Muriah D. Wheelock

Threat-related learning relies on distinct dorsal prefrontal cortex network connectivity☆

Conditioned changes in the emotional response to threat (e.g. aversive unconditioned stimulus; UCS) are mediated in part by the prefrontal cortex (PFC). Unpredictable threats elicit large emotional responses, while the response is diminished when the threat is predictable. A better understanding of how PFC connectivity to other brain regions varies with threat predictability would provide important insights into the neural processes that mediate conditioned diminution of the emotional response to threat. The present study examined brain connectivity during predictable and unpredictable threat exposure using a fear conditioning paradigm (previously published in Wood et al., 2012) in which unconditioned functional magnetic resonance imaging data were reanalyzed to assess effective connectivity. Granger causality analysis was performed using the time series data from 15 activated regions of interest after hemodynamic deconvolution, to determine regional effective connectivity. In addition, connectivity path weights were correlated with trait anxiety measures to assess the relationship between negative affect and brain connectivity. Results indicate the dorsomedial PFC (dmPFC) serves as a neural hub that influences activity in other brain regions when threats are unpredictable. In contrast, the dorsolateral PFC (dlPFC) serves as a neural hub that influences the activity of other brain regions when threats are predictable. These findings are consistent with the view that the dmPFC coordinates brain activity to take action, perhaps in a reactive manner, when an unpredicted threat is encountered, while the dlPFC coordinates brain regions to take action, in what may be a more proactive manner, to respond to predictable threats. Further, dlPFC connectivity to other brain regions (e.g. ventromedial PFC, amygdala, and insula) varied with negative affect (i.e. trait anxiety) when the UCS was predictable, suggesting that stronger connectivity may be required for emotion regulation in individuals with higher levels of negative affect.

Influence of Early Life Stress on Intra- and Extra-Amygdaloid Causal Connectivity

Animal models of early life stress (ELS) are characterized by augmented amygdala response to threat and altered amygdala-dependent behaviors. These models indicate the amygdala is a heterogeneous structure with well-differentiated subnuclei. The most well characterized of these being basolateral (BLA) and central nucleus (CeA). Parallel human imaging findings relative to ELS also reveal enhanced amygdala reactivity and disrupted connectivity but the influence of ELS on amygdala subregion connectivity and modulation of emotion is unclear. Here we employed cytoarchitectonic probability maps of amygdala subregions and Granger causality methods to evaluate task-based intra-amygdaloid and extra-amygdaloid connectivity with the network underlying implicit regulation of emotion in response to unconditioned auditory threat in healthy controls with ELS (N=20) and without a history of ELS (N=14). Groups were determined by response to the Childhood Trauma Questionnaire and threat response determined by unpleasantness ratings. Non-ELS demonstrated narrowly defined BLA-driven intra-amygdaloid paths and concise orbitofrontal cortex (OFC)–CeA-driven extra-amygdaloid connectivity. In contrast, ELS was associated with extensive and robust CeA-facilitated intra- and extra-amygdaloid paths. Non-ELS findings paralleled the known anatomical organization and functional relationships for both intra- and extra-amygdaloid connectivity, while ELS demonstrated atypical intra- and extra-amygdaloid CeA-dominant paths with compensatory modulation of emotion. Specifically, negative causal paths from OFC/BA32 to BLA predicted decreased threat response among non-ELS, while a unique within-amygdala path predicted modulation of threat among ELS. These findings are consistent with compensatory mechanisms of emotion regulation following ELS among resilient persons originating both within the amygdala complex as well as subsequent extra-amygdaloid communication.

Controllability modulates the neural response to predictable but not unpredictable threat in humans

Stress resilience is mediated, in part, by our ability to predict and control threats within our environment. Therefore, determining the neural mechanisms that regulate the emotional response to predictable and controllable threats may provide important new insight into the processes that mediate resilience to emotional dysfunction and guide the future development of interventions for anxiety disorders. To better understand the effect of predictability and controllability on threat-related brain activity in humans, two groups of healthy volunteers participated in a yoked Pavlovian fear conditioning study during functional magnetic resonance imaging (fMRI). Threat predictability was manipulated by presenting an aversive unconditioned stimulus (UCS) that was either preceded by a conditioned stimulus (i.e., predictable) or by presenting the UCS alone (i.e., unpredictable). Similar to animal model research that has employed yoked fear conditioning procedures, one group (controllable condition; CC), but not the other group (uncontrollable condition; UC) was able to terminate the UCS. The fMRI signal response within the dorsolateral prefrontal cortex (PFC), dorsomedial PFC, ventromedial PFC, and posterior cingulate was diminished during predictable compared to unpredictable threat (i.e., UCS). In addition, threat-related activity within the ventromedial PFC and bilateral hippocampus was diminished only to threats that were both predictable and controllable. These findings provide insight into how threat predictability and controllability affects the activity of brain regions (i.e., ventromedial PFC and hippocampus) involved in emotion regulation, and may have important implications for better understanding neural processes that mediate emotional resilience to stress.

Open label smoking cessation with varenicline is associated with decreased glutamate levels and functional changes in anterior cingulate cortex: preliminary findings

Rationale: Varenicline, the most effective single agent for smoking cessation, is a partial agonist at α4β2 nicotinic acetylcholine receptors. Increasing evidence implicates glutamate in the pathophysiology of addiction and one of the benefits of treatment for smoking cessation is the ability to regain cognitive control. Objective: To evaluate the effects of 12-week varenicline administration on glutamate levels in the dorsal anterior cingulate cortex (dACC) and functional changes within the cognitive control network. Methods: We used single-voxel proton magnetic resonance spectroscopy (1H-MRS) in the dACC and functional MRI (fMRI) during performance of a Stroop color-naming task before and after smoking cessation with varenicline in 11 healthy smokers (open label design). Using the dACC as a seed region, we evaluated functional connectivity changes using a psychophysiological interaction (PPI) analysis. Results: We observed a significant decrease in dACC glutamate + glutamine (Glx)/Cr levels as well as significant blood oxygen level-dependent signal (BOLD) decreases in the rostral ACC/medial orbitofrontal cortex and precuneus/posterior cingulate cortex. These BOLD changes are suggestive of alterations in default mode network (DMN) function and are further supported by the results of the PPI analysis that revealed changes in connectivity between the dACC and regions of the DMN. Baseline measures of nicotine dependence and craving positively correlated with baseline Glx/Cr levels. Conclusions: These results suggest possible mechanisms of action for varenicline such as reduction in Glx levels in dACC and shifts in BOLD connectivity between large scale brain networks. They also suggest a role for ACC Glx in the modulation of behavior. Due to the preliminary nature of this study (lack of control group and small sample size), future studies are needed to replicate these findings.

Exploring the Neurocircuitry Underpinning Predictability of Threat in Soldiers with PTSD Compared to Deployment Exposed Controls.

Background: Prior work examining emotional dysregulation observed in posttraumatic stress disorder (PTSD) has primarily been limited to fear-learning processes specific to anticipation, habituation, and extinction of threat. In contrast, the response to threat itself has not been systematically evaluated. Objective: To explore potential disruption in fear conditioning neurocircuitry in service members with PTSD, specifically in response to predictable versus unpredictable threats. Method: In the current study, active-duty U.S. Army soldiers with (PTSD group; n = 38) and without PTSD (deployment-exposed controls; DEC; n = 40), participated in a fear-conditioning study in which threat predictability was manipulated by presenting an aversive unconditioned stimulus (UCS) that was either preceded by a conditioned stimulus (i.e., predictable) or UCS alone (i.e., unpredictable). Threat expectation, skin conductance response (SCR), and functional magnetic resonance imaging (fMRI) signal to predictable and unpredictable threats (i.e., UCS) were assessed. Results: Both groups showed greater threat expectancy and diminished threat-elicited SCRs to predictable compared to unpredictable threat. Significant group differences were observed within the amygdala, hippocampus, insula, and superior and middle temporal gyri. Contrary to our predictions, the PTSD group showed a diminished threat-related response within each of these brain regions during predictable compared to unpredictable threat, whereas the DEC group showed increased activation. Conclusion: Although, the PTSD group showed greater threat-related diminution, hypersensitivity to unpredictable threat cannot be ruled out. Furthermore, pre-trauma, trait-like factors may have contributed to group differences in activation of the neurocircuitry underpinning fear conditioning.

The hippocampal response to psychosocial stress varies with salivary uric acid level

Uric acid is a naturally occurring, endogenous compound that impacts mental health. In particular, uric acid levels are associated with emotion-related psychopathology (e.g., anxiety and depression). Therefore, understanding uric acids impact on the brain would provide valuable new knowledge regarding neural mechanisms that mediate the relationship between uric acid and mental health. Brain regions including the prefrontal cortex, amygdala, and hippocampus underlie stress reactivity and emotion regulation. Thus, uric acid may impact emotion by modifying the function of these brain regions. The present study used functional magnetic resonance imaging (fMRI) during a psychosocial stress task to investigate the relationship between baseline uric acid levels (in saliva) and brain function. Results demonstrate that activity within the bilateral hippocampal complex varied with uric acid concentrations. Specifically, activity within the hippocampus and surrounding cortex increased as a function of uric acid level. The current findings suggest that uric acid levels modulate stress-related hippocampal activity. Given that the hippocampus has been implicated in emotion regulation during psychosocial stress, the present findings offer a potential mechanism by which uric acid impacts mental health.

Affective state and locus of control modulate the neural response to threat

The ability to regulate the emotional response to threat is critical to healthy emotional function. However, the response to threat varies considerably from person-to-person. This variability may be partially explained by differences in emotional processes, such as locus of control and affective state, which vary across individuals. Although the basic neural circuitry that mediates the response to threat has been described, the impact individual differences in affective state and locus of control have on that response is not well characterized. Understanding how these factors influence the neural response to threat would provide new insight into processes that mediate emotional function. Therefore, the present study used a Pavlovian conditioning procedure to investigate the influence individual differences in locus of control, positive affect, and negative affect have on the brain and behavioral responses to predictable and unpredictable threats. Thirty-two healthy volunteers participated in a fear conditioning study in which predictable and unpredictable threats (i.e., unconditioned stimulus) were presented during functional magnetic resonance imaging (fMRI). Locus of control showed a linear relationship with learning-related ventromedial prefrontal cortex (PFC) activity such that the more external an individuals locus of control, the greater their differential response to predictable versus unpredictable threat. In addition, positive and negative affectivity showed a curvilinear relationship with dorsolateral PFC, dorsomedial PFC, and insula activity, such that those with high or low affectivity showed reduced regional activity compared to those with an intermediate level of affectivity. Further, activity within the PFC, as well as other regions including the amygdala, were linked with the peripheral emotional response as indexed by skin conductance and electromyography. The current findings demonstrate that the neural response to threat within brain regions that mediate the peripheral emotional response is modulated by an individuals affective state as well as their perceptions of an events causality.

Prefrontal Cortex Activity Is Associated with Biobehavioral Components of the Stress Response

Contemporary theory suggests that prefrontal cortex (PFC) function is associated with individual variability in the psychobiology of the stress response. Advancing our understanding of this complex biobehavioral pathway has potential to provide insight into processes that determine individual differences in stress susceptibility. The present study used functional magnetic resonance imaging to examine brain activity during a variation of the Montreal Imaging Stress Task (MIST) in 53 young adults. Salivary cortisol was assessed as an index of the stress response, trait anxiety was assessed as an index of an individual’s disposition toward negative affectivity, and self-reported stress was assessed as an index of an individual’s subjective psychological experience. Heart rate and skin conductance responses were also assessed as additional measures of physiological reactivity. Dorsomedial PFC, dorsolateral PFC, and inferior parietal lobule demonstrated differential activity during the MIST. Further, differences in salivary cortisol reactivity to the MIST were associated with ventromedial PFC and posterior cingulate activity, while trait anxiety and self-reported stress were associated with dorsomedial and ventromedial PFC activity, respectively. These findings underscore that PFC activity regulates behavioral and psychobiological components of the stress response.

Neural mechanisms of human temporal fear conditioning.

Learning the temporal relationship between a warning cue (conditioned stimulus; CS) and aversive threat (unconditioned stimulus; UCS) is an important aspect of Pavlovian conditioning. Although prior functional magnetic resonance imaging (fMRI) research has identified brain regions that support Pavlovian conditioning, it remains unclear whether these regions support time-related processes important for this type of associative learning. Elucidating the neural substrates of temporal conditioning is important for a complete understanding of the Pavlovian conditioning process. Therefore, the present study used a temporal Pavlovian conditioning procedure to investigate brain activity that mediates the formation of temporal associations. During fMRI, twenty-three healthy volunteers completed a temporal conditioning procedure and a control task that does not support conditioning. Specifically, during the temporal conditioning procedure, the UCS was presented at fixed intervals (ITI: 20s) while in the control condition the UCS was presented at random intervals (Average ITI: 20s, ITI Range: 6-34s). We observed greater skin conductance responses and expectancy of the UCS during fixed (i.e., temporal conditioning) relative to random (i.e., control procedure) interval trials. These findings demonstrate fixed trials support temporal conditioning, while random trials do not. During fixed interval trials, greater conditioned fMRI signal responses were observed within dorsolateral prefrontal cortex, inferior parietal lobule, inferior and middle temporal cortex, hippocampus, and amygdala. The current findings suggest these brain regions constitute a neural circuit that encodes the temporal information necessary for Pavlovian fear conditioning.

Anticipation and the Neural Response to Threat

An important function of emotion is that it allows one to respond more effectively to threats in our environment. The response to threat is an important aspect of emotional behavior given the direct biological impact it has on survival. More specifically, survival is dependent upon the ability to avoid, escape, or defend against a threat once it is encountered. Anticipatory processes supported by neural circuitry that includes the prefrontal cortex and amygdala are critical for the expression and regulation of the emotional response. Further, these anticipatory processes appear to regulate the response to the threat itself. Healthy emotional function is characterized by anticipatory processes that diminish the emotional response to threat. In contrast, emotional dysfunction is characterized by anticipatory processes that lead to an exaggerated threat response. Thus, anticipatory mechanisms play an important role in both healthy and dysfunctional emotional behavior.