Simultaneous brain, brainstem, and spinal cord pharmacological-fMRI reveals involvement of an endogenous opioid network in attentional analgesia
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Evaluation Summary:
This paper will be of great interest to researchers interested in cognitive modulations of sensory processing as well as in the brain mechanisms of pain. It shows that attentional modulations of pain are associated with changes in neural communication between cortical areas, brainstem and spinal cord which are sensitive to opioidergic but not to noradrenergic modulations. These findings are conclusively supported by state-of-the-art simultaneous pharmacological fMRI of the brain and the spinal cord.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
Pain perception is decreased by shifting attentional focus away from a threatening event. This attentional analgesia engages parallel descending control pathways from anterior cingulate (ACC) to locus coeruleus, and ACC to periaqueductal grey (PAG) – rostral ventromedial medulla (RVM), indicating possible roles for noradrenergic or opioidergic neuromodulators. To determine which pathway modulates nociceptive activity in humans, we used simultaneous whole brain-spinal cord pharmacological-fMRI (N = 39) across three sessions. Noxious thermal forearm stimulation generated somatotopic-activation of dorsal horn (DH) whose activity correlated with pain report and mirrored attentional pain modulation. Activity in an adjacent cluster reported the interaction between task and noxious stimulus. Effective connectivity analysis revealed that ACC interacts with PAG and RVM to modulate spinal cord activity. Blocking endogenous opioids with Naltrexone impairs attentional analgesia and disrupts RVM-spinal and ACC-PAG connectivity. Noradrenergic augmentation with Reboxetine did not alter attentional analgesia. Cognitive pain modulation involves opioidergic ACC-PAG-RVM descending control which suppresses spinal nociceptive activity.
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Evaluation Summary:
This paper will be of great interest to researchers interested in cognitive modulations of sensory processing as well as in the brain mechanisms of pain. It shows that attentional modulations of pain are associated with changes in neural communication between cortical areas, brainstem and spinal cord which are sensitive to opioidergic but not to noradrenergic modulations. These findings are conclusively supported by state-of-the-art simultaneous pharmacological fMRI of the brain and the spinal cord.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
This study investigates the brain mechanisms serving attentional modulations of pain. To this end, 39 healthy human participants performed an attention-demanding visual task with simultaneous application of painful thermal stimuli to the arm. In a 2x2 factorial design, visual task difficulty and thermal stimulus intensity were varied. To investigate the contributions of opioidergic and noradrenergic signalling to the attentional modulations, the paradigm was performed three times, i.e. after application of an opioid antagonist, a noradrenergic agonist and a placebo drug. During the paradigm, simultaneous fMRI of the brain and the spinal cord was performed. The results show that the opioid antagonist reduces attentional modulations of pain and changes connectivity between the anterior cingulate cortex, the …
Reviewer #1 (Public Review):
This study investigates the brain mechanisms serving attentional modulations of pain. To this end, 39 healthy human participants performed an attention-demanding visual task with simultaneous application of painful thermal stimuli to the arm. In a 2x2 factorial design, visual task difficulty and thermal stimulus intensity were varied. To investigate the contributions of opioidergic and noradrenergic signalling to the attentional modulations, the paradigm was performed three times, i.e. after application of an opioid antagonist, a noradrenergic agonist and a placebo drug. During the paradigm, simultaneous fMRI of the brain and the spinal cord was performed. The results show that the opioid antagonist reduces attentional modulations of pain and changes connectivity between the anterior cingulate cortex, the brainstem, and the spinal cord. Such changes were not observed after application of the noradrenergic agonist. Together, the findings convincingly demonstrate that attentional modulations of pain are associated with opioid-sensitive changes of cortical-brainstem-spinal connectivity.
Strengths:
• The brain mechanisms serving attentional modulations of pain is a timely and relevant topic with potential clinical implications.
• Simultaneous fMRI of the brain and spinal cord is a cutting-edge neuroimaging approach which uniquely allows for cerebral-spinal connectivity analysis.
• Comparing attentional modulations after opioidergic and noradrenergic modulations is innovative and offers a translational perspective.
Weaknesses:
• The comparison of the opioidergic, noradrenergic and placebo manipulations are particularly interesting. These results are mostly based on the presence of effects in the opioidergic as compared to the placebo condition but not in the noradrenergic as compared to the placebo condition. Thus, the negative findings in the noradrenergic condition play an important role. This part might be strengthened by using Bayesian statistics which allow for distinguishing between evidence of absence and absence of evidence. Moreover, directly contrasting the opioidergic and noradrenergic conditions might further strengthen the case.
• A crucial part of the reasoning is the correspondence between behavioral and neuroimaging effects. So far, the correspondence is mostly based on similar patterns of modulations on the group level. Extending this correspondence to the individual level might provide further support. For instance, the authors might relate the individual behavioral effects to the individual neural effects. This would substantially strengthen the relationship between behavioral and neural effects.
• The crucial attentional effects on pain ratings and fMRI responses are interactions between task difficulty and stimulus intensity. These findings are in line with previous findings from the same group. However, a main effect of task difficulty might also be reasonable. This should be discussed with reference to previous studies on attentional effects on pain.
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Reviewer #2 (Public Review):
In this impressive study, Oliva and colleagues used a placebo-controlled, double-blind, within-subject, three-armed pharmacological challenge with simultaneous imaging of the entire central nervous system (CNS) of healthy volunteers during attentional modulation of pain. They observed that during a distraction-induced reduction of perceived pain, the first station of nociceptive processing in the CNS - i.e. the spinal cord - exhibited functional magnetic resonance imaging (fMRI) signal changes that went along with the behavioural data. fMRI signal changes in the spinal cord could furthermore be related to connectivity changes with brainstem areas known from animal experiments to influence spinal cord nociceptive processing. Finally, the authors demonstrated how these behavioural and neurobiological effects …
Reviewer #2 (Public Review):
In this impressive study, Oliva and colleagues used a placebo-controlled, double-blind, within-subject, three-armed pharmacological challenge with simultaneous imaging of the entire central nervous system (CNS) of healthy volunteers during attentional modulation of pain. They observed that during a distraction-induced reduction of perceived pain, the first station of nociceptive processing in the CNS - i.e. the spinal cord - exhibited functional magnetic resonance imaging (fMRI) signal changes that went along with the behavioural data. fMRI signal changes in the spinal cord could furthermore be related to connectivity changes with brainstem areas known from animal experiments to influence spinal cord nociceptive processing. Finally, the authors demonstrated how these behavioural and neurobiological effects were disrupted by a blockade of the opioidergic system, but not of the noradrenergic system, conferring a certain pharmacological specificity.
From a technical point of view this is a formidable feat: due to the complexities of data acquisition, there are only a handful of whole-CNS imaging studies and none of them had yet paired this with a pharmacological challenge and connectivity down to the spinal cord. By targeting both the noradrenergic and opioidergic system and obtaining results from the spinal cord, brainstem and brain simultaneously during an analgesic manipulation, the authors provide a so-far missing link between an extensive animal literature that has examined the relevant spinal (and brainstem) processes and human studies that have focussed to a large extent on supra-spinal cortical and sub-cortical processes. Here, especially the connectivity results that provide a critical link from (cortex via) brainstem to the spinal cord are of note.
Nevertheless, there are several - mostly methodological - points that the authors will need to address in order to substantiate the reported results (some of which might simply be addressed by adding currently missing information). These include i) missing statistical tests, ii) a possible bias in the connectivity results, iii) their approach towards identifying the small target areas of interest in the brainstem and spinal cord, iv) the success of double-blinding and v) the quality of the fMRI data.
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Reviewer #3 (Public Review):
The strengths of the paper include the comprehensiveness of the experimental design, which involves the spinal-brainstem-whole brain simultaneous fMRI with pharmacological treatment (naltrexone and reboxetine).
The weaknesses of the paper include the insufficient description of experimental methods, statistical analyses, and results. My biggest concerns are mostly about statistical analyses and how they described the statistical analysis results. Most importantly, in their descriptions of results, it was difficult to get details about statistical analyses and tests (e.g., thresholding, masks, etc.) and also quantitative information about the results (e.g., effect size, and test statistics, p-values, etc.).
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