Editor's Note: In this One-on-One, Medscape Editor-in-Chief Eric Topol talks with neuroscientist Adam Gazzaley, MD, PhD, about his pioneering work harnessing the therapeutic potential of video games, which may one day help treat depression, post-traumatic stress disorder, autism, and Alzheimer disease.

Setting Out to Understand the Brain

Eric J. Topol, MD: Hello. I am Eric Topol, editor-in-chief of Medscape. Today I am privileged to have with me Adam Gazzaley, who heads up the Neuroscience Imaging Center at the University of California, San Francisco (UCSF). We are going to be talking about the pioneering work that Adam and his whole team have been doing. Let's start with your background, Adam. You are a New Yorker and a Bronx High School of Science graduate, and then you went on to the Mt. Sinai Medical Science Training Program and Berkeley.

Adam Gazzaley, MD, PhD: I did a neurology residency at [the University of Pennsylvania] after receiving my MD/PhD at UCSF, then went to Berkeley for a postdoc in human cognitive neuroscience, and then I went back to UCSF.

Dr Topol: You have been at UCSF for not quite a decade?

Dr Gazzaley: A little bit over a decade now.

Dr Topol: When you were in training, did you have any idea that you would end up working on the use of video games to change medicine?

Dr Gazzaley: No. That was not on my agenda. I always wanted to do research that informed our basic understanding of the brain but that also helped people. That was always a vision, but as we all know, it is very hard to do both. In terms of using technology like video games as a therapeutic tool, that was nowhere on my horizon. When I joined UCSF, that was not in my job pitch.

Dr Topol: What was your pitch at that time?

Dr Gazzaley: At that time, my plan was to integrate multiple different tools, like functional brain imaging, EEG, and transcranial magnetic stimulation, to manipulate neural networks and understand how these complex interactions between brain areas underlie the interface of attention and memory. I pitched that program to integrate across these tools and wound up publishing that in Nature Neuroscience[1] 5 years later. My goal was basic cognitive neuroscience to understand neural networks and the aging brain.

Dr Topol: Using these different imaging modalities to zoom in and understand networks?

Dr Gazzaley: Exactly.

Dr Topol: As a child, were you playing Atari? What were you into?

Dr Gazzaley: Atari. You are exactly right. I was really into video games growing up. I remember hacking them and reprogramming them with friends. There were all of these holes in those early video games that actually were the most fun. Asteroids was the first game that I cleared. Many people do not know that you can actually win on Asteroids. It takes many hours and then it is just a sheet [on the screen]. I had a dry spell during med school and residency, but it is always something I liked.

Dr Topol: Did your parents ever tell you, "Adam, no, you cannot do this"?

Dr Gazzaley: They did not. We did not watch a lot of television growing up. When video games first appeared, no one knew much about them, so we had a reprieve and played them for ridiculous numbers of hours.

Games for the Aging Brain

Dr Topol: You are now on the cutting edge of neuroimaging. You have a very interesting background, not just in neurology but also the cognitive background. When did you have this eureka moment, this switch to get into video games as therapy?

Dr Gazzaley: A lot of my research was focused on the aging brain and trying to dissect what happens with healthy aging, independent of Alzheimer's disease and other causes of dementia. What leads to impairments in how we interact fluidly with the world around us as we get older? We were finding that there was a burden of distraction and multitasking that everyone faces but which gets worse as we get older. We characterized the networks and the reasons for these changes. I started giving more talks for the public. AARP invited me to give a keynote address to an older audience, explaining what is happening in our brains as we get older.

Dr Topol: You were trying to explain why everyone's brains rot away as they get older?

Dr Gazzaley: Exactly. It was about memory and aging. When you give a scientific talk on this topic, with sophisticated imaging modalities, academics are fascinated. When you give a talk to a group of older adults who are not scientists, and you end the talk saying, "That's all I have," it is like a movie ending where everyone dies and the credits roll early. That is not a very satisfying movie.

I remember looking at their faces and thinking, "Wow. This is not how I want my story to end, with the bad news." That was a transition point, when I began thinking beyond just understanding the brain to how we can use new approaches to improve these very deficits that we are describing in the lab. That was the motivation. It happened through interacting with the public.

Dr Topol: Until then, everybody was pushing all of these different drugs. It was all a drug story. Had anyone been enlightened to say, "Maybe we could use video games to do this"?

Dr Gazzaley: Not really. In the early 2000s, literature emerged showing that if you brought young people who played first-person shooter and action video games into a laboratory and studied their cognitive abilities, especially cognitive control—attention, selective attention, resisting distraction, and task switching—they were superior to their peers who did not play games. If you took naive younger adults and had them play, they also started showing improvements in these areas. These are the same abilities that we see declining with aging.

As a neurologist, I was very frustrated with the tools on hand. The medications that we give are nontargeted, so we see side effects. They are nonpersonalized in terms of how we prescribe them because the data are based on large populations. It is very unsatisfying. We did actually start some drug trials back then to see whether it could help.

Dr Topol: You looked at imaging to determine the effects of drugs.

Dr Gazzaley: Exactly. We looked to see whether we could change these abilities. I started in that more traditional world. What drove me was trying to find a way to activate the brain selectively—to activate the underlying computational unit of the brain, the neural network, as opposed to neurotransmitters, which are going to be blunt because they are all over the brain. Thinking about how to activate the brain selectively led me to the very tools that we use to study the brain selectively, which are these cognitive paradigms, these psychological tests.

The idea was that if we know that they activate the brain selectively—which makes sense, [because] they are an experience and our brains respond selectively to experience—could we have them essentially "play" our tasks to activate them? And then, because the brain is plastic, even the older brain, it would learn how to do better. The problem was that no one would ever do our tasks for any amount of time because they were incredibly boring. That is what led to the eureka moment of using video games. They engage you in a challenge and they are immersive and fun. They lead to deep game play. That was the idea: to use what we were doing in the lab already, which was designing these tasks not to sample how the brain works, but to put pressure on the very systems that we are activating.

Game Designers Enter the Fold

Dr Topol: Did you have to make a connection because you didn't make your own video games?

Dr Gazzaley: This is the fun of being alive; random events can occur along your path. I happen to be good friends with a couple of guys from LucasArts, Matt Omernick and Dmitry Andreev. They were my buddies. And I was always in awe of what they did—they created Star Wars games. They were really excited about the brain, as most people are. We used to trade off: I went up to Skywalker Ranch and saw all of the amazing production of a Triple-A video game, and they would come down to the lab and see what we do in terms of brain imaging.

We always thought it would be fun to work together someday, but not until that moment when I thought of video games did I think of asking them, "Do you have any time to volunteer in the lab?" I had a design for this video game. It came in a dream, which is surreal but true. I knew we could not build it in our lab. I reached out to them and said, "What do you think about this idea of improving the cognitive abilities of older adults using a custom-designed video game that you will help me build?" They were really excited about it.

He said, 'I have been teaching teenagers how to kill aliens my entire life. I am ready to use my skills for something different.'

I remember Matt's first reaction. He said, "I have been teaching teenagers how to kill aliens my entire life. I am ready to use my skills for something different." That was this.

Dr Topol: Was this the game Neuroracer?

Dr Gazzaley: Yes, that was the game.

Dr Topol: That was on the cover of Nature[2] in 2013. That was a signal that something was going on, because to have a Nature article on video games for therapy had never happened before. Things were taking off, and you were talking not just to the science community but even more to the public because you have a therapy.

At this point you are doing trials, actually doing the things that go to the US Food and Drug Administration (FDA) as if it were a drug. You have the potential to affect many different neurologic conditions; the list includes autism, Alzheimer's disease, attention-deficit/hyperactivity disorder (ADHD), and traumatic brain injury. The list is long. Where are you headed now?

Dr Gazzaley: We built the game and did the study. It was a pivotal moment for us. Do we go back to the traditional therapies, or was this a signal of something? Two things happened. I moved the game out of the laboratory into industry to scale it and do large studies. I have learned that you can build prototypes in an academic lab, but they're nothing that is going to get into people's hands. I wanted that to happen.

Not Your Typical Video Games

Dr Topol: Was the company Akili?

Dr Gazzaley: Yes. Akili Interactive is a company that we cofounded. The folks from Lucas came over full-time. Matt Omernick is our chief creative officer. It is located in Boston and in Marin, right here in Northern California. I serve as a science advisor and keep my day job at the University. We had a dream of taking the engine behind Neuroracer into a game that was much more fun, with higher levels of music, art, and story so that it was more engaging, and with tighter closed loops, which are the active ingredient in the game. That allows very rapid updating based on your performance in real time.

That is why our games are not normal video games. They are constantly assessing how accurate and rapid you are, and then adjusting and scaling the difficulty in a personalized way. You could think of it as a personal trainer—every single second pushing on these [cognitive] systems in a selective way as they get better through plasticity. The company now has a large team that has designed these closed loops in an even more intricate way than we did in Neuroracer.

A polarizing decision was made to not just put the game out there in the consumer market, but to lock it down for clinical trials, which have been going on. I am really just an advisor.

Dr Topol: Which trial is furthest along?

Dr Gazzaley: The ADHD study yielded very exciting pilot data. There are interesting preliminary data in depression, post-traumatic stress disorder, autism, and Alzheimer's disease. They all have interesting data, some of which we collected just days ago. The ADHD population was identified as the first target. In surveys, almost 100% of parents would consider a nonpharmaceutical alternative for their children who have been diagnosed with ADHD.

It is in every way a drug trial, except it is a video game and not a pill.

Dr Topol: That would be very popular.

Dr Gazzaley: It is. The need was felt to be very great. That game has left the mechanistic, feasibility clinical phase and entered a full-approval multisite trial, involving hundreds of children, for a clinical indication for ADHD treatment.

Dr Topol: This is a true randomized trial in which a control group does not get the game treatment?

Dr Gazzaley: They get something else. It is in every way a drug trial, except it is a video game and not a pill. The goal was to play by the current set of rules. It is a challenge in many ways to the incumbent system. We said that we will do it exactly the same way. Once things progress, we are aware that some changes to the system will be necessary. Games iterate, unlike drugs, in a different way.

Dr Topol: The Medscape audience, and doctors in general, do not appreciate how big the gaming world really is. This is just extraordinary.

The video game industry is bigger than the movie and music industries combined in the United States.

Dr Gazzaley: The video game industry is bigger than the movie and music industries combined in the United States. It is completely global, and equal numbers of males and females play video games. Many older adults play them. The average gamer is almost 40 years old now. It is just going to increase. It is the most powerful form of interactive media. In itself, it is already a strong influencer of behavior, but if you can design in a very careful way and validate in a high-level way, you create something new.

Dr Topol: I particularly admire that not only are you doing randomized trials, but you also are going to the FDA. You did not have to do that. You have done neuroimaging to see the actual effects. You are getting to the science of video games. It is fantastic.

Dr Gazzaley: We are still neuroscientists in our lab. We build many other games. Neuroracer has left the lab. Akili is working on these large validation trials to essentially create the first prescribable video games as therapeutics. In the lab, we are now incubating new games. That is where I enjoy working the most—coming up with the design for the game that challenges a certain neural system, and then bringing on professionals. We have our own internal game team now and we have multiple games.

Dr Topol: Do you wait for your dreams for these designs?

Dr Gazzaley: No. Unfortunately, I have not dreamed another game. I wish I had. We do the deepest dive ever into figuring out what [the games] change. From MRI (structural and functional) and EEG, we do stress testing. We do, obviously, an extensive cognitive battery and now blood work, looking at inflammatory markers, hormones, and epigenetic changes. If it can change, we are monitoring it.

Is It Real?

Dr Topol: That is fascinating. While you have been doing this stuff in a high-science way, there are other brain-food games, such as Luminosity. What are your thoughts about those? Do they do anything?

Dr Gazzaley: The whole field is built on a solid foundation: that our brains are plastic and they can modify in response to experience. That is why all of this can happen in the first place—there is that strong basis in plasticity. However, not everything we do for our brains is going to be equally effective or even good, just like not everything you put in your mouth is going to be equally good for your body. Video games are also a massive category, not unlike drugs or food. There are many different types.

The foundation is good, but you cannot just build something and say that because the brain is plastic, this is going to help your memory. The challenge is to not just build, but also to validate and treat it very seriously, to know who it is working on and what the ideal doses are. That has not been done to the degree that we need. That is why you see confusion in the marketplace with consumers and regulatory agencies. If it is not the FDA, it is the FTC [Federal Trade Commission]. People ask, "What is going on here?"

My mission is to slow it down and ask whether there is something real here. We see the signals in our lab. I do not even say anything more than, "We have a signal." We have enough reason to look more deeply and to be very rigorous about it. That is what we have to do now.

Dr Topol: This has been a nice review of the exciting work you have been doing to determine how video games can change neuroplasticity.

Thanks for joining us as we continue to bring some of those interesting people in medicine to Medscape.