Q&A with Michael Yassa
Alzheimer’s is a growing epidemic, with the disease and related dementia affecting some 45 million people worldwide. Although treatment has been elusive, discoveries that advance our understanding of the disease have been coming fast and furious over the last several years, due in no small part to advances in animal and computational model. At the forefront has been Michael Yassa, a cognitive neuroscientist at the University of California, Irvine (UCI).
His work to understand how exactly how the medial temporal lobes in the brain process memories is changing how we diagnose and think about Alzheimer’s and dementia. As Yassa describes it, what we know now about the disease would have been surprising to researchers a decade ago: that it is a disease of hyperactivity in certain brain regions rather than one of reduced activity.
A co-recipient of the CNS Young Investigator Award, Yassa will describe this body of work, along with some thoughts about the need to support basic scientific research and for young scientists to embrace failure in order to move toward translational work, at the CNS annual meeting in Boston this March. We spoke with him about all that and more.
CNS: How did you become interested in cognitive neuroscience, and memory and aging/disease in particular? And what drives your work?
Yassa: During my undergraduate years at Johns Hopkins, I became fascinated with the brain and took every neuroscience course I possibly could. I remember having the good fortune to sit down with Vernon Mountcastle almost 20 years ago to talk about the future of neuroscience. He was the one who first suggested to me that brain imaging will shape the future of the field. I have been in cognitive neuroscience ever since.
My particular interest in aging and neurological illness came a bit later as I started to work with clinical populations in the departments of psychiatry and neurology at Hopkins. I was involved in clinical research studies where I saw firsthand the impact of cognitive disorders on patients and families. It gave me purpose. While my work over the years has had elements of both fundamental and clinical/translational work, the application to neurological and neuropsychiatric illness has been a consistent and major driving force.
CNS: Briefly, what do scientists know now about the role of the medial temporal lobes in memory?
Yassa: We know quite a bit, but we are constantly surprised still. We know that the medial temporal lobes are critical for some forms of learning and memory but not others. We know that the dependency on this system can appear to be transient, although data are still inconsistent in this regard. We know that there are numerous circuits and networks within the medial temporal lobes, with enough complexity to keep us busy with experiments for a long time. We also know that some of these circuits are more vulnerable than others to particular forms of neurological illness.
Above all, we know that the medial temporal lobes do not operate in a vacuum. They are connected to the rest of the brain and if we are to try to understand cognition in all of its complexity, we have to focus on examining systems interacting with one another.
Establishing early markers for disease diagnosis and prediction in Alzheimer’s disease is of utmost importance to the development of effective treatments.
CNS: What contribution to this body of work are you most excited to share in your upcoming CNS 2018 talk in Boston?
Yassa: One of the most exciting research avenues in the lab has focused on identifying the division of labor in information flow within the medial temporal lobes and applying this knowledge to aging and dementia. Led by my brilliant former student, Zach Reagh (now postdoc at UC Davis), the work has delineated functional-structural relationships within the entorhinal cortex that have only been previously noted in animal studies. We showed that subdivisions of the entorhinal cortex (lateral vs. medial) support object and spatial processing, respectively. We then went on to examine this division of labor in older adults and found evidence for a selective vulnerability in one pathway but not the other (Reagh et al., Neuron in press).
The work has translational possibilities to Alzheimer’s disease as we are finding that the lateral (anterolateral in humans) entorhinal cortex is selectively vulnerable to pathology. Particularly exciting for us is that there is some convergence on these ideas from colleagues in the field, including CNS YIA co-awardee Morgan Barense.
CNS: Can you describe a little more about how can the new information you are learning informs clinical work on Alzheimer’s disease?
Yassa: Establishing early markers for disease diagnosis and prediction in Alzheimer’s disease is of utmost importance to the development of effective treatments. My laboratory’s work has focused on identifying biomarkers for cognitive decline in the prodromal or preclinical phase, as well as discovering and testing novel therapeutics for neurodegenerative disease.
Using high-resolution fMRI, we showed that in older adults, memory impairment is linked to hyperactivity in particular hippocampal subfields. We then showed that reversing the hyperactivity with an anti-epileptic can rescue cognition in individuals with mild cognitive impairment. This work has led to a number of exciting new developments with numerous groups and companies developing therapeutics targeting hyperexcitability.
A decade ago this would have been very surprising to anyone working in the Alzheimer’s disease field, where the central dogma was that Alzheimer’s is a disease of reduced excitation rather than the opposite, and that increased excitation is an adaptive, compensatory response rather than an index of dysfunction. Our work changed this particular understanding of the impact of Alzheimer’s disease on memory networks. We are now testing the role of different lifestyle interventions, such as diet and exercise, on changing this biomarker signature in older adults.
We are trying to train a new generation of neuroscientists with very different skill sets than when I was training. Cognitive neuroscience has evolved to become a very multifaceted discipline.
CNS: What are some other next steps for your work?
Yassa: There are a number of future avenues we are pursuing. On the clinical side, as I just mentioned, we are now examining how various lifestyle factors perturb medial temporal lobe information processing abilities. This includes sleep, exercise, diet, and use of psychostimulants. We are also disseminating tasks, methods, and code to many colleagues and collaborators so that they can conduct their experiments in new model systems and other clinical conditions.
On the fundamental side, we are working very closely with colleagues at UCI and beyond to build vertically integrated research programs on memory all the way from the molecular end to full-fledged cognitive architectures embedded in robotic applications. The key is to use information from the different levels of analysis to constrain our hypothesis testing and to use the data we generate to better inform studies at other levels. This type of integration is particularly exciting for us. The most compelling next steps are going to be via team science approaches.
CNS: How do you want to see the field move in the next 25 years in terms of its pursuit of cognitive neuroscience discoveries?
Yassa: We are trying to train a new generation of neuroscientists with very different skill sets than when I was training. Cognitive neuroscience has evolved to become a very multifaceted discipline. It is significantly informed by computational neuroscience and neural network modeling. It is no longer limited to humans, as examining cognition in animals during large-scale neural recordings is not only feasible but becoming commonplace.
The nature of the discoveries will also be different. We are no longer engaged in “blobology” as a field. We are much more interested in networks and interactions. We hope to understand different brain states and the role of different rhythms in supporting cognition. We aspire to model cognition in all of its complexity using real-world stimuli with real-world problem-solving. The cognitive architectures that will be built will be imbued with this knowledge to create much more mature and comprehensive AI. That’s what I envision for the fundamental aspects of cognitive neuroscience.
On the clinical slide, the key over the next 25 years is to see how much of the fundamental knowledge is able to inform translation and clinical care. The promise of precision medicine is such that we can understand every individual’s risks and vulnerabilities based on combining information from their genome, epigenome, metabolome, lipidome, functional and structural connectome and every other -ome you can imagine. This will allow us to tailor therapeutics for neurological and neuropsychiatric illness but perhaps most importantly it will allow us to detect risk and employ prevention very early.
That being said, I could have never predicted where we are today 25 or 20 or even 15 years ago. Science is not linear. It’s very difficult to imagine what will happen in 25 years. Maybe we will be asking the same questions as we are today but addressing them with more sophisticated tools. I would like to think that the future will be more interesting than just new tools, however. I would like to see us start to ask questions we could not ask before.
Hundreds of clinical trials in neuroscience have failed, and in most of those cases, it is clear that the translation from “bench to bedside” happens too quickly or too naïvely without adequate fundamental discovery.
CNS: What do you most want people to understand about your work? And why should they come to your award talk?
Yassa: Aside from the specifics of the work, what I hope to convey especially to students is the tremendous value of fundamental science and the basic discovery process to clinical translation. Hundreds of clinical trials in neuroscience have failed, and in most of those cases, it is clear that the translation from “bench to bedside” happens too quickly or too naïvely without adequate fundamental discovery. Pharmaceutical companies like Pfizer are either shutting down their neuroscience branches or are cutting down their investments. The situation is untenable and has to be remedied.
What I see as a clear issue is that basic science is not usually incentivized by funding agencies, and the emphasis on “rapid translation” due to various pressures has led to an increase in these failures. The NIH, foundations, and industry have to shift their focus to support sufficient amounts of basic discovery to prevent “premature translation.”
Our work is not perfect by any means, but we have consciously attempted to conduct thorough fundamental investigations before applying them to the clinical realm. We have been moderately successful thus far. That, I hope, will be the biggest take home message. As for why folks should come to the talk, I promise I will make at least one really bad joke.
CNS: What are you most looking forward to about the CNS meeting in Boston?
Yassa: I am very excited about the meeting and about the incredible lineup of speakers and talks. I’m particularly excited about Mike Gazzaniga’s keynote. I show Mike’s videos with Alan Alda in my classes all the time when I discuss split brain patients and have been inspired by his seminal work for the last two decades.
I am also looking forward to hearing Morgan Barense’s award talk. We have many common interests and intersecting themes, which made sharing with her the YIA all the more delightful. I am also very much looking forward to the CNS Trainees Professional Development Panel, which I was invited to join this year.
Finally, I hear something about a gala. That should be fun too! 🙂
-Lisa M.P. Munoz
For more on Yassa’s work, check out:
Thanks for the Memories, JHU Arts and Sciences Magazine
How I Fail: Mike Yassa, veronikach.com
