Ph.D Thesis

Ph.D StudentPlaksin Michael
SubjectNanoscale Membrane Vibrations and Currents Underlying
Neuro-Physical Excitation
DepartmentDepartment of Nanoscience and Nanotechnology
Supervisors PROFESSOR EMERITUS Eitan Kimmel
PROF. Shy Shoham


Different physical modalities can directly excite or suppress central nervous system (CNS) neuronal activity on a short time scale, including low intensity ultrasound (US) and a multitude of thermal excitation techniques. While scientific and medical applications for these neuro-physical phenomena are already emerging, the underlying biophysics remains largely unclear. Recent hypotheses put forward to explain neuron excitation highlighted nanoscale plasma membrane effects mediated by the physical waves: US-induced pulsating nano-bubbles inside the bilayer plasma membrane inducing 'intramembrane cavitation' vibrations (the bilayer sonophore or BLS model), membrane area changes by acoustic radiation pressure, and membrane charge redistribution mediated by temperature transients. In this work, we developed a comprehensive novel modeling framework that provides a detailed, quantitative and predictive view of the biophysical effects of these nanoscale membrane interactions.

We analyzed the relevant experimental literature using modified Rayleigh-Plesset intramembrane cavitation BLS biomechanics and acoustic radiation pressure (ARP) gradients - induced membrane dynamics. By coupling these biomechanical models to biophysical membrane models through membrane capacitance changes, we predict dynamical biophysical responses of artificial bilayer membranes, and of three common neocortical single cell Hodgkin-Huxley (H&H) type models: i) Regular spiking (RS) cortical pyramidal neuron, ii) Fast spiking (FS) cortical inhibitory neuron and iii) Low threshold spiking (LTS) cortical inhibitory neuron and RS-FS-LTS H&H based network model. In addition, brain tissue ARP-gradients subjected areal strains were evaluated in a viscoelastic brain model. To explore thermal effects on membranes' biophysics, a Gouy-Chapman-Stern-based model was developed.

The Neuronal Intramembrane Cavitation Excitation (NICE) models were able to explain US-induced action potential generation through BLS-type pulsating nano-bubbles inside the bilayer plasma membrane: the leaflets' periodic vibrations induce US-frequency membrane capacitance and potential oscillations, leading to slow charge accumulation across the membrane (on a time scale of tens of milliseconds), until action potentials are generated. In contrast, the analysis of ARP-gradients-induced membrane capacitance variations associated with membrane area changes explain artificial membrane results, but were found to be highly unlikely sources for neural excitation, when considering the areal strains expected to form in brain tissue during normal sonication. Further, the NICE-LTS inhibitory neurons show a much higher relative sensitivity to sparse ultrasonic stimulation compared to the other neurons, resulting from their T-type voltage gated calcium channels. This model-based prediction was found to explain the results of a body of suppression and excitation experimental studies, including in humans. Finally, an analysis of thermal effects on neural membranes identifies the underlying phenomenon as resulting from an axial narrowing and lateral expansion of the membrane's core and thermal changes in its surrounding dielectric properties. This mechanism fully explains the highly reproducible ~0.3%/oC capacitance increases rates observed and allows to rigorously dissect thermal neural excitation. It further explains the results of multiple experiments, contradicting a popular earlier model.

In conclusion, the study has the potential to pave the way towards new CNS therapeutic protocols, using US and thermal neuro-physical modalities like infrared neural stimulation (INS) as promising targeted neuromodulation methods with spatial resolutions spanning from micrometers to millimeters essentially anywhere in the CNS.