Despite the significant morbidity and mortality associated with bipolar disorder, the neurophysiological basis of the development of this illness is poorly understood. Adolescence is the most common period of onset of bipolar disorder. Moreover, offspring of bipolar parents have an elevated risk of developing bipolar disorder compared with the general population. Therefore, one approach toward clarifying neurodeveloprriental models of the early progression of bipolar disorder and identifying potential neurobiological predictors of incipient mood episodes is to study young subjects who are at risk for developing bipolar disorder (i.e., have a bipolar parent), but do not yet have a mood disorder themselves. Bipolar disorder is characterized by disruption of mood and attention. The anterior limbic network, which involves the ventral prefrontal cortex, thalamus, amygdala, and striatum, appears to regulate these these processes. Consequently, we hypothesize that the symptoms of bipolar disorder arise from dysfunction within this network. Specifically, functional imaging (fMRI) studies suggest that the anterior limbic network may be excessively activated in bipolar patients, thereby producing the symptoms of this condition. Additionally, magnetic resonance spectroscopy (MRS) studies suggest that hypermetabolism may underlie the excessive anterior limbic activation. Specifically, MRS studies have found that bipolar patients exhibit excessive glutamate (Glu) and myoinositol (ml) concentrations compared with healthy subjects. With these consideration in mind, the goals of this study are: 1) To use fMRI and 1H MRS to assess functional and metabolic anterior limbic abnormalities in adolescent and young adult offspring of bipolar parents (at-risk);2) To use fMRI and 1H MRS to evaluate functional and metabolic anterior limbic abnormalities as potential markers for incipient mood disorders in at-risk adolescents and young adults;and 3) To examine the progression of anterior limbic abnormalities in at-risk adolescents and young adults who develop a mood disorder. In order to accomplish these aims, we will acquire neurometabolic (MRS) and neurofunctional (fMRI) measurements in 140 subjects without any mood disorder and with a bipolar parent (at-risk, AR) and 40 subjects without a first-degree relative with a mood disorder (healthy, HC) for the proposed longitudinal study. Comparisons between offspring of bipolar and healthy parents will define baseline fMRI and 1H MRS abnormalities and longitudinal follow-up of both groups will identify predictors and markers of incipient mood episodes, as well as neurodevelopmental changes that are unique to the development of mood episodes in those at risk for bipolar disorder (Center Goals 1-3). We believe this information may ultimately, clarify neurophysiological models of bipolar disorder (Center Goal 1) and provide neurophysiological treatment targets in order to prevent the onset of bipolar disorder in those with a familial risk for developing the illness (Center goals 2 &3).
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