Stuart R. Hameroff

Information processing in microtubules.

Abstract Biological information processing, storage, and transduction are theorized to occur by “computer-like” transfer and resonance among subunits of polymerized cytoskeletal proteins: microtubules. Biological information functions (ciliary and flagellar control, axoplasmic transport, conscious awareness) could be explained by comparing microtubule structure and activities to Boolean switching matrices, parallel computers, and such technologies as transistor circuits, magnetic bubble memory, charge transfer devices, surface acoustic wave resonators, and/or holography.

Orchestrated reduction of quantum coherence in brain microtubules: a model for consciousness

Features of consciousness difficult to understand in terms of conventional neuroscience have evoked application of quantum theory, which describes the fundamental behavior of matter and energy. In this paper we propose that aspects of quantum theory (e.g. quantum coherence) and of a newly proposed physical phenomenon of quantum wave function “self-collapse” (objective reduction: OR - Penrose, 1994) are essential for consciousness, and occur in cytoskeletal microtubules and other structures within each of the brains neurons. The particular characteristics of microtubules suitable for quantum effects include their crystal-like lattice structure, hollow inner core, organization of cell function and capacity for information processing. We envisage that conformational states of microtubule subunits (tubulins) are coupled to internal quantum events, and cooperatively interact (compute) with other tubulins. We further assume that macroscopic coherent superposition of quantum-coupled tubulin conformational states occurs throughout significant brain volumes and provides the global binding essential to consciousness. We equate the emergence of the microtubule quantum coherence with pre-conscious processing which grows (for up to 500 ms) until the mass-energy difference among the separated states of tubulins reaches a threshold related to quantum gravity. According to the arguments for OR put forth in Penrose (1994), superpositioned states each have their own space-time geometries. When the degree of coherent mass-energy difference leads to sufficient separation of space-time geometry, the system must choose and decay (reduce, collapse) to a single universe state. In this way, a transient superposition of slightly differing space-time geometries persists until an abrupt quantum → classical reduction occurs. Unlike the random, “subjective reduction” (SR, or R) of standard quantum theory caused by observation or environmental entanglement, the OR we propose in microtubules is a self-collapse and it results in particular patterns of microtubule-tubulin conformational states that regulate neuronal activities including synaptic functions. Possibilities and probabilities for post-reduction tubulin states are influenced by factors including attachments of microtubule-associated proteins (MAPs) acting as “nodes” which tune and “orchestrate” the quantum oscillations. We thus term the self-tuning OR process in microtubules “orchestrated objective reduction” (“Orch OR”), and calculate an estimate for the number of tubulins (and neurons) whose coherence for relevant time periods (e.g. 500 ms) will elicit Orch OR. In providing a connection among (1) pre-conscious to conscious transition, (2) fundamental space-time notions, (3) non-computability, and (4) binding of various (time scale and spatial) reductions into an instantaneous event (“conscious now”), we believe Orch OR in brain microtubules is the most specific and plausible model for consciousness yet proposed.

The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

Alzheimers disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-β protein (Aβ), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive Aβ accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Aβ and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Aβ-amyloid deposits (Aβ oligomers and plaques) not only drives Aβ aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal Aβ deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal Aβ amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on β-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized microtubules, their binding to MAP-tau, and molecular dynamics involved in cognition. Further, our theory supports novel AD therapeutic strategies targeting intra-neuronal zinc homeostasis and microtubule dynamics to prevent neurodegeneration and cognitive decline.

Computational connectionism within neurons: a model of cytoskeletal automata subserving neural networks

Abstract “Neural network” models of brain function assume neurons and their synaptic connections to be the fundamental units of information processing, somewhat like switches within computers. However, neurons and synapses are extremely complex and resemble entire computers rather than switches. The interiors of the neurons (and other eucaryotic cells) are now known to contain highly ordered parallel networks of filamentous protein polymers collectively termed the cytoskeleton. Originally assumed to provide merely structural “bone-like” support, cytoskeletal structures such as microtubules are now recognized to organize cell interiors dynamically. The cytoskeleton is the internal communication network for the eucaryotic cell, both by means of simple transport and by means of coordinating extremely complicated events like cell division, growth and differentiation. The cytoskeleton may therefore be viewed as the cells “nervous system”. Consequently the neuronal cytoskeleton may be involved in molecular level information processing which subserves higher, collective neuronal functions ultimately relating to cognition. Numerous models of information processing within the cytoskeleton (in particular, microtubules) have been proposed. We have utilized cellular automata as a means to model and demonstrate the potential for information processing in cytoskeletal microtubules. In this paper, we extend previous work and simulate associative learning in a cytoskeletal network as well as assembly and disassembly of microtubules. We also discuss possible relevance and implications of cytoskeletal information processing to cognition.

Transdermal Fentanyl: Pharmacokinetics and Preliminary Clinical Evaluation

A new transdermal drug‐delivery system that administers the synthetic opioid fentanyl through intact skin was evaluated for 24 hours postoperatively in eight patients who had undergone orthopedic surgery. Plasma samples were obtained over a 72‐hour period for pharmacokinetic analysis in five patients. The patients were also evaluated intensively for adequacy of analgesia, frequency of nausea and sedation, and occurrence of ventilatory depression. A median lag time of 2.25 hours after application of the transdermal system was observed before the appearance of fentanyl in the blood. Median peak concentration and time to peak were 1.0 ng/ml and 22 hours, respectively. The apparent elimination of fentanyl after transdermal administration is prolonged relative to previously reported values. Absorption analysis indicates zero‐order fentanyl administration, and in addition, suggests deposition of drug in an epidermal site, with the resultant prolonged absorption process giving the appearance of slow elimination. No significant toxicities were observed. Four patients required no additional analgesia. No consistent correlations among fentanyl concentration and any clinical values were observed. Transdermal administration of fentanyl appears to be a viable alternative to conventional routes of narcotic administration and warrants further study.

Cytoskeletal Signaling: Is Memory Encoded in Microtubule Lattices by CaMKII Phosphorylation?

Memory is attributed to strengthened synaptic connections among particular brain neurons, yet synaptic membrane components are transient, whereas memories can endure. This suggests synaptic information is encoded and ‘hard-wired’ elsewhere, e.g. at molecular levels within the post-synaptic neuron. In long-term potentiation (LTP), a cellular and molecular model for memory, post-synaptic calcium ion (Ca2+) flux activates the hexagonal Ca2+-calmodulin dependent kinase II (CaMKII), a dodacameric holoenzyme containing 2 hexagonal sets of 6 kinase domains. Each kinase domain can either phosphorylate substrate proteins, or not (i.e. encoding one bit). Thus each set of extended CaMKII kinases can potentially encode synaptic Ca2+ information via phosphorylation as ordered arrays of binary ‘bits’. Candidate sites for CaMKII phosphorylation-encoded molecular memory include microtubules (MTs), cylindrical organelles whose surfaces represent a regular lattice with a pattern of hexagonal polymers of the protein tubulin. Using molecular mechanics modeling and electrostatic profiling, we find that spatial dimensions and geometry of the extended CaMKII kinase domains precisely match those of MT hexagonal lattices. This suggests sets of six CaMKII kinase domains phosphorylate hexagonal MT lattice neighborhoods collectively, e.g. conveying synaptic information as ordered arrays of six “bits”, and thus “bytes”, with 64 to 5,281 possible bit states per CaMKII-MT byte. Signaling and encoding in MTs and other cytoskeletal structures offer rapid, robust solid-state information processing which may reflect a general code for MT-based memory and information processing within neurons and other eukaryotic cells.

The "conscious pilot"-dendritic synchrony moves through the brain to mediate consciousness

Cognitive brain functions including sensory processing and control of behavior are understood as “neurocomputation” in axonal–dendritic synaptic networks of “integrate-and-fire” neurons. Cognitive neurocomputation with consciousness is accompanied by 30- to 90-Hz gamma synchrony electroencephalography (EEG), and non-conscious neurocomputation is not. Gamma synchrony EEG derives largely from neuronal groups linked by dendritic–dendritic gap junctions, forming transient syncytia (“dendritic webs”) in input/integration layers oriented sideways to axonal–dendritic neurocomputational flow. As gap junctions open and close, a gamma-synchronized dendritic web can rapidly change topology and move through the brain as a spatiotemporal envelope performing collective integration and volitional choices correlating with consciousness. The “conscious pilot” is a metaphorical description for a mobile gamma-synchronized dendritic web as vehicle for a conscious agent/pilot which experiences and assumes control of otherwise non-conscious auto-pilot neurocomputation.

The entwined mysteries of anesthesia and consciousness : Is there a common underlying mechanism?

THE mechanism by which general anesthetics prevent consciousness remains unknown largely because the mechanism by which brain physiology produces consciousness is unexplained. But the two mysteries seem to share a critical feature—both consciousness and actions of anesthetic gases are mediated through extremely weak London forces (a type of van der Waals force) acting in hydrophobic pockets within dendritic proteins arrayed in synchronized brain systems. Unraveling this common thread may reveal not only how anesthetics act, but also why we are conscious in the first place. What is anesthesia? Anesthesia provides immobility, amnesia, and loss of conscious awareness, although the latter—loss of consciousness—is often omitted from operational definitions. In recent years, putative sites of anesthetic action for immobility (spinal cord), amnesia (dorsolateral prefrontal cortex, amygdala), and loss of consciousness (networks involving thalamocortical and intracortical—corticocortical—loops, prefrontal cortex, and other areas) have been discriminated both anatomically and in terms of sensitivity to anesthetics. Immobility is least sensitive to anesthetics, followed by loss of consciousness and then amnesia, which is most anesthetic sensitive. (Implicit memory may occur without consciousness or movement, but at light levels of anesthetic.) Therefore, lack of movement—even though mediated by spinal cord rather than brain—in the absence of muscle relaxants is a good indicator of both loss of consciousness and amnesia. Autonomic responses are even less anesthetic sensitive than immobility and, in the absence of autonomic-blocking drugs, are thus useful (although not perfectly reliable) early warning indicators of changes in anesthetic depth. What is consciousness? Unlike other receptor-mediated pharmacologic targets, consciousness is ill-defined, cannot be measured, and generates heated debate about its very nature. Indeed, except for the “dark age” of behaviorism in psychology during most of the 20th century (in which consciousness was, almost literally, a dirty word), conscious awareness has been a prominent mystery in science and philosophy. However, many articles promising to discuss consciousness avoid the issue, e.g., using bait-and-switch techniques to describe memory, learning, sleep, or other related activities. Others deconstruct consciousness into a group of cognitive functions so that the essential feature—conscious awareness—gets lost in the shuffle. In this article, consciousness will be considered equivalent to even minimal awareness, the ineffable phenomenon of pure subjective experience—our “inner life.” Thus, conscious awareness can exist irrespective of memory, cognition, or organizational sophistication (e.g., reflective self-consciousness, higher-order thought, human—as opposed to animal—consciousness). These more complex levels, although difficult to explain, are relatively straightforward compared with the issue of why or how even a slight glimmer of any form of conscious experience occurs at all. Anesthesia offers a unique and profound opportunity to understand consciousness because it is relatively selective—many brain activities (e.g., evoked potentials, slower electroencephalography, and autonomic drives) continue during anesthesia while conscious awareness disappears. Thus, details of anesthetic mechanism may illuminate how the brain specifically produces consciousness and vice versa. This article reviews what is known about mechanisms of consciousness and anesthesia, finding that the “fine grain” of neuronal activities supporting consciousness and the molecular actions of anesthetic gases are one and the same—van der Waals London forces acting in hydrophobic pockets of coherently synchronized dendritic brain proteins. London forces are not chemical bonds but weak quantum interactions (in this regard, anesthetic gases differ in their actions from all other pharmacologic agents). Thus, the relative selectivity of anesthetic gases implies that the quantum nature of London forces may play an essential role in brain function leading to consciousness. Because consciousness is not directly measurable or observable, we begin with brain functional organization, systems, and activities known to correlate with consciousness. * Professor Emeritus, Departments of Anesthesiology and Psychology, and Director, Center for Consciousness Studies, The University of Arizona.

Phase space electroencephalography (EEG): A new mode of intraoperative EEG analysis

Intraoperative monitoring of electroencephalography (EEG) data can help assess brain integrity and/or depth of anesthesia. We demonstrate a computer generated technique which provides a visually robust display of EEG data plotted as ‘phase space trajectories’ and a mathematically derived parameter (‘dimensionality’) which may correlate with depth of anesthesia. Application of nonlinear mathematical analysis, used to describe complex dynamical systems, can characterize ‘phase space’ EEG patterns by identifying attractors (geometrical patterns in phase space corresponding to specific ordered EEG data subjects) and by quantifying the degree of order and chaos (calculation of dimensionality). Dimensionality calculations describe the degree of complexity in a signal and may generate a clinically useful univariate EEG descriptor of anesthetic depth.In this paper we describe and demonstrate phase space trajectories generated for sine waves, mixtures of sine waves, and white noise (random chaotic events). We also present EEG phase space trajectories and dimensionality calculations from a patient undergoing surgery and general anesthesia in 3 recognizable states: awake, anesthetized, and burst suppression. Phase space trajectories of the three states are visually distinguishable, and dimensionality calculations indicate that EEG progresses from ‘chaos’ (awake) to progressively more ‘ordered’ attractors (anesthetized and burst suppression).

Local anesthetics and wound healing

Abstract The effects of local anesthetics, lidocaine and bupivacaine, were tested in tissue cultures of 3T3 and W1-38 fibroblasts, in slices of newborn rat skin and in vivo in granuloma tissue induced by subcutaneous implantation of stainless steel cylinder in rats. The effects on the synthesis or amounts of DNA, collagen, glycosaminoglycans (GAG), noncollagenous proteins, and the activity of prolyl hydroxylase were studied. We found that irrespective of the biological system used, both anesthetics inhibit the synthesis of collagen to a greater extent than noncollagenous proteins. The synthesis of GAG was inhibited as well. We observed no effect on the synthesis or amount of DNA. We conclude that local anesthetics inhibit wound healing by inhibiting the synthesis of major structural macromolecules, collagen and GAG.