Human Studies

Despite the high prevalence and socioeconomic impact of chronic low back pain (cLBP), treatments for cLBP are often unsatisfactory, and effectiveness varies widely across patients. Recent neuroimaging studies have demonstrated abnormal resting-state functional connectivity (rsFC) of the default mode, salience, central executive, and sensorimotor networks in chronic pain patients, but their role as predictors of treatment responsiveness has not yet been explored. In this study, we used machine learning approaches to test if pre-treatment rsFC can predict responses to both real and sham acupuncture treatments in cLBP patients. Fifty cLBP patients participated in 4 weeks of either real (N = 24, age = 39.0 ± 12.6, 16 females) or sham acupuncture (N = 26, age = 40.0 ± 13.7, 15 females) treatment in a single-blinded trial, and a resting-state fMRI scan prior to treatment was used in data analysis. Both real and sham acupuncture can produce significant pain reduction, with those receiving real treatment experiencing greater pain relief than those receiving sham treatment. We found that pre-treatment rsFC could predict symptom changes with up to 34% and 29% variances for real and sham treatment, respectively, and the rsFC characteristics that were significantly predictive for real and sham treatment differed. These results suggest a potential way to predict treatment responses and may facilitate the development of treatment plans that optimize time, cost, and available resources.

Pain and depression have been shown to have a bidirectional interaction. Although several outcome studies have been conducted, it is still unclear if and how depression influences pain outcome. The current study aims to further clarify this relationship by comparing the predicting value of an interview- and a questionnaire-based assessment of depression.

A decrease in glutamate in the medial prefrontal cortex (mPFC) has been extensively found in animal models of chronic pain. Given that the mPFC is implicated in emotional appraisal, cognition and extinction of fear, could a potential decrease in glutamate be associated with increased pessimistic thinking, fear and worry symptoms commonly found in people with chronic pain? To clarify this question, 19 chronic pain subjects and 19 age- and gender-matched control subjects without pain underwent magnetic resonance spectroscopy. Both groups also completed the Temperament and Character, the Beck Depression and the State Anxiety Inventories to measure levels of harm avoidance, depression, and anxiety, respectively. People with chronic pain had significantly higher scores in harm avoidance, depression and anxiety compared to control subjects without pain. High levels of harm avoidance are characterized by excessive worry, pessimism, fear, doubt and fatigue. Individuals with chronic pain showed a significant decrease in mPFC glutamate levels compared to control subjects without pain. In people with chronic pain mPFC glutamate levels were significantly negatively correlated with harm avoidance scores. This means that the lower the concentration of glutamate in the mPFC, the greater the total scores of harm avoidance. High scores are associated with fearfulness, pessimism, and fatigue-proneness. We suggest that chronic pain, particularly the stress-induced release of glucocorticoids, induces changes in glutamate transmission in the mPFC, thereby influencing cognitive, and emotional processing. Thus, in people with chronic pain, regulation of fear, worry, negative thinking and fatigue is impaired.

Fear of movement-related pain significantly contributes to musculoskeletal chronic pain disability. Previous research has shown that fear of movement-related pain can be classically conditioned. That is, in a differential fear conditioning paradigm, after (repeatedly) pairing a neutral joystick movement (conditioned stimulus; CS+) with a painful stimulus (unconditioned stimulus; pain-US), that movement in itself starts to elicit self-reported fear and elevated psychophysiological arousal compared to a control joystick movement (CS-) that was never paired with pain. Further, it has been demonstrated that novel movements that are more similar to the original CS+ elicit more fear than novel movements that are more similar to the CS-, an adaptive process referred to as . By default, movement/action takes place in reference to the three-dimensional space: a movement thus not only involves proprioceptive information, but it also contains spatiotopic information. Therefore, the aim of this study was to investigate to what extent spatiotopic information (i.e., endpoint location of movement) contributes to the acquisition and generalization of such fear of movement-related pain besides proprioception (i.e., movement direction). In a between-subjects design, the location group performed joystick movements from the middle position to left and right; the movement group moved the joystick from left and right to the middle. One movement (CS+) was paired with pain, another not (CS-). between CSs typically reduces differential learning. The endpoint of both CSs in the movement group is an overlapping feature whereas in the location group the endpoint of both CSs is distinct; therefore we hypothesized that there would be less differential fear learning in the movement group compared to the location group. We also tested generalization to movements with similar proprioceptive features but different endpoint location. Following the principle of stimulus generalization, we expected that novel movements in the same direction as the CS+ but with a different endpoint would elicit more fear than novel movement in the same direction of the CS- but with a different endpoint. Main outcome variables were self-reported fear and pain-US expectancy and eyeblink startle responses (electromyographic). Corroborating the feature overlap hypothesis, the location group showed greater differential fear acquisition. Fear generalization emerged for both groups in the verbal ratings, suggesting that fear indeed accrued to proprioceptive CS features; these effects, however, were not replicated in the startle measures.