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Author(s): Dev, Sheena Isha | Advisor(s): Eyler, Lisa T | Abstract: Rationale: Bipolar disorder (BD) is associated with deficits in executive functions and processing speed, yet little is known about risk factors that contribute to the development and sustainment of these deficits. Studies have demonstrated chronic inflammation, characterized by high levels of pro-inflammatory interleukin-6 (IL-6) and C-reactive protein (CRP), and reduced physical activity in BD. Both chronic inflammation and low physical activity are linked to cognitive deficits in other clinical populations, though less is known about these associations in BD. The current dissertation project proposed to a) explore associations between cognition, inflammation and physical activity in BD; and b) examine potential lagged influences between variable mood symptoms, a primary clinical feature of BD, and the amount of daily physical activity exhibited.Design: Thirty-eight BD and 68 healthy comparison participants underwent psychiatric interview, neuropsychological assessment of executive functioning and processing speed, and a 15ml blood draw analyzed for blood serum concentration of IL-6 and CRP. For the following two weeks, participants submitted thrice-daily mood ratings on a smartphone device and wore an actigraphy watch designed to measure physical activity. Linear regression analyses determined associations between inflammation, cognition, and physical activity. Mixed effects linear regression determined the impact of mood on subsequent levels of physical activity. Results: BD patients exhibited worse executive functioning and processing speed, less physical activity, and greater levels of IL-6 and CRP; higher BMI in the BD group appeared to explain group differences in inflammation and physical activity. There were no significant associations between inflammation, physical activity, and cognition in BD. Further, mood ratings did not predict subsequent levels of physical activity exhibited by BD individuals. Conclusion: This study is among the first to examine relationships between inflammation, physical activity, and cognition in BD. Results suggest that inflammation and physical activity are not significant correlates of cognition in middle-aged BD individuals, and daily mood ratings do not predict next-day physical activity. Future studies are needed to better understand individual differences in cognitive performance in BD, as well as associations between inflammation and physical activity, in order to develop targeted treatment strategies aimed to reduce functional disability in this population.

Preserved cognitive performance is a key feature of successful aging. Several theoretical models (compensation, hemispheric asymmetry reduction, and posterior-anterior shift) have been proposed to explain the putative underlying relationship between brain function and performance. We aimed to review imaging studies of the association between brain functional response and cognitive performance among healthy younger and older adults in order to understand the neural correlates of successful cognitive aging. MEDLINE-indexed articles published between January 1989 and May 2008, and bibliographies of these articles and related reviews were searched. Studies that measured brain function using fMRI or PET, evaluated cognitive performance, analyzed how cognitive performance related to brain response, and studied healthy older individuals were included. Forty-seven of 276 articles met these criteria. Eighty-one percent of the studies reported some brain regions in which greater activation related to better cognitive performance among older participants. This association was not universal, however, and was seen mainly in frontal cortex brain response and seemed to be more common among older compared to younger individuals. This review supports the notion of compensatory increases in brain activity in old age resulting in better cognitive performance, as suggested by hemispheric asymmetry reduction and posterior-anterior shift models of functional brain aging. However, a simple model of bigger structure → greater brain response → better cognitive performance may not be accurate. Suggestions for future research are discussed.

Background Although global brain structure is highly heritable, there is still variability in the magnitude of genetic influences on the size of specific regions. Yet, little is known about the patterning of those genetic influences, i.e., whether the same genes influence structure throughout the brain or whether there are regionally specific sets of genes. Methods We mapped the heritability of cortical thickness throughout the brain using three-dimensional structural magnetic resonance imaging in 404 middle-aged male twins. To assess the amount of genetic overlap between regions, we then mapped genetic correlations between three selected seed points and all other points comprising the continuous cortical surface. Results There was considerable regional variability in the magnitude of genetic influences on cortical thickness. The primary visual (V1) seed point had strong genetic correlations with posterior sensory and motor areas. The anterior temporal seed point had strong genetic correlations with anterior frontal regions but not with V1. The middle frontal seed point had strong genetic correlations with inferior parietal regions. Conclusions These results provide strong evidence of regionally specific patterns rather than a single, global genetic factor. The patterns are largely consistent with a division between primary and association cortex, as well as broadly defined patterns of brain gene expression, neuroanatomical connectivity, and brain maturation trajectories, but no single explanation appears to be sufficient. The patterns do not conform to traditionally defined brain structure boundaries. This approach can serve as a step toward identifying novel phenotypes for genetic association studies of psychiatric disorders and normal and pathological cognitive aging.

Background: According to cognitive diathesis-stress theories, a latent cognitive vulnerability to depression is activated by negative affect in individuals at risk for depressive relapse. This vulnerability can manifest as mood-congruent memory during sad mood and may involve amygdala response, which is implicated in memory for emotionally arousing stimuli. This study examined whether amygdala modulates memory for negatively valenced words before and after a sad mood induction in healthy individuals with and without a history of recurrent major depression. Methods: Fourteen unmedicated remitted depressed (RD) and 14 matched never depressed (ND) individuals were scanned using functional magnetic resonance imaging (fMRI) while performing a self-referent encoding/evaluation task (SRET) preceding and following a sad mood challenge. After each SRET, participants’ free recall was assessed. Results: Following sad mood induction, bilateral amygdala response during encoding of valenced words predicted increased recall of negative self-referent words for a subset of RD participants. This association was not present before the sad mood induction and was not evident in individuals without a history of depression, regardless of mood state. Conclusions: These results are consistent with cognitive diathesis-stress theories and suggest a role for the amygdala in modulating mood-congruent memory during transient sad mood in individuals who are vulnerable to depression relapse.

Structural brain abnormalities such as ventricular enlargement are robust correlates of schizophrenia, but the degree of difference compared with unrelated normal controls is only moderate (< 1 standard deviation), and only 40% of patients have values on these measures that fall outside of the normal distribution. Family studies can help to clarify the meaning of this overlap by controlling for some of the non-schizophrenia-related genetic variation in neuroanatomical traits. Computerized tomographic scans of the brain were used to measure ventricular and sulcal cerebrospinal fluid (CSF) to brain ratios (VBR and SBR) for each hemisphere in 16 pairs of discordant siblings from the Copenhagen Schizophrenia High-Risk Project. Schizophrenics' values for VBR and SBR exceeded those of their nonschizophrenic siblings in 75% of the pairs; on average, patients' values on these measures were 1 and 5 standard deviations larger, respectively, than those of their nonschizophrenic siblings. Sulcal and left hemisphere effects were significantly more pronounced than ventricular and right hemisphere effects. After controlling for between-family variation, structural brain abnormalities appear to be more prevalent and more pronounced in schizophrenia than has previously been assumed, with relatively greater deviation observed for cortical and left hemisphere measures of CSF space enlargement.