The M1/M4 agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain

AbstractCholinergic drugs acting at M1/M4 muscarinic receptors hold promise for the treatment of symptoms associated with brain disorders characterized by cognitive impairment, mood disturbances or psychosis, such as Alzheimer’s disease or schizophrenia. However, the brain-wide functional substrates engaged by muscarinic agonists remain poorly understood. Here we used a combination of pharmacological fMRI (phMRI), resting-state fMRI (rsfMRI) and resting-state quantitative EEG (qEEG) to investigate the effects of a behaviorally-active dose of M1/M4 agonist xanomeline on brain functional activity in the rodent brain. We investigated both the effects of xanomeline per se and its modulatory effects on signals elicited by the NMDA-receptor antagonists phencyclidine (PCP) and ketamine. We found that xanomeline induces robust and widespread BOLD signal phMRI amplitude increases and decreased high frequency qEEG spectral activity. rsfMRI mapping in the mouse revealed that xanomeline robustly decreased neocortical and striatal connectivity but induces focal increases in functional connectivity within the nucleus accumbens and basal forebrain. Notably, xanomeline pre-administration robustly attenuated both the cortico-limbic phMRI response and the fronto-hippocampal hyper-connectivity induced by PCP, enhanced PCP-modulated functional connectivity locally within the nucleus accumbens and basal forebrain, and reversed the gamma and high frequency qEEG power increases induced by ketamine. Collectively, these results show that xanomeline robustly induces both cholinergic-like neocortical activation and desynchronization of functional networks in the mammalian brain. These effects could serve as a translatable biomarker for future clinical investigations of muscarinic agents, and bear mechanistic relevance for the putative therapeutic effect of these class of compounds in brain disorders.

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Altered functional connectivity of the nucleus accumbens subdivisions in amphetamine-type stimulant abusers: a resting-state fMRI study

BMC Neuroscience ◽

10.1186/s12868-019-0548-y ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Yun Wang ◽

Kai-Juan Yan ◽

Chen-Xiao Fan ◽

Xiao-Nian Luo ◽

Yuan Zhou

Keyword(s):

Nucleus Accumbens ◽

Functional Connectivity ◽

Resting State ◽

Inferior Frontal Gyrus ◽

Resting State Fmri ◽

Resting State Functional Connectivity ◽

Functional Architecture ◽

Superior Frontal Gyrus ◽

Eyes Closed ◽

Orbital Part

Abstract Background The growing abuse of amphetamine-type stimulants leads to new challenges to human health. A possible addiction mechanism has been proposed by altered functional architecture of the nucleus accumbens (NAc) during resting state. NAc contains different subdivisions and they may play different roles in addiction. The aim of the present study was to examine whether there are common or distinct patterns of functional connectivity of the NAc subdivisions in amphetamine-type stimulant abusers (ATSAs). Methods The present study recruited 17 male ATSAs and 22 healthy male controls. All the subjects underwent resting-state functional magnetic resonance imaging (fMRI) with their eyes closed. The NAc was divided into core-like and shell-like subdivisions. We used seed-based resting-state functional connectivity (RSFC) analyses to identify differences in brain functional architecture between ATSAs and healthy controls (HCs). Results ATSAs had lower positive RSFCs with all of the NAc subdivisions over the left orbital part of superior frontal gyrus and higher positive RSFCs with the NAc subdivisions over the left opercular part of inferior frontal gyrus than HCs, which indicates common abnormalities across the NAc subdivisions in ATSAs. In addition, the RSFCs between the NAc subdivisions and the left orbital part of superior frontal gyrus were negatively correlated with the addiction severity in ATSAs. Conclusion These results provide evidence that there are common RSFC patterns of the NAc subdivisions in ATSAs. The abnormality indicated by disrupted functional connectivity between the NAc subdivisions and prefrontal cortex suggests abnormal interaction between the rewarding process and cognitive control in ATSAs. Our results shed insight on the neurobiological mechanisms of ATSA and suggest potential novel therapeutic targets for treatment and intervention of ATSAs.

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Altered Functional Connectivity of the Insula and Nucleus Accumbens in Internet Gaming Disorder: A Resting State fMRI Study

European Addiction Research ◽

10.1159/000440716 ◽

2016 ◽

Vol 22 (4) ◽

pp. 192-200 ◽

Cited By ~ 16

Author(s):

Chiao-Yun Chen ◽

Ju-Yu Yen ◽

Peng-Wei Wang ◽

Gin-Chung Liu ◽

Cheng-Fang Yen ◽

...

Keyword(s):

Nucleus Accumbens ◽

Functional Connectivity ◽

Frontal Lobe ◽

Resting State ◽

Internet Gaming Disorder ◽

Resting State Fmri ◽

Gaming Disorder ◽

Internet Gaming ◽

Left Dlpfc ◽

The Right

Aims: A possible addiction mechanism has been represented by altered functional connectivity (FC) in the resting state. The aim of this study was to evaluate the FCs of the insula and nucleus accumbens among subjects with Internet gaming disorder (IGD). Methods: We recruited 30 males with IGD and 30 controls and evaluated their FC using functional magnetic imaging scanning under resting, a state with relaxation, closed eyes, with inducement to think of nothing systematically, become motionless, and instructed not to fall asleep. Results: Subjects with IGD had a lower FC with the left insula over the left dorsolateral prefrontal cortex (DLPFC) and orbital frontal lobe and a higher FC with the insula with the contralateral insula than controls. The inter-hemispheric insula connectivity positively correlated with impulsivity. Further, they had lower FC with the left nucleus accumbens over the left DLPFC and with the right nucleus accumbens over the left DLPFC, and insula and a higher FC with that over the right precuneus. Conclusion: The elevated inter-hemispheric insula FC is found to be associated with impulsivity and might explain why it is involved in IGD. The attenuated frontostriatal suggests that the emotion-driven gaming urge through nucleus accumbens could not be well regulated by the frontal lobe of subjects with IGD.

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Personalized intrinsic network topography mapping and functional connectivity deficits in Autism Spectrum Disorder

10.1101/161893 ◽

2017 ◽

Cited By ~ 1

Author(s):

Erin W. Dickie ◽

Stephanie H. Ameis ◽

Joseph D. Viviano ◽

Dawn E. Smith ◽

Navona Calarco ◽

...

Keyword(s):

Functional Connectivity ◽

Resting State ◽

Resting State Fmri ◽

Autism Spectrum ◽

Brain Disorders ◽

Resting State Networks ◽

Cross Sectional ◽

Novel Approach ◽

Specific Variation ◽

Spatial Locations

AbstractBackgroundRecent advances demonstrate individually specific variation in brain architecture in healthy individuals using fMRI data. To our knowledge, the effects of individually specific variation in complex brain disorders have not been previously reported.MethodsWe developed a novel approach (Personalized Intrinsic Network topography, PINT) for localizing individually specific resting state networks using conventional resting state fMRI scans. Using cross-sectional data from participants with ASD (n=393) and TD controls (n=496) across 15 sites we tested: 1) effect of diagnosis and age on the variability of intrinsic network locations and 2) whether prior findings of functional connectivity differences in ASD as compared to TD remain after PINT application.ResultsWe found greater variability in the spatial locations of resting state networks within individuals with ASD as compared to TD. In TD participants, variability decreased from childhood into adulthood, and increased again in late-life, following a ‘U-shaped’ pattern, which was not present in those with ASD. Comparison of intrinsic connectivity between groups revealed that the application of PINT decreased the number of hypo-connected regions in ASD.ConclusionsOur results provide a new framework for measuring altered brain functioning in neurodevelopmental disorders that may have implications for tracking developmental course, phenotypic heterogeneity, and ultimately treatment response. We underscore the importance of accounting for individual variation in the study of complex brain disorders.

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