Alpha band frontal connectivity is a state-specific electroencephalographic correlate of unresponsiveness during exposure to dexmedetomidine and propofol

Background: Coherent alpha electroencephalogram (EEG) rhythms in the frontal cortex have been correlated with the hypnotic effects of propofol and dexmedetomidine, but less is known about frontal connectivity as a state-specific correlate of unresponsiveness as compared with long-range connectivity. We aimed to distinguish dose- and state-dependent effects of dexmedetomidine and propofol on EEG connectivity.Methods: Forty-seven healthy males received either dexmedetomidine (n=23) or propofol (n =24) as target-controlled infusion with stepwise increments until loss of responsiveness (LOR). We attempted to arouse participants during constant dosing (return of responsiveness [ROR]), and the target concentration was then increased 50% to achieve presumed loss of consciousness. We collected 64-channel EEG data and prefrontal-frontal and anterior-posterior functional connectivity in the alpha band (8-14 Hz) was measured using coherence and weighted phase lag index (wPLI). Directed connectivity was measured with directed phase lag index (dPLI).Results: Prefrontal-frontal EEG-based connectivity discriminated the states at the different drug concentrations. At ROR, prefrontal-frontal connectivity reversed to the level observed before LOR, indicating that connectivity changes were related to unresponsiveness rather than drug concentration. Unresponsiveness was associated with emergence of frontal-to-prefrontal dominance (dPLI: -0.13 to -0.40) in contrast to baseline (dPLI: 0.01-0.02). Coherence, wPLI, and dPLI had similar capability to discriminate the states that differed in terms of responsiveness and drug concentration. In contrast, anterior-posterior connectivity in the alpha band did not differentiate LOR and ROR.Conclusions: Local prefrontal-frontal EEG-based connectivity reflects unresponsiveness induced by propofol or dexmedetomidine, suggesting its utility in monitoring the anaesthetised state with these agents.Clinical trial registration:NCT01889004</div

Foundations of human consciousness: Imaging the twilight zone

What happens in the brain when conscious awareness of the surrounding world fades? We manipulated consciousness in two experiments in a group of healthy males and measured brain activity with positron emission tomography. Measurements were made during wakefulness, escalating and constant levels of two anesthetic agents (Experiment 1, n=39) and during sleep-deprived wakefulness and Non-Rapid Eye Movement sleep (Experiment 2, n=37). In Experiment 1, the subjects were randomized to receive either propofol or dexmedetomidine until unresponsiveness. In both experiments, forced awakenings were applied to achieve rapid recovery from an unresponsive to a responsive state, followed by immediate and detailed interviews of subjective experiences during the preceding unresponsive condition. Unresponsiveness rarely denoted unconsciousness, as the majority of the subjects had internally generated experiences. Unresponsive anesthetic states and verified sleep stages, where a subsequent report of mental content included no signs of awareness of the surrounding world, indicated a disconnected state. Functional brain imaging comparing responsive and connected vs. unresponsive and disconnected states of consciousness during constant anesthetic exposure revealed that activity of the thalamus, cingulate cortices and angular gyri are fundamental for human consciousness. These brain structures were affected independent from the pharmacologic agent, drug concentration and direction of change in the state of consciousness. Analogous findings were obtained when consciousness was regulated by physiological sleep. State-specific findings were distinct and separable from the overall effects of the interventions, which included widespread depression of brain activity across cortical areas. These findings identify a central core brain network critical for human consciousness.</p

On no man’s land: Subjective experiences during unresponsive and responsive sedative states induced by four different anesthetic agents

To understand how anesthetics with different molecular mechanisms affect consciousness, we explored subjective experiences recalled after responsive and unresponsive sedation induced with equisedative doses of dexmedetomidine, propofol, sevoflurane, and S-ketamine in healthy male participants (N = 140). The anesthetics were administered in experimental setting using target-controlled infusion or vapouriser for one hour. Interviews conducted after anesthetic administration revealed that 46.9% (n = 46) of arousable participants (n = 98) reported experiences, most frequently dreaming or memory incorporation of the setting. Participants receiving dexmedetomidine reported experiences most often while S-ketamine induced the most multimodal experiences. Responsiveness at the end of anesthetic administration did not affect the prevalence or content of reported experiences. These results demonstrate that subjective experiences during responsive and unresponsive sedation are common and anesthetic agents with different molecular mechanisms of action may have different effects on the prevalence and complexity of the experiences, albeit in the present sample the differences between drugs were minute.</p

Probing the (Un)Conscious Brain : EEG and PET Studies on Healthy Human Subjects Using Propofol, Dexmedetomidine and Natural Sleep

Consciousness cannot be objectively measured. By employing anesthesia and neurophysiologic measurements to study human consciousness, unconsciousness has been found to associate with suppression of regional brain activity and with breakdown of communication between different brain areas. However, due to conceptual and methodological heterogeneity, a unified theory on the “mechanisms” of (un)consciousness is lacking. Many anesthesia studies have employed arbitrary dosing schemes and disregarded the pharmacologic effects of the used drugs. Thus, many inferences on human consciousness have been premature. The aim of this study was to use rigorous experimental protocols to study human consciousness in healthy subjects. Two anesthetics (propofol and dexmedetomidine) and natural sleep were used. First, we explored EEG changes in association to different states of consciousness during increasing doses and a steady-state infusion of two anesthetics. Second, by measuring N400 event related potentials, we explored whether or not sematic processing persists during an unresponsive state induced by the two drugs. Finally, positron emission tomography (PET) imaging was conducted to reveal brain activity alterations between connected and disconnected states (confirmed by subjective reports of mental content) induced by anesthesia and sleep. Based on EEG and PET findings, we discovered that the state-related changes were distinct and separable from the overall effects of the different interventions. At awakening from steady-state anesthesia, spectral EEG patterns only partially reverted towards baseline values despite a restored conscious state, illustrating the multifaceted nature of anesthesia-EEG. PET imaging revealed that activity of a core brain network correlated best to the connected state per se. Furthermore, unresponsiveness and sleep rarely depicted unconsciousness (i.e., complete absence of subjective experiences) and semantic processing was partly preserved during dexmedetomidine-induced unresponsiveness. This study highlights the multidimensional nature of human consciousness and the related experimental challenges.Tietoisuutta ei voi mitata objektiivisesti. Anestesia- ja neurofysiologiset tutkimukset ovat osoittaneet tajuttomuuden liittyvän eri aivoalueiden aktiivisuuden vaimenemiseen sekä niiden välisten yhteyksien heikkenemiseen. Käsitteellisen ja metodologisen monimuotoisuuden vuoksi yhtenäinen tajuttomuuden ”mekanismi” on kuitenkin vielä löytämättä. Monissa anestesiatutkimuksissa lääkkeiden annostelu on umpimähkäistä ja lääkkeiden farmakologiset vaikutukset on jätetty huomiotta. Näin ollen monet johtopäätökset tietoisuudesta ovat olleet ennenaikaisia. Tämän työn tavoitteena oli käyttää tarkkoja koeasetelmia ja terveitä koehenkilöitä ihmisen tietoisuuden tutkimiseen. Tutkimuksessa käytettiin kahta anestesia-ainetta (propofoli ja deksmedetomidiini) sekä luonnollista unta. Ensimmäiseksi tutkimme aivosähkökäyrämuutoksia eri tajunnantiloissa nousevien ja tasaisten lääkepitoisuuksien aikana. Toiseksi tutkimme aivojen kielellistä prosessointia (N400 herätevasteet) kahdella lääkkeellä aiheutetun reagoimattoman tilan aikana. Lopuksi, aivojen aktiivisuusmuutoksia tutkittiin positroniemissiotomografia (PET) - kuvauksilla, erityisesti vertaamalla kytkeytyneitä sekä lääkkeellisesti ja fysiologisesti aiheutettuja irtikytkeytyneitä tiloja keskenään. Tajunnantilat varmistettiin subjektiivisin haastatteluin. EEG ja PET tulokset osoittivat että tajunnantilan vaihteluun liittyvät aivotoiminnan muutokset ovat erillisiä ja eroteltavissa eri interventioiden kokonaisvaikutuksista. Koehenkilön herättäminen tasaisen lääkeannostelun aikana palautti vain osittain EEG:n spektrimuutokset, ja tämä osoittaa anestesia-EEG:n moniulotteisen luonteen. PET-kuvaukset osoittivat että aktiivisuusmuutokset aivojen syvien rakenteiden verkostossa korreloivat parhaiten tajunnantilan vaihteluun. Lisäksi, reagoimaton tila ja luonnollinen uni merkitsi vain harvoin tajuttomuutta (subjektiivisten kokemusten puuttumista). Kielellinen prosessointi säilyi osittain deksmedetomidiinin aiheuttaman reagoimattomuuden aikana. Tutkimuksemme havainnollistaa ihmisen tietoisuuden moniulotteisuuden ja kokeellisen tietoisuustutkimuksen sudenkuopat

Single-subject analysis of N400 event-related potential component with five different methods

There are several different approaches to analyze event-related potentials (ERPs) at single-subject level, and the aim of the current study is to provide information for choosing a method based on its ability to detect ERP effects and factors influencing the results. We used data from 79 healthy participants with EEG referenced to mastoid average and investigated the detection rate of auditory N400 effect in single-subject analysis using five methods: visual inspection of participant-wise averaged ERPs, analysis of variance (ANOVA) for amplitude averages in a time window, cluster-based non-parametric testing, a novel Bayesian approach and Studentized continuous wavelet transform (t-CWT). Visual inspection by three independent raters yielded N400 effect detection in 85% of the participants in at least one paradigm (active responding or passive listening), whereas ANOVA identified the effect in 68%, the cluster-method in 59%, the Bayesian method in 89%, and different versions of t-CWT in 22–59% of the participants. Thus, the Bayesian method was the most liberal and also showed the greatest concordance between the experimental paradigms (active/passive). ANOVA detected significant effect only in cases with converging evidence from other methods. The t-CWT and cluster-based method were the most conservative methods. As we show in the current study, different analysis methods provide results that do not completely overlap. The method of choice for determining the presence of an ERP component at single-subject level thus remains unresolved. Relying on a single statistical method may not be sufficient for drawing conclusions on single-subject ERPs.Peer reviewe

The influence of dexmedetomidine and propofol on circulating cytokine levels in healthy subjects

Background: Surgery and diseases modify inflammatory responses and the immune system. Anesthetic agents also have effects on the human immune system but the responses they induce may be altered or masked by the surgical procedures or underlying illnesses. The aim of this study was to assess how single-drug dexmedetomidine and propofol anesthesia without any surgical intervention alter acute immunological biomarkers in healthy subjects. Methods: Thirty-five healthy, young male subjects were anesthetized using increasing concentrations of dexmedetomidine (n = 18) or propofol (n = 17) until loss of responsiveness (LOR) was detected. The treatment allocation was randomized. Multi-parametric immunoassays for the detection of 48 cytokines, chemokines and growth factors were used. Concentrations were determined at baseline and at the highest drug concentration for each subject. Results: The changes in the concentration of eotaxin (decrease after dexmedetomidine) and platelet-derived growth factor (PDGF, increase after propofol) were statistically significantly different between the groups. Significant changes were detected within both groups; the concentrations of monocyte chemotactic protein 1, chemokine ligand 27 and macrophage migration inhibitory factor were lower in both groups after the drug administration. Dexmedetomidine decreased the concentration of eotaxin, interleukin-18, interleukin-2Ra, stem cell factor, stem cell growth factor and vascular endothelial growth factor, and propofol decreased significantly the levels of hepatocyte growth factor, IFN-.-induced protein 10 and monokine induced by IFN-gamma, and increased the levels of interleukin-17, interleukin-5, interleukin-7 and PDGF. Conclusions: Dexmedetomidine seemed to have an immunosuppressive effect on the immune system whereas propofol seemed to induce mixed pro- and anti-inflammatory effects on the immune system. The choice of anesthetic agent could be relevant when treating patients with compromised immunological defense mechanisms. Trial registration: Before subject enrollment, the study was registered in the European Clinical Trials database (EudraCT number 2013-001496-21, The Neural Mechanisms of Anesthesia and Human Consciousness) and in ClinicalTrials.gov (Principal Investigator: Harry Scheinin, number NCT01889004, The Neural Mechanisms of Anesthesia and Human Consciousness, Part 2, on the 23rd of June 2013)

Alpha band frontal connectivity is a state-specific electroencephalographic correlate of unresponsiveness during exposure to dexmedetomidine and propofol

Background herent alpha electroencephalogram (EEG) rhythms in the frontal cortex have been correlated with the hypnotic effects of propofol and dexmedetomidine, but less is known about frontal connectivity as a state-specific correlate of unresponsiveness as compared with long-range connectivity. We aimed to distinguish dose- and state-dependent effects of dexmedetomidine and propofol on EEG connectivity. thods rty-seven healthy males received either dexmedetomidine (n=23) or propofol (n=24) as target-controlled infusion with stepwise increments until loss of responsiveness (LOR). We attempted to arouse participants during constant dosing (return of responsiveness [ROR]), and the target concentration was then increased 50% to achieve presumed loss of consciousness. We collected 64-channel EEG data and prefrontalâ\u80\u93frontal and anteriorâ\u80\u93posterior functional connectivity in the alpha band (8â\u80\u9314 Hz) was measured using coherence and weighted phase lag index (wPLI). Directed connectivity was measured with directed phase lag index (dPLI). sults efrontalâ\u80\u93frontal EEG-based connectivity discriminated the states at the different drug concentrations. At ROR, prefrontalâ\u80\u93frontal connectivity reversed to the level observed before LOR, indicating that connectivity changes were related to unresponsiveness rather than drug concentration. Unresponsiveness was associated with emergence of frontal-to-prefrontal dominance (dPLI: â\u80\u930.13 to â\u80\u930.40) in contrast to baseline (dPLI: 0.01â\u80\u930.02). Coherence, wPLI, and dPLI had similar capability to discriminate the states that differed in terms of responsiveness and drug concentration. In contrast, anteriorâ\u80\u93posterior connectivity in the alpha band did not differentiate LOR and ROR. nclusions cal prefrontalâ\u80\u93frontal EEG-based connectivity reflects unresponsiveness induced by propofol or dexmedetomidine, suggesting its utility in monitoring the anaesthetised state with these agents. inical trial registrationCC BY-NC-ND. 4.0</p

Subjective experiences during dexmedetomidine- or propofol-induced unresponsiveness and non-rapid eye movement sleep in healthy male subjects

Background: Anaesthetic-induced unresponsiveness and non-rapid eye movement (NREM) sleep share common neural pathways and neurophysiological features. We hypothesised that these states bear resemblance also at the experiential level. Methods: We compared, in a within-subject design, the prevalence and content of experiences in reports obtained after anaesthetic-induced unresponsiveness and NREM sleep. Healthy males (N=39) received dexmedetomidine (n=20) or propofol (n=19) in stepwise doses to induce unresponsiveness. Those rousable were interviewed and left unstimulated, and the procedure was repeated. Finally, the anaesthetic dose was increased 50%, and the participants were interviewed after recovery. The same participants (N=37) were also later interviewed after NREM sleep awakenings. Results: Most subjects were rousable, with no difference between anaesthetic agents (P=0.480). Lower drug plasma concentrations were associated with being rousable for both dexmedetomidine (P=0.007) and propofol (P=0.002) but not with recall of experiences in either drug group (dexmedetomidine: P=0.543; propofol: P=0.460). Of the 76 and 73 interviews performed after anaesthetic-induced unresponsiveness and NREM sleep, 69.7% and 64.4% included experiences, respectively. Recall did not differ between anaesthetic-induced unresponsiveness and NREM sleep (P=0.581), or between dexmedetomidine and propofol in any of the three awakening rounds (P&gt;0.05). Disconnected dream-like experiences (62.3% vs 51.1%; P=0.418) and memory incorporation of the research setting (88.7% vs 78.7%; P=0.204) were equally often present in anaesthesia and sleep interviews, respectively, whereas awareness, signifying connected consciousness, was rarely reported in either state. Conclusions: Anaesthetic-induced unresponsiveness and NREM sleep are characterised by disconnected conscious experiences with corresponding recall frequencies and content. Clinical trial registration: Clinical trial registration. This study was part of a larger study registered at ClinicalTrials.gov (NCT01889004). CC BY 4.0© 2023 The AuthorsAvailable online 31 May 2023Corresponding author: E-mail: [email protected] of Finland, Helsinki, Finland (266467 and 266434); Jane and Aatos Erkko Foundation, Helsinki, Finland; VSSHP-EVO (13323 and L3824); Doctoral Program of Clinical Investigation, University of Turku Graduate School, Turku, Finland to LR and AS; The Paulo Foundation, Espoo, Finland to AS; The Finnish Medical Foundation, Helsinki, Finland to AS; The Orion Research Foundation, Espoo, Finland to AS; Signe and Ane Gyllenberg Foundation, Helsinki, Finland to KV.</p

Circulating oxylipin and bile acid profiles of dexmedetomidine, propofol, sevoflurane, and S-ketamine : a randomised controlled trial using tandem mass spectrometry

Background This exploratory study aimed to investigate whether dexmedetomidine, propofol, sevoflurane, and S-ketamine affect oxylipins and bile acids, which are functionally diverse molecules with possible connections to cellular bioenergetics, immune modulation, and organ protection. Methods In this randomised, open-label, controlled, parallel group, Phase IV clinical drug trial, healthy male subjects (n=160) received equipotent doses (EC50 for verbal command) of dexmedetomidine (1.5 ng ml−1; n=40), propofol (1.7 μg ml−1; n=40), sevoflurane (0.9% end-tidal; n=40), S-ketamine (0.75 μg ml−1; n=20), or placebo (n=20). Blood samples for tandem mass spectrometry were obtained at baseline, after study drug administration at 60 and 130 min from baseline; 40 metabolites were analysed. Results Statistically significant changes vs placebo were observed in 62.5%, 12.5%, 5.0%, and 2.5% of analytes in dexmedetomidine, propofol, sevoflurane, and S-ketamine groups, respectively. Data are presented as standard deviation score, 95% confidence interval, and P-value. Dexmedetomidine induced wide-ranging decreases in oxylipins and bile acids. Amongst others, 9,10-dihydroxyoctadecenoic acid (DiHOME) –1.19 (–1.6; –0.78), P&lt;0.001 and 12,13-DiHOME –1.22 (–1.66; –0.77), P&lt;0.001 were affected. Propofol elevated 9,10-DiHOME 2.29 (1.62; 2.96), P&lt;0.001 and 12,13-DiHOME 2.13 (1.42; 2.84), P&lt;0.001. Analytes were mostly unaffected by S-ketamine. Sevoflurane decreased tauroursodeoxycholic acid (TUDCA) –2.7 (–3.84; –1.55), P=0.015. Conclusions Dexmedetomidine-induced oxylipin alterations may be connected to pathways associated with organ protection. In contrast to dexmedetomidine, propofol emulsion elevated DiHOMEs, oxylipins associated with acute respiratory distress syndrome, and mitochondrial dysfunction in high concentrations. Further research is needed to establish the behaviour of DIHOMEs during prolonged propofol/dexmedetomidine infusions and to verify the sevoflurane-induced reduction in TUDCA, a suggested neuroprotective agent. Clinical trial registration NCT02624401.CC BY 4.0 DEEDCorresponding author: Aleksi Nummela, Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland. E-mail: [email protected]:Academy of Finland (266467 and 266434); Emil Aaltonen Foundation to LL; Finnish Medical Foundation, Eero Matti Raninen Fund to AN; Jane and Aatos Erkko Foundation; Orion Research Foundation to LL; The Paulo Foundation to LL; Signe and Ane Gyllenberg Foundation to KV; University of Turku Graduate School, University of Turku to AN.</p