Anesthetic-induced unresponsiveness: Electroencephalographic correlates and subjective experiences

Anesthetic drugs can induce reversible alterations in responsiveness, connectedness and consciousness. The measures based on electroencephalogram (EEG) have marked potential for monitoring the anesthetized state because of their relatively easy use in the operating room. In this study, 79 healthy young men participated in an awake experiment, and 47 participants continued to an anesthesia experiment where they received either dexmedetomidine or propofol as target-controlled infusion with stepwise increments until the loss of responsiveness. The participants were roused during the constant drug infusion and interviewed. The drug dose was increased to 1.5-fold to achieve a deeper unresponsive state. After regaining responsiveness, the participants were interviewed. EEG was measured throughout the experiment and the N400 event-related potential component and functional and directed connectivity were studied. Prefrontal-frontal connectivity in the alpha frequency band discriminated the states that differed with respect to responsiveness or drug concentration. The net direction of connectivity was frontal-to-prefrontal during unresponsiveness and reversed back to prefrontal-to-frontal upon return of responsiveness. The understanding of the meaning of spoken language, as measured with the N400 effect, was lost along with responsiveness but, in the dexmedetomidine group, the N400 component was preserved suggesting partial preservation of the processing of words during anesthetic-induced unresponsiveness. However, the N400 effect could not be detected in all the awake participants and the choice of analysis method had marked impact on its detection rate at the individual-level. Subjective experiences were common during unresponsiveness induced by dexmedetomidine and propofol but the experiences most often suggested disconnectedness from the environment. In conclusion, the doses of dexmedetomidine or propofol minimally sufficient to induce unresponsiveness do not render the participants unconscious and dexmedetomidine does not completely abolish the processing of semantic stimuli. The local anterior EEG connectivity in the alpha frequency band may have potential in monitoring the depth of dexmedetomidine- and propofol-induced anesthesia.Anesteettien aiheuttama vastauskyvyttömyys: aivosähkökäyräpohjaiset korrelaatit ja subjektiiviset kokemukset Anestesialääkkeillä voidaan saada aikaan palautuvia muutoksia vastauskykyisyydessä, kytkeytyneisyydessä ja tajunnassa. Aivosähkökäyrään (EEG) pohjautuvat menetelmät tarjoavat lupaavia mahdollisuuksia mitata anestesian vaikutusta aivoissa, sillä niitä on suhteellisen helppo käyttää leikkaussalissa. Tässä tutkimuksessa 79 tervettä nuorta miestä osallistui valvekokeeseen ja 47 heistä jatkoi anestesiakokeeseen. Anestesiakokeessa koehenkilöille annettiin joko deksmedetomidiinia tai propofolia tavoiteohjattuna infuusiona nousevia annosportaita käyttäen, kunnes he menettivät vastauskykynsä. Koehenkilöt herätettiin tasaisen lääkeinfuusion aikana ja haastateltiin. Koko kokeen ajan mitattiin EEG:tä, josta tutkittiin N400-herätevastetta sekä toiminnallista ja suunnattua konnektiivisuutta. Prefrontaali-frontaalivälillä mitattu konnektiivisuus alfa-taajuuskaistassa erotteli toisistaan tilat, jotka erosivat vastauskykyisyyden tai lääkepitoisuuden suhteen. Konnektiivisuuden vallitseva suunta oli frontaalialueilta prefrontaalialueille vastauskyvyttömyyden aikana, mutta se kääntyi takaisin prefrontaalisesta frontaaliseen kulkevaksi koehenkilöiden vastauskyvyn palatessa. N400-efektillä mitattu puhutun kielen ymmärtäminen katosi vastauskyvyn menettämisen myötä. Deksmedetomidiiniryhmässä N400-komponentti säilyi, mikä viittaa siihen, että anesteettien aiheuttaman vastauskyvyttömyyden aikana sanojen prosessointi voi säilyä osittain. Yksilötasolla N400-efektiä ei kuitenkaan havaittu edes kaikilla hereillä olevilla henkilöillä, ja analyysimenetelmän valinnalla oli suuri vaikutus herätevasteen havaitsemiseen. Subjektiiviset kokemukset olivat yleisiä deksmedetomidiinin ja propofolin aiheuttaman vastauskyvyttömyyden aikana, mutta kokemukset olivat usein ympäristöstä irtikytkeytyneitä. Yhteenvetona voidaan todeta, että deksmedetomidiini- ja propofoliannokset, jotka juuri ja juuri riittävät aikaansaamaan vastauskyvyttömyyden, eivät aiheuta tajuttomuutta. Deksmedetomidiini ei myöskään täysin estä merkityssisällöllisten ärsykkeiden käsittelyä. Frontaalialueen sisällä EEG:llä mitattu konnektiivisuus alfataajuuskaistassa saattaa olla tulevaisuudessa hyödyllinen menetelmä deksmedetomidiini- ja propofolianestesian syvyyden mittaamiseksi

Increased incidence of melanoma in children and adolescents in Finland in 1990-2014 : nationwide re-evaluation of histopathological characteristics

Background Changes in the incidence of melanoma in children and adolescents have been reported in Europe and in the USA in the recent decades. Aims The aim of this study was to examine the incidence of paediatric and adolescent melanomas in Finland in 1990-2014, and the associated clinical and histopathological characteristics to reveal temporal trends, such as changes in diagnostic sensitivity of Spitzoid melanomas. Methods Information on 122 patients diagnosed with cutaneous melanoma at 0-19 years of age in Finland in 1990-2014 were retrieved from the Finnish Cancer Registry. 73 primary melanoma archival samples were re-evaluated by two dermatopathologists to allow comparability over time. Results A 5.6% annual increase was observed in the incidence of melanoma among children and adolescents during the study period. Fifty-six tumours were confirmed as malignant melanomas in the re-evaluation. After correction for tumour misclassification in the Cancer Registry, the age-adjusted annual incidence was estimated to have increased from 1.4/1 000 000 in 1990-1994 to 5.8/1 000 000 in 2010-2014. The change in incidence was most prominent among adolescents and in Spitzoid melanoma subtype. Melanomas diagnosed 1990-2002 and 2003-2014 did not differ in terms of their clinicopathological characteristics or prognosis (hazard ratio for melanoma-related death 1.53, 95% CI 0.30 to 7.88). Spitzoid melanomas were diagnosed at a younger age, were of higher stage and had higher Clark level than other melanomas, yet the hazard ratio for death was 0.52 (95% CI 0.10 to 2.58) for Spitzoid versus other melanomas. Conclusions The incidence of cutaneous melanoma has clearly increased among the young in Finland, especially among adolescents. No evidence for overdiagnosis of Spitzoid melanomas as the underlying cause of the increased incidence was observed. Key message A nationwide retrospective re-evaluation of the cutaneous melanomas recorded in the Finnish Cancer Registry among patients aged 0-19 years in Finland in 1990-2014 revealed an approximately 4-fold increase in the incidence. The increase in the incidence was most prominent among adolescents and in the Spitzoid melanoma subtype. Our results contrast those reported in other countries, where the incidence of melanoma among adolescents has declined.Peer reviewe

Increased incidence of melanoma in children and adolescents in Finland in 1990-2014: nationwide re-evaluation of histopathological characteristics

BackgroundChanges in the incidence of melanoma in children and adolescents have been reported in Europe and in the USA in the recent decades.AimsThe aim of this study was to examine the incidence of paediatric and adolescent melanomas in Finland in 1990-2014, and the associated clinical and histopathological characteristics to reveal temporal trends, such as changes in diagnostic sensitivity of Spitzoid melanomas.MethodsInformation on 122 patients diagnosed with cutaneous melanoma at 0-19 years of age in Finland in 1990-2014 were retrieved from the Finnish Cancer Registry. 73 primary melanoma archival samples were re-evaluated by two dermatopathologists to allow comparability over time.ResultsA 5.6% annual increase was observed in the incidence of melanoma among children and adolescents during the study period. Fifty-six tumours were confirmed as malignant melanomas in the re-evaluation. After correction for tumour misclassification in the Cancer Registry, the age-adjusted annual incidence was estimated to have increased from 1.4/1 000 000 in 1990-1994 to 5.8/1 000 000 in 2010-2014. The change in incidence was most prominent among adolescents and in Spitzoid melanoma subtype. Melanomas diagnosed 1990-2002 and 2003-2014 did not differ in terms of their clinicopathological characteristics or prognosis (hazard ratio for melanoma-related death 1.53, 95% CI 0.30 to 7.88). Spitzoid melanomas were diagnosed at a younger age, were of higher stage and had higher Clark level than other melanomas, yet the hazard ratio for death was 0.52 (95% CI 0.10 to 2.58) for Spitzoid versus other melanomas.ConclusionsThe incidence of cutaneous melanoma has clearly increased among the young in Finland, especially among adolescents. No evidence for overdiagnosis of Spitzoid melanomas as the underlying cause of the increased incidence was observed.Key messageA nationwide retrospective re-evaluation of the cutaneous melanomas recorded in the Finnish Cancer Registry among patients aged 0-19 years in Finland in 1990-2014 revealed an approximately 4-fold increase in the incidence. The increase in the incidence was most prominent among adolescents and in the Spitzoid melanoma subtype. Our results contrast those reported in other countries, where the incidence of melanoma among adolescents has declined.</p

An assessment of prevalence of Type 1 CFI rare variants in European AMD, and why lack of broader genetic data hinders development of new treatments and healthcare access

PurposeAdvanced age-related macular degeneration (AAMD) risk is associated with rare complement Factor I (FI) genetic variants associated with low FI protein levels (termed 'Type 1'), but it is unclear how variant prevalences differ between AMD patients from different ethnicities.MethodsCollective prevalence of Type 1 CFI rare variant genotypes were examined in four European AAMD datasets. Collective minor allele frequencies (MAFs) were sourced from the natural history study SCOPE, the UK Biobank, the International AMD Genomics Consortium (IAMDGC), and the Finnish Biobank Cooperative (FINBB), and compared to paired control MAFs or background population prevalence rates from the Genome Aggregation Database (gnomAD). Due to a lack of available genetic data in non-European AAMD, power calculations were undertaken to estimate the AAMD population sizes required to identify statistically significant association between Type 1 CFI rare variants and disease risk in different ethnicities, using gnomAD populations as controls.ResultsType 1 CFI rare variants were enriched in all European AAMD cohorts, with odds ratios (ORs) ranging between 3.1 and 7.8, and a greater enrichment was observed in dry AMD from FINBB (OR 8.9, 95% CI 1.49-53.31). The lack of available non-European AAMD datasets prevented us exploring this relationship more globally, however a statistical association may be detectable by future sequencing studies that sample approximately 2,000 AAMD individuals from Ashkenazi Jewish and Latino/Admixed American ethnicities.ConclusionsThe relationship between Type 1 CFI rare variants increasing odds of AAMD are well established in Europeans, however the lack of broader genetic data in AAMD has adverse implications for clinical development and future commercialisation strategies of targeted FI therapies in AAMD. These findings emphasise the importance of generating more diverse genetic data in AAMD to improve equity of access to new treatments and address the bias in health care.Peer reviewe

Early DNA methylation changes in children developing beta cell autoimmunity at a young age

Aims/hypothesis Type 1 diabetes is a chronic autoimmune disease of complex aetiology, including a potential role for epigenetic regulation. Previous epigenomic studies focused mainly on clinically diagnosed individuals. The aim of the study was to assess early DNA methylation changes associated with type 1 diabetes already before the diagnosis or even before the appearance of autoantibodies. Methods Reduced representation bisulphite sequencing (RRBS) was applied to study DNA methylation in purified CD4(+) T cell, CD8(+) T cell and CD4(-)CD8(-) cell fractions of 226 peripheral blood mononuclear cell samples longitudinally collected from seven type 1 diabetes-specific autoantibody-positive individuals and control individuals matched for age, sex, HLA risk and place of birth. We also explored correlations between DNA methylation and gene expression using RNA sequencing data from the same samples. Technical validation of RRBS results was performed using pyrosequencing. Results We identified 79, 56 and 45 differentially methylated regions in CD4(+) T cells, CD8(+) T cells and CD4-CD8- cell fractions, respectively, between type 1 diabetes-specific autoantibody-positive individuals and control participants. The analysis of pre-seroconversion samples identified DNA methylation signatures at the very early stage of disease, including differential methylation at the promoter of IRF5 in CD4(+) T cells. Further, we validated RRBS results using pyrosequencing at the following CpG sites: chr19:18118304 in the promoter of ARRDC2; chr21:47307815 in the intron of PCBP3; and chr14:81128398 in the intergenic region near TRAF3 in CD4(+) T cells. Conclusions/interpretation These preliminary results provide novel insights into cell type-specific differential epigenetic regulation of genes, which may contribute to type 1 diabetes pathogenesis at the very early stage of disease development. Should these findings be validated, they may serve as a potential signature useful for disease prediction and management.Peer reviewe

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

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

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

Early DNA methylation changes in children developing beta cell autoimmunity at a young age

Aims/hypothesis Type 1 diabetes is a chronic autoimmune disease of complex aetiology, including a potential role for epigenetic regulation. Previous epigenomic studies focused mainly on clinically diagnosed individuals. The aim of the study was to assess early DNA methylation changes associated with type 1 diabetes already before the diagnosis or even before the appearance of autoantibodies.Methods Reduced representation bisulphite sequencing (RRBS) was applied to study DNA methylation in purified CD4(+) T cell, CD8(+) T cell and CD4(-)CD8(-) cell fractions of 226 peripheral blood mononuclear cell samples longitudinally collected from seven type 1 diabetes-specific autoantibody-positive individuals and control individuals matched for age, sex, HLA risk and place of birth. We also explored correlations between DNA methylation and gene expression using RNA sequencing data from the same samples. Technical validation of RRBS results was performed using pyrosequencing.Results We identified 79, 56 and 45 differentially methylated regions in CD4(+) T cells, CD8(+) T cells and CD4-CD8- cell fractions, respectively, between type 1 diabetes-specific autoantibody-positive individuals and control participants. The analysis of pre-seroconversion samples identified DNA methylation signatures at the very early stage of disease, including differential methylation at the promoter of IRF5 in CD4(+) T cells. Further, we validated RRBS results using pyrosequencing at the following CpG sites: chr19:18118304 in the promoter of ARRDC2; chr21:47307815 in the intron of PCBP3; and chr14:81128398 in the intergenic region near TRAF3 in CD4(+) T cells.Conclusions/interpretation These preliminary results provide novel insights into cell type-specific differential epigenetic regulation of genes, which may contribute to type 1 diabetes pathogenesis at the very early stage of disease development. Should these findings be validated, they may serve as a potential signature useful for disease prediction and management.</p

Cargo-specific recruitment in clathrin- and dynamin-independent endocytosis

Spatially controlled, cargo-specific endocytosis is essential for development, tissue homeostasis and cancer invasion. Unlike cargo-specific clathrin-mediated endocytosis, the clathrin- and dynamin-independent endocytic pathway (CLIC-GEEC, CG pathway) is considered a bulk internalization route for the fluid phase, glycosylated membrane proteins and lipids. While the core molecular players of CG-endocytosis have been recently defined, evidence of cargo-specific adaptors or selective uptake of proteins for the pathway are lacking. Here we identify the actin-binding protein Swiprosin-1 (Swip1, EFHD2) as a cargo-specific adaptor for CG-endocytosis. Swip1 couples active Rab21-associated integrins with key components of the CG-endocytic machinery-Arf1, IRSp53 and actin-and is critical for integrin endocytosis. Through this function, Swip1 supports integrin-dependent cancer-cell migration and invasion, and is a negative prognostic marker in breast cancer. Our results demonstrate a previously unknown cargo selectivity for the CG pathway and a role for specific adaptors in recruitment into this endocytic route.Moreno-Layseca et al. identify Swip1 as an integrin-specific endocytic adaptor controlling the dynamics of integrin adhesion complexes as well as the migration and invasion of breast cancer cells