#57 Autism: Unraveling the Spectrum

Connie Putterman, Advocate for autism research and MSc candidate


March 27, 2019

In the past, the term autism was used to describe the symptoms of schizophrenia and was (incorrectly!) thought to have been caused by apathetic "refrigerator mothers". Today, we use the term autism spectrum disorder (ASD) to describe developmental conditions that affect the communication and behaviour of individuals, with a wide range of symptoms and severities. Clearly, ASD is a complex condition and our understanding of it is constantly evolving. In this episode, you'll hear from two clinician-scientists at CAMH, Dr. Meng-Chuan Lai and Dr. Stephanie Ameis, who cover all the basics on ASD, and some newer research topics like sex and gender differences in autism. Dr. Stephen Scherer, a senior scientist at The Hospital for Sick Children, told us about his work on MSSNG, an exciting collaboration with Google and Autism Speaks, to uncover the genetic basis of ASD. You'll also hear from Connie Putterman, telling the story of her son's ASD diagnosis and how she came to be an advocate for autism research, as well as Rouya Botlani, who shares what she's learned through her work with students who have autism, at U of T Accessibility Services.

Written by: Thamiya Vasanthakumar

POND Network
Connie Putterman's The Parent Link
Connie Putterman's TedX Talk

Connie Putterman [0:00] So it was 20, almost 20 years ago or 19, actually. My son was just over a year old. And he started showing some signs of not engaging with my husband and I. He was our firstborn. He was an infant, but he didn't make eye contact. He looked often away. He also stared a lot at moving things. The best way I can describe it is, if you picture an old stereo, I don't know if they even still have these where you see the digital bars moving, he would sit in front of that as an infant and just stare at the moving parts of a stereo. And he did that just even as he was just learning to sit. He was a really fussy baby. And we had some suspicions that something was not right.

Thamiya Vasanthakumar [0:58] You just heard from Connie Putterman, a Master's student in Translational Health Research at the University of Toronto, reflecting back to when her son initially started presenting with symptoms of autism spectrum disorder, or ASD.

James Saravanamuttu [1:10] Since her son was diagnosed with ASD in 2000. Connie has become a strong advocate for autism research. She has a TEDx talk on the realities of having a child with autism, and is the founder of the Canada Israel Autism Research Initiative. You'll hear more from Connie throughout the episode, as she discusses her personal experience of navigating her son's ASD diagnosis.

Thamiya Vasanthakumar [1:31] I'm Thamiya.

James Saravanamuttu [1:32] And I'm James. Welcome to Episode 57 of Raw Talk.

Thamiya Vasanthakumar [1:48] The prevalence of ASD in the year 2000 was far less than it is today. About one in 150 children were diagnosed 20 years ago. Now that number has gone up to approximately one in 60. As the prevalence of ASD has increased, so has our understanding of this condition.

James Saravanamuttu [2:04] On this episode, we'll hear from scientists at the Center for Addiction and Mental Health, as well as the Hospital for Sick Children who are conducting cutting edge research to elucidate the genetic basis and heterogeneity of autism spectrum disorder.

Thamiya Vasanthakumar [2:18] Before we dive into their research, let's go back to Connie describing her initial response to receiving her son's diagnosis 20 years ago.

Connie Putterman [2:26] We brought him to our pediatrician. And our pediatrician suggested we see a developmental pediatrician at SickKids. With some advocacy on my part, to get an appointment, we got him in at a very young age and he was seen by a developmental pediatrician who ran the Autism Research Unit in child development center at SickKids. And he was diagnosed right away. So it was again, like I say, it still resonates with me when you ask me, but it was a long time ago. And you know, the the emotions that I felt then they stay with you in the experience of feeling lost. And that's something that I still remember. And so I can still relate now to parents who might have experienced that. And that feeling of being lost and not knowing what to do. It's almost like falling down a rabbit hole.

Aditi Desai [3:31] No one to sort of to help you pull you out right there.

Connie Putterman [3:33] And you say, Oh my goodness, what do we do now? So that's the initial feelings of first learning about autism and not really knowing what it was. So even though I didn't know a lot about autism, I started reading up a little bit about it. While we were pursuing this avenue. And as soon as she said it, I felt absolute fear, and also relief because I knew she was right. And the fact that the pediatrician was so definitive was a blessing because it meant that we could then focus on figuring out what kind of interventions and treatments we needed to do.

James Saravanamuttu [4:17] Connie's son's pediatrician was able to give them a definitive diagnosis. But what does that really mean? How is autism defined? We go to Dr. Meng-Chuan Lai, a clinician scientist at CAMH who is studying the cognitive and neurobiological basis of autism, specifically focusing on sex differences.

Dr. Meng-Chuan Lai [4:37] Autism Spectrum Disorder. This is a medical term used in the DSM V system currently defined as a medical condition that's early onset characterized by two major domains of issues one being social communication challenges that involves social emotional reciprocity, communications via verbal and nonverbal means, or understanding or managing social relationships, understanding social aspects. And the other domains what we call restricted and repetitive behavior, which is characterized by stereotyped behaviours, repetitions, narrow interest, adherence to routines, and sensory, like atypical sensory experiences. And these are meant to be what we call early onset. So that usually shows their characteristics early in life in the first three years of life, you'll see something going on. And then it's meant to be kind of persistent. So it is part of one's makeup. The characteristics are usually long lasting, but they will change in their quality and extent. This was considered as a purely certain medical diagnosis in the past. But now people are aware that it's also part of human variations. So now people are using more of the terms like autism spectrum conditions, or simply calling autism spectrum or autism. Because people who are having Autism Spectrum Disorder diagnosis do not necessarily always have dysfunction, or disability, but they always also have other cognitive strength and characteristics. Those are not necessarily disabilities. So it's kind of like having a dual nature, you have two variations and differences, but also it's highly related to disabilities and adaptive malfunction as well.

Thamiya Vasanthakumar [6:23] The Diagnostic and Statistical Manual of Mental Disorders, or DSM is the resource used to define and classify mental disorders. In 2013, a new version of the DSM was released, in which the diagnosis of three separate disorders, autism disorder, Asperger's Syndrome, and pervasive developmental disorder not otherwise specified, were collapsed and classified under one umbrella term Autism Spectrum Disorder. Dr. Stephanie Ameis, a clinician-scientist at CAMH told us more about this.

Dr. Stephanie Ameis [6:53] It really hasn't changed how we diagnose autism. We still diagnose autism the same way. So the way we diagnose autism in the clinic is talking to parents, family, about what the person has been like from a very early age to figure out whether they've had real problems and with respect to social communication, and inflexibility of behaviors that has always been there and has caused them impairment. So that's part of the diagnosis, as well as spending some time with the individual themselves to see whether the criteria for autism spectrum disorder is present, and then pooling all that information together to make a clinical opinion. So the way we diagnose has not changed.

James Saravanamuttu [7:40] Over the past decade or so, we've come to understand that there's a strong genetic basis to ASD. To learn more about this complex topic and what it might mean for families, we reached out to Dr. Steve Scherer, professor at UofT, as well as the Director of the Center for Applied Genomics at SickKids Hospital.

Dr. Stephen Scherer [7:59] We know that autism spectrum disorder or ASD, I'll call it ASD, or autism, depending on how I present things in my presentation, is very complex. There's actually at least 100 different forms of autism that we know about. And these can be very severe forms of autism, that affect functioning and language, to less severe forms of autism. So autism, can come about in high-functioning individuals, so called neurotypical individuals, even they just have subtle signs of autism. And often when I present to lay audiences that we present autism, as every person is like a snowflake - they have their own form of autism. And that's why we're doing genetic research to try to understand what the genetic factors are that contribute to these different types of autism. So in Ontario, here, there's roughly 5000 or so genetic tests done per year on individuals, mainly with a suspected diagnosis of autism. So there's a technology called chromosome microarray technology that scans the DNA to look for these copy number variable genes I talked about. In fact, that's done here at the Hospital for Sick Children. But it's presented to the families in a confirmatory way. So there may be a suspected diagnosis. The child's having some challenges, for example, and we don't know why. And then the genetic test actually is pretty straightforward. You can do you take some blood, you make DNA, and you can do the experiment in about 48 hours or so. And then check to see if any of these so called autism genes may be affected in that individual. Okay, so that's happening all the time, but in a confirmatory way, and roughly maybe 10% of families when they have a second child, if the first is on the spectrum. The second child is also on the spectrum. So families want to know very early on if they have a family history if later born children And may also exhibit signs of autism because there are quite effective behavioral intervention therapies that exist. But you have to start early. So if there's a family history, and you can identify that say later born child or relative, you know, a relative, a cousin, for example, is tested and they have the same genetic alteration, those children need to be followed much closer. And then if they develop signs of autism enrolled right away with a genetic confirmation that they should be paid special attention to. So at any given time in Toronto, there's, I'm told there's about 500 or so or more children are waiting to get a formal diagnosis from a developmental pediatrician, there's just so many new diagnoses coming, we can do the genetics much faster. And for about 20% of those kids, we could do a genetic test and explain to their families we found a genetic clue. And that genes are probably involved in this in this child. And that they should actually then be characterized as being an autism spectrum, looked at closer, and then get into the right protocols for for therapies and things. So that's from the diagnostic now, I just quickly want to touch on what's coming in the science going forward. In the last decade, really, for the very first time now we've identified these genetic pathways, there, there is no effective medicine that's on the market yet for the the essential features of autism. Okay, so the core features of autism, it can't there's no medicine that modulates those right now. And the reason for that, we think, is that we didn't know what the genetic pathways were up until recently. And, and we do now, we for some forms of autism. So there, there are targets, and there's several biotech and pharmaceutical companies now making medications, drugs that will hopefully modulate those genetic pathways. And some of those are going through clinical trial testing now here at Holland bloorview. We work very closely with them. And what we're trying to do is to match the genetics to the biology, and how they these individuals respond to the medicines to make it is a so called precision medicine or personalized approach. That's all happened in the last few years is because we finally have some genetic targets Now,

James Saravanamuttu [12:15] in addition to the complex genetic pathways, contributing to ASD development, and the huge variation and presentation and severity of symptoms, individuals often present with comorbidities. As Dr. Lai explains, the prevalence of other mental and physical health conditions can be higher in individuals with ASD.

Dr. Meng-Chuan Lai [12:35] The general finding in the field is that people with autism are on the autism spectrum tend to have heightened rates have a range of other health conditions, including physical health and mental health conditions. So in the domain of physical health, we know there's heightened rate of epilepsy, there is heightened rate of gastrointestinal problems, there's heightened rate of immunological issues like allergies and atopic dermatitis or range of atopy, or even asthma. And in the neurodevelopmental and mental health related domains, we know that it's highly associated with other forms of developmental disability, such as intellectual developmental disability or intellectual disability, or language disorders, learning disabilities, ADHD, tic disorders, Tourettes syndromes, and other early onset neurodevelopmental conditions. And just an example, the rates of intellectual disability in autism in general seems to be like around 50% from the data nowadays is really highly correlated. And in terms of the rates of mental health diagnosis, our team with Dr. Stacy, Stephanie Ameis and other people recently did a meta analysis. And we found that the estimated proportion of autistic people who have a concurrent mental health diagnosis is roughly about 20 to 23% of them having a confirmed diagnosis of anxiety disorder, about 10% of them having depression that basically depressive disorders, and about 5-6% of them having when they're older, having schizophrenia spectrum disorder, or bipolar disorder, and again about 10% of them having obsessive compulsive disorders and other what we call disruptive behavior disorder diagnosis. Now, the reasons for these high occurrence could be multiple. So one could be that there are shared biological underpinnings. And this could be demonstrated by issues like epilepsy, intellectual disability, or gastrointestinal issues, and not to say sleep disorders is also quite prevalent. So it seems to be possible that there is some underlying shared biology. In the mental health domain, some of them are likely also related to something happening early on like anxiety and ADHD so it could be, you know, shared biological pathways or even like early new neuro development that's contributing to those. And actually, there are quite a bit of developmental psychology studies as well as genetic studies showing high shared genetic variances, as well as, like early phenotypic variances in these domains. Interestingly, there are other domains that might be related also to living with autism, or how the person is treated by the environment. Because the environment tends to be quite challenging for many autistic people, if there's no accommodations provided, or even if there's a lot of misunderstanding. So the formulation for that would be the high rates of depression and high rates of suicidal risk, even like, unfortunately, the success rate of suicide, mortality due to suicide basically, are remarkably higher in people on the spectrum. And it's pretty likely that these are related to the life experiences of being on the spectrum. There could also be some shared shared behavior characteristics. But the problem lies in that psychiatric diagnosis system themselves, that they don't really differentiate things well, or they actually don't have a clear distinction between those concepts. So for example, there are studies showing that adults with autism spectrum disorder having been diagnosed on the autism spectrum, if you conduct a structured interview for personality disorders, you actually get high rates of personality disorder diagnosis. It could be up to more than 50% of them will meet with diagnostic criteria for one personality disorder diagnosis. And the problem there is that is that true co-occurrence, or it's simply some phenotypic overlap and the psychiatrists and people defining these conditions haven't really gotten together and talk about what are the what, what are the distinctions between the two and what are the conceptual overlaps between those things. So that's still for me that a still unresolved issue. So some of the core currents, especially about personality disorders may be actually due to definition, problems that people really haven't ironed them out.

James Saravanamuttu [17:15] As Dr. Lai mentioned, about half of individuals with ASD have an intellectual disorder, also called an ID. This is quite a large proportion. However, this group is underrepresented in research, as ID is often part of the exclusion criteria for studies.

Dr. Meng-Chuan Lai [17:31] Actually a very nice reason meta analysis just published by Ginni Rasul et al., looking at the bias towards excluding people with intellectual disability in autism research in general. And what they found was that, actually, it could be said more than 80%, or even 90% of studies are actually excluding people with intellectual disabilities when it comes to autism research of different kinds, from intervention to neurobiology to psychology, and other kinds. This might be less of an issue for studies involving early interventions, because at the early stages, like many studies are focusing on like child's development in general. So they wouldn't use intellectual disability as exclusion criteria. But for its studies, in later ages like school age and even beyond for adulthood, especially for newer imaging studies, or other studies that require some cognitive performances, that's the case that the studies aren't designed in a way that's adequate to detect the domains of characteristics that you would hope to detect in people with intellectual disability and autism. So that's a huge heterogeneity issue. And also, there is a recent study actually showing that maybe the family history, family mental health history associates, are somehow different between those people who are on the autism spectrum, and having intellectual disability versus those who's on spectrum but do not have intellectual disability. So some additional suggestions that, well, maybe there's quite a bit of a heterogeneity lies in between whether you have intellectual disability or not, or the level of intellectual disability that you have. That's just one source of heterogeneity, which is related to your cognitive abilities that could also be related to your sex, your gender, there could also be related to your cognitive aspects. So for example, we know that there are people who, despite the idea that autism is associated with those who have cognitive difficulties, there are people on the spectrum who actually score quite highly on social cognitive measures, versus those who are actually scored really poorly on social cognitive measures. And they all have a clinical label of autism. But whether the cognitive basis as well as the neurobiological basis associated with various social cognition may actually be quite different.

Thamiya Vasanthakumar [19:56] In addition to the sources of heterogeneity, as well as underlying genetics. There's also a lot of variation and those diagnosed with autism spectrum disorder at the neurobiological level. Over the last two decades, there have been hundreds of studies devoted to understanding the brains of those diagnosed with ASD. And despite all that effort, there's still a long way to go.

Dr. Stephanie Ameis [20:16] What we know is when we look at groups of children with autism, compared to what we call healthy controls, who wouldn't have a diagnosis of autism or other psychiatric disorders, the brain looks a bit different on the group level. It's not really striking differences. They're really quantitative differences, where we know that aspects of white matter that connect different parts of the brain, or if you're looking at brain activity, that there are slight differences at the group level between people with autism versus healthy controls. But if you look from study to study, there's not a lot of consistency. And that's the thing that makes it difficult to interpret. So there's a lot of heterogeneity. So on the whole, we can say that in autism, the brain imaging science has told us that there are indications that the brain might be less connected, or have a different way of being connected, then in people who don't have autism. But exactly what the differences are at the disorder level, we still don't know because each individual with autism is probably very different from every other individual. And we actually have some research that shows us that if you look at a group of healthy controls, versus a group of people with autism, healthy controls, their brains look more like the other healthy controls. And the brains of people with autism look very different from each other and are more different from each other than the group of healthy controls. So we know that there's a lot of variation in the brain. And maybe that's because the brain develops a little bit differently. And so there's different strategies of doing the same tasks. So there's still a lot of heterogeneity that we really haven't figured out yet. At the whole, we think that maybe connections are different across the brain and people with autism, but exactly where and and whether that is really consistent a lot across people our research is telling us know,

Thamiya Vasanthakumar [22:24] Many people may have preconceived notions of what someone with ASD might look like, how they behave and how they interact with others. The reality is, there's no single way to characterize or recognize someone who has ASD.

Rouya Botlani [22:37] I think a lot of people when it comes to just thinking about attributes that people with autism are near diverse students have, they're not really thinking very broadly. So they're thinking that there must be something very identifiably different about the student or about this person. And that's not really the case.

Thamiya Vasanthakumar [22:57] That was Rouya Botlani, the coordinator of student learning and transition at the University of Toronto Accessibility Services. She also runs the Social Association for students with autism or SASA, a group that meets weekly on campus and provides a space for U of T students with ASD to connect with their peers. Rouya told us about some of the things she's realized through her work with this group.

Rouya Botlani [23:19] Autism is really interesting in that sense in that because it is a spectrum disorder, it is very varied. And the way that the students are navigating their disability on campus is very different per student. And that's the beauty of neurodiverse students and neurodiverse people is that no one person looks or acts the same way.

James Saravanamuttu [23:38] Dr. Ameis has similar experiences with people she sees in her clinic.

Dr. Stephanie Ameis [23:42] If you were to come to my clinic, and you would meet some of the people with autism that come in, they're really different from each other. If we even take females versus males that come in and get a diagnosis of autism spectrum disorder, their presentation of autism is really different. We see huge variation in terms of people's interest in social interaction. So some people are not that interested in having friendships who get the diagnosis of autism. Some people with the diagnosis really, really want to relate to other people. And they have a lot of difficulty figuring out what the best strategy is to make friends or keep friends or interact with other people, but they're really motivated to. So there's a lot of variation in that regard. There's a lot of variation in terms of mental health diagnoses that are also present. So people with autism spectrum disorder will have higher rates of other mental health diagnoses. So higher rates of attention deficit hyperactivity disorder, depression, anxiety, irritability or emotional dysregulation. So there's a lot a lot of variation in presentation and then development is a moving target. So younger people can look different than older people. Sometimes, social difficulties can be more pronounced in younger people. And then, as people get older, they learn strategies to work around their difficulties and they practice and they get better. So there's a lot a lot of variation. It's kind of like asking, you know, how different people are different. You see lots of different ways that autism spectrum disorder presents itself. And that's why it's still an area where we're learning a lot and trying to figure out what is different about the brain and about people who have that diagnosis, to try and support them better.

Thamiya Vasanthakumar [25:38] Dr. Lai's research focuses specifically on sex and gender differences in ASD. It was previously thought that ASD was much more prevalent in males at a ratio as high as 10 males to one female. It's now known that the difference in prevalence between genders is much smaller.

Dr. Meng-Chuan Lai [25:56] Autism was conceptualized in the past as a male predominant condition. And its effect the male female ratio in the past was even reported as as high to 8-10 to 1, like 8-10 males to 1 female, and that was about like 30 years ago. The commonly quoted number was about 4-5:1 male to female. But nowadays, we understand that from research showing that well, if you look at data from the clinical databases, or educational database, you see a male-female ratio of four to five to one. But if you look at the general population-based data is about closer to 3:1. So this implies that there might be some other recognitions of growth and women on the spectrum. And by definition, males and females or other genders when they're diagnosed with autism, they share similarities. So these similarities are defined by the social communication challenges as well as restricted repetitive behaviors. So what may be different are the content of the certain characteristics. So let's give you an example. Narrow interest is one of the characteristics for autism spectrum. And because of the research was primarily based on males, in the past, people's conception about their interest would be mathematics, dinosaurs, space, trains, and transportation systems. But interestingly, now we know that many of the narrow interests probably in growth and women's have the same intensity and the same like exclusivity, meaning that they're focusing on this interest, but not others. But the content could be related to animals could be related to literature to be related to fashions, soap operas, or like really, things that may be viewed as not so idiosyncratic or atypical. That may be one thing that's related to what we call gender differences in autism in terms of behavior presentation. Another one, interestingly, is that it seems to be the case girls who are on the spectrum, especially those who are recognized later in life, tend to show more social interest in social motivations. And there are more initiatives to for example, making friends but probably still encounter difficult scenarios, especially understanding or navigating the complicated like friendship processes. And also, we learned that, again, for those who are recognized later in life, they tend to learn how to fit in. So there's a term what we used called camouflaging, or people using compensation or masking basically, representing that girls who are on the spectrum may have a higher tendency to learn how to act neurotypical, by learning and then maybe because of that, they are recognized later in life or they're even misrecognized as not having autism but having other mental health conditions instead. The first thing that I learned from working with autistic girls and women and their family is that their life experiences do matter. And when life experiences that, how they present themselves in social environments, in fitting and in facing all the life challenges are associated with how they are affected by the gendered or cultural norms. So, they're actually exploring not only social norms, but they're also exploring gender norms. When I say that, one example would be that hypothetically, why we might observe more desire to fit in or camouflaging or masking in girls and women on the spectrum who are not recognized early in life. Maybe that it because they are actually expected to be more social, and they're expected to make friends. They're expected to be friendly, and to have patience and to be empathetic. They have lots of expectations, which would actually be doubly challenging for them, maybe even compared to boys on the spectrum, simply because they may actually have similar levels of difficulties, but the expectations are higher longstandingly for girls and then maybe because of that they're putting into much more effort to learn. And we heard from parents may be using the term people-pleaser to describe many girls on the spectrum and they struggle, but they struggle to fit in. And it's challenging, and it consuming lots of mental energies basically. And that has an impact, because that could bring the sense of exhaustion, sense of even loss of identity for themselves at a later stage of life, or mental health, consequences, anxiety, depression, many of them may be related to these. So I think the first thing that stood up stood out for me is really the impact of gender the environment in gendered contexts to how they present themselves in the social environment. And maybe that is why many of them actually really need a lot of time to be with themselves and relaxed and de-stress, because they're constantly acting when there is social interactions and interpersonal interactions.

Thamiya Vasanthakumar [31:33] Where did this misconception come from that ASD is so much more prevalent in males than in females? Part of this is that the original concept of ASD was developed based on research and case studies made up primarily of males.

James Saravanamuttu [31:45] This has led to a bias in recognition of symptoms in girls compared to boys, even if the underlying reasons for the behaviors are the same, in that they're reflecting social cognitive problems, repetitive behaviors, and sensory issues. However, beyond a bias in the recognition of ASD in girls, there still seems to be a greater prevalence in boys that might be related to the biology.

Thamiya Vasanthakumar [32:09] We wanted to investigate a little bit more about where these differences come from. Are there biological differences in the brains of girls and boys with ASD?

Dr. Meng-Chuan Lai [32:18] So that's something really we are working on. And also a lot of researchers in the world are looking into more nowadays. And I don't think there's a conclusion so far, to be honest, simply because first of all, data that can give enough power to detect how organisms like associated with brain is not much in girls, and not to say in people are not male, so people with other sexes or genders. So basically, because the of the male bias, the data set that's available are like prevalent with males, but not the others. So we don't have enough power on that. The neuroimaging data, for example, nowadays tend to have a maximum a number of females with autism, or autistic females, around 50 to 60. For the meta analysis that has been conducted, this could be up to more than 100 or something, but still it's not a large data set at all. So we don't have definite answer. However, from what we learned from the current available data, it seems to be the case that there seems to be more differences and similarities. So you tend to find if you have kind of like autism- nonautism, male-female designs, it's quite likely that you get something called diagnosis by sex interaction, meaning that the differences between autistic and non autistic people seems to be different in males versus females. But again, these findings are usually from relatively moderately sized data. So you know, between 30 to maybe 60 to a group. So I think there are lots of studies needs to be done in the future to replicate and reproduce these findings.

James Saravanamuttu [34:05] As Dr. Lai mentions emerging research shows that there may be biological differences in males versus females with autism, but not enough studies have been done to confirm this hypothesis. However, it is often the case that certain defining features of autism, such as the inability to maintain eye contact, and delayed or impaired development of speech and language are present in both sexes. Connie's son presented with these Hallmark features, and we asked her how she navigated the healthcare system to address some of these symptoms.

Connie Putterman [34:37] I need to write a book about it. Not an easy answer. It was persistence, and it was investigation on my part. And I still think some of this applies to parents today, that I really tried to understand the needs of my child and where I thought he was. I really listened to the health care providers that that we did reach out to that were, I mean, there were people that we were referred to,

Aditi Desai [35:10] Were they - sorry to cut you off - were they like social workers, or what kind of health care professionals were they?

Connie Putterman [35:15] Immediately we refer to speech and language therapists, and also to the new government funded ABA program in Ontario. So that that was called the Toronto preschool autism service. So it was a government funded ABA program, and it was new. So my son was one of the first kids in that program. So that was a government funded, but the other we pursued private options as well to augment those, and they were speech and language and occupational therapists. And we started working right away on the areas where everybody as a team felt he needed support. So it was starting at the beginning. Okay, what does that mean? Well, he didn't make eye contact. So the first thing he needed to learn was how to make eye contact. And I always go back to that, as part of a plan that he needs to look first before he can do anything else. So that's where we started.

Aditi Desai [36:19] I guess, a part of his treatment was subsidized by the government such as the, the ABA school program that you mentioned. But you also had to spend money out of your own pocket. Was it because the interventions weren't sufficient enough, or you just wanted to increase the ways in which he was looked after?

Connie Putterman [36:43] No, I would say that it was not because it wasn't sufficient enough. I think that we really strongly believe that there was a multi-disciplinary approach needed, and so that ABA was great for what it was starting to teach him. But we need to supplement with other things to either reinforce, or to start to teach him communication skills. A lot of what we focused on in the beginning was, as I said, eye contact, but also reciprocity, the idea of, and it's not something that we think about if we learn it automatically, but just the idea of looking at each other, and reciprocal communication in terms of relationship building, in terms of communication, in terms of eye contact, in terms of nonverbal language cues, that's all give and take between people. And he had to learn that at the same time as all the other things he was learning in ABA. So we felt this was important to get solidified early, and at a young age. And he started learning skills to to learn how to exchange cues or language or pre-language communication. And then it became language and he needed to learn language skills, so a lot on language, because he was, he was younger than two. So if you think about it, most kids start to speak at around one and a half at age two. So we were already starting to teach him those skills.

Thamiya Vasanthakumar [38:17] Navigating the healthcare system and the resources available for children with ASD is not straightforward. As some children with ASD enter adulthood and gain independence, there are other challenges they may begin to face that they're not prepared for. As Rouya explains, there's a lack of social supports available for adults with ASD.

Rouya Botlani [38:36] My understanding is that there's a lot of supports for people with autism and neurodiverse people up until the age of 21. Then after that, they're expected to just have mastered everything and mastered every skill that they need to know in life. And then it's sort of they're on their own. And it would be really great to see some community resources that are focusing on adults who are neurodiverse. Because some of those needs, what it looks like to navigate disability as a child is very different than what it looks like to navigate disability as an adult.

James Saravanamuttu [39:06] Over the past few decades, there's been a lot of research devoted to improving treatment options. There's still a long road ahead of us, but progress has been made. Here's Dr. Ameis elaborating on the current interventions available.

Dr. Stephanie Ameis [39:18] So in terms of treatments that are available for people with autism spectrum disorder, the most widely used treatment and the one that our government pays for, for access to his early behavioral intervention or intensive behavioral intervention. And so this is where you use a behavioral approach to try and teach kids to attend to certain things that they don't otherwise attend to. And it's supposed to be intensive for at least 20 hours a week. It's usually for a lengthy period of time and what the research says is that some children really improve in terms of their communication skills, and their functional skills. Even their IQ goes up when they are in that kind of intensive behavioral intervention approach. Other than that type of early approach, there's lots of different types of behavioral approaches that are used in the school systems that can be used in an academic setting. In people who have autism spectrum disorder with typical IQ. There's some good evidence that social skills training can help with certain social abilities. And if you look at people's ability to do certain social tasks before and after they've done social skills training, they can improve. And there's good research that cognitive behavioral therapy can be used in autism, to help with anxiety disorders, in a similar way, as when kids are being treated with cognitive behavioral therapy who don't have autism spectrum disorder. For people who are 13 to 30. There isn't a lot that has a lot of evidence in terms of improving long term outcomes. And so that's an area that we really need more treatment development. There's also good research that certain medications can be helpful. So stimulants, and non-stimulant medications that are often used for children who have attention deficit hyperactivity disorder who don't have ASD can be very helpful in kids who have ASD and those symptoms. And there's also certain medications that are approved, not in Canada, but in the US by the FDA, for treatment of irritability. So that's self injurious behaviors, aggressive behaviors towards others. So there's a number of different treatment options out there.

Thamiya Vasanthakumar [41:52] As techniques get more sophisticated, newer treatment options have started surfacing for people with ASD, including repetitive transcranial magnetic stimulation, or rTMS. We talked more about this non-invasive brain stimulation tool in our episodes on movement disorders, depression, and cannabis. Check them out if you want to learn more.

Dr. Stephanie Ameis [42:12] So repetitive transcranial magnetic stimulation is a form of brain stimulation where use magnetic coil to allow for an electric current to pass into the brain and activate neurons that are just below the superficial cortex that are just below the skull level. rTMS has become an area of a lot of excitement in research because it's a tool that can be used for treatments, and you can actually target specific areas in the brain to modify brain activity and hopefully, improve functioning. It's best known for as a treatment for depression and it's an approved treatment for depression. We're trying to look in the autism community as to whether rTMS can be helpful. It's become an area where people are really interested. But it's a very new area of research. So most of the studies out there are small studies with a small number of people and using different rTMS methods. So we don't know very clearly what the best method is or what the best area of the brain is to target. In my research program, we've looked at rTMS as a treatment for executive functioning deficits. So those are difficulties with shifting attention with keeping information in your head for a short period of time with stopping yourself or inhibiting yourself from doing something. So those are kind of different executive functionings that people with autism often have difficulty with. And so we've just completed a study where we've had a group of 40 young people with autism who have typical IQ, who are about 16 to 35, who have felt that they have executive function difficulties have come in for four week intervention. And we did that study over about two and a half years. A lot of people were interested in being part of the study, and they tolerated it really well. And we have some promising early data that it might be helpful for a subgroup of people but probably not for everybody. So it gets back to that issue of heterogeneity. And that there's probably not a one size fits all way of improving certain functions and we're not treating ASD we're actually treating executive functions. So things that people are finding are interfering with their everyday performance.

Thamiya Vasanthakumar [44:45] Dr. Scherer is leading a groundbreaking project called MSSNG. It's a collaboration involving Google and Autism Speaks with the goal of creating one of the world's largest genomic databases on autism.

Dr. Stephen Scherer [44:56] We were invited by Autism Speaks, which is an international organization, but it's also run out of Manhattan and out of New York City. We launched a project to sequence the genomes of 10,000 families with autism. It was a kind of a back of the envelope calculation a few of us made in the community. We thought if we did that many, we could find all of the the so-called low hanging fruit, or the high impact genetic changes I talked about, and then start to really tease apart get that 20% number up to maybe 40%. It was really a hypothesis. So just you're here at a good time. We're just finishing the 10,000 this week, actually.

James Saravanamuttu [45:40] That's a huge milestone.

Dr. Stephen Scherer [45:41] Yeah. So we'll be convening a team of analysts from around the world, but it'll be centralized here. And we use the cloud based computing and AI. We have experts from everything ranging from metabolics to geneticists to physicist, you name it, there'll be different eyes looking at this data. So it's really quite exciting. You mentioned our work on the Genome Project back in chromosome seven. When we did that in 2003. I remember sitting in a very small office, there was probably 12 of us crammed in that office working hard. And now we have the whole floor here, 30,000 square feet, but the entire group will be working on one big project, which is always exciting, because that's where there's a lot of create creativity comes out of that kind of camaraderie and right and interaction.

James Saravanamuttu [46:31] How did you go about finding those collaborators? Or did they kind of come to you because had that MSSNG name?

Dr. Stephen Scherer [46:37] Well, you know, again, this organization is really quite spectacular. They raise money from walks across North America. Pretty much every family that has autism will know about this organization. The project, we we launched it now, five years ago. I think we've probably spent about $30 million on the project. The idea was that is you just want to do the experiment once to get the data out there. And there's only certain laboratories that could do the experiment. This is one of them here in Toronto. There are others as maybe a half dozen or so around the world. We were focused on autism from our early days. We had a lot of Canadian families collected already and consented. It's really important. In fact, we had 3000 families were falling across Canada already, that it's signed research ethics, consents to be involved in our research, and for the very first time, do a whole genome sequence and then put that data into a computer-based cloud. And we did this with Google, so that any scientists that had a question on autism, so they have to have to apply. And once it's approved, they can take their question to the MSSNG cloud at Google and ask their question for free. They don't have to pay for the sequencing. They don't have to pay for the compute time, the storage of this massive data. I'll tell you about that in a second. They can just take their question if it's on autism, or something related to autism, because it's so complex, and asked that. The idea was, is we can get that out there, there might be some really smart person who's got a new entry point, maybe using deep learning approach, maybe looking at a question we had thought about before matching families that have different characteristics, all these different things. That could be a company, it could be an academic could be a student, it could actually be a citizen, it could be a person with autism, and we've had all these. So we have hundreds of people from around the world who are registered, and who are using this data, even though we haven't got to the 10,000 yet. They're already using and there's been a lot of publications on this. So that was that we made that decision. It was a little bit probably closer to seven years ago. But we started say this putting the data five years ago. The very first data transfer we we made to Google, it was about five years ago, came from this floor. And at that time, it was the largest data transfer to Google in their history. So this data is deep and immense, it's huge. They've learned how to deal with it was just at the time, this was kind of a unique data set. So many ways this is big data. This is information science, your genome is the ultimate form of information, and we wanted to get it out there. And the payback for us was by getting it out there, someone else paid for it. Because I was paying this off my grants for a long time. And abroad, a lot of smart people. So you asked about the team. We have our team here, but now we've got a worldwide virtual team looking at this data. And that's exceptionally exciting because it's so complex. We need as many minds thinking about it as possible.

James Saravanamuttu [49:50] As you mentioned, much of your findings rely on the size of the data set. I was wondering what role does communicating your science and what you're trying to do to the public play in terms of encouraging families to participate and get their genome sequence so that you have more to work with.

Dr. Stephen Scherer [50:09] Right. So that actually hasn't been a problem for autism. It's been a problem for a lot of other disorders, diseases, conditions, depending on how you categorize what you're studying. Autism, the families are highly engaged, highly motivated. And this has been the case, over the history of autism research, we've never had problems enrolling families. They know that the answers are in embedded in the science, and we need to understand the science so they enroll. What they want is they want feedback, they want interaction. So if we find something, they want to know what it is. We have regular workshops with the Ontario brain Institute. And before that a few of us in our academic labs did this kind of thing. But we'll invite pretty much all the families enrolled in our studies to come in once or so a year to see the latest research and to hear what we're doing next. And also ask questions, and they come for tours and things. And if we have something that consents that they've signed is we actually will return what we think is relevant to them, if we don't find anything, because there's so many people, we can always say we didn't find anything. So we developed that and it was embedded in the philosophy of the project of the science that was very important. That was really important. Because when we asked them, are you willing to put your data, your genome data into the cloud, even though it's protected, it's actually safer than it's sitting here. And the high performance computing facility, people had to be educated on this. They essentially their responses, we trust the scientists involved, if you guys think it's a good idea, we're okay with it. Although we checked everybody, everybody had to be consented for this. But sometimes the science moves faster than the last consent they sign. So then we have to go back and update the consent, but we just kind of ask everyone, "Are you guys okay with this?", is really, really important. And I think, you know, this is a Canadian project, the relationship,we have, and when we find something, we can go back and actually find the people enrolled our studies in the United States, this is a real problem. This is one of the reasons that the US came up to Canada to do this is people move around a lot more, and they have different health care providers and payers. And it's very hard to find the person enrolled in your study. But the 10,000 number is significant. We want to think about ways to do it more efficiently now, to have people register online on the web. What I didn't say is is the advantage to is if they enroll in the study, the family gets deep clinical analysis. So we bring them in, and they get seen as part of the workup before we take their blood by the top developmental pediatricians and psychiatrists in the world. So we can standardize all the clinical data so we can do a genetic and clinical correlation later.

James Saravanamuttu [53:01] Dr. Scherer mentioned how many families are eager to get involved with research, Connie and her family are a prime example of that.

Aditi Desai [53:08] In general, I feel like a lot of focus is put on the challenges that come with caring for a child with developmental disabilities. But when I read your story, it was incredibly inspiring to read, as you turn this difficult experience into a very meaningful cause. I think you mentioned that you quit your job full time to focus on advocating for autism research. So can you elaborate on some of those advocacy endeavors and any projects that you're currently a part of?

Connie Putterman [53:42] What inspired me really was that the way in which I learned to cope with all of my own understanding of autism, and the the uncertainty of having a child with a developmental disability is that I needed to educate myself and learn and immerse myself in understanding autism. So for me, I really needed to get involved. And that's where I started to get involved with autism research organizations. And how I did that was that, and I say this a little bit in my TED talk, but I started getting involved in studies mostly as a subject or participant, answering a lot of questions, giving feedback, a lot of qualitative research studies, getting a chance to talk about my experiences. Both me and my husband also participated in some of those studies, so did our family. We participated very early on, and it really helped me to start to understand where researchers were thinking, what they were thinking about by the questions they were asking me and so I kept volunteering my time. I was lucky enough to be able to leave my job even though it's also a mixed blessing, because we had to make sacrifices and my husband continued to work and I gave up my job and my career but I was able to do it, where many parents cannot leave their work. I was able to do it to devote my time to understanding and getting involved in autism research committees.

Aditi Desai [55:30] These are parent committees or what kind of committees?

Connie Putterman [55:32] What I was, at first involved with was, if I think about it, I was sitting on committees that were, they were a number of people in the autism field. So they were clinicians, there were some family members, there were some service providers. And there were some researchers all on committees. And it was run through SickKids. And it was looking at how to improve the experiences of families who are diagnosed with autism. They were multidisciplinary teams at SickKids. It was a high level committee to try and understand better the pathways or the autism journey of families. So we looked at strategies and how we might be able to improve that through the system. Early on, I was sitting at the table giving my story, telling my story. That's how I volunteered my time early on. And then I volunteered on some other studies to be part of the committee. They're called the patient advisory committees of projects, and participated in that way. And then my son and I, when he got a little bit older, participated in some actual studies that were going on at York University at the time to do some cognitive behavioral therapy where both parents and their children were involved. So I got involved in all kinds of projects to be both advising and participating. So that for me is what helped me navigate and understand.

Thamiya Vasanthakumar [56:14] Connie is a part of the patient advisory committee for POND, which stands for the Province of Ontario Neurodevelopmental Network. It's one of the largest consortiums dedicated to understanding neurodevelopmental disorders such as ASD. Dr. Lai, Dr. Scherer and Dr. Ameis are also a part of POND.

Dr. Stephanie Ameis [57:35] It's a Ontario-wide initiative that is funded by OBI, the Ontario Brain Institute. And it's led by a number of other people across Ontario, and I'm a co investigator with POND. What's great about POND is that it's brought many different sites together to try and pull resources to recruit a big sample of individuals, not just with autism spectrum disorder, but with obsessive compulsive disorder and attention deficit hyperactivity disorder, as well as intellectual disability. At the core of POND is actually a clinical trials network. The idea is to bring together different sites so certain treatment innovation options that have really good preliminary data can actually be rigorously studied than the network within individuals who are interested in clinical trials and who are eligible for those studies. And then branching out of POND there is a very rich characterization process to acquire data about people from a genetic level from an epigenetic level, behaviorally, clinically, and cognitively. It's also an incredible resource for research because POND is accessible by a lot of people to be able to study the data and look at it in different ways and try and figure out again, what's distinct or not distinct about children with autism spectrum disorders, obsessive compulsive disorders, ADHD, and intellectual disability. And so we finished a study a couple years ago now that was looking at the diffusion weighted imaging from POND. So that's imaging that looks at white matter connections, so connections from different parts of the brain. We looked across the sample and we found that there were differences between our different neurodevelopmental disorder groups. So we looked at OCD, ADHD and ASD compared to healthy controls in one area of the white matter that connects the left and right parts of the brain called the corpus callosum. So a major connection. What we found was that each of those disorders were different in that area from healthy controls. But none of those disorders were actually different from each other when we looked across the brain and across those groups. We also looked at whether symptoms that are consistent with an OCD diagnosis and autism diagnosis and ADHD diagnosis related to white matter connections across the sample. We actually didn't find that, but we did find that adaptive functioning related across the sample. So again, adaptive functioning is your everyday functional level, your ability to function at a social communication and daily living level. And what we found was that the higher your functional ability, your white matter connections look different. And the lower your functional ability, the more different your white matter connections looked in the other way, whether you had a diagnosis of autism, ADHD, or OCD. So there was something similar, whereby across the brain across a lot of the white matter connections, your white matter connections seem to have different structure if you had higher functional levels.

James Saravanamuttu [1:01:05] The PONDs study provides a great opportunity to study the heterogeneity in ASD, as well as its overlaps and similarities with other neurodevelopmental disorders.

Dr. Meng-Chuan Lai [1:01:15] We know that there are two major approaches. So one is we can borrow the statistical language of supervised learning approach. So we know that there might be some factors that are associated with heterogeneity by our prior knowledge, or in theory. So this could be as we discussed, the presence or not for intellect, disability, the presence of other co-occurring mental health conditions like epilepsy or ADHD, anxiety, sex and gender, onset of autism characteristics, the presence or not of what we call regression. People develop, like sound skills in early years, but then they regress afterwards versus those who actually had a gradual onset of autism characteristics. So things like these are likely resources for us to delineate heterogeneity. The other possibility, again, barring statistical language would be what we call the unsupervised approaches. So if in the case that we have large enough pool of people with autism, and we also have a range of different data for these, these people, what we call deep phenotyping. So from behavior down to neurobiology down to even genetics, then we can use the state of the art of clustering algorithms, for example, and trying to identify from the data, what are the possible subgroups, imbedded in this phenotypic term of autism spectrum. And this approach can also cut across the clinical diagnostic labels. Like many work done here in Toronto, we are looking at these clustering across diagnostic categories. So we're basically informed by the data structure that can help us to understand the subgroups. And the next step would be the validation of those subgroups. Basically, how are they meaningful in terms of neurobiological substrates in terms of likely treatment responses or their phenotypes? Or even to some extent, would they be corresponding to our prior knowledge, which is that what extent these are correlated to the supervised learning that we we derived from the existing knowledge. So I believe that it needs to be taken in multiple approaches and we do need to have big data. When I say big data is actually large amount of sample sizes, but also deep phenotyping, and really large amount of feature spaces as well and across levels because this is really what we need to rely on in order to adequately cluster or subgroup people who are having a same cycle phenotypic label, which may or may not be a valid one, to be honest.

Thamiya Vasanthakumar [1:04:12] Future studies need to not only recruit more adults and children with ASD, but more specifically, they need to recognize and recruit diverse subpopulations. As Connie mentioned, establishing a sense of trust between researchers and families is imperative to increasing their involvement in research.

Connie Putterman [1:04:29] The idea is that I think what I give is my opinion and feedback but it's not always based on just what I need. It's based on just what I think and what what I've experienced but it's also based more on the fact that I've built relationships of trust with groups of researchers. It's based on trusting relationships and building those partnerships. So, to have the quality input into research is to really be valued as an equal participant or having a voice at the table, based on a trusted relationship. It's not just based on what my experience was versus somebody else's, because everybody has a different experience. It's just based on knowing and appreciating and respecting what they're bringing to the table to be able to give my feedback and to feel comfortable in doing that. I've had many years now of experience of doing that. And that's what motivated me to go back to school and study in the health sciences and really understand how research can have more impact into the lives of patients and their families. I think that research can be misunderstood, like you say, of scientists in a back room and what how do they know and relate to families and what they're going through and that they really do really do want to understand and want to engage and want to know what the issues are and want to be inspired by by families and patients and are inspired.

James Saravanamuttu [1:06:09] Moving forward. This promise that the research happening right here in Toronto, will lead to a better understanding of ASD, as well as better interventions for those affected by it.

Thamiya Vasanthakumar [1:06:19] Thank you to our guests, Connie Putterman and Rouya Botlani for sharing their personal experiences, as well as Dr. Steve Scherer, Dr. Stephanie Ameis and Dr. Meng-Chuan Lai, for telling us about the exciting research that they're conducting to better understand ASD.

James Saravanamuttu [1:06:34] Content development for this episode was done by Grace, Aditi, Thamiya and myself. Audio Engineering was done by Kat. Don't forget to check out the show notes for more resources. Until next time, keep it raw.

Thamiya Vasanthakumar [1:06:46] Raw Talk Podcast is a student presentation of the Institute of Medical Science in the Faculty of Medicine at the University of Toronto. The opinions expressed on the show are not necessarily those of the IMS, the Faculty of Medicine, or the University. To learn more about the show, visit our website rawtalkpodcast.com and stay up to date by following us on Twitter, Instagram and Facebook at @rawtalkpodcast. support the show by using the affiliate link on our website when you shop on Amazon. Also, don't forget to subscribe on iTunes, Spotify, or wherever else you listen to podcasts and rate us five stars. Until next time, keep it raw.