Brain Mechanisms of Anticipated Painful Movements
and Their Modulation by Manual Therapy
in Chronic Low Back PainThis section is compiled by Frank M. Painter, D.C.
Send all comments or additions to: Frankp@chiro.org
FROM: J Pain 2018 (Nov); 19 (11): 1352–1365 ~ FULL TEXT
OPEN ACCESS Dan-Mikael Ellingsen • Vitaly Napadow • Ekaterina Protsenko • Ishtiaq Mawla
Matthew H Kowalski • David Swensen • Deanna O'Dwyer-Swensen
Robert R Edwards • Norman Kettner • Marco L Loggia
A. A. Martinos Center for Biomedical Imaging,
Department of Radiology,
Massachusetts General Hospital,
Harvard Medical School,
Boston, Massachusetts.
Heightened anticipation and fear of movement-related pain has been linked to detrimental fear-avoidance behavior in chronic low back pain (cLBP). Spinal manipulative therapy (SMT) has been proposed to work partly by exposing patients to nonharmful but forceful mobilization of the painful joint, thereby disrupting the relationship among pain anticipation, fear, and movement. Here, we investigated the brain processes underpinning pain anticipation and fear of movement in cLBP, and their modulation by SMT, using functional magnetic resonance imaging. Fifteen cLBP patients and 16 healthy control (HC) subjects were scanned while observing and rating video clips depicting back-straining or neutral physical exercises, which they knew they would have to perform at the end of the visit. This task was repeated after a single session of spinal manipulation (cLBP and HC group) or mobilization (cLBP group only), in separate visits. Compared with HC subjects, cLBP patients reported higher expected pain and fear of performing the observed exercises. These ratings, along with clinical pain, were reduced by SMT. Moreover, cLBP, relative to HC subjects, demonstrated higher blood oxygen level-dependent signal in brain circuitry that has previously been implicated in salience, social cognition, and mentalizing, while observing back straining compared with neutral exercises. The engagement of this circuitry was reduced after SMT, and especially the spinal manipulation session, proportionally to the magnitude of SMT-induced reduction in anticipated pain and fear. This study sheds light on the brain processing of anticipated pain and fear of back-straining movement in cLBP, and suggests that SMT may reduce cognitive and affective-motivational aspects of fear-avoidance behavior, along with corresponding brain processes. PERSPECTIVE: This study of cLBP patients investigated how SMT affects clinical pain, expected pain, and fear of physical exercises. The results indicate that one of the mechanisms of SMT may be to reduce pain expectancy, fear of movement, and associated brain responses.
Keywords: Expectation; Fear-avoidance; Pain anticipation; Physical exercise; Spinal Manipulative Therapy; chronic Low Back Pain; functional Magnetic Resonance Imaging.
Highlights
Patients with chronic low back pain (cLBP) show higher blood oxygen level–dependent signal when observing physical exercises.
Spinal manipulative therapy (SMT) reduces clinical pain, expected pain, and fear of movement in cLBP.
SMT manipulation and mobilization equally improve clinical outcomes.
SMT reduces brain responses to observing back-straining exercises in cLBP.
From the FULL TEXT Article:
Background
Elevated anticipation of motion-related pain is common in chronic low back pain (cLBP), [69] and is associated with fear of movement and excessive avoidance behavior, which can be detrimental to health and quality of life, and prevent recovery. [50] Higher fear-avoidant behavior is associated with higher disability, [12, 29, 68, 69, 71] and reduction in fear/anxiety can predict successful therapy. [70] The fear-avoidance model of chronic pain posits that chronification of pain is often characterized by a vicious cycle whereby catastrophizing about pain leads to fear of movement and hypervigilance, which in turn can incite hypersensitization and exacerbation of pain, leading to yet more avoidance. [40] This cycle has been linked to Pavlovian and operant conditioning, [21, 67] in which pain initially represents an unconditioned response to a nociceptive unconditioned stimulus, but may be elicited by a progressively wider range of nonharmful movements (conditioned stimulus). [27, 46] While a large literature implicates psychological mechanisms of fear-avoidance behavior in pain, less is known about the brain mechanisms involved in the anticipation and fear of movement-evoked pain. Understanding these mechanisms is critically important, as they influence behavioral decisions to approach or avoid situations where a perceived harmful physical movement may occur.
Initial neuroimaging studies of cLBP patients observing back-straining maneuvers have found increased sympathetic responses [25] and altered brain processing in circuitry consistent with social cognition, salience, and mentalizing, such as the ventrolateral (vlPFC) and dorsomedial (dmPFC) prefrontal cortex, mid-anterior insula (m/aINS), middle temporal gyrus (MTG), superior temporal sulcus (STS), and amygdala. Notably, in these studies, participants passively viewed static pictures [4, 5, 61] or videos [43, 44] depicting people in back-straining positions, without any actual prospect of executing physical activity by the participants themselves. Thus, the behavioral relevance of the context — and in turn fear — may have been limited.
Conditioned responses — such as fear of potentially harmful maneuvers — can be “unlearned” when the conditioned stimulus or conditioned response consistently occurs without leading to unconditioned response (eg, a perceived harmful motion is not followed by pain or harm). There is evidence that exposing patients to (feared) nonharmful physical activity, to extinguish fear responses, can reduce avoidance behavior in chronic musculoskeletal pain. [20, 67, 70] Interestingly, one proposed effect of spinal manipulative therapy (SMT), which involves salient sensory and proprioceptive feedback through passive mobilization of spine joints, is that it might help disrupt the association between fear, back-motion, and pain. [9, 74] However, it has not yet been investigated whether SMT affects motivational aspects relevant to avoidance — such as anticipated pain and fear of movement. Moreover, very little is known about how SMT affects brain processing. [22]
Here, we investigated the brain-based underpinnings anticipated pain and fear of physical exercises, and the effect of 2 SMT techniques (grade 3 mobilization and grade 5 manipulation) on these outcomes. We hypothesized that, in cLBP, observation of back-straining, relative to neutral, exercises would elicit brain responses in circuitry involved in social cognition, fear, salience, and pain processing (eg, the anterior cingulate cortex, insulae, and amygdalae), in addition to visual and frontoparietal attention regions. Further, we hypothesized that SMT would reduce clinical pain, as well as fear, expected pain of back-straining exercises, and corresponding brain responses to observation of such exercises. Finally, we hypothesized that these effects would be stronger for SMT manipulation relative to mobilization, reflecting a dose response.
Methods
Subjects
Fifteen patients with cLBP (8 women, mean age 37.7 ± 9.7 years) and 16 individually age- and sex-matched healthy control (HC) subjects (8 women, mean age 38.2 ± 10.4 years) were enrolled. One HC subject was excluded from final paired analyses, as we were not able to recruit an age- and sex-matched cLBP patient for this individual. All subjects provided written informed consent before participation. The study was approved by the Human Research Committee of Massachusetts General Hospital and was conducted in accordance with the Declaration of Helsinki.
Inclusion criteria for cLBP patients included age ≥21 years and ≤65 years, nonspecific low back pain, diagnosed >6 months before enrollment, and ongoing pain that averaged at least 4 on a 0 to 10 scale of pain during the week before enrollment. Exclusion criteria included radicular pain (ie, pain radiating down below the knee); neural deficit in the lower extremity; positive dural tension signs; surgery within the past year related to back pain; pain management procedures during the study period; contraindications to functional MRI (fMRI); current or past history of major medical, neurological, or psychiatric illness other than chronic pain; peripheral nerve injury; diabetes; pregnancy; breast feeding; <6 months postpartum; history of head trauma; high blood pressure; use of opioid medications; use of recreational drugs; history of substance abuse; and back pain due to cancer, fracture, or infection. Exclusion criteria for HC subjects were, in addition to those for cLBP, chronic or acute low back pain.
Experimental Protocol
The study involved 3 study visits for cLBP patients — an initial behavioral visit, an MRI visit with SMT mobilization (ie, grade III of the Maitland Joint Mobilization Grading Scale), [28] and an MRI visit with SMT manipulation (ie, grade V of the Maitland Joint Mobilization Grading Scale). The order of the MRI visits was counterbalanced across subjects (mean interval between MRI visits was 24.7 ± 22.9 days). The HC group completed 2 study visits — an initial behavioral visit and an MRI visit with grade V SMT. As we did not anticipate SMT-induced changes in clinical outcomes for HC subjects, we did not include an SMT mobilization visit for this group, as the comparison between SMT manipulation and SMT mobilization was aimed at investigating differences in clinical outcomes and associated brain responses. Therefore, our study had a mixed design, with both a within-subject (grade III vs grade V in cLBP patients) as well as a between-subject (Grade V in cLBP vs healthy participants) component. All visits took place at the MRI facilities at Martinos Center for Biomedical Imaging, Massachusetts General Hospital, between September 2014 and November 2016.Behavioral Visit
Following informed consent, a licensed chiropractor performed a clinical evaluation (including history and physical examination) to further characterize the nature of the pain symptoms (or, in the case of healthy volunteers, to exclude the presence of back pain) and to determine the suitability and safety of manual therapy. All participants were also asked to perform a series of back-straining (eg, sit-ups, thrusts, leg lifts, pelvic tilts) and non–back-straining (eg, arm lifts, flexion-extension of the arms) physical exercises repeated 3 times each, rating the intensity (0 = no pain, 100 = the most intense pain tolerable) and unpleasantness (0 = neutral, 100 =extremely unpleasant) of their back pain after each repetition. The patients’ responses to these exercises were used to guide the selection of subject-specific videos that most reliably exacerbated the patients’ pain for use in the subsequent MRI visits.
MRI Visits
Figure 1 Participants were placed in a supine position in a 3T Siemens Skyra whole-body MRI scanner (Siemens Medical Systems, Erlangen, Germany). In each of 4 separate fMRI runs (~4.5 minutes each, 2 before and 2 after SMT), participants were shown 4 videos (20 seconds each) — 2 depicting +high back-straining exercises (BSE) and 2 depicting low back-straining exercises (Neutral) — in a pseudorandomized order (Figure 1, for illustrations of all the video material, see Supplemental Digital Content 1). For each cLBP patient, as well as his/her age- and sex-matched control subject, the BSE videos depicted an actor (sex-matched to the participant) performing the 2 back-straining exercises that most reliably elicited pain in the cLBP patient during the behavioral visit; in the control videos, the same actor performed non–back-straining exercises (identical in all participants). We decided to use videos rather than still images, as they are able to show the full dynamic of physical exercises, which likely increases their salience.
To maximize the emotional impact of observing back-straining exercises, at the beginning of the imaging visit the participants were informed that at the end of the imaging visit they would be asked to perform the exercises they observed in the videos. Eight seconds after each video, the subjects were prompted to rate how much pain they expected from performing the exercise they saw on the previous video clip and how fearful they were of performing that exercise.
After the first 2 fMRI runs, participants rated their clinical pain and were temporarily removed from the MRI bore, received SMT (either manipulation or mobilization) while on the scanner bed, rated their clinical pain again, and then were placed back into the MRI bore and completed the 2 final fMRI runs.
At the end of the first visit, participants performed 5 repetitions of each of the back-straining and neutral exercises corresponding to the videos they had seen, in keeping with the instructions. The main purpose of this procedure was to ensure that the experimental induction of anticipation of clinical pain exacerbation would be still credible during the subsequent visit.Psychophysical Measures
During the scanning procedures subjects used a button box for ratings, using scales displayed with E-Prime software version 1.1 (Psychology Software Tools, Sharpsburg, PA). Numerical rating scales (0–100) were used for low back pain (0 = no pain, 100 = the most intense pain tolerable) before and after the pre-SMT fMRI and the post-SMT fMRI runs. The same button box was used for ratings of expected pain from exercise (How painful do you think it will be?; 0 = no pain, 100 = the most intense pain tolerable) and fearfulness (How fearful are you of performing this exercise?; 0 = not at all fearful, 100 = extremely fearful).
At the training visit, participants filled out the following validated questionnaires for facilitating clinical characterization of the sample groups:Tampa Scale of Kinesiophobia (TSK), [45]
Pain Catastrophizing Scale (PCS), [59]
Beck Depression Inventory (BDI), [6]
Brief Pain Inventory (BPI), [60]and a 5-point Likert-type treatment credibility scale modified from Sherman et al [57] (1 = definitely, 5 = definitely not).
Additionally, they rated bothersomeness of low back pain on a visual analog scale (VAS) (0 = not at all bothersome, 100 = extremely bothersome), expected relief from SMT on a VAS (0 = does not work at all, 10 = complete relief), and desire for relief (0 = no desire for pain relief, 10 = the most intense desire for relief imaginable).
Psychophysics Data Analysis
To compare cLBP and HC groups on basic demographic, trait, and clinical characteristics, we performed paired t tests of age, TSK, PCS, BDI, and BPI scores; credibility of SMT; clinical pain at baseline; anxiety at baseline; low back bothersomeness; expected relief from SMT; and desire for relief.
To confirm that cLBP expected more pain from, and were more fearful of, performing back-straining relative to neutral exercises, we performed a mixed-design analysis of variance (ANOVA) with the factors group (cLBP, HC) and video exercise (BSE, Neutral), using baseline (pre-SMT) ratings from the first visit.
To investigate whether SMT affected cLBP patients’ clinical pain, we performed an ANOVA with the factors SMT technique (manipulation, mobilization), and time (pre-SMT, post-SMT). Scan order (manipulation first, mobilization first) was included as a categorical covariate of no interest.
To investigate whether SMT affected cLBP patients’ expected pain and fear of performing exercises, we used 2 separate repeated measures ANOVAs using each patient's mean expected pain and fearfulness (averaged across BSE and Neutral videos, separately), with the factors SMT technique (manipulation, mobilization), video exercise (BSE, Neutral), and time (pre-SMT, post-SMT). Scan order (manipulation first, mobilization first) was included as a categorical covariate of no interest.
We calculated Pearson correlation coefficients to investigate the relationship between SMT-induced change in clinical pain (post-SMT – pre-SMT) versus change in expected pain and change in fearfulness. To investigate the impact of positive expectation, we calculated Pearson correlation coefficients between expected relief from SMT versus SMT-induced changes in clinical pain, expected pain, and fearfulness. Behavioral data were analyzed using JASP (version 0.8.1.5 JASP Team, Amsterdam, Netherlands).
MRI Data Acquisition and Preprocessing
Blood oxygen level–dependent (BOLD) fMRI data were collected using a whole brain, simultaneous multislice, T2*-weighted gradient echo BOLD echo-planar imaging pulse sequence (repetition time = 1,250 ms, echo time = 33 ms, flip angle = 65°, voxel size = 2 mm isotropic, number of slices = 75, Simultaneous Multi-Slice (SMS) factor = 5). A high-resolution structural volume (multiecho MPRAGE) was collected for the purposes of anatomical localization and spatial normalization (repetition time = 2,530 ms, echo time = 1.69 ms, flip angle = 7°, voxel size = 1 mm isotropic).
fMRI data processing and analysis was carried out using FEAT (FMRI Expert Analysis Tool) Version 6.0, part of FSL (FMRIB's Software Library; www.fmrib.ox.ac.uk/fsl). The following preprocessing was applied: slice-timing correction, motion correction using MCFLIRT, [32] field map–based echo-planar imaging unwarping using PRELUDE and FUGUE, [30, 31] nonbrain removal using BET, [58] spatial smoothing (full width at half maximum = 4mm), temporal high-pass filter (.011 Hz as computed by FSL's cutoffcalc), and grand-mean intensity normalization by a single multiplicative factor. All 4 runs were realigned (6 degrees of freedom) to a common space (the seventh volume of the first fMRI run) before first-level general linear model (GLM) analyses. The transformation matrix for the registration from functional to the high-resolution anatomical image was computed using Boundary Based Registration (FreeSurfer's bbregister tool). [26] For structural-to-standard space registration, we used the FSL's Linear registration tool (FLIRT, 12 degrees of freedom) [32, 33] followed by FSL's nonlinear registration tool (FNIRT). [1] All single-subject analyses were performed in functional space, and registration to standard space (Montreal Neurological Institute 152) was applied before group analyses.
fMRI Data Analysis
Single-subject GLM analyses were carried out using FILM with local autocorrelation correction. For each run (2 pre-SMT and 2 post-SMT), we modeled the epochs corresponding to the video presentation (BSE, Neutral) as regressors in a GLM. In the same design matrix we also modeled rating periods, the first temporal derivative of each time course, and the 6 motion parameters as regressors of no interest. From this first-level analyses we computed a total of 6 contrasts: BSE—rest, Neutral—rest, BSE—Neutral, and their opposites. In a second-level fixed-effect analysis, we averaged the contrast maps across both pre-SMT runs and across both post-SMT runs separately, resulting in 2 sets of contrasts of parameter estimates for each contrast (pre-SMT and post-SMT).
To investigate brain responses to observing back-straining and neutral exercises, we carried out whole-brain voxelwise group GLMs separately for cLBP and HC subjects from the baseline (pre-SMT) scans at the first visit, for each of the 6 contrasts. Because the patient and control groups were recruited in a matching-pairs design (with each patient matched for age and sex to a control subject), the group contrasts were evaluated using paired t tests comparing age- and sex-matched cLBP and HC groups. Group inference was performed using FLAME (FMRIB's Local Analysis of Mixed Effects) 1 + 2, and the resulting statistical maps were cluster corrected for multiple comparisons using a cluster-forming voxelwise threshold of Z > 2.3, and a (corrected) cluster significance threshold of P < .05.
We then conducted whole-brain voxelwise GLMs to investigate SMT-induced change in BOLD responses (post-SMTBSE-Neutral – pre-SMTBSE-Neutral) in cLBPmanip relative to cLBPmobil, and cLBPmanip relative to HC subjects.
To investigate whether SMT-induced changes in expected pain and fear of movement were associated with changes in brain responses to these videos, we carried out whole-brain voxelwise regression analyses (post-SMTBSE-Neutral – pre-SMTBSE-Neutral) with SMT-induced changes in expected pain and fearfulness ratings (post-SMTBSE-Neutral – pre-SMTBSE-Neutral) as regressors of interest. These regression analyses were performed separately for SMTmanip and SMTmobil, and for cLBP participants only since the HC group, as anticipated, did not show enough dynamic range in ratings of expected pain (12 of 15 rated expected pain as 0 both before and after SMT).
Visualization of brain imaging data was produced using FSL's FSLView for data displayed on volumes (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FslView), FreeSurfer's Freeview for brain surfaces (https://surfer.nmr.mgh.harvard.edu), and Caret for cerebellar surfaces (http://www.nitrc.org/projects/caret/).10,65
Results
Demographic, Trait, and Clinical Characteristics
Table 1 CLBP and HC groups did not significantly differ in age, TSK or BDI scores, perceived credibility of SMT, and expected relief from SMT (Table 1). We found significantly higher PCS scores, clinical pain (baseline VAS, BPI, and low back bothersomeness), baseline anxiety, and desire for relief for cLBP compared with HC subjects. For 1 cLBP patient, we did not obtain BDI, credibility, clinical pain, and anxiety. However, all participants were retained for data collection of all other data for both imaging visits.
cLBP Patients, Relative to HC Subjects, Expected More Pain From,
and Were More Fearful of, Performing Back-Straining Exercises
Figure 2 A mixed-design ANOVA confirmed that cLBP patients, relative to HC subjects, anticipated the exercises depicted in the videos, when performed in first-person at the end of the visit, to be more painful (main effect of group: F1,13 = 31.54, P < .001, η² p = .71). Furthermore, a main effect of video exercise confirmed higher expected pain from BSE relative to Neutral (F1,13 = 35.87, P < .001, η² p = .73).
Most importantly, there was a group × video exercise interaction (F1,13 = 32.38, P < .001, η² p = .71). A paired t test between cLBP patients and HC subjects revealed that the difference in expected pain between BSE and Neutral conditions was significantly greater (t14 = 5.82, P < .001, d = 1.50) for cLBP patients (23.84 ± 15.32) compared with HC subjects (1.25 ± 2.60). The mean and SD data of the video ratings are presented in Figure 2.
A repeated-measures ANOVA confirmed higher fear of performing the exercises depicted in the videos for cLBP patients relative to HC subjects (main effect of group: F1,13 = 6.88, P = .021, η² p = .35). A main effect of video exercise confirmed higher fearfulness of BSE relative to Neutral exercises (F1,13 = 2.79, P < .001, η² p = .62). Importantly, there was a group × video exercise interaction (F1,13 = 12.35, P = .004, η² p = .49). This difference was significantly greater (t14 = 3.77, P = .002, d = .97) for cLBP patients (6.75 ± 6.01) compared with HC subjects (.25 ± 1.36).
Brain Responses to the Observation of Back Straining
Relative to Neutral Physical Exercises
Figure 3 Baseline group brain responses to BSE and Neutral videos, compared with rest, are shown in Supplementary Figure 1. When observing BSE, compared with Neutral exercises, cLBP patients showed higher BOLD signal in multiple regions including visual areas (V) 1, 4, and 5; supramarginal gyrus; angular gyrus; 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; anterior mid-cingulate cortex (aMCC); ventrolateral (vlPFC), dorsomedial (dmPFC), and dorsolateral (dlPFC) prefrontal cortices; thalamus; caudate; putamen; and cerebellum (Figure 3A).
The HC group also demonstrated higher BOLD signal during BSE relative to Neutral videos, but in a smaller number of regions (V5, supramarginal gyrus, TPJ, lateral PFC, aMCC, thalamus, putamen, and caudate) (Fig 3B).
A direct group comparison (cLBP vs HC) of the BSE–Neutral contrast revealed statistically significant clusters in bilateral dlPFC, left vlPFC/aINS, left STS/MTG, left TPJ, and dmPFC (Fig 3C, top). As illustrated by extracted mean Z scores in these regions (Fig 3C, bottom), cLBP patients demonstrated significant activations during observation of back-straining exercises, compared with no activation (or, in some cases, deactivation) when observing the neutral exercises. The HC subjects, on the other hand, showed no significant activation in response to either of the videos, and little or no difference across video type. A binarized mask created from regions significant in the cLBPBSE-Neutral -HCBSE-Neutral contrast was used for the subsequent region of interest (ROI)–based investigation of the effects of SMT on the brain responses to observing exercises.
SMT Reduced Clinical Pain, Expected Pain,
and Fear of Performing Physical ExercisesClinical Pain
Figure 4
page 8A significant ANOVA main effect of time (F1,13 = 13.34, P = .003, η² p = .51) indicated that clinical pain was reduced after SMT (31.12 ± 16.83) relative to the pre-SMT baseline (41.69 ± 18.11). There was no main effect of SMT technique (F1,13 = .25, P = .63, η² p = .02) and no time × SMT technique interaction (F1,13 = .22, P = .65, η² p = .02). Thus, the data did not support the hypothesis that the effect of SMT on clinical pain is different between manipulation and mobilization (Figure 4A).
Expected Pain
A significant ANOVA main effect of time (F1,13 = 8.99, P = .01, η² p = .41) indicated that expected pain from the exercises was reduced after SMT (20.94 ± 16.97) relative to before (24.87 ± 19.08). As hypothesized, there was a significant main effect of video exercise (F1,13 = 29.85, P < .001, η² p = .70), with BSE (34.95 ± 13.86) rated higher than Neutral (10.86 ± 13.15). There was a significant time × video exercise interaction (F1,13 = 6.28, P = .026, η² p = .33).
In line with our hypothesis, a direct t test indicated that the SMT-induced reduction was stronger for BSE (Δ[post-SMT – pre-SMT]: –5.66 ± 7.6) than for Neutral (Δ[post-SMT – pre-SMT]: –2.21 ± 2.27) videos (t14 = 1.99, P = .034) (Fig 4B).
There was a significant SMT technique × scan order interaction (F1,13 = 4.92, P = .045, η² p = .27). There were no significant interactions between time × SMT technique (F1,13 = .25, P = .62, η² p = .02) and time × video exercise × SMT technique (F1,13 = 1.35, P = .27, η² p = .09). Thus, the data did not suggest that that the effect of SMT on expected pain was different depending on the SMT technique used.
Fear of Movement
A significant main effect of time (F1,13 = 4.89, P = .046, η² p = .27) indicated fearfulness was reduced after SMT (7.13 ± 10.47) relative to before (7.91 ± 11.35) (Fig 4C). As expected, there was also a main effect of video exercise (F1,13 = 25.37, P > .001, η² p = .66), showing higher fearfulness ratings of BSE (11.80 ± 11.13) relative to Neutral videos (3.24 ± 8.82). There were no other significant main effects or interactions (all Ps > .06). Thus, the data did not suggest that an SMT-induced reduction in fearfulness was different across different video types or SMT techniques.Relationship Between Clinical Pain Versus Expected Pain and Fearfulness
cLBP patients’ change in clinical pain (post-SMT – pre-SMT) correlated significantly with change in expected pain (post-SMTBSE-Neutral – pre-SMTBSE-Neutral) (r = .58, P = .02), indicating that patients with the greatest reduction in clinical pain following SMT also had the greatest reduction in expected pain from performing the observed back-straining exercises (Fig 4D). We did not find a statistically significant correlation between change in fearfulness and change in clinical pain (r = .17, P = .55).
Relationship Between Expected Relief of SMT Versus SMT Outcomes
cLBP patients’ expected relief of SMT correlated significantly with change in clinical pain (r = .67, P = .006) and expected pain from performing exercise (post-SMTBSE-Neutral – pre-SMTBSE-Neutral) (r = –.64, P = .01). There was no significant correlation between expected relief from SMT and change in fearfulness (r = –.22, P = .44).
SMT Reduced Brain Responses in Circuitry Involved
in Processing Observed Back-Straining Exercises
Figure 5 A whole-brain voxelwise within-group interaction in the cLBP group (cLBPmanip[post-SMTBSE-Neutral – pre-SMTBSE-Neutral] – cLBPmobil [post-SMTBSE-Neutral – pre-SMTBSE-Neutral]) showed a statistically significant difference in the effect of technique (manipulation vs mobilization) in left STS, right aINS, right S1, right superior temporal gyrus (STG), bilateral dlPFC, vlPFC, vmPFC, posterior insula, paracingulate, medial occipital cortex, and cerebellum (Figure 5A).
Furthermore, a between-group interaction (cLBPmanip[post-SMTBSE-Neutral – pre-SMTBSE-Neutral] – HC [post-SMTBSE-Neutral – pre-SMTBSE-Neutral]) indicated the presence of a statistically significant difference in the effect of manipulation across groups (cLBP vs HC) (Fig 5A) in left TPJ and bilateral aINS, vlPFC, dlPFC, STS/MTG, medial occipital cortex, and right cerebellum (Fig 5B). The examination of Z-stat values from these regions suggested that the interaction was driven by a BOLD contrast reduction following SMTmanip, when observing back-straining exercises (BSE-Neutral) for cLBP patients, compared with an increase for HC subjects (Fig 5C). Exploratory contrasts showing the contrast (post-SMTBSE-Neutral – pre-SMTBSE-Neutral) separately for cLBPmanip and cLBPmobil are shown in Supplementary Figure 2.
SMT-Induced Change in Expected Pain Correlated With
SMT-Induced Change in Brain Responses to Observation
of Back-Straining Exercises
Figure 6
page 10A whole-brain voxelwise regression analysis indicated that, for cLBPmanip, those patients with the largest SMT-induced reduction in expected pain from performing back-straining exercises also had the largest SMT-induced reduction in BOLD fMRI responses to videos in right TPJ, left STS/STG, left m/aINS, aMCC, and SMA (Figure 6A, left). To illustrate this relationship, we extracted mean Z scores from 2 ROIs (aINS and STS) identified by the intersection of the correlation map and with the activation map from the baseline (cLBP BSE-Neutral -HCBSE-Neutral) contrast (Fig 3C), and plotted these values against SMT-induced Δexpected pain (BSE-Neutral) (Fig 6A, right).
There was no significant correlation between SMT-induced change in expected pain and BOLD responses to videos for cLBPmobil. For cLBPmanip, there was a significant correlation between SMT-induced change in fear of movement and BOLD responses to videos (BSE-Neutral) in right MTG, right lateral occipital cortex, medial thalamus, and the periaqueductal gray matter (Fig 6B). For cLBPmobil there was a significant correlation between SMT-induced change in fear of movement and BOLD responses to videos (BSE-Neutral) in left STS/MTG, left mid-posterior insula, posterior cingulate cortex, precuneus, medial occipital cortex, and cerebellum (Fig 6C).
Conclusions
We used fMRI to investigate brain processes supporting fear of movement and anticipated pain of back-straining exercises in cLBP patients, and modulation of this brain circuitry by SMT. cLBP, relative to age- and sex-matched HC subjects, reported higher fear, and anticipated pain, of performing back-straining exercises depicted by observed videos, which was accompanied by increased BOLD fMRI responses in brain circuitry involved in social processing, emotion regulation, and salience. SMT reduced clinical pain, fear of movement, and expected pain from back-straining exercises. Furthermore, reductions in fear and expected pain correlated with reductions in BOLD responses to observing back-straining exercises.
Although there were no differences between SMT techniques on self-report assessment, SMTmanip was associated with stronger reduction in BOLD responses, relative to SMTmobil and HC subjects.
These results shed light on1) the brain processing underpinning aversive anticipation of back-straining movements in cLBP and
2) how SMT might affect these motivational processes.We found that cLBP patients, relative to HC subjects, showed greater BOLD responses in the vlPFC, aINS, dmPFC, dlPFC, TPJ, and STS/MTG when observing videos of individuals performing back-straining relative to neutral exercises. Several of these regions (dmPFC, aINS, and dlPFC) are known nodes of the salience network, [7] and have been implicated in pain anticipation. [23, 48] These regions have also been implicated in goal formation, prediction error processing, and top-down modulation of pain. [37, 47, 52, 72] Furthermore, vlPFC, TPJ, and STS have been consistently implicated in mentalizing, theory of mind, and social cognition more generally. [18, 55, 56, 66] Finally, the STS/MTG cluster is consistent with the extrastriate body area, which is implicated in processing observed bodies and body parts. [14, 36]
Previous studies investigating fear of movement in cLBP have produced mixed results. Consistent with our findings, 1 recent study found that cLBP relative to HC showed increased activation of vlPFC, aINS, STG/STS, and dmPFC/ACC in response to observing images of back-straining relative to neutral activities. [61] Another study also found increased vlPFC and amygdala activation for videos showing back-straining versus back-neutral activities, albeit no BOLD contrast difference between cLBP and HC. [44] Another study found increased hippocampal activation for high-fear cLBP patients compared with HC subjects, [5] while an earlier study found no patient versus HC subject contrast in fMRI response to still images of back-straining maneuvers. [4] These discrepancies may be due to protocol differences. Our study differs from earlier reports in 2 important ways. First, while most previous studies (except [61]) used a preselected pool of aversive stimuli, we used individually tailored back-straining videos for each patient based on which exercises were most painful, maximizing the contrast between back-straining and neutral stimuli. Second, our stimuli were likely more behaviorally relevant than in previous studies, as the participants knew they would be asked to perform the same exercises depicted in the videos. This may have improved our sensitivity in recording relevant brain processes.
We did not find increased BOLD responses in circuitry typically associated with fear, such as the amygdala, aMCC, and subgenual ACC. One reason may be that, despite significantly higher cLBP fear ratings for back-straining compared with neutral videos, and compared with HC subjects, the task did not appear to induce intense kinesiophobia, with relatively small magnitude of fear overall, and with several patients reporting no fear at all. Thus, it is still possible that amygdala/subgenual ACC play important roles for chronic pain-related kinesiophobia in real-life situations involving stronger fear. [54] Moreover, previous studies have also reported limited fear and perceived aversiveness of specifically designed “fear-evoking” visual stimuli, [4, 5, 44] some of which nevertheless reported increased BOLD responses in the amygdala. [42, 44] Future studies may use brainstem-optimized acquisition to investigate the involvement of other key structures important for fear conditioning, such as the posterior and medial hypothalamic nuclei, [16, 19, 64, 73] dorsal periaqueductal gray matter, [62, 64] and the superior colliculus. [41]
Notably, we observed higher ratings of expected pain compared with fear, suggesting patients still found the observed exercises aversive, but perhaps on a more cognitive level, with limited affect. Expectations play a crucial role in pain. Expectations about whether pain will improve or worsen following an intervention can lead to hypo- or hyperalgesia, respectively. [2, 17, 34, 51] Importantly, expectations and beliefs about the outcome of certain actions guide behavioral decisions on whether to approach or avoid. [72] Interestingly, we found that initial expectations of treatment relief correlated with reduction in expected pain from back-straining exercises (Fig 3E). Fear responses likely play a crucial role in the acquisition of avoidance behavior, and are elicited in situations where such feared movements are likely to occur. Nevertheless, explicit fear may potentially be limited during abstract cognitive evaluation of the outcomes of movement — such as in the context of our study — during which avoidance decisions are often made. [35]
We found that SMT reduced not only patients’ clinical back pain, but also the aversiveness of the observed back-straining exercises (ie, both fear and expected pain). Moreover, this correlated with SMT-induced reduction in BOLD responses. Specifically, patients with stronger reduction in expected pain also had stronger reduction in BOLD responses in aINS, STS/STG, aMCC, and Secondary Somatosensory Area II (SII) (SMTmanip) and for reduction in fear and BOLD responses in STS/MTG, posterior insula, posterior cingulate cortex, and cerebellum (SMTmobil). One possibility is that SMT may disrupt the association between low back movement, fear, and pain. [9, 74] Within the fear-avoidance framework, SMT elicits salient sensory and proprioceptive input from the painful region (low back), presumably followed by not only an absence of a unconditioned stimulus/unconditioned response (nociception/pain), but also a reduction of pain. This might help disrupt the association between low back sensations and fear responses — somewhat reminiscent of exposure therapy — which may in turn reduce the aversiveness of back-straining exercises. [67] Alternatively, the reduction in fear and expected pain could be a direct consequence of reduced clinical pain, as people are more aversive to movements when in more pain. [15, 63] If so, we would expect a similar reduction regardless of the location or mode of analgesia. [13] Future studies should systematically compare these motivational aspects during pain relief from treatments involving exteroceptive/proprioceptive stimuli of the painful limb (eg, SMT for cLBP) versus treatment that does not (eg, pharmacotherapy). According to the fear-avoidance model, fear learning is a key component of chronification of pain (and emerging avoidance behavior), and unlearning (eg, through exposure to motion) is suggested as a key mechanism to reduce avoidance behavior and disability. [20, 67] Pharmacological treatment alone has limited prolonged efficacy for chronic pain, [3] potentially due to an inability to target the deeply engrained association between pain anticipation, fear, physical maneuvers, and pain. [21, 24] SMT, either as monotherapy or potentially in combination with psychological therapy such as cognitive behavioral therapy, may have the advantage of targeting this learning aspect of chronic pain, along with other putative mechanisms such as counterirritation and improved local circulation due to reduced muscle tension. [8, 38]
We did not find evidence that different techniques of SMT had a differential effect on clinical pain, fear of movement, or expected pain. Previous studies have similarly not found notable differences in efficacy between techniques. [11, 22, 39, 49, 53] However, we did find differences between techniques in brain responses to the observations of back-straining exercises. cLBP patients relative to HC subjects showed widespread reductions in BOLD responses to back-straining videos after SMTmanip, notably in circuitry identified in the baseline contrast, such as the dlPFC, aINS, vlPFC, TPJ, and STS/MTG. Direct comparison indicated that, for cLBP, SMTmanip induced stronger BOLD contrast reductions in the dlPFC, vlPFC, aINS, posterior STS/STG, and dmPFC, relative to SMTmobil. Taken together, these results suggest that in cLBP patients, SMTmanip induced stronger reduction of BOLD responses in circuitry involved in processing observed back-straining relative to neutral exercises, compared with SMTmobil. This is in line with our hypothesis that SMTmanip, which involves greater amplitude of manipulation directed to the spine joints, would elicit stronger effects on clinical outcomes. However, the lack of a difference in subjective reports warrants a more cautious interpretation.
There are several limitations in our study. First, we assessed outcomes from only a single session of SMTmanip and SMTmobil. Longitudinal studies involving multiple sessions may better parse SMT-induced changes in brain responses with clinically relevant outcomes. Second, we did not observe group differences (cLBP/HC) in trait kinesiophobia. [45] Importantly however, cLBP showed significantly higher fear and expected pain from observed back-straining exercises compared with neutral, which is more central for testing our hypotheses. Furthermore, we observed similar trait kinesiophobia scores as previous studies. [4, 5, 43, 44] Notably, previous studies have also shown no differences in trait kinesiophobia between chronic pain samples and HC subjects, [44] highlighting the possibility that generalized trait kinesiophobia might not be as relevant for chronic pain as situational kinesiophobia that is being acquired through individualized history of movement, fear, and pain. Another limitation is that the sample size, while similar to those of many other fMRI studies, was relatively limited and may be susceptible to type II errors. As such, this study should be followed up by replication in larger samples. This would also allow more advanced (eg, mediation and moderation) analyses aimed at more directly evaluating the possible causal relationship between brain and behavioral changes induced by SMT.
In conclusion, we found that observation of back-straining exercises was associated with increased fear and expected pain of performance in cLBP patients compared with HC subjects, and elicited increased BOLD responses in vlPFC, aINS, dlPFC, dmPFC, TPJ, and STS/MTG. In cLBP patients, both SMTmanip and SMTmobil reduced both clinical pain and aversiveness (fear and expected pain) of observed back-straining exercises. Although the 2 techniques did not differentially affect these clinical outcomes, SMTmanip relative to SMTmobil elicited stronger overall reduction of brain circuitry involved in appraisal of observed back-straining exercises. Importantly, stronger reduction in averseness (fear and expected pain) was associated with stronger reduction in BOLD responses in this circuitry to observing back-straining exercises. Potentially, SMT might modulate the aversiveness of performing back-straining maneuvers through disruption of the association between these (exteroceptive and proprioceptive) sensations and fear/pain. Future studies should address the effect of therapies such as SMT on motivational aspects and avoidance behavior more directly, and include multiple sessions of therapy.
Appendix Supplementary Materials (16)
Supplemental Figure 2 Whole-brain analyses of SMT effects on BOLD
responses to observing physical exercises. PDF (780.63 KB
We conduced whole-brain voxel-wise analyses contrasting BOLD responses to videos (BSE – Neutral) before and after SMT. Activation maps show significant SMT-induced BOLD changes for(A) cLBPmanip and
(B) for cLBPmobil.
There were no SMT-induced changes in BOLD responses for the HC group.
cLBP = chronic Low-Back Pain;
manip = SMT grade V manipulation;
mobil = SMT grade III mobilization;
BSE = Back straining exercises;
Ant. = Anterior;
Post. = Posterior;
HC = Healthy Controls;
SMT = Spinal Manipulative Therapy.
References:
Andersson J, Jenkinson M, Smith S:
Non-linear registration, aka spatial normalisation,
FMRIB technical report TR07JA2, 2010.Atlas, LY, Bolger, N, Lindquist, MA
Brain mediators of predictive cue effects on perceived pain
J Neurosci. 2010; 30:12964-12977Ballantyne, JC, Mao, J
Opioid therapy for chronic pain
N Engl J Med. 2003; 349:1943-1953Barke, A, Baudewig, J, Schmidt-Samoa, C
Neural correlates of fear of movement in high and low
fear-avoidant chronic low back pain patients:
an event-related fMRI studyBarke, A, Preis, MA, Schmidt-Samoa, C
Neural correlates differ in high and low fear-avoidant
chronic low back pain patients when imagining
back-straining movements
J Pain. 2016; 17:930-943Beck AT, Steer RA, Brown GK:
Beck depression Depression inventoryInventory-II.
(Corporation, P., Ed.), San Antonio, TX,
Psychological Corporation, 1996.Beckmann, CF, DeLuca, M, Devlin, JT
Investigations into resting-state connectivity using
independent component analysis
Philos Trans R Soc Lond B Biol Sci. 2005; 360:1001-1013Bialosky, JE, Bishop, MD, Price, DD
The mechanisms of manual therapy in the treatment of
musculoskeletal pain: a comprehensive model
Man Ther. 2009; 14:531-538Bishop, MD, Torres-Cueco, R, Gay, CW
What effect can manual therapy have on a patient's pain experience
Pain Manag. 2015; 5:455-464Chou, R, Shekelle, P
Will this patient develop persistent disabling low back pain
JAMA. 2010; 303:1295-1302Cleland, JA, Glynn, P, Whitman, JM
Short-term effects of thrust versus nonthrust mobilization/
manipulation directed at the thoracic spine in patients
with neck pain: a randomized clinical trial
Phys Ther. 2007; 87:431-440Cook, AJ, Brawer, PA, Vowles, KE
The fear-avoidance model of chronic pain: validation and
age analysis using structural equation modeling
Pain. 2006; 121:195-206Coronado, RA, Gay, CW, Bialosky, JE
Changes in Pain Sensitivity Following Spinal Manipulation:
A Systematic Review and Meta-analysis
J Electromyogr Kinesiol. 2012 (Oct); 22 (5): 752–767Costantini, M, Urgesi, C, Galati, G
Haptic perception and body representation in lateral and
medial occipito-temporal cortices
Neuropsychologia. 2011; 49:821-829Crombez, G, Eccleston, C, Van Damme, S
Fear-avoidance model of chronic pain: the next generation
Clin J Pain. 2012; 28:475-483dos Anjos-Garcia, T, Ullah, F, Falconi-Sobrinho, LL
CB1 cannabinoid receptor-mediated anandamide signalling reduces the
defensive behaviour evoked through GABA(A) receptor blockade in
the dorsomedial division of the ventromedial hypothalamus
Neuropharmacology. 2017; 113:156-166Ellingsen, DM, Wessberg, J, Eikemo, M
Placebo improves pleasure and pain through opposite
modulation of sensory processing
Proc Natl Acad Sci U S A. 2013; 110:17993-17998Etkin, A, Buchel, C, Gross, JJ
The neural bases of emotion regulation
Nat Rev Neurosci. 2015; 16:693-700Falconi-Sobrinho, LL, dos, Anjos-Garcia, T
Unravelling cortico-hypothalamic pathways regulating unconditioned
fear-induced antinociception and defensive behaviours
Neuropharmacology. 2017; 113:367-385Fordyce, WE, Shelton, JL, Dundore, DE
The modification of avoidance learning pain behaviors
J Behav Med. 1982; 5:405-414Gatzounis, R, Schrooten, MG, Crombez, G
Operant learning theory in pain and chronic pain rehabilitation
Curr Pain Headache Rep. 2012; 16:117-126Gay, CW, Robinson, ME, George, SZ
Immediate changes after manual therapy in resting-state functional
connectivity as measured by functional magnetic resonance
imaging in participants with induced low back pain
J Manipulative Physiol Ther. 2014; 37:614-627Geuter, S, Koban, L, Wager, TD
The cognitive neuroscience of placebo effects: concepts,
predictions, and physiology
Annu Rev Neurosci. 2017; 40:167-188Giles, LG, Muller, R
Chronic spinal pain: a randomized clinical trial comparing
medication, acupuncture, and spinal manipulation
Spine. 2003; 28:1490-1502 discussion 1502-1503Glombiewski, JA, Riecke, J, Holzapfel, S
Do patients with chronic pain show autonomic arousal when confronted
with feared movements? An experimental investigation of the fear-avoidance model
Pain. 2015; 156:547-554Greve, DN, Fischl, B
Accurate and robust brain image alignment using boundary-based registration
Neuroimage. 2009; 48:63-72Harvie, DS, Moseley, GL, Hillier, SL
Classical conditioning differences associated with chronic pain:
a systematic review
J Pain. 2017; 18:889-898Hengeveld, E, Banks, K (Editors)
Maitland's Vertebral Manipulation:
Management of Neuromusculoskeletal Disorders
Churchill-Livingstone-Elsevier, London, 2014Houben, RM, Leeuw, M, Vlaeyen, JW
Fear of movement/injury in the general population: factor structure
and psychometric properties of an adapted version of
the Tampa Scale for Kinesiophobia
J Behav Med. 2005; 28:415-424Jenkinson, M
Fast, automated, N-dimensional phase-unwrapping algorithm
Magn Reson Med. 2003; 49:193-197Jenkinson, M
Improving the registration of B0-distorted EPI images
using calculated cost function weights
Presented at the International Conference on Human Brain Mapping
(HBM); June 13-17, 2004Jenkinson, M, Bannister, P, Brady, M
Improved optimization for the robust and accurate linear
registration and motion correction of brain images
Neuroimage. 2002; 17:825-841Jenkinson, M, Smith, S
A global optimisation method for robust affine
registration of brain images
Med Image Anal. 2001; 5:143-156Jensen, KB, Kaptchuk, TJ, Kirsch, I
Nonconscious activation of placebo and nocebo pain responses
Proc Natl Acad Sci U S A. 2012; 109:15959-15964Kirsch, I, Lynn, SJ, Vigorito, M
The role of cognition in classical and operant conditioning
J Clin Psychol. 2004; 60:369-392Kitada, R, Yoshihara, K, Sasaki, AT
The brain network underlying the recognition of hand gestures in
the blind: the supramodal role of the extrastriate body area
J Neurosci. 2014; 34:10096-10108Kucyi, A, Davis, KD
The dynamic pain connectome
Trends Neurosci. 2015; 38:86-95Lascurain-Aguirrebena, I, Newham, D, Critchley, DJ
Mechanism of action of spinal mobilizations:
a systematic review
Spine. 2016; 41:159-172Leaver, AM, Maher, CG, Herbert, RD
A randomized controlled trial comparing manipulation with
mobilization for recent onset neck pain
Arch Phys Med Rehabil. 2010; 91:1313-1318Lethem, J, Slade, PD, Troup, JD
Outline of a fear-avoidance model of exaggerated pain perception–I
Behav Res Ther. 1983; 21:401-408Li, L, Feng, XL, Zhou, Z
Stress accelerates defensive responses to looming in mice and
involves a locus coeruleus-superior colliculus projection
Curr Biol. 2018; 28:859-871.e5Meier, ML, Stämpfli, P, Humphreys, BK
The impact of pain-related fear on neural pathways of
pain modulation in chronic low back pain
Pain Rep. 2017; 2:e601Meier, ML, Stampfli, P, Vrana, A
Fear avoidance beliefs in back pain-free subjects are
reflected by amygdala-cingulate responses
Front Hum Neurosci. 2015; 9:424Meier, ML, Stampfli, P, Vrana, A
Neural correlates of fear of movement in patients with
chronic low back pain vs. pain-free individuals
Front Hum Neurosci. 2016; 10:386Miller, RP, Kori, SH, Todd, DD
The Tampa Scale: A measure of kinisophobia
Clin J Pain. 1991; 7:51Moseley, GL, Vlaeyen, JW
Beyond nociception: the imprecision hypothesis of chronic pain
Pain. 2015; 156:35-38Onat, S, Buchel, C
The neuronal basis of fear generalization in humans
Nat Neurosci. 2015; 18:1811-1818Palermo, S, Benedetti, F, Costa, T
Pain anticipation: an activation likelihood estimation
meta-analysis of brain imaging studies
Hum Brain Mapp. 2015; 36:1648-1661Penza, CW, Horn, ME, George, SZ
Comparison of two lumbar manual therapies on temporal
summation of pain in healthy volunteers
J Pain. 2017; 18:1397-1408Rainville, J, Smeets, RJ, Bendix, T
Fear-avoidance beliefs and pain avoidance in low back
pain–translating research into clinical practice
Spine J. 2011; 11:895-903Reicherts, P, Gerdes, AB, Pauli, P
Psychological placebo and nocebo effects on pain rely
on expectation and previous experience
J Pain. 2016; 17:203-214Roy, M, Shohamy, D, Daw, N
Representation of aversive prediction errors in
the human periaqueductal gray
Nat Neurosci. 2014; 17:1607–1612Salom-Moreno, J, Ortega-Santiago, R, Cleland, JA
Immediate changes in neck pain intensity and widespread pressure pain
sensitivity in patients with bilateral chronic mechanical neck pain:
a randomized controlled trial of thoracic thrust manipulation
vs non-thrust mobilization
J Manipulative Physiol Ther. 2014; 37:312-319Salomons, TV, Davis, KD
Fear avoidance and neuroimaging: falsification or just failure to confirm?
Pain. 2012; 153:511-512Schurz, M, Radua, J, Aichhorn, M
Fractionating theory of mind: a meta-analysis of
functional brain imaging studies
Neurosci Biobehav Rev. 2014; 42:9-34Schurz, M, Tholen, MG, Perner, J
Specifying the brain anatomy underlying temporo-parietal junction
activations for theory of mind: A review using probabilistic
atlases from different imaging modalities
Hum Brain Mapp. 2017; 38:4788–4805Sherman, KJ, Hogeboom, CJ, Cherkin, DC
Description and validation of a noninvasive placebo acupuncture procedure
J Altern Complement Med. 2002; 8:11-19Smith, SM
Fast robust automated brain extraction
Hum Brain Mapp. 2002; 17:143-155Sullivan, MJL, Bishop, SR, Pivik, J
The Pain Catastrophizing Scale: development and validation
Psychol Assess. 1995; 7:524-532Tan, G, Jensen, MP, Thornby, JI
Validation of the Brief Pain Inventory for chronic nonmalignant pain
J Pain. 2004; 5:133-137Taylor, AM, Harris, AD, Varnava, A
A functional magnetic resonance imaging study to investigate the utility
of a picture imagination task in investigating neural responses in
patients with chronic musculoskeletal pain to
daily physical activity photographs
PLoS One. 2015; 10, e0141133Tracey, I, Ploghaus, A, Gati, JS
Imaging attentional modulation of pain in the periaqueductal gray in humans
J Neurosci. 2002; 22:2748-2752Trost, Z, France, CR, Thomas, JS
Exposure to movement in chronic back pain: evidence of
successful generalization across a reaching task
Pain. 2008; 137:26-33Ullah, F, dos Anjos-Garcia, T, dos Santos, IR
Relevance of dorsomedial hypothalamus, dorsomedial division of the
ventromedial hypothalamus and the dorsal periaqueductal gray
matter in the organization of freezing or oriented and
non-oriented escape emotional behaviors
Behav Brain Res. 2015; 293:143-152Van Essen, DC
Windows on the brain: the emerging role of atlases and databases in neuroscience
Curr Opin Neurobiol. 2002; 12:574-579Van Overwalle, F
A dissociation between social mentalizing and general reasoning
Neuroimage. 2011; 54:1589-1599Vlaeyen, JW
Learning to predict and control harmful events: chronic pain and conditioning
Pain. 2015; 156(Suppl 1):S86-S93Vlaeyen, JW, Kole-Snijders, AM, Boeren, RG
Fear of movement/(re)injury in chronic low back pain and
its relation to behavioral performance
Pain. 1995; 62:363-372Vlaeyen, JW, Kole-Snijders, AM, Rotteveel, AM
The role of fear of movement/(re)injury in pain disability
J Occup Rehabil. 1995; 5:235-252Vlaeyen, JW, Morley, S, Linton, SJ
Pain-Related Fear: Exposure Based Treatment for Chronic Pain
IASP Press, Seattle, 2012Wertli, MM, Rasmussen-Barr, E, Weiser, S
The role of fear avoidance beliefs as a prognostic factor for outcome
in patients with nonspecific low back pain: a systematic review
Spine J. 2014; 14:816-836Wiech, K, Tracey, I
Pain, decisions, and actions: a motivational perspective
Front Neurosci. 2013; 7:46Wilent, WB, Oh, MY, Buetefisch, CM
Induction of panic attack by stimulation of the ventromedial hypothalamus
J Neurosurg. 2010; 112:1295-1298Zusman, M
Mechanisms of musculoskeletal physiotherapy
Phys Ther Rev. 2013; 9:39-49
Return to LOW BACK PAIN
Since 9-03-2025
| Home Page | Visit Our Sponsors | Become a Sponsor |
Please read our DISCLAIMER |