Research Review By Dr. Demetry Assimakopoulos©


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Date Posted:

February 2020

Study Title:

Evidence for Decreased Neurologic Pain Signature Activation Following Thoracic Spinal Manipulation in Healthy Volunteers and Participants with Neck Pain


Weber KA, Wager TD, Mackey S. Elliott JM, Liu W & Sparks CL

Author's Affiliations:

Systems Neuroscience and Pain Lab, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, CA, United States; Psychology and Neuroscience, Center for Neuroscience, Institute of Cognitive Science, University of Colorado Boulder, CO, United States; Northern Sydney Local Health District, The Kolling Research Institute and The Faculty of Health Sciences, The University of Sydney, NSW, Australia; Center for Collaborative Brain Research, Department of Radiology, OSF HealthCare Saint Francis Medical Center, IL, United States; Center of Expertise, Rehabilitation and Occupational Health, OSF HealthCare; School of Physical Therapy, South College, Knoxville, TN, United States.

Publication Information:

Neuroimage: Clinical 2019; 24: 102042.

Background Information:

Spinal pain is one of the leading causes of disability worldwide (1). Spinal manipulation (SMT) is a common treatment for spinal pain that is supported and endorsed by multiple clinical guidelines (2-5). The clinical rationale for SMT has long been mechanical in nature (6); however, a purely biomechanical mechanism remains debatable, as studies have failed to link specific mechanical effects to meaningful clinical improvement (7, 8). It has been theorized that SMT’s therapeutic mechanism of action may be (at least) partially mediated by functional CNS changes (9, 10).

In light of this, these authors performed a secondary analysis of two fMRI studies investigating the effect of thoracic SMT on pain-related brain activity. Using a multivariate brain-based model of physical pain called the Neurologic Pain Signature (NPS), the authors explored the effect of SMT on brain activity within brain regions predictive of physical pain (11). Therein, the authors endeavored to: 1) Introduce brain-based models of pain for spinal pain and manual therapy research; 2) characterize the distributed central mechanisms of SMT and; 3) advance the preliminary validation of brain-based models as potential clinical biomarkers of pain. They hypothesized that NPS activation and perceived pain decreases following SMT and that NPS activation will be positively correlated to pain.

Pertinent Results:

There were no dropouts or reported adverse events. Age and gender did not statistically differ between the groups. Baseline evoked pain was significantly lower for the Study 2 (neck pain) verum (true) SMT group compared to the Study 1 (healthy) verum SMT group, and Study 2 sham SMT group. This latter finding indicates that while the same stimulus intensity was used for each participant, baseline evoked pain was not matched across the groups.

Study 1: Healthy Volunteers

Evoked pain significantly decreased from 4.50 +/- 0.34 to 2.30 +/- 0.34 post-intervention. NPS activation also significantly decreased from 1760.17 +/- 201-79 to 1174.60 +/- 112.42 post-intervention. Activation within the NPS positive sub-regions (rS2_Op and dACC) significantly decreased post-intervention. NO significant changes in activation within the NPS negative sub-regions were present. NPS activation was strongly correlated to evoked pain within the NPS sub-regions showing significant changes. dACC activation was also strongly correlated to evoked pain, while rS2_Op activation tended to be moderately correlated to evoked pain.

Study 2: Neck Pain Volunteers

Evoked pain was 2.58 +/- 0.43 and 4.50 +/- 0.51 pre-intervention and 2.17 +/- 0.39 and 3.75 +/- 0.6 post-intervention for the verum (true) and sham SMT groups, respectively. Evoked pain did not significantly change in either the verum or sham SMT groups. Neck pain significantly decreased, however, from 2.08 +/- 0.63 to 0.83 +/- 0.30 post-intervention in the verum SMT group. No significant change in neck pain was identified following sham SMT. Neck pain for the sham SMT group was 2.67 +/- 0.69 and 3.00 +/- 0.62 pre- and post-intervention, respectively. NPS activation significantly decreased from 1288.95 +/- 233.84 to 890.47 +/- 166.04 post-intervention in the verum SMT group. No significant changes in NPS activation were identified in the sham group. No significant changes in activation were present within in the NPS positive sub-regions. Activation significantly decreased in the NPS positive sub-regions (rpLOC and pgACC) post-intervention. No significant changes in NPS activation within the positive or negative sub-regions were identified in the sham SMT group.

Clinical Application & Conclusions:

The authors performed a secondary analysis measuring Neurologic Pain Signature (NPS) activation based on data collected from two studies.

Study 1 was a non-controlled and non-blinded study in healthy volunteers receiving verum (true) SMT. The authors showed that evoked pain intensity, NPS activation and activation within the NPS positive sub-regions (dorsal anterior cingulate cortex [dACC] and right secondary somatosensory cortex/operculum [rS2_Op]) decreased post-intervention. Evoked pain was strongly and positively correlated to overall NPS activation and to activation within the dACC. These results support the association between SMT-induced changes in evoked pain and NPS activation in asymptomatic participants.

Study 2 utilized a controlled study design in participants with acute or subacute neck pain. Study 2 provided further evidence of decreased NPS activation following verum (true) thoracic SMT in neck pain patients, but not sham SMT. The associations between changes in NPS activation, evoked pain and neck pain in clinical populations with neck pain were not significant and less clear (Reviewer’s comment: the study was significantly underpowered; see limitations section below). These findings imply that SMT may alter pain-related brain activity within brain regions specific to the processing of physical pain, supporting a possible central mechanism to SMT.

Collectively, the findings of both studies may provide validation of the NPS as a clinical biomarker of pain.

Correction of aberrant spinal joint mechanics has been long cited by clinicians to justify utilization of SMT in practice. However, the link between biomechanical changes and clinical improvements have only been weakly supported (7, 8). To counter this, the authors cite a growing body of evidence pointing towards spinal and supraspinal neurophysiological mechanisms underlying the pain modulating effects of SMT (9, 10). The reduction in NPS activation suggests a decrease in the nociceptive information reaching supraspinal areas, perhaps by activating large diameter mechanoreceptors which inhibit nociceptive signal transmission within the spinal cord (12), or by activating descending pain inhibitory pathways (Reviewer’s note: this description is very similar to the Melzack and Wall’s Gate Theory). Still, segmental inhibition, descending inhibition and other supra-spinal processes are not yet fully understood, and exactly how these neurophysiological functions contribute to the overall therapeutic action of SMT remains unknown.

Employing methods similar to the NPS, brain-based models could be developed to predict treatment response by using experimentally evoked brain pain maps, clinical pain maps, resting state fMRI measures or any combination of these features. The predictive brain regions could provide valuable information on the neurobiological mechanisms of treatment and neurobiological state of treatment responders.

Reviewer’s comment: Melzack proposed and developed the Neuromatrix Theory over multiple decades (1970s – 2010s). The theory posits that all emotional, cognitive and sensory inputs are processed in a widespread fashion throughout the brain, leading to an output that is appropriate for the situation. One potential output is pain perception, but outputs also include stress-regulation and action programs. Given this understanding that pain perception may be an orchestrated CNS output, later groups tried to identify pain-specific areas in the brain using neuroimaging. While some pain-specific areas have been identified, these areas are small and sparsely distributed in space. Also, some of these supposedly nociceptive-specific neurons also respond to non-nociceptive inputs, such as threatening visual stimuli. Given this, some neuroimaging laboratories around the world dispute the existence of a specific “Pain Matrix” in favour of more widespread neuroimaging response reflecting a function that is crucial for all sensory systems: the ability to detect and react to salient (and possibly threatening) sensory input, leading to a behavioural change. For more information on this, check out this reference: Iannetti GD & Moureaux A. From the Neuromatrix to the Pain Matrix (and Back). Exp Brain Res 2010; 205: 1-12.

Study Methods:

The authors used de-identified datasets from two previously published fMRI studies that investigated changes in pain-related brain activity following thoracic SMT using univariate analysis (13, 14). The design of Study 1 was a non-controlled, non-blinded study in healthy volunteers receiving verum SMT only (n = 10), while Study 2 was a controlled study in participants with acute or subacute neck pain. The studies utilized the following inclusion and exclusion criteria:

Study 1 Inclusion Criteria:
  • Right-handed participants
  • No current history of pain, or orthopedic or systemic condition
Study 1 Exclusion Criteria:
  • Non-fluent in English
  • Pregnancy or possibility of pregnancy
  • Contraindications to MRI or thoracic SMT
Study 2 Inclusion Criteria:
  • Right-handed patients
  • Neck pain < 6-weeks’ duration
Study 2 Exclusion Criteria:
  • Patients not fluent in English
  • Patients with contraindications to MRI or thoracic SMT
  • Pregnant patients
  • Patients with a history of traumatic neck pain, cervical surgery, cervical radiculopathy, myelopathy, fibromyalgia, vascular disease, Raynaud’s phenomenon
  • The presence of red flags
The authors applied a noxious mechanical stimulus to the right index finger with von Frey filaments to study the effects of SMT on pain-related brain activity. In Study 1, participants underwent a pain threshold procedure on the day prior to imaging. Each von Frey stimulation lasted 5-seconds at 20-second inter-stimulus intervals. Pain threshold was identified at the least intensity at which the stimulus changed from pressure to pain. Functional imaging was performed in 5-minute runs during alternating 15-second blocks of noxious mechanical stimulation of the right index finger cuticle and no stimulation pre-and post-intervention. The stimulation protocol was designed to elicit temporal summation of second pain (TSSP), which is known to be a human analog to the animal “wind-up” phenomenon. TSSP and wind-up are theorized to be centrally mediated. Following each run, participants rated the intensity of the index finger stimulus using a 0-10 numerical pain scale (NPRS).

The authors also used the Numeric Pain Rating Scale (NPRS) in Study 2 to rate their neck pain at baseline and pre- and post-intervention. Functional imaging was performed during noxious mechanical stimulation of the right great toe pre- and post-intervention. However, since the right great toe stimulation was not performed in Study 1, these findings were not included in the present analysis. The great toe stimulation was performed in separate functional imaging runs from the index finger stimulation and the index finger stimulation runs always preceded the great toe stimulation.

Participants received a single session of either verum/true (Studies 1 and 2) or sham (Study 2) thoracic SMT immediately following the pre-intervention functional imaging. In Study 2, patients were randomly assigned to the verum or sham intervention. The verum (true) SMT intervention consisted of a high-velocity, low-amplitude, end-range force applied manually along an anterior-to-posterior vector through the elbows and to the mid-thoracic spine (15, 16). For the sham intervention, the experimenters’ hands were placed in the same position as the true intervention, only the investigator’s hands slid across the skin with the minimal pressure.

The NPS activation pre- and post-intervention was assessed using the open sourced collection of tools from the Cognitive and Affective Neuroscience Lab. NPS activation was calculated by taking the dot product of the NPS pattern weights and the stimulus parameter estimate images from each participant’s first-level analysis. Activation was then further explored in the NPS sub-regions with positive (higher predicted pain with higher activity) and negative (lower predicted pain with higher activity) predictive weights. The NPS positive sub-regions were the vermis, right mid-insula (rIns), right primary visual cortex (rV1), right thalamus (rTHal), left mid-insula (lIns), right dorsal posterior insula (rdplns), right secondary somatosensory cortex/operculum (rSQ_Op) and dorsal anterior cingulate cortex (dACC). The NPS negative sub-regions include the right lateral occipital complex (rLOC), left lateral occipital complex (ILOC), right posterior lateral occipital complex (rpLOC), pregenual anterior cingulate cortex (pgACC), left superior temporal sulcus (ISTS), right inferior parietal lobule (rIPL) and posterior cingulate cortex (PCC).

One-tailed statistical tests were performed to investigate the effect of time (pre- and post-intervention) on evoked pain and NPS activation in Study 1, and in Study 2 only, neck pain. All other analyses were performed using two-tailed tests, which included the exploratory analysis of activation within the different NPS sub-regions.

Study Strengths / Weaknesses:

  • The design of Study 1 (non-controlled, non-blinded study of healthy volunteers) prevents drawing any causal conclusions, as experimenter and observer bias, placebo, habituation and demand characteristics may have confounded the findings.
  • The use of healthy volunteers in Study 1 reduces generalization of findings to clinical populations. The authors attempted to account for these limitations by using neck pain subjects in Study 2; however, the associations between changes in NPS activation, evoked pain and neck pain in this clinical population was not significant and less clear.
  • Challenges exist on how to neuroimage the clinical pain experience; evoked mechanical pain may be useful in fibromyalgia patients, but it is uncertain if this is an ideal surrogate of pain in other clinical pain conditions (such as neck pain). This limitation may explain some of the discrepancies in the reported findings: in Study 1, evoked pain decreased post-SMT and was strongly correlated to NPS activation, while in Study 2, true SMT decreased NPS activation but did not decrease mechanical pain. Also, in Study 2, no significant associations between NPS activation, evoked pain and neck pain were present. Evoked mechanical pain and the experience of neck pain were not equivalent in Study 2 and as such, the presence of one may have influenced the perception of the other.
  • Small sample sizes in both studies; this was particularly evident in Study 2, which was not powered well enough to identify between-group differences in NPS activation, limiting the analysis to within-group differences. (Reviewer’s comment: This theme of underpowered studies seems to be a common occurrence in this type of neurophysiological research, which limits generalizability. It would be nice to see larger, better powered and longer controlled trials emerge in the future.)
  • Therapy for neck pain in Study 2 was limited to a single session of thoracic SMT, which does not translate to the pragmatic, often multi-modal nature of clinical practice.
  • The adequacy of the blinding intervention was not assessed, and as such, a placebo response cannot be excluded.
  • There were a number of competing interests that the authors declared.
  • The authors endeavored to study the effects of thoracic SMT on NPS in both healthy and neck-pained individuals, and demonstrated inter-group alterations that should certainly stimulate further work in this area.

Additional References:

  1. Hoy D., Brooks P., Blyth F. & Buchbinder, R. The epidemiology of low back pain. Best practice & research Clinical rheumatology 2010; 24 (6): 769–781.
  2. Blanpied PR., Gross AR., Elliott JM., et al. Neck pain: Revision. J Orthop Sports Phys Ther; 2007; 47(7): A1–a83.
  3. Delitto A., George SZ., Van Dillen LR., et al. Low back pain. J Orthop Sports Phys Ther 2012; 42(4): A1–57.
  4. Oliveira CB., Maher CG., Pinto RZ., et al. Clinical practice guidelines for the management of non-specific low back pain in primary care: an updated overview. Eur Spine J 2018; 27(11): 791–2803.
  5. Bussieres AE, Stewart G, Al-Zoubi F, et al. Spinal manipulative therapy and other conservative treatments for low back pain: a guideline from the Canadian chiropractic guideline initiative. J Manipulative Physiol Ther 2018; 41 (4): 265–293.
  6. Evans DW. Mechanisms and effects of spinal high-velocity, low-amplitude thrust manipulation: previous theories. J Manipulative Physiol Ther 2002; 25 (4): 251–262.
  7. Lascurain-Aguirrebena I., Newham D., Critchley DJ. Mechanism of action of spinal mobilizations: A systematic review. Spine 2016; 41(2): 159–172.
  8. Xia T., Long CR., Vining RD., et al. Association of lumbar spine stiffness and flexion-relaxation phenomenon with patient-reported outcomes in adults with chronic low back pain - a single-arm clinical trial investigating the effects of thrust spinal manipulation. BMC Complement Altern Med 2017; 17(1): 303.
  9. Bialosky JE, Bishop MD, Price DD, Robinson ME, George SZ. The mechanisms of manual therapy in the treatment of musculoskeletal pain: a comprehensive model. Man Ther 2009; 14(5): 531–538.
  10. Haavik, H., Murphy, B., 2012. The role of spinal manipulation in addressing disordered sensorimotor integration and altered motor control. J Electromyogr Kinesiol 2012; 22(5): 768–776.
  11. Wager TD, Atlas LY, Lindquist MA. An fMRI based neurologic signature of physical pain. New Engl J Med 2013; 368(15): 1388–1397.
  12. Pickar JG.. Neurophysiological effects of spinal manipulation. Spine J 2002; 2(5): 357–371.
  13. Sparks C, Cleland JA, Elliott JM et al. Using functional magnetic resonance imaging to determine if cerebral hemodynamic responses to pain change following thoracic spine thrust manipulation in healthy individuals. J Orthop Sports Phys Ther 2013; 43(5): 340–348.
  14. Sparks CL, Liu WC, Cleland JA, et al. Functional magnetic resonance imaging of cerebral hemodynamic responses to pain following thoracic thrust manipulation in individuals with neck pain: a randomized trial. J Manipulative Physiol Ther 2017; 40(9): 625–634.
  15. Cleland JA, Childs JD, Fritz JM. Development of a clinical prediction rule for guiding treatment of a subgroup of patients with neck pain: use of thoracic spine manipulation, exercise, and patient education. Phys Ther 2007; 87(1): 9–23.
  16. Puentedura EJ, Landers MR, Cleland JA et al. Thoracic spine thrust manipulation versus cervical spine thrust manipulation in patients with acute neck pain: a randomized clinical trial. J Orthop Sports Phys Ther 2011; 41(4): 208–220.