Electrophysiological-mechanical coupling in the neuronal membrane and its role in ultrasound neuromodulation and general anaesthesia.

The current understanding of the role of the cell membrane is in a state of flux. Recent experiments show that conventional models, considering only electrophysiological properties of a passive membrane, are incomplete. The neuronal membrane is an active structure with mechanical properties that modulate electrophysiology. Protein transport, lipid bilayer phase, membrane pressure and stiffness can all influence membrane capacitance and action potential propagation. A mounting body of evidence indicates that neuronal mechanics and electrophysiology are coupled, and together shape the membrane potential in tight coordination with other physical properties. In this review, we summarise recent updates concerning electrophysiological-mechanical coupling in neuronal function. In particular, we aim at making the link with two relevant yet often disconnected fields with strong clinical potential: the use of mechanical vibrations-ultrasound-to alter the electrophysiogical state of neurons, e.g., in neuromodulation, and the theories attempting to explain the action of general anaesthetics.

[1]  P. Delmas,et al.  Molecular mechanisms of mechanotransduction in mammalian sensory neurons , 2011, Nature Reviews Neuroscience.

[2]  N. P. Franks,et al.  Where do general anaesthetics act? , 1978, Nature.

[3]  A. Jákli Liquid crystals of the twenty-first century – nematic phase of bent-core molecules , 2013 .

[4]  R. Eckenhoff,et al.  Anesthetic potency of two novel synthetic polyhydric alkanols longer than the n-alkanol cutoff: evidence for a bilayer-mediated mechanism of anesthesia? , 2005, Journal of medicinal chemistry.

[5]  Hongchae Baek,et al.  A review of low-intensity focused ultrasound for neuromodulation , 2017, Biomedical Engineering Letters.

[6]  Mathias Winterhalter,et al.  The temperature dependence of lipid membrane permeability, its quantized nature, and the influence of anesthetics. , 2008, Biophysical Journal.

[7]  V. Ferrera,et al.  Modulation of Brain Function and Behavior by Focused Ultrasound , 2018, Current Behavioral Neuroscience Reports.

[8]  C. Jack,et al.  Decreased brain stiffness in Alzheimer's disease determined by magnetic resonance elastography , 2011, Journal of magnetic resonance imaging : JMRI.

[9]  M. Goodman,et al.  DEG/ENaC but Not TRP Channels Are the Major Mechanoelectrical Transduction Channels in a C. elegans Nociceptor , 2011, Neuron.

[10]  R. FitzHugh Impulses and Physiological States in Theoretical Models of Nerve Membrane. , 1961, Biophysical journal.

[11]  R. Rabbitt,et al.  Hair Cell Bundles: Flexoelectric Motors of the Inner Ear , 2009, PloS one.

[12]  Eva Syková,et al.  Extracellular space volume changes in the rat spinal cord produced by nerve stimulation and peripheral injury , 1991, Brain Research.

[13]  K. Tamm,et al.  On mathematical modelling of solitary pulses in cylindrical biomembranes , 2015, Biomechanics and modeling in mechanobiology.

[14]  Sven Bestmann,et al.  Transcranial electrical stimulation , 2017, Current Biology.

[15]  F Sachs,et al.  Voltage-induced membrane movement , 2001, Nature.

[16]  H. Kamaya,et al.  High pressure antagonism of alcohol effects on the main phase-transition temperature of phospholipid membranes: biphasic response. , 1991, Biochimica et biophysica acta.

[17]  P. Sharma,et al.  A Theory of Flexoelectric Membranes and Effective Properties of Heterogeneous Membranes , 2014 .

[18]  Nir Lipsman,et al.  Blood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound , 2018, Nature Communications.

[19]  Jean-François Aubry,et al.  Offline impact of transcranial focused ultrasound on cortical activation in primates , 2018, bioRxiv.

[20]  K. Iwasa,et al.  Swelling of nerve fibers associated with action potentials. , 1980, Science.

[21]  T. Heimburg,et al.  The thermodynamics of general anesthesia. , 2006, Biophysical journal.

[22]  Elisa E. Konofagou,et al.  Non-invasive, Focused Ultrasound-Facilitated Gene Delivery for Optogenetics , 2017, Scientific Reports.

[23]  B. Salzberg,et al.  A mechanical spike accompanies the action potential in Mammalian nerve terminals. , 2007, Biophysical journal.

[24]  W. R. Lieb,et al.  Role of hydrogen bonding in general anesthesia. , 1991, Journal of pharmaceutical sciences.

[25]  K Kusano,et al.  Rapid mechanical and thermal changes in the garfish olfactory nerve associated with a propagated impulse. , 1989, Biophysical journal.

[26]  M. Kringelbach,et al.  Translational principles of deep brain stimulation , 2007, Nature Reviews Neuroscience.

[27]  R. Tsien Fluorescent probes of cell signaling. , 1989, Annual review of neuroscience.

[28]  L. Gavrilov,et al.  Application of focused ultrasound for the stimulation of neural structures. , 1996, Ultrasound in medicine & biology.

[29]  K. Iwasa,et al.  Rapid pressure changes and surface displacements in the squid giant axon associated with production of action potentials. , 1982, The Japanese journal of physiology.

[30]  Priya Bansal,et al.  Neuromodulation with single‐element transcranial focused ultrasound in human thalamus , 2018, Human brain mapping.

[31]  Edward H. Smith,et al.  A propofol binding site on mammalian GABAA receptors identified by photolabeling , 2013, Nature chemical biology.

[32]  S. Shoham,et al.  Intramembrane Cavitation as a Predictive Bio-Piezoelectric Mechanism for Ultrasonic Brain Stimulation , 2013, 1307.7701.

[33]  Gary R. Lewin,et al.  Sensory mechanotransduction at membrane-matrix interfaces , 2014, Pflügers Archiv - European Journal of Physiology.

[34]  Elasticity and electric manifestations in the nerve in distribution of irritation , 1955 .

[35]  A. Jérusalem,et al.  Computational model of the mechanoelectrophysiological coupling in axons with application to neuromodulation. , 2019, Physical review. E.

[36]  E. Overton Studien über die Narkose : zugleich ein Beitrag zur allgemeinen Pharmakologie , 1901 .

[37]  F. Sachs,et al.  The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4. , 2011, Biochemistry.

[38]  W. Fry,et al.  Production of reversible changes in the central nervous system by ultrasound. , 1958, Science.

[39]  James J. Choi,et al.  Ultrasound-induced blood-brain barrier opening. , 2012, Current pharmaceutical biotechnology.

[40]  A. Hodgkin,et al.  A quantitative description of membrane current and its application to conduction and excitation in nerve , 1952, The Journal of physiology.

[41]  B. Khuri-Yakub,et al.  Dynamic Response of Model Lipid Membranes to Ultrasonic Radiation Force , 2013, PloS one.

[42]  T. Heimburg,et al.  Solitary electromechanical pulses in lobster neurons. , 2015, Biophysical chemistry.

[43]  Karl Deisseroth,et al.  Optogenetics in Neural Systems , 2011, Neuron.

[44]  P. Skolnick,et al.  Isoflurane anesthesia is stereoselective. , 1992, European journal of pharmacology.

[45]  Cory D. Gloeckner,et al.  Ultrasound Produces Extensive Brain Activation via a Cochlear Pathway , 2017, Neuron.

[46]  L. Gavrilov,et al.  Use of focused ultrasound for stimulation of nerve structures. , 1984, Ultrasonics.

[47]  R. Hochmuth,et al.  Micropipette aspiration of living cells. , 2000, Journal of biomechanics.

[48]  Andrew D. Jackson,et al.  Towards a thermodynamic theory of nerve pulse propagation , 2009, Progress in Neurobiology.

[49]  L. R. Gavrilov,et al.  Focused ultrasound as a tool to input sensory information to humans (Review) , 2012 .

[50]  Daniel L. Albaugh,et al.  Advances in optogenetic and chemogenetic methods to study brain circuits in non-human primates , 2018, Journal of Neural Transmission.

[51]  N. Vykhodtseva,et al.  Steady Potential Changes and Spreading Depression in Rat Brains Produced by Focused Ultrasound , 2006 .

[52]  K. Simons,et al.  Caveolae, DIGs, and the dynamics of sphingolipid-cholesterol microdomains. , 1997, Current opinion in cell biology.

[53]  B. Antkowiak,et al.  Molecular and neuronal substrates for general anaesthetics , 2004, Nature Reviews Neuroscience.

[54]  Natalia Vykhodtseva,et al.  Acoustic neuromodulation from a basic science prospective , 2016, Journal of therapeutic ultrasound.

[55]  Ursula van Rienen,et al.  A Comparison of the Hodgkin–Huxley Model and the Soliton Theory for the Action Potential in Nerves , 2012 .

[56]  C. Stucky,et al.  TRPA1 Mediates Mechanical Sensitization in Nociceptors during Inflammation , 2012, PloS one.

[57]  Frederick Sachs,et al.  Stretch-activated ion channels: what are they? , 2010, Physiology.

[58]  F. F. Weight,et al.  Cutoff in potency implicates alcohol inhibition of N-methyl-D-aspartate receptors in alcohol intoxication. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[59]  S. Tucker,et al.  Ultrasound-induced changes in rates of influx and efflux of potassium ions in rat thymocytes in vitro. , 1980, Ultrasound in medicine & biology.

[60]  M. Dyson,et al.  The effect of therapeutic ultrasound on calcium uptake in fibroblasts. , 1988, Ultrasound in medicine & biology.

[61]  R F Kilcoyne,et al.  Acceleration of tibial fracture-healing by non-invasive, low-intensity pulsed ultrasound. , 1994, The Journal of bone and joint surgery. American volume.

[62]  T. Heimburg The capacitance and electromechanical coupling of lipid membranes close to transitions: the effect of electrostriction. , 2012, Biophysical journal.

[63]  K. Tamm,et al.  On the complexity of signal propagation in nerve fibres , 2018 .

[64]  K. Miller,et al.  The pressure reversal of general anesthesia and the critical volume hypothesis. , 1973, Molecular pharmacology.

[65]  D. Meaney,et al.  Pharmacologically induced calcium oscillations protect neurons from increases in cytosolic calcium after trauma , 2006, Journal of neurochemistry.

[66]  J. Baber,et al.  Distribution of general anesthetics in phospholipid bilayers determined using 2H NMR and 1H-1H NOE spectroscopy. , 1995, Biochemistry.

[67]  P. P. Yupapin,et al.  Solitonic conduction of electrotonic signals in neuronal branchlets with polarized microstructure , 2017, Scientific Reports.

[68]  L. Firestone,et al.  Does general anesthetic-induced desensitization of the Torpedo acetylcholine receptor correlate with lipid disordering? , 1994, Molecular pharmacology.

[69]  S. Curry,et al.  Probing the molecular dimensions of general anaesthetic target sites in tadpoles (Xenopus laevis) and model systems using cycloalcohols , 1991, British journal of pharmacology.

[70]  H. Seung,et al.  Noncontact measurement of nerve displacement during action potential with a dual-beam low-coherence interferometer. , 2004, Optics letters.

[71]  Wei Zhang,et al.  Drosophila NOMPC is a mechanotransduction channel subunit for gentle-touch sensation , 2012, Nature.

[72]  H. Aranda‐Espinoza,et al.  Cortical Neuron Outgrowth is Insensitive to Substrate Stiffness , 2010 .

[73]  B. Roth,et al.  Chemogenetic tools to interrogate brain functions. , 2014, Annual review of neuroscience.

[74]  J. Connor,et al.  Theory of electromechanical effects in nerve , 1983, Cellular and Molecular Neurobiology.

[75]  Elise Spedden,et al.  Neuron Biomechanics Probed by Atomic Force Microscopy , 2013, International journal of molecular sciences.

[76]  P. Seeman,et al.  The membrane actions of anesthetics and tranquilizers. , 1972, Pharmacological reviews.

[77]  D. Cranston,et al.  A review of high intensity focused ultrasound in relation to the treatment of renal tumours and other malignancies. , 2015, Ultrasonics sonochemistry.

[78]  Amit P. Mulgaonkar,et al.  A review of low-intensity focused ultrasound pulsation , 2011, Brain Stimulation.

[79]  Jong-Hwan Lee,et al.  Focused ultrasound modulates region-specific brain activity , 2011, NeuroImage.

[80]  M. Agüero,et al.  Non-Topological Solitons as Traveling Pulses along the Nerve , 2013 .

[81]  R. Cantor,et al.  The influence of membrane lateral pressures on simple geometric models of protein conformational equilibria. , 1999, Chemistry and physics of lipids.

[82]  Linear oscillatory dynamics of flexoelectric membranes embedded in viscoelastic media with applications to outer hair cells , 2012 .

[83]  Jean-François Aubry,et al.  Potential impact of thermal effects during ultrasonic neurostimulation: retrospective numerical estimation of temperature elevation in seven rodent setups , 2018, Physics in medicine and biology.

[84]  Shamit Shrivastava,et al.  Collision and annihilation of nonlinear sound waves and action potentials in interfaces , 2018, Journal of The Royal Society Interface.

[85]  S. Yoo,et al.  Suppression of EEG visual-evoked potentials in rats through neuromodulatory focused ultrasound , 2015, Neuroreport.

[86]  Byoung-Kyong Min,et al.  Transcranial focused ultrasound to the thalamus alters anesthesia time in rats , 2011, Neuroreport.

[87]  J. Gleeson,et al.  Converse flexoelectric effect in a bent-core nematic liquid crystal. , 2008, Physical review. E, Statistical, nonlinear, and soft matter physics.

[88]  M. Lazdunski,et al.  TRAAK Is a Mammalian Neuronal Mechano-gated K+Channel* , 1999, The Journal of Biological Chemistry.

[89]  M. Sheetz,et al.  Biophysics of substrate interaction: Influence on neural motility, differentiation, and repair , 2011, Developmental neurobiology.

[90]  A. Morel,et al.  High‐intensity focused ultrasound for noninvasive functional neurosurgery , 2009, Annals of neurology.

[91]  J. Thomas Mortimer,et al.  A Technique for Collision Block of Peripheral Nerve: Frequency Dependence , 1981, IEEE Transactions on Biomedical Engineering.

[92]  Ferenc A. Jolesz,et al.  Local and reversible blood–brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications , 2005, NeuroImage.

[93]  N. Vykhodtseva,et al.  Cortical and subcortical spreading depression in rats produced by focused ultrasound , 2005, Neurophysiology.

[94]  A. T. Todorov,et al.  Flexoelectricity of lipid bilayers , 1990 .

[95]  Yusuf Tufail,et al.  Pain: Noninvasive functional neurosurgery using ultrasound , 2010, Nature Reviews Neurology.

[96]  Martin Chalfie,et al.  The mechanosensory protein MEC-6 is a subunit of the C. elegans touch-cell degenerin channel , 2002, Nature.

[97]  Matthias F. Schneider,et al.  Similarities between action potentials and acoustic pulses in a van der Waals fluid , 2018, Scientific Reports.

[98]  G. W. Moss,et al.  Anesthetic inhibition of firefly luciferase, a protein model for general anesthesia, does not exhibit pressure reversal. , 1991, Biophysical journal.

[99]  R. Kothary,et al.  Integrin Signaling in Oligodendrocytes and Its Importance in CNS Myelination , 2010, Journal of signal transduction.

[100]  G. R. ter Haar,et al.  Ultrasound bioeffects and safety , 2010 .

[101]  G. Lewin,et al.  Voltage gating of mechanosensitive PIEZO channels , 2018, Nature Communications.

[102]  Yusuf Tufail,et al.  Ultrasonic neuromodulation by brain stimulation with transcranial ultrasound , 2011, Nature Protocols.

[103]  Michael J. Berry,et al.  Piezoelectric nanoribbons for monitoring cellular deformations. , 2012, Nature nanotechnology.

[104]  P. Tsui,et al.  In vitro effects of ultrasound with different energies on the conduction properties of neural tissue. , 2005, Ultrasonics.

[105]  B. Mohammadi,et al.  2,6 Di-tert-butylphenol, a Nonanesthetic Propofol Analog, Modulates &agr;1β Glycine Receptor Function in a Manner Distinct from Propofol , 2004, Anesthesia and analgesia.

[106]  K. Iwasa,et al.  Shortening of nerve fibers associated with propagated nerve impulse. , 1980, Biochemical and biophysical research communications.

[107]  K. Tamm,et al.  On solutions of a Boussinesq-type equation with displacement-dependent nonlinearities: the case of biomembranes , 2016, 1606.07678.

[108]  Sreekanth H. Chalasani,et al.  Imaging neural activity in worms, flies and mice with improved GCaMP calcium indicators , 2009, Nature Methods.

[109]  M. Philen,et al.  A comprehensive flexoelectric model for droplet interface bilayers acting as sensors and energy harvesters , 2016 .

[110]  P. Sharma,et al.  Flexoelectricity in soft materials and biological membranes , 2014 .

[111]  A. Popel,et al.  A membrane bending model of outer hair cell electromotility. , 2000, Biophysical journal.

[112]  S. Yoo,et al.  Image-Guided Transcranial Focused Ultrasound Stimulates Human Primary Somatosensory Cortex , 2015, Scientific Reports.

[113]  Jochen Guck,et al.  Viscoelastic properties of individual glial cells and neurons in the CNS , 2006, Proceedings of the National Academy of Sciences.

[114]  Sung Eun Kim,et al.  Piezos are pore-forming subunits of mechanically activated channels , 2011, Nature.

[115]  B. Orser,et al.  Emerging molecular mechanisms of general anesthetic action. , 2005, Trends in pharmacological sciences.

[116]  Stephen A. Sarles,et al.  Capacitive Detection of Low-Enthalpy, Higher-Order Phase Transitions in Synthetic and Natural Composition Lipid Membranes. , 2017, Langmuir : the ACS journal of surfaces and colloids.

[117]  F. Sachs,et al.  Voltage-dependent Membrane Displacements Measured by Atomic Force Microscopy , 1998, The Journal of general physiology.

[118]  M. Mitchell,et al.  Substitutions and deletions in the cytoplasmic domain of the phagocytic receptor Fc gamma RIIA: effect on receptor tyrosine phosphorylation and phagocytosis. , 1994, Blood.

[119]  A. Petrov Flexoelectric Model for Active Transport , 1975 .

[120]  P. Skolnick,et al.  Stereospecific actions of the inhalation anesthetic isoflurane at the GABAA receptor complex , 1993, Brain Research.

[121]  T. Heimburg,et al.  On soliton propagation in biomembranes and nerves. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[122]  O. Thoumine,et al.  Microplates: a new tool for manipulation and mechanical perturbation of individual cells. , 1999, Journal of biochemical and biophysical methods.

[123]  Kim Butts Pauly,et al.  Localization of ultrasound-induced in vivo neurostimulation in the mouse model. , 2014, Ultrasound in medicine & biology.

[124]  D. Cockayne,et al.  Acid‐sensing ion channels ASIC2 and ASIC3 do not contribute to mechanically activated currents in mammalian sensory neurones , 2004, The Journal of physiology.

[125]  Diane Dalecki,et al.  Mechanical bioeffects of ultrasound. , 2004, Annual review of biomedical engineering.

[126]  J. Ratnanather,et al.  Electromechanical Models of the Outer Hair Cell Composite Membrane , 2006, The Journal of Membrane Biology.

[127]  J. A. Lundbæk Regulation of membrane protein function by lipid bilayer elasticity—a single molecule technology to measure the bilayer properties experienced by an embedded protein , 2006, Journal of physics. Condensed matter : an Institute of Physics journal.

[128]  Yunze Yang,et al.  Imaging Action Potential in Single Mammalian Neurons by Tracking the Accompanying Sub-Nanometer Mechanical Motion. , 2018, ACS nano.

[129]  F. Johnson,et al.  Hydrostatic pressure reversal of narcosis in tadpoles. , 1950, Science.

[130]  R. Yasuda,et al.  The mechanisms underlying the spatial spreading of signaling activity , 2011, Current Opinion in Neurobiology.

[131]  Stefan Schinkinger,et al.  Optical deformability as an inherent cell marker for testing malignant transformation and metastatic competence. , 2005, Biophysical journal.

[132]  S. Hameroff,et al.  Transcranial Ultrasound (TUS) Effects on Mental States: A Pilot Study , 2013, Brain Stimulation.

[133]  K. S. Krishnamurthy,et al.  Converse flexoelectric effect in bent-core nematic liquid crystals. , 2009, The journal of physical chemistry. B.

[134]  Iman Ghodrati Toostani,et al.  A Review on Brain Stimulation Using Low Intensity Focused Ultrasound , 2016, Basic and clinical neuroscience.

[135]  C. Moritz,et al.  Increased Anatomical Specificity of Neuromodulation via Modulated Focused Ultrasound , 2014, PloS one.

[136]  H. Khandelia,et al.  Quantifying the Relationship between Curvature and Electric Potential in Lipid Bilayers. , 2016, The journal of physical chemistry. B.

[137]  M. Hemphill,et al.  Traumatic Brain Injury and the Neuronal Microenvironment: A Potential Role for Neuropathological Mechanotransduction , 2015, Neuron.

[138]  S. Terakawa,et al.  Electrical responses to mechanical stimulation of the membrane of squid giant axons , 1982, Pflügers Archiv.

[139]  R. Pastor,et al.  Time Scales of Lipid Dynamics and Molecular Dynamics , 1996 .

[140]  Z. Al-Rekabi,et al.  Cross talk between matrix elasticity and mechanical force regulates myoblast traction dynamics , 2013, Physical biology.

[141]  M. Chalfie,et al.  Eukaryotic mechanosensitive channels. , 2010, Annual review of biophysics.

[142]  Matthias F. Schneider,et al.  Collision of two action potentials in a single excitable cell. , 2017, Biochimica et biophysica acta. General subjects.

[143]  B. Sakmann,et al.  Patch clamp characterization of sodium channels expressed from rat brain cDNA , 1987, European Biophysics Journal.

[144]  Jizhe Hao,et al.  Multiple Desensitization Mechanisms of Mechanotransducer Channels Shape Firing of Mechanosensory Neurons , 2010, The Journal of Neuroscience.

[145]  G. Lynch,et al.  Integrin signaling cascades are operational in adult hippocampal synapses and modulate NMDA receptor physiology , 2005, Journal of neurochemistry.

[146]  M. Maze,et al.  Xenon: from stranger to guardian , 2005, Current opinion in anaesthesiology.

[147]  Mervyn Maze,et al.  Molecular Mechanisms Transducing the Anesthetic, Analgesic, and Organ-protective Actions of Xenon , 2006, Anesthesiology.

[148]  N. Vykhodtseva,et al.  6A-4 Focused Ultrasound Potential to Initiate Spreading Depression for Disruption of Blood Brain Barrier , 2007, 2007 IEEE Ultrasonics Symposium Proceedings.

[149]  B. C. Hill,et al.  Laser interferometer measurement of changes in crayfish axon diameter concurrent with action potential. , 1977, Science.

[150]  T. Bliss,et al.  Differential modulation of NMDA‐induced calcium transients by arachidonic acid and nitric oxide in cultured hippocampal neurons , 2003, The European journal of neuroscience.

[151]  L. Freund,et al.  Forced detachment of a vesicle in adhesive contact with a substrate , 2007 .

[152]  Kristina Haase,et al.  Investigating cell mechanics with atomic force microscopy , 2015, Journal of The Royal Society Interface.

[153]  Vesna Zderic,et al.  Mechanical bioeffects of pulsed high intensity focused ultrasound on a simple neural model. , 2012, Medical physics.

[154]  A. Patapoutian,et al.  Trp ion channels and temperature sensation. , 2006, Annual review of neuroscience.

[155]  C. Stucky,et al.  TRPA1 Mediates Mechanical Currents in the Plasma Membrane of Mouse Sensory Neurons , 2010, PloS one.

[156]  M. Nitsche,et al.  Studying and modifying brain function with non-invasive brain stimulation , 2018, Nature Neuroscience.

[157]  D. Attwell,et al.  Potentiation of NMDA receptor currents by arachidonic acid , 1992, Nature.

[158]  F. F. Weight,et al.  Alcohol action on a neuronal membrane receptor: evidence for a direct interaction with the receptor protein. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[159]  T. Bliss,et al.  A synaptic model of memory: long-term potentiation in the hippocampus , 1993, Nature.

[160]  K. Hynynen,et al.  Focused ultrasound effects on nerve action potential in vitro. , 2009, Ultrasound in medicine & biology.

[161]  A. Patapoutian,et al.  A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition , 2007, Molecular pain.

[162]  M. Fink,et al.  Influence of the pressure field distribution in transcranial ultrasonic neurostimulation. , 2013, Medical physics.

[163]  J. Grandl,et al.  Touch, Tension, and Transduction - The Function and Regulation of Piezo Ion Channels. , 2017, Trends in biochemical sciences.

[164]  T. Heimburg,et al.  The thermodynamics of general and local anesthesia. , 2013, Biophysical journal.

[165]  P. Ascher,et al.  Internal Mg2+ block of recombinant NMDA channels mutated within the selectivity filter and expressed in Xenopus oocytes , 1998, The Journal of physiology.

[166]  C. Fang-Yen,et al.  Label-free imaging of membrane potential using membrane electromotility. , 2012, Biophysical journal.

[167]  S. Yoo,et al.  Focused Ultrasound-mediated Non-invasive Brain Stimulation: Examination of Sonication Parameters , 2014, Brain Stimulation.

[168]  Boris Martinac,et al.  Mechanosensitive ion channels: molecules of mechanotransduction , 2004, Journal of Cell Science.

[169]  J. A. Encinar,et al.  Lipid modulation of ion channels through specific binding sites. , 2014, Biochimica et biophysica acta.

[170]  William J Tyler,et al.  Ultrasonic neuromodulation , 2017, 2017 IEEE International Ultrasonics Symposium (IUS).

[171]  U. Keyser,et al.  Phase-state dependent current fluctuations in pure lipid membranes. , 2009, Biophysical journal.

[172]  William J Tyler,et al.  A quantitative overview of biophysical forces impinging on neural function , 2013, Physical biology.

[173]  Alexander G. Petrov,et al.  Flexoelectricity of Charged and Dipolar Bilayer Lipid Membranes Studied by Stroboscopic Interferometry , 1994 .

[174]  A. Kurosky,et al.  TRPC1 forms the stretch-activated cation channel in vertebrate cells , 2005, Nature Cell Biology.

[175]  R. Dingledine,et al.  The glutamate receptor ion channels. , 1999, Pharmacological reviews.

[176]  D. Cafiso,et al.  Contrasting membrane localization and behavior of halogenated cyclobutanes that follow or violate the Meyer-Overton hypothesis of general anesthetic potency. , 1997, Biophysical journal.

[177]  J. Ellory,et al.  The role of swelling-induced anion channels during neuronal volume regulation , 1996, Molecular Neurobiology.

[178]  S. Shoham,et al.  Intramembrane cavitation as a unifying mechanism for ultrasound-induced bioeffects , 2011, Proceedings of the National Academy of Sciences.

[179]  R. Roth,et al.  Bubbles, gating, and anesthetics in ion channels. , 2008, Biophysical journal.

[180]  Doris Y. Tsao,et al.  Ultrasonic Neuromodulation Causes Widespread Cortical Activation via an Indirect Auditory Mechanism , 2017, Neuron.

[181]  S. Pedersen,et al.  Cell swelling activates cloned Ca(2+)-activated K(+) channels: a role for the F-actin cytoskeleton. , 2003, Biochimica et biophysica acta.

[182]  M. Ridding,et al.  Determinants of the induction of cortical plasticity by non‐invasive brain stimulation in healthy subjects , 2010, The Journal of physiology.

[183]  Kuo-Kang Liu,et al.  Optical tweezers for single cells , 2008, Journal of The Royal Society Interface.

[184]  Enrico Gratton,et al.  Fluid Shear Stress on Endothelial Cells Modulates Mechanical Tension across VE-Cadherin and PECAM-1 , 2013, Current Biology.

[185]  Thibault P. Prevost,et al.  Biomechanics of single cortical neurons. , 2010, Acta biomaterialia.

[186]  Wonhye Lee,et al.  Image-Guided Focused Ultrasound-Mediated Regional Brain Stimulation in Sheep. , 2016, Ultrasound in medicine & biology.

[187]  S. L. Chan,et al.  A possible molecular mechanism for the pressure reversal of general anaesthetics: Aggregation of halothane in POPC bilayers at high pressure , 2012 .

[188]  Matthias F. Schneider,et al.  It sounds like an action potential: unification of electrical, chemical and mechanical aspects of acoustic pulses in lipids , 2018, Journal of the Royal Society Interface.

[189]  H. Kamaya,et al.  Anesthesia cutoff phenomenon: interfacial hydrogen bonding. , 1990, Science.

[190]  Clifford J. Woolf,et al.  TRPA1 Contributes to Cold, Mechanical, and Chemical Nociception but Is Not Essential for Hair-Cell Transduction , 2006, Neuron.

[191]  P. Reeh,et al.  Sensory receptors in mammalian skin in an in vitro preparation , 1986, Neuroscience Letters.

[192]  Yusuf Tufail,et al.  Remote Excitation of Neuronal Circuits Using Low-Intensity, Low-Frequency Ultrasound , 2008, PloS one.

[193]  Clifford R. Jack,et al.  Magnetic resonance elastography of the brain , 2008, NeuroImage.

[194]  J. Trudell,et al.  A Unitary Theory of Anesthesia Based on Lateral Phase Separations in Nerve Membranes , 1977, Anesthesiology.

[195]  Patricia C. Rinaldi,et al.  Modification by focused ultrasound pulses of electrically evoked responses from an in vitro hippocampal preparation , 1991, Brain Research.

[196]  Q. Deng,et al.  Apparent flexoelectricity in lipid bilayer membranes due to external charge and dipolar distributions. , 2013, Physical review. E, Statistical, nonlinear, and soft matter physics.

[197]  F. Abboud,et al.  The Ion Channel ASIC2 Is Required for Baroreceptor and Autonomic Control of the Circulation , 2009, Neuron.

[198]  Taner Akkin,et al.  Depth-resolved measurement of transient structural changes during action potential propagation. , 2007, Biophysical journal.

[199]  F. F. Weight,et al.  Lipid vs protein theories of alcohol action in the nervous system. , 1996, Annual review of pharmacology and toxicology.

[200]  B. Chait,et al.  The structure of the potassium channel: molecular basis of K+ conduction and selectivity. , 1998, Science.

[201]  T. Akkin,et al.  Optical Coherence Tomography Phase Measurement of Transient Changes in Squid Giant Axons During Activity , 2009, Journal of Membrane Biology.

[202]  Z. Gil,et al.  Voltage-induced membrane displacement in patch pipettes activates mechanosensitive channels. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[203]  A. Williams,et al.  Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans , 2014, Nature Neuroscience.

[204]  L A Crum,et al.  The significance of membrane changes in the safe and effective use of therapeutic and diagnostic ultrasound. , 1989, Physics in medicine and biology.

[205]  K. Rhodes,et al.  Identification of a cytoplasmic domain important in the polarized expression and clustering of the Kv2.1 K+ channel , 1996, The Journal of cell biology.

[206]  Shinsuk Park,et al.  Transcranial Focused Ultrasound to the Thalamus Is Associated with Reduced Extracellular GABA Levels in Rats , 2012, Neuropsychobiology.

[207]  Akira Chiba,et al.  Mechanical tension contributes to clustering of neurotransmitter vesicles at presynaptic terminals , 2009, Proceedings of the National Academy of Sciences.

[208]  P. Brick,et al.  Structural basis for the inhibition of firefly luciferase by a general anesthetic. , 1998, Biophysical journal.

[209]  Shinsuk Park,et al.  Estimation of the spatial profile of neuromodulation and the temporal latency in motor responses induced by focused ultrasound brain stimulation , 2013, Neuroreport.

[210]  A. Gefen,et al.  Age-dependent changes in material properties of the brain and braincase of the rat. , 2003, Journal of neurotrauma.

[211]  Pradeep Sharma,et al.  Flexoelectricity: A Perspective on an Unusual Electromechanical Coupling , 2016 .

[212]  P. P. Lele The effects of focused ultrasonic radiation on the peripheral nerves, with observations on local heating: Exper. Neurol., 8, No. 1, p. 47 (1963) , 1963 .

[213]  Z. Al-Rekabi,et al.  Multifrequency AFM reveals lipid membrane mechanical properties and the effect of cholesterol in modulating viscoelasticity , 2018, Proceedings of the National Academy of Sciences.

[214]  Jesper Andersson,et al.  A multi-modal parcellation of human cerebral cortex , 2016, Nature.

[215]  David P. Corey,et al.  TRP channels in mechanosensation: direct or indirect activation? , 2007, Nature Reviews Neuroscience.

[216]  Mechanical surface waves accompany action potential propagation , 2015 .

[217]  R. Eckenhoff,et al.  Steric hindrance is not required for n-alkanol cutoff in soluble proteins. , 1999, Molecular pharmacology.

[218]  A. Petrov,et al.  Flexoelectricity of model and living membranes. , 2002, Biochimica et biophysica acta.

[219]  Pavlo Zubko,et al.  Flexoelectric Effect in Solids , 2013 .

[220]  Charles Tator,et al.  Normal and abnormal calcium homeostasis in neurons: a basis for the pathophysiology of traumatic and ischemic central nervous system injury. , 1996, Neurosurgery.

[221]  Pere Roca-Cusachs,et al.  Stretchy proteins on stretchy substrates: the important elements of integrin-mediated rigidity sensing. , 2010, Developmental cell.

[222]  Susan E. Brockerhoff,et al.  Mechanism of anesthesia: Anesthetics may restructure the hydrogen belts of membranes , 1990, Neurochemistry International.

[223]  William J. Tyler,et al.  The mechanobiology of brain function , 2012, Nature Reviews Neuroscience.

[224]  William J Tyler,et al.  Ultrasonic modulation of neural circuit activity , 2018, Current Opinion in Neurobiology.

[225]  Steven L Shafer,et al.  Is a New Paradigm Needed to Explain How Inhaled Anesthetics Produce Immobility? , 2008, Anesthesia and analgesia.

[226]  W. Brownell,et al.  Cell membrane tethers generate mechanical force in response to electrical stimulation. , 2010, Biophysical journal.

[227]  R. Albrecht,et al.  Speculations on the molecular nature of anesthesia. , 1988, General pharmacology.

[228]  K. Hynynen,et al.  MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study , 2013, The Lancet Neurology.

[229]  S. Yoshizawa,et al.  An Active Pulse Transmission Line Simulating Nerve Axon , 1962, Proceedings of the IRE.

[230]  Jianmin Cui,et al.  Ultrasound modulates ion channel currents , 2016, Scientific Reports.

[231]  A. Lee Interactions between anaesthetics and lipid mixtures. Amines. , 1976, Biochimica et biophysica acta.

[232]  Byoung-Kyong Min,et al.  Focused ultrasound-mediated suppression of chemically-induced acute epileptic EEG activity , 2011, BMC Neuroscience.

[233]  S. Gruner,et al.  Is the Mechanism of General Anesthesia Related to Lipid Membrane Spontaneous Curvature? a , 1991, Annals of the New York Academy of Sciences.

[234]  D. B. Goldstein,et al.  The effects of drugs on membrane fluidity. , 1984, Annual review of pharmacology and toxicology.

[235]  Mark Farrant,et al.  NMDA receptor subunits: diversity, development and disease , 2001, Current Opinion in Neurobiology.

[236]  A. Petrov,et al.  Is flexoelectricity the coupling factor between chemical energy and osmotic work in the pump? A model of pump. , 1986, General physiology and biophysics.

[237]  Kai Bodensiek,et al.  Cell Visco-Elasticity Measured with AFM and Optical Trapping at Sub-Micrometer Deformations , 2012, PloS one.

[238]  Manuela Schmidt,et al.  Piezo1 ion channel pore properties are dictated by C-terminal region , 2015, Nature Communications.

[239]  E. Waxman,et al.  N-methyl-D-aspartate Receptor Subtypes: Multiple Roles in Excitotoxicity and Neurological Disease , 2005, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[240]  M. Tanter,et al.  Low intensity focused ultrasound modulates monkey visuomotor behavior , 2013, Current Biology.

[241]  J L Robinson,et al.  The stereospecific effects of isoflurane isomers in vivo. , 1994, European journal of pharmacology.

[242]  Dagmar Krefting,et al.  The Influence of Physiological Aging and Atrophy on Brain Viscoelastic Properties in Humans , 2011, PloS one.

[243]  I. Tasaki A macromolecular approach to excitation phenomena: mechanical and thermal changes in nerve during excitation. , 1988, Physiological chemistry and physics and medical NMR.

[244]  Scott Waddell,et al.  Understanding the brain by controlling neural activity , 2015, Philosophical Transactions of the Royal Society B: Biological Sciences.

[245]  F. Dunn,et al.  Interaction of ultrasound and model membrane systems : analyses and predictions , 1992 .

[246]  Yan Xu,et al.  Different distribution of fluorinated anesthetics and nonanesthetics in model membrane: a 19F NMR study. , 1997, Biophysical journal.

[247]  C. Bear A nonselective cation channel in rat liver cells is activated by membrane stretch. , 1990, The American journal of physiology.

[248]  J. Mortimer,et al.  A Technique for Collision Block of Peripheral Nerve: Single Stimulus Analysis , 1981, IEEE Transactions on Biomedical Engineering.

[249]  James J. Choi,et al.  Noninvasive, transcranial and localized opening of the blood-brain barrier using focused ultrasound in mice. , 2007, Ultrasound in medicine & biology.

[250]  G Wilson Miller,et al.  Noninvasive neuromodulation and thalamic mapping with low-intensity focused ultrasound. , 2017, Journal of neurosurgery.

[251]  Ethan R. Buch,et al.  Noninvasive brain stimulation: from physiology to network dynamics and back , 2013, Nature Neuroscience.

[252]  R. Harris,et al.  Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors , 1997, Nature.

[253]  Jong-Hwan Lee,et al.  Transcranial focused ultrasound stimulation of human primary visual cortex , 2016, Scientific Reports.

[254]  S. J. Smith,et al.  Neuronal cytomechanics: the actin-based motility of growth cones. , 1988, Science.

[255]  H. Meyer Zur Theorie der Alkoholnarkose , 1899, Archiv für experimentelle Pathologie und Pharmakologie.

[256]  E. N. Harvey,et al.  THE EFFECT OF HIGH FREQUENCY SOUND WAVES ON HEART MUSCLE AND OTHER IRRITABLE TISSUES , 1929 .

[257]  E. Bell,et al.  Progress and problems in the neurological applications of focused ultrasound. , 1960, Journal of neurosurgery.

[258]  P. Ascher,et al.  Opposite modulation of NMDA receptors by lysophospholipids and arachidonic acid: common features with mechanosensitivity , 1998, The Journal of physiology.

[259]  A. Petrov,et al.  Electricity and mechanics of biomembrane systems: flexoelectricity in living membranes. , 2006, Analytica chimica acta.

[260]  M. Klein,et al.  Modification of optical responses associated with the action potential of lobster giant axons. , 1975, Biochimica et biophysica acta.

[261]  Alexander G. Petrov The Lyotropic State of Matter: Molecular Physics and Living Matter Physics , 1999 .

[262]  W. Tyler Noninvasive Neuromodulation with Ultrasound? A Continuum Mechanics Hypothesis , 2011, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[263]  Alexander G. Petrov,et al.  First observation of the converse flexoelectric effect in bilayer lipid membranes , 1994 .

[264]  Hyungmin Kim,et al.  Creation of various skin sensations using pulsed focused ultrasound: Evidence for functional neuromodulation , 2014, Int. J. Imaging Syst. Technol..

[265]  M. Nitsche,et al.  Physiological Basis of Transcranial Direct Current Stimulation , 2011, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[266]  M. Akabas,et al.  The Location of a Closed Channel Gate in the GABAA Receptor Channel , 2007, The Journal of general physiology.

[267]  W. Schafer,et al.  Specific roles for DEG/ENaC and TRP channels in touch and thermosensation in C. elegans nociceptors , 2010, Nature Neuroscience.

[268]  M. Chalfie,et al.  MEC-2 regulates C. elegans DEG/ENaC channels needed for mechanosensation , 2002, Nature.

[269]  A. Mol'nar,et al.  Capacitive and ionic currents in BLM from phosphatidic acid in Ca2+-induced phase transition. , 1985, Biochemical and biophysical research communications.

[270]  M. Salter Cellular signalling pathways of spinal pain neuroplasticity as targets for analgesic development. , 2005, Current topics in medicinal chemistry.

[271]  V. S. Sokolov,et al.  Curvature-electric effect in black lipid membranes , 1986, European Biophysics Journal.

[272]  P. Sharma,et al.  Flexoelectricity and thermal fluctuations of lipid bilayer membranes: Renormalization of flexoelectric, dielectric, and elastic properties , 2013 .

[273]  Max Wintermark,et al.  A pilot study of focused ultrasound thalamotomy for essential tremor. , 2013, The New England journal of medicine.

[274]  Corina S. Drapaca An electromechanical model of neuronal dynamics using Hamilton's principle , 2015, Front. Cell. Neurosci..

[275]  W. Newsome,et al.  Effective parameters for ultrasound-induced in vivo neurostimulation. , 2013, Ultrasound in medicine & biology.

[276]  A. Grinnell,et al.  Integrins and modulation of transmitter release from motor nerve terminals by stretch. , 1995, Science.

[277]  Kai Simons,et al.  Membrane organization and lipid rafts. , 2011, Cold Spring Harbor perspectives in biology.

[278]  H. Wachtel,et al.  Temporally-specific modification of myelinated axon excitability in vitro following a single ultrasound pulse. , 1990, Ultrasound in medicine & biology.

[279]  W. Stein,et al.  Dynamics of signal propagation and collision in axons. , 2015, Physical review. E, Statistical, nonlinear, and soft matter physics.

[280]  Caroline Schnakers,et al.  Non-Invasive Ultrasonic Thalamic Stimulation in Disorders of Consciousness after Severe Brain Injury: A First-in-Man Report , 2016, Brain Stimulation.

[281]  Andrew D. Jackson,et al.  On the action potential as a propagating density pulse and the role of anesthetics , 2006 .

[282]  K. Iwasa,et al.  Mechanical changes in squid giant axons associated with production of action potentials. , 1980, Biochemical and biophysical research communications.

[283]  R. Eckenhoff,et al.  Identification of Propofol Binding Sites in a Nicotinic Acetylcholine Receptor with a Photoreactive Propofol Analog* , 2013, The Journal of Biological Chemistry.

[284]  B Sakmann,et al.  Patch clamp techniques for studying ionic channels in excitable membranes. , 1984, Annual review of physiology.

[285]  Barclay Morrison,et al.  Mechanical heterogeneity of the rat hippocampus measured by atomic force microscope indentation. , 2007, Journal of neurotrauma.

[286]  André Fabio Kohn,et al.  Experimental and Simulated EMG Responses in the Study of the Human Spinal Cord , 2013 .

[287]  Frauke Zipp,et al.  MR-elastography reveals degradation of tissue integrity in multiple sclerosis , 2010, NeuroImage.

[288]  Zhenwei Su,et al.  Mechanosensitivity is mediated directly by the lipid membrane in TRAAK and TREK1 K+ channels , 2014, Proceedings of the National Academy of Sciences.

[289]  Chih-Cheng Chen,et al.  Neurosensory mechanotransduction through acid-sensing ion channels , 2013, Journal of cellular and molecular medicine.

[290]  M. Payne,et al.  Isoflurane does not aggregate inside POPC bilayers at high pressure: Implications for pressure reversal of general anaesthesia , 2015 .

[291]  A. D. Jackson,et al.  The stability of solitons in biomembranes and nerves , 2005, The European physical journal. E, Soft matter.

[292]  M. Chalfie,et al.  The MEC-4 DEG/ENaC channel of Caenorhabditis elegans touch receptor neurons transduces mechanical signals , 2005, Nature Neuroscience.

[293]  K. Miller,et al.  The perturbation of lipid bilayers by general anesthetics: a quantitative test of the disordered lipid hypothesis. , 1980, Molecular pharmacology.

[294]  Jason Wu,et al.  Localized force application reveals mechanically sensitive domains of Piezo1 , 2016, Nature Communications.

[295]  N. P. Franks,et al.  Do general anaesthetics act by competitive binding to specific receptors? , 1984, Nature.

[296]  Barclay Morrison,et al.  Bioeffective Ultrasound at Very Low Doses: Reversible Manipulation of Neuronal Cell Morphology and Function in Vitro , 2009 .

[297]  Boris Martinac,et al.  Liposome reconstitution and modulation of recombinant N-methyl-d-aspartate receptor channels by membrane stretch , 2007, Proceedings of the National Academy of Sciences.

[298]  Oliver Beckstein,et al.  A hydrophobic gate in an ion channel: the closed state of the nicotinic acetylcholine receptor , 2005, Physical biology.

[299]  P. Sharma,et al.  Flexoelectricity in two-dimensional crystalline and biological membranes. , 2015, Nanoscale.

[300]  C. Morris,et al.  Nav channel mechanosensitivity: activation and inactivation accelerate reversibly with stretch. , 2007, Biophysical journal.

[301]  A. Rey,et al.  Bioinspired model of mechanical energy harvesting based on flexoelectric membranes. , 2013, Physical review. E, Statistical, nonlinear, and soft matter physics.

[302]  J. Fredberg,et al.  Fast and slow dynamics of the cytoskeleton , 2006, Nature materials.

[303]  K. Pauly,et al.  Hearing out Ultrasound Neuromodulation , 2018, Neuron.

[304]  J. Felmlee,et al.  Mechanical transient‐based magnetic resonance elastography , 2005, Magnetic resonance in medicine.

[305]  Actuation of flexoelectric membranes in viscoelastic fluids with applications to outer hair cells , 2014, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[306]  D. Prince,et al.  Temperature dependence of intrinsic membrane properties and synaptic potentials in hippocampal CA1 neurons in vitro , 1985, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[307]  Huajian Gao,et al.  An electromechanical liquid crystal model of vesicles , 2008 .

[308]  D. Ingber Tensegrity I. Cell structure and hierarchical systems biology , 2003, Journal of Cell Science.