Nathaniel G. Harnett

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.

Pavlovian conditioned diminution of the neurobehavioral response to threat

HighlightsHealthy emotional function depends on the ability to appropriately cope with threats.Prior Pavlovian conditioning research has largely focused on anticipation of threat.We review recent findings on the regulation of the emotional response to threat.The PFC, hippocampus, and amygdala modulate threat‐elicited emotional responses.This research has important implications for emotion regulation and stress resilience. ABSTRACT An important function of emotion is that it motivates us to respond more effectively to threats in our environment. Accordingly, healthy emotional function depends on the ability to appropriately avoid, escape, or defend against threats we encounter. Thus, from a functional perspective, it is important to understand the emotional response to threat. However, prior work has largely focused on the emotional response in anticipation of threat, rather than the emotional response to the threat itself. The current review is focused on recent behavioral, psychophysiological, and neural findings from Pavlovian conditioning research that is centered on the expression and regulation of the emotional response to threat. The current evidence suggests that a neural network that includes the prefrontal cortex, hippocampus, and amygdala underlies learning, expression, and regulation processes that modulate emotional responses to threat. This line of research has important implications for our understanding of emotion regulation and stress resilience.

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.

Glutamate/glutamine concentrations in the dorsal anterior cingulate vary with Post-Traumatic Stress Disorder symptoms

Trauma and stress-related disorders (e.g., Acute Stress Disorder; ASD and Post-Traumatic Stress Disorder; PTSD) that develop following a traumatic event are characterized by cognitive-affective dysfunction. The cognitive and affective functions disrupted by stress disorder are mediated, in part, by glutamatergic neural systems. However, it remains unclear whether neural glutamate concentrations, measured acutely following trauma, vary with ASD symptoms and/or future PTSD symptom expression. Therefore, the current study utilized proton magnetic resonance spectroscopy (1H-MRS) to investigate glutamate/glutamine (Glx) concentrations within the dorsal anterior cingulate cortex (ACC) of recently (i.e., within one month) traumatized individuals and non-traumatized controls. Although Glx concentrations within dorsal ACC did not differ between recently traumatized and non-traumatized control groups, a positive linear relationship was observed between Glx concentrations and current stress disorder symptoms in traumatized individuals. Further, Glx concentrations showed a positive linear relationship with future stress disorder symptoms (i.e., assessed 3 months post-trauma). The present results suggest glutamate concentrations may play a role in both acute and future post-traumatic stress symptoms following a traumatic experience. The current results expand our understanding of the neurobiology of stress disorder and suggest glutamate within the dorsal ACC plays an important role in cognitive-affective dysfunction following a traumatic experience.

Anticipatory prefrontal cortex activity underlies stress-induced changes in Pavlovian fear conditioning

ABSTRACT Excessive stress exposure often leads to emotional dysfunction, characterized by disruptions in healthy emotional learning, expression, and regulation processes. A prefrontal cortex (PFC)‐amygdala circuit appears to underlie these important emotional processes. However, limited human neuroimaging research has investigated whether these brain regions underlie the altered emotional function that develops with stress. Therefore, the present study used functional magnetic resonance imaging (fMRI) to investigate stress‐induced changes in PFC‐amygdala function during Pavlovian fear conditioning. Participants completed a variant of the Montreal Imaging Stress Task (MIST) followed (25min later) by a Pavlovian fear conditioning task during fMRI. Self‐reported stress to the MIST was used to identify three stress‐reactivity groups (Low, Medium, and High). Psychophysiological, behavioral, and fMRI signal responses were compared between the three stress‐reactivity groups during fear conditioning. Fear learning, indexed via participant expectation of the unconditioned stimulus during conditioning, increased with stress reactivity. Further, the High stress‐reactivity group demonstrated greater autonomic arousal (i.e., skin conductance response, SCR) to both conditioned and unconditioned stimuli compared to the Low and Medium stress‐reactivity groups. Finally, the High stress group did not regulate the emotional response to threat. More specifically, the High stress‐reactivity group did not show a negative relationship between conditioned and unconditioned SCRs. Stress‐induced changes in these emotional processes paralleled changes in dorsolateral, dorsomedial, and ventromedial PFC function. These findings demonstrate that acute stress facilitates fear learning, enhances autonomic arousal, and impairs emotion regulation, and suggests these stress‐induced changes in emotional function are mediated by the PFC. HIGHLIGHTSAcute stress leads to abrupt shifts in emotional learning and regulation processes.Altered PFC‐amygdala function may underlie disruption of these emotion processes.Psychosocial stress was induced prior to a Pavlovian fear conditioning task.Behavior and fMRI signal during conditioning were compared with stress‐reactivity.Stress appears to disrupt anticipatory PFC functions that mediate emotional processes.

Anticipatory stress associated with functional magnetic resonance imaging: Implications for psychosocial stress research

Stress tasks performed during functional magnetic resonance imaging (fMRI) elicit a relatively small cortisol response compared to stress tasks completed in a traditional behavioral laboratory, which may be due to apprehension of fMRI that elicits an anticipatory stress response. The present study investigated whether anticipatory stress is greater prior to research completed in an MRI environment than in a traditional behavioral laboratory. Anticipatory stress (indexed by cortisol) was greater prior to testing in the MRI environment than traditional behavioral laboratory. Furthermore, anticipation of fMRI elicited a cortisol response commensurate with the response to the stress task in the behavioral laboratory. However, in the MRI environment, post-stress cortisol was significantly lower than baseline cortisol. Taken together, these findings suggest the stress elicited by anticipation of fMRI may lead to acute elevations in cortisol prior to scanning, which may in turn disrupt the cortisol response to stress tasks performed during scanning.

Psychosocial stress reactivity is associated with decreased whole-brain network efficiency and increased amygdala centrality.

Cognitive and emotional functions are supported by the coordinated activity of a distributed network of brain regions. This coordinated activity may be disrupted by psychosocial stress, resulting in the dysfunction of cognitive and emotional processes. Graph theory is a mathematical approach to assess coordinated brain activity that can estimate the efficiency of information flow and determine the centrality of brain regions within a larger distributed neural network. However, limited research has applied graph-theory techniques to the study of stress. Advancing our understanding of the impact stress has on global brain networks may provide new insight into factors that influence individual differences in stress susceptibility. Therefore, the present study examined the brain connectivity of participants that completed the Montreal Imaging Stress Task (Goodman et al., 2016; Wheelock et al., 2016). Salivary cortisol, heart rate, skin conductance response, and self-reported stress served as indices of stress, and trait anxiety served as an index of participant’s disposition toward negative affectivity. Psychosocial stress was associated with a decrease in the efficiency of the flow of information within the brain. Further, the centrality of brain regions that mediate emotion regulation processes (i.e., hippocampus, ventral prefrontal cortex, and cingulate cortex) decreased during stress exposure. Interestingly, individual differences in cortisol reactivity were negatively correlated with the efficiency of information flow within this network, whereas cortisol reactivity was positively correlated with the centrality of the amygdala within the network. These findings suggest that stress reduces the efficiency of information transfer and leaves the function of brain regions that regulate the stress response vulnerable to disruption.