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. 2024 Feb 23;19(2):e0298345. doi: 10.1371/journal.pone.0298345

CT-optimal touch and chronic pain experience in Parkinson’s Disease; An intervention study

Larissa L Meijer 1,*, Carla Ruis 1,2, Zoë A Schielen 1, H Chris Dijkerman 1, Maarten J van der Smagt 1
Editor: Julian Packheiser3
PMCID: PMC10890780  PMID: 38394218

Abstract

One of the most underdiagnosed and undertreated non-motor symptoms of Parkinson’s Disease is chronic pain. This is generally treated with analgesics which is not always effective and can cause several side-effects. Therefore, new ways to reduce chronic pain are needed. Several experimental studies show that CT-optimal touch can reduce acute pain. However, little is known about the effect of CT-optimal touch on chronic pain. The aim of the current study is to investigate whether CT-optimal touch can reduce the chronic pain experience in Parkinson patients. In this intervention study, 17 Parkinson patients underwent three conditions; no touch, CT-optimal touch and CT non-optimal touch with a duration of one week each. During each touch week, participants received touch from their partners twice a day for 15 minutes. Results show that both types of touch ameliorate the chronic pain experience. Furthermore, it appears that it is slightly more beneficial to apply CT-optimal touch also because it is perceived as more pleasant. Therefore, we argue that CT-optimal touch might be used when immediate pain relief is needed. Importantly, this study shows that CT-optimal touch can reduce chronic pain in Parkinson’s Disease and can be administered by a partner which makes it feasible to implement CT-optimal touch as daily routine.

Introduction

In Parkinson’s Disease (PD) 30–85% of the patients suffers from chronic pain, one of the most underdiagnosed and undertreated non-motor symptoms of PD [1–3]. Chronic pain is defined as ongoing disabling pain which often results in reduced well-being and a lower quality of life [4]. The most commonly reported form of pain in PD is musculoskeletal, which is mostly treated by analgesics [2]. However, analgesia can have several unpleasant side effects such as nausea, headaches, constipation, confusion and memory problems [5]. Furthermore, PD patients who are treated with medication do not always report a decrease in discomfort [6]. In order to develop novel interventions to reduce chronic pain in PD, it is important to understand its underlying mechanisms.

When a noxious stimulus innervates the skin (of healthy individuals), the pain signal is processed through two systems: the lateral and the medial pain system [7]. The lateral system is involved in the sensory and discriminative aspects of pain, which represents the pain threshold (the minimum level at which a stimulus is perceived as painful) [8]. The medial system is crucial for the affective/motivational aspect of pain, which is associated with pain tolerance (the maximum level at which a pain stimulus is tolerated) [9]. In PD both the lateral and medial pain system appear to be overactive, which results in a lowered pain threshold and pain tolerance [6, 10, 11]. This means that PD patients experience pain more severely than individuals without PD [11]. Moreover, research shows that not only central pain processing systems are disrupted, but that PD also causes changes in peripheral pain transmission [1, 6]. These changes in central and peripheral pain processing complicate current pain management [10].

Interestingly, recent research suggests that CT-optimal touch might be a novel non-pharmacological alternative to alleviate pain. CT-optimal touch is a gentle stroking of the skin, which activates the small unmyelinated C-Tactile (CT) afferent nerves [12]. This tactile system can be activated by stroking between 1–10 cm/s, optimal speed is around 3 cm/s, with a soft brush or hand [13, 14]. As this type of touch can also elicit a pleasant sensation it is also referred to as affective touch [15]. Interestingly, recent behavioral research shows that CT-optimal touch can reduce pain experience in healthy individuals [16–18]. These behavioral findings can be explained by a novel model suggesting that the CT-afferent system interacts with the medial pain system at different levels of the central nervous system [19]. In particular, it may inhibit pain signals at the level of the dorsal horn of the spinal cord and as a consequence prevent higher order processing of the pain signal [20]. In addition, it may downregulate several cortical areas such as the insula and anterior cingulate cortex, which are important for the affective aspects of pain experience [16, 21, 22].

However, the above-mentioned studies have focused on acute pain experience in an experimental setting including healthy individuals. Currently, little is known about the effect of CT-optimal touch in people suffering from chronic pain [23]. One study shows that after 11 minutes of CT-optimal touch, chronic pain significantly reduced in patients suffering from primary chronic pain, secondary musculoskeletal pain and neuropathic pain [24]. As the majority of PD patients suffer from musculoskeletal pain, CT-optimal touch might reduce chronic pain in PD patients as well.

In the current 3-week intervention study, participants diagnosed with PD and suffering from chronic pain report their pain experience before the intervention and during a CT-optimal touch as well as a CT non-optimal touch intervention. Based on previous studies we hypothesize that CT-optimal touch may reduce chronic pain in PD patients, and to a larger extent than CT non-optimal touch. Touch will be administered by the partner, as this enhances the positive effect of CT-optimal touch on pain [22]. We can hereby also explore whether implementing CT-optimal touch in daily life and longitudinal administration is feasible. In addition to the effect of CT-optimal touch on chronic pain, the pleasantness of this type of touch will also be recorded. Based on the study of Kass‐Iliyya, Leung [25], which investigated CT-optimal touch perception in Parkinson patients, we expect that CT-optimal touch is perceived as more pleasant than CT non-optimal touch. Furthermore, we will investigate whether there is a relationship between pleasantness ratings and the relieving effect of CT-optimal touch. If so, this might indicate that the pain-relieving effect is merely related to having a concurrent pleasant sensation, rather than the specific activation of the CT-system. However, previous studies of von Mohr, Krahé [22] and Meijer, Schielen [26] into the effect CT-optimal touch on respectively acute pain and itch have failed to show such a relationship between the perceived pleasantness of CT-optimal touch and its relieving effect, suggesting it is not the experienced pleasantness per se that causes the pain reduction. Finally, if CT-optimal touch can ameliorate pain this might also positively influence mood and affect [27].

Materials and methods

Participants

Participants who experience chronic pain and suffer from PD were recruited through ParkinsonNEXT, an online platform connecting researchers with aspiring participants diagnosed with PD (https://www.parkinsonnext.nl). Recruitment took place from September 2020 until December 2022. A total of 57 participants signed up for the study of which 31 were eligible for participation. Inclusion criteria were; age ≥18, PD diagnosis, pain associated with PD (musculoskeletal, dystonic, akathisia) and/or pain worsened by PD (i.e. (osteo)arthritis, other age-related pain conditions), pain present for at least 3 months, with clear impact on physical/psychological functioning (measured with the King’s Parkinson’s Disease Pain Scale), which must be assessed as at least moderate in intensity (≥4 points on an 11-point Likert pain scale) and the ability to provide informed consent. Exclusion criteria were incapability of giving informed consent, inability to understand questionnaires, suffering from conditions that affect the ability to feel or process touch, pain conditions that can also influence the perception and processing of touch; i.e. neuropathic pain, a history of cerebral traumata or psychiatric disorders unrelated to PD and currently suffering from a mood disorder. During the study 12 participants dropped out because: during the first week of the study they did not report to experience pain (N = 4); it was to difficult to combine this 3-week intervention with their daily-working-schedules (N = 5); their partner was not able to provide touch frequently due to physical limitations (N = 2). One participant dropped out because of a painful sensation elicited by CT non-optimal touch. As a result, 19 participants (8 women), aged between 31 and 76 years (M = 65.47, SD = 11.22) and mostly suffering from musculoskeletal pain successfully participated in the study (for more descriptives see S1 Table in S1 File). In addition, one participant was excluded as technical problems with Gorilla (an online survey tool) resulted in too many missing and invalid data.

One other participant was excluded from the sample. During the intervention it became plausible that this participant mainly suffered from neuropathic pain, which was one of the exclusion criteria. As this was not formally diagnosed at first, it was decided that the participant was eligible for participation. This participant’s chronic pain appeared fully diminished after the end of the study, and such an effect of CT-optimal touch had not been reported by any of the other participants from this sample. Therefore, the results of this participant are reported in a single case report [28] and this patient was not included in the current study. Thus, data of 17 participants was used for the analyses. All participants provided written informed consent, which were stored separately from all anonymized data. The study was performed in agreement with the Declaration of Helsinki and has been approved by the medical research ethics committee at the UMC Utrecht (NL71563.041.20).

Design

This was a 3-week intervention study with a within-subjects design which included a baseline condition (‘no touch’ week) and two experimental conditions (CT-optimal touch and CT non-optimal touch). The order of the experimental conditions was counterbalanced across participants. The primary outcome measure was the subjective pain experience measured with the Color Analogue Scale (CAS) and Faces Pain Scale-Revised (FPS-R).

Procedure

After an aspiring participant signed up through ParkinsonNEXT, contact information was sent to the experimenter. When a participant was interested in participating, had read the information letter and met the inclusion criteria, the experimenter made an appointment. During the first appointment the experimenter provided information regarding the procedure, the Montreal Cognitive Assessment (MoCa) or Telephone Interview for Cognitive status Modified (TICS-M) and Pain Intensity Scale (PIS)were filled out, informed consent was given and hereafter the Kings Parkinson Disease Pain Scale (KPDPS) and Quality of Relationship Inventory (QRI) were filled out. Hereafter, the experimenter demonstrated the two types of touch and asked the partner to apply touch so the experimenter could check whether the instructions were clear. The experienced pleasantness of both types of touch was also measured by asking the patient to rate touch on a scale from 0 to 10, to control for possible unpleasant sensations elicited by either type of touch.

During the study, all participants partook in the following sequence: one week of pain registrations only (no-touch), one week of CT-optimal touch (and pain registrations) and one week of CT non-optimal touch (and pain registrations) (see Fig 1 for an outline of the procedure). Upon completion of the experiment, or when participants preliminary withdrew from the experiment, they were debriefed.

Fig 1. Outline of the intervention.

Fig 1

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One week of pain registrations only (‘no touch’ week)

Starting the day after the pre-intervention baseline measurement, participants reported their pain experience, measured by the CAS and the FPS-R, three times a day for one week to control for normally present pain fluctuation. The questionnaires were provided by Gorilla Experiment Builder (www.gorilla.sc), a survey tool. Two participants were not able to use Gorilla and were therefore provided with a hardcopy of the questionnaires.

One week of CT-optimal touch/CT non-optimal touch

The procedure for both touch weeks was identical. Before the start of the touch week the experimenter video-called the participant during which the type of touch was demonstrated again, and the procedure was explained. The next day the participant and partner started with one week of touch stimulation. Touch was administered twice a day (morning and evening, 15 min) by the partner of the patient. Pain ratings (CAS Pain Scale and FPS-R) were measured before (at 0 min), during (at 5 and 10 min) and after the stimulation (at 15 min). Partners kept track of time by using a (stop)watch. In addition, the pleasantness of the stimulation was also measured during (at 5 and 10 min) and after touch stimulation (at 15 min) with the VAS pleasantness scale. To assess whether there were any long(er) term effects of touch stimulation during the day, pain ratings (CAS Pain Scale and FPS-R) were also measured in the afternoon. Halfway through the week, the experimenter video-called the participant and partner to ensure uniform touch administration. The partner was asked to perform the touch without any prior instruction, so that the experimenter could check whether touch was still applied correctly. This call was recorded, anonimized and touch performance of most of the participants was also checked by the other research team members. On the first and last day of the touch week participants filled out the Positive and Negative Affect Scale (PANAS).

Materials and measures

Several questionnaires were administered before and during the study. The questionnaires are categorized based on the moment of administration.

Before the start of the study

Pain intensity. The Pain Intensity Scale (PIS) was used to measure the intensity of the experienced chronic pain at that particular moment; the participant filled out a 11-point Likert pain scale for pain intensity. A score of <4 points was used as an exclusion criterion.

Chronic pain. The participants’ chronic pain experience was measured using the Kings Parkinson’s Disease Pain Scale (KPDPS). This was used as a baseline pain measurement. The KPDPS measures the intensity and severity of pain as well as localization and its relationship with motor fluctuations or musculoskeletal pain. This is an interviewer-based questionnaire with 7 domains which are based on common types of chronic pain in Parkinson patients. The total score is the sum of all domains, which are based on the severity multiplied by frequency [29].

Cognition. To assess whether participants were able to provide informed consent the Montreal Cognitive Assessment (MoCa) or Telephone Interview for Cognitive status Modified (TICS-M) was administered. Research shows that in PD patients, the MoCa can detect the likelihood of impaired cognitive capacity in which a cut-off score of ≤22 is most sensitive (94%) [30]. As face-to-face testing was not always feasible due to the COVID-19 pandemic, the TICS-M was also used to assess the ability to provide informed consent. The TICS reflects general cognitive ability and can detect cognitive impairments, a cut-off score of <34 was used as this might indicate mild cognitive impairment [31].

Quality of relationship. As the partner of the participant provided touch during the study, we wanted to check whether there was no discrepancy between perceived quality of the relationship of the participant and their partner, as this might influence the way touch was applied and/or how touch was perceived. The quality of the relationship in terms of perceived support of the participant and partner was assessed through the Quality of Relationships Inventory (QRI) short form [32].

During the study

Pain intensity. The Colour Analogue Scale (CAS) was used to measure pain intensity. The CAS is a questionnaire that measures pain intensity by using different colours: the white-coloured bottom represents ‘no pain’ and the dark red top represents ‘extreme pain’ (see Fig 2). These colours are linked to a numeric scale from 0–10 which is not visible for the participant [33]. In this study the CAS was used digitally (computer, phone or tablet) by clicking with a mouse or finger (touch screen) on a point in the scale which represent the current pain intensity.

Fig 2. Color Analogue Scale.

Fig 2

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Adapted from [34].

Pain severity. The Faces Pain Scale-Revised (FPS-R) was used to measure the severity of pain and the affective component. The FPS-R that contains six faces, on the left a neutral face and moving to the right five faces which express increasing feelings of pain (see Fig 3). The neutral face represents 0 ‘no pain’ and the five painful faces represent an ascending score of 2, 4, 6, 8, 10 of which the latter represent ‘severe pain’ [33, 35, 36]. The FPS-R was used digitally by clicking (or touching) on the face representing the participants pain severity.

Fig 3. Faces Pain Scale-Revised.

Fig 3

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Adapted from [35].

Pleasantness. The pleasantness of both types of touch was registered by a Visual Analogue Scale (VAS) ranging from 0–10, in which 0 represented ‘unpleasant’ and 10 ‘pleasant’.

Mood/affect. To assess the two dimensions of mood, namely positive- and negative affect, the Positive and Negative Affect Scale (PANAS) was used. This is a 20-item questionnaire, which has been shown to be a reliable, valid and efficient measure for positive- and negative affect [37]. The PANAS was provided before (day 1)- and after (day 7) each touch intervention week, to measure if touch also influenced the participants affect in general.

Other. Participants received a diary in which relevant information could be reported, this included usage of pain medication, changes in daily activities which might influence pain and changes in quality of sleep.

Tactile stimulation

Two types of touch were administered to the participant. CT-optimal touch was administered by the participant’s partner by stroking the dorsal forearm of the participant with the hand at a slow but natural speed of around 3 cm/s. This was done by moving from elbow to wrist in approximately 6 seconds. As a control condition CT non-optimal touch was administered by stroking the forearm at a faster but still natural speed of around 18 cm/s. This was done by moving from elbow to wrist in approximately 1 second. Partners received a demonstration and an instruction sheet on how to apply the type of touch. In addition, they also received a video in which the touch was demonstrated so they were able to look back and consult the demonstration at any time.

Statistical analysis

All data was processed using Microsoft Excel (version 2208) and analysed with SPSS Statistics (version 28). Due to technical problems some participants unfortunately had trouble with reporting their pain experience in Gorilla, especially with the CAS Pain Scale. Therefore, the data of the CAS Pain Scale was deemed invalid and excluded from analyses. As we do not know from previous studies when and how possible pain reduction through CT-optimal touch compared to CT non-optimal touch may occur, several analyses were done. An apriori power calculation for a repeated measures ANOVA with expected power (.80), medium effect size Cohen’s F (.25) and alpha (.05) recommend a sample size of 24. However, the observed power for the main analysis is .995 which reflects high statistical power for N = 17.

Before analyzing, several steps were taken to process the data. First, data was retrieved from Gorilla and processed in Excel by creating different tabs for the no touch, CT-optimal touch and CT non-optimal touch condition. Second, to analyze the ‘overall-effect’ of the touch intervention, averages of the FPS-R data for day 1 –day 7 were calculated. For the no touch week this means the average of the morning, afternoon and evening data points. For the CT-optimal touch and CT non-optimal touch condition this means the average of the morning and evening data when touch was administered and the afternoon data points when no touch was administered. This data was analyzed in SPSS with a 3 (no touch, CT-optimal touch and CT non-optimal touch) x 7 (days) repeated measures ANOVA. Data was normally distributed, sphericity was violated for the touch x day interaction effect therefore Greenhouse-Geisser corrections were used. A Bonferroni post-hoc comparison was used to analyze the difference between the three conditions.

To analyze whether there is a difference between the pain ameliorating effect of CT-optimal touch and CT non-optimal touch during the stroking, i.e., ’short-term effect’, data from the different timepoints (0min, 5min, 10min, 15min) were used. An average day score for every timepoint was calculated for both types of touch. This data was then analyzed in SPSS with a 2 (CT-optimal touch and CT non-optimal touch) x 7 (days) x 4 (0min, 5min, 10min, 15min) repeated measures ANOVA. Data was normally distributed, sphericity was mildly violated for some factors therefore the Greenhouse-Geisser correction was used.

The pleasantness of both types of touch was calculated by averaging the VAS data points on 5min, 10min and 15min for morning and evening; this was done for every day. This data was analyzed in SPSS with a 2 (CT-optimal touch and CT non-optimal touch) x 7 (days) repeated measures ANOVA. Not all data was normally distributed according to the Shapiro–Wilk test. As a non-parametric alternative for a factorial ANOVA is not readily available and it has been shown that Type 1 error and power of the F-statistic are not necessarily altered by violation of normality [38], we decided that it was permitted to use a parametric test. Sphericity was violated, therefore Greenhouse-Geisser corrections were used.

For the PANAS scores a positive- and negative affect score was calculated. For the positive affect score, the scores on items 1, 3, 5, 9, 10, 12, 14, 16, 17, 19 were added. For the negative affect score, the scores on items 2, 4, 6, 7, 8, 11, 13, 15, 18, 20 were added. This was done for day 1 and day 7 and for CT-optimal touch and CT non-optimal touch condition. The PANAS score of both types of touch were analyzed with a 2 (CT-optimal and CT non-optimal touch) x 2 (positive- and negative effect) x 2 (days) repeated measures ANOVA.

To analyze the relation between the pain ameliorating effect of touch and perceived pleasantness a FPS-R difference score was calculated. First, an average score for 0min and 15min was calculated for every day. The FPS-R difference score was calculated by substracting 0min from 15min. This was done for every day, whereafter data over the week was calculated by averaging day 1 –day 7. The average VAS pleasantness score was used as a measure for perceived pleasantness. Which was than analyzed with a Spearman correlation. In addition, to analyze the relationship between perceived pleasantness and quality of the relationship (measured with the QRI), first a QRI total score was calculated for the participant and the partner. A difference score was then calculated by substracting the partner score from the participant score. A Spearman correlation was used to analyze the relation between the VAS pleasantness and QRI difference score.

Results

Before the start of the study participants’ average PIS was 5.85 (SD = 1.55) and for the KPDPS the average score was 38.06 (SD = 15.43). The participants’ total score on the QRI was 16.06 (SD = 1.95) and the partner’s score was 15.38 (1.80). The information reported in the diary was checked by the experimenter after participants finished the study. No changes or particularities were reported. To provide a clear-overview of the collected data and used analyses, outcomes are described as the overall-effect, short-term effect including optimal touch duration, pleasantness, affect, relationship between pleasantness and short-term effect and relationship between pleasantness and quality of the relationship.

Overall- effect

The average FPS-R pain day scores for the three conditions NT, CT- optimal touch and CT non-optimal touch were analyzed with a repeated measures ANOVA, which showed a significant main effect of touch F(2,32) = 14.28, p < .001, partial η2 = .47 and observed power of .995. There was a significant effect for day F(6,96) = 3.05, p = .016, partial η2 = .16. There was no significant interaction between touch x day (p = .061). A bonferonni corrected post-hoc comparison showed a significant effect between NT–CT-optimal touch (p < .001) and NT–CT non-optimal touch (p = .003). There was no significant difference between CT-optimal touch–CT non-optimal touch (p = 1.00). Thus, the FPS-R scores were significantly lower for the CT-optimal touch and CT non-optimal touch conditions compared to the no-touch condition (see Table 1 and Fig 4).

Table 1. Mean (SD) pain scores on the FPS-R per condition over the days.

No touch CT-optimal touch CT non-optimal touch
Day 1 4.63 (1.42) 3.39 (1.67) 3.51 (1.65)
Day 2 4.12 (1.69) 2.90 (1.38) 2.93 (1.40)
Day 3 5.41 (2.03) 3.19 (1.61) 3.14 (1.35)
Day 4 4.00 (1.68) 3.89 (1.17) 3.42 (1.61)
Day 5 3.49 (1.40) 2.99 (1.20) 3.02 (1.68)
Day 6 4.08 (1.84) 3.29 (1.29) 3.39 (1.99)
Day 7 3.88 (1.46) 3.27 (1.45) 3.31 (1.56)
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Fig 4. Scatterplot depicting FPS-R difference scores per day for CT-optimal touch—NT and CT non-optimal touch—NT.

Fig 4

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The dots represent individual datapoints, the lines show the sample mean.

As the type of touch was counterbalanced between participants, the data was checked for a possible order effect. An average week FPS-R score was calculated for every condition and hereafter a difference score was calculated by substracting the CT-optimal touch and CT non-optimal touch week from the NT week. A touch (2 levels) x order (2 levels) repeated measures ANOVA was used to analyze the data. There was no significant difference between NT minus CT-optimal touch and NT minus CT non-optimal touch over the week F(1,15) = .48, p = .499. There was also no significant interaction effect between touch x order F(1,15) = .15, p = .702.

Short-term effect

To analyze the difference between touch conditions and the different timepoints, first for both touch conditions an average FPS-R score for every timepoint was calculated per day. The latter was done to also analyze whether there are any differences over the 7 days (see Table 2 and Fig 5).

Table 2. FPS-R scores (mean (SD)) for CT-optimal touch and CT non-optimal touch for the different timepoints.

CT-optimal touch CT non-optimal touch
0min 3.61 (1.16) 3.53 (1.31)
5min 3.25 (1.13) 3.28 (1.39)
10min 2.94 (1.16) 3.03 (1.25)
15min 2.78 (1.13) 3.01 (1.31)
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Fig 5. Scatterplot depicting the difference in FPS-R scores during touch (5, 10, 15min) compared to no touch (0min).

Fig 5

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The dots represent individual datapoints, the lines show the sample mean.

A touch (2 levels) x day (7 levels) x timepoint (4 levels) repeated measures ANOVA was done to analyze the difference between timepoints for CT-optimal touch and CT non-optimal touch. There was no significant main effect for type of touch F(1,16) = .10, p = .760 or for day F(6,96) = 1.57, p = .191. There was a significant main effect for timepoint F(3,48) = 40,77, p < .001, partial η2 = .72. There was also a significant interaction between touch x timepoint F(3,48) = 3.75, p = .033, partial η2 = .19, indicating a slightly larger ameliorating effect for CT-optimal touch compared to CT non-optimal touch. There was no significant interaction between touch x day (p = .975) or day x timepoint (p = .495) nor for touch x day x timepoint (p = .693). A bonferonni corrected post-hoc comparison was used to analyze the difference between time-points for CT-optimal touch and CT non-optimal touch. For CT-optimal touch there is a significant difference between 5min– 0min (p = .005), 10min– 0min (p < .001), 15min– 0min (p < .001), 10min– 5min (p = .001) and 15min– 5min (p < .001), but not between 15min– 10min (p = .079). For CT non-optimal touch there is a significant difference between 5min– 0min (p = .003), 10min– 0min (p < .001), 15min– 0min (p < .001), 10min– 5min (p = .009) and 15min– 5min (p = .013), but not between and 15min– 10min (p = 1.00) (see S2 Table in S1 File).

Pleasantness

The difference in VAS pleasantness scores for CT-optimal touch and CT non-optimal touch were analyzed with a 2 (touch) x 7 (days) repeated measures ANOVA. There was a significant main effect for type of touch F(1,16) = 17.84, p < .001, partial η2 = .53. There was no significant main effect for day (p = .676) or for the interaction between touch x day (p = .720) (see Table 3).

Table 3. Mean (SD) pleasantness scores for CT-optimal touch and CT non-optimal touch over the days.

CT-optimal touch CT non-optimal touch
Day 1 7.49 (1.87) 6.33 (1.79)
Day 2 7.82 (2.22) 6.30 (1.93)
Day 3 7.75 (2.18) 6.19 (2.04)
Day 4 7.81 (2.01) 6.22 (1.89)
Day 5 7.98 (2.00) 6.35 (1.90)
Day 6 7.85 (2.02) 6.22 (1.96)
Day 7 7.88 (2.10) 6.35 (2.02)
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Affect

The PANAS scores at day 1 and day 7 were used to analyze if there is a difference in positive or negative affect during the CT-optimal touch and CT non-optimal touch condition (see Table 4). Several participants did not fill out (parts of) the PANAS due to technical difficulties, therefore N = 14. A touch (2 levels) x Positive or negative affect (2 levels) x day (2 levels) ANOVA was used to analyze the data. There was no significant main effect for touch F(1,13) = .37, p = .555 or day F(1,13) = .03, p = .867 and there was also no significant interaction between touch x day F(1,13) = .05, p = .829. As there is no significant difference, the PANAS scores were not further analyzed.

Table 4. The mean (SD) PANAS scores for the positive and negative affect scale on day 1 and 7.

Positive affect Positive affect Negative affect Negative affect
Day 1 Day 7 Day 1 Day 7
CT-optimal touch 26.79 (7.23) 27.86 (8.21) 17.14 (6.72) 16.29 (4.83)
CT non-optimal touch 27.36 (7.30) 26.57 (7.28) 17.57 (7.05) 17.79 (7.18)
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Pleasantness and short-term effect CT-optimal touch

To analyze whether the short-term effect of CT-optimal touch may be related to the perceived pleasantness of this type of touch, a Spearman correlation was used. No significant correlation was apparent between the short-term effect of CT-optimal touch and its perceived pleasantness, ρ = -.31, p = .228.

Pleasantness and quality of the relationship

To analyze whether the quality of the relationship influenced how both types of touch were perceived, a Spearman correlation was used. There was no significant correlation between the QRI difference score and VAS pleasantness for CT-optimal touch (ρ = .02, p = .943) and for CT non-optimal touch (ρ = .05, p = .865). We therefore assume that quality of the relationship did not influence touch perception.

Discussion

Previous studies have shown that CT-optimal touch can reduce acute pain in an experimental setting [17, 18, 21, 22]. However, only little is known about the effect of CT-optimal touch on chronic pain and this was tested in an experimental setting [23, 24]. As PD patients are known to suffer severely from chronic pain and currently effective treatment is missing [6], the aim of the current study was to investigate the influence of CT-optimal touch on chronic pain experience in PD in a non-experimental setting. By doing so, the feasibility of CT-optimal touch application by a partner in daily life could also be explored.

As this is, as far as we know, the first study into the effects of CT-optimal touch on chronic pain in PD, several analyses were conducted to investigate if and when pain amelioration occurs. The results show that both types of touch significantly reduce experienced pain compared to the no touch condition. That is, both CT-optimal touch and CT non-optimal touch are effective in reducing the chronic pain experience in PD, and the order of the touch condition did not influence this result. In addition to this overall-effect, the results show (by the interaction between touch and timepoint, see also Fig 5) that CT-optimal touch appears to reduce the chronic pain experience slightly more than CT non-optimal touch.

The current results show that compared to the no touch condition, CT non-optimal touch may be almost as effective in reducing chronic pain as CT-optimal touch. Based on the study of Di Lernia, Lacerenza [24] and the underlying mechanisms of both types of touch, this was unexpected. However, in the study of Di Lernia, Lacerenza [24] the control condition was touch vibration applied by a device instead of CT non-optimal touch applied by a partner. CT non-optimal touch is a faster touch which is naturally applied with more force than CT-optimal touch, most likely activating the Aβ-fibers [22, 39]. From previous research it is known that the Aβ-fibers interact with pain on the level of the spinal cord. This is also referred to as the gate-control theory, which however has been criticized and might not fully explain the effect of CT non-optimal touch in the current study [40]. Interestingly, as touch has been applied by the partner, the social component underlying touch might have added to the pain reducing effect of CT non-optimal touch, similar to the pain reducing effect that can be observed as a result of handholding, which also appears to rely mostly on the Aβ-fibers [41]. Receiving social touch, such as caressing, handholding and massages has also been shown to have a positive influence on pain experience [42]. Another explanation might be that with a velocity of 18 cm/s the CT-afferents were activated as well. Even though microneurography studies show that the optimal velocity to activate the CT-fibers is 1–10 cm/s and faster stimuli (>10 cm/s) only activate a handful of CT-afferents, it has so far not been tested whether the CT-afferents react to 18 cm/s [43].

Interestingly, it appears that it might be slightly more beneficial to use CT-optimal touch compared to CT non-optimal touch. There is an interaction effect between touch and timepoint which reflects the steeper slope and larger difference between 0 minutes and 15 minutes for CT-optimal touch as observed in Fig 5. This is in line with previous studies into acute pain and chronic pain in an experimental setting, in which CT-optimal touch was effective in reducing pain experience [16, 22, 24].

In addition, CT-optimal touch is also rated as significantly more pleasant than CT non-optimal touch. Furthermore, at least 10 participants and their partners subjectively reported at the end of the study, before debriefing, that they were planning on continuing CT-optimal touch administration as it felt most effective in diminishing their pain and it was more natural and pleasant to receive and apply. Participants who had higher pain levels during the evening also subjectively reported that it felt that CT-optimal touch effectively reduced this “worst pain”, and this also improved their quality and ability to sleep through the night. So, there appears to be a clear preference for CT-optimal touch by participants and their partners.

As CT-optimal touch is clearly perceived as more pleasant, a possible relation between the effects of CT-optimal touch on pain and perceived pleasantness is of interest. We therefore investigated whether there is a relation between the effect of CT-optimal touch and its perceived pleasantness. Since no such relation was found, the pain-relieving effect of CT-optimal touch appears to be independent of its perceived pleasantness. A similar result has been reported before by von Mohr, Krahé [22], Meijer, Schielen [26] and Meijer, Ruis [28]. From the model of Meijer, Ruis [19] it follows that CT-optimal touch may reduce pain, based on a bottom-up as well as a top-down process. As the patients in the current study were suffering from (lower) back pain and/or pain in the shoulders/neck, and touch was applied on the forearm, one could argue that it is more likely that top-down processes are involved instead of peripheral bottom-up processes. The top-down process relies on downregulation of pain regions involved in the motivational aspects of pain processing, i.e. the Insula and ACC, regions which are also highly involved in the perceived pleasantness of CT-optimal touch [44]. As we did not find a relationship between perceived pleasantness and the pain-relieving effect of CT-optimal touch, we speculate that this top-down process (i.e. downregulation through the Insula and ACC) might therefore rely on the activation of the CT-fibers instead of activation by the perceived pleasantness of touch. This would mean that the top-down influence is not necessarily a pleasantness related regulatory system but relies on input from the CT-fibers. This notion is important as chronic pain can also affect how we perceive touch, e.g. neuropathic pain, and it has therefore been suggested that CT-optimal touch might be ineffective in this patient group [45]. However, the current results indicate that how CT-optimal touch is perceived, i.e. pleasant vs unpleasant, does not influence its pain ameliorating properties, a notion also emphasized by the single case report of Meijer, Ruis [28] and the study of Di Lernia, Lacerenza [24].

The above mentioned case report of [28] describes a participant who was excluded from the participant sample in the current study. Overall, the current study and the case report both show that CT-optimal touch can reduce chronic pain experience. However, in the case report CT-optimal touch fully diminished the experienced chronic pain which has not been reported by one of the participants in the current study. This might be explained by a different chronic pain pathology [46]. The participant in the case report suffered from a burning pain in his hands possibly caused by neuropatic pain, while the participants in the current study suffered from musculoskeletal and radicular pain. Therefore, different underlying mechanisms could be involved which might also respond differently to CT-optimal touch. Another explanation might be related to touch application site. As touch was always applied on the forearm, for the patient described in the case report touch was applied on the same body part as where chronic pain was experienced, for the participants in the current study touch was applied on a different body part than where the chronic pain was experienced. As mentioned, we speculate that for the current study pain reduction through CT-optimal touch might rely more on top-down processes. For the case report on the other hand, pain reduction might rely more on bottom-up pheripheral process which in this case appears highly effective. So compared to the current study, the case report highlights that certain individuals do experience additional benefits from CT-optimal touch and therefore further longitudinal research into the effect of CT-optimal touch on chronic pain experience is warranted.

Further research into the optimal duration of applying touch is warranted as well. It appears that the effect of touch on pain experience levels off between 10–15 minutes. Therefore, we carefully conclude that to reduce chronic pain touch should be applied at least 10 minutes. This is in line with the study of Di Lernia, Lacerenza [24] in which CT-optimal touch appears effective after 11 minutes. However, as we did not investigate what happens directly after touch application has stopped, we also do not know whether a reduction in pain would still occur after 15 minutes even when touch is applied for only 5–10 minutes. Therefore, further investigation into the optimal duration of applying touch is necessary.

The current study has several strengths and limitations. A first strength is that this is the first study in which the effects of CT-optimal touch on chronic pain are studied over a more prolonged period of time. In addition, this study shows that CT-optimal touch can be used in a home-setting and application can be done by a partner who received a short and simple training. Participants and partners reported they never missed a touch application throughout the study. However, there were also 5 participants who dropped out because it was difficult to combine this intervention with their daily-working schedules. As this was merely linked to the tight schedule of this study and not to administration of CT-optimal touch, we believe that it is feasible to implement CT-optimal touch in daily life to reduce the chronic pain experience. The current study also has a number of limitations. One is that due to technical issues, resulting in problems with reporting chronic pain experience, the reliability of the data might be affected (possibly obscuring effects). Second, we have a relatively small sample size of n = 17, which negatively influences the ability to generalize the results to a larger population. A third, important, limitation is that we did not use a control condition. We used the ‘no touch’ week as a control condition for every participant. As we did not use a 3-week no touch control condition we do not know whether pain experience would also have changed over time. However, as the experienced chronic pain needed to be present for at least 3 months one would not expect a significant difference over a 3-week time period without any treatment. In addition, we did not use any other form of affectionate behavior as a control condition. As mentioned before, touch by a partner has a strong social component which could explain why CT non-optimal touch also reduced chronic pain experience [42]. So, it could be that any form of affectionate behavior might have similar effects [47]. This is in line with previous studies showing that the mere presence of a partner, as a form of passive social support, can reduce pain as well [48]. Finally, as this study is a within-subject design, participants and their partners were not blinded. Even though the terms CT-optimal- or affective touch have not been used and the theoretical background was discussed with participants only during the debriefing, it could be that during the study participants became aware of the differences in presumed effectiveness of the types of touch. However, we think it unlikely this would have influenced our results as we found no significant order effect. Based on our current study, we suggest that future studies employ a Randomized Control Design and administer touch for more than one week.

To conclude, the current study investigated whether CT-optimal touch can reduce chronic pain experience in PD patients. Overall, both CT-optimal and CT non-optimal touch are effective in relieving chronic pain compared to no touch. Furthermore, it appears that it is slightly more beneficial to apply CT-optimal touch. As it is also perceived as more pleasant and reported to be more feasible to apply, we speculate that CT-optimal touch might be used when there is a need for immediate pain relief. Furthermore, our current study shows that CT-optimal touch application by the partner is feasible, which further emphasizes the possibilities of using CT-optimal touch as a treatment for chronic pain.

Supporting information

S1 File

(DOCX)

pone.0298345.s001.docx (21.3KB, docx)

Data Availability

Fully anonymized data generated during and/or analyzed during the current study are available in the YODA repository, DOI: 10.24416/UU01-KZ91OM.

Funding Statement

Funding was obtained by Meijer, Dijkerman and Smagt. There is no Grant number. The Dutch Stichting Parkinsonfonds offered the Grant. https://www.parkinsonfonds.nl/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Julian Packheiser

22 Aug 2023

PONE-D-23-21643Affective touch and chronic pain experience in Parkinson’s Disease; A longitudinal intervention studyPLOS ONE

Dear Dr. Meijer,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Additional Editor Comments:

Dear Larissa Meijer and colleagues,

attached you will find the reviewers' comments who have provided careful and constructive feedback on your manuscript. They acknowledge the merit and interest of the findings for the field of touch and I fully agree that this is a highly interesting study. They however also raised concerns that need to be addressed before the manuscript can become suitable for publication. During your revision, please pay attention especially towards the re-calculation of the results using a linear mixed model and a potential Bayesian counterpart to make more accurate statements about absence of evidence. Since the authors use SPSS where mixed modelling is possible in the frequentist domain, Bayesian models are not supported by that software. They can however be implemented using for example the brm function in R if the authors want to calculate a Bayesian model likewise. In the discussion, the limitation of the lack of a control group needs to be highlighted as potential pain attentuating effects could be for example attributed to temporal effects across the three weeks that are not associated with the treatment. While this is certainly less likely, other potential confounding factors need to be acknowledged and discussed due to a missing no touch control over the course of the experiment. As reviewer 2 notes, the graphical presentation of the study could be improved for easier accessibility of the results. Please keep in mind that showing raw data points in graphs is generally much more informative about data distributions rather than presenting means and SDs alone. I am looking forward to your revised manuscript!

Julian Packheiser

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Reviewers' comments:

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Reviewer #2: Partly

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5. Review Comments to the Author

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Reviewer #1: This study investigates if touch (slow and faster touch) can reduce chronic pain in patients with Parkinson’s Disease. Patients received both of these touch types in counterbalanced order from their partner. The main finding was that pain reports were lower following both touch types. Thus, a simple intervention provided by the partner at home can improve patients’ pain experience.

The research question is relevant and the manuscript is clearly written. The findings are of interest to the readers of PlosOne and to researchers in the field of touch and PD, and they also have clinical implications. However, there are shortcomings in the design and the analysis that need to be addressed before this manuscript can be recommended for publication.

Firstly, the design lacks a control group. This shortcoming is so far not discussed at all. Patient studies are rare and difficult to do, so the results can still be of interest, but the lack of a control group needs to be addressed. Secondly, whereas the data are carefully analysed, the type of analysis chosen is not optimal and should be modified. Thirdly, the authors claim to compare CT-optimal to CT-non-optimal touch by using stroking velocities of 3 and 18 cm/s. However, how CTs behave when being stroked with 18cm/s has never been investigated, so this term does not seem appropriate.

The authors should discuss the lack of a control group, change the analysis and the wording of “CT-non-optimal” throughout the text.

These and other points are further detailed here (comments in the order of the points in the manuscript they refer to):

1. Title and entire manuscript. The term “longitudinal” is somewhat misleading, as this term is typically used for interventions that run longer than just 3 weeks, often for years or even decades. I would suggest to remove that term to avoid confusion.

2. Abstract “patients underwent one week of pain registration, one week of affective touch and one week of non-affective touch”. This wording is unfortunate, as it give the impression that pain was only registered in the first week. Consider rewording “pain registration” to “baseline” or “no touch”.

3. Introduction, page 3, line 52. “affective touch (…) activates (….) C-Tactile afferent nerves”. Here you should cite a reference that actually measured whether gentle stroking activates CTs, i.e. one that used microneurography (e.g. Löken et al. Nat Neurosci 2009).

4. Materials and Methods, page 5. I suggest you move the points “Design” and “Procedure” at the beginning of the Materials and Measures section. It appears to be more logical to first provide the big picture, and then the details of the specific measures.

5. If possible, I also suggest to move the paragraph “Outline of data processing” from the Supplementary Materials into the methods. The paragraph “Statistical analysis” in the main text is not understandable without the paragraph “Outline of data processing”, and if it all were in the same place the reader would not have to scroll back and forth.

6. How was the sample size motivated? Can you provide a power calculation?

7. Quality of relationship, page 6, line 136 “discrepancy”, and Supplementary Materials Table S1, and Results page 10, line 246 “we assumed that the quality of their relationship did not influence touch perception”. I cannot find how this was analysed, but it seems that independent samples t-tests with the means of each group were calculated? With this method, you can arrive at exactly the same mean in both groups despite quite high differences in each pair. Thus, if the means are similar, it does not say anything about the discrepancy in each pair, and the conclusion that relationship quality not influence touch perception is not valid. If you are after that, you should calculate the differences for each pair and for example, correlate them to the pleasantness ratings.

8. Tactile stimulation, page 7, last paragraph. Please specify if the dorsal (or ventral) forearm was stroked.

9. Tactile stimulation, page 7, last paragraph. “CT non-optimal touch was administered by stroking (…) at (…) 18cm/s”. The velocity of 18 cm/s never been used in microneurography experiments that measured CT and Aβ activation. Thus, it is not known how CTs respond to velocities of 18 cm/s, and it is not known if 10 and 18 cm/s would give significantly different mean CT instantaneous firing frequencies. The wording “CT non-optimal” is not appropriate when it has never been tested. You could consider, for example, calling these velocities “slower” and “faster”.

10. Procedure. Figure 3 shows the big timeline of the intervention, but readers would probably appreciate a more fine-grained figure that also shows the single measurements (i.e., the time points at which the ratings are measured).

11. It is unclear if VAS pleasantness ratings were collected 3 or 4 times. Was there also a measurement before the very start of the 15 min period, i.e. at time point 0?

12. Statistical analysis, page 10. The authors performed a careful analysis of the data, but it does not seem optimal in several points. Firstly, Table 2 indicates that six t-tests are performed to compare faster and slower touch, and they seem not to have been corrected for multiple comparisons. Some correction for multiple comparison is required, and then the p-values will probably not survive the threshold. This would not make the findings less interesting. Thus, any number of t-tests calculated should be adjusted for multiple comparisons.

Secondly, there are three different repeated-measures-Anovas that can either be combined into one, or even better, be replaced by a linear mixed model (multilevel model). If a repeated measures Anova is calculated, it could be with the factors condition (no touch, fast, slow) and another factor timepoint (0, 5, 10, 15 minutes). This could nicely replace the different analyses for overall effect, short-term effect, and the one for “optimal duration”. Calculating the difference between timepoints as for the current “short-term effect” is then no longer required. If this approach is chosen, the factors and their levels should clearly be specified in the description of the analysis. This is currently not the case.

However, the better solution would be a linear mixed model, firstly because the information of the single trials would be used, rendering a higher power, and also because missing cases can be handled instead of the whole case being dropped as happens with repeated-measures Anova. I therefore ask the authors to calculate a linear mixed model with their data. For this, the single touch trials could be nested within one session (morning, afternoon). This would also allow to take into account the variability across stroking trials, which is interesting with respect to potential touch satiety.

13. Page 11, Table 1. For the reader it would be interesting to not only see the means, but also the data of each single subject. I suggest to move the table to the Supplements, and present a graph here where both the means and the individual data points are visible.

14. Page 14, line 315. It would be interesting to see (in a graph) how the pleasantness ratings change or do not change over time (i.e. 0,5,10, 15 min of stroking). Given the research on touch satiety (e.g. Triscoli et al. PLOS One 2014) and affective habituation (Dijksterhuis and Smith, Emotion 2002), one wonders if such a habituation process is abolished when stroking contributes to reduce pain. A closer look at this aspect may also help you further to disentangle pleasantness from pain effects. In particular, check out the paper by Taneja et al. (Front Pain Res 2021) who measured pain in addition to touch satiety.

15. Discussion, page 16 ff. The lack of a control condition needs to be discussed. The authors hint at the “social component underlying touch” (line 365), but need to make this aspect much more explicit. The current design of the study does not allow to state if the pain-relieving effects are due to touch itself or to what the authors call the “social component”. Since there was no control group, the results do not allow to conclude if the pain reduction has something to do with touch at all. Maybe the attention provided by the partner could be enough for such an effect, and pain would also be relieved if the partner painted the nails of the patient or performed a motivational interview? Note that touch by a partner conveys an intention of care, of being secure, and the availability of social support (Jakubiak and Feeney; Personality and Social Psychology Review 2017). Any other behaviour conveying similar intentions might have had the same effect. This does not reduce the importance of the current findings, but should be openly stated and reflected upon.

16. Page 17, lines 382-383 (“the pain ameliorating effect (…) is most effective between 10-15 min. If the authors find this interesting, they could relate this interval to other studies who investigated how the beneficial effects of slow touch evolve over time, for example heart rate (e.g. Püschel et al. Physiol Behav 2022; Triscoli et al., Biol Psychol 2017).

17. Page 18, first paragraph. It is very positive that the authors report how the patients commented the intervention. This adds important information. In this context, I wonder if the patients mentioned that they speak with each other during stroking? Do you have any information about that? To stroke or be stroked 15 minutes without saying anything appears rather awkward and boring for both parties. If the stroking was followed by (occasional) talking, this could on the one hand explain the overall high pleasantness ratings also for the faster touch, and maybe also have contributed to the pain-reducing effects of the intervention.

Reviewer #2: This longitudinal cross-over study tested the effects of affective touch from a partner on chronic pain in Parkison’s disease. Both affective and non-affective touch was effective in ameliorating pain on a day-to-day basis. In addition, affective touch had a stronger immediate (5-minute scale) on perceived pain.

This is a well-designed study on an important topic. I specifically applaud the effort to design the study in a way that allows for relatively direct application of the results as a clinical intervention.

Methods

- [major] One participant was excluded from the study “as the origin of his pain and study outcome were very different from the other participants in this study”. A more specific explanation is necessary. What was the exact difference between the origin of pain of the excluded participant, and which outcome parameters were different? Was this difference quantified in any way?

Results

- [major] Most data (except for the overall-effect) are presented in tables i.s.o. graphs. I think a more graphical presentation of the result would aid interpretation of the findings. I think this is especially important for the short-term effects, but also for example for the effects of (non-)affective touch on pleasantness scores. Preferably, these graphs would contain individual datapoints (or at least some information on the distributions).

- [major] There is a strong overlap between two analyses of the short-term effects. The first analysis consists of multiple paired t-tests for a touch-treatment effect on the baseline-corrected pain scores at different time points. The third analysis in this section is a repeated measures ANOVA of the raw pain scores with the factors time and touch-treatment (this analysis approach seems most comprehensive to me). The significant paired t-test for the 15min-0min pain score and the significant time x touch-treatment interaction seem to reflect the same underlying effect. I do not think it is appropriate to present them as entirely separate. I think the interaction effect is the most convincing result (a steeper slope for pain scores during affective touch).

- [minor] P. 17: “… the F-values are very low which indicates a low probability of a significant difference.” This suggests evidence for absence of an effect. Correct me if I am wrong, but I believe that this is not appropriate when using a frequentist approach (I think Bayesian modelling can be used to find evidence for the null hypothesis).

- [minor] The values for the “0min” touch in table 3 and table 4 differ. Should these values not be the same?

Discussion

- [major] The case report of the excluded participant (Meijer et al., 2023, journal of neuropsychology) ends with the remark that “further research in a larger clinical sample is warranted”. The current study seems like a prime example of such further research. I missed a discussion of how the current study relates to the case report (either explaining if the results of the current study support the previously reported findings, or explaining why such a comparison is not possible).

- [minor] The conclusion that CT-optimal touch is most effective after at least 10-15 minutes is too strong, given the available evidence: (1) Effects may appear earlier, but may just not have been detectable in the current study, given the relatively low sample size (2) It has not been tested if the pain reduction continues after the touch is finished. It is possible, for example, that a reduction in pain ratings still occurs at 15 minutes even if the touch is only applied for, say, 5 mins. This second point is relevant for the implementation of affective touch as a treatment.

- [minor] I was wondering if hormonal effects (e.g. oxytocin) may play a role in the potential underlying mechanisms, especially because the touch occurs between romantic partners.

- [minor] The discussion on conduction velocities (p. 23). The authors correctly mention that even though CT-fiber velocities are relatively slow (compared to A� fibers), they are still processed within seconds, whereas the (additive) effects of affective touch only occur in 10-15 minutes. However, the authors also seem to suggest that the fact that effects of affective touch occurs relatively late is somehow related to differences in velocities between A� fibers and CT-fibers. I cannot follow this reasoning.

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PLoS One. 2024 Feb 23;19(2):e0298345. doi: 10.1371/journal.pone.0298345.r002

Author response to Decision Letter 0

17 Nov 2023

Response to reviewers

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Additional Editor Comments:

Dear Larissa Meijer and colleagues,

attached you will find the reviewers' comments who have provided careful and constructive feedback on your manuscript. They acknowledge the merit and interest of the findings for the field of touch and I fully agree that this is a highly interesting study. They however also raised concerns that need to be addressed before the manuscript can become suitable for publication. During your revision, please pay attention especially towards the re-calculation of the results using a linear mixed model and a potential Bayesian counterpart to make more accurate statements about absence of evidence. Since the authors use SPSS where mixed modelling is possible in the frequentist domain, Bayesian models are not supported by that software. They can however be implemented using for example the brm function in R if the authors want to calculate a Bayesian model likewise. In the discussion, the limitation of the lack of a control group needs to be highlighted as potential pain attentuating effects could be for example attributed to temporal effects across the three weeks that are not associated with the treatment. While this is certainly less likely, other potential confounding factors need to be acknowledged and discussed due to a missing no touch control over the course of the experiment. As reviewer 2 notes, the graphical presentation of the study could be improved for easier accessibility of the results. Please keep in mind that showing raw data points in graphs is generally much more informative about data distributions rather than presenting means and SDs alone. I am looking forward to your revised manuscript!

Julian Packheiser

Dear Julian Packheiser,

First of all, thank you very much for the opportunity to revise our manuscript. In addition, we thank the editor en the reviewers for their constructive feedback and suggestions to improve the manuscript. Below, in red we addressed every point from the reviewers. We would also like to address some of the suggestions from the editor here.

In regard to the data analysis, we looked into all possibilities to perform a linear mixed model as well as Bayesian Statistics. Unfortunately, it was not possible to perform these analyses due to the large and complex structure of the dataset. Therefore, we decided to perform 2 mixed model ANOVA’s as main analysis. Regarding the lack of a control group, as participants started with one week of only reporting their pain experience and this study was a within-subject design participants were their own control group. This was done because every individual experiences chronic pain differently, e.g. some have more pain in the evening others in the morning. Therefore, it was necessary to compare this within participants instead of only between. In addition, as pain needs to be present for at least 3 months to be classified as chronic pain it was not expected that the pain experience would change over time in such way that it is significantly lower at day 21 compared to day 1 of this study. However, we do agree that this is a limitation and therefore added this to the discussion. We created to new graphs in which individual datapoints as well as the mean are depicted.

We hope that the changes made are sufficient and you would consider this manuscript for publication.

Kind regards also on behalf of the co-authors,

Larissa Meijer

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

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Reviewer #1: Partly

Reviewer #2: Partly

________________________________________

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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5. 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: This study investigates if touch (slow and faster touch) can reduce chronic pain in patients with Parkinson’s Disease. Patients received both of these touch types in counterbalanced order from their partner. The main finding was that pain reports were lower following both touch types. Thus, a simple intervention provided by the partner at home can improve patients’ pain experience.

The research question is relevant and the manuscript is clearly written. The findings are of interest to the readers of PlosOne and to researchers in the field of touch and PD, and they also have clinical implications. However, there are shortcomings in the design and the analysis that need to be addressed before this manuscript can be recommended for publication.

Firstly, the design lacks a control group. This shortcoming is so far not discussed at all. Patient studies are rare and difficult to do, so the results can still be of interest, but the lack of a control group needs to be addressed. Secondly, whereas the data are carefully analysed, the type of analysis chosen is not optimal and should be modified. Thirdly, the authors claim to compare CT-optimal to CT-non-optimal touch by using stroking velocities of 3 and 18 cm/s. However, how CTs behave when being stroked with 18cm/s has never been investigated, so this term does not seem appropriate.

The authors should discuss the lack of a control group, change the analysis and the wording of “CT-non-optimal” throughout the text.

These and other points are further detailed here (comments in the order of the points in the manuscript they refer to):

1. Title and entire manuscript. The term “longitudinal” is somewhat misleading, as this term is typically used for interventions that run longer than just 3 weeks, often for years or even decades. I would suggest to remove that term to avoid confusion.

We removed the term from the title and also changed this within the manuscript.

2. Abstract “patients underwent one week of pain registration, one week of affective touch and one week of non-affective touch”. This wording is unfortunate, as it give the impression that pain was only registered in the first week. Consider rewording “pain registration” to “baseline” or “no touch”.

We changed this sentence accordingly. Line number 19-20.

3. Introduction, page 3, line 52. “affective touch (…) activates (….) C-Tactile afferent nerves”. Here you should cite a reference that actually measured whether gentle stroking activates CTs, i.e. one that used microneurography (e.g. Löken et al. Nat Neurosci 2009).

We changed the reference accordingly, line 57.

4. Materials and Methods, page 5. I suggest you move the points “Design” and “Procedure” at the beginning of the Materials and Measures section. It appears to be more logical to first provide the big picture, and then the details of the specific measures.

We placed the Design and Procedure sections below the Participants section. From line 129 – 176.

5. If possible, I also suggest to move the paragraph “Outline of data processing” from the Supplementary Materials into the methods. The paragraph “Statistical analysis” in the main text is not understandable without the paragraph “Outline of data processing”, and if it all were in the same place the reader would not have to scroll back and forth.

Outline of data processing has been added to the Statistical analysis paragraph. It has therefore een removed from the Supplementary materials. Line numbers 283 – 335.

6. How was the sample size motivated? Can you provide a power calculation?

The apriori sample size calculation has been added to the method section (line numbers 290 - 293), as well as the observed power of the main analysis (.995) which shows that there is high statistical power for N=17.

7. Quality of relationship, page 6, line 136 “discrepancy”, and Supplementary Materials Table S1, and Results page 10, line 246 “we assumed that the quality of their relationship did not influence touch perception”. I cannot find how this was analysed, but it seems that independent samples t-tests with the means of each group were calculated? With this method, you can arrive at exactly the same mean in both groups despite quite high differences in each pair. Thus, if the means are similar, it does not say anything about the discrepancy in each pair, and the conclusion that relationship quality not influence touch perception is not valid. If you are after that, you should calculate the differences for each pair and for example, correlate them to the pleasantness ratings.

We replaced the t-test with a Spearman correlation between the QRI difference score and VAS pleasantness for CT-optimal touch and CT non-optimal touch. This is described in the result section line numbers 476 – 481.

8. Tactile stimulation, page 7, last paragraph. Please specify if the dorsal (or ventral) forearm was stroked.

This was the dorsal part (hairy skin), this has been specified at line number 233.

9. Tactile stimulation, page 7, last paragraph. “CT non-optimal touch was administered by stroking (…) at (…) 18cm/s”. The velocity of 18 cm/s never been used in microneurography experiments that measured CT and Aβ activation. Thus, it is not known how CTs respond to velocities of 18 cm/s, and it is not known if 10 and 18 cm/s would give significantly different mean CT instantaneous firing frequencies. The wording “CT non-optimal” is not appropriate when it has never been tested. You could consider, for example, calling these velocities “slower” and “faster”.

We agree with the reviewer that the velocity of 18 cm/s has not been studied specifically in microneurography experiments. However, we do know from these studies that the optimal velocity for CT-optimal touch is 3 cm/s with a range of 1 – 10 cm/s and that when faster stimuli >10cm/s are applied that only a handful of spike with lower frequency respond compared to optimal velocity 1 -10cm/s (Ackerley, Sci Rep 2022) Therefore, we consider 18 cm/s non-optimal as this is faster than the 10 cm/s which is considered a CT-optimal velocity. In addition to this, this term has been used before by other others as well (see von Mohr et al Soc Cog & Aff Neurosc 2018) but also in our own previous studies (see Meijer et al JNP 2022, Meijer et al Sci Rep 2022).

Taken together, we would prefer to keep the term CT non-optimal touch to stay in line with previous studies. As we do agree that we do not know exactly how the CT-fibers react to 18 cm/s we added this in the discussion section line numbers 515 - 519.

10. Procedure. Figure 3 shows the big timeline of the intervention, but readers would probably appreciate a more fine-grained figure that also shows the single measurements (i.e., the time points at which the ratings are measured).

This has been added to Figure 3.

11. It is unclear if VAS pleasantness ratings were collected 3 or 4 times. Was there also a measurement before the very start of the 15 min period, i.e. at time point 0?

There were 3 measurements at 5, 10, 15 min so after every 5min of touch administration. This has been clarified in the Procedure section line number 167 – 168.

12. Statistical analysis, page 10. The authors performed a careful analysis of the data, but it does not seem optimal in several points. Firstly, Table 2 indicates that six t-tests are performed to compare faster and slower touch, and they seem not to have been corrected for multiple comparisons. Some correction for multiple comparison is required, and then the p-values will probably not survive the threshold. This would not make the findings less interesting. Thus, any number of t-tests calculated should be adjusted for multiple comparisons.

Secondly, there are three different repeated-measures-Anovas that can either be combined into one, or even better, be replaced by a linear mixed model (multilevel model). If a repeated measures Anova is calculated, it could be with the factors condition (no touch, fast, slow) and another factor timepoint (0, 5, 10, 15 minutes). This could nicely replace the different analyses for overall effect, short-term effect, and the one for “optimal duration”. Calculating the difference between timepoints as for the current “short-term effect” is then no longer required. If this approach is chosen, the factors and their levels should clearly be specified in the description of the analysis. This is currently not the case.

However, the better solution would be a linear mixed model, firstly because the information of the single trials would be used, rendering a higher power, and also because missing cases can be handled instead of the whole case being dropped as happens with repeated-measures Anova. I therefore ask the authors to calculate a linear mixed model with their data. For this, the single touch trials could be nested within one session (morning, afternoon). This would also allow to take into account the variability across stroking trials, which is interesting with respect to potential touch satiety.

We agree that a linear mixed model would be the better solution. We tried performing a linear mixed model but unfortunately this was not possible. SPSS as well as JASP could not run the analysis as there were too many levels and factors. Even when we nested trials in different categories or used average FPS-R scores, we received a warning that parameters could not be estimated and that we needed to reduce the random effects structure. This was not possible.

As such we decided to run two repeated measures ANOVA. We could not use one repeated measures ANOVA for all data, as suggested, because the factor timepoint is not included in the no touch condition. As we agree that we lose a lot of variability by calculating week averages, we decided to include the factor days into the analysis. As such one participant was excluded from the analysis as there was too much missing data possibly invalidating the individual data as well. This has been changed in the result section line numbers 367 – 442.

13. Page 11, Table 1. For the reader it would be interesting to not only see the means, but also the data of each single subject. I suggest to move the table to the Supplements, and present a graph here where both the means and the individual data points are visible.

We made a new graph with individual data points see Figure 4. Here we calculated FPS-R difference scores for CT-optimal touch – no touch and CT non-optimal touch – no touch. This was done for every participant and every day of the week.

14. Page 14, line 315. It would be interesting to see (in a graph) how the pleasantness ratings change or do not change over time (i.e. 0,5,10, 15 min of stroking). Given the research on touch satiety (e.g. Triscoli et al. PLOS One 2014) and affective habituation (Dijksterhuis and Smith, Emotion 2002), one wonders if such a habituation process is abolished when stroking contributes to reduce pain. A closer look at this aspect may also help you further to disentangle pleasantness from pain effects. In particular, check out the paper by Taneja et al. (Front Pain Res 2021) who measured pain in addition to touch satiety.

To illustrate the difference between 5, 10, 15min we calculated the average per individual for these different timepoints, as shown in the graph this is stable per individual. Furthermore, the pleasantness analysis has been changed to a mixed Anova including the factor day as well. As there is no interaction between touch x day it appears that touch perception is stable over time. We did not include this in the manuscript for now, as the manuscript is already dense but if necessary, we could add this in the supplementary material file.

15. Discussion, page 16 ff. The lack of a control condition needs to be discussed. The authors hint at the “social component underlying touch” (line 365), but need to make this aspect much more explicit. The current design of the study does not allow to state if the pain-relieving effects are due to touch itself or to what the authors call the “social component”. Since there was no control group, the results do not allow to conclude if the pain reduction has something to do with touch at all. Maybe the attention provided by the partner could be enough for such an effect, and pain would also be relieved if the partner painted the nails of the patient or performed a motivational interview? Note that touch by a partner conveys an intention of care, of being secure, and the availability of social support (Jakubiak and Feeney; Personality and Social Psychology Review 2017). Any other behaviour conveying similar intentions might have had the same effect. This does not reduce the importance of the current findings, but should be openly stated and reflected upon.

We agree that this is an important limitation, this has been added to the discussion at line numbers 634 – 645.

16. Page 17, lines 382-383 (“the pain ameliorating effect (…) is most effective between 10-15 min. If the authors find this interesting, they could relate this interval to other studies who investigated how the beneficial effects of slow touch evolve over time, for example heart rate (e.g. Püschel et al. Physiol Behav 2022; Triscoli et al., Biol Psychol 2017).

We decided to only mention this briefly as there are several things we still do not know regarding touch duration and therefore do not want to make strong statements regarding this point. See line numbers 529 – 533.

17. Page 18, first paragraph. It is very positive that the authors report how the patients commented the intervention. This adds important information. In this context, I wonder if the patients mentioned that they speak with each other during stroking? Do you have any information about that? To stroke or be stroked 15 minutes without saying anything appears rather awkward and boring for both parties. If the stroking was followed by (occasional) talking, this could on the one hand explain the overall high pleasantness ratings also for the faster touch, and maybe also have contributed to the pain-reducing effects of the intervention.

We asked the participants to perform touch in a quite environment with no distractions and also to not talk and really be in the moment and have their attention fully on the touch experience. This is something we could not control for of course because we were not present during the touch administration. However, participants and their partners subjectively reported that for them it was not awkward or strange to be quite as they felt really connected and in the moment when they were having 15 min with just the two of them.

Reviewer #2: This longitudinal cross-over study tested the effects of affective touch from a partner on chronic pain in Parkison’s disease. Both affective and non-affective touch was effective in ameliorating pain on a day-to-day basis. In addition, affective touch had a stronger immediate (5-minute scale) on perceived pain.

This is a well-designed study on an important topic. I specifically applaud the effort to design the study in a way that allows for relatively direct application of the results as a clinical intervention.

Methods

- [major] One participant was excluded from the study “as the origin of his pain and study outcome were very different from the other participants in this study”. A more specific explanation is necessary. What was the exact difference between the origin of pain of the excluded participant, and which outcome parameters were different? Was this difference quantified in any way?

We added more information regarding the exclusion of this particular case from the larger sample. See line numbers 117 – 125.

Results

- [major] Most data (except for the overall-effect) are presented in tables i.s.o. graphs. I think a more graphical presentation of the result would aid interpretation of the findings. I think this is especially important for the short-term effects, but also for example for the effects of (non-)affective touch on pleasantness scores. Preferably, these graphs would contain individual datapoints (or at least some information on the distributions).

We made a new graph with individual data points see Figure 4. Here we calculated FPS-R difference scores for CT-optimal touch – no touch and CT non-optimal touch – no touch. This was done for every participant and every day of the week.

- [major] There is a strong overlap between two analyses of the short-term effects. The first analysis consists of multiple paired t-tests for a touch-treatment effect on the baseline-corrected pain scores at different time points. The third analysis in this section is a repeated measures ANOVA of the raw pain scores with the factors time and touch-treatment (this analysis approach seems most comprehensive to me). The significant paired t-test for the 15min-0min pain score and the significant time x touch-treatment interaction seem to reflect the same underlying effect. I do not think it is appropriate to present them as entirely separate. I think the interaction effect is the most convincing result (a steeper slope for pain scores during affective touch).

We agree with this important point therefore we decided to only report the repeated measures ANOVA in which we included the factor days instead of only looking at the data over the week. Here we find an interaction effect between touch x timepoint in which there is indeed a steeper slope for CT-optimal touch compared to CT non-optimal touch. This is also visualized in Figure 5. See the result section line numbers 393 – 442.

- [minor] P. 17: “… the F-values are very low which indicates a low probability of a significant difference.” This suggests evidence for absence of an effect. Correct me if I am wrong, but I believe that this is not appropriate when using a frequentist approach (I think Bayesian modelling can be used to find evidence for the null hypothesis).

We removed this sentence. In addition, we also tried Bayesian modelling on the overall and short-term effect. However, for the short-term effect the error % were around 99 reflecting an inaccuracy of the model, which is likely related to the large and complex dataset. Therefore we decided to not include Bayesian modelling.

- [minor] The values for the “0min” touch in table 3 and table 4 differ. Should these values not be the same?

We removed Table 3, only Table 4 is included in the text.

Discussion

- [major] The case report of the excluded participant (Meijer et al., 2023, journal of neuropsychology) ends with the remark that “further research in a larger clinical sample is warranted”. The current study seems like a prime example of such further research. I missed a discussion of how the current study relates to the case report (either explaining if the results of the current study support the previously reported findings, or explaining why such a comparison is not possible).

We wrote a new paragraph on this comparison within the discussion section. Line numbers 602 – 619.

- [minor] The conclusion that CT-optimal touch is most effective after at least 10-15 minutes is too strong, given the available evidence: (1) Effects may appear earlier, but may just not have been detectable in the current study, given the relatively low sample size (2) It has not been tested if the pain reduction continues after the touch is finished. It is possible, for example, that a reduction in pain ratings still occurs at 15 minutes even if the touch is only applied for, say, 5 mins. This second point is relevant for the implementation of affective touch as a treatment.

This is indeed a relevant point, which we added to the discussion. We also changed this paragraph a little to make the statement less strong. Line numbers 520 – 533.

- [minor] I was wondering if hormonal effects (e.g. oxytocin) may play a role in the potential underlying mechanisms, especially because the touch occurs between romantic partners.

This is an interesting point that warrants further investigation. However, we believe this is beyond the scope of the current study.

- [minor] The discussion on conduction velocities (p. 23). The authors correctly mention that even though CT-fiber velocities are relatively slow (compared to A� fibers), they are still processed within seconds, whereas the (additive) effects of affective touch only occur in 10-15 minutes. However, the authors also seem to suggest that the fact that effects of affective touch occurs relatively late is somehow related to differences in velocities between A� fibers and CT-fibers. I cannot follow this reasoning.

We believed this point made things unclear and was highly speculative as we did not use microneurography. Therefore we removed this part.

________________________________________

Attachment

Submitted filename: Response to reviewers.docx

pone.0298345.s002.docx (35.5KB, docx)

Decision Letter 1

Julian Packheiser

18 Dec 2023

PONE-D-23-21643R1CT-optimal touch and chronic pain experience in Parkinson’s Disease; An intervention studyPLOS ONE

Dear Dr. Meijer,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

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Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: The authors present a fine revision of their manuscript and have well answered to my questions and comments. I only have a few minor suggestions and a more important one for interpreting the results.

Abstract: I think it should read “treated with analgesics” (not analgesia)

Line 67: “appreciation” means recognizing the good qualities of something (Oxford dictionary). I don’t think this is what is meant here.

Line 108: explain what “Gorilla” is when it is mentioned for the first time.

Figure 4 and 5: Say in the caption what the line shows (mean values I assume).

Line 329. There is no “S2 Table”. Do you mean “Table 2”?

Line 380 ff. “an immediate effect of touch on chronic pain experience was also investigated. Here, the results showed that CT-optimal touch reduces the chronic pain experience significantly more compared to CT non-optimal touch”. This appears to be the interpretation of the results in lines 324-329. However, this interpretation does not seem justified. Similar to a pain reduction of CT-optimal touch, namely a significant difference between 0 and 5 minutes, and between 0 and 10, there is also a significant difference for CT-non-optimal touch between 0 and 5 minutes, and between 0 and 10. Thus, there is also a short-time pain-reducing effect of CT-non-optimal touch.

The only difference between CT-optimal and non-optimal touch is that for CT-optimal touch, there is an additional significant difference for the time interval between 5 and 10 minutes, which is not present for CT-non-optimal touch. For the other four intervals, CT and non-CT touch yield similar results. Thus, the interpretation that CT-touch is more efficient than non-CT-touch for short-term pain relief is on shaky grounds as it is based on just this one difference (one out of five). Consequently, it should be amended in both the discussion and the abstract. The conclusion appears to rather be that CT and non-CT touch are equally effective in short- as well as long-term pain reduction, which is perfectly fine. This would also fit to the findings from studies showing that even mere partner presence without touch can reduce pain (e.g.; Duschek et al, Scand J Pain 2019). I suggest you consider that it might be the support communicated through touch (or other means) that is crucial for pain amelioration, and not the type of touch itself. I leave this to the authors, but it might be interesting to discuss this aspect. Personally, I think this would be more beneficial to the reader than exaggerating the small CT effects.

Line 481 “So, it could be that any form of affectionate touch might have similar effects”. This sentence is not understandable unless the authors want to say that only touch that is performed with CT-optimal velocity is affectionate? This claim seems to not be justified since other forms of touch such as hugs and handholding can certainly be perceived as affectionate. Do the authors mean “Any form of affectionate behaviour”, e.g. verbal support? This would make sense. Please reformulate.

Line 482 “as there is an additional relieving effect of CT-optimal touch”. This is an overstatement, see comment further up. I would suggest to remove this sentence.

Reviewer #2: All my coments have been addressed and the report has definitely been improved.

For future reference: the line numbers in the response letter did not match the manuscript (if I'm correct). I also think that the language can be improved here and there.

**********

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PLoS One. 2024 Feb 23;19(2):e0298345. doi: 10.1371/journal.pone.0298345.r004

Author response to Decision Letter 1

22 Dec 2023

Response to reviewers

Dear Julian Packheiser,

First of all, we would like to thank the editor and reviewers for the opportunity to address these minor revisions. These extra valuable comments have improved the manuscript even more. We sincerely hope that it now meets the criteria for publication in PLOSone. Below, in red we addressed every point from the reviewers. The line numbers refer to the manuscript with track changes.

Thank you again for considering our manuscript and we would like to wish you a Merry Christmas and a Happy New Year.

Kind regards also on behalf of the co-authors,

Larissa Meijer

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

The reference list has been checked and is correct, no adjustments have been made.

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Reviewer #1: (No Response)

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: Partly

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: No

________________________________________

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: The authors present a fine revision of their manuscript and have well answered to my questions and comments. I only have a few minor suggestions and a more important one for interpreting the results.

Abstract: I think it should read “treated with analgesics” (not analgesia)

This is indeed wrong, we changed it to analgesics at line number 13.

Line 67: “appreciation” means recognizing the good qualities of something (Oxford dictionary). I don’t think this is what is meant here.

We changed this sentence to ‘which are important for the affective aspects of pain experience’ at line numbers 61-62.

Line 108: explain what “Gorilla” is when it is mentioned for the first time.

We added the following ‘’ Gorilla (an online survey tool)… “ at line number 110.

Figure 4 and 5: Say in the caption what the line shows (mean values I assume).

This has been added to the figure captions (see Figure file).

Line 329. There is no “S2 Table”. Do you mean “Table 2”?

We were referring to the S2 Table. I have checked the revised supplementary File as a supporting information file, the S2 Table is available there. This has been done according to the submission guidelines from PLOSone.

Line 380 ff. “an immediate effect of touch on chronic pain experience was also investigated. Here, the results showed that CT-optimal touch reduces the chronic pain experience significantly more compared to CT non-optimal touch”. This appears to be the interpretation of the results in lines 324-329. However, this interpretation does not seem justified. Similar to a pain reduction of CT-optimal touch, namely a significant difference between 0 and 5 minutes, and between 0 and 10, there is also a significant difference for CT-non-optimal touch between 0 and 5 minutes, and between 0 and 10. Thus, there is also a short-time pain-reducing effect of CT-non-optimal touch.

The only difference between CT-optimal and non-optimal touch is that for CT-optimal touch, there is an additional significant difference for the time interval between 5 and 10 minutes, which is not present for CT-non-optimal touch. For the other four intervals, CT and non-CT touch yield similar results. Thus, the interpretation that CT-touch is more efficient than non-CT-touch for short-term pain relief is on shaky grounds as it is based on just this one difference (one out of five). Consequently, it should be amended in both the discussion and the abstract. The conclusion appears to rather be that CT and non-CT touch are equally effective in short- as well as long-term pain reduction, which is perfectly fine. This would also fit to the findings from studies showing that even mere partner presence without touch can reduce pain (e.g.; Duschek et al, Scand J Pain 2019). I suggest you consider that it might be the support communicated through touch (or other means) that is crucial for pain amelioration, and not the type of touch itself. I leave this to the authors, but it might be interesting to discuss this aspect. Personally, I think this would be more beneficial to the reader than exaggerating the small CT effects.

We fully agree that this is effect is overstated. These statements were based on the previously reported t-test. As we removed this analysis, these statements should be adjusted as well. Based on the interaction effect between touchxtimepoint and the steeper slope of CT-optimal touch in Fig 5, it appears that it is slightly more beneficial to use CT-optimal touch at the 15min timepoint compared to CT non-optimal touch. As it was also perceived as more pleasant and more feasible to apply for the partners, we do believe CT-optimal touch would be the preferable choice compared to CT non-optimal touch. We also added some information regarding the mere presence of partner as a form of passive social support at line numbers 508-509.

However, as mentioned this was still overstated so we changed this throughout the manuscript at line numbers: 21-22, 331-332, 390-392, 413-416, 476-486 and 522-526.

Line 481 “So, it could be that any form of affectionate touch might have similar effects”. This sentence is not understandable unless the authors want to say that only touch that is performed with CT-optimal velocity is affectionate? This claim seems to not be justified since other forms of touch such as hugs and handholding can certainly be perceived as affectionate. Do the authors mean “Any form of affectionate behaviour”, e.g. verbal support? This would make sense. Please reformulate.

As we indeed wanted to make this exact point, we reformulated this to affectionate behaviour at line number 507.

Line 482 “as there is an additional relieving effect of CT-optimal touch”. This is an overstatement, see comment further up. I would suggest to remove this sentence.

We removed this sentence and were more cautious with the other statements regarding the additional effect of CT-optimal touch. Also see the changes mentioned above.

Reviewer #2: All my coments have been addressed and the report has definitely been improved.

For future reference: the line numbers in the response letter did not match the manuscript (if I'm correct). I also think that the language can be improved here and there.

________________________________________

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Attachment

Submitted filename: Response to reviewers v2.docx

pone.0298345.s003.docx (22.5KB, docx)

Decision Letter 2

Julian Packheiser

23 Jan 2024

CT-optimal touch and chronic pain experience in Parkinson’s Disease; An intervention study

PONE-D-23-21643R2

Dear Dr. Meijer,

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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Kind regards,

Julian Packheiser

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Julian Packheiser

14 Feb 2024

PONE-D-23-21643R2

PLOS ONE

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    pone.0298345.s002.docx (35.5KB, docx)
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    pone.0298345.s003.docx (22.5KB, docx)

    Data Availability Statement

    Fully anonymized data generated during and/or analyzed during the current study are available in the YODA repository, DOI: 10.24416/UU01-KZ91OM.

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