Background: consciousness-altering anesthetic agents disturb connectivity between brain regions composing the resting-state consciousness networks (Rsns). The default mode network (dMn), executive control network, salience network (saLn), auditory network, sensorimotor network (sMn), and visual network sustain mentation. Ketamine modifies consciousness differently from other agents, producing psychedelic dreaming and no apparent interaction with the environment. The authors used functional magnetic resonance imaging to explore ketamine-induced changes in Rsns connectivity. Methods: Fourteen healthy volunteers received stepwise intravenous infusions of ketamine up to loss of responsiveness. Because of agitation, data from six subjects were excluded from analysis. Rsns connectivity was compared between absence of ketamine (wake state [W1]), light ketamine sedation, and ketamine-induced unresponsiveness (deep sedation [s2]). Results: increasing the depth of ketamine sedation from W1 to s2 altered dMn and saLn connectivity and suppressed the anticorrelated activity between dMn and other brain regions. during s2, dMn connectivity, particularly between the medial prefrontal cortex and the remaining network (effect size β [95% ci]: W1 = 0.20 [0.18 to 0.22]; s2 = 0.07 [0.04 to 0.09]), and dMn anticorrelated activity (e.g., right sensory cortex: W1 = −0.07 [−0.09 to −0.04]; s2 = 0.04 [0.01 to 0.06]) were broken down. saLn connectivity was nonuniformly suppressed (e.g., left parietal operculum: W1 = 0.08 [0.06 to 0.09]; s2 = 0.05 [0.02 to 0.07]). executive control networks, auditory network, sMn, and visual network were minimally affected. Conclusions: Ketamine induces specific changes in connectivity within and between Rsns. Breakdown of frontoparietal dMn connectivity and dMn anticorrelation and sensory and sMn connectivity preservation are common to ketamine and propofol-induced alterations of consciousness.

Committee number: 'Comité d'Ethique Hospitalo-Facultaire Universitaire de Liège' (707); EudraCT number: 2012-003562-40; internal reference: 20121/135; accepted on August 31, 2012; Chair: Prof G. Rorive. As it was considered a phase I clinical trial, this protocol does not appear on the EudraCT public website.

To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brain’s rich neurotransmitter landscape. Here, we bridge microscale molecular chemoarchitecture and pharmacologically induced macroscale functional reorganization, by relating the regional distribution of 19 neurotransmitter receptors and transporters obtained from positron emission tomography, and the regional changes in functional magnetic resonance imaging connectivity induced by 10 different mind-altering drugs: propofol, sevoflurane, ketamine, lysergic acid diethylamide (LSD), psilocybin, N,N-Dimethyltryptamine (DMT), ayahuasca, 3,4-methylenedioxymethamphetamine (MDMA), modafinil, and methylphenidate. Our results reveal a many-to-many mapping between psychoactive drugs’ effects on brain function and multiple neurotransmitter systems. The effects of both anesthetics and psychedelics on brain function are organized along hierarchical gradients of brain structure and function. Last, we show that regional co-susceptibility to pharmacological interventions recapitulates co-susceptibility to disorder-induced structural alterations. Collectively, these results highlight rich statistical patterns relating molecular chemoarchitecture and drug-induced reorganization of the brain’s functional architecture.

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