Mechanics in Brain Biology
Mechanical interactions within the brain are crucial to its biological functions, influencing cellular and sub-cellular activities. Characterizing the biomechanics of brain tissue is challenging due to its complex, multilevel structure and its integration with neuronal activity. Brain tissue is multiphasic, involving various loading modes and regional differences in mechanical properties. Mechanical forces interact with structures such as the cell membrane, cytoskeleton, and associated proteins, impacting numerous neural functions. For instance, physical stimuli can directly gate and activate ion channels, mechanical tension can affect synaptic vesicle clustering and neurotransmission, and force generation is essential for axonal growth cone dynamics. While mechanobiology's link to neuronal signaling is evident, the connection between mechanics and cellular function remains underexplored. Understanding brain and neuronal biomechanics and linking neurological activity to changes in the mechanical environment could significantly advance our knowledge of brain function.
Multiphysics Coupling in the Neuronal Membrane
Historically, neurons and their electrophysiology have been modeled using the Hodgkin-Huxley framework, which describes action potentials as purely electrical phenomena. The action potential arises from the depolarization and repolarization of the neuronal membrane in response to chemical fluxes, generating electrical currents. However, recent research highlights a more complex coupling between mechanical and electrophysiological properties in neurons. Experimental evidence suggests that nerve pulses involve more than just electrical components and are accompanied by small, rapid surface motions. Additionally, mechanical forces play a significant role in propagating action potentials within neurons and modulating the functioning of membrane proteins like ion channels.
The lipid bilayer of the neuronal cell membrane plays a central role in the coupling of mechanical and electrochemical properties. Traditional models view cell membranes as passive 2D Newtonian fluids with lateral diffusion of embedded proteins. Recent research, however, emphasizes the active nature of neuronal membranes, which are influenced by mechanical factors such as protein transport, membrane pressure, cholesterol content, lipid bilayer phase, and stiffness. Changes in these mechanical properties modulate membrane behavior and action potential propagation. Incorporating this coupling into neuroscience models could enhance our understanding of neuronal function.
Modeling Neurons and the Brain
Despite extensive theoretical and computational work on neuron and neuronal bilayer mechanics, most current models and simulation techniques often neglect the coupling of mechanical, electrophysiological, and chemical properties. Existing models of the lipid bilayer typically focus on equilibrium states, linearized settings, or simplified mechanical dynamics. Some numerical models couple electrophysiological and mechanical properties, but they often rely on the Hodgkin-Huxley framework and remain limited in scope. A more comprehensive approach is needed to integrate mechanical evolution with electrical and chemical responses of neuronal membranes.
We propose developing a coupled biochemical-mechano-electrophysiological model for neuronal membranes, including responses to anesthetics and ultrasound neuromodulation. The Onsager variational principle, which extends Rayleigh’s principle of least energy dissipation to nonlinear systems, provides a powerful tool for modeling the coupled behavior of neuronal membranes. This principle, previously applied to deformable membranes, could enhance our understanding of neuronal membrane dynamics.
Importance to Neuromodulation
A consistent multiphysics model of neurons could significantly impact neurological modeling and medical procedures. Recent studies have shown that the anesthetic isoflurane decreases electrophysiological activity and correlates with changes in neuronal viscoelasticity. Similarly, mechanical vibrations at ultrasonic frequencies have been shown to alter electrophysiological properties. The proposed research aims to develop models that explore these neuromodulation techniques.
Low-intensity, low-frequency ultrasound (LILFU) is emerging as a precise tool for modulating neural activity deep within the brain. Evidence suggests LILFU can either excite or suppress neuronal activity, but the underlying micromechanisms remain unclear. Theories such as acoustic radiation force, cavitation, and sonoporation have been proposed, but it appears that ultrasound affects neural activity through changes in neuronal membrane states and ion channel dynamics.
General anesthetics, crucial for modern medicine, enable various surgical procedures, but their mechanisms are not fully understood. Recent research suggests that anesthetics interact with membranes, ion channels, and other subcellular structures, affecting cytoskeletal dynamics, cell contractile activity, lipid membrane fluidity, and lipid raft formation. These changes can alter membrane mechanics and influence charge distribution and intermolecular interactions within cells.
Understanding neuromodulation techniques like LILFU and anesthetics requires an integrated approach combining biochemistry, electrophysiology, and mechanics. A multiphysics approach could lead to new insights and technologies, enhancing safety, protocol design, and diagnostic capabilities in clinical settings, and facilitating advanced surgical interventions.
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