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Oby: From the campus of Harvard Medical School, this is Think Research, a podcast devoted to the stories behind clinical research. I'm Oby.

Brendan: And I'm Brendan. And we are your hosts. Think Research is brought to you by Harvard Catalyst, Harvard University's Clinical and Translational Science Center.

Oby: And by NCATS, the National Center for Advancing Translational Sciences.

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Brendan: In many common brain disorders, symptoms often manifest in ways many of us would not expect or understand. In addition to manic episodes and the clinical implications of living with psychiatric disorders, visual hallucinations create a different experience for many individuals. With a recently awarded Harvard Catalyst pilot grant, Dr. PAULO Lizano is looking to further understand the visual system and cognitive functioning in people with psychosis. PAULO Lizano is an instructor in Psychiatry at Beth Israel Deaconess Medical Center.

Oby: Good morning Dr. Lizano, welcome to the show.

Paulo Lizano: Good morning.

Oby: How are you holding up? How are you doing in this time?

Paulo Lizano: I think I'm doing all right. Things are quite busy, but I think that that's great. I thrive in having to balance many different things. I find this quite a fun part of research and clinical work.

Oby: So you were awarded a Harvard Catalyst pilot grant to improve visual hallucinations in people with schizophrenia and other psychosis. Why do you want to focus on visual hallucinations?

Paulo Lizano: Yeah, so this is a great question and once that I asked myself quite a bit. I've had a long, winding road to psychiatry and to studying psychiatric disorders, in particular psychosis. But the work that I've done in my time doing research in psychiatry and the work of others have motivated me to try and better understand the visual system and how the visual system works in psychiatric disorders, and in particular psychosis, and how they lead to visual hallucinations.

And so while the visual system has been increasingly been recognized as an important site of pathology in patients with schizophrenia and other psychoses, they are often understudied and overlooked since researchers primarily focus on studying auditory hallucinations. And this is despite the fact that we know that visual hallucinations are often associated with greater overall hallucinations and delusions, and that this results in poorer performance on processing visual information, as well as with greater negative symptoms that are highly implicated with social functioning in patients with psychotic disorders.

Another reason for studying the visual system is my work with studying the eye as the window into the brain. Which we've been able to show that there are changes that occur in the brains of individuals with psychosis that can be visualized through the eye, and that these changes in the eye are associated with symptoms of psychosis, overall cognitive functioning, as well as functioning in the real world.

But the most important link that I think is the most exciting is the fact that relatively recently, we learned about a causal location in the brain that is associated with visual hallucinations. And this is-- was led by the work by group-- in Dr. Michael Fox's group, who used to be at Beth Israel Deaconess Medical Center, where they found a causal location in the brain that's associated with visual hallucinations.

This, when taken together with other correlational data demonstrating that this same region of the brain is associated with visual processing and potentially, visual hallucinations in people with psychotic disorders, we thought that this was a great opportunity to target this brain region with a non-invasive way of stimulating the brain to see if we can improve visual hallucinations and visual processing in individuals with psychosis.

Oby: How much do we know about visual hallucinations? Where do they come from?

Paulo Lizano: This is another great question. And despite visual hallucinations being a known entity in psychiatric disorders, in particular in psychosis, for a long time, we actually don't know a lot about where they come from, how they manifest, who is more likely to be implicated, and lastly, where are they coming from, as you mentioned.

And so over time, there have been numerous hypotheses that have been suggested to explain the origin of visual hallucinations. And these include a psychophysiologic, which can be due to a disturbance of the structure of the brain. This could be due to psychobiochemical changes, which can be a change in the neurotransmitters in the brain. And then an area that psychiatry is predominantly focused on is the psychodynamic aspect, which is an emergence of the unconscious into consciousness.

And so, you know, we've learned about visual hallucinations by the work done, actually, in other fields. And so in ophthalmology and in neurology. And so there are disorders that are primarily affect the eye or primarily affects the brain and are thought to be organic causes of visual hallucinations. And so these have been well described. And often, our colleagues in neurology and ophthalmology can make a diagnosis based off of the clinical presentation.

However, this does not exist, or has not existed in psychiatry. And this is an area that's often, in my opinion, under taught in psychiatry residency training. And so you know, part-- this is partly due to there isn't a lot of information out there. But also this is due to a lack of interest in learning about visual hallucinations, given that auditory hallucinations are provided with much more attention.

However, there was a study by Gauntlet Gilbert 2003, where he descriptively described visual hallucinations and how they occur in people with psychiatric disorders, not just psychotic disorders. And he was able to describe in quite a bit of detail-- and I can sort of name a few of those things. But he noted that in individuals with psychiatric disorders, they often experience visual hallucinations as a supernatural occurrence. They were usually humanoid figures, and there was a wide range of visual forms. So what this means is that individuals noted changes in color, in shape, in movement of objects in their vision.

And what they also found is that these visual hallucinations often occurred during times of stress, when individuals are feeling lonely, or when they were in an area of low visual sensory input-- so dark places. Or you can think of, you know, if you're sitting in a place where it's dark, you're feeling lonely and you're stressed, this could be an area of vulnerability. And while these episodes are usually short in individuals experiencing visual hallucinations, they often result in delusions, which can be difficult to shake. And this leaves people feeling overwhelmed and frightened when they're experiencing these visual hallucinations.

Oby: Wow. So in the study, you're using electrical stimulation to try to improve hallucinations. Can you talk about this treatment and how it's been used in the past?

Paulo Lizano: Yes. This is an area that I'm quite excited about because non-invasive brain stimulation, which is the one proposed in this study, can be used as the word describes-- non-invasively. So minimal side effects and can be targeted to a specific location in the brain. And so what we're able to do is take information from neuroscience about how the brain works and what brain regions are associated with visual hallucinations, in this case. And we can design a targeted treatment or targeted stimulation to a particular area.

Since the advent of transcranial direct current stimulation, there has been technological advances which have increased the and improved upon the spatial accuracy of brain stimulation. And so now we're able to, with greater full focality, target a particular region.

On top of that, they've developed electrical modeling of the brain. And so what you can do is, using sophisticated software, is determine what a stimulation in one area will do to the current flow in the brain and will also inform you of what other brain regions might be impacted, either positively or negatively.

And so what we're able to do in this study is take the finding of a particular brain region-- in this case, the association of visual cortex, being associated with visual hallucinations, and taking this high special def-- spatial definition technique for brain stimulation such that we're able to target the specific region with this high definition transcranial direct current stimulation to see if we can improve symptoms and visual processing in patients with psychotic disorders experiencing visual hallucinations.

Oby: Wow. That's pretty incredible. So you're an instructor in psychiatry, but you started out in medical school interested in cardiovascular research. What made you change your focus?

Paulo Lizano: I did. I ask myself this question all the time. I feel like it's constantly evolving. But as I mentioned earlier that my path to psychiatry has been long, winding, and a very formative path. I started off interested in oncology after I participated in a summer research program in New York City. And this program is geared toward providing research opportunities to underrepresented minorities. And so this really provided me with the excitement and stimulation needed to help me advanced in what my teenage self wanted to do. Because I had no idea.

And so I worked-- I had the opportunity to work in a lab that was focused on detecting cancer during the earliest stages of metastasis. And I found this work fascinating, and the science fascinating, and the clinical applications were amazing, in that we can use laboratory techniques to be able to identify something so early. I encountered several mentors along my path who guided me towards what may be a potentially good next step for me, because, again I still wasn't fully aware of what that might be.

So, you know, with their help, I applied to a combined MD-PhD program and I attended this program at New Jersey Medical School in New Jersey. And during my PhD, I was introduced to cardiovascular research. And here's where I started my work on identifying molecular pathways that can enhance cardiac survival after an ischemic heart injury. And this really led me down the path of trying to figure out what are molecular mechanisms associated with injury, how can we reverse those, and how can we target at them in a specific way?

However, it wasn't until my last years of medical school that I discovered the field of psychiatry. And I was really drawn to it because of the multidisciplinary approach to care and the human connection that I felt was missing from oncology and cardiology, at least in my opinion. It was also helpful that psychiatry has a great work-life balance, which is a huge draw for me. I had met my wife during my PhD years and she got into medical school, and we ended up being in the same class.

Oby: Nice.

Paulo Lizano: So that was great and reaping the benefits of the work-life balance now. But but also, at least at the time, looking at how far psychiatry has advanced from a translational neuroscience perspective. Compared to the experience that I had with oncology and cardiovascular research, it just-- there was a lot left to be desired. And so I felt that with my past experience, I could potentially positively contribute to this field from a science or scientific perspective to enhance how we understand, diagnose, prognosticate, and treat psychiatric disorders and, in my case particularly, psychotic disorders.

Oby: So you've talked a little bit about how you made the switch from cardiovascular research to psychiatry and a little bit of why you're interested in it. But can you give a little more about what interests you about psychiatry and studying schizophrenia and psychosis?

Paulo Lizano: Sure. So, similar to before, this is still an evolving area for myself, as well. But it's been such a wonderful field. I'm so glad that this is where I ended up. And so, as a psychiatrist, you know, you're not only able to join your patients on their past, present, and future journeys, but you're also able to grow and learn through them as well. So I feel like I've become a better, more rounded person because of the work with my patients. And I hope that I provided them with the same level of growth, as well.

During residency training, I became particularly drawn to patients with psychotic disorders. And this is because they were primarily young, came from a highly traumatized background, and/or were underprivileged, which, you know, some of those spoke to some of my upbringing. And so I felt that I was able to relate to them better than some of my other patients. And I felt that I could offer them some help in navigating life through a most difficult time for them.

Oby: How does studying the visual system allow us to understand more about the brain?

Paulo Lizano: So this is a great question. So unlike other parts of the brain and how the brain functions, this visual system is actually one that's one of the most well studied regions of the brain. We actually do know a-- know a lot about how it works. So how is information from a visual signal-- how is that information encoded in the eye. And how that information is translated from the eye to the brain's visual cortex. And how this information then feeds forward this information to other parts of the brain that allows a person to respond to that visual input. And this could trigger a memory from our past.

However, despite the depth of knowledge, we know very little about how the visual system from the eye to the brain is impaired in individuals with psychosis. And how I mentioned previously, that some of the work that we do is trying to map out this pathway and trying to see if we can identify peripheral markers in the eye, using eye imaging techniques borrowed from ophthalmology that can be informative of the structural or functional changes that are happening in the brain, as well as learning about what these changes mean regarding a person's real life functioning and their psychosis symptoms.

So I'm really excited about how this body of work-- this eye imaging that I'm doing, and this brain stimulation of the association of the visual cortex will come together to create a program where we're providing a line of care for people with not just psychosis, you know, people experiencing these visual hallucinations, or visual perceptual abnormalities, or visual processing deficits, so that we can provide a way to not only evaluate and diagnose these issues that the individuals might experience, but also provide a way to stratify the patient so that we can provide some form of treat. And one of those being transcranial direct current stimulation.

Oby: So we've talked a little bit about your study, but can you talk to us about more of the details of the study and how it's being conducted?

Paulo Lizano: So we're excited that Harvard Catalyst-- the vision scientist pilot study provided us with the funding to carry out this pilot study. And so, in a small number of people-- so we're going to examine about 10 participants with a history of visual hallucinations and who are also experiencing moderate symptoms of visual hallucinations. And we will be targeting that brain location that was identified in the lesion network analysis. And we're going to be targeting that bilaterally, so on each side of the association visual cortex.

And we're going to be determining whether at one week or one month they've had symptomatic improvement in regards to their visual hallucinations. We're also going to be determining whether they've had any improvement in the processing of visual information, as well as some other symptoms that are important in psychosis, so negative symptoms which I've mentioned earlier. These include apathy and poor social functioning, which really can impair a person's real life functioning with psychotic disorders.

We also want to check to see if we're engaging the target, which is a term commonly used in the field of research. So we want to make sure that we're targeting this brain region, but that there are electrical changes that are occurring due to this stimulation and that those changes in those electrical signals are associated with the improvements that we're seeing in, or that we hope to see in symptoms and cognition.

Oby: What are the next steps after the study is concluded?

Paulo Lizano: Yes, so again, we're really excited. We're hoping that the results are positive. It's going to be the first study to use this lesion network guided approach to treatment. And there's enough convergent evidence to suggest that this is a causal important region. And so we really have high hopes that the positive results from this study will lead us to proposing a treatment protocol that could safely engage the target and improve symptoms of visual hallucinations in people with psychosis. So this study, while small, will allow us to calculate how many subjects we'll need in a subsequent study that would likely be much larger. And so, you know, that's going to set us up pretty well for a subsequent submission.

The results from this study will also tell us whether or not we're using the right form of stimulation, and for the right amount of duration, and for the correct number of days. So it could be that the stimulation that we're proposing may need to be tweaked in one or more ways to try and enhance the effect that we're seeing. There's different ways of doing that with transcranial direct current stimulation. And so we hope that with this pilot data in hand, we would be competitive to apply for funding from the National Institute of Mental Health, be it R21, which can be used for the development, as needed, or an R01, if the utility of this treatment paradigm needs to be tested in a larger sample of patients.

Oby: Well, that sounds incredible. We look forward to what your research brings. Thank you so much for joining us today.

Paulo Lizano: Thank you so much for having me.

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Brendan: Thank you for listening. If you've enjoyed this podcast, please rate us on iTunes and help us spread the word about the amazing research taking place across the Harvard community.

Oby: To learn more about the guests on this episode, visit our website, catalyst.harvard.edu/thinkresearch.