Spanish Version of the Whiplash Disability Questionnaire in Adults With Acute Whiplash-Associated Disorders.

OBJECTIVE: The purpose of this study was to develop and validate a Spanish version of the Whiplash Disability Questionnaire (WDQ) for the Spanish population with acute whiplash-associated disorder (WAD). METHODS: This was a cross-sectional questionnaire validation study. Adults with acute WAD (grade I to III) were enrolled within 3 weeks of their injury. A blinded forward and back translation of the WDQ was made from English to Spanish, and the resulting back-translation version was compared with the original. Patients with WAD completed the Spanish version of the 13-item WDQ. The developed questionnaire was assessed using psychometric statistical analysis including correlation with the numerical rating score for pain, Northwick Park Neck Pain Questionnaire, Neck Disability Index, and 36-item Short Form Health Survey. RESULTS: Fifty-six patients completed the questionnaire, the mean age was 33.9 years (standard deviation [SD] = 10.5), and 76.8% were women. Participants were enrolled 13.9 days (SD 4.9) after the injury, with 14.3% presenting with WAD grade I and 85.7% with WAD grade II. The mean WDQ score was 62 (SD = 31). Two factors were detected, and the factor structure remained stable after translation. Positive correlations were identified between the total WDQ score and the numerical rating score, Neck Pain Questionnaire, and Neck Disability Index results, with a strong negative correlation with the 36-item Short Form Health Survey. CONCLUSION: The Spanish version of WDQ is psychometrically reliable and a valid instrument to measure the disability status in patients with acute WAD within the clinic.

The role of Omega-3 and Omega-9 fatty acids for the treatment of neuropathic pain after neurotrauma.

Omega-3 polyunsaturated fatty acids (PUFAs), such as docosaexaenoic acid (DHA) and eicosapentaenoic acid (EPA), mediate neuroactive effects in experimental models of traumatic peripheral nerve and spinal cord injury. Cellular mechanisms of PUFAs include reduced neuroinflammation and oxidative stress, enhanced neurotrophic support, and activation of cell survival pathways. Bioactive Omega-9 monounsaturated fatty acids, such as oleic acid (OA) and 2-hydroxy oleic acid (2-OHOA), also show therapeutic effects in neurotrauma models. These FAs reduces noxious hyperreflexia and pain-related anxiety behavior following peripheral nerve injury and improves sensorimotor function following spinal cord injury (SCI), including facilitation of descending inhibitory antinociception. The relative safe profile of neuroactive fatty acids (FAs) holds promise for the future clinical development of these molecules as analgesic agents. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.

Longitudinal estimation of intramuscular Tibialis Anterior coherence during subacute spinal cord injury: relationship with neurophysiological, functional and clinical outcome measures.

BACKGROUND: Estimation of surface intramuscular coherence has been used to indirectly assess pyramidal tract activity following spinal cord injury (SCI), especially within the 15-30 Hz bandwidth. However, change in higher frequency (>40 Hz) muscle coherence during SCI has not been characterised. Thus, the objective of this study was to identify change of high and low frequency intramuscular Tibialis Anterior (TA) coherence during incomplete subacute SCI. METHODS: Fifteen healthy subjects and 22 subjects with motor incomplete SCI (American Spinal Injury Association Impairment Scale, AIS, C or D grade) were recruited and tested during 4 sessions performed at 2-week intervals up to 8 months after SCI. Intramuscular TA coherence estimation was calculated within the 10-60 Hz bandwidth during controlled maximal isometric and isokinetic foot dorsiflexion. Maximal voluntary dorsiflexion torque, gait function measured with the WISCI II scale, and TA motor evoked potentials (MEP) were recorded. RESULTS: During subacute SCI, significant improvement in total lower limb manual muscle score, TA muscle strength and gait function were observed. No change in TA MEP amplitude was identified. Significant increase in TA coherence was detected in the 40-60 Hz, but not the 15-30 Hz bandwidth. The spasticity syndrome was associated with lower 15-30 Hz TA coherence during maximal isometric dorsiflexion and higher 10-60 Hz coherence during fast isokinetic movement (p < 0.05). CONCLUSIONS: Longitudinal estimation of neurophysiological and clinical measures during subacute SCI suggest that estimation of TA muscle coherence during controlled movement provides indirect information regarding adaptive and maladaptive motor control mechanisms during neurorehabilitation.

Soleus H-reflex modulation following transcutaneous high- and low-frequency spinal stimulation in healthy volunteers.

The main aim of this work was to investigate the difference in the excitability of the soleus H-reflex in healthy volunteers following spinal transcutaneous electrical nerve stimulation (TENS) and high-frequency alternating current (HFAC) at a frequency of 10 kHz applied at the lower thoracic spinal level (T10-T12). A double-blind, randomized, crossover, controlled clinical trial was designed. Participants received three randomized interventions (TENS, 10 kHz, and sham stimulation) during 40 min. The amplitude and latency of the soleus H-reflex were registered prior to, during, and 10 min following stimulation. Twenty-four participants completed the study. A significant inhibition of H-reflex amplitude was observed following transcutaneous spinal TENS (12.7%; 95% CI 1.5-22.2%) when compared with sham stimulation (5.5%; 95% CI 3.6-14.5%; p = 0.03). An increase in H-reflex latency was also observed following transcutaneous spinal stimulation at 10 kHz (2%; 95% CI 1.4-2.5%) as compared with sham stimulation (0.7%; 95% CI 0.07-1.3%; p < 0.01). No differences were found between TENS and 10 kHz for H-reflex modulation. Transcutaneous spinal TENS and HFAC at a frequency of 10 kHz had a modulatory effect on the soleus H-reflex when compared to sham stimulation; however, no differences were found between these two interventions.

Deficient Inhibitory Endogenous Pain Modulation Correlates With Periaqueductal Gray Matter Metabolites During Chronic Whiplash Injury.

OBJECTIVES: This study examined predictive correlations between periaqueductal gray (PAG) and anterior cingulate cortex (ACC) metabolite levels with deficient inhibitory endogenous pain modulation (EPM), including sensory and affective measures of pain during chronic whiplash injury (WHI). MATERIALS AND METHODS: Healthy patients, and participants with chronic WHI, without (WHI-noP) or with pain (WHI-P), were screened with the Douleur Neuropathique 4 tool (DN4). EPM was assessed with C6 tonic heat pain stimuli with a Conditioned Pain Modulation (CPM) protocol. Magnetic resonance spectroscopy quantified ACC and PAG metabolite levels. RESULTS: WHI-P participants were characterized with high pain intensity and interference, and lower quality of life scores, compared with WHI-noP. Inhibitory CPM at 30 seconds was identified in the healthy noninjured (-45±16%; P<0.001) and WHI-noP groups (-36±8%; P<0.001). However, inhibitory EPM was not detected in the WHI-P group (-25±15%; P=0.06). Best fit and stepwise multiple regression revealed that the PAG glutamate/myoinositol metabolite ratio (P=0.01) and total creatine levels (P=0.02) predicted loss of EPM in the WHI-P group (r=0.71, α=0.97). Although myoinositol predicted loss of EPM in the ACC (P=0.04), this was below statistical power (r=0.31; α=0.56). The ACC N-acetyl-aspartate/myoinositol ratio (P=0.006) predicted chronic pain (DN4, r=0.53; α=0.87). DISCUSSION: The results of this study demonstrate deficient EPM at 30 seconds during tonic heat pain stimulation in WHI-P participants, compared with noninjured healthy volunteers or individuals with WHI-noP. In addition, quantification of PAG and ACC metabolites related to glutamate and glia predicted central chronic pain mechanisms related to loss of inhibitory EPM, while ACC metabolites characterized chronic pain described by descriptors and sensory changes.

Afferent stimulation inhibits abnormal cutaneous reflex activity in patients with spinal cord injury spasticity syndrome.

BACKGROUND: Tibialis Anterior (TA) cutaneous reflex (CR) activity evoked following cutaneous stimulation of the plantar (Pl) surface (Pl-TA CR) has demonstrated hyperreflexia and damage of inhibitory mechanisms in subjects with spinal cord injury (SCI) and spasticity. OBJECTIVES: To modulate Pl-TA CR and Soleus H-reflex activity with transcutaneous electrical nerve stimulation (TENS) and vibratory stimulation of the plantar pad during rest and controlled isometric plantarflexion. METHODS: Non-injured subjects (n = 11) and individuals with incomplete SCI with (n = 14) and without spasticity (n = 14) were recruited. The effect of TENS and vibratory stimuli on Pl-TA CR and soleus H-reflex activity were assessed during rest and controlled ramp-and-hold plantarflexion. RESULTS: Vibration failed to inhibit H-reflex activity during rest or plantarflexoin following SCI compared to healthy subjects. In contrast, vibration-induced inhibition of Pl-TA CR was specifically detected in SCI spastic subjects during both rest and the hold phase of plantarflexion. TENS inhibited Pl-TA CR activity in the SCI spasticity group only during hold plantarflexion. CONCLUSIONS: Plantar vibratory stimuli inhibited the pl-TA CR, but not the H reflex, during rest and controlled movement in SCI spastic subjects. Assessment of Pl-TA CR modulation should contribute to the development of modality-specific sensory stimuli programmes for the neurorehabilitation of SCI spasticity.

Assessing sensorimotor excitability after spinal cord injury: a reflex testing method based on cycling with afferent stimulation.

Several studies have examined spinal reflex modulation during leg cycling in healthy and spinal cord injury (SCI) subjects. However, the effect of cutaneous plantar afferent input on spinal excitability during leg cycling after SCI has not been characterised. The aim of the study was to test the feasibility of using controlled leg cycling in combination with plantar cutaneous electrical stimulation (ES) cycling to assess lower limb spinal sensorimotor excitability in subjects with motor complete or incomplete SCI. Spinal sensorimotor excitability was estimated by measuring cutaneomuscular-conditioned soleus H-reflex activity. Reflex excitability was tested before and after a 10-min ES cycling session in 13 non-injured subjects, 6 subjects with motor incomplete SCI (iSCI) who had moderately impaired gait function, 4 subjects with motor iSCI who had severely impaired gait function, and 5 subjects with motor complete SCI (cSCI). No modulation of soleus H-reflex with plantar cutaneous stimuli was observed after either iSCI or cSCI when compared to non-injured subjects. However, after ES cycling, reflex excitability significantly increased in subjects with iSCI and moderately impaired gait function. ES cycling facilitated spinal sensorimotor excitability only in subjects with motor iSCI with residual gait function. Increased spinal excitability induced with a combination of exercise and afferent stimulation could be adopted with diagnostic and prognostic purposes to reveal the activity-based neurorehabilitation profile of individual subjects with motor iSCI. TRIAL REGISTRATION: ISRCTN 26172500 ; retrospectively registered on 15 July 2016 Graphical abstract ᅟ.

Treatment with albumin-hydroxyoleic acid complex restores sensorimotor function in rats with spinal cord injury: Efficacy and gene expression regulation.

Sensorimotor dysfunction following incomplete spinal cord injury (SCI) is often characterized by paralysis, spasticity and pain. Previously, we showed that intrathecal (i.t.) administration of the albumin-oleic acid (A-OA) complex in rats with SCI produced partial improvement of these symptoms and that oral 2-hydroxyoleic acid (HOA, a non-hydrolyzable OA analogue), was efficacious in the modulation and treatment of nociception and pain-related anxiety, respectively. Here we observed that intrathecal treatment with the complex albumin-HOA (A-HOA) every 3 days following T9 spinal contusion injury improved locomotor function assessed with the Rotarod and inhibited TA noxious reflex activity in Wistar rats. To investigate the mechanism of action of A-HOA, microarray analysis was carried out in the spinal cord lesion area. Representative genes involved in pain and neuroregeneration were selected to validate the changes observed in the microarray analysis by quantitative real-time RT-PCR. Comparison of the expression between healthy rats, SCI rats, and SCI treated with A-HOA rats revealed relevant changes in the expression of genes associated with neuronal morphogenesis and growth, neuronal survival, pain and inflammation. Thus, treatment with A-HOA not only induced a significant overexpression of growth and differentiation factor 10 (GDF10), tenascin C (TNC), aspirin (ASPN) and sushi-repeat-containing X-linked 2 (SRPX2), but also a significant reduction in the expression of prostaglandin E synthase (PTGES) and phospholipases A1 and A2 (PLA1/2). Currently, SCI has very important unmet clinical needs. A-HOA downregulated genes involved with inflammation and upregulated genes involved in neuronal growth, and may serve to promote recovery of function after experimental SCI.

Maintenance of cutaneomuscular neuronal excitability after leg-cycling predicts lower limb muscle strength after incomplete spinal cord injury.

OBJECTIVE: Controlled leg-cycling modulates H-reflex activity after spinal cord injury (SCI). Preserved cutaneomuscular reflex activity is also essential for recovery of residual motor function after SCI. Here the effect of a single leg-cycling session was assessed on cutaneomuscular-conditioned H-reflex excitability in relation to residual lower limb muscle function after incomplete SCI (iSCI). METHODS: Modulation of Soleus H-reflex activity was evaluated following ipsilateral plantar electrical stimulation applied at 25-100ms inter-stimulus intervals (ISI's), before and after leg-cycling in ten healthy individuals and nine subjects with iSCI. RESULTS: Leg-cycling in healthy subjects increased cutaneomuscular-conditioned H-reflex excitability between 25 and 75ms ISI (p<0.001), compared to a small loss of excitability at 75ms ISI after iSCI (p<0.05). In addition, change in cutaneomuscular-conditioned H-reflex excitability at 50ms and 75ms ISI in subjects with iSCI after leg-cycling predicted lower ankle joint hypertonia and higher Triceps Surae muscle strength, respectively. CONCLUSION: Leg-cycling modulates cutaneomuscular-conditioned spinal neuronal excitability in healthy subjects and individuals with iSCI, and is related to residual lower limb muscle function. SIGNIFICANCE: Cutaneomuscular-conditioned H reflex modulation could be used as a surrogate biomarker of both central neuroplasticity and lower limb muscle function, and could benchmark lower-limb rehabilitation programs in subjects with iSCI.

Early treatment with UR13870, a novel inhibitor of p38α mitogenous activated protein kinase, prevents hyperreflexia and anxiety behaviors, in the spared nerve injury model of neuropathic pain.

Microglia cell activation plays a role in the development of neuropathic pain partly due to the activation of the p38α MAPK signaling pathway after nerve injury. In this study we assessed the effect of UR13870, a p38α MAPK inhibitor, in the "spared nerve injury" (SNI) model, to study its effects on modulation of spinal microglial activation and to test behavioral hyperreflexia responses and cerebral-mediated pain behavior. The effect of daily administration of UR13870 (10mg/kg p.o.) and Pregabalin (50mg/kg p.o.) on reflex hypersensitivity to mechanical and cold test stimuli and on affective related pain responses measured with the place escape avoidance paradigm and the open field-induced anxiety test, were evaluated after SNI in Sprague Dawley rats. Microglial reactivity in the ipsilateral lumbar laminae I/II dorsal horn was evaluated with OX-42 immunohistochemistry. UR13870 treatment significantly decreased hindlimb hyperreflexia to both mechanical and cold stimuli after SNI without loss of general motor function, in addition to a reduction in pain-related anxiety behavior at day 21 after SNI, accompanied by normalization of OX-42 immunoreactivity within the ipsilateral lumbar dorsal horn. Pregabalin treatment only reduced mechanical hyperreflexia and affected general motor function. Oral administration of the p38α MAPK inhibitor, UR13870, mediates antinociception to both mechanical and cold stimuli, and significantly restored inner-zone exploration in the open field test, accompanied by normalization in dorsal horn microglial activation in the SNI model.

Oral administration of the p38α MAPK inhibitor, UR13870, inhibits affective pain behavior after spinal cord injury.

The p38α mitogenous activated protein kinase (MAPK) cell signaling pathway is a key mechanism of microglia activation and has been studied as a target for neuropathic pain. The effect of UR13870, a p38α MAPK inhibitor, on microglia expression in the anterior cingulate cortex (ACC) and spinal dorsal horn was addressed after T9 contusion spinal cord injury (SCI) in the rat, in addition to behavioral testing of pain-related aversion and anxiety. Administration of intravenous UR13870 (1mg/kg i.v.) and pregabalin (30 mg/kg i.v.) reduced place escape avoidance paradigm (PEAP) but did not affect open-field anxiety behavior 42 days after SCI. PEAP behavior was also reduced in animals administered daily with oral UR13870 (10mg/kg p.o.) and preserved spinal tissue 28 days after SCI. Although UR13870 (10mg/kg p.o.) failed to reduce OX-42 and glial fibrillar acid protein immunoreactivity within the spinal dorsal horn, a reduction toward the control level was observed close to the SCI site. In the anterior cingulate cortex (ACC), a significant increase in OX-42 immunoreactivity was identified after SCI. UR13870 (10mg/kg p.o.) treatment significantly reduced OX-42, metabotropic glutamate type 5 receptor (mGluR5), and NMDA (N-methyl-d-aspartate) 2B subunit receptor (NR2B) expression in the ACC after SCI. To conclude, oral treatment with a p38α MAPK inhibitor reduces the affective behavioral component of pain after SCI in association with a reduction of microglia and specific glutamate receptors within the ACC. Nevertheless the role of neuroinflammatory processes within the vicinity of the SCI site in the development of affective neuropathic pain cannot be excluded.

Spinal cord injury induced changes of nuclear receptors PPARα and LXRß and modulation with oleic acid/albumin treatment.

In previous studies with animal models of spinal cord injury (SCI) pharmacological activation of peroxisome proliferator activated receptors (PPAR) and liver X receptors (LXR) were used to reduce tissue damage and promote behavioral recovery in animal models. We have studied the endogenous expression of the transcription factors PPARα and LXRß in the chronic stage after SCI in rats. The immunohistochemical investigation revealed a long lasting increase in the level of PPARα in white matter in the vicinity of the lesion site. The source of this signal was identified in a subpopulation of astrocytes outside of the glial scar area. Intrathecal injections of oleic acid/albumin reduced the lesion-induced PPARα immunoreactivity. In addition, ependymal cells displayed a prominent PPARα signal in the non-injured spinal cord, and continued to express the receptor as they proliferated and migrated within the damaged tissue. The nuclear receptor LXRß was detected at similar levels after SCI as in sham operated animals. We found high levels of immunoreactivity in the gray matter, while in the white matter it was present in subpopulations of astrocytes and oligodendrocytes. Macrophages that had accumulated within the center of the lesion contained LXRß in their cell nuclei. Possible endogenous functions of PPARα and LXRß after SCI are discussed, specifically the control of fatty acid and cholesterol metabolism and the regulation of inflammatory reactions.

Modulation of thermal somatosensory thresholds within local and remote spinal dermatomes following cervical repetitive magnetic stimulation.

BACKGROUND: Repetitive magnetic stimulation (rMS) modulates thermal somatosensory function at both low (0.2-1.0Hz) and high (5.0-20.0Hz) frequencies within the conditioned dermatome. However the effects of 1Hz and 20Hz cervical (C6-C7) rMS on thermosensory thresholds and contact heat evoked potentials (CHEPs) tested within local and remote spinal dermatomes are not known. METHODS: Thirty healthy subjects participated in the study. Warm and cold detection threshold, heat and cold pain thresholds, and Cz/Fz CHEPs were evaluated within the C6, T10 and extrasegmental V3 control dermatome, before and after random assignment of subjects to sham, 1 or 20Hz C6-C7 rMS. RESULTS: Following both 1 and 20Hz cervical rMS, warm detection threshold increased within the local C6 dermatome. Furthermore 1Hz cervical rMS increased warm detection threshold within the remote T10 dermatome, but not within the V3-trigeminal control area. Cervical rMS failed to modulate cold detection threshold, heat and cold pain threshold or Cz/Fz CHEP amplitude from the dermatomal test sites. CONCLUSION: Both 1 and 20Hz cervical rMS modulated warm detection threshold within the locally conditioned C6 dermatome. The concomitant increase in warm detection threshold within the T10 dermatome following 1Hz rMS provides evidence for remote neuromodulation of thermosensory function via intraspinal control mechanisms.

Treatment of rat spinal cord injury with the neurotrophic factor albumin-oleic acid: translational application for paralysis, spasticity and pain.

Sensorimotor dysfunction following incomplete spinal cord injury (iSCI) is often characterized by the debilitating symptoms of paralysis, spasticity and pain, which require treatment with novel pleiotropic pharmacological agents. Previous in vitro studies suggest that Albumin (Alb) and Oleic Acid (OA) may play a role together as an endogenous neurotrophic factor. Although Alb can promote basic recovery of motor function after iSCI, the therapeutic effect of OA or Alb-OA on a known translational measure of SCI associated with symptoms of spasticity and change in nociception has not been studied. Following T9 spinal contusion injury in Wistar rats, intrathecal treatment with: i) Saline, ii) Alb (0.4 nanomoles), iii) OA (80 nanomoles), iv) Alb-Elaidic acid (0.4/80 nanomoles), or v) Alb-OA (0.4/80 nanomoles) were evaluated on basic motor function, temporal summation of noxious reflex activity, and with a new test of descending modulation of spinal activity below the SCI up to one month after injury. Albumin, OA and Alb-OA treatment inhibited nociceptive Tibialis Anterior (TA) reflex activity. Moreover Alb-OA synergistically promoted early recovery of locomotor activity to 50 ± 10% of control and promoted de novo phasic descending inhibition of TA noxious reflex activity to 47 ± 5% following non-invasive electrical conditioning stimulation applied above the iSCI. Spinal L4-L5 immunohistochemistry demonstrated a unique increase in serotonin fibre innervation up to 4.2 ± 1.1 and 2.3 ± 0.3 fold within the dorsal and ventral horn respectively with Alb-OA treatment when compared to uninjured tissue, in addition to a reduction in NR1 NMDA receptor phosphorylation and microglia reactivity. Early recovery of voluntary motor function accompanied with tonic and de novo phasic descending inhibition of nociceptive TA flexor reflex activity following Alb-OA treatment, mediated via known endogenous spinal mechanisms of action, suggests a clinical application of this novel neurotrophic factor for the treatment of paralysis, spasticity and pain.