Connectivity Between White and Gray Matter Abnormalities in Pediatric Bipolar Disorder: A Developmental Model of Brain Pathophysiology

Lay Summary

Using Imaging to Understand the Brain Basis of Bipolar Disorder in Children

Researchers will use fMRI to pinpoint areas in the brain’s gray matter (nerve cells) involved in childhood bipolar disorder, and use DTI to identify the white matter areas (the cells’ communication cables) that connect these affected gray matter regions.

The investigators will enroll 30 newly diagnosed manic children and teens (aged 10-20) with bipolar disorder who have not yet begun treatment, and 30 healthy “control” participants to undertake fMRI imaging and DTI imaging to investigate brain function.  The fMRI will examine blood flow changes, while DTI will assess tracts of nerve axons (the communication cables). These complementary methods will identify affected brain cell areas and the neural pathways that connect these affected regions.  They hypothesize that activity will be reduced in brain areas involved in cognitive processing, while activity will be increased in areas involved in affective processing, such as the amygdala. This dysfunctional “top-down” regulation, they suggest, will impair the interface between cognitive and affective neural networks.  They also hypothesize that the axon fiber tracts (white matter) that connect these frontal and limbic areas will show damage.  They speculate that dysregulated affect triggered by negative emotions also interferes with cognitive systems.

Significance:  The findings may identify biomarkers of pediatric bipolar disease, which could contribute to early diagnosis and intervention, provide a means for predicting responses to various types of treatment, and lead to a better understanding of the workings of emotion.

Abstract

Connectivity Between White and Gray Matter Abnormalities in Pediatric Bipolar Disorder: A Developmental Model of Brain Pathophysiology

Objective: Pediatric bipolar disorder (PBD) has extremely high morbidity and mortality. Understanding the abnormalities in brain function is the first critical step in identifying the biomarkers of pathophysiology and treatment predictors. Together, functional magnetic neuroimaging (fMRI) and diffusion tensor imaging (DTI) act as complementary methods in pinpointing the abnormalities in gray matter regions and white matter tracts in PBD patients.

Aims:
1.To characterize interfacing cognitive and affective circuitries in PBD using fMRI technology.
2. To assess axonal organization and/or integrity, myelinization and fiber tract coherence of white matter fiber tracts that link the areas connecting fronto-limbic circuitry identified on fMRI using DTI.

Methods: Subjects include 30 manic, never-treated bipolar disorder type I PBD patients age 10-20 years and 30 healthy adolescents matched for age, gender, educational level, IQ, socioeconomic status, and ethnic background. Data will be collected using 3T scanner. Tasks for the fMRI study include an N-Back task with emotional faces to emotionally challenge subjects while performing a working memory task with facial stimuli; a Stop signal task to probe response inhibition; and an Affective Stroop task to probe the impact of negative emotions on attention. The fMRI data processing involves FIASCO software (http://www.stat.cmu.edu/~fiasco/) for motion correction and preprocessing which will yield t-maps.

We will use AFNI software to superimpose activation maps on anatomic images, to create group statistical maps and perform group statistical comparisons in Talairach space. A set of DTI images will be acquired along with the fMRI data acquisition and analyzed using customized software. For each subject, fractional anisotropy (FA), increased apparent diffusion coefficient (ADC), and decreased fiber coherence index (FCI) maps will be computed, and region of interest (ROI) analyses will be performed on the five white-matter fiber tracts bilaterally with the seed voxel being in the ROI that defines the gray matter ROI.

Using these methods, we will test the hypothesis that activation of higher cortical areas of cognitive and affective processing, namely the dorsolateral prefrontal cortex (DLPFC) and ventro lateral prefrontal cortex (VLPFC) will be reduced, and activation of subcortical regions of affective processing, such as amygdala, will be increased in individuals with pediatric bipolar disorder (PBD). This dysfunctional top-down regulation will impair the cognitive and affective circuitry interface. We hypothesized that the white matter fiber tracts connecting these fronto-limbic areas such as anterior corona radiate (ACR), inferior longitudinal fasciculus (ILF) and superior longitudinal fasciculus (SLF) will demonstrate decreased FA, increased ADC, and decreased FCI.