2015 — 2018 |
Joshi, Shantanu H. |
K25Activity Code Description: Undocumented code - click on the grant title for more information. |
Modeling of Joint Face-Brain Dysmorphology in Fetal Alcohol Spectrum Disorder @ University of California Los Angeles
? DESCRIPTION (provided by applicant): Fetal alcohol spectrum disorder (FASD) is caused due to teratogenic insults to the brain resulting from the effects of alcohol exposure, in utero, and is estimated to occur in 1% of births. It is an important public health concern as it is completely preventable, yet at the same time is the leading known cause of neurodevelopmental disability. A more extreme form of this disorder is also known as fetal alcohol syndrome, whose key defining characteristics are facial dysmorphology, pre- and post-natal growth deficiency, and central nervous system (CNS) dysfunction. Presently, almost all neuroscientific studies focusing on this disorder have studied the face, and the brain separately. Furthermore, at the lower end of this spectrum disorder, the CNS deficits may be present without the visually observable facial malformations leading to a potential under- diagnosis. The objective of the proposed research is to overcome these limitations by combining the facial dysmorphic features, and the neurostructural abnormalities in a common shape analysis framework. Specifically, this proposal aims at integrating information from different sources such as structural neuroimaging using MRI and DTI, and 3D photographs of the face. The proposed research will i) conduct a joint morphometric analysis for the brain and face by incorporating facial landmarks, and cortical features, ii) derive combined face-brain imaging biomarkers for the purpose of FASD classification, iii) collect new longitudinal data for charting the neurodevelopmental and facial progression and deficits, and finally iv) investigate the structural connectivity mapping of the brain and face using DTI modalities. This work will lead to a better understanding of the intricate morphological relationships between the brain and the face in FASD, and further promote early detection strategies above and beyond what is achieved by the current diagnostic criteria alone. The candidate's formal training will take advantage of the rich morphometric and imaging experience of his mentors, as well as alcohol related research and neuroimaging resources at UCLA and CHLA, and will include eight formal training courses, two intensive workshops and regular weekly seminars designed to augment the candidate's prior image analysis experience with new knowledge in alcohol research, neurodevelopmental, and craniofacial anatomy, helping him to develop the skills for conducting an independent longitudinal FASD project.
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2019 — 2021 |
Donald, Kirsty Joshi, Shantanu H. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Tracking and Prediction of Early Brain-Face Biomarkers of Prenatal Alcohol Exposure From Neonates to Children @ University of California Los Angeles
Maternal substance use disorders are a substantial public health concern and the neurological consequences of prenatal exposure are a major threat to the long-term health of offspring. Globally, prevalence of Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Spectrum Disorders (FASD) is between 2-7 and 20-50 per 1000, respectively. By contrast, in certain high-risk communities in South Africa, prevalence is reported to be as high as 63 and 155 per 1000, respectively. Though prenatal alcohol exposure (PAE) is known to affect the central nervous system, to date, little data exists in respect of the impact of PAE in early childhood, before both higher-level brain networks are established and other potentially confounding post- natal environmental influences have come into play. For neurodevelopmental disorders, studies have consistently shown that early intervention, based on detection and targeted interventions, leads to better long-term outcomes. We aim to address this precise gap in knowledge by imaging the brain and 3D face across the FASD continuum to investigate early biomarkers, trajectories and functional correlates of PAE in a cohort followed prospectively from birth to age 6 years. Data: Our cohort includes a well characterized subsample of children (PAE and healthy controls) enrolled in the Drakenstein Child Health Study in Cape Town, South Africa, who have been scanned as neonates and at 2-3 years of age. Preliminary published data shows highly significant relationships between PAE and regional gray and white matter changes, already discernible in newborns, well before the age FASD is typically diagnosed. An additional longitudinal assessment at 6-years will yield a unique FASD sample with 3 distinct time points (infants, toddlers and children), allowing characterization of brain and face morphology and brain structure and function in this previously understudied early developmental period. This proposal addresses fundamental gaps concerning the presence, timing and regional specificity of altered brain morphology and structural and functional connectivity in association with the effects of PAE on the developing brain from birth to 6 years, and the relationships with facial dysmorphology. The research team has successfully gathered data from the proposed cohort as neonates and at 2?3 years of age. The benefits of extending this research to a subsequent imaging time-point, with a larger range of developmental and neurobehavioral assessments, provides an unprecedented opportunity to determine longitudinal effects of PAE on the trajectory of the developing brain in these critical early years, the links between neural and face predictors of PAE and the long-term clinical significance of these findings. This research will illuminate early neurodevelopmental mechanisms leading to subsequent behavioral and neurological disturbances, which may allow opportunities for targeting interventions when brain plasticity is still relatively fluid. This project might also lead to new strategies for early diagnosis using both face and brain biomarkers.
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2021 |
Joshi, Shantanu H. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Brain Connectivity Signatures of Behavior and Cognition in Duchenne Muscular Dystrophy @ University of California Los Angeles
PROJECT SUMMARY Therapies (drugs and genetics-based) in Duchenne Muscular Dystrophy (DMD) are targeted towards improving muscle function and arresting the progression of disease. As a result, the skeletal and even the cardiac musculature are well researched. However, studies focusing on brain structure have been sparse even though varying cognitive deficits have been reported across the spectrum. With advancing treatments, such as exon skipping, as well as steroid alternatives such as VBP15 moving to human trials, there is renewed optimism about improving the life expectancy and quality of patients with DMD. Consequently, a better understanding of the brain structure and its putative link with cognitive function becomes important. Our plan is to collect pilot brain imaging data in 36 children (24 children with DMD and 12 healthy controls, both 8~21 years) using cutting-edge imaging protocols from the Human Connectome Project. Our overarching goal is to identify a brain connectivity biomarker of cognition in DMD by investigating the potential of structural neuroimaging signatures and functional connectomic motifs and relating them to gene expression profiles in the brain.
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