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.
Building a brain requires intricate cross-talk between various cell types: listening in may offer clues about neurodevelopmental disabilities
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
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
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
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
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
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
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.