As a psychiatric postdoc working with mice in the wet lab 15 years ago, Paulo Lizano, MD, PhD, found himself yearning for more (human) interaction. He pivoted to neuroimaging in clinical psychiatry but became disillusioned by the idea that finding targets for actual intervention could take decades. He pivoted again, still searching for the research track that would define his career.

A pilot award in 2020 from Harvard Catalyst changed everything. Lizano used the seed funding to investigate converging lines of evidence from his own basic and clinical research around visual hallucinations in people with psychosis, building the foundation for a research track that continues in earnest today. We caught up with him as he awaited word from the NIH on the next step in that research.

Following years as a translational neuroscience researcher in psychiatry at Beth Israel Deaconess Medical Center (BIDMC), Lizano recently moved to the University of Rochester Medical School (URMC), where he is associate professor in psychiatry, academic chief of the community division, and directs the Early Psychosis Research Program. He currently leads an effort to build a multi-faceted early psychosis center that will serve a diverse population in upstate New York.

Your 2020 award funded a pilot clinical trial to test transcranial cortical stimulation. Why did this track appeal to you?

This opportunity to do a clinical trial based on some converging evidence in my lab came together at a time when I had made a career leap to studying visual system in patients suffering from psychosis.

My team and I had been using retinal imaging to show that the visual system is impaired in people with psychosis. A study from Michael Fox‘s group, who was also at BIDMC at the time, and is now at Mass General Brigham, had used a technique called lesion network mapping to provide a more causal linkage between a brain area – in this case, the bilateral extrastriate visual cortex (V5/MT) — and symptoms. Their study identified the same region that we ended up targeting, which meant we had cross-sectional evidence from our work in patients with psychosis, plus their data on causal-region network mapping.

That was kind of an “aha” moment. This new technique gave us more causal inference, and at the same time, we were using brain stimulation to modulate that area. It was an exciting time.

It was also a period of transition for me, in both my work and interests. Things were converging and aligning; I was succeeding at getting early grants, and then this opportunity to apply for pilot funding came through to bring it all together. The support enabled us to go from association to “maybe we can do something about this”. It allowed us to do a prospective clinical study investigating whether leisure network mapping is a good way to target stimulation.

Where are you with that research currently?

The preliminary evidence demonstrated that we should keep trying to study this question, so I applied for an NIH grant based on the results. It did not get funded initially, but the reviewers were excited about it, and we have resubmitted to address areas that needed improvement.

Additional funding will allow us to conduct a much larger trial focused on finding the optimal dose of transcranial stimulation. We believe that we were underdosing the stimulation in our first trial. Can we find out what the optimal dose is? And, can we deliver it in a more accelerated fashion, with more sessions over fewer days?

We believe these factors would increase engagement and reduce some of the patient burden related to the way the original study was designed. If all goes well, we would be testing this over the next five years to see if we can replicate what we found in our pilot study and maybe get an even stronger signal than we saw there.

So six years later, the pilot work is paying forward. How else did that initial grant catalyze this research?

The initial pilot also helped to set up the infrastructure to use this same combination of cross-sectional evidence and network mapping in two other grants we received, one from the American Philosophical Society and another from the Milken Institute. In the American Philosophical Society study, we targeted auditory hallucinations in a different brain region, the right superior temporal sulcus. We’ve published this work, including one paper currently in peer review, and my post-doctoral student, Rebekah Trotti, has obtained NIH funding for related work based on these results.

The third study that we’re now wrapping up focuses on reward mechanisms and mania in bipolar disorder. We’ve presented our first papers from that study at scientific meetings and are submitting papers for peer review.

The funding support got us going with this idea of combining regional network mapping with cross-sectional mapping to identify targets for non-invasive neurostimulation.

How did the award advance the science of transcranial stimulation?

The funding support got us going with this idea of combining regional network mapping with cross-sectional mapping to identify targets for non-invasive neurostimulation. We were able to connect that with a concept called target engagement, meaning that we not only want to simulate a specific target, but we want to see if the target changes in some way as a result.

We do that by using EEG to measure electrical activity around the same time that we’re stimulating and by looking at changes in symptoms and/or behavior. That gives us more objective measures of our method. Then we can target a particular area, predict how it’s going to change with stimulation, track if the stimulation is changing the way we predicted, and determine if that change in engagement of the target is associated with the clinical change.

That is critical in psychiatry, where so much of what we do is trial and error. Right now, the success of our treatments is based on a patient’s subjective experience, right? We can’t measure somebody’s serotonin level changing, or whether their BDNF (Brain-derived neurotrophic factor) level is increasing to determine whether that change can be associated with clinical improvement.

Using target engagement in neurostimulation, we’ll be able to get closer to that. We’d be able to see if the target we’re engaging is actually associated with the symptomatic change or improvement that we’re hoping for. Then we could determine who might be most likely to benefit up front.

What got you interested in schizophrenia research?

I was doing cardiovascular research in mice as a PhD student and I found the wet lab very isolating. I wanted to do something that involved interacting with people, so I started doing more clinical neuroscience, including neuroimaging in patients with psychosis. Then I started to question: What is it that we’re doing? Why? I realized this could take 10 or 20 years before anything potentially targetable is found with these methods.

But advances in non-invasive neuromodulation made it possible to do cause-and-effect studies safely with our patient population. I found all of that really exciting, just from a research standpoint.

From a clinical standpoint, some of my more formative experiences were with people who had early psychosis, people within the first three to five years of illness. I found that I really connected with them the most. They tend to be younger people from underserved populations in which social deprivation and trauma are common.

In 2012, when I was making this transition, this was one of the areas of psychiatry that was more biological than we knew at the time. I selected BIDMC for my training because, among all of the Harvard-affiliated hospitals, it had such a large psychiatric program.

I think these Harvard Catalyst grants are really wonderful opportunities for young people who are trying to figure out what they’re going to do with their lives, especially within a competitive funding environment.

When you connect that with Harvard Medical School, the potential for identifying mentors in different areas of research was great, whether I decided to continue to pursue basic neuroscience in the wet lab, or if I wanted to do more clinical-oriented research, or if I wanted to do something in the middle, within translational neuroscience.

That’s really where I find myself fitting in the best: borrowing from clinical studies and from basic research studies and incorporating the fields to more rapidly accelerate how we can care for our patients.

Any advice for young investigators?

I think these Harvard Catalyst grants are really wonderful opportunities for young people who are trying to figure out what they’re going to do with their lives, especially within a competitive funding environment. Even though it’s not a large source of funding, it can be critical for supporting somebody’s time when they’re early in their career, or for a novel idea that may be risky but could have significant benefits if it works. It can help set up an infrastructure for continuing research.

For myself, this pilot grant helped support my time and hire staff to move these projects forward. I learned how to run a clinical trial, and that project is still bearing fruit. So it doesn’t just benefit me; it benefits my team, my co-investigators, and other researchers. Hopefully at the end of the day, it also can lead to changes in how we practice psychiatry to benefit our patients. I think that’s a doable goal.