Biology subjects

Mehta, M. A.

Publications and source records attributed to Mehta, M. A..

8 recordsLinked to original sources

bioRxiv2026

Spatial collinearity constrains multivariate molecular-enriched network estimation

Analyses of neuroimaging data increasingly leverage the distribution of neurotransmitter receptors derived from Positron Emission Tomography (PET) to bridge the gap between micro- and macro-scale brain function. However, these receptor maps are highly spatially overlapping which can give rise to interpretive and analytical challenges. Here, we systematically investigate the impact of spatial collinearity among PET maps in the context of Receptor-Enriched Analysis of functional Connectivity by Targets (REACT), a method that uses receptor maps as spatial regressors to derive subject-level molecular-enriched functional connectivity networks. Exhaustive combinatorial analysis across 19 receptor and transporter maps showed that collinearity scales rapidly with the number of receptors modelled simultaneously, and that this was relatively stable across parcellation scales, reflecting the intrinsic organisation of neurotransmitter systems. Using test-retest fMRI data from the Human Connectome Project, we demonstrate that modelling greater numbers of receptors degrades the reliability of molecular-enriched networks derived from conventional multivariate REACT models, and that collinearity among receptor maps drives this degradation. An alternative univariate approach, in which each receptor is modelled independently, yielded more reliable networks and, when applied to a within-subjects study of LSD compared to placebo, better recovered the role of the 5HT-2A receptor in LSDs neural effects. These findings identify spatial collinearity as a fundamental constraint on multivariate molecular-enriched network estimation and support univariate modelling as a more robust default for this class of analysis.

neuroscience↗

bioRxiv2023

D2/D3 dopamine supports the precision of mental state inferences and self-relevance of joint social outcomes

Striatal dopamine is important in paranoid attributions, although its computational role in social inference remains elusive. We employed a simple game theoretic paradigm and computational model of intentional attributions to investigate the effects of dopamine D2/D3 antagonism on ongoing mental state inference following social outcomes. Haloperidol, compared to placebo, enhanced the impact of partner behaviour on beliefs about the harmful intent of partners, and increased learning from recent encounters. These alterations caused significant changes to model covariation and negative correlations between self-interest and harmful intent attributions. Our findings suggest haloperidol improves belief flexibility about others and simultaneously reduces the self-relevance of social observations. Our results may reflect the role of D2/D3 dopamine in supporting self-relevant mentalisation. Our data and model bridge theory between general and social accounts of value representation. We demonstrate initial evidence for the sensitivity of our model and short social paradigm to drug intervention and clinical dimensions, allowing distinctions between mechanisms that operate across traits and states. Data AvailabilityAll data and code are available online: https://github.com/josephmbarnby/Barnby_etal_2023_D2D3Modelling Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/539031v6_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@8bd39borg.highwire.dtl.DTLVardef@1f18845org.highwire.dtl.DTLVardef@2986b4org.highwire.dtl.DTLVardef@4abd90_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

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

Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) is a novel analytical strategy that enriches functional connectivity (FC) information from functional MRI (fMRI) with molecular information on the neurotransmitter distribution density in the human brain, providing a biological basis to the FC analysis. So far, this integrative approach has been used in blood oxygen level-dependent (BOLD) fMRI studies only, providing new insights into the brain mechanisms underlying specific disorders and its response to pharmacological challenges. In this study, we demonstrate that the application of REACT can be further extended to arterial spin labelling (ASL) fMRI. Some of the advantages of this extension include the combination of neurotransmitter specific information provided by molecular imaging with a quantitative marker of neuronal activity, the suitability of ASL for pharmacological MRI (phMRI) studies assessing drug effects on baseline brain function, and the possibility to acquire images that are not affected by susceptibility artifacts in the regions linked to major neurotransmitter systems. In this work, we tested the feasibility of applying REACT to resting state ASL fMRI and compared the molecular-enriched FC maps derived from ASL data with those derived from BOLD data. We applied REACT to high-resolution, whole-brain simultaneous ASL/BOLD resting-state fMRI data of 29 healthy subjects and estimated the ASL- and BOLD-based FC maps related to six molecular systems, including the transporters of dopamine, noradrenaline, serotonin and vesicular acetylcholine, and the GABA-A and mGlu5 receptors. We then compared the ASL and BOLD FC maps in terms of spatial similarity, using the Dice Similarity Index and the voxel-wise spatial correlation. On a data subsample (N=19) we also evaluated the test-retest reproducibility of each modality using the regional intraclass correlation coefficient, and compared the two modalities. Our results showed robust spatial patterns of molecular-enriched functional connectivity for both modalities, moderate to high similarity between BOLD- and ASL-derived FC maps and mixed results in terms of reproducibility (i.e., none of the modalities outperformed the other). Overall, our findings show that the ASL signal is as informative as BOLD in detecting functional circuits associated with specific molecular pathways, and that the two modalities may provide complementary information related to these circuits. Considering the more direct link of ASL imaging with neuronal acrivity compared to BOLD and its suitability for phMRI studies, this new integrative approach could become a valuable asset in clinical studies investigating functional alterations in patients with brain disorders, or in pharmacological studies investigating the effects of new or existing compounds on the brain.

neuroscience↗

bioRxiv2020

JuSpace: A tool for spatial correlation analyses of magnetic resonance imaging data with positron emission tomography derived neurotransmitter maps

Recent studies have shown that drug-induced spatial alteration patterns in resting state functional activity as measured using magnetic resonance imaging (rsfMRI) are associated with the distribution of specific receptor systems targeted by respective compounds. Based on this approach, we introduce a toolbox (JuSpace) allowing for cross-modal correlation of MRI- based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, and GABAergic (gamma- aminobutric acid) neurotransmission. We apply JuSpace to two datasets covering Parkinsons disease patients (PD) and risperidone-induced changes in rsfMRI and cerebral blood flow (CBF). Consistently with the predominant neurodegeneration of dopaminergic and serotonergic system in PD, we find significant spatial associations between rsfMRI activity alterations in PD and dopaminergic (D2) and serotonergic systems (5-HT1b). Risperidone induced CBF alterations were correlated with its main targets in serotonergic and dopaminergic systems. JuSpace provides a biologically meaningful framework for linking neuroimaging to underlying neurotransmitter information.

neuroscience↗

bioRxiv2020

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

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. Results showed a significant MPH-induced FC increase in sensorimotor areas in the functional circuit associated with DAT. We also found that MPH-induced variations in DAT-and NET-enriched FC were significantly correlated with inter-individual differences in effects of MPH on key behavioural responses associated with the reinforcement-learning task. Our findings show that MPH-related FC changes are specifically associated with DAT and provide evidence 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 distinct molecular targets.

neuroscience↗

bioRxiv2019

Dopamine modulates paranoid social inferences: a double-blind, within-subject, randomised control study in a healthy population.

Altered dopamine transmission is thought to influence the formation of persecutory delusions. However, despite extensive evidence from clinical studies there is little experimental evidence on how modulating the dopamine system changes social attributions related to paranoia, and the salience of beliefs more generally. 27 healthy male participants received 150mg L-DOPA, 3mg haloperidol, or placebo in a double blind, randomised, placebo-controlled study, over three within-subject sessions. Participants completed a multi-round Dictator Game modified to measure social attributions, and a measure of belief salience spanning themes of politics, religion, science, morality, and the paranormal. We preregistered predictions that altering dopamine function would affect i) attributions of harmful intent and ii) salience of paranormal beliefs. As predicted, haloperidol reduced attributions of harmful intent across all conditions compared to placebo. L-DOPA reduced attributions of harmful intent in fair conditions compared to placebo. Unexpectedly, haloperidol increased attributions of self-interest for opponents decisions. There was no change in belief salience within any theme. These results could not be explained by scepticism or subjective mood. Our findings demonstrate the selective involvement of dopamine in social inferences related to paranoia in healthy individuals.

neuroscience↗

bioRxiv2018

Increased Cerebral Blood Flow after single dose of antipsychotics in healthy volunteers depends on dopamine D2 receptor density profiles.

As a result of neuro-vascular coupling, the functional effects of antipsychotics in human brain have been investigated in both healthy and clinical populations using haemodynamic markers such as regional Cerebral Blood Flow (rCBF). However, the relationship between observed haemodynamic effects and the pharmacological action of these drugs has not been fully established. Here, we analysed MRI-based rCBF data from a placebo-controlled study in healthy volunteers, who received a single dose of three different D2 receptor antagonists and tested the association of the main effects of the drugs on rCBF against normative population maps of D2R protein density and gene-expression data. In particular, we correlated CBF changes after antipsychotic administration with non-displaceable binding potential (BPND) template maps of the high affinity D2-antagonist Positron Emission Tomography (PET) ligand [18F]Fallypride and brain post-mortem microarray mRNA expression data for the DRD2 gene. For all antipsychotics, rCBF changes were directly proportional to brain D2R densities and DRD2 mRNA expression measures, although PET BPND spatial profiles explained more variance as compared with mRNA profiles (PET R2 range= 0.20-0.60, mRNA PET R2 range 0.04-0.20, pairwise-comparisons all p<0.05). In addition, the spatial coupling between {Delta}CBF and D2R profiles varied between the different antipsychotics tested, possibly reflecting differential affinities. Overall, these results indicate that the functional effects of antipsychotics as measured with rCBF are tightly correlated with the distribution of their target receptors in striatal and extra-striatal regions. Our results further demonstrate the link between neurotransmitter targets and haemodynamic changes reinforcing rCBF as a robust in-vivo marker of drug effects. This work is important in bridging the gap between pharmacokinetic and pharmacodynamics of novel and existing compounds.

pharmacology and toxicology↗

bioRxiv2017

A proof-of-principle study of the effect of combined haloperidol and levodopa administration on working memory-related brain activation in humans

Background and PurposeCognitive deficits including impaired working memory are a hallmark feature of schizophrenia. Changes in prefrontal cortex function modulated by dopamine D1 receptors, play a potentially important role in the pathology underlying such deficits. However, pharmacological interventions that selectively engage the D1 receptor are severely restricted for research in humans. The present study is a proof-of-principle for enhancing cognitive performance and associated brain activation via indirect D1 stimulation. Here, we combine the non-selective dopamine agonist L-dopa with the D2-antagonist haloperidol, theoretically producing increased stimulation at the D1 receptor.\n\nExperimental ApproachFourteen healthy volunteers received placebo or combined carbidopa (125 mg, 100mg L-dopa) plus haloperidol (2 mg) orally on two separate occasions according to a within-subjects cross-over design. Drug-induced differences in brain activity were assessed during an N-back working memory task in a 3T magnetic resonance imaging environment.\n\nKey ResultsDrug treatment was associated with a reduction in activity in a large number of brain areas, most prominently occipital/temporal brain areas during 2-back performance, which may be due to the effects of haloperidol specifically. Drug treatment was also associated with greater functional connectivity within parts of the salience network during all N-back trials.\n\nConclusion and ImplicationsThis preliminary study provides initial evidence for combined L-dopa/haloperidol modulation in cognition-related brain areas and networks, which is relevant for the treatment of cognitive impairments in mental illness.

neuroscience↗