sit-to-stand-walk-from-120-knee-height-novel-approach-to-assess

Sit-to-stand-and-walk from 120% Knee Height: A Novel Approach to Assess Dynamic Postural Control Independent of Lead-limb

Individuals with sensorimotor pathology e.g., stroke have difficulty executing the common task of rising from sitting and initiating gait (sit-to-walk: ...

King's College London

Guy's & St Thomas' NHS Foundation Trust, London

Damage to the peripheral nervous system often leads to chronic neuropathic pain characterized by spontaneous pain and an exaggerated response to painful and/or innocuous stimuli. This pain condition is extremely debilitating and usually difficult to treat. Although inflammatory and neuropathic pain syndromes are often considered distinct entities, emerging evidence belies this strict dichotomy. Inflammation is a well-characterized phenomenon, which involves a cascade of different immune cell types, such as mast cells, neutrophils, macrophages, and T lymphocytes. In addition, these cells release numerous compounds that contribute to pain. Recent evidence suggests that immune cells play a role in neuropathic pain in the periphery. In this review we identify the different immune cell types that contribute to neuropathic pain in the periphery and release factors that are crucial in this particular condition.

Pathophysiology of peripheral neuropathic pain: immune cells and molecules.

While neuroimmune interactions are increasingly recognized as important in nociceptive processing, the nature and functional significance of these interactions is not well defined. There are multiple reports that the activation of spinal microglia is a critical event in the generation of neuropathic pain behaviors but the mediators of this activation remain disputed. Here we show that the chemokine CCL2, produced by both damaged and undamaged primary sensory neurons in neuropathic pain states in rats, is released in an activity dependent manner from the central terminals of these fibres. We also demonstrate that intraspinal CCL2 in naïve rats leads to activation of spinal microglia and neuropathic pain-like behavior. An essential role for spinal CCL2 is demonstrated by the inhibition of neuropathic pain behavior and microglial activation by a specific neutralising antibody to CCL2 administered intrathecally. Thus, the neuronal expression of CCL2 provides a mechanism for immune activation, which in turn regulates the sensitivity of pain signaling systems in neuropathic pain states.

CCL2 is a key mediator of microglia activation in neuropathic pain states.

Neuropathic pain. Management is more than pills.

Enhancing the neurologist's role in complex regional pain syndrome.

There is increasing evidence that chronic pain problems are characterised by alterations in brain structure and function. Chronic back pain is no exception. There is a growing sentiment, with accompanying theory, that these brain changes contribute to chronic back pain, although empirical support is lacking. This paper reviews the structural and functional changes of the brain that have been observed in people with chronic back pain. We cast light on the clinical implications of these changes and the possibilities for new treatments but we also advise caution against concluding their efficacy in the absence of solid evidence to this effect.

Cortical changes in chronic low back pain: current state of the art and implications for clinical practice.

Sarcoidosis is a polygenic disease with diverse phenotypic presentations characterized by an abnormal antigen-mediated Th1 type immune response. At present, progress towards understanding sarcoidosis disease mechanisms and the development of novel treatments is limited by constraints attendant to conducting human research in a rare disease in the absence of relevant animal models. We sought to develop a computational model to enhance our understanding of the pathological mechanisms of and predict potential treatments of sarcoidosis.

An in silico modeling approach to understanding the dynamics of sarcoidosis.

First-person neuroscience and the understanding of pain.

Increasing evidence suggests a central nervous system (CNS) component underpinning persistent pain disease states. This study was undertaken to determine regional cerebral blood flow (rCBF) changes representing ongoing pain experienced by patients with painful osteoarthritis (OA) of the carpometacarpal (CMC) joint and to examine rCBF variability across sessions. We used pulsed continuous arterial spin labeling (pCASL), a perfusion magnetic resonance imaging (MRI) technique.

Alterations in resting-state regional cerebral blood flow demonstrate ongoing pain in osteoarthritis: An arterial spin-labeled magnetic resonance imaging study.

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.

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

Arterial spin labelling (ASL) is increasingly being applied to study the cerebral response to pain in both experimental human models and patients with persistent pain. Despite its advantages, scanning time and reliability remain important issues in the clinical applicability of ASL. Here we present the test-retest analysis of concurrent pseudo-continuous ASL (pCASL) and visual analogue scale (VAS), in a clinical model of on-going pain following third molar extraction (TME). Using ICC performance measures, we were able to quantify the reliability of the post-surgical pain state and ΔCBF (change in CBF), both at the group and individual case level. Within-subject, the inter- and intra-session reliability of the post-surgical pain state was ranked good-to-excellent (ICC > 0.6) across both pCASL and VAS modalities. The parameter ΔCBF (change in CBF between pre- and post-surgical states) performed reliably (ICC > 0.4), provided that a single baseline condition (or the mean of more than one baseline) was used for subtraction. Between-subjects, the pCASL measurements in the post-surgical pain state and ΔCBF were both characterised as reliable (ICC > 0.4). However, the subjective VAS pain ratings demonstrated a significant contribution of pain state variability, which suggests diminished utility for interindividual comparisons. These analyses indicate that the pCASL imaging technique has considerable potential for the comparison of within- and between-subjects differences associated with pain-induced state changes and baseline differences in regional CBF. They also suggest that differences in baseline perfusion and functional lateralisation characteristics may play an important role in the overall reliability of the estimated changes in CBF. Repeated measures designs have the important advantage that they provide good reliability for comparing condition effects because all sources of variability between subjects are excluded from the experimental error. The ability to elicit reliable neural correlates of on-going pain using quantitative perfusion imaging may help support the conclusions derived from subjective self-report.

Quantifying the test-retest reliability of cerebral blood flow measurements in a clinical model of on-going post-surgical pain: A study using pseudo-continuous arterial spin labelling.

There has been a widespread call for an ethics in the management of patients with chronic pain which is patient centered and takes into account the lived experience of the patient. It has been argued in literature that current "duty" or principlist-based models of ethics (so-called 3rd person ethics) have not adequately addressed the needs of either patients or practitioners in this area.

The moral experience of the patient with chronic pain: bridging the gap between first and third person ethics.

In an attempt to shed light on management of chronic pain conditions, there has long been a desire to complement behavioral measures of pain perception with measures of underlying brain mechanisms. Using functional magnetic resonance imaging (fMRI), we undertook this study to investigate changes in brain activity following the administration of naproxen or placebo in patients with pain related to osteoarthritis (OA) of the carpometacarpal (CMC) joint.

Pharmacologic modulation of hand pain in osteoarthritis: a double-blind placebo-controlled functional magnetic resonance imaging study using naproxen.

Nonopioid agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are the most commonly used class of analgesics. Increasing evidence suggests that cyclooxygenase (COX) inhibition at both peripheral and central sites can contribute to the antihyperalgesic effects of NSAIDs, with the predominant clinical effect being mediated centrally. In this study, we examined the cerebral response to ibuprofen in presurgical and postsurgical states and looked at the analgesic interaction between surgical state and treatment. We used an established clinical pain model involving third molar extraction, and quantitative arterial spin labelling (ASL) imaging to measure changes in tonic/ongoing neural activity. Concurrent to the ASL scans, we presented visual analogue scales inside the scanner to evaluate the subjective experience of pain. This novel methodology was incorporated into a randomized double-blind placebo-controlled design, with an open method of drug administration. We found that independent of its antinociceptive action, ibuprofen has no effect on regional cerebral blood flow under pain-free conditions (presurgery). However, in the postsurgical state, we observed increased activation of top-down modulatory circuits, which was accompanied by decreases in the areas engaged because of ongoing pain. Our findings demonstrate that ibuprofen has a measurable analgesic response in the human brain, with the subjective effects of pain relief reflected in two distinct brain networks. The observed activation of descending modulatory circuits warrants further investigation, as this may provide new insights into the inhibitory mechanisms of analgesia that might be exploited to improve safety and efficacy in pain management.

Cerebral analgesic response to nonsteroidal anti-inflammatory drug ibuprofen.

Pain is an experience that powerfully influences the way we interact with our environment. What is less clear is the influence that pain has on the way we perceive our environment. We investigated the effect that the anticipation of experimental pain (THREAT) and its relief (RELIEF) has on the visual perception of space. Eighteen (11F) healthy volunteers estimated the distance to alternating THREAT and RELIEF stimuli that were placed within reachable space. The results determined that the estimated distance to the THREAT stimulus was significantly underestimated in comparison to the RELIEF stimulus. We conclude that pain-evoking stimuli are perceived as closer to the body than otherwise identical pain-relieving stimuli, an important consideration when applied to our decisions and behaviors in relation to the experience of pain.

The close proximity of threat: altered distance perception in the anticipation of pain.

The experience of chronic pain critically alters one's ability to interact with their environment. One fundamental issue that has received little attention, however, is whether chronic pain disrupts how one perceives their environment in the first place. The Economy of Action hypothesis purports that the environment is spatially scaled according to the ability of the observer. Under this hypothesis it has been proposed that the perception of the world is different between those with and without chronic pain. Such a possibility has profound implications for the investigation and treatment of pain. The present investigation tested the application of this hypothesis to a heterogenous chronic pain population.

Perceptual Inference in Chronic Pain: An Investigation Into the Economy of Action Hypothesis.

Sit-to-walk (STW) is a common transitional motor task not usually included in rehabilitation. Typically, sit-to-stand (STS), pause, then gait initiation (GI) before walking is used, which we term sit-to-stand-and-walk (STSW). Separation between centre-of-pressure (COP) and whole-body centre-of-mass (BCOM) during GI is associated with dynamic postural stability. Rising from seats higher than knee-height (KH) is more achievable for patients, but whether this and/or lead-limb significantly affects task dynamics is unclear. This study tested whether rising from seat-heights and lead-limb affects STW and STSW task dynamics in young healthy individuals.

Sit-to-walk and sit-to-stand-and-walk task dynamics are maintained during rising at an elevated seat-height independent of lead-limb in healthy individuals.

Article	Year
Pathophysiology of peripheral neuropathic pain: immune cells and molecules. Anesthesia and analgesia\| PubMed ID: 17717248	2007
CCL2 is a key mediator of microglia activation in neuropathic pain states. European journal of pain (London, England)\| PubMed ID: 18554968	2009
Neuropathic pain. Management is more than pills. BMJ (Clinical research ed.)\| PubMed ID: 19723716	2009
Enhancing the neurologist's role in complex regional pain syndrome. Annals of neurology\| PubMed ID: 20373360	2010
Cortical changes in chronic low back pain: current state of the art and implications for clinical practice. Manual therapy\| PubMed ID: 20655796	2011
An in silico modeling approach to understanding the dynamics of sarcoidosis. PloS one\| PubMed ID: 21637752	2011
First-person neuroscience and the understanding of pain. The Medical journal of Australia\| PubMed ID: 22471546	2012
Alterations in resting-state regional cerebral blood flow demonstrate ongoing pain in osteoarthritis: An arterial spin-labeled magnetic resonance imaging study. Arthritis and rheumatism\| PubMed ID: 22933378	2012
Perceptual bias in pain: a switch looks closer when it will relieve pain than when it won't. Pain\| PubMed ID: 23726934	2013
Quantifying the test-retest reliability of cerebral blood flow measurements in a clinical model of on-going post-surgical pain: A study using pseudo-continuous arterial spin labelling. NeuroImage. Clinical\| PubMed ID: 24143296	2013
The moral experience of the patient with chronic pain: bridging the gap between first and third person ethics. Pain medicine (Malden, Mass.)\| PubMed ID: 24308326	2014
Pharmacologic modulation of hand pain in osteoarthritis: a double-blind placebo-controlled functional magnetic resonance imaging study using naproxen. Arthritis & rheumatology (Hoboken, N.J.)\| PubMed ID: 25533872	2015
Cerebral analgesic response to nonsteroidal anti-inflammatory drug ibuprofen. Pain\| PubMed ID: 25851460	2015
The close proximity of threat: altered distance perception in the anticipation of pain. Frontiers in psychology\| PubMed ID: 26029151	2015
Perceptual Inference in Chronic Pain: An Investigation Into the Economy of Action Hypothesis. The Clinical journal of pain\| PubMed ID: 26418359	2016
Sit-to-walk and sit-to-stand-and-walk task dynamics are maintained during rising at an elevated seat-height independent of lead-limb in healthy individuals. Gait & posture\| PubMed ID: 27336849	2016

Michael Thacker

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