It's really a great pleasure to welcome you here in San Francisco to our symposium, Comprehensive Assessment, New Treatment Developments in Autism Spectrum Disorders. My name is Eric Hollander from Albert Einstein College of Medicine in New York. We have a very distinguished panel, including Ron D. Hagerman from UC Davis Mind Institute and also Cassara Ferretti from Albert Einstein and Montefiore Medical Center in New York. We do have a few seats up in front for those people who are in the back. So we have an hour and a half. Each of the speakers will be speaking for about 20 minutes. That'll leave about 10 minutes for questions and answers. If you all have questions, I'll invite you to come to the microphones. And I'm going to start then. So I'm going to talk about, from a psychiatric standpoint, how to comprehensively assess patients with ASD. And then I'm going to talk about some new treatment developments in the field as well. And from Albert Einstein, the Psychiatric Research Institute at Montefiore Einstein and Spectrum Neuroscience Institute. The funding for this work comes from the Department of Defense, the Food and Drug Administration, Roche, JAS, and Brainsway. And this symposium is in support of our textbook of autism spectrum disorders. It's the second edition. It's come out recently and published by American Psychiatric Association Publishing. So if you enjoy the symposium, I urge you to go out and buy the textbook. Okay. So here we have autism. Here we have the core symptom domains and the associated symptom domains. To get the diagnosis, you need to have the social deficits and the repetitive behaviors. The speech and communication has been merged into this social communication domain. But there's a lot of heterogeneity, and people present at different stages of their life with different types of symptoms. And these associated symptoms really shape the expression of the illness in any particular individual. So you can have some individuals with lots of ADHD symptoms and hyperactivity. You can have some individuals with a lot of impulsive, aggressive kind of behaviors, so disruptive behaviors. You can see some patients with severe obsessions and compulsions, some individuals with epilepsy or EEG abnormalities, and it comes in different sort of packages for different individuals. So depending on who's the population that you're seeing, you're going to see very different presenting symptoms. Young children often get first identified because they have a delay in language. They're not speaking. Or they can come in because they have disruptive behaviors. So they're having self-injury, they're having aggression, they're having meltdowns or temper tantrums. You can see many individuals with hyperactivity, and there's some shared features with ADHD with respect to that. Some patients may not be responding to their name. As they get a little bit older, then it becomes clear that they have social communication deficits in interacting with their peers, so they don't play well with other kids. Then you can see that they can be rigid, they can have repetitive behaviors or compulsions, or a lot of self-stimulatory or rewarding-type repetitive behaviors. Then in maybe middle school or high school, individuals can complain of social anxiety. They can become depressed. They can also present with symptoms of post-traumatic stress disorder. And then as they get a little bit older, they may present with problems in relationships. So their spouse may bring things to light. Or they can have problems in the workplace, difficulty interacting with co-workers or bosses in the workplace. And then finally, they may have impulse control problems or internet addiction or other compulsive and impulsive problems. So if you're dealing with young children, that may be different than if you're dealing with middle school kids or if you're dealing with young adults or older adults. Presenting symptoms may be very different. So in terms of the assessment, this is what I do. I take a comprehensive psychiatric history. I'm interested in the prior medication trials and whether they've had some benefit from that or had some side effects. I look at whether or not they've had behavioral or occupational or speech therapy or other kinds of educational therapies. I look at whether they've had any dietary manipulations. See if they've had a history of seizures or febrile seizures. Assess whether or not there's evidence for immune dysfunction, allergies, or asthma. Gastrointestinal problems, sleep problems are really a big problem at different stages. And then I look very carefully for comorbid conditions. Sensitivity is the rule rather than the exception. And the comorbid mental health problems are often associated with negative outcomes. So I look for obsessive compulsive disorder or attention deficit disorder, comorbid bipolar disorder or anxiety disorders. Look at sensory sensitivities, intellectual difficulties, and then try to rule out syndromal forms of autism, Fragile X or Rett's or Prader-Willi syndrome. So those are conditions that are not idiopathic. They have a known genetic cause. And then they're taken out of DSM-5 and placed somewhere else. I assess for the family history to see if autoimmune problems run in the family, whether there are mood disorders, bipolar disorder, anxiety, or OCD. I ask about whether or not family members have had a good response or a poor response to other types of treatments and whether or not they've tolerated them and had some side effects. Take a careful developmental history. And then in terms of the social history, very interested in whether or not individuals have some kind of a routine or a structure to their days. People often have a lot of structure within school. Once they graduate from school, they may be in a situation where they have no structure or no routines. It's going to be difficult to treat them unless they have some kind of a routine and structure. Next in terms of genetic testing, I mentioned that we look for syndromal or known genetic causes of autism, like Prader-Willi syndrome or Fragile X or Rett's. We can look for rare genes on autism panels. There are literally hundreds of different genes that are associated with autism. And there are these panels that screen for many of these genes. Or there are commercial panels that can look at common gene variants, like the genome test that help in terms of pharmacokinetics or pharmacogenetics, whether patients may be likely to have side effects, for example, with certain approaches. We often will look for inflammatory markers and basic immune assessments. So we look at the white blood cell count, the C-reactive protein, the SED rate, look on whether they have anti-strep antibodies or mycoplasma or Lyme, and recently starting to look at things like lipidomics, metabolomics, and endocannabinoid measures. Clinical testing is really important to get a good picture of the strengths and weaknesses for any individual. And then the gold standard diagnostic tests, like the ADI and ADOS, and you'll hear more about that from Kasara. Individuals often may benefit from EEG or sleep EEG, and structural imaging, like MRI and CT. So let's take a look at the different symptom domains, like the social deficits. Well, the primary issue here is a reciprocal social interaction, the give and take of social interactions with other individuals. Eye gaze is also something that we'll look at. Are they looking at you in the eyes? Next the repetitive behavior domain. We look for these different four factors, intrusive, obsessive, disturbing thoughts. Individuals with ASD do have intrusive obsessions. Typical OCD-like compulsive behaviors, washing, checking, symmetry. The lower order self-stimulatory, more reward-seeking behaviors, including self-injurious behavior and hand flapping and things like that. And then hoarding behaviors. So we've developed the Montefiore-Einstein rigidity scale to get at rigid behavior in children and adults. We look for behavioral rigidity, how people deal with unexpected change in the environment, like unexpected change in a schedule. Cognitive rigidity is a lack of flexible thinking, and protest is what individuals experience when there's a deviation from their expectation, they experience a lot of discomfort, and then they protest, or they can have a temper tantrum. So this is a novel idea that the protest domain can actually be part of the rigidity domain. So I'm going to talk a little about cognitive inflexibility. I think you'll hear a little more from Kassara as well. This is difficulty with rigid thinking, the ability to do set switching, and it's characterized often by black and white thinking, the inability to transition from one thought to another, the focus on one's own thoughts as opposed to others. It interferes with flexible problem solving, it interferes with the ability to adapt to a changing environment. So we have a new environment post-COVID, it's a new world, and we have to adapt to change in the world. People with cognitive inflexibility have a hard time adapting to a changing environment. And these symptoms are actually very hard to treat and have a broad public health implication. Now this idea of inflexible thinking is not unique to autism, because you can have inflexible thinking and problematic use of the internet, body image problems, mood disorders, anorexia, obsessive-compulsive personality disorder, OCD, and others. So you think of it as a trans-diagnostic symptom domain that cuts across different conditions and involves a particular way of thinking and adapting to the world. So kids with autism start off with inflexible thinking. They can have social difficulties as well, and they may not fit in that well at school. In the middle school years, they may be seen as different, and people can pick on them or be bullied. They be very sensitive to trauma-related symptoms and have emotion regulation problems. And then as they grow up, they can develop either externalizing behavior, so becoming very angry and exploding, or internalizing behavior, mood or anxiety or self-injurious behavior. One of the things that's interesting is that these individuals with autism and inflexible thinking who have been traumatized and are going on to develop post-traumatic stress disorder, the way they get there is through this morbid preoccupation and brooding that constantly occurs and gets them to think about these earlier unfair events that contribute to explosive behaviors. So what are the standard medication treatments for autism? Well, there's the atypicals, Risperidone and Aripiprazole, or approved by the FDA for kids with a lot of disruptive behavior and irritability. They have a high effect size, so they work, but they're complicated by having significant weight gain and metabolic issues. The SSRIs were really borrowed as a treatment from OCD and then applied to individuals with ASD. They can help with the repetitive behaviors, but individuals with autism may be sensitive to becoming activated on SSRIs and then either having more explosive behavior or sleep issues. Anticonvulsants that are good to treat epilepsy also can be very helpful for ASD in normalizing this excitation inhibition imbalance, but can have some side effects. And then stimulants that are used to treat ADHD can also be used to treat ADHD symptoms or hyperactivity in individuals with ASD. So SSRIs can reduce obsessive thoughts and compulsive behavior, but can be associated with activation. We've been interested in these medicines that work on the Sigma-1 receptor, so escatamine, which is being used these days for treatment-resistant depression, and the dextromethorphan quinidine combination or Nudextra, which is used for pseudobulbar affect, dysregulation in the expression of emotion. These medicines can be helpful for rumination and flexibility and explosive episodes. Rondi is going to tell you about some studies with metformin. We think that the GLP-1 agonists like semaglutide, which are used for type 2 diabetes and weight loss, can be of help in this population where there's a high rate of obesity and overweight and metabolic issues. I'm going to talk a little bit about our work with cannabinoids, with oxytocin and vasopressin, agents with neuromodulation, and talk about some of the challenges in terms of understanding placebo response in this population. So Newsweek had an article about the blunt truth about weed and autism, and this comes from the idea that many families around the country who have kids who have terrible temper tantrums and explosive behavior have found that cannabis can be helpful for the meltdowns or the explosive behaviors. Often in that situation it's used as a PRN to head off these explosive episodes. We have an endocannabinoid or an endogenous cannabinoid system in the brain and in the immune system. Anandamine or AEA is one of the endocannabinoids and 2AG. These compounds bind to the CB1 receptor in the nervous system, central and peripheral, and the CB2 receptor in the immune system. We also have plant-based cannabinoids like THC, which gets you high, and CBD and CBDV, which really don't have those psychoactive effects. The THC binds to the CB1 receptor. The CBD and CBDV do not. The endogenous cannabinoid system is influenced by lots of things, stress, glucocorticoids, obesity, food, time of day exercise, inflammation and tissue injury can alter endocannabinoid function, which can then affect mood and anxiety, food intake, lipid breakdown, satiety, and it can affect cytokines and T-cell migration. The THC binds to the CB1 receptor, activates the second messenger, the MAPK and mTOR pathway, and influences GABA glutamate balance. CBD and CBDV don't bind to the CB1 receptor. They bind to this GPR55 receptor, which also plays an important role in modulating excitation inhibition or glutamate GABA balance. There are lipids in neuronal membranes, this LPI, that bind to the GPR55 receptor. When people take CBDV or CBD, they bind to the lipids and pull them off of that receptor and reestablish normal EI balance. We have a study where we're comparing the CBDV to placebo in a large group of children with ASD. We go up to 800 milligrams a day, which is the high dose, and we look at the effects of irritability, repetitive behaviors, and social communication. If you can normalize excitation inhibition, you may decrease irritability and repetitive behaviors. In addition to CBDV, we're looking at complex botanicals that have a low dose of THC, to see if that may be even more effective, and a pha inhibitor, which is an enzyme that breaks down the endogenous endocannabinoids. That's been studied in some other conditions as well. We've also been interested in the oxytocin and vasopressin system. Mice that lack oxytocin have a hard time with social recognition, they don't recognize others. Variations of vasopressin tightly correlate with variations in social bonding and social affiliation. We were very excited in the initial studies with Balovoptin, which is a vasopressin 1A antagonist, which was studied in high-functioning young adults with autism, where at the higher doses there was a significant improvement in social communication. The FDA was very excited about that as well. We had sort of a moderate effect on this domain. Then we did a larger phase three study in children, and we really didn't replicate that. This vasopressin agent didn't really seem to have any impact on social communication. The higher the blood level, we didn't see any changes, for example, in social communication. We really didn't see changes in terms of global functioning, and unfortunately we didn't see changes in irritability or stereotypy, hyperactivity, or social functioning. So that was a bust, but then it got us thinking, well, what are some of the factors that are associated with a high placebo response in our trials? Your patients come in, they get excited about participating, they get a lot of structure and support from the research team, and we found in pooling the data from three different studies with ballovaptin in adults and children, that the higher the social dysfunction influenced the overall placebo response. Also the levels of compulsivity influenced it. Comorbid depression and ADHD influenced placebo response. If sites get to know their patients very well, they interact with them, they hold onto them for a long time, they enter a lot of patients, and they get a lot of patients through the trials, there's a much lower placebo response rate. And also, if you have a high BMI, then that interferes. You get a bigger placebo response rate. So we need to get better outcome measures, develop better biomarkers. These may not be sensitive to expectation bias. If people have a high expectation that they may get better, well, it could influence the ratings. And then we have to look better at subtypes and genetic variations. I'm gonna say a few words about neuromodulation, and we can modulate the activity of neurons in the brain through chemical, sound, light, or electromagnetic stimuli. And there are a number of regions of the brain that can be targets for noninvasive or invasive stimulation. So the supplementary motor area, the dorsolateral prefrontal cortex, the anterior cingulate in the orbital frontal cortex are good targets for stimulation that's noninvasive. The anterior cingulate, the nucleus accumbens, the subthalamic nuclei are also targets for invasive forms of stimulation. So there are a number of TMS devices that are now approved for the treatment of obsessions and compulsions and OCD. That can be borrowed to treat obsessive-compulsive symptoms in patients with ASD. In one study using this deep transcranial magnetic stimulation with very rapid stimulation to the anterior cingulate cortex, we got a nice reduction in both the obsessions and the compulsions compared to a sham treatment. So that's a type of an approach that could be helpful for obsessive thoughts and compulsive behaviors. That can be expensive and time-consuming. Transcranial direct current stimulation is much more portable, a lower cost. You could take this home, and then you can just stimulate different regions. In this study, in this FEATSOC trial, they compared the orbital frontal cortex on the left side to the supplementary motor area and found that stimulating the orbital frontal cortex was more effective, had a moderate effect size. As long as you continue to do the stimulation 20 minutes twice a day, patients continue to get benefit. When they stop, the symptoms returned. Now, we have some severe ASD patients who have a lot of explosive behaviors and severe repetitive behaviors. Some of those individuals will end up getting ECT because they can have catatonic excitement or multiple trips to the emergency room for explosive behavior. These individuals may be getting ECT. ECT can be helpful for the explosive episodes, for the catatonic excitement. Interestingly, it can also be helpful in terms of the intense obsessive-compulsive symptoms. And although there haven't been good randomized trials on these large case series, there are relatively large improvements in the obsessions and compulsions on rating scales. And then finally, for those most severe patients who are completely refractory, who are having terrible explosive behavior due to their inflexible thinking and really aren't able to function, they actually may have a blade of surgery or a neurosurgery. And these can include things like the cingulotomy, the subcaudate tractotomy. When the cingulotomy and the subcaudate tractotomy are done together, that's a limbic leucotomy. And you can get these lesions in different ways. You can heat the tip of a fine electrode to cause a lesion, or you can use a focused gamma knife or a focused ultrasound to create a lesion. Interestingly, these procedures are actually associated with a high effect size, a large effect size of about 1.43. But obviously, they can be associated with significant adverse events or side effects. So the key here is sort of balancing the risks versus the benefits in these individuals. In our therapeutic trials, we target the right circuits, try to reduce excitation and inhibition imbalance and try to reduce inflammation. We also study some rare orphan disorders to try to get more genetic homogeneity and are trying to understand what contributes to large placebo response in trials and develop better biomarkers that may not be associated with ascertainment bias. In terms of clinical treatment, I think you wanna pick what are the core symptoms and the associated symptoms that are causing the most distress and interfering with functioning. You wanna combine the psychosocial treatments with your medicine approaches. You wanna make sure that people have some structure and routine, because without that, the treatment is doomed to fail. You wanna try to address this inflexible thinking that can be very tough to treat. And then you also wanna treat the psychiatric and medical comorbidity as well. So thanks, I think we have a little bit of time for questions and answers. Thank you. We have the new president of the APA. President-elect. Thank you. What about the cow's milk and opioids in the milk playing a role? Is there any validity to it? I'm not sure I heard the whole question. What about opiates? There is the A2 cow's milk versus the regular cow's milk. They are saying there are some opioids in the regular cow's milk which have toxic effect on the hippocampus. Whereas the A2 cow's milk, which is predominant in the rest of the world, including Australia, has different opioids which are not toxic to the brain. If I understand it, the question was in terms of cow's milk that there are opiate-like things that can be toxic to certain regions of the brain. It's a challenge. There are strong genetic factors. If you look at the overall genetic load, that contributes a lot to ASD. There can be a range of environmental factors that may shape the expression of the illness. In vulnerable individuals, it can cause somebody to progress down the pathway towards ASD. Whether it's sort of things in cow's milk, whether it's in utero factors that the mother is exposed to during the pregnancy, actually, there are a range of factors. The challenge here is to try to look at all of the different confounders and try to pull that out and then see whether these other environmental factors are associated with a substantial increase in the odds ratio or hazard risk or something like that. It certainly is possible. For each of the different environmental factors, you want to take a look at it and then kind of sort out the confounders to see whether they can be a factor. But it may be that there are some genetically vulnerable individuals who are particularly sensitive to certain environmental triggers. And along those lines, in terms of autoimmune and along with the genetic susceptibility, what about folate receptor autoantibodies? Right. So people have looked at a range of autoantibodies, both in like OCD or in pediatric autoimmune neuropsychiatric disorder, PANS, or whether it's in POTS or with COVID also. You know, COVID really told us that, you know, we're surrounded by all kinds of viruses and other things that can trigger immune inflammatory processes. And people may have very different reactions to different immune inflammatory triggers, really. So the folate receptor autoantibodies has been one thing that people have focused on and others as well. Yeah. Thank you. Okay. Thanks. I have a question about the use of weed because are we not exposing these kids to future psychosis? Because as they grow into adolescence, they're more vulnerable for psychosis. By giving the weed in the early childhood to, you know, control the temper tantrums or meltdown states, are we really exposing these kids to future psychotic states? And if I understand that question, is it weed? Like gluten? Cannabis. Cannabis. Weed. Yeah. So, well, there's a concern. I mean, in San Francisco, you see weed is kind of everywhere out in the environment. In the developing nervous system, you have to have some concern about the effects of THC, for example, in altering the, you know, the brain development. So in general, you wouldn't want to use that kind of approach in young children and you wouldn't want to use that kind of approach on an as-needed basis. I mean, our original approach was to use cannabinoids that don't include THC that work not through the CB1 receptor. I mean, there are some vulnerable individuals who can develop psychosis in response to THC and its effect on the CB1 receptor. So definitely a balanced risk and benefit. Yeah. Thank you, sir, for good presentations. And, sir, what I want to know, is there any dietary restrictions somehow some psychologists or some of us suggested, like restriction of sweets and all and some? Is there any evidence-based study support that? Number one. Number two, is there any role in L-carnosine in case of autistic spectrum disorder? Right. Well, so there are a lot of complementary and alternative or integrative medicine approaches which, you know, can be tried and the idea there is to use ABA design. You try something, you see whether or not it has any effect, you take them off that, you see if there's any effect in taking them off it. You put them back on it and see if the change occurs again. That's the best way to try to understand in an individual case whether or not there's a relationship or improvement with a particular approach. I mean, often people will eliminate, you know, gluten and milk, for example, in diet, give it an eight or 12-week trial, see if it has any effect. If it has an effect, you could continue it. If it doesn't, you can stop it. And I think that's sort of the general idea, to be open to different approaches to see whether or not it's having an effect and then try to see whether or not taking it on or taking it off make any difference. I guess we have time for just one or two quick questions. Okay. Hello. Hello. My question is about ASD and hypersexuality. And if there is a treatment for boys or girls who are online doing sexual gratification, I don't know the word because I had to do a forensic report for someone who had like 40 terabytes child pornography and he just denied that he didn't do it. Yeah. Well, that's a big topic is sexuality and autism. You know, individuals with autism are humans first and humans have all kinds of sexual thoughts and urges. Sometimes the expression of those sexual thoughts and urges can be inappropriate. And so that's where training could be helpful. So individuals can, you know, accept their sexuality but not express it in ways that are going to get them into trouble. And as I mentioned, many individuals with ASD have some problems with impulse control on the Internet and, you know, you can be exposed to all kinds of sexual-related material there. So that is actually a big issue, yeah. Next question. Thank you for your presentation. Something related to the use of THC here. I wanted to bring to your attention that is, I'm glad to hear that these are not CV-1 driven compounds, the ones that you are going to try to use for them. Because recently, this month actually, there was an NIH press release about a study that was done in Denmark, it was a follow-up during 50 years of it, where they said that young men, more than young women, have a risk of being schizophrenic if they have used cannabis. 30% of them at the early age group, between 20 something until 30 or so. I mean, this is very, very, something to really think about when we use THC. The comment that I wanted actually to say was about, I do have some of these individuals on mood stabilizers, and I do see the influences of food, mainly sugary food, and also caffeine as triggers for irritability and anger. There were very, very sensitive individuals to those compounds. Do you have a similar experience? Well, first I would say that it is true that young men who have a history of schizophrenia or bipolar disorder, and a family history of schizophrenia and bipolar disorder, may be at increased risk for developing psychosis with sustained use of high-dose THC. It does seem actually that low-dose THC, and if it's paired with CBD and CBDV, may in part mitigate that risk or reduce the possibility. If it's used on a PRN basis, as a rescue for explosive behavior, that may be different than smoking high doses on an ongoing basis. I think I'm going to stop at that point, just to let Dr. Hagerman come up and get started. Hi, I'm from the MIND Institute at UC Davis, University of California, Davis Medical Center. I'm going to focus on my favorite topic, which is Fragile X Syndrome and Fragile X Associated Disorders, which is an important cause, the most common inherited cause of intellectual disability and the most common single-gene cause of autism. I do have some conflicts in that companies have funded studies. I'll talk a little bit about the Zanerba topical CBD and the Tetra study to increase cyclic AMP. I have also been funded to do the Acadia study of Trophenetide, an IGF-1 analog, and Rett Syndrome. I also have NIH funding for carriers of Fragile X, and the Azraeli Foundation funded a multi-center metformin study in Fragile X Syndrome. So the Fragile X gene, called FMR1, which used to stand for Fragile X Mental Retardation 1, but got renamed Fragile X Associated Messenger Ribonucleoprotein, it got renamed because the families wanted to eliminate mental retardation and use intellectual disability instead. But it was discovered in 1991. So after that, a DNA test became available. And it's important for you to know that if you order a microarray, it won't detect Fragile X. It'll detect a point mutation in FMR1, but it won't detect the CGG expansion. You have to order a Fragile X DNA test in order to see that. So the general recommendation is, in the workup of ASD, is you order a Fragile X DNA test and a microarray or a CGH array test to find multiple genetic causes. And if that's negative, then you have to go on to whole genome sequencing or whole exome sequencing. So in individuals with Fragile X, about 60% have ASD. And the rest have poor eye contact, hand flapping, hand biting, unusual hand mannerisms. So they often get a diagnosis of autism spectrum before they get a diagnosis of Fragile X syndrome. And for those with autism who have Fragile X DNA testing, anywhere from 2% to 5% have a Fragile X mutation, usually a full mutation. So before the DNA testing became available, people were doing cytogenetic testing and looking for the fragile site on the bottom end of the X chromosome. And that's a more laborious type of test. So the Fragile X DNA test has been available since the early 1990s. It's important for you to understand that there's two different mutations in the FMR1 gene. The full mutation, which leads to Fragile X syndrome, has more than 200 repeats. And all of those repeats lead to methylation of the gene, which shuts off the gene so that there's no message or no protein produced. Now girls are different because they have a normal X. And depending on the X activation ratio or what percentage of the Xs is active, they'll produce about 50% or less of the normal levels of FMRP. The pre-mutation, and the full mutation is about 1 in 4,000 to 1 in 5,000 in the general population. The pre-mutation is much, much more common. By pre-mutation, I mean 55 to 200 repeats. Usually there's no methylation. So the gene is very active. And in fact, the problem is that it's too active and produces way too much messenger RNA. And that causes what we call RNA toxicity. So the mechanism of involvement is very different from the pre-mutation to the full mutation. They're typically producing normal amounts of protein, sometimes in the upper end of the pre-mutation, slightly less protein. But the pre-mutation is the most common genetic cause of primary ovarian insufficiency or FACS-POI, meaning menopause before age 40. So OB-GYN doctors are often testing for a Fragile X pre-mutation. Just order a Fragile X DNA test. Send it to any university or commercial lab like LabCorg, Genentech, or whatever, and you'll get the number of repeats. The worst problem with the pre-mutation is called the Fragile X-associated tremor ataxia syndrome or FACS-TAS. And this is a neurodegenerative disorder that usually presents with tremor, often misdiagnosed with Parkinson's disease, can also be ataxia or balance problems, frequent falling, and then about 50% of the males get dementia or very significant cognitive decline. A little bit less so in females. But the most common problem of the pre-mutation is FACSAN. That stands for Fragile X Associated Neuropsychiatric Disorders. And that is significant depression, anxiety, ADHD, ASD can also occur. And about 10% to 15% of males with the pre-mutation have autism spectrum disorders. Many women can have chronic fatigue, chronic pain, fibromyalgia. So these are very common in pre-mutation carriers, particularly females have fibromyalgia, chronic pain, et cetera. So you as psychiatrists will be seeing these problems very frequently, and again, the highest rate is about one in 130 females with the pre-mutation. So there's probably a couple pre-mutation carriers right in this room, okay? And you won't know it in your practice unless you order a Fragile X DNA test. So it's easy to say, easy to do. Just a few CCs and a purple top, going to the lab, and you'll get the exact number of CGG repeats. So again, this demonstrates the elevated messenger RNA that occurs in this pre-mutation range. And then the level of the Fragile X protein is normal for most of the pre-mutation, but it goes down about 30% at the end of the pre-mutation. So these individuals can have slightly prominent ears, hyperextensible finger joints, and some features of Fragile X, because the Fragile X protein is slightly lower. And then once you cross 200 repeats, usually methylation sets in. It's a rare case that has a lack of methylation. Sometimes there's partial methylation, and that is associated with higher functioning individuals with Fragile X. So the spectrum of pre-mutation involvement is quite broad. FETI and ADHD, even ASD, very common in childhood. Usually most individuals with the pre-mutation have a normal IQ. Faxan is many psychiatric problems. Also thyroid dysfunction is common, endocrine problems. Faxpoi, early menopause, they are at a higher risk for autoimmune disease, and so they have a higher risk for atherosclerosis, atherosclerosis, fibromyalgia is considered autoimmune. Lupus and MS occur in about 5% of pre-mutation women. And then they can have neurological symptoms. They have a much higher rate of migraine headaches, sleep apnea, restless leg syndrome. Then they get memory problems and foggy thinking. They also have hypertension. And the males get erectile dysfunction and that sets in. And FaxTest, the tremor and ataxia, usually starts in the 60s, sometimes in the 50s. And again, tremor, ataxia, Parkinsonian features, executive function deficits, memory problems, and cognitive decline. Now I wanna point out that there's a variety of molecular problems that are associated with RNA toxicity. The excessive RNA binds to proteins that are important for neuronal function, and that can cause inclusions in different parts of the brain and also in different parts of the body. There's white matter disease on the MRI, as I'll show you in a moment, but there's also environmental exacerbating problems like alcoholism. Pre-mutation neurons die earlier in culture than regular neurons. So they're very sensitive to environmental toxins like alcohol, like opioid addiction, chemotherapy. Smoking causes a lot of oxidative stress, chronic traumatic encephalopathy, individuals that played soccer or football in high school and college. And then there's also iron deposition that occurs in the brain. So we don't allow them to take iron. So again, you'll see tremor ataxia or FaxTest. It affects about 40% of the males in their 50s and about 16% of females, but then it increases in prevalence with age. And when they're in their 80s, about 75% of pre-mutation carriers have FaxTest. We described it in 2001 and we named it in 2003. And I'm just gonna show you a picture of a woman with the pre-mutation in FaxTest. So this is an action tremor. Again, it's related to excess messenger RNA, sequestering proteins, very important for neuronal function. These proteins that are sequestered cause inclusions in the nucleus. We see that on postmortem studies. Notice she doesn't have a resting tremor, although that can occur on occasion, but mostly it's an action tremor that interferes with handwriting. This shows the degree of brain atrophy. Actually, this is the worst at brain atrophy that I've seen. But they get white matter disease in the middle cerebellar peduncles and the inclusions noted in red here are throughout the brain, including the amygdala, which is probably related to why there's such significant psychiatric problems. Now, the lack of FMRP. Why is FMRP so important? It's important for cell development and throughout life, and it's kind of a mother protein. It controls translation of hundreds of genes, including 30% of all of the proteins that are associated with autism when mutated. So it controls a lot of, that's why there's such a cross relationship between Fragile X and other forms of autism. Because FMRP controls a lot, it controls some aspects of not only translation, but transcription. It controls the splicing of RNA or RNA editing for hundreds of genes. It controls the stability of the RNA. It even controls ionic channels, like the BK channel, the big potassium channel, that when it blows, if it doesn't have FMRP modulating it or controlling it, when there's a lot of environmental stimulation, it blows and causes sometimes seizure-like behavior. And this is thought to be related to the outbursts, the aggressive outbursts that many with Fragile X have. So when you're seeing one kid like this boy here with autism and you do a Fragile X DNA test, well, you'll find a lot of others in the family. The sister here has a full mutation and she has a borderline IQ. The mother here, 38 years old, she has FACS-POI, early menopause, FACS-AN, lifelong anxiety, she has neuropathy pain, she has muscle pain, she also has lupus. And her mother here has FACS-TAS or tremor and ataxia. She doesn't have cognitive decline yet. She has FACS-POI, early menopause. And the great-grandfather here has FACS-TAS, cognitive decline, neuropathy. So you gotta do a family history because once you find one, there's a whole big pedigree. And if you're in a country like Mexico or Colombia where there's pockets of Fragile X, sometimes a carrier male will have 10 daughters and each of the daughters go on to have a child with the full mutation. When you see the full mutation, it always comes from the mother. So only a carrier mom or a full mutation mom has the expansion to a full mutation. But a carrier father, all of his daughters get his only pre-mutation X chromosome. And in many countries, he might have 10 children and they all go on to have Fragile X syndrome in the offspring of the daughters. So hand flapping, poor eye contact, hand biting. Here's three brothers who are Hispanic in California. And I like it because they demonstrate all the characteristics of Fragile X syndrome. Tactile defensiveness, unusual sensory responses. A lot of kids tighten up their fists and I call it a power salute because my kids, when they were little, would do a power salute in their high chairs when they got mad and that was reminiscent of black power from the Olympics in those days. But kids with Fragile X do power salutes and it doesn't go away at two or three when it usually would go away in a normal child and it stays through life. They're usually happy but they almost always have anxiety. This boy has a Prader-Willi phenotype. He doesn't have a 15Q deletion but he has the Prader-Willi phenotype of Fragile X. Hyperphagia, massive obesity, lack of satiation after meals and we see that in about 10%. So this guy, he's actually having a power salute because I'm taking too many pictures of him in the photography studio and there is a GABA deficit in Fragile X. So when you have an inhibitory deficit or a GABA deficit, you can't habituate to sensory stimuli. Here is an electrodermal study in a normal patient. These vertical lines represent repetitive stimuli and as you can see, whether it's auditory, tactile, olfactory, whatever, you learn how to habituate. But in Fragile X, they don't have good GABA inhibition. They can't habituate and they escalate in their behavior and that can lead to major outbursts. So they have an enhanced sympathetic response to sensory stimuli and decreased parasympathetic response. So that causes a lot of anxiety. We treat the anxiety with SSRIs and other meds that I'll show you in a moment. They can have loose connective tissue, double-jointed thumbs, hyperextensible finger joints going up to 90 degrees and the most famous physical feature is macro-orchidism, which means big testicles. So the lower three lines are testicle size in the general population. The upper three lines are in Fragile X syndrome. So their testicles are two to three times normal or big testicles. They can also have strabismus. This boy has a little bit of interning of his right eye and you have to send them to ophthalmology to avoid amblyopia and to get treatment. They can have a slightly long face and prominent ears in childhood, but about 30% don't necessarily have that. They chew on their clothes, as you can see here. That's very typical. Now, because FMRP has many functions, I'm gonna focus on three things that go wrong with lowered FMRP levels. Too much glutamate, too little GABA, and lowered cyclic AMP levels. And targeted treatments have been developed for all of that. This is a complex slide showing that mGluR5 antagonists to lower the amount of glutamate stimulation have not worked. And the last study, which was on three to six-year-olds called the Fragile X Learned Study, showed a lack of efficacy. Arbaclofen, which is a GABA agonist, has been helpful. Minocycline, which lowers MMP9, can be somewhat helpful. Ganaxalone and acamprosate, which work on the GABA system, can be helpful. Lithium can even be helpful for down-regulating this. Lovastatin, marginally helpful for lowering MEK-ERK pathways. I'm gonna talk about metformin, which lowers the mTOR pathway in a minute. But first I wanna mention about sertraline. A control trial that we did in early childhood using low-dose sertraline in young children showed efficacy. I'll show you that in a moment. It was an open-label trial in kids 12 to 50 months of age. And the ones that were on sertraline, as you can see here, compared to the ones not treated with sertraline in expressive language scores, they did much better on sertraline and receptive language much better on sertraline here than not treated with sertraline. And that was preliminary data that got us funding for a control trial of low-dose sertraline between 2.5 to 5 milligrams per day using the Mullen scales of early learning as an outcome measure. This just shows how many months of improvement we're seeing on sertraline compared to placebo and several outcome measures were significant here in the p-values. So we do use a lot of low-dose sertraline in young kids with Fragile X. It seems to help not only in language, particularly those with autism, it helps the most with language, but also in other aspects of development, including motor behavior. Now, CBD can be helpful. You know, CBD is also a GABA agonist. It's a GABA agonist. That's why it's used for seizures, okay? Epidiolex is a good example. It basically inhibits pro-inflammatory cytokines and stimulates anti-inflammatory cytokines, helps mitochondrial function, counteracts the effect of THC, and it has basically a lot of effects in the CNS. So Zinurba, the company that made a topical CBD ointment that was manufactured, so not from plants, and it has no THC in it, did demonstrate efficacy in first 12-week controlled trial of their CBD versus placebo, and then in an ongoing open label, a lot of the benefits were maintained. But they saw that it was only with those with a full mutation that had 90% methylation who did best, and their primary outcome measure was social avoidance on the aberrant behavior checklist, and that reached efficacy. But because it was only those with greater than 90 or 100% methylation that showed efficacy, the FDA said, okay, you gotta do another study where that is what you're looking at. And so they started a ReConnect study focusing on the methylation groupings, and hopefully it'll be beneficial. In my estimation, I think the quality of life for the many families really improved, so they didn't have to put up with tantrums when they took their kids out to dinner or to restaurants, and I think it really improved the anxiety along with the social avoidance and aberrant behavior. So Metformin is a type 2 diabetes med that's been around for a long, long time. Believe it or not, it was around in ancient Egypt, 1500 BC, they got it from this French lilac plant, and there's a lot been written about it in some of the ancient writings from Egypt. Then in 1954, a French physician put it on the market to treat type 2 diabetes. It's known to help with overeating and obesity, can prevent cognitive deficits and diabetics, and the two Fragile X animal models, the Drosophila and the mouse model, showed dramatic improvement in the Fragile X phenotype in those animals. So I thought, wow, I have a lot of obese patients with the Prader-Willi phenotype, I'm just gonna try Metformin. Why didn't I try this years before? But I did try it in them, and I even threw in some non-obese patients, and we published that in 2017. It was just an open label, and it really helped the obesity, the weight gain. But the families came up to me, and they said, you know, Dr. Hageman, what it helps the most with is I'm able to carry out a conversation with my kid now, whereas I couldn't do it before. So I thought, ah, language benefits. So in our control trial, we have the expressive language outcome measure, which was developed by Lem Abedudo. So usually IQ goes down over time in individuals with Fragile X. We haven't published the result of the control trial yet, but we've seen improvements in IQ, even in adulthood. This is an obese patient that really did well. And the other thing is, when he started on Metformin, he was not into puberty, and a couple years later, when he was Tanner stage three, his testicles weren't large. They were normal size. So I thought, wow, at least I fixed the macro-orchidism, and I've seen that before. But I think it does help. The control trial is young and adult Fragile X individuals funded by Azraeli, which is a foundation from Canada and Israel. So they didn't want to do the control trial unless I had two sites in Canada. So my friend in Montreal, Sebastian Giacomo, and also a colleague in Edmonton are the two other sites. And it's just a four-month control trial. We finished this control trial two years ago, and Canada is still enrolling. They were supposed to enroll 60 patients, and Azraeli won't let me break the code until we get more patients in Canada. Of course, COVID and a lot of snow in Canada interfered with enrollment, but I hope to break the code by the end of this year. We're just giving them a little more time. I want to talk about the Tetra studies. So Tetra is a company that developed a medication, BPN-14770, that enhances cyclic AMP levels. So cyclic AMP is too low. That's an energy compound that connects neurons. And with BPN-14770, it is a phosphodiesterase inhibitor. So it inhibits the protein that breaks down cyclic AMP. So cyclic AMP levels go up. And in the adult studies of Fragile X, 30 adult studies that Liz Berry-Kravitz carried out at Rush University in Chicago, there was pretty significant improvement in many aspects of cognition, oral reading, picture vocabulary, cognition crystallized compounds, cognition crystallized composite score, and also the visual analog scale also did much better. So everybody is very excited about the Tetra studies in adolescents and adults, and it'll also be carried out in children. I just want to mention, I think my time is about up, but psilocybin, a tetramine derivative in magic mushrooms is being studied now by Novamentis in Australia to see if this can help Fragile X syndrome because it helped the knockout mouse model. And I want to thank my collaborators all around the world, and I will give more time to Kisara here. Thank you. Okay, we'll take questions at the end. Uh, okay. Okay, so I'm going to be talking about a strength and family-based approach to autism spectrum disorder. I don't have any conflicts or disclosures for this presentation. So I know Eric already covered a little bit of the background on autism, but just to review a little bit, autism is a heterogeneous neurodevelopmental condition right now. The 2% worldwide prevalence rate, and the CDC currently reports that 1 in 36 children have a diagnosis of autism, which is higher than last year, which was 1 in 44. So each year the prevalence increases, and as Eric mentioned, there's genetic and environmental factors that are kind of intertwining that might be contributing to that, in addition to us understanding more how these symptoms present in people that we previously weren't diagnosing them in. And right now, 2% of adults in the U.S. have an ASD diagnosis. And these symptoms that Eric also covered, they change across the lifespan, but something that we do see is that cognitive and behavioral rigidity, these insistence on sameness and restricted and repetitive behaviors, they do tend to worsen with age across most individuals with autism. And something important that I think clinicians should focus on is how important the family is in treating and working with someone with autism. Those with ASD require lifelong family assistance, in addition to a lot of outside services and supports. And most of the interventions that we currently have require caregivers and family participation. So they're really a key part of providing treatment. So this is a figure similar to Eric's that kind of shows all of the different symptom domains of autism, the social communication, and the restricted and repetitive behaviors. Oh, is it not advancing? I'm sorry. I don't know why. Sorry. Yeah, let me try that. Okay. Apologies. Okay. Thank you. Okay. So the social communication domain and the restricted and repetitive behavior domain. And there are a lot of comorbid and associated symptoms of autism. In addition to what we tend to see for referral is protest behaviors, irritability, agitation, and aggression is often the primary complaint that brings children and adults in because those externalizing behaviors are what they need the most help with. We might not see a patient initially for social communication deficits, but that may become more present once we're doing our clinical interview. So just reviewing again these core diagnostic features. So persistent deficits in social communication, social interaction. So people with autism, we often think about the abnormal or lack of eye contact. But a lot of it is in these communication that we have with each other where we look at someone and then we look at something else and we expect them to follow our eye gaze. People with autism have trouble following eye gaze, following joint attention. They have trouble integrating gestures with their speech, with their facial expression, with their eye contact. All of that is kind of thrown off, which might be due to some cerebellar abnormalities. So that's something that you really want to pay attention to in addition to that abnormal eye gaze is those types of difficulties in communication and socialization. And all of that contributes to their challenges in making and maintaining friendships because it takes them so much more effort to remain engaged in conversations and relationships and understanding other people's facial expressions and gestures and reading that in addition to maintaining their own and mirroring what they're seeing. And then that other symptom domain is the restricted and repetitive patterns of behavior and interest. So in children, we might see stimming. You might see peering at objects really closely. We might see lining up toys. But this changes as people with autism develop. We will see maybe a very highly restricted, fixated interest in trains or cars. With internet addiction, we might see more focus on certain video games, other things on the internet. We also see this insistence on sameness where there's this really difficulty in dealing with changes to routines and changes in the environment. And I'm going to get into that a little bit more later. But that domain, that inflexible thinking and that cognitive and behavioral rigidity is really important. I think one of the symptoms that causes the most challenges to functioning, and just as Eric mentioned, as we're adapting to new environments, people with inflexible thinking really struggle. So going into that a little bit more, we're tending to think of inflexible thinking more as a transdiagnostic endophenotype, something that crosses multiple disorders, not only autism but OCD, people with anxiety, people with anorexia also have inflexible thinking. It's related to higher levels of anxiety and depression, aggression, opposition. It contributes to lifelong challenges with social communication and interpersonal and relationship issues. We've also seen that it's related to the metabolomic, lipidomic, and immune biomarkers, particularly insulin resistance. And that's not only in the autism community. That's also in people with obesity and type 2 diabetes that have higher levels of inflexible thinking. And additionally, it exists at both the individual and the family level. So we might see an individual with inflexible thinking, but the family members, the parents, the siblings, they will also have cognitive and behavioral rigidity. So there is some interrelational dynamics and family dynamics at play that really are important when we're working with a person with autism and their family. Other important things to consider when you're diagnosing and working with someone with autism is that even though, according to the GSM, symptoms must be present in early development, we might miss and under-diagnose people with autism. We're still understanding this disorder. And a lot of symptoms might, if we don't have this classic presentation, a lot of these symptoms might not present until later in life. And we see adults who are misdiagnosed who have treatment-resistant OCD or other diagnoses. And it often is because they have a comorbid diagnosis of autism. And especially women, there's a large proportion of women who present with ASD, and they're very good at camouflaging and masking and may present with more internalizing disorders like anxiety and depression because of this. But a lot of it is also because of these underlying autism spectrum features. And as Eric also mentioned, there's a lot of associated and comorbid symptoms of autism that we really need to be aware of. People will tend to present often because of irritability and aggression and these externalizing behaviors, but we also need to be aware of intellectual impairment, speech and language delays, motor delays. There's a lot of hyper and hyposensory issues in people with autism, which could present a sensory integration disorder and require an occupational therapist to be working with the individual and the family, particularly when they're children. We need to be aware of all these medical conditions as well and comorbid psychiatric issues, including higher rates of suicidality. So I want to shift into talking about neurodiversity and neurodivergence. So this quote from Simon Berrigan Cohen, fish will appear as having a disability if required to climb a tree. We are freshwater fish in saltwater. Put us in freshwater and we are fine. Put us in saltwater and we struggle to survive. So in thinking about this neurodiversity movement, we're thinking that we want to shift the focus to thinking about autism as completely problematic and something we need to fix and change and cure to thinking more about it existing as a part of the person, right? And how can we think about the strengths of autism in addition to the challenges that it might present to functioning? Not all symptoms of autism cause people distress and the distress might more be because we expect them to be like everyone else. So we really want to think about and change the focus from normalizing these behaviors and thinking about how we might be able to incorporate these, what we call symptoms, into society. What are the strengths of autism? How can people with autism really fit and how can we make our workplaces and schools more incorporating of these individuals and what they could contribute to society? So rather than thinking of autism as something that somebody has, we might think of it as part of their identity. And there is a split in the community about this because there are people with severe, profound autism who really struggle and need a lot of treatment and help. And then there is a group of people that have high-functioning autism who kind of eschew treatments and may not want to be part of the pharmacological studies and trials that we do. So there is a bit of a divide. But we need to consider both viewpoints. So there might be people who want to be referred to as autistic individuals who celebrate their autism as part of their identity. And there might be a group of people who want to be referred to as a person with autism. And that's something to really think about when you're working with these families. Which kind of camp are they in? How do we want to think about this disorder and how it impacts this person? So in kind of shifting our perspective, because in using our medical model, we know that even if the symptoms don't cause everybody distress, we want to think about what causes an impact on functioning for that person in society. How can we help them function better? So some of these traits of autism might be context-dependent. In certain situations, they could be advantageous. In some situations, they could harm the individual. Some people could work better in a quiet environment without distractions. Some individuals can't be out and work in an environment that has a lot of individuals and people around and might be suited to different workplaces. So we need to really think about what traits are helpful and what traits are causing that person impairment. So in thinking about the strengths from different perspectives, we want to think about from a clinical perspective and a research perspective what strengths there are. And then from the individual with autism perspectives, what strengths they believe they have, and then from a parent perspective, since parents and caregivers are involved in people with autism's lives throughout the lifespan. So clinically what we see is there's enhanced visual stimuli, discrimination abilities, and an ability to focus on detail. And this is related to that kind of insistence on sameness and difficulty with changes in environment, because they're able to detect changes in the environment better than other people. They have a higher ability to detect deviation. They're also seeing that there's, even though that they struggle with imagination, that there's more creativity. We're also, from a self-report perspective, people with autism report they are better able to focus on things, that they have attention to detail and good memory and are creative. And a parent report, right, we want to think about, we don't want to always be painting children with autism as being a problem. We want parents to view their child with love and think about their strengths. So parents report that children with autism are loving and caring, they're better, they're able to navigate technology, and that they have some cognitive and recreational skills. So thinking about clinically, right, what are these strengths that we're seeing from a research perspective? So using visual search and visual mismatch negativity tasks, these electrophysiological measures, we're seeing that they're really able to look at local and unique and non-social stimuli and focus on that and identify changes in the environment better than their neurotypical peers. So there's less attentional shift and bias and augmented perceptual capacity. From a psychological testing perspective, we find that they do better on the embedded figures test and the Wechsler block design test, which are visual processing tests. So we realize that maybe not all people with autism, but some have enhanced visual processing skills, and this could be advantageous in certain job areas and school areas. And that second area of creativity and creative problem-solving, we see that even though, so when we measure creativity in research, we look at divergent thinking tasks where we might ask them to come up with a certain number of words or a different way of using a pin or a brick. So even though they have decreased fluency on these tests, they don't come up with as many answers. They come up with more unusual answers. So they do have higher rates of creativity. So there is some strengths and the executive strategies that are needed to generate really highly unusual and novel responses. So we want to think about that when we're working with people with autism as well. So what is the impact of using a strength-based approach? So on an individual level, we're fostering a positive self-identity. We're increasing their self-worth. We're reducing criticism. We're also motivating this individual to use support services, right? If you feel more engaged in your treatment and that your provider is aligned with you, then you're more likely to reach out and use what you need to function better in society. We're also trying to find a better goodness of fit and help people use strategies like inhibition and self-control to moderate these traits when they might be in a situation where it's not advantageous for them. And we're also trying to de-stigmatize autism. On a parent- caregiver level, there's a lot of caregiver burden in families with autism. So we really want to reframe these negative attributions and support positive parent-child interactions. We want to improve our relationship with parents and work to develop individualized intervention plans. There's no one-size-fits-all for autism. It's a very heterogeneous disorder. We really need to think of each child and each individual with autism on a case-by-case basis. We know that how a person views their child can affect their decision-making process and how they seek out treatment. So really changing those parental attributions into a more positive viewpoint could help someone engage with treatment services in a better way. And we also want to reduce parental stress because we know that there is a- that increased parental stress can also increase the maladaptive behaviors of the child with autism. And I'm going to show that in a second. Okay. So also, and Eric touched on this a bit, there is a bit of a challenge right now in the transition from adolescence to adulthood. When children have autism, we have a lot of services in place for them. They're often diagnosed through early intervention. They can get speech, occupational therapy, physical therapy, and there's all this structure and support provided. However, once they cross this threshold into adulthood, there's really a lack of services and resources for them. And then this causes increased anxiety and depression, suicidality. They have a lack of skill and resources to function in educational systems and getting employment. There's lower rates of employment for people with autism. Caregivers need to think about medical and financial decision-making issues in terms of where is this child going to live when I pass. So we really, as clinicians, as we see our clients progress, we need to advise parents on how to proceed and think about what supports need to be in place well before they cross the threshold into adulthood. And some other challenges, as I mentioned, there's struggle with employment. So only one-third of people with ASD obtain paid employment, and they're very underrepresented compared with people with other developmental disabilities and the general population. And we're really not taking advantage of these strengths that we see in the community. So we really need to work on developing better vocational programs that assist with job training and finding jobs that are a good fit for the skills that we're seeing. And this will also help with economic, societal, and governmental costs, right, because more people that aren't working, the more struggle there is on multiple levels of society. So there are a few groups that have been working to develop jobs based on ASD strengths. That includes, really interesting, the Israeli Defense Force, who has a whole division dedicated to utilizing that enhanced detail processing strength of people with ASD. So they use them to analyze satellite images and find differences in the satellite images to help them in combat and, you know, other defense strategizing. There's also the Joy Do Foundation, which also utilizes a lot of that enhanced visual processing skill. One of the job categories they have is to look at radiographs, mammograms, to look at changes over time to find tumors. And then there is some Eye Care for Autism has some educational outreach as well. So we really would benefit from creating jobs tailored to these ASD strengths, including that visual processing and enhanced detail perception, so that we could increase employment rates and quality of life. Now coming back to the whole family system, which is actually what my dissertation is looking at. So families of people with autism are extremely impacted from the point of diagnosis through the lifespan. There's lower marital and family satisfaction. Siblings are often parentified, causing poor sibling relationships. There's poor maternal mental health and well-being. There's a greater uncertainty of illness because we've really, right, autism, we don't have a set known cause. We don't know the known trajectory of what will happen for this child. So there's all this uncertainty of illness and ambiguity. And then ASD symptom severity changes across the lifespan. So what we see is that an increase in maladaptive ASD behaviors increases parental stress, which results in poor parental physical and mental health, which results in them changing their parental behaviors and worsens family functioning, which continues the cycle of worsening ASD behaviors. So family therapy and really working at the family level can really also help the individual in reducing their maladaptive behaviors. So and there are a lot of theories about the mechanisms of functioning in families with ASD, including thinking about the constructs of cohesion and flexibility. A healthy family has balanced levels of cohesion and flexibility. And then when a healthy family is confronted with a new diagnosis of a family member, that shifts everything. And a family will become first more chaotic and enmeshed. They'll pull together. They'll deal with the chaos of figuring out this diagnosis. Then they'll become more rigid. And they'll follow the set plans of instructions. How do we treat this? What do we do? And over time, the family then gets back into a balanced level of cohesion and flexibility. But what we see with families with autism is they don't really return to that balanced state. And they may remain more enmeshed and rigid than other families. And we're not really sure if that continues. Right now it's only been looked at in children. I'm looking at it in adults to see if it continues across the lifespan. And we're not sure if that makes this family healthier. Is this a normalized healthy way of having a family with an individual with autism? Or does it cause detriment? And it might do both. So some of the detrimental effects, rape enmeshment and rigidity could impact maternal mental health. It worsens maternal satisfaction and marital satisfaction. But, beneficially, there are stronger child caregiver bonds. There might be better coping skills in the family level. And a higher family quality of life. So we really need to explore this further in research. And in, you know, just working one-on-one with our families. Because if we if we approach our individuals with autism on a family level and encourage all these family members to support and understand the diagnosis and reduce that patient identification in the family, we really could create a healthier family system overall. And make that person with autism feel like they have a function and a purpose. Rather than that they're a problem in the family. Which over time increases their anxiety and depression. And worsens their maladaptive behaviors. So we really need to kind of examine these factors of resilience and growth and family connectedness. So, in sum, a strengths-based approach to treating autism can improve outcomes across multiple levels. And I highly encourage people to think about the whole family when they're working with someone with autism. Thank you. All right. And I'll invite Dr. Hagerman to come up. And we have questions for either Kisara or Rondi. If there are questions, please come up to the microphone. Excellent talks. My name's Justin. I work in Denver in college health. I'm a psychiatrist and a family doc. I came to this because I have not kept up on literature research about autism. But I'm increasingly seeing it, especially self-reported, by a lot of my students that I work with. One thing I'm curious about that I don't think I heard anyone mention, but I had recalled in this area before, was the concept of neuronal pruning. And I don't know if that's fallen out of favor. But thinking about connectomes, and the way the brain communicates within itself, and the idea that if neuronal pruning doesn't happen adequately in the brain, that there may be pathways that are over-signaling, or cluttered, or under-signaling. And could that relate to some of the hypersensitivities that are seen, and the lateral thinking, and some of the kind of unusual ideas that people with autism can come up with? Anything to this idea of a lack of neuronal pruning and an increase in connectomes? Rhonda, do you want to answer? Sure. I can say that there is a lack of appropriate neuronal pruning when FMRP is lacking, and the dendritic spines are more immature. There's more of them. And that may change with age. And what's interesting is a lot of the studies of autism brains, where there's not a fragile X mutation, have lowered levels of FMRP. So you can get lowered FMRP probably from a variety of reasons. And that's true of something, a protein, that is controlling many things in the brain. There's probably other pathways that control it, even when there's not a fragile X mutation. So that may be something seen in many other forms of autism, particularly genetic forms of autism. I might just add that with the maternal immune activation, so that can have big impacts in terms of pruning deficits as well. And whether it's ASD or whether it's ADHD, there's impairment in connectivity patterns associated with that. If I may ask a quick question to Dr. Hollander. So thank you so much for a great session. I wonder what are your thoughts on the use of better blockers such as propranolol for ASD? The use of what? The use of propranolol. Oh, propranolol? Well, I think propranolol is often used for performance anxiety. It can be helpful for aggression as well. So I think that it can be used on a sort of as-needed basis for those kind of symptoms. It can be helpful in fragile X to lowering anxiety, lowering maybe the sympathetic hyperarousal. Hey. So do you guys know of maybe good or preferred maybe measures or screeners for these people that are maybe, quote unquote, high functioning autism adults that may have more subtle presentations? And I'm thinking about measures or screeners that might help to tease apart the differential a bit better. Any thoughts? The quickest screener is the autism quotient scale by Simon Baron Cohen. It's pretty short and could be administered. I mean, it doesn't really tease apart the domains. Other scales that might be helpful are the aberrant behavior checklist, which gets more at different symptom categories. The repetitive behavior scale revised also is helpful to get at those inflexible thinking characteristics. And diagnostically, the ADOS and the ADIR are the gold standard measures, but they're longer and need more training to do. Thanks. I'm Larry Miller from Philadelphia. I came to this workshop because I have a long-term patient. It's a very high level functioning person academically, but not socially. And I think I'm his only real contact in life. He does have a son who also turns out to have a spectrum. He's way on the spectrum. My patient's on 450 on Welbutrin on a stimulants, and he had that before I saw him. And he's a high functioning, fully tenured academic because he was brilliant when he was younger. But now, I don't know what I'm doing. I'm like a family person or a support friend, all those kind of things. And I want to do more, and I don't know what to do. And occasionally, I've gotten him to date, and nothing works, and nothing changes. Is it responsible for me to just do this? And for the next 20 years, maybe 10 years, I will be supporting him. And what happens when I'm not here anymore? How do I prepare him for that? Good question. I mean, I would encourage, do you have any social skills or groups that he could be a part of to? Not interested. Does he work? He's a full time faculty person in the science, and he teaches. He does, it's a disappointment to them. He was a brilliant technical kind of person early on. I would just tease his basic starting students in the department. But he works, but he can't do anything about it because he's fully tenured. Doesn't develop any relationships with the people at work? No, not really. And twice now, he's gotten a relationship with women, but he always, it turns out, sour. And they're not necessarily healthy people. And now his son has graduated from college, and he's totally on the spectrum as well. So we talk about his son, but he can't do anything with him. Like I can't even do anything with my patient, he can't get his son to do anything. So I'm not unhappy, but I kind of feel like I'm not. What if he had a better therapist who had a lot of experience with autism? I don't know. And you said you were in Philadelphia? Yeah. The Center for Autism Research at CHOP, I think they might have quite a few resources. I know my grandson is involved in that, actually. But he wouldn't do anything. I mean, I don't, I'm asking an impossible question. What can I do that makes something different? He would not go anywhere or do anything, no matter what. Well, at least he's seen you. That's good that he has you. I'll be talking to him while I'm here, the only patient. Acceptance and Commitment Therapy has been showing some good ACT, Acceptance and Commitment Therapy. It kind of focuses on mindfulness and acceptance aspects of DBT. And it's been shown to really help with inflexible thinking. And it's more, we haven't really gotten to look at it as much in autism. But it could be a helpful, different strategy to try. What about TMS? Yeah, I guess it depends on the target symptom and his sort of interest. It sounds like he doesn't really want to pursue many other opportunities. And that he does have sort of a stable, long-term connection with you, which probably is pretty valuable in his life. I mean, it is interesting that his son now is presenting with similar kinds of issues. But I would say that you're having an impact on his life. I don't think I'm guilty of malpractice. But I would like to be able to do better. After all this time, I care about him. But I'm not able to make any changes, and it's frustrating. OK, well, thanks very much. Time for a couple more questions. Hi, I'm a child psychiatrist. And I work with adolescents and young adults. And I have many who I've seen for five years who've kind of gone from kind of teen to kind of young adults. I've seen many on the spectrum level one who have present more than my caseload without autism of gender dysphoria. And is that something that's in the literature? I've just seen it so, so often. OK. So yeah, there's a chapter in our textbook dedicated to that topic. And Jonathan Strang has done a lot of work as well. So there is a lot of research looking at that. And there are a lot of good hypotheses, too, on why there are higher rates of gender dysphoria in autism as well. Do you want to say something about that, why? Well, there's some hypotheses about kind of the male brain theory and different higher levels of testosterone that might be present that could be affecting identification with male to female or female to male. So I know women with autism, even traditionally, even women with ADHD, might tend to present with more masculine characteristics as well. And then males with autism might tend to veer towards non-binary in some instances and maybe transgender female, but as more of a rarity. But there is more work being done to look at that. And it definitely increases rates of suicide, anxiety, and depression, because we know that that community itself is marginalized. And then when you add on having autism, it kind of limits your ability to reach out and connect as well. So yeah, there is work being done. So we're getting there. We're trying to, yes. And my question has to do with work to improve multitasking. Obviously, some of the strengths is focus, the weakness socially, and certainly professionally driving, et cetera, is difficulty with multitasking. I know we live in a more complex society, which may account for people instead of just learning a task and staying in family and stuff years ago. It's a very complex society. But it seems like one of the real problems as people get older and becoming more independent is the inability to multitask, both socially and professionally. And I have noticed I've had a couple of patients who are just absolutely brilliant. I mean, their IQ is most about 180. And they could do a lot better, because they're so goddamn smart. And this one guy, I remember, he said, well, I just watch people imitate them. I don't like it, but I can. And he was so smart, he could start teaching German class after three days of being in it. He could just imitate stuff. But then I thought, well, and I'm not fluid, and I'm an old guy, but would there be computer programs or things that could help people develop enhanced multitasking skills, as opposed to focusing skills, which computers often may exaggerate their problems. That's all the goddamn thing they do, is focus on the same thing all the time. Well, that's kind of the issue with this inflexible thinking, is difficulty with being able to disconnect from one thought and then refocus. So that set-switching type executive function. You want to say anything more about that, or either? I mean, executive functioning, coaching, and kind of focusing on organizational strategies, that could be beneficial to help people with. I mean, set-switching, like Eric said. Like multitasking, I know we're trying to veer away from, right? But the ability to set-switch rapidly is really necessary in our society. But it also uses up a lot of cognitive resources, particularly for people with autism. So yeah, I guess work on the inflexible thinking. And some gamification approach is also to enhance that, that switching through. There's the new video game approved for ADHD. I'm blanking on its name at the moment, but that's supposed to improve attentional features in ADHD. Hi, I'm Sujeev, and I work in Melbourne. This question is for Professor Hegeman. Have you had any evidence of relationship between FX-AND and Ehlers-Danlos Syndrome? Yes, so individuals with Fragile X Syndrome usually don't get diagnosed with Ehlers-Danlos, but individuals with the pre-mutation often do. And so we've written papers on that, and we recommend that those pre-mutation individuals that get diagnosed with Ehlers-Danlos and have some other pre-mutation problems, they should go through Fragile X DNA testing. So that's often confused. And why the pre-mutation has more connective tissue problems, we've seen SCAD, Spontaneous Coronary Artery Dissection. We reported that in three females. We oftentimes see aneurysms. So we're looking at how often that occurs. But that's kind of like the vascular Ehlers-Danlos, although the hyperextensibility Ehlers-Danlos is more common. Hi, Marianne Shepard, California. And I see a lot of ID and autistic patients every day. I would love to have a group like you to be able to consult with the very, very difficult ones. So think about that and getting a grant to do that. I have a whole slew of families that have up to three to four children that have no genetic, at least when we do the testing, anything. But they have three to four children that are impacted. And as I was listening to you, I thought about the pre-mutations. I'm wondering if indeed in the past, 10 years ago or 15 years ago, was that being picked up? And should I go ahead and redo it? Oh, yeah. Absolutely. The microarray has gotten better. Fragile X DNA testing has gotten more specific. But whole exome and whole genome sequencing. So if those other two are negative, if the fragile X DNA and the CGH array or microarray are negative, then whole genome testing would be even better than whole exome. And before, it was pretty expensive. Now, it's down to about $1,000. And oftentimes, covered by insurance. OK. Well, it's been a great symposium. I really wanted to thank the speakers who did an outstanding job. And I want to thank you all for attending.

symposium

San Francisco

comprehensive assessments

treatment developments

autism spectrum disorders

Eric Hollander

psychiatric assessments

genetic testing

cannabinoids

neuromodulation

early diagnosis

personalized treatment

fragile X syndrome

family-based approach