Budhachandra Khundrakpam, PhD
Impact of substance use on adolescent brain development and mental health outcomes
It is widely accepted that adolescence is a critical developmental period with dramatic changes in brain structure and function. As adolescents transition from childhood to adulthood, they enjoy novel experiences, take more risks, thus testing limits. Although crucial for healthy development; but certainly, for many adolescents, it also comprises several unsafe behaviors such as experimenting with addictive substances including alcohol, tobacco, marijuana and other drugs. Additionally, since important brain regions are not yet fully developed, those substances may have lasting effects on the adolescent brains and later mental health outcomes.
Advances in neuroimaging have led to better understanding about the impact of substance use on the brain; however, several questions remain concerning how substance use alters adolescent brain trajectories, and consequently how they interfere with later health outcomes such as addiction and mental illnesses. Prospective, longitudinal assessment of adolescents’ neuroimaging data along with concurrent measures of substance use and mental health measures will allow us to define normative neurodevelopmental trajectories with which we can study the interactive relations between substance use, brain development and later mental health outcomes.
We are developing frameworks for assessing normative trajectories of cortical development in adolescents, which will allow us to evaluate deviant cortical trajectories with substance use. The study is designed to address three specific questions in 9-year old children (who will be followed through the next ten years): i) whether children with substance use show deviant neurodevelopmental trajectories; ii) which brain regions show the deviant neurodevelopmental trajectories; and iii) whether the deviant neurodevelopmental trajectories predict later mental health outcomes.
Integrative genomic and neuroimaging analysis of autism using clinical and general population
Autism spectrum disorders (ASD) comprise of a collection of neurodevelopmental conditions characterized by difficulties with social interactions, verbal and nonverbal communication, and repetitive behaviors. ASD is highly prevalent (~ 1 in 59 individuals) and highly heritable. ASD is conceptualized as a brain disorder, with several neuroimaging studies showing cortical alterations in individuals with ASD compared to healthy individuals (controls, CTL). However, these studies so far have, as with other traditional approaches in psychiatric imaging research, compared cases to controls (yes/no for ASD), and ignore the possibility of intermediate outcomes.
In contrast, an emerging viewpoint suggests ASD as a continuum with a normal distribution of autistic tendencies in the general population, where a full diagnosis is at the severe tail of the distribution. For instance, considerable variability in social communication and social interaction capabilities has been observed in the general population. Additionally, subthreshold autistic traits have been observed in unaffected siblings and family members of people with ASD. The idea of continuum models for phenotypes is not new and has been shown for phenotypes that are easily quantifiable (such as intellectual disability). Treating ASD as continuum will enable study of intermediate levels of ASD in larger more accessible samples. This is particularly important since ASD studies are usually of small sample size, thereby limiting our capability to detect robust brain biomarkers. A continuum model of ASD in the general population will allow investigation of the underlying mechanisms of ASD without the potential confounding effect of clinical state. Such approach has been beneficial for depression, where studying subclinical levels of depression largely highlights similar genetic mechanisms. We propose using a similar approach in ASD. However, traditionally such approach is limited by the fact that not many biological cohorts have included a continuum measure of ASD.
The main objective of the project is to study the genetic potential for ASD in general population using polygenic risk scores. The polygenic risk score (PRS) for ASD is made up of the additive effects of individual single nucleotide polymorphisms (SNPs), which collectively capture the variance explained by common alleles. This way, the brain patterns of autistic-like traits can be studied in any cohort, with genetic and brain information available. The next objective is to investigate whether the neural correlates of high PRS for ASD in general population overlap with ASD-related cortical abnormalities using an independent clinical dataset comprising of healthy controls (CTL) and individuals with ASD.
