A unitary quantum hypothesis of anesthetic action
S.
Hameroff (Departments of Anesthesiology and Psychology, The University
of Arizona, Tucson, Arizona 85724, USA.), R. Penrose
General anesthetic gases reversibly ablate consciousness by van der Waals interactions in hydrophobic pockets of a class of neural proteins. The following questions loom: 1) Why are certain proteins susceptible to anesthesia, and others are not? 2) Why does anesthetic occupancy (by weak, physical forces) of pockets (roughly 1/30 of the protein's volume) alter the protein's function (conformational responsiveness)? 3) How does anesthetic mechanism relate to consciousness? Question 1: In Louria and Hameroff (1995) an anesthetic-sensitive enzyme (papain) is identified, and computer simulation/calculation indicate that anesthetics lower van der Waals energies in its hydrophobic pocket (and presumably other anesthetic-sensitive proteins), but not anesthetic-insensitive proteins Question 2: Mobility of delocalizable electrons in hydrophobic pockets may regulate the protein's conformation (e.g. Frohlich, 1968). Reduction of van der Waals energies therein can immobilize electrons and therefore impair protein conformational regulation (e.g. Hameroff and Watt, 1983). Question 3: Theories of consciousness which attempt to deal with subjective experience (Chalmers, 1995), unitary binding (`self') and non-algorithmic thought (`non-computability') appeal to fundamental behavior at the smallest levels: quantum theory. Startlingly, when isolated, atoms and sub-atomic particles can exist in `coherent superposition' of different states (i.e. simultaneously having different or opposite spins, locations, and/or momenta). For reasons described in Marshall (1989), Beck and Eccles (1992), Stapp (1993), Penrose (1994) and Penrose and Hameroff (1995), quantum superposition may be essential for consciousness. Quantum effects demand isolation (and electron delocalizability) which hydrophobic pockets within neural proteins can provide in strategic locations. Roitberg et al (1995) have shown functional vibrations in the protein BPTI which depend on quantum effects centered in two hydrophobic phenylalanine residues. Accordingly, we propose a unitary quantum hypothesis: 1) Consciousness depends on quantum superposition of delocalizable electrons in hydrophobic pockets of certain brain proteins. 2) By lowering van der Waals energy, anesthetics prevent electron mobility and quantum superposition necessary for consciousness in these pockets.One must be precise here. Since the electron's position in the hydrophobic pocket is entangled with the conformation of the dimer as a whole, the superposition must be of the entire electron-dimer complex not just the electron by itself which will locally have an incoherent reduced density matrix. It gets even more complicated because the forces coupling the different dimers mean that we must consider entangled states of N electron-dimer complexes where N is very large in order to get the collective Frohlich mode. The population-inversion corresponding to an effective negative quantum temperature of the pumped Frohlich mode is what makes the surrounding water "ordered" dampening out the decoherence of the classical positive temperature random thermal impacts. Order replaces thermal randomness allowing the back-action quantum friction of orchestrated objective reduction to control the quantum computing process leading to a conscious decision to act. The finite heat capacity of the ordered water boundary layer means that the temperature of the ordered water phase is much lower that bulk body temperature. A far-from equilibrium quasi-steady state is reached in accordance with Prigogine's theory of dissipative structures. This is a consequence of the second law of thermodynamics. Thus, the thermal shielding is the result of "ice" on the scale of a few nanometers from the surface of the microtubules as a testable prediction of my pilot wave theory.
An information processing theory of anaesthesia
H.
A theory of anaesthesia is presented. It consists of four hypotheses: (1) The occurrence of states of consciousness causally depends on the formation of transient higher-order, self-referential mental representations.The key words are "mental representations". What are they exactly? In my theory they are the shapes of the pilot wave in Hilbert space. You have to give a physical substrate for these "representations".
The occurrence of such states is identical with the appearance of conscious phenomena.Yes, this is the case in my quantum pilot wave field of qualia.
Loss of consciousness will occur, if and only if the brain's representational activity falls below a critical threshold. (2) Mental representations are instantiated by neural cell assemblies. (3) The formation of assemblies involves the activation of the NMDA receptor channel complex. The activation state of this receptor determines the rate at which assemblies are generated. (4) General anaesthetics have a common operative mechanism: they directly or indirectly affect the function of the NMDA system.
Computer simulation of anesthetic action
D. Louria (Department
of Anesthesiology, The University of Arizona, Tucson, Arizona 85724,
USA), S. Hameroff
SUMMARY: General anesthetic gases are considered to act in hydrophobic pockets of a class of brain proteins (e.g. Franks and Lieb, 1985). This study attempts to look more closely at anesthetic effects within these pockets. INTRODUCTION: We examine anesthetic effects in proteins whose tertiary structure including hydrophobic regions is known. This excludes membrane and cytoskeletal proteins, leaving, in general, soluble enzymes. We chose 5 such enzymes (hexokinase, G3PD, acetylcholinesterase, chymotrypsin and papain) and performed spectroscopic analysis of their enzymatic activity both in the presence and absence of halothane. We then simulated hydrophobic-anesthetic interactions in anesthetic-sensitive and insensitive enzymes. METHODS: Spectroscopic analysis of the 5 enzymes showed that only papain was clearly inhibited by halothane. Coordinate structural data for the five enzymes were obtained from the Brookhaven National Databank, and 3-dimensional models constructed on a UNIX based Silicon Graphics workstation using the INSIGHT II molecular graphics program. Hydrophobic regions were localized and color-coded using amino acid hydrophobicity profiles. Models of halothane, methoxyflurane and nitrous oxide were `docked1 in the hydrophobic pockets, optimized by energy minimization [' delta-G(delta-G)', e.g. Franks and Lieb, (1992)]. Total pocket energies with and without anesthetics were also calculated, and subdivided into electrostatic and van der Waals contributions. RESULTS: delta-G(delta-G) approached -1 kcal between anesthetics and papain (and to a lesser extent G3PD). All other anesthetic-protein interaction energies approximated zero. Anesthetic-papain energy reduction derived almost exclusively from lowered van der Waals energy. DISCUSSION: Of 5 enzymes studied, only papain's activity was inhibited by halothane, and only papain's hydrophobic pocket-van der Waals energy was markedly reduced by computer calculation. We conclude that reduction of van der Waals energy in hydrophobic pockets of certain brain proteins is required for the mechanism of general anesthesia.
Differentiating states of consciousness using inter-frequency
phase-coherence of cortical EEG
R.C. Watt (Department of Anesthesiology,
University of Arizona, Tucson, Arizona 85724, USA), C.S. Sismore <>,
A. Kanemoto, T.P. Malan, E.J. Frink
The various states of anesthesia provide an intriguing and useful platform from which to study consciousness. The goals of modern anesthesia include hypnosis, analgesia, and amnesia. Thus, anesthetic states can be considered an ablation of the primary components of conscious awareness. By studying gradations of anesthetic depth (levels of unconsciousness) it may be possible to learn more about conscious processes. Bispectral analysis is a sophisticated tool (capable of detecting inter-frequency phase-coherence) which we have applied to characterization of the EEG during anesthesia. In this study artificial neural networks (ANN) have been used with bispectral analysis patterns for classification of dose-dependent changes during sevoflurane anesthesia. With Human Subjects Committee approval, six human volunteer subjects were studied at three anesthetic levels (1.0, 1.5, 2.0 MAC). For each subject at each level, 10 sixteen second sample epochs of EEG were digitized at 256 Hz (4096 points). Conventional power spectral analysis was used to create a 64 point spectral signature for each sample epoch. A bispectral algorithm was developed to produce a 256 point two dimensional array for each EEG sample. ANNs consisting of three layer back propagation networks (64 or 256 input nodes, 6 or 18 hidden nodes, and 3 output nodes) were implemented and categorization results were obtained by training an ANN on all of the spectral signatures except the one under test. ANN trained on the bispectral output matrix were able to correctly identify the anesthetic level of unknown data with an overall accuracy of 89%. ANN trained on conventional spectral signatures were able to correctly identify anesthetic level with an overall accuracy of 83 %. Bispectral analysis has not been widely applied to EEG analysis, is technically difficult to implement, and produces a two dimensional output array which is more difficult to interpret than conventional power spectrum analysis. In this study we have shown that ANNs can be successfully applied to this pattern recognition task. A correlation between inter-frequency phase coherence of cortical EEG and levels of unconsciousness suggests intriguing possibilities about the underlying physiologic mechanisms of cortical EEG changes and consciousness. Phase coherence implies synchronization over large spatial regions which may be mediated by deeper brain structures.This kind of technique, when more fully developed, can be used by police and intelligence units interrogating prisoners. It is obviously relevant to "mind-control" technology.
Facial electromyography: assessing arousal levels and pain
during anesthesia
S.C Freeman <scf@unlgrad1. unl.edu> (University
of Nebraska-Lincoln, Department of Psychology, Lincoln, Nebraska),
N. Gondringer, S. Roesch, R.A. Dienstbier, W. Sime
The focus of this research is on two interrelated issues. The first is to assess intraoperative arousal and pain sensation in an anesthetized patient by implementing new technology. The second important issue of this project is comparing the effectiveness of a relaxation treatment for surgery preparation with the typical routine used in hospitals. By providing training to patients, a more tranquil patient will arrive to surgery, resulting in improved patient comfort during and after surgery. This project focuses on the growing concern of patient awareness during surgery. Recent findings are equivocal in whether information is processed while under general anesthesia (Wang & Russell, 1995; Bennett, 1990). In consideration of the possibility, the patients in this project listen to relaxation instruction tapes throughout the surgical procedure. Besides possible auditory processing during surgery, occasionally the patient may regain consciousness without the knowledge of the anesthesia provider. The patient's awareness of pain and the inability to communicate this awareness (due to muscle relaxants) during the procedure can have severe psychological consequences, such as post traumatic stress disorder and sleep phobia. Recent research has suggested that heart rate and blood pressure are not correlated with a patient's report of awareness during surgery (Russell, 1995). These measures are presently used by anesthesia providers to identify awareness during surgery, but since this problem is one of the top ten reasons for litigation against anesthesia providers, a better indicator is obviously warranted. The technology used in this research (FACE) uses electromyography to detect extremely minute electrical stimulation of those facial muscles used for pain expression, thus providing an additional dimension of intraoperative physiological arousal. Prior research using this technology provided evidence sufficient to warrant further investigation (Freeman, Ekstrum, Roesch, Dienstbier & Sime, in preparation, 1995). If this instrument can provide useful additional information, a major improvement toward preventing awareness during anesthesia will be gained. Concerns of patient satisfaction, competition for low cost/high quality health care, spiraling health care costs and a renewed interest in holistic approaches to medicine have generated interest in improving patient recovery from surgery. A critical factor in recovery from surgery is the deleterious effect of preoperative anxiety resulting from fear of anesthesia, pain and death. Studies by Williams, Jones, and Williams (1969, 1975) showed this high level of anxiety can be self defeating and have dangerous consequences for the patient throughout the surgical procedure and during recovery. Previous studies on preparation for surgery have examined the anxiety reducing effects of behavioral training, modeling, cognitive behavioral preparation, biofeedback, systematic desensitization and hypnotic preparation. Though their impacts are generally positive on recovery, there is not one technique considered highly effective for most patients and easily incorporated in hospital protocol. In sum, by assessing the effectiveness of the FACE instrument for use in anesthesiology, important insight will be gained concerning patient intraoperative awareness. In addition, by providing an effective method of surgery preparation, this method is expected to significantly reduce pharmacological needs while improving patient comfort and outcome.Obviously this is a valuable contribution to the conference.
Molecular mechanisms of general anaesthesia
N. Franks
(Biophysics Section, The Blackett Laboratory, Imperial College of
Science, Technology and Medicine, London SW7 2BZ), W.R. Franks
General anesthetics induce a wide spectrum of different effects in humans, ranging from sedation to oblivion. The molecules that cause these effects are as varied as the effects themselves and include inert gases (such as xenon) and complex agents such as steroids and barbiturates. This very diversity led to the traditional view that anesthetics acted `non-specifically' by disrupting the structures of nerve membranes. We now know that this view is mistaken; general anesthetics are much more specific than previously thought and probably act at a relatively small number of crucial targets. I will review the evidence leading to this conclusion and describe a genetically-related superfamily of ion channels which displays an unusual sensitivity to anesthetics. I will describe the molecular nature of general anesthetic binding sites and discuss how the use of optical isomers of anesthetics can be used to pin-point those targets which are relevant to the state of anaesthesia and those which are not. I will briefly review the evidence that bears on the idea that microtubules are involved in the actions of general anesthetics.This is another good paper. I seem to recall that his author in his talk threw some doubt on Hameroff's hydrophobic pocket model discussed above.
M.T.
Alkire (Departments of Anesthesiology, Pediatrics and Neurology, University
of California, Irvine Medical Center, Orange, California. 92668, USA.
), R.J. Haier, S.J. Barker, N.K. Shah, B.P. Jacobsen
INTRODUCTION: To investigate the neuroanatomy behind the transition from consciousness to unconsciousness during the induction of anesthesia, we used positron emission tomography (PET) to assess brain metabolism during various states of consciousness in volunteers. Additionally, to identify brain regions involved with conscious and unconscious memory we correlated cognitive memory tests to regional cerebral metabolism during different states of consciousness. METHODS: After IRB approval and consent, ten male volunteers each underwent up to three PET scans during three levels of consciousness; one while awake, one during propofol sedation, and one during unconsciousness with propofol anesthesia. The mean (+/-SD) propofol infusion rate was 4.5 +/- 1.0 mg/kg/hr during sedation, and 8.8 + 2.2 mg/kg/hr during anesthesia. Scans were obtained with a NeuroEcat PET scanner using the Fluorodeoxyglucose technique. During each scan subjects listened to an audio-tape that repeatedly played a list of ten words. Conscious and unconscious memory of the words was assessed at 24 hours using free recall and forced choice testing. RESULTS: Awake whole-brain glucose metabolic rate (GMR) averaged 29 +/- 7 umol/100gm/min (n=8). Sedation GMR and anesthetized GMR averaged 21 +/- 3 (n=6), and 14 +/- 3 umol/100gm/min (n=10), respectively. Regional changes during anesthesia were consistent with previous findings. However, relative basal ganglia metabolism was notably increased during sedation. Subtraction images, between sedate and anesthetized conditions, revealed that the transition from consciousness to unconsciousness was accompanied by a fairly uniform reduction of metabolism throughout the brain. However, the reduction was not completely uniform, suggesting the possibility that some brain regions may be more important than others in producing the unconscious state. Following the general anesthesia scans, subjects appeared to demonstrate an unconscious memory effect on the forced choice test. Even though subjects claimed no recognition memory for the words heard during anesthesia, on the forced choice test they still correctly selected nearly 50% of the words presented during anesthesia (Mean +/- SEM = 4.7 +/- 0.3). This performance was statistically better than expected by chance alone (p< 0.01). Correlation images, linking memory performance scores to regional cerebral metabolism during both conscious-baseline and unconscious-anesthetized conditions (p < 0.05), revealed that those subjects with better memory performance had regionally higher metabolism in specific verbal memory areas of the brain. Conscious and unconscious verbal memory showed considerable anatomic overlap with a limited exception related to the mediodorsal nucleus of the thalamus, and a small part of the right caudate. Conscious verbal recall correlated with mediodorsal thalamic activity, whereas, unconscious recognition memory did not. DISCUSSION: These data demonstrate that the transition from consciousness (sedation) to unconsciousness (anesthesia) in humans is accompanied by a generalized reduction of cerebral metabolism during propofol anesthesia. The finding that mediodorsal thalamic activity is correlated during conscious memory but not during unconscious memory strongly implicates this region in conscious memory phenomena. We propose that this brain region may be important in the subjective sensation of consciousness by facilitating the ongoing comparison of the present moment with the past. It may be that the subjective awareness of this ongoing comparison process is a large part of what is experienced by an organism as consciousness.This is another obviously valuable paper which is also relevant to "mind-control" technology. This paper alone would more than justify surreptitious funding of this conference and others like it by intelligence agencies.