BNST neurocircuitry in humans
Introduction
Elucidating the neural basis of common psychiatric disorders, such as anxiety and addiction, can guide the development of novel preventions and therapeutics. Complex states likely result from alterations in underlying neurocircuitry, and both structural and functional measures of connectivity show promise as disease biomarkers. Neuroimaging methods provide a powerful tool for examining neural circuits in vivo and progress has been made in identifying the neurocircuitry of anxiety (Shin and Liberzon, 2010) and addiction (Koob and Volkow, 2010). However, most investigations have focused on larger brain regions due to concerns about the ability of neuroimaging methods to measure smaller structures. With advances in imaging technology and analytic techniques, the exploration of circuits involving smaller brain regions is now possible.
A prime candidate for this type of investigation is the bed nucleus of the stria terminalis (BNST), a small structure in the basomedial forebrain. Research in rodents has established that the BNST mediates sustained anxiety responses (Davis et al., 1997, Hammack et al., 2004, Lungwitz et al., 2012, Sullivan et al., 2004, Waddell et al., 2006). Preliminary evidence also links BNST function to anxiety in non-human primates (Fox et al., 2008, Kalin et al., 2005) and humans (Alvarez et al., 2011, Grupe et al., 2013, Hasler et al., 2007, Somerville et al., 2013, Somerville et al., 2010). BNST function also mediates reward-seeking and addictive behaviors in rodents (Dumont et al., 2005, Kash et al., 2008, Koob and Le Moal, 2008, Leri et al., 2002, Silberman and Winder, 2013) and humans (O'Daly et al., 2012).
Specific neural circuits—rather than specific brain regions—are crucial for complex behaviors, as recently demonstrated using optogenetics (Jennings et al., 2013, Kim et al., 2013). Most of our knowledge about BNST structural connectivity comes from tracer studies in rodents, which have shown that the BNST has extensive connections to other limbic regions—including the amygdala, hypothalamus, hippocampus, periaqueductal gray, and infralimbic cortex (Dong and Swanson, 2006b, Dong and Swanson, 2006c, Dong and Swanson, 2004a, Dong and Swanson, 2004b, Dong and Swanson, 2006a, Dong et al., 2001b)—and striatal regions, including the nucleus accumbens and ventral tegmental area (Dong et al., 2001b). In primates, however, surprisingly little is known about BNST neurocircuitry. Tract-tracing studies in non-human primates have focused predominantly on relationships between the BNST and other limbic structures (Price and Amaral, 1981). In a single study using functional connectivity in humans and non-human primates, Oler et al. (2012) demonstrated that the BNST is functionally connected with the central nucleus of the amygdala, consistent with previously demonstrated rodent and non-human primate anatomical connections (Dong et al., 2001a). The BNST is much larger and more developed in humans than in rodents (Lesur et al., 1989), suggesting that BNST circuits may be altered in humans; however, to our knowledge, no studies have examined BNST structural or functional connectivity across the whole human brain. In the present study, we used diffusion tensor imaging (DTI) and resting state functional MRI (rs-fMRI) methods to identify patterns of BNST structural and functional connectivity in humans.
Section snippets
Participants
We selected 82 DTI scans and 99 rs-fMRI scans of healthy controls with no psychiatric illnesses from two ongoing studies for this analysis. Scans were selected based on the following criteria: 1) the participant had no current or past psychiatric disorders, as determined by the Structured Clinical Interview for the DSM-IV (SCID I-P) (First et al., 2002); 2) participants were not on any psychotropic medications (within the past 6 months); and 3) the scan was determined to have good data quality
Structural and functional connectivity of the BNST
Of the 108 target regions tested using structural connectivity, 17 regions showed significant likelihood of structural connectivity with the BNST (Figs. 4A, C). As expected, these included several regions of the basal ganglia (accumbens, caudate, putamen, and pallidum), limbic system (amygdala, subcallosal cortex, and hippocampus), and thalamus, indicating evolutionarily-conserved connections across species. We also identified a connection with the temporal pole which has not been previously
Discussion
The goal of this study was to describe the structural and functional connectivity of the BNST in humans. Using DTI and rs-fMRI, we provide a preliminary characterization of human BNST neurocircuitry. The BNST was structurally and functionally connected with multiple subcortical regions, including limbic, thalamic, and basal ganglia structures, replicating structural findings in rodents (Dong and Swanson, 2006a, Dong and Swanson, 2004a, Dong et al., 2001b). We also identified two novel
Acknowledgments
Research reported in this publication was supported in part by funding from the National Institute of Mental Health (K01-MH083052, JUB; F30-MH097344-01A1, JAC; and T32-MH018921), the Vanderbilt Institute for Clinical and Translational Research (NCRR UL1-RR024975; TL1-RR024978), and the Vanderbilt University Institute of Imaging Science. The research was also supported by the Vanderbilt Psychiatric Genotype/Phenotype Project, the Vanderbilt Brain Institute, and the Vanderbilt Medical Scientist
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Both authors contributed equally to this work.