Discussion
amnesia
EVENTS, CORTEX
We found that decreased metabolic activity of the thalamus was specifically associated with disconnectedness during ECSeveral studies and theories of anesthetic mechanisms of action have indicated a critical role for the thalamus in regulating consciousness (Transitions between global states of consciousness during constant-dose anesthesia have previously been associated with brain activity changes in the thalamus, midline cortical areas and inferolateral parietal cortex (As cortical reactivity to sensory stimulation is relatively preserved in the primary sensory areas during anesthesia (Our findings with propofol and sevoflurane suggest that preferential cortical suppression, as witnessed in sedated but responsive subjects, precedes the transition from a connected to a disconnected state. This likely reflects a combination of direct and indirect (mediated through inhibition of the arousal nuclei) cortical drug-effects. Instead, preferential suppression of the thalamus was specifically associated with disconnectedness. With dexmedetomidine, we found the thalamus to be preferentially suppressed already in responsive subjects, possibly reflecting inhibition of arousal pathways through αExposure to S-ketamine was not associated with similar state-related metabolic effects as with other agents. The dissociative state characteristic of (S-)ketamine is likely caused by preferential antagonism of NMDA receptors in GABAergic interneurons leading to disinhibition of excitatory pyramidal neurons (A notable limitation of the current study is that the interviews used for verifying disconnectedness were only obtained at the end of the experiment. Report analysis suggested profound amnesia since awareness of external events was only reported by one responsive subject from the S-ketamine group (The frequently repeated testing for responsiveness revealed important information about the labile nature of the state of consciousness at the estimated ECThe most notable strength of the study is the use of four anesthetics with different primary mechanisms of action in the same experimental settings while allowing distinction between the state-related and drug-related effects. In summary, we found consistent evidence that decreased thalamic activity is a specific correlate of disconnectedness for three commonly used anesthetics representing three different primary mechanisms of action. Our results highlight the need for carefully designed studies to elucidate the neural mechanisms associated with specific states of consciousness.This work was supported by Academy of Finland, Helsinki, Finland Grant Numbers 266467 and 266434; Jane and Aatos Erkko Foundation, Helsinki, Finland; VSSHP-EVO Grant Numbers 13323 and L3824, Turku, Finland; Doctoral Programme of Clinical Investigation, University of Turku Graduate School, Turku, Finland (O.K., A.S., L.R.); Paulo Foundation, Espoo, Finland (A.S.); Finnish Medical Foundation, Helsinki, Finland (O.K., A.S.); The Orion Research Foundation, Espoo, Finland (A.S.); Signe and Ane Gyllenberg Foundation (O.K.); and Emil Aaltonen Foundation (O.K., L.L., R.E.K.). We thank the radiographers and anesthesia nurses at Turku PET Centre for excellent technical assistance and Ms. Saija Sirén, Lic. Phil., for the analysis of drug concentrations in plasma.M.S. declares consultancy and contract research relationships with Orion Pharma, the original manufacturer of dexmedetomidine. Orion Pharma was not involved in the planning or execution of the current study. M.S. was also listed as inventor in Orion Pharma's United States Patent Application US5344840A from 1993, “4-substituted imidazole derivatives useful in perioperative care,” now expired. M.S. declares no current competing financial interests in the study. All other authors declare no competing financial interests.