Cortical influences on brainstem circuitry responsible for conditioned pain modulation in humans

Abstract

Conditioned pain modulation (CPM) is a powerful endogenous analgesic mechanism which can completely inhibit incoming nociceptor signals at the primary synapse. The circuitry responsible for CPM lies within the brainstem and involves the subnucleus reticularis dorsalis (SRD). While the brainstem is critical for CPM, the cortex can significantly modulate its expression, likely via the brainstem circuitry critical for CPM. Since higher cortical regions such as the anterior, mid-cingulate, and dorsolateral prefrontal cortices are activated by noxious stimuli and show reduced activations during other analgesic responses, we hypothesized that these regions would display reduced responses during CPM analgesia. Furthermore, we hypothesized that functional connectivity strength between these cortical regions and the SRD would be stronger in those that express CPM analgesia compared with those that do not. We used functional magnetic resonance imaging to determine sites recruited during CPM expression and their influence on the SRD. A lack of CPM analgesia was associated with greater signal intensity increases during each test stimulus in the presence of the conditioning stimulus compared to test stimuli alone in the mid-cingulate and dorsolateral prefrontal cortices and increased functional connectivity with the SRD. In contrast, those subjects exhibiting CPM analgesia showed no change in the magnitude of signal intensity increases in these cortical regions or strength of functional connectivity with the SRD. These data suggest that during multiple or widespread painful stimuli, engagement of the prefrontal and cingulate cortices prevents the generation of CPM analgesia, raising the possibility altered responsiveness in these cortical regions underlie the reduced CPM observed in individuals with chronic pain. Hum Brain Mapp 37:2630-2644, 2016. © 2016 Wiley Periodicals, Inc.

In child and adult migraineurs the somatosensory cortex stands out … again: An arterial spin labeling investigation

“…Instead, consistent reductions in grey matter volume have been observed in higher brain sites, including the dorsolateral prefrontal cortex [Rocca et al, ; Schmidt‐Wilcke et al, ], and it may be these reductions in grey matter volume that drive the functional alterations observed in migraine. For example, migraine patients' exhibit altered pain modulation [Sandrini et al, ] and sensory processing, both of which can be modulated by the dorsolateral prefrontal cortex [Lorenz et al, ; O'Reilly, ; Sandrini et al, ; Youssef et al, ]. Alternatively, it may reflect technical constraints.…”

Pain Modulation: From Conditioned Pain Modulation to Placebo and Nocebo Effects in Experimental and Clinical Pain

“…A recent study using functional magnetic resonance imaging (fMRI) to determine the precise brainstem sites responsible for CPM in healthy individuals observed an association between expression of analgesia and reduction of signal in brainstem regions following counter-irritation: the caudalis subdivision of the spinal trigeminal nucleus, i.e., the primary synapse, the region of the subnucleus reticularis dorsalis (SRD) and the dorsolateral pons in the region of the parabrachial nucleus (Youssef, Macefield, & Henderson, 2016a). In comparison to subjects exhibiting CPM analgesia, those with impaired CPM showed greater signal intensity increases in the mid-cingulate and dorsolateral prefrontal cortices and increased functional connectivity with the SRD following counter-irritation (Youssef, Macefield, & Henderson, 2016b). The SRD conveys widespread descending inhibition to spinal secondary neurons via the dorsolateral funiculi (Nir & Yarnitsky, 2015).…”

A study of cortical and brainstem mechanisms of diffuse noxious inhibitory controls in anaesthetised normal and neuropathic rats

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