Old theory, new evidence: inhalational anesthetics disrupt a collective quantum state of intraneuronal microtubules to cause unconsciousness

Contemporary researchers tend to assume that inhalational anesthetics cause unconsciousness by targeting a varying combination of ion channels and receptors, synaptic proteins, mitochondria, and cytoskeletal proteins including microtubules (MTs). However, this viewpoint does not account for striking empirical facts suggesting that unconsciousness is mediated by a single primary molecular target instead (Figure 1A and B). First, the effective dose (Figure 1A, vertical axis) of chemically diverse anesthetics is predicted by their solubility in olive oil (horizontal axis). The (log-)linear relation in Figure 1A is known as the Meyer-Overton rule or correlation. Drug binding to biological receptors typically depends on highly specific "lock and key" matching between the drug's chemical (electronic) configuration and the structure of the receptor. The anesthetic compounds shown in Figure 1A are chemically diverse, even including elements, which suggests a weak, non-specific physical interaction at an evolutionarily conserved lipophilic target, rather than chemically specific lock-and-key binding. A second fact is the approximate additivity of effective doses (of "MACs"; Figure 1B). That is, one-half the effective dose of one anesthetic plus one half the effective dose of another anesthetic equals one effective dose, even when the two anesthetics have very different effects on a particular ion channel, arguing against ion channels as the primary functional target of inhalational anesthetics. A comprehensive analysis culminating in 2008 ruled out multiple ion channel types as the potential primary target of these medically miraculous molecules1; but cytoskeletal MTs were not ruled out.Figure 1: MTs may be the primary functional target of volatile anesthetics.(A, B) Anesthetic properties suggesting a common molecular target. (C) Rats given an MT-binding drug were resistant to isoflurane anesthesia, suggesting the molecular target may be MTs. epoB: Epothilone B; MAC: minimum alveolar concentration; MT: microtubule; LORR: loss of righting reflex. Figure 1B was reprinted with permission from Eger et al.1Figure 1C was reprinted with permission from Khan et al.2My lab recently reported that rats given a brain-penetrant MT-binding drug (0.75 mg/kg epothilone B epoB) were resistant to isoflurane anesthesia,2 suggesting that the molecular target may be MTs (Figure 1C). The standard proxy for time to fall unconscious in rodents is the latency to loss of righting reflex, meaning that a rat placed on its back does not right itself. The average loss of righting reflex latency was 69 seconds higher in the post-epoB condition as compared with the pre-epoB average, and this difference was statistically significant (n = 8 rats; P = 0.0016; Cohen's d = 1.9, a "large" effect), suggesting the epoB interfered with isoflurane's binding to MTs. We also have direct evidence that targeting MTs can be sufficient for general anesthesia, in tadpoles.3 Consistent with this result, humans given MT-binding drugs against cancer (which generally penetrate poorly into the brain) showed slight resistance to anesthesia during surgery.4 In addition, a detailed quantum chemical modeling study found that the potencies of several volatile anesthetics were predicted by their binding affinity to delocalized electron sites within the tubulin subunits that make up MTs.5 These theoretical results essentially reproduce the Meyer-Overton correlation (Figure 1A) by assuming that inhalational anesthesia is primarily mediated by MTs. This cannot be said for any other candidate molecular target. Thus, MTs could be the primary molecular target that mediates the unconsciousness caused by inhalational anesthetics. This is not to say that no other molecular targets besides MTs contribute to unconsciousness induced by volatile anesthetics. If MTs are the primary target, contributions from other molecular targets might represent the deviations from the linear relationship visible in Figure 1A. For instance, multiple anesthetics tend to activate sleep-promoting neurons, contributing to the unconscious state. This might be a contribution to unconsciousness that is independent of the MT pathway. However, it is also possible that the effect of isoflurane on MTs is somehow altered in those neurons, for example by MT-associated proteins, so that their involvement will also be explained in terms of binding to MTs. Under a classical model of consciousness, binding to MTs could conceivably contribute to unconsciousness by interfering with the intracellular transport of synaptic proteins, resulting in synaptic failures and reduced neural activity contributing to unconsciousness. In fact, isoflurane does affect synaptic transmission. However, current experimental data show that this effect is mediated by mitochondria and synaptic protein syntaxin 1A rather than MTs.2 So, the current evidence does not support a classical explanation of the role of MTs in mediating anesthesia. Instead, multiple lines of evidence support the hypothesis, central to the Orchestrated Objective Reduction theory (Orch OR) of Penrose and Hameroff,6 that consciousness is a collective quantum vibrational state of intraneuronal MTs that is disrupted by anesthetic binding. This hypothesis explains why these drugs appear to specifically abolish consciousness (at moderate doses) despite binding promiscuously to hydrophobic pockets in many proteins: the delicate quantum coherence of the conscious MT state is vulnerable to disruption. In contrast, other proteins are already incoherent, so while their functions may be modulated quantitatively, they are not arrested completely. Since the 1990s, the vulnerability of macroscopic quantum states to decoherence at body temperature has been the primary reason this hypothesis was considered implausible. However, we now have definitive biophysical evidence that MTs support quantum optical effects at room temperature.7 Moreover, those quantum effects get stronger as the MTs are joined into larger structures, rather than weaker. Underappreciated work from Anirban Bandyopadhyay and colleagues has demonstrated MT resonances that control membrane spiking activity in living neurons, and that these resonances span multiple neurons.2,8 Another remarkable series of recent experiments appears to have demonstrated a macroscopic quantum state in the living human brain whose integrity is correlated with working memory performance and the conscious state itself in waking versus sleep.9 On that basis, those authors concluded that the quantum state they measured in the human brain was probably related to consciousness and cognitive function. Similarly, the fact that nuclear spin can affect anesthetic potency is baffling from a classical point of view, but understandable under Orch OR.2 This is because standard chemical interactions are based purely on electronic configurations, whereas the quantum model opens up the possibility of coupling between electronic and nuclear spins. We thus have strong and varied theoretical and experimental evidence supporting that MTs are the dominant molecular target of inhalational anesthetics and the quantum physical substrate of consciousness. In addition to the evidence reviewed above, there are also momentous conceptual advantages of the quantum Orch OR theory over competing classical models of consciousness. These include the ability to account for a selective advantage conferred by conscious brain processes, and thus account for the evolution of useful conscious states like ours (e.g., pain is good advice to "take your hand out of the fire"). The ability of the quantum model to account for the evolution of consciousness is tied to its ability to account for the unity of consciousness. In other words, Orch OR also solves the so-called phenomenal Binding Problem. This problem refers to the fact that neural signals representing specific contents of consciousness are distributed across the cortex, yet we somehow experience the multiple features as a unified whole. The quantum model accounts for this naturally, because quantum states are irreducible causally efficacious wholes. This property is what allows quantum processes to achieve classically impossible computational feats including associative memory with an exponential capacity advantage over classical memory models such as the Hopfield model, whose capacity grows only linearly with the size of the network. In contrast, classical models are ruled out because every larger-scale whole in a classical model can in principle be eliminated from the description, since all classical models are local, meaning they are totally reducible to neighbor interactions among microscopic elements of a system. That means that even if we postulate conscious experiences to accompany certain classical brain states, they must necessarily be epiphenomenal,10 so they cannot confer any selective advantage. Again, the quantum model can account for the evolution of complex but irreducibly integrated conscious states like ours; a classical model simply cannot. Moreover, the quantum approach also enables a solution to the famous Hard Problem, i.e., explaining how physical brain properties could ever amount to or imply an associated conscious experience. The solution is to admit they cannot, and postulate a fundamental mental property of physical systems. This approach is known as panpsychism or dual-aspect monism. It solves the Hard Problem in principle but cannot account for how the "micro-consciousness" of microscopic classical parts could ever combine into a larger-scale consciousness such as we experience. Because the quantum model solves this Binding Problem, it makes panpsychism viable as a solution to the Hard Problem.10 The significance of this conclusion is hard to overstate, because it means we can finally bring consciousness within the scope of science. Orch OR can also potentially account for the psychological arrow of time and non-algorithmic human understanding.10 These are all unique advantages of Orch OR. These developments have potentially far-reaching medical implications. First, the likelihood that brain-penetrant taxane chemotherapy (i.e., MT-stabilizers) may lead to anesthetic resistance in humans as we found it does in rats, suggests extra caution during surgical procedures with these patients. Second, knowing the actual molecular basis of anesthesia should catalyze efforts to develop more targeted and effective anesthetics, as well as prevent failures of anesthesia during surgery (thankfully these are already rare). This knowledge will also facilitate dissecting the precise mechanisms of the distinct components of the anesthetic state, which include analgesia, immobility, and amnesia in addition to unconsciousness. Similarly, clinicians may gain a more effective therapeutic handle on postoperative cognitive dysfunction caused by anesthesia. There is already an established literature connecting postoperative cognitive dysfunction with MTs and associated proteins like tau.11 This is consistent with the intimate relationship between consciousness and declarative memory, and with the known role of the cytoskeleton in memory-related neural plasticity. Similarly, the primary pathogenic insult in Alzheimer's disease is hyper-phosphorylated tau protein—and again, tau is a MT-associated protein. Classical memory models are based on physiological long-term potentiation and depression of synaptic connections. They certainly contain a kernel of truth. However, as noted above, they have a memory capacity problem (their capacity is at most linear in the number of neural units) that is solved by quantum associative memory models with exponentially greater capacity.10 Thus, a deeper understanding of MT physiology will likely be central to understanding the brain's basis of memory as well as consciousness. The new quantum perspective on neural mechanisms will likely also have deep implications for understanding neuropsychological disorders that affect consciousness in distinct ways, such as schizophrenia, depression, post-traumatic stress disorder, and many others. Psychopharmacology will have a new foundation. For example, we may finally understand the effects of mysterious, chemically simple drugs such as lithium on states of consciousness, or psychogenic effects of potent molecules such as lysergic acid diethylamide. A better understanding of the molecular basis of consciousness will also allow us to diagnose consciousness in unresponsive patients much more effectively. Noninvasive devices for measuring high-frequency MT resonances in humans are already in development by the Bandyopadhyay lab,12 so such applications may be closer to realization than one might guess. The unforeseeable applications and implications may be even more exciting and profound. Open access statement:This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0.