Differences in white matter structure and cortical thickness between patients with traumatic and idiopathic chronic neck pain: Associations with cognition and pain modulation?

Brain alterations are hypothesized to be present in patients with chronic whiplash-associated disorders (CWAD). The aim of this case-control study was to examine alterations in cortical thickness and white matter (WM) structure, and the presence of brain microhemorrhages in a patient group encountering chronic neck pain of traumatic origin (i.e., CWAD) when compared with a patient group characterized by nontraumatic chronic neck pain [i.e., chronic idiopathic neck pain (CINP)], and healthy controls. Furthermore, we aimed to investigate associations between brain structure on one hand and cognitive performance and central sensitization (CS) on the other hand. T1-weighted, diffusion-weighted and T2*-weighted magnetic resonance images of the brain were acquired in 105 women (31 controls, 37 CINP, 37 CWAD) to investigate regional cortical thickness, WM structure, and microhemorrhages, respectively. Next, cognitive performance, and CS encompassing distant hyperalgesia and conditioned pain modulation (CPM) efficacy were examined. Cortical thinning in the left precuneus was revealed in CWAD compared with CINP patients. Also, decreased fractional anisotropy, together with increased values of mean diffusivity and radial diffusivity could be observed in the left cingulum hippocampus and tapetum in CWAD compared with CINP, and in the left tapetum in CWAD patients compared with controls. Moreover, the extent of WM structural deficits in the left tapetum coincided with decreased CPM efficacy in the CWAD group. This yields evidence for associations between decreased endogenous pain inhibition, and the degree of regional WM deficits in CWAD. Our results emphasize the role of structural brain alterations in women with CWAD compared with CINP.

Abnormal Pain Response to Visual Feedback During Cervical Movements in Chronic Whiplash: An Experimental Study.

BACKGROUND: Whiplash-associated disorders (WAD) are a debilitating condition. In chronic WAD, sensorimotor incongruence exacerbates symptoms. Sensorimotor incongruence occurs when somatosensory input and predicted motor output are in conflict, which can trigger pain. On the other hand, there is evidence that visual feedback can decrease pain in certain chronic pain conditions. Therefore, the aim of this study was to examine the effect of visual feedback and sensorimotor incongruence on pain thresholds in chronic WAD. METHODS: Sixty-four participants (healthy controls and patients with chronic WAD) were subjected to six experimental conditions. Participants watched correct real-time or modified visual feedback of the neck or hand (without movement as well as during repetitive neck lateroflexion). Sensorimotor incongruence was induced by manipulating visual feedback. Pressure pain thresholds were measured at baseline and during each condition. RESULTS: Marked between-group differences were observed. Visual feedback of the neck-correct or modified-did not influence pain thresholds in chronic WAD. In contrast, healthy controls had significantly higher pain thresholds when provided with the correct or modified visual feedback. When a movement of the neck was added during visual feedback, patients with chronic WAD showed no significant difference in pain thresholds, while an increase in pain thresholds was found in the healthy control group. CONCLUSION: In contrast to the healthy controls, visual feedback and sensorimotor incongruence did not alter pain thresholds in patients with chronic WAD. These findings suggest an abnormal pain response to visual feedback and somatosensory incongruence as well as failing mechanisms of pain inhibition in chronic WAD.

Gray Matter Adaptations to Chronic Pain in People with Whiplash-Associated Disorders are Partially Reversed After Treatment: A Voxel-based Morphometry Study.

Gray matter (GM) changes are often observed in people with chronic spinal pain, including those with chronic whiplash-associated disorders (CWAD). These GM adaptations may be reversed with treatment, at least partially. Pain neuroscience education combined with exercise (PNE+Exercise) is an effective treatment, but its neural underlying mechanisms still remain unexplored in CWAD. Here, we performed both cross-sectional and longitudinal voxel-based morphometry to 1) identify potential GM alterations in people with CWAD (n = 63) compared to age- and sex-matched pain-free controls (n = 32), and 2) determine whether these GM alterations might be reversed following PNE+Exercise (compared to conventional physiotherapy). The cross-sectional whole-brain analysis revealed that individuals with CWAD had less GM volume in the right and left dorsolateral prefrontal cortex and left inferior temporal gyrus which was, in turn, associated with higher pain vigilance. Fifty individuals with CWAD and 29 pain-free controls were retained in the longitudinal analysis. GM in the right dorsolateral prefrontal cortex increased after treatment in people with CWAD. Moreover, the longitudinal whole-brain analysis revealed that individuals with CWAD had decreases in GM volumes of the left and right central operculum and supramarginal after treatment. These changes were not specific to treatment modality and some were not observed in pain-free controls over time. Herewith, we provide the first evidence on how GM adaptations to CWAD respond to treatment. PERSPECTIVE: This article presents which gray matter adaptations are present in people with chronic pain after whiplash injuries. Then, we examine the treatment effect on these alterations as well as whether other neuroplastic effects on GM following treatment occur.

The Role of Serotonergic and Noradrenergic Descending Pathways on Performance-Based Cognitive Functioning at Rest and in Response to Exercise in People with Chronic Whiplash-Associated Disorders: A Randomized Controlled Crossover Study.

(1) Background: Dysregulation in serotonergic and noradrenergic systems may be implicated in the neurobiophysiological mechanisms underlying pain-related cognitive impairment in chronic whiplash-associated disorders (CWAD). This study aimed to unravel the role of serotonergic and noradrenergic descending pathways in cognitive functioning at rest and in response to exercise in people with CWAD. (2) Methods: 25 people with CWAD were included in this double-blind, randomized, controlled crossover study. Endogenous descending serotonergic and noradrenergic inhibitory mechanisms were modulated by using a single dose of a selective serotonin reuptake inhibitor (Citalopram) or a selective norepinephrine reuptake inhibitor (Atomoxetine). Cognitive performance was studied at rest and in response to exercise (1) without medication intake; (2) after intake of Citalopram; and (3) after intake of Atomoxetine. (3) Results: After Atomoxetine intake, selective attention improved compared with the no medication day (p < 0.05). In contrast, a single dose of Citalopram had no significant effect on cognitive functioning at rest. When performing pairwise comparisons, improvements in selective attention were found after exercise for the no medication condition (p < 0.05). In contrast, after intake of Citalopram or Atomoxetine, selective and sustained attention worsened after exercise. (4) Conclusions: A single dose of Atomoxetine improved selective attention only in one Stroop condition, and a single dose of Citalopram had no effect on cognitive functioning at rest in people with CWAD. Only without medication intake did selective attention improve in response to exercise, whereas both centrally acting medications worsened cognitive performance in response to a submaximal aerobic exercise bout in people with CWAD.

Unravelling Impaired Hypoalgesia at Rest and in Response to Exercise in Patients with Chronic Whiplash-Associated Disorders: Effects of a Single Administration of Selective Serotonin Reuptake Inhibitor versus Selective Norepinephrine Reuptake Inhibitor.

(1) Background: Noradrenaline and serotonin have modulatory roles in pain signaling and in exercise-induced hypoalgesia. Patients with chronic whiplash-associated disorders often show impaired exercise-induced hypoalgesia. Therefore, this study aimed to examine the isolated effect of activating serotonergic or noradrenergic descending pathways on hypoalgesia at rest and in response to exercise in patients with chronic WAD by using respectively a single dose of a selective serotonin reuptake inhibitor (SSRI) and a selective norepinephrine reuptake inhibitor (NRI). (2) Methods: Twenty-five people with chronic WAD participated in this double-blind randomized controlled crossover experiment. Serotonin and noradrenaline concentrations were modulated by the oral ingestion of a single dose of citalopram (i.e., SSRI) or atomoxetine (i.e., SNRI). Quantitative sensory testing (including pressure pain thresholds and conditioned pain modulation) was measured before and after exercise in combination with no medication (1), atomoxetine (2), or citalopram (3) at three different test days. (3) Results: Random-intercept linear mixed models analysis was used to analyze pain outcomes (i.e., pain at rest and exercise-induced hypoalgesia) before and after exercise over the three conditions in patients with chronic WAD. No differences in pain at rest were found between the three conditions before exercise. The effect of exercise on pain outcome measures was not influenced by medication intake. The occupational status of the participants had a significant influence on the effect of exercise and medication on pain outcomes (p < 0.05). Patients working full-time had some positive effect of atomoxetine on pain facilitation (p < 0.05). Unemployed patients had some negative effect of citalopram on pain tolerance and experienced exercise-induced hypoalgesia (p < 0.05). (4) Conclusions: A single dose of citalopram or atomoxetine did not result in changes in hypoalgesia at rest and in response to exercise. These results do not support the use of SSRI or selective NRI to overcome impaired hypoalgesia at rest or in response to exercise in people with chronic WAD. Effect of exercise and medication on pain in patients with chronic WAD is influenced by the occupational status.

Event-Related Potentials Following Cutaneous Electrical Stimulation in Patients With Chronic Whiplash-Associated Disorders.

BACKGROUND: Whiplash injuries typically occur from a motor vehicle collision and lead to chronic whiplash-associated disorders (CWAD) in 20% to 50% of cases. Changes in neurotransmission, metabolism, and networks seem to play a role in the pathogenic mechanism of CWAD. OBJECTIVES: To further elucidate the functional brain alterations, a neurophysiological study was performed to investigate the somatosensory processing of CWAD patients by comparing the event-related potentials (ERPs) resulting from electrical nociceptive stimulation between patients suffering from CWAD and healthy controls (HC). STUDY DESIGN: Case-control study. SETTING: University Hospital in Ghent. METHODS: In this case-control study (CWAD patients/HC: 50/50), ankle and wrist electrical pain thresholds (EPT), and amplitude and latency of the event-related potentials (ERPs) resulting from 20 electrical stimuli were investigated. Correlations between the ERP characteristics, EPT, self-reported pain, disability, pain catastrophizing, and self-reported symptoms of central sensitization were investigated. RESULTS: Only the latency of the P3 component after left wrist stimulation (t = -2.283; P = 0.023) differed between both groups. In CWAD patients, the ankle EPT correlated with the amplitude of the corresponding P1 (rho s = 0.293; P = 0.044) and P3 (rho s = 0.306; P = 0.033), as well as with the amplitude of the P3 to left wrist stimulation (rho s = 0.343; P = 0.017). Self-reported symptoms of CS correlated with right wrist P3 amplitude (rho s = 0.308; P = 0.030) and latency (rho s = -0.341; P = 0.015), and the worst pain reported during the past week was correlated with left wrist P1 latency (rho s = 0.319; P = 0.029). LIMITATIONS: Although the inclusion criteria stated that CWAD patients had to report a moderate-to-severe pain-related disability, 8 of the included CWAD patients (that scored above this threshold in the inclusion questionnaire), scored below the required cutoff at baseline. CONCLUSIONS: The CWAD patients did not show signs of hypersensitivity, but their ERP characteristics were related to the intensity of the applied stimulus, self-reported symptoms of CS, and the worst pain reported during the past week.

A contemporary neuroscience approach compared to biomedically focused education combined with symptom-contingent exercise therapy in people with chronic whiplash associated disorders: a randomized controlled trial protocol.

BACKGROUND: To address the need for a better treatment of chronic whiplash associated disorders (WAD), a contemporary neuroscience approach can be proposed. OBJECTIVE: To examine the effectiveness of a contemporary neuroscience approach, comprising pain neuroscience education, stress management, and cognition-targeted exercise therapy versus conventional physical therapy for reducing disability (primary outcome measure) and improving quality of life and reducing pain, central sensitization, and psychological problems (secondary outcome measures) in people with chronic WAD. METHODS: The study is a multi-center, two-arm randomized, controlled trial with 1-year follow-up and will be performed in two university-based and one regional hospital. People with chronic WAD (n=120) will be recruited. The experimental group will receive pain neuroscience education followed by cognition-targeted exercise therapy, and stress management. The control group will receive biomedically focused education followed by graded and active exercise therapy focusing on muscle endurance, strength, and flexibility, and ergonomic principles. The treatment will have a duration of 16 weeks. Functional status (Neck Disability Index) is the primary outcome measure. Secondary outcome measures include quality of life, pain, central sensitization, and psychological and socio-economic factors. In addition, electroencephalography will measure brain activity at rest and during a conditioned pain modulation paradigm. Assessments will take place at baseline, immediately post-treatment and at 6 and 12 months follow-up. CONCLUSIONS: This study will examine whether a contemporary neuroscience approach is superior over conventional physical therapy for improving functioning, quality of life, and reducing pain, central sensitization, and psychological problems in people with chronic WAD.

Enhanced amygdala-frontal operculum functional connectivity during rest in women with chronic neck pain: Associations with impaired conditioned pain modulation.

BACKGROUND: Chronic neck pain is a leading cause of disability worldwide, affecting the lives of millions of people. Research investigating functional brain alterations in relation to somatosensory function is necessary to better understand mechanisms underlying pain development and maintenance in individuals with chronic neck pain, yet remains scarce. This case-control study aimed to examine resting-state functional connectivity alterations and associations with pain outcomes, self-reported central sensitization-related symptoms and quantitative sensory testing (QST) measures in patients with chronic non-traumatic (idiopathic/CINP) neck pain and chronic traumatic (whiplash associated/CWAD) neck pain compared to pain-free controls. METHODS: Resting-state functional magnetic resonance images were acquired in 107 female participants (38 CINP, 37 CWAD, 32 healthy controls). After data pre-processing, seed-to-seed analyses were conducted focusing on resting-state functional connectivity involving pre-defined regions of interest that have previously been observed to be structurally or functionally altered and/or associated with pain-related measures in this patient population. RESULTS: Findings demonstrate enhanced left amygdala functional coupling during rest with the left frontal operculum in women with CINP and CWAD compared to controls. This increased resting-state functional connectivity was associated with more self-reported symptoms related to central sensitization and decreased efficacy of conditioned pain modulation. Furthermore, enhanced connectivity between the left amygdala and left frontal orbital cortex, and between the left pallidum and the left frontal operculum was observed only in patients with CWAD compared to healthy controls. In patients, additional associations between local hyperalgesia and enhanced connectivity between the left superior parietal cortex and the left and right precentral gyrus were found. CONCLUSIONS: In line with our hypotheses, patients with CWAD showed the most pronounced alterations in resting-state functional connectivity, encompassing subcortical limbic (amygdala) and basal ganglia (pallidum), and ventral frontal regions (frontal operculum, orbitofrontal cortex) when compared to CINP and controls. Findings are generally in line with the idea of a continuum, in absence of significant group differences across CINP and CWAD. Enhanced amygdala-frontal operculum functional connectivity was the most robust and only connectivity pair in the cluster that was associated with QST (i.e., dynamic QST; endogenous pain inhibition), and that was observed in both patient groups. In addition, independent of group differences, enhanced resting-state functional connectivity between superior parietal cortex (involved in attention) and primary motor cortex was associated with static QST (i.e., greater local hyperalgesia). Taken together, our findings show a key role for enhanced amygdala-ventral frontal circuitry in chronic neck pain, and its association with diminished endogenous pain inhibition further emphasizes the link between cognitive-affective and sensory modulations of pain in women with chronic non-traumatic and traumatic neck pain.