Ashley N. Sutherland

Antipsychotic Effects on Prepulse Inhibition in Normal ‘Low Gating’ Humans and Rats

Development of new antipsychotics and their novel applications may be facilitated through the use of physiological markers in clinically normal individuals. Both genetic and neurochemical evidence suggests that reduced prepulse inhibition of startle (PPI) may be a physiological marker for individuals at-risk for schizophrenia, and the ability of antipsychotics to normalize PPI may reflect properties linked to their clinical efficacy. We assessed the effects of the atypical antipsychotic quetiapine (12.5 mg po) on PPI in 20 normal men with a ‘low PPI’ trait, based on PPI levels in the lowest 25% of a normal PPI distribution. The effects of quetiapine (7.5 mg/kg s.c.) on PPI were then assessed in rats with phenotypes of high PPI (Sprague Dawley (SD)) and low PPI (Brown Norway (BN)); effects of clozapine (7.5 mg/kg i.p.) and haloperidol (0.1 mg/kg s.c.) on PPI were also tested in SD rats. At a time of maximal psychoactivity, quetiapine significantly enhanced PPI to short prepulse intervals (20–30 ms) in ‘low gating’ human subjects. Quetiapine increased PPI in low gating BN rats for prepulse intervals <120 ms; this effect of quetiapine was limited to 20 ms prepulse intervals in SD rats, who also exhibited this pattern in response to clozapine but not haloperidol. In both humans and rats, normal ‘low gating’ appears to be an atypical antipsychotic-sensitive phenotype. PPI at short intervals may be most sensitive to pro-gating effects of these drugs.

Abnormalities of brain response during encoding into verbal working memory among euthymic patients with bipolar disorder

Individuals with bipolar disorder (BD) have trait‐like deficits in attention and working memory (WM). A fundamental dissociation for most verbal WM theories involves the separation of sensory‐perceptual encoding, reliant upon attention, from the maintenance of this information in WM proper. The present study examined if patients with BD demonstrate differential neural changes in encoding and maintenance WM processes that underlie cognitive impairment.

Fusing Functional MRI and Diffusion Tensor Imaging Measures of Brain Function and Structure to Predict Working Memory and Processing Speed Performance among Inter-episode Bipolar Patients.

Evidence for abnormal brain function as measured with diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) and cognitive dysfunction have been observed in inter-episode bipolar disorder (BD) patients. We aimed to create a joint statistical model of white matter integrity and functional response measures in explaining differences in working memory and processing speed among BD patients. Medicated inter-episode BD (n=26; age=45.2±10.1 years) and healthy comparison (HC; n=36; age=46.3±11.5 years) participants completed 51-direction DTI and fMRI while performing a working memory task. Participants also completed a processing speed test. Tract-based spatial statistics identified common white matter tracts where fractional anisotropy was calculated from atlas-defined regions of interest. Brain responses within regions of interest activation clusters were also calculated. Least angle regression was used to fuse fMRI and DTI data to select the best joint neuroimaging predictors of cognitive performance for each group. While there was overlap between groups in which regions were most related to cognitive performance, some relationships differed between groups. For working memory accuracy, BD-specific predictors included bilateral dorsolateral prefrontal cortex from fMRI, splenium of the corpus callosum, left uncinate fasciculus, and bilateral superior longitudinal fasciculi from DTI. For processing speed, the genu and splenium of the corpus callosum and right superior longitudinal fasciculus from DTI were significant predictors of cognitive performance selectively for BD patients. BD patients demonstrated unique brain-cognition relationships compared to HC. These findings are a first step in discovering how interactions of structural and functional brain abnormalities contribute to cognitive impairments in BD.

Increased Cerebral Blood Flow Associated with Better Response Inhibition in Bipolar Disorder

Impairment on inhibitory tasks has been well documented in bipolar disorder (BD). Differences in cerebral blood flow (CBF) between BD patients and healthy comparison (HC) participants have also been reported. Few studies have examined the relationship between cognitive performance and regional CBF in this patient population. We hypothesized that group differences on an inhibitory task (the Delis-Kaplan Executive Function Scales Color-Word Inhibition task) would be associated with differential CBF in bilateral anterior cingulate cortex (ACC), inferior parietal lobule (IPL) and dorsolateral prefrontal cortex (DLPFC) regions. Whole brain resting CBF was measured using Multiphase Pseudocontinuous Arterial Spin Labeling MR imaging for 28 euthymic BD and 36 HC participants. Total gray matter (GM) CBF was measured, and regional CBF values were extracted for each region of interest (ROI) using Freesurfer-based individual parcellations. Group, CBF, and group-by-CBF interaction were examined as predictors of inhibition performance. Groups did not differ in age, gender or education. BD patients performed significantly worse on Color-Word inhibition. There were no significant group differences in CBF in either total GM or in any ROI. There was a group by CBF interaction in the bilateral ACC, right IPL and right DLPFC such that better inhibitory performance was generally associated with higher resting state CBF in BD subjects, but not HC participants. Although CBF was not abnormal in this euthymic BD sample, results confirm previous reports of inter-episode inhibitory deficits and indicate that the perfusion-cognition relationship is different in BD compared to HC individuals.

Steeper Slope of Age-Related Changes in White Matter Microstructure and Processing Speed in Bipolar Disorder

OBJECTIVES Bipolar disorder (BD) is associated with compromised white matter (WM) integrity and deficits in processing speed (PS). Few studies, however, have investigated age relationships with WM structure and cognition to understand possible changes in brain health over the lifespan. This investigation explored whether BD and healthy counterpart (HC) participants exhibited differential age-related associations with WM and cognition, which may be suggestive of accelerated brain and cognitive aging. DESIGN Cross-sectional study. SETTING University of California San Diego and the Veterans Administration San Diego Healthcare System. PARTICIPANTS 33 euthymic BD and 38 HC participants. MEASUREMENTS Diffusion tensor imaging was acquired as a measure of WM integrity, and tract-specific fractional anisotropy (FA) was extracted utilizing the Johns Hopkins University probability atlas. PS was assessed with the Number and Letter Sequencing conditions of the Delis-Kaplan Executive Function System Trail Making Test. RESULTS BD participants demonstrated slower PS compared with the HC group, but no group differences were found in FA across tracts. Multiple linear regressions revealed a significant group-by-age interaction for the right uncinate fasciculus, the left hippocampal portion of the cingulum, and for PS, such that older age was associated with lower FA values and slower PS in the BD group only. The relationship between age and PS did not significantly change after accounting for uncinate FA, suggesting that the observed age associations occur independently. CONCLUSIONS Results provide support for future study of the accelerated aging hypothesis by identifying markers of brain health that demonstrate a differential age association in BD.

Disruptions in resting state functional connectivity in euthymic bipolar patients with insomnia symptoms

Insomnia is prevalent in bipolar disorder (BD) even during periods of euthymic mood. We compared resting state brain activity and cognitive function between euthymic BD with and without insomnia, and secondarily to healthy individuals. BD patients with insomnia symptoms showed a significantly lower functional connectivity within the task-positive network, compared to those without insomnia. They also showed significantly slower cognitive processing speed. These two features of BD with insomnia appeared relatively independent of each other. Preliminary findings suggest that exploration of the mechanisms of sleep disturbance in BD could lead to improved understanding and treatment of inattention in BD.

298. Peripheral inflammation, Physical Activity and Cognition in Bipolar Disorder

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.