Background & Aims
Conditioned Pain Modulation (CPM) describes the inhibition of a painful stimulus by the simultaneous application of a second noxious stimulus at another body site. Preclinical studies have indicated that CPM is mediated by a brainstem circuit primarily involving the subnucleus reticularis dorsalis (SRD) within the lower medulla, and recently, the A5 noradrenergic region. A human 3 Tesla functional magnetic resonance imaging (fMRI) study supported the role of the SRD in CPM analgesia and reported CPM-related signal changes in the dorsolateral pons (Youssef et al., 2016). Whilst this fMRI study was the first to focus on the brainstem’s role in CPM in humans, it was limited by the spatial resolution possible at the time. The recent advent of ultra-high field 7T fMRI has made it possible to explore the human brainstem at millimetre resolutions allowing us for the first time to accurately identify brainstem regions underlying CPM. This study aims to use 7T fMRI to resolve the precise brainstem CPM circuitry in pain-free individuals.
Methods
Forty-five pain-free participants (22 males, 23 females, mean [± SEM] age: 31.14 [± 1.51]) were scanned in a 7T MRI scanner (MAGNETOM, Siemens). Following the collection of a T1-weighted anatomical series, a set of fMRI images were collected where 8 moderately painful thermal stimuli were delivered to the right side of the lip using a 3 x 3cm MRI compatible Peltier-element thermode (Medoc, Israel). Participants rated their pain using a Visual Analogue Scale in real time. Subsequently, this procedure was repeated in a second fMRI series following induction of muscle pain by bolus injection (1 mL) of 5% hypertonic saline into the right tibialis anterior muscle; pain intensity of the lip was continuously rated. Participants were placed into “responder” or “non-responder” groups using permutation testing. Results were generated using SPM12 and the Spatially Unbiased Infratentorial Template toolbox to investigate brainstem signal intensity changes occurring during CPM.
Results
Permutation testing categorised 18 individuals who demonstrated a CPM response (responders) and 27 non-responders based on their pain rating changes across the two functional scans. On average, pain ratings of responders reduced by 11.3% during CPM while that of non-responders increased by 2.8%. Responders showed greater signal intensity changes associated with CPM in regions of the A5, cuneiform and substantia nigra, whilst greater changes were observed in the SRD and trigeminal nerve entry in non-responders. Using the SRD and A5 as seeds, pain-related signal coupling changes with brainstem areas were determined. Responders showed greater SRD coupling changes with pain modulatory areas such as the medial parabrachial nucleus and trigeminal nerve entry while non-responders exhibited greater changes with the cuneiform. A5 connectivity changes were observed with the caudal SRD, rostral ventromedial medulla, and locus coeruleus in non-responders compared to responders.
Conclusions
Our results add to the accumulating evidence that brainstem nuclei including the SRD and A5 are involved in the CPM analgesic circuitry. CPM has received significantly increased attention due to reported impairments in chronic pain populations and its association with persistent post-operative pain. Alterations of the brainstem regions identified are known to reduce one’s ability to modulate pain and create a pro-nociceptive environment conducive to the development of ongoing pain. Our next critical steps are to define connectivity changes within this circuitry, investigate cortical influences on CPM ability, and undertake these studies in people with chronic pain, in whom we predict that CPM will be attenuated. These approaches will provide insights into the interaction of CPM with chronic pain as well potential therapeutic targets for the restoration of pain modulatory systems and reduction of pain persistence.
References
LE BARS, D., VILLANUEVA, L., BOUHASSIRA, D. & WILLER, J. C. 1992. Diffuse noxious inhibitory controls (DNIC) in animals and in man. Patol Fiziol Eksp Ter, 55-65.
YOUSSEF, A. M., MACEFIELD, V. G. & HENDERSON, L. A. 2016. Pain inhibits pain; human brainstem mechanisms. NeuroImage, 124, 54-62.
Presenting Author
Ashleigh Wake
Poster Authors
Ashleigh Wake
BSc (Hons)
School of Medical Sciences, The University of Sydney, Sydney NSW, Australia
Lead Author
Lewis Crawford
PhD
School of Medical Sciences, The University of Sydney, Sydney NSW, Australia
Lead Author
Noemi Meylakh BA
BSc
School of Medical Sciences, The University of Sydney, Sydney NSW, Australia
Lead Author
Vaughan G Macefield BSc
PhD
Department of Neuroscience, Monash University, Melbourne VIC, Australia
Lead Author
Kevin Keay
PhD
School of Medical Sciences, The University of Sydney, Sydney NSW, Australia
Lead Author
Luke A. Henderson
School of Medical Sciences, The University of Sydney, Sydney NSW, Australia
Lead Author
Topics
- Pain Imaging