Functional Development Abnormalities Associated with Genetic Risk of Bipolar during Infancy

2013 Award: $71,302

Bipolar disorder (BD) is a common psychiatric illness affecting ~1% to 2% of the population, which is characterized by affective symptoms varying between depression and mania. However, there is a profound lack of knowledge regarding the brain’s functional disruption mechanism underlying this disorder, especially during early childhood which is increasingly recognized as a critical time for this neurodevelopmental disorder. The use of neuroimaging technology to study infants with a genetic risk of BD (biological mother diagnosed with BD) provides a wonderful opportunity to investigate the earliest functional disruption mechanisms related to this disorder, which is critical for the derivation of new early diagnosis and intervention strategies.

Dr. Wei Gao, Assistant Professor of Radiology and Biomedical Imaging Research Center (BRIC) at the University of North Carolina at Chapel Hill (UNC-CH), has developed a dedicated framework to study the brain’s functional network development during the critical first two years of life using the resting-state functional magnetic resonance imaging (rsfMRI) technique. In this project, he will: 1) compare infants at high risk of BD with normal controls to delineate the potential abnormalities in the brain’s functional interaction mechanism at the regional, network, and whole brain system level; and 2) correlate earlier functional abnormalities with prospective measures of behavior to characterize the predictive power of earlier imaging phenotypes for behavioral outcomes.

Dr. Gao expects that high-risk BD infants would show early signs of abnormalities in different mode-regulating circuits as well as a disrupted whole brain efficiency. “The delineation of the early brain’s abnormal working mechanism associated with BD”, says Dr. Gao, “would profoundly improve our understanding of this debilitating disorder and has the potential for imaging-based early diagnosis of risk factors which is critical for more effective intervention.”

Wei Gao, PhD

In this study, we will utilize data from 37 infants at high risk of bipolar (biological mother diagnosed with bipolar) which were longitudinally scanned using rsfMRI at 0, 1, and 2 years of age and 142 normal developing controls scanned at the same age intervals. By carrying out a longitudinal study combining advanced neuroimaging and detailed neurobehavioral assessments, the proposed study would be the first to unveil the potential abnormal functional network development associated with bipolar disorder during an unstudied period from neonates through age two. Specifically, we propose to achieve the following two aims.
Aim 1: Characterize the abnormal development of specific functional circuits associated with genetic risk of bipolar and its behavioral correlations during the first two years of life. Various bipolar-related functional circuits associated with emotion, especially those centered at the amygdala, orbitofrontal cortex, insula, temporopolar cortex, and anterior cingulate cortex, will be systematically studied. Moreover, given the reported relevance of motor and cognitive functions in BD, circuits centered at motor-sensory cortices and dorsal lateral prefrontal cortex will also be studied. The longitudinal growth trajectories of the local specialization and long-range integration of all circuits will be delineated and their relationship with different domains of behavior including gross and fine motor, receptive and expressive language, as well as visual spatial working memory will be quantified. We hypothesize: (1) BD-related functional circuits will show abnormal growth trends in infants with a genetically high risk of BD compared with normal controls; (2) functional circuit abnormalities will be significantly associated with corresponding behavioral measurements.

Aim 2: Characterize the abnormal development of whole brain organization properties associated with genetic risk of bipolar and its behavioral correlations during the first two years of life. Building on individual functional circuits, the whole brain operates as an integrated system. Recent developments in quantitatively characterizing the information processing properties of the whole brain system based on graph-theoretical analysis have greatly improved our understanding of normal brain functioning. More importantly, disruptions of such whole brain graph measures have been reported in different brain disorders, including BD. Therefore, we will characterize the potential abnormal development of graph properties associated with genetic risk of BD in this aim.

Overall, the proposed study represents the first step in trying to delineate the brain circuit abnormalities associated with genetic risk for bipolar disorder during infancy. Insights from this study will not only significantly improve our understanding of the developmental pathophysiology of bipolar disorder, but will also provide far-reaching benefits for early identification of risk factors and intervention.