Focused Ultrasound Neuromodulation

Ultrasound has been consistently reported for neuronal stimulation for several decades in both animals and humans including eliciting brain activity detected by functional MRI and electroencephalography. In addition, this knowledge can be used to understand the differences between normal and pathological brains to treat patients. In the peripheral nervous system, the leading technique to treat peripheral neurological disorders is implantation of electrodes along the peripheral nerve and stimulating the nerve with electrical current. A noninvasive alternative that could treat neuropathic pain and suppress nerve activity constitutes thus an important challenge in interventional neurology.Our group has been studying the noninvasive stimulation or inhibition of both the central and peripheral nervous system in live animals. In the brain, we have shown that focused ultrasound is capable of noninvasively stimulating paw movement as well as sensory responses such as pupil dilation and eye movement when different brain regions are targeted, showing for the first time that ultrasound can trigger both motor and sensory brain responses. In the periphery, when the ultrasound beam is focused on the sciatic nerve in a live, anesthetized animal, the thigh muscle becomes activated and muscle twitches can be induced at low ultrasonic intensities while the same twitches can be inhibited at higher intensities due to associated temperature rise that inhibits nerve firing. In humans, a peripheral sensory response has also been elicited. Cellular and fiber responses in excised tissue have confirmed the live animal responses. An overview of the aforementioned findings together with the most recent results will be presented.

Transcranial focused ultrasound (tFUS)-based strategies for non-invasive and localized neuromodulation are rapidly expanding; however, the effects of plasma protein binding (PPB), which plays an important role in drug pharmacokinetics, particularly for central nervous system drugs, have long been overlooked. We demonstrate the non-invasive and localized unbinding of PPB from phenytoin, an anti-epileptic drugs with high affinity to albumin, using FUS delivered at a fundamental frequency of 250 kHz in a pulsed manner (55 ms tone burst duration, 4 Hz pulse repetition frequency), at 5 W/cm2 spatial peak pulse average intensity (Isppa). No microbubble-based ultrasound contrast agent was used. Equilibrium dialysis was performed on the sonicated buffered-saline containing therapeutic concentration of phenytoin and bovine serum albumin, and yielded a 27.7% elevation in the level of unbound phenytoin compared to an unsonicated control. Sonication of a brain hemisphere in rats (n = 10) that received intraperitoneal phenytoin, though immunohistochemistry (IHC) assessment, showed elevated regional phenytoin uptake compared to the unsonicated hemisphere, without actively disrupting the BBB. Temperature change was not seen. These findings demonstrate the use of FUS as a novel technique for spatially-selective unbinding of PPB, which may alter a wide range of drug–plasma protein interactions. The study suggests the utiliy of trancranial FUS in elevating local concentration of a free, unbound pharmaceutical agent and subseuqent neuromodulatory effects by the agent.

Low intensity transcranial focused ultrasound (LIFU) is a promising non-surgical low-energy technique for transient neuromodulation with high spatial resolution and adjustable focus suitable for targeting cortical and sub-cortical human brain regions. Here, we will discuss current state of the art as well as progress and challenges for developing LIFU for human clinical applications. 

Research by Professor Antoine Jerusalem and his team focusses on electrophysiological-mechanical coupled pulses in neural membranes. This endeavour is set to benefit the medical community in the diagnosis, prognosis, and treatment of Traumatic Brain Injury and Spinal Cord Injury, both major, global public health issues, while providing new avenues for non-invasive electrophysiological control, such as pain management.

FUS Foundation

Director of Clinical Relationships

With her prior clinical experience as a neuroradiologist and having performed hundreds of focused ultrasound procedures, Suzanne LeBlang, MD, now represents the Foundation by interacting with various manufacturers and clinicians to foster collaborations. She interfaces with the medical community including clinicians and societies at various meetings in order to update the Foundation staff. In coordination with the communications team, she helps increase awareness through oral presentations and articles. She also assists the Chairman and the development team with building relationships with individuals and other foundations. She has published papers and delivered numerous scientific talks in the field of focused ultrasound. Suzanne received her B.A. in Biology and M.D. degree from the University of Miami 6 year Honors Program in Medical Education. She serves on the faculty at the University of Miami Medical School where she is the Radiology Clinical Coordinator for 3rd year M.D./M.P.H. students, and she teaches at the Florida Atlantic University Schmidt College of Medicine. She has been visiting faculty at several institutions including Harvard University and Ohio State University.

To understand brain circuits we need to more than measurement; we need to modulate neural activity as well. This is even more critical in a clinical context. Current interference techniques are either highly invasive, or restricted to the surface of the brain. Focused transcranial ultrasound has the potential to overcome these limitations. I will discuss how we can use low-intensity ultrasound to safely stimulate deep brain structures, such as the amygdala, with high precision. To date, effects were short-lived, limiting its relevance to the clinic. In pioneering non-human primate work, we showed how a novel repetitive protocol induces hour-long plastic changes. Whole-brain fMRI allowed us to track how ultrasound impacted both local and remote circuits. Behavioural measurements revealed the specific consequences of a focal neural perturbation on cognitive computations. I will discuss work on the causal roles of the anterior cingulate cortex, amygdala, basal forebrain, and ventromedial prefrontal cortex in decision-making and learning.

The soliton theory provides an alternative explanation for the nervous impulse based on cooperative melting transitions in the biomembrane.  It relies on reversible electromechanical processes and the thermodynamics of membranes. During the nervous impulse, the membrane is shifted through its transition, with associated changes in heat capacity, compressibility and inherent time-scales. The latent heat of the transition explains the sign and the magnitude of the experimentally observed reversible heat production of the action potential and the observed changes in nerve dimension (shortening and increase in membrane thickness). The dimensional changes give rise to the possibility to excite the nerve mechanically or thermally.

In the transition, one finds fluctuations in the membrane permeability corresponding to spontaneous pore formation, which in a patch clamp experiment are indistinguishable from the quantized current events usually attributed to protein channels.  They show most features of protein channels including temperature- and mechano-sensitivity, and voltage-gating. Their characteristic open time scales can be understood in the context of the fluctuation theorems applied to a membrane.

Membrane fluctuations therefore provide an estimate for the most suitable time-scale of membrane excitation. After a perturbation, relaxation processes in artificial membranes may display relaxation time scales up to several seconds. In biomembranes close to transitions, the expected relaxation time scales are expected to be in the millisecond regime. This is also the time scale of the open-lifetimes of membrane pores - and as it happens, the typical lifetime of protein channels. Therefore, we argue that this is also the time-scale of the most effective nerve membrane excitation.

Focused Transcranial Ultrasound Stimulation enables us to non-invasively and transiently modulate activity in subcortical and deep cortical brain structures, without the need of any surgical procedure. I am particularly interested in using low-intensity ultrasound stimulation to investigate the neural and behavioural effects resulting from a transient interference of neural communication between different brain regions within a circuitry. The capacity of transcranial focused ultrasound stimulation to alter activity in regions located deep below cortex will allow us to better understand the contribution of these structures to normal and pathological cognition.