Mechanisms of Post-Stroke Fatigue: A Follow-Up From the Third Stroke Recovery and Rehabilitation Roundtable.

BACKGROUND: Post-stroke fatigue (PSF) is a significant and highly prevalent symptom, whose mechanisms are poorly understood. The third Stroke Recovery and Rehabilitation Roundtable paper on PSF focussed primarily on defining and measuring PSF while mechanisms were briefly discussed. This companion paper to the main paper is aimed at elaborating possible mechanisms of PSF. METHODS: This paper reviews the available evidence that potentially explains the pathophysiology of PSF and draws parallels from fatigue literature in other conditions. We start by proposing a case for phenotyping PSF based on structural, functional, and behavioral characteristics of PSF. This is followed by discussion of a potentially significant role of early inflammation in the development of fatigue, specifically the impact of low-grade inflammation and its long-term systemic effects resulting in PSF. Of the many neurotransmitter systems in the brain, the dopaminergic systems have the most evidence for a role in PSF, along with a role in sensorimotor processing. Sensorimotor neural network dynamics are compromised as highlighted by evidence from both neurostimulation and neuromodulation studies. The double-edged sword effect of exercise on PSF provides further insight into how PSF might emerge and the importance of carefully titrating interventional paradigms. CONCLUSION: The paper concludes by synthesizing the presented evidence into a unifying model of fatigue which distinguishes between factors that pre-dispose, precipitate, and perpetuate PSF. This framework will help guide new research into the biological mechanisms of PSF which is a necessary prerequisite for developing treatments to mitigate the debilitating effects of post-stroke fatigue.

A multi-centre study to explore the feasibility and acceptability of collecting data for complex regional pain syndrome clinical studies using a core measurement set: Study protocol.

OBJECTIVES: This international, multicentre study will inform the final data collection tools and processes which will comprise the first international, clinical research registry for complex regional pain syndrome (CRPS). This study will: (a) test the feasibility and acceptability of collecting outcome measurement data using a patient reported, questionnaire core measurement set (COMPACT [Core Outcome Measurement set for complex regional PAin syndrome Clinical sTudies]); and (b) test and refine an electronic data management system to collect and manage the data. METHODS: A maximum of 240 adults, meeting the Budapest diagnostic clinical criteria for CRPS type I or II, will be recruited across eight countries. The COMPACT questionnaire will be completed on two occasions: at baseline (T1) and 6 months later (T2). At T2, participants will choose to complete COMPACT using a paper or electronic version. Participants will be asked to feed back on their experience of completing COMPACT via a questionnaire. A separate questionnaire will ask clinicians to feed back their experience of data collection. ANALYSIS: The study is not aiming to derive statistically significant data but to ascertain the practicalities of collecting data, using the COMPACT questionnaire set, across a range of different cultures and populations. At the end of the study, a single workshop will be convened to review the findings and agree the final documents and processes for the international registry.

The pain of tendinopathy: physiological or pathophysiological?

Tendon pain remains an enigma. Many clinical features are consistent with tissue disruption-the pain is localised, persistent and specifically associated with tendon loading, whereas others are not-investigations do not always match symptoms and painless tendons can be catastrophically degenerated. As such, the question 'what causes a tendon to be painful?' remains unanswered. Without a proper understanding of the mechanism behind tendon pain, it is no surprise that treatments are often ineffective. Tendon pain certainly serves to protect the area-this is a defining characteristic of pain-and there is often a plausible nociceptive contributor. However, the problem of tendon pain is that the relation between pain and evidence of tissue disruption is variable. The investigation into mechanisms for tendon pain should extend beyond local tissue changes and include peripheral and central mechanisms of nociception modulation. This review integrates recent discoveries in diverse fields such as histology, physiology and neuroscience with clinical insight to present a current state of the art in tendon pain. New hypotheses for this condition are proposed, which focus on the potential role of tenocytes, mechanosensitive and chemosensitive receptors, the role of ion channels in nociception and pain and central mechanisms associated with load and threat monitoring.

Limb-specific autonomic dysfunction in complex regional pain syndrome modulated by wearing prism glasses.

In unilateral upper-limb complex regional pain syndrome (CRPS), the temperature of the hands is modulated by where the arms are located relative to the body midline. We hypothesized that this effect depends on the perceived location of the hands, not on their actual location, nor on their anatomical alignment. In 2 separate cross-sectional randomized experiments, 10 (6 female) unilateral CRPS patients wore prism glasses that laterally shifted the visual field by 20°. Skin temperature was measured before and after 9-minute periods in which the position of one hand was changed. Placing the affected hand on the healthy side of the body midline increased its temperature (Δ°C=+0.47 ± 0.14°C), but not if prism glasses made the hand appear to be on the body midline (Δ°C=+0.07 ± 0.06°C). Similarly, when prism glasses made the affected hand appear to be on the healthy side of the body midline, even though it was not, the affected hand warmed up (Δ°C=+0.28 ± 0.14°C). When prism glasses made the healthy hand appear to be on the affected side of the body midline, even though it was not, the healthy hand cooled down (Δ°C=-0.30 ± 0.15°C). Friedman's analysis of variance and Wilcoxon pairs tests upheld the results (P<0.01 for all). We conclude that, in CRPS, cortical mechanisms responsible for encoding the perceived location of the limbs in space modulate the temperature of the hands.

Perceptual bias in pain: a switch looks closer when it will relieve pain than when it won't.

Pain is fundamental to survival, as are our perceptions of the environment. It is often assumed that we see our world as a read-out of the sensory information that we receive; yet despite the same physical makeup of our surroundings, individuals perceive differently. What if we "see" our world differently when we experience pain? Until now, the causal effect of experimental pain on the perception of an external stimulus has not been investigated. Eighteen (11 female) healthy volunteers participated in this randomised repeated-measures experiment, in which participants estimated the distance to a switch placed on the table in front of them. We varied whether or not the switch would instantly stop a stimulus, set to the participant's pain threshold, being delivered to their hand, and whether or not they were required to reach for the switch. The critical result was a strong interaction between reaching and pain [F(1,181)=4.8, P=0.03], such that when participants experienced pain and were required to reach for a switch that would turn off the experimental stimulus, they judged the distance to that switch to be closer, as compared to the other 3 conditions (mean of the true distance 92.6%, 95% confidence interval 89.7%-95.6%). The judged distance was smaller than estimates in the other 3 conditions (mean±SD difference >5.7%±2.1%, t(181) >3.5, P<0.01 for all 3 comparisons). We conclude that the perception of distance to an object is modulated by the behavioural relevance of the object to ongoing pain.

The effect of tactile discrimination training is enhanced when patients watch the reflected image of their unaffected limb during training.

In patients with phantom limb pain or complex regional pain syndrome (CRPS), sensory discrimination training increases tactile acuity, normalises cortical reorganisation and decreases pain. In healthy people, sensory cortical response, and tactile acuity, are greater if the participant looks towards the body part being stimulated. Does this effect enhance tactile training in CRPS patients? Ten patients underwent a 30-min tactile discrimination training session under four conditions (order randomised) in a 2 x 2 design: looking towards or away from the stimulated limb and seeing or not seeing skin. Tactile training imparted long-term improvement in tactile acuity when patients watched the reflected image of their unaffected limb in a mirror during training (that is, they looked towards the stimulated body part and could see the skin of the opposite body part in the mirror): two-point discrimination threshold (TPD) was 8mm less 2 days after training than it was before training ([95% CI=1.5-14.3mm], p<0.001). Although this condition also imparted a greater reduction in resting pain at post-treatment than the other conditions, and change in pain and change in TPD over the session were strongly related (r=0.83, p<0.001), there was no residual effect on pain at 2-day follow-up. In the other conditions, tactile acuity had returned to pre-training levels at 2-day follow-up. The results should directly improve management of CRPS, and have implications for rehabilitation of other conditions associated with nervous system injury or disease, for example stroke, in which tactile recovery is a major objective of rehabilitation.

Why do some patients keep hurting their back? Evidence of ongoing back muscle dysfunction during remission from recurrent back pain.

Approximately thirty-four percent of people who experience acute low back pain (LBP) will have recurrent episodes. It remains unclear why some people experience recurrences and others do not, but one possible cause is a loss of normal control of the back muscles. We investigated whether the control of the short and long fibres of the deep back muscles was different in people with recurrent unilateral LBP from healthy participants. Recurrent unilateral LBP patients, who were symptom free during testing, and a group of healthy volunteers, participated. Intramuscular and surface electrodes recorded the electromyographic activity (EMG) of the short and long fibres of the lumbar multifidus and the shoulder muscle, deltoid, during a postural perturbation associated with a rapid arm movement. EMG onsets of the short and long fibres, relative to that of deltoid, were compared between groups, muscles, and sides. In association with a postural perturbation, short fibre EMG onset occurred later in participants with recurrent unilateral LBP than in healthy participants (p=0.022). The short fibres were active earlier than long fibres on both sides in the healthy participants (p<0.001) and on the non-painful side in the LBP group (p=0.045), but not on the previously painful side in the LBP group. Activity of deep back muscles is different in people with a recurrent unilateral LBP, despite the resolution of symptoms. Because deep back muscle activity is critical for normal spinal control, the current results provide the first evidence of a candidate mechanism for recurrent episodes.

I can't find it! Distorted body image and tactile dysfunction in patients with chronic back pain.

The conscious sense of our body, or body image, is often taken for granted, but it is disrupted in many clinical states including complex regional pain syndrome and phantom limb pain. Is the same true for chronic back pain? Body image was assessed, via participant drawings, in six patients with chronic back pain and ten healthy controls. Tactile threshold and two-point discrimination threshold (TPD) were assessed in detail. All the patients, and none of the controls, showed disrupted body image of the back. Five patients were unable to clearly delineate the outline of their trunk and stated that they could not "find it". TPD was greatly increased in the same zone as the absence or disruption of body image, but was otherwise similar to controls. The disturbance of body image and decrease in tactile acuity coincided with the normal distribution of pain, although there was no allodynia and there was no relationship between resting pain level and TPD. Tactile threshold was unremarkable for patients and controls. These preliminary data indicate that body image is disrupted, and tactile acuity is decreased, in the area of usual pain, in patients with chronic back pain. This finding raises the possibility that training body image or tactile acuity may help patients in chronic spinal pain, as it has been shown to do in patients with complex regional pain syndrome or phantom limb pain.

Tactile discrimination, but not tactile stimulation alone, reduces chronic limb pain.

Chronic pain is often associated with reduced tactile acuity. A relationship exists between pain intensity, tactile acuity and cortical reorganisation. When pain resolves, tactile function improves and cortical organisation normalises. Tactile acuity can be improved in healthy controls when tactile stimulation is associated with a behavioural objective. We hypothesised that, in patients with chronic limb pain and decreased tactile acuity, discriminating between tactile stimuli would decrease pain and increase tactile acuity, but tactile stimulation alone would not. Thirteen patients with complex regional pain syndrome (CRPS) of one limb underwent a waiting period and then approximately 2 weeks of tactile stimulation under two conditions: stimulation alone or discrimination between stimuli according to their diameter and location. There was no change in pain (100 mm VAS) or two-point discrimination (TPD) during a no-treatment waiting period, nor during the stimulation phase (p > 0.32 for both). Pain and TPD were lower after the discrimination phase [mean (95% CI) effect size for pain VAS = 27 mm (14-40 mm) and for TPD = 5.7 mm (2.9-8. ), p < 0.015 for both]. These gains were maintained at three-month follow-up. We conclude that tactile stimulation can decrease pain and increase tactile acuity when patients are required to discriminate between the type and location of tactile stimuli.

Using visual illusion to reduce at-level neuropathic pain in paraplegia.

Neuropathic pain after spinal cord injury is not well understood and is difficult to treat. One possible cause is mismatch between motor commands and sensory feedback. This two-part study in five paraplegic patients investigated whether a visual illusion aimed to correct this mismatch reduces pain. In study 1, patients undertook three conditions: (i) virtual walking: with a mirror placed in front of a screen, patients aligned their own upper body with a film of a lower body walking. Patients imagined walking and 'watched themselves' walk; (ii) guided imagery; (iii) watching a film. One patient withdrew from virtual walking because of distress. For all patients, the mean (95% CI) decrease in pain (100 mm VAS) was 42 mm (approximately 65%) (11-73 mm) for virtual walking, 18 mm (4-31 mm) for guided imagery and 4mm (-3 to 11 mm) for watching the film. Mean (95% CI) time to return to pre-task pain was 34.9 min (20.1-49.8 min) for virtual walking; 13.9 min (-0.9 to 28.8 min) for the guided imagery and 16.3 min (1.5-31.2 min) for the film. To investigate its clinical utility, four patients underwent virtual walking every weekday for 3 weeks. Mean (95% CI) decrease in pain was 53 mm (45-61 mm) at post training and 43 mm (27-58 mm) at 3-month follow-up. Virtual walking may be a viable treatment for pain after spinal cord injury. A clinical trial seems warranted.

Unraveling the barriers to reconceptualization of the problem in chronic pain: the actual and perceived ability of patients and health professionals to understand the neurophysiology.

To identify why reconceptualization of the problem is difficult in chronic pain, this study aimed to evaluate whether (1) health professionals and patients can understand currently accurate information about the neurophysiology of pain and (2) health professionals accurately estimate the ability of patients to understand the neurophysiology of pain. Knowledge tests were completed by 276 patients with chronic pain and 288 professionals either before (untrained) or after (trained) education about the neurophysiology of pain. Professionals estimated typical patient performance on the test. Untrained participants performed poorly (mean +/- standard deviation, 55% +/- 19% and 29% +/- 12% for professionals and patients, respectively), compared to their trained counterparts (78% +/- 21% and 61% +/- 19%, respectively). The estimated patient score (46% +/- 18%) was less than the actual patient score (P <.005). The results suggest that professionals and patients can understand the neurophysiology of pain but professionals underestimate patients' ability to understand. The implications are that (1) a poor knowledge of currently accurate information about pain and (2) the underestimation of patients' ability to understand currently accurate information about pain represent barriers to reconceptualization of the problem in chronic pain within the clinical and lay arenas.

Combined physiotherapy and education is efficacious for chronic low back pain.

Manual therapy, exercise and education target distinct aspects of chronic low back pain and probably have distinct effects. This study aimed to determine the efficacy of a combined physiotherapy treatment that comprised all of these strategies. By concealed randomisation, 57 chronic low back pain patients were allocated to either the four-week physiotherapy program or management as directed by their general practitioners. The dependent variables of interest were pain and disability. Assessors were blind to treatment group. Outcome data from 49 subjects (86%) showed a significant treatment effect. The physiotherapy program reduced pain and disability by a mean of 1.5/10 points on a numerical rating scale (95% CI 0.7 to 2.3) and 3.9 points on the 18-point Roland Morris Disability Questionnaire (95% CI 2 to 5.8), respectively. The number needed to treat in order to gain a clinically meaningful change was 3 (95% CI 3 to 8) for pain, and 2 (95% CI 2 to 5) for disability. A treatment effect was maintained at one-year follow-up. The findings support the efficacy of combined physiotherapy treatment in producing symptomatic and functional change in moderately disabled chronic low back pain patients.