Lesion studies in animals have identified a critical role of the hippocampus in context fear conditioning. To extend these findings to human volunteers, we used functional magnetic resonance imaging to investigate neural responses associated with context fear conditioning in humans. Our novel conditioning paradigm consisted of aversive electrical shocks (unconditioned stimulus) that were delivered either cue or context related. Differential evoked responses, related to the conditioned stimulus (CS), were found in the anterior cingulate cortex and the bilateral insular cortices, regions that have been implicated in anticipatory anxiety. In case of context conditioning, a similar pattern was observed during the presentation of the entire context. In line with previous conditioning studies, differential responses in the amygdala showed a time by stimulus interaction, suggesting rapid adaptation of CS-specific responses. More importantly, a similar differential decay of activation was observed during context conditioning in the hippocampus, in agreement with a role of the hippocampus in the acquisition phase of human context fear conditioning.

Current fear-avoidance models consider fear of pain as a key factor in the development of chronic musculoskeletal pain. Generally, the idea is that by virtue of the formation of associations or acquired propositional knowledge about the relation between neutral movements and pain, these movements may signal pain, and hence start to elicit defensive fear responses (eg, avoidance behavior). This assumption has never been investigated experimentally. Therefore, we developed a pain-relevant fear conditioning paradigm using a movement as a conditioned stimulus (CS) and a painful electrocutaneous stimulus as an unconditioned stimulus (US) to examine the acquisition of fear of movement-related pain in healthy subjects. In a within-subjects design, participants manipulated a joystick to the left/right in the experimental (predictable) condition, and upward/downward in the control (unpredictable) condition or vice versa. In the predictable condition, one movement direction (CS+), and not the other (CS-), was followed by painful stimuli. In the unpredictable condition, painful stimuli were always delivered during the intertrial interval. Both fear of movement-related pain ratings and eyeblink startle measures were more elevated in response to the CS+ than to the CS-, whereas no differences occurred between both unreinforced CSs in the control condition. Participants were slower initiating a CS+ movement than a CS- movement, while response latencies to CSs in the control condition did not differ. These data support the acquisition of fear of movement-related pain by associative learning. Results are discussed in the broader context of the acquisition of pain-related fear in patients with musculoskeletal pain.

Slow breathing is widely applied to improve symptoms of hyperarousal, but it is unknown whether its beneficial effects relate to the reduction in respiration rate per se, or, to a lower inhalation/exhalation (i/e) ratio. The present study examined the effects of four ventilatory patterns on heart rate variability and self-reported dimensions of relaxation. Thirty participants were instructed to breathe at 6 or 12 breaths/min, and with an i/e ratio of 0.42 or 2.33. Participants reported increased relaxation, stress reduction, mindfulness and positive energy when breathing with the low compared to the high i/e ratio. A lower compared to a higher respiration rate was associated only with an increased score on positive energy. A low i/e ratio was also associated with more power in the high frequency component of heart rate variability, but only for the slow breathing pattern. Our results show that i/e ratio is an important modulator for the autonomic and subjective effects of instructed ventilatory patterns.

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