Background & Aims

Placebo analgesia is a pain modulatory phenomenon that leverages specific cortical and brainstem circuitry to alter one’s perception of pain. It has recently been shown that the lateral column of the midbrain periaqueductal gray (PAG) is critically involved in human expression of placebo analgesia (Crawford et al. 2021). Furthermore, it has also been shown that the lateral PAG is somatotopically organized with respect to acute noxious stimuli, where stimuli applied to the face activates a more rostral region than stimuli applied to the body (Tinoco Mendoza et al. 2023). It remains unknown if a similar somatotopic organization of the lateral PAG also exists for placebo analgesia expression. We aim to determine the precise distribution of activation associated with placebo analgesia elicited on the lower limb (shin), upper limb (arm) and face, and investigate if a somatotopic activation pattern of placebo-related activity exists within the lateral PAG.

Methods

85 healthy controls (58 females; mean ± SEM age: 24.8 ± 0.9 years) were deceptively conditioned to expect a reduction in thermal cutaneous pain relative to a negative control, when the noxious stimulus was applied to an “analgesic” cream. After reinforcement on the successive day, participants underwent ultra-high field functional magnetic resonance imaging (7T-fMRI). Three functional series were acquired (134 volumes, TR=2.5s, voxel size = 1x1x1.2mm) where each cream site (control versus “analgesia”) was stimulated at an identical moderate intensity on the shin, arm and face, and real-time pain ratings collected. Anatomical and functional images were pre-processed using SPM12 and brainstem-specific software. Participants were grouped as either responder or non-responder based on permutation testing. Regression analyses were performed using placebo-responsiveness as a covariate for investigating activation patterns (p<0.01) and functional connectivity during shin, arm and face placebo.

Results

Placebo trials on the shin, arm and face evoked peak activation in the lateral PAG column in responders. Exploration of peak placebo-related activations during shin and arm stimuli revealed a distinct rostro-caudal pattern; that is, placebo responders during the shin and arm paradigms were associated with a similar caudal level of PAG activation. In contrast, our preliminary analysis of the face placebo trials revealed a peak placebo-related activation more rostrally in the lateral PAG. In addition, for all three stimulation sites, significant positive correlations between placebo responsiveness and activations occurred within the rostral anterior cingulate cortex (rACC; Shin: r=0.59; Arm_r=0.64; Face: r=0.45; p<0.05) and negative correlations within the contralateral dorsolateral prefrontal cortex (dlPFC; Shin: r=-0.66; Arm: r=-0.64; Face: r=-0.51).

Conclusions

We demonstrate a placebo-related somatotopy within the lateral PAG that follows the same rostro-caudal pattern during acute noxious stimulation. Accordingly, recruitment of the lateral PAG during placebo analgesia elicits a top-down response that is body-site specific. This somatotopic organization of the lateral PAG can be linked to the relationship between expectancies and opioid systems associated within the PAG. The network involving the ACC and dlPFC may be critical in driving the sensation that shapes placebo analgesia, regardless of body site. However, cortical engagement of the lateral PAG appears to relate directly to the body site where expected pain relief is directed. In this way, we provide evidence that the PAG activates neurochemical systems during placebo analgesia that are confined to specific neuronal networks and circuits. Endogenous pain modulation is therefore able to leverage the most appropriate defensive response towards a localized source of noxious stimulation

References

Crawford LS, Mills EP, Hanson T, Macey PM, Glarin R, Macefield VG, Keay KA, Henderson LA. Brainstem Mechanisms of Pain Modulation: A within-Subjects 7T fMRI Study of Placebo Analgesic and Nocebo Hyperalgesic Responses. J Neurosci. 2021 Nov 24;41(47):9794-9806. doi: 10.1523/JNEUROSCI.0806-21.2021. Epub 2021 Oct 25. PMID: 34697093; PMCID: PMC8612641.

Tinoco Mendoza FA, Hughes TES, Robertson RV, Crawford LS, Meylakh N, Macey PM, Macefield VG, Keay KA, Henderson LA. Detailed organisation of the human midbrain periaqueductal grey revealed using ultra-high field magnetic resonance imaging. Neuroimage. 2023 Feb 1;266:119828. doi: 10.1016/j.neuroimage.2022.119828. Epub 2022 Dec 20. PMID: 36549431.

Presenting Author

Fernando Tinoco Mendoza

Poster Authors

Fernando Tinoco Mendoza

BSc(Hons)

The University of Sydney

Lead Author

E-mail

Lewis Crawford

PhD

The University of Sydney

Lead Author

E-mail

Isabella Z Vatovec

BSc (Hons)

University of Sydney

Lead Author

E-mail

Vaughan G Macefield

BSc (Hons)

Monash University

Lead Author

E-mail

Rebecca V Robertson

BSc (Hons)

University of Sydney

Lead Author

E-mail

Kevin Keay

PhD

The University of Sydney

Lead Author

E-mail

Topics

  • Pain Imaging