A candidate neuroimaging biomarker for detection of neurotransmission-related functional alterations and prediction of pharmacological analgesic response in chronic pain

Abstract

Chronic pain is a world-wide clinical challenge. Response to analgesic treatment is limited and difficult to predict. Functional MRI has been suggested as a potential solution. However, while most analgesics target specific neurotransmission pathways, functional MRI-based biomarkers are not specific for any neurotransmitter system, limiting our understanding of how they might contribute to predict treatment response. Here, we sought to bridge this gap by applying Receptor-Enriched Analysis of Functional Connectivity by Targets to investigate whether neurotransmission-enriched functional connectivity mapping can provide insights into the brain mechanisms underlying chronic pain and inter-individual differences in analgesic response after a placebo or duloxetine. We performed secondary analyses of two openly available resting-state functional MRI datasets of 56 patients with chronic knee osteoarthritis pain who underwent pre-treatment brain scans in two clinical trials. Study 1 (n = 17) was a 2-week single-blinded placebo pill trial. Study 2 (n = 39) was a 3-month double-blinded randomised trial comparing placebo to duloxetine, a dual serotonin-noradrenaline reuptake inhibitor. Across two independent studies, we found that patients with chronic pain present alterations in the functional circuit related to the serotonin transporter, when compared to age-matched healthy controls. Placebo responders in study 1 presented with higher pre-treatment functional connectivity enriched by the dopamine transporter compared to non-responders. Duloxetine responders presented with higher pre-treatment functional connectivity enriched by the serotonin and noradrenaline transporters as compared to non-responders. Neurotransmission-enriched functional connectivity mapping might hold promise as a new mechanistic-informed biomarker for functional brain alterations and prediction of response to pharmacological analgesia in chronic pain.

Molecular-enriched functional connectivity in the human brain using multiband multi-echo simultaneous ASL/BOLD fMRI

“…The main hub of the DAT-enriched network corresponds to the striatum (i.e., caudate and putamen), although it is also possible to identify other key cortical and subcortical regions as belonging to this network, including the thalamus, anterior cingulate gyrus, paracingulate gyrus, insula, central opercular cortex, precentral and postcentral gyri, supplementary motor cortex, frontoparietal operculum cortex, superior temporal gyrus and temporal pole. The key regions of the NAT-enriched network identified by both datasets are the brainstem, thalamus, pre- and postcentral gyri, supplementary motor cortex and part of the anterior cingulate cortex, as previously reported in other studies (Cercignani et al, 2021; Martins et al, 2021). The SERT-enriched network is mainly localized in the thalamus, putamen, midbrain, insula, anterior cingulate gyrus and frontal orbital cortex, with the two datasets showing a wider or a smaller involvement of each of these areas.…”

“…The NAT-enriched functional network shows high positive FC partly in the brainstem, which is the major site of noradrenergic neurons (mainly the locus coeruleus), but also in the thalamus and sensorimotor regions, in line with the modulatory effect of noradrenergic pathways on processing of salient sensory information via actions on sensory, attentional and motor processes (Berridge and Waterhouse, 2003). Importantly, the spatial configuration of such functional networks is also comparable with the functional networks reported in previous REACT-based studies using BOLD fMRI data (Cercignani et al, 2021; Dipasquale et al, 2020; Dipasquale et al, 2019; Martins et al, 2021).…”

“…A detailed explanation of the REACT methodology and its applications can be found elsewhere (Dipasquale et al, 2019; Martins et al, 2021). In brief, the functional circuits related to the six molecular systems were estimated using a two-step multivariate regression analysis.…”

“…The application of REACT to clinical and pharmacological blood oxygen leveldependent (BOLD) fMRI studies has demonstrated its ability to uncover new patterns of functional alterations in neurotransmission-related circuits in patients with brain disorders and suggests potential drug-target mechanisms at the system level that could underlie the functional effects of pharmacological treatment (Cercignani et al, 2021; Dipasquale et al, 2020; Dipasquale et al, 2019; Martins et al, 2021; Wong et al, 2021). However, the BOLD signal is an indirect measure of neuronal activity, resulting from the combination of changes in both oxygen consumption and regional cerebral blood flow (CBF), as well as changes in regional blood volume (CBV) (Buxton et al, 2004).…”

The Effects of Propofol Anaesthesia on Molecular-enriched Networks During Resting-state and Naturalistic Stimulation

“…One solution to this has been to incorporate molecular information from positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) into fMRI analyses, as in Receptor-Enriched Analysis of functional connectivity by targets (REACT), to help bridge the gap between these micro-and macroscale systems (Dipasquale et al, 2019). The resultant receptor-enriched networks have demonstrated alterations under pharmacological challenge (Dipasquale et al, 2019(Dipasquale et al, , 2020Lawn et al, 2022) and within disease states (Cercignani et al, 2021;Martins et al, 2022;Wong et al, 2022), but also offer a promising tool to probe the molecular substrates of cognition and consciousness. Each modulatory system engages with a set of target receptors which exhibit diversity in their patters of expression as well as downstream effects which interact in a complex pleiotropic manner.…”