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Dopaminergic brainstem disconnection is common to pharmacological and pathological consciousness perturbation.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Spindler, Lennart RB 
Adapa, Ram M 
Craig, Michael M 
Coppola, Peter 

Abstract

Clinical research into consciousness has long focused on cortical macroscopic networks and their disruption in pathological or pharmacological consciousness perturbation. Despite demonstrating diagnostic utility in disorders of consciousness (DoC) and monitoring anesthetic depth, these cortico-centric approaches have been unable to characterize which neurochemical systems may underpin consciousness alterations. Instead, preclinical experiments have long implicated the dopaminergic ventral tegmental area (VTA) in the brainstem. Despite dopaminergic agonist efficacy in DoC patients equally pointing to dopamine, the VTA has not been studied in human perturbed consciousness. To bridge this translational gap between preclinical subcortical and clinical cortico-centric perspectives, we assessed functional connectivity changes of a histologically characterized VTA using functional MRI recordings of pharmacologically (propofol sedation) and pathologically perturbed consciousness (DoC patients). Both cohorts demonstrated VTA disconnection from the precuneus and posterior cingulate (PCu/PCC), a main default mode network node widely implicated in consciousness. Strikingly, the stronger VTA-PCu/PCC connectivity was, the more the PCu/PCC functional connectome resembled its awake configuration, suggesting a possible neuromodulatory relationship. VTA-PCu/PCC connectivity increased toward healthy control levels only in DoC patients who behaviorally improved at follow-up assessment. To test whether VTA-PCu/PCC connectivity can be affected by a dopaminergic agonist, we demonstrated in a separate set of traumatic brain injury patients without DoC that methylphenidate significantly increased this connectivity. Together, our results characterize an in vivo dopaminergic connectivity deficit common to reversible and chronic consciousness perturbation. This noninvasive assessment of the dopaminergic system bridges preclinical and clinical work, associating dopaminergic VTA function with macroscopic network alterations, thereby elucidating a critical aspect of brainstem-cortical interplay for consciousness.

Description

Keywords

brainstem, consciousness, disorders of consciousness, dopamine, neurotransmitter, Adolescent, Adult, Aged, Brain Injuries, Traumatic, Brain Stem, Case-Control Studies, Connectome, Consciousness Disorders, Dopamine, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Propofol, Ventral Tegmental Area, Wakefulness, Young Adult

Journal Title

Proc Natl Acad Sci U S A

Conference Name

Journal ISSN

0027-8424
1091-6490

Volume Title

118

Publisher

Proceedings of the National Academy of Sciences
Sponsorship
Wellcome Trust (083660/Z/07/Z)
Medical Research Council (MR/M009041/1)
This work was supported by a grant from the Wellcome Trust: Clinical Research Training Fellowship [to R.A.] (Contract grant number: 083660/Z/07/Z). The work was also supported by grants from the UK Medical Research Council (U.1055.01.002.00001.01) [to J.D.P.]; The James S. McDonnell Foundation [to J.D.P.]; The Canadian Institute for Advanced Research (CIFAR) [to D.K.M. and E.A.S.]; The National Institute for Health Research (NIHR, UK), Cambridge Biomedical Research Centre and NIHR Senior Investigator Awards [to J.D.P. and D.K.M.]; The British Oxygen Professorship of the Royal College of Anaesthetists [to D.K.M.]; The Cambridge International Trust and the Cambridge European Scholarship [to LRBS.]; The Evelyn Trust, Cambridge and the EoE CLAHRC fellowship [to J.A.]; The Stephen Erskine Fellowship, Queens’ College, University of Cambridge [to E.A.S.] and the Gates Cambridge Trust [to A.I.L.]. The research was also supported by the NIHR Brain Injury Healthcare Technology Cooperative based at Cambridge University Hospitals NHS Foundation Trust and University of Cambridge. Computing infrastructure at the Wolfson Brain Imaging Centre. (WBIC-HPHI) was funded by MRC research infrastructure award (MR/M009041/1).