Effect of blood flow restriction training on pressure pain threshold and hand function among adults with persistent neck pain: A study protocol for a randomized controlled trial

Background Persistent neck pain is a prevalent musculoskeletal condition that affects the quality of life and functional abilities of individuals. Blood Flow Restriction Training (BFRT) is a novel therapeutic approach that involves restricting blood flow to exercising muscles to enhance strength and function. However, limited research has been conducted on the effects of BFRT on pressure pain threshold and hand function in adults with persistent neck pain. This randomized controlled trial aims to investigate the potential benefits of BFRT as a treatment intervention for this population. Methods This study will be a prospective 1:1 allocation, parallel group active controlled trail conducted at Physiotherapy Department, Galgotias University. The trial was prospectively registered with the Clinical Trial Registry India CTRI/2023/06/053439. Informed consent will be obtained from all the participants who are eligible to be included in the study. A total of 110 patients with persistent neck pain will be randomly allocated into two groups. The BFRT group will receive supervised training sessions three times a week for eight weeks, performing low-load resistance exercises with blood flow restriction applied using personalized cuff pressure. The control group will receive standard care for neck pain, which may include general advice, manual therapy, and/or home exercises without BFRT. The primary outcome measures will be the pressure pain threshold, assessed using a pressure Algometer, and hand function, evaluated using standardized tests such as Hand Grip Strength and Purdue Peg board Test. Results The data obtained will be analyzed using appropriate statistical methods, and the significance level will be set at p<0.05. Conclusion This trial will contribute valuable contribution highlighting the potential benefits of BFR training in improving pressure pain threshold and hand function in adults with persistent neck pain.


Background
Persistent neck pain is a prevalent musculoskeletal condition that affects the quality of life and functional abilities of individuals.Blood Flow Restriction Training (BFRT) is a novel therapeutic approach that involves restricting blood flow to exercising muscles to enhance strength and function.However, limited research has been conducted on the effects of BFRT on pressure pain threshold and hand function in adults with persistent neck pain.This randomized controlled trial aims to investigate the potential benefits of BFRT as a treatment intervention for this population.

Introduction
Persistent neck pain is a prevalent and debilitating condition that affects a significant number of adults worldwide. 1he burden of this condition on individuals' quality of life and productivity underscores the need for effective and innovative interventions to alleviate pain and improve functional outcomes. 2Exercise serves as the principal nonpharmacological approach to ameliorate function in musculoskeletal disorders that cause pain.Resistance training regimen for the muscles has been shown to increase pain threshold and improve function, thereby alleviating discomfort.
In order to induce muscle strength gain, the American College of Sports Medicine (ACSM) advises a resistance load of 60% to 70% of one repetition maximum (RM).At the same time, studies have reported that resistance training with increased loads leads to heightened stress levels, consequently resulting in increased pain, reduced patient adherence, and potential condition deterioration.Therefore, researchers have turned their attention towards developing a suitable resistance training program that is less taxing and more tolerable for individuals suffering with painful neck conditions.BFRT is one method that permits a pairing with low intensity resistance load while still offering the potential to generate an equivalent increase in muscular strength as the advised resistance training regimens with relatively high loads.
Beneficial physiological effects of BFRT include recruitment of type II muscle fibers and stimulation of growth hormone activity induced by partial vascular occlusion, in addition to its mechanical advantages.BFRT procedure paired with low intensity resisted exercise are proposed to cause pain modulation by exercise induced hypoalgesia (EIH) and conditioned pain modulation (CPM) pathways by activating descending pain inhibition.
Blood flow restriction (BFR) training has emerged as a promising technique that has shown potential benefits in enhancing muscular strength and promoting tissue adaptation without subjecting the body to high-intensity exercises. 3espite its applications in various musculoskeletal conditions, the potential efficacy of BFR training in managing persistent neck pain remains relatively unexplored.This study protocol aims to investigate the effect of blood flow restriction training on pressure pain threshold and hand function among adults suffering from persistent neck pain.Utilizing a randomized controlled trial design, this research seeks to provide valuable insights into the role of BFR training as a potential therapeutic option for this challenging and often refractory condition.The rationale for examining pressure pain threshold lies in its significance as a common clinical measure for assessing pain sensitivity and tolerance, particularly in musculoskeletal pain conditions. 4Understanding the impact of BFR training on pressure pain threshold will offer valuable information on the technique's ability to modulate pain perception in individuals with persistent neck pain.Additionally, assessing hand function is of paramount importance, as neck pain can often result in functional limitations that affect daily activities and work performance. 5Investigating the effects of BFR training on hand function will shed light on whether this intervention can lead to functional improvements and enhance the overall well-being of individuals experiencing neck pain.The results obtained from this research hold the potential to inform healthcare practitioners, physiotherapists, and other relevant professionals about the feasibility and effectiveness of incorporating BFR training into the management strategies for individuals with persistent neck pain.By addressing the current research gap and exploring the impact of BFR training on pressure pain threshold and hand function, this study protocol aspires to contribute to evidence-based practices in pain management and rehabilitation, ultimately enhancing the quality of life for those affected by persistent neck pain.
Objectives I. To evaluate the effect of BFRT in alleviating neck pain and improving the hand function among adults with persistent neck pain.II.To study the impact of BFRT on activities of daily living and quality of life among patients with persistent neck pain.
III.To study the long term effect of BFRT on precision and power grip among adults with persistent neck pain.

REVISED Amendments from Version 1
This version is updated with a scientific explanation of the mechanism of BFRT training and the importance of its potential therapeutic implications in neck pain conditions.Further, this version also contains scientific rationale proposing the pain modulation pathways that are effected by BFRT and how BFRT paired with low intensity resistance training shall be an potential alternative for high intensity resistance training with no compromise in improving muscle strength.
Any further responses from the reviewers can be found at the end of the article

Study design
This study will be a prospective 1:1 allocation, parallel group active controlled trail conducted at Physiotherapy Department, Galgotias University.Ethical clearance has been obtained from Departmental Ethics Committee on 19/ 05/2023 with reference number DEC/PT/GU/2023 and the trial was prospectively registered with the Clinical Trial Registry India CTRI/2023/06/053439. Informed consent will be obtained from all the participants who are eligible to be included in the study.

Null hypothesis
There is no difference between the BFRT and conventional physiotherapy group in alleviation of pain, and hand function among adults with neck pain.
Alternate hypothesis BFRT will have a significant impact in reducing pressure pain threshold and improving hand function in patients with persistent neck pain among adults.

Subjects
One hundred and ten self-reporting persistent neck pain for more than three months duration will be screened for eligibility and recruited in the study.After obtaining informed consent, the participants will be randomly allocated in 1:1 ratio to the BFR training group and the control group using a computer-generated randomization sequence.Allocation concealment will be ensured to maintain blinding and reduce potential bias.Sample size was calculated using Gpower version 3.1.9.4 for Windows by assuming effect size of 0.5(Cohen's D medium size effect was assumed) with the margin of error (α) to test the level of significance was set at 0.05 and (1-α) 80% βpower and confidence interval at 95%, the final derived sample with added 10% of contingency was n=112 6 (Figure 1).See Figure 2 for central and non-central distributions.

Eligibility criteria
Participants aged 18 and above years, both male and females, and those who self-reported non-specific neck pain for more than 3 months duration, and also present with weak power grip and/or impaired hand precision functions, and those who will be able to prospectively visit the study center will be invited to participate in the trial.

Exclusion criteria
The exclusion criteria will be patients those who have history of receiving BFRT, deformity of upper extremity, spinal deformity, unhealed injuries in spine and upper extremity, uncontrolled hypertension, history of deep vein thrombosis and medically diagnosed neurological conditions that interfere with hand function or causes pain.

Methods
Written informed consent will be obtained from all the participants who are eligible to be included in the study.The diagnosis of persistent neck pain will be made based on previous history and duration.Patients with radiating pain to shoulders or hands will be excluded.Enrolment, intervention, and assessment will be done as per the SPIRIT guideline (Table 1).Participants will be obtained from the OPD of Physiotherapy Department and from all over the university including the teaching, non-teaching staff, from camps nearby and students.Ethical clearance has been obtained from Departmental Ethics Committee on 19/05/2023 with reference number DEC/PT/GU/2023 and the Trial has been registered with Clinical Trial Registry India CTRI/2023/06/053439.All patients diagnosed with chronic neck pain and weak hand function will sign the informed consent.Demographic data, history and other data will be obtained at the baseline.The study will be done in accordance to the declaration of Helsinki. 7tervention All patients will receive standard physiotherapy care.It will include thermo therapy, neck isotonic exercises.
The Experimental group will also receive BFR with single session with 75 vol LOP 40 to 50 % for upper grip ball exercise (Light resistance) wrist curls and wrist extension using long leavers Flexibar radial and ulnar deviation.Follow up will be done for the patients on second visit after 8 weeks and long-term follow up after 6 months for others on phones who fail to come for follow up.All the patients will be explained about the possible benefits and complete procedure of the study and consent will be signed by each patient who is willing to participate in the study.They will be told its voluntary and they can withdraw anytime from the study and it won't affect their treatment if they refuse to be part of the study.Patient information will be kept confidential.Each individual will serve as self-control to report about the possible benefit in pain score after receiving BFRT and after follow up.See Table 2 for the full BFRT protocol. 8tcome measures Pressure pain threshold using Algometer Using an algometer, a portable instrument that measures pressure sensitivity at particular anatomical locations in the neck region, the pressure pain threshold (PPT) will be determined.The algometer consists of a gauge with a pressuresensing tip attached that measures applied pressure in kilopascals (kPa).Before the assessments begins, the algometer will be calibrated to ensure accuracy and consistency of measurements.Participants will be comfortably seated in an upright position with their neck muscles relaxed.It is essential to explain the procedure to the participant, ensuring they understand the assessment and can provide feedback on their pain perception.Specific anatomical points in the neck region will be chosen for the assessment.Commonly, these points include the trapezius, levator scapulae, and sternocleidomastoid muscles.The researcher will progressively apply pressure to the selected spots using the algometer.A button must be pressed to cease the pressure application or the participant must verbally report feeling pain for the pressure to increase at a constant rate (for example, 1 kPa/s).

Neck Outcome Score
The Neck Outcome Score (NOS) is a self-reported questionnaire that assesses various aspects of neck pain and its impact on daily activities and quality of life.Participants will be provided with the NOS questionnaire, and the research team will explain its purpose and how to complete it.It's important to ensure that participants understand the questions and how to score their responses accurately.The NOS typically includes questions related to pain intensity, pain-related disability, functional limitations, and the impact of neck pain on quality of life.

Grip strength using hand help dynamometer
Grip strength will be measured using a handheld dynamometer.We will ensure that the participant is well-rested and not fatigued before the measurement.We will also inform the participant about the purpose of the grip strength measurement and the procedure involved.The dynamometer will be adjusted to fit the participant's hand size.The participant will be seated on a chair without armrests, ensuring proper posture with their back straight, feet flat on the ground, and forearm resting on a flat surface.We will instruct the participant to hold the dynamometer in their dominant hand.When the participant is ready, they should be instructed to squeeze the dynamometer handle with maximum effort for about 3 to 5 seconds.The researcher can provide encouragement to the participant during the measurement to ensure they exert their maximum effort.The highest grip strength measurement achieved during the trial will be recorded.

WHO-5 quality of life index questionnaire
The WHO-5 quality of life index questionnaire is used to assess an individual's subjective well-being and quality of life.We will briefly explain the purpose of the WHO-5 questionnaire to the participant and let them know that it's designed to assess their emotional well-being and quality of life.Participants will rate their agreement with each statement on a scale from 0 to 5, where 0 indicates "at no time" and 5 indicates "all of the time".After participants have provided their responses, we can assist them in calculating their total score.A higher score on the WHO-5 indicates better emotional well-being and quality of life.

Statistical analysis
Data will be analysed using IBM Statistical Package for Social Sciences version 21 for Windows.The patient characteristics at the baseline will be presented as mean, standard deviation and proportion with 95% confidence interval.
The kolmogorov-smirnov and Shapiro Wilk test will be performed to assess the normality distribution of all the outcome scores.The student's t-test and paired t-test will be used to compare between the groups and intra group and multiple regression analysis will be done to check for any correlation or any factor influencing the outcomes of the study.

Discussion
The present study protocol presents a RCT testing the effectiveness of BFRT on pressure pain threshold and hand function among adults with persistent neck pain.The intervention aims to reduce pain and hand function by the proposed mechanism.The study intends to employ a randomized controlled trial design, ensuring scientific rigor and minimizing bias.By comparing the BFR training intervention group with a control group, researchers seek to assess the impact of this innovative technique on two primary outcomes: pressure pain threshold and hand function.Therefore, we expect that the adults with neck pain and compromised hand function in the BFRT group will exhibit improvement in terms of pain and hand function in comparison to the neck pain patients in the conventional group.The significance of this research lies in its potential to contribute valuable insights into managing neck pain and improving hand function using a novel approach like BFR training.If the results show positive effects, it could pave the way for a non-invasive, safe, and cost-effective intervention for individuals dealing with persistent neck pain.Ultimately, this study may have a meaningful impact on the quality of life for those suffering from this prevalent issue, offering hope for improved pain management and functional recovery.
Study Status: At the moment the authors are involved in training the assessors and physiotherapists those who will be involved in interventions and we are planning to start screening after one month.

Social and research benefit
The chronic neck pain may progress to cause disability and diminished quality of life.A non-invasive timely intervention may cause halting adverse effects of central sensitization in patients suffering chronic neck pain.A simple and novel intervention may be incorporated.

Yujiro Yamada
The University of Mississippi, Oxford, Mississippi, USA General Comments: The authors of the manuscript proposed the study protocol to investigate the effect of adding blood flow restriction (BFR) training to standard physiotherapy care on pressure pain threshold in the neck region and hand function in adults with persistent neck pain, using a randomized controlled trial design.I would think this study idea would add valuable insight into the literature on BFR and pain.However, I have multiple parts that are not clear in the manuscripts, especially in the protocol section.Also, there is a suggestion of using a prospective mediation analysis rather than or in addition to the multiple correlation analysis.I would like the authors to consider these

INTRODUCTION
Comments for Authors Thank you for the concise introduction.
○ "…subjecting the body to high-intensity exercises."I would avoid using "high intensity" in the context.It would be rather suitable to use "high-load" since high intensity could also refer to how much "effort" the individuals put in during the exercise (Steele 2014, [Ref 1]).For instance, performing the "lowload resistance exercise" can be a "high-effort" exercise when the exercise is taken near or to momentary failure.please report the number of repetitions completed in each set when reporting the results in the future since some participants might not be able to complete the predetermined repetitions.For pressure, is the author progressing the pressure as well from 40 -80% AOP?Why does it say AOP but in the text it says LOP? Please be consistent throughout the manuscript.Same as rest periods…, if the author gives the range, please specify whether the rest period would be progressed to be shorter from 60 to 30 seconds or rather specify the rest period.Same comment for the exercise speed.

○ ○
"Follow up will be done for patients on the second visit after 8 weeks and long term follow up after 6 months for others on phones who fail to come for follow up" Please clarify the sentence.Please revise the second visit as a "post-training visit" to avoid confusion from readers.This reads as if the participants cannot come to the post-training visit, they will be followed up by phone after 6 months, which does not make sense to me.

○ ○
"Each individual will serve as self-control to report about the possible benefit in pain score after receiving BFR and after follow up" It is a good idea to report the participants' expectations about the intervention in both groups at baseline and post-intervention, and 6-month follow-up.But, I don't think it is correct to say "self-control" in this context.I do not understand how this variable will be used as "self-control." Please clarify what parts are supervised and unsupervised in the intervention.

○
Please give a more specific description of the anatomical points in the neck region or provide a diagram or picture for clarity.

○
For statistical analysis, the authors may consider reporting the variables as median if the variables are not normally distributed.

○
As mentioned, in the introduction, mediation analysis could give better insight into the potential relationship between the outcome variables rather than multiple correlation analysis.If the author wants to report the correlation analysis, please specify which variables will be used for the analysis.I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.
threshold and hand function among adults with persistent neck pain.There are major concerns that need to be addressed by the authors.

Abstract :
The authors don't need to mention ethical clearance in the abstract Introduction: The importance, role and mechanism of blood flow restriction training is not well highlight in this section as a therapeutic potential in neck pain and hand function 1.
Which part of the pain pathway is targeting ? 2.
The reason for choosing the blood floe restriction training to reduce pain and increase hand function is not well explained 3.

Objective :
The objective of the study must be inline with the title.The author mentioned the impact of BRT on disability.How the disability is measured ?

Methods
The determination of the diagnosis is not clear ?Who diagnosed the patients ? 1.
In table 1, the author must be explain the abbreviations 2.
Intervention : How is the author determine 1 RM? 3.
In table 2 : How is the author determine restriction form continuous or intermittent ? 4.

Are the datasets clearly presented in a useable and accessible format? Partly
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: wet cupping therapy, pain, stroke I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Introduction, objectives, and hypotheses
The rationale for evaluating BFR training for neck needs to be more explicit 1.
The authors focused more on highlighting the potential benefit of the new intervention, which could turn out to be as effective as the standard care.

2.
This is a protocol, the write-up should be presented in the future tense 3. I would also advise the authors to evaluate outcomes at 4 weeks 5.

The
Hypotheses are not well constructed and no need to add the null hypothesis in the article write-up.The heading should just read "Hypotheses" The hypotheses should indicate the comparison between the groups.

Methodology
The authors mentioned 6 months as long term, this is often considered to be intermediate term.Long-term periods typically involved 12 months or 1 year or above 1.
The authors mentioned that participants will be assigned into two groups equally but the type of randomization to achieve this equal allocation (i.e.block randomization with the block sizes) is not mentioned.

2.
Figures 1 and 2 for sample size calculations are not needed.Please consider deleting 3.
Why was the effect size of 0.50 selected?The authors have not made it clear if the primary outcome -pressure pain threshold or hand function has been used in the determination of effect size assumptions.Please clarify.

4.
The reliability of using Algometer for measuring Pressure pain threshold and a hand help dynamometer for measuring hand function should be reported 5.
I suggest the authors should also evaluate the intensity of neck pain using the Numerical Pain Rating Scale or Visual Analogue Scale.

6.
Reliability (ICC and Cronbach's alpha) and validity for the Neck Outcome Score (NOS) and WHO-5 quality of life index questionnaire should be briefly reported.

7.
Is the rationale for, and objectives of, the study clearly described?Yes

Are sufficient details of the methods provided to allow replication by others? Partly
Are the datasets clearly presented in a useable and accessible format?

Not applicable
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Musculoskeltal disorders, clinical epidemiology, cross-cultural research I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.
Figures 1 and 2 for sample size calculations are not needed.Please consider deleting 3.
Why was the effect size of 0.50 selected?The authors have not made it clear if the primary outcome -pressure pain threshold or hand function has been used in the determination of effect size assumptions.Please clarify.

4.
The reliability of using Algometer for measuring Pressure pain threshold and a hand help dynamometer for measuring hand function should be reported 5.
I suggest the authors should also evaluate the intensity of neck pain using the Numerical Pain Rating Scale or Visual Analogue Scale.

6.
Reliability (ICC and Cronbach's alpha) and validity for the Neck Outcome Score (NOS) and WHO-5 quality of life index questionnaire should be briefly reported.
2.The authors don't need to mention informed consent in the abstract 2.
3.110 patients should be written in words 3.
4.In reporting study protocol, no need to have a results section 4.
5.The conclusion should be revised for grammar.

5.
Background: Persistent neck pain is a prevalent musculoskeletal condition that affects the quality of life and functional abilities of individuals.Blood Flow Restriction Training (BFRT) is a novel therapeutic approach that involves restricting blood flow to exercising muscles to enhance strength and function.However, limited research has been conducted on the effects of BFRT on pressure pain threshold and hand function in adults with persistent neck pain.This randomized controlled trial aims to investigate the potential benefits of BFRT as a treatment intervention for this population.Methods: This study will be a prospective parallel group active controlled trail to be conducted at Physiotherapy Department, Galgotias University.Ethical clearance has been obtained from Departmental Ethics Committee on 19/05/2023 with reference number DEC/PT/GU/2023 and the Trial has been registered with Clinical Trial Registry India CTRI/2023/06/053439.One hundred and ten patients with persistent neck pain will be randomly allocated into two groups.The BFRT group will receive supervised training sessions three times a week for eight weeks, performing low-load resistance exercises with blood flow restriction applied using personalized cuff pressure.The control group will receive standard care for neck pain, which may include general advice, manual therapy, and/or home exercises without BFRT.The primary outcome measures will be the pressure pain threshold, assessed using a pressure Algometer, and hand function, evaluated using standardized tests such as Hand Grip Strength and Purdue Peg board Test.

Conclusion:
This study aims to provide significant insights into the potential advantages of BFR training for enhancing pressure pain threshold and hand function among adults experiencing persistent neck pain.

Methodology
The rationale for evaluating BFR training for neck needs to be more explicit Recent research has offered insights indicating that both low-load training until volitional fatigue and low-load blood flow restriction (BFR) training have the potential to induce muscle size gains comparable to high-load training.
The authors focused more on highlighting the potential benefit of the new intervention, which could turn out to be as effective as the standard care.Thank you for your thoughtful feedback.We appreciate your observation regarding our focus on highlighting the potential benefits of the new intervention in comparison to standard care.We acknowledge the importance of addressing this concern and will make sure to provide a more balanced discussion in our revised manuscript.We will include a more comprehensive analysis that considers the effectiveness of both the new intervention and standard care to ensure a thorough and well-rounded presentation of our findings.This is a protocol, the write-up should be presented in the future tense The results obtained from this research might hold the potential to inform healthcare practitioners, physiotherapists, and other relevant professionals about the feasibility and effectiveness of incorporating BFR training into the management strategies for individuals with persistent neck pain.

Figure 2 .
Figure 2. Plot showing central and non-central distributions.
objectives are not clearly outlined.What about the comparison between the BFR training and standard care?The authors mentioned long-term, what about short-term? 4.

1 .
The objectives are not clearly outlined.What about the comparison between the BFR training and standard care?The authors mentioned long-term, what about short-term?Revised Objectives are To evaluate the potential effect of BFRT in alleviating neck pain and improving the hand function among adults with persistent neck pain.To study the impact of BFRT on disability and quality of life among patients with persistent neck pain threshold, the Cohen's d effect of 0.5 for medium effect was used.Sample size was calculated for the variable pressure pain threshold assessed by algometer using G power version 3.1.9.4 for Windows.A priori power analysis with the assumed Cohen's d medium effect size of 0.5, with the margin of error (α) to test the level of significance, power of study (1 -β) was set at 80%, and the confidence interval at 95%.Assuming a drop out of up to 10%, a target sample of n= 112 was estimated.The reliability of using Algometer for measuring Pressure pain threshold and a hand help dynamometer for measuring hand function should be reportedThe hand-held algometer demonstrated a reliability of r 0.990[Bala J1] for average force application of 80 Newton's.and the Jamar hand-held dynamometer showed a reliability of 0.94[Bala J2] .I suggest the authors should also evaluate the intensity of neck pain using the Numerical Pain Rating Scale or Visual Analogue Scale.Since, one of the sub-domain of the Neck Outcome Score (NOOS) measure the pain intensity, we thought that would address the self-reported pain intensity.Reliability (ICC and Cronbach's alpha) and validity for the Neck Outcome Score (NOS) and WHO-5 quality of life index questionnaire should be briefly reported.The Neck Outcome score (NOOS) subscales was reported to have a good to excellent reliability (ICC 0.88 -0.95[Bala J3] ) among participants with neck pain.Further, NOOS was found to have a minimal detectable changes ranging between 1.1 and 1.9.The WHO-5 wellbeing index showed an acceptable internal consistency of 0.79 among Indian adults[Bala J4] .among the Adult Population Living in a Chronically Arsenic Affected Area of Rural West Bengal in India.Indian Journal of Public Health Research & Development.2020 Mar 1;11(3).Competing Interests: Authors declare no conflict of interest.The benefits of publishing with F1000Research: Your article is published within days, with no editorial bias • You can publish traditional articles, null/negative results, case reports, data notes and more • The peer review process is transparent and collaborative • Your article is indexed in PubMed after passing peer review • Dedicated customer support at every stage • For pre-submission enquiries, contact research@f1000.com
If so, the authors could propose to perform mediation analysis, which tests whether the improvement in grip strength occurs through the potential greater pain reduction in BFR training than in standard care.Different from the correlation analysis, this mediation analysis can test the causal relationship by using the rigorous linear regression approach.You might consider this approach and this paper as guidance(Valente MJ, et.al., 2017 [Ref 3]) Only at the first visit?Table 2 will leave me with many questions about the exercise protocol.This table is very similar to Table 1 of Patterson et al. 2019, which is the guideline paper for BFR.Please be specific about the protocol.The load, 20 -40% 1RM: Does it mean the exercise is going to be progressive from 20 -40% 1RM?If so, how would the load be progressed (like a 5% increase every other week?).The cuff size: Which cuff would the author use for the exercise, small, medium, or large cuff?The length can differ depending on the size of the participants; however, the cuff width should be consistent since it affects the arterial occlusion pressure and possible discomfort.Repetitions & pressure: ○ ○ "Despite its application in various musculoskeletal conditions" This sentence acknowledges that there are studies examining the effect of BFR training on pain reduction; however, it is unclear whether BFR training worked for these conditions and no citation was provided.For instance, a review article summarized the acute and chronic effects of BFR exercise on pain reduction, and some included studies showed the greater pain-reducing effect of BFR training compared to high-load resistance training in adults after ACL (Song JS, et al., 2021 [Ref 2]).No need to be this paper, but please consider citing a work for this part of the sentence.○○ I am not sure I understand, but the authors noted that neck pain can result in functional limitations that affect daily activities and work performance.Is there any relationship between neck pain and grip strength at baseline or any evidence or physiological rationale that changing one leads to change in another?○ ○"weak power grip, impaired hand precision function" How will the authors determine "weak handgrip, impaired hand function"?Please provide reasonable inclusion criteria for the relatively weak handgrip and function for

the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? No Are the datasets clearly presented in a useable and accessible format
Steele J: Intensity; in-ten-si-ty; noun. 1. Often used ambiguously within resistance training.2. Is it time to drop the term altogether?.Br J Sports Med.2014; 48 (22): 1586-8 PubMed Abstract | Publisher Full Text 2. Song JS, Spitz RW, Yamada Y, Bell ZW, et al.: Exercise-induced hypoalgesia and pain reduction following blood flow restriction: A brief review.Phys Ther Sport.
○References1.?Not applicableCompeting Interests: No competing interests were disclosed.Reviewer Expertise: Blood flow restriction, resistance training, pressure pain threshold, blood pressure measurements, strength assessments, ultrasound muscle thickness assessment, and cognitive function assessment.