The Human BNST: Functional Role in Anxiety and Addiction

Abstract

The consequences of chronic stress on brain structure and function are far reaching. Whereas stress can produce short-term adaptive changes in the brain, chronic stress leads to long-term maladaptive changes that increase vulnerability to psychiatric disorders, such as anxiety and addiction. These two disorders are the most prevalent psychiatric disorders in the United States, and are typically chronic, disabling, and highly comorbid. Emerging evidence implicates a tiny brain region-the bed nucleus of the stria terminalis (BNST)-in the body's stress response and in anxiety and addiction. Rodent studies provide compelling evidence that the BNST plays a central role in sustained threat monitoring, a form of adaptive anxiety, and in the withdrawal and relapse stages of addiction; however, little is known about the role of BNST in humans. Here, we review current evidence for BNST function in humans, including evidence for a role in the production of both adaptive and maladaptive anxiety. We also review preliminary evidence of the role of BNST in addiction in humans. Together, these studies provide a foundation of knowledge about the role of BNST in adaptive anxiety and stress-related disorders. Although the field is in its infancy, future investigations of human BNST function have tremendous potential to illuminate mechanisms underlying stress-related disorders and identify novel neural targets for treatment.

Figure 1

Human anxiety and addiction circuits. The BNST is a central node in both anxiety and addiction neurocircuitry. (left) The BNST is centrally located to influence human anxiety responses, with connections to multiple limbic and brainstem regions that mediate defensive response to threat, including the amygdala, anterior insula, hippocampus, hypothalamus, and periaqueductal gray (adapted from Grupe and Nitschke, 2013). (right) The BNST is engaged during the negative emotional stage of withdrawal and interacts with the amygdala and ventral striatum, including the shell of the nucleus accumbens and ventral tegmental area, to mediate negative reinforcement (adapted from Koob and Volkow, 2010). AI, anterior insula; Amyg, amygdala; BNST, bed nucleus of the stria terminalis; Hy, hypothalamus; PAG, periaqueductal gray; VS, ventral striatum.

Figure 2

The human bed nucleus of the stria terminalis (BNST). (Left) The human brain is shown as an illustration with the BNST highlighted in yellow (Gray, 1918). (Middle) For reference, a similar slice is shown for fixed tissue (Mai et al, 2008). (Right) Our BNST mask is outlined in yellow on a 7T gradient spin echo (GRASE) magnetic resonance image (adapted from Avery et al, 2014). Note that in the 7T mask we use the anterior commissure as the ventral boundary of the BNST—the subcommissural extent of the BNST is difficult to distinguish with certainty from surrounding tissue because of MRI partial volume effects and its small size.

Figure 3

A model for anxiety and fear in rodents and humans. There are similarities between the defensive distance continuum demonstrated in rodents and the analogous predictable threat continuum in humans. Stages of threat can vary along either physical or psychological spectra ranging from distant–close physical threat and unpredictable–predictable psychological threat. In rodents, distant threats elicit anxiety-like behaviors mediated by the BNST; as threats move closer, amygdala-mediated fear behaviors become prominent. In humans, anxiety is elicited by unpredictable threat tasks; anticipation of unpredictable threat engages the BNST; in contrast, predictable threat tasks engage the amygdala. These findings in humans parallel the neural dissociation observed in rodents, suggesting a parallel model in rodents and humans: threats that are spatially and temporally distant provoke anxiety and are mediated by the BNST, whereas threats that are spatially or temporally close provoke fear and are mediated by the amygdala.

Figure 4

Meta-analysis of BNST findings in human threat anticipation studies. We performed a GingerALE meta-analysis of the reported BNST coordinates from nine human imaging studies, thresholded at P<0.001 (top); included studies are marked with an asterisk in Table 1. Our BNST mask overlays the meta-analysis (bottom). The color map represents activation likelihood values.

Figure 5

Structural and functional connectivity of the human BNST. (a) Our structural connectivity analysis reveals anatomical connections between the BNST and multiple limbic and striatal structures, largely confirming anatomical connections in rodents (Avery et al, 2014). (b) Our resting-state functional connectivity analysis reveals a network of connections mostly overlapping with BNST anatomical connections, with the addition of a novel prefrontal cortex connection (Avery et al, 2014). Functional connections are not constrained by direct structural connections, instead providing evidence of the broader network of regions involved in accomplishing a task. (c) Importantly, the BNST functional connectivity network has been replicated in a recent study (McMenamin et al, 2014).