Unfolding the direct connectivity of the occipital cortex with the hypothalamic, septal and BNST nuclei of the human brain.

The hypothalamus plays essential roles in the human brain by regulating feeding, fear, aggression, reproductive behaviors, and autonomic activities. The septal nuclei and the bed nucleus of stria terminalis (BNST) are also known to be involved in control of autonomic, motivational, learning, emotional and associative processes in the human brain. Multiple animal dissection studies have revealed direct connectivity between central limbic gray matter nuclei and occipital cortex, particularly from the hypothalamic, septal and BNST nuclei. However, the detailed anatomy of this connectivity in the human brain has yet to be determined. The primary objective of this study was to explore the utility of high spatial and high angular resolution diffusion weighted tractography techniques for mapping the connectivity pathways between the occipital cortex and central limbic gray matter nuclei in the human brain. We studied 30 healthy adult human brains, delineated, and reconstructed the trajectory of the occipito-hypothalamic/septal/BNST for the first time in the human brain.

Aberrant functional connectivity of the bed nucleus of the stria terminalis and its age dependence in children and adolescents with social anxiety disorder.

BACKGROUND: Social anxiety disorder (SAD) is a prevalent and impairing mental disorder among children and adolescents. The bed nucleus of the stria terminalis (BNST) plays a critical role in anxiety disorders, including valence surveillance and hypervigilance for potential threats. However, the role of BNST and its related functional network in children and adolescents with SAD has not been fully investigated. This study examined the aberration of BNST's functional connectivity and its age dependence in adolescents with SAD. METHODS: Using a sample of 75 SAD patients and 75 healthy controls (HCs) children aged 9-18 years old, we delineated the group-by-age interaction of BNST-seeded functional connectivity (FC) during resting state and movie-watching. The relationships between BNST-seeded FC and clinical scores were also examined. RESULTS: During movie viewing, the FC between the right BNST and the left amygdala, bilateral posterior cingulate cortex (PCC), bilateral superior temporal cortex, and right pericalcarine cortex showed a diagnostic group-by-age interaction. Compared to HCs, SAD patients showed a significant enhancement of the above FC at younger ages. Meanwhile, they showed an age-dependent decrease in FC between the right BNST and left amygdala. Furthermore, for SAD patients, FC between the right BNST and left amygdala during movie viewing was positively correlated with separation anxiety scores. CONCLUSIONS: The right BNST plays an essential role in the aberrant brain functioning in children and adolescents with SAD. The atypicality of BNST's FC has remarkable age dependence in SAD, suggesting an association of SAD with neurodevelopmental traits.

Alterations in BNST Intrinsic Functional Connectivity in Early Abstinence from Alcohol Use Disorder.

AIMS: Maintaining abstinence from alcohol use disorder (AUD) is extremely challenging, partially due to increased symptoms of anxiety and stress that trigger relapse. Rodent models of AUD have identified that the bed nucleus of the stria terminalis (BNST) contributes to symptoms of anxiety-like behavior and drug-seeking during abstinence. In humans, however, the BNST's role in abstinence remains poorly understood. The aims of this study were to assess BNST network intrinsic functional connectivity in individuals during abstinence from AUD compared to healthy controls and examine associations between BNST intrinsic functional connectivity, anxiety and alcohol use severity during abstinence. METHODS: The study included resting state fMRI scans from participants aged 21-40 years: 20 participants with AUD in abstinence and 20 healthy controls. Analyses were restricted to five pre-selected brain regions with known BNST structural connections. Linear mixed models were used to test for group differences, with sex as a fixed factor given previously shown sex differences. RESULTS: BNST-hypothalamus intrinsic connectivity was lower in the abstinent group relative to the control group. There were also pronounced sex differences in both the group and individual analyses; many of the findings were specific to men. Within the abstinent group, anxiety was positively associated with BNST-amygdala and BNST-hypothalamus connectivity, and men, not women, showed a negative relationship between alcohol use severity and BNST-hypothalamus connectivity. CONCLUSIONS: Understanding differences in connectivity during abstinence may help explain the clinically observed anxiety and depression symptoms during abstinence and may inform the development of individualized treatments.

Subiculum-BNST structural connectivity in humans and macaques.

Invasive tract-tracing studies in rodents implicate a direct connection between the subiculum and bed nucleus of the stria terminalis (BNST) as a key component of neural pathways mediating hippocampal regulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis. A clear characterisation of the connections linking the subiculum and BNST in humans and non-human primates is lacking. To address this, we first delineated the projections from the subiculum to the BNST using anterograde tracers injected into macaque monkeys, revealing evidence for a monosynaptic subiculum-BNST projection involving the fornix. Second, we used in vivo diffusion MRI tractography in macaques and humans to demonstrate substantial subiculum complex connectivity to the BNST in both species. This connection was primarily carried by the fornix, with additional connectivity via the amygdala, consistent with rodent anatomy. Third, utilising the twin-based nature of our human sample, we found that microstructural properties of these tracts were moderately heritable (h2 ∼ 0.5). In a final analysis, we found no evidence of any significant association between subiculum complex-BNST tract microstructure and indices of perceived stress/dispositional negativity and alcohol use, derived from principal component analysis decomposition of self-report data. Our findings address a key translational gap in our knowledge of the neurocircuitry regulating stress.

Bed nucleus of the stria terminalis and amygdala responses to unpredictable threat in children.

Substantial evidence from studies in humans suggests the amygdala is pivotal for anxiety. Findings from animal models and translational studies suggests the bed nucleus of the stria terminalis (BNST) is also critical for anxiety and the anticipation of unpredictable threat in adults. However, it remains unknown whether the BNST is involved in unpredictable threat anticipation in children. Forty-two 8-10-year-olds completed resting-state functional magnetic resonance imaging (fMRI) scans and an unpredictable threat fMRI task in which they were trained to associate cues with images. Intrinsic connectivity analyses were performed to establish functional BNST and amygdala networks. BNST and amygdala activation to cues and images was tested. Significant findings were followed by task-based functional connectivity analyses. Children showed evidence for BNST and amygdala intrinsic connectivity that was similar to previous patterns observed in adults. In response to unpredictable cues relative to neutral face cues, children had a significant amygdala response but no response in the BNST. The amygdala, but not the BNST, also showed a significantly greater response to fear face images relative to neutral images. Thus, unpredictable threat activated the amygdala, but not BNST, in children. This finding is contrary to studies showing robust BNST activation to unpredictable threat in adults and may suggest that the BNST's role in threat processing emerges later in development.

A deep learning toolbox for automatic segmentation of subcortical limbic structures from MRI images.

A tool was developed to automatically segment several subcortical limbic structures (nucleus accumbens, basal forebrain, septal nuclei, hypothalamus without mammillary bodies, the mammillary bodies, and fornix) using only a T1-weighted MRI as input. This tool fills an unmet need as there are few, if any, publicly available tools to segment these clinically relevant structures. A U-Net with spatial, intensity, contrast, and noise augmentation was trained using 39 manually labeled MRI data sets. In general, the Dice scores, true positive rates, false discovery rates, and manual-automatic volume correlation were very good relative to comparable tools for other structures. A diverse data set of 698 subjects were segmented using the tool; evaluation of the resulting labelings showed that the tool failed in less than 1% of cases. Test-retest reliability of the tool was excellent. The automatically segmented volume of all structures except mammillary bodies showed effectiveness at detecting either clinical AD effects, age effects, or both. This tool will be publicly released with FreeSurfer (surfer.nmr.mgh.harvard.edu/fswiki/ScLimbic). Together with the other cortical and subcortical limbic segmentations, this tool will allow FreeSurfer to provide a comprehensive view of the limbic system in an automated way.

Drinking reduction during cognitive behavioral therapy for alcohol use disorder is associated with a reduction in anterior insula-bed nucleus of the stria terminalis resting-state functional connectivity.

BACKGROUND: Connectivity between the anterior insula (AI) and the bed nucleus of the stria terminalis (BNST) may play a role in negative emotions that drive compulsive drinking in patients with alcohol use disorder (AUD). We hypothesized that reductions in drinking during cognitive behavioral therapy (CBT), an effective treatment that teaches regulation (coping) skills for managing negative emotions during abstinence, would be associated with reductions in resting-state functional connectivity (RSFC) between the AI and the BNST. METHODS: We included 18 patients with a Diagnostic and Statistical Manual of Mental Disorders, fifth edition diagnosis of AUD who were (1) seeking treatment and (2) drinking heavily at baseline. We measured RSFC as Pearson's correlation between the BNST and multiple regions of interest in the insula at baseline and after completion of 12 weeks of a single-arm clinical trial of outpatient CBT. We also assessed the number of heavy drinking days over the previous 28 days (NHDD) at both time points. We used 1-sample t-tests to evaluate AI-BNST RSFC at baseline, paired t-tests to evaluate changes in AI-BNST RSFC from pre-CBT to post-CBT, and linear regression to evaluate the relationship between changes in AI-BNST RSFC and NHDD. RESULTS: We found a significant positive RSFC between the AI and the BNST at baseline (p = 0.0015). While there were no significant changes in AI-BNST RSFC from pre- to post-CBT at the group level (p = 0.42), we found that individual differences in reductions in AI-BNST RSFC from pre- to post-CBT were directly related to reductions in NHDD from pre- to post-CBT (r = 0.73, p = 0.0008). CONCLUSIONS: These findings provide preliminary evidence that reduced AI-BNST RSFC may be a mechanism of drinking reduction in AUD and that AI-BNST RSFC may be a target for CBT and possibly other treatments.

Neural substrates of human fear generalization: A 7T-fMRI investigation.

Fear generalization - the tendency to interpret ambiguous stimuli as threatening due to perceptual similarity to a learned threat - is an adaptive process. Overgeneralization, however, is maladaptive and has been implicated in a number of anxiety disorders. Neuroimaging research has indicated several regions sensitive to effects of generalization, including regions involved in fear excitation (e.g., amygdala, insula) and inhibition (e.g., ventromedial prefrontal cortex). Research has suggested several other small brain regions may play an important role in this process (e.g., hippocampal subfields, bed nucleus of the stria terminalis [BNST], habenula), but, to date, these regions have not been examined during fear generalization due to limited spatial resolution of standard human neuroimaging. To this end, we utilized the high spatial resolution of 7T fMRI to characterize the neural circuits involved in threat discrimination and generalization. Additionally, we examined potential modulating effects of trait anxiety and intolerance of uncertainty on neural activation during threat generalization. In a sample of 31 healthy undergraduate students, significant positive generalization effects (i.e., greater activation for stimuli with increasing perceptual similarity to a learned threat cue) were observed in the visual cortex, thalamus, habenula and BNST, while negative generalization effects were observed in the dentate gyrus, CA1, and CA3. Associations with individual differences were underpowered, though preliminary findings suggested greater generalization in the insula and primary somatosensory cortex may be correlated with self-reported anxiety. Overall, findings largely support previous neuroimaging work on fear generalization and provide additional insight into the contributions of several previously unexplored brain regions.

Corticotropin-releasing factor neurons in the bed nucleus of the stria terminalis exhibit sex-specific pain encoding in mice.

The bed nucleus of the stria terminalis (BNST) plays an emerging role in pain regulation. Pharmacological studies have found that inhibiting corticotropin-releasing factor (CRF) signaling in the BNST can selectively mitigate the sensory and affective-motivational components of pain. However, mechanistic insight on the source of CRF that drives BNST responses to these harmful experiences remains unknown. In the present study, we used a series of genetic approaches to show that CRF in the BNST is engaged in the processing and modulation of pain. We conducted cell-type specific in vivo calcium imaging in CRF-Cre mice and found robust and synchronized recruitment of BNSTCRF neurons during acute exposures to noxious heat. Distinct patterns of recruitment were observed by sex, as the magnitude and timing of heat responsive activity in BNSTCRF neurons differed for male and female mice. We then used a viral approach in Floxed-CRF mice to selectively reduce CRF expression in the BNST and found it decreased nociceptive sensitivity for both sexes and increased paw attending for females. Together, these findings reveal that CRF in the BNST influences multiple facets of the pain experience to impact the sex-specific expression of pain-related behaviors.

Optimization of whole-brain rabies virus tracing technology for small cell populations.

The lateral hypothalamus (LH) is critically involved in the regulation of homeostatic energy balance. Some neurons in the LH express receptors for leptin (LepRb), a hormone known to increase energy expenditure and decrease energy intake. However, the neuroanatomical inputs to LepRb-expressing LH neurons remain unknown. We used rabies virus tracing technology to map these inputs, but encountered non-specific tracing. To optimize this technology for a minor cell population (LepRb is not ubiquitously expressed in LH), we used LepRb-Cre mice and assessed how different titers of the avian tumor virus receptor A (TVA) helper virus affected rabies tracing efficiency and specificity. We found that rabies expression is dependent on TVA receptor expression, and that leakiness of TVA receptors is dependent on the titer of TVA virus used. We concluded that a titer of 1.0-3.0 × 107 genomic copies per µl of the TVA virus is optimal for rabies tracing. Next, we successfully applied modified rabies virus tracing technology to map inputs to LepRb-expressing LH neurons. We discovered that other neurons in the LH itself, the periventricular hypothalamic nucleus (Pe), the posterior hypothalamic nucleus (PH), the bed nucleus of the stria terminalis (BNST), and the paraventricular hypothalamic nucleus (PVN) are the most prominent input areas to LepRb-expressing LH neurons.

Alterations in connectivity of the bed nucleus of the stria terminalis during early abstinence in individuals with alcohol use disorder.

BACKGROUND: For individuals with Alcohol Use Disorder (AUD), long-term recovery is difficult in part due to symptoms of anxiety that occur during early abstinence and can trigger relapse. Research in rodent models of AUD has identified the bed nucleus of the stria terminalis (BNST), a small, sexually dimorphic, subcortical region, as critical for regulating anxiety-like behaviors during abstinence, particularly in female mice. Furthermore, prolonged alcohol use and subsequent abstinence alter BNST afferent and efferent connections to other brain regions. To our knowledge, however, no studies of early abstinence have investigated BNST structural connectivity in humans during abstinence; this study addresses that gap. METHODS: Nineteen participants with AUD currently in early abstinence and 20 healthy controls completed a diffusion tensor imaging (DTI) scan. BNST structural connectivity was evaluated using probabilistic tractography. A linear mixed model was used to test between-groups differences in BNST network connectivity. Exploratory analyses were conducted to test for correlations between BNST connectivity and alcohol use severity and anxiety within the abstinence group. Sex was included as a factor for all analyses. RESULTS: The BNST showed stronger structural connectivity with the BNST network in early abstinence women than in control women, which was not seen in men. Women also showed region-specific differences, with stronger BNST-hypothalamus structural connectivity but weaker vmPFC-BNST structural connectivity than men. Exploratory analyses also demonstrated a relationship between alcohol use severity and vmPFC-BNST structural connectivity that was moderated by sex. CONCLUSIONS: This study is the first to demonstrate BNST structural connectivity differences in early abstinence and revealed key sex differences. The sex-specific differences in BNST structural connectivity during early abstinence could underlie known sex differences in abstinence symptoms and relapse risk and help to inform potential sex-specific treatments.

Opposing relationships of childhood threat and deprivation with stria terminalis white matter.

While stress may be a potential mechanism by which childhood threat and deprivation influence mental health, few studies have considered specific stress-related white matter pathways, such as the stria terminalis (ST) and medial forebrain bundle (MFB). Our goal was to examine the relationships between childhood adversity and ST and MFB structural integrity and whether these pathways may provide a link between childhood adversity and affective symptoms and disorders. Participants were young adults (n = 100) with a full distribution of maltreatment history and affective symptom severity. Threat was determined by measures of childhood abuse and repeated traumatic events. Socioeconomic deprivation (SED) was determined by a measure of childhood socioeconomic status (parental education). Participants underwent diffusion spectrum imaging. Human Connectome Project data was used to perform ST and MFB tractography; these tracts were used as ROIs to extract generalized fractional anisotropy (gFA) from each participant. Childhood threat was associated with ST gFA, such that greater threat was associated with less ST gFA. SED was also associated with ST gFA, however, conversely to threat, greater SED was associated with greater ST gFA. Additionally, threat was negatively associated with MFB gFA, and MFB gFA was negatively associated with post-traumatic stress symptoms. Our results suggest that childhood threat and deprivation have opposing influences on ST structural integrity, providing new evidence that the context of childhood adversity may have an important influence on its neurobiological effects, even on the same structure. Further, the MFB may provide a novel link between childhood threat and affective symptoms.

Effective connectivity between bed nucleus of the stria terminalis and amygdala: Reproducibility and relation to anxiety.

In a previous study, we investigated the resting-state fMRI effective connectivity (EC) between the bed nucleus of the stria terminalis (BNST) and the laterobasal (LB), centromedial (CM), and superficial (SF) amygdala. We found strong negative EC from all amygdala nuclei to the BNST, while the BNST showed positive EC to the amygdala. However, the validity of these findings remains unclear, since a reproduction in different samples has not been done. Moreover, the association of EC with measures of anxiety offers deeper insight, due to the known role of the BNST and amygdala in fear and anxiety. Here, we aimed to reproduce our previous results in three additional samples. We used spectral Dynamic Causal Modeling to estimate the EC between the BNST, the LB, CM, and SF, and its association with two measures of self-reported anxiety. Our results revealed consistency over samples with regard to the negative EC from the amygdala nuclei to the BNST, while the positive EC from BNST to the amygdala was also found, but weaker and more heterogenic. Moreover, we found the BNST-BNST EC showing a positive and the CM-BNST EC, showing a negative association with anxiety. Our study suggests a reproducible pattern of negative EC from the amygdala to the BNST along with weaker positive EC from the BNST to the amygdala. Moreover, less BNST self-inhibition and more inhibitory influence from the CM to the BNST seems to be a pattern of EC that is related to higher anxiety.

Extended-amygdala intrinsic functional connectivity networks: A population study.

Pre-clinical and human neuroimaging research implicates the extended-amygdala (ExtA) (including the bed nucleus of the stria terminalis [BST] and central nucleus of the amygdala [CeA]) in networks mediating negative emotional states associated with stress and substance-use behaviours. The extent to which individual ExtA structures form a functionally integrated unit is controversial. We utilised a large sample (n > 1,000 healthy young adult humans) to compare the intrinsic functional connectivity networks (ICNs) of the BST and CeA using task-free functional magnetic resonance imaging (fMRI) data from the Human Connectome Project. We assessed whether inter-individual differences within these ICNs were related to two principal components representing negative disposition and alcohol use. Building on recent primate evidence, we tested whether within BST-CeA intrinsic functional connectivity (iFC) was heritable and further examined co-heritability with our principal components. We demonstrate the BST and CeA to have discrete, but largely overlapping ICNs similar to previous findings. We found no evidence that within BST-CeA iFC was heritable; however, post hoc analyses found significant BST iFC heritability with the broader superficial and centromedial amygdala regions. There were no significant correlations or co-heritability associations with our principal components either across the ICNs or for specific BST-Amygdala iFC. Possible differences in phenotype associations across task-free, task-based, and clinical fMRI are discussed, along with suggestions for more causal investigative paradigms that make use of the now well-established ExtA ICNs.

Anxiety and the Neurobiology of Temporally Uncertain Threat Anticipation.

When extreme, anxiety-a state of distress and arousal prototypically evoked by uncertain danger-can be debilitating. Uncertain anticipation is a shared feature of situations that elicit signs and symptoms of anxiety across psychiatric disorders, species, and assays. Despite the profound significance of anxiety for human health and wellbeing, the neurobiology of uncertain-threat anticipation remains unsettled. Leveraging a paradigm adapted from animal research and optimized for fMRI signal decomposition, we examined the neural circuits engaged during the anticipation of temporally uncertain and certain threat in 99 men and women. Results revealed that the neural systems recruited by uncertain and certain threat anticipation are anatomically colocalized in frontocortical regions, extended amygdala, and periaqueductal gray. Comparison of the threat conditions demonstrated that this circuitry can be fractionated, with frontocortical regions showing relatively stronger engagement during the anticipation of uncertain threat, and the extended amygdala showing the reverse pattern. Although there is widespread agreement that the bed nucleus of the stria terminalis and dorsal amygdala-the two major subdivisions of the extended amygdala-play a critical role in orchestrating adaptive responses to potential danger, their precise contributions to human anxiety have remained contentious. Follow-up analyses demonstrated that these regions show statistically indistinguishable responses to temporally uncertain and certain threat anticipation. These observations provide a framework for conceptualizing anxiety and fear, for understanding the functional neuroanatomy of threat anticipation in humans, and for accelerating the development of more effective intervention strategies for pathological anxiety.SIGNIFICANCE STATEMENT Anxiety-an emotion prototypically associated with the anticipation of uncertain harm-has profound significance for public health, yet the underlying neurobiology remains unclear. Leveraging a novel neuroimaging paradigm in a relatively large sample, we identify a core circuit responsive to both uncertain and certain threat anticipation, and show that this circuitry can be fractionated into subdivisions with a bias for one kind of threat or the other. The extended amygdala occupies center stage in neuropsychiatric models of anxiety, but its functional architecture has remained contentious. Here we demonstrate that its major subdivisions show statistically indistinguishable responses to temporally uncertain and certain threat. Collectively, these observations indicate the need to revise how we think about the neurobiology of anxiety and fear.

Anterior Limb of Internal Capsule and Bed Nucleus of Stria Terminalis Stimulation for Gilles de la Tourette Syndrome with Obsessive-Compulsive Disorder in Adolescence: A Case of Success.

Gilles de la Tourette syndrome (GTS) is a neurobehavioral disorder comprising motor and vocal tics. In most cases it is associated with other disorders such as obsessive-compulsive disorder (OCD). In refractory cases deep brain stimulation (DBS) is a valid treatment option. This paper describes the case of a 15-year-old adolescent with an extremely refractory GTS with associated OCD. The patient developed catatonia associated with OCD, which partially remitted after electroconvulsive therapy. At the peak of the disease the Yale Global Tic Severity Scale (YGTSS) was 100 and the patient required sedation and intubation. All medical treatment options were unsuccessful. Bilateral DBS of the anterior limb of internal capsule (ALIC)/bed nucleus of stria terminalis (BST) region was performed, using a target below the BST and a trajectory through the ALIC, with stimulation of contacts 0 and 3. Two weeks after surgery sedatives were suspended and the patient was successfully extubated. One year after surgery the patient reached a YGTSS of 19, representing an 81% improvement. OCD completely resolved. Adverse events were a superficial infection and weight gain. In conclusion, this ALIC/BST stimulation appears to have been an effective and safe treatment for GTS with OCD in this case. Young age should not be an exclusion criterion for DBS in severe GTS and OCD. Further studies should be pursued for this target.

BNST-insula structural connectivity in humans.

The bed nucleus of the stria terminalis (BNST) is emerging as a critical region in multiple psychiatric disorders including anxiety, PTSD, and alcohol and substance use disorders. In conjunction with growing knowledge of the BNST, an increasing number of studies examine connections of the BNST and how those connections impact BNST function. The importance of this BNST network is highlighted by rodent studies demonstrating that projections from other brain regions regulate BNST activity and influence BNST-related behavior. While many animal and human studies replicate the components of the BNST network, to date, structural connections between the BNST and insula have only been described in rodents and have yet to be shown in humans. In this study, we used probabilistic tractography to examine BNST-insula structural connectivity in humans. We used two methods of dividing the insula: 1) anterior and posterior insula, to be consistent with much of the existing insula literature; and 2) eight subregions that represent informative cytoarchitectural divisions. We found evidence of a BNST-insula structural connection in humans, with the strongest BNST connectivity localized to the anteroventral insula, a region of agranular cortex. BNST-insula connectivity differed by hemisphere and was moderated by sex. These results translate rodent findings to humans and lay an important foundation for future studies examining the role of BNST-insula pathways in psychiatric disorders.

Stria terminalis, amygdala, and temporoparietal junction networks facilitate efficient emotion processing under expectations.

Rapid emotion processing is an ecologically essential ability for survival in social environments in which threatening or advantageous encounters dynamically and rapidly occur. Efficient emotion recognition is subserved by different processes, depending on one's expectations; however, the underlying functional and structural circuitry is still poorly understood. In this study, we delineate brain networks that subserve fast recognition of emotion in situations either congruent or incongruent with prior expectations. For this purpose, we used multimodal neuroimaging and investigated performance on a dynamic emotion perception task. We show that the extended amygdala structural and functional networks relate to speed of emotion processing under threatening conditions. Specifically, increased microstructure of the right stria terminalis, an amygdala white-matter pathway, was related to faster detection of emotion during actual presentation of anger or after cueing anger. Moreover, functional connectivity of right amygdala with limbic regions was related to faster detection of anger congruent with cue, suggesting selective attention to threat. On the contrary, we found that faster detection of anger incongruent with cue engaged the ventral attention "reorienting" network. Faster detection of happiness, in either expectancy context, engaged a widespread frontotemporal-subcortical functional network. These findings shed light on the functional and structural circuitries that facilitate speed of emotion recognition and, for the first time, elucidate a role for the stria terminalis in human emotion processing.

Stria terminalis microstructure in humans predicts variability in orienting towards threat.

Current concepts of the extended amygdala posit that basolateral to central amygdala projections mediate fear-conditioned autonomic alerting, whereas projections to the bed nucleus of the stria terminalis mediate sustained anxiety. Using diffusion tensor imaging tractography in humans, we show that microstructure of the stria terminalis correlates with an orienting bias towards threat in a saccade decision task, providing the first evidence that this circuit supports decisions guiding evaluation of threatening stimuli.

Resting-state connectivity of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in clinical anxiety

Background: The central nucleus of the amygdala and bed nucleus of the stria terminalis are involved primarily in phasic and sustained aversive states. Although both structures have been implicated in pathological anxiety, few studies with a clinical population have specifically focused on them, partly because of their small size. Previous work in our group used high-resolution imaging to map the restingstate functional connectivity of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in healthy subjects at 7 T, confirming and extending structural findings in humans and animals, while providing additional insight into cortical connectivity that is potentially unique to humans. Methods: In the current follow-up study, we contrasted resting-state functional connectivity in the bed nucleus of the stria terminalis and central nucleus of the amygdala at 7 T between healthy volunteers (n = 30) and patients with generalized and/or social anxiety disorder (n = 30). Results: Results revealed significant voxel-level group differences. Compared with healthy volunteers, patients showed stronger resting-state functional connectivity between the central nucleus of the amygdala and the lateral orbitofrontal cortex and superior temporal sulcus. They also showed weaker resting-state functional connectivity between the bed nucleus of the stria terminalis and the dorsolateral prefrontal cortex and occipital cortex. Limitations: These findings depart from a previous report of resting-state functional connectivity in the central nucleus of the amygdala and bed nucleus of the stria terminalis under sustained threat of shock in healthy volunteers. Conclusion: This study provides functional MRI proxies of the functional dissociation of the bed nucleus of the stria terminalis and central nucleus of the amygdala, and suggests that resting-state functional connectivity of key structures in the processing of defensive responses do not recapitulate changes related to induced state anxiety. Future work needs to replicate and further probe the clinical significance of these findings.