Stephen Wilson 0:05 Welcome to Episode Eight of the Language Neuroscience Podcast. I'm Stephen Wilson and I'm a neuroscientist at Vanderbilt University Medical Center in Nashville, Tennessee. Thank you for listening. Today, my guest is Julius Fridriksson, who is Professor of Communication Sciences and Disorders at the University of South Carolina. Julius's lab is called the Aphasia Lab and he's also the director of C-STAR, the Center for the Study of Aphasia Recovery. Julius is one of the world's leading aphasia researchers. He leads a staggering array of projects ranging from clinical trials on aphasia treatment, to studies using structural and functional imaging to investigate the neural mechanisms of language and aphasia, and much more besides. Today, we're going to talk mostly about aphasia treatment and its neural basis. As a disclaimer, I've been friends with Julius for a long time. We are co-authors on one paper from 2018. We co-wrote a chapter in 2019. We have one ongoing collaboration that we're not going to talk about today. And I'm a member of the advisory board for C-STAR. Okay, let's get to it. Hey, Juli, how are you? Julius Fridriksson 1:04 I'm doing great, Stephen. How are you doing? Stephen Wilson 1:07 I'm doing good. How are things in Colombia? Julius Fridriksson 1:10 Things are going really well. You know, we are starting to get people with aphasia to come back to the lab. And so we're starting our studies again. So things are on the up and up for sure. Stephen Wilson 1:22 So before we start talking about our topic for today, which is mostly aphasia treatment, I always like to learn a bit about how people came to be interested in what they're interested in. So can you tell me about when you were a kid? Did you have any interests that would point the way to what you later ended up doing with your life? Julius Fridriksson 1:38 No, I mean, I was always interested in science, but I kind of just came up on this field of speech and hearing sciences by an accident. I was kind of floundering as a student didn't really know what to do. And I have an uncle who is an ear, nose, and throat specialist. So he's a physician, and he was telling me we really need speech language pathologists in Iceland. So I started looking into it. And I thought this seems pretty cool. Then I went to the States, first at the University of Central Florida and then University of Arizona and got my PhD. And the rest is history, I guess. Stephen Wilson 2:14 Okay. So I was also, as you know, at the University of Arizona. You were there before me, and you worked with Audrey Holland. Did you want to talk a little bit about what you did during your dissertation? Julius Fridriksson 2:25 So Audrey Holland was a very unique mentor in that she was very hands off as a mentor. She would allow her students to explore different things. At the time, she was very much into what we call today, it's sort of the functional approach to aphasia management. But I was interested more in the neural mechanisms of aphasia, so I spent a lot of my time in the Department of Neurology and ended up doing my dissertation on some of the stuff that Argye Hillis was pioneering at that time. So changes in cerebral perfusion, and recovery from acute aphasia. So that was the topic of my dissertation. Stephen Wilson 3:09 Right. And I noticed that you went straight from your PhD into your faculty position, which you've been in ever since at the University of South Carolina. You didn't do a postdoc. Obviously, things worked out great for you. How did that work out for you? Would you recommend it to others? Julius Fridriksson 3:29 No, that's a good point. So I would not recommend it to others. For example, when I came out of University of Arizona, our department was not very productive as far as federal funding for example. If somebody like myself was applying for a job at the University of South Carolina today, they would not have a chance to even get an interview. So I was ABD (all but dissertation), no postdoc, maybe two or three pubs. I just wouldn't have been competitive. The other reason why I highly recommend doing a postdoc is, I think it's a really a time to kind of find yourself and find what really tickles your fancy. And I look at all of my postdocs, and I think they're having a great time, which sets them up to become a faculty member. As opposed to me, I came from Arizona here and it was really a frantic pace going immediately on the tenure track. So I sort of wish that I would have had that intermediary phase where I could have, I don't know, published a little bit more gotten to know the methods a little bit better, at least for neuroimaging, and it certainly would have made those initial years easier. Stephen Wilson 4:46 Yeah, well, it turned out okay. But I hear what you're saying. And I would always advocate a postdoc too. Julius Fridriksson 4:53 Yeah, a lot of the reason why I've been successful is more a function of the people that I've tried to collaborate with. I've been very lucky. And I've worked with some spectacular folks like, I mentioned Argye Hillis and Chris Rorden, Leo Bonhilla, and more recently, Greg Hickok. Those kinds of folks. If you find the right collaborators who kind of push you, it's hard not to become successful, I think. Stephen Wilson 5:22 Yeah, you do work with a really great team. Okay, so, I'd like to talk mostly today about aphasia treatment, by which I mean behavioral treatment, which I think you call aphasia therapy. Our podcast kind of covers a lot of ground in language neuroscience. And I don't think that all of our listeners are going to be familiar with treatment for aphasia at all, really. So could you start by kind of telling us, what are the major classes of treatment that are out there? Like, how would they categorized? What are people using? Julius Fridriksson 5:52 I would say, in the broadest terms, people split it into what they would call impairment based treatment. So that is working directly on language processing. So finding what are the limits of what you can and cannot do. And then trying to, with different behavioral manipulations, trying to get to improve your language. More functional approaches is something that instead of focusing specifically on the language itself, it's focusing, for example, on a given task. Trying to master a task like ordering at a restaurant, or calling 911 or something like that. So they're not completely incompatible. But I think that in general, people distinguish them by and large in that way. Stephen Wilson 6:40 Okay, so that contrast between impairment-based approaches and functional approaches. How about the life participation approach? How does that fit into that? Or is that a third kind of category? Julius Fridriksson 6:50 So I would not call the life participation approach a treatment approach. It's more like an approach to managing aphasia, so living successfully with aphasia. It doesn't necessarily have to involve treatment. So that's things like, you know, Andrey Holland, for example, developed, and other people developed it too, something that is called conversational coaching where you spend time with not just the person with aphasia but for example, their spouse. You're trying to figure out what are the most effective ways to communicate. And then you try to sort of reinforced that that's something that you should use more rather than less. And it's an approach that I think is extremely important for many different reasons, not the least because traditional approaches to aphasia treatment have not been that effective. So I think that anything that helps people deal with the impairment and sort of try to go on with their lives, whatever that life might be, like, after aphasia. I think that's very positive. Stephen Wilson 7:58 Right. You mentioned that aphasia treatments don't work terribly well. So what is the strength of evidence behind these different approaches, the impairment based approaches as well as the functional approaches, as of now, in your view? Julius Fridriksson 8:14 So it depends on what perspective you take. I think that for people with chronic aphasia, that anything that can improve your ability to communicate has to be viewed as being very positive. I think that for most people with aphasia, what they're looking for is something that results in drastic improvements. I don't think there are many approaches that lead to drastic improvements of aphasia. I think that it's something that you have to work out for a very long time, you have to get a lot of therapy, and then you might see incremental changes. So let's say that, from one year to the next, you might see, yeah, substantial changes. But from one week to the next or one month to the next I think that major improvements are very limited. Now from the perspective of the scientific literature, there is this metaanalysis by Brady et al. from 2016 in the Cochrane report, which is cited very widely. I think that it does suggest that aphasia therapy has positive effects on on outcome and aphasia. But the paper that I really like to, and I come back to quite a bit is Breitenstein et al. from 2017 in Lancet. They combined both functional and impairment based treatment in people with chronic aphasia. It was a randomized control trial. And found that it does improve speech production, so functional speech production as well as communicative quality of life. The effect sizes were not huge. And of course, there was a huge range across participants in with regards to response to treatment. But nevertheless, on average, what that study shows is that aphasia therapy, even for just three weeks, can lead to lasting improvements in language processing. Stephen Wilson 10:13 Right? So, Breitenstein et al. 2017 is, in your mind the most compelling, randomized controlled trial of aphasia treatment to date? Julius Fridriksson 10:21 Absolutely. Stephen Wilson 10:22 And interestingly, yeah, it was only three weeks. And I think it was pretty intensive. Right? They were doing maybe three hours of therapy a day. And it was tailored to each individual. Julius Fridriksson 10:31 Yes. And they also were, if I remember correctly, I think they augmented it with computerized therapy. I can't remember. It's been a while since I looked at it, but it was pretty intensive. But you know, only three weeks, if that can lead to a medium size effect size that's going to be worthwhile. Stephen Wilson 10:54 Right. Yeah. So I know that you've got your own treatment study going right now called POLAR. Can you tell us what POLAR stands for? Julius Fridriksson 11:06 Predicting outcome of language, language therapy and aphasia. I can't remember exactly what the acronym is for. I wrote this in a grant like eight years ago, Stephen. Stephen Wilson 11:19 Okay. I'll just fill it in later, just paste it in. Julius Fridriksson 11:23 Yeah, sure. I was just gonna go on and tell you about the study itself. So it's a clinical trial that has, it's not an efficacy trial. It's a crossover study that looks at the effect of semantically focused therapy versus phonologically focused therapy, where all participants go through both phases. So three weeks of one type of therapy, four weeks off, and then they cross over to do the other therapy approach. And what we're looking at is two things. Is there a difference with regards to response? And can we predict overall therapy outcome? And can we predict separately who responds to semantic treatment as opposed to who responds to phonological treatment? Stephen Wilson 12:10 Okay, before we go further, in talking about like, what you've found so far, can you tell us more about what the semantic treatment and the phonological treatment actually involve? Just put us in the, you know, imagine we're a fly on the wall in one of those treatment sessions. What is the SLP doing with the patient exactly? Julius Fridriksson 12:27 So this semantic approach, these are not approaches that we invented. We simply went to the literature and looked at what are approaches that seem to be working more on the semantic side rather than phonological? Of course, you know, it's impossible to completely isolate, whether you're working on semantics or phonology. We simply went for, how is it described by the authors. And then we group those together. So the semantic treatment approach includes VNeST (Verb Network Strengthening Treatment), semantic feature analysis, and a sort of a semantic grouping task. Which is kind of like, it's a little bit like PACE (Promoting Aphasics' Communicative Effectiveness). So we combine those. The participant works on each one of those for about 15 minutes in each one of the sessions, and the session is about one hour at a time. So that's five times a week for three weeks. Stephen Wilson 13:23 Hang on a sec, sorry. Just imagine that people are not SLPs at all. I mean, I don't want you to go through like all three of those treatment approaches, but can you kind of, maybe just pick one, a representative one. I just kind of want to have a picture of what is happening between the SLP and the patient. Julius Fridriksson 13:41 So for example, in this semantic feature analysis, what they do is that, for example, they might see a given word. And what they do is that they focus on what are the features of that item. They go through all those features, they repeat it. They may match the different features for different items. So it's really just working on what I would call sort of like, as the name implies, the semantic features of a given item. They do that for 15 minutes in sort of like a hierarchical manner. And they try to go from simpler to more difficult. The treatment is designed, the way that we do it, is that we tried to tailor it towards that participants ability at that time. So it's not like we start from scratch, the next time they show up for therapy. Stephen Wilson 14:39 What's the rationale behind why exploring or discussing the semantic features of a word would be beneficial for language recovery, Julius Fridriksson 14:48 Because for many people you assume that there has been a disconnection between the semantic features and the lexical item. So the idea here is to try to rebuild connection so that when the patient tries to retrieve a given word, they're trying to name a dog and they don't say cat, for example. That's a really simplified version of this. But it's really trying to strengthen the lexical-semantic relationship. Stephen Wilson 15:17 Okay, that makes a whole lot of sense. You want to move on to the phonological arm? Julius Fridriksson 15:23 Yeah, so just like with semantic approach, the phonological approach also includes three different sort of subapproaches. One is phonological feature analysis. One is a version of phono-motor treatment. And then the third one is a phonological feature task, which is very similar to the semantic feature task. So instead of focusing on the semantic features of the given item, they focus on breaking down the phonology of a word, for example. Trying to build that word up to a single word. Stephen Wilson 16:01 Okay, so kind of like phonological awareness. Julius Fridriksson 16:03 Yeah, exactly. Stephen Wilson 16:05 And again, what is the rationale for these kind of metalinguistic tasks building phonological processing skills? Julius Fridriksson 16:15 Yeah, sure. So from the impairment based point of view is that what has broken down is the actual phonological assembly. And so what you're working on here is exactly that. Trying to strengthen the phonological representation by going through these different drills. Stephen Wilson 16:35 Alright. Okay, so what kind of outcome measures do you use to figure out whether this is working and which one's working better than the other and for whom? Julius Fridriksson 16:45 Like probably 90% of all aphasia treatment studies, we look at naming. So the Philadelphia Naming Test, which is from Myrna Schwartz et al. That's a test that is being used, I think more and more in the literature. It's 175 item test, and it's just confrontation naming. that person sees a picture, and they're supposed to name it. And then we score it based on accuracy and the different types of errors that they make. That is assessed twice at baseline, and then once at several different points before and after the different treatment phases. We also look at discourse. But I've found that there's a lot of hype around discourse in the field, I think that we still lack a lot of rigor with regards to how you measure discourse. So the discourse outcome measures that we've looked at, we've very much relied on AphasiaBank, which is Brian McWhinney's stuff. At least on this point, and I hope I'll be proven wrong, I have not found it to be very useful. Because there's so much variability. And it's very subjective how you score so many of the things with regards to discourse. There are some people who are trying to improve the methods that we use to measure discourse, but at least the way that the field is right now, I think we have a long way to go. Stephen Wilson 18:18 Yeah, I agree. I mean, we've worked on this a little bit in my lab, too. We have this approach that we call APROCSA, which stands for Auditory-Perceptual Rating Of Connected Speech in Aphasia. And we are looking into the psychometric properties of that. I wouldn't advocate it for immediate use in clinical trials. And like you said, it's very subjective. You would certainly have to be completely, you'd really have to make sure that your raters were completely blinded. I'm sure you would for scoring the PNT too. But it would be even more important that they not be cued in any way as to which data they're assessing. Julius Fridriksson 18:56 Yeah, I think that for a crossover trial where we really have no, we really did not expect one treatment approach to be better than the other. I think the blinding is probably not as crucial. But if you want to use it for a randomized control trial, and you're trying to prove that a given treatment approach works, yeah, blinding would be absolutely crucial. Stephen Wilson 19:16 So why is naming such an outstanding proxy for aphasia severity, which I know you've discussed. It just correlates really highly with, for instance, the western aphasia battery aphasia quotient. Why does it correlate so highly? Julius Fridriksson 19:32 I think that it's not a coincidence that anomia, or the inability or the impairment to name, has been described as the hallmark impairment in aphasia. I mean, think about people, at least people with mild to moderate aphasia. All the time they describe the one of their greatest difficulties is coming up with the right words. So I think that naming per se gives you a very good idea of the underlying system. That is, maybe you could call it wellness, or, you know, the health of the underlying system. I think that, yeah, I don't think it's a coincidence. I don't know if you saw that I posted this picture on Twitter, the correlation between accuracy on the PNT and WAB. So the aphasia quotient, which is a measure of severity on the Western Aphasia Battery, correlation is like 0.92. So you literally if you know how somebody did on the PNT, you can predict with fairly good accuracy, what their overall severity is. Stephen Wilson 20:36 Yeah, I mean, there is like a naming component in the WAB too. It might not be quite that high if you took that out. But yeah, I agree, it's shockingly high. Julius Fridriksson 20:48 Now I got to do that analysis. I got to look at it because I'll bet you the correlation will be really high. Stephen Wilson 20:55 I don't doubt that it'll be really, really high. Julius Fridriksson 20:57 Yeah, I. So I think that naming gets a very sort of, I don't know I think a lot of people criticize it. Because naming per se, that task is weird. It's not like something that seems very ecologically balanced. But that's not the point of it. You're doing it because you're trying to get an idea about how impaired is the overall system. And if that's something that you think is useful, then naming is probably not that bad a task. Stephen Wilson 21:32 Yeah, I mean, I don't think that tasks are, you know, measures in and of themselves need to be ecologically valid if they are predictive of an ecologically valid measure that you do care about and have good psychometric properties. Julius Fridriksson 21:45 That's exactly right. And then people say, well, you know, all measures in aphasia correlate with each other. Well, then you got to start thinking, you got to go for the measures that are most, you got to go for measures that are reliable, that you can use again and again and not get a different result. And if they give you an idea, for example, I'm just taking this as an example, of how well the person does in real life. You can't ignore that. Stephen Wilson 22:12 Alright, so we've kind of talked about the nature of the treatments, the nature of the outcome measure. I know that you have a paper that's under re-review describing some of the first results of your study. So you want to kind of share with us like what you found so far. Julius Fridriksson 22:29 Yeah, I'd be happy to. So the lead author on that paper, and I want to give credit to, is Sigfus Kristinsson. Sigfus is a PhD student in my lab. What that study revealed, it's really basic analysis of the initial results. So looking at which one is more effective, the semantic approach or the phonological approach. And in our study, this semantic approach clearly gives you a superior outcome compared to the phonological approach. If I remember correctly, the improvement is almost three times greater with the semantic as opposed to the phonological. Stephen Wilson 23:11 That's a pretty important observation, right? Julius Fridriksson 23:14 Yeah, I think it is very important. But there's a caveat in that the people that respond well to the semantic treatment tend to have mild to moderate aphasia. The people with very severe aphasia just don't respond to that at all. But if you look at the phonological treatment by itself, the reverse actually is true in that the people with the most severe aphasia tend to respond to the phonological treatment. And not surprisingly, apraxia of speech, for example, the severity of apraxia of speech is a predictor of outcome there. So the folks that benefited the most tend to be the folks that also had apraxia of speech. Now, there's a lot more in this paper. But I would say that overall, this starts getting us into the direction of being able to do sort of personalized aphasia rehabilitation, to say that I'm not going to choose what I'm working on with you simply based on my prior experience. I'm going to be able to use empirical data to say this is the best starting point for you. Stephen Wilson 24:26 Okay. So the most important behavioral factors seem to be severity, right? You're saying that the people who are mild to moderate do better with semantic treatment. People who are more severe do better with phonological. Julius Fridriksson 24:37 Yes. Stephen Wilson 24:37 So in this paper, you're looking at behavioral factors. Have you also started to look at imaging factors that could predict who's going to benefit most from which kind of treatment? Julius Fridriksson 24:46 Yeah, and I would have to say the imaging, I haven't done fMRI in aphasia in a long time just because, maybe your recent paper with Sarah (Schneck) basically gets to this, that the literature was kind of all over the place. I have been very encouraged by the fMRI results that we have found. Again, I don't want to steal the thunder of my students who are going to be publishing this. But if we look at overall prediction of treatment outcome in aphasia, looking at biographical and behavioral factors, we can explain somewhere between 10 and 20% of the variance. If we start from the premise that you can combine those factors with lesion factors, you can start building models that explain probably somewhere between 20 and 35% of the variance. But once you add fMRI, you actually do quite a bit better, which was surprising to me. If you know what is either baseline fMRI activation or changes in activation over time, you actually see a huge increase in the amount of areas that you can explain. Stephen Wilson 25:58 Well, that's really interesting. I mean, I think changes over time is tricky because of potential circularity. Okay, no, I wouldn't say circularity. But, you know, if you're improving performance over time, then you're also very likely to see fMRI changes over time just because you're going to be doing differently in the scanner. But if you'll be able to predict from pretreatment fMRI, that becomes very useful, right? So what kind of activation differences pre-treatment are predicting people's subsequent course? Julius Fridriksson 26:33 So not surprisingly, again, I don't want to I don't want to give all the details because I want my students, for example, to be able to talk about this at different conferences. But in general, greater language activation when you've had taken lesion into account, greater language related activation in the left hemisphere, better long term outcome. Now, I'll just say one thing about the changes, greater right hemisphere changes, better improvement? Stephen Wilson 27:04 Well, that's kind of surprising. Julius Fridriksson 27:06 And disappointing, right? Stephen Wilson 27:08 I don't, I wouldn't be disappointed if it turns out to be true. But yeah, we'll have to wait and see. Julius Fridriksson 27:16 I mean, it is what it is. What I was surprised was that I thought that perilesional activity, probably both at baseline and changes, probably had a lot to do with treatment recovery. So that changes there would be predicting outcome. We did not find that. Maybe some of the perilesional activity at baseline predicts outcome, but certainly not changes. Stephen Wilson 27:44 Right. Yeah, changes are tricky. Changes are very hard. Julius Fridriksson 27:50 Yeah. Stephen Wilson 27:52 I mean it's hard to analyze. But I mean, I don't want to get into all the details without having read your paper, which doesn't exist yet. Right? Or even submitted yet. Julius Fridriksson 28:01 Yeah. But what I liked about the way that Sigfus approached is that he basically had a plan at baseline, and he just ran through it. And, you know, we're gonna publish whatever we found. There's no mucking around with the data. It is what it is. And hopefully, it'll be out there soon. Stephen Wilson 28:17 Yeah, so the paper you mentioned, by Sarah Schneck and myself, a meta-analysis of all fMRI studies of aphasia (PET studies too), we do not believe there's any convincing evidence for neural changes associated with aphasia treatment ever. The only longitudinal findings that we find somewhat compelling are the ones that took place over the first year of recovery, and Dorothee Saur and colleagues 2006 paper. So I guess I would ask you, do you agree that it hasn't been demonstrated yet? Or do you think that there are... Julius Fridriksson 29:00 That functional changes actually drive recovery? Stephen Wilson 29:03 Oh, I mean, I'm sure that they do. But like, we haven't seen them yet. Julius Fridriksson 29:09 Yeah. No, I'm not convinced. I mean, our study includes 104 participants. I think that just based on those data, I think it's probably the largest sample size in aphasia treatment study. It seems to me that the evidence is pretty robust. We haven't done for example, cross validation yet to show how robust these findings are. But yeah, I would not, there's really no single study that I would endorse at this point as being sort of definitive study on brain activation changes that drive recovery. I just can't point to a single one. Stephen Wilson 29:53 Right. And I was going to kind of ask you like what you would have predicted but you basically already answered that. You were hoping to see perilesional changes associated with recovery. Instead, you saw right hemisphere changes increase in activation. I'm guessing you're using a picture naming task. Julius Fridriksson 30:11 Oh, yeah, I know you're really high on that. So that's why we keep using it. So yeah, absolutely. Stephen Wilson 30:18 Yeah. I love picture naming. You know, it's funny, like, I actually think it's a really good proxy, like we just talked about before. I think picture naming is a great proxy for aphasia severity. I don't think it's a great fMRI task, as we've talked about, at length. So I'm not going to push you too hard on this. Julius Fridriksson 30:35 We'll make that a debate on the Neurobiology of Language conference sometime. Stephen Wilson 30:39 I would love to. I'd love to do that one. Julius Fridriksson 30:43 Exactly. But it would probably have to be like a satellite debate. Nobody would be interested. It would have to be like, at a local bar. Stephen Wilson 30:48 That would make it even better. I don't know if you want to tell me because you've got to work in progress. But like, in what brain area in the right hemisphere did you see increased activation associated with extent of recovery? Julius Fridriksson 31:03 Posterior insula. So I can't remember exactly off the top of my head, Stephen. If I remember correctly, it's posterior insula, posterior superior temporal gyrus, and I think frontal? No, I think it was mostly posterior regions. We looked at domain general regions as well. And there seem to be absolutely no action there. Stephen Wilson 31:31 Yeah, that's kind of what we found in our meta-analysis. I think others are starting to come around that that's probably not a major part of the part of the story. Julius Fridriksson 31:41 No, and, you know, our study is the treatment is impairment based, we are trying to improve language per se. If I had to guess, whatever neural changes are taking place are probably in areas that were doing language before. Stephen Wilson 32:02 Yeah, or their homotopic counterparts perhaps? Maybe didn't want to see it but that's what you're seeing. Julius Fridriksson 32:12 I don't know. But that that that would be my hunch right now, based on the literature that we have. And our results are certainly not, you know, they suggest that that's certainly the case. Stephen Wilson 32:26 But I thought you were saying it's that you're seeing the changes in the right hemisphere? Julius Fridriksson 32:31 Well, I'd like to say that some of the right hemisphere does language, right. Stephen Wilson 32:38 Okay, well, we're not going to come to agreement on that. I can't wait to see the paper. Probably don't send it to me for review. Julius Fridriksson 32:52 I'll send it to you ahead of time, except maybe the people that are writing it are not gonna be very happy when they hear this podcast. Stephen Wilson 33:03 Okay. So you know, you've got these significant individual differences that you've kind of alluded to. Some people responding to semantic treatment, others to phonological? Probably some people are responding very well to treatment in general and others not at all. This is something that you've talked about before. What does this mean for the field going forward? Like how does this affect how clinical trials should be designed for aphasia treatment? Julius Fridriksson 33:33 I want to start with saying what it means for clinical care. I think that most people who've been treating aphasia, understand that the treatment needs to be tailored towards the needs of the participant. And there are many different ways to evaluate that, not the least what is the participant interested in improving? And what what does the participant think is going to improve their life the most. Those are things that you need to take into account. But the most important point is that rehabilitation needs to be personalized. And if you look at medicine, certainly, you know, cancer treatment, pretty much anywhere you dip down in medicine right now. The importance of personalized personalized treatment is certainly being emphasized more and more. I don't think it's any different in rehabilitation. We see a huge range of responses to both treatment approaches that we used. And maybe a little bit surprisingly, improvement with phonological treatment does not predict improvement in semantic treatment and vice versa. That means that there are people that may not respond to either treatment, there are some people that might respond to both, but most people only respond to one and not the other. So it means that as a speech language pathologist, you need to know what are the sort of the baseline factors that are important for predicting what kind of therapy that person is most likely to respond to. And that would cut down on sort of trial and error in clinical practice trying to figure out for how many sessions, what is the most likely approach to work for this person? At least you can start from an informed perspective that in a previous study for somebody like the impairment that you have, based on that this is where we're going to start. Does that makes sense? Stephen Wilson 35:38 Yeah. Julius Fridriksson 35:39 I think for clinical trials, I think that Breitenstein et al. had a very good idea in that they tried to personalize the therapy as much as they could. Now, as far as I can tell, the rubric that they used, was maybe not as standardized as I would like it, I guess. But it was something. I think that most therapists today tried, like I said, tried to personalize the treatment based on the wants and needs and maybe the impairment profile of the patient. But we need what I would call a dashboard. We need sort of a way for a clinician to take the data and baseline to be able to plug it into something and then say, this is what is gonna work best for you. And it doesn't just have to be the baseline data. The behavioral data, it could be age, it could be whatever factor you might think is important. Stephen Wilson 36:45 Yeah, education potentially. Julius Fridriksson 36:47 Yeah. Well, at the very least... Stephen Wilson 36:50 Lesion location. Julius Fridriksson 36:51 Yeah. lesion location. Absolutely. We found in the fMRI study, we factor out lesion location at baseline. We basically said, what are the lesion locations that predict response to therapy. Not surprisingly, it's the posterior middle temporal gyrus. We built that into the fMRI model, and then see, how does fMRI improve outcome? So yeah, lesion location definitely predicts outcome in therapy. Stephen Wilson 37:22 So would you like to see more targeted clinical trials that are kind of focused on subsets of the population that sort of recruit specific patients, and then, you know, use a particular treatment approach? Julius Fridriksson 37:35 Yes. And I think that those trials probably potentially have a chance to show much larger effects. I think the Breitenstein trial was very important. They basically took all comers. So therefore, their effects are sort of diluted because of the great variability in the kinds of participants that they included. But if you took, if you took that trial, and you looked at let's say the top 30% of the responders, did the same trial again, obviously, that's not how you would want to do it. But you can think about how you would sort of stratify a sample in the next clinical trial, your effect size would be a bunch larger. Stephen Wilson 38:21 So you've written about how aphasia treatment. The first person to describe aphasia treatment was Broca in 1865. You also called Broca pompous, which I agree with. What would you say are the landmark advances in aphasia treatment since then? Julius Fridriksson 38:38 So the landmark, as a whole, I have to say that I've not been very impressed with how quickly the field has advanced. I was recently doing a, I was taking a look at what kind of aphasia therapy, for example, were soldiers getting post-World War II in the United States. It seemed to me that some of the approaches that were already in use then, are some of the approaches that you might perhaps get in a local rehabilitation facility. That seems pretty crazy that somebody was getting treatment in 1945 or '46, would be getting the same kind of treatment that somebody gets now. You could say, well, it was really potent, therefore, that's the reason why it has is still around. But that's probably not the case. Stephen Wilson 39:34 I don't think so. So why do you think so little progress has been made? Julius Fridriksson 39:39 There's probably different reasons. To make progress you need a lot of resources. For the longest time, I think aphasia therapy didn't get a lot of respect because most of the studies were very small. I understand why they're small. It takes a lot of effort, a lot of time, a lot of money to do aphasia treatment studies. A lot of treatment studies are done by people who are on the tenure track, for example, here in the United States. If you want to get tenure, you're not doing aphasia treatment studies, because you might get one publication out of something that took you two or three years to do. So there are many different factors. I am very heartened by these recent developments to do large scale clinical trials in aphasia. And there are several that have been published in the last few years, a couple of them are very promising. We talked about Breitenstein et al. There's another one called Big CACTUS that looked at computerized therapy for improvement in both language and functional communication. There are a couple of negative trials that were both in acute care, the VERSE trial and RATS-3 trial. So I'm very encouraged by people doing these large scale clinical trials, what I think we need, however, we need much greater progress in the actual treatment approaches themselves. And those have been stagnant. And I've written about this on my blog. I can't remember what I titled it, but something like "breakthroughs are needed". And I truly believe that and I stand by it. I think that people with aphasia, if they understood how little progress has been made in the last 50 years, I think most of them would be pretty discouraged. Stephen Wilson 41:43 Yeah, I think so. So, making progress on the actual treatments themselves means, you know, having a theory of what would be involved, of learning in a damaged brain, right? I mean, is that kind of like what it's all about? It's, it's thinking about, well, is language recovery a kind of learning? Julius Fridriksson 42:07 Yeah, it's reestablishing a fragmented system. Right. I have to say, though, even though I think that progress is needed on the behavioral side, I happen to think that major gains or major improvements in treatment outcomes is going to be on the biological side. I think it's going to come from things like brain stimulation. I think it's just a matter of time before we will have a neural prosthesis that improves treatment outcome. Those kinds of approaches that are looking to basically repair the damage that occurred or at least compensate for it. I think that that's where we're gonna see major improvements in the outcomes of treatment studies. Stephen Wilson 43:04 You've talked about your vision for how brain computer interface could be used to treat aphasia. Do you want to kind of outline like, what's the rationale for that? How do you how do you envisage that working? Julius Fridriksson 43:17 Yeah, at a very basic level, I think aphasia in some ways is a disconnection syndrome. For many patients, that posterior and anterior language regions need to work in harmony to be able to process language. I do think that if you were able to reconnect those areas, I know it maybe sounds a little bit crazy, but at least, if you were able to get those posterior and anterior regions to start talking, again, if you will. That could give you a brain that is more likely to improve as a result of aphasia treatment. I'm not saying that you implant somebody with a neural prosthesis, and therefore, they're going to be great. I still think that the aphasia treatment is going to be absolutely integral. But I do think that may be approach like that could perhaps vastly improve your potential for better outcome. Stephen Wilson 44:21 Yeah, traditionally, conduction aphasia was seen as a disconnection syndrome. I know that you've advocated brain computer interfaces as an approach to maybe Broca's aphasia, even which is not traditionally seen as a disconnection syndrome. In Broca's aphasia, is there anything frontal to reconnect? Julius Fridriksson 44:44 Well, it depends. I mean, you talked to a couple of scientists recently, who were talking about the lesion location that predicts nonfluent speech, which is certainly very much associated with Broca's aphasia. I think most persons with Broca's aphasia, at least based on Our fMRI studies, they tend to have still residual frontal activation. Now whether that's crucial to language production, I don't know. But my hunch is that those anterior regions are still trying to participate. And if you were able to reconnect them with posterior cortex, residual cortex, which is, by the way, where I think most of the language processing happening happens anyway. Stephen Wilson 45:28 Yeah, I agree with that. Julius Fridriksson 45:30 That's something that should sort of catapult the patient forward with regards to potential for better outcome. Stephen Wilson 45:38 Yeah, I agree with you that most people, even with large perisylvian strokes, when you do fMRI with them, you do tend to see residual frontal and temporal activations in all, but the largest lesions. But I wonder how important that residual frontal activity is. And I wonder if maybe you want to connect, maybe not so much reconnect, but connect left posterior language regions to right speech motor regions? Julius Fridriksson 46:07 Yeah, that's a great question. So we have another paper that is in, revise-and-resubmit. Looking at functional connectivity during speech entrainment. I can explain the entrainment really quickly. Stephen Wilson 46:21 I think you'd better. Julius Fridriksson 46:22 It's this notion that you can watch a another speaker, and you mimic that person in real time. So let's say that you're talking and I'm talking in basically trying to mimic you exactly at the same time. And what has been known for a long time is that people that Broca's aphasia, when they do this, when they mimic another person, they can actually produce fluent speech. We think that this has potential as an approach to rehabilitate nonfluent speech. Stephen Wilson 46:52 So I mean, do they do it kind of on the fly first time? Or do they have to be trained repeatedly on some phrase that they're going to learn how to reproduce that? Julius Fridriksson 47:01 Here's the surprising thing about speech entrainment, is that most people with Broca's aphasia, if you show them, you know, it has to be audio visual speech. We published that in Brain back in 2012. It's very important that the visual component be there. But if you show them, let's say, we call them scripts, so videos of continuous speech for about a minute. You show them this script initially, and then on the second try, you ask them to imitate it in real time. The vast majority of people that Broca's aphasia can do it right off the bat. And I asked Leo Bonilha, my collaborator at MUSC to see whether he could actually do this in acute care in nonfluent patients. He had great success with it. The way that I describe it is like, your annoying sibling, they used to do it like at the dinner table. Drive everybody nuts that would mimic your, I don't know, maybe your kids have done this? Stephen Wilson 47:01 Yeah, of course. Julius Fridriksson 47:04 So most people, when we put them in the scanner, like we have normal controls of those. We ask them to go in the scanner and do this. And people are always like, well, I don't know what the person is gonna say. Initially, we'd really had to prepare people. After a while we're like, yeah, don't worry about that. Just give it a shot. And everybody can do it. Stephen Wilson 48:22 Okay, so just to kind of recap, your critical finding from almost 10 years ago now is that many people with Broca's aphasia do spectacularly better when speaking in a speech entrainment context compared to what they can produce in spontaneous speech. Yeah, and you've done several studies, trying to understand why that is. And I guess this is the new work in progress. Julius Fridriksson 48:45 Yeah. So we actually, Leo Bonilha and I have a phase-two clinical trial trying to get at what is the optimal dosage for that kind of treatment. So I'm hoping that we can capitalize that to do a large scale clinical trial in people with Broca's aphasia. We've already enrolled, I don't know, I think like 20 participants. Just anecdotally, it's looking pretty good. But we'll see. The other thing that I would say about speech entrainment before we go back to the brain data. People with Broca's aphasia, especially those who've had Broca's aphasia for years, and try this for the first time, the effect can be very, I would say emotional, because all of a sudden you're producing fluent speech. And we've seen that quite a bit. So this is not something that just like slightly improves your speech output. You can literally go from being able to say maybe five or six words tops, to literally producing fluent speech for a minute straight. Stephen Wilson 49:50 I know you've got some videos, which I guess I will link to on the podcast website, because it really is quite spectacular. Julius Fridriksson 49:58 Yeah, yeah. I've tried to argue with several different people that this actually tells you something about normal organization on speech and language. But it I still think it does. And that's probably something for a different podcast. But I think that speech entrainment reveals something about the normal mechanism. Stephen Wilson 50:20 Yeah, I agree with you. I think it reveals something very important, but I just don't understand what it is. And I've read your explanations of what it is. And I still don't understand what it is. Julius Fridriksson 50:29 Well, here's what I would say. And I'm not so sure you need to include this in the podcast. So I think that the role of efference copy in speech production is very strong. And I think that what is happening in people with Broca's aphasia, that this ability to predict this feedforward model is lost. And I think that was speech entrainment does is that it provides another mechanism to sort of provide prediction in real time. So you're basically adapting your speech to an external model, rather than an internal model that you already have, which is something that you and I have, what people in Broca's aphasia have lost. Stephen Wilson 51:10 Yeah, I understand that. I don't understand why it explains it, though. Because essentially, when you're giving the entrainment stimulus, it's going into posterior brain areas, right, whether they be auditory or visual. And I still don't understand how that helps, you know, frontal production mechanisms. Julius Fridriksson 51:30 I think the frontal production mechanism is totally gated by the posterior language or regions. 'Gated' is not the right word. It's guided. So it has a prediction model. What I think what's happening in Broca's aphasia is that the template that you're going to match your speech to is literally either it's generated, but it doesn't reach those frontal regions, or it's not generated at all. So whenever you and I speak, before the speeches realized there is an internal model, I can't see how it would work any other way. I think that's that model that is missing. And that's, of course, just a hypothesis. I can't say that I have a good way of testing it though. But that's sort of the working model that I'm going by. The other thing that I would say, Stephen, is, people always say, oh, you've got to know the mechanism before you can bring it into treatment. I don't believe that. I think that if it works, go for it. We don't have another 20-30 years to figure out what the mechanism is. I think it's sort of like training for a marathon. Well, the best thing to do is just to run, you know. I don't have to figure out the mechanism on running before I can start training for a marathon. I think it's the same thing for patients. If you can get somebody to produce fluent speech, and they can practice that repeatedly, as much as they want, I think that that has a potential to improve their speech production. Stephen Wilson 53:08 Yeah. So you want to talk about the new brain data that you have on connectivity? Julius Fridriksson 53:15 Yeah, so this is actually something that I've been working with Lisa Johnson on. Looking at connectivity during speech entrainment as opposed to what we just call spontaneous speech. So asking people to speak about their day while they're in the scanner. And what we find is that, surprisingly, the connectivity between posterior left regions, and arrive emptier regions is very much increased when you do speech entrainment compared to spontaneous speech, which suggests to me that you're engaging the right frontal region to be able to accomplish this. Stephen Wilson 53:59 Well. Yeah. I mean, what else you're going to use if you have Broca's aphasia, right? Julius Fridriksson 54:05 Yeah. Stephen Wilson 54:09 I think we've all kind of come to a consensus, even if it hasn't made it into the textbooks yet, that the critical speech motor regions are more posterior than Broca thought, but we still think that they're lateralized. But you know, when they're destroyed, then the right hemisphere homotopic regions are really the only candidate for motor speech. Julius Fridriksson 54:32 I believe that. Now, of course, we're gonna start getting into, you know, were these regions important for speech before, or have they acquired, has this now been sort of transferred to the right hemisphere. And we cannot tell that with our data, because it's just a single shot assessment. But I gotta ask you, Stephen, what do you think? Do you think those right anterior regions are contributing to speech production in the first place. Stephen Wilson 55:04 In neurologically normal people? Well, I mean that at a low level, certainly. Speech motor control is bilateral. But as you move further deeper into the system, then it becomes more lateralized. Julius Fridriksson 55:21 So when you say it's always bilateral. So do you mean like at the level of what, phonetic or like? Stephen Wilson 55:26 So at the level of M1, primary motor cortex, then I think speech production is probably almost entirely symmetrical. Left and right motor cortices are equally involved. But as you go to premotor cortex, I think it becomes more left lateralized. And as you go further back in the system, to phonological encoding regions in the inferior parietal lobe, and then ultimately to the temporal lobe, I think it becomes very left lateralized. So I do think that the right frontal motor areas play a role in speech, but they wouldn't normally have the ability to do everything that they need to do and so they would have to be a recovery process involved or some changes would have to take place. Julius Fridriksson 55:35 Yeah, I can't say that I disagree with that. Stephen Wilson 56:16 Well, we agree on something. That's lovely. Julius Fridriksson 56:19 Oh, come on. We agree all the time. Stephen Wilson 56:20 Yeah, that's true. Julius Fridriksson 56:25 The optimal fMRI task for people with aphasia is something we haven't come to a conclusion on yet. Stephen Wilson 56:33 What do you mean by a conclusion? A conclusion is when people agree? Julius Fridriksson 56:39 Yeah, I mean, at least the best tasks that we know, at the current time to use for people with aphasia? Stephen Wilson 56:46 Yeah. Okay, I'm gonna cut this part. Julius Fridriksson 56:50 Definitely. Alright. Stephen Wilson 56:54 So where do you see our field going in the next few decades? What do you hope to see happening in our field? Julius Fridriksson 57:00 Yeah, that's a great question. So probably at this time in my career, I'm definitely past midpoint. I've been a professor at the University of South Carolina for 20 years. And I can't imagine, well, I hope maybe I'll still be doing research 20 years from now. But I hope that we will have seen much greater improvement in aphasia treatment studies between now and 20 years from now than what we've seen in the last 20 years. And I think that many of the things that I've written about aphasia therapy, maybe they may sound a little bit desperate. But I really want to see, for many different reasons, and not the least that we need to make changes or improvements that result in something tangible for people with aphasia. I want us to change course, with regards to what we have been doing, so that we're not just going to be cruising forward at the pace that we have been in the last 20 years. Does that make sense? Stephen Wilson 58:10 Yeah. So what would you say to a young person, maybe just starting their PhD? What do they need to be doing so that in 20 years, they can be driving things forward at a better pace than what we are doing right now. Julius Fridriksson 58:23 I think what our field lacks, and I alluded to this earlier, is more of a biological approach. I think that you if you are interested in making a difference for people with aphasia, not just a little improvement, but a major improvement, start from the standpoint of neurobiology and neuroscience. Ultimately, I think that's where the breakthroughs are gonna come from, I might be wrong. But if I had to bet on one area, that's where I think we're gonna see the major improvements. Also areas like biomedical engineering with regards to neural prostheses and things like that. This does not mean that I don't think things like LPAA, or life participation approaches, aren't important. I think they're hugely important. But I think that for young people, look at certainly tried to understand where the field is. Try to understand, make sure you take your classes about language, about speech. But learn things like to code, that's a hugely important skill to have. And that's something that, going back to when we were talking about the postdoc, I really didn't know coding at all when I finished as a PhD student. And so what I was doing at the beginning, it was all self taught. Now, I'm lucky that now I have students that take care of most of that. So I can't say that I made any, you know, major progress in that area. But initially, as a faculty member, it was very important So I would encourage young people getting into the field, don't neglect the neurobiology and learning how to code and things like that. Stephen Wilson 1:00:13 Great. Well, I think I've probably taken enough of your time. Thank you very much for doing this with me today. Julius Fridriksson 1:00:22 Absolutely. It was delightful. I love talking about this stuff. And I appreciate being on your podcast. Stephen Wilson 1:00:26 Yeah. It's a pleasure to have you. Well, take care and I'll talk to you again soon. Julius Fridriksson 1:00:31 All right, take care, Stephen. Bye. Stephen Wilson 1:00:33 Bye. Okay, well, that's it for Episode Eight. If you'd like to learn more about Julius's work, I've linked his lab website, the C-STAR website, and some of the papers we discussed, on the podcast website, which is www.langneurosci.org/podcast. I'd be grateful for any feedback. You can reach me at smwilsonau@gmail.com or @smwilsonau on Twitter. I'd like to thank Latane Bullock for editing the transcript of this episode. And thank you all for listening. See you next time.