Parallel cortical-brainstem pathways to attentional analgesia

Abstract

13Pain perception is diminished when attention is diverted. Our previous human fMRI study, using a 14 2x2 factorial design with thermal stimuli and concurrent visual attention task, linked the brainstem 15 triad of locus coeruleus (LC), rostroventromedial medulla (RVM) and periaqueductal grey (PAG) to 16 attentional analgesia. This study was repeated with a larger cohort, replicating our earlier findings. 17 Pain intensity was encoded by the RVM, whilst activity in the contralateral LC correlated with the 18 magnitude of attentional analgesia. Psycho-Physiological Interaction analysis informed subsequent 19 Dynamic Causal Modelling and identified two parallel paths between forebrain and the brainstem 20 regions involved in analgesia. These cortico-brainstem connections were modulated by attentional 21 demand: a bidirectional anterior cingulate cortex (ACC)right-LC loop, and a top-down influence 22 of task on ACC-PAG-RVM. Under conditions of competing attentional demands the ACC recruits 23 discrete brainstem circuits to modulate nociceptive input. 24 25 Parallel cortical-brainstem pathways to attentional analgesia activation of the ACC-PAG-RVM and/or the ACC-LC system still needs to be demonstrated in 595humans. It is known that both pathways could involve opioids (Fields, 2004) and so previous studies 596 using naloxone do not discriminate between these possibilities. A connectivity analysis examining 597 the network activity between cortical territories, brainstem nuclei and dorsal horn in toto may help to 598 define the key pathway in attentional analgesia. We further postulate that this network may be of 599 importance in chronic conditions where disruption of attention and cognition (i.e. fibromyalgia) are 600 co-morbid alongside pain.

Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats

“…The PAG is a key node in the DPMS but also an important orchestrator of autonomic and sensorimotor systems that is engaged to support mPFC function in aversive learning, emotional modulation and pain modulation which are all relevant to the chronic pain phenotype (Keay and Bandler, 2001;Franklin et al, 2017;Rozeske et al, 2018;Huang et al, 2019). In humans, changes in functional connectivity between the mPFC/ACC, and the PAG are commonly observed in experimental paradigms that produce emotional, attentional and placebo/nocebo influences on pain as well following delivery of analgesic drugs and often interpreted as reflecting engagement of the DPMS (Wager et al, 2004;Wiech et al, 2014;Wanigasekera et al, 2018;Oliva et al, 2020). Moreover, changes in the functional connectivity between regions of the mPFC and the PAG are often correlated with changes in pain perception and/or disease progression, (Cifre et al, 2012;Hemington and Coulombe, 2015;Harper et al, 2018;Segerdahl et al, 2018;Wanigasekera et al, 2018;González-Roldán et al, 2020).…”

Simultaneous Brain, Brainstem and Spinal Cord pharmacological-fMRI reveals endogenous opioid network interactions mediating attentional analgesia

“…A total of 39 subjects (mean age 23.7, range [18 -45] years, 18 females) completed the fMRI imaging sessions with a 2*2 factorial experimental design (RSVP task easy / hard and high / low thermal stimulus) with a different drug administered orally before each session (naltrexone (50mg), reboxetine (4mg) or placebo, Figure 1). The behavioural signature of attentional analgesia is a task*temperature interaction, driven by a reduction in pain ratings during the high temperature-hard task condition (Brooks et al, 2017;Oliva et al, 2021;Oliva et al, 2020). A first level analysis of the pooled pain data across all experimental sessions showed: a main effect of temperature (F (1,38) = 221, P=0.0001) with higher scores under the high temperature condition; a main effect of task (F (1,38) = 4.9, P=0.03); and importantly demonstrated the expected task*temperature interaction consistent with attentional pain modulation (F (1, 38) = 10.5, P = 0.0025, Figure 2).…”

“…We have shown that two parallel pathways are implicated in driving brainstem activity related to attentional analgesia (Brooks et al, 2017;Oliva et al, 2020). Projections from rostral anterior cingulate cortex (rACC) were found to drive the periaqueductal grey (PAG) and rostral ventromedial medulla (RVM), which animal studies have shown to work in concert using opioidergic mechanisms to regulate spinal nociception (Fields, 2004;Fields and Basbaum, 1978;Heinricher et al, 1994;Ossipov et al, 2010).…”

“…To address this issue, we conducted a double-blind, placebo-controlled, three arm, cross-over pharmacological-fMRI experiment to investigate attentional analgesia using whole neuraxis imaging and a well validated experimental paradigm. To engage attention, we utilised a rapid serial visual presentation (RSVP) task (Brooks et al, 2017;Oliva et al, 2020;Potter and Levy, 1969) with individually calibrated task difficulties (easy or hard), which was delivered concurrently with thermal stimulation adjusted per subject to evoke different levels of pain (low or high). We took advantage of recent improvements in signal detection (Duval et al, 2015) and pulse sequence design to simultaneously capture activity across the brain, brainstem, and spinal cord (i.e.…”

“…To resolve the relative contributions from the opioidergic and noradrenergic systems, subjects received either the opioid antagonist naltrexone, the noradrenaline re-uptake inhibitor reboxetine, or placebo. By measuring the influence of these drugs on pain perception, BOLD activity and effective connectivity between a priori specified regions known to be involved in attentional analgesia (rACC, PAG, LC, RVM, spinal cord (Brooks et al, 2017;Oliva et al, 2020;Sprenger et al, 2012)), we sought to identify the network interactions and neurotransmitter mechanisms mediating this cognitive modulation of pain.…”