Different Brain Circuitries Mediating Controllable and Uncontrollable Pain.

UNLABELLED: Uncontrollable, compared with controllable, painful stimulation can lead to increased pain perception and activation in pain-processing brain regions, but it is currently unknown which brain areas mediate this effect. When pain is controllable, the lateral prefrontal cortex (PFC) seems to inhibit pain processing, although it is unclear how this is achieved. Using fMRI in healthy volunteers, we examined brain activation during controllable and uncontrollable stimulation to answer these questions. In the controllable task, participants self-adjusted temperatures applied to their hand of pain or warm intensities to provoke a constant sensation. In the uncontrollable task, the temperature time courses of the controllable task were replayed (yoked control) and participants rated their sensation continuously. During controllable pain trials, participants significantly downregulated the temperature to keep their sensation constant. Despite receiving the identical nociceptive input, intensity ratings increased during the uncontrollable pain trials. This additional sensitization was mirrored in increased activation of pain-processing regions such as insula, anterior cingulate cortex, and thalamus. Further, increased connectivity between the anterior insula and medial PFC (mPFC) in the uncontrollable and increased negative connectivity between dorsolateral PFC (dlPFC) and insula in the controllable task were observed. This suggests a pain-facilitating role of the mPFC during uncontrollable pain and a pain-inhibiting role of the dlPFC during controllable pain, both exerting their respective effects via the anterior insula. These results elucidate neural mechanisms of context-dependent pain modulation and their relation to subjective perception. SIGNIFICANCE STATEMENT: Pain control is of uttermost importance and stimulus controllability is an important way to achieve endogenous pain modulation. Here, we show differential effects of controllability and uncontrollability on pain perception and cerebral pain processing. When pain was controllable, the dorsolateral prefrontal cortex downregulated pain-evoked activation in important pain-processing regions. In contrast, sensitization during uncontrollable pain was mediated by increased connectivity of the medial prefrontal cortex with the anterior insula and other pain-processing regions. These novel insights into cerebral pain modulation by stimulus controllability have the potential to improve treatment approaches in pain patients.