5. thomas lew how anaesthetic works (and why knowing matters)
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a better understanding of sleep and coma may lead to new approaches to general anesthesia based on new ways to alter consciousness,29,97,98 provide analgesia,99,100 induce amnesia, and provide muscle relaxation.66
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5. thomas lew how anaesthetic works (and why knowing matters)
- 1. How Anaesthesia Works: And Why Knowing Matters Thomas WK Lew Mmed, EDIC Department of Anaesthesiology, Intensive Care & Pain Medicine Tan Tock Seng Hospital, Singapore March 2016
- 2. Panel from monument in Boston commemorating Morton's demonstration of the anesthetic use of ether Safe anaesthesia has been widely accepted as one of the greatest medical advancements in the modern era: Are we saving lives every day or harming lives?
- 3. Panel from monument in Boston commemorating Morton's demonstration of the anesthetic use of ether Ether – Medicine or Industrial Solvent?
- 4. We starting getting patients to breathe industrial solvents……. And become unconscious General anaesthesia is, in fact, a reversible drug-induced coma. At levels appropriate for surgery, general anaesthesia can functionally approximate brain-stem death, because patients are unconscious, have depressed brain-stem reflexes, do not respond to nociceptive stimuli, have no apnoeic drive, and require cardiorespiratory and thermoregulatory support.
- 5. • “How consciousness arises in the brain remains unknown. Yet, for nearly two centuries our ignorance has not hampered the use of general anesthesia for routinely extinguishing consciousness during surgery.” • Michael T. Alkire,1 Anthony G. Hudetz,2 Giulio Tononi3* • 7 NOVEMBER 2008 VOL 322 SCIENCE
- 6. •What are the key characteristics of Anaesthesia •Analgesia? •Unconsciousness? •Loss of Sensory perception? •Loss of reaction to sensory perception? •Motor Relaxation? •Amnesia?
- 7. Outline • Overarching Theories of Consciousness • The Neurobiology of Anaesthetics • Theories of Consciousness (and Unconsciousness in anaesthesia) • Role of the thalamus; fronto-parietal cortical loops; integration, feedback, discrimination • Making sense of clinical signs & symptoms of anaesthetic depth and responses • Consciousness, Making sense of information – integration; feedback; discrimination • Making sense of clinical signs & symptoms of anaesthetic depth, responses, and their implications • EEG signals of General Anaesthesia • Some drugs and their effects on consciousness • Using this information clinically • Effects of anaesthesia on consciousness to study pathological states affecting consciousness • EEG patterns to assess anaesthetic depth of different GA agents • Burst suppression – role in emergence delirium and dementia • General considerations fro Neurotoxicity
- 8. Outline • Overarching Theories of Consciousness • The Neurobiology of Anaesthetics • Theories of Consciousness (and Unconsciousness in anaesthesia) • Role of the thalamus; fronto-parietal cortical loops; integration, feedback, discrimination • Making sense of clinical signs & symptoms of anaesthetic depth and responses • Consciousness, Making sense of information – integration; feedback; discrimination • Making sense of clinical signs & symptoms of anaesthetic depth, responses, and their implications • EEG signals of General Anaesthesia • Some drugs and their effects on consciousness • Using this information clinically • Effects of anaesthesia on consciousness to study pathological states affecting consciousness • EEG patterns to assess anaesthetic depth of different GA agents • Burst suppression – role in emergence delirium and dementia • General considerations fro Neurotoxicity
- 9. Where is consciousness? • Two primary components of consciousness: • 1) Contents of consciousness • Generally thought to be cortical. • Cortical lesions change the nature of a person’s consciousness according to the area that is damaged • 2) Level of consciousness • Generally thought to be subcortical. • Mid-line brain structures contribute to the level of consciousness • Brainstem lesions change the level of a person’s consciousness. Arousal is needed for awareness • Anesthetic effects in both areas will likely impact consciousness
- 10. WHAT IS CONSCIOUNESS Integrated Unified Whole of the Brain (“Global neuroal workspace”) Diversity of sensory inputs - Fronto-parietal corticocortical exchanges Dependent on active feedback loops and connectivity Exchanges from non-specific thalamocortical pathways
- 12. Outline • Overarching Theories of Consciousness • The Neurobiology of Anaesthetics • Theories of Consciousness (and Unconsciousness in anaesthesia) • Role of the thalamus; fronto-parietal cortical loops; integration, feedback, discrimination • Making sense of clinical signs & symptoms of anaesthetic depth and responses • Consciousness, Making sense of information – integration; feedback; discrimination • Making sense of clinical signs & symptoms of anaesthetic depth, responses, and their implications • one-arm tourniquet test, • Arousal versus awareness • Consciousness versus memory and amnesia • Clinical & Pathophysiological implications • Dosing • Awareness; Amnesia • Complications – elderly; cognitive disorder; young – neurotoxicity theories • Opportunities for new technology – EEG Symmetry and synchrony • Lessons for pathological states of nonawareness and consciousness
- 13. The neurobiology of anaesthetics • Site of Action: • Receptor site inhibition (e.g., NMDA) or potentiation (e,g,, GABA) • Potassium-ion channels • regulate synaptic transmission and membrane potentials in key regions of the brain and spinal cord. • Targets are differentially sensitive to various anaesthetic agents • Neuronal ionic flux • hyperpolarize neurons by increasing inhibition or decreasing excitation and alter neuronal activity. • Neuronal output • As anaesthetic depth increases, transition from the low voltage, high-frequency pattern of wakefulness (known as activated EEG), to the slow-wave EEG of deep NREM sleep, and finally to an EEG burst-suppression pattern • Transition from a tonic to a burst (and) suppression characterises general anaesthesia
- 14. Ionic mechanisms and Targets of some anaesthetics
- 15. Privotal roles of the GABA(alpha) and NMDA receptors in cortex, brainstem, thalamus, striatum targets small number of inhibitory interneurons control large number of excitatory pyramidal neurons
- 16. Neurotoxicity of Anesthetics • As many as one-third of all synapses in Mammalian brains are GABAnergic. • GABAA receptors, which are chloride- permeable, ligand-gated ion channels. • Inhibitory function in synaptic transmission • Activation generally leads to an influx of chloride, hyperpolarization of cell membrane, shunting of excitatory input, and reduced excitability of the neurons.
- 17. The neurobiology of anaesthetics • Site of Action: • Receptor site inhibition (e.g., NMDA) or potentiation (e,g,, GABA) • Potassium-ion channels • regulate synaptic transmission and membrane potentials in key regions of the brain and spinal cord. • Targets are differentially sensitive to various anaesthetic agents • Neuronal ionic flux • hyperpolarize neurons by increasing inhibition or decreasing excitation and alter neuronal activity. • Neuronal output • As anaesthetic depth increases, transition from the low voltage, high-frequency pattern of wakefulness (known as activated EEG), to the slow-wave EEG of deep NREM sleep, and finally to an EEG burst-suppression pattern • Transition from a tonic to a burst (and) suppression characterises general anaesthesia
- 19. The neurobiology of anaesthetics • Site of Action: • Receptor site inhibition (e.g., NMDA) or potentiation (e,g,, GABA) • Potassium-ion channels • regulate synaptic transmission and membrane potentials in key regions of the brain and spinal cord. • Targets are differentially sensitive to various anaesthetic agents • Neuronal ionic flux • hyperpolarize neurons by increasing inhibition or decreasing excitation and alter neuronal activity. • Neuronal output • As anaesthetic depth increases, transition from the low voltage, high-frequency pattern of wakefulness (known as activated EEG), to the slow-wave EEG of deep NREM sleep, and finally to an EEG burst-suppression pattern • Transition from a tonic to a burst (and) suppression characterises general anaesthesia
- 20. • Most anaesthetics potentiate GABA and inhibit NMDA receptors in the cortex, thalamus, brainstem and striatum • Potentiate inhibitory interneurons – control large numbers of excitatory pyramidal neurons, efficiently inactivate large regions of the brain and contribute to unconsciousness Propofol binds post-synaptically and enhances GABAergic inhibition, counteracting arousal inputs to the pyramidal neuron, decreasing its excitatory activity, and contributing to unconsciousness
- 21. Outline • Overarching Theories of Consciousness • The Neurobiology of Anaesthetics • Theories of Consciousness (and Unconsciousness in anaesthesia) • Role of the thalamus; fronto-parietal cortical loops; integration, feedback, discrimination • Making sense of clinical signs & symptoms of anaesthetic depth and responses • Consciousness, Making sense of information – integration; feedback; discrimination • Making sense of clinical signs & symptoms of anaesthetic depth, responses, and their implications • one-arm tourniquet test, • Arousal versus awareness • Consciousness versus memory and amnesia • Clinical & Pathophysiological implications • Dosing • Awareness; Amnesia • Complications – elderly; cognitive disorder; young – neurotoxicity theories • Opportunities for new technology – EEG Symmetry and synchrony • Lessons for pathological states of nonawareness and consciousness
- 22. • Low doses – causes profound amnesia • Higher doses – unable to respond because working memory is blocked and immediately forget what to do • Somewhere between flat EEG and this state – unconsciousness must ensue • E.g., isolated forearm technique • The most consistent regional effect produced by anesthetics at (or near) loss of consciousness is a reduction of thalamic metabolism and blood flow (Fig. 1), suggesting that the thalamus may serve as a consciousness switch
- 23. The Thalamus: Centre of Consciousness or “Postbox”? Approx 50 nuclei and subnuclei with rich interconnections to other structures in the brain. Thalamic nuclei can be classified as specific (mediating relay of peripheral information to a particular area of sensory cortex) and nonspecific (mediating multimodal integration of information) MT Alkire, AG Hudetz, G Tononi; 37 NOVEMBER 2008 VOL 322 SCIENCE
- 24. 4 possible roles of thalamus in “unconsciousness” • Thalamus as a “switch” of anesthetic-induced unconsciousness • Pivotal “Causal” Role: Based neuroimaging, pivotal depression of thalamus ‘switches’ off consciousness in the brain in both VA & TIVA • Thalamus as a “read-out” of anaesthetic-induced unconsciousness • Passenger “Effect” role: Cortex is the site mediating anaesthetic-induced unconsciousness; thalamus depression is a consequence of / and occurs after the cortical events • Thalamus as a “participant” in anaesthesia-induced unconsciousness • Under GA, thalamus generates synchronous alpha oscillations, thus interrupting flexible corticocortical communications; interrupts external sensory inputs from periphery to cortex • Thalamus as “epiphenomenal” to anaesthetic-induced unconsciousness • Thalamus is not critical to maintenance of consciousness – athalamic animals are seemingly conscious (but oblivious to their srroundings – due to lack of sensory awareness) • Mashour GA, Alkire MT Anesthesiology 2013; 118:13-5
- 25. Role of the Thalamus • Role of the thalamus in propofol-induced unconsciousness: • Studied 8 patients in deep sedation using MRI • Connectivity analysis using specific and non-specific thalamic nuclei mapped to cortical regions • Findings: • Sensory transfer from the periphery (via specific nuclei) were well preserved • Functional (non-specific) nuclei mediating integration of cortical computation were reduced. • Strongest correlation of cognitive function with non-specific nuclei activity • Findings reversible on restoration of consciousness • Liu X, Lauer KK, Ward BD, Li S-J, Hudetz AG: Anesthesiology 2013; 118:59–69
- 26. Role of the thalamus in propofol-induced unconsciousness: • Relates primarily to the functional connections of nonspecific nuclei to the cortex (i.e., mediating multimodal integration of information) and not to specific sensory nuclei mediating flow of information to cortex • Thalamus as a “switch” - Does not relate primarily to specific sensory nuclei • Thalamus as a “read-out”- Does not answer this question directly • Thalamus as a “participant” Propofol does not seem to affect sensory inputs relay nuclei • Thalamus as “epiphenomenal” – not true
- 27. WHAT IS CONSCIOUNESS Integrated Unified Whole of the Brain (“Global neuronal workspace”) Diversity of sensory inputs - Fronto-parietal corticocortical exchanges Dependent on active feedback loops and connectivity Exchanges from non-specific thalamocortical pathways
- 28. UNCONSCIOUNESS Failure of whole brain to act as an integrated whole – anaesthetics (causes a loss of cortical interactions & a loss of cortical capacity for information exchange) Homogeneity of Inputs (“Coherence” of EEG from both hemispheres) Loss of activation of higher- order associative cortices (fronto-parietal cortical pathways) WHAT IS CONSCIOUNESS Integrated Unified Whole of the Brain (“Global neuronal workspace”) Diversity of sensory inputs - Fronto-parietal corticocortical exchanges Dependent on active feedback loops and connectivity Exchanges from non-specific thalamocortical pathways
- 29. Outline • Overarching Theories of Consciousness • The Neurobiology of Anaesthetics • Theories of Consciousness (and Unconsciousness in anaesthesia) • Role of the thalamus; fronto-parietal cortical loops; integration, feedback, discrimination • Making sense of clinical signs & symptoms of anaesthetic depth and responses • Consciousness, Making sense of information – integration; feedback; discrimination • Making sense of clinical signs & symptoms of anaesthetic depth, responses, and their implications • EEG signals of General Anaesthesia • Some drugs and their effects on consciousness • Clinical & Pathophysiological implications • Dosing • Awareness; Amnesia • Complications – elderly; cognitive disorder; young – neurotoxicity theories • Opportunities for new technology – EEG Symmetry and synchrony • Lessons for pathological states of nonawareness and consciousness
- 30. Emery Brown, Ralph Lydic, Nicholas D. Schiff, N Engl J Med. 2010 December 30; 363(27): 4 EEG Patterns in GA: • Phase 1: Light GA >Delta Alpha < Beta (Slower waves) • Phase 2: Intermediate GA>Delta Alpha < Beta & Anteriorization • Phase 3: Deeper GA– Burst suppression – flat with Alpha Beta • Phase 4: Longer suppression to isoelectric EEG • burst suppression is believed to be a strong, synchronized outflow of thalamic discharges to a widely unresponsive cortex (Fig. 1).
- 31. Emery Brown, Ralph Lydic, Nicholas D. Schiff, N Engl J Med. 2010 December 30; 363(27): 4 EEG Patterns in GA: • Phase 1: Light GA >Delta Alpha < beta • Phase 2: Intermediate>Delta Alpha < beta & Anteriorization • Phase 3: Deeper– Burst suppression – flat with Alpha Beta • Phase 4: Longer suppression to isoelectric EEG
- 32. Brown E., NEJM 2010
- 33. Outline • Overarching Theories of Consciousness • The Neurobiology of Anaesthetics • Theories of Consciousness (and Unconsciousness in anaesthesia) • Role of the thalamus; fronto-parietal cortical loops; integration, feedback, discrimination • Making sense of clinical signs & symptoms of anaesthetic depth and responses • Consciousness, Making sense of information – integration; feedback; discrimination • Making sense of clinical signs & symptoms of anaesthetic depth, responses, and their implications • EEG signals of General Anaesthesia • Some drugs and their effects on consciousness • Using this information clinically • Effects of anaesthesia on consciousness to study pathological states affecting consciousness • EEG patterns to assess anaesthetic depth of different GA agents • Burst suppression – role in emergence delirium and dementia • General considerations fro Neurotoxicity
- 34. Study Disorders of Consciousness: Anaesthetic Coma • Anaesthesia represents reversible coma – studies of disorders of consciousness (DOC) – what ‘happens” in anaesthetic coma? • Disorders of Consciousness (DOC) • Brainstem coma (irreversible = brainstem / brain death) • Not awake; not aware ; no brainstem reflexes • Comas • Not awake; not aware • “vegetative state” or Unresponsive Wakefulness Syndrome. • Awake; Not aware • minimally conscious state • Awake; minimally aware
- 35. Disorder of Consciousness & Anaesthetic Coma • Anaesthesia represents reversible coma – • study of disorders of consciousness (DOC) – what ‘lights-up” in anaesthetic coma? • Disorders of Consciousness (DOC) • Brainstem coma (irreversible = brainstem / brain death) • Not awake; not aware ; no brainstem reflexes • Comas • Not awake; not aware (Anaesthetic Coma Model – Classic Agents) • “vegetative state” or unresponsive wakefulness syndrome. • Not aware; awake (Dissociative Anaesthesia e.g., Ketamine – Agents difficult to study) • minimally conscious state • minimally aware; awake (Sedation model)
- 36. • Using GA “Model”: Disorders of Consciousness (DOC) studies show: • That a specific brain region is, to some degree, still able to activate and process relevant sensory stimuli (as viewed via neuroimaging protocol) does not = consciousness • Anesthetic coma show residual activation of segregated cortical islands in response to external stimuli (auditory, visual, or somatosensory) encompassing the brainstem, thalamus, and “low-level” primary cortices, similar to findings obtained in unconscious DOC patients. • A large frontoparietal network encompassing bilateral frontal and temporo- parietal associative cortices (‘higher-order) has its activity commonly impaired during altered states of consciousness • Laureys et al. Brain connectivity in pathological and pharmacological Frontiers in Systems Neuroscience 20 December 2010
- 37. Opioids, Ketamine, Dexmedetomidine Neostigmine & Actions • Fentanyl & Morphine • Risk of awareness with high dose morphine alone • Fentanyl is anti-cholinergic – bradycardia • Ketamine • excitatory state with altered consciousness • Dexmedetomidine • anti-noradrenergic pathway to sedation • Role of Neostigmine in reversing emergence delirium • Neostogmine being pre-cholinergic – acts against propofol induced anti- cholinergic pathways • Avoid Atropine because of anti-cholinergic effect in CNS
- 38. • Opioids reduce arousal by inhibiting the release of acetylcholine from neurons projecting to the medial pontine reticular formation and to the thalamus, by binding to opioid receptors in the periaqueductal gray and rostral ventral
- 39. (A) Ketamine binds preferentially to N-methyl-D-aspartate (NMDA) receptors on inhibitory interneurons in the cortex, limbic system (amygdala), and hippocampus, promoting an uncoordinated increase in neural activity, an active EEG pattern, and Unconsciousness (B) In the spinal cord, ketamine decreases arousal by blocking NMDA glutamate (Glu)–mediated nociceptive signals from peripheral afferent neurons in the dorsal-root ganglion to projecting neurons, Hallucinations may result because the aberrant activation allows the association of information in a manner that is inconsistent in time and space. The hallucinations can be mitigated by the concurrent administration of a benzodiazepine, which presumably acts to enhance GABAA-mediated activity of the inter-neurons and hence leads to sedation.
- 40. (A) Ketamine binds preferentially to N-methyl-D-aspartate (NMDA) receptors on inhibitory interneurons in the cortex, limbic system (amygdala), and hippocampus, promoting an uncoordinated increase in neural activity, an active EEG pattern, and Unconsciousness (B) In the spinal cord, ketamine decreases arousal by blocking NMDA glutamate (Glu)–mediated nociceptive signals from peripheral afferent neurons in the dorsal-root ganglion to projecting neurons, Hallucinations may result because the aberrant activation allows the association of information in a manner that is inconsistent in time and space. The hallucinations can be mitigated by the concurrent administration of a benzodiazepine, which presumably acts to enhance GABAA-mediated activity of the inter-neurons and hence leads to sedation. Ketamine messes up the Brain normal transmissions by generating a disorderly & active EEG
- 41. • Dexmedetomidine INHIBITS THE INHIBITOR OF an INHIBITOR NUCLEUS (VLPON) • binds to α2 receptors on neurons from the locus ceruleus, inhibiting norepinephrine release (dashed line) in the ventrolateral preoptic nucleus, as shown in Panel B. The disinhibited ventrolateral preoptic nucleus reduces arousal by means of GABAalpha-mediated and galanin-mediated inhibition of the midbrain, hypothalamic, and pontine arousal nuclei.
- 42. Outline • Overarching Theories of Consciousness • The Neurobiology of Anaesthetics • Theories of Consciousness (and Unconsciousness in anaesthesia) • Role of the thalamus; fronto-parietal cortical loops; integration, feedback, discrimination • Making sense of clinical signs & symptoms of anaesthetic depth and responses • Consciousness, Making sense of information – integration; feedback; discrimination • Making sense of clinical signs & symptoms of anaesthetic depth, responses, and their implications • EEG signals of General Anaesthesia • Some drugs and their effects on consciousness • Using this information clinically • Effects of anaesthesia on consciousness to study pathological states affecting consciousness • EEG patterns to assess anaesthetic depth of different GA agents
- 43. • We are familiar with spectral analysis of EEG breaking down into the relative strengths of power and frequency
- 44. (Purdon et al, 2013, PNAS) Coherence is the measurement of homogenous outputs (from different hemisphere) and EEG pattern seen from bilateral hemispheres – with the onset of Loss of Consciousness
- 45. (Purdon et al, 2013, PNAS) Coherence is the measurement of homogenous outputs (from different hemisphere) and EEG pattern seen from bilateral hemispheres – with the onset of Loss of Consciousness Another investigation proposed hypersynchrony of α as a mechanism of propofol-induced unconsciousness, with the alternative interpretation that flexible corticocortical communication is interrupted as a result of stereotyped oscillations. (Supp GG, Siegel M, Hipp JF, Engel AK: Cortical hypersynchrony predicts breakdown of sensory processing during loss of consciousness. Curr Biol 2011; 21:1988–93)
- 47. Power Spectogram with coherence as signals densities shows a time- sensitive pattern of change with induction, LOC and emergence from GA e.g., Propofol Pattern shows strong alpha waves n the frontal cortices bilaterally (anteriorization)
- 51. Outline • Overarching Theories of Consciousness • The Neurobiology of Anaesthetics • Theories of Consciousness (and Unconsciousness in anaesthesia) • Role of the thalamus; fronto-parietal cortical loops; integration, feedback, discrimination • Making sense of clinical signs & symptoms of anaesthetic depth and responses • Consciousness, Making sense of information – integration; feedback; discrimination • Making sense of clinical signs & symptoms of anaesthetic depth, responses, and their implications • EEG signals of General Anaesthesia • Some drugs and their effects on consciousness • Using this information clinically • Effects of anaesthesia on consciousness to study pathological states affecting consciousness • EEG patterns to assess anaesthetic depth of different GA agents • Anaesthetic Depth and Post-operative Cognitive Decline or Delirium
- 52. Depth of Anaesthesia and Delirium/POCD • Study group–Patients >6o years of age undergoing surgery (n=1,657) • Interventions – BIS---guided anesthesia vs. standard care • Results –OR for delirium with BIS–0.58(0.41---0.80), cognitive performance was similar between groups at 1week after surgery, patients in the BIS group had a lower rate of POCD at 3month compared with routine care (10.2%vs.14.7%; adjusted OR 0.67(0.32--- 0.98) • Conclusion – BIS---guided anesthesia reduced anesthetic exposure and decreased POD and the risk of POCD at 3months, but not at 1week after surgery • Chan et al. J Neurosurg Anesthesiol 2013;25:33
- 53. BIS & Postoperative delirium and POCD • Study group–Patients undergoing surgery (n=1,277) • Interventions - BIS-guided anaesthesia . Standard care, anaesthesia not standardized, BIS levels not standardized • Results Postoperative delirium - 16.7% in BIS group vs. 21.4% in control group. BIS<20 predictive of delirium. No difference in POCD on postop day 7 • Conclusion–BIS---guided anesthesia reduced postoperative delirium, possibly by reducing extreme low BIS values • Radtke et al. Br J Anaesth2013;110:i98
- 54. Sedation Depth During Spinal Anesthesia for Hip Fracture • Study group – double-blind, randomized controlled trial at an academic medical center of elderly patients (≥65 years) without preoperative delirium or severe dementia who underwent hip fracture repair under spinal anesthesia with propofol sedation. (n=114) • Intervention – patients were randomized to receive either deep (BIS, approximately 50) or light (BIS, ≥80) sedation. Delirium measured on POD 2 using CAM. • Results – delirium 19% in light sedation vs. 40% in deep sedation • Conclusion – limiting depth of sedation during spinal anesthesia may reduce postoperative delirium • Sieber et al. Mayo Clin Proc 2010;85:18-26
- 56. Research Question: Whether general anaesthesia in infancy has any effect on neurodevelopmental outcome. Secondary outcome of neurodevelopmental outcome at 2 years of age in the General Anaesthesia compared to Spinal anaesthesia (GAS) trial. Subjects: Infants younger than 60 weeks postmenstrual age, born at greater than 26 weeks’ gestation, and who had inguinal herniorrhaphy, Centres: 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand; randomly assigned (1:1) awake-regional anaesthesia or sevoflurane-GA Lancet 2016; 387: 239–50
- 57. Outcome Measures: Lancet 2016; 387: 239–50 The primary outcome of the trial will be the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale Intelligence Quotient score at age 5 years. The secondary outcome, reported here, is the composite cognitive score of the Bayley Scales of Infant and Toddler Development III, assessed at 2 years. The analysis was as per protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. Results : 2007 – 2013: 724 infants randomised. Outcome data were available for 238 children in the awake-regional group and 294 in the general anaesthesia group. In the as-per-protocol analysis, the cognitive composite score (mean [SD]) was 98·6 (14·2) in the awake- regional group and 98·2 (14·7) in the general anaesthesia group. There was equivalence in mean between groups (awake-regional minus general anaesthesia 0·169, 95% CI –2·30 to 2·64). The median duration of anaesthesia in the general anaesthesia group was 54 min. Interpretation: For this secondary outcome, we found no evidence that just less than 1 h of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake- regional anaesthesia.
- 58. Preventing Emergence Delirium • Avoidance of anti-cholinergics – Use of glycopyrrolate and not atropine because of anti- cholinergic effect in CNS • Role of Neostigmine in reversing emergence delirium • Neostigmine being pre-cholinergic – acts against propofol induced anti- cholinergic pathways – Avoiding burst suppression in anaesthetic depth? • Selective Amnesia helpful in preventing awareness as trend towards lighter GA evolves
- 59. 1846 – 2016 How understanding the Neurobiology of anaesthetics within the Neuroanatomical Circuitry of the brain enable us to understand it roles in Reversible Unconsciousness Understand the Neuroimaging, EEG and correlation with Clinical signs during GA Study DOC, tailor safer therapies, better monitoring, lower complications, understand place of General Anaesthesia in Modern MedicineMichael T Alkire
- 60. Outline • Overarching Theories of Consciousness • The Neurobiology of Anaesthetics • Theories of Consciousness (and Unconsciousness in anaesthesia) • Role of the thalamus; fronto-parietal cortical loops; integration, feedback, discrimination • Making sense of clinical signs & symptoms of anaesthetic depth and responses • Consciousness, Making sense of information – integration; feedback; discrimination • Making sense of clinical signs & symptoms of anaesthetic depth, responses, and their implications • one-arm tourniquet test, • Arousal versus awareness • Consciousness versus memory and amnesia • Clinical & Pathophysiological implications • Dosing • Awareness; Amnesia • Complications – elderly; cognitive disorder; young – neurotoxicity theories • Opportunities for new technology – EEG Symmetry and synchrony • Lessons for pathological states of nonawareness and consciousness
Editor's Notes
- Anaesthesia has been widely conceived as one of the greatest advancements in medicine in the modern era Are we saving lives every day or harming lives? Born in Charlton, Massachusetts, William T. G. Morton was the son of James Morton, a farmer, and Rebecca (Needham) Morton. William found work as a clerk, printer, and salesman in Boston before entering Baltimore College of Dental Surgery in 1840. In 1841, he gained notoriety for developing a new process to solder false teeth onto gold plates.[2] In 1842, he left college without graduating to study in Hartford, Connecticut with dentist Horace Wells, with whom Morton shared a brief partnership. In 1843 Morton married Elizabeth Whitman of Farmington, Connecticut, the niece of former Congressman Lemuel Whitman. Her parents objected to Morton&apos;s profession and only agreed to the marriage after he promised to study medicine. In the autumn of 1844, Morton entered Harvard Medical School and attended the chemistry lectures of Dr. Charles T. Jackson, who introduced Morton to the anesthetic properties of ether. Morton then also left Harvard without graduating. Replica of the inhaler used by William T. G. Morton in 1846 in the first public demonstration of surgery using ether. On September 30, 1846, Morton performed a painless tooth extraction after administering ether to a patient. Upon reading a favorable newspaper account of this event, Boston surgeon Henry Jacob Bigelow arranged for a now-famous demonstration of ether on October 16, 1846 at the operating theater of the Massachusetts General Hospital. At this demonstration Dr. John Collins Warren painlessly removed a tumor from the neck of a Mr. Edward Gilbert Abbott. The theatre came to be known as the Ether Dome and has been preserved as a monument to this historic event.[3] Following the demonstration, Morton tried to hide the identity of the substance Abbott had inhaled, by referring to it as &quot;Letheon&quot;, but it soon was found to be ether.[4] A month after this demonstration, a patent was issued for &quot;letheon&quot;, although it was widely known by then that the inhalant was ether. The medical community at large condemned the patent as unjust and illiberal in such a humane and scientific profession.[5] Morton assured his colleagues that he would not restrict the use of ether among hospitals and charitable institutions, alleging that his motives for seeking a patent were to ensure the competent administration of ether and to prevent its misuse or abuse, as well as to recoup the expenditures of its development. Morton&apos;s pursuit of credit for and profit from the administration of ether was complicated by the furtive and sometimes deceptive tactics he employed during its development, as well as the competing claims of other doctors, most notably his former mentor, Dr. Jackson. Morton&apos;s own efforts to obtain patents overseas also undermined his assertions of philanthropic intent. Consequently, no effort was made to enforce the patent, and ether soon came into general use. In December 1846, Morton applied to Congress for &quot;national recompense&quot; of $100,000, but this too was complicated by the claims of Jackson and Wells as discoverers of ether, and so Morton&apos;s application proved fruitless. He made similar applications in 1849, 1851, and 1853, and all failed. He later sought remuneration for his achievement through a futile attempt to sue the United States government. The lawyer who represented him was Richard Henry Dana, Jr. In 1852 he received an honorary degree from the Washington University of Medicine in Baltimore, which later became the College of Physicians and Surgeons.[6] Panel from monument in Boston commemorating Morton&apos;s demonstration of the anesthetic use of ether. In the spring of 1857, Amos Lawrence, a wealthy Bostonian, together with the medical professionals and influential citizens of Boston, developed a plan to raise $100,000 as a national testimonial to Morton, receiving contributions from both public and private citizens. Morton&apos;s notoriety only increased when he served as the star defense witness in one of the most notable trials of the nineteenth century, that of John White Webster who had been accused of the murder of Dr. George Parkman. Morton&apos;s rival, Dr. Jackson, testified for the prosecution, and the residents of Boston were anxious to witness these nemeses in courtroom combat.[7] Morton performed public service yet again in the autumn of 1862 when he joined the Army of the Potomac as a volunteer surgeon, and applied ether to more than two thousand wounded soldiers during the battles of Fredericksburg, Chancellorsville, and the Wilderness. Morton was in New York City in July 1868 when he went to Central Park to seek relief from a heat wave, where he collapsed and died soon after. He is buried at Mount Auburn Cemetery in Watertown and Cambridge, Massachusetts. In 1871, a committee of those involved in raising the aforementioned national testimonial published The Historical Memoranda Relative to the Discovery of Etherization to establish Morton as the inventor and revealer of anesthetic inhalation and to justify pecuniary reward to Morton&apos;s family for the &quot;fearful moral and legal responsibility he assumed in pursuit of this discovery.&quot;[8] Morton&apos;s life and work were later to become the subject of the 1944 Paramount Pictures film The Great Moment. The first use of ether as an anesthetic is commemorated in the Ether Monument in the Boston Public Garden, but the designers were careful not to choose sides in the debate over who should deserve credit for the discovery. Instead, the statue depicts a doctor in medieval Moorish robes and turban. [edit] Predecessor Morton&apos;s first successful public demonstration of ether as an inhalation anesthetic was such an historic and widely-publicized event that many consider him to be the &quot;inventor and revealer&quot; of anesthesia. However, Morton&apos;s work was preceded by that of Georgia surgeon Crawford Williamson Long, who employed ether as an anesthetic on March 30, 1842. Although Long demonstrated its use to physicians in Georgia on numerous occasions, he did not publish his findings until 1849, in The Southern Medical and Surgical Journal.[9] These pioneering uses of ether were key factors in the medical and scientific pursuit now referred to as anesthesiology, and allowed the development of modern surgery. Spread of the news of this &quot;new&quot; anesthetic was helped by the subsequent feud that developed between Morton and Horace Wells and Charles T. Jackson. [edit] See also Chloroform Humphry Davy James Young Simpson Nitrous oxide [edit] References ^ Fenster, J. M. (2001). Ether Day: The Strange Tale of America&apos;s Greatest Medical Discovery and the Haunted Men Who Made It. New York, NY: HarperCollins. ISBN 978-0060195236. ^ Packard, Francis Randolph (1901). The History of Medicine in the United States. Philadelphia and London: J. B. Lippincott Company. pp. 475. http://books.google.com/?id=6hIJAAAAIAAJ&pg=PA474&lpg=PA474&dq=Morton+solder+gold+teeth. ^ &quot;National Historic Landmarks Program: Ether Dome, Massachusetts General Hospital&quot;. http://tps.cr.nps.gov/nhl/detail.cfm?ResourceId=249&ResourceType=Building. Retrieved 2010-11-02. ^ &quot;&quot;Letheon&quot; Inhaler&quot;. http://www.general-anaesthesia.com/images/the-letheon.html. Retrieved 2009-05-01. ^ Smith, Stephen (1862). &quot;The Ether Patent&quot;. Medical Times 4 (January to July): 83–84. http://books.google.com/?id=-C4TAAAAYAAJ&pg=PA83&lpg=PA83&dq=%22ether+patent%22. ^ Pinsker, Sheila; Harding, Robert S. (1986). &quot;The Morton Family Collection 1849-1911&quot;. http://americanhistory.si.edu/archives/d8118.htm. Retrieved 2008-12-02. ^ Sullivan, Robert (1971). The Disappearance of Dr. Parkman. Little, Brown, and Company. http://books.google.com/?id=KNi0HQAACAAJ&dq=The+Disappearance+of+Dr.+Parkman/. ^ Committee of Citizens of Boston (1871). Historical Memoranda Relative to the Discovery of Etherization and to the Connection with it of the Late William T.G. Morton. Boston: Rand, Avery, and Frye. http://books.google.com/?id=ax8JAAAAIAAJ&dq=William+T.G.+Morton&printsec=frontcover. ^ See Books.Google.com. (Edward J. Huth and T. J. Murray) [edit] Further reading Alper M. H. (1964). &quot;The Ether Controversy Revisited (Morton WT), (Jackson CT)&quot;. Anesthesiology 25: 560–3. PMID 14192801. Andreae H. (December 1969). &quot;The discoverer of ether anesthesia, dentist Morton, born 150 years ago [The discoverer of ether anesthesia, dentist Morton, born 150 years ago]&quot; (in German). Zahnärztliche Praxis 20 (23): 276. PMID 5263393. Asbell M. B. (October 1970). &quot;William Thomas Green Morton&quot;. Worcester Medical News 35 (2): 15–8. PMID 5277344. Ash H. L. (1985). &quot;Anesthesia&apos;s dental heritage (William Thomas Green Morton)&quot;. Anesthesia Progress 32 (1): 25–9. PMC 2175398. PMID 3888002. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2175398. Deranian H. M. (1997). &quot;The great Morton-Jackson debate&quot;. Journal of the Massachusetts Dental Society 46 (2): 24–5. PMID 9540719. Figuier, Louis (1851). &quot;Expérience d&apos;Horace Wels à l&apos;hôpital de Boston avec je gaz hilarant&quot; (in French). Exposition et histoire des principales découvertes scientifiques modernes. 1. Paris: Masson. p. 212. OCLC 312611474. http://books.google.com/books?id=4M8EAAAAYAAJ&pg=RA1-PA212. Contains an account, in French, of the discovery of anaesthesia with ether by Morton and Jackson and of its reception in Europe. Heynick F (March 2003). &quot;William T. G. Morton and &apos;The Great Moment&apos;&quot;. Journal of the History of Dentistry 51 (1): 27–35. PMID 12641171. Keys T. E. (March 1973). &quot;William Thomas Green Morton (1819-1868)&quot;. Anesthesia and Analgesia 52 (2): 166. doi:10.1213/00000539-197303000-00004. PMID 4572338. Leonard A. G. (May 1985). &quot;Stamp recognition for William Morton&quot;. British Dental Journal 158 (9): 345. doi:10.1038/sj.bdj.4805605. PMID 3890908. Morton, William T. G. (1847). Remarks on the Proper Mode of Administering Sulphuric Ether by Inhalation. Boston: Button and Wentworth. OCLC 14825070. http://www.ncbi.nlm.nih.gov/books/bookres.fcgi/history/pdf_morton.pdf. Retrieved 22 July 2009. Morton W. T. (November 1996). &quot;SMW 100 years ago. William Thomas Green Morton and the discovery of anesthesia [SMW 100 years ago. William Thomas Green Morton and the discovery of anesthesia]&quot; (in German). Schweizerische Medizinische Wochenschrift 126 (47): 2040–2. PMID 8984612. Pavlovskiĭ L. N. (2005). &quot;Dentist William Morton is a founder of general anesthesia [Dentist William Morton is a founder of general anesthesia]&quot; (in Russian). Likars&apos;ka Sprava (1–2): 111–5. PMID 15916010. Rozar L. B. (July 1975). &quot;Dr. William T. G. Morton D.D.S., discoverer of surgical anesthesia&quot;. CAL 39 (1): 6–8. PMID 795512. Shampo M. A., Kyle R. A. (January 1987). &quot;Morton: pioneer in the use of ether&quot;. Mayo Clinic Proceedings 62 (1): 56. PMID 3540476. Vandam L. D. (January 1994). &quot;Benjamin Perley Poore and his historical materials for a biography of W.T.G. Morton, M.D&quot;. Journal of the History of Medicine and Allied Sciences 49 (1): 5–23. doi:10.1093/jhmas/49.1.5. PMID 8151115. Vandam L. D. (September 1996). &quot;The last days of William Thomas Green Morton&quot;. Journal of Clinical Anesthesia 8 (6): 431–4. doi:10.1016/0952-8180(96)00125-0. PMID 8872680. Westhorpe R (October 1996). &quot;William Morton and the first successful demonstration of anaesthesia&quot;. Anaesthesia and Intensive Care 24 (5): 529. PMID 8909661. &quot;Wimmiam McLintock Morton, T.D., L.D.S&quot;. British Dental Journal 146 (4): 128. February 1979. doi:10.1038/sj.bdj.4804211. PMID 367405. &quot;Two tormented lives. Horace Wells and William Morton [Two tormented lives. Horace Wells and William Morton]&quot; (in Spanish). Boletin De Información 15 (117): 17–21 passim. April 1971. PMID 5283677. , (October 1965). &quot;William T.G. Morton (1819-1868), demonstrator of ether anesthesia&quot;. JAMA 194 (2): 190–1. doi:10.1001/jama.194.2.190. PMID 5319582. &quot;William Thomas Green Morton&quot; (in Spanish). Revista Española De Anestesiología 3 (4): 380–3. October 1956. PMID 13389978. [edit] External links &quot;William Thomas Morton&quot;. Find a Grave. http://www.findagrave.com/cgi-bin/fg.cgi?page=gr&GRid=1759. Retrieved 2008-12-02. &quot;Boyhood Home Sign in Charlton, Massachusetts&quot;. http://img.geocaching.com/cache/120e0605-793f-40fe-84a0-baff7629c173.jpg. &quot;Centennial of First Man to Employ Anaesthetic&quot;. Miami Herald Record. 1919 July 13. http://infoweb.newsbank.com.proxy1.library.jhu.edu/iw-search/we/HistArchive/?p_product=EANX&p_theme=ahnp&p_nbid=I6EC62JXMTIyNDcxODczOS40MzEyMzg6MToxMjoxMjguMjIwLjguMTU&p_action=doc&s_lastnonissuequeryname=3&d_viewref=search&p_queryname=3&p_docnum=19&p_docref=v2:114CF48AE24B9638@EANX-1190F44183842D50@2422154-1190F441D599ADA8@3-1190F4432010A610@Gentennial+of+First+Man+to+Employ+an+Anaesthetic. &quot;Men Who Have Eased the World&apos;s Pain&quot;. Kansas City Star. 1913 December 29. http://infoweb.newsbank.com.proxy1.library.jhu.edu/iw-search/we/HistArchive/?p_product=EANX&p_theme=ahnp&p_nbid=I6EC62JXMTIyNDcxODczOS40MzEyMzg6MToxMjoxMjguMjIwLjguMTU&p_action=doc&s_lastnonissuequeryname=3&d_viewref=search&p_queryname=3&p_docnum=16&p_docref=v2:1126152C152E4978@EANX-119AD8F7317502C0@2420131-119AD8F79FB48038@11-119AD8F94179B368@Men+Who+Have+Eased+the+World%27s+Paon+William+T.+G.+Morton. &quot;Surgery Was Agony&quot;. Worcester Daily Spy. 1893 April 23. http://infoweb.newsbank.com.proxy1.library.jhu.edu/iw-search/we/HistArchive/?p_product=EANX&p_theme=ahnp&p_nbid=J66I53LHMTIyODA3MjU1OC4xNDQwODQ6MToxMjoxMjguMjIwLjguMTU&p_action=doc&s_lastnonissuequeryname=3&d_viewref=search&p_queryname=3&p_docnum=1&p_docref=v2:11C12F6287BB7190@EANX-11ED9B31D1760820@2412577-11ED9B321415E438@7-11ED9B334125A3E0@Surgery+Was+Agony.+until+a+World%27s+Benefactor+Used+an+Esthetics. Persondata Name Morton, William T. G. Alternative names Short description Date of birth August 9, 1819 Place of birth Charlton, Massachusetts Date of death July 15, 1868 Place of death New York City
- Anaesthesia industrial solvent or medicine Interest in how it works = impact on our understanding and study of its toxicity in the extremes of age Receptor theory has taken hold, yet we see it as Consciousness Then the question arises – what is consciousness? Anaesthesia has been widely conceived as one of the greatest advancements in medicine in the modern era Are we saving lives every day or harming lives? Born in Charlton, Massachusetts, William T. G. Morton was the son of James Morton, a farmer, and Rebecca (Needham) Morton. William found work as a clerk, printer, and salesman in Boston before entering Baltimore College of Dental Surgery in 1840. In 1841, he gained notoriety for developing a new process to solder false teeth onto gold plates.[2] In 1842, he left college without graduating to study in Hartford, Connecticut with dentist Horace Wells, with whom Morton shared a brief partnership. In 1843 Morton married Elizabeth Whitman of Farmington, Connecticut, the niece of former Congressman Lemuel Whitman. Her parents objected to Morton&apos;s profession and only agreed to the marriage after he promised to study medicine. In the autumn of 1844, Morton entered Harvard Medical School and attended the chemistry lectures of Dr. Charles T. Jackson, who introduced Morton to the anesthetic properties of ether. Morton then also left Harvard without graduating. Replica of the inhaler used by William T. G. Morton in 1846 in the first public demonstration of surgery using ether. On September 30, 1846, Morton performed a painless tooth extraction after administering ether to a patient. Upon reading a favorable newspaper account of this event, Boston surgeon Henry Jacob Bigelow arranged for a now-famous demonstration of ether on October 16, 1846 at the operating theater of the Massachusetts General Hospital. At this demonstration Dr. John Collins Warren painlessly removed a tumor from the neck of a Mr. Edward Gilbert Abbott. The theatre came to be known as the Ether Dome and has been preserved as a monument to this historic event.[3] Following the demonstration, Morton tried to hide the identity of the substance Abbott had inhaled, by referring to it as &quot;Letheon&quot;, but it soon was found to be ether.[4] A month after this demonstration, a patent was issued for &quot;letheon&quot;, although it was widely known by then that the inhalant was ether. The medical community at large condemned the patent as unjust and illiberal in such a humane and scientific profession.[5] Morton assured his colleagues that he would not restrict the use of ether among hospitals and charitable institutions, alleging that his motives for seeking a patent were to ensure the competent administration of ether and to prevent its misuse or abuse, as well as to recoup the expenditures of its development. Morton&apos;s pursuit of credit for and profit from the administration of ether was complicated by the furtive and sometimes deceptive tactics he employed during its development, as well as the competing claims of other doctors, most notably his former mentor, Dr. Jackson. Morton&apos;s own efforts to obtain patents overseas also undermined his assertions of philanthropic intent. Consequently, no effort was made to enforce the patent, and ether soon came into general use. In December 1846, Morton applied to Congress for &quot;national recompense&quot; of $100,000, but this too was complicated by the claims of Jackson and Wells as discoverers of ether, and so Morton&apos;s application proved fruitless. He made similar applications in 1849, 1851, and 1853, and all failed. He later sought remuneration for his achievement through a futile attempt to sue the United States government. The lawyer who represented him was Richard Henry Dana, Jr. In 1852 he received an honorary degree from the Washington University of Medicine in Baltimore, which later became the College of Physicians and Surgeons.[6] Panel from monument in Boston commemorating Morton&apos;s demonstration of the anesthetic use of ether. In the spring of 1857, Amos Lawrence, a wealthy Bostonian, together with the medical professionals and influential citizens of Boston, developed a plan to raise $100,000 as a national testimonial to Morton, receiving contributions from both public and private citizens. Morton&apos;s notoriety only increased when he served as the star defense witness in one of the most notable trials of the nineteenth century, that of John White Webster who had been accused of the murder of Dr. George Parkman. Morton&apos;s rival, Dr. Jackson, testified for the prosecution, and the residents of Boston were anxious to witness these nemeses in courtroom combat.[7] Morton performed public service yet again in the autumn of 1862 when he joined the Army of the Potomac as a volunteer surgeon, and applied ether to more than two thousand wounded soldiers during the battles of Fredericksburg, Chancellorsville, and the Wilderness. Morton was in New York City in July 1868 when he went to Central Park to seek relief from a heat wave, where he collapsed and died soon after. He is buried at Mount Auburn Cemetery in Watertown and Cambridge, Massachusetts. In 1871, a committee of those involved in raising the aforementioned national testimonial published The Historical Memoranda Relative to the Discovery of Etherization to establish Morton as the inventor and revealer of anesthetic inhalation and to justify pecuniary reward to Morton&apos;s family for the &quot;fearful moral and legal responsibility he assumed in pursuit of this discovery.&quot;[8] Morton&apos;s life and work were later to become the subject of the 1944 Paramount Pictures film The Great Moment. The first use of ether as an anesthetic is commemorated in the Ether Monument in the Boston Public Garden, but the designers were careful not to choose sides in the debate over who should deserve credit for the discovery. Instead, the statue depicts a doctor in medieval Moorish robes and turban. [edit] Predecessor Morton&apos;s first successful public demonstration of ether as an inhalation anesthetic was such an historic and widely-publicized event that many consider him to be the &quot;inventor and revealer&quot; of anesthesia. However, Morton&apos;s work was preceded by that of Georgia surgeon Crawford Williamson Long, who employed ether as an anesthetic on March 30, 1842. Although Long demonstrated its use to physicians in Georgia on numerous occasions, he did not publish his findings until 1849, in The Southern Medical and Surgical Journal.[9] These pioneering uses of ether were key factors in the medical and scientific pursuit now referred to as anesthesiology, and allowed the development of modern surgery. Spread of the news of this &quot;new&quot; anesthetic was helped by the subsequent feud that developed between Morton and Horace Wells and Charles T. Jackson. [edit] See also Chloroform Humphry Davy James Young Simpson Nitrous oxide [edit] References ^ Fenster, J. M. (2001). Ether Day: The Strange Tale of America&apos;s Greatest Medical Discovery and the Haunted Men Who Made It. New York, NY: HarperCollins. ISBN 978-0060195236. ^ Packard, Francis Randolph (1901). The History of Medicine in the United States. Philadelphia and London: J. B. Lippincott Company. pp. 475. http://books.google.com/?id=6hIJAAAAIAAJ&pg=PA474&lpg=PA474&dq=Morton+solder+gold+teeth. ^ &quot;National Historic Landmarks Program: Ether Dome, Massachusetts General Hospital&quot;. http://tps.cr.nps.gov/nhl/detail.cfm?ResourceId=249&ResourceType=Building. Retrieved 2010-11-02. ^ &quot;&quot;Letheon&quot; Inhaler&quot;. http://www.general-anaesthesia.com/images/the-letheon.html. Retrieved 2009-05-01. ^ Smith, Stephen (1862). &quot;The Ether Patent&quot;. Medical Times 4 (January to July): 83–84. http://books.google.com/?id=-C4TAAAAYAAJ&pg=PA83&lpg=PA83&dq=%22ether+patent%22. ^ Pinsker, Sheila; Harding, Robert S. (1986). &quot;The Morton Family Collection 1849-1911&quot;. http://americanhistory.si.edu/archives/d8118.htm. Retrieved 2008-12-02. ^ Sullivan, Robert (1971). The Disappearance of Dr. Parkman. Little, Brown, and Company. http://books.google.com/?id=KNi0HQAACAAJ&dq=The+Disappearance+of+Dr.+Parkman/. ^ Committee of Citizens of Boston (1871). Historical Memoranda Relative to the Discovery of Etherization and to the Connection with it of the Late William T.G. Morton. Boston: Rand, Avery, and Frye. http://books.google.com/?id=ax8JAAAAIAAJ&dq=William+T.G.+Morton&printsec=frontcover. ^ See Books.Google.com. (Edward J. Huth and T. J. Murray) [edit] Further reading Alper M. H. (1964). &quot;The Ether Controversy Revisited (Morton WT), (Jackson CT)&quot;. Anesthesiology 25: 560–3. PMID 14192801. Andreae H. (December 1969). &quot;The discoverer of ether anesthesia, dentist Morton, born 150 years ago [The discoverer of ether anesthesia, dentist Morton, born 150 years ago]&quot; (in German). Zahnärztliche Praxis 20 (23): 276. PMID 5263393. Asbell M. B. (October 1970). &quot;William Thomas Green Morton&quot;. Worcester Medical News 35 (2): 15–8. PMID 5277344. Ash H. L. (1985). &quot;Anesthesia&apos;s dental heritage (William Thomas Green Morton)&quot;. Anesthesia Progress 32 (1): 25–9. PMC 2175398. PMID 3888002. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2175398. Deranian H. M. (1997). &quot;The great Morton-Jackson debate&quot;. Journal of the Massachusetts Dental Society 46 (2): 24–5. PMID 9540719. Figuier, Louis (1851). &quot;Expérience d&apos;Horace Wels à l&apos;hôpital de Boston avec je gaz hilarant&quot; (in French). Exposition et histoire des principales découvertes scientifiques modernes. 1. Paris: Masson. p. 212. OCLC 312611474. http://books.google.com/books?id=4M8EAAAAYAAJ&pg=RA1-PA212. Contains an account, in French, of the discovery of anaesthesia with ether by Morton and Jackson and of its reception in Europe. Heynick F (March 2003). &quot;William T. G. Morton and &apos;The Great Moment&apos;&quot;. Journal of the History of Dentistry 51 (1): 27–35. PMID 12641171. Keys T. E. (March 1973). &quot;William Thomas Green Morton (1819-1868)&quot;. Anesthesia and Analgesia 52 (2): 166. doi:10.1213/00000539-197303000-00004. PMID 4572338. Leonard A. G. (May 1985). &quot;Stamp recognition for William Morton&quot;. British Dental Journal 158 (9): 345. doi:10.1038/sj.bdj.4805605. PMID 3890908. Morton, William T. G. (1847). Remarks on the Proper Mode of Administering Sulphuric Ether by Inhalation. Boston: Button and Wentworth. OCLC 14825070. http://www.ncbi.nlm.nih.gov/books/bookres.fcgi/history/pdf_morton.pdf. Retrieved 22 July 2009. Morton W. T. (November 1996). &quot;SMW 100 years ago. William Thomas Green Morton and the discovery of anesthesia [SMW 100 years ago. William Thomas Green Morton and the discovery of anesthesia]&quot; (in German). Schweizerische Medizinische Wochenschrift 126 (47): 2040–2. PMID 8984612. Pavlovskiĭ L. N. (2005). &quot;Dentist William Morton is a founder of general anesthesia [Dentist William Morton is a founder of general anesthesia]&quot; (in Russian). Likars&apos;ka Sprava (1–2): 111–5. PMID 15916010. Rozar L. B. (July 1975). &quot;Dr. William T. G. Morton D.D.S., discoverer of surgical anesthesia&quot;. CAL 39 (1): 6–8. PMID 795512. Shampo M. A., Kyle R. A. (January 1987). &quot;Morton: pioneer in the use of ether&quot;. Mayo Clinic Proceedings 62 (1): 56. PMID 3540476. Vandam L. D. (January 1994). &quot;Benjamin Perley Poore and his historical materials for a biography of W.T.G. Morton, M.D&quot;. Journal of the History of Medicine and Allied Sciences 49 (1): 5–23. doi:10.1093/jhmas/49.1.5. PMID 8151115. Vandam L. D. (September 1996). &quot;The last days of William Thomas Green Morton&quot;. Journal of Clinical Anesthesia 8 (6): 431–4. doi:10.1016/0952-8180(96)00125-0. PMID 8872680. Westhorpe R (October 1996). &quot;William Morton and the first successful demonstration of anaesthesia&quot;. Anaesthesia and Intensive Care 24 (5): 529. PMID 8909661. &quot;Wimmiam McLintock Morton, T.D., L.D.S&quot;. British Dental Journal 146 (4): 128. February 1979. doi:10.1038/sj.bdj.4804211. PMID 367405. &quot;Two tormented lives. Horace Wells and William Morton [Two tormented lives. Horace Wells and William Morton]&quot; (in Spanish). Boletin De Información 15 (117): 17–21 passim. April 1971. PMID 5283677. , (October 1965). &quot;William T.G. Morton (1819-1868), demonstrator of ether anesthesia&quot;. JAMA 194 (2): 190–1. doi:10.1001/jama.194.2.190. PMID 5319582. &quot;William Thomas Green Morton&quot; (in Spanish). Revista Española De Anestesiología 3 (4): 380–3. October 1956. PMID 13389978. [edit] External links &quot;William Thomas Morton&quot;. Find a Grave. http://www.findagrave.com/cgi-bin/fg.cgi?page=gr&GRid=1759. Retrieved 2008-12-02. &quot;Boyhood Home Sign in Charlton, Massachusetts&quot;. http://img.geocaching.com/cache/120e0605-793f-40fe-84a0-baff7629c173.jpg. &quot;Centennial of First Man to Employ Anaesthetic&quot;. Miami Herald Record. 1919 July 13. http://infoweb.newsbank.com.proxy1.library.jhu.edu/iw-search/we/HistArchive/?p_product=EANX&p_theme=ahnp&p_nbid=I6EC62JXMTIyNDcxODczOS40MzEyMzg6MToxMjoxMjguMjIwLjguMTU&p_action=doc&s_lastnonissuequeryname=3&d_viewref=search&p_queryname=3&p_docnum=19&p_docref=v2:114CF48AE24B9638@EANX-1190F44183842D50@2422154-1190F441D599ADA8@3-1190F4432010A610@Gentennial+of+First+Man+to+Employ+an+Anaesthetic. &quot;Men Who Have Eased the World&apos;s Pain&quot;. Kansas City Star. 1913 December 29. http://infoweb.newsbank.com.proxy1.library.jhu.edu/iw-search/we/HistArchive/?p_product=EANX&p_theme=ahnp&p_nbid=I6EC62JXMTIyNDcxODczOS40MzEyMzg6MToxMjoxMjguMjIwLjguMTU&p_action=doc&s_lastnonissuequeryname=3&d_viewref=search&p_queryname=3&p_docnum=16&p_docref=v2:1126152C152E4978@EANX-119AD8F7317502C0@2420131-119AD8F79FB48038@11-119AD8F94179B368@Men+Who+Have+Eased+the+World%27s+Paon+William+T.+G.+Morton. &quot;Surgery Was Agony&quot;. Worcester Daily Spy. 1893 April 23. http://infoweb.newsbank.com.proxy1.library.jhu.edu/iw-search/we/HistArchive/?p_product=EANX&p_theme=ahnp&p_nbid=J66I53LHMTIyODA3MjU1OC4xNDQwODQ6MToxMjoxMjguMjIwLjguMTU&p_action=doc&s_lastnonissuequeryname=3&d_viewref=search&p_queryname=3&p_docnum=1&p_docref=v2:11C12F6287BB7190@EANX-11ED9B31D1760820@2412577-11ED9B321415E438@7-11ED9B334125A3E0@Surgery+Was+Agony.+until+a+World%27s+Benefactor+Used+an+Esthetics. Persondata Name Morton, William T. G. Alternative names Short description Date of birth August 9, 1819 Place of birth Charlton, Massachusetts Date of death July 15, 1868 Place of death New York City
- Amnesia, motor paralysis, unconsciousness, analgesia, loss of sensation, Final analysis, its amnesia and motor paralysis
- Clinical & Pathophysiological implications Dosing Awareness; Amnesia Complications – elderly; cognitive disorder; young – neurotoxicity theories Opportunities for new technology – EEG Symmetry and synchrony Lessons for pathological states of nonawareness and consciousness
- Clinical & Pathophysiological implications Dosing Awareness; Amnesia Complications – elderly; cognitive disorder; young – neurotoxicity theories Opportunities for new technology – EEG Symmetry and synchrony Lessons for pathological states of nonawareness and consciousness
- level of consciousness and the integrity of arousal determined by the subcortical structures
- Ether – industrial solvent Anesthesia-induced loss of consciousness was also shown to correlate with a global decrease in cortico-cortical and thalamo-cortical connectivity in both intrinsic and extrinsic networks, but not in auditory, or visual networks. In anesthesia, unconsciousness was also associated with a loss of cross-modal interactions between networks. These results suggest that conscious awareness critically depends on the functional integrity of thalamo-cortical and cortico-cortical frontoparietal connectivity within and between “intrinsic” and “extrinsic” brain networks. Recent studies in patients with disorders of consciousness (DOC) tend to support the view that awareness is not related to activity in a single brain region but to thalamo-cortical connectivity in the frontoparietal network. Functional neuroimaging studies have shown preserved albeit disconnected low-level cortical activation in response to external stimulation in patients in a “vegetative state” or unresponsive wakefulness syndrome. While activation of these “primary” sensory cortices does not necessarily reflect conscious awareness, activation in higher-order associative cortices in minimally conscious state patients seems to herald some residual perceptual awareness. PET studies have identified a metabolic dysfunction in a widespread frontoparietal “global neuronal workspace” in DOC patients including the midline default mode network (“intrinsic” system) and the lateral frontoparietal cortices or “extrinsic system.” Recent studies have investigated the relation of awareness to the functional connectivity within intrinsic and extrinsic networks, and with the thalami in both pathological and pharmacological coma. In brain damaged patients, connectivity in all default network areas was found to be non-linearly correlated with the degree of clinical consciousness impairment, ranging from healthy controls and locked-in syndrome to minimally conscious, vegetative, coma, and brain dead patients. Anesthesia-induced loss of consciousness was also shown to correlate with a global decrease in cortico-cortical and thalamo-cortical connectivity in both intrinsic and extrinsic networks, but not in auditory, or visual networks. In anesthesia, unconsciousness was also associated with a loss of cross-modal interactions between networks. These results suggest that conscious awareness critically depends on the functional integrity of thalamo-cortical and cortico-cortical frontoparietal connectivity within and between “intrinsic” and “extrinsic” brain networks.
- Anesthetics hyperpolarize neurons by increasing inhibition or decreasing excitation (9) and alter neuronal activity: The sustained firing typical of the aroused brain changes to a bistable burst-pause pattern (10) that is also observed in non–rapideye- movement (NREM) sleep. At intermediate anesthetic concentrations, neurons begin oscillating, roughly once a second, between a depolarized up-state and a hyperpolarized down-state (11). The up-state is similar to the sustained depolarization of wakefulness. The down-state shows complete cessation of synaptic activity for a tenth of a second or more, after which neurons revert to another up-state. As anesthetic doses increase, the up-state turns to a short burst and the down-state becomes progressively longer. These changes in neuronal firing patterns are reflected in the electroencephalogram (EEG) (electrical recording from the scalp) as a transition from the lowvoltage, high-frequency pattern of wakefulness (known as activated EEG), to the slow-wave EEG of deep NREM sleep, and finally to an EEG burst-suppression pattern (12). The Anesthetized Patient: Unconscious or Unresponsive? Clinically, at low-sedative doses anesthetics cause a state similar to drunkenness, with analgesia, amnesia, distorted time perception, depersonalization, and increased sleepiness. At slightly higher doses, a patient fails to move in response to a command and is considered unconscious. This behavioral definition of unconsciousness, which was introduced with anesthesia over 160 years ago, while Despite different mechanisms and sites of action, most anesthetic agents appear to cause unconsciousness by targeting, directly or indirectly, a posterior lateral corticothalamic complex centered around the inferior parietal lobe, and perhaps a medial cortical core. Whether the medial or lateral component is more important, and whether anterior cortical regions are critical primarily for executive functions and perhaps self-reflection, remain questions for future work. Second, anesthetics can cause unconsciousness not just by deactivating this posterior corticothalamic complex, but also by producing a functional disconnection between subregions of this complex. Third, although assessing loss of consciousness with verbal commands may usually be adequate, it may occasionally be misleading. Finally, one theoretical framework that seems to fit well with current empirical data suggests that consciousness requires an integrated system with a large repertoire of discriminable states. According to this framework, anesthetics would produce unconsciousness either by preventing integration (blocking the interactions among specialized brain regions) or by reducing information (shrinking the number of activity patterns available to cortical networks). Other frameworks for consciousness, emphasizing access to a global workspace (66, 67), or the formation of large coalitions of neurons (43), are also consistent with many of the findings described here, especially those concerning the role of cortical integration. Together, these ideas should help in developing agents with more specific actions, in better monitoring their effects on consciousness, and in using anesthesia as a tool for characterizing the neural substrates of consciousness.
- Despite different mechanisms and sites of action, most anesthetic agents appear to cause unconsciousness by targeting, directly or indirectly, a posterior lateral corticothalamic complex centered around the inferior parietal lobe, and perhaps a medial cortical core. Whether the medial or lateral component is more important, and whether anterior cortical regions are critical primarily for executive functions and perhaps self-reflection, remain questions for future work. Second, anesthetics can cause unconsciousness not just by deactivating this posterior corticothalamic complex, but also by producing a functional disconnection between subregions of this complex. Third, although assessing loss of consciousness with verbal commands may usually be adequate, it may occasionally be misleading. Finally, one theoretical framework that seems to fit well with current empirical data suggests that consciousness requires an integrated system with a large repertoire of discriminable states. According to this framework, anesthetics would produce unconsciousness either by preventing integration (blocking the interactions among specialized brain regions) or by reducing information (shrinking the number of activity patterns available to cortical networks). Other frameworks for consciousness, emphasizing access to a global workspace (66, 67), or the formation of large coalitions of neurons (43), are also consistent with many of the findings described here, especially those concerning the role of cortical integration. Together, these ideas should help in developing agents with more specific actions, in better monitoring their effects on consciousness, and in using anesthesia as a tool for characterizing the neural substrates of consciousness.
- GABAA and N-methyl-Daspartate (NMDA) receptors in the cortex, thalamus, brain stem, and striatum as two of the important targets of hypnotic drugs.36,37 Because small numbers of inhibitory interneurons control large numbers of excitatory pyramidal neurons, the enhanced GABAA inhibition induced by general anesthesia can efficiently inactivate large regions of the brain and contribute to unconsciousness (Fig. 2A).38,39
- Best Answer - Chosen by Voters An ionotropic receptor, when activated, directly affects the activity of a cell by directly opening ion channels.A metabotropic receptor influences the activity of a cell indirectly by first initiating a metabolic change in the cell. This metabolic change may ultimately affect the opening or closing of an ion channel or may alter some other activity of the cell such as protein transcription.The ionotropic receptor is actually a class of chemically-gated ion channel. The open or closed state of this class of chemically-gated channel is regulated by the binding of a neurotransmitter to an external domain on the ion channel. For ionotropic receptors, the receptor and primary effector are actually parts of the same macromolecule since the ion channel itself is the primary effector (the entity that initiates the change in the functional status of the neuron). Eg. the nicotinic acetylcholine receptor, the acetylcholine molecule binds to the receptor portion of the channel. Upon binding, the channel opens, changing the ionic permeability and hence changing the membrane potential.In contrast to the ion channel that comprises the ionotropic receptor, metabotropic receptors are comprised of a single membrane-spanning protein. An extracellular region of this protein has a high affinity for a neurotransmitter and functions as the binding site. When a neurotransmitter binds to the binding site of a metabotropic receptor, the receptor undergoes a configurational change that either directly or indirectly activates an enzyme. This enzyme, representing the primary effector, commonly catalyzes a change in the metabolism of the neuron by converting some substrate into an intracellular bioactive metabolite known as a second messenger. The extracellular first messenger, which is the neurotransmitter, has now led to production of an intracellular second messenger. The second messenger may in turn activate a secondary effector within the neuron that can carry out subsequent metabolic changes. Thus, the production of the second messenger is often the initial link in a chain of physiological alterations that ultimately lead to the biological response of the neuron.
- GABAA receptors clustered at postsynaptic terminals are activated by a near-saturating concentration of GABA. GABA transmits information to inhibitory synapse by generating the fast and transient inhibitory postsynaptic currents (IPSCs) (Fig. 1) [18]. For many years, enhancement of fast synaptic inhibition was widely thought to be the primary mechanism underlying the actions of many GABAergic drugs. Over the past decade, however, a persistent form of tonic inhibition has been identified in several brain regions. Tonic currents are known to be generated as GABA acts on the GABAA receptor at the extrasynapse, not on synapse (Fig. 1) [8,19]. This tonic inhibitory conductance is generated by high-affinity, slowly desensitizing GABAA receptors that are activated by low ambient concentration of GABA [20-22]. Tonic currents are generated in several types of cells including CA1 pyramidal [8,23], granule cells [24], and interneurons [19,25] of the hippocampus. In the hippocampus, the tonic conductance is also activated by GABA released by action potential dependent vesicular mechanism [26]. The tonic conductance has been shown to regulate neuronal excitability and information processing [19,27].
- Anesthetics hyperpolarize neurons by increasing inhibition or decreasing excitation (9) and alter neuronal activity: The sustained firing typical of the aroused brain changes to a bistable burst-pause pattern (10) that is also observed in non–rapideye- movement (NREM) sleep. At intermediate anesthetic concentrations, neurons begin oscillating, roughly once a second, between a depolarized up-state and a hyperpolarized down-state (11). The up-state is similar to the sustained depolarization of wakefulness. The down-state shows complete cessation of synaptic activity for a tenth of a second or more, after which neurons revert to another up-state. As anesthetic doses increase, the up-state turns to a short burst and the down-state becomes progressively longer. These changes in neuronal firing patterns are reflected in the electroencephalogram (EEG) (electrical recording from the scalp) as a transition from the lowvoltage, high-frequency pattern of wakefulness (known as activated EEG), to the slow-wave EEG of deep NREM sleep, and finally to an EEG burst-suppression pattern (12). The Anesthetized Patient: Unconscious or Unresponsive? Clinically, at low-sedative doses anesthetics cause a state similar to drunkenness, with analgesia, amnesia, distorted time perception, depersonalization, and increased sleepiness. At slightly higher doses, a patient fails to move in response to a command and is considered unconscious. This behavioral definition of unconsciousness, which was introduced with anesthesia over 160 years ago, while Despite different mechanisms and sites of action, most anesthetic agents appear to cause unconsciousness by targeting, directly or indirectly, a posterior lateral corticothalamic complex centered around the inferior parietal lobe, and perhaps a medial cortical core. Whether the medial or lateral component is more important, and whether anterior cortical regions are critical primarily for executive functions and perhaps self-reflection, remain questions for future work. Second, anesthetics can cause unconsciousness not just by deactivating this posterior corticothalamic complex, but also by producing a functional disconnection between subregions of this complex. Third, although assessing loss of consciousness with verbal commands may usually be adequate, it may occasionally be misleading. Finally, one theoretical framework that seems to fit well with current empirical data suggests that consciousness requires an integrated system with a large repertoire of discriminable states. According to this framework, anesthetics would produce unconsciousness either by preventing integration (blocking the interactions among specialized brain regions) or by reducing information (shrinking the number of activity patterns available to cortical networks). Other frameworks for consciousness, emphasizing access to a global workspace (66, 67), or the formation of large coalitions of neurons (43), are also consistent with many of the findings described here, especially those concerning the role of cortical integration. Together, these ideas should help in developing agents with more specific actions, in better monitoring their effects on consciousness, and in using anesthesia as a tool for characterizing the neural substrates of consciousness.
- GABAA receptors clustered at postsynaptic terminals are activated by a near-saturating concentration of GABA. GABA transmits information to inhibitory synapse by generating the fast and transient inhibitory postsynaptic currents (IPSCs) (Fig. 1) [18]. For many years, enhancement of fast synaptic inhibition was widely thought to be the primary mechanism underlying the actions of many GABAergic drugs. Over the past decade, however, a persistent form of tonic inhibition has been identified in several brain regions. Tonic currents are known to be generated as GABA acts on the GABAA receptor at the extrasynapse, not on synapse (Fig. 1) [8,19]. This tonic inhibitory conductance is generated by high-affinity, slowly desensitizing GABAA receptors that are activated by low ambient concentration of GABA [20-22]. Tonic currents are generated in several types of cells including CA1 pyramidal [8,23], granule cells [24], and interneurons [19,25] of the hippocampus. In the hippocampus, the tonic conductance is also activated by GABA released by action potential dependent vesicular mechanism [26]. The tonic conductance has been shown to regulate neuronal excitability and information processing [19,27].
- to: navigation, search Bicuculline Systematic (IUPAC) name (6R)-6-[(5S)-6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinolin-5-yl]furo[3,4-e][1,3]benzodioxol-8(6H)-one Clinical data Pregnancy cat. ? Legal status ? Identifiers CAS number 485-49-4 Y ATC code None PubChem CID 10237 IUPHAR ligand 2312 ChemSpider 9820 Y UNII Y37615DVKC N ChEBI CHEBI:3092 N ChEMBL CHEMBL417990 N Chemical data Formula C20H17NO6 Mol. mass 367.352 g/mol SMILES eMolecules & PubChem InChI[show] InChI=1S/C20H17NO6/c1-21-5-4-10-6-14-15(25-8-24-14)7-12(10)17(21)18-11-2-3-13-19(26-9-23-13)16(11)20(22)27-18/h2-3,6-7,17-18H,4-5,8-9H2,1H3/t17-,18+/m0/s1 YKey:IYGYMKDQCDOMRE-ZWKOTPCHSA-N Y N (what is this?) (verify)Bicuculline is a light-sensitive competitive antagonist of GABAA receptors. It was originally identified in 1932 in plant alkaloid extracts[1] and has been isolated from Dicentra cucullaria, Adlumia fungosa, Fumariaceae, and several Corydalis species. Since it blocks the inhibitory action of GABA receptors, the action of bicuculline mimics epilepsy. This property is utilized in laboratories across the world in the in vitro study of epilepsy, generally in hippocampal or cortical neurons in prepared brain slices from rodents. This compound is also routinely used to isolate glutamatergic (excitatory amino acid) receptor function. Bicuculline is also a pharmcological agent that, when used, increases the frequency of occurrence of ocular saccades during visual fixation.[2][citation needed] The action of bicuculline is primarily on the ionotropic GABAA receptors, which are ligand-gated ion channels concerned chiefly with the passing of chloride ions across the cell membrane, thus promoting an inhibitory influence on the target neuron. These receptors are the major targets for benzodiazepines and related anxiolytic drugs
- Anesthetics hyperpolarize neurons by increasing inhibition or decreasing excitation (9) and alter neuronal activity: The sustained firing typical of the aroused brain changes to a bistable burst-pause pattern (10) that is also observed in non–rapideye- movement (NREM) sleep. At intermediate anesthetic concentrations, neurons begin oscillating, roughly once a second, between a depolarized up-state and a hyperpolarized down-state (11). The up-state is similar to the sustained depolarization of wakefulness. The down-state shows complete cessation of synaptic activity for a tenth of a second or more, after which neurons revert to another up-state. As anesthetic doses increase, the up-state turns to a short burst and the down-state becomes progressively longer. These changes in neuronal firing patterns are reflected in the electroencephalogram (EEG) (electrical recording from the scalp) as a transition from the lowvoltage, high-frequency pattern of wakefulness (known as activated EEG), to the slow-wave EEG of deep NREM sleep, and finally to an EEG burst-suppression pattern (12). The Anesthetized Patient: Unconscious or Unresponsive? Clinically, at low-sedative doses anesthetics cause a state similar to drunkenness, with analgesia, amnesia, distorted time perception, depersonalization, and increased sleepiness. At slightly higher doses, a patient fails to move in response to a command and is considered unconscious. This behavioral definition of unconsciousness, which was introduced with anesthesia over 160 years ago, while Despite different mechanisms and sites of action, most anesthetic agents appear to cause unconsciousness by targeting, directly or indirectly, a posterior lateral corticothalamic complex centered around the inferior parietal lobe, and perhaps a medial cortical core. Whether the medial or lateral component is more important, and whether anterior cortical regions are critical primarily for executive functions and perhaps self-reflection, remain questions for future work. Second, anesthetics can cause unconsciousness not just by deactivating this posterior corticothalamic complex, but also by producing a functional disconnection between subregions of this complex. Third, although assessing loss of consciousness with verbal commands may usually be adequate, it may occasionally be misleading. Finally, one theoretical framework that seems to fit well with current empirical data suggests that consciousness requires an integrated system with a large repertoire of discriminable states. According to this framework, anesthetics would produce unconsciousness either by preventing integration (blocking the interactions among specialized brain regions) or by reducing information (shrinking the number of activity patterns available to cortical networks). Other frameworks for consciousness, emphasizing access to a global workspace (66, 67), or the formation of large coalitions of neurons (43), are also consistent with many of the findings described here, especially those concerning the role of cortical integration. Together, these ideas should help in developing agents with more specific actions, in better monitoring their effects on consciousness, and in using anesthesia as a tool for characterizing the neural substrates of consciousness.
- Panel A shows a GABAergic inhibitory interneuron (orange) synapsing on a pyramidal neuron (gray) receiving excitatory inputs from ascending arousal pathways. The monoaminergic pathways arise from the locus ceruleus, which releases norepinephrine; the raphe, which releases serotonin; the tuberomammillary nucleus, which releases histamine; and the ventral teg-mental area, which releases dopamine. The cholinergic pathways, which release acetylcholine, arise from the basal forebrain, the lateral dorsal tegmental nuclei, and the pedunculopontine tegmental nuclei. Lateral hypothalamic neurons release orexin. Propofol binds post-synaptically and enhances GABAergic inhibition, counteracting arousal inputs to the pyramidal neuron, decreasing its excitatory activity, and contributing to unconsciousness. Dexmedetomidine binds to α2 receptors on neurons from the locus ceruleus, inhibiting norepinephrine release (dashed line) in the ventrolateral preoptic nucleus, as shown in Panel B. The disinhibited ventrolateral preoptic nucleus reduces arousal by means of GABAA-mediated and galanin-mediated inhibition of the midbrain, hypothalamic, and pontine arousal nuclei. As shown in Panel C, opioids reduce arousal by inhibiting the release of acetylcholine from neurons projecting from the lateral dorsal and pedunculopontine tegmental nuclei to the medial pontine reticular formation and to the thalamus, by binding to opioid receptors in the periaqueductal gray and rostral ventral medulla, and by binding presynaptically and postsynaptically to spinal cord opioid receptors at the synapses between peripheral afferent neurons in the dorsal-root ganglion and projecting neurons. evidence of cortical mechanisms of unconsciousness induced by general anesthesia. In vivo and in vitro molecular pharmacologic studies have identified GABAA and N-methyl-D-aspartate (NMDA) receptors in the cortex, thalamus, brain stem, and striatum as two of the important targets of hypnotic drugs.36,37 Because small numbers of inhibitory interneurons control large numbers of excitatory pyramidal neurons, the enhanced GABAA inhibition induced by general anesthesia can efficiently inactivate large regions of the brain and contribute to unconsciousness
- Neurobiologically, the thalamus is a bilateral structure in the diencephalon comprising approximately 50 nuclei and subnuclei with rich interconnections to other structures in the brain. Thalamic nuclei can be classified as specific (mediating relay of peripheral information to a particular area of sensory cortex) and nonspecific (mediating multimodal integration of information)
- Liu X, Lauer KK, Ward BD, Li S-J, Hudetz AG: Differential effects of deep sedation with propofol on the specific and nonspecific thalamocortical systems: A functional magnetic resonance imaging study. Anesthesiology 2013; 118:59–69
- Liu X, Lauer KK, Ward BD, Li S-J, Hudetz AG: Differential effects of deep sedation with propofol on the specific and nonspecific thalamocortical systems: A functional magnetic resonance imaging study. Anesthesiology 2013; 118:59–69
- Ether – industrial solvent Anesthesia-induced loss of consciousness was also shown to correlate with a global decrease in cortico-cortical and thalamo-cortical connectivity in both intrinsic and extrinsic networks, but not in auditory, or visual networks. In anesthesia, unconsciousness was also associated with a loss of cross-modal interactions between networks. These results suggest that conscious awareness critically depends on the functional integrity of thalamo-cortical and cortico-cortical frontoparietal connectivity within and between “intrinsic” and “extrinsic” brain networks. Recent studies in patients with disorders of consciousness (DOC) tend to support the view that awareness is not related to activity in a single brain region but to thalamo-cortical connectivity in the frontoparietal network. Functional neuroimaging studies have shown preserved albeit disconnected low-level cortical activation in response to external stimulation in patients in a “vegetative state” or unresponsive wakefulness syndrome. While activation of these “primary” sensory cortices does not necessarily reflect conscious awareness, activation in higher-order associative cortices in minimally conscious state patients seems to herald some residual perceptual awareness. PET studies have identified a metabolic dysfunction in a widespread frontoparietal “global neuronal workspace” in DOC patients including the midline default mode network (“intrinsic” system) and the lateral frontoparietal cortices or “extrinsic system.” Recent studies have investigated the relation of awareness to the functional connectivity within intrinsic and extrinsic networks, and with the thalami in both pathological and pharmacological coma. In brain damaged patients, connectivity in all default network areas was found to be non-linearly correlated with the degree of clinical consciousness impairment, ranging from healthy controls and locked-in syndrome to minimally conscious, vegetative, coma, and brain dead patients. Anesthesia-induced loss of consciousness was also shown to correlate with a global decrease in cortico-cortical and thalamo-cortical connectivity in both intrinsic and extrinsic networks, but not in auditory, or visual networks. In anesthesia, unconsciousness was also associated with a loss of cross-modal interactions between networks. These results suggest that conscious awareness critically depends on the functional integrity of thalamo-cortical and cortico-cortical frontoparietal connectivity within and between “intrinsic” and “extrinsic” brain networks.
- Ether – industrial solvent Anesthesia-induced loss of consciousness was also shown to correlate with a global decrease in cortico-cortical and thalamo-cortical connectivity in both intrinsic and extrinsic networks, but not in auditory, or visual networks. In anesthesia, unconsciousness was also associated with a loss of cross-modal interactions between networks. These results suggest that conscious awareness critically depends on the functional integrity of thalamo-cortical and cortico-cortical frontoparietal connectivity within and between “intrinsic” and “extrinsic” brain networks. Recent studies in patients with disorders of consciousness (DOC) tend to support the view that awareness is not related to activity in a single brain region but to thalamo-cortical connectivity in the frontoparietal network. Functional neuroimaging studies have shown preserved albeit disconnected low-level cortical activation in response to external stimulation in patients in a “vegetative state” or unresponsive wakefulness syndrome. While activation of these “primary” sensory cortices does not necessarily reflect conscious awareness, activation in higher-order associative cortices in minimally conscious state patients seems to herald some residual perceptual awareness. PET studies have identified a metabolic dysfunction in a widespread frontoparietal “global neuronal workspace” in DOC patients including the midline default mode network (“intrinsic” system) and the lateral frontoparietal cortices or “extrinsic system.” Recent studies have investigated the relation of awareness to the functional connectivity within intrinsic and extrinsic networks, and with the thalami in both pathological and pharmacological coma. In brain damaged patients, connectivity in all default network areas was found to be non-linearly correlated with the degree of clinical consciousness impairment, ranging from healthy controls and locked-in syndrome to minimally conscious, vegetative, coma, and brain dead patients. Anesthesia-induced loss of consciousness was also shown to correlate with a global decrease in cortico-cortical and thalamo-cortical connectivity in both intrinsic and extrinsic networks, but not in auditory, or visual networks. In anesthesia, unconsciousness was also associated with a loss of cross-modal interactions between networks. These results suggest that conscious awareness critically depends on the functional integrity of thalamo-cortical and cortico-cortical frontoparietal connectivity within and between “intrinsic” and “extrinsic” brain networks.
- Anaesthetics by blocking the channels of the connectivitiy between diff parts of the cortex, particularly at the level of the thalamic nuclei acting mainy on the inhibitory interneurons,
- Figure 1. Electroencephalographic (EEG) Patterns during the Awake State, General Anesthesia, and Sleep Panel A shows the EEG patterns when the patient is awake, with eyes open (left) and the alpha rhythm (10 Hz) with eyes closed (right). Panel B shows the EEG patterns during the states of general anesthesia: paradoxical excitation, phases 1 and 2, burst suppression, and the isoelectric tracing. Panel C shows the EEG patterns during the stages of sleep: rapid-eye movement (REM) sleep; stage 1 non-REM sleep; stage 2 non-REM sleep, and stage 3 non- REM (slow-wave) sleep. The EEG patterns during recovery from coma — coma, vegetative state, and minimally conscious state — resemble the patterns during general anesthesia, sleep, and the awake state. EEG tracings during sleep are from Watson et al.5 Four EEG patterns define the phases of the maintenance period (Fig. 1). Phase 1, a light state of general anesthesia, is characterized by a decrease in EEG beta activity (13 to 30 Hz) and an increase in EEG alpha activity (8 to 12 Hz) and delta activity (0 to 4 Hz).22 During phase 2, the intermediate state, beta activity decreases and alpha and delta activity increases, with so-called anteriorization — that is, an increase in alpha and delta activity in the anterior EEG leads relative to the posterior leads.22,23 The EEG in phase 2 resembles that seen in stage 3, non-REM (or slow-wave) sleep. Phase 3 is a deeper state, in which the EEG is characterized by flat periods interspersed with periods of alpha and beta activity — a pattern called burst suppression.15 As this state of general anesthesia deepens, the time between the periods of alpha activity lengthens, and the amplitudes of the alpha and beta activity decrease. Surgery is usually performed during phases 2 and 3. In phase 4, the most profound state of general anesthesia, the EEG is isoelectric (completely flat). An isoelectric EEG may be purposely induced by the administration of a barbiturate or propofol to protect the brain during neurosurgery24 or to stop generalized seizures.25,26
- Figure 1. Electroencephalographic (EEG) Patterns during the Awake State, General Anesthesia, and Sleep Panel A shows the EEG patterns when the patient is awake, with eyes open (left) and the alpha rhythm (10 Hz) with eyes closed (right). Panel B shows the EEG patterns during the states of general anesthesia: paradoxical excitation, phases 1 and 2, burst suppression, and the isoelectric tracing. Panel C shows the EEG patterns during the stages of sleep: rapid-eye movement (REM) sleep; stage 1 non-REM sleep; stage 2 non-REM sleep, and stage 3 non- REM (slow-wave) sleep. The EEG patterns during recovery from coma — coma, vegetative state, and minimally conscious state — resemble the patterns during general anesthesia, sleep, and the awake state. EEG tracings during sleep are from Watson et al.5 Four EEG patterns define the phases of the maintenance period (Fig. 1). Phase 1, a light state of general anesthesia, is characterized by a decrease in EEG beta activity (13 to 30 Hz) and an increase in EEG alpha activity (8 to 12 Hz) and delta activity (0 to 4 Hz).22 During phase 2, the intermediate state, beta activity decreases and alpha and delta activity increases, with so-called anteriorization — that is, an increase in alpha and delta activity in the anterior EEG leads relative to the posterior leads.22,23 The EEG in phase 2 resembles that seen in stage 3, non-REM (or slow-wave) sleep. Phase 3 is a deeper state, in which the EEG is characterized by flat periods interspersed with periods of alpha and beta activity — a pattern called burst suppression.15 As this state of general anesthesia deepens, the time between the periods of alpha activity lengthens, and the amplitudes of the alpha and beta activity decrease. Surgery is usually performed during phases 2 and 3. In phase 4, the most profound state of general anesthesia, the EEG is isoelectric (completely flat). An isoelectric EEG may be purposely induced by the administration of a barbiturate or propofol to protect the brain during neurosurgery24 or to stop generalized seizures.25,26
- Figure 3. Paradoxical Excitation, Cerebral Metabolism, and Electroencephalographic (EEG) Activity in Stages of Coma Recovery Cortical damage causes loss of excitatory inputs from the frontal cortex to the median spiny neurons in the striatum, as shown in Panel A. Normal striatal inhibition of the globus pallidus interna is lost, and the globus pallidus interna tonically inhibits the thalamus. Zolpidem and propofol may bind to GABAA1 receptors in the globus pallidus interna, blocking its inhibitory inputs to the thalamus; as a result, excitatory cortical inputs from the thalamus are restored, causing paradoxical excitation.73 (ie normally inhibitory role of G pallidus interna – when propofol binds to GABA, this inhibition role is inhibited – resulting in unrestrained excitatory cortical inputs from the thalamus) Panel B schematically depicts changes in cerebral metabolism as measured by positron emission tomographic (PET) scanning and on electroencephalography (EEG) at different stages of coma recovery. In the awake state, the EEG pattern is active and cerebral metabolism is globally active. Paradoxical excitation induced by the administration of zolpidem, which is associated with behavioral improvement in some minimally conscious patients, is reflected by an active EEG pattern with reduced prefrontal cortex metabolism. Patients in minimally conscious and vegetative states may show EEG anteriorization, with alpha, theta, and delta EEG patterns and decreased metabolism in the frontal cortex, striatum, and thalamus. Burst suppression in coma correlates with globally depressed metabolism. General anesthesia results in similar EEG patterns. A denotes anterior, and P posterior. The globus pallidus interna normally provides tonic inhibitory inputs to the central thalamus that are opposed by striatal inhibition of the pallidum. Binding of zolpidem in the GABAA1-receptor–rich globus pallidus interna may suppress this tonic inhibitory input to the thalamus,75 fostering activation of thalamocortical and thalamostriatal circuits and, consequently, enhancing arousal (Fig. 3A). For anesthetic drugs that promote GABAA inhibition, paradoxical excitation may be explained by a similar action in these circuits. This hypothesis could also account for the paradoxical excitation observed during endoscopy and the delirium observed in intensive care units that is commonly associated with sedation induced with benzodiazepines, which are GABAA agonists.76,77 The fact that purpose-less movements are associated with paradoxical excitation is consistent with a possible basal ganglia mechanism.13 An imaging study in humans suggests a role for the corticobasal
- Clinical & Pathophysiological implications Dosing Awareness; Amnesia Complications – elderly; cognitive disorder; young – neurotoxicity theories Opportunities for new technology – EEG Symmetry and synchrony Lessons for pathological states of nonawareness and consciousness
- The clinical definition of consciousness distinguishes between two components, namely wakefulness and awareness (Laureys, 2005). Patients in coma are unconscious because they cannot be awakened (i.e., the never open the eyes). Following coma, some patients may “awaken” (meaning they open the eyes) but remain unaware. This condition is called the “vegetative state” (Jennett and Plum, 1972) recently renamed “unresponsive wakefulness syndrome” (Laureys et al., 2010). Minimally conscious state refers to patients who are unable to reliably communicate but show reproducible albeit fluctuating behavioral evidence of awareness (i.e., non-reflex movements or command following; Giacino et al., 2002). Locked-in syndrome patients (Plum and Posner, 1972) are fully conscious but are completely paralyzed except for small movements of the eyes or eyelids. Frontiers in Systems Neuroscience Brain connectivity in pathological and pharmacological 20 December 20 Quentin Noirhomme1*†, Andrea Soddu1†, Rémy Lehembre1,2, Audrey Vanhaudenhuyse1, Pierre Boveroux1,3, Mélanie Boly1 and Steven Laureys1 published: 20 December 2010 doi: 10.3389/fnsys.2010.00160
- The clinical definition of consciousness distinguishes between two components, namely wakefulness and awareness (Laureys, 2005). Patients in coma are unconscious because they cannot be awakened (i.e., the never open the eyes). Following coma, some patients may “awaken” (meaning they open the eyes) but remain unaware. This condition is called the “vegetative state” (Jennett and Plum, 1972) recently renamed “unresponsive wakefulness syndrome” (Laureys et al., 2010). Minimally conscious state refers to patients who are unable to reliably communicate but show reproducible albeit fluctuating behavioral evidence of awareness (i.e., non-reflex movements or command following; Giacino et al., 2002). Locked-in syndrome patients (Plum and Posner, 1972) are fully conscious but are completely paralyzed except for small movements of the eyes or eyelids. Frontiers in Systems Neuroscience Brain connectivity in pathological and pharmacological 20 December 20 Quentin Noirhomme1*†, Andrea Soddu1†, Rémy Lehembre1,2, Audrey Vanhaudenhuyse1, Pierre Boveroux1,3, Mélanie Boly1 and Steven Laureys1 published: 20 December 2010 doi: 10.3389/fnsys.2010.00160
- The clinical definition of consciousness distinguishes between two components, namely wakefulness and awareness (Laureys, 2005). Patients in coma are unconscious because they cannot be awakened (i.e., the never open the eyes). Following coma, some patients may “awaken” (meaning they open the eyes) but remain unaware. This condition is called the “vegetative state” (Jennett and Plum, 1972) recently renamed “unresponsive wakefulness syndrome” (Laureys et al., 2010). Minimally conscious state refers to patients who are unable to reliably communicate but show reproducible albeit fluctuating behavioral evidence of awareness (i.e., non-reflex movements or command following; Giacino et al., 2002). Locked-in syndrome patients (Plum and Posner, 1972) are fully conscious but are completely paralyzed except for small movements of the eyes or eyelids. Frontiers in Systems Neuroscience Brain connectivity in pathological and pharmacological 20 December 20 Quentin Noirhomme1*†, Andrea Soddu1†, Rémy Lehembre1,2, Audrey Vanhaudenhuyse1, Pierre Boveroux1,3, Mélanie Boly1 and Steven Laureys1 published: 20 December 2010 doi: 10.3389/fnsys.2010.00160
- The active EEG patterns observed during REM sleep are due in part to strong cholinergic inputs from the lateral dorsal tegmental and pedunculopontine tegmental nuclei to the medial pontine reticular formation and thalamus and from the basal forebrain to the cortex.56 The synthetic opioid fentanyl decreases arousal by reducing acetylcholine in the medial pontine reticular formation, whereas morphine decreases arousal by inhibiting the neurons in the lateral dorsal teg-mental nucleus, medial pontine reticular formation,56 and basal forebrain57 (Fig. 2C). Opioids further contribute to unconsciousness by binding to opioid receptors in the periaqueductal gray,58 rostral ventral medulla,58,59 spinal cord,59 and possibly peripheral tissue60 to reduce nociceptive transmission in the central nervous system. That opioids act primarily in the nociceptive pathways rather than in the cortex to alter arousal and to partially alter cognition helps explain the high incidence of postoperative awareness in patients undergoing cardiac surgery, for which high-dose opioids have, until recently, been the primary anesthetic.61,62 unconsciousness induced by propofol can be reversed by the administration of the cholinomimetic agent physostigmine.63 A combination of imaging,31 molecular,37 and neurophysiological30 studies suggests that propofol acts, in part, by enhancing GABAA-mediated inhibition by interneurons of pyramidal neurons in the cortex and subcortical areas,50 whereas physostigmine counteracts this effect by enhancing cholinergic activity throughout the cortex (Fig. 2A). Physostigmine is a standard treatment for emergence delirium,64,65 a state of confusion seen on emergence from general anesthesia. Finally, burst suppression is believed to be a strong, synchronized outflow of thalamic discharges to a widely unresponsive cortex82 (Fig. 1). It is a deeper state of general anesthesia than is phase 2 of the maintenance period, which resembles the tonic bursting mode of the thalamus seen in slow-wave sleep. Bursts become more widely separated during burst suppression as the level of general anesthesia deepens. This suggests that a larger fraction of the cortex is inactive during burst suppression relative to phase 2 of general anesthesia or slow-wave sleep. Supporting this hypothesis is the observation that burst suppression is also seen in coma due to diffuse anoxic damage,83 induced hypothermia,84 and epilepsy due to the Ohtahara syndrome.85 The absence of burst suppression during sleep is an important electrophysiological distinction between sleep and general anesthesia.
- As shown in Panel C, opioids reduce arousal by inhibiting the release of acetylcholine from neurons projecting from the lateral dorsal and pedunculopontine tegmental nuclei to the medial pontine reticular formation and to the thalamus, by binding to opioid receptors in the periaqueductal gray and rostral ventral medulla, and by binding presynaptically and postsynaptically to spinal cord opioid receptors at the synapses between peripheral afferent neurons in the dorsal-root ganglion and projecting neurons. Panel A shows a GABAergic inhibitory interneuron (orange) synapsing on a pyramidal neuron (gray) receiving excitatory inputs from ascending arousal pathways. The monoaminergic pathways arise from the locus ceruleus, which releases norepinephrine; the raphe, which releases serotonin; the tuberomammillary nucleus, which releases histamine; and the ventral teg-mental area, which releases dopamine. The cholinergic pathways, which release acetylcholine, arise from the basal forebrain, the lateral dorsal tegmental nuclei, and the pedunculopontine tegmental nuclei. Lateral hypothalamic neurons release orexin. Propofol binds post-synaptically and enhances GABAergic inhibition, counteracting arousal inputs to the pyramidal neuron, decreasing its excitatory activity, and contributing to unconsciousness. Dexmedetomidine binds to α2 receptors on neurons from the locus ceruleus, inhibiting norepinephrine release (dashed line) in the ventrolateral preoptic nucleus, as shown in Panel B. The disinhibited ventrolateral preoptic nucleus reduces arousal by means of GABAA-mediated and galanin-mediated inhibition of the midbrain, hypothalamic, and pontine arousal nuclei.
- Figure 4. Unconsciousness and Active Brain States Ketamine binds preferentially to N-methyl-D-aspartate (NMDA) receptors on inhibitory interneurons in the cortex, limbic system (amygdala), and hippocampus, promoting an uncoordinated increase in neural activity, an active electroencephalographic pattern, and unconsciousness, as shown in Panel A. In the spinal cord, ketamine decreases arousal by blocking NMDA glutamate (Glu)–mediated nociceptive signals from peripheral afferent neurons in the dorsal-root ganglion to projecting neurons, as shown in Panel B. In contrast to unconsciousness induced by most hypnotic agents, which is predominantly associated with slow EEG patterns, unconsciousness induced by the NMDA antagonist ketamine is associated with active EEG patterns.86,87 Seizures are commonly associated with active, highly organized EEG patterns. Unconsciousness due to seizures most likely results from organized, aberrant brain activity that impedes the normal communications necessary to maintain arousal and cognition.88 Similarly, a highly active brain state most likely plays a role in unconsciousness induced by ketamine. Ketamine preferentially inhibits NMDA-mediated glutamatergic inputs to GABAergic interneurons, leading to aberrant excitatory activity in the cortex, hippocampus, and limbic system and ultimately unconsciousness (Fig. 4).89,90 Hallucinations may result because the aberrant activation allows the association of information in a manner that is inconsistent in time and space. The hallucinations can be mitigated by the concurrent administration of a benzodiazepine,91 which presumably acts to enhance GABAA-mediated activity of the interneurons and hence leads to sedation. The potent antinociceptive effects of ketamine on NMDA receptors in the spinal cord and its inhibition of acetylcholine release from the pons also contribute to unconsciousness (Fig. 4).92–94
- Figure 4. Unconsciousness and Active Brain States Ketamine binds preferentially to N-methyl-D-aspartate (NMDA) receptors on inhibitory interneurons in the cortex, limbic system (amygdala), and hippocampus, promoting an uncoordinated increase in neural activity, an active electroencephalographic pattern, and unconsciousness, as shown in Panel A. In the spinal cord, ketamine decreases arousal by blocking NMDA glutamate (Glu)–mediated nociceptive signals from peripheral afferent neurons in the dorsal-root ganglion to projecting neurons, as shown in Panel B. In contrast to unconsciousness induced by most hypnotic agents, which is predominantly associated with slow EEG patterns, unconsciousness induced by the NMDA antagonist ketamine is associated with active EEG patterns.86,87 Seizures are commonly associated with active, highly organized EEG patterns. Unconsciousness due to seizures most likely results from organized, aberrant brain activity that impedes the normal communications necessary to maintain arousal and cognition.88 Similarly, a highly active brain state most likely plays a role in unconsciousness induced by ketamine. Ketamine preferentially inhibits NMDA-mediated glutamatergic inputs to GABAergic interneurons, leading to aberrant excitatory activity in the cortex, hippocampus, and limbic system and ultimately unconsciousness (Fig. 4).89,90 Hallucinations may result because the aberrant activation allows the association of information in a manner that is inconsistent in time and space. The hallucinations can be mitigated by the concurrent administration of a benzodiazepine,91 which presumably acts to enhance GABAA-mediated activity of the interneurons and hence leads to sedation. The potent antinociceptive effects of ketamine on NMDA receptors in the spinal cord and its inhibition of acetylcholine release from the pons also contribute to unconsciousness (Fig. 4).92–94
- Panel A shows a GABAergic inhibitory interneuron (orange) synapsing on a pyramidal neuron (gray) receiving excitatory inputs from ascending arousal pathways. The monoaminergic pathways arise from the locus ceruleus, which releases norepinephrine; the raphe, which releases serotonin; the tuberomammillary nucleus, which releases histamine; and the ventral teg-mental area, which releases dopamine. The cholinergic pathways, which release acetylcholine, arise from the basal forebrain, the lateral dorsal tegmental nuclei, and the pedunculopontine tegmental nuclei. Lateral hypothalamic neurons release orexin. Propofol binds post-synaptically and enhances GABAergic inhibition, counteracting arousal inputs to the pyramidal neuron, decreasing its excitatory activity, and contributing to unconsciousness. Dexmedetomidine binds to α2 receptors on neurons from the locus ceruleus, inhibiting norepinephrine release (dashed line) in the ventrolateral preoptic nucleus, as shown in Panel B. The disinhibited ventrolateral preoptic nucleus reduces arousal by means of GABAA-mediated and galanin-mediated inhibition of the midbrain, hypothalamic, and pontine arousal nuclei. As shown in Panel C, opioids reduce arousal by inhibiting the release of acetylcholine from neurons projecting from the lateral dorsal and pedunculopontine tegmental nuclei to the medial pontine reticular formation and to the thalamus, by binding to opioid receptors in the periaqueductal gray and rostral ventral medulla, and by binding presynaptically and postsynaptically to spinal cord opioid receptors at the synapses between peripheral afferent neurons in the dorsal-root ganglion and projecting neurons.
- Clinical & Pathophysiological implications Dosing Awareness; Amnesia Complications – elderly; cognitive disorder; young – neurotoxicity theories Opportunities for new technology – EEG Symmetry and synchrony Lessons for pathological states of nonawareness and consciousness
- Clinical & Pathophysiological implications Dosing Awareness; Amnesia Complications – elderly; cognitive disorder; young – neurotoxicity theories Opportunities for new technology – EEG Symmetry and synchrony Lessons for pathological states of nonawareness and consciousness
- Background Preclinical data suggest that general anaesthetics aff ect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia can have an increased risk of poor neurodevelopmental outcome. We aimed to establish whether general anaesthesia in infancy has any eff ect on neurodevelopmental outcome. Here we report the secondary outcome of neurodevelopmental outcome at 2 years of age in the General Anaesthesia compared to Spinal anaesthesia (GAS) trial. Methods In this international assessor-masked randomised controlled equivalence trial, we recruited infants younger than 60 weeks postmenstrual age, born at greater than 26 weeks’ gestation, and who had inguinal herniorrhaphy, from 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand. Infants were randomly assigned (1:1) to receive either awake-regional anaesthesia or sevofl urane-based general anaesthesia. Web-based randomisation was done in blocks of two or four and stratifi ed by site and gestational age at birth. Infants were excluded if they had existing risk factors for neurological injury. The primary outcome of the trial will be the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale Intelligence Quotient score at age 5 years. The secondary outcome, reported here, is the composite cognitive score of the Bayley Scales of Infant and Toddler Development III, assessed at 2 years. The analysis was as per protocol adjusted for gestational age at birth. A diff erence in means of fi ve points (1/3 SD) was predefi ned as the clinical equivalence margin. This trial is registered with ANZCTR, number ACTRN12606000441516 and ClinicalTrials.gov, number NCT00756600. Findings Between Feb 9, 2007, and Jan 31, 2013, 363 infants were randomly assigned to receive awake-regional anaesthesia and 359 to general anaesthesia. Outcome data were available for 238 children in the awake-regional group and 294 in the general anaesthesia group. In the as-per-protocol analysis, the cognitive composite score (mean [SD]) was 98·6 (14·2) in the awake-regional group and 98·2 (14·7) in the general anaesthesia group. There was equivalence in mean between groups (awake-regional minus general anaesthesia 0·169, 95% CI –2·30 to 2·64). The median duration of anaesthesia in the general anaesthesia group was 54 min. Interpretation For this secondary outcome, we found no evidence that just less than 1 h of sevofl urane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anaesthesia.
- The active EEG patterns observed during REM sleep are due in part to strong cholinergic inputs from the lateral dorsal tegmental and pedunculopontine tegmental nuclei to the medial pontine reticular formation and thalamus and from the basal forebrain to the cortex.56 The synthetic opioid fentanyl decreases arousal by reducing acetylcholine in the medial pontine reticular formation, whereas morphine decreases arousal by inhibiting the neurons in the lateral dorsal teg-mental nucleus, medial pontine reticular formation,56 and basal forebrain57 (Fig. 2C). Opioids further contribute to unconsciousness by binding to opioid receptors in the periaqueductal gray,58 rostral ventral medulla,58,59 spinal cord,59 and possibly peripheral tissue60 to reduce nociceptive transmission in the central nervous system. That opioids act primarily in the nociceptive pathways rather than in the cortex to alter arousal and to partially alter cognition helps explain the high incidence of postoperative awareness in patients undergoing cardiac surgery, for which high-dose opioids have, until recently, been the primary anesthetic.61,62 unconsciousness induced by propofol can be reversed by the administration of the cholinomimetic agent physostigmine.63 A combination of imaging,31 molecular,37 and neurophysiological30 studies suggests that propofol acts, in part, by enhancing GABAA-mediated inhibition by interneurons of pyramidal neurons in the cortex and subcortical areas,50 whereas physostigmine counteracts this effect by enhancing cholinergic activity throughout the cortex (Fig. 2A). Physostigmine is a standard treatment for emergence delirium,64,65 a state of confusion seen on emergence from general anesthesia. Finally, burst suppression is believed to be a strong, synchronized outflow of thalamic discharges to a widely unresponsive cortex82 (Fig. 1). It is a deeper state of general anesthesia than is phase 2 of the maintenance period, which resembles the tonic bursting mode of the thalamus seen in slow-wave sleep. Bursts become more widely separated during burst suppression as the level of general anesthesia deepens. This suggests that a larger fraction of the cortex is inactive during burst suppression relative to phase 2 of general anesthesia or slow-wave sleep. Supporting this hypothesis is the observation that burst suppression is also seen in coma due to diffuse anoxic damage,83 induced hypothermia,84 and epilepsy due to the Ohtahara syndrome.85 The absence of burst suppression during sleep is an important electrophysiological distinction between sleep and general anesthesia. See comment in PubMed Commons belowAnesthesiology. 2000 Sep;93(3):708-17. Physostigmine reverses propofol-induced unconsciousness and attenuation of the auditory steady state response and bispectral index in human volunteers. Meuret P1, Backman SB, Bonhomme V, Plourde G, Fiset P. Author information 1Department of Anaesthesia, Royal Victoria Hospital, Montreal, Quebec, Canada. Abstract BACKGROUND: It is postulated that alteration of central cholinergic transmission plays an important role in the mechanism by which anesthetics produce unconsciousness. The authors investigated the effect of altering central cholinergic transmission, by physostigmine and scopolamine, on unconsciousness produced by propofol. METHODS: Propofol was administered to American Society of Anesthesiologists physical status 1 (n = 17) volunteers with use of a computer-controlled infusion pump at increasing concentrations until unconsciousness resulted (inability to respond to verbal commands, abolition of spontaneous movement). Central nervous system function was assessed by use of the Auditory Steady State Response (ASSR) and Bispectral Index (BIS) analysis of electrooculogram. During continuous administration of propofol, reversal of unconsciousness produced by physostigmine (28 microgram/kg) and block of this reversal by scopolamine (8.6 microgram/kg) were evaluated. RESULTS: Propofol produced unconsciousness at a plasma concentration of 3.2 +/- 0.8 (+/- SD) microgram/ml (n = 17). Unconsciousness was associated with reductions in ASSR (0.10 +/- 0.08 microV [awake baseline 0.32 +/- 0.18 microV], P &lt; 0.001) and BIS (55.7 +/- 8.8 [awake baseline 92.4 +/- 3.9], P &lt; 0.001). Physostigmine restored consciousness in 9 of 11 subjects, with concomitant increases in ASSR (0.38 +/- 0.17 microV, P &lt; 0.01) and BIS (75.3 +/- 8.3, P &lt; 0.001). In all subjects (n = 6) scopolamine blocked the physostigmine-induced reversal of unconsciousness and the increase of the ASSR and BIS (ASSR and BIS during propofol-induced unconsciousness: 0.09 +/- 0.09 microV and 58.2 +/- 7.5, respectively; ASSR and BIS after physostigmine administration: 0.08 +/- 0.06 microV and 56.8 +/- 6.7, respectively, NS). CONCLUSIONS: These findings suggest that the unconsciousness produced by propofol is mediated at least in part via interruption of central cholinergic muscarinic transmission.
- Anaesthetics by blocking the channels of the connectivitiy between diff parts of the cortex, particularly at the level of the thalamic nuclei acting mainy on the inhibitory interneurons,