Resting-State Functional Connectivity fMRI : A new approach for assessing functional neuroanatomy in humans with applications to neuroanatomical, developmental and clinical questions

Article history: Received 1 July 2008 Revised 28 October 2008 Accepted 12 November 2008 Available online 9 December 2008 The amygdala is composed of structurally and functionally distinct nuclei that contribute to the processing of emotion through interactions with other subcortical and cortical structures. While these circuits have been studied extensively in animals, human neuroimaging investigations of amygdala-based networks have typically considered the amygdala as a single structure, which likely masks contributions of individual amygdala subdivisions. The present study uses resting state functional magnetic resonance imaging (fMRI) to test whether distinct functional connectivity patterns, like those observed in animal studies, can be detected across three amygdala subdivisions: laterobasal, centromedial, and superficial. In a sample of 65 healthy adults, voxelwise regression analyses demonstrated positively-predicted ventral and negatively-predicted dorsal networks associated with the total amygdala, consistent with previous animal and human studies. Investigation of individual amygdala subdivisions revealed distinct differences in connectivity patterns within the amygdala and throughout the brain. Spontaneous activity in the laterobasal subdivision predicted activity in temporal and frontal regions, while activity in the centromedial nuclei predicted activity primarily in striatum. Activity in the superficial subdivision positively predicted activity throughout the limbic lobe. These findings suggest that resting state fMRI can be used to investigate human amygdala networks at a greater level of detail than previously appreciated, allowing for the further advancement of translational models. © 2008 Elsevier Inc. All rights reserved. The central role of the amygdala in processing emotions and mediating fear responses is well established (LeDoux, 2000). Tucked away in the medial temporal lobe and comparatively small in size, the human amygdala is not easily studied in vivo. Further, the amygdala is not a single structure, but a complex of structurally and functionally heterogeneous nuclei which have been examined extensively in rodents and non-human primates, but not in humans. In recent years, advances have also beenmade in the study of the amygdaloid complex in humans. For example, using cytoarchitectonic mapping methods similar to those used in animal studies, Amunts et al. (2005) delineated probabilistic maps of amygdala subregions. Neuroimaging studies have also demonstrated structural (Sheline et al., 1998) as well as functional (Morris et al., 2001; Ball et al., 2007; Kim et al., 2003; Whalen et al., 2004) distinctions in the human amygdala that parallel those observed in animals. Translational models implicating specific amygdala nuclei in processes such as fear learning and extinction are beginning to inform our understanding of anxiety and related psychopathology in humans, making more detailed evaluations of the amygdala and its circuits even more essential (Davis, 2006; Akirav and Maroun, 2007). Considering the amygdala as a single unit, as is common in most human neuroimaging studies, potentially overlooks the independent functions and patterns of connectivity of individual subdivisions (laterobasal, centromedial, and superficial), and their component nuclei, that have been discerned in animals (Pitkanen, 2000; Russchen et al., 1985; Davis, 2006). The laterobasal group of nuclei includes the lateral, basolateral, basomedial, and basoventral nuclei. These nuclei facilitate associative learning processes such as fear conditioning through afferents from cortical and subcortical regions, including thalamus, hippocampus, and prefrontal cortex (LeDoux, 2003; Phelps and LeDoux, 2005). The centromedial group, composed of the central and medial nuclei, plays a significant role in generating behavioral responses through projections to the brainstem, as well as cortical and striatal regions such as the caudate (Davis, 1997; LeDoux, 2003). The superficial subdivision of the amygdala lies adjacent to the laterobasal group and includes the cortical nuclei involved in olfactory (Heimer and Van Hoesen, 2006; Price, 2003) and affective processes (Gonzalez-Lima and Scheich, 1986). Task-based fMRI studies have begun to identify distinct patterns of activation in subregions of the amygdala, primarily making distinctions NeuroImage 45 (2009) 614–626 ⁎ Corresponding author. NYU Child Study Center 215 Lexington Avenue, 13th Floor New York, N.Y. 10016, USA. Fax: +1 212 263 3691. E-mail address: amy.roy@nyumc.org (A.K. Roy). 1053-8119/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage. 2008.11. 030