Elsevier

NeuroImage

Volume 60, Issue 4, 1 May 2012, Pages 2054-2061
NeuroImage

Sex differences in amygdala subregions: Evidence from subregional shape analysis

https://doi.org/10.1016/j.neuroimage.2012.02.025Get rights and content

Abstract

Each subregion of the amygdala is characterized by a distinct cytoarchitecture and function. However, most previous studies on sexual dimorphism and aging have assessed differences in the structure of the amygdala at the level of the amygdala in its entirety rather than at the subregional level. Using an amygdala subregional shape analysis, we investigated the effects of sex, age, and the sex × age interaction on the subregion after controlling for intracranial volume. We found the main effect of age in the subregions and the effect of sex in the superficial nucleus, which showed that men had a larger mean radius than women. We also found a sex × age interaction in the centromedial nucleus, in that the radius of the centromedial nucleus showed a steeper decline with age in women compared with men. Regarding the amygdala volume as a whole, we found only an age effect and did not find any other significant difference between genders. The sex difference in the amygdala subregion and its relevance to the circulating gonadal hormone were discussed.

Introduction

The amygdalae are almond-shaped structure in the right and left medial temporal lobes of the brain. Each amygdala consists of multiple subregions with distinct functions (Aggleton, 2000, Phillips and LeDoux, 1992, Swanson and Petrovich, 1998). The amygdala can be divided in a number of manners according to brain anatomical parcellation schemes. A widely accepted way of dividing the amygdala is to partition it into three subregions: the laterobasal group (LB), the superficial group (SF), and the centromedial group (CM) (Amunts et al., 2005, Bloom et al., 1999). The LB, which consists of the lateral, basolateral, basomedial, and paralaminar nuclei, mediates motor responses to fearful stimuli and processes emotional memory. The SF, which includes the anterior amygdaloid area, the amygdalopyriform transition area, the amygdaloid-hippocampal area, and the ventral and posterior cortical nuclei, receives input from the olfactory system and is involved in affective processing. The CM, which consists of the central and medial nuclei, mediates autonomic and endocrine responses and also modulates emotional responses. In animal studies, the medial nucleus has been shown to receive input from the accessory olfactory system, which is essential for normal reproductive behavior (Amunts et al., 2005, Bloom et al., 1999, Cooke et al., 1999, González-Lima and Scheich, 1986, LeDoux and Gorman, 2001, Swanson and Petrovich, 1998).

A large body of research has assessed the effect of sex and age on brain structures using magnetic resonance imaging (MRI). These neuroimaging studies have suggested that aging is associated with a reduction in the volume or thickness of the cerebral cortex, cerebellum, and other brain substructures (Cowell et al., 1994, Fjell et al., 2009b, Gur et al., 1991, Good et al., 2001, Pfefferbaum et al., 1994, Raz et al., 1997, Resnick et al., 2000, Sullivan et al., 1995, Walhovd et al., 2005). For example, both cross-sectional and longitudinal imaging investigations have revealed a significant age-related decrease in the volume of the amygdala (Fjell et al., 2009a, Jack et al., 1997, Mu et al., 1999, Walhovd et al., 2005). Sex differences may also have an impact on amygdala volume. Some studies have reported that the volume of the amygdala was greater in men compared with women after controlling for intracranial volume (ICV). Other studies have found no such association (Fjell et al., 2009b, Goldstein et al., 2001, Gur et al., 2002, Pruessner et al., 2000).

Previous functional MRI (fMRI) studies have also revealed gender differences in amygdala activity (Cahill, 2006). The amygdalae of men showed greater activation in response to sexual stimuli compared with the amygdalae of women (Gizewski et al., 2006, Hamann et al., 2004). Moreover, men had stronger activity in the amygdala in response to affectively positive stimuli, while women had stronger activity in response to negative stimuli (Wrase et al., 2003). Amygdala responses to affective facial images also showed gender specificity in the aging pattern (Killgore et al., 2000), with a greater decline in negative face perception associated with elderly female vs. male subjects.

Most of the previous work, however, assessed the effect of sex and age at the level of the entire amygdaloid complex rather than at the level of its constituent subregions, each of which has its own distinct cytoarchitecture and pattern of distribution of hormonal receptors. In this regard, methods for assessing the shape contour of the amygdala were developed and successfully applied to detect small changes in the amygdalae of patients with psychiatric or neurological diseases (Chung et al., 2010, Kim et al., 2010, Peterson et al., 2007, Plessen et al., 2006, Qiu et al., 2009, Shenton et al., 2002, Styner et al., 2003, Tamburo et al., 2009, Yang et al., 2009). The shape analysis method is now regarded as an acceptable, albeit indirect, alternative for the assessment of subregional changes. In addition to the analysis of shape contour, we developed a new method for measuring the mean radius of each subregion of the amygdala (Kim et al., 2011). This method employed probabilistic maps of amygdala subregions (Amunts et al., 2005, Eickhoff et al., 2005) to calculate the probability of each subregion's occurrence at every point on the amygdala surface.

As mentioned above, the amygdalae of men showed greater activity in response to sexual or positive emotional stimuli compared with the amygdalae of women. Of all the subregions, the cortical nucleus within the SF and the medial nucleus within the CM had the most important roles in processing these stimuli (Lehman and Winans, 1982). Sexual behavior is closely related to olfaction, and these nuclei receive input from both the main and accessory olfactory bulbs. Therefore, we hypothesized that the SF and CM of male subjects would have larger mean radii than the corresponding amygdala subregions in female subjects. Hence, we used the recently-developed amygdala subregional analysis to investigate sex-dependent differences in the radii of the SF, CM, and LB, as well as the effects of age and the sex × age interaction on these radii.

Section snippets

Participants

We recruited 123 healthy volunteers into the study through advertisements in local newspapers and bulletins. These participants consisted of 62 men and 61 women ranging in age from 20 to 79 years. All participants underwent medical evaluations to exclude current or previous disorders that could affect brain structure. The exclusion criteria were as follows: 1) a history of psychiatric disorders, neurological diseases, or drug abuse; 2) exposure to any drugs, including antidepressants,

Results

In the subregional analysis, the main effect of age was significant (F1,116 = 7.50, p = 0.007), indicating that the mean radius of the subregions decreased with age. However, the effects of sex and age × sex were not significant (F1,116 = 0.30, p = 0.58; F1,116 = 1.46, p = 0.23, respectively). A significant effect of the ICV (F1,116 = 50.78, p < 0.0001) indicated that the differences in the ICV accounted for some of the variance in the mean radii of the subregions. The effect of subregion was significant (F2,232 =

Superficial nucleus

As hypothesized above, amygdala subregional analysis showed that the mean radius of the SF in men was larger than that in women, whereas there was no significant difference in the volume of the amygdala between the genders after controlling for age and ICV. The SF includes the cortical nucleus and the transition area between the amygdala and adjacent brain structures. Neurons that express high levels of androgen receptor (AR) and estrogen receptor (ER) mRNAs were observed in the cortical

Acknowledgments

This research was supported in part by a grant from the Korea Basic Science Institute (T30403, G.C.), National Research Foundation of Korea grants funded by the Korean government (Ministry of Education and Human Resources Development, KRF-2007-511-H00002, H.J.K.; Ministry of Education, Science and Technology, 2010–0023051, N.K.), and a Korea Healthcare Technology R&D Project grant funded by the Ministry of Health, Welfare and Family Affairs (A090754, G.C.).

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