BrainSonix | Research
BrainSonix has developed and intends to manufacture and market a medical device platform based on the Company’s proprietary Low Intensity Focused Ultrasound Pulse (“LIFUP”) technology to modulate the brain function non-invasively without any harmful or irreversible effects on the brain and body.
Low Intensity Focused Ultrasound Pulse, LIFUP, brain neuromodulation, deep brain stimulation, Repetitive Transcranial Magnetic Stimulation, Alexander Bystritsky, Woody Wurster, Mark Schafer, Alex Korb, BrainSonix, John Marlow
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Research

LIFUP: A NEW BRAIN STIMULATION METHOD

Neuromodulation has become increasingly relevant to clinical research with the recent approval by the Food and Drug Administration of Deep Brain Stimulation, vagus nerve stimulation, and repetitive transcranial magnetic stimulation. However, these techniques have significant drawbacks including the lack of special specificity and depth for the rTMS, and invasiveness and cumbersome maintenance for DBS.
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Using a new brain stimulation method called Low-Intensity Focused Ultrasound Pulsation (LIFUP), we now have the ability to utilize ultrasound to focus non-invasively through the skull anywhere within the brain, together with concurrent imaging techniques.
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The following research articles provide an overview of our progress thus far:

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EARLY WORK ON LIFUP

Although the first attempts to study the effect of US on neuronal tissue began nearly 80 years ago, systematic scientific exploration of this field did not start until the 1950s. At that time, several articles, in different languages, described the effect of US on neuronal tissues, with the most relevant English language articles arising from Fry’s laboratory. The studies demonstrated that US could induce reversible physiologic effects on nervous tissue, which ranging from increased activity to reversible suppression of visual evoked potentials. Notably, Fry’s studies documented both excitation and inhibition of neuronal tissue without concomitant histologic changes in the sonicated area.
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Between 1960 and 1990, only a few papers were published on this topic. Much of the data came from the laboratory of Gavrilov in Moscow. These reports showed that FUS, in both humans and animals, was capable of stimulating inner ear structures, as well as the auditory nerve directly. With respect to safety, these studies further documented reversible neuromodulation with US, without observable damage of neuronal tissue. Several other laboratories, also exploring the effects of US on neuronal tissue, found similar results. All of the above studies found reversible enhancement, or depression, of neuronal activity in brain slices or in peripheral nerves of animals and humans without histologic findings characteristic of thermal
damage or cavitation.
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The 1990s saw an increased interest in the use of FUS for several practical applications: use of HIFU for ablation, stroke thrombolysis, and peripheral nerve blocking. Interest increased with the discovery that FUS can be used also to open the blood brain barrier (BBB), and deliver drugs to the brain focally. Disrupting the BBB with US could be done with or without use of a contrast agent that enchases the cavitations at lower power of ultrasonic application. Disruption of the BBB at lower powers was usually reversible, and accompanied only by minimal evidence for apoptosis and ischemia. Although disruption of the BBB opens another chapter in direct drug delivery to specific areas within the brain a full review of this topic is beyond the scope of this manuscript. Low-energy FUS has also been effective therapeutically for accelerating oostfracture healing time in bone. However, functional modulation of brain activity remains one of the most interesting possible applications of FUS.

RECENT EXPERIMENTAL LITERATURE

The last decade has seen an increased interest in research on the neuromodulating properties of LIFUP. With advancements in multi array transcranial transmission of US and real time functional imaging for guidance, the possibility of LIFUP for human brain mapping is approaching rapidly. Tsui found US parameters that lead to modulation of action potentials in peripheral nerves. Shorter duration pulses of US seem to activate, whereas longer pulses seem to inhibit, the amplitude and velocity of action potentials. A recent publication by a University of Arizona group not only confirmed reports of LIFUP induced neuromodulation in mouse hippocampal preparations, but also offered insight into possible mechanisms of this effect, such as influencing voltage gated sodium and calcium channels. Later, a paper by the same group described for the first time neuromodulation using US pulsation in vivo in the motor cortex of mice. Using LIFUP focused on motor cortex, they were able to evoke movements of the paws during transcranial stimulation. In this same report, when focusing LIFUP on the hippocampus, they were able to increase spike activity in CA1. In both cases, they found no evidence of BBB disruption or apoptosis.
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Several studies on modulation of nerve conduction by FUS were recently reported from the Brigham and Women’s Hospital, Harvard Medical School. In a recent paper, Colucci et al. investigated the safety thresholds for conductivity suppression using LIFUP in sciatica nerve of bullfrogs. The authors determined that stimulation of the nerve with FUP could suppress conductivity reversibly for up to 45 minutes. Some of the effects were found to be thermally mediated, and some could not be explained by the thermal suppression. Specifically, non thermal effects were present with low frequency sanitation (650 kHz). Yoo et al. investigated low intensity for an in vivo real time functional MRI (rtfMRI) neuromodulation study in rabbits. LIFUP caused observable changes in the blood oxygenation level dependent (BOLD) fMRI signal, but did not interfere with the recording. Both activation and suppression of the BOLD signal could be achieved by varying FUS pulse parameters. Visual cortex responses to a strobe light stimulation could be suppressed reversibly for up to 11 minutes without causing BBB or tissue damage on postmortem histologic analysis.
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Since then, the Brigham and Women’s Hospital group have confirmed BOLD signal suppression using EEG visual evoked potentials (VEP), and studied the suppression effect on epileptic seizures. The rat pentylenetetrazol (PTZ) seizure model was used, wherein the rats were injected with PTZ and then underwent the LIFUP stimulation to suppress the seizures. The results from a study of 30 animals reveal that low-intensity, pulsed FUS sanitation suppressed the number of epileptic signal bursts observed in EEG recordings after the induction of acute epilepsy via intraperitoneal injection of PTZ. These finding suggest a potential role for LIFUP in the treatment of epilepsy, but this has not yet been tested in human experiments.

BARRIERS TO PROGRESSION TO HUMAN TRIALS

Our review of past literature and recent experiments in several laboratories around the country confirms that neuromodulation of central neuronal circuits using LIFUP is possible, and most likely safe. Our experiments demonstrated that this technology could be used simultaneously with rtfMRI and navigated by MRI. Most of the scientific literature agree that low-intensity FUS does not damage tissue unless excess thermal effects are present.
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In our recent study, we were able to measure temperature in the focus of LIFUP during stimulation. We did not find any temperature elevation, even when using prolonged stimulation. We also identified both excitatory and inhibitory sanitation parameters, which we successfully used in vivo in rabbits and rats. In addition to our in vivo research, Tyler and his group at the University of Arizona demonstrated activation in vivo in mice. This group also elucidated possible mechanisms of the LIFUP effect on neuronal tissue. Thus, many of the issues we discussed in the ‘‘potential challenges’’ have been studied. However, much more work needs to be done. Unfortunately, some of this work, such as precise focusing and navigation of LIFUP through the human skull, and identification of the effective and safe human parameters of this technique, can be done only in humans. We believe that it is time to carefully precede to the first human use trials.
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The arguments for human trials are the following:
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1. All of the more than 30 publications described in this review using LIFUP in different experimental setups (brains, peripheral nerves, and neuronal tissues) demonstrated biologic effects without damaging the tissues when sub thermal stimulation was used.
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2. Recent experiments in BWH and University of Arizona demonstrated safety and biologic effects (i.e., motoric activation and seizure suppression) in several different types of animals including (frogs, mice, rats, and rabbits).
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3. Focused US has been used in humans in the United States and in Switzerland for ablation, which is destructive to the tissue in the focus. Outside the focus, the energy of the ablative ultrasound still exceeds the energy level at the focus of LIFUP device. However, no tissue damage was found in any other location but US focus
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4. Doppler US, which has been used extensively on the brains of adults and children, is similar to the energy that we use in the LIFUP method.
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5. US is used in surgical guidance with energies that exceed LIFUP in dental. For example, US in nasopharyngeal surgery navigation, or for blood clot dissolution, has been safely used in humans.

FUTURE EXPERIMENTS

We believe that future experiments will need to focus on several aspects of LIFUP such as pulse parameters for delivery through human skull. This problem has been solved in many ways in the application of HIFU for surgical ablation. However, it is still unclear that low-intensity US pulsations would be able to penetrate into deep areas of the brain and be precisely navigated through an intact human skull, though there appears to be no a priori theoretical limitation. Some of this work could be done in phantom simulations and human skulls, but the final test will need to be done in humans. The effects of LIFUP on larger brains have not been reported; pig or monkey experiments are to document the safety of LIFUP in larger volume brains. Those experiments are indeed on the way in several university laboratories. For example, we have recently stimulated the hypothalamic area of a mini pig using LIFUP transcranially. The stimulation was delivered through the lower plate of the skull, which is similar in thickness to a human skull. In five experiments, stimulating the hypothalamic area consistently increased both blood pressure and heart rate demonstrating an effect similar to that usually evoked by DBS in the same region.
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Given that the focusing of US in complex structures such as the human head is difficult, to optimize the localization of stimulation, imaging will likely remain an important component of the practical application of LIFUP. A variety of methods have been put forward to guide ablative, HIFU therapy, such as MR thermometry and more recently acoustic radiation force imaging (ARFI). However, higher sensitivity could be required to visualize the effects of lower intensity sanitation. For better navigation, and monitoring of thermal and BOLD effects, it is necessary to optimize the parameters to be used in the fMRI environment. Similarly, a more systematic, and broader, evaluation is needed of the duration of optimal treatment in different neuronal circuits, and structures, as well as how many treatments are needed to modify the circuits for a prolonged period.

FUTURE APPLICATION: BRAIN MAPPING AND THERAPEUTIC POTENTIAL

Focused US, combined with rtfMRI, could potentially be used for brain mapping paradigms that help identify and diagnose functional disorders of the brain that currently lack clear neuronal underpinnings. For example, bipolar mania, OCD, depression, autism, and others could benefit from these studies. Treatment of neurologic disorders such as chronic pain, obesity, and Parkinson’s might be possible via LIFUP induced neuroinhibition, as it may reach deep brain areas non invasively. Pain, obesity, epilepsy, OCD, and other mental disorders, Parkinson’s, and other movement disorders, that is, the therapeutic areas where DBS has shown some promise all may be treatable with LIFUP.
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Therapy with LIFUP may find a niche between medication treatments (which are still most convenient) and invasive strategies (i.e., ablation and DBS) that should be reserved for the most severe conditions that require permanent disruption or attenuation of neuronal circuitry. The unique properties of the LIFUP, which include noninvasiveness, small focus, and real time feedback from fMRI imaging could provide us with better understanding of brain function and better targeted treatment of mental and neurologic disorders.
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NOTE: Please reference “A review of low-intensity focused ultrasound pulsation” published in Brain Stimulation Journal (July 2011) for the complete article including citations.