Electronic Energy Migration in Microtubules.

The repeating arrangement of tubulin dimers confers great mechanical strength to microtubules, which are used as scaffolds for intracellular macromolecular transport in cells and exploited in biohybrid devices. The crystalline order in a microtubule, with lattice constants short enough to allow energy transfer between amino acid chromophores, is similar to synthetic structures designed for light harvesting. After photoexcitation, can these amino acid chromophores transfer excitation energy along the microtubule like a natural or artificial light-harvesting system? Here, we use tryptophan autofluorescence lifetimes to probe energy hopping between aromatic residues in tubulin and microtubules. By studying how the quencher concentration alters tryptophan autofluorescence lifetimes, we demonstrate that electronic energy can diffuse over 6.6 nm in microtubules. We discover that while diffusion lengths are influenced by tubulin polymerization state (free tubulin versus tubulin in the microtubule lattice), they are not significantly altered by the average number of protofilaments (13 versus 14). We also demonstrate that the presence of the anesthetics etomidate and isoflurane reduce exciton diffusion. Energy transport as explained by conventional Förster theory (accommodating for interactions between tryptophan and tyrosine residues) does not sufficiently explain our observations. Our studies indicate that microtubules are, unexpectedly, effective light harvesters.

Consciousness, Cognition and the Neuronal Cytoskeleton - A New Paradigm Needed in Neuroscience.

Viewing the brain as a complex computer of simple neurons cannot account for consciousness nor essential features of cognition. Single cell organisms with no synapses perform purposeful intelligent functions using their cytoskeletal microtubules. A new paradigm is needed to view the brain as a scale-invariant hierarchy extending both upward from the level of neurons to larger and larger neuronal networks, but also downward, inward, to deeper, faster quantum and classical processes in cytoskeletal microtubules inside neurons. Evidence shows self-similar patterns of conductive resonances repeating in terahertz, gigahertz, megahertz, kilohertz and hertz frequency ranges in microtubules. These conductive resonances apparently originate in terahertz quantum dipole oscillations and optical interactions among pi electron resonance clouds of aromatic amino acid rings of tryptophan, phenylalanine and tyrosine within each tubulin, the component subunit of microtubules, and the brain's most abundant protein. Evidence from cultured neuronal networks also now shows that gigahertz and megahertz oscillations in dendritic-somatic microtubules regulate specific firings of distal axonal branches, causally modulating membrane and synaptic activities. The brain should be viewed as a scale-invariant hierarchy, with quantum and classical processes critical to consciousness and cognition originating in microtubules inside neurons.

How COVID-19 Hijacks the Cytoskeleton: Therapeutic Implications.

The SARS-CoV-2 virus invades and replicates within host cells by "hijacking" biomolecular machinery, gaining control of the microtubule cytoskeleton. After attaching to membrane receptors and entering cells, the SARS-CoV-2 virus co-opts the dynamic intra-cellular cytoskeletal network of microtubules, actin, and the microtubule-organizing center, enabling three factors that lead to clinical pathology: (1) viral load due to intra-cellular trafficking, (2) cell-to-cell spread by filopodia, and (3) immune dysfunction, ranging from hyper-inflammatory cytokine storm to ineffective or absent response. These factors all depend directly on microtubules and the microtubule-organizing center, as do cell functions such as mitosis and immune cell movement. Here we consider how the SARS-CoV-2 virus may "hijack" cytoskeletal functions by docking inside the microtubule-organizing center's centriole "barrels", enabling certain interactions between the virus's positively charged spike ("S") proteins and negatively charged C-termini of the microtubules that the centriole comprises, somewhat like fingers on a keyboard. This points to the potential benefit of therapies aimed not directly at the virus but at the microtubules and microtubule-organizing center of the host cell on which the virus depends. These therapies could range from anti-microtubule drugs to low-intensity ultrasound (megahertz mechanical vibrations) externally applied to the vagus nerve at the neck and/or to the spleen (since both are involved in mediating inflammatory response). Given that ultrasound imaging machines suitable for vagal/splenic ultrasound are available for clinical trials in every hospital, we recommend an alternative therapeutic approach for COVID-19 based on addressing and normalizing the host cell microtubules and microtubule-organizing centers co-opted by the SARS-CoV-2 virus.

'Orch OR' is the most complete, and most easily falsifiable theory of consciousness.

The 'Orch OR' theory attributes consciousness to quantum computations in microtubules inside brain neurons. Quantum computers process information as superpositions of multiple possibilities (quantum bits or qubits) which, in Orch OR, are alternative collective dipole oscillations orchestrated ('Orch') by microtubules. These orchestrated oscillations entangle, compute, and terminate ('collapse of the wavefunction') by Penrose objective reduction ('OR'), resulting in sequences of Orch OR moments with orchestrated conscious experience (metaphorically more like music than computation). Each Orch OR event selects microtubule states which govern neuronal functions. Orch OR has broad explanatory power, and is easily falsifiable.

Transcranial Focused Ultrasound to the Right Prefrontal Cortex Improves Mood and Alters Functional Connectivity in Humans.

Transcranial focused ultrasound (tFUS) is an emerging method for non-invasive neuromodulation akin to transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). tFUS offers several advantages over electromagnetic methods including high spatial resolution and the ability to reach deep brain targets. Here we describe two experiments assessing whether tFUS could modulate mood in healthy human volunteers by targeting the right inferior frontal gyrus (rIFG), an area implicated in mood and emotional regulation. In a randomized, placebo-controlled, double-blind study, participants received 30 s of 500 kHz tFUS or a placebo control. Visual Analog Mood Scales (VAMS) assessed mood four times within an hour (baseline and three times after tFUS). Participants who received tFUS reported an overall increase in Global Affect (GA), an aggregate score from the VAMS scale, indicating a positive shift in mood. Experiment 2 examined resting-state functional (FC) connectivity using functional magnetic resonance imaging (fMRI) following 2 min of 500 kHz tFUS at the rIFG. As in Experiment 1, tFUS enhanced self-reported mood states and also decreased FC in resting state networks related to emotion and mood regulation. These results suggest that tFUS can be used to modulate mood and emotional regulation networks in the prefrontal cortex.

Anesthetic Alterations of Collective Terahertz Oscillations in Tubulin Correlate with Clinical Potency: Implications for Anesthetic Action and Post-Operative Cognitive Dysfunction.

Anesthesia blocks consciousness and memory while sparing non-conscious brain activities. While the exact mechanisms of anesthetic action are unknown, the Meyer-Overton correlation provides a link between anesthetic potency and solubility in a lipid-like, non-polar medium. Anesthetic action is also related to an anesthetic's hydrophobicity, permanent dipole, and polarizability, and is accepted to occur in lipid-like, non-polar regions within brain proteins. Generally the protein target for anesthetics is assumed to be neuronal membrane receptors and ion channels, however new evidence points to critical effects on intra-neuronal microtubules, a target of interest due to their potential role in post-operative cognitive dysfunction (POCD). Here we use binding site predictions on tubulin, the protein subunit of microtubules, with molecular docking simulations, quantum chemistry calculations, and theoretical modeling of collective dipole interactions in tubulin to investigate the effect of a group of gases including anesthetics, non-anesthetics, and anesthetic/convulsants on tubulin dynamics. We found that these gases alter collective terahertz dipole oscillations in a manner that is correlated with their anesthetic potency. Understanding anesthetic action may help reveal brain mechanisms underlying consciousness, and minimize POCD in the choice and development of anesthetics used during surgeries for patients suffering from neurodegenerative conditions with compromised cytoskeletal microtubules.

Anesthetics act in quantum channels in brain microtubules to prevent consciousness.

The mechanism by which anesthetic gases selectively prevent consciousness and memory (sparing non-conscious brain functions) remains unknown. At the turn of the 20(th) century Meyer and Overton showed that potency of structurally dissimilar anesthetic gas molecules correlated precisely over many orders of magnitude with one factor, solubility in a non-polar, 'hydrophobic' medium akin to olive oil. In the 1980s Franks and Lieb showed anesthetics acted in such a medium within proteins, suggesting post-synaptic membrane receptors. But anesthetic studies on such proteins yielded only confusing results. In recent years Eckenhoff and colleagues have found anesthetic action in microtubules, cytoskeletal polymers of the protein tubulin inside brain neurons. 'Quantum mobility' in microtubules has been proposed to mediate consciousness. Through molecular modeling we have previously shown: (1) olive oil-like non-polar, hydrophobic quantum mobility pathways ('quantum channels') of tryptophan rings in tubulin, (2) binding of anesthetic gas molecules in these channels, and (3) capabilities for π-electron resonant energy transfer, or exciton hopping, among tryptophan aromatic rings in quantum channels, similar to photosynthesis protein quantum coherence. Here, we show anesthetic molecules can impair π-resonance energy transfer and exciton hopping in tubulin quantum channels, and thus account for selective action of anesthetics on consciousness and memory.

The feasibility of coherent energy transfer in microtubules.

It was once purported that biological systems were far too 'warm and wet' to support quantum phenomena mainly owing to thermal effects disrupting quantum coherence. However, recent experimental results and theoretical analyses have shown that thermal energy may assist, rather than disrupt, quantum coherent transport, especially in the 'dry' hydrophobic interiors of biomolecules. Specifically, evidence has been accumulating for the necessary involvement of quantum coherent energy transfer between uniquely arranged chromophores in light harvesting photosynthetic complexes. The 'tubulin' subunit proteins, which comprise microtubules, also possess a distinct architecture of chromophores, namely aromatic amino acids, including tryptophan. The geometry and dipolar properties of these aromatics are similar to those found in photosynthetic units indicating that tubulin may support coherent energy transfer. Tubulin aggregated into microtubule geometric lattices may support such energy transfer, which could be important for biological signalling and communication essential to living processes. Here, we perform a computational investigation of energy transfer between chromophoric amino acids in tubulin via dipole excitations coupled to the surrounding thermal environment. We present the spatial structure and energetic properties of the tryptophan residues in the microtubule constituent protein tubulin. Plausibility arguments for the conditions favouring a quantum mechanism of signal propagation along a microtubule are provided. Overall, we find that coherent energy transfer in tubulin and microtubules is biologically feasible.

Quantum effects in the understanding of consciousness.

This paper presents a historical perspective on the development and application of quantum physics methodology beyond physics, especially in biology and in the area of consciousness studies. Quantum physics provides a conceptual framework for the structural aspects of biological systems and processes via quantum chemistry. In recent years individual biological phenomena such as photosynthesis and bird navigation have been experimentally and theoretically analyzed using quantum methods building conceptual foundations for quantum biology. Since consciousness is attributed to human (and possibly animal) mind, quantum underpinnings of cognitive processes are a logical extension. Several proposals, especially the Orch OR hypothesis, have been put forth in an effort to introduce a scientific basis to the theory of consciousness. At the center of these approaches are microtubules as the substrate on which conscious processes in terms of quantum coherence and entanglement can be built. Additionally, Quantum Metabolism, quantum processes in ion channels and quantum effects in sensory stimulation are discussed in this connection. We discuss the challenges and merits related to quantum consciousness approaches as well as their potential extensions.

Quantum walks in brain microtubules--a biomolecular basis for quantum cognition?

Cognitive decisions are best described by quantum mathematics. Do quantum information devices operate in the brain? What would they look like? Fuss and Navarro () describe quantum lattice registers in which quantum superpositioned pathways interact (compute/integrate) as 'quantum walks' akin to Feynman's path integral in a lattice (e.g. the 'Feynman quantum chessboard'). Simultaneous alternate pathways eventually reduce (collapse), selecting one particular pathway in a cognitive decision, or choice. This paper describes how quantum walks in a Feynman chessboard are conceptually identical to 'topological qubits' in brain neuronal microtubules, as described in the Penrose-Hameroff 'Orch OR' theory of consciousness.

Consciousness in the universe: a review of the 'Orch OR' theory.

The nature of consciousness, the mechanism by which it occurs in the brain, and its ultimate place in the universe are unknown. We proposed in the mid 1990's that consciousness depends on biologically 'orchestrated' coherent quantum processes in collections of microtubules within brain neurons, that these quantum processes correlate with, and regulate, neuronal synaptic and membrane activity, and that the continuous Schrödinger evolution of each such process terminates in accordance with the specific Diósi-Penrose (DP) scheme of 'objective reduction' ('OR') of the quantum state. This orchestrated OR activity ('Orch OR') is taken to result in moments of conscious awareness and/or choice. The DP form of OR is related to the fundamentals of quantum mechanics and space-time geometry, so Orch OR suggests that there is a connection between the brain's biomolecular processes and the basic structure of the universe. Here we review Orch OR in light of criticisms and developments in quantum biology, neuroscience, physics and cosmology. We also introduce a novel suggestion of 'beat frequencies' of faster microtubule vibrations as a possible source of the observed electro-encephalographic ('EEG') correlates of consciousness. We conclude that consciousness plays an intrinsic role in the universe.

Quantum mathematical cognition requires quantum brain biology: the "Orch OR" theory.

The "Orch OR" theory suggests that quantum computations in brain neuronal dendritic-somatic microtubules regulate axonal firings to control conscious behavior. Within microtubule subunit proteins, collective dipoles in arrays of contiguous amino acid electron clouds enable "quantum channels" suitable for topological dipole "qubits" able to physically represent cognitive values, for example, those portrayed by Pothos & Busemeyer (P&B) as projections in abstract Hilbert space.

Transcranial ultrasound (TUS) effects on mental states: a pilot study.

BACKGROUND/OBJECTIVE: Transcranial ultrasound (TUS) can modulate brain function. To assess possible TUS modulation of mental states, we investigated effects on subjective reports of pain and mood of sub-thermal TUS versus placebo applied to frontal scalp and brain of chronic pain patient volunteers. METHODS: With IRB approval and informed consent, subjects with chronic pain completed two visual analog scales for pain (NRS) and mood (VAMS/Global Affect), and their vital signs were recorded 10 min prior to, and 10 min and 40 min following exposure to either subthermal TUS (8 MHz) or placebo (in a double blind crossover study) using the 12L-RS probe of a LOGIQe ultrasound imaging machine (General Electric, USA). A physician, also blinded for TUS versus placebo, applied the probe (with gel) to scalp over posterior frontal cortex, contralateral to maximal pain, for 15 seconds. A second investigator operated the ultrasound machine, randomizing TUS versus placebo. The process was then repeated, applying the opposite modality (TUS or placebo). RESULTS: Subjective reports of Mood/Global Affect were improved 10 min (P = 0.03) and 40 min (P = 0.04) following TUS compared with placebo. NRS pain reports slightly improved following TUS (P = 0.07) at 40 min. CONCLUSION: We found improvement in subjective mood 10 min and 40 min after TUS compared to placebo. TUS can have safe neurophysiological effects on brain function, and is a promising noninvasive therapy for modulating conscious and unconscious mental states and disorders. We suggest TUS acts via intra-neuronal microtubules, which apparently resonate in TUS megahertz range.

How quantum brain biology can rescue conscious free will.

Conscious "free will" is problematic because (1) brain mechanisms causing consciousness are unknown, (2) measurable brain activity correlating with conscious perception apparently occurs too late for real-time conscious response, consciousness thus being considered "epiphenomenal illusion," and (3) determinism, i.e., our actions and the world around us seem algorithmic and inevitable. The Penrose-Hameroff theory of "orchestrated objective reduction (Orch OR)" identifies discrete conscious moments with quantum computations in microtubules inside brain neurons, e.g., 40/s in concert with gamma synchrony EEG. Microtubules organize neuronal interiors and regulate synapses. In Orch OR, microtubule quantum computations occur in integration phases in dendrites and cell bodies of integrate-and-fire brain neurons connected and synchronized by gap junctions, allowing entanglement of microtubules among many neurons. Quantum computations in entangled microtubules terminate by Penrose "objective reduction (OR)," a proposal for quantum state reduction and conscious moments linked to fundamental spacetime geometry. Each OR reduction selects microtubule states which can trigger axonal firings, and control behavior. The quantum computations are "orchestrated" by synaptic inputs and memory (thus "Orch OR"). If correct, Orch OR can account for conscious causal agency, resolving problem 1. Regarding problem 2, Orch OR can cause temporal non-locality, sending quantum information backward in classical time, enabling conscious control of behavior. Three lines of evidence for brain backward time effects are presented. Regarding problem 3, Penrose OR (and Orch OR) invokes non-computable influences from information embedded in spacetime geometry, potentially avoiding algorithmic determinism. In summary, Orch OR can account for real-time conscious causal agency, avoiding the need for consciousness to be seen as epiphenomenal illusion. Orch OR can rescue conscious free will.

Computational predictions of volatile anesthetic interactions with the microtubule cytoskeleton: implications for side effects of general anesthesia.

The cytoskeleton is essential to cell morphology, cargo trafficking, and cell division. As the neuronal cytoskeleton is extremely complex, it is no wonder that a startling number of neurodegenerative disorders (including but not limited to Alzheimer's disease, Parkinson's disease and Huntington's disease) share the common feature of a dysfunctional neuronal cytoskeleton. Recently, concern has been raised about a possible link between anesthesia, post-operative cognitive dysfunction, and the exacerbation of neurodegenerative disorders. Experimental investigations suggest that anesthetics bind to and affect cytoskeletal microtubules, and that anesthesia-related cognitive dysfunction involves microtubule instability, hyper-phosphorylation of the microtubule-associated protein tau, and tau separation from microtubules. However, exact mechanisms are yet to be identified. In this paper the interaction of anesthetics with the microtubule subunit protein tubulin is investigated using computer-modeling methods. Homology modeling, molecular dynamics simulations and surface geometry techniques were used to determine putative binding sites for volatile anesthetics on tubulin. This was followed by free energy based docking calculations for halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) on the tubulin body, and C-terminal regions for specific tubulin isotypes. Locations of the putative binding sites, halothane binding energies and the relation to cytoskeleton function are reported in this paper.

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 (Ca²âº) flux activates the hexagonal Ca²âº-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 Ca²âº 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.