Studying the effect of expectations on high-frequency electrical stimulation-induced pain and pinprick hypersensitivity.

Negative expectations can increase pain, but can they promote the development of central sensitization? This study used an inert treatment and verbal suggestions to induce expectations of increased high-frequency electrical stimulation (HFS)-induced pain and assessed their effects on pain ratings during HFS and HFS-induced pinprick hypersensitivity. Fifty healthy volunteers were randomly allocated to either a control group (N=25) or a nocebo group (N=25). Participants in both groups received a patch containing water on the right forearm. The nocebo group was told that the patch contained capsaicin that sensitized their skin, while the control group was told that the patch contained water that had no effect on skin sensitivity. Before and after patch attachment, single electrical stimuli were delivered to the area of the patch to measure the perceived intensity to these stimuli. After patch removal, and after the participant rated expected pain and fear for HFS, HFS was delivered to the same skin site, followed by the assessment of pinprick sensitivity. The nocebo group rated the perceived intensity for the single electrical stimulus after removal of the patch as more intense compared to the control group, indicating that our manipulation worked. Yet, this effect did not transfer to expected pain for HFS, nor did it affect pain intensity ratings during HFS. HFS increased pinprick sensitivity but no group differences were found. Because of the lack of differences in expected pain and pain intensity ratings for HFS between groups, no firm conclusions can be drawn regarding their effect on pinprick hypersensitivity. PERSPECTIVE: This study shows that sham treatment combined with verbal suggestions induces a nocebo effect, but does not necessarily change expectations and experience of upcoming pain.

Fear of pain changes movement: Motor behaviour following the acquisition of pain-related fear.

BACKGROUND: According to current fear-avoidance models, changes in motor behaviour (e.g. avoidance) are a key component in the development and maintenance of chronic pain complaints. Yet, experimental research assessing actual behavioural changes following painful events is relatively sparse. This study investigated the effects of pain anticipation on changes in motor behaviour using a fear conditioning paradigm and robot-generated standardized movement trajectories of the upper extremities. METHODS: Pain-free participants (N = 20) performed clockwise and counterclockwise fixed, circular movements with a robotic arm without receiving visual feedback. During fear acquisition, moving in one direction (CS+) was paired with a painful stimulus (pain-US) whereas moving in the other direction (CS-) was not. During the subsequent extinction phase, the pain-US was omitted. We assessed self-reported pain-related fear and urge to avoid the movement, as well as several behavioural measures: Velocity, acceleration, exerted force and force direction. RESULTS: Movements that were paired with pain were associated with increased self-reported pain-related fear and urge to avoid. Moreover, movements that were associated with pain were performed faster, more forcefully and more accurately than movements that were not associated with pain. All these differences diminished during the extinction phase. CONCLUSIONS: The present study demonstrates the utility of robot-generated force feedback in the study of pain-related fear and associated changes in motor behaviour. SIGNIFICANCE: Fear of pain changes movement: Movements associated with pain are performed faster, with more force and higher accuracy than movements that are not associated with pain. These changes can inform us how fear of pain translates into avoidance and escape behaviour, two important constructs in the maintenance of chronic pain.

TFR2-related haemochromatosis in the Netherlands: a cause of arthralgia in young adulthood.

BACKGROUND: Type 3 hereditary haemochromatosis (HH) is a rare iron overload disorder caused by variants in the transferrin 2 receptor (TFR2) gene. We aim to present characteristics of patients diagnosed with TFR2-HH in the Netherlands, in order to increase knowledge and awareness of this disease. METHODS: We collected clinical, biochemical and genetic data from four patients from three families diagnosed with HH type 3 in the Netherlands between 2009 and 2016. RESULTS: Three women and one man diagnosed with HH type 3 presented with arthralgia and elevated ferritin levels and transferrin saturation (TSAT) at ages 25-41 years. The hepcidin/ferritin ratio as measured in three patients was low. Liver iron content in two patients as assessed by MRI or liver biopsy was highly increased (250 and 362.7 µmol iron/g dry weight, respectively, reference < 35 µmol/g). DNA analysis revealed four different TFR2 pathogenic variants: one nonsense, one splicing and two missense variants, of which three are novel. Phlebotomy decreased the serum iron parameters but did not relieve the arthralgia. CONCLUSION: In patients with a combination of elevated TSAT and ferritin in the absence of anaemia, and after exclusion of HFE-related HH, rare forms of HH should be considered. In these cases, presentation with arthralgia in young adulthood, low hepcidin/ferritin ratio and/or liver iron content > 100 µmol/g form an indication for analysis of the TFR2 gene. Although type 3 HH is extremely rare, awareness of the disease among physicians is important in order to achieve an early diagnosis and prevent complications, such as liver damage.

Executive functions deficits impair extinction of generalization of fear of movement-related pain.

BACKGROUND: Generalization of fear of movement-related pain across novel but similar movements can lead to fear responses to movements that are actually not associated with pain. The peak-shift effect describes a phenomenon whereby particular novel movements elicit even greater fear responses than the original pain-provoking movement (CS+), because they represent a more extreme version of the CS+. There is great variance in the propensity to generalize as well as the speed of extinction learning when these novel movements are not followed by pain. It can be argued that this variance may be associated with executive function capacity, as individuals may be unable to intentionally inhibit fear responses. This study examined whether executive function capacity contributes to generalization and extinction of generalization as well as peak-shift of conditioned fear of movement-related pain and expectancy. METHODS: Healthy participants performed a proprioceptive fear conditioning task. Executive function tests assessing updating, switching, and inhibition were used to predict changes in (extinction of) fear of movement-related pain and pain expectancy generalization. RESULTS: Low inhibitory capacity was associated with slower extinction of generalized fear of movement-related pain and pain expectancy. Evidence was found in favor of an area-shift, rather than a peak-shift effect, which implies that the peak conditioned fear response extended to, but did not shift to a novel stimulus. CONCLUSIONS: Participants with low inhibitory capacity may have difficulties withholding fear responses, leading to a slower decrease of generalized fear over time. The findings may be relevant to inform treatments. SIGNIFICANCE: Low inhibitory capacity is not associated with slower generalization, but extinction of fear generalization. Fear elicited by a novel safe movement, situated outside the CS+/- continuum on the CS+ side, can be as strong as to the original stimulus predicting the pain-onset.