Acute alcohol administration dampens central extended amygdala reactivity.

Alcohol use is common, imposes a staggering burden on public health, and often resists treatment. The central extended amygdala (EAc)-including the bed nucleus of the stria terminalis (BST) and the central nucleus of the amygdala (Ce)-plays a key role in prominent neuroscientific models of alcohol drinking, but the relevance of these regions to acute alcohol consumption in humans remains poorly understood. Using a single-blind, randomized-groups design, multiband fMRI data were acquired from 49 social drinkers while they performed a well-established emotional faces paradigm after consuming either alcohol or placebo. Relative to placebo, alcohol significantly dampened reactivity to emotional faces in the BST. To rigorously assess potential regional differences in activation, data were extracted from unbiased, anatomically predefined regions of interest. Analyses revealed similar levels of dampening in the BST and Ce. In short, alcohol transiently reduces reactivity to emotional faces and it does so similarly across the two major divisions of the human EAc. These observations reinforce the translational relevance of addiction models derived from preclinical work in rodents and provide new insights into the neural systems most relevant to the consumption of alcohol and to the initial development of alcohol abuse in humans

Neural Substrates of Fear Generalization and Its Associations with Anxiety and Intolerance of Uncertainty

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, the proposed project utilized high resolution spatial resolution of 7T fMRI to (1) characterize the neural circuits involved in threat discrimination and generalization, and (2) examine 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, CA3, and basal nucleus of the amygdala. Associations with individual differences were limited, though greater generalization in the insula and primary somatosensory cortex was 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

UNDERSTANDING THE CONTRIBUTION OF THE CENTRAL EXTENDED AMYGDALA TO DISPOSITIONAL NEGATIVITY

Dispositional negativity (DN) is a key risk factor for a spectrum of adverse outcomes, including anxiety disorders, depression, and comorbid substance abuse. The central extended amygdala (EAc; an anatomical concept encompassing the bed nucleus of the stria terminalis [BST] and central nucleus of the amygdala [Ce]) is implicated in the development and maintenance of these disorders. However, disorders, like other psychological processes, reflect the coordinated actions of widely distributed networks. Yet, the functional architecture of the human EAc and its relation to individual differences in DN remains poorly understood. We investigated intrinsic functional connectivity (iFC) of the EAc in 185 healthy adults. Whole-brain regression analyses revealed that the BST and Ce show iFC with one another via the sublenticular extended amygdala. While both regions showed significant iFC with the ventromedial prefrontal cortex and with cingulate territories involved in adaptive control of anxiety-related behavior, the BST showed more robust coupling. Contrary to expectations, EAc iFC was not significantly associated with individual differences in DN. These observations provide a novel neurobiological framework for understanding a range of stress-sensitive disorders

An ontology-based segmentation scheme for tracking postnatal changes in the developing rodent brain with MRI

The postnatal period of neurodevelopment has been implicated in a number of brain disorders including autism and schizophrenia. Rodent models have proven to be invaluable in advancing our understanding of the human brain, and will almost certainly play a pivotal role in future studies on postnatal neurodevelopment. The growing field of magnetic resonance microscopy has the potential to revolutionize our understanding of neurodevelopment, if it can be successfully and appropriately assimilated into the vast body of existing neuroscience research. In this study, we demonstrate the utility of a developmental neuro-ontology designed specifically for tracking regional changes in MR biomarkers throughout postnatal neurodevelopment. Using this ontological classification as a segmentation guide, we track regional changes in brain volume in rats between postnatal day zero and postnatal day 80 and demonstrate differential growth rates in axial versus paraxial brain regions. Both the ontology and the associated label volumes are provided as a foundation for future MR-based studies of postnatal neurodevelopment in normal and disease states

Threat vigilance and intrinsic amygdala connectivity

A well-documented amygdala-dorsomedial prefrontal circuit is theorized to promote attention to threat (“threat vigilance”). Prior research has implicated a relationship between individual differences in trait anxiety/vigilance, engagement of this circuitry, and anxiogenic features of the environment (e.g., through threat-of-shock and movie-watching). In the present study, we predicted that—for those scoring high in self-reported anxiety and a behavioral measure of threat vigilance—this circuitry is chronically engaged, even in the absence of anxiogenic stimuli. Our analyses of resting-state fMRI data (N = 639) did not, however, provide evidence for such a relationship. Nevertheless, in our planned exploratory analyses, we saw a relationship between threat vigilance behavior (but not self-reported anxiety) and intrinsic amygdala-periaqueductal gray connectivity. Here, we suggest this subcortical circuitry may be chronically engaged in hypervigilant individuals, but that amygdala-prefrontal circuitry may only be engaged in response to anxiogenic stimuli

Understanding the anxiolytic effects of alcohol on the central extended amygdala in humans

The anxiety-reducing properties of alcohol are thought to contribute to development of alcohol dependence, particularly among individuals with anxiety disorders. Remarkably little is known, however, about the neural circuitry underlying anxiolytic effects of alcohol in humans. In a sample of 72 healthy adults, we employed the novel MultiThreat Countdown (MTC) task to investigate the dose-dependent consequences of acute alcohol intoxication (BAL range: 0.061 - 0.145%) during anticipation of certain or uncertain threat, compared to placebo. Focal analyses of the central extended amygdala revealed significant activation during threat in the right, but not left, hemisphere for both the central nucleus [Ce] and bed nucleus of the stria terminalis [BST]. Increasing BALs were associated with decreasing activation in right BST and self-reported fear/anxiety levels during threat. This effect did not differ between certain and uncertain threat. These results build upon converging lines of evidence and suggest involvement of BST in alcohol-induced anxiolysis

Prior Experiences of Racial Discrimination Impact Acute Resting-State Connectivity of the BNST as a Predictor of PTSD in Black Adults

Altered resting-state activity of the bed nucleus of the stria terminalis (BNST) – which mediates anxious arousal and threat monitoring – is implicated in the etiology of posttraumatic stress disorder (PTSD). Experiences of racial discrimination can also increase one’s risk for developing PTSD by eliciting chronic states of hypervigilance, which impair essential resting-state processes related to fear extinction. Considering the frequency in which Black Americans experience racial discrimination, the current study investigated acute BNST resting-state functional connectivity as a predictor of future PTSD symptoms, as well as the impact of racial discrimination on the BNST as a predictor of PTSD. Black adults (N = 95) who experienced a traumatic injury were recruited from the emergency department. Data was collected at two time points: (1) two-weeks post-trauma, where participants underwent a resting-state fMRI scan, and their baseline PTSD symptoms and history of racial discrimination were assessed; (2) six-months post-trauma, where their PTSD symptoms were reassessed. Results indicated that two-week BNST resting-state connectivity prospectively predicted PTSD symptoms six-months post-trauma. Additionally, prior experiences of racial discrimination moderated the relationship between acute BNST resting-state connectivity and future PTSD symptoms. Thus, in the acute aftermath of a traumatic event, resting-state connectivity of the BNST could be a useful biomarker of risk for PTSD in Black Americans, particularly for individuals who have experienced more racial discrimination throughout their lifetime

Anxiety and how to control it: the functional role of the bed nucleus of the stria terminalis.

Anxiety disorders afflict up to one third of the population. Research to date has primarily focused on the amygdala, however, new perspectives suggest that a tiny basal forebrain region known as the bed nucleus of the stria terminalis (BNST) may hold key insights into understanding and treating anxiety disorders. Therefore, my first aim was to empirically investigate the importance and influence of the BNST in anxiety processing. Using fearful faces and human screams as aversive stimuli, two threat conditions were created: one in which threats were certain and predictable (fear) and another in which threats were uncertain and unpredictable (anxiety). Results indicated that the amygdala showed preferential engagement during fear and displayed functional connectivity with regions involved in stimulus processing and motor response. By contrast, the BNST preferentially responded during anxiety and exhibited functional connectivity with prefrontal regions underlying interoception and rumination. Together, this suggests that the amygdala and BNST play distinct but complementary roles during threat processing, with the BNST specializing in the detection of potential threats to promote hypervigilant monitoring. A primary mechanism of impaired functioning in anxiety disorders is emotion dysregulation, and has been another key focus in research. However, most emotion regulation (ER) paradigms use explicitly cued pictorial stimuli (negative scenes or faces) that induce disgust, when anxiety, by definition, is a sustained response to uncertain or unpredictable prospective threats. Therefore, my second aim was to specifically investigate anxiety regulation. 30 participants underwent high-resolution fMRI (1.5 mm3) while performing a novel task — a hybrid of the previous task and a canonical ER task – in order to: 1) investigate whether the BNST can be downregulated during uncertain anticipation, and 2) characterize the prefrontal regulatory mechanisms. Results showed that anxiety regulation was associated with pronounced BNST downregulation, enhanced activation of prefrontal regions (right middle frontal gyrus [rMFG], right inferior frontal gyrus [rIFG]), and increased connectivity between the rIFG and BNST while simultaneously decreasing connectivity among attentional circuits. These results provide the first evidence that the BNST can be volitionally downregulated and further suggest that anxiety regulation modulates higher-order attentional systems to putatively reduce vigilance

Prior Experiences of Racial Discrimination Impact Acute Resting-state Connectivity of the Bnst as a Predictor of PTSD in Black Adults

Altered resting-state activity of the bed nucleus of the stria terminalis (BNST) – which mediates anxious arousal and threat monitoring – is implicated in the etiology of posttraumatic stress disorder (PTSD). Experiences of racial discrimination can also increase one’s risk for developing PTSD by eliciting chronic states of hypervigilance, which impair essential resting-state processes related to fear extinction. Considering the frequency in which Black Americans experience racial discrimination, the current study investigated acute BNST resting-state functional connectivity as a predictor of future PTSD symptoms, as well as the impact of racial discrimination on the BNST as a predictor of PTSD. Black adults (N = 95) who experienced a traumatic injury were recruited from the emergency department. Data was collected at two time points: (1) two-weeks post-trauma, where participants underwent a resting-state fMRI scan, and their baseline PTSD symptoms and history of racial discrimination were assessed; (2) six-months post-trauma, where their PTSD symptoms were reassessed. Results indicated that two-week BNST resting-state connectivity prospectively predicted PTSD symptoms six-months post-trauma. Additionally, prior experiences of racial discrimination moderated the relationship between acute BNST resting-state connectivity and future PTSD symptoms. Thus, in the acute aftermath of a traumatic event, resting-state connectivity of the BNST could be a useful biomarker of risk for PTSD in Black Americans, particularly for individuals who have experienced more racial discrimination throughout their lifetime

Resting state connectivity of the human habenula at ultra-high field

The habenula, a portion of the epithalamus, is implicated in the pathophysiology of depression, anxiety and addiction disorders. Its small size and connection to other small regions prevent standard human imaging from delineating its structure and connectivity with confidence. Resting state functional connectivity is an established method for mapping connections across the brain from a seed region of interest. The present study takes advantage of 7T fMRI to map, for the first time, the habenula resting state network with very high spatial resolution in 32 healthy human participants. Results show novel functional connections in humans, including functional connectivity with the septum and bed nucleus of the stria terminalis (BNST). Results also show many habenula connections previously described only in animal research, such as with the nucleus basalis of Meynert, dorsal raphe, ventral tegmental area (VTA), and periaqueductal grey (PAG). Connectivity with caudate, thalamus and cortical regions such as the anterior cingulate, retrosplenial cortex and auditory cortex are also reported. This work, which demonstrates the power of ultra-high field for mapping human functional connections, is a valuable step toward elucidating subcortical and cortical regions of the habenula network