From Mitochondria to Music: Integrative Neurological Care for Autism with Suzanne Goh, MD

Suzanne Goh, MD, is a board-certified pediatric neurologist and an expert in evaluating and treating children with neurological conditions. Dr. Goh shares the latest research on underlying causes of autism and how to address those causes therapeutically.

The Institute for Functional Medicine (IFM) in collaboration with Cleveland Clinic Center for Functional Medicine is pleased to share lectures from the Grand Rounds presentations. A series featuring pioneers and thought leaders in Functional Medicine.

Video Transcript

0:00:00.1 Mark Hyman: I'm Dr. Mark Hyman. I'm the Director of the Cleveland Clinic Center for Functional Medicine. I'm really excited to have Dr. Suzanne Goh here. She's an extraordinary physician, researcher and has really explored the world of autism in a unique way, looking at it from a systems perspective, and through a lens of not just behavioral pediatrics, but through the lens of more of a comprehensive view, looking at all the aspects that affect autism, including biochemistry, neurophysiology, communication, family systems, and many, many of inputs, and her talk today is going to be on mitochondria, music, and autism. This really is a kind of a unique view of how to access the autistic brain. 

0:00:41.6 MH: She's a board-certified neurologist, pediatric behavioral neurologist and neuroscientist researcher, author. She was born here in Ohio, in Toledo. She went to Harvard undergraduate, Oxford, as a Rhodes Scholar, Harvard Medical School and did her peds internship at Mass General, and her pediatric neurology residency at UCSF. Her research really focuses on autism as a metabolic disease. And it's very different than our current approaches, as it uses brain imaging to identify differences in brain circuits in autism. So, she's really focused on researching and developing theories for neurological conditions and the impact in childhood brain development. She's published widely in many journals, including Pediatric Neurology, Annals of Neurology, JAMA Psychiatry, which I read last night, Developmental Cognitive Neuroscience and more. She's served as the associate research scientist and assistant professor of clinical neurology and the Division of Child Psychiatry at Columbia University. And she's the former co-director of the Columbia University developmental neuropsychiatry program for autism and related disorders. So, she also wrote an extraordinary book called Spectacular Bond: Reaching A Child With Autism. She's the founder and chief medical officer of Cortica, and the creator of the Cortica Care Model. So, thank you, Dr. Goh, for coming to Cleveland, and welcome. Love that you're here. 

0:02:04.4 Dr. Suzanne Goh: As you see from the title of today's talk, we're going to to be talking about a very broad range of topics, from mitochondrial dysfunction in autism to use of music therapy for autism and many other related topics. I wonder if I could just get a quick show of hands of how many of you are medical practitioners? Great, and how many in another, a non-medical field? Okay, great. So, these are our learning objectives for today: To define the causative factors for autism; to recognize neurophysiological and metabolic disturbances to brain development in autism; to describe a range of therapeutic approaches, physiological and behavioral that have a role in autism treatment; and to cite recent research findings that impact treatment for autism. And in navigating these topics, we'll look at early theories, current understanding, and future directions. I have two disclosures, so one is that I'm co-founder and chief medical officer of Cortica, which is a multidisciplinary care center for the comprehensive treatment of autism. We're located in San Diego and opening a clinic in Irvine next month. And I'm co-founder and chief medical officer of MitoMedical, which is a nutritional supplement company that focuses on mitochondrial therapies. 

0:03:23.5 DG: So, what is autism?

0:03:50.2 DG: The first description of autism in the medical literature was in 1943, by Leo Kanner, who was a child psychiatrist and the founding chief of the first child psychiatry department in the US, which was at Johns Hopkins University. And in this case series called Autistic Disturbances Of Affective Contact, he and many parents provide a very rich description of autism in a group of children of varying ages. And I wanted to show you this video of a young child with autism. This is the girl that we feature in the book, Spectacular Bond: Reaching The Child With Autism, which I co-wrote with the developmental psychologist, Marion Blank, and Susan DeLand, who is the mother of this girl. And you'll hear Susan speaking in the video. What I find striking about this video is that it exemplifies many of the features that were described in Kanner's first publication. Some of the parents reported their children acting as though in a shell, and as though other people weren't there. So, I'll show you this video. 

[video playback] 

0:05:31.7 DG: In thinking about how our understanding of autism has changed over the years, I recommend to you this really fascinating book which was co-written by a historian Rabb Houston and a neuroscientist, Uta Frith. They describe the symptoms of a gentleman from 18th century Scotland, whose life was documented in legal archives. And it's fascinating to think about how his differences were understood and described by those around him, and then how autism manifests in our world today. In the 1960s, there emerged several theories about the causes of autism, and one is shown here in this book on the left by Bruno Bettelheim, who was a psychoanalyst, and he put forth the theory that autism was caused by mothers who showed emotional frigidity to their children, or what he called refrigerator mothers. This documentary shown here on the right, Refrigerator Mothers, was released by PBS in 2002, and gave a voice to mothers who were able to describe their experience of self-doubt and guilt as a consequence of this theory, which had a foothold in the medical community. 

0:06:51.1 DG: Now, also in the 1960s, research was being done by this psychologist shown here, Dr. Lovaas, who was a psychologist and professor at UCLA. These are images taken from a Life Magazine publication, a magazine article in 1965 describing some of the techniques that were used. Now, these images are hard to look at, and even the title is, I think, hard for us, given our lens to see, but I think it's important that we recognize all the different aspects of the history of our field, and I think too it's important to say that Dr. Lovaas' work was some of the earliest work to suggest that autism was something other than a static encephalopathy, that it could be changed, and that children's symptoms could improve. And that was also a very important milestone in the history of our field. 

0:07:45.2 DG: Now, applied behavior analysis, which is the technique that Dr. Lovaas developed, comes out of the field of psychology called behaviorism. And behaviorism very specifically limits its purview to observable behavior, and that was because at the time, very little was known about "unobservable" activity, such as that that was happening in the brain. So, in a sense, it was very appropriate to not be speculating about what was happening in the brain because very little was known. But since the 1960s, behaviorism has been largely replaced by cognitive psychology and neuroscience. But ABA still has a very important and prominent role in autism treatment, and we'll talk a little bit more about ABA and how it's practiced today. 

0:08:33.4 DG: Now, even though autism was described in 1943 in the medical literature, it didn't appear in the DSM until 1980. And the DSM is the Diagnostic and Statistical Manual of Mental Disorders published by the American Psychiatric Association, and the formal definition of autism has undergone several revisions. The most recent edition of the DSM, DSM-5 defines autism according to these five diagnostic criteria: Persistent deficits in social communication and social interaction across multiple contexts; restricted repetitive patterns of behavior, interest, or activities; onset in the early developmental period; clinically significant impairment in social, occupational, or other important areas of functioning, and not better explained by intellectual disability or global developmental delay. Now also another very interesting aspect of the history of autism is that this book by Bernard Rimland, in which he proposed a physiological neurological theory of autism, was actually published in 1964, so three years prior to Bettelheim's book, but in many ways was overshadowed. And so, it raises the question of what gives power and influence to certain ideas in medicine, and what does that tell us about how certain social or cultural forces may shape the way that we practice medicine?  

0:09:53.9 DG: So, given all of that background, I wanted to share with you this image, which is sometimes referred to as the duck, rabbit, optical illusion. It was made famous by the philosopher Wittgenstein, to show that the same information can be viewed in entirely different ways. And this image was also used by the philosopher of science, Thomas Kuhn, in his book, The Structure Of Scientific Revolutions, in which he introduced the concept of a paradigm shift. And the idea that scientific fields undergo periodic shifts in which new ways of understanding are possible that were not possible according to previous explanatory models. So, let's... 

0:10:35.5 MH: What was the image?  

[laughter] 

0:10:38.8 Speaker 3: It looks like a bird, but I think... I don't know. 

0:10:43.6 DG: Can you see the rabbit?  

0:10:45.4 S3: Oh yeah. 

[laughter] 

0:10:56.9 DG: So, let's think about now our current understanding of what autism is and what causes autism. I wanted to refer you to a really useful website, which is the Interagency Autism Coordinating Committee's website. They're a part of the Department of Health and Human Services. And they provide a regularly updated and very thorough review of research literature on the causes of autism. And so, what we know now, or what we believe now is that there are many different routes with both genetic and environmental contributions that can lead to the symptoms of autism. And how many different genes seem to increase risk for autism? The number is estimated to be close to 1000, which is nearly 5% of the human genome. And not surprisingly, many of those genes and gene loci are involved in aspects of brain development like neuronal migration, synapse function and synapse formation. 

0:11:54.3 DG: But it's clear that there are mechanisms beyond genetic variants, whether inherited or spontaneous genetic variants, there are mechanisms beyond those that are necessary for understanding the complex causes of autism, and there are clear environmental contributions. So early studies suggest increased risk for autism associated with prenatal maternal infection, prematurity, advanced maternal and paternal age, short interpregnancy interval, certain air pollutants, and endocrine disrupting chemicals, including organophosphates and phthalates, and that there's a protective effect from maternal intake of prenatal vitamins prior to and in the first trimester of pregnancy. And the body of research literature showing developmental toxicity of certain environmental chemicals is growing. And this is a review paper that was published in Lancet Neurology a few years ago. 

0:12:51.8 DG: And in it, the authors review the research literature demonstrating 11 different industrial chemicals and pesticides that have toxicity to the developing brain, and they write, "Neurodevelopmental disabilities including autism, ADHD, dyslexia and other cognitive impairments affect millions of children worldwide, and some diagnosis seem to be increasing in frequency. Industrial chemicals that injure the developing brain are among the known causes for this prevalence. To control the pandemic of developmental neurotoxicity, we propose that untested chemicals should not be presumed to be safe to the brain development and chemicals in existing use and all new chemicals be tested for developmental neurotoxicity." I think what's surprising is that this isn't already the case, and that the call to action is simply that the chemicals be tested for development neurotoxicity. 

0:13:43.2 DG: Now, let's shift our focus now to look at the what is known about the neuro-physiological and metabolic disturbances in autism. So, neurophysiology is a broad term used to refer to the electrical and the electrochemical activity of the nervous system, and there are many ways in which neurophysiology has been demonstrated to be disrupted in autism. So, one is an impairment in synaptic pruning with an over-abundance of synapses and cells in the brain, especially in the first years of life. Another is an excess of local connections and a relative impairment of long-range connectivity. Another is an increased ratio of excitatory to inhibitory neurotransmission, and signs of neuroinflammation with microbial activation. And one of the most striking clinical manifestations of the disturbance in neurophysiology in autism is the high rate of seizures. How common are seizures in autism? While the prevalence of epilepsy in the typically developing population is 1 to 2%, and in those with autism is estimated in research studies to be between 20 to 50%, depending on the population, the specific population that's studied. 

0:15:05.8 DG: And the prevalence of an abnormal EEG in the typically developing population is between 2 to 5%, and in those with autism has been estimated to be as high as 80%. So clear disturbance in the neurophysiology of the brain in children with autism. Many different seizure types are known to occur in autism both generalized and focal and seizures may appear only as brief alterations of awareness and attention, or subtle interruptions to ongoing behavior. And I'd like to show you a few examples of seizure types that are known to occur in autism, and this first is a type of seizure called generalized tonic-clonic seizure. 

[video playback] 

0:16:07.5 DG: So generalized tonic-clonic seizure tends to be the type that we think of, it's the most apparent loss of consciousness and shaking movements of the entire body. Here's a seizure type that's more subtle, this is an absence seizure. 

[video playback] 

0:16:40.2 DG: So, you can see there a few seconds where the child stared off and had some blinking and some movements of the mouth, could very easily be missed. This is an example of a child who's having myoclonic seizures. 

[video playback] 

0:17:20.4 DG: And this is an example of a child who's having a complex partial seizure. 

[video playback] 

0:17:50.7 DG: So, you can see there that awareness is partially altered, and there are also some movements that we call automotive movements, chewing movements of the mouth, and some movements of the hands and fingers. A very important question in our field has been, in children with autism and epilepsy, could treatment for epilepsy lead to improvement in the symptoms of autism, and for a very long time, the answer was thought to be no. But based on more recent research, the feeling now in the field is that for many children with autism and epilepsy, treatment of the epilepsy may help to improve the cognitive and behavioral symptoms of autism and in some cases, potentially reverse the symptoms as well. 

0:18:40.5 DG: Now, in thinking about the metabolic disturbances to the brain in autism, it's a really vast, vast territory, and the part that I'd like to focus on, and which has a large body of research evidence to support it now is mitochondrial dysfunction, and these are just some of the research studies that have been published in recent years demonstrating mitochondrial dysfunction in individuals with autism, and most of these are either post-mortem studies or studies of peripheral tissues. 

0:19:10.0 DG: This was a very important study published in JAMA in 2010, in which researchers at UC Davis demonstrated that children with autism had multiple biochemical markers of mitochondrial dysfunction, including reduced function of a portion of the respiratory chain complex I. And this was a research paper, a brain imaging study that we did at Columbia University and published in 2015, in which we looked directly in brain tissue using MR spectroscopy to look for evidence of mitochondrial dysfunction in a large sample of children and adults with autism compared to typically developing controls. And this image here in the middle multi-planar chemical shift imaging, shows the technique that we used. 

0:19:56.5 DG: So, we looked at each cubic centimeter voxel of brain tissue, and in a single brain, they're approximately 1200 to 1400 cubic centimeters of tissue. We looked at each voxel to see if we could detect an elevation of lactate, which is a biomarker of mitochondrial dysfunction. And I just want to contrast that technique with a technique that had been used in two prior studies. Now, the conclusion of the earlier studies was that there was no evidence for brain mitochondrial dysfunction and autism, but the technique that was used in those studies was this one here shown in the lower right corner, and the red and the green bars here show you essentially large slabs of brain tissue through which signal was averaged, and there were large territories of brain that were left unexamined. So, using a more high-resolution technique, we were able to show that indeed there was a statistically significant higher rate of lactate elevation in those with autism. It was detected in 13% of the autism group of 1% of controls. We think that is likely to be an underestimate because of the limitations of the technology. 

0:21:03.2 DG: This diagram here shows an example of a spectra from one of our autism participants. The spectra correspond to the voxel in the basal ganglia, shown in the red square, and off to the right, you can see the peak that corresponds to the detection of lactate elevation. What we have here are composite maps, so we took the findings from the entire autism group, and these boxes show you the areas of the brain in which lactate elevation was detected across the entire group. The most common location is shown in red and then yellow and then blue, and lactate was detected most commonly in this area shown here, highlighted in red, which is the cingulate gyrus, and the cingulate gyrus is a very important part of the brain that functions in the integration and regulation of higher order cognitive processes, mood and behavior. So, we think what we've identified is both the mechanism and the brain region that may underlie the symptoms of autism in a subset of individuals. 

0:22:10.7 DG: I won't take time now to talk about mitochondrial approaches and therapies, but we have to answer questions about that. I'd like to move on to look a little bit more broadly at different therapeutic approaches that have a role in autism treatment. I think all of you understand quite well the need to create new models and new frameworks when developing new approaches to the practice of medicine. And that's what this represents. So, this is a very simple framework that we use in our clinic simply to show that there are many different domains that are worth addressing as part of a comprehensive treatment program for autism. And we talk a little bit about neurophysiology and biochemistry, and I'd like to turn now to think about sensory motor integration, communication, cognition, and behavior. 

0:23:00.5 DG: Now, therapies to address child development in these domains have historically not had a lot to do with neuroscience, and my feeling is that the research literature has progressed to a stage now where that's possible, and it can lead us in some very exciting directions. This image, it's a little bit hard to see, but that's okay. So, this image shows essentially the explosion of brain imaging studies of autism over the past 30 years with three research papers published in 1984, and a steady increase and 327 papers published in 2016 alone. So, a lot is known about autism from brain imaging studies, and this slide just shows some of the techniques, structural and functional imaging techniques that have been applied to the study of autism. 

0:23:58.2 DG: And this was a review paper that I published with Brad Peterson, who at the time was the chief of child psychiatry at Columbia. We reviewed all of the brain imaging studies that have been done in autism up to that point, and what we found was evidence for disturbances to multiple learning and memory systems, including declarative memory for facts and events, which relies heavily on structures in the medial temporal lobe, disturbances to procedural learning, memory systems for skills and habits, which relies heavily on the striatum and striatal networks, and other learning and memory systems that rely on the cortex, amygdala and cerebellum. And what's believe now is that this widespread disturbance is one of connectivity, and that there is impaired long-range, structural functional connectivity in autism with reduced long-range connections, but excessive local connectivity, and that this disturbance happens early in development and that it impacts function across social language, cognitive, motor, and sensory domains. 

0:25:05.5 DG: So, what's emerging is a view of autism that is not solely a social and communicative disorder, but one in which cognitive motor and sensory systems are also impacted and should be targets of therapy. What does the new understanding of the disturbances to neural networks in autism mean for treatment? Well, I would propose that the goal of treatment should be to aim to build neural networks that underlie flexible and coordinated functioning across social language, cognitive, sensory, and motor domains. But conventional therapeutic approaches often attempt to address these functions in isolation, but we know that these neural networks don't act in isolation or develop in isolation. For example, communication, which is the receiving and delivering of messages, requires sensory perception and integration. 

0:26:04.8 DG: Communication also requires motor control. So, to deliver a message requires motor control, initiating, sustaining, or inhibiting movement. So, I challenge you to try to communicate with another person, either without sensory perception or without motor control. It's not possible. So, communication is inherently a sensory motor ability. This is a quote by from a book by the Pulitzer Prize winning biologist EO Wilson. He was a professor at Harvard at the time that I was an undergraduate there studying the history of medicine. He writes, "the ongoing fragmentation of knowledge and resulting chaos are not reflections of the real world, but artifacts of scholarship. The way that we approach treatment for autism and treatment of many other chronic conditions, I feel is more reflection of scholarship and not a reflection of the human brain or human physiology. 

0:27:03.8 DG: Now there are several emerging techniques for what I call multimodal therapy in autism, which cross disciplinary boundaries. And one of them is music therapy with a specific neurodevelopmental approach. It involves the therapeutic application of the tools of music, to cognitive, sensory and motor dysfunction due to disorders of the nervous system and is increasingly being applied to autism. So some examples of what this approach to music therapy targets are psychomotor regulation or cognitive control over movement, sensory motor integration, for example, employing a rhythmic framework that promotes predictability and tolerability for incoming auditory, visual, tactile, proprioceptive, and vestibular information; arousal using music to modulate a child's level of arousal; executive function, so using the tools of music to develop skills for initiation, inhibition, sustaining and switching task; and working memory, targeting working memory through music making. These are just some examples of how music therapy can be applied to neurodevelopmental disorders. 

0:28:14.2 DG: And this is a review article that was published by one of the music therapists in my center, Michelle Hardy, who's been very active in leading and developing new practices to apply music therapy to the treatment of autism. She's a collaborator with a professor at Colorado State University, Blythe LaGasse. And in this review article, they discuss the use of rhythm as a means for habilitation across a very wide range of sensory motor, cognitive and communication goals in autism. Another emerging technique for multimodal therapy in autism has to do with the use of writing and typing. So, a lot of research now demonstrates that there's an auditory processing impairment in many individuals with autism but enhanced visual processing. And this manifests... One of the ways that this manifests is as hyperlexia or the precocious ability to read before two years of age, which is associated with autism. 

0:29:13.6 DG: Temple Grandin named her book Thinking In Pictures, describing the phenomenon of the enhanced visual processing capability that she experiences. And so, in therapies, we see the emergence of an increased use of reading, writing and typing to foster speech language development, particularly in those children who are non-verbal or minimally verbal. And language is presented not just spoken, but also written. And this is a research study that we published in the International Journal of Developmental Disabilities in 2013, where we looked at a group of non-speaking nonverbal children with autistic disorder ages 5 to 13. And we enrolled them in a nine-month trial of a reading and writing program and were able to demonstrate that children could learn to read and write with comprehension, even in the absence of spoken language. 

0:30:11.2 DG: So enhanced visual processing in autism means that written language can and should be used to help build a complete language system. And to demonstrate for you what it can be like to have difficulty with auditory processing, and then to be helped by some visual processing supports, I wanted to share with you this clip from Carpool Karaoke and I'll let you see this. 

[video playback] 

0:31:45.7 DG: I don't know how that exercise is for you, but that certainly exceeded my auditory processing capability. And what strategies would help you with that task? A visual prompt. 

0:31:58.2 MH: Rewind. 

0:31:58.9 DG: [laughter] So maybe given the chance to read and study this, it would make the auditory processing task easier. So, I want to draw your attention to these words highlighted in green here. These words fall into a category of words that we've called non-content words. Non-content words, take much of their meaning from the words around them. So, the context of sentences and the paragraphs that they're in. Non-content words make up most words that we see on any written page and the majority of words that we hear spoken around us. 

0:32:36.6 DG: In the past, speech language therapy for children with autism has attempted to simplify their approach by removing these words. And so, in therapies, you might hear things like touch boy or touch sitting, meaning, identify the boy that is sitting or identify the figure that's sitting. But by removing these words, we've unintentionally made it more difficult for our children to ultimately learn them. And so, one of the things that we do in our clinic is that we have programs which teach non-content words right from the very beginning, and we found that to be a very useful approach. 

0:33:18.2 DG: And then the words here, highlighted in red are the words that children with autism more often do remember, in part because they have a more concrete meaning and in part because they come at the end of the phrase or the sentence, and so the working memory demand is less. Now, I would propose that even though the way that many of the therapists who treat autism are trained, which is largely in silos of academic scholarship, that there's a real need now for integration collaboration, a common understanding of autism, and that these domains don't map neatly to a single specialty or a single type of intervention, that in fact, therapists across all of these different specialties are working across domains, and that multimodal therapies have an important role in the future of autism treatment. 

0:34:21.8 DG: Now, to bring a lot of this together, I wanted to share with you a case. And I selected the case of a young man from our clinic in part, to illustrate some of the changes that are possible in young adults. We hear so much about changes that can occur in very young children, but changes in adolescence and adults are also very possible. So, this is a 19-year-old man with autism. He was diagnosed with PDD-NOS, pervasive developmental disorder NOS at age two. That diagnosis is no longer in the DSM, but at the time it was a diagnosis given to children with autism who were felt to be milder. And over the years, his parents reported minimal progress in therapies. They had... This was a family that had a lot of resources, and he had access to a lot of good quality therapies, but he didn't seem to make good progress and even had periods of regression. And he developed a high level of rigid repetitive behaviors and had rare spontaneous language. 

0:35:29.7 DG: Prior to them coming to our clinic, he had a three-month escalation and agitation, aggression, self-injury, and destructive behavior, and those included grabbing and hitting his mother, throwing objects, destroying walls and furniture, and inappropriate public behavior, namely public masturbation. What is the conventional treatment approach for an adult with autism who has aggressive self-injurious and destructive behaviors?  

0:36:00.3 MH: Antipsychotics. 

0:36:01.7 DG: Antipsychotics. Yeah, so medications. Any other?  

0:36:07.4 MH: Restraining. Restraint. 

0:36:07.6 DG: Restraint, yeah. So very often, what you might consider as strict behavioral approach, where restraint may be used and often residential living, so these types of behaviors make it difficult for a child or an adult to stay in the home environment. Any other thoughts about? Dr. Madison, any thoughts. 

0:36:33.4 DG: And indeed we... In our center, we do work with quite a few young adults with autism who come to us on an array of anti-psychotics, mood stabilizers, anti-anxiety medications, anti-depressants, anti-epileptics, and with a range of side effects from those, and we work to try to reduce the number of medications they're on. So, for this young man, we proceeded with a range of tests, chromosomal microarray analysis, which is now considered a first-line genetic test for all those with autism, but many adolescents and adults with autism haven't seen a physician in quite some time and many have not had these tests done. The microarray analysis looks in very high resolution at reasons of chromosome to see if there are duplications or deletions, and the yield is estimated to be about 10-15% for a finding an individual with autism. 

0:37:35.0 DG: We also proceeded with a gene sequencing panel for gene mutations that are known to be involved in brain development, and we also proceeded with a 24-hour ambulatory EEG. For him, those tests came back normal, so there were no treatment implications from those, but from his blood and urine testing for metabolic disturbances and nutritional deficiencies, there were some findings. And in fact, I didn't include all the details here, but for him, one of the most useful tests that we did was for food sensitivity and allergy testing. And the reason that that ended up being so useful was that it prompted a dramatic change in his diet. So, his parents implemented, with high fidelity, a four-day rotation diet with elimination of certain foods including gluten and dairy foods, and the adherence to that was very strong and we saw benefits from that. But most of his nutritional supplementation plan was guided less by test results and more by symptom targeting symptoms, and his level of anxiety and repetitive behaviors or obsessive-compulsive tendencies was so high that we really selected supplements to target those. So, he was started on 5-HTP, he was started on a blend, a mixture of GABA, glycine and L-theanine, low-dose Naltrexone and N-acetyl cysteine, and as part of a treatment program, we did quite intensive modification to the home environment and parent training. 

0:39:15.6 DG: Changes to the environment and to interpersonal interaction with his parents that helped to avoid sensory overload. He also started a program of occupational therapy, speech language therapy, music therapy, ABA, typing for communication and neurofeedback. And in the past two years... So, he's now 21 years old, there have been some important achievements. He was able to attend his sibling's wedding. He's been able to travel across the country with his parents. He's had musical experiences, including piano lessons, and learning to play the guitar. He's been involved in athletics, including tennis. And he's also become quite an avid runner, so every morning he runs three to five miles. And he's had meaningful communication through typing with his family and therapists. And this is an email that his parents sent to us. 

0:40:06.3 DG: " N is revealing a completely different person that lives inside his mind, one with a tremendous vocabulary and broad knowledge of many subjects. In the last week, he's revealed a keen interest in learning more history and science. He actually typed today at school, 'I want to read like the 21-year-old I am.' He's requested that we read history books to him while he eats his lunch. And last night, he took a college history book from his brother's room and sat paging through it at home. We are simply stunned. As his latent communication skills are emerging, his overall behavior is improving as well. He's finding new outlets, and it makes a big difference." Because there are so many components that have a role in a comprehensive autism treatment program, we have a model that helps us to organize and prioritize and helps parents to participate in and to understand our approach. And so, we begin by thinking about the long-term goals of recreation, social relationships, independent living and occupation. And I like to say these are goals that all of us share. 

0:41:12.2 DG: And it starts with a foundation in the family and home that involves the parents, the child, siblings, and other caregivers. And some of the fundamentals of health in the family and home have to do with nutrition, sleep quality and overall well-being. And then we can move on to think about neurophysiology and biochemistry, and these are terms that I've used to capture what I think are the important components of treatment, of physiological treatment. So, within neurophysiology, electrical activity, neurotransmitter function. Within biochemistry, I include things like gastrointestinal health, endocrine health, mitochondrial function, immune health, and others like methylation and sulfation. And then we can move on to think about neural networks for sensory motor integration, communication, behavior and cognition. At the same time, working toward life-long health, relational health, so health in one's relationships with other people. Functional health, the ability to function in our society. 

0:42:15.1 DG: Psychological health, freedom from symptoms of anxiety, depression, OCD and others, and physical health. And we continue to educate the individuals across the major systems of knowledge that include athletics, music, language, both spoken and written, and math. And we find very often that a child can be mainstream in school when this foundation is in place. And of course, this model is a oversimplification, and all of these elements interact continuously. Any model of child development will be a simplification, but we find it's very helpful in identifying where there are gaps and what to prioritize and to organize the overall approach. The future direction of autism treatment, I would propose, can be based on a simple model, which is a foundation of neuroscience, integration and community. And if we have some time, I have a video here that we created. One of the initiatives that we have at our center is to create what I view as an oral history of the experiences of the children and the families. And so, this is... This video follows the experience of three children and families through our program. I think I'll show you just a few minutes. It's a nine, 10-minute video. I'll show you just a few minutes to introduce you to the families, and you could find the whole video on our website. 

[video playback] 

0:45:55.0 Speaker 4: Or the therapist had all the information. It's tough. It literally is a whole job by itself. He went to a non-public school, because in the public school, they just "couldn't handle him and his behaviors" and the amount of support he needed. And they said at that point, you're non-diploma bound. And so, he literally had the same goals from pre-school until he was nine, the same goals. They would talk about transitions and they would talk about job placement, and I cried and I'm like, "That's horrible." 

0:46:36.5 Speaker 5: Basically, she required 24/7 shadowing. Somebody had to be with her around the clock. She would unpredictably go from one place to the next and not have a sense of danger. Through school, she was doing multiple therapies and it was very much, we couldn't crack that window, we couldn't reach her. I think the first time was when we had... When we started it with Dr. Go, when Lauren had just turned six years old, we were able to see a huge difference in such a short amount of time. I remember my husband saying, "She's done more in six weeks than she's done in six years." 

0:47:21.6 Speaker 6: I remember going into our first meeting there, and that was probably the first doctor that we went to that wasn't thrown back by Rowan's behavior or dismiss Rowan's behavior. It was, she was right on it and she just kind of give us hope. It's the first time we kind of had hope. 

0:47:45.1 Speaker 7: We have hope for a child's future and a family's future because we know the accomplishments, the abilities, the joy that is possible and we get to see that every day. We like to use the word bounded hope, hope for progress, hope for change, hope for stability, hope for community, hope for the growth of new and astonishing and stunning abilities for that child. The whole practice is just amazing, and to... 

0:48:25.8 DG: In the interest of time, I think I'll pause it there and I'll just share with you our website, where you can find more information about our clinical programs, the research that supports our care model, the experiences of the families we serve, and about our incredible team of clinicians. So, I want to thank you all and I'd be happy to take any questions. Thank you. 

0:48:49.3 MH: Thank you so much Dr. Go. That was really extraordinary window into your work. Does anybody have any questions?  

[overlapping conversation] 

0:49:07.4 MH: I'll ask her. You can repeat the question. 

0:49:10.7 Speaker 8: My question is about, looking at the mitochondrial dysfunction that's going on, are you using targeted therapies when you're working to define that? You showed an example with the 19-year-old. Or are you using more global mitochondria support, CoQ10, carnitine, NAC, that kind of stuff?  

0:49:30.3 DG: Yeah, it is more global, so I'd say they're probably close to two dozen different supplements that we would consider and are guided very much by testing. CoQ10 is often the first line therapy, but certainly if there's a low level of CoQ10 or if there's a pattern that really does point to sort of a mitochondrial respiratory chain defect, but it can include creatine, carnitine, B vitamins, vitamin C, vitamin E, D-ribose, NAC. There are a lot to select from, and often it's a process of beginning a few, checking in on the progress and layering them in. With young children, there's the added challenge of it being very difficult to get children to take a large quantity of supplements. So, it does vary by the individual case, but it's a big part of what we do, and we use a wide range of nutritional supplements. 

0:50:30.9 S8: And then in looking at mitochondrial dysfunction, are you looking to understand the root cause underneath in terms of inflammation, oxidative stress, the developmental toxicity that you talked about? Maybe if you could just give us an idea of how do you begin to assess that in a child with autism. 

0:50:50.3 DG: Sure, and I'll say part of our... And certainly, our clinical protocols are guided by my own training and background, so we prioritize many of the neurological tests, so EEG that captures both wakefulness and sleep, is a real priority. The panel of metabolic test is one that incorporates... And again, we're limited by... There's so much to do early on, and we are limited by things like a child's ability to take supplements or by the amount of blood that we can draw. So, it often takes multiple... It takes many months and many series of lab tests. But the protocol for mitochondrial testing that we follow is one that was developed at Kennedy Krieger Institute by Richard Kelley, and that entire clinical protocol written up in detail by Dr. Kelley is available on our website. It's a practice parameter. 

0:51:55.4 DG: So, we do four to five hours postprandial, we'll check a full set of labs that includes LFTs, plasma amino acids, urine organic acids, CoQ10 level, acylcarnitine profile, and a few other labs. So that's pretty standard. 

0:52:12.0 S8: Including lactate and... 

0:52:13.6 DG: Lactate? Mm-hmm. 

0:52:15.0 S8: And pyruvate and... 

0:52:16.4 DG: Lactate and pyruvate. Lactate is tricky because of the nature of the blood draw and the use of the tourniquet, and often the child is struggling at the time of the blood draw, so interpretation of lactate is tricky. So, even if it's not... When it's elevated, you have to take that into account. But the other, it's really a pattern of abnormalities that you get from doing the whole panel that's helpful. 

0:52:44.4 DG: The way that I think about the ideology for the mitochondrial impairment is that there are so many potential contributors and usually multiple contributing factors. And so, steps to target many of them at once often are the most effective, like lifestyle modifications and nutritional modifications. So dietary interventions. So, oxidative stress is... There are so many contributing factors to oxidative stress to inflammation. Sometimes individuals are on drugs or are on medications that have known adverse effects to mitochondria. And so, to simply removing those is one step. And well risperidone, valproic acid are two that are very commonly used in those with autism and can have effects on mitochondrial function. 

0:53:42.1 DG: And it's important not to forget psychosocial stressors. And especially for young children, those can include entry into daycare, moving home, a change at home, travel to a foreign environment, the birth of a second... Of another child, of a sibling, or a procedure requiring anesthesia, for example, a placement of ear tubes or correction of an inguinal hernia or some fairly minor procedure, which in a vulnerable period, presents a stressor that can have consequences to the function of mitochondria in an individual who already has that vulnerability. Thanks. 

[background conversation] 

0:54:41.6 S3: Given the multiple factors that you're intervening in, can you describe a treatment failure? And what you do? Whatever you're doing does not it make a difference. 

0:54:53.4 DG: Yeah. So the question is, what does it look like when the treatments that we're applying don't seem to have the benefit that we would like, where progress doesn't come, despite trying a whole range of therapies?" That certainly happens. There are instances where the tools that we have don't lead to the changes that we would like them to have. And I think that has to do with the fact that our tools... Even the best tools that we have used in an integrated way and a thoughtful way may not be enough to overcome the biological obstacle, the block that is impeding brain development. There are many, for example, genetic syndromes, where the molecular mechanism is known and characterized very well, it may be something like a channelopathy. So the mechanism of action is understood at that detailed level and yet, we don't have the medications or other treatment modalities to target that. So there... 

0:56:12.7 S3: You know that though, if nothing you do makes a difference with it, how do you know that it's... A certain element or an abnormality or a difference in a child's physiology is the thing that's making a difference and if there's nothing really that you can use to impact?  

0:56:36.9 DG: Well, I think that's the assumption. So that the initial... The planning, the testing that we can do, the planning of treatment, putting in place the highest quality program that we can, and getting the participation of the family and caregivers at as high level as is possible, that's the starting point. And there will be a group of individuals that respond well and a group that don't. And for the group that don't, my sense is that it may be a limitation of the tools that are available, and a limitation of the implementation, and limitations in our understanding at this point in time. Yeah. Thanks. 

0:57:30.2 Speaker 9: Yes. I was just... Okay. I was just wondering if you have any recommendations of resources, if we want to learn more about the understanding that you have, and we should take. 

0:57:38.3 DG: Sure. So, we do have, there is a blog on our website that lists out about 60 or 70 of the research articles and resources that have been influential in my learning and very much inform our care model and is organized according to topic. So, their section... There's a section on epilepsy and autism, and there's a section on metabolism, mitochondrial function and on all the different domains. I will say that the work of the Developmental Psychologist Marion Blank has been very influential. And she has published a whole series of language programs, reading programs. And the work of the Medical Academy of Pediatric Special Needs has also been very informative. 

0:58:29.5 S9: Thank you. 

0:58:33.8 DG: Thanks. 

0:58:33.9 MH: You had a question?  

0:58:34.8 Speaker 10: I was wondering, are there specific companies you would consistently use for testing? 

0:58:42.3 DG: I'm actually sort of in the process of deciding what company will best serve our needs. So, there isn't one in particular now, but I'd be happy to talk with you maybe offline about a few that we use. Thanks.

0:58:56.1 MH: Well, thank you so much for coming to Cleveland. 

0:59:00.0 DG: Thank you.