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Volume 33, Issue 2, Pages 117-124 (February 2010)


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The Relationship of the Audible Pop to Hypoalgesia Associated With High-Velocity, Low-Amplitude Thrust Manipulation: A Secondary Analysis of an Experimental Study in Pain-Free Participants

Joel E. Bialosky, PT, PhDaCorresponding Author Informationemail address, Mark D. Bishop, PT, PhDbemail address, Michael E. Robinson, PhDcemail address, Steven Z. George, PT, PhDdemail address

Received 26 March 2009; received in revised form 17 July 2009; accepted 29 July 2009.

Abstract 

Objective

High-velocity, low-amplitude (HVLA) manipulation is an effective treatment of low back pain (LBP); however, the corresponding mechanisms are undetermined. Hypoalgesia is associated with HVLA manipulation and suggests specific mechanisms of action. An audible pop (AP) is also associated with HVLA manipulation; however, the influence of the AP on the hypoalgesia associated with HVLA manipulation is not established. The purpose of the current study was to observe the influence of the AP on hypoalgesia associated with HVLA manipulation.

Methods

The current study represents a secondary analysis of 40 participants. All participants underwent thermal pain sensitivity testing to their leg and low back using protocols specific to Aδ fiber-mediated pain and temporal summation. Next, participants received HVLA manipulation to their low back, and the examiner recorded whether an AP was perceived. Finally, participants underwent immediate follow-up thermal pain sensitivity testing using the same protocols. Separate repeated-measure analyses of variance (ANOVAs) were used to observe changes in pain sensitivity before and immediately after HVLA manipulation.

Results

Hypoalgesia of Aδ fiber-mediated pain was observed in the low back after HVLA (P < .05), and this was independent of whether an AP was perceived (P > .05). Hypoalgesia of temporal summation was observed in the lower extremity after HVLA (P < .05), and this was independent of whether an AP was perceived (P = .08). However, a moderate effect size for temporal summation was observed favoring participants in whom an AP was perceived.

Conclusion

The current study suggests hypoalgesia is associated with HVLA manipulation and occurs independently of a perceived AP. Inhibition of lower extremity temporal summation may be larger in individuals in whom an AP is perceived, but further study is necessary to confirm this finding.

Article Outline

Abstract

Methods

Participants

Measures

Demographic Questionnaire

Psychologic Questionnaires

Pain Catastrophizing Scale

Fear of Pain Questionnaire-III

Anxiety Visual Analog Scale

Thermal Pain Sensitivity

Numeric Rating Scale

Aδ Fiber-Mediated Pain (First Pain)

Temporal Summation

HVLA Intervention

Statistical Analysis

Results

Aδ Fiber-Mediated Pain Perception

Lower Extremity

Low Back

Temporal Summation

Lower Extremity

Low Back

Discussion

Limitations

Conclusion

Funding Sources and Potential Conflicts of Interest

Acknowledgment

References

Copyright

High-velocity, low-amplitude (HVLA) thrust manipulation is suggested as an effective intervention in the treatment of low back pain (LBP).1, 2, 3, 4 An audible “pop” (AP) is characteristic of HVLA and may distinguish these interventions from other forms of manual therapy such as massage and mobilization. Although the AP is associated with HVLA manipulation, a consensus is currently lacking as to the clinical relevance. For example, manuscripts have been published suggesting biomechanically efficient ways to achieve the AP,5, 6 research studies have used the AP as an indication of a successfully applied HVLA manipulation,7, 8 and sham HVLA manipulation techniques have been designed based on an avoidance of the AP.9, 10 In contrast, clinical studies11, 12, 13 and a literature review14 have reported a lack of association between the AP and clinical outcomes.

Hypoalgesia, or a decrease in pain perception in response to an unchanging stimulus, is associated with HVLA manipulation.15, 16, 17, 18 For example, HVLA manipulation corresponds to an increase in pain pressure threshold15 and a decrease in pain perception to unchanging thermal stimuli.16 Hypoalgesia after HVLA manipulation is hypothesized to indicate potential neurophysiologic mechanisms of action.19, 20

Central sensitization is an exaggerated pain response characterized by allodynia (pain perception to a previously nonpainful stimulus) and hyperalgesia (heightened pain severity in response to a previously painful stimulus). High-velocity, low-amplitude is hypothesized to affect musculoskeletal pain through the alteration of changes associated with central sensitization,19 and immediate hypoalgesia may be a clinical indicator of such an effect. Temporal summation is a clinical measure of central sensitization. Specifically, temporal summation is an increase in pain perception to an unchanging repetitive, painful stimulus applied at a frequency of 3 seconds or less and is observed in both healthy individuals and, to a greater extent, in those experiencing pain conditions.21, 22 We have previously observed hypoalgesia of temporal summation after HVLA manipulation to the lumbar spine that was not observed in comparison groups riding a stationary bike or performing lumbar extension ROM exercises.16 In contrast, hypoalgesia for Aδ fiber-mediated pain perception did not differ between the 3 groups.16 Subsequently, HVLA manipulation may produce a hypoalgesic response that differs from other common rehabilitation interventions due to a specific effect on temporal summation.

The influence of the AP on immediate hypoalgesia corresponding to HVLA manipulation is not clear. Hypoalgesia represents a potential neurophysiologic mechanism behind the clinical effectiveness of HVLA manipulation. An association between hypoalgesia and an AP would suggest a greater neurophysiologic response corresponding to the AP with implications for a potential mechanism of HVLA manipulation. Therefore, the purpose of the present study was to assess the role of the AP in HVLA manipulation-associated thermal pain sensitivity to both Aδ fiber-mediated pain perception and temporal summation after HVLA manipulation. We hypothesized that the AP would not be associated with greater hypoalgesia to thermal pain perception, similar to the findings of prior studies related to clinical pain.11, 12, 13, 14

Methods 

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The current study represented a planned secondary analysis. The protocol and results of the primary study are provided in detail elsewhere.23 Briefly, in the primary study, we studied the association between expectation and changes in thermal pain sensitivity associated with HVLA manipulation in 60 healthy participants. The purpose of the primary study was to examine the influence of expectation on thermal pain sensitivity outcomes. Including the AP in our primary analysis would have required a larger sample size to ensure adequate power, and we had no specific hypotheses about the interaction between the AP and expectation. In addition, we would have had less control over balance of the groups due to the unpredictability of achieving an AP. Subsequently, we tracked the AP in the primary study for the express purpose of performing a secondary analysis. In the primary study, a negative treatment effect was observed in one of our intervention groups. Therefore, the current analysis only included participants in the 2 remaining intervention groups in whom a treatment effect was not observed (n = 40).

Participants 

The University of Florida Institutional Review Board (Gainesville, Fla) approved the current study. A sample of convenience was recruited from the University of Florida Health Science Center community by flyer and word of mouth. Potential participants were screened for appropriateness by a study representative and those wishing to participate signed an informed consent form. Inclusion criterion was age 18 to 60 and exclusion criteria were non-English speaking, systemic medical conditions (eg, diabetes, hypertension), current use of psychiatric medication, pregnancy, regular use of prescription medication for management of pain, presently experiencing LBP, or history of surgery to the low back.

Measures 

Demographic Questionnaire 

Participants completed a demographic questionnaire regarding age, sex, race, education, and history of LBP.

Psychologic Questionnaires 

Psychologic questionnaires specific to pain catastrophizing, fear of pain, and anxiety were included due to a known influences on experimental pain.24, 25, 26, 27 We chose to evaluate for baseline group differences in these factors to account for potential confounders that could affect reporting of thermal pain sensitivity.

Pain Catastrophizing Scale 

The Pain Catastrophizing Scale consists of 13 items specific to individual coping styles with pain that are each quantified with a 5-point ordinal scale. Higher scores indicate greater levels of catastrophizing. The score may be taken as a whole or as individual factors of rumination, helplessness, and magnification. Prior studies have validated the factor structure and found good internal consistency reliability and validity of the Pain Catastrophizing Scale.25,28, 29, 30

Fear of Pain Questionnaire-III 

The Fear of Pain Questionnaire-III31 consists of 30 items, each scored on a 5-point adjectival scale, which measures fear of normally painful situations. Higher scores indicate greater pain-related fear. The Fear of Pain Questionnaire has demonstrated sound psychometric properties in both experimental and clinical pain studies.26, 31, 32

Anxiety Visual Analog Scale 

Anxiety was measured through a 10-cm visual analog scale. Participants were asked to indicate along the visual analog scale anchored with none and most severe anxiety imaginable the amount of anxiety they were currently feeling regarding the experimental pain task they were about to experience. Visual analog scales have been used to measure anxiety in other studies and have demonstrated sound psychometric properties.33, 34, 35, 36

Thermal Pain Sensitivity 

Thermal pain sensitivity testing was performed using the Medoc Neurosensory Analyzer (TSA-2001, Ramat Yishai, Israel) with handheld peltier-element-based stimulator. We included previously established protocols biased toward Aδ fiber-mediated pathways and temporal summations.21, 37 Participants first underwent a practice session to familiarize themselves with the pain testing protocol immediately followed by the full QST.

Numeric Rating Scale 

Numeric rating scales (NRSs) were used as a measure of evoked thermal pain sensitivity. Participants were asked to quantify any evoked pain using a NRS anchored by “0” (no pain at all) and “100” (worst imaginable pain). The NRS is frequently used as a measure of both clinical and experimental pain and has demonstrated sound psychometric properties in previous studies.38, 39, 40, 41

Aδ Fiber-Mediated Pain (First Pain) 

Aδ fiber-mediated pain was assessed in the nondominant posterior calf and adjacent to the nondominant posterior-superior iliac spine through the application of heat pulses of 3-second duration. The baseline temperature of the thermode was 35°C and rose at a rate of 10°C/s to 47°C or 49°C. All participants received pulses of both 47°C and 49°C in a random order. The research assistant recorded NRS ratings of pain intensity for each heat pulse. Participants were asked to rate their “first” pain intensity felt, believed to be primarily mediated by input from Aδ fibers.21, 37 Participants underwent the protocol 2 times at each anatomical site waiting 60 seconds between trials. Pain sensitivity scores in response to both the 47°C and 49°C heat pulses were pooled, and the average NRS rating of the combined temperatures in both the low back and the lower extremity served as the measure of pain sensitivity at each location.

Temporal Summation 

Temporal summation was assessed in the nondominant plantar surface of the foot and the nondominant posterior-superior iliac spine following a previously established protocol.21, 37 A train of 10 consecutive heat pulses of less than 1-second duration at an interstimulus frequently of .33 Hz (temporal summation) was applied with a baseline temperature of 35°C and peak temperature of 51°C. Participants were asked to rate their delayed (second) pain using an NRS, and the average of the first 5 pulses served as the measure of pain perception.

HVLA Intervention 

The HVLA technique has been shown to be effective in the treatment of LBP in participants meeting a clinical prediction rule.7, 8 Similar to the protocol used in a prior study,16 we performed the technique (Fig 1) 2 times on each side, regardless, of whether an AP was perceived. Immediately after the HVLA manipulation, the researcher marked on an intake form whether an AP had occurred during any of the thrusts. The determination of an AP having occurred was based upon the researcher's perception of either having felt or heard an AP during the application of the technique. This method of identifying an AP has been reported as valid.42 After the application of the HVLA manipulation, the same quantitative sensory testing protocol was performed.


View full-size image.

Fig 1. High-velocity, low-amplitude thrust technique used in this study. Reprinted from Cibulka MT. The treatment of the sacroiliac joint component to low back pain: a case report. Phys Ther. 1992;72:917-922, with the permission of the American Physical Therapy Association. This material is copyrighted, and any further reproduction or distribution is prohibited.


Statistical Analysis 

Descriptive statistics were generated for continuous and categorical measures. Univariate ANOVA was used to assess differences in continuous variables of demographic, psychologic, and baseline thermal testing measures between participants in whom an AP was perceived and those in whom an AP was not perceived. χ2 analysis was used to assess differences in categorical demographic variables between participants in whom an AP was perceived and those in whom an AP was not perceived. We assessed baseline measures to account for differences in potential confounding variables between individuals in whom an AP was perceived and those in whom one was not.

To assess the influence of the AP on pain perception after HVLA manipulation, we performed separate 2 × 2 repeated measure ANOVAs for each of the pain protocols (Aδ and temporal summation) at each anatomical location (lower extremity and low back). The AP status (perceived or not perceived) served as the between subject factor and time of thermal pain sensitivity assessment (pre to post-HVLA) as the within subject factor. α levels were set at .05, and all analysis were performed using the SPSS statistical package version 16.0 (SPSS Inc, Chicago, IL).

Results 

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Forty participants were included in this analysis. Baseline demographic, thermal pain threshold, and psychologic variables did not differ by participants on AP status, with the exception of those in whom an AP was perceived having less education (Table 1).

Table 1.

Baseline measures of demographics, thermal pain threshold, and psychologic variables comparing participants in whom an AP was perceived and not perceived

AP
No AP
Total sample
P
Sex
Male549
Female131831.47
Age, y (SD)22.17 (1.72)23.73 (3.37)23.03 (2.83).08
Race
White141832
African American202
Other246.34
Education, y (SD)15.67 (1.14)16.67 (1.46)16.21 (1.40).02
History of LBP
Yes538
No121729.52
Threshold pain temperature (SD)43.41 (2.53)42.13 (5.17)42.70 (4.20).35
Threshold pain rating (NRS [SD])15.1 (13.6)18.1 (19.0)16.8 (16.6).57
Psychologic questionnaires
PCS (SD)16.44 (8.49)14.05 (10.08)16.22 (9.29).90
PQ (SD)78.11 (19.07)75.50 (15.66)76.68 (17.10).64
Anxiety VAS (SD)19.11 (19.12)25.52 (21.93)22.56 (20.67).34

NRS indicates numeric rating scale from 0 = no pain at all to 100 = the worst pain imaginable; PCS, Pain Catastrophizing Scale; FPQ, Fear of Pain Questionnaire; VAS, visual analog scale from 0 = none at all to 100 = worst imaginable.

Aδ Fiber-Mediated Pain Perception 

Lower Extremity 

Neither a significant group (AP perceived vs AP not perceived) by time (pre to post-HVLA) interaction (F(1,38) = 0.97; P = .33; partial η2 = 0.03) nor a main treatment effect for time (F(1,38) = 0.50; P = .48; partial η2 = 0.01) were observed in the lower extremity of participants for Aδ fiber-mediated pain perception (Table 2; Fig 2).

Table 2.

Summary of comparison of within group and between group changes in Aδ fiber-mediated pain sensitivity

Pre
Post
Mean difference
95% confidence interval
Effect size (Cohen's d)
Within group comparisons
Low back
AP35.7 (20.4)30.1 (17.0)5.6 (11.0)0.1 to 11.1a0.30
No AP36.5 (20.4)29.9 (22.3)6.6 (12.3)1.1 to 12.1a0.31
Lower extremity
AP31.1 (19.4)28.3 (17.0)2.8 (11.7)−1.4 to 7.10.15
No AP31.7 (22.1)32.2 (26.1)−0.5 (12.0)−5.8 to 4.8−0.02
Between group comparisons (change scores)
Low back
AP × no AP −1.0 (11.3)−6.5 to 8.6−0.09
Lower extremity
AP × no AP 3.3 (10.3)−10.1 to 3.50.32

Pain sensitivity assessed with 101-point NRS anchored with 0 = no pain and 100 = worst pain sensation imaginable. All findings are presented in mean (SD).

a

Significant at P < .05.


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Fig 2. Pain perception to Aδ fiber-mediated pain. Pre to post-HVLA thrust manipulation change in self-report of pain to standard thermal stimuli. Positive numbers on the y-axis indicate hypoalgesia, whereas negative numbers indicate hyperalgesia. NRS indicates numeric rating scale anchored with 0 = no pain at all and 100 = worst pain imaginable. Error bars indicate 1 SEM.


Low Back 

No significant group (AP perceived vs AP not perceived) by time (pre to post-HVLA) interaction was observed in the low back (F(1,38) = 0.07; P = .79; partial η2 < 0.01) for Aδ fiber-mediated pain perception. Conversely, a significant main treatment effect for time was present (F(1,38) = 10.67; P < .01; partial η2 = 0.22). These findings corresponded to a mean hypoalgesia of 6.2 and Cohen's d = 0.30.

Temporal Summation 

Lower Extremity 

A significant group (AP perceived vs AP not perceived) by time (pre to post-HVLA) interaction was neared (F(1,38) = 3.35; P = .08; partial η2 = 0.08) favoring the participants in whom an AP was perceived. A significant main effect for time was observed suggesting hypoalgesia to temporal summation occurred regardless of whether an AP was perceived (F(1,38) = 15.12; P < .01; partial η2 = 0.29). This finding corresponded to a mean hypoalgesia of 6.2 and Cohen's d = 0.26 (Table 3; Fig 3).

Table 3.

Summary of comparison of within group and between group changes in temporal summation

Pre
Post
Mean difference
95% confidence interval
Effect size (Cohen's d)
Within group comparisons
Low back
AP47.9 (24.0)44.1 (22.1)3.7 (9.5)−1.0 to 8.50.16
No AP51.0 (27.2)48.8 (25.9)2.2 (13.8)−3.9 to 8.40.08
Lower extremity
AP35.3 (23.6)25.8 (19.4)9.5 (11.7)3.6 to 15.3a0.44
No AP33.8 (26.4)30.4 (26.9)3.4 (9.3)−0.7 to 7.50.13
Between group comparisons (change scores)
Low back
AP × no AP 1.5 (11.8)−9.2 to 6.30.13
Lower extremity
AP × no AP 6.1 (10.2)−12.8 to 0.60.60

Pain sensitivity assessed with 101-point NRS anchored with 0 = no pain and 100 = worst pain sensation imaginable. All findings are presented in mean (SD).

a

Significant at P < .05.


View full-size image.

Fig 3. Change in temporal summation. Pre to post-HVLA thrust manipulation change in self-report of pain to standard thermal stimuli. Positive numbers on the y-axis indicate hypoalgesia. NRS indicates numeric rating scale anchored with 0 = no pain at all and 100 = worst pain imaginable. Error bars indicate 1 SEM.


Low Back 

Neither a group (AP perceived vs AP not perceived) by time (pre to post-HVLA) interaction (F(1,38) = 0.15; P = .70; partial η2 < 0.01) nor a main treatment effect for time were observed in the low back for the temporal summation pain protocol (F(1,38) = 2.43; P = .13; partial η2 = 0.06).

Discussion 

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Central sensitization is characterized by allodynia and hyperalgesia. Clinical signs of central sensitization have been observed in individuals experiencing LBP.43, 44, 45 For example, generalized hyperalgesia44 and lower pain thresholds and greater cortical activation in response to evoked pain45 have been observed in individuals with chronic LBP in comparison to healthy controls. Central sensitization is theorized as instrumental in the progression of acute pain to chronic pain and in the maintenance of chronic pain.46, 47, 48 Subsequently, interventions effective in altering central sensitization may be particularly beneficial in the treatment of LBP. Similar to prior studies,15, 16, 17 we observed hypoalgesia associated with HVLA manipulation suggestive of a mechanism of action upon central sensitization of pain; however, this finding was independent of whether an AP was recorded by the practitioner. These findings are similar to prior studies observing the lack of an association between the AP and the clinical effectiveness11, 12, 13 or mechanisms of HVLA manipulation.49 Our findings suggest that HVLA manipulation is associated with hypoalgesia to Aδ fiber-mediated pain and temporal summation regardless of whether an AP is perceived.

Interestingly, a trend of moderate magnitude was observed suggesting greater hypoalgesia to temporal summation in the lower extremity in individuals in whom an AP was perceived. Prior mechanistic studies have not consistently supported a relationship between neurophysiologic effects and the AP. For example, Herzog et al49 observed electromyogram responses associated with high-velocity spinal manipulative treatments that occurred independently of an AP. Conversely, Teodorczyk-Injeyan et al9 observed a reduction of proinflammatory cytokine secretion in participants receiving HVLA manipulation with an AP in comparison to those without an AP. In a separate study, Teodorczyk-Injeyan et al10 observed staphylococcal protein A induced secretion of immunoregulatory cytokine interleukin-2 increased significantly after HVLA manipulation regardless of whether an AP was perceived. However, a trend was observed for 2 hours for a reduction of this finding in participants in whom an AP was not observed in comparison to those in whom AP was observed. Similar to Teodorczyk-Injeyan et al,9, 10 our findings suggest neurophysiologic effects corresponding with HVLA manipulation may be of a greater magnitude when associated with an AP. We have previously observed greater hypoalgesia to temporal summation in healthy participants receiving HVLA manipulation in comparison to those performing lumbar extension exercises or riding a stationary bike.16 These findings suggest a mechanism of action related to hypoalgesia of temporal summation at the dorsal horn of the spinal cord and specific to HVLA manipulation. The present study suggests this specific potential mechanism of HVLA manipulation may be magnified in individuals in whom an AP is perceived.

Clinically, HVLA manipulation is frequently applied with a biomechanical emphasis. For example, a misaligned or hypomobile segment is identified through careful examination and then a specific HVLA manipulation is applied to correct the noted fault. A number of inconsistencies are related to this method of clinical practice. Specifically, the biomechanical examination is unreliable,50, 51 techniques are not specific to a targeted vertebral level,52, 53, 54 and lasting positional changes are not obvious following the interventions.55 Despite these inconsistencies, HVLA manipulation is an effective intervention for certain types of musculoskeletal pain suggesting a mechanism of action not specific to a biomechanical effect. Neurophysiologic mechanisms are suggested as pertinent in the mechanisms behind the clinical effectiveness of HVLA manipulation and may provide a more reasonable explanation than a strictly biomechanical effect. Our findings suggest that a neurophysiologic mechanism, hypoalgesia is associated with HVLA manipulation and that this potential mechanism may be enhanced when HVLA manipulation is accompanied by an AP.

Limitations 

The present study included only participants who were pain-free and experience evoked pain of a relatively brief duration. We are uncertain if similar findings would have occurred in participants experiencing LBP because response to the AP may be different in a clinical sample of individual experiencing LBP. We used protocols that are currently considered to discriminate between Aδ fiber-mediated pain processes and temporal summation but do not directly measure these processes in human subjects. Therefore, our thermal pain sensitivity measures are not definitively directly linked to the development of chronic pain syndromes. Furthermore, expectation has been observed as influential in the outcomes associated with manual therapy.23, 56 We did not assess individual expectation specific to the AP, and future studies should consider this factor. We did not ask individual participants whether they perceived an AP and a prior study11 using both researcher and participant perception reported higher rates of an AP occurrence than we observed in the present study. Subsequently, a greater number of participants may have experienced an AP undetected by the study representative. Finally, our relatively low P value and moderate effect size for hypoalgesia to temporal summation in the lower extremity favoring participants in whom an AP was perceived suggests that we may have been underpowered to observe these differences. A subsequent power analysis indicated that we would have required 35 participants in each group to observe significant group differences at P < .05 with β more than .80 at a similar effect size. Subsequently, future studies should attempt to replicate our findings in a larger sample.

Conclusion 

return to Article Outline

Hypoalgesia to thermal pain was observed in pain-free participants regardless of whether an AP was perceived. A trend was observed for a greater magnitude of hypoalgesia to lower extremity temporal summation in participants in whom an AP was perceived, but future research is necessary to confirm this finding.

Practical Applications 

return to Article Outline


An AP is associated with HVLA manipulation; however, the clinical and mechanistic relevance of the pop is not known.

We observed HVLA manipulation-related hypoalgesia to thermal pain sensitivity, and this finding was not dependent upon the presence of a pop.

Funding Sources and Potential Conflicts of Interest 

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The project was supported by grant no. R-21 AT002796-01 from the National Institutes of Health—National Center for Complimentary and Alternative Medicine (SZG, MDB, MER). JEB received support from the National Institutes of Health T-32 Neural Plasticity Research Training Fellowship (T32HD043730). No conflicts of interest were reported for this study.

Acknowledgment 

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The authors thank Valdora Martelli, Lauren Gates, and Josh Barabas who assisted with the data collection for this study.

References 

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a Clinical Assistant Professor, University of Florida Department of Physical Therapy, Gainesville, Fla

b Assistant Professor, University of Florida Department of Physical Therapy, Gainesville, Fla

c Professor, University of Florida Department of Clinical and Health Psychology, Gainesville, Fla

d Assistant Professor, University of Florida Department of Physical Therapy, Gainesville, Fla

Corresponding Author InformationSubmit requests for reprints to: Joel E. Bialosky, PT, PhD, Clinical Assistant Professor, University of Florida Department of Physical Therapy, P.O. Box 100154, Gainesville, FL 32610

 The project was supported by grant no. R-21 AT002796-01 from the National Institutes of Health—National Center for Complimentary and Alternative Medicine (SZG, MDB, MER).

 JEB received support from the National Institutes of Health T-32 Neural Plasticity Research Training Fellowship (T32HD043730)

PII: S0161-4754(09)00320-0

doi:10.1016/j.jmpt.2009.12.008


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