Effect of local versus remote tonic heat pain during training on acquisition and retention of a finger-tapping sequence task.

Although pain is present in a large proportion of patients receiving rehabilitation, its impact on motor learning is still unclear, especially in the case of neuropathic pain that is not tightly linked to specific movements. The aim of this study was to determine the effect of local and remote tonic cutaneous heat pain applied during training on motor learning of a finger-tapping sequence task. Forty-five healthy participants, randomized to the control, local pain or remote pain groups, were trained to perform an explicit finger motor sequence of five items as fast as possible. During the 10 training blocks (30 s each), local pain and remote pain groups received a heat pain stimulus on the wrist or leg, respectively. Performance was tested in the absence of pain in all groups before (baseline), immediately after (post-immediate), 60 min after (post-60 min) and 24 h after training (post-24 h) to assess both acquisition and next-day retention. Speed increased over time from baseline to post-24 h (p < 0.001), without any significant effect of group (p = 0.804) or time × group interaction (p = 0.385), indicating that the acquisition and retention were not affected by the presence of pain during training. No changes were observed on error rates, which were very low even at baseline. These results with experimental heat pain suggest that the ability to relearn finger sequence should not be affected by concomitant neuropathic pain in neurorehabilitation. However, these results need to be validated in the context of chronic pain, by including pain as a co-variable in motor rehabilitation trials.

Real-time modulation of visual feedback on human full-body movements in a virtual mirror: development and proof-of-concept.

BACKGROUND: Virtual reality (VR) provides interactive multimodal sensory stimuli and biofeedback, and can be a powerful tool for physical and cognitive rehabilitation. However, existing systems have generally not implemented realistic full-body avatars and/or a scaling of visual movement feedback. We developed a "virtual mirror" that displays a realistic full-body avatar that responds to full-body movements in all movement planes in real-time, and that allows for the scaling of visual feedback on movements in real-time. The primary objective of this proof-of-concept study was to assess the ability of healthy subjects to detect scaled feedback on trunk flexion movements. METHODS: The "virtual mirror" was developed by integrating motion capture, virtual reality and projection systems. A protocol was developed to provide both augmented and reduced feedback on trunk flexion movements while sitting and standing. The task required reliance on both visual and proprioceptive feedback. The ability to detect scaled feedback was assessed in healthy subjects (n = 10) using a two-alternative forced choice paradigm. Additionally, immersion in the VR environment and task adherence (flexion angles, velocity, and fluency) were assessed. RESULTS: The ability to detect scaled feedback could be modelled using a sigmoid curve with a high goodness of fit (R2 range 89-98%). The point of subjective equivalence was not significantly different from 0 (i.e. not shifted), indicating an unbiased perception. The just noticeable difference was 0.035 ± 0.007, indicating that subjects were able to discriminate different scaling levels consistently. VR immersion was reported to be good, despite some perceived delays between movements and VR projections. Movement kinematic analysis confirmed task adherence. CONCLUSIONS: The new "virtual mirror" extends existing VR systems for motor and pain rehabilitation by enabling the use of realistic full-body avatars and scaled feedback. Proof-of-concept was demonstrated for the assessment of body perception during active movement in healthy controls. The next step will be to apply this system to assessment of body perception disturbances in patients with chronic pain.

Multimodal and widespread somatosensory abnormalities in persistent shoulder pain in the first 6 months after stroke: an exploratory study.

OBJECTIVE: To explore the role of multimodal and widespread somatosensory abnormalities in the development of persistent poststroke shoulder pain (pPSSP) in the first 6 months after stroke. DESIGN: Prospective inception cohort study. SETTING: Stroke units of 2 teaching hospitals. PARTICIPANTS: The data of a strict selection of patients (N=31) with a clinical diagnosis of stroke were analyzed. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The development of pPSSP within the first 6 months after stroke. Bilateral sensation and pain thresholds at 3 (t1) and 6 (t2) months, and conditioned pain modulation (CPM) at 3 months after stroke. Clinical examination within 2 weeks after stroke (t0), at t1, and at t2. RESULTS: pPSSP (n=9) was associated with increased sensation and pain threshold ratios at the affected side (t1, t2), and with reduced cold pain tolerance at the unaffected side (t1). CPM was not different from patients without pPSSP (n=22). Notably, in patients with pPSSP reporting increased sensation on clinical examination, multiple body sites across multiple stimulus modalities were involved, and increased sensation persisted from t1 to t2. CONCLUSIONS: pPSSP in the first 6 months after stroke was associated with somatosensory loss to both innocuous and noxious stimuli (affected side). In addition, pPSSP was associated with sensitization to cold pain (unaffected side) and with widespread sensitization to multimodal innocuous stimuli (affected side). The results support the notion that central somatosensory sensitization could play an important role in the development of pPSSP, the maintenance of pPSSP, or both.

Persistent shoulder pain in the first 6 months after stroke: results of a prospective cohort study.

OBJECTIVE: To identify factors associated with persistent poststroke shoulder pain (pPSSP) in the first 6 months after stroke. DESIGN: Prospective inception cohort study. SETTING: Stroke units of 2 teaching hospitals. PARTICIPANTS: Patients (N=31) with a clinical diagnosis of stroke. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The development of pPSSP within the first 6 months after stroke. Clinical assessment of motor, somatosensory, cognitive, emotional, and autonomic functions, undertaken within 2 weeks (t0), at 3 months (t1), and at 6 months (t2) after stroke. RESULTS: Patients with pPSSP (n=9) were compared with patients without pPSSP (n=22). Bivariate logistic regression analyses showed that pPSSP was significantly associated with impaired voluntary motor control (t0, t1, t2), diminished proprioception (t0, t1), tactile extinction (t0), abnormal sensation (t1, t2), spasticity of the elbow flexor muscles (t1, t2), restricted range of motion (ROM) for both shoulder abduction (t2) and shoulder external rotation (t1, t2), trophic changes (t1), and type 2 diabetes mellitus (t0). CONCLUSIONS: These findings suggest a multifactorial etiology of pPSSP. The association of pPSSP with restricted, passive, pain-free ROM and signs indicative of somatosensory sensitization may implicate a vicious cycle of repetitive (micro)trauma that can establish itself rapidly after stroke. Intervention should therefore be focused on maintaining and restoring joint ROM as well as preventing injury and somatosensory sensitization. In this perspective, strategies that aim to intervene simultaneously at various levels of function can be expected to be more effective than treatment directed at merely 1 level.

Locally increased P-glycoprotein function in major depression: a PET study with [11C]verapamil as a probe for P-glycoprotein function in the blood-brain barrier.

The aetiology of depressive disorder remains unknown, although genetic susceptibility and exposure to neurotoxins are currently being discussed as possible contributors to this disorder. In normal circumstances, the brain is protected against bloodborne toxic influences by the blood-brain barrier, which includes the molecular efflux pump P-glycoprotein (P-gp) in the vessel wall of brain capillaries. We hypothesized that P-gp function in the blood-brain barrier is changed in patients with major depression. Positron emission tomography was used to measure brain uptake of [11C]verapamil, which is normally expelled from the brain by P-gp. Cerebral volume of distribution (V(T)) of [11C]verapamil was used as a measure of P-gp function. Both region-of-interest (ROI) analysis and voxel analysis using statistical parametric mapping (SPM2) were performed to assess regional brain P-gp function. We found that patients with a major depressive episode, using antidepressants, compared to healthy controls showed a significant decrease of [11C]verapamil uptake in different areas throughout the brain, in particular in frontal and temporal regions. The decreased [11C]verapamil uptake correlates with an increased function of the P-gp protein and may be related to chronic use of psychotropic drugs. Our results may explain why treatment-resistant depression can develop.

Promoting Gait Recovery and Limiting Neuropathic Pain After Spinal Cord Injury.

Most persons living with a spinal cord injury experience neuropathic pain in the months following their lesion, at the moment where they receive intensive gait rehabilitation. Based on studies using animal models, it has been proposed that central sensitization in nociceptive pathways (maladaptive plasticity) and plasticity related to motor learning (adaptive plasticity) share common neural mechanisms and compete with each other. This article aims to address the discrepancy between the growing body of basic science literature supporting this hypothesis and the general belief in rehabilitation research that pain and gait rehabilitation represent two independent problems. First, the main findings from basic research showing interactions between nociception and learning in the spinal cord will be summarized, focusing both on evidence demonstrating the impact of nociception on motor learning and of motor learning on central sensitization. Then, the generalizability of these findings in animal models to humans will be discussed. Finally, the way potential interactions between nociception and motor learning are currently taken into account in clinical research in patients with spinal cord injury will be presented. To conclude, recommendations will be proposed to better integrate findings from basic research into future clinical research in persons with spinal cord injury.

Interactive virtual feedback improves gait motor imagery after spinal cord injury: An exploratory study.

PURPOSE: Motor imagery can improve motor function and reduce pain. This is relevant to individuals with spinal cord injury (SCI) in whom motor dysfunction and neuropathic pain are prevalent. However, therapy efficacy could be dependent on motor imagery ability, and a clear understanding of how motor imagery might be facilitated is currently lacking. Thus, the aim of the present study was to assess the immediate effects of interactive virtual feedback on motor imagery performance after SCI. METHODS: Nine individuals with a traumatic SCI participated in the experiment. Motor imagery tasks consisted of forward (i.e. simpler) and backward (i.e. more complex) walking while receiving interactive versus static virtual feedback. Motor imagery performance (vividness, effort and speed), neuropathic pain intensity and feasibility (immersion, distraction, side-effects) were assessed. RESULTS: During interactive feedback trials, motor imagery vividness and speed were significantly higher and effort was significantly lower as compared static feedback trials. No change in neuropathic pain was observed. Adverse effects were minor, and immersion was reported to be good. CONCLUSIONS: This exploratory study showed that interactive virtual walking was feasible and facilitated motor imagery performance. The response to motor imagery interventions after SCI might be improved by using interactive virtual feedback.

Augmented Pain Processing in Primary and Secondary Somatosensory Cortex in Fibromyalgia: A Magnetoencephalography Study Using Intra-Epidermal Electrical Stimulation.

The aim of this study was to investigate augmented pain processing in the cortical somatosensory system in patients with fibromyalgia (FM). Cortical evoked responses were recorded in FM (n = 19) and healthy subjects (n = 21) using magnetoencephalography after noxious intra-epidermal electrical stimulation (IES) of the hand dorsum (pain rating 6 on a numeric rating scale, perceptually-equivalent). In addition, healthy subjects were stimulated using the amplitude corresponding to the average stimulus intensity rated 6 in patients with FM (intensity-equivalent). Quantitative sensory testing was performed on the hand dorsum or thenar muscle (neutral site) and over the trapezius muscle (tender point), using IES (thresholds, ratings, temporal summation of pain, stimulus-response curve) and mechanical stimuli (threshold, ratings). Increased amplitude of cortical responses was found in patients with FM as compared to healthy subjects. These included the contralateral primary (S1) and bilateral secondary somatosensory cortices (S2) in response to intensity-equivalent stimuli and the contralateral S1 and S2 in response to perceptually-equivalent stimuli. The amplitude of the contralateral S2 response in patients with FM was positively correlated with average pain intensity over the last week. Quantitative sensory testing results showed that patients with FM were more sensitive to painful IES as well as to mechanical stimulation, regardless of whether the stimulation site was the hand or the trapezius muscle. Interestingly, the slope of the stimulus-response relationship as well as temporal summation of pain in response to IES was not different between groups. Together, these results suggest that the observed pain augmentation in response to IES in patients with FM could be due to sensitization or disinhibition of the cortical somatosensory system. Since the S2 has been shown to play a role in higher-order functions, further studies are needed to clarify the role of augmented S2 response in clinical characteristics of FM.

Assessing the perception of trunk movements in military personnel with chronic non-specific low back pain using a virtual mirror.

Chronic pain, including chronic non-specific low back pain (CNSLBP), is often associated with body perception disturbances, but these have generally been assessed under static conditions. The objective of this study was to use a "virtual mirror" that scaled visual movement feedback to assess body perception during active movement in military personnel with CNSLBP (n = 15) as compared to military healthy control subjects (n = 15). Subjects performed a trunk flexion task while sitting and standing in front of a large screen displaying a full-body virtual mirror-image (avatar) in real-time. Avatar movements were scaled to appear greater, identical, or smaller than the subjects' actual movements. A total of 126 trials with 11 different scaling factors were pseudo-randomized across 6 blocks. After each trial, subjects had to decide whether the avatar's movements were "greater" or "smaller" than their own movements. Based on this two-alternative forced choice paradigm, a psychophysical curve was fitted to the data for each subject, and several metrics were derived from this curve. In addition, task adherence (kinematics) and virtual reality immersion were assessed. Groups displayed a similar ability to discriminate between different levels of movement scaling. Still, subjects with CNSLBP showed an abnormal performance and tended to overestimate their own movements (a right-shifted psychophysical curve). Subjects showed adequate task adherence, and on average virtual reality immersion was reported to be very good. In conclusion, these results extend previous work in patients with CNSLBP, and denote an important relationship between body perception, movement and pain. As such, the assessment of body perception during active movement can offer new avenues for understanding and managing body perception disturbances and abnormal movement patterns in patients with pain.

Disinhibition of the primary somatosensory cortex in patients with fibromyalgia.

Fibromyalgia (FM) is a chronic widespread pain condition linked to central sensitization. Altered excitability of sensorimotor cortex has been proposed as an underlying pathology of FM. This study aimed to investigate intracortical excitability of the primary somatosensory cortex (S1) and its potential role in clinical pain in patients with FM. Somatosensory evoked magnetic fields were recorded in 17 right-handed females with FM and 21 age-, sex-, and handedness-matched healthy control subjects. Paired-pulse median nerve stimulation was delivered to the left and right wrist. We assessed the peak-to-peak amplitudes of the N20m-P35m and peak amplitude of each N20m and P35m component. Paired-pulse suppression (PPS) of the second response was quantified as the ratio of the amplitudes of the second to the first response. Patients with FM displayed significantly higher PPS ratio for the N20m-P35m in both hemispheres, indicating reduced intracortical inhibition in the S1. Notably, PPS ratio for the P35m was higher in patients with FM than in healthy controls, whereas no differences were apparent in PPS ratio for the N20m in both hemispheres. For both the N20m-P35m and the P35m in the left hemisphere, PPS ratios were positively associated with the sensory pain on the short-form McGill Pain Questionnaire. This study demonstrated that intracortical inhibition in the S1 is compromised bilaterally in patients with FM, and the extent of disinhibition can be closely associated with increased clinical pain. Our results suggest that changes of intracortical inhibition of the S1 may contribute to the pathophysiology of FM pain.

Towards a mechanism-based view on post-stroke shoulder pain: theoretical considerations and clinical implications.

The assessment and treatment of post-stroke shoulder pain (PSSP) is largely based on the assumption that pain is due to biomechanical alterations within the shoulder joint after stroke. However, current treatment often provides limited pain relief, leading to a considerable number of patients with persistent pain. This suggests that PSSP may not be merely due to simple nociception from the shoulder joint. A better understanding of the neurophysiological mechanisms underlying the development and perpetuation of PSSP is needed. Here, a theoretical framework for presumed PSSP mechanisms and their assessment is presented based on key concepts applied in pain research. This theoretical framework assumes that although pain may be localized in one region of the body, the mechanisms causing pain may occur at any level of the somatosensory neuro-axis. Detailed assessment of pain complaints and somatosensory abnormalities should, therefore, be a key element in clinical PSSP research. Studies aiming to further characterize somatosensory functions in patients with PSSP (initially) need to take a broad methodological approach including both clinical as well as more experimental pain research tools, such as quantitative sensory testing. A better understanding of pain mechanisms may explain why persistent PSSP and unsatisfactory pain relief are common despite active prevention and treatment strategies and may provide a basis for improved clinical management of PSSP.

Classifying post-stroke shoulder pain: can the DN4 be helpful?

The etiology of post-stroke shoulder pain (PSSP) is largely unclear and may involve both nociceptive and neuropathic mechanisms. No gold standard is present for PSSP diagnosis. The neuropathic pain diagnostic questionnaire (DN4), was originally developed to identify neuropathic pain in the clinical context. In this study we used the DN4 to categorize PSSP patients and compared symptoms and signs suggestive of either nociceptive or neuropathic pain. Pain complaints and sensory functions were compared between patients with chronic PSSP scoring at least four (DN4+, n=9) or less than four (DN4-, n=10) on the DN4. Pain was assessed using a numeric rating scale and the McGill pain questionnaire. Sensory functions were assessed using clinical examination and quantitative sensory testing combined with a cold pressor test. Patients classified as DN4+ reported constant pain, higher pain intensity, a higher impact of pain on daily living, more frequent loss of cold sensation, reduced QST thresholds at the unaffected side and increased QST thresholds at the affected side. Notably, several symptoms and signs suggestive of either neuropathic or nociceptive pain corresponded to the subgroups DN4+ and DN4- respectively. However, since the pathophysiological mechanisms remain unclear and none of the sensory signs could be exclusively related to either DN4+ or DN4-, PSSP prognosis and treatment should not be solely based on the DN4. Nonetheless, a thorough assessment of neuropathic and nociceptive pain complaints and somatosensory functions should be included in the diagnostic work-up of PSSP.

Altered cortical somatosensory processing in chronic stroke: A relationship with post-stroke shoulder pain.

Post-stroke shoulder pain (PSSP), traditionally regarded as purely nociceptive pain, is often persistent and the mechanisms underlying the pain complaints are not well understood. This explorative study is the first to address the possible changes in cortical somatosensory processing in patients with PSSP. Cortical potentials were recorded following intracutaneous electrostimulaton in stroke patients with chronic PSSP (n= 6), pain-free stroke patients (PF, n=14) and healthy controls (HC, n=20) using EEG. Amplitudes and latencies of both sensory discriminative (N90) as well as cognitive evaluative (N150, P200, the N150-P200 peak-to-peak difference and P300) evoked potential components were evaluated. Stroke was associated with reduced N150 and P300 amplitudes and increased N90, N150 and P300 latencies at both sides. Compared to PF and HC, the P200 and N150-P200 latencies were increased in PSSP patients after stimulation at both sides, even when comparing subgroups with similar lesion size and location. Stroke was associated with reduced sensory-discriminative as well as with reduced cognitive-evaluative cortical somatosensory processing. This reduction was more pronounced in patients with PSSP and may be related to the central effects of persistent nociceptive pain.

Somatosensory symptoms and signs and conditioned pain modulation in chronic post-stroke shoulder pain.

UNLABELLED: Persistent shoulder pain is a common complication after stroke. Its etiology and underlying mechanisms are not well understood and treatment is generally unsatisfactory. The objective of this study was to assess the role of central sensitization and disinhibition in chronic stroke patients with chronic PSSP (n = 19), pain-free stroke patients (n = 29), and healthy controls (n = 23). Positive and negative somatosensory symptoms and signs were assessed using clinical examination and electrical and mechanical quantitative sensory testing (QST). Conditioned pain modulation (CPM) was assessed by comparing QST thresholds before and after applying a cold pressor test. Sensory abnormalities were more frequently observed and more severe in patients with PSSP, including positive signs such as allodynia at the affected side and generalized hyperalgesia at the unaffected side. CPM was similar in stroke patients and healthy controls. This study showed that chronic PSSP was associated with several positive and negative somatosensory signs, implicating a role for central sensitization and possibly for disinhibition. Since the causal relationship remains unclear, and may be related to either neuroplasticity induced by ongoing nociception as well as to the neuropathic brain lesion, prospective studies are warranted. PERSPECTIVE: The assessment of somatosensory symptoms and signs and endogenous pain modulation demonstrated a role for central sensitization and possibly for disinhibition in chronic PSSP. Prevention and treatment of PSSP could benefit from a more detailed analysis of both peripheral and central pain mechanisms.

Corticospinal excitability during observation and imagery of simple and complex hand tasks: implications for motor rehabilitation.

Movement observation and imagery are increasingly propagandized for motor rehabilitation. Both observation and imagery are thought to improve motor function through repeated activation of mental motor representations. However, it is unknown what stimulation parameters or imagery conditions are optimal for rehabilitation purposes. A better understanding of the mechanisms underlying movement observation and imagery is essential for the optimization of functional outcome using these training conditions. This study systematically assessed the corticospinal excitability during rest, observation, imagery and execution of a simple and a complex finger-tapping sequence in healthy controls using transcranial magnetic stimulation (TMS). Observation was conducted passively (without prior instructions) as well as actively (in order to imitate). Imagery was performed visually and kinesthetically. A larger increase in corticospinal excitability was found during active observation in comparison with passive observation and visual or kinesthetic imagery. No significant difference between kinesthetic and visual imagery was found. Overall, the complex task led to a higher corticospinal excitability in comparison with the simple task. In conclusion, the corticospinal excitability was modulated during both movement observation and imagery. Specifically, active observation of a complex motor task resulted in increased corticospinal excitability. Active observation may be more effective than imagery for motor rehabilitation purposes. In addition, the activation of mental motor representations may be optimized by varying task-complexity.