Restoration of normal central pain processing following manual therapy in nonspecific chronic neck pain

Josu Zabala Mata; Jon Jatsu Azkue; Joel E Bialosky; Marc Saez; Estíbaliz Dominguez López; Maialen Araolaza Arrieta; Ion Lascurain-Aguirrebeña

doi:10.1371/journal.pone.0294100

. 2024 May 23;19(5):e0294100. doi: 10.1371/journal.pone.0294100

Restoration of normal central pain processing following manual therapy in nonspecific chronic neck pain

Josu Zabala Mata ^1,^2,^*,^#, Jon Jatsu Azkue ^2,^#, Joel E Bialosky ^3,^4,^‡, Marc Saez ^5,^6,^‡, Estíbaliz Dominguez López ^2,^‡, Maialen Araolaza Arrieta ^1,^‡, Ion Lascurain-Aguirrebeña ^7,^#

Editor: Shahnawaz Anwer⁸

PMCID: PMC11115211 PMID: 38781273

Abstract

Objective

To determine if a 4-week manual therapy treatment restores normal functioning of central pain processing mechanisms in non-specific chronic neck pain (NSCNP), as well as the existence of a possible relationship between changes in pain processing mechanisms and clinical outcome.

Design

Cohort study.

Methods

Sixty-three patients with NSCNP, comprising 79% female, with a mean age of 45.8 years (standard deviation: 14.3), received four treatment sessions (once a week) of manual therapy including articular passive mobilizations, soft tissue mobilization and trigger point treatment. Pressure pain thresholds (PPTs), conditioned pain modulation (CPM) and temporal summation of pain (TSP) were evaluated at baseline and after treatment completion. Therapy outcome was measured using the Global Rating of Change Scale (GROC), the Neck disability Index (NDI), intensity of pain during the last 24 hours, Tampa Scale of Kinesiophobia (TSK) and Pain Catastrophizing Scale (PCS). Two sets of generalized linear mixed models with Gaussian response and the identity link were employed to evaluate the effect of the intervention on clinical, psychological and psychophysical measures and the association between psychophysical and clinical outcomes.

Results

Following treatment, an increased CPM response (Coefficient: 0.89; 95% credibility interval = 0.14 to 1.65; P = .99) and attenuated TSP (Coefficient: -0.63; 95% credibility interval = -0.82 to -0.43; P = 1.00) were found, along with amelioration of pain and improved clinical status. PPTs at trapezius muscle on the side of neck pain were increased after therapy (Coefficient: 0.22; 95% credibility interval = 0.03 to 0.42; P = .98), but not those on the contralateral trapezius and tibialis anterior muscles. Only minor associations were found between normalization of TSP/CPM and measures of clinical outcome.

Conclusion

Clinical improvement after manual therapy is accompanied by restoration of CPM and TSP responses to normal levels in NSCNP patients. The existence of only minor associations between changes in central pain processing and clinical outcome suggests multiple mechanisms of action of manual therapy in NSCNP.

Introduction

Neck pain is among the top five causes of disability in middle- and high-income countries and among the top ten as a cause of global disability [1]. Despite investment in research, the prevalence of neck pain has not declined substantially in the last two decades [2]. Since little relationship with radiological findings and no specific cause is found to explain symptoms, patients are usually classified as suffering from non-specific neck pain (NSCNP) [3].

Guidelines advocate treating patients with NSCNP with exercise and manual therapy [4, 5]. However, systematic reviews assessing clinical outcomes of manual therapy, including for example cervical manipulation, thoracic manipulation, cervical mobilization and massage, report low to moderate treatment effects at best [6]. Such relatively modest benefit from current therapeutic interventions should be of no surprise, in light that critical aspects of treatment remain to be established, such as optimal dosage and clinical parameters, best indicated forms of mobilization, and possible target patient subpopulations. This may be partly due to the fact that mechanisms of action of manual therapy are not yet fully understood. Although biomechanical effects, neural hysteresis, and segmental neurological modulation have long been postulated as underlying mechanisms of action of manual therapy, hypotheses have in recent years shifted towards a potential role of altered pain processing in the central nervous system [7].

Inter-individual variability in the functioning of central pain processing mechanisms has been postulated as an alternative framework to understand heterogeneity of treatment outcomes [8]. Several studies have reported disturbances in central pain processing in patients with NSCNP [9–11]. A meta-analysis has confirmed the occurrence of hyperalgesia distal to the most painful site [12], a probable indication of the occurrence of central sensitization in the NSCNP population. Central sensitization (CS) refers to a state of increased central responsiveness to nociceptive inputs associated with plastic changes in nociceptive circuits and pathways [13]. There is consistent evidence of altered central pain processing in patients with NSCNP, including both pronociceptive and antinociceptive mechanisms. Temporal summation of pain (TSP), a gradual increment of the pain sensation elicited by repeated C-fiber–mediated stimuli which is evaluated as a measure of pronociceptive mechanisms, is enhanced in NSCNP patients [9, 11, 14]. In addition, disruption of endogenous antinociception has also been found, such as the impairment of the so-termed Conditioned Pain Modulation (CPM) [10, 11].

Although changes in central pain processing have been reported following manual therapy (Mulligan’s mobilization with movement, cervical manipulation, anteroposterior mobilisations, lateral glide mobilization, Maitlands passive accesory mobilization, etc.), most studies have relied on static psychophysical measures (largely assessment of pressure pain thresholds) and found amelioration of local [12, 15, 16] and in some cases distal hyperalgesia [17]. However, studies assessing the effects of manual therapy using dynamic psychophysical tests are scarce, and relatively little is known on the effects of manual therapy on central pain processing mechanisms. Dynamic psychophysical tests have been postulated to better assess pain processing in the central nervous system [18] as they evaluate central processing systems rather than pain perception. Although a systematic review showed that physical therapy may reverse alterations in pain processing that accompany several musculoskeletal conditions [19], few studies have specifically addressed the effect of manual therapy, and, of these, only one included patients with NSCNP [20]. This latter study evaluated the effect of neurodynamic upper limb mobilizations, and found beneficial effects of therapy on CPM but not on TSP. Other studies that have assessed the effect of physiotherapy other than manual therapy in NSCNP have found no effects of therapeutic exercise and virtual reality on TSP [21, 22] and CPM [22]. Currently, the effect of manual therapy on central pro- and antinociceptive processing in patients with this condition is unknown.

For restoration of normal central pain processing to be considered as a potential mechanism of action of manual therapy, it should be associated with improvements in clinical status [7]. The only studies that have so far addressed this issue failed to find associations between clinical improvement and changes in mechanical pain thresholds [23, 24], and none has assessed a possible association between restoration of normal central pain processing and clinical outcomes of manual therapy.

The present study directly addresses the previously identified research gaps of 1) failure to determine the effects of manual therapy on dynamic measures of quantitative sensory testing i.e. TSP and CPM and 2) failure to link changes in pain sensitivity processing to clinical outcomes. Consequently, we aimed to determine whether manual therapy restores normal functioning of central pain processing mechanisms in patients with NSCNP. As a secondary aim, we sought to evaluate the relationship between clinical outcome and changes in central pain processing mechanisms following manual therapy.

Methods

A single-center, prospective study was conducted at a primary care physiotherapy clinic in the Bizkaia region of Spain between March 2020 and July 2021. All patients provided written consent before data collection and their rights were protected. The study was approved by the institutional review board at the University of the Basque Country–UPV/EHU (Ethical approval reference: M10_2018_160MR1_ZABALA MATA) and registered before study commencement (ClinicalTrials.gov record number: ACTRN12620000163909).

Participants

In a two-sided test, assuming an alpha of 5% and an statistical power of 80% a sample size of 63 subjects (observed longitudinally up to 3 times) were required to detect a minimum difference of 10% in TSP and CPM measures [25]. A difference of less than 10% was considered negligible. We used the ’pwr’ package, in the free statistical environment R (version 4.3.2), based on the formula provided by Cohen [25, 26]. People seeking treatment for NSCNP at a primary care physiotherapy clinic were invited to participate. Individuals were included in the study if they met the following inclusion criteria: pain of mechanical origin (i.e. pain is reproduced by neck movements or positions) and non-traumatic (insidious) onset. They were excluded if they presented: a whiplash associated disorder pathology; widespread, non-anatomical distribution of pain; stimulus-independent spontaneous pain; neurological (either sensory or motor) deficit; radicular pain; had undergone or were awaiting neck surgery, or referral to other health professional to exclude non- musculoskeletal causes of their neck pain (ex. cancer) was required.

Clinical assessment

Age, sex, height, and weight were recorded from participants, and patients completed the Neck Disability Index (NDI), the Pain Catastrophizing Scale (PCS) and The Tampa Scale of Kinesophobia (TSK) questionnaires. The NDI is the most frequently used, self-administered questionnaire for assessing cervical disability. The questionnaire consists of 10 items on activities of daily living, and each item is scored from 0 to 5, where higher scores indicate greater disability. It has demonstrated good to excellent internal consistency and moderate to excellent test-retest reliability [27]. The validated Spanish version was used [28]. The PCS is a 13-item questionnaire that measures catastrophic thoughts and feelings about pain. Total scores range from 0 to 52, and higher scores indicate higher levels of pain-related catastrophizing. This questionnaire has demonstrated high internal consistency and discriminative validity in adult community and pain outpatient samples [29]. The validated Spanish version was used [30]. Pain-related fear of movement was assessed using the 11-item TSK; scores on each item range from 1 to 4, where higher scores are indicative of greater fear [31]. This questionnaire has exhibited satisfactory internal consistency and demonstrated significant validity [32], including its validated Spanish version, which was used for the current study [33].

Maximum and mean intensities of pain experienced over the last 24 hours, and pain experienced during neck movements (flexion, extension, right and left rotation and side flexion) were recorded using a 0–10 numeric rating scale anchored with 0 = no pain at all to 10 = worst pain imaginable. Patients were also asked to complete the Patient Specific Functional Scale (PSFS) [34], a self-reported measure of perceived level of disability on specific items relevant for them. The PSFS has excellent reliability and moderate to strong validity [35].

In addition, patients were asked to rate their perceived treatment effect using the Global Rating of Change Scale (GROC). The GROC is a 15-point scale where clinical change is rated from -7 (a very great deal worse), through 0 (no change), to +7 (a great deal better) [36]. This questionnaire has shown excellent reliability [37].

All clinical measures except GROC (recorded only post-treatment) were obtained in single sessions both at baseline and after treatment completion. A maximum of 24 hours elapsed both from the first clinical assessment session to treatment initiation, and from the last treatment session to the second clinical assessment.

Psychophysical assessment

Pressure Pain Thresholds (PPT), defined as the minimum pressure at which pressure sensation becomes a painful sensation [38], were measured at several locations using a digital hand-held algometer with a 1-cm²-diameter rubber tip (Fisher, Pain Diagnostics and Thermography Inc, Great Neck, NY, USA). For local assessment of pain sensitivity, PPTs were measured bilaterally at the angle of the upper trapezius fibers, 5 and 8 cm above and medial to the superior angle of the scapula, and remote sensitivity was assessed on the tibialis anterior at a location 2.5 cm lateral and 5 cm inferior to the anterior tibial tuberosity. Subjects were instructed to report their first perceived pain sensation during an incremental pressure application at 1 kg/ sec. The same procedure was repeated three times, 1 min apart, and the mean of three measurements was used for analysis. Patients were familiarized with the measurement protocol prior to the actual measurements. This procedure has shown high reliability in neck pain patients [39].

For assessing TSP, patients were seated in a quiet room with their hand rested on a table (same side as neck pain, or the side of most painful neck pain in patients with bilateral pain) and two adhesive Ag/AgCl electrodes were placed on the hand dorsum, 2 cm apart. Electrical stimuli consisting of brief bursts of five, 1 ms-long positive-square pulses, were generated by a constant current electrical stimulator (DS7; Digitimer Ltd, Welwyn Garden City, UK) and delivered at 200 Hz [40], which were perceived by the participant as single stimuli. Electrical pain thresholds were first determined using the increasing and decreasing staircase method with 0.2 mA stimulus increments/decrements. The electrical pain threshold was defined as the minimum current intensity evoking a sensation rated as painful in an incremental series or the current intensity no longer evoking pain in a decremental series, and the final value was recorded as the mean of three consecutive incremental and three decremental measures. For assessing TSP, a single stimulus was administered at 1.2 times the electrical pain threshold intensity, and the participant was asked to rate the evoked pain sensation on a 0–100 numeric scale where 0 denotes no pain at all and 100 indicates the worst pain imaginable. Two minutes thereafter, 5 consecutive stimuli of the same current intensity were delivered at a frequency of 2 Hz (2.5-millisecond total stimulus duration), and the participant was asked to rate the pain sensation evoked by the stimulus perceived as the most painful. The ratio of the second rating to the first was used as the TSP measure [41]. A higher ratio was indicative of greater TSP. This protocol has been previously used [42] and is based on well-known parameters for evaluating TSP [40].

For CPM assessment, PPT was measured first on the trapezius muscle as above, and the participant was then asked to immerse his/her contralateral foot in cold water (kept at 10° C) for 2 minutes or until pain became unbearable. Immediately thereafter, the PPT was measured again at the same location. The CPM response was obtained by subtracting the second measure from the first [43]. A greater value was indicative of higher endogenous pain inhibition. This procedure has demonstrated good to very good reliability [44].

Intervention

Patients received a 45-minute session of manual therapy once a week for 4 weeks. Treatments consisted of articular passive mobilizations, soft tissue mobilization, and trigger point treatment performed by the clinician following clinical reasoning. Passive mobilization treatment consisted of passive, low-speed movements performed on hypomobile and pain-reproducing spinal segments in the cervical and thoracic spine [36], including grade II–III posterior-anterior and/or antero-posterior mobilizations following the movement plane of the cervical zygapophyseal joints (upslope and downslope mobilizations) [45–48], with the patient in a supine position (Fig 1). All passive mobilizations were performed using oscillatory techniques, comprising sets of 6 oscillations. The procedure continued until the hypomobile segments regained motion, or alternatively, a maximum of 4 sets was reached. The direction and intensity of the technique were determined by the clinician based on prior clinical assessment. Soft tissue mobilization (gentle longitudinal and transverse stroking) of neck muscles was administered in order to improve connective tissue function and reduce myofascial pain [49]. This was accompanied by a trigger point ischemic compression technique on neck muscles where appropriate. In this technique, the therapist gradually applied increasing pressure to trigger points until the onset of pain. Pressure was sustained until pain was relieved or the treatment surpassed one minute, whichever occurred first. Subsequently, the pressure was increased until discomfort was felt again. The therapist repeated this procedure approximately three–four times [50]. This procedure has been found effective to reduce muscular pain in NSCNP [51]. All treatments were administered by the same physiotherapist with postgraduate training and 15 years of experience in musculoskeletal physiotherapy, which was blinded to the baseline and post-treatment clinical and neurophysiological assessments.

Statistical analysis

Two sets of generalized linear mixed model (GLMM), with Gaussian response and the identity link (i.e. equivalent to a linear regression) and heteroskedastic variance (since subjects were observed more than once), were used to assess the effect of the intervention on clinical, psychological and psychophysical measures, and the association between treatment-induced psychophysical changes and clinical and psychological outcomes. Analyses were controlled for sex, age, BMI, baseline value of the variables of interest, and individual heterogeneity. Individual heterogeneity, controlled for including a random effect, collects unobserved invariant variables over time that are specific to each individual participant, i.e. residual confounding. Such random effect also controlled the dependence between observations, since subjects were observed at least twice (in some variables three). Given the complexity of the models, we performed inferences using a Bayesian framework. In particular, we followed the Integrated Nested Laplace Approximation (INLA) approach [52, 53]. In addition to the coefficient estimators and their 95% credibility intervals, the probability of the coefficient estimator (an absolute value being more than 1 (Prob(|estimator|)>1), Prob, was also computed (note that this is unilateral and may not coincide with the credibility interval). Unlike the p-value in a frequentist approach, this probability allows us to make inferences about associations between dependent and independent variables. For the sake of simplicity, Prob values exceeding 0.95 are equivalent to p < .05 in a non-Bayesian context. All analyses were conducted using the open access software R (version 4.2.2) [54] available through the INLA package [52, 53, 55]

Results

Sixty-three participants took part in the study between 03/03/2020 and 21/07/2021. Demographics and baseline clinical characteristics are shown in Table 1. All participants attended the scheduled therapy sessions and completed the treatment, and there were no drop outs (Fig 2).

Table 1. Demographics and clinical characteristics.

Values are mean (SD), number of cases or percentage as outlined below.

N	63
Sex (f/m)	50(79%)/13
Age (y)	45.8 (14.3)
BMI	23.5 (3.2)
Neck pain duration (y)	6.7 (5.2)
Mean pain 24 hours (0–10)	4.72 (1.83)
Maximum pain 24 hours (0–10)	6.26 (1.82)
NDI (0–50)	11.56 (5.23)
PCS (0–52)	15.38 (9.28)
TSK (0–44)	23.99 (7.29)
PSFS (0–10)	4.24 (1.93)
Pain on movement	3.48 (2.03)

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Abbreviations: BMI, body mass index; NDI, neck disability index; PCS, pain catastrophizing scale; TSK, Tampa scale kinesophobia; PSFS, Patient specific functional scale; TSP, temporal summation pain; CPM, conditioned pain modulation.

Changes in pain processing, and clinical and psychological outcomes after treatment

Patients showed an improvement in central pain processing following manual therapy. Namely, the intervention both attenuated TSP response (Coefficient: -0.63; 95% credibility interval = -0.82 to -0.43; P = 1.00) and improved conditioned modulation of pain (Coefficient: 0.89; 95% credibility interval = 0.14 to 1.65; P = .99). In addition, manual therapy increased PPT on the trapezius muscle on the side of neck pain (Coefficient: 0.22; 95% credibility interval = 0.03 to 0.42; P = .98), but not on the contralateral trapezius (Coefficient: 0.01; 95% credibility interval = -0.19 to 0.21; P = .54) or the tibialis anterior muscle (ipsilateral Coefficient: -0.03; 95% credibility interval = -0.29 to 0.22; P = .59 on the side of neck pain. Contralateral coefficient: 0.01; 95% credibility interval = -0.26 to 0.29; P = .54 contralaterally) (Table 3).

Table 3. Association between changes in central pain processing mechanisms and clinical/psychological variables.

Model adjusted for sex, age, BMI and individual heterogeneity (random effect).

	Change in CPM
	Coefficient	95% Credibility Interval	P
Change in NDI	-0.57	-1.75 to 0.59	0.83
Change in PCS	-0.24	-2.16 to 1.66	0.60
Change in TKS	0.43	-1.01 to 1.88	0.72
Change in PSFS	-0.65	-1.22 to -0.07	0.98^*
Change in Max pain 24h	0.10	-0.55 to 0.75	0.61
Change in Mean pain 24h	-0.40	-0.92 to 0.11	0.93
Change in Pain on movement	-0.17	-0.40 to 0.05	0.93
Change in GROC	0.28	-0.29 to 0.87	0.83
	Change in TSP
	Coefficient	95% Credibility Interval	P
Change in NDI	0.45	-0.65 to 1.57	0.79
Change in PCS	0.18	-1.74 to 2.10	0.57
Change in TKS	1.09	-0.28 to 2.48	0.94
Change in PSFS	-0.41	-1.25 to 0.42	0.83
Change in Max pain 24h	0.22	-0.38 to 0.83	0.76
Change in Mean pain 24h	0.21	-0.25 to 0.69	0.82
Change in Pain on movement	0.42	0.10 to 0.74	0.99^*
Change in GROC	-0.19	-1.37 to 5.29	0.87

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Abbreviations: BMI, body mass index; NDI, neck disability index; PCS, pain catastrophizing scale; TSK, Tampa scale kinesophobia; PSFS, Patient specific functional scale; PPT, pressure pain threshold; TA, tibialis anterior; TSP, temporal summation pain; CPM, conditioned pain modulation; GROC, global rating of change.

* Statistically significant at p < 0.05.

Clinical pain was also ameliorated following manual therapy, as shown by the reduction in mean pain ratings at 24 hours (Coefficient: -2.52; 95% credibility interval = -2.92 to -2.13; P = 1.00), maximal pain ratings at 24 hours (Coefficient: -3.07; 95% credibility interval = -3.54 to -2.59; P = 1.00) and pain ratings during neck movements (Coefficient: -2.19; 95% credibility interval = -2.51 to -1.87; P = 1.00) (Table 3). The majority of patients reported feeling “a very great deal better” or “a great deal better” (21% and 33% respectively) following treatment, 16% reported feeling “quite a bit better”, 12% “moderately better”, 5% “somewhat better”, 5% “a little bit better”, 6% “a tiny bit better” and 2% “about the same”. Favorable changes in functional and psychological status were also noted, as shown by statistically significant improvements in measures of disability (Coefficient: 2.24; 95% credibility interval = 1.28 to 3.19; P = .99), function (Coefficient: 2.58; 95% credibility interval = 1.89 to 3.26; P = 1.00), fear of movement (Coefficient: -4.04; 95% credibility interval = -5.24 to -2.85; P = 1.00) and catastrophization (Coefficient: -7.41; 95% credibility interval = -9.00 to -5.82; P = 1.00) (Table 2).

Table 2. Effect of intervention on clinical, psychological and psychophysical variables.

Model adjusted for sex, age, BMI, individual heterogeneity (random effect) and baseline value of variable.

Variables	Coefficient	95% Credibility Interval	P
NDI (50)	-2.23	1.29 to 3.17	0.99 ^*
PCS (52)	-7.43	-9.01 to -5.85	1.00 ^*
TSK (44)	-4.07	-5.25 to -2.88	1.00 ^*
PSFS_mean	2.58	1.89 to 3.26	1.00 ^*
Maximum pain 24h	-3.05	-3.53 to -2.58	1.00 ^*
Mean pain 24h	-2.52	-2.91 to -2.13	1.00 ^*
Pain on movement	-2.19	-2.51 to -1.87	1.00 ^*
PPT ipsilateral trapezius	0.22	0.03 to 0.42	0.98 ^*
PPT contralateral trapezius	0.01	-0.19 to 0.21	0.54
PPT ipsilateral TA	-0.02	-0.28 to 0.23	0.59
PPT contralateral TA	0.01	-0.25 to 0.29	0.54
TSP change (ratio)	-0.63	-0.82 to -0.43	1.00 ^*
CPM change (absolute)	0.89	0.14 to 1.65	0.99 ^*

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* Statistically significant change.

Association between changes in central pain processing and clinical and psychological outcomes

Improvements in the functioning of central pain processing mechanisms (CPM and TSP) following intervention were found to be very weakly associated with only few measures of clinical and psychological outcome as shown in Table 3. Improvement in the CPM response was found to be negatively correlated with changes in PSFS (Coefficient: -0.65; 95% credibility interval = -1.22 to -0.07; P = 0.98), and attenuation of TSP was found to be associated with a greater improvement in pain during movement (Coefficient: 0.42; 95% credibility interval = 0.10 to 0.74; P = 0.99).

Discussion

The present work provides novel evidence of restoration of normal central pain processing following manual therapy in NSCNP patients, as shown by TSP, CPM and PPT values returning to levels comparable to normative data collected in our lab [11]. In addition, clinical pain was ameliorated following treatment, and both functional and psychological measures were improved.

Significant attenuation of TSP was found here following manual therapy, an observation in keeping with previous reports using this therapeutic modality both in healthy volunteers [56] and pain conditions such as low back pain [57] and carpal tunnel syndrome [58]. It is noteworthy, however, that studies conducted so far specifically in patients with NSCNP have failed to report changes in TSP following a variety of interventions other than manual therapy, including virtual reality [22], cervical therapeutic exercise [22, 59] and a combined protocol of electrotherapy and cervical therapeutic exercise [15]. This raises an interesting question as to the ability of different therapy modalities to influence TSP, a scenario where manual therapy has proven to exert a significant attenuating effect as shown here and may therefore be best indicated in patients with a pronounced pronociceptive profile at baseline. Future studies using a wider range of therapeutic approaches are expected to provide further insights into this issue.

Alternatively, differences in stimulation techniques used to evoke the TSP response might have contributed to the disparity of results, considering that previous studies in NSCNP relied on mechanical stimuli as opposed to electrical stimuli as used here. Unfortunately, no comparative or validity studies are yet available in this regard, despite good reliability of various methodological approaches for assessing TSP [60–62]. Whereas mechanical stimuli used by previous studies such as weighted pinprick stimuli [21] or pressure exerted by either a cuff [59] or an algometer [22] stimulate superficial and deep mechanical nociceptors, electrical pulses largely bypass nociceptors to directly recruit afferent C-fibers [63]. Direct stimulation of C-fibers is considered as a robust mechanism to elicit the originally described wind-up phenomenon in spinal dorsal horn neurons in animal models, whose perceptual correlate is assessed by quantifying TSP [64, 65].

We found that manual therapy also restored a normal CPM response in our cohort. This finding is consistent with a previous study where neurodynamic treatment, i.e. a form of manual therapy, improved CPM in a similar patient population [16]. Indeed, several studies have shown a general normalizing effect of treatment on the CPM response both in NSCNP [20, 59, 66] and other pain conditions [67, 68] regardless of the therapeutic approach. It thus appears that restoration of the CPM response to normal levels is a frequent outcome of treatment, and little dependent on the type of treatment or target population.

The relationship between an increased TSP response and the level of perceived pain in the NSCNP population is not entirely clear. Although a systematic review with meta-analysis did find some association in a population of back pain patients [69], two recent case-control studies studying NSCNP failed to do so [11, 70]. Considering that the expression of wind-up at spinal cord neurons may be genetically encoded [71], an enhanced TSP may be viewed as an indication of higher propensity to developing pain hypersensitivity. In support of this notion, a number of studies have shown TSP to be a predictor of pain prospectively [72–74]. From a neurophysiological standpoint, temporal summation is considered as one of the initiating neuroplastic mechanisms of central sensitization [75, 76]. On the other hand, wind-up as the correlate of TSP in animal models has also been found to be profoundly influenced by descending supraspinal modulation [77–79]. It thus seems reasonable to assume that attenuation of TSP following manual therapy as shown here may, at least in part, be mediated by recruitment of central pain modulatory mechanisms. This view is further supported by the enhancing effect of manual therapy on the CPM response in patients with NSCNP as shown here. The CPM paradigm is an experimental model to assess the functional state of the so-termed Diffuse Noxious Inhibitory Controls, a widespread modulatory mechanism arising from the brainstem and operating on second order, wide dynamic range neurons in the spinal dorsal horn via the spinal dorsolateral funiculi [80]. An enhanced CPM is considered to reflect greater efficacy of endogenous analgesia mechanisms and thus a more favorable position to control central excitation induced by incoming peripheral nociceptive input [81].

A comprehensive model of the underlying mechanisms of manual therapy based on current research in neuroscience has been postulated which emphasizes the importance of neurophysiological responses to the mechanical stimulus of a manual therapy intervention [82]. Our present study provides further support to that view in showing that both central pain processing and clinical status were indeed improved following manual therapy. Interestingly, however, we found no distinct associations between the two types of outcomes, suggesting that restoration of central pain processing to normal levels may contribute to general clinical improvement in parallel or rather independently from a number of other non-neural mechanisms. For instance, dynamic magnetic resonance imaging has revealed improvements in local cervical segmental mobility following treatment with posterior-to-anterior cervical mobilizations [83–85], enhanced muscle function [47, 86, 87] and attenuation of stiffness at specific spinal segments [88–90] has also been observed following treatment with passive spinal mobilizations. Such interventions have also been associated with changes in sympatoexcitatory activation [48, 86, 91, 92] and a reduction in the concentration of inflammatory markers such as substance P [93]. In addition, several studies have reported significant within-group changes following sham manual therapy treatments [46–48, 94] which also suggests the involvement of contextual mechanisms. None of the above studies evaluated concomitant changes in central pain processing. Collectively, the available evidence provides support to the view that the mechanism of action of manual therapy may be inherently multifactorial. This rather broad range multiplicity of mechanisms may, as suggested by our present study, include the restoration of both pro-nociceptive and anti-nociceptive central pain processing mechanisms to normal levels.

On the other hand, it is possible that the characteristics of our sample may have contributed, at least in part, to this observed lack of association. Thus, although central pain processing mechanisms were indeed significantly altered prior to treatment in the study sample as compared to controls [11], those baseline alterations and clinical status were both modest [95], rendering any possible associations between improvements in both types of outcomes after therapy rather hard to detect.

Limitations

Since no control group was used, changes in both clinical and pain measures noted here cannot unequivocally be attributed to the intervention. Factors such as the natural course of the condition and the potential influence of the placebo effect need to be considered. Nonetheless, no study has thus far reported spontaneous normalization of central pain processing, and the fact that clinical improvement following the intervention was achieved after three months of persisting clinical manifestations renders an alternative explanation rather unlikely.

The generalizability of our findings is constrained by the specificity of our studied population within the NSCNP, which comprised individuals who sought treatment in a private clinical setting and exhibited only mild clinical symptoms. Therefore, caution should be exercised when extrapolating these results to broader or more severe NSCNP populations.

The present study only measured outcomes in the short term, and thus whether the observed changes are long lasting was not determined.

Conclusion

The physiological mechanisms underlying the clinical effect of manual therapy on NSCNP remain unclear. Collectively, however, the present observed beneficial effects on TSP and CPM responses support the notion that manual therapy may operate, to some extent, by influencing central pain processing to ameliorate pain and improve clinical status. Nonetheless, the fact that no clear association was observed between restoration of normal central pain processing and clinical outcome suggests a plurality of underlying mechanisms that may also likely involve biomechanical, physiological and psychological changes. Further studies are needed to determine specifically which mechanisms of action influence the clinical improvement of NSCNP with manual therapy.

Supporting information

S1 Checklist. CONSORT 2010 checklist of information to include when reporting a randomised trial*.

(DOC)

pone.0294100.s001.doc^{(218.5KB, doc)}

S2 Checklist. STROBE statement—Checklist of items that should be included in reports of cohort studies.

Checklist annotated according to the manuscript, “Restoration of normal central pain processing following manual therapy in nonspecific chronic neck pain“.

(DOCX)

pone.0294100.s002.docx^{(32.9KB, docx)}

S1 File

(PDF)

pone.0294100.s003.pdf^{(144.2KB, pdf)}

S1 Data

(SAV)

pone.0294100.s004.sav^{(23.1KB, sav)}

Acknowledgments

The authors would like to express their gratitude to Hiru Fisioterapia for generously providing their facilities for conducting the present study.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

References

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PLoS One. doi: 10.1371/journal.pone.0294100.r001

Decision Letter 0

Shahnawaz Anwer

19 Dec 2023

PONE-D-23-34005Restoration of normal central pain processing following manual therapy in nonspecific chronic neck painPLOS ONE

Dear Dr. Zabala,

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.

==============================

ACADEMIC EDITOR: Three expert reviewers assessed the manuscript. Although they have considered this manuscript, they have raised some significant comments and feedback. In my opinion, the inclusion of those comments will greatly enhance the quality of this manuscript. Furthermore, I have a few comments and recommendations as well.

==============================

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PLOS ONE

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Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: No

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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: A single cohort study was conducted which aimed to investigate whether a 4-week manual therapy treatment intervention restores normal functioning of central pain processing mechanisms in non-specific chronic neck pain. In addition, the relationship between changes in pain processing mechanisms and clinical outcome was assessed. The study showed an increase in CPM response and TSP. Weak associations were found between TSP/CPM measures and clinical outcomes.

Minor revisions:

1- Abstract: State the statistical testing methods and summary statistics or p-values to support the results.

2- Line 111: Indicate the statistical method which achieves 80% power. The power calculation should include: (1) the estimated outcomes in each group; (2) the α (type I) error level; (3) the statistical power (or the β (type II) error level); (4) the target sample size and (5) the statistical testing method and (6) for continuous outcomes, the standard deviation of the measurements.

3- The standard statistical term for average is mean.

4- Line 197: Label this section, “Statistical Analysis”.

5- Line 197: Indicate the underlying covariance structure used in the generalized linear mixed model and the criteria for selecting it.

6- Table 2: In addition to the frequency, provide the percentage female.

7- Table 2: Indicate if the underlying distribution of the data in Table 2 was checked for normality.

Reviewer #2: Reviewer's Report:

Title: Restoration of normal central pain processing following manual therapy in nonspecific chronic neck pain.

Abstract:

1. Lack of Specific Results: The abstract mentions that "an increased CPM response and attenuated TSP were found," but it does not provide specific quantitative results or effect sizes, making it difficult for readers to assess the significance of these findings.

2. Minor Associations: The abstract states that "only minor associations were found between normalization of TSP/CPM and measures of clinical outcome," which raises questions about the clinical significance of the observed changes in central pain processing.

3. Limited Information on Participants: It would be helpful to include some basic demographic information about the participants in the abstract to provide context for the study findings.

Introduction:

The introduction section provides valuable background information on the prevalence and challenges associated with non-specific chronic neck pain (NSCNP). However, there are some points to consider:

1. Lack of Clarity on Research Gap: While the introduction highlights the need for better understanding the mechanisms of manual therapy, it does not clearly specify the research gap or the specific questions the study aims to address.

2. Reference to Guidelines: The introduction mentions guidelines advocating exercise and manual therapy for NSCNP but does not provide specific references or citations, which could enhance the credibility of the claims.

3. Lengthy Background Information: The introduction contains extensive background information on the prevalence of neck pain, which, while informative, could be condensed for brevity.

Methods:

1. Sample Size Justification: The rationale for the sample size of 63 participants is based on the detection of a maximum difference of 10% in TSP and CPM measures, but it would be beneficial to provide more information on how this specific effect size was determined.

2. Lack of Control Group: The study lacks a control group, which makes it challenging to establish causation and attribute the observed changes solely to the manual therapy intervention.

3. Treatment Description: The methods describe the manual therapy intervention broadly but do not provide specific details about the techniques used or the treatment protocol, which limits the ability to replicate the study.

4. Statistical Analysis: While the statistical approach is mentioned, the methods could benefit from a more detailed explanation of the statistical models used and the rationale for choosing the Bayesian approach.

Results and Discussion

1. Lack of Control Group: One of the major limitations of this study is the absence of a control group. Without a control group, it is challenging to attribute the observed improvements in central pain processing and clinical outcomes solely to the manual therapy intervention. It is essential to account for the natural course of the condition and any potential placebo effects.

2. Weak Associations: The study reports very weak associations between changes in central pain processing mechanisms and clinical/psychological variables. This suggests that other factors or mechanisms might be at play in explaining the clinical improvement following manual therapy. The authors acknowledge this limitation but do not provide a more in-depth discussion on possible alternative explanations or mechanisms.

3. Methodological Differences: The authors mention methodological differences in stimulus types used in previous studies and the current study for evaluating central pain processing (TSP). However, the significance and potential implications of these differences are not discussed in detail in the Discussion section.

4. Implications for Clinical Practice: The manuscript could benefit from a more comprehensive discussion of the clinical implications of the findings. How can these results inform clinical practice, and what recommendations can be made for manual therapy in the treatment of NSCNP patients?

5. Sample Characteristics: The manuscript briefly mentions that the sample presented only mild baseline disability. This should be discussed more thoroughly, as it may have implications for the generalizability of the findings to the broader NSCNP population.

6. Limitations: The limitations section is somewhat brief. It would be beneficial to provide a more extensive discussion of the study's limitations, including the potential impact of the lack of a control group and the generalizability of the findings.

Conclusion: Authors did not written conclusion

Reviewer #3: The manuscript aims to investigate whether a 4-week manual therapy treatment restores normal central pain processing in non-specific chronic neck pain. While the topic is clinically relevant, the current manuscript requires clarity improvements to effectively convey necessary information to readers.

Language: Some sentences are lengthy and intricate, and simplifying them would enhance readability.

Title: The title could be more concise and directly convey the primary study outcome.

Abstract: It is recommended to specify the exact manual therapy techniques used in the abstract.

Introduction:

The references to previous studies in the manuscript lack specificity and detail regarding their methodologies and findings. The introduction and previous literature sections lack explicit mention of the manual therapy techniques employed in these referenced studies. Including specific details about the manual therapy techniques used in relevant studies is essential for providing context and understanding the existing body of literature. This addition would contribute to a more comprehensive and informed discussion of the background and rationale for the current study.

Method:

Inclusion/exclusion criteria should be presented in the text.

The rationale for choosing these specific techniques, their potential benefits for NSCNP, and details about why only one session was utilized need further clarification, ideally with the inclusion of figures.

The table format does not adhere to scientific writing standards, and

Include detailed information on questionnaire reliability and validity. If translated into your language, provide references for reliability and validity.

Discussion:

The discussion mainly repeats results without in-depth analysis or comparisons with previous literature. More extensive discussion on methodology, manual therapy techniques, and clinical applications is needed. The conclusion lacks clarity, and future research directions should be elaborated upon.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Sahar Boozari

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Attachment

Submitted filename: Reviewers comments for neck pain study.docx

pone.0294100.s005.docx^{(15.3KB, docx)}

PLoS One. 2024 May 23;19(5):e0294100. doi: 10.1371/journal.pone.0294100.r002

Author response to Decision Letter 0

15 Feb 2024

1. Submission requirements

1.1. PLOS ONE's style requirements

- An asterisk has been added to the corresponding author (page 1, line 3).

- Authors' complete affiliations have been included (page 1, line 7-24).

- The current address of the corresponding author has been included (page 1, line 23-24).

- The name for the picture file has been changed (submission process).

1.2. Data Availability

All necessary data to replicate the results have been uploaded as Supporting Information (submission process).

1.3. Captions for your Supporting Information files

Captions have been included for the Supporting Information files at the end of our manuscript (page 31, lines 688-695), and in-text citations have been updated accordingly.

2. Editors’ and reviewers’ comments

2.1. Title

Reviewers' comment

The title could be more concise and directly convey the primary study outcome.

Authors' response

We respectfully disagree, as we believe the current title express the primary study outcome as directly as possible. We have carefully considered replacing "central pain processing" with terms such as "central pro- and antinociceptive mechanisms" or "temporal summation and conditioned pain modulation"; however, are concerned this would come across as wordy. Nevertheless, we will be happy to amend it if the editor or reviewers consider it appropriate.

2.2. Abstract

2.2.1 Reviewers' comment

State the statistical testing methods and summary statistics or p-values to support the results.

Authors' response

Statistical testing methods (page 2-3, lines 43-46) and summary statistics (page 3, lines 47-51) were added.

2.2.2. Reviewers' comment

Lack of Specific Results: The abstract mentions that "an increased CPM response and attenuated TSP were found," but it does not provide specific quantitative results or effect sizes, making it difficult for readers to assess the significance of these findings.

Authors' response

Specific quantitative data have now been added (page 3, lines 47-51).

2.2.3. Reviewers' comment

Minor Associations: The abstract states that "only minor associations were found between normalization of TSP/CPM and measures of clinical outcome," which raises questions about the clinical significance of the observed changes in central pain processing.

Authors' response

We agree with the reviewer in that the strength of the association is weak; hence, rather than stating that the observed associations were of high clinical relevance, we stated that our data "suggests multiple mechanisms of action of manual therapy". We feel this statement is an accurate reflection of the results, in that it acknowledges some association between clinical outcome and normalization of pain processing (albeit small) but at the same time clearly states that mechanisms of manual therapy are most likely multifactorial in light of the small association we have found.

2.2.4. Reviewers' comment

Limited Information on Participants: It would be helpful to include some basic demographic information about the participants in the abstract to provide context for the study findings.

Authors' response

We have added gender and age characteristics of our sample (page 2, lines 37-38).

2.2.5. Reviewers' comment

It is recommended to specify the exact manual therapy techniques used in the abstract.

Authors' response

We have added a more detailed description of the manual therapy techniques used in the intervention (page 2, line 39).

2.3. Introduction

2.3.1. Reviewers' comment

Lack of Clarity on Research Gap: While the introduction highlights the need for better understanding the mechanisms of manual therapy, it does not clearly specify the research gap or the specific questions the study aims to address.

Authors' response

No study has so far assessed the effect of manual therapy on central pain processing mechanisms in NSCNP, and no prior study has explored associations between improvements in central pain processing and improvements in clinical status after manual therapy. Both are research gaps that our present study aims to address. We have modified the second part of the Introduction section in order to convey this issue more clearly.

2.3.2. Reviewers' comment

Reference to Guidelines: The introduction mentions guidelines advocating exercise and manual therapy for NSCNP but does not provide specific references or citations, which could enhance the credibility of the claims.

Authors' response

Additional references to guidelines have been included (4,5).

2.3.3. Reviewers' comment

Lengthy Background Information: The introduction contains extensive background information on the prevalence of neck pain, which, while informative, could be condensed for brevity.

Authors' response

We have removed the following sentence on the prevalence of neck pain; “Moreover, recurrence reaches 50-75% within the next 5 years following the first episode, (3,4) and 68% of individuals experiencing an episode of acute neck pain will become chronic neck pain sufferers(5).”

2.3.4. Reviewers' comment

Authors' response

We have included additional information and details regarding manual therapy techniques in the treatment of NSCNP (page 4, lines 68-69) and other pathologies (page 5, lines 91-92) .

2.4. Methods

2.4.1. Reviewers' comment

Line 111: Indicate the statistical method which achieves 80% power. The power calculation should include: (1) the estimated outcomes in each group; (2) the α (type I) error level; (3) the statistical power (or the β (type II) error level); (4) the target sample size and (5) the statistical testing method and (6) for continuous outcomes, the standard deviation of the measurements.

Authors' response

Further information has been added in the revised version of the manuscript.

2.4.2. Sample Size Justification: The rationale for the sample size of 63 participants is based on the detection of a maximum difference of 10% in TSP and CPM measures, but it would be beneficial to provide more information on how this specific effect size was determined.

Authors' response

We have corrected an error (it should be “minimum” rather than “maximum”) and provided further information in this regard.

2.4.3. Reviewers' comment

Lack of Control Group: The study lacks a control group, which makes it challenging to establish causation and attribute the observed changes solely to the manual therapy intervention.

Authors' response

We acknowledge that this is a limitation of the study; as such we have commented on this issue in the discussion, in a subsection named "Limitations". Since there is no previous evidence of spontaneous normalization of central pain processing in such a small period of time (4 weeks) in chronic pain patients, we consider that the effects are most likely caused by the intervention (manual therapy). Nevertheless, in light of the reviewer´s comment, we have now further commented (limitations section) on the fact that changes could be due to the natural course of the condition and the potential influence of the placebo effects.

2.4.4. Reviewers' comment

The standard statistical term for average is mean.

Authors' response

The term “average” has been replaced by "mean”.

2.4.5. Reviewers' comment

Line 197: Label this section, “Statistical Analysis”.

Authors' response

This section has been labeled as suggested.

2.4.6. Reviewers' comment

Line 197: Indicate the underlying covariance structure used in the generalized linear mixed model and the criteria for selecting it.

Authors' response

Further information has been added in the revised version of the manuscript.

2.4.7. Reviewers' comment

Treatment Description: The methods describe the manual therapy intervention broadly but do not provide specific details about the techniques used or the treatment protocol, which limits the ability to replicate the study.

Authors' response

We have provided greater details about the treatment techniques in the intervention section (pages 10-11).

2.4.8. Reviewers' comment

Statistical Analysis: While the statistical approach is mentioned, the methods could benefit from a more detailed explanation of the statistical models used and the rationale for choosing the Bayesian approach.

Authors' response

We appreciate the reviewer’s comment and the opportunity to more strongly justify our analytic approach. As stated in the original submission of the manuscript (page 10, lines 201 to 204) models present great complexity because of data variability. First, there is individual heterogeneity, which comprises unobserved invariant variables over time that are specific to each individual participant, i.e. residual confounding. Second, each subject has at least two observations (in most cases three), and such non-independence must also be controlled for.

Each observation must allow estimating three sources of variability, the parameters (i.e., the model coefficients) and the variances of the random effects (individual heterogeneity and dependence). This cannot be done using non-Bayesian methods. We have provided further information in the revised version of the manuscript (page 11).

2.4.9. Reviewers' comment

Inclusion/exclusion criteria should be presented in the text.

Authors' response

The inclusion/exclusion criteria have been added to the text (page 7, line 130-136), and the corresponding table has been removed in order to avoid replication of information.

2.4.10. Reviewers' comment

Authors' response

Patients received four 45-minute sessions of manual therapy, once a week for 4 weeks. Careful consideration was given to the type and dosage of manual therapy included in the current study. Our dosage aligns with many other studies of manual therapy (1–5) and the included interventions have previously been found effective for the treatment of patients with NSCNP (6–11). We have incorporated in the manuscript (intervention section, page 10) additional references justifying our selected approach.

2.4.11. Reviewers' comment

The table format does not adhere to scientific writing standards.

Authors' response

We thank the reviewer for bringing this to our attention. We have revised the format of all tables to ensure consistency and alignment with established scientific writing conventions.

2.4.12. Reviewers' comment

Include detailed information on questionnaire reliability and validity. If translated into your language, provide references for reliability and validity.

Authors' response

We have provided further information regarding the validity and reliability of questionnaires (pages 7-8).

2.5. Results and Discussion

2.5.1. Reviewers' comment

Table 2: In addition to the frequency, provide the percentage female.

Authors' response

The percentage female has been provided (Table 2 of the original submission is now Table 1).

2.5.3. Reviewers' comment

Table 2: Indicate if the underlying distribution of the data in Table 2 was checked for normality.

Authors' response

Although the dependent variables are continuous, the small sample size leads to the rejection of the null hypothesis of normality in all cases (Shapiro-Wilk test). However, and as a sensitivity analysis, we repeated the main analyzes using, as an alternative link function, the normal-inverse Gaussian(12). These types of models are a flexible extensions of Gaussian models because they contain the Gaussian model as a special case. Using these models, the results were practically the same.

2.5.4. Reviewers' comment

Lack of Control Group: One of the major limitations of this study is the absence of a control group. Without a control group, it is challenging to attribute the observed improvements in central pain processing and clinical outcomes solely to the manual therapy intervention. It is essential to account for the natural course of the condition and any potential placebo effects.

Authors' response

As discussed above in point 2.4.3, we acknowledge that this is a limitation of the study and comment on this in the section named “limitations”. Furthermore, in this section we have now further commented on the fact that changes could be due to the natural course of the condition and the potential influence of the placebo effects.

2.5.5. Reviewers' comment

Weak Associations: The study reports very weak associations between changes in central pain processing mechanisms and clinical/psychological variables. This suggests that other factors or mechanisms might be at play in explaining the clinical improvement following manual therapy. The authors acknowledge this limitation but do not provide a more in-depth discussion on possible alternative explanations or mechanisms.

Authors' response

In the last paragraph of the Discussion section of the present revised version we now provide two avenues to interpret this finding. Firstly, a straightforward interpretation is seeing our results as suggesting other alternative mechanisms at play. Since confirmatory evidence regarding possible mechanisms is rather limited, we can only speculate by enumerating potential mechanisms supported by little literature, which we have in the present version. Secondly, the occurrence of weak associations might be related to characteristics of the sample, which showed only mild alterations at baseline. The latter may be seen as a limitation to the study and would justify further studies in neck pain patients with a broader clinical presentation.

2.5.6. Reviewers' comment

Methodological Differences: The authors mention methodological differences in stimulus types used in previous studies and the current study for evaluating central pain processing (TSP). However, the significance and potential implications of these differences are not discussed in detail in the Discussion section.

Authors' response

We have added a more detailed discussion about the methodological differences (page 19, lines 329-338).

2.5.7. Reviewers' comment

Implications for Clinical Practice: The manuscript could benefit from a more comprehensive discussion of the clinical implications of the findings. How can these results inform clinical practice, and what recommendations can be made for manual therapy in the treatment of NSCNP patients?

Authors' response

We have delved more deeply into this topic at the end of the discussion section, however, since our study is grounded in fundamental research focused on understanding mechanisms of action of manual therapy, the possibility of making direct immediate recommendations for clinical practice are limited.

2.5.8. Reviewers' comment

Sample Characteristics: The manuscript briefly mentions that the sample presented only mild baseline disability. This should be discussed more thoroughly, as it may have implications for the generalizability of the findings to the broader NSCNP population.

Authors' response

This has been discussed in the limitations section.

2.5.9. Reviewers' comment

Limitations: The limitations section is somewhat brief. It would be beneficial to provide a more extensive discussion of the study's limitations, including the potential impact of the lack of a control group and the generalizability of the findings.

Authors' response

In addition to expanding on the limitations related to the lack of a control group, we have included a paragraph addressing the constraints on the generalizability of our results (page 21, lines 396-399).

2.5.10. Revi

PLoS One. doi: 10.1371/journal.pone.0294100.r003

Decision Letter 1

Shahnawaz Anwer

19 Mar 2024

PONE-D-23-34005R1Restoration of normal central pain processing following manual therapy in nonspecific chronic neck painPLOS ONE

Dear Dr. Zabala,

==============================

ACADEMIC EDITOR:Dear Authors!

While your revised manuscript read better, there are still some important comments raised by the reviewers. Please address all the reviewer comments carefully.

==============================

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Academic Editor

PLOS ONE

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Additional Editor Comments:

Dear Authors!

While your revised manuscript read better, there are still some important comments raised by the reviewers. Please address all the reviewer comments carefully.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: All comments have been addressed

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #1: Only one prior comment was not adequately addressed. in the sample size justification section, indicate the statistical testing METHOD which achieves 80% power.

Reviewer #2: Restoration of normal central pain processing following manual therapy in nonspecific chronic neck pain. Manuscript is written very well, methodology need more detail, study findings are very interesting There are a few points that need to be addressed. The study is good and very helpful for clinical Physical Therapy Health Professionals.

1- Abstract: Revised abstract sound good.

2- What was reason of high percentage of female participants with NSCNP, is there any reference supporting high prevalence of pain in female.

3- Methodology: Need more detailed procedure for manual therapy, like who did this procedure of mobilization, is it the same researcher, who evaluated pre-and post intervention outcomes or other, was he certified manual therapist with how many years of experience?

4- P-A mobilization with how many, thrust or oscillations in each direction.

5- Mobilization force was applied at spinous process or at transvers process, if so how did you identified or located these landmarks.

6- While giving mobilization force vertebra was stabilized for example C4-C5 vertebra there is hypomobility.

7- How did authors gave A-P mobilizations at cervical spine.

8- Please attach few pictures of manual therapy, placement of hands, direction of mobilization etc..

9- How did authors calculated sample size (63), please write formula.

10- How reliable and valid was the Questionnaire used in this study?

11- Findings are very interesting.

Thanks & Regards.

Reviewer #3: (No Response)

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Sahar Boozari

**********

Attachment

Submitted filename: Review comments for- NSCNP- manual therapy-PLOSOne.docx

pone.0294100.s006.docx^{(14.2KB, docx)}

PLoS One. 2024 May 23;19(5):e0294100. doi: 10.1371/journal.pone.0294100.r004

Author response to Decision Letter 1

9 Apr 2024

We are once again grateful for your thorough review. We are committed to implementing all of your suggestions to improve the quality of the article. Below, we provide explanations for the points raised.

Editors’ and reviewers’ comments

Reviewers' comment

In the sample size justification section, indicate the statistical testing METHOD which achieves 80% power.

Authors' response

We used the 'pwr' package, in the free statistical environment R (version 4.3.2)(1,2), based on the formula provided by Cohen:

Power=h√(n/2)-z_(1-α⁄2)

Where z_(1-α⁄2) is the normal curve α/2th percentile; h=ϕ_1-ϕ_2; and ϕ=2 arcsin⁡√p; where p denoted the proportion (i.e., p1 of the treatment group, and p2 of the treatment group).

Reviewers' comment

What was reason of high percentage of female participants with NSCNP, is there any reference supporting high prevalence of pain in female.

Authors' response

The literature consistently demonstrates a higher prevalence of neck pain among women(3–5), even emerging as a risk factor in its own right(6). Our recruitment process involved enrolling patients as they presented with neck pain at our clinic, without making any exceptions based on gender. This approach ensured that our study population closely mirrors the gender distribution observed for this condition.

Reviewers' comment

Methodology: Need more detailed procedure for manual therapy, like who did this procedure of mobilization, is it the same researcher, who evaluated pre-and post intervention outcomes or other, was he certified manual therapist with how many years of experience?

Authors' response

All treatments were administered by the same therapist, who is also the primary researcher. As indicated in the intervention section, the therapist possesses postgraduate training and over 15 years of experience in musculoskeletal physiotherapy. Evaluation of both clinical and neurophysiological outcomes was conducted by another researcher, Estibaliz Dominguez. This setup ensured that the therapist administering the treatments remained blinded to the baseline and post-treatment measures. This supplementary information has been included in the intervention section (page 11, lines 222-224).

Reviewers' comment

P-A mobilization with how many, thrust or oscillations in each direction.

Authors' response

To provide clarification regarding manual therapy passive mobilizations, we have included the following paragraph in the intervention section: “All passive mobilizations were performed using oscillatory techniques, comprising sets of 6 oscillations. The procedure continued until the hypomobile segments regained motion, or alternatively, a maximum of 4 sets was reached. The direction and intensity of the technique were determined by the clinician based on prior clinical assessment.”

Reviewers' comment

Mobilization force was applied at spinous process or at transvers process, if so how did you identified or located these landmarks.

Authors' response

We conducted mobilizations both at spinous process and transvers process, depending on the intended purpose of the technique, whether it was unilateral or bilateral. The identification of these landmarks was achieved based on the therapist anatomical and clinical expertise.

Reviewers' comment

While giving mobilization force vertebra was stabilized for example C4-C5 vertebra there is hypomobility.

Authors' response

This depended on the technique employed; in some instances, the patient's degree of flexion was utilized to stabilize one portion of the spine, while in others, the therapist's non-mobilizing hand provided stabilization. Specifically, in the case of bilateral hypomobility between C4-C5, a posterior-to-anterior mobilization in the prone position did not require specific stabilization; instead, force was applied directly to the spinous process of C4.

Reviewers' comment

How did authors gave A-P mobilizations at cervical spine.

Authors' response

This technique was performed with the patient lying supine, with the therapist accessing the transverse processes from the front of the neck and gently applying antero-posterior forces.

Reviewers' comment

Please attach few pictures of manual therapy, placement of hands, direction of mobilization etc..

Authors' response

These techniques represent a subset of those employed in the study.

Suboccipital Muscle Treatment

Upper Trapezius Myofascial Trigger Point treatment

Upslope and Downslope Mobilisation

ECOM Myofascial Trigger Point treatment

Central Posterior-Anterior Mobilisation

Unilateral Anterior-Posterior Mobilisation

Reviewers' comment

How did authors calculated sample size (63), please write formula.

Authors' response

The response to this comment has been previously addressed in point 1.1.

Reviewers' comment

How reliable and valid was the Questionnaire used in this study?

Authors' response

In this study, three questionnaires were utilized: the Neck Disability Index (NDI), the Pain Catastrophizing Scale (PCS), and the Tampa Scale of Kinesiophobia (TSK). The reliability and validity of these questionnaires are detailed in the clinical assessment section (page 7, lines 138-151).

PLoS One. doi: 10.1371/journal.pone.0294100.r005

Decision Letter 2

Shahnawaz Anwer

26 Apr 2024

Restoration of normal central pain processing following manual therapy in nonspecific chronic neck pain

PONE-D-23-34005R2

Dear Dr. Zabala,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Shahnawaz Anwer, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Authors are congratulated for their diligent work and significant revisions made based on the reviewer comments. Manuscript is significantly improved.

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0294100.r006

Acceptance letter

Shahnawaz Anwer

3 May 2024

PONE-D-23-34005R2

PLOS ONE

Dear Dr. Mata,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Checklist. CONSORT 2010 checklist of information to include when reporting a randomised trial*.

(DOC)

pone.0294100.s001.doc^{(218.5KB, doc)}

S2 Checklist. STROBE statement—Checklist of items that should be included in reports of cohort studies.

Checklist annotated according to the manuscript, “Restoration of normal central pain processing following manual therapy in nonspecific chronic neck pain“.

(DOCX)

pone.0294100.s002.docx^{(32.9KB, docx)}

S1 File

(PDF)

pone.0294100.s003.pdf^{(144.2KB, pdf)}

S1 Data

(SAV)

pone.0294100.s004.sav^{(23.1KB, sav)}

Attachment

Submitted filename: Reviewers comments for neck pain study.docx

pone.0294100.s005.docx^{(15.3KB, docx)}

Attachment

Submitted filename: Review comments for- NSCNP- manual therapy-PLOSOne.docx

pone.0294100.s006.docx^{(14.2KB, docx)}

Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

Restoration of normal central pain processing following manual therapy in nonspecific chronic neck pain

Josu Zabala Mata

Jon Jatsu Azkue

Joel E Bialosky

Marc Saez

Estíbaliz Dominguez López

Maialen Araolaza Arrieta

Ion Lascurain-Aguirrebeña

Roles

Abstract

Objective

Design

Methods

Results

Conclusion

Introduction

Methods

Participants

Clinical assessment

Psychophysical assessment

Intervention

Fig 1. Upslope and downslope mobilization.

Statistical analysis

Results

Table 1. Demographics and clinical characteristics.

Fig 2. Flow diagram.

Changes in pain processing, and clinical and psychological outcomes after treatment

Table 3. Association between changes in central pain processing mechanisms and clinical/psychological variables.

Table 2. Effect of intervention on clinical, psychological and psychophysical variables.

Association between changes in central pain processing and clinical and psychological outcomes

Discussion

Limitations

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Shahnawaz Anwer

Roles

Author response to Decision Letter 0

Decision Letter 1

Shahnawaz Anwer

Roles

Author response to Decision Letter 1

Decision Letter 2

Shahnawaz Anwer

Roles

Acceptance letter

Shahnawaz Anwer

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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