Ongoing Genetic Research with Tourettic Mice

In this episode, I'm joined by the brilliant Drs. Jay and Max Tischfield, father and son renowned Tourette researchers at Rutgers University. They share their fascinating journey into the world of Tourette Syndrome research, discussing how they use genetic data to create groundbreaking mouse models that mimic the human condition. We delve into the intricacies of gene mutations, the challenges of studying tics in mice, and the potential for these models to lead to effective treatments.

You'll hear about the Tischfields' unique father-son dynamic in the lab, their collaborative work with the NJCTS Sharing Repository, and the exciting prospects of using AI and advanced genetic editing to further understand and treat Tourette Syndrome. This episode offers a peek into the cutting-edge science that's pushing the boundaries of what we know about TS.

Episode Highlights:

[02:06] Jay's unexpected journey into TS research, sparked by a passionate advocate.

[05:35] Max's fascination with using gene editing to create Tourette-like mouse models.

[07:58] The promise of using these models to test potential treatments.

[13:23] Exploring the complexities of identifying tics in mice.

[16:49] How human studies guide mouse model research and the role of sensory motor gating.

[24:42] Discussing the genetic landscape of Tourette Syndrome.

[28:30] The future of drug testing on TS mouse models.

[37:11] Cognitive Behavioral Intervention Therapy (CBIT) and its role in treating tics.

[43:02] How listeners can contribute to the NJCTS Sharing Repository.

Links & Resources:

New Jersey Center for Tourette Syndrome: https://njcts.org/ 

Dr. Max Tischfield’s Website: http://www.maxtischfieldlab.org/ 

Remember, each story shared on this podcast brings light and understanding to the diverse experiences within the Tourette's community. Your journey is your own, and it's filled with potential and promise. If this episode resonated with you, I encourage you to like, share, and leave a review to help us connect with more listeners.

Transcript

Dr. Jay Tischfield: 0:00

The evidence is in ways that Tourette's kids are not neurotypical. That's a word that people toss around a lot today, Tourette's kids might be even more competent than their non Tourette's, of course, Tourette's, unfortunately comes frequently as a package with OCD, and ADHD and sometimes even autism. So these things in general, may or unlikely, although OCD sometimes makes people a bit more competent if they choose the right careers and right things to do. But I think we can say with confidence that there's no real deficit in Tourette Syndrome. There's behavior that disturbs the people they interact with and and sometimes the kids who were affected, but there's no reason that they shouldn't read, highly productive watch.

Michael Leopold: 0:52

Welcome to the uptick, brought to you by The New Jersey Center for Tourette syndrome and associated disorders, empowering children and adults through education, advocacy and research by sharing the stories and experiences relevant to the TMS community. Welcome to the objec. I'm thrilled to be speaking with Drs. J And Max Titchfield. They are Tourette researchers at Rutgers University and they work for the world's largest genetics sharing repository for Tourette syndrome. The repository was founded in 2007, in partnership with the New Jersey Center for Tourette syndrome as a way for researchers around the world to gather and study genetic data on Tourette patients and their families and also genetic info and other conditions. The repository is recognized and funded by the National Institute of Mental Health. And through its work, we've been able to identify gene mutations that are thought to be implicated in Tourette Syndrome. So they're doing some really phenomenal, groundbreaking work here. I want to start with the biggest most important question I have. You are a father and a son both involved with Tourette research. So I'm dying to know in your family, what are the dinner table conversations like

Dr. Jay Tischfield: 2:06

we just tick?

Dr. Max Tischfield: 2:09

No, it's present in our family. But neither of us have a diagnosis. My DNA is part of that large collection you talk about. And within that study, I think I'm coded as a partially affected individual meaning that I have some traits that you might find in someone in Tourette's, like repetitive motor behaviors to some degree, but I don't actually have a diagnosis.

Michael Leopold: 2:33

What got you both interested in Tourette research?

Dr. Jay Tischfield: 2:36

I wasn't interested in Tourette research until perhaps 20 years ago, I was doing other things. And I know that much about Tourette's except I had an effective son, Max was not her only child or he acts like it. Then this woman called me, and that was faith rights. She said, are you doing threat research? And I said no. And she said, why not? I saw I don't have a slightest idea why I'm not doing anything. She said, Well, you have to trust research. She said, I'm coming to your office, and I'm bringing a whole bunch of families with me. We're going to talk to you into doing it. And she talked me into it. And I went to one of the galas right after that. And there's another one by the way, next year. And Tim Howard was there. I met Tim and I don't know I just got roped into it. And it was a smart move. Most of the time when I do smart things is because of the people telling me to do them. We decided to how we could start and the main issue was a lack of human samples. There were none available anywhere, not in the National Institute of Mental Health repository, which I ran. So I knew about and not elsewhere, the few that had been collected by what used to be CIA, the national organization, were not available to other people. They were used by some researchers. So we decided to start the NJ CTS sharing repository. And a few years later, we were quite successful. We gathered together a lot of small, meaning children and parents and few large families, including grandparents and some other relatives. It was impressive enough for us to get federal funding at that point. So we apply and that's how I got interested in Tourette's. And then max came along corrupters I guess I was faked rice to him. I said Why aren't you doing Tourette's research? It's a good disease and you can get funded and accomplish something. And the rest is history. So fairly correct

Dr. Max Tischfield: 4:45

Max? Yeah, I wouldn't call it a certainly a good disease. I think that Tourette's is a disorder that compared to its cousin, autism, there's a really a lot less known. There's a paucity of basic clinical Baby

Dr. Jay Tischfield: 5:01

wants a room for researchers to discover stuff. Yeah. 1000 people doing autism research now because there's so much money in it. There was no money in Tourette's. Let me just say, I think Tourette's is a good disease. The study I obviously don't name includes disease to have a because not only does it have a psychiatric component, but most physicians would say, the movement component is the key feature. And movement is something you can see, it's much easier to diagnose than the autism syndrome traits. Yeah.

Dr. Max Tischfield: 5:35

So when I was looking for an independent faculty position in 2017, I was intrigued by the idea that with the discovery of the first high confidence gene mutations linked to the Tourette disorder, we could use DNA editing technology to introduce these mutations into a mouse model, thereby generate the first ever mouse models that actually harbored a mutation found in a human. And the question then became, can we use these mice to actually model the underpinnings of Tourette disorder? And can we really start to break open or illuminate this black box that it really eluded researchers for a long time. And just a little bit more about my background, and I think this would underscore why this was a mission that I really wanted to take, in addition to having Tourette's in our family, my training, so I was an undergraduate at Rutgers I majored in cell biology and neuroscience. And then I went on to train in Harvard's program in neurobiology in particular, I trained with a neurologist named Elizabeth Engel. And she was involved in basically characterizing rare neurological disorders. So these were disorders that were not present in the literature, or if they were, there was no known cause. Really, my training then became to understand how do we take a gene mutation that we find any human, put that into a mouse, and actually model the key features of that syndrome. So then we can describe that to clinicians, and they can then better diagnose and treat their patients. And I've got a

Dr. Jay Tischfield: 7:04

secondary interest. Max's a neuroscientist, I'm a geneticist. And I've worked with NJ CTS at the Tim Howard Academy and what used to be called Camp Bernie in the various events. We just had one, maybe a month ago with a meet and greet with families to talk about current research. And the question I'm asked most frequently, and I don't have an answer is what medications are going to be most effective. Nobody has developed any drugs, specifically for Tourette's. And I thought if there were a good animal model, and a person like Max could show that, then we would have an animal to test drugs on and we could really rapidly screen either known compounds or new compounds for the roof, their effect on Tourette's, like symptoms in mice could then go to humans. It's interesting.

Michael Leopold: 7:59

I mean, you're both you're both Dr. Titchfield. So I'm going to call you Dr. Jay versus Dr. Max, just so we're clear here. Okay, I want to be respectful,

Dr. Jay Tischfield: 8:07

better basketball than

Michael Leopold: 8:09

I like. OJ, I remember you telling me I asked you at the Academy a couple years back as a result of the research, how many unique genetic profiles have we found that can lead to Tourette syndrome? And if I recall, you said it was like 500, or something like a large number.

Dr. Jay Tischfield: 8:25

Rove is the number we found and the number that we statistically proposed, based on what we found there. 500 is the Latin number. Okay, we think that could be as many, we have about a half dozen at this point. Or if we count the old literature, it might even be a dozen genes with three or four being very high confidence, the one that Max is working on this. So cool cells are three is a very high confidence in

Michael Leopold: 8:54

the challenge I see is if people with Tourette there's different genetic chemistry is underneath that. How do we find and prioritize one that would lead to a drug that helps the most people? Do we find that like, yes, there's a lot of genetic diversity under Tourette. But people tend to cluster into these, okay, this gene gets mutated a lot, this one gets muted a lot. How easy is that? How complex is that Tourette's

Dr. Jay Tischfield: 9:17

from the point of a clinician has a common diagnosis of motor and verbal tics. So all of these different genetic causes, may have one or several common intersections. If one can target these intersections with a drug, then you could have a drug effective with different kinds of turrets. But I will add

Dr. Max Tischfield: 9:39

that there's a challenge to this. We believe that these are mutations that are associated with the disorder. We gain confidence when we sequence the DNA of these hundreds of individuals. And in some cases, what we'll discover is that there are changes in a very specific gene that one individual has that another unrelated Each individual has. So when you start binding multiple unrelated individuals, and they all have a distinct change in the same gene, it doesn't necessarily have to be the same mutation. If it is, that's great evidence. But if they have mutations changes in the same gene, and they're unrelated, and if their parents who are unaffected, also do not have that change. So it arose spontaneously in the individual with Tourette's, we gain confidence that we have a good gene Kennedy. That's why we start using the term high confidence, the false discovery rate is such that we believe that this gene is indeed associated with the disorder. Now, that's great. We get excited when we find those genes. But we now have the next challenge. And that is how do we really show you know prove that these genes are indeed linked to Tourette's? Can we do that in an animal model that is potentially fraught with difficulties, for example, we're not quite sure, if mice, which is the model organism that we typically use, if they actually tick like a human, what is a tick in an animal, and we don't have a good definition, yet of what that is. So what we tend to do is we take these genes of interest, let's say we have a gene that Jane mentioned salsa, or three, and we have nine different individuals in our study that have a unique mutation in that gene. And what we've done is we've selected a subset of those mutations. And we've used a DNA editing technology called CRISPR. Cast nine, many have heard of this is one the Nobel Prize a couple years ago, it's now being used for gene therapy, and we CRISPR, where we edit the genome of these mice, and we put these different mutations in, you can watch

Dr. Jay Tischfield: 11:48

some of the genes in mice and humans are almost identical, it becomes an easier test. From that point of view, I would add that while not looking, if we saw something like human tick, we'd be ecstatic. But assuming we're not going to see something or drag, we look at all the behavioral parameters of the mice. And next, we'll say more about that. But we look at all the parameters to see how they differ from their non mutant littermates.

Dr. Max Tischfield: 12:18

And that's a challenge, you know, how do you pick that parameter? How do you pick a test? So we have this mouse, this quote, unquote, Tourette like mouse? What are we going to do with this mouse? And I will tell you that when you look at the mouse, just with your naked eye, you don't see much, right. And that's typical of many individuals with Tourette's, you don't notice it at first glance, right? Sometimes you really have to pay attention, tics wax and wane. And in these mice, how are we going to approach this? For example, we could look at general levels of activity with the idea that potentially the hyperactivity in some forms of Tourette's might be present in these animals, we can look for changes to motor behaviors that might be repetitive like such, for example, mice like to rear on their back hind limb, so they're rear up in the air. And the one domain that we actually look at and actually is increased in our mice, by

Dr. Jay Tischfield: 13:09

the animal to do it very quantitatively, you can't just sit around and say, Oh, he's visor, you have to have a mechanism. Yeah. And we do that using AI learning programs. Can

Michael Leopold: 13:19

you elaborate on what ticks and mice look like? Yeah,

Dr. Max Tischfield: 13:23

this is a really important question. I would say, again, we don't have any basis or any real strict criteria that we can use to find a tick. And that that really brings up problems in the literature. And we've encountered this ourselves, we have to be very careful how we describe some of the motor behaviors, those that are very close to the field of Tourette's will argue that what you find you can't really call a tick, you have to just describe it for what it is. Whereas other people in the literature, you'll see commonly the phrase tick like stereotypies. That's

Michael Leopold: 13:56

how they Cushing. Yeah. Or,

Dr. Max Tischfield: 13:59

I would say that there's one mouse out there that has been around for a long time. And it's a mouse that they basically played around with the dopamine sibling in a way that's very artificial. They did something that you would never find in the human is supposed to basically mimic higher states of dopamine in certain parts of the brain. And that mouse has probably the most tick like movements of any mouse out there. But the problem is, it doesn't actually resemble in any way any type of DNA change, or a change that we can say this is what a person with Tourette actually has

Dr. Jay Tischfield: 14:37

to do or change has never been observed in humans just hypothesize. This

Dr. Max Tischfield: 14:42

mouse is particularly one called the D one C T seven mouse. They just found a way to activate the dopamine type one receptor in the forebrain. And that mouse has a lot of interesting phenotypes and does very much look like it ticks. But it's problematic in that we can't trust the underlying Change has anything to really do with what you would see in a human. Now one thing I will add, there is a behavior that has been documented in humans that you can study in mice. And this is something called pre pulse inhibition. And this is a test in which you basically start with a mouse with a loud sound, it could be a sound or tactile stimulus, it processes that initial startle. And then you start it again. And what the mouse will do is jump in the beginning to that initial startle, if I clap my hands in front of you really quickly, and you're like, Whoa, when you jump up, but let's say 10 seconds later, I clap my hands in front of you, again, you've kind of habituated to that stimulus, so you don't shock as high or you're not as surprised. And that's kind of what that's exactly what we test in our mice. And individuals with Tourette's in human studies have been shown to lack the ability to kind of filter to properly filter or process that first stimulus. It's called a sensory motor gating deficit. Sure enough, we did this behavioral paradigm in our mouse models, because it's very similar to what you would do in a human. And very interestingly, our mice, almost all of the models we've made thus far, both males and females show a deficit in pre pulse inhibition. We propose based upon our mouse models that looking for sensory motor gating deficits could be a core behavioral finding, in a mouse model. With that, you could ask does it respond to drugs that you would prescribe to a subject that has Tourette's it back in the day, it used to be hella Peridot, these are drugs that work on dopamine. And what we're finding is indeed, the drugs that are used in humans are actually showing effects in mice, and especially in the sensorimotor, gating deficit assays? Well,

Dr. Jay Tischfield: 16:49

that's very encouraging. Based on what I said before about drug development, these

Dr. Max Tischfield: 16:54

results should all be out early next year. And I think it just goes to show that the goodwill of those who donated their DNA into this DNA Cell repository has led to tangible results that we were able to then go into a mouse will look at these mutations and say, Wow, we may have the first real valid models of a Tourette like mouse, we may have finally generated the first one,

Dr. Jay Tischfield: 17:17

I think Max even understates the case, I have a longer perspective due to age, there are people walking around that have the exact same mutation, as our mice, or it's actually the other way around, the mice have the exact same mutation, we put it in as the humans, we want to take it to the next step. If we have enough people, and we really do need more, we can start finding more genes and looking for those common intersections where the gene affects my meat. I don't think there are any other large groups funded for threats. We are the only ones in the federal government. And we have to convince them to give us another 10 or 20 million bucks.

Michael Leopold: 18:04

But the neat thing is, once it's processed, that genetic data is available online for any for researchers all over the world as part of this collaborative data,

Dr. Jay Tischfield: 18:12

the actual samples, oh,

Michael Leopold: 18:14

they can get the samples too. Oh, yes. Why might they want to do that, as opposed to just having it sequenced?

Dr. Jay Tischfield: 18:21

Let me just say, we've done nor make mice, we've also made what are called IPSC induced pluripotent stem cells. And you read a lot about stem cells. Today, we're also studying these and the stem cells, we use the same kind of CRISPR technology, or we use the blood of the patients depending on the circumstance, or where it came from, such as we have this collection of stem cells that also models, all the mutations that we've collected in Tourette's. So we have a mouse and a human resource, and of course, are subjects that can contribute to this research. And I

Michael Leopold: 19:02

want to give our listeners some info on that I participated in it a number of years ago, so you should still have my my my sample. It's

Dr. Jay Tischfield: 19:10

all anonymized. I don't know which sample is yours.

Michael Leopold: 19:12

I mean, there's somewhere in my trio is because actually, my whole family did it because I have two of my three siblings also have an active Tourette diagnosis, and we believe it came through my mom's side, but I did the blood sample, I filled out a we each filled out a lengthy questionnaire about all of our tics and CO occurring conditions, family background, they were looking for all a lot of different variables to understand. I think there was a meeting with Dr. King to discuss the process, you kind of manage that and what would happen next. And that was it. I filled out the form had the interview, the blood was drawn. And then I mean, the highlight for me was really every year at the Tim Howard Academy, we take the students through the repository so they actually get to see the lab where this data gets worked on. That was really neat and really made a lot of this come to life.

Dr. Jay Tischfield: 19:56

Next year will be super big growing Have we actually finished construction of the new repository, which is many times larger than the old one? And people were impressed by the size of the old one?

Michael Leopold: 20:11

I'm looking forward to that. What would you say are some common misconceptions or just assumptions we had about Tourette genetics, that your research has helped clarify, demystify, explore.

Dr. Jay Tischfield: 20:27

There are a lot of social issues as you well know, surrounding Tourette's and how society treats people with Tourette's. There are there were questions. I think they've been well settled now as to whether or not people with Tourette's are less confident. Tim Howard said in his book and said to me personally, that he always felt he reacted quicker, because he had Tourette's, I don't know if that's true is no one's like 10 hours. He's a special guy, ya know, he's reaches like 60 to 80 or something. But we've seen a very large number of Tourette subjects now. And we've actually made mice the mice are easily as competent. In fact, they may be quicker learners of certain things. So Max can talk about that. In terms of his habit formation theory of Tourette's, the evidence is in ways that Tourette's kids are not neurotypical. That's a word that people tossed around a lot today, Tourette's kids may be some of them might be even more competent than their non Tourette's, of course, Tourette's, unfortunately, comes frequently as a package with OCD, and ADHD, and sometimes even autism. So these things in general, may or are unlikely, although obviously, these sometimes makes people a bit more competent if they choose the right careers and right things to do. But I think we can say with confidence that there is no real deficit in Tourette Syndrome. There is behavior that disturbs the people they interact with, and and sometimes the kids who are affected, but there's no reason that they shouldn't bleed, highly productive. Watch Tourette in

Dr. Max Tischfield: 22:27

one individual is not going to be the same as Tourette's in another interview. And any type of spectrum disorder. That's what we call these disorders, right, where there's a whole spectrum of different types of symptoms, whether it might be associated OCD, ADHD, I mean, the list goes on conduct disorders, whether or not there might be higher incidence of substance abuse, that there's really a large gamut. And we can't necessarily put everyone into the same box. And as a researcher, it's very important to understand that, because when we read the literature, and the literature says, Tourette's is caused by this, based upon this study with 30 individuals, you have to take that with a grain of salt. And oftentimes, these studies, clinicians are trying their best, but they're based on a limited sample number. And some results are not reproduced. But yet these studies kind of set the standard or the basis for what we think is Tourette's, and what we think causes Tourette's, we want to take everyone's findings, we want to take them seriously and test them. But in some cases, I think it's important to realize what we think we know about Tourette's is based upon imperfect models, maybe imperfect experiments. The hope is over time that we can develop these better models and with tools through artificial intelligence, can we harness these new technologies with these better models to gain a better representation of what Tourette might be? In terms of brain changes?

Dr. Jay Tischfield: 24:01

We've been using these artists a these AI machine learning models on the maze to characterize their movements. And now we've actually like we have no generics there. They're just working on it. With us. We'd like to do the same thing with humans.

Michael Leopold: 24:16

Wow. Yeah. So because it sounds like even if these mice have that we give them that genetic mutation that some people with Tourette have the manifestation of it isn't going to be the same. They're not going to get the tics as we do. So but yeah, and we still study it and how does family history influence the likelihood of developing Tourette so that J this may be more your wheelhouse the genetics of Tourette? What are some patterns and trends we've observed in the genetic data?

Dr. Jay Tischfield: 24:42

Remember that in our current collection, everything is skewed toward new mutations. We look for trios, where there's no family history, where there is only one affected sip, and that increases the likelihood that that child is a consequence of a new mutation. Because when we look at the parents, we don't find the mutation that child has, we think perhaps about 15% of the Tourette's cases are a consequence of new mutations, then you have some well documented cases, our colleague, Matt states, Doc, and I was a co author, we document a family 25 years ago, that had a huge number of cases, because of a specific mutation and a particular pathway. So Tourette's and that family was inherited the same way in every person, by we have published in what's called a polygenic, risk score, PRs for short, that looks at all the genetic background, all the mutations, all the variants of all the genes that we can test, as many as 18 20,000. And it calculates a score based on what we see in Tourette's patients. And that score has useful but minimal predictive ability. When we look at somebody who's diagnosis, we don't know, there are at least three kinds of genetic Tourettes, there are new mutations, there are inherited mutations. And there are lots of small mutations which cumulatively cause Tourette's, but it may be gene function can be influenced by environment. This is a field called epigenetics. And epigenetic changes can mimic mutations. They're not inherited generally the same way as mutations. But functionally they mimic mutations. So it could be and I don't really have an answer, that a large number of Tourette's cases are the result of environmental factors. And we've looked at some of these nothing really stands out thus far. I

Michael Leopold: 26:59

love how you broke it down into the three big kind of buckets or clusters, you acquire the mutation from your parents, it's a new mutation, or it's a accumulation of many smaller kind of mutations that add up and lead interact, are we able to say with any level of specificity, like what percentage of our population falls into each of these categories?

Dr. Jay Tischfield: 27:17

That's a good question. But so let's say 15% of the subjects patients are new mutations, and let's say just round numbers, so right, I'm gonna have to use my calculator. Let's say one and 100 people in the population have threats. So 15% of that one and 100, I need to just do the math. I can't say with any certainty, what percent are inherited. But I my guess, is its guess it's at least 15%. And this one mutations, probably somewhere in that range. So I would say that maybe as close to half of all Tourette's is a consequence of mutation. So one in 200 have mutations. When it

Michael Leopold: 28:16

comes to the treatment? Have we tried giving specific drug candidates that are in the pipeline? Do we give any of these experimental drugs to the mice to see if they can do anything with the at the mice that we've now imbued with this mutation? This gene? That's

Dr. Max Tischfield: 28:30

the hope that's what we would say is the promise, potentially of a really good model. Now that we have confidence that these mice are expressing what we call Tourette like behaviors, we can ask how experimental drugs or experimental therapies may work in those mice to mitigate these Tourette like behaviors. And that's certainly something that we're interested in doing in going forward. We're in the process of or actively seeking out partnerships with pharmaceutical companies who want to test their drug candidate in our animal models with the hope that the evidence that you might gain from that study could motivate the onset of a clinical trial, for example, where this drug may then be tried to see its effects on a specific, let's say, subdomain of Tourette's motor behavior. But that's clearly what we hope to do. But beyond that, I would say that the neuroscientist and me, I was trained as a geneticist originally, but my degree is in neurobiology, I think what we want to do is not just necessarily throw all these drugs at these mice and see what they do, but ask why they're doing that. Therefore, we can start to tailor you know, better treatments for individuals that might have different types of Tourette's. And

Dr. Jay Tischfield: 29:51

also, let me just say, if you're going to an event, invent the drug from scratch, the process of using it on people is very complicated. You start with Adam, the model is just thought with bacteria, you have to show the drugs, not poison. It's not mutagen in what I'm looking for, if I had my way, once Max figures out how these mutations work, I would see if we have any drugs on the shelf. Yeah, that were created for other purposes that might be repurposed for Tourette's. And if we have these drugs on the shelf, and I've been involved, not with Tourette's, but were other diseases, where this has been a remarkable success and Zico, progeria, for example, if the drugs have been approved for human use, that it's much easier to go right to humans and do a clinical trial.

Michael Leopold: 30:43

I was surprised and honestly disappointed to hear that when we imbue mice with these mutations that they don't exhibit the text as we see them. You know, the motor, you know, oh, yeah, you

Dr. Jay Tischfield: 30:54

know, you're always disappointed, but I was

Michael Leopold: 30:56

I was hoping you. I was hoping you'd say oh, they squeak more. Okay, great vocal tics. Oh, and they do they do more movements. Okay, great.

Dr. Jay Tischfield: 31:03

Actually, we haven't tested that mice squeak at ultrasonic frequencies that humans can hear. Oh, man, I just set up a new lab just today. Actually, I bought the gadgetry that one needs to listen to mouse vocalizations. And we're actually going to see if they sweet more. But

Michael Leopold: 31:24

really, so we had an exploit that before think

Dr. Max Tischfield: 31:26

about ticks for what we perceive them to be, whether it be a mood or tick or vocal team. But I would really stress that we need to ask, what is the underlying basis of a tick, not just the ticket itself? But what's causing the tick? And can we model that in a mouse, something that might pose to you Michael, when you have a tick yourself? Do you ever find yourself ticking in a particular time or a particular location? Or in particular context?

Michael Leopold: 31:54

Absolutely, yeah. Yeah, definitely patterns. And

Dr. Max Tischfield: 31:57

when you think about a pattern, something you do often what would you call that? A habit? That's right. There are studies in humans that suggest that those who Tourette's may be more habitual, meaning that they may rely more on habits than other types of strategies. And the idea that tics might actually be a maladaptive habit in response to urges and unpleasant sensory stimuli such that in the beginning, when you learn it, I think you could probably sit here and say, Yeah, I remember when I learned that tic, or I wasn't around this person, and I picked up that tick, you learned it. Now, the same mechanisms as our brains learn us to learn things, dopamine, for example. These are pathways and neuromodulators that are involved with not only how we learn to do something for a goal to achieve something, but after a while, if you repeat that enough, it becomes a habit and habits are elicited unconsciously. They're elicited by sensory cues in your environment. They're elicited by emotions, feelings, something that you associate with something that you've done in the past has led to a reward. So if you learn to tick in the beginning, and you feel an urge, and you tick, and you get that relief, if you repeat that enough, that becomes habitual. And what we have discovered, and this is actually very exciting. This is where our unpublished research is going, is that our mice are more habitual, like a study in humans, published seven years ago suggested that patients may rely more on habitual strategies, we have been testing mice, it's a 40 day procedure, you have to sit down with these mice, sometimes for 10 to 14 hours a day for 40 days straight. There's no Saturday or Sunday off. Even going grocery shopping for my students is tough. During these assays, wow. We teach mice to form habits. And then we teach them to suppress their habits. tics are hard to suppress, you can do it. Right. It's tough. And what we have learned, and this is kind of interesting, and I think this is what che went on to say that sometimes Tourette's can be, there are qualities of Tourette's that can be gift, like you have super, I want to say superhuman qualities. But what we find is that these mice develop habits much quicker. They have difficulty suppressing them or breaking them. What's interesting in the beginning stages of a habit, what do we see? What we noticed is that these mice are super motivated. They work really hard. If you put a mouse if you put a Tourette mouse quote unquote, rat mouse next to its uninfected sibling, and you give that mouse a reward. But let's say that the there's an uncertainty to the delivery of that reward. When the mouse knows that if I poke my nose in this hole, I will get that reward. But I don't know when it's going to happen. So I just got to poke. What we find is that the Tourette mice quickly, very quickly learn. They elevate their nose poking. So hi, the radar knows that they're not going to miss that chance to get on that tree. They want their reward perception, the idea of what that tree is to them. It may have a higher incentive value such that they're more motivated to go for it. And they repeat that action over and over again. And you see that very quickly. So they show elevated motivation, they show higher degrees of motor responding. Now when you tabulate who wins the most rewards, the Tourette mice, always, when the most rewards, always, the normal mice, they have that intrinsic motivation. But once they stop those goals, there's a trade off for everything in life. That trade off that Tim Howard might say, gives them that extra motivation or that determination. A lot of this is fueled by that neuromodulator dopamine. Dopamine is very big, It powers our motivation, it determines our ability to perceive a reward, it also invigorates our motor system, you might have more dopamine, it might make you more motivated, it might make you more likely to repeat things, for example, or just to consolidate as we say motor movements. What it also might do is potentiate systems in our brain that learn to associate a sensory cue with an action, such that when we put our mouse back in our chambers, they have these specific chambers. And when they go inside, they see the nose port, they see the chamber, these are the sensory cues that the mouse has learned to associate, I'm in this assay. I'm supposed to nose poke, as we say in our lab, start poking these sensory motor transformations, or potentiate it in these mice. So the same dopamine, you know, it's working to help the motivation, it's working on the reward system. It's probably all we're also working on strengthening stimulus response associations that ultimately elicit an emotion, a motor behavior, such that that's exciting. Yeah, you learn quicker. But these were ideas that were postulated from a single human study. And I should add that those that were on dopamine blocking medications, did not show this habit phenotype in humans. What did you go? Yeah. So what have we learned our mice are actually mimicking this theory of Tourette's. And we should add cognitive behavioral intervention therapy, Habit Reversal therapy,

Michael Leopold: 37:07

that's the main gold standard treatment now for ticks in the therapeutic

Dr. Max Tischfield: 37:11

right. And through these mice, we're starting to learn there's a reason for that. And that's because the habit activating centers of most of your brain that control habit, like behaviors are affected in Tourette's, through the lice, we're now starting to say what are those particular neurons? And you actually do and this is exciting. The student in my lab, the grad student who has Tourette's, who, who works on these mice, and in fact, has developed, knows poking ticks. By watching the mice behave,

Michael Leopold: 37:38

we have the first species to species example of tick contagion. Wow. That's a dialect document that wow,

Dr. Max Tischfield: 37:47

yeah, no, she said, she went from the head twitches to no smoking. Wow. And so and again, that just really shows you that these traits can be learned. But what she's doing now with her student who also has Tourette's, we have multiple individuals in the lab, who not only work on these mice, but they've lived with it their whole life, what they can do now is they can use these new technologies we can put in sensors that allow us to detect dopamine life. And we can put a fiber optic cable into the brains of these mice. And while they behave, we can actually image moment by actually, I should say, millisecond by millisecond, that dopamine changes in the brain. And we can start ascribing these changes to the particular behaviors while they're forming a habit. So oh, that's huge. It's huge. And then we can ever late so the bigger

Dr. Jay Tischfield: 38:37

question and people why do we do what we do? Yeah, this

Michael Leopold: 38:41

is some biofeedback. I mean, I would love to know what's going on in my brain like walleye and get Alright, so when I'm getting a new tech or when I'm ticking, like, I would love to have that data. And if

Dr. Jay Tischfield: 38:52

your tick is just an exaggeration, of a normal behavior, in fact, we have the ability using these mice to understand the normal behaviors and how they work. We

Dr. Max Tischfield: 39:04

can use the same technologies to ask okay, what did we see in a non medicated mouse? What did we see in a medicated mouse? How are these drugs working to modulate these neural signatures that we're recording? Really what I'm trying to say here is that don't be disappointed that a mouse doesn't vocalize or having an actual tip, Robert over over. You don't know that.

Michael Leopold: 39:24

Yeah, they could have coprolalia for all we're gonna find out

Dr. Max Tischfield: 39:27

and I just can't hear them cursing at me. That's very,

Dr. Jay Tischfield: 39:31

I was a mouse said go after yourself.

Dr. Max Tischfield: 39:33

Yeah, but I really look at it deeper than that than neuroscientists to me and I say, mice form habits. We can do this. We can get into the underlying basis of what it tickets because on the kicks are so different and everyone thinks can be compulsive. They can you don't even know what to tick sometimes, right? There could be behaviors that you don't really know are a tick. The idea is that there's an underlying basis to these and we're gonna go fine.

Michael Leopold: 39:58

They know you definitely challenged my paradigm. on that, and that that makes a lot of sense, like, what is, you know, deeper going on when we have a tick, just as ticks can vary dramatically between individuals. But it's not about mimicking that exact kind of tick that we see in people. It's about whatever's going on underneath, in case any of our listeners are concerned about these mice, and they hear us talking about giving them mutations, and they're having these, these changes. Jay, I'm reminded of something you said at the academy that that research is expensive. Research also takes a lot of time. And especially when you're doing genetic studies, where you need to get multiple generations we're looking at, okay, we gave them this mutation, does it get passed down to their offspring, if a mouse dies in the midst of research, that's a lot of money down the drain, and all the time those 16 hour days, Max, you mentioned, like, do

Dr. Jay Tischfield: 40:46

die. So from Yeah, causes our mice are looked after very carefully. Every day, an animal technician looks in the cage. And what you only have is five mice per cage maximum, and looks for any of mice that appear unhealthy. And sometimes they tell us how to treat the mice, we may have throat some ointment on, or something like that. Or sometimes they tell us that Miles is not going to live them, we have to get rid of it cost.

Dr. Max Tischfield: 41:17

Each cage is something called something like$1.30 or $1.40 a day. And we have like 300 cages. This one Oh, that's every day. There's a reason why we use mice. And that is because they're the lowest vertebrate species that can mimic the human brain and the human physiology. There's certainly ethical reasons why we don't use monkeys, or why we don't use other mammals, you know, but mice can reproduce our physiology to a degree and also mice as many who might have a mouse problem in their house. They can have litters eight to 10 Pups, every time a mouse gets a litter, you might have five newborns that carry that specific mutation. Mice are the cheapest vertebra to keep in numbers.

Dr. Jay Tischfield: 42:04

There's nothing cheaper rats are much bigger. And then much more expensive. People have been using mice well over 100 years now. And there's I don't know how many zillion papers involving mice. But it's a very well studied, well documented. We know its anatomy. We know a bit about its behavior. We know its genetics.

Michael Leopold: 42:25

I remember you saying Jay that you found we treat mice, our lab mice better than we treat people that are worldwide on a societal level, like we care about our research by the owner, they're getting the best food, they're getting exercise they're getting, like when they're sick. You're you guys, your research assistants are rubbing the lotion on them. I mean, when

Dr. Jay Tischfield: 42:42

they're sick, we actually have a veterinarian who comes in and looks at them. It's not. So make decisions on how to treat most vets,

Michael Leopold: 42:51

they get specialized care. mice

Dr. Jay Tischfield: 42:53

in the wild don't live very long. Because we treat them so well. We actually live longer, and our mice will live one and a half to two years. So

Michael Leopold: 43:03

we're getting to the end of time here. I want to say briefly if there's any of our listeners who would like to take part in the Gen X repository have their information stored. Max Ajay, what would you recommend? Where do they go to get started with that process?

Dr. Max Tischfield: 43:16

Our contact information is widely available on the web. We'll put

Michael Leopold: 43:20

it up with the podcast as well so they can go to their to reach out

Dr. Max Tischfield: 43:24

contact us through NJ CTS or through our websites and we'd be happy to connect you.

Michael Leopold: 43:29

Thank you both so much. It's been a riveting conversation. And I wish you both a wonderful evening. Yeah, no, thank

Dr. Max Tischfield: 43:35

you very much, Michael. It's a pleasure.

Michael Leopold: 43:39

Thank you for listening to the uptick, brought to you by The New Jersey Center for Tourette syndrome and Associated Disorders empowering you to stretch the boundaries to live your best life. The NJ center for Tourette syndrome and Associated Disorders NJ CTS, its directors and employees assume no responsibility for the accuracy, completeness, objectivity, or usefulness of the information presented on this podcast. We do not endorse any recommendation or opinion made by any guest nor do we advocate any treatment