Young Investigator Profile: Norman Spivak

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Key Points

  • Norman Spivak is an MD/PhD student conducting research on low-intensity focused ultrasound neuromodulation for treating disorders in psychiatry and neurosurgery. 
  • Learn more about his work and where he sees the future of focused ultrasound neuromodulation. 

Norman Spivak is an MD/PhD student at the University of California Los Angeles (UCLA), where he is conducting research on low-intensity focused ultrasound neuromodulation for applications in psychiatry and neurosurgery. His work has included the development of clinical trials investigating the technology for treating disorders of consciousness and generalized anxiety. 

Learn more about his work and where he sees the future of focused ultrasound neuromodulation. 

Focused Ultrasound Work 

When and how did you get interested in focused ultrasound? 

I first learned of focused ultrasound when I was working with Alexander Bystritsky, MD, PhD, at UCLA. I had become disillusioned with the limitations of transcranial magnetic stimulation (TMS), and Dr. Bystritsky pointed me toward ultrasound. I went on to complete my senior thesis under him exploring changes in brain tissue due to differing levels of ultrasound intensity. We published that study in 2021. 

I then spent three years working at UCLA, both with Dr. Bystritsky in the psychiatry department and with Martin Monti, PhD, in the neurosurgery department, working on various focused ultrasound clinical trials. I also started a clinical trial with Susan Bookheimer, PhD, investigating focused ultrasound for generalized anxiety disorder. Dr. Monti and I completed pivotal work in disorders of consciousness. 

I am continuing my MD, PhD training at UCLA, and I have approximately two more years of medical school after I finish my PhD. I have the honor and privilege of being jointly supervised by Profs. Susan Bookheimer and Martin Monti for my PhD work. 

What are your areas of interest in focused ultrasound? 

For my PhD thesis, I am translating research on an in-vivo intracranial human acoustic radiation force impulse (ARFI) technique for magnetic resonance imaging in humans and validating the current models of brain targeting. Abbreviated MR-ARFI, I am studying its use with low-intensity focused ultrasound neuromodulation. 

We tout focused ultrasound neuromodulation as being highly precise. But at the same time, we know that skull, skin, and hair distort and change the shape of the ultrasound focus. This problem is solved with high-intensity focused ultrasound because MR thermometry allows physicians to visualize the sonication area. However, MR thermometry is not effective in the lower intensity neuromodulatory work that I do – because, thankfully, any changes in temperature are below the threshold of detection with MR thermometry. 

There has been a lot of research in the last decade developing computational models of ultrasound where patient MR and CT scans are inputted along with the ultrasound parameters. The models calculate the location of the ultrasonic focus. My work involves validating these models empirically. 

What is the overall goal of your work? 

Long term, I would like to see low-intensity focused ultrasound act as an intermediary between diagnosis and final treatment with high-intensity, ablative focused ultrasound. As we learn about the different circuits that underlie disorders like depression and anxiety, I think low-intensity ultrasound allows us to really probe the network and see what part of the brain contains the most effective stimulation target. Then, there may be a place for high-intensity ablative procedures for a more durable solution. 

Research Details 

What device do you use for your work? 

I am using the BrainSonix system

What mechanisms and clinical indications do you study? 

I’m not certain where I want to focus my research, but I am interested in anxiety disorders and disorders of consciousness. 

Explain more about your disorders of consciousness work. 

The American Academy of Neurology classifies a disorder of consciousness as acute or chronic, based on how long it has been since the patient has entered the disorder and whether it is due to a traumatic or non-traumatic etiology. In our case, most of the patients had suffered a traumatic brain injury (TBI), so if it was less than one year from the TBI, it was acute. If it was more than one year out, it was chronic. 

We initially conducted a study using neuromodulation in an acute coma patient, and that case report was published in 2016. However, the problem was that sometimes acute patients spontaneously recovered, so we were having difficulty distinguishing whether the effect was due to the ultrasound. That led to the chronic arm of our project, where we would bring patients with a chronic disorder of consciousness to UCLA for a day of focused ultrasound neurostimulation and then follow them after they returned home. Because their condition was chronic, they were considered to be much more stable, so it would be clearer if the ultrasound was having an effect. 

What did you discover before publishing your latest paper? 

We recently published “Transcranial Focused Ultrasound Targeting the Amygdala May Increase Psychophysiological and Subjective Negative Emotional Reactivity in Healthy Older Adults” in Biological Psychiatry: Global Open Science. This study was conducted in healthy volunteers who underwent two days of neuromodulatory stimulation, two weeks apart. On one day we stimulated the amygdala, and on the other day we stimulated the entorhinal cortex. Before and after each stimulation, the participants completed an emotional reactivity task. We found that after the amygdala was stimulated, emotional reactivity went up, but we did not see a change after entorhinal cortex stimulation. 

Ongoing Clinical Trials 

Do you have any clinical trials currently ongoing? 

We are taking part in a multisite clinical trial (NCT04557891), alongside colleagues at Massachusetts General Hospital and the Medical University of South Carolina, exploring the use of focused ultrasound neuromodulation to treat patients with refractory generalized anxiety disorder. Our goal is to stimulate the amygdala and collect metrics in real time. In all, we plan to treat 50 patients across three sites, and we just passed the halfway mark.  

As an add-on to this trial, I plan to do the MR-ARFI sequence to visualize exactly where the ultrasound is targeting. Then, I’ll correlate the distance between the desired target and the actual target and assess the change in symptomology. My theory is that increased precision leads to a greater reduction in symptoms. 

Is there a patient whose story sticks with you? 

The first patient in the chronic arm of the coma study was a man in his mid-50s who had suffered a stroke. He had been in a minimally conscious state for about 18 months when his wife enrolled him in our trial. When we went to assess him at his home a few days after the treatment, it was clear that he was more alert than he had been. His wife asked him something like “Do you still love me?” and he was able to blink “yes.” His wife was in tears. This was essentially the first communication she had had with her husband in a year and a half. Seeing the tangible impact that my work is having on the lives of people around me is probably my biggest motivator in this work. 

Team Members 

Who are your team members? 

In addition to my advisors, I have wonderful undergraduate volunteers who help with recruitment for the clinical trials. I also collaborate with Noah Philip, MD (Brown University), Darin Dougherty, MD (Harvard Medical School), Mark S. George, MD (Medical University of South Carolina), and Mark Schafer, PhD (Drexel). 

What do you see as impediments to your success? 

I think a major roadblock is patient access to MRI scans. I do not think it is possible to do focused ultrasound neuromodulation or ablation on the deep brain structures like the amygdala, hippocampus, and thalamus without MR guidance. Unfortunately, we are never going to get to a point in time where we can routinely get MRIs on every single patient that walks in through our door. Secondly, I think there is a lot more research to be done to determine exactly how ultrasound works and the ideal parameter settings for the various targets for different diseases. 

Funding 

What are your funding sources? 

As an MD/PhD student, I received funding from the National Institutes of Health through a T32 grant that was awarded to UCLA. Just a few weeks ago, I was also awarded an F30 grant from the National Institute of Mental Health. My PhD supervisors, Dr. Bookheimer and Dr. Monti, have a variety of funding sources for their projects. 

Has the Foundation played a role in your work? 

The Foundation does a great job at keeping the community up to date on the latest news. There has really been an explosion in the last five years or so in the number of papers, and it is hard to keep track. The Foundation helps organize and promote it all, especially through its newsletter. The Foundation is present at various societal meetings and takes pride in sponsoring workshops that bring together experts in the field. These workshops are a platform for collaboration among engineers, researchers, clinicians, industry professionals, and regulatory agencies, all working together to advance focused ultrasound technology. The foundation also publishes white paper readouts of these workshops to keep those unable to attend and the broader community informed about critical updates, further pushing the field forward, and it is thus instrumental in laying the path ahead.