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Contents lists available at ScienceDirect
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Experimentally induced central sensitization in the cervical spine evokes postural stiffening strategies in healthy young adults Andrew H. Huntley *, John Z. Srbely, John L. Zettel Human Health and Nutritional Sciences, University of Guelph, Canada
A R T I C L E I N F O
A B S T R A C T
Article history: Received 6 June 2014 Received in revised form 26 November 2014 Accepted 16 January 2015
Dysequilibrium of cervicogenic origin can result from pain and injury to cervical paraspinal tissues postwhiplash; however, the specific physiological mechanisms still remain unclear. Central sensitization is a neuradaptive process which has been clinically associated with conditions of chronic pain and hypersensitivity. Strong links have been demonstrated between pain hypersensitivity and postural deficits post-whiplash; however, the precise mechanisms are still poorly understood. The purpose of this study was to explore the mechanisms of cervicogenic disequilibrium by investigating the effect of experimentally induced central sensitization in the cervical spine on postural stability in young healthy adults. Sixteen healthy young adults (7 males (22.6 1.13 years) and 9 females (22 2.69 years)) performed 30-s full-tandem stance trials on an AMTI force plate under normal and centrally sensitized conditions. The primary outcome variables included the standard deviation of the center of pressure (COP) position in medio–lateral (M–L) and antero–posterior (A–P) directions; sway range of the COP in M–L and A–P directions and the mean power frequency (MPF) of the COP and horizontal ground shear forces. Variability and sway range of the COP decreased with experimental induction of central sensitization, accompanied by an increase in MPF of COP displacement in both M–L and A–P directions, suggesting an increase in postural stiffening post-sensitization versus non-sensitized controls. Future studies need to further explore this relationship in clinical (whiplash, chronic pain) populations. ß 2015 Published by Elsevier B.V.
Keywords: Balance Cervicogenic dysequilibrium Central sensitization Pain
1. Introduction Balance disorders are an extremely common and significant health concern in older adults. These disorders are reported in 30% of people over 65 years and are the most common presenting complaint in patients over 75 years of age [1]. Balance disorders have a significant impact on the health delivery system, accounting for 39% of falls in the elderly and eight million primary care visits in the United States annually [1]. Dizziness and vertigo are the two most common balance disorders encountered in primary care [2]. While both similarly characterized by disequilibrium, dizziness is defined as a lightheadedness or unsteadiness whereas vertigo is considered a subgroup of dizziness defined as the perception of spinning or rotation of either the subject or environment [3]. Dysequilibrium
* Corresponding author at: Human Health and Nutritional Sciences, University of Guelph, 50 Stone Road East, Guelph, Ontario N1G 2W1, Canada. Tel.: +1 519 824 4120x58359. E-mail address: [email protected] (A.H. Huntley).
of cervicogenic origin is defined as vertigo or dizziness that results from disorders of the cervical spine [4]. Somatosensory information from the cervical spine and associated paraspinal tissues is integrated with both vestibular and visual afferents to determine spatial orientation of the head with respect to the body and its environment [5]. Previous research demonstrates that pain and injury to cervical paraspinal tissues, particularly upper cervical/ suboccipital spine, can significantly alter proprioceptive inputs to affect balance [4], however, the underlying physiological mechanisms are still poorly understood. Central sensitization is a neuradaptive process characterized by an increasing input response profile of second order neurons [6]. It is clinically associated with a number of persistent chronic pain hypersensitivity conditions including whiplash [7] and myofascial pain [8]. In particular, a strong clinical association between pain hypersensitivity, postural control deficits [9] and neurological symptoms (eye movement control, blurred vision, gaze stability) has been observed post-whiplash [10]; however, the causal relationship between these clinical manifestations is still unclear. The purpose of this study was to explore potential mechanisms of cervicogenic dysequilibrium by investigating the impact of
http://dx.doi.org/10.1016/j.gaitpost.2015.01.017 0966-6362/ß 2015 Published by Elsevier B.V.
Please cite this article in press as: Huntley AH, et al. Experimentally induced central sensitization in the cervical spine evokes postural stiffening strategies in healthy young adults. Gait Posture (2015), http://dx.doi.org/10.1016/j.gaitpost.2015.01.017
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central sensitization on quiet standing balance in young healthy subjects. This study investigated the hypothesis that experimentally evoking central sensitization within the cervical spinal segments will decrease frontal plane postural stability during quiet, full tandem standing balance in young healthy subjects. A link between the neuradaptive phenomenon of central sensitization and chronic pain and inflammation has been previously established in the literature [8]; we hypothesize that persistent pain and inflammation in injured cervical spinal tissues may be the underlying physiological basis for the modulation of proprioceptive input leading to cervicogenic dysequilibrium. This study is the first to experimentally investigate the causal relationship between the experimental induction of central sensitization and cervicogenic dysequilibrium in humans, aiming to enhance our understanding of the physiologic mechanisms of cervicogenic dysequilibrium and informing future research in the advancement of targeted therapeutic approaches for balance disorders of cervicogenic origin. 2. Methods This single-subject design study was approved by the Research Ethics Board at the University of Guelph and was conducted according to the ethical principles for medical research involving human subjects as set out by the Declaration of Helsinki (2008). Each participant provided written informed consent and no one withdrew from the study. 2.1. Participants A total of sixteen healthy young adults (7 males (22.6 1.13 years) and 9 females (22 2.69 years)) were randomly recruited from the student population at the University of Guelph. All subjects were screened prior to testing to exclude pre-existing neurological, musculoskeletal, cardiovascular and/or visual conditions that may impact normal somatosensory processing and balance. Participants were required to be free of pain during testing.
Fig. 1. (A) Anatomic boundaries of topical capsaicin (5 mL) applied to the C3–C7 dermatomes. Dashed lines indicate the superior boundary of the occiput, inferior boundary of the transverse line connecting the acromioclavicular joints bilaterally, and lateral boundaries of the sternocleidomastoid muscle. (B) Pain score reported from subjects, both prior and post application of topical capsaicin. The y-axis represents the 11-point pain scale in arbitrary units, while the x-axis represents the time (min) pain was recorded.
2.2. Protocol Participants executed the balance task by standing on a force plate (AMTI ACG, Watertown, MA, USA) as still as possible while in full tandem stance (left foot forward) with eyes closed for 30 s. A trace of the feet in tandem stance was made, thus allowing consistent foot placement between trials. Participants held their arms to their sides and were instructed not to use their arms to aid with postural control during the trials. Prior to data collection, the balance task was practiced by the subject three times. Actual trials began with the adoption of the tandem stance and eyes closed; collection began after the participant verbally confirmed their readiness. We employed the Heat-Capsaicin technique to evoke pain and sensitization within the targeted cervical spinal segments [11]. Test subjects received 5 mL of topical capsaicin cream (Zostrix, 0.075%; Hi-Tech Pharmacal, Amityville, NY, USA) to the C3–C7 dermatomes (Fig. 1A) which is anatomically bordered by the occiput superiorly, laterally by the sternocleidomastoid muscle and inferiorly by a transverse line connecting the acromioclavicular joints bilaterally. Prior to capsaicin application, the skin region was warmed for 10 min using moist towels maintained at 40 8C in a temperature controlled water bath. The cream was applied using latex gloves until completely absorbed. Standing balance trials were performed at 5-min intervals up to 30 min post-intervention. Three control trials were performed prior to the pain trials, with all trials done on the same day. The trials were non-fatiguing, and 1 min seated breaks were provided between control trials (along with the 5 min
rest period between pain trials) to minimize fatigue. A total of 9 trials were completed by each subject. Pain was self-reported by participants at the end of every trial using the 11 point pain scale [12], with 0 being no pain and 10 being the worst pain. We validated the presence of central sensitization using dynamic mechanical (brush allodynia) testing [13]. Brush allodynia testing was conducted on the right shoulder using a small, fine paint brush. The brush was lightly applied in a small circular pattern to the skin starting at the distal end of the shoulder and slowly moving proximally. When a change (increase) in skin sensitivity was noted by the subject, that point was marked using a non-toxic marker and the distance from that point to the lateral border of capsaicin application was recorded. 2.3. Measurement and analysis Ground reaction forces were sampled at 100 Hz for the 30 s duration of the trial, then low-pass filtered at a 5 Hz cutoff with a dual pass Butterworth filter. Center of pressure (COP) was calculated using the following equation: COP M-L ¼
My Mx ; COP A-P ¼ Fz Fz
Several measures of the horizontal shear forces and COP recorded in the anterior–posterior (A–P) and medio–lateral (M–L) axes were used to quantify postural sway behavior. Primary
Please cite this article in press as: Huntley AH, et al. Experimentally induced central sensitization in the cervical spine evokes postural stiffening strategies in healthy young adults. Gait Posture (2015), http://dx.doi.org/10.1016/j.gaitpost.2015.01.017
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outcome variables include: (1) variability (standard deviation) of the COP position; (2) sway range of the COP; (3) the mean power frequency (MPF) of the COP and horizontal ground shear forces. For velocity, the COP was differentiated using the first central difference method. The COP frequency spectrum and shear forces were determined from the 30 s trial using a discrete Fourier transform, and the mean power frequency (MPF) was then calculated. As the tandem stance preferentially challenged stability in the M–L direction, analysis focused on sway measures in this axis. 2.4. Statistical analysis The data from one subject was omitted as the capsaicin cream did not induce pain (NPRS of 0.5). Measured variables, along with the pain rating and brush allodynia values, were tested for significant differences (p 0.05) between the pain and control conditions using a one-way repeated measures analysis of variance (RMANOVA). Previous research demonstrates that the pain response from topical capsaicin peaks between 15 and 20 min post-application [14]; thus, trials more than 20 min post application were not included in the RMANOVA. To ascertain whether the pain level differed at time post-application, another RMANOVA was conducted comparing the pain level at the different times (i.e. every 5 min post-application). A Tukey’s honestly significant difference test was applied to identify any differences between levels of time. Where necessary, rank transformations were used to normalize the data and/or stabilize the variance, prior to performing each ANOVA. To explore whether the magnitude of pain intensity was related to the measures of postural stability, a correlation analysis was performed to evaluate the relationship between the pain rating and measured sway variables. This was conducted by correlating the mean sway variables to mean pain rating at each pain rating collection every 5 min post application of the topical cream. All values are reported as mean and standard deviation. All statistical analysis was performed using SAS (v9.2).
3. Results Participants reported no pain in the control conditions (pain level = 0) versus an average pain score of 4.6 2.2 across all pain trials post-capsaicin (to 30 min post application). Self-reported pain peaked at 10 min post-capsaicin (5.9 1.7), as seen in Fig. 1B. The pain at 10 min post-capsaicin was significantly greater (F(5, 15) = 6.53, p < 0.0001) than that at 25 (3.7 2.2) and 30 (2.7 1.9) min, however, it was statistically equivalent to self-reported pain scores at 5 (5.7 1.7), 15 (5.4 2.1), and 20 (4.4 2.1) min. Furthermore, the pain level was significantly less at 30 min as compared to 5, 10, and 15 min post-application times. The brush allodynia score measuring change in central sensitization demonstrated significant increase from
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baseline (pre-capsaicin) after 10 min of application and remained consistent over the remaining record period (F(5, 15) = 1.69, p < 0.14), as seen in Fig. 2. Variability of the COP in the M–L axis significantly decreased (p < 0.05) in the pain (0.0078 0.0039 m) as compared to the control (0.0094 0.0044 m) trials (Fig. 3A). Likewise, M–L COP sway range decreased in the pain (0.053 0.043 m) as compared to the control (0.082 0.149 m) condition (F(1, 15) = 5.66, p = 0.02) (Fig. 3B). Furthermore, an increase in the MPF of the COP displacement between control (0.598 0.301 Hz) and pain (0.827 0.351 Hz) trials (F(1, 15) = 15.30, p = 0.0002) was seen (Fig. 3C), as well as an increase in the M–L shear force frequency (which is directly related to the acceleration of the body center of mass (COM)). The M– L shear force frequency increased from the control (1.588 0.298 Hz) to the pain (1.809 0.322 Hz) condition (F(1, 15) = 14.70, p = 0.0002) (Fig. 3D). Decreases were observed in the pain condition in A–P COP variability (F(1, 15) = 4.70, p = 0.03; 0.0088 0.0026 m) and sway range (F(1, 15) = 8.69, p = 0.004; 0.046 0.022 m) as compared to control trials (variability: 0.0095 0.0019 m; range: 0.060 0.079 m) (Fig. 4A and B, respectively). The pain condition increased the MPF of the A–P COP (F(1, 15) = 5.31, p = 0.02; 0.64 0.18 Hz) and shear force (F(1, 15) = 5.76, p = 0.02; 1.66 0.28 Hz) from the control condition (COP: 0.56 0.19 Hz; force: 1.54 0.32 Hz) (Fig. 4C and D, respectively). The correlation analysis showed significant, but weak, correlations between the sway measures and the level of reported pain, and these correlations were limited to the frequency measures. The level of pain was significantly correlated with both the COP (p = 0.001) and shear force (p = 0.0003) MPF in M–L axis, however, the Pearson correlation coefficients were relatively low for each (R2 = 0.27 and 0.30, respectively). A significant correlation also existed between the A–P COP and pain score (p = 0.003; R2 = 0.24), but the correlation only approached significance with A–P shear ground reaction force (p = 0.07; R2 = 0.15). In both axes, the COP range and standard deviation did not correlate with the level of pain (p’s > 0.20; R2 = 0.03 to 0.11).
4. Discussion The results of our study do not support our hypothesis that inducing central sensitization within the cervical spinal segments increases M–L sway and decreases stability during quiet standing balance in young healthy adults. Experimentally inducing central sensitization resulted in decreased COP variability and sway range, along with increases in the MPF of COP displacement and shear force frequencies reflecting a tightening postural strategy and increased stability. Previous literature shows increased COP variability and range is commonly observed in the elderly population which is strongly associated with an increased risk of falls [15]. While the preponderance of literature links increased variability with instability, some research has shown decreased variability may be related to postural instability [28]. Although the precise mechanisms are still poorly understood, impaired neuromuscular and postural control associated with chronic pain is believed to stem from alteration of proprioceptive input from central modulation of these inputs [5,16]. Persistent pain and inflammation associated with peripheral injury has been shown to significantly modulate central processing of peripheral afferent
Fig. 2. Brush allodynia score measured both prior and post application of topical capsaicin. The y-axis represents the allodynia score in centimeters, while the x-axis represents the time (min) that it was recorded. *Significant increase from baseline measure (p < 0.05).
Please cite this article in press as: Huntley AH, et al. Experimentally induced central sensitization in the cervical spine evokes postural stiffening strategies in healthy young adults. Gait Posture (2015), http://dx.doi.org/10.1016/j.gaitpost.2015.01.017
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Fig. 3. Effects of the application of topical capsaicin on balance variables in the M–L direction, including COP variability (m) (Panel A), COP sway range in meters (Panel B), mean power frequency (Hz) (Panel C), and shear force frequency (Hz) (Panel D). The results are separated by pre (control) and post (pain) application time. *Significant difference between pain and control trials (p < 0.05).
input. A study of stimulus-response profiles within the spinal cord demonstrated prolonged increase and intensity of dorsal horn excitability post injury, leading to significant gain/amplification of somatosensory afferent signals within dorsal horn neurons
[17]. Research has demonstrated a link between central sensitization and whiplash [10], suggesting that central sensitization may be an important underlying mechanism responsible for the constellation of symptoms. The present study is the first to
Fig. 4. Effects of application of topical capsaicin on balance variables in the A–P direction, including COP Variability (m) (Panel A), COP sway range (m) (Panel B), mean power frequency (Hz) (Panel C), and shear force frequency (Hz) (Panel D). The results are separated by pre (control) and post (pain) application time. *Significant difference between pain and control trials (p < 0.05).
Please cite this article in press as: Huntley AH, et al. Experimentally induced central sensitization in the cervical spine evokes postural stiffening strategies in healthy young adults. Gait Posture (2015), http://dx.doi.org/10.1016/j.gaitpost.2015.01.017
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investigate the causal relationship between experimental induction of central sensitization within the cervical segments and changes in quiet standing balance in humans in vivo. The ability to establish head position with respect to body and space is highly dependent upon integration of somatosensory information from the neck with vestibular and visual information [5]. The rich innervation of the cervical joints and paraspinal musculature, along with their anatomic connections to central vestibular, visual and postural control pathways, highlights the importance of cervical somatosensory input to balance and postural control [18]. Previous research reports that experimental neck muscle vibration [19] and neck extensor fatigue [20] both lead to increased body sway, while injection of local anesthetics into the deep cervical paraspinal tissues evokes vertigo, ataxia and nystagmus in humans [21]. Somatosensory input from the upper cervical segments is particularly important to balance as evidenced by the significant gait disturbances observed in animals following section [22] of the upper cervical nerve roots [18]. Dysequilibrium of cervicogenic origin has been observed in both experimentally induced and in vivo pain and/or pathology affecting the cervical spine, including those of traumatic, degenerative or mechanical origin [4]. Experimentally induced acute neck muscle pain has demonstrated the capacity to destabilize standing balance and posture in young healthy humans [23]. Similarly, subjects suffering from chronic neck pain often exhibit impaired postural control and decreased proprioceptive acuity during quiet standing trials [16] while post-whiplash patients exhibit deficits in neck proprioception and assessing neutral neck position [24]. In contrast, treatment of the cervical spine leads to significant improvements in standing balance outcomes [4]. Our findings of decreased COP variability and range may appear in direct contrast to the prevailing body of literature, however, there are several possible explanations for this. Firstly, we are the first group to investigate the immediate postural responses to experimentally induced central sensitization [14], whereas the prevalence of research in this area has studied responses to acute pain interventions. Previous research reporting increased variability and range after experimentally induced acute pain employed very brief 20 s cutaneous electrical stimulation to the trapezius muscle only during the recording of postural outcomes [23]; this study did not address central sensitization. Another study experimentally induced acute pain in the neck muscles of healthy young adults and whiplash patients by injecting hypertonic saline [25], however no change in postural stability was found in the healthy young adults, nor did they address central sensitization. Furthermore, evidence suggests that experimental acute pain of high intensity and longer duration may be necessary to adversely impact postural control [26]; our topical capsaicin (0.075%) model has been shown to evoke a mild and short-lasting sensitization response [27]. Dysequilibrium is the clinical manifestation of the integration of cervical proprioceptive input with the autonomic, vestibular and visual systems. Prior work suggests that altered cervical somatosensory input may not directly impact cervicogenic dysequilibrium; however, persistent or unresolved proprioceptive alterations may lead to secondary impairment of muscle spindles, autonomic, vestibular and/or visual systems leading to clinical manifestations of cervicogenic dysequilibrium [28]. This latency of symptom onset is highlighted clinically in whiplash patients, typically presenting symptoms of dysequilibrium 1–4 weeks post trauma [29]. In this study, we investigated the immediate (30 min) causal relationship between pain/central sensitization and changes in postural control, precluding the delayed onset adaptations typically observed in vivo. A primary limitation to this study was that we were unable to quantify the degree of sensitization evoked by the topical capsaicin
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protocol. Although we detected significant decreases in sway, we are unable to correlate postural disturbance to the degree of sensitization. Previous clinical research has established strong correlations between the severity of dizziness and pain [4], thus our results may not be extrapolated to clinical pain populations. Future research should aim to address this question in clinical trials using chronic pain populations. The results of this study demonstrate that experimentally induced central sensitization in the cervical segments decreases postural sway in normal healthy young adults. This is the first study to investigate the causal relationship between experimentally induced central sensitization within cervical spinal segments and quiet standing balance. Our study aims to contribute to the understanding of the role central sensitization may play in the pathophysiology of cervicogenic vertigo. It also provides a basis to inform future research into both the mechanisms and targeted therapeutic interventions for the treatment and management of cervicogenic vertigo. Acknowledgements The authors would like to thank Erik Prout, Serena Burkhardt, and Sarah Zammit for their assistance with data collection.
Conflict of interest The authors have no conflict of interest to disclose.
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Contents lists available at ScienceDirect
Gait & Posture journal homepage: www.elsevier.com/locate/gaitpost
Experimentally induced central sensitization in the cervical spine evokes postural stiffening strategies in healthy young adults Andrew H. Huntley *, John Z. Srbely, John L. Zettel Human Health and Nutritional Sciences, University of Guelph, Canada
A R T I C L E I N F O
A B S T R A C T
Article history: Received 6 June 2014 Received in revised form 26 November 2014 Accepted 16 January 2015
Dysequilibrium of cervicogenic origin can result from pain and injury to cervical paraspinal tissues postwhiplash; however, the specific physiological mechanisms still remain unclear. Central sensitization is a neuradaptive process which has been clinically associated with conditions of chronic pain and hypersensitivity. Strong links have been demonstrated between pain hypersensitivity and postural deficits post-whiplash; however, the precise mechanisms are still poorly understood. The purpose of this study was to explore the mechanisms of cervicogenic disequilibrium by investigating the effect of experimentally induced central sensitization in the cervical spine on postural stability in young healthy adults. Sixteen healthy young adults (7 males (22.6 1.13 years) and 9 females (22 2.69 years)) performed 30-s full-tandem stance trials on an AMTI force plate under normal and centrally sensitized conditions. The primary outcome variables included the standard deviation of the center of pressure (COP) position in medio–lateral (M–L) and antero–posterior (A–P) directions; sway range of the COP in M–L and A–P directions and the mean power frequency (MPF) of the COP and horizontal ground shear forces. Variability and sway range of the COP decreased with experimental induction of central sensitization, accompanied by an increase in MPF of COP displacement in both M–L and A–P directions, suggesting an increase in postural stiffening post-sensitization versus non-sensitized controls. Future studies need to further explore this relationship in clinical (whiplash, chronic pain) populations. ß 2015 Published by Elsevier B.V.
Keywords: Balance Cervicogenic dysequilibrium Central sensitization Pain
1. Introduction Balance disorders are an extremely common and significant health concern in older adults. These disorders are reported in 30% of people over 65 years and are the most common presenting complaint in patients over 75 years of age [1]. Balance disorders have a significant impact on the health delivery system, accounting for 39% of falls in the elderly and eight million primary care visits in the United States annually [1]. Dizziness and vertigo are the two most common balance disorders encountered in primary care [2]. While both similarly characterized by disequilibrium, dizziness is defined as a lightheadedness or unsteadiness whereas vertigo is considered a subgroup of dizziness defined as the perception of spinning or rotation of either the subject or environment [3]. Dysequilibrium
* Corresponding author at: Human Health and Nutritional Sciences, University of Guelph, 50 Stone Road East, Guelph, Ontario N1G 2W1, Canada. Tel.: +1 519 824 4120x58359. E-mail address: [email protected] (A.H. Huntley).
of cervicogenic origin is defined as vertigo or dizziness that results from disorders of the cervical spine [4]. Somatosensory information from the cervical spine and associated paraspinal tissues is integrated with both vestibular and visual afferents to determine spatial orientation of the head with respect to the body and its environment [5]. Previous research demonstrates that pain and injury to cervical paraspinal tissues, particularly upper cervical/ suboccipital spine, can significantly alter proprioceptive inputs to affect balance [4], however, the underlying physiological mechanisms are still poorly understood. Central sensitization is a neuradaptive process characterized by an increasing input response profile of second order neurons [6]. It is clinically associated with a number of persistent chronic pain hypersensitivity conditions including whiplash [7] and myofascial pain [8]. In particular, a strong clinical association between pain hypersensitivity, postural control deficits [9] and neurological symptoms (eye movement control, blurred vision, gaze stability) has been observed post-whiplash [10]; however, the causal relationship between these clinical manifestations is still unclear. The purpose of this study was to explore potential mechanisms of cervicogenic dysequilibrium by investigating the impact of
http://dx.doi.org/10.1016/j.gaitpost.2015.01.017 0966-6362/ß 2015 Published by Elsevier B.V.
Please cite this article in press as: Huntley AH, et al. Experimentally induced central sensitization in the cervical spine evokes postural stiffening strategies in healthy young adults. Gait Posture (2015), http://dx.doi.org/10.1016/j.gaitpost.2015.01.017
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central sensitization on quiet standing balance in young healthy subjects. This study investigated the hypothesis that experimentally evoking central sensitization within the cervical spinal segments will decrease frontal plane postural stability during quiet, full tandem standing balance in young healthy subjects. A link between the neuradaptive phenomenon of central sensitization and chronic pain and inflammation has been previously established in the literature [8]; we hypothesize that persistent pain and inflammation in injured cervical spinal tissues may be the underlying physiological basis for the modulation of proprioceptive input leading to cervicogenic dysequilibrium. This study is the first to experimentally investigate the causal relationship between the experimental induction of central sensitization and cervicogenic dysequilibrium in humans, aiming to enhance our understanding of the physiologic mechanisms of cervicogenic dysequilibrium and informing future research in the advancement of targeted therapeutic approaches for balance disorders of cervicogenic origin. 2. Methods This single-subject design study was approved by the Research Ethics Board at the University of Guelph and was conducted according to the ethical principles for medical research involving human subjects as set out by the Declaration of Helsinki (2008). Each participant provided written informed consent and no one withdrew from the study. 2.1. Participants A total of sixteen healthy young adults (7 males (22.6 1.13 years) and 9 females (22 2.69 years)) were randomly recruited from the student population at the University of Guelph. All subjects were screened prior to testing to exclude pre-existing neurological, musculoskeletal, cardiovascular and/or visual conditions that may impact normal somatosensory processing and balance. Participants were required to be free of pain during testing.
Fig. 1. (A) Anatomic boundaries of topical capsaicin (5 mL) applied to the C3–C7 dermatomes. Dashed lines indicate the superior boundary of the occiput, inferior boundary of the transverse line connecting the acromioclavicular joints bilaterally, and lateral boundaries of the sternocleidomastoid muscle. (B) Pain score reported from subjects, both prior and post application of topical capsaicin. The y-axis represents the 11-point pain scale in arbitrary units, while the x-axis represents the time (min) pain was recorded.
2.2. Protocol Participants executed the balance task by standing on a force plate (AMTI ACG, Watertown, MA, USA) as still as possible while in full tandem stance (left foot forward) with eyes closed for 30 s. A trace of the feet in tandem stance was made, thus allowing consistent foot placement between trials. Participants held their arms to their sides and were instructed not to use their arms to aid with postural control during the trials. Prior to data collection, the balance task was practiced by the subject three times. Actual trials began with the adoption of the tandem stance and eyes closed; collection began after the participant verbally confirmed their readiness. We employed the Heat-Capsaicin technique to evoke pain and sensitization within the targeted cervical spinal segments [11]. Test subjects received 5 mL of topical capsaicin cream (Zostrix, 0.075%; Hi-Tech Pharmacal, Amityville, NY, USA) to the C3–C7 dermatomes (Fig. 1A) which is anatomically bordered by the occiput superiorly, laterally by the sternocleidomastoid muscle and inferiorly by a transverse line connecting the acromioclavicular joints bilaterally. Prior to capsaicin application, the skin region was warmed for 10 min using moist towels maintained at 40 8C in a temperature controlled water bath. The cream was applied using latex gloves until completely absorbed. Standing balance trials were performed at 5-min intervals up to 30 min post-intervention. Three control trials were performed prior to the pain trials, with all trials done on the same day. The trials were non-fatiguing, and 1 min seated breaks were provided between control trials (along with the 5 min
rest period between pain trials) to minimize fatigue. A total of 9 trials were completed by each subject. Pain was self-reported by participants at the end of every trial using the 11 point pain scale [12], with 0 being no pain and 10 being the worst pain. We validated the presence of central sensitization using dynamic mechanical (brush allodynia) testing [13]. Brush allodynia testing was conducted on the right shoulder using a small, fine paint brush. The brush was lightly applied in a small circular pattern to the skin starting at the distal end of the shoulder and slowly moving proximally. When a change (increase) in skin sensitivity was noted by the subject, that point was marked using a non-toxic marker and the distance from that point to the lateral border of capsaicin application was recorded. 2.3. Measurement and analysis Ground reaction forces were sampled at 100 Hz for the 30 s duration of the trial, then low-pass filtered at a 5 Hz cutoff with a dual pass Butterworth filter. Center of pressure (COP) was calculated using the following equation: COP M-L ¼
My Mx ; COP A-P ¼ Fz Fz
Several measures of the horizontal shear forces and COP recorded in the anterior–posterior (A–P) and medio–lateral (M–L) axes were used to quantify postural sway behavior. Primary
Please cite this article in press as: Huntley AH, et al. Experimentally induced central sensitization in the cervical spine evokes postural stiffening strategies in healthy young adults. Gait Posture (2015), http://dx.doi.org/10.1016/j.gaitpost.2015.01.017
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outcome variables include: (1) variability (standard deviation) of the COP position; (2) sway range of the COP; (3) the mean power frequency (MPF) of the COP and horizontal ground shear forces. For velocity, the COP was differentiated using the first central difference method. The COP frequency spectrum and shear forces were determined from the 30 s trial using a discrete Fourier transform, and the mean power frequency (MPF) was then calculated. As the tandem stance preferentially challenged stability in the M–L direction, analysis focused on sway measures in this axis. 2.4. Statistical analysis The data from one subject was omitted as the capsaicin cream did not induce pain (NPRS of 0.5). Measured variables, along with the pain rating and brush allodynia values, were tested for significant differences (p 0.05) between the pain and control conditions using a one-way repeated measures analysis of variance (RMANOVA). Previous research demonstrates that the pain response from topical capsaicin peaks between 15 and 20 min post-application [14]; thus, trials more than 20 min post application were not included in the RMANOVA. To ascertain whether the pain level differed at time post-application, another RMANOVA was conducted comparing the pain level at the different times (i.e. every 5 min post-application). A Tukey’s honestly significant difference test was applied to identify any differences between levels of time. Where necessary, rank transformations were used to normalize the data and/or stabilize the variance, prior to performing each ANOVA. To explore whether the magnitude of pain intensity was related to the measures of postural stability, a correlation analysis was performed to evaluate the relationship between the pain rating and measured sway variables. This was conducted by correlating the mean sway variables to mean pain rating at each pain rating collection every 5 min post application of the topical cream. All values are reported as mean and standard deviation. All statistical analysis was performed using SAS (v9.2).
3. Results Participants reported no pain in the control conditions (pain level = 0) versus an average pain score of 4.6 2.2 across all pain trials post-capsaicin (to 30 min post application). Self-reported pain peaked at 10 min post-capsaicin (5.9 1.7), as seen in Fig. 1B. The pain at 10 min post-capsaicin was significantly greater (F(5, 15) = 6.53, p < 0.0001) than that at 25 (3.7 2.2) and 30 (2.7 1.9) min, however, it was statistically equivalent to self-reported pain scores at 5 (5.7 1.7), 15 (5.4 2.1), and 20 (4.4 2.1) min. Furthermore, the pain level was significantly less at 30 min as compared to 5, 10, and 15 min post-application times. The brush allodynia score measuring change in central sensitization demonstrated significant increase from
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baseline (pre-capsaicin) after 10 min of application and remained consistent over the remaining record period (F(5, 15) = 1.69, p < 0.14), as seen in Fig. 2. Variability of the COP in the M–L axis significantly decreased (p < 0.05) in the pain (0.0078 0.0039 m) as compared to the control (0.0094 0.0044 m) trials (Fig. 3A). Likewise, M–L COP sway range decreased in the pain (0.053 0.043 m) as compared to the control (0.082 0.149 m) condition (F(1, 15) = 5.66, p = 0.02) (Fig. 3B). Furthermore, an increase in the MPF of the COP displacement between control (0.598 0.301 Hz) and pain (0.827 0.351 Hz) trials (F(1, 15) = 15.30, p = 0.0002) was seen (Fig. 3C), as well as an increase in the M–L shear force frequency (which is directly related to the acceleration of the body center of mass (COM)). The M– L shear force frequency increased from the control (1.588 0.298 Hz) to the pain (1.809 0.322 Hz) condition (F(1, 15) = 14.70, p = 0.0002) (Fig. 3D). Decreases were observed in the pain condition in A–P COP variability (F(1, 15) = 4.70, p = 0.03; 0.0088 0.0026 m) and sway range (F(1, 15) = 8.69, p = 0.004; 0.046 0.022 m) as compared to control trials (variability: 0.0095 0.0019 m; range: 0.060 0.079 m) (Fig. 4A and B, respectively). The pain condition increased the MPF of the A–P COP (F(1, 15) = 5.31, p = 0.02; 0.64 0.18 Hz) and shear force (F(1, 15) = 5.76, p = 0.02; 1.66 0.28 Hz) from the control condition (COP: 0.56 0.19 Hz; force: 1.54 0.32 Hz) (Fig. 4C and D, respectively). The correlation analysis showed significant, but weak, correlations between the sway measures and the level of reported pain, and these correlations were limited to the frequency measures. The level of pain was significantly correlated with both the COP (p = 0.001) and shear force (p = 0.0003) MPF in M–L axis, however, the Pearson correlation coefficients were relatively low for each (R2 = 0.27 and 0.30, respectively). A significant correlation also existed between the A–P COP and pain score (p = 0.003; R2 = 0.24), but the correlation only approached significance with A–P shear ground reaction force (p = 0.07; R2 = 0.15). In both axes, the COP range and standard deviation did not correlate with the level of pain (p’s > 0.20; R2 = 0.03 to 0.11).
4. Discussion The results of our study do not support our hypothesis that inducing central sensitization within the cervical spinal segments increases M–L sway and decreases stability during quiet standing balance in young healthy adults. Experimentally inducing central sensitization resulted in decreased COP variability and sway range, along with increases in the MPF of COP displacement and shear force frequencies reflecting a tightening postural strategy and increased stability. Previous literature shows increased COP variability and range is commonly observed in the elderly population which is strongly associated with an increased risk of falls [15]. While the preponderance of literature links increased variability with instability, some research has shown decreased variability may be related to postural instability [28]. Although the precise mechanisms are still poorly understood, impaired neuromuscular and postural control associated with chronic pain is believed to stem from alteration of proprioceptive input from central modulation of these inputs [5,16]. Persistent pain and inflammation associated with peripheral injury has been shown to significantly modulate central processing of peripheral afferent
Fig. 2. Brush allodynia score measured both prior and post application of topical capsaicin. The y-axis represents the allodynia score in centimeters, while the x-axis represents the time (min) that it was recorded. *Significant increase from baseline measure (p < 0.05).
Please cite this article in press as: Huntley AH, et al. Experimentally induced central sensitization in the cervical spine evokes postural stiffening strategies in healthy young adults. Gait Posture (2015), http://dx.doi.org/10.1016/j.gaitpost.2015.01.017
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Fig. 3. Effects of the application of topical capsaicin on balance variables in the M–L direction, including COP variability (m) (Panel A), COP sway range in meters (Panel B), mean power frequency (Hz) (Panel C), and shear force frequency (Hz) (Panel D). The results are separated by pre (control) and post (pain) application time. *Significant difference between pain and control trials (p < 0.05).
input. A study of stimulus-response profiles within the spinal cord demonstrated prolonged increase and intensity of dorsal horn excitability post injury, leading to significant gain/amplification of somatosensory afferent signals within dorsal horn neurons
[17]. Research has demonstrated a link between central sensitization and whiplash [10], suggesting that central sensitization may be an important underlying mechanism responsible for the constellation of symptoms. The present study is the first to
Fig. 4. Effects of application of topical capsaicin on balance variables in the A–P direction, including COP Variability (m) (Panel A), COP sway range (m) (Panel B), mean power frequency (Hz) (Panel C), and shear force frequency (Hz) (Panel D). The results are separated by pre (control) and post (pain) application time. *Significant difference between pain and control trials (p < 0.05).
Please cite this article in press as: Huntley AH, et al. Experimentally induced central sensitization in the cervical spine evokes postural stiffening strategies in healthy young adults. Gait Posture (2015), http://dx.doi.org/10.1016/j.gaitpost.2015.01.017
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investigate the causal relationship between experimental induction of central sensitization within the cervical segments and changes in quiet standing balance in humans in vivo. The ability to establish head position with respect to body and space is highly dependent upon integration of somatosensory information from the neck with vestibular and visual information [5]. The rich innervation of the cervical joints and paraspinal musculature, along with their anatomic connections to central vestibular, visual and postural control pathways, highlights the importance of cervical somatosensory input to balance and postural control [18]. Previous research reports that experimental neck muscle vibration [19] and neck extensor fatigue [20] both lead to increased body sway, while injection of local anesthetics into the deep cervical paraspinal tissues evokes vertigo, ataxia and nystagmus in humans [21]. Somatosensory input from the upper cervical segments is particularly important to balance as evidenced by the significant gait disturbances observed in animals following section [22] of the upper cervical nerve roots [18]. Dysequilibrium of cervicogenic origin has been observed in both experimentally induced and in vivo pain and/or pathology affecting the cervical spine, including those of traumatic, degenerative or mechanical origin [4]. Experimentally induced acute neck muscle pain has demonstrated the capacity to destabilize standing balance and posture in young healthy humans [23]. Similarly, subjects suffering from chronic neck pain often exhibit impaired postural control and decreased proprioceptive acuity during quiet standing trials [16] while post-whiplash patients exhibit deficits in neck proprioception and assessing neutral neck position [24]. In contrast, treatment of the cervical spine leads to significant improvements in standing balance outcomes [4]. Our findings of decreased COP variability and range may appear in direct contrast to the prevailing body of literature, however, there are several possible explanations for this. Firstly, we are the first group to investigate the immediate postural responses to experimentally induced central sensitization [14], whereas the prevalence of research in this area has studied responses to acute pain interventions. Previous research reporting increased variability and range after experimentally induced acute pain employed very brief 20 s cutaneous electrical stimulation to the trapezius muscle only during the recording of postural outcomes [23]; this study did not address central sensitization. Another study experimentally induced acute pain in the neck muscles of healthy young adults and whiplash patients by injecting hypertonic saline [25], however no change in postural stability was found in the healthy young adults, nor did they address central sensitization. Furthermore, evidence suggests that experimental acute pain of high intensity and longer duration may be necessary to adversely impact postural control [26]; our topical capsaicin (0.075%) model has been shown to evoke a mild and short-lasting sensitization response [27]. Dysequilibrium is the clinical manifestation of the integration of cervical proprioceptive input with the autonomic, vestibular and visual systems. Prior work suggests that altered cervical somatosensory input may not directly impact cervicogenic dysequilibrium; however, persistent or unresolved proprioceptive alterations may lead to secondary impairment of muscle spindles, autonomic, vestibular and/or visual systems leading to clinical manifestations of cervicogenic dysequilibrium [28]. This latency of symptom onset is highlighted clinically in whiplash patients, typically presenting symptoms of dysequilibrium 1–4 weeks post trauma [29]. In this study, we investigated the immediate (30 min) causal relationship between pain/central sensitization and changes in postural control, precluding the delayed onset adaptations typically observed in vivo. A primary limitation to this study was that we were unable to quantify the degree of sensitization evoked by the topical capsaicin
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protocol. Although we detected significant decreases in sway, we are unable to correlate postural disturbance to the degree of sensitization. Previous clinical research has established strong correlations between the severity of dizziness and pain [4], thus our results may not be extrapolated to clinical pain populations. Future research should aim to address this question in clinical trials using chronic pain populations. The results of this study demonstrate that experimentally induced central sensitization in the cervical segments decreases postural sway in normal healthy young adults. This is the first study to investigate the causal relationship between experimentally induced central sensitization within cervical spinal segments and quiet standing balance. Our study aims to contribute to the understanding of the role central sensitization may play in the pathophysiology of cervicogenic vertigo. It also provides a basis to inform future research into both the mechanisms and targeted therapeutic interventions for the treatment and management of cervicogenic vertigo. Acknowledgements The authors would like to thank Erik Prout, Serena Burkhardt, and Sarah Zammit for their assistance with data collection.
Conflict of interest The authors have no conflict of interest to disclose.
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