Unravelling the effects of methylphenidate on the dopaminergic and noradrenergic functional circuits

Abstract

Functional magnetic resonance imaging (fMRI) can be combined with drugs to investigate the system-level functional responses in the brain to such challenges. However, most psychoactive agents act on multiple neurotransmitters, limiting the ability of fMRI to identify functional effects related to actions on discrete pharmacological targets. We recently introduced a multimodal approach, REACT (Receptor-Enriched Analysis of functional Connectivity by Targets), which offers the opportunity to disentangle effects of drugs on different neurotransmitters and clarify the biological mechanisms driving clinical efficacy and side effects of a compound. Here, we focus on methylphenidate (MPH), which binds to the dopamine transporter (DAT) and the norepinephrine transporter (NET), to unravel its effects on dopaminergic and noradrenergic functional circuits in the healthy brain at rest. We then explored the relationship between these target-enriched resting state functional connectivity (FC) maps and inter-individual variability in behavioural responses to a reinforcement-learning task encompassing a novelty manipulation to disentangle the molecular systems underlying specific cognitive/behavioural effects. Our main analysis showed a significant MPH-induced FC increase in sensorimotor areas in the functional circuit associated with DAT. In our exploratory analysis, we found that MPH-induced regional variations in the DAT and NET-enriched FC maps were significantly correlated with some of the inter-individual differences on key behavioural responses associated with the reinforcement-learning task. Our findings show that main MPH-related FC changes at rest can be understood through the distribution of DAT in the brain. Furthermore, they suggest that when compounds have mixed pharmacological profiles, REACT may be able to capture regional functional effects that are underpinned by the same cognitive mechanism but are related to engagement of distinct molecular targets.

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

“…The resulting maps coherently show high FC values in the core areas of the molecular systems investigated and are in line with the molecular-enriched FC circuits described in previous REACT-based fMRI studies. 23 , 24 , 45 …”

“…A detailed explanation of the REACT methodology and its applications can be found elsewhere. 23 , 24 In brief, the functional circuits related to the DAT, NET, SERT and µ-opioid receptor systems were estimated using a two-step multivariate regression analysis 39 , 40 implemented with the fsl_glm command of FSL. In the first step, the rs-fMRI volumes were masked using a binarized mask derived from the molecular atlases to restrict the analysis to the voxels for which the density information of the neurotransmitter was available in the templates.…”

“…To test these hypotheses, we performed secondary analyses of two openly available resting-state functional MRI (rs-fMRI) data sets 22 using the recently developed Receptor-Enriched Analysis of Functional Connectivity by Targets (REACT) multimodal framework ( Box 1 ), 23 which enriches rs-fMRI analysis with information about the distribution density of molecular targets derived from PET and single-photon emission computerized tomography (SPECT) imaging. 23 , 24 These data sets included HCs ( n = 20) and patients with chronic knee osteoarthritis (OA) pain ( n = 56) who underwent pre-treatment brain scans in two clinical trials. Study 1 ( n = 17) was a 2-week single-blinded placebo pill trial.…”

Serotonin regulation of behaviour via large-scale neuromodulation of serotonin receptor networks

“…Although the idea of enriching fMRI with molecular information is not new in human neuroimaging [54][55][56][57] , here we used transcriptomic-neuroimaging mapping to study the effects of an acute pharmacological manipulation on DRN serotonin optogenetic activation. We showed that the SSRI uoxetine evoked bidirectional changes in the effect of optogenetic manipulation on the SRNs.…”

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

“…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).…”