Covariance modeling of MRI brain volumes in memory circuitry in schizophrenia: Sex differences are critical

Abstract

Women have consistently demonstrated better verbal memory on tests that evaluate immediate and delayed free recall. In patients with schizophrenia, these verbal memory processes are relatively more preserved in women than men. However an understanding of the brain anatomy of the female advantage for verbal memory is still unclear.

29 females and 59 males with schizophrenia made comparable to 21 female and 27 male healthy volunteers were scanned using structural magnetic resonance imaging (sMRI) in order to assess volumes of regions across the entire brain. Sex differences within and between groups in the covariance structure of memory circuitry regions were evaluated using a novel approach to covariance analysis (the Box M Test). Brain areas of interest included the prefrontal cortex (PFC), inferior parietal lobule (iPAR), anterior cingulate gyrus (ACG), parahippocampus, and hippocampus (HIPP).

Results showed significant differences in the covariance matrices of females and males with schizophrenia compared with their healthy counterparts, in particular the relationships between iPAR–PFC, iPAR–ACG, and HIPP–PFC. Sex differences in the iPAR–PFC relationship were significantly associated with sex differences in verbal memory performance. In control women, but not in men ACG volume correlated strongly with memory performance. In schizophrenia, ACG volume was reduced in females, but not in men, relative to controls.

Findings suggest that the relationship between iPAR and PFC is particularly important for understanding the relative preservation of verbal memory processing in females with schizophrenia and may compensate for ACG volume reductions. These results illustrate the utility of a unique covariance structure modeling approach that yields important new knowledge for understanding the nature of schizophrenia.

Introduction

There is a well-documented tendency for healthy adult women to score higher than healthy men on verbal memory tests (Herlitz et al., 1999, Joseph et al., 1982, Kail and Siegel, 1977, Kramer et al., 1988, Larrabee and Crook, 1993, Larrabee et al., 2000, Norman et al., 2000, Schaie and Willis, 1993, Trahan and Quintana, 1990, Van Der Elst et al., 2005, West et al., 1992, Youngjohn et al., 1991, Zelinski et al., 1993), particularly on free and delayed recall measures of verbal declarative memory (e.g., Delis et al., 1988, Gale et al., 2007, Hazlett et al., 2010, Herlitz et al., 1999, Kail and Siegel, 1977, Kramer et al., 1988, Larrabee and Crook, 1993, Larrabee et al., 2000, Van Der Elst et al., 2005). However, there is little understanding of the anatomy underlying the effect. Typically, differences are on the order of a quarter to half of a standard deviation and are independent of age, education, and other sociodemographic characteristics (Norman et al., 2000, Paolo et al., 1997, Rabbitt et al., 1995, Schaie and Willis, 1993, West et al., 1992, Zelinski et al., 1993). Reports suggest that the female advantage in memory in part is due to the organization of recall and efficient use of memory strategies, such as a semantic-based organizational strategy (Kramer et al., 1988, Kramer et al., 1997, Van Der Elst et al., 2005). In fact, even on visual declarative memory tasks where it is possible to verbally encode items, women have shown better memory than men (Kramer et al., 1997, Lewin et al., 2001).

When no significant difference between males and females is reported, the measure of recall typically involves a limited (or closed) set of items, such as digits and letters (Jahoda, 1981, Orsini et al., 1987). Closed stimulus sets may make the memory task easier or raise the potential for guessing (Larrabee and Crook, 1993, Larrabee et al., 2000). Differences also have not been found on tests of recognition memory (Herlitz et al., 1999, Joseph et al., 1982, Kramer et al., 1988, Kramer et al., 1997, Kramer et al., 2003), cued recall (Saykin et al., 1995) or other forced-recall strategies, including the story-based recall associated with the Wechsler Memory Scale (e.g., Wechsler, 1997) Logical Memories subtests (Dodrill, 1979, Saykin et al., 1995).

This cognitive sex difference raises the possibility that these effects, at least in part, are associated with structural brain differences between the sexes. Sex differences in memory performance in healthy individuals are consistent with sex differences in structural brain volumes (relative to cerebrum size) in areas known to contribute to verbal declarative memory function, including the prefrontal cortex (PFC; Allen et al., 2003, Goldstein et al., 2001, Luders et al., 2009, Schlaepfer et al., 1995), anterior cingulate gyrus (ACG; Allen et al., 2003, Chen et al., 2007, Goldstein et al., 2001, Good et al., 2001, Pujol et al., 2002), hippocampus (HIPP; Filipek et al., 1994, Giedd et al., 1996, Goldstein et al., 2001), and parietal cortex (PAR; Allen et al., 2003, Chen et al., 2007, Goldstein et al., 2001, Good et al., 2001, Nopoulos et al., 2000, Schlaepfer et al., 1995). These studies show that the PFC, ACG, HIPP, and PAR are larger in the healthy female brain, relative to the size of the cerebrum, than in males. Women have also been found to have larger neuron somata in these regions (Rabinowicz et al., 1999, Rabinowicz et al., 2002), larger gray/white matter ratio (Allen et al., 2003, Rabinowicz et al., 1999, Rabinowicz et al., 2002, Sowell et al., 2007), and thicker gray matter in the dorsolateral prefrontal cortex (DLPFC; Luders et al., 2009, Sowell et al., 2007) and PAR (Cosgrove et al., 2007, Luders et al., 2009, Sowell et al., 2007, Witelson et al., 1995).

Systematic examinations of sex differences in declarative verbal memory using functional magnetic resonance imaging (fMRI) are lacking, but other imaging work suggests a functional sexual dimorphism that complements the structural one. A positron emission tomography (PET) study by Nyberg et al. (2000) compared glucose metabolism during encoding and retrieval using a CVLT-like task. Women showed a greater increase in relative glucose metabolism during retrieval in bilateral ACG and right anterior PAR. Men showed a greater increase in relative metabolism in a more posterior area of PAR, which was bilateral rather than the lateralized effect seen in women (Nyberg et al., 2000). This higher glucose metabolism in women during retrieval in a CVLT-like task has recently been replicated (Hazlett et al., 2010). Furthermore, an fMRI study of estrogen replacement therapy (ERT) in post-menopausal women showed higher blood-oxygen-level-dependent (BOLD) signal change during encoding in DLPFC and PAR with ERT (Persad et al., 2009). In fact, most study participants are tested without regard to menstrual cycle, thereby potentially obscuring beneficial effects of cycle-time-dependent hormones, which have been found on verbal memory measures in regularly cycling females (Otero Dadin et al., 2009, Rosenberg and Park, 2002), postmenopausal females (e.g., Maki and Resnick, 2000), and transsexual males (Miles et al., 1998).

Taken together, previous studies indicate that healthy women compared to healthy men perform better on verbal memory tasks, have larger volumes of memory-related brain areas (relative to overall brain volume), and show greater activation in brain areas related to verbal declarative memory function. Additionally, these differences have been shown to be driven, in part, by gonadal hormones (e.g., McEwen and Woolley, 1994, Protopopescu et al., 2008). The present investigation examines the extent to which the covariance of structural brain regions can explain sex differences in verbal memory. Specifically, we are interested in explaining a relative preservation of verbal memory in females with schizophrenia compared to their male counterparts.

Sex differences in the healthy population have implications for understanding cognitive and anatomical abnormalities in schizophrenia, the magnitude of which varies by sex. Verbal memory is one of the most affected cognitive domains in first-episode and chronic patients with schizophrenia (Aleman et al., 1999, Cirillo and Seidman, 2003, Heinrichs and Zakzanis, 1998, Mesholam-Gately et al., 2009). Brain regions, such as frontal, temporal, and hippocampal areas, underlie verbal declarative memory and show some of the largest volumetric reductions in schizophrenia (Ellison-Wright et al., 2008, Honea et al., 2008, Seidman et al., 2002, Shenton et al., 1992, Wright et al., 2000). Within the frontal cortex, there are reductions in ACG and DLPFC, with a greater DLPFC reduction in chronic patients with schizophrenia (Ellison-Wright et al., 2008), that are related to verbal memory impairments, especially impairments to encoding processes (Antonova et al., 2004, Baaré et al., 1999, Ho et al., 2006, Maher et al., 1995, Matsui et al., 2008, Olli et al., 2009, Sanfilipo et al., 2002, Seidman et al., 2002, Thoma et al., 2009, Turetsky et al., 2002, Wexler et al., 2009).

Men with schizophrenia are more impaired on verbal memory tasks than women in small samples when controlled for sampling and other potential confounds (Goldstein et al., 1998, Goldstein et al., 1994, Nopoulos et al., 2000). Importantly, sex differences between patients with schizophrenia are larger than sex differences in verbal memory in the healthy population, which suggests that sex differences in patients are not simply a reflection of normative sex differences. This cognitive difference may be related to the propensity for greater severity of illness among men than women with schizophrenia (Goldstein, 1988, Goldstein et al., 1990, Haas and Castle, 1997, Häfner et al., 1993, Leung and Chue, 2000).

The goal of the analysis presented here is to contribute to understanding the neuroanatomical underpinnings of sex differences in verbal memory function in schizophrenia. We will examine the covariance structure of memory-related brain regions (i.e., a memory network) in males and females with and without schizophrenia. These areas include the posterior cingulate (BA 23, 29, and 30), inferior parietal (BA 40), parahippocampus (as well as entorhinal cortex), HIPP, ACG (BA 24, 33, 32), inferior frontal gyrus (BA 44 and 45), and PFC (BA 8, 9, 6, 36) (Cabeza et al., 2008, Cirillo and Seidman, 2003, Eichenbaum, 2004, Golby et al., 2001, Goldman-Rakic, 1988, Goldman-Rakic et al., 1984; Krause et al., 1999, Mesulam, 1990, Moscovitch, 2008, Petrides et al., 1993, Schacter et al., 2007, Skinner and Fernandes, 2007, Squire et al., 2004, Stone et al., 2005, Thermenos et al., 2007, Tulving, 2002). Relating observed sex differences in covariance structure to sex differences in verbal memory performance will contribute to understanding the relative preservation of verbal memory performance in women compared to men with schizophrenia. To achieve these aims, we applied the Box M Test (Box, 1949) in a novel way to test for covariance differences between the sexes for patients and healthy controls. Our goal was to study the network of brain regions supporting memory function, test whether the illness differentially affected the relationships between brain volumes by sex, and determine what role this differential effect might play in explaining sex differences in verbal memory in schizophrenia.