS in contrast to control subjects that were age and gender matched.

There were no findings that indicate a difference between the 2 groups in the manual straightahead while there are ambiguous evidences for deviations towards the unaffected side („neglect- like“) from other studies.

You present an established paradigm and adeaquately point out the difference between the different reference frames and therefor the reasoning for choosing the presented paradigm over VSM. I wish we could compare the results of VSM to MSA in the same subjects to compare the methods which would give us more insights on the different mechanisms of the two tasks and the involved pathophysiologic basis. But anyways from most of the studies there is no effect in VSM as there is no effect in MSA. Yet, your paradigm is not very innovative from my point of view but the statistical approach indeed is (to be honest: I think analysing all the negative studies on pointing tasks in a similar way as you did might lead to comparable results).

I do not fully agree with the notion that involving the sensory system in terms of proprioception in a pointing task will improve the egocentricness of this task as sensory symptoms and muscular changes affecting proprioception are part of the diagnosis of CRPS and impaired hand size estimation (Petz et al. 2011) is also a symptom of CRPS as well as loss of proprioceptive accuracy in positioning tasks (Lewis 2010, which you also cite but maybe interpret it in a more „centralistic“ way than I do), so I would argue against any positive finding of the MSA- pointing showing a between groups effect as aequivalent of egocentric representation which is not the case in this study so may be not a problem but maybe you should weigh the effects of sensory symptoms in the reasoning of choosing your paradigm and reconsider the CRPS- unbiased egocentricness of it always keeping in mind that we are seaching for central representation meachnisms and not peripheral effects of CRPS.

This is in some way adressed in lines 139 ff. but in the paragraphs before concepts get a bit mixed up.

Though not really large, the group of patients is larger than in comparison to other studies with manual straightahead pointing tasks but on the other hand the effects one would expect from those studies are not that large that I can imagine that those studies went into power calculation for the study presented here.

The choosing of sample sizes for pragmatic reasons is really honest but does not seem very scientific to me, which is my ponit of biggest concern and which limits the impact of the findings a lot ( see also next paragraph). Anyways you present not only the absence of evidence for a difference between groups (which would be most likely of doubt because of the number of subjects) but the actual evidence for absence of difference between groups. So leaving the generally sparse (and certainly underpowered from a statistical point of view) number of subjects out of the scope, what seems like a statistical trick at first sight, might indeed add some crucial point to the scientific debate (if maybe it is only to stop doing pointing tasks with our patients).

I personally think that scientific studies for CRPS should not include subjects with the diagnosis CRPS NOS but only CRPS –patients at least fulfilling clinical criteria. I would be interested in the results of the study when leaving CRPS NOS- patients out of the statistical consideration. It might even improve the results due to loss of variance or due to loss of power lower the effect size.

I would also not include patients with other pain disorders such as FMS, knee damage or migraine in CRPS- studies.

Did you test for the effect of handedness in your statistical model and the interaction term of affected * dominance? What we know from other studies is that people tend to bisect a room more on the left side so I think that we need to account for the amount of pseudoneglect, which is more pronounced in right handed subjects than in left handed subjects as baseline correction of the statistcal model or try to explore the interactionterms.

What are your thoughts about the negative significant correlation between the error of the affected side and the error of the affected side? Maybe they can elaborate on that in your discussion a bit more.

Concerning line 240 ff. : I think that we learned a lot about the influence of anxiety and kinesiophobia in CRPS in the recent years and their interrelation with peripersonal space and extrapersonal allodynia. Maybe we need to consider not only allocentric/egocentric reference frame but also the nearness of the task target to the peripersonal space. You adressed that in your conclusions but it might be a crucial point here.

Some minor non- scientific remarks:

Line 40-41 this sentence is a bit unclear, what is meant by „and according to the arm used“, I think this refers to „We compared endpoint errors“, but the sentence is a bit odd.

Lines 43 and 44 Groups is spelled with a capital G.

Line 48 „This study is consistent …“

Line 58 „although see“ --> rest of the sentence is missing

Line 66 „VSA is thought to reflect any lateral shifts of…“ --> missing word

Line 106 CRSP --> CRPS

Line 133 Groups and Side of Body spelled with capitals

Line 135 „we would expect to see a greater“ (the „a“ is a word to much)

Table 1 migraines --> migraine

Line 185 questionnaires measures („s“ or „measures“ to much)

Line 229 Groups and Side of Body spelled with capitals

Line 246 and 247 Groups and Side of Body spelled with capitals

Line 251 Groups and Side of Body spelled with capitals

So in general I think this is a interesting footnote to the scientific debate rather than a very innovative fully grown paper. My greatest concern is the selection of subjects for your study and the number of subjects in your study which can not be improved post hoc but maybe should be adressed in a „limitations“- section.

Best regards

Reviewer #2: The authors have now addressed all concerns sufficiently and I now suggest to accept the manuscript as it stands now.

**********

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Reviewer #2: Yes: Martin Lotze

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2 Nov 2021

Please see the attached file labeled "Response to reviewers_Rev1".

Submitted filename: Response to reviewers Rev1.docx

Click here for additional data file.

7 Dec 2021

Normal manual straight ahead pointing in Complex Regional Pain Syndrome

PONE-D-21-14359R2

Dear Dr. Vittersø,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear authors, thank you for the in depth revision of your manuscript and the comprehensive answers to my questions/ remarks as well as pointing out some aspects, that I might have overseen in the debate about neglect-like symptoms in CRPS and hints to some additional interesting articles to read, which again took me a while.

You are completely right with time and financial constraints in science and I highly appreciate your honesty in this point. You are completely right also choosing a realistic group of CRPS- patients (i.e. with comorbidities and different criteria) keeping that point in mind and as you show in your review (rev-fig 1, rev-fig2) choosing the sample in the way you did does not really affect variance (maybe variance is a bit higher in the patients with CRPS research criteria while pointing with the affected hand). So I am fine with your revision on that point and I agree that statistical tests between the subsets do not really make sense given the sparse cell numbers. I also agree with your elaborations on sample size and power in the revised manuscript and the conclusions drawn from the datasplit.

Thank you also for sharing your thoughts about the negative significant correlations and adding those to the manuscript. I think without overinterpreting it, that this might be an interesting finding.

Overall I think that you adressed all my concerns and cherry-pickings in an apropriate and comprehensive way not only scratching the surface. Thanks a lot for that effort.

Reviewer #2: (No Response)

**********

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Reviewer #1: No

Reviewer #2: Yes: Martin Lotze

10 Dec 2021

PONE-D-21-14359R2

Normal manual straight ahead pointing in Complex Regional Pain Syndrome

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