IDDRC Research Findings
The UC Davis MIND Institute’s Intellectual and Developmental Disabilities Research Center (IDDRC) supports interdisciplinary research focused on understanding, treating and preventing the challenges associated with intellectual and developmental disabilities. Below are summaries of recent findings from UC Davis MIND Institute projects supported by the IDDRC.
Study identifies early signs of FXTAS, a neurodegenerative disease associated with fragile X syndrome
By Susan Rivera and David Hessl
A full mutation of the FMR1 gene on the X chromosome has long been known to cause fragile X syndrome, a genetic condition associated with intellectual disability. More recently, researchers have shown that some older individuals, particularly men, who have a different variation in the FMR1 gene known as a “premutation,” are at high risk for developing a debilitating neurodegenerative disease known as fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS causes both cognitive decline and movement issues similar to Parkinson’s Disease later in life. However, not everyone who carries the FMR1 premutation develops FXTAS, and little is known about the earliest signs of FXTAS.
A team of UC Davis MIND Institute scientists co-led by David Hessl and Susan Rivera has provided important insights into how FXTAS first develops. Their study has been tracking men who carry the FMR1 premutation, many for 15 years or more, starting from before they showed any signs of FXTAS. The men returned for several study visits at 2- to 3-year intervals. They completed a set of cognitive and motor tasks at each visit in order to track how they were changing over time. This is the first study to use a long-term, or longitudinal, design to follow FMR1 premutation carriers. Of the 64 study participants, 18 have developed FXTAS so far.
Results published recently in the Journal of Neurodevelopmental Disorders showed that there were a number of early indicators that indicated the men were developing FXTAS before they showed obvious cognitive symptoms or motor signs that a neurologist might see in an exam. These included declines in visual working memory, manual dexterity and movement speed.
Clarifying how individuals with FXTAS change over time is an enormous benefit for both clinical researchers and families. These trajectories can be used to identify the earliest possible opportunities for intervention and to measure patient responses to therapy. In addition, as new treatments emerge, the information from this study could help guide the care of these individuals.
Brain development linked to anxiety in autistic youth
By Derek Andrews
Autistic individuals experience high rates of anxiety disorders, such as generalized anxiety or specific phobias that are also common in the general population. However, recent research suggests that autistic individuals can also experience forms of anxiety that traditional assessments fail to capture. For example, autistic children may experience anxiety in social situations due to confusion rather than the fear of being judged negatively as in traditional social anxiety. We call these autism-distinct forms of anxiety.
The current study is the latest from the UC Davis MIND Institute’s Autism Phenome Project, which has followed a large cohort of autistic children at multiple timepoints from 2 years of age into adolescence. In this study, we examined the development of the amygdala, a brain region critical for detecting threats and assigning importance to things in our environment, and its role in the emergence of anxiety disorders.
We used anxiety assessments that were specifically designed to diagnose both traditional and autism-distinct forms of anxiety. Interestingly, we found different – and opposite - patterns of amygdala development based on the type of anxiety experienced. Autistic children with traditional anxieties had larger amygdala size than other autistic and non-autistic individuals across all of childhood, starting at age 3. In contrast, autistic children with autism-distinct forms of anxiety had slower amygdala growth from 2.5-12 years and smaller amygdala volumes than other individuals by middle childhood. This research highlights the importance of developing anxiety measures specifically for autistic children and indicates the amygdala as a possible marker of different forms of anxiety in autistic children.
Bringing evidence-based intervention strategies to autistic students in public schools statewide: The California Autism Professional Training and Information Network (CAPTAIN)
By Aubyn Stahmer
It is important for teachers and other educators working with autistic individuals in public schools to be trained in intervention strategies that have been researched and shown to work. Using these evidence-based practices is required by federal legislation and leads to better outcomes for autistic students. The challenge is that educators don’t always have adequate training on how to implement evidence-based strategies.
The California Autism Professional Training and Information Network (CAPTAIN) is a state-wide network that aims to encourage the use of high-quality, evidence-based strategies in the education of autistic individuals throughout the state. CAPTAIN has over 200 trainers who work in schools to provide instruction to almost 20,000 educators and individualized coaching to over 6,500 educators each year. A recent study published in the journal Autism by Aubyn Stahmer and colleagues tested whether being trained by CAPTAIN helps educators use evidence-based strategies more effectively in their classrooms.
The study was conducted at UC Davis and San Diego State University. The researchers surveyed educators trained by CAPTAIN and those not trained by CAPTAIN about their use of evidence-based practices, then compared the answers.
They found that CAPTAIN-trained educators reported better attitudes toward using evidence-based practices, were more likely to use the strategies correctly and used them more often with students. They had more in-depth knowledge of their primary intervention strategy and better ratings of classroom quality than educators who did not get CAPTAIN training. These findings show great promise for CAPTAIN as a model to support statewide use of better evidence-based strategies for autism. More studies are needed to see how the use of these practices improves student outcomes.
Many expectant mothers get sick sometime during their pregnancy. They recover and the developing fetus is protected by the maternal immune system. However, there is evidence that a small number of children born to women exposed to viral or bacterial infection during pregnancy will be diagnosed with a neurodevelopmental disability such as autism or schizophrenia. We believe that the mother’s immune response might be the key link between exposure to infection and changes in the developing fetal brain. This is perhaps not surprising, as recent research investigating links between the brain and the immune system has revealed that immune-signaling molecules help to shape the developing fetal brain and play an important role in healthy brain function. Thus, challenges to the mother’s immune system during pregnancy may impact the finely orchestrated events of neurodevelopment.
It is important to note that most pregnancies are resilient to maternal infection. Most women will experience at least one cold or illness during pregnancy, and the vast majority of children will not go on to receive a neurodevelopmental diagnosis of any type. However, for a subset of women, the maternal immune response triggered by viral or bacterial infections may alter fetal neurodevelopment and lead to a disability. A number of factors, including genetic susceptibility, timing and intensity of the maternal immune response, and the presence of additional prenatal or postnatal adversities likely determines which pregnancies are at risk and which are resilient. At the moment, we do not know how to predict which pregnancies may be affected and why the susceptible ones lead to neurodevelopmental disabilities.
Research in preclinical (animal) models that artificially stimulate the maternal immune response in a controlled environment are providing important insight into the long-lasting effect of the maternal immune response on the developing brain. To that end, a recent collaborative effort by UC Davis Conte Center investigators has developed a nonhuman primate model to explore the impact of the maternal immune response on offspring. This study, published in December 2021 in The Journal of Neuroscience, found that offspring born to monkeys who experienced an immune response in the late first trimester demonstrate subtle changes in cognitive development. They also had smaller brain volumes in the frontal lobes throughout development. This unique research combines long-term brain scans with behavioral assessments to document neurodevelopmental changes in offspring whose mothers were sick during pregnancy. It’s the first paper in a series of studies on the subject. These findings extend research in rodent models into a species more closely related to humans and provide a platform to explore novel therapeutic interventions.
The ongoing COVID-19 pandemic highlights an urgent need to better understand the link between maternal infection and offspring neurodevelopment. Our future studies will leverage this nonhuman primate model to better understand risk and resilience to maternal infection and improve the translation from animal models to human populations. Our goal is to utilize these findings to develop evidence-based guidelines to manage infection during pregnancy. We also hope to identify and provide early intervention to improve the lives of affected individuals.
The immune system has a distinct role in many bodily functions across the lifespan, extending well beyond its capacity to fend off infections. Indeed, substantial research suggests that immune cells and their molecules are important orchestrators in early development, tissue maintenance, and healthy aging. Unsurprisingly, given this broad influence, dysregulation of the immune system has been linked to a multitude of conditions, including neurodevelopmental disabilities such as autism.
Research in Judy Van de Water’s lab has focused on understanding the role of the immune system in autism to provide insight about the biological basis of this neurodevelopmental condition. One major finding from this work has been that nearly 20% of mothers with children on the spectrum also present with specific patterns of circulating antibodies to self-proteins, known as autoantibodies.
A recent collaborative effort by MIND Institute Intellectual and Developmental Disabilities Research Center (IDDRC) investigators Judy Van de Water, Jill Silverman, and Jacqueline Crawley, as well as researchers from Canada and the United Kingdom, used an animal model to evaluate the effects of these maternal autoantibodies on offspring brain development. This study, published in July 2021 in the journal Molecular Psychiatry, found that mice exposed to autism-specific maternal autoantibodies during gestation displayed increased brain size, similar to that seen in autistic individuals born to mothers with these autoantibodies. It was also apparent that certain regions in the brain, such as the amygdala and white matter areas, were more affected by maternal autoantibody exposure than others. Finally, the differences in brain volume observed in mice also related to altered social and repetitive behaviors and affected male and female offspring differently.
These results suggest that maternal autoantibodies have a direct impact on the way that the brain grows and develops, and that these changes may underlie the development of autism in a subset of individuals. Current efforts are focused on understanding how these autoantibodies lead to altered outcomes using a combination of approaches. These include looking at the molecular and cellular level using mRNA sequencing and cell culture techniques. The overarching goal of our research program is to enhance the ability for early intervention and implementation of services to improve the lives of affected individuals.
Autism characteristics in individuals with Down syndrome
By Amanda Dimachkie Nunnally
Individuals with Down syndrome are diagnosed with autism at a much higher rate than the general population, with prevalence estimates ranging from 16-42% in Down syndrome compared to 1.9% in the general population. There is still much to be understood about the presentation of autism symptoms in individuals with Down syndrome, as some of the core characteristics of autism may overlap with intellectual disability. Individuals with Down syndrome and co-occurring autism tend to have more severe rigid and repetitive behaviors and greater challenges with social communication than do individuals with Down syndrome alone. However, the degree to which symptoms can be attributed to each condition remains understudied.
In a recent study published in Brain Science, we explored the presence and presentation of autism characteristics in 83 individuals with Down syndrome, aged between 6 and 23 years. We found that 37% of our sample met criteria for a diagnosis of autism using the Autism Diagnostic Observation Schedule 2 (ADOS-2), consistent with what prior studies have reported. Next, we explored which skills on the ADOS-2 differentiated individuals in our sample who met autism classification from those who did not. Skills such as eye gaze, use of gestures, quality of social overtures and rapport were more impaired in individuals with Down syndrome who met autism classification compared to those who did not. This finding is consistent with the notion that while individuals with Down syndrome may experience difficulties in social communication, individuals with both Down syndrome and autism experience more substantial difficulties in this area. Lastly, upon examining whether the two groups differed in language and cognitive abilities, we discovered that individuals with Down syndrome who met classification for autism demonstrated more limited language skills, particularly expressive grammar, than those with Down syndrome alone.
Altogether, our findings confirm earlier studies reporting higher rates of co-occurring autism in individuals with Down syndrome. They also confirm more severe impairments on specific social measures and language skills in individuals with Down syndrome who met classification for autism compared to those who did not. Additionally, for individuals in our sample with more limited language skills, the presence of restricted and repetitive behaviors no longer differentiated individuals with Down syndrome who classified for autism from those who did not. This suggests shared characteristics between autism and Down syndrome. The findings presented in this study build upon earlier studies by examining the presentation of autism characteristics in individuals with Down syndrome using the largest sample to date, describing for the first time the profile of symptoms in these individuals, and establishing a role for expressive language in the emergence of autism symptoms. Our findings demonstrate the need for more research exploring the complexities of diagnosing autism in individuals with Down syndrome, particularly the relationship between language and the presentation of autism characteristics.
Changes in neuronal structure are at the heart of neuropsychiatric conditions such as depression, substance use disorder, and post-traumatic stress disorder (PTSD), as well as developmental conditions such as schizophrenia and autism. The development of safe medications that could reverse or repair these neuronal alterations is an active area of research. In 2018, David E. Olson and his lab discovered that psychedelics, like LSD and MDMA, promote neuroplasticity and facilitate the growth of cortical neurons—a finding that could explain why psychedelics produce long-lasting therapeutic effects after a single dose. Though psychedelics are demonstrating promising results for treating depression, PTSD, and social anxiety in adults with autism under carefully controlled and monitored conditions, the wider use of these treatments is limited by their hallucinogenic effects, potential for heart damage, and/or psychostimulant properties.
To solve this issue, the Olson Lab has engineered several non-hallucinogenic versions of psychedelics that produce therapeutic effects in preclinical models with improved safety profiles. Their non-hallucinogenic version of the drug ibogaine, known as tabernanthalog (TBG) was described in a paper published in Nature last December. It produces therapeutic effects in models of depression, opioid use disorder, and alcohol use disorder, though the compound has not yet been tested in humans.
More recently, the Olson Lab partnered with Lin Tian’s group to develop psychLight—the first ever optical test for determining the hallucinogenic potential of specific compounds . In a paper published in Cell, the team used psychLight to identify AAZ-A-154 (AAZ), a non-hallucinogenic MDMA-like compound with long-lasting antidepressant effects but no psychostimulant properties. Olson and his team are currently testing the effects of AAZ in experiments relevant to treating PTSD and social anxiety in adults with autism. Olson Lab research also led to the founding of Delix Therapeutics—a biotech company focused on using non-hallucinogenic analogs of psychedelics to treat a variety of neuropsychiatric and neurodegenerative conditions.
The first signs of autism usually appear in the first two years of life, but exactly when they occur can vary quite a bit from child to child. Our lab has followed infants from shortly after birth until age 3, through the window when autism characteristics develop. We see the children multiple times so that we can directly measure the timing of onset. Past studies that have similarly followed babies over the first few years of life have found that children who developed autism showed declines in social-communication behavior, such as looking at the faces of other people or smiling at others, between 6 and 36 months.
In 2010, the Ozonoff lab reported that infants who were diagnosed with autism at age 3 showed a decline in how often they directed their gaze toward an adult who was interacting with them as early as 12 months of age. However, that study was conducted in a relatively small group of children, so it was important to replicate these findings to make sure that they are accurate. In a new paper, we followed two independent groups of infants from 6 to 36 months (155 children in one group and 126 in the other) and examined their gaze behavior in different settings and contexts. This included interacting with an adult, either during developmental testing or during play with toys. We found the same results as the original study. Across both groups of children—and both settings—most children who were diagnosed with autism at 36 months showed sharp decreases in how often they looked at the faces of the adult they were interacting with relative to children without autism, including those with other developmental conditions, such as language delays. Children with autism showed lower levels of gaze to the adult’s face by 6-12 months of age than children who did not develop autism.
These findings add to our understanding of typical and atypical trajectories of social-communicative behaviors and the early development of autism characteristics, suggesting that declining developmental trajectories in some social-communicative behaviors across infancy may occur in most children diagnosed with autism by age 3. Key social behaviors, like looking at or smiling toward other people, could be tracked at every well-child visit and charted, much like doctors do for height and weight, to be sure that a child’s social development is on track and does not show declines. Such methods might allow children to be identified during the decline of skills and participate in helpful early intervention, even before meeting criteria for a full diagnosis of autism. This study used a time-intensive, laboratory-based method to examine social-communicative behaviors, and our lab is currently working on methods of evaluating these behaviors that could be applied outside the laboratory, such as in a doctor’s office, through a video-based screening tool.
My colleagues and I recently published a study that helps to explain differences in the development of the brain’s wiring in autism, and how these differences are associated with changes in autism symptoms across childhood.
Within the brain, white matter serves as connective tissue, “wiring” different parts of the brain together (like bundles of wires). These structural connections provide critical pathways for different brain regions to communicate with each other to produce a desired behavior. It is widely theorized that autistic characteristics, including social communication challenges and restricted repetitive behaviors arise from alterations in brain connectivity. A type of magnetic resonance imaging (MRI) scan called diffusion weighted MRI is particularly well suited to investigate the white matter pathways in the brain and has been utilized by several previous studies of autism. These studies have consistently found alterations in white matter structure in autism; however, little is known about when these differences develop.
This recent study leveraged diffusion weighted MRI scans from the UC Davis Autism Phenome Project, which was first initiated in 2006 by Professors David Amaral and Christine Wu Nordahl. This project continues to follow children at multiple points across childhood starting from around three years of age, near the time when an autism diagnosis is first possible. By acquiring multiple brain scans longitudinally across childhood, we were able to chart the developmental course of white matter pathways in autism compared to typical development. We found that in autism, white matter differences in these pathways emerge over early childhood due to slower white matter development and might not be present, or even have differences in the opposite direction closer to three years of age. Importantly, slower white matter development was found to be associated with a trajectory of increasing autism characteristics. This provides new evidence that white matter development may serve as an important indicator of the progression of autism.
We hope in the near future that measurements such as this can both identify children who would benefit from more intensive intervention and serve as a marker to determine the effectiveness of interventions. Accomplishing this would allow us to better tailor interventions for individual children and hopefully improve the quality of their lives.
The American Academy of Pediatrics (AAP) recommends no independent screen time (i.e., digital media use) for children younger than age 2, and no more than one hour per day for children 2–5 years of age. These guidelines are based on research indicating that children who engage in less screen time generally have higher language and developmental scores.
Most prior screen time research has involved the general population. However, children with developmental delays and those with behavior problems may be the most vulnerable to the negative impacts of excess screen time. That’s because screen time may replace developmentally beneficial interactions.
A recent study in our lab examined screen time in 36-month-old children at increased likelihood for autism spectrum disorder (ASD), language delays, and attention deficit/hyperactivity disorder (ADHD) due to family history. The sample also included a comparison group of children with no family history of neurodevelopmental conditions.
Parents reported how much time their child spent watching television programs, movies, streamed media content or YouTube videos. Children received assessments in the laboratory to evaluate their behavior and language development. Based on these, children were grouped into three categories: ASD diagnosis group, elevated ADHD symptom group, and Comparison group (any children who did not meet criteria for the other two groups).
Results showed that, on average, children in all groups exceeded the daily recommended screen time guidelines of one hour per day. Children with increased symptoms of inattention and hyperactivity had the most screen time, with an average of 2.33 hours per day. In addition, more screen time was associated with lower expressive and receptive language scores in all groups, including the comparison group who showed no signs of either ADHD or ASD symptoms.
Because our study evaluated behavior at a single time point we cannot determine the cause of the associations. Some parents may wonder if allowing their child to watch television or videos at an early age may cause ASD or ADHD. A causal association between screen time, ASD and ADHD is not indicated in prior research or in our study. More research is needed to understand whether increased screen time contributes to language delays, inattention, and hyperactivity, or if children in these groups engage in more screen time for other reasons (e.g., preference for visual input, parental viewing habits, sleep habits, etc.).
Our results do indicate that the negative associations found between screen time, language development, and inattentive/hyperactive behaviors demonstrated in community samples of children in previous studies are also evident in children at risk for neurodevelopmental conditions. Our findings provide additional support for the AAP’s current recommendation to limit screen time in young children.
Developing innovative methods to study the human genome
By Fereydoun Hormozdiari
The human genome is the complete set of DNA that makes up a person. It consists of a long stretch of over 3 billion nucleotides that combine in a certain order to form thousands of genes. These genes, in turn, encode proteins, which are the building blocks of each cell. Genomes contain each person’s unique genetic code and are responsible for various complex traits and common diseases. Genetic variations, or mutations, are differences in these genetic codes that arise when the genome sequences are modified through small or large changes.
Structural variations (SVs) are defined as medium and large genomic rearrangements, involving more than 50 base pairs (sets of nucleotide) changes. These rearrangements to the genomic sequence may be in the form of insertions, deletions, or inversions of nucleotides. A growing body of evidence has shown that SVs in a person’s genome are a major contributing factor to diseases (such as cancer) as well as neurodevelopmental conditions (like autism). There are still many unknowns about SVs including their diversity, complexity, distribution in the population, and their exact impact in biology. These are some of the reasons that my lab is conducting a major project, funded by the National Science Foundation CAREER Award, to develop new computational methods to study SVs.
Recent advances in sequencing technology have allowed us to investigate the complexity of SVs and their direct contribution to different diseases or traits. To fully investigate these variants, we need accurate and efficient computational approaches to discover and characterize different types of complex SVs. The goal of our project is to develop novel methods to provide researchers with necessary tools to better capture the diversity of SVs and study their contribution to biology.
As part of this project, novel methods will be developed for efficient and accurate genotyping of any type of SV. These tools will be directly applicable to studying the impact of both common and rare SVs on neurodevelopmental conditions such as autism. To establish the utility of these methods, we will analyze publicly available whole-genome sequence data. This project will also achieve a broader impact by providing training opportunities for both undergraduate and graduate students interested in computational genomics. The results of the projects will be available at www.hormozdiarilab.org.
Over the last few decades, we have learned a great deal about the early development of autism. For example, we know that for most children on the spectrum, the signs of autism emerge over the first few years of life. Despite advances in early identification, there remain significant barriers to families’ access to high-quality evaluations and services. These include long waitlists for evaluations, lack of specialized expertise in community settings and provider hesitancy to refer young infants for further evaluation. Families are often told to ‘wait and see’. To help increase access to early evaluations, we have developed a telehealth-based early developmental evaluation for infants, the TEDI. Using video telecommunication technologies such as Zoom, families are able to connect with experts and access autism evaluations from their own homes. Importantly, developing a telehealth-based assessment for autism will increase access for families in rural and low-resourced areas.
In one of our research studies, we are examining whether this telehealth-based approach is feasible for clinicians and researchers in terms of our ability to capture key infant behaviors. We are also gathering feedback from families about whether the TEDI meets their needs, as well as any ideas for improvement. Preliminary findings suggest that examiner-scored behavioral ratings from video sessions were reliable and that infants’ behavior was stable across multiple observation sessions. Sessions were completed with minimal technological problems, and families rated the TEDI as highly acceptable in terms of the technology used, assessment components included, and the convenience of telehealth-delivered sessions. We are now examining these same features in a larger sample of infants, recruited nationwide, whose parents have concerns about their social communication development. Recruitment for this larger study is ongoing through September 2021.
In a second recently awarded grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, we will be examining another aspect of the TEDI. We need to see how the TEDI compares to existing standardized and validated measures collected in a traditional laboratory setting. This next step is crucial for demonstrating that this telehealth-based approach can be reliably used to evaluate infants’ behavior. We will be asking families who are receiving existing gold-standard in-person assessments through another project at the MIND Institute, the LAAMB study, to participate in an additional telehealth session using the TEDI from home. This will allow us to compare infants’ behavior across the two study settings. We’ll do this at three ages: 6 or 9 months, 12 months, and 18 months. Other MIND Institute faculty involved in this project include Meghan Miller, who directs the LAAMB study, and Gregory Young and Sarah Dufek. We are so grateful to all the families who have participated so far!
Building a brain requires intricate cross-talk between various cell types: listening in may offer clues about neurodevelopmental disabilities
By Stephen Noctor
A pair of studies recently published in Cerebral Cortex by the MIND Institute’s Noctor lab shed light on complex mechanisms of prenatal brain development that may reveal clues about neurodevelopmental disabilities. Notably, the team made the discovery that developing blood vessels and certain types of immune cells are more closely involved in the creation of neurons and glia (the two types of cells found in the brain) than previously realized. This interaction takes place in germinal zones – a region of the prenatal brain where neural stem cells produce the neurons and glia that populate the mature brain.
The first study showed that developing blood vessels in germinal zones of the prenatal brain extend fine thread-like processes, called filopodia, that directly contact two cell types in the fetal brain: neural stem cells and immune system cells of the brain called microglia. Neural stem cells and microglia return the favor, contacting the blood vessels and thereby creating a highly interconnected mesh between key cell types during crucial stages of brain growth. These new findings suggest that normal development relies on proper communication between these three systems in the fetal brain. The study also suggested possible ways that prenatal brain development may be impacted by alterations in gene expression or exposure to factors such as external pathogens.
Indeed, the second study published by the laboratories of Dr. Alice F. Tarantal at the California National Primate Research Center and the Noctor lab in the MIND Institute, demonstrated that exposure to Zika virus during the first trimester of pregnancy in non-human primates resulted in profound abnormalities in germinal zones of the fetal brain. At three weeks after exposure to Zika, the size of blood vessels and the number of microglia increased two-fold, neural stem cells’ position in the germinal zones was abnormal, and the developing gray matter was significantly thinner. These striking abnormalities were also present in a separate cohort of primates at three months after infection.
Together, these studies showed that key components in the fetal brain are tightly integrated, and yet susceptible to pathogen exposure. By demonstrating the strong and persistent effect of Zika virus infection on central features of fetal brain development, UC Davis researchers highlight our need to more fully understand the range of factors that can impact brain development during gestation.
Early signs of autism and risk for ADHD sometimes overlap
By Meghan Miller
Studies of familial risk for autism have consistently found that if an older sibling is diagnosed with autism, the younger sibling has a higher risk of also being diagnosed with autism. Prior research from the Miller lab has found that having an older sibling with autism also increases the risk for ADHD in the younger sibling. Likewise, having an older sibling with ADHD increases the risk for the younger sibling to develop ADHD, but also autism. Other research has suggested that autism and ADHD may share genetic causes, which could mean that some early signs of the two conditions may also be similar.
A recent study out of our lab explored this question in a group of infants with a family history of autism, a family history of ADHD, or no family history of either, who we closely followed over the first several years of life. In this study, published in the Journal of Autism & Developmental Disorders, we examined whether infants respond when their name is called. Diminished response to name is typically thought to be a specific early indicator of autism, but because it involves attentional skills, and because attentional skills may also be affected in ADHD, we wondered whether reduced response to name might also be evident in infants at risk for ADHD.
In this study, infants were evaluated in the lab at 6, 12, 18, 24, and 36 months of age. While they were seated on their caregiver’s lap and playing with toys, an examiner called the infant’s name several times during the assessment session. The infant’s behavior was observed to determine whether or not they responded to their name by making eye contact with the examiner. We found that reduced response to name may in fact be a general risk marker for both autism and ADHD earlier in infancy (from 12-18 months) but become a more specific indicator of autism by 24 months of age. This suggests that response to name behavior may reflect more basic attentional skills implicated in both autism and ADHD early on, gradually shifting to reflect the social difficulties implicated in autism by toddlerhood.
Ultimately, these findings suggest that there may be overlap between early behavioral symptoms across neurodevelopmental disorders like autism and ADHD which may wax and wane across development. Better understanding these similarities and differences may help us to refine early detection and diagnosis of both conditions.
Cord blood DNA holds clues for early autism diagnosis
By Janine La Salle
This study, published in October 2020 in the journal Genome Medicine, identified a novel molecular signature in the cord blood DNA of newborns who were later diagnosed with autism. The research used a genome-wide approach of detecting DNA methylation, a chemical modification to DNA that reflects both genetics and environmental factors. We demonstrated that genes on the X chromosome and those involved in brain development were most affected. We used cord blood samples collected at birth from pregnancies in the UC Davis MIND Institute MARBLES study, which examines early markers for autism risk. Babies at high risk for autism are followed from birth through 3 years of age, when a diagnosis of autism can be determined. Identifying earlier biological risk factors for autism is an ongoing goal for scientists because earlier identification and diagnosis could lead to earlier intervention and better outcomes. Our results suggest that cord blood, which is frequently discarded at birth, could serve as an important time capsule of DNA methylation differences in autism. Despite no behavioral signs of autism at birth, we were able to identify differences in DNA methylation of certain genes expressed in the brain in babies who were diagnosed with autism three years later. Many of these genes also overlapped with those known to increase genetic risk for autism. Because autism occurs at different rates in boys and girls (about four boys are diagnosed for every one girl), we were interested in seeing whether there were any differences in DNA methylation between boys and girls. We made the important discovery that genes with altered DNA methylation in autism were overrepresented on the X chromosome, which is one of the chromosomes that determines a child’s biological sex (females have two X chromosomes while males have one X and one Y chromosome). Having a second X chromosome as a ‘back up’ may be protective in females and could contribute to why fewer girls have autism. Promising behavioral interventions in autism are most effective when started early. While it is still too early to use DNA methylation to diagnose autism in babies, the results of this study suggest the possibility that a newborn screen could be developed to identify babies at highest risk for developing autism.
Gestational age is related to symptoms of attention-deficit/hyperactivity disorder in late-preterm to full-term children and adolescents with Down syndrome
By Laura del Hoyo Soriano
This study, published last month in Scientific Reports, found that earlier gestational age was related to later inattentive and hyperactive/impulsive symptoms in 105 children and adolescents with Down syndrome, after controlling for several socio-demographic and clinical variables. The study included children born at 35 weeks gestation or later. In addition, greater ADHD symptoms were found in the younger participants and the degree of cognitive delay was not related to ADHD symptoms. Given the high prevalence and variable presentation of ADHD symptoms in the Down syndrome population, we thought that it was important to identify factors related to this variability as a key challenge to understanding mechanisms underlying ADHD in Down syndrome. For example, the fact that gestational age is also related to ADHD symptoms in the general population suggests that ADHD is not inherent in Down syndrome, but more likely the result of additional factors. We also found that younger children with Down syndrome generally showed more ADHD symptoms than older ones, which is, again, in line with what is reported in the general population. Finally, the fact that the degree of cognitive delay was not related to the main symptoms of ADHD suggests that hyperactivity, impulsivity and inattention-related symptoms in those with Down syndrome are not a consequence of the intellectual disability; therefore, ADHD difficulties may be best conceptualized as comorbid challenges. Our take home message is that more attention needs to be paid to the care and follow-up of infants born pre-term, even those between 35 and 39 weeks, and perhaps even more so for those with Down syndrome since the implications for early interventions could be significant.
Studies focus on environmental health risks and neurodevelopmental disorders
By Jill Silverman
We highlight findings from a unique collaboration between MIND Institute faculty members Jill Silverman, associate professor in the Department of Psychiatry and Behavioral Sciences, whose primary focus is rare genetic mutations that cause intellectual disability, and world-renowned neurotoxicologist, Pamela J Lein, professor in the Department of Molecular Biosciences. Their recent findings about the association between traffic-related air pollution and neurodevelopmental disorders were published in Translational Psychiatry.
Converging evidence from research on environmental health and epidemiology suggests that air pollutants from high traffic and long commutes adversely affect neurodevelopment. Multiple epidemiological studies from various urban locations have reported associations between exposure to air pollution and neurodevelopmental conditions such as autism and ADHD. Silverman and Lein used a rat model to study the effects of breathing toxic traffic air on developmental milestones, social behavior, activity, and brain pathology. In one study, the team discovered that living in close proximity to highly trafficked roadways during early life alters early development in rats. They identified several delays in attaining developmental milestones, including delayed psychomotor reflexes and abnormal locomotor activity. Rat pups exposed to near-roadway traffic pollution also had reduced ultrasonic vocalizations, which are a form of social communication between rodent pups and their mothers, as well as altered social play.
In a companion study, the team investigated the effects of traffic-related air pollution on brain development and found the air pollution-exposed group had increased inflammation markers in key brain regions. In addition, there were sex differences in the effects of exposure to air pollutants. Male and female pollution-exposed animals exhibited different profiles of inflammatory cytokines. Collectively, these data indicate that exposure to real-world levels of traffic-related air pollution during gestation and early postnatal development can affect neurodevelopmental growth and behavior. Results from these studies support epidemiological evidence of an association between air pollution and neurodevelopmental conditions. Animal models provide the opportunity to investigate the mechanisms underlying the association.
Collaborative studies utilizing interventional genetics to develop therapies for neurodevelopmental disorders
By David Segal
Neurodevelopmental disorders such as Angelman, Dup15q, Jordan and Rett Syndromes and CDKL5 deficiency are caused by spontaneous mutations in a single gene and result in an intense and debilitating quality of life for patients and caregivers. Affected individuals have severe intellectual disabilities, lack communication, have prevalent, pervasive seizures and severe sleep disruption.
The Interventional Genetics team, composed of MIND Institute IDDRC investigators, David Segal, professor in the Department of Biochemistry and Molecular Medicine, Kyle Fink, assistant professor in the Department of Neurology, and Jill Silverman, associate professor in the Department of Psychiatry and Behavioral Sciences, are focused on leveraging their expertise to bring curative therapies to these rare, genetically linked disorders. The Fink and Segal labs have developed gene editing tools in cell models to fix the genetic deficit. These advances are now being translated into therapeutic platforms evaluated in animal models by the Silverman lab. The group develops novel therapeutics targeted to the underlying genetic condition by either binding to the DNA directly or producing a novel compound that acts on the DNA to start the process of transcription (i.e., making its product). They also use novel technologies like CRISPR/Cas9. The team has utilized their knowledge around DNA binding, not to cut DNA, which they worry could cause off-target or undesirable side effects, but rather to modify gene expression to provide a molecular rescue. Publications from the group indicate that these technologies are effectively rescuing the genetic problem of Angelman Syndrome and CDKL5 Deficiency Syndrome, proving that gene therapy is a reality and no longer science fiction.
The team then translates the gene editing techniques into genetic mouse and rat models of the various neurodevelopmental disorders. This allows them to test the effects of the gene editing in therapeutically relevant ways. They analyze functional improvements in the animal models pre and post gene editing, testing behavioral and neurophysiological assays that are relevant to each of the conditions. The coordinated efforts of Segal, Fink and Silverman, as a team, work toward the common goal of bringing ‘curative’ therapies to people with rare genetic disorders.
Trajectories of Autism Symptom Severity Change During Early Childhood
by David Amaral
While Autism Spectrum Disorder (ASD) is commonly considered to be stable throughout life, evidence now indicates that at least some individuals demonstrate substantial changes in symptoms and functioning over time. To better characterize these changes, we evaluated autism symptom severity change in children diagnosed with ASD. One hundred and twenty five children were assessed at approximately 3 years of age (Time 1) and again at about 6 years (Time 3) for autism symptom severity, IQ and adaptive functioning. Each child was assigned a change score, representing the difference between ADOS Calibrated Severity Scores (CSS) at Times 1 and 3. Children were grouped according to shared patterns of change. A Decreased Severity Group (28.8%) decreased by 2 or more points; a Stable Severity Group (54.4%) changed by 1 point or less; and an Increased Severity Group (16.8%) increased by 2 or more points. Girls showed a greater tendency to decrease in severity and a weaker tendency to increase in severity than boys. Both the Decreased Severity and Stable Severity groups made IQ gains over time, while the Increased Severity Group did not. At Time 3, the Decreased Severity Group had higher mean IQ scores and adaptive functioning levels than the other groups. Surprisingly, the Increased Severity Group had the lowest initial autism severity level. However, by Time 3, the Increased Severity Group had the highest severity level and the lowest IQ and adaptive functioning scores. There was no clear relationship between intervention history and membership in the groups. These findings show autism symptom severity can change substantially during early childhood, and patterns of change are associated with factors such as sex, IQ and adaptive functioning. Study authors include Einat Waizbard-Bartov, Emilio Ferrer, Gregory Young, Brianna Heath, Sally Rogers, Christine Wu Nordahl, Marjorie Solomon, and David Amaral.
This study, published in January 2020 in the Journal of the American Academy of Child & Adolescent Psychiatry, found that preschool-aged girls with autism face greater challenges than autistic boys with emotional and behavioral problems that go beyond the core symptoms of autism. Moreover, the size of the amygdala, a brain region involved in emotion regulation and threat detection, is associated with these symptoms more so in girls than in boys. Researchers thought that it was important to identify children who have these additional problems because they may be at higher risk for developing co-occurring conditions such as anxiety or ADHD at later ages. They found that overall, about one quarter (27%) of 3-year-olds with autism experience these additional emotional and behavioral problems. Surprisingly, almost half of the girls in the study were in this subgroup, compared to only 20% of boys. The researchers also found that the size of the amygdala was associated with these problem behaviors in girls but not in boys with autism. This finding suggests that even though outwardly, boys and girls may have similar behaviors, the underlying brain mechanisms might be different. This is important to keep in mind when examining causes of autism as well as developing targeted treatments. We cannot assume that boys and girls with autism are the same, in fact, the study suggests that there are differences in both their behaviors and underlying brain mechanisms. The take-home message from this study is that parents should be aware that their autistic girls may be facing greater challenges with emotional and behavioral problems that may be warning signs for anxiety and ADHD. On a hopeful note, there are treatments for these types of problems – if we can detect them early, we may be able to intervene earlier and improve outcomes in later childhood and adolescence. Study authors include Christine Wu Nordahl, Ana-Maria Iosif, Gregory S. Young, Alexa Hechtman, Brianna Heath, Joshua K. Lee, Lauren Libero, Vanessa P. Reinhardt, Breanna Winder-Patel, David G. Amaral, Sally Rogers, Marjorie Solomon, and Sally Ozonoff.