| 1. |
- Kantonen, Oskari, et al.
(författare)
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Decreased thalamic activity is a correlate for disconnectedness during anesthesia with Propofol, Dexmedetomidine and Sevoflurane but not S-ketamine
- 2023
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Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 43:26, s. 4884-4895
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Tidskriftsartikel (refereegranskat)abstract
- Establishing the neural mechanisms responsible for the altered global states of consciousness during anesthesia and dissociating these from other drug-related effects remains a challenge in consciousness research. We investigated differences in brain activity between connectedness and disconnectedness by administering various anesthetics at concentrations designed to render 50% of the subjects unresponsive. One hundred and sixty healthy male subjects were randomized to receive either propofol (1.7 μg/ml; n = 40), dexmedetomidine (1.5 ng/ml; n = 40), sevoflurane (0.9% end-tidal; n = 40), S-ketamine (0.75 μg/ml; n = 20), or saline placebo (n = 20) for 60 min using target-controlled infusions or vaporizer with end-tidal monitoring. Disconnectedness was defined as unresponsiveness to verbal commands probed at 2.5-min intervals and unawareness of external events in a postanesthesia interview. High-resolution positron emission tomography (PET) was used to quantify regional cerebral metabolic rates of glucose (CMRglu) utilization. Contrasting scans where the subjects were classified as connected and responsive versus disconnected and unresponsive revealed that for all anesthetics, except S-ketamine, the level of thalamic activity differed between these states. A conjunction analysis across the propofol, dexmedetomidine and sevoflurane groups confirmed the thalamus as the primary structure where reduced metabolic activity was related to disconnectedness. Widespread cortical metabolic suppression was observed when these subjects, classified as either connected or disconnected, were compared with the placebo group, suggesting that these findings may represent necessary but alone insufficient mechanisms for the change in the state of consciousness.
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| 2. |
- Kantonen, Oskari, et al.
(författare)
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Decreased Thalamic Activity Is a Correlate for Disconnectedness during Anesthesia with Propofol, Dexmedetomidine and Sevoflurane But Not S-Ketamine
- 2023
-
Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 43:26, s. 4884-4895
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Tidskriftsartikel (refereegranskat)abstract
- Establishing the neural mechanisms responsible for the altered global states of consciousness during anesthesia and dissociating these from other drug-related effects remains a challenge in consciousness research. We investigated differences in brain activity between connectedness and disconnectedness by administering various anesthetics at concentrations designed to render 50% of the subjects unresponsive. One hundred and sixty healthy male subjects were randomized to receive either propofol (1.7 μg/ml; n = 40), dexmedetomidine (1.5 ng/ml; n = 40), sevoflurane (0.9% end-tidal; n = 40), S-ketamine (0.75 μg/ml; n = 20), or saline placebo (n = 20) for 60 min using target-controlled infusions or vaporizer with end-tidal monitoring. Disconnectedness was defined as unresponsiveness to verbal commands probed at 2.5-min intervals and unawareness of external events in a postanesthesia interview. High-resolution positron emission tomography (PET) was used to quantify regional cerebral metabolic rates of glucose (CMRglu) utilization. Contrasting scans where the subjects were classified as connected and responsive versus disconnected and unresponsive revealed that for all anesthetics, except S-ketamine, the level of thalamic activity differed between these states. A conjunction analysis across the propofol, dexmedetomidine and sevoflurane groups confirmed the thalamus as the primary structure where reduced metabolic activity was related to disconnectedness. Widespread cortical metabolic suppression was observed when these subjects, classified as either connected or disconnected, were compared with the placebo group, suggesting that these findings may represent necessary but alone insufficient mechanisms for the change in the state of consciousness.
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| 3. |
- Scheinin, Annalotta, et al.
(författare)
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Foundations of human consciousness : Imaging the twilight zone
- 2021
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Ingår i: Journal of Neuroscience. - : The Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 41:8, s. 1769-1778
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Tidskriftsartikel (refereegranskat)abstract
- 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. SIGNIFICANCE STATEMENT Trying to understand the biological basis of human consciousness is currently one of the greatest challenges of neuroscience. While the loss and return of consciousness regulated by anesthetic drugs and physiological sleep are employed as model systems in experimental studies on consciousness, previous research results have been confounded by drug effects, by confusing behavioral "unresponsiveness" and internally generated consciousness, and by comparing brain activity levels across states that differ in several other respects than only consciousness. Here, we present carefully designed studies that overcome many previous confounders and for the first time reveal the neural mechanisms underlying human consciousness and its disconnection from behavioral responsiveness, both during anesthesia and during normal sleep, and in the same study subjects.
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| 4. |
- Cajander, Per, 1976-, et al.
(författare)
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Effects of dexmedetomidine on pharyngeal swallowing and esophageal motility : A double-blind randomized cross-over study in healthy volunteers
- 2023
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Ingår i: Neurogastroenterology and Motility. - : Wiley-Blackwell Publishing Inc.. - 1350-1925 .- 1365-2982. ; 35:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Sedative agents increase the risk of pulmonary aspiration, where an intact swallowing function is an important defense mechanism. Dexmedetomidine is an α2 -adrenoceptor agonist widely used during procedural sedation due to beneficial properties with minimal respiratory effects. The effects of dexmedetomidine on pharyngeal swallowing and esophageal motility are not known in detail.METHODS: To determine the effects of dexmedetomidine on pharyngeal swallowing and esophageal motility, nineteen volunteers were included in this double-blinded, randomized placebo-controlled cross-over study. Study participants received target-controlled dexmedetomidine and placebo infusions. Recordings of pressure and impedance data were acquired using a manometry and impedance solid-state catheter. Data were analyzed from three bolus swallows series: baseline, during dexmedetomidine/placebo infusion at target plasma concentrations 0.6 ng ml-1 and 1.2 ng ml-1 . Subjective swallowing difficulties were also recorded.KEY RESULTS: On pharyngeal swallowing, dexmedetomidine affected the upper esophageal sphincter with decreased pre- and post-swallow contractile pressures and an increase in residual pressure during swallow-related relaxation. On esophageal function, dexmedetomidine decreased contractile vigor of the proximal esophagus and increased velocity of the peristaltic contraction wave. Residual pressures during swallow-related esophagogastric junction (EGJ) relaxation decreased, as did basal EGJ resting pressure. The effects on the functional variables were not clearly dose-dependent, but mild subjective swallowing difficulties were more common at the higher dose level.CONCLUSIONS AND INFERENCES: Dexmedetomidine induces effects on pharyngeal swallowing and esophageal motility, which should be considered in clinical patient management and also when a sedative agent for procedural sedation or for manometric examination is to be chosen.
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| 5. |
- Cajander, Per, 1976-, et al.
(författare)
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Response to Letter to the Editor
- 2023
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Ingår i: Neurogastroenterology and Motility. - : Wiley-Blackwell. - 1350-1925 .- 1365-2982. ; 35:8
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Tidskriftsartikel (refereegranskat)abstract
- It is crucial to consider the possible influence of anesthetic agents on esophageal function testing. Dexmedetomidine has been shown to affect primary peristalsis during esophageal manometry. In the two case reports presented by Toaz et al., secondary peristalsis during FLIP panometry was also affected. This may be attributed to an alternate pharmacodynamic effect, with a transient direct α2-mediated effect on esophageal smooth muscle, associated with a high plasma concentration following bolus injection, prior to the onset of sympathetic inhibition.
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| 6. |
- Cajander, Per, 1976-, et al.
(författare)
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Effects of remifentanil on pharyngeal swallowing and esophageal motility : no impact of different bolus volumes, and partial antagonism by methylnaltrexone
- 2021
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Ingår i: American Journal of Physiology - Gastrointestinal and Liver Physiology. - : HighWire Press. - 0193-1857 .- 1522-1547. ; 321:4, s. G367-G377
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Tidskriftsartikel (refereegranskat)abstract
- Background: Remifentanil impairs swallowing, and disturbed accommodation to bolus volume may be one of the underlying causes. It is not fully understood whether remifentanil-induced swallowing dysfunction is mediated by peripheral or central mechanisms.Aims: To investigate if remifentanil-induced swallowing dysfunction is dependent on the bolus volume and whether the effect of remifentanil could be counteracted by methylnaltrexone, a peripherally acting opioid antagonist.Methods: Nineteen healthy volunteers were included in this double-blinded, randomized, placebo-controlled, crossover study. Study participants received target-controlled remifentanil infusions and placebo infusions in a randomized order. Methylnaltrexone was administered by intravenous injection of doses of 0.3 mg/kg. Recordings of pressure and impedance data were acquired using a combined manometry and impedance solid state catheter. Data was analyzed from three series of bolus swallows, baseline, during remifentanil exposure, and 15 min after methylnaltrexone.Results: Remifentanil induced significant effects on multiple pharyngeal and esophageal function parameters. No significant differences in remifentanil-induced swallowing dysfunction related to different bolus volumes were found. Pharyngeal effects of remifentanil were not significantly counteracted by methylnaltrexone, whereas on the distal esophageal level, effects on distension pressures were counteracted. Conclusions Changes in pharyngeal and esophageal pressure flow variables were consistent with previous results on remifentanil-induced swallowing dysfunction, and uniform across all bolus volumes. The effects of remifentanil on the pharyngeal level and on the proximal esophagus appear to be predominantly centrally mediated, whereas the effects of remifentanil on the distal esophagus may be mediated by both central and peripheral mechanisms.NEW & NOTEWORTHY: In this randomized controlled trial, we used the "Swallow Gateway" online platform to analyze the effects of remifentanil on pharyngeal and esophageal swallowing. It is not fully understood whether remifentanil-induced swallowing dysfunction is mediated by peripheral or central mechanisms. By using methylnaltrexone, we demonstrated that effects of remifentanil on pharyngeal swallowing were predominantly centrally mediated, whereas its effects on the distal esophagus may be mediated by both central and peripheral mechanisms.
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| 7. |
- Johansson, Jarkko, et al.
(författare)
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Intranasal naloxone rapidly occupies brain mu-opioid receptors in human subjects
- 2019
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Ingår i: Neuropsychopharmacology. - : Nature Publishing Group. - 0893-133X .- 1740-634X. ; 44:9, s. 1667-1673
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Tidskriftsartikel (refereegranskat)abstract
- Nasal spray formulations of naloxone, a mu-opioid receptor (MOR) antagonist, are currently used for the treatment of opioid overdose. They may have additional therapeutic utility also in the absence of opioid agonist drugs, but the onset and duration of action at brain MORs have been inadequately characterized to allow such projections. This study provides initial characterization of brain MOR availability at high temporal resolution following intranasal (IN) naloxone administration to healthy volunteers in the absence of a competing opioid agonist. Fourteen participants were scanned twice using positron emission tomography (PET) and [11C]carfentanil, a selective MOR agonist radioligand. Concentrations of naloxone in plasma and MOR availability (relative to placebo) were monitored from 0 to 60 min and at 300–360 min post naloxone. Naloxone plasma concentrations peaked at ~20 min post naloxone, associated with slightly delayed development of brain MOR occupancy (half of peak occupancy reached at ~10 min). Estimated peak occupancies were 67 and 85% following 2 and 4 mg IN doses, respectively. The estimated half-life of occupancy disappearance was ~100 min. The rapid onset of brain MOR occupancy by IN naloxone, evidenced by the rapid onset of its action in opioid overdose victims, was directly documented in humans for the first time. The employed high temporal-resolution PET method establishes a model that can be used to predict brain MOR occupancy from plasma naloxone concentrations. IN naloxone may have therapeutic utility in various addictions where brain opioid receptors are implicated, such as gambling disorder and alcohol use disorder.
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| 8. |
- Lind, Ulrika, et al.
(författare)
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Octopamine receptors from the barnacle balanus improvisus are activated by the alpha2-adrenoceptor agonist medetomidine.
- 2010
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Ingår i: Molecular pharmacology. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 1521-0111 .- 0026-895X. ; 78:2, s. 237-48
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Tidskriftsartikel (refereegranskat)abstract
- G protein-coupled octopamine receptors of insects and other invertebrates represent counterparts of adrenoceptors in vertebrate animals. The alpha(2)-adrenoceptor agonist medetomidine, which is in clinical use as a veterinary sedative agent, was discovered to inhibit the settling process of barnacles, an important step in the ontogeny of this crustacean species. Settling of barnacles onto ship hulls leads to biofouling that has many harmful practical consequences, and medetomidine is currently under development as a novel type of antifouling agent. We now report that medetomidine induces hyperactivity in the barnacle larvae to disrupt the settling process. To identify the molecular targets of medetomidine, we cloned five octopamine receptors from the barnacle Balanus improvisus. We show by phylogenetic analyses that one receptor (BiOctalpha) belongs to the alpha-adrenoceptor-like subfamily, and the other four (BiOctbeta-R1, BiOctbeta-R2, BiOctbeta-R3, and BiOctbeta-R4) belong to the beta-adrenoceptor-like octopamine receptor subfamily. Phylogenetic analyses also indicated that B. improvisus has a different repertoire of beta-adrenoceptor-like octopamine receptors than insects. When expressed in CHO cells, the cloned receptors were activated by both octopamine and medetomidine, resulting in increased intracellular cAMP or calcium levels. Tyramine activated the receptors but with much lesser potency than octopamine. A hypothesis for receptor discrimination between tyramine and octopamine was generated from a homology three-dimensional model. The characterization of B. improvisus octopamine receptors is important for a better functional understanding of these receptors in crustaceans as well as for practical applications in development of environmentally sustainable antifouling agents.
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| 9. |
- Snapir, Amir, et al.
(författare)
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The insertion/deletion variation in the alpha2B-adrenoceptor does not seem to modify the risk for acute myocardial infarction, but may modify the risk for hypertension in sib-pairs from families with type 2 diabetes
- 2003
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Ingår i: Cardiovascular Diabetology. - : Springer Science and Business Media LLC. - 1475-2840. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: An insertion/deletion polymorphism in the alpha2B-adrenoceptor (AR) has been associated with the risk for acute myocardial infarction (AMI) and sudden cardiac death. In this study we tested whether this polymorphism is associated with the risk for AMI among members of families with type 2 diabetes. METHODS: 154 subjects with a history of AMI were matched for age and sex with one of their siblings who did not have a history of AMI. The prevalence of the genotypes of the alpha2B-AR insertion/deletion polymorphism was compared between the siblings using McNemar's test. We also explored the data to see whether this genetic variation affects the risk for hypertension by using logistic regression models in the two subpopulations of subjects, with and without a history of AMI. RESULTS: Among all study subjects, 73 (24%) carried the alpha2B-AR deletion/deletion genotype, 103 (33%) carried the insertion/insertion genotype, and 132 (43%) were heterozygous. The distribution of genotypes of the alpha2B-AR insertion/deletion variation in the group of subjects with a history of AMI and their phenotype-discordant siblings did not statistically significantly differ from that expected by random distribution (p = 0.52): the deletion/deletion genotype was carried by 34 subjects with AMI (22%), and by 39 subjects without AMI (25%). Neither did we observe any significant difference in deletion allele frequencies of the alpha2B-AR insertion/deletion polymorphism between patients with a history of AMI (0.44) and their sib-pair controls (0.46, p = 0.65). In an exploratory analysis, the alpha2B-AR deletion/deletion genotype was associated with increased odds for hypertension compared with subjects carrying any of the other genotypes. CONCLUSIONS: The deletion/deletion genotype of the alpha2B-AR does not emerge in this study as a risk factor for AMI among members of families with type 2 diabetes; however, it might be involved in the development of hypertension.
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