The VKC recognizes the vital importance of supporting early-stage, innovative research in intellectual and developmental disabilities (IDD) that has the potential to have meaningful impact on people with IDD and their families. Oftentimes, such early-stage research needs initial seed funding to support the development of sufficient evidence in order to develop competitive applications for larger externally funded grants. With this in mind, each year the VKC IDDRC provides pilot grant funding through two internal grant mechanisms: Nicholas Hobbs Discovery Awards and Director’s Strategic Priorities Grants (DSPG). Hobbs Awards are named for the first director of the VKC and have been supported through generous philanthropic donations to the VKC. Since 1998, 92 awards have been given to VKC Members. These awards support IDD pilot studies that bring together multidisciplinary teams using innovative methods. Hobbs Awards have been remarkably successful in the development of foundational work subsequently supported by externally funded grants. The DSPG mechanism, initiated in 2017 by VKC director Jeffrey Neul, M.D., Ph.D., provides pilot funding directed toward annually defined targeted IDDRC priority areas such as neuro-engineering, neurodiversity, and utilization of advanced technologies such as artificial intelligence or neuromodulation, with the goal of expanding methods and researchers targeted towards IDD-related inquiry. Read on to learn about some of the recent pilot studies made possible by these grants.
My team has been evaluating the development of early responses to sensory stimuli such as sights and sounds in the environment (we call this “sensory responsiveness”) and links with developmental outcomes like language in infants at increased likelihood for the development of autism. This relation is relatively understudied but has great potential to further our understanding of the emergence of sensory differences in autism and of the extent to which such alterations may contribute to language learning challenges in autistic individuals.
Unfortunately, our ongoing longitudinal study was significantly disrupted by the COVID pandemic in 2020. Funding support from a VKC Hobbs Discovery Award allowed us to complete comprehensive diagnostic assessments (in some cases even traveling across the country to collect data from families who had moved over the course of the pandemic!) and to obtain “clinical best estimate” outcomes for ALL of participants who had missing data. The information gained due to the Hobbs funding provided empirical support for the initial hypothesis we put forth in a prior National Institutes of Health (NIH) grant, enabled dissemination of findings for longitudinal links between early sensory alterations and developmental outcomes of infants at high and low likelihood for a future diagnosis of autism, and provided the necessary preliminary data to support a successful NIH R01 grant that started in 2022. Thank you, VKC!
Miriam Lense, Ph.D.
A music-based telehealth parent-mediated approach to supporting early social communication development Project PI: Miriam Lense, Ph.D. (Otolaryngology)
In young children (toddlers/preschool aged) with autism spectrum disorder (ASD), there is a critical need to enhance the development of early social communication skills. An intervention that could be easily taught to parents and then effectively delivered by parents to their children would enable widespread use. Recent evidence from our team and others suggests that highly rhythmic and predictable multimodal communication, such as provided by child-directed singing and musical games, helps support important fundamental social skills such as imitation and social attention in ASD. Song and music-based games may provide a vehicle for delivering evidence-based naturalistic developmental behavioral interventions (NDBIs) for children with ASD as NDBIs already utilize predictable, structured scenarios that employ repetition and routine to support children’s social behavior.
The VKC Hobbs Discovery Award to our group provides funding to establish the feasibility of the use of a telehealth-based, parent-mediated adaptation of music-enhanced Reciprocal Imitation Training (tele-meRIT). Current findings support the feasibility of this novel approach, with all parents being able to effectively and faithfully deliver the meRIT strategies during parent-child interactions, increasing the musicality of their parent-child interactions, and reporting positively on their and their child’s experience with the program.
These findings were shared at -both the International Society for Autism Research (INSAR) and the Society for Music Perception and Cognition (SMPC) in 2022, and a manuscript based on these findings is in preparation and expected to be submitted for publication shortly.
Autumn Kujawa, Ph.D.
Neurocognitive effects of neonatal opioid withdrawal syndrome Project PI: Autumn Kujawa, Ph.D. (Psychology and Human Development)
The opioid crisis has resulted in increasing rates of in utero opioid exposure, raising concerns about the potential long-term effects to babies born after such in utero exposure. Unfortunately, relatively little is known about the extent to which opioid exposure impacts cognitive development beyond the effects of associated factors that may co-occur with parental opioid use (e.g., psychosocial stressors, foster care and adoption, lower socioeconomic status). In February 2020, we were awarded a VKC Hobbs Discovery Grant to examine neural and behavioral markers of cognitive control in preschool-aged children (3 to 5 years old) with and without histories of prenatal opioid exposure. The COVID-19 pandemic required adaptations to our research methods such as completing assessments using videoconferencing techniques, but we were able to incorporate extensive safety protocols to minimize the spread of COVID-19 and complete electroencephalogram (EEG) assessments on participants starting in the fall of 2020. The Hobbs funding supported the ability to flexibly implement these adaptations and exceed our recruitment goals, enrolling 21 children with prenatal opioid exposure and 23 comparison children in the study.
We found that children with prenatal opioid exposure exhibited a reduced error-related negativity (ERN) component of the EEG when making an error on a developmentally appropriate Go/No-Go task. This suggests difficulty with cognitive control, specifically performance monitoring, in young children with opioid exposure. This effect persisted when accounting for income-to-needs ratio, age, and gender, suggesting that it is not fully explained by other factors. Interestingly, no significant effects of prenatal opioid exposure were observed on behavioral measures of cognitive control, suggesting that EEG may detect more subtle alterations in cognitive functioning, but children with prenatal opioid exposure did experience elevated emotional and behavioral problems across domains compared to children without prenatal opioid exposure.
The findings from this work have contributed to a number of manuscripts in preparation and supported the submission of a grant application to the National Institute on Drug Abuse.
Loss-of-function mutations in the X chromosome-linked MeCP2 gene result in a neurodevelopmental disorder known as Rett syndrome (RTT). MeCP2 is a transcription factor that functions as a molecular bridge to “read” methylation marks on DNA and modulate gene expression. MeCP2 mutations lead to symptoms such as loss of spoken language, repetitive hand movements, gait problems, seizures, and breathing irregularities. Excitingly, symptoms in mouse models of RTT can be reversed by correcting the genetic abnormality, even after symptom onset, which has led to the exploration of novel therapeutic approaches. Unfortunately, one challenge that has plagued clinical development for neurodevelopmental disorders is the lack of objective biomarkers and outcome measures, making assessments of efficacy complex.
In our VKC DSPG project, we used neurophysiological assessments such as EEG and auditory event related potentials (AEPs) as pharmacodynamic biomarkers to serve as translational outcome measures to support both preclinical research and clinical trials for RTT. Overall, our current findings suggest that potentiation of the M1 muscarinic receptor can functionally improve neural circuit synchrony to auditory stimuli in RTT animals, but that the effect is limited to low doses. We anticipate that this acute response could represent a pharmacodynamic biomarker useful for dose finding and guiding future pre-clinical or clinical trials.
We recently presented these findings at the 2022 Society for Neuroscience meeting in San Diego and are currently preparing this work for publication.
Alan Lewis, M.D., Ph.D.
Exploring memory circuit changes in neurodevelopmental disorders Project PI: Alan Lewis, M.D., Ph.D. (Psychiatry & Behavioral Sciences and Neurology)
The focus of our project is understanding how genetic risk for neuropsychiatric disorders affects hippocampal structure and function. Our goal is to develop new methods to improve cognition, especially learning and memory, in people with neurodevelopmental disorders.
Toward this goal, the VKC award has supported our studies in a mouse model of 22q11.2 deletion syndrome, which confers significant risk for schizophrenia, autism, and learning disabilities. We have found that mossy cells, which are neurons in the hippocampus critical for novelty detection and pattern separation, are reduced in number in adult 22q11.2 mice, especially in the ventral hippocampus. To investigate potential molecular causes of this neuron loss, we have performed RNA-sequencing studies from the ventral hippocampus, and found reduction in two genes, Fos and JunB, that are components of the activator protein 1 transcription factor. This transcription factor is important for linking gene response to many external stimuli, and we are currently investigating whether this pathway is involved in our reduced mossy cell findings.
In parallel to these studies, we have worked on identifying novel methods to pharmacologically stimulate ventral mossy cells, both as a neuroprotective strategy and to try and restore lost functional effects. This work has found the glucagon-like peptide-1 receptor (GLP-1R) is highly and selectively expressed on ventral mossy cells, and that systemic administration of GLP-1R agonist can activate the ventral hippocampus. The studies were recently published in the journal Hippocampus.
The above findings as well as several other experiments have helped to support the preparation of R01 and R21 grant proposals to the National Institute of Mental Health and will contribute to the publication of future manuscripts as well. We sincerely appreciate the support of the VKC in supporting our research.
