Key Points
- Dr. Murphy has developed new technologies for rapidly optimizing ultrasound neuromodulation.
- Learn more about his recent discoveries and a new company that is developing a wearable focused ultrasound neuromodulation device.
In 2022, Keith Murphy, PhD, was completing a postdoctoral research fellowship at Stanford University when he earned a Focused Ultrasound Foundation–sponsored award for his presentation at that year’s Focused Ultrasound Neuromodulation (FUN) meeting. We recently caught up with him to hear about what has happened in his career since then.
Read on to learn more about Dr. Murphy’s discoveries while studying cell- and region-specific parameters for ultrasound neuromodulation and how he intends to translate them to patients with psychiatric disorders and other conditions through the launch of a company and the development of a new wearable device.
When you received the award at the 2022 FUN meeting, what was your project?
The project was developing a high-throughput method combining deep brain optical recording with focused ultrasound neuromodulation. We were able to measure different cell-type sensitivities to ultrasound pressure. It was encouraging to be noticed by the Foundation and the community. The award certificate was signed by Til Ole Bergmann, who has been a long-time friend and mentor of mine, so I’ve always felt it was special – I still have it hanging on my fridge!
For the project, I worked with a great team of engineers, scientists, and translational researchers, which highlighted the diverse community and complexity of the space. Luis de Lecea, PhD, and I worked with Pierre Khuri-Yakub, PhD, and his team to build at least five iterations of the tool before landing on something we felt research laboratories could quickly pick up and use for their own interest. As an early demonstration of the tool’s capabilities, we simultaneously imaged excitatory and inhibitory neurons of the hippocampus, which allowed us to establish parameters for net excitation and bimodal modulation. Later, we teamed up with Ivan Soltesz, PhD, and Jordan Farrell, PhD, to show that focused ultrasound could suppress epileptiform activity in an epilepsy model, a feat that Ivan’s lab had previously shown by manipulating those cell types with genetic techniques.
What is unique about the tool that you developed during your postdoc?
At the time, all of the photometry-integrated tools out there required animals to be kept in place, through a head mount or anesthesia. Ours was the first that could be used in freely behaving animals, and we made it seamless with existing photometry implants and techniques. The ease of use sped up our ability to address fundamental questions about the way that different brain circuits respond to ultrasound. Our discoveries were published in the Proceedings of the National Academy of Sciences (PNAS). See A tool for monitoring cell type–specific focused ultrasound neuromodulation and control of chronic epilepsy. While this work gave us some conviction that focused ultrasound could be used as a reversible therapeutic, it also led us to the realization of a much larger problem for the field: Nobody knew exactly which parameters were best to use for clinical research.
Throughout the project, we spent more than 300 hours recording from the mouse brain while incessantly changing the parameters across five different brain regions. Honestly, it was a pretty boring most of the time, without any obvious end of the tunnel. However, we did eventually land on a highly sensitive brain area and, with just the right pulsing scheme, we could reliably make animals walk around like zombies; that was incredible. Importantly, it was a clearly visible behavioral readout that the field really needed, since a lot of the other readouts are anesthesia-dependent or just difficult to measure.
Did your research ever send you down unexpected paths?
Definitely. In fact, one of the most interesting findings came from trying to directly measure temperature rise in the brain during stimulation. Counterintuitively, our recordings kept showing us cooling, and everyone kept telling us it was an artifact no matter how many times we tried it. But we kept going and, after a lot of validation with various techniques, we concluded that excitatory protocols cause widespread vasoconstriction of blood vessels. Anyhow, we never explicitly tested this, but our hypothesis is that cool cerebrospinal fluid (CSF) is flushing into the empty space created by shrinking blood vessels, mixing with warmer deep brain fluids, and lowering the deep brain temperature. We hope that others might follow up on this work since the cooling and fluid mixing has broader implications for treating neurodegenerative disorders (by clearing toxins from the brain). This work was published in the October 2024 issue of the journal Neuron. See Optimized ultrasound neuromodulation for non-invasive control of behavior and physiology.
What have you done since completing your postdoctoral fellowship?
I started a deep brain stimulation company called Attune Neurosciences alongside Rajiv Mahadevan, MBA, a co-founder and our CEO. The company was founded with the intention of improving the ultrasound neuromodulation usability and form factor to bring the treatment closer to comfort, and eventually at home. We’ve always been confident that this will be important for longer treatment and exploration needed for personalizing therapies. Our device is a mechanically and optically registered, MR-guided, wearable headset with 128 transducers; (64 on each side), and you can rapidly move the focus to a variety of important deep brain targets. Our hope is that the technology will be useful for numerous indications in patients with multiple co-morbidities, which is often the case with psychiatric disorders. We see our technology as an at-home multi tool for the brain that can be used to replace many types of medication. However, we recognize there is a long journey ahead to demonstrate safety and efficacy, and even longer to create something people want to use on a regular basis.
What applications will Attune Neurosciences be pursuing?
We are looking at sleep/wake, substance abuse, obsessive-compulsive disorder (OCD), depression, schizophrenia, chronic pain, and ataxia telangiectasia. To date, our studies show the device is safe and well tolerated, and we have definitely seen a lot of potential as a therapeutic. Beyond psychiatric and neurological disorders (which are a large part of our company), we are also interested in the quantity and quality of slow wave sleep. If we can improve sleep, we think we can improve many other conditions, since poor sleep is an extremely common comorbidity. There is also interest in enhancing cognition, for which we have received funding from the United States Special Operations Command, DARPA (Defense Advanced Research Projects Agency), and the US Air Force.
Tell us about your recent work on depression.
We teamed up with Andrew Krystal, MD, the Ray and Dagmar Dolby Distinguished Professor in the Departments of Psychiatry and Neurology at the University of California–San Francisco (UCSF), and Joline Fan, MD, MS, an assistant professor of neurology at the UCSF Weill Institute for Neurosciences, with the idea that we could use focused ultrasound to explore therapeutic brain areas the same way they had done in the past with DBS leads. I’m happy to report that, for our first subject, we found an area that reliably helped him; there is a case report on this recently published in Brain Stimulation (see Thalamic transcranial ultrasound stimulation in treatment resistant depression). This trial is ongoing and has been expanded to include mood changes in healthy individuals. We’ve taken a similar approach with OCD in a partnership with Elsa Fouragnan, PhD, at the University of Plymouth. There are a lot of brain areas involved in OCD, and we’ve had some really exciting results so far.
What did you recently discover about one of the regions of the brain?
There is an area of the brain called the anterior nucleus of the thalamus (ANT), which is heavily networked with emotional brain areas. Although it’s targeted in epilepsy, a side effect of treatment can be mood worsening, which can be enough of a reason to avoid it. Intriguingly, stimulating the ANT with focused ultrasound ended up improving the subjects’ mood; the change was reliable across sessions, even while mixing up the protocols. When we looked at the brain using functional MRI, we found that the treatment substantially normalized the subjects default mode network, which regulates ruminative thinking. We think this discovery may have applications for improving meditation, decreasing anxiety, and treating post-traumatic stress disorder (PTSD), so we are planning studies in these areas.
Is there anything else you would like to add?
Yes, we’ve been working tirelessly on an extensive practical guide through the International Transcranial Ultrasonic Stimulation Safety and Standards (ITRUSST) consortium, a group envisioned by Lennart Verhagen, PhD, as a means to synchronize and safely advance the field. If you’re interested in this space and current best practices, we’ve made it publicly available through arXiv open-access archive. See A Practical Guide to Transcranial Ultrasonic Stimulation from the IFCN-endorsed ITRUSST Consortium. Also, if you’re interested in some speculation on where the field is headed, take a look at an opinion piece I wrote with Elsa that was published in PLOS Biology and highlighted on The Engineer and MedImaging.net.
See The future of transcranial ultrasound as a precision brain interface.