Structure–function associations in hippocampus in bipolar disorder

Abstract

Hippocampus volume decreases and verbal memory deficits have been reported in bipolar disorder (BD) as independent observations. We investigated potential associations between these deficits in subjects with BD. Hippocampus volumes were measured on magnetic resonance images of 31 subjects with BD and 32 healthy comparison (HC) subjects. The California Verbal Learning Test-Second Edition (CVLT) assessed verbal memory function in these subjects. Compared to the HC group, the BD group showed both significantly smaller hippocampus volumes and impaired performance on CVLT tests of immediate, short delay and long delay cued and free recall. Further, smaller hippocampus volume correlated with impaired performance in BD. Post hoc analyses revealed a trend towards improved memory in BD subjects taking antidepressant medications. These results support associations between morphological changes in hippocampus structure in BD and verbal memory impairment. They provide preliminary evidence pharmacotherapy may reverse hippocampus-related memory deficits.

Introduction

Converging evidence implicates the hippocampus in bipolar disorder (BD). Findings from both postmortem histochemical studies and neuroimaging research demonstrate structural hippocampal abnormalities in BD, including decreased cell density, abnormal markers of neuronal function and plasticity, and decreases in hippocampus volume (Bearden et al., 2008, Chepenik et al., 2009, Frazier et al., 2005, Hauser et al., 1989, Noga et al., 2001, Savitz and Drevets, 2010, Strasser et al., 2005, Swayze et al., 1992). Medications used to treat BD are thought to function, at least in part, by stimulating neurogenesis and neuroprotection within hippocampus (Chen et al., 2000, Hao et al., 2004, Manji et al., 2000, Walz et al., 2008).

Consistent with these neurobiological findings, deficits in verbal memory functions that are subserved by the hippocampus are the cognitive abnormalities most consistently identified in individuals with BD (Robinson et al., 2006). These deficits are present across all mood states in BD including euthymia (Cavanagh et al., 2002, Clark et al., 2001, Deckersbach et al., 2004, Glahn et al., 2005, Martinez-Aran et al., 2004a, Martinez-Aran et al., 2004b, Matsuo et al., 2009, Pavuluri et al., 2006, van Gorp et al., 1999, Wolfe et al., 1987). They have been identified in both children and adults with BD (Cavanagh et al., 2002, Clark et al., 2001, Deckersbach et al., 2004, Glahn et al., 2005, Pavuluri et al., 2006, van Gorp et al., 1999, Wolfe et al., 1987) and in their unaffected siblings (Gourovitch et al., 1999, Keri et al., 2001, Kieseppa et al., 2005).

The California Verbal Learning Test (CVLT) is a widely used measure of declarative verbal memory functions, including episodic verbal learning and recall, shown to be associated with hippocampus functioning and disrupted in individuals with hippocampus pathology (Deweer et al., 1995, Kohler et al., 1998, Lepage et al., 1998, Libon et al., 1998, Tischler et al., 2006, Yucel et al., 2007). Although the CVLT also tests various other constructs, subjects with BD tend to demonstrate difficulty on the CVLT measures of immediate and delayed recall (Altshuler et al., 2004, Cavanagh et al., 2002, Glahn et al., 2005, Martinez-Aran et al., 2004a, Martinez-Aran et al., 2004b, Senturk et al., 2007, Simonsen et al., 2008, van Gorp et al., 1998). Together with the findings described above, these results suggest verbal memory dysfunction is a pervasive problem in BD and may reflect an underlying vulnerability in the disorder for hippocampus disturbances. However, no study has yet demonstrated a direct association between hippocampus volume and verbal memory dysfunction in BD.

The present study tested the hypotheses that BD individuals would demonstrate decreases in hippocampus volume, as well as decreased verbal memory functioning as measured by the CVLT, relative to healthy comparison (HC) subjects. It was further hypothesized there would be an association between the magnitude of hippocampus volume decreases and verbal memory decreases in subjects with BD.