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Published in final edited form as: Biol Psychol. 2012 Feb 10;90(1):18–22. doi: 10.1016/j.biopsycho.2012.01.008

Structure-Function Associations in Hippocampus in Bipolar Disorder

Lara G Chepenik 1,3, Fei Wang 1,3, Linda Spencer 1,3, Marisa Spann 4, Jessica H Kalmar 1, Fay Womer 1, Erin Edmiston 1, Brian Pittman 1, Hilary P Blumberg 1,2,3
PMCID: PMC3319637  NIHMSID: NIHMS356697  PMID: 22342942

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.

Keywords: CVLT, Memory, Hippocampus, Magnetic Resonance Imaging, Bipolar Disorder

1. 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., 2004; Senturk et al., 2007; Simonsen et al., 2007, 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.

2. MATERIALS AND METHODS

2.1 Subjects

Subjects included 31 adults with BD (58% female, ages 20–58 years) and 32 HC individuals (68% female, ages 19–58 years). Study subjects were recruited through the Veterans Affairs Connecticut Health Care System (West Haven, CT), the Yale School of Medicine (New Haven, CT), clinicians in the community and from advertisement in local newspapers. All subjects provided written, informed consent for participation in this study protocol as approved by the Yale School of Medicine and Department of Veterans Affairs institutional review boards.

Presence or absence of DSM-IV Axis I disorders was confirmed using the Structured Clinical Interview for DSM-IV Axis I Disorders, Version 2.0 (First et al., 1995). None of the participants had an intelligence quotient below 80, a major neurological illness or history of loss of consciousness >5 minutes. Three (10%) individuals with BD had treated thyroid dysfunction. HC subjects also lacked a personal history of a mood, psychotic or substance use disorder.

The mean length of illness duration for the subjects with BD was 19 years (SD = 11 years; range = 1– 38 years). Number of psychiatric hospitalizations included none (11, 35%), 1–5 (16, 52%) and >5 (4, 13%). Eleven (35%) of the BD subjects met criteria for rapid-cycling. Seventeen (55%) of the subjects with BD were euthymic at time of scan, 7 (23%) were depressed and 7 (23%) were in a manic, hypomanic or mixed state. Thirteen (42%) of the BD subjects had experienced past psychotic symptoms that occurred within the context of a mood episode. None of the subjects were psychotic at time of scan.

Among individuals with BD, history of comorbid psychiatric disorder included panic disorder (6, 19%), specific phobia (4, 13%), post-traumatic stress disorder (4, 13%) or generalized anxiety disorder (1, 3%). Eight (26%) BD subjects had a prior history of substance dependence, which included alcohol (2, 3%), cannabis (1, 3%), sedatives (2, 6%), opiates (1, 3%), and polysubstances (3, 10%). Seven subjects with BD (23%) had a prior history of substance abuse. Subjects were in remission from substance dependence for an average period of over 5 years, and from abuse for an average period of over 4 years. Ten (30%) individuals with BD were unmedicated at time of scan. The remaining subjects were prescribed lithium carbonate (8, 26%), an anticonvulsant (15, 48%), an atypical antipsychotic (12, 39%), an antidepressant (8, 26%), a benzodiazepine (6, 19%) or a stimulant (2, 6%).

2.2 Neuropsychological Assessment

The American version of the Nelson Adult Reading Test (AMNART) (Grober and Sliwinski, 1991) and the vocabulary and matrix reasoning subtests of the Wechsler Abbreviated Scale of Intelligence (WASI) (Wechsler, 1999)provided estimates of subjects’ pre-morbid and current Intelligence Quotient (IQ), respectively. Subjects were administered the California Verbal Learning Test-Second Edition (CVLT) (Delis et al., 2000).

2.3 Acquisition and Processing of Magnetic Resonance Images

MRI scans were obtained using a single 3-T Trio MR scanner (Siemens, Erlangen, Germany). Head position was standardized using canthomeatal landmarks and anatomic data collected using a T1-weighted 3-dimensional magnetization prepared rapid acquisition gradient echo pulse sequence (repetition time, 1500 ms; echo time, 2.83 ms; flip angle, 15°; matrix, 256×256; field of view, 256×256 mm2; slice thickness, 1.0 mm without gap; 160 contiguous slices; and 2 excitations).

2.4 Hand-delineation of Hippocampus Region of Interest (ROI)

A single individual blind to subject diagnosis performed the morphometric analyses. Stripping of the skull and brain segmentation were performed as described previously (Chepenik et al., 2009). Total brain volume (TBV) was calculated as the sum of cerebral gray matter volume and white matter volume. Hippocampus tracings were performed in the coronal plane according to methods previously described (Kates et al., 1997; Peterson et al., 2001). Briefly, the slice at which the temporal horn shifts from a lateral to superior position in relation to the hippocampus defined the anterior of the hippocampus. The slice in which the splenium of the corpus callosum begins to join the fornix defined the posterior boundary. Final tracings were confirmed in orthogonal views. Intra-rater reliability was 95% and inter-rater reliability was 96% as determined by delineation of hippocampus from 10 scans not included in the dataset.

2.5 Statistical Analysis

Differences in demographic variables between BD and HC groups (age, sex, years of education, pre-morbid and current IQ) were assessed using t-tests and chi-square analysis where appropriate.

Analysis of CVLT performance was completed using group (BD vs. HC) as a between subjects factor in an ANCOVA model adjusted for AMNART scores. Dependent measures of CVLT performance included subscores for total immediate recall (trials 1–5), short delay cued and free recall and long delay cued and free recall, standardized for age, sex and years of education (Delis et al., 2000).

A linear mixed model was used to evaluate hippocampus volume using group (BD vs. HC) as a between subjects factor, hemisphere as a within-subjects factor and subject as the clustering factor. TBV served as a covariate to account for general scaling effects. All significant (p<0.05) main, 2- and 3-way interactions are reported. Least squares (ls) means were calculated from the mixed models and plotted to interpret significant effects.

ANCOVA was used to investigate potential associations between clinical variables and either CVLT performance or hippocampus volume in subjects with BD, controlling for AMNART and TBV respectively. Clinical variables were tested one at a time and included length of time with symptoms of BD, number of hospitalizations, history of psychosis, rapidcycling, mood state at time of scan and medication status (overall and for lithium carbonate, anticonvulsants, atypical antipsychotics and antidepressants).

Partial correlations were used to assess potential associations between CVLT performance and mean hippocampus volume (mean of left and right volume) within each diagnostic group, after adjustment for TBV and AMNART scores.

All of the above analyses were performed using SAS, version 9.1 (Cary, NC).

Voxel-based morphometry was used to explore additional brain regions that correlated with CVLT performance measures. Images were processed and analyzed using Statistical Parametric Mapping 5 (SPM5) (http://www.fil.ion.ucl.ac.uk/spm) as detailed in our previous publications (Kalmar et al., 2009; Wang et al., 2011). Whole-brain linear regression analysis was performed separately for the BD and HC groups using SPM5 to investigate the potential relationship between gray matter volume and the above CVLT performance measures. Findings were considered significant at a height threshold of p< 0.005 uncorrected for multiple comparisons, and an extent threshold of 20 voxels.

3. RESULTS

3.1 Demographic Variables

The groups did not significantly differ in age, education, sex distribution, pre-morbid or current IQ (Table 1).

Table 1. Demographic Variables for the Bipolar Disorder and Healthy Comparison Groups.
BD HC
Mean (SEM) Mean (SEM) Statistic P-value
Age (years) 33.2 (2.1) 30.3 (1.9) t(61)=1.0 0.31
Education (years) 14.8 (0.3) 15.6 (0.4) t(61)=1.7 0.10
WASI IQ 114.1 (2.5) 115.4 (2.3) t(56)=0.39 0.70
AMNART 117.2 (1.5) 115.7 (1.3) t(60)=0.79 0.43
Sex M/F 13/18 10/22 Χ2(1)=0.78 0.38
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Abbreviations: BD, bipolar disorder; HC, healthy control; SEM, standard error; M, male; F, female; WASI IQ, Wechsler Abbreviated Scale of Intelligence-Intelligence Quotient; AMNART, American Version of the Nelson Adult Reading Test score

3.2 CVLT Assessment

AMNART was significantly associated with total immediate recall [F(1,59)=4.9, p=0.031]. Compared to the HC group, the group with BD demonstrated significantly impaired performance on total immediate recall, short delay cued and free recall and long delay cued recall (Table 2). The group with BD demonstrated a trend towards impaired performance on long delay free recall, relative to the HC group (Table 2). None of the clinical factors present in subjects with BD were significantly associated with CVLT performance, including length of time ill, number of hospitalizations, presence of rapid cycling, mood state, co-morbid substance dependence, abuse or other psychiatric illness, and medication status. However, there were non-significant trends towards better performance on short delay free recall [F(1,27)=3.14, p=0.088], short delay cued recall [F(1,27)=4.17, p=0.051] and long delay free recall [F(1,27)=3.72, p=0.064] in participants prescribed antidepressants.

Table 2. California Verbal Learning Test Measures for the Bipolar Disorder and Healthy Control Groups.

Least square means adjusted for American version of the Nelson Adult Reading Test (AMNART) scores

BD HC
Mean (SEM) Mean (SEM) F(1, 59)*= P-value
Immediate Recall 50 (2.1) 57.2 (2.0) 6.11 0.016
Short Delayed Free Recall −0.25 (0.25) 0.52 (0.24) 4.93 0.03
Short Delayed Cued Recall −0.32 (0.22) 0.49 (0.21) 7.19 0.01
Long Delayed Free Recall −0.18 (0.19) 0.34 (0.18) 3.76 0.057
Long Delayed Cued Recall −0.30 (0.20) 0.26 (0.20) 3.96 0.051
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*

adjusted for AMNART scores

Abbreviations: CVLT, California Verbal Learning Test; BD, bipolar disorder; HC, healthy control; SEM, standard error

3.3 Hippocampus Volume

TBV was significantly associated with hippocampus volumes [F(1,60)=27.9, p<0.0001]. As depicted in Figure 1, hippocampus volumes were significantly smaller in BD subjects (ls mean 2588 ± SE 43) compared to HC subjects (ls mean 2748 ± 42) [F(1,60)=7.0, p=0.010]. No hemispheric differences were observed [F(1,61)=1.73, p=0.19]. Rapid-cycling BD participants demonstrated significantly larger hippocampus volumes (rapid-cycling BD ls mean=2737 ± SE 62, non-rapid cycling BD ls mean=2525 ± 45), [F(1,28)=7.3, p=0.012]. None of the other clinical factors present in subjects with BD were significantly associated with hippocampus volume, including length of time ill, number of hospitalizations, mood state, co-morbid substance dependence, abuse or other psychiatric illness, and medication status.

Figure 1. Hippocampus Volume in the Bipolar Disorder and Healthy Control Groups.

Figure 1

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The graph displays ls means and standard errors for hippocampus volumes (mm3) by diagnosis, adjusted for total brain volume. The BD group had significantly smaller hippocampus volumes compared to the HC group (p=0.01).

Abbreviations: BD, bipolar disorder; HC, healthy control; ls, least square

3.4 Correlations

After adjustment for TBV and AMNART scores, subjects with BD demonstrated positive associations between hippocampus volume and CVLT performance for total immediate recall (r=0.52, p=0.005), short delay cued recall (r=0.39, p=0.04), long delay free recall (r=0.40, p=0.036) and long delay cued recall (r=0.44, p=0.019). There were no significant correlations between hippocampus volume and CVLT performance measures in the HC group. The whole brain voxel-based exploratory analyses did not reveal additional brain regions for which volume was significantly associated with CVLT measures.

4. DISCUSSION

This study demonstrated a positive correlation between hippocampus volume and CVLT performance in individuals with BD. These findings bring together for the first time the separate observations that hippocampus size is reduced and its function is reduced in adults with BD, compared to healthy individuals. The presence of a correlation between these findings suggests morphological differences in hippocampus in BD may be associated with measurable verbal memory dysfunction.

The mechanisms that underlie structural abnormalities in hippocampus and associated dysfunction are not known. Abnormalities in hippocampus plasticity have been implicated in disease pathology in mood disorders (Czeh et al., 2001; Duman et al., 1997). In BD, postmortem molecular studies demonstrate abnormal hippocampus levels of markers associated with neuronal sprouting and plasticity (Dowlatshahi et al., 2000; Fatemi et al., 2001; MacDonald et al., 2006). In addition, magnetic resonance spectroscopy studies demonstrate abnormalities in markers of cell density are present in hippocampus early in BD disease onset (Atmaca et al., 2006; Blasi et al., 2004) and could potentially reflect early dysfunction in cell growth and plasticity. Decreased regional blood flow in hippocampus during verbal memory encoding in subjects with BD, compared to HC subjects, suggests possible functional effects of these cellular changes (Deckersbach et al., 2006).

The observation antidepressants and mood-stabilizing medications have neurotrophic effects in hippocampus (Atmaca et al., 2007; Bearden et al., 2008; Chen et al., 2000; Czeh et al., 2001; Duman et al., 1997; Madsen et al., 2000; Malberg et al., 2000; Manev et al., 2001; Santarelli et al., 2003) suggests these treatments might induce morphological changes in hippocampus in BD which could also lead to improved cognitive function. This hypothesis is supported by the longitudinal study of twelve individuals with BD treated with lithium carbonate who demonstrated increased hippocampus volume in association with improved performance on the CVLT (Yucel et al., 2007). Since this research lacked a comparison group without BD, the magnitude of difference from healthy individuals could not be determined. In the present study, there was no association between treatment with lithium and CVLT performance. Subjects prescribed antidepressants did demonstrate a non-significant trend towards improved memory performance, an observation also described in subjects with major depressive disorder (Deuschle et al., 2004). Antidepressants were not associated with hippocampus volume, however. Possible explanations might include greater CVLT sensitivity to neurotrophic changes in hippocampus than gross volume measures. It is also possible an alternate mechanism underlies the observed memory effects. These results should be considered very preliminary given the level of significance, small sample size, lack of systematic treatment assignment and regimens of more than one medication for many subjects. Further studies with systematic medication assignment in larger sample sizes might reveal salutary effects of medication on hippocampus-related impairments.

The CVLT measures a spectrum of cognitive constructs (Elwood, 1995), including repetition learning and semantic organization. Performance on these various measures has been reported to also engage brain regions other than hippocampus, including the putamen, thalamus and prefrontal cortex (Albuquerque et al., 2008; Baldo et al., 2002; DiStefano et al., 2000; Savage et al., 2001; Ystad et al., 2010). In this study, whole brain voxel-based exploratory analysis did not demonstrate any significant associations between additional brain regions and CVLT measures of recall. However, it is possible these methods were not sensitive to subtle differences in additional brain regions.

The post-hoc exploratory analyses showed a correlation between rapid-cycling in BD and increased hippocampus size. The mechanisms to explain rapid-cycling in BD are not understood, but may include genetic pathways related to stress and plasticity (Muller et al., 2006; Serretti et al., 2006). The serotonin transporter polymorphism (5-HTTLPR, locus SLC6A4) has been associated with rapid-cycling and antidepressant induced mania in BD (Cusin et al., 2001; Ferreira Ade et al., 2009; Mundo et al., 2001; Rousseva et al., 2003), as well as altered hippocampus volume in major depressive disorder (Frodl et al., 2004; Taylor et al., 2005). Whereas homozygosity for the val allele of the Val66Met brain derived neurotrophic growth factor gene is associated with susceptibility to BD and rapid-cycling, the met allele is associated with decreases in hippocampus volume (Chepenik et al., 2009; Geller et al., 2004; Matsuo et al., 2009; Muller et al., 2006; Sklar et al., 2002). This suggests that the val allele may be associated with vulnerability to cycling, while BD carriers of the met allele may be vulnerable to cognitive dysfunction. Future studies that explore potential interactions amongst these genetic factors, clinical course and hippocampus structure and function are warranted.

In sum, this work demonstrates a positive correlation between smaller hippocampus volume and performance deficits on the CVLT in individuals with BD. Preliminary evidence suggests antidepressant treatment may reverse hippocampus-related memory deficits. However, the association between rapid-cycling and higher hippocampus volumes suggests optimized treatment might target a relatively narrow range of hippocampus structure and function to both minimize cognitive dysfunction, as well as tendency towards mood cycling. Future research that includes systematic study of medication and clinical course, as well as exploration of the genetic mechanisms that underlie the hippocampus morphological changes in BD, are needed.

Highlights.

California Verbal Learning Test (CVLT) performance is decreased in bipolar disorder

MRI showed hippocampus volumes are decreased in bipolar disorder

Hippocampus volume was associated with CVLT performance in bipolar disorder

ACKNOWLEDGEMENTS

We thank Kathleen Colonese, Susan Quatrano, Philip Markovich and Allison McDonough for their work with the study participants and database management, Hedy Sarofin, Karen Martin, and Terry Hickey for their technical expertise, and the research subjects for their participation.

We also thank Dr. Brenda Milner for her expert scientific consultation.

FUNDING SOURCES:

Grant Sponsor: the Department of Veterans Affairs Research Enhancement Award Program, Grant Sponsor: the National Institute of Mental Health; Grant numbers: R01MH69747, R01MH070902, K01MH086621, UL1 RR0249139, T32MH14276, Grant Sponsor: National Institute of Health National Center for Research Resources; CTSA Grant Number: UL1 RR0249139, Grant Sponsors: the National Alliance for Research on Schizophrenia and Depression, The Attias Family Foundation, Marcia Simon Kaplan, Women' Investigator Program – The Ethel F. Donaghue Women’s Health Investigator Program at Yale, and the Klingenstein Foundation.

Footnotes

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