Development of a transcranial focused ultrasound device for the modulation of brain activity

Principal investigator: Tamás Kiss <kiss.t@wigner.hu>

Noninvasive ultrasound methods related to studying or modifying brain function have been investigated for more than 70 years now, and recently it was shown that transcranial focused ultrasound (tFUS) stimulation in the CNS can directly excite or inhibit neuronal activity, as well as affect perception and behavior. One particular application of this technology might be the suppression of aberrant brain activity to treat certain conditions, including for example epilepsy, Parkinson’s disease or depression. tFUS is particularly advantageous as it is capable to reversibly inhibit neuronal action potential generation, even in deep structures. While the application of tFUS is gaining momentum, precise mechanisms of how ultrasound is capable of modulating neuronal activity is still under debate.

Our group has recently initiated theoretical and experimental research on one hand, to use tFUS in animal models for the modulation of cortical brain activity, and on the other, to gain a better understanding of sub-cellular processes facilitating neuromodulatory effect of ultrasound at the cellular level.

This project is supported by the HUNRENTECH — Technology Transfer Grant, TECH-2024-020 of the Hungarian Research Network.

Systems level application of tFUS

We have started an extensive literature research and numerical simulations of ultrasonic wave propagation in brain tissue. We studied approaches to focus sound beams of a miniature ultrasound transducer to reach either cortical or deep brain areas in the rodent brain.

In collaboration with Medi-CAD Kft. we developed a miniature ultrasound transducer that can be attached to the skull of a freely moving mouse and modulate its brain activity on-line. Concurrently, we conduct electrophysiological recordings collecting electroencephalography, electromyography and electrocardiography data to detect the vigilance state of behaving animals. A combination of sensor data collection, real-time detection of behavioral state, and an ability to stimulate using our tFUS system will allow us to modulate ongoing pathological brain activity on-line.

These plans have now reached their first in vivo results. Using our miniaturized device in anesthetized rats, transcranial focused ultrasound directed at the motor cortex produced motor responses — limb movements time-locked to the ultrasound pulses — demonstrating that the device can drive cortical output through the intact skull. In the same preparation, ultrasound reliably evoked electrical responses recorded by EEG over the frontal and parietal cortex, and these evoked potentials were robust and reproducible across multiple animals. Together these findings are a first proof of concept that our transducer can non-invasively modulate cortical activity in the living brain. (See our posters in the Dissemination section below on some figures showing our new results.)

In silico exploration of sub-cellular effects of ultrasound

Building on a long-lasting tradition of the group in biophysical modeling of individual neurons, as well as small neural networks, we are aiming at using computer modeling to understand sub-cellular processes that play key roles in modulating neural electrical activity resulting from ultrasonic stimulation. At present, there are three dominant mechanisms considered by the community: cavitation, temperature change, and mechanical deformation. Whilst changes in temperature and mechanical deformation of the cellular membrane might lead to modulated ionic flow across the membrane either by modulating ion channel behavior directly or via disrupting lipid rafts, cavitation (the formation of bubbles inside the neuronal membrane) results in capacitance changes or fracture of the cell membrane. Using detailed biophysical modeling, we aim at dissecting the effect of each of these phenomena, and map out their effect on neuromodulation.

Direct cellular evidence: in vitro patch-clamp recordings

To test these mechanisms directly, we recorded from individual mouse hippocampal neurons in culture using whole-cell patch-clamp, before and about 20 minutes after a brief (1 minute) low-intensity ultrasound exposure. By pharmacologically blocking synaptic transmission we isolated each neuron, so that any change we measured reflected the cell’s own membrane rather than network activity.

A single short exposure produced lasting changes that outlived the stimulation itself. Sonicated neurons showed a persistent depolarization of the resting membrane potential and a marked increase in membrane-potential noise, while remaining morphologically healthy and firing normally; sham-treated cells did not change. Modelling each neuron as a simple electrical circuit revealed the underlying cause: ultrasound reduced the membrane capacitance by roughly a third and shifted the leak reversal potential in the depolarizing direction, without changing how leaky the membrane was. Because the membrane conductance was unchanged, the effect is not membrane damage or pore formation; and because it persisted with synapses blocked, it reflects a receptor-independent, membrane-level mechanism. These two passive changes alone can account for the observed shifts in resting potential and excitability, pointing to the lipid
membrane itself as a route through which ultrasound leaves a lasting “offline” mark on neurons.

Dissemination of our work