Abstract:Diverse translational and research applications could benefit from the noninvasive ability to reversibly modulate (excite or suppress) CNS activity using ultrasound pulses, however, without clarifying the underlying mechanism, advanced design-based ultrasonic neuromodulation remains elusive. Recently, intramembrane cavitation within the bilayer membrane was proposed to underlie both the biomechanics and the biophysics of acoustic bio-effects, potentially explaining cortical stimulation results through a neuron… Show more
“…For example, we note that membrane mechanoelectrical effects involving dimensional changes were suggested in other contexts involving changes in intramembranal forces, including action potential-related intramembrane thickness variations [51][52][53] and ultrasoundinduced formation of intramembrane cavities (or "bilayer sonophores" [54]). The neuronal intramembrane cavitation excitation theoretical framework putatively explains ultrasonic neuromodulation phenomena (suppression and excitation [55]) and predicts the results of a significant number of related experimental studies [56,57].…”
Modern advances in neurotechnology rely on effectively harnessing physical tools and insights towards remote neural control, thereby creating major new scientific and therapeutic opportunities. Specifically, rapid temperature pulses were shown to increase membrane capacitance, causing capacitive currents that explain neural excitation, but the underlying biophysics is not well understood. Here, we show that an intramembrane thermal-mechanical effect wherein the phospholipid bilayer undergoes axial narrowing and lateral expansion accurately predicts a potentially universal thermal capacitance increase rate of ∼0.3%=°C. This capacitance increase and concurrent changes in the surface charge related fields lead to predictable exciting ionic displacement currents. The new MechanoElectrical Thermal Activation theory's predictions provide an excellent agreement with multiple experimental results and indirect estimates of latent biophysical quantities. Our results further highlight the role of electro-mechanics in neural excitation; they may also help illuminate subthreshold and novel physical cellular effects, and could potentially lead to advanced new methods for neural control.
“…For example, we note that membrane mechanoelectrical effects involving dimensional changes were suggested in other contexts involving changes in intramembranal forces, including action potential-related intramembrane thickness variations [51][52][53] and ultrasoundinduced formation of intramembrane cavities (or "bilayer sonophores" [54]). The neuronal intramembrane cavitation excitation theoretical framework putatively explains ultrasonic neuromodulation phenomena (suppression and excitation [55]) and predicts the results of a significant number of related experimental studies [56,57].…”
Modern advances in neurotechnology rely on effectively harnessing physical tools and insights towards remote neural control, thereby creating major new scientific and therapeutic opportunities. Specifically, rapid temperature pulses were shown to increase membrane capacitance, causing capacitive currents that explain neural excitation, but the underlying biophysics is not well understood. Here, we show that an intramembrane thermal-mechanical effect wherein the phospholipid bilayer undergoes axial narrowing and lateral expansion accurately predicts a potentially universal thermal capacitance increase rate of ∼0.3%=°C. This capacitance increase and concurrent changes in the surface charge related fields lead to predictable exciting ionic displacement currents. The new MechanoElectrical Thermal Activation theory's predictions provide an excellent agreement with multiple experimental results and indirect estimates of latent biophysical quantities. Our results further highlight the role of electro-mechanics in neural excitation; they may also help illuminate subthreshold and novel physical cellular effects, and could potentially lead to advanced new methods for neural control.
“…47 The study suggested that FUS intensity dictates whether a net outcome is an excitation or an inhibition as much as does a specific FUS pulsing protocol. In particular, short, repetitive pulses of the FUS—which correspond to low values of the duty cycle—are more likely to produce an inhibition, whereas longer repetitive pulses—higher duty cycle values—are more likely to lead to an excitation.…”
“…39 FUS can excite or inhibit cellular activity, depending on specific stimulation parameters. 47 FUS can cause a transient increase in firing rates in motor cortex and in the retina with short latency, 39,55 and thus has a direct capability to influence cellular discharge. It has been hypothesized that these effects are mediated by ion channels that can detect changes in membrane stretch following a propagating pressure wave.…”
“…This hypothesis has not, thus far, found robust experimental support. 50,51 A relatively recent model based on this idea, “intramembrane cavitation,” 29,47,48 predicts a profound drop of the membrane potential in response to FUS onset. The proposed drop measures ≥ 100 mV in the hyperpolarizing direction and can be observed for a period of several milliseconds.…”
Section: Mechanism Of Ultrasonic Neuromodulationmentioning
confidence: 99%
“…This dependence reflects the proposition that the activity of certain classes of ion channels can be sensitive to the duty cycle. 47 For example, low-threshold spiking interneurons expressing T-type calcium channels may be activated using pulses of short duty cycles, which may lead to a net inhibition. 47 …”
The understanding of brain function and the capacity to treat neurological and psychiatric disorders rest on the ability to intervene in neuronal activity in specific brain circuits. Current methods of neuromodulation incur a tradeoff between spatial focus and the level of invasiveness. Transcranial focused ultrasound (FUS) is emerging as a neuromodulation approach that combines noninvasiveness with focus that can be relatively sharp even in regions deep in the brain. This may enable studies of the causal role of specific brain regions in specific behaviors and behavioral disorders. In addition to causal brain mapping, the spatial focus of FUS opens new avenues for treatments of neurological and psychiatric conditions. This review introduces existing and emerging FUS applications in neuromodulation, discusses the mechanisms of FUS effects on cellular excitability, considers the effects of specific stimulation parameters, and lays out the directions for future work.
Neuromodulation is a clinical tool used for treating chronic neuropathic pain by transmitting controlled physical energy to the pre‐identified neural targets in the central nervous system. Its drug‐free, nonaddictive, and improved targeting characteristics have attracted increasing attention among neuroscience research and clinical practices. This article provides a brief overview of the neuropathic pain and pharmacological routines for treatment, summarizes both the invasive and noninvasive neuromodulation modalities for pain management, and highlights an emerging brain stimulation technology, transcranial focused ultrasound (tFUS), with a focus on ultrasound transducer devices and the achieved neuromodulation effects and applications on pain management. Practical considerations of spatial guidance for tFUS are discussed for clinical applications. The safety of transcranial ultrasound neuromodulation and its future prospectives on pain management are also discussed.
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