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.

Interrelationships between pain processing, cortisol and cognitive performance in chronic whiplash-associated disorders.

The present study aims at studying interactions between cognitive performance and conditioned pain modulation in patients with chronic whiplash-associated disorders (WAD) and healthy controls. In addition, the relation between cortisol concentrations and cognitive performance will be studied in patients with chronic WAD. Thirty-one subjects, 16 healthy subjects and 15 patients with chronic WAD, were enrolled and subjected to several self-report and physiological measures. Self-report measures encompassed pain rating during a procedure evaluating conditioned pain modulation. Afterward, they were subjected to physiological measures, which are cognitive tests (Stroop task, psychomotor vigilance task, and operation span task) preceded and followed by salivary cortisol concentration measurements. Chronic WAD patients performed worse in recall at the operation span task and presented longer reaction times at the psychomotor vigilance task and at the Stroop task when sleep-related words were shown (p < .05). Conditioned pain modulation and cortisol concentrations were not significantly different between patients and controls (p > .05). Only in the healthy subjects, conditioned pain modulation and baseline cortisol concentrations were correlated to cognitive performance (p < .05). This is the first study addressing the relation between pain inhibition and cognitive performance in chronic WAD. We did not reveal impaired pain inhibition but did reveal cognitive dysfunctions in patients with chronic WAD. In healthy subjects, pain inhibition was related to cognitive performance but not in the patient group.

Osteopathic manipulative treatment for facial numbness and pain after whiplash injury.

Whiplash injury is often caused by rear-end motor vehicle collisions. Symptoms such as neck pain and stiffness or arm pain or numbness are common with whiplash injury. The author reports a case of right facial numbness and right cheek pain after a whiplash injury. Osteopathic manipulative treatment techniques applied at the level of the cervical spine, suboccipital region, and cranial region alleviated the patient's facial symptoms by treating the right-sided strain of the trigeminal nerve. The strain on the trigeminal nerve likely occurred at the upper cervical spine, at the nerve's cauda, and at the brainstem, the nerve's point of origin. The temporal portion of the cranium played a major role in the strain on the maxillary.

The failure response of the human cervical facet capsular ligament during facet joint retraction.

Studies implicate the cervical facet joint and its capsule as a primary anatomical site of injury during whiplash exposures to the neck. Although the facet joint is known to undergo stretch as the superior vertebra is retracted relative to the inferior vertebra during the whiplash kinematic, the response of the facet capsular ligament and its microstructure during failure in joint retraction is unknown. Polarized light imaging and vector correlation analysis were used to measure the collagen fiber alignment in the human capsular ligament, together with traditional mechanical metrics, during joint retraction sufficient to induce ligament failure. Anomalous fiber realignment occurs at 2.95±1.66mm of displacement, which is not different from the displacement when the ligament first yields (2.77±1.55mm), but is significantly lower (p=0.016) than the displacement at tissue failure (5.40±1.65mm). The maximum principal strain at the first detection of anomalous fiber realignment (0.66±0.39) also is significantly lower (p=0.046) than the strain at failure (1.39±0.64), but is not different from the strains at yield or partial failure. The onset of collagen fiber realignment determined in this study corresponds to the ligament's yielding and supports assertions that the facet capsule can undergo tissue injury during joint retraction. Further, such microstructural responses may indicate tissue damage in the absence of rupture.

Whiplash-like facet joint loading initiates glutamatergic responses in the DRG and spinal cord associated with behavioral hypersensitivity.

The cervical facet joint and its capsule are a common source of neck pain from whiplash. Mechanical hyperalgesia elicited by painful facet joint distraction is associated with spinal neuronal hyperexcitability that can be induced by transmitter/receptor systems that potentiate the synaptic activation of neurons. This study investigated the temporal response of a glutamate receptor and transporters in the dorsal root ganglia (DRG) and spinal cord. Bilateral C6/C7 facet joint distractions were imposed in the rat either to produce behavioral sensitivity or without inducing any sensitivity. Neuronal metabotropic glutamate receptor-5 (mGluR5) and protein kinase C-epsilon (PKCε) expression in the DRG and spinal cord were evaluated on days 1 and 7. Spinal expression of a glutamate transporter, excitatory amino acid carrier 1 (EAAC1), was also quantified at both time points. Painful distraction produced immediate behavioral hypersensitivity that was sustained for 7 days. Increased expression of mGluR5 and PKCε in the DRG was not evident until day 7 and only following painful distraction; this increase was observed in small-diameter neurons. Only painful facet joint distraction produced a significant increase (p<0.001) in neuronal mGluR5 over time, and this increase also was significantly elevated (p≤0.05) over responses in the other groups at day 7. However, there were no differences in spinal PKCε expression on either day or between groups. Spinal EAAC1 expression was significantly increased (p<0.03) only in the nonpainful groups on day 7. Results from this study suggest that spinal glutamatergic plasticity is selectively modulated in association with facet-mediated pain.

Spinal cord metabolism and muscle water diffusion in whiplash.

STUDY DESIGN: Case series. OBJECTIVES: To quantify spinal cord metabolites and neck muscle fast and slow water diffusion in a small sample of patients with chronic whiplash and healthy controls. SETTING: Brisbane, Queensland, Australia. METHODS: In five subjects with chronic whiplash and seven controls, we performed magnetic resonance spectroscopy (MRS) of the cervical spinal cord and diffusion-weighted imaging (DWI) of the cervical multifidus muscle. RESULTS: Significant reductions in N-acetylaspartate/creatine ratios were found in subjects with chronic whiplash when compared with healthy controls (P = 0.02). Significantly higher fast apparent diffusion coefficients (ADCs) were found in chronic whiplash when compared with the healthy controls (P = 0.01). There was no difference in slow ADCs between the two groups (P = 0.3). CONCLUSION: The potential value of MRS and DWI to quantify the presence of neuromuscular degeneration as a potential mechanism underlying chronic whiplash is recognized. Larger-scaled prospective studies are warranted and required.

The potential contribution of stress systems to the transition to chronic whiplash-associated disorders.

STUDY DESIGN: A narrative description highlighting preclinical and clinical evidence that physiologic stress systems contribute to whiplash-associated disorders (WAD) pathogenesis. OBJECTIVE: To present several lines of evidence supporting the hypothesis that physiologic stress systems contribute to WAD pathogenesis. SUMMARY OF BACKGROUND DATA: In addition to subjecting soft tissue to biomechanical strain, a motor vehicle collision (MVC) event is also an acute stressor which activates physiologic stress systems. Increasing data from animal and human studies suggest that the activation of these stress systems may contribute to long-lasting changes in pain sensitivity after tissue injury. METHODS: Nonsystematic review of several lines of evidence that together suggest that physiologic systems involved in the stress response may contribute to the development of WAD. RESULTS: Stress systems which appear capable of producing hyperalgesia and allodynia include catecholaminergic systems, serotonin systems, and the hypothalamic-pituitary-adrenocortical system. Evidence for the role of these systems comes, in part, from studies examining the association between genetic variants and chronic pain outcomes. For example, in a recent study of acute neck pain after MVC, patients with certain genotypes of an enzyme involved in catecholamine metabolism were more than twice as likely to report moderate or severe neck pain in the emergency department. Such pain vulnerability because of stress system function may interact with the effects of biomechanical injury and psychobehavioral responses to influence the development of WAD. CONCLUSION: More research examining the influence of stress systems on WAD are needed. If these systems do influence WAD outcomes, then treatments which diminish the adverse effects of stress systems may be a useful component of multimodal therapeutic interventions for individuals at risk of chronic pain development after MVC.

Correlation between expectations of recovery and injury severity perception in whiplash-associated disorders.

OBJECTIVE: To assess the correlation between expectations of recovery and whiplash patients' perceptions of injury severity using a simplified instrument. Expectations of recovery have been shown to predict rate of recovery from whiplash injury in population-based studies. The perception of having more severe pathology or more ominous diagnostic labels has also been associated with a worse prognosis. METHODS: Consecutive patients with whiplash-associated disorder grade 1 or 2, presenting in the acute stage to a primary care centre, were asked "do you think that your injury will…" with response options "get better soon; get better slowly; never get better; don't know." Injury severity perception (ISP) was measured with a numerical rating scale which ranged from 0-10, on which subjects were asked to rate how severe (in terms of damage) they thought their injury was. The anchors were labeled "no damage" (0) and "severe, and maybe permanent damage" (10). The primary outcome measure was the correlation between the subject's ISP score and expectation of recovery. RESULTS: A total of 94 subjects (34 males, 60 females, and mean age (40.6 ± 10.0) years, range 19-60 years) were included. The initial responses to expectation of recovery were: get better soon (29/94); get better slowly (22/94); never get better (11/94); don't know (32/94). The mean ISP score was 4.9 ± 1.7 (range 2-9 out of 10). There was a high correlation between expectations and ISP scores (Spearman's rank correlation coefficient 0.68). Those who expected to recover soon and those who expected to get better slowly had the lowest ISP scores. CONCLUSIONS: The more slowly whiplash patients expect to recover, or the less sure they are of recovery, the more severe their initial perceptions of injury.

Ventromedial prefrontal neurokinin 1 receptor availability is reduced in chronic pain.

Neurokinin 1 (NK1) receptors are involved in pain and anxiety behaviors in animals, but little is known about central alterations in this receptor system in human pain. With positron emission tomography, using a [11]-Carbon labeled NK1 receptor antagonist, we demonstrate attenuated NK1 receptor availability in frontal, insular and cingulate cortex, as well as the hippocampus, amygdala and the periaqueductal gray area in patients with chronic pain. The reduced availability was most pronounced in the ventromedial prefrontal cortex (vmPFC), where attenuations correlated to measures of fear and avoidance of movement. Further, vmPFC NK1 levels also displayed opposing influences in patients as compared to controls on regional cerebral blood flow in the anterior cingulate. We conclude that the central NK1 receptor system is altered in human chronic pain. The results suggest that NK1 receptors in the vmPFC modulate motor inhibition, and contribute to fear and avoidance of movement.

Simulated whiplash modulates expression of the glutamatergic system in the spinal cord suggesting spinal plasticity is associated with painful dynamic cervical facet loading.

The cervical facet joint and its capsule have been reported to be injured during whiplash scenarios and are a common source of chronic neck pain from whiplash. Both the metabotropic glutamate receptor 5 (mGluR5) and the excitatory amino acid carrier 1 (EAAC1) have pivotal roles in chronic pain. In this study, spinal mGluR5 and EAAC1 were quantified following painful facet joint distraction in a rat model of facet-mediated painful loading and were evaluated for their correlation with the severity of capsule loading. Rats underwent either a dynamic C6/C7 joint distraction simulating loading experienced during whiplash (distraction; n = 12) or no distraction (sham; n = 6) to serve as control. The severity of capsular loading was quantified using strain metrics, and mechanical allodynia was assessed after surgery. Spinal cord tissue was harvested at day 7 and the expression of mGluR5 and EAAC1 were quantified using Western blot analysis. Mechanical allodynia following distraction was significantly (p < 0.001) higher than sham. Spinal expression of mGluR5 was also significantly (p < 0.05) greater following distraction relative to sham. However, spinal EAAC1 was significantly (p = 0.0003) reduced compared to sham. Further, spinal mGluR5 expression was significantly positively correlated to capsule strain (p < 0.02) and mechanical allodynia (p < 0.02). Spinal EAAC1 expression was significantly negatively related to one of the strain metrics (p < 0.003) and mechanical allodynia at day 7 (p = 0.03). These results suggest that the spinal glutamatergic system may potentiate the persistent behavioral hypersensitivity that is produced following dynamic whiplash-like joint loading; chronic whiplash pain may be alleviated by blocking mGluR5 expression and/or enhancing glutamate transport through the neuronal transporter EAAC1.

Bradykinin and kallidin levels in the trapezius muscle in patients with work-related trapezius myalgia, in patients with whiplash associated pain, and in healthy controls - A microdialysis study of women.

The origins of chronic muscle pain development and maintenance are debated regarding the relative contributions of peripheral nociception and central pain processing. Bradykinin (BKN) and kallidin (KAL) have been suggested to be algesic kinins involved in muscle pain. This in vivo study investigates whether there were significant differences in interstitial muscle concentrations of BKN and KAL between chronic work-related trapezius myalgia (TM), chronic whiplash associated disorders (WAD), and healthy controls (CON). These subjects were studied at rest, during a 20-min repetitive low-force exercise and recovery. The interstitial concentrations of BKN and KAL of trapezius were determined using the microdialysis technique. The interstitial concentration of KAL was overall significantly higher in TM than in CON. [KAL] and [BKN] increased significantly during the brief exercise in all groups. The increase in [BKN] during exercise was significantly higher in TM than in the other two groups, whereas the increase in [KAL] during exercise was highest in WAD. In chronic pain, positive correlations existed between the two kinins and the difference in pain intensity between recovery and baseline. In this in vivo study of two groups of patients with chronic pain clinically involving the trapezius muscle, we found alterations - most prominent in TM - in the interstitial concentrations of BKN and KAL. The results indicated that the two kinins were involved in aspects of hyperalgesia.

Axonal injury and the neuropathology of shaken baby syndrome.

We examined an autopsy series of 14 children with shaken baby syndrome (SBS) who lacked skull fracture. Evidence of axonal injury was sought using immunohistochemical stains for neurofilament, 68-kDa neurofilament and beta-amyloid precursor protein (betaAPP). BetaAPP-positive axons were present in the cerebral white matter of all cases of SBS but were also present in 6 of 7 children dying of non-traumatic hypoxic ischemic encephalopathy (HIE). Swollen axons were present in 11 of 14 cases of SBS and in 6 of 7 cases of HIE. BetaAPP-positive axons were present in both groups in the midbrain and medulla. The cervical spinal cord in SBS contained betaAPP-positive axons in 7 of 11 cases; 5 of 7 contained swollen axons within the white matter tracts; in 2 immunoreactivity was localized to spinal nerve roots; in all 7 there was a predilection for staining at the glial head of the nerve root. Among cases of HIE, none showed abnormal axons or betaAPP-positive reactivity in the cervical cord white matter. We conclude that cerebral axonal injury is common in SBS, and may be due in part to hypoxic/ischemic injury. Cervical cord injury is also common, and cannot be attributed to HIE. These findings corroborate suggestions that flexion-extension injury about the cervical spinal column may be important in the pathogenesis of SBS.

Hemodynamic, behavioral and biochemical disturbances induced by an experimental cranio-cervical injury (whiplash) in rats.

Two days after an experimental whiplash performed on anesthetized Long-Evans female rats, without any direct blow to the head, we observed: (1) a hypotension (in supine position) (P less than 0.01), (2) a disturbance of the postural regulation of cerebral blood flow (P less than 0.01), (3) a disturbance of learning behavior characterized by decreased acquisition and retention (conditioned avoidance response and labyrinth tests), (4) an increase of the dopamine level (whole brain, cerebellum, thalamus + hypothalamus, corpus striatum and rest), (5) a decrease of the noradrenaline level in whole brain (P less than 0.05) and in the medulla oblongata but an increase in thalamus plus hypothalamus, hippocampus and corpus striatum, (6) an increased reactivity of the peripheral alpha and beta receptors, determined by analyzing the hemodynamic consequences of i.v. injection of norepinephrine or isoproterenol, (7) there was no modification of the brain content of water or of serotonin and (8) finally, the injured rats displayed a remarkably aggressive behavior, though this was not quantified. These results are in agreement with the hypothesis that a change in brain amines metabolism could explain the different functional effects of whiplash. We therefore believe that the postconcussion syndrome is not subjective and that the neck injury is primary in the determination of the syndrome.

[Memorization and central catecholamines after a craniocervical injury carried out in rats: influence of imipramine administration (author's transl)]. / Mémorisation et catécholamines centrales après un traumatisme cranio-cervical expérimental chez le rat: influence d'une administration d'imipramine.

A craniocervical injury has been carried out in rats (with head free to move) so that they get through a whiplash without any coma. Two days after the whiplash, comparable with a postcommotional syndrome, the acquisition of a labyrinth behavior is disturbed and, 7 days later, the retention is still disturbed. This disturbance of retention is not observed when the acquisition is performed before the whiplash. These data agree with the clinical observations, and we hypothesize a possible causal relation between the disturbance of learning behavior and the decrease of noradrenaline cerebral level induced by the whiplash. Treatment with imipramine (1 mg/kg) after the whiplash is able to remove these behavioral and biochemical disturbances.