Research Review By Dr. Ceara Higgins©


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Date Posted:

January 2019

Study Title:

Brain mechanisms of anticipated painful movements and their modulation by manual therapy in chronic low back pain


Ellingsen DM, Napadow V, Prosenko E, et al.

Author's Affiliations:

A.A. Martinos Center for Biomedical Imaging, Harvard Medical School, Boston, MA, USA; University of California, San Francisco CA, USA; University of Michigan Medical School, Ann Arbor MI, USA; Brigham and Women’s Hospital, Boston MA, USA; Logan University, Chesterfield MO, USA.

Publication Information:

Journal of Pain 2018; 19(11): 1352-1365. doi: 10.1016/j.jpain.2018.05.012.

Background Information:

Patients with chronic low back pain (cLBP) commonly show elevated anticipation of motion-related pain (13), which is associated with fear of movement and excessive avoidance behaviours. These can have a negative impact on quality of life and also prevent recovery and impair response to treatment (11). In chronic pain, the avoidance model can result in a vicious cycle, where pain catastrophizing leads to fear of movement and hypervigilance, which can then incite hypersensitization and increased pain, leading to further avoidance (10). Our job as clinicians is to interrupt this cycle somehow!

While there is a great deal of literature connecting psychological mechanisms of fear-avoidance behaviour with pain, there is not as great an understanding regarding the brain mechanisms involved in anticipation and fear of movement-evoked pain. Neuroimaging studies of patients with cLBP simply observing back-straining maneuvers have shown increased sympathetic responses (8) and changes in brain processing in areas consistent with social cognition, salience, and mentalizing.

Conditioned responses, such as fear of movement, can fortunately be unlearned when those movements consistently occur without leading to pain or harm. Exposing patients to feared, non-harmful physical activity can extinguish fear responses, and reduce avoidance behaviours in patients with chronic musculoskeletal pain (6). Although very little is known about the effect of spinal manipulative therapy (SMT) on brain processing, one proposed effect of SMT is the disruption of the association between fear, back motion, and pain (3).

This study examined the brain activation associated with anticipated pain and fear of physical exercise and the effects of SMT (grade 3 mobilization and grade 5 manipulation) on these outcomes in cLBP patients compared to healthy controls. The authors hypothesized that observation of back-straining exercises would elicit brain responses in areas associated with social cognition, fear, salience, and pain processing, as well as the visual and fronto-parietal attention regions. Further, they hypothesized that SMT would reduce clinical pain, fear, expected pain of back-straining exercises and the corresponding brain responses to the observation of these exercises. These effects were expected to be stronger for the SMT manipulation relative to the grade 3 mobilization.

Pertinent Results:

The cLBP and healthy control (HC) groups showed no significant differences in age, Tampa Scale of Kinesiophobia or Beck’s Depression Inventory scores, perceived credibility of SMT, or expected relief from SMT. The cLBP group showed significantly higher Pain Catastrophization Scale scores, clinical pain as measured by VAS, Brief Pain Inventory, and Low Back Bothersomeness, baseline anxiety, and desire for relief when compared to the HC group. Patients with cLBP also expected more pain from, and were more fearful of, performing back-straining exercises (BSE)…(not surprising!).

fMRI Results:
When observing BSE, cLBP patients exhibited higher blood oxygen level-dependent (BOLD) signal in Visual areas 1, 4, and 5, Supramarginal gyrus (SMG), Angular gyrus (AngG), Temporoparietal junction (TPJ), a cluster in the Superior Parietal Sulcus (STS)/Middle Temporal Gyrus (MTG) compatible with the extrastriate body area, anterior Insula (aINS), Posterior Cingulate Cortex (PCC), anterior Mid-Cingulate Cortex (aMCC), ventrolateral (vlPFC), dorsomedial (dmPFC), and dorsolateral (dlPFC) Prefrontal Cortices, thalamus, caudate, putamen, and cerebellum. The healthy control group showed higher BOLD signals while observing BSE only in the V5, SMG, TPJ, lateral PFC, aMCC, thalamus, putamen, and caudate. As well, the cLBP group showed significantly higher levels of activation in the bilateral dlPFC, left vlPFC/aINS, left STS/MTG, left TPJ, and dorsomedial PFC when observing BSE compared to when observing neutral exercises, when there was no activation, and in some cases, deactivation of those regions. The healthy control group showed no significant activation when observing any of the videos with little to no difference across video type.

Effect of SMT:
Both SMT manipulation (grade 5) and SMT mobilization (grade 3) reduced clinical pain and expected pain and fear of performing physical exercises. However, contrary to the authors’ hypothesis, there was no difference seen between manipulation and mobilization. The patients who showed the greatest reduction in clinical pain following SMT also showed the greatest reduction in expected pain from performing BSE, however, the correlation did not reach statistical significance. As well, no significant correlation was found between expected relief from SMT and changes in fearfulness.

A statistically significant difference was found favoring SMT (grade 5 manipulation) in the reduction in BOLD signal in the left Superior Parietal Sulcus, right aINS, right S1, right Superior Temporal Gyrus (STG), bilateral dlPFC, vlPFC, vmPFC, pINS, paracingulate, medial occipital cortex, and cerebellum. As well, SMT (grade 5 manipulation) was found to have a statistically significantly higher effect in the cLBP group on reducing activation of the left TJP, bilateral aINS, vlPFC, dlPFC, STS/MTG, medial occipital cortex, and right cerebellum. Patients showing the largest SMT-induced reduction in expected pain from performing BSE also showed the largest SMT-induced reduction in BOLD fMRI responses to videos in the right TPJ, left Superior Parietal Sulcus/STG, left m/aINS, aMCC, and SMG.

Clinical Application & Conclusions:

Patients with cLBP reported higher fear and anticipated pain of performing ‘back-straining exercises’ (BSE) as depicted in observed videos, when compared to age- and sex-matched healthy controls. This was accompanied in the cLBP group by an increase in blood oxygen level-dependent (BOLD) fMRI responses in brain circuitry involved in social processing, emotion regulation, and salience. SMT was found to reduce clinical pain, fear of movement, and expected pain from BSE. The reductions in fear and expected pain correlated with reductions in BOLD-responses to observing BSE.

cLBP patients showed greater BOLD responses in a number of brain areas while observing videos pf BSE relative to neutral exercises, compared with HC. The dmPFC, dlPFC and aINS (specifically) are known nodes of the salience network (2) and have been implicated in pain anticipation (7). These regions have also been implicated in goal formation, prediction error processing, and top down modulation of pain (9). As well, the vlPFC, TPJ, and Superior Parietal Sulcus are consistently implicated in mentalizing, theory-of-mind, and social cognition (5), and the Superior Parietal Sulcus/MTG cluster is consistent with the extrastriate Body Area, which is involved in processing observed bodies and body parts (4).

Patient expectations as to whether an intervention will improve or worsen their pain can lead to hypo- or hyperalgesia, respectively (1). These expectations can also guide their behavioural decisions in daily life. This study found that patients’ expectations regarding relief from SMT correlated with reductions in both clinical back pain and expected pain from observed BSE after SMT. This suggests that SMT may interrupt the association between low back movement, fear, and pain. The manual therapy technique used did not seem to change its effect on clinical pain, fear of movement, or expected pain. However, there was a stronger BOLD response in the brain to high-velocity (grade 5) manipulation than grade 3 mobilization. From a clinical standpoint, both manipulation and mobilization seem to be equally effective for reducing patient-reported pain and the aversiveness of observed BSE.

Study Methods:

15 patients with cLBP and 16 individually age- and sex-matched controls were recruited for this study. Inclusion criteria for cLBP patients included:
  • Age between 21 and 65
  • Nonspecific low back pain diagnosed > 6 months prior to study enrollment
  • Ongoing pain that averaged at least 4/10 on a 0-10 scale of pain during the week prior to enrollment
Exclusion criteria for cLBP patients:
  • Radicular pain
  • Neural deficit in the lower extremity
  • Positive dural tension signs
  • Surgery related to back pain within the past year
  • Pain management procedures during the study period
  • Contraindications to functional Magnetic Resonance Imaging (fMRI)
  • Current or past history of major medical, neurological, or psychiatric illness other than chronic pain
  • Peripheral nerve injury
  • Diabetes
  • Pregnancy, breast feeding, or less than 6 months postpartum
  • History of head trauma
  • High blood pressure
  • Use of opioid medications, recreational drugs, or history of substance abuse
  • Back pain due to cancer, fracture, or infection
Healthy controls (HC) followed the same exclusion criteria, with the addition of chronic or acute low back pain.

The cLBP group attended 3 study visits. An initial behavioral visit, and MRI visit with SMT (grade 3 mobilization), and an MRI visit with SMT (high-velocity manipulation – grade 5). The HC group attended 2 study visits: an initial behavioural visit and an MRI visit with SMT (high-velocity manipulation). Note, the HC group only received the high-velocity (grade 5) manipulation, as the authors did not anticipate any SMT-induced changes in clinical outcomes in this group. Also noteworthy is the lack of description of the SMT techniques utilized. The initial behavioral visit included informed consent, a clinical evaluation by a licensed chiropractor (including both history and physical examination), and the performance of a series of back-straining and non-back-straining physical exercises repeated 3 times each, with participants rating the intensity (0 = no pain to 100 = the most intense pain tolerable) and unpleasantness (0= neutral to 100 = extremely unpleasant) of their back pain after each repetition. Patients responses were used to guide the selection of the subject-specific videos that were used in subsequent MRI visits.

During the MRI visits, patients were placed supine in the whole-body MRI scanner. Four fMRI runs were performed, during which, participants were shown four videos (20 seconds each). Two of the videos showed ‘high back-straining exercises’ (BSE) and two showed ‘low back-straining exercises’ (Neutral), in a pseudorandomized order. Each BSE video showed an actor, who was sex-matched to the participant, performing the two BSEs that had most reliably elicited pain in the cLBP patient during the behavioural visit. In the Neutral videos, the same actor performed non-back straining exercises that were identical for all participants. In order to obtain the maximal emotional impact from the observation of back-straining exercises, participants were told at the beginning of the imaging visits that they would have to perform the observed exercises at the end of the visit. Eight seconds after the end of each video, the participants were asked to rate how much pain they expected to experience from performing the exercise shown using a numerical rating scale (0 = no pain to 100 = the most intense pain tolerable), and how fearful they were of performing the exercise (0 = not at all fearful to 100 = extremely fearful). After two fMRI runs, participants rated their pain, were removed from the MRI bore, received either SMT manipulation or the grade 3 mobilization while on the scanner bed, rated their pain again, and then were returned to the MRI bore to complete two more fMRI runs. At the end of the first visit, participants performed five repetitions of each of the back straining and neutral exercises they had been shown in order to make sure that the experimental induction of anticipation of pain would still be credible during the following visit.

During the training visit, participants also filled out the Tampa Scale of Kinesiophobia, Pain Catastrophizing Scale, Beck’s Depression Inventory, Brief Pain Inventory, and a treatment credibility scale modified from Sherman, et al (12). As well, they rated the bothersomeness of low-back pain (0 = not at all bothersome, 100 = extremely bothersome), expected relief from SMT (0= does not work at all, 100 = complete relief), and desire for relief (0 = no desire for pain relief, 100 = the most intense desire for relief imaginable).

Study Strengths / Weaknesses:

  • This study used individually tailored back-straining exercise videos based on the exercises patients identified as most painful, in order to maximize the contrast between the back-straining and neutral exercise stimuli. Most previous studies used a pre-selected pool of videos.
  • Participants were told they would be asked to perform the exercises they were shown, which made the stimuli more behaviourally relevant and may have improved the sensitivity of the testing.
  • The study did not appear to produce strong kinesiophobia as evidenced by a lack of increased BOLD fMRI responses in areas of the brain associated with fear, such as the amygdala and aMCC.
  • This study showed higher ratings of expected pain than ratings of fear. This suggests that the patients may have found the observed exercises more aversive from a cognitive level which may limit their effect.
  • Outcomes were only assessed from a single session of SMT manipulation and SMT mobilization. Further research utilizing multiple sessions may be warranted to evaluate ongoing or evolving effects of care.
  • The sample size was relatively small (not surprising, as fMRI is an expensive resource to use!).

Additional References:

  1. Atlas LY, Lindquest MA, Wager TD. Brain mediators of predictive cue effects on perceived pain. J Neurosci 2010; 30: 12964-12977.
  2. Beckmann CF, DeLuca M, Devlin JT, et al. Investigations into resting-state connectivity using independent component analysis. Philos Trans R Soc Lond B Biol Sci 2005; 360: 1001-1013.
  3. Bishop MD, Torres-Cueco R, Gay CW, et al. What effect can manual therapy have on a patient’s pain experience? Pain Manag 2015; 5: 455-464.
  4. Costantini M, Urgesi C, Galati G, et al. Haptic perception and body representation in lateral and medial occipito-temporal cortices. Neuropsychologia 2011; 49: 821-829.
  5. Etkin A, Buchel C, Gross JJ. The neural bases of emotion regulation. Net Rev Neurosci 2015; 16: 693-700.
  6. Fordyce WE, Shelton JL, Dundore DE. The modification of avoidance learning pain behaviours. J Behav Med 1982; 5: 405-414.
  7. Geuter S, Koban L, Wager TD. The cognitive neuroscience of placebo effects: Concepts, predictions, and physiology. Ann Rev Neurosci 2017; 40: 167-188.
  8. Glombiewski JA, Riecke J, Holzapfel S, et al. Do patients with chronic pain show autonomic arousal when confronted with feared movements? An experimental investigation of the fear-avoidance model. Pain 2015; 156: 547-554.
  9. Kucyi A, Davis KD. The dynamic pain connectome. Trends Neurosci 2015; 38: 86-95.
  10. Lethem J, Slade PD, Troup JD, et al. Outline of a fear-avoidance model of exaggerated pain perception –I. Behav Res Ther 1983; 21: 401-408.
  11. Rainville J, Smeets RJ, Bendix T, et al. Fear-avoidance beliefs and pain avoidance in low back pain-translating research into clinical practice. Spine J 2011; 11: 895-903.
  12. Sherman KJ, Hogeboom CJ, Cherkin DC, et al. Description and validation of a noninvasive placebo acupuncture procedure. J Altern Complement Med 2002; 8: 11-19.
  13. Vlaeyen JW, Kole-Snijders AM, Rotteveel AM, et al. The role of fear of movement/(re)injury in pain disability. J Occup Rehabil 1995; 5: 235-252.