Background Delineating specific clinical phenotypes of anxiety disorders is a crucial step toward better classification and understanding of these conditions. The present study sought to identify differential aversive responses to predictable and unpredictable threat of shock in healthy comparisons and in non-medicated anxiety patients with and without a history of panic attacks (PAs). Method 143 adults (72 healthy controls; 71 patients with generalized anxiety disorder (GAD) or/and social anxiety disorder (SAD), 24 with and 47 without PAs) were exposed to three conditions: 1) predictable shocks signaled by a cue, 2) unpredictable shocks, and 3) no shock. Startle magnitude was used to assess aversive responses. Results Across disorders, a PA history was specifically associated with hypersensitivity to unpredictable threat. By disorder, SAD was associated with hypersensitivity to predictable threat, whereas GAD was associated with exaggerated baseline startle. Conclusions These results identified three physiological patterns. The first is hypersensitivity to unpredictable threat in individuals with PAs. The second is hypersensitivity to predictable threat, which characterizes SAD. The third is enhanced baseline startle in GAD, which may reflect propensity for self-generated anxious thoughts in the absence of imminent danger. These results inform current thinking by linking specific clinical features to particular physiology profiles.

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Background. Laboratory tasks to delineate anxiety disorder features are used to refine classification and inform our understanding of etiological mechanisms. The present study examines laboratory measures of response inhibition, specifically the inhibition of a pre-potent motor response, in clinical anxiety. Data on associations between anxiety and response inhibition remain inconsistent, perhaps because of dissociable effects of clinical anxiety and experimentally manipulated state anxiety. Few studies directly assess the independent and interacting effects of these two anxiety types (state v. disorder) on response inhibition. The current study accomplished this goal, by manipulating state anxiety in healthy and clinically anxious individuals while they complete a response inhibition task. Method. The study employs the threat-of-shock paradigm, one of the best-established manipulations for robustly increasing state anxiety. Participants included 82 adults (41 healthy; 41 patients with an anxiety disorder). A go/nogo task with highly frequent go trials was administered during alternating periods of safety and shock threat. Signal detection theory was used to quantify response bias and signal-detection sensitivity. Results. There were independent effects of anxiety and clinical anxiety on response inhibition. In both groups, heightened anxiety facilitated response inhibition, leading to reduced nogo commission errors. Compared with the healthy group, clinical anxiety was associated with excessive response inhibition and increased go omission errors in both the safe and threat conditions. Conclusions. Response inhibition and its impact on go omission errors appear to be a promising behavioral marker of clinical anxiety. These results have implications for a dimensional view of clinical anxiety.

Human platelet hALOX12 (hALOX12 or h12-LOX) has been implicated in a variety of human diseases. The present study investigates the active site of hALOX12 to more thoroughly understand how it positions the substrate and achieves nearly perfect regio-and stereo-specificities (i.e., 100 +/− 5% of the 12(S)-hydroperoxide product), utilizing site-directed mutagenesis. Specifically, we have determined that Arg402 is not as important in substrate binding as previously seen for hALOX15, but that His596 may play a role in anchoring the carboxy terminal of the arachidonic acid during catalysis. In addition, Phe414 creates a pi-stacking interaction with a double bond of arachidonic acid (∆ 11), and Ala417/Val418 define the bottom of the cavity. However, the influence of Ala417/Val418 on the profile is markedly less for hALOX12 than that seen in hALOX15. Mutating these two residues to larger amino acids (Ala417Ile/Val418Met), only increased the generation of 15-HpETE by 24+/− 2%, but conversely smaller residues at these positions converted hALOX15 to almost 100% hALOX12 reactivity (JBC, 1996, 271, 25412-25418). However, we were able to increase 15-HpETE to 46+/− 3% by restricting the width of the active site with the Ala417Ile/Val418Met/Ser594Thr mutation, indicating both depth and width of the active site are important. Finally, residue Leu407 is shown to play a critical role in positioning the substrate correctly, as seen by the increase of 15-HpETE to 21+/− 1% for the single Leu407Gly mutant. These results outline critical differences between the active site requirements of hALOX12 relative to hALOX15, and explain both their product specificity and inhibitory differences.

Anxiety can be broken down into multiple facets including behavioral components, such as defensive reactivity, and cognitive components, such as distracting anxious thoughts. In a previous study, we showed that anticipation of unpredictable shocks facilitated response inhibition to infrequent nogo trials during a go/nogo task. The present study extends this work to examine the distinct contribution of defensive reactivity, measures with fear-potentiated startle, and anxious thought, assessed with thought probes, on go and nogo performance. Consistent with our prior findings, shock anticipation facilitated response inhibition (i.e., reduced errors of commission) on the nogo trials. Regression analyses showed that 1) nogo accuracy was positively associated with fear-potentiated startle and negatively associated with threat-related/task-unrelated thoughts and 2) go accuracy correlated negatively with fear-potentiated startle. Thus, while the present findings confirm the influence of anxiety on response inhibition, they also show that such influence reflects the balance between the positive effect of defensive reactivity and the negative effect of distracting anxious thoughts.

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Abstract Systemic inflammation is increasingly appreciated as a predictor of health and well-being. Further, inflammation has been shown to influence and be influenced by affective experiences. Although prior work has substantiated associations between inflammatory and affective processes, fewer studies have investigated the neurobiological correlates that underlie links between systemic, low-grade inflammation and affective reactivity. Thus, the current study examined whether markers of systemic inflammation (i.e. interleukin-6, C-reactive protein) are associated with differential patterns of neural activation and connectivity in corticolimbic regions in response to affective images. We investigated this question in a sample of 66 adults (44 women, M age = 54.98 years, range = 35–76) from the Midlife in the United States study. Higher levels of inflammation were associated with lower activity in limbic regions (i.e. amygdala, hippocampus, anterior insula, temporal pole) when viewing positive (vs neutral) images. Higher levels of inflammation were also associated with greater connectivity between the hippocampus and the medial prefrontal cortex in response to positive images. Inflammatory markers were not associated with significant differences in activation or connectivity to negative images. These findings highlight the utility of health neuroscience approaches in demonstrating that physiological processes such as inflammation are related to how our brains respond to affective information.

Racial disparities in health are a major public health problem in the United States, especially when comparing chronic disease morbidity and mortality for Black versus White Americans. These health disparities are primarily due to insidious anti-Black racism that permeates American history, current culture and institutions, and interpersonal interactions. But how does racism get under the skull and the skin to influence brain and bodily processes that impact the health of Black Americans? In the present article, we present a model describing the possible neural and inflammatory mechanisms linking racism and health. We hypothesize that racism influences neural activity and connectivity in the salience and default mode networks of the brain and disrupts interactions between these networks and the executive control network. This pattern of neural functioning in turn leads to greater sympathetic nervous system signaling, hypothalamic-pituitary-adrenal axis activation, and increased expression of genes involved in inflammation, ultimately leading to higher levels of proinflammatory cytokines in the body and brain. Over time, these neural and physiological responses can lead to chronic physical and mental health conditions, disrupt wellbeing, and cause premature mortality. Given that research in this area is underdeveloped to date, we emphasize opportunities for future research that are needed to build a comprehensive mechanistic understanding of the brain-body pathways linking anti-Black racism and health.