Exaggerated neurobiological sensitivity to threat as a mechanism linking anxiety with increased risk for diseases of aging

Abstract

Anxiety disorders increase risk for the early development of several diseases of aging. Elevated inflammation, a common risk factor across diseases of aging, may play a key role in the relationship between anxiety and physical disease. However, the neurobiological mechanisms linking anxiety with elevated inflammation remain unclear. In this review, we present a neurobiological model of the mechanisms by which anxiety promotes inflammation. Specifically we propose that exaggerated neurobiological sensitivity to threat in anxious individuals may lead to sustained threat perception, which is accompanied by prolonged activation of threat-related neural circuitry and threat-responsive biological systems including the hypothalamic-pituitary-adrenal (HPA) axis, autonomic nervous system (ANS), and inflammatory response. Over time, this pattern of responding can promote chronic inflammation through structural and functional brain changes, altered sensitivity of immune cell receptors, dysregulation of the HPA axis and ANS, and accelerated cellular aging. Chronic inflammation, in turn, increases risk for diseases of aging. Exaggerated neurobiological sensitivity to threat may thus be a treatment target for reducing disease risk in anxious individuals.

Copyright © 2012 Elsevier Ltd. All rights reserved.

Figures

Fig. 1

A broad overview of cognitive-behavioral responses to perceived threats in anxious and non-anxious individuals. Anxious individuals show cognitive biases toward threatening information, which leads them to detect threatening stimuli (e.g., angry faces or predatory animals) more quickly than non-anxious individuals, and to appraise both ambiguous and threatening stimuli as more threatening. Anxious individuals also show a tendency to engage in cognitive-behavioral avoidance, which limits their ability to challenge inappropriate threat perception, confront and resolve threatening situations, and reshape expectations for the future. The ultimate result of this process is failure to achieve resolution of perceived threats, resulting in sustained threat perception.

Fig. 2

Hypothetical model of the neural systems involved in detecting threats, and regulating behavioral and biological responses to threat. Central to this network is the amygdala, which responds quickly to potential threats in the environment and plays a key role in determining whether environments are perceived as safe or dangerous. The amygdala functions in concert with other brain regions including the hippocampus and medial prefrontal cortex, which can up-regulate or down-regulate amygdalar responses to threat. Moreover, behavioral and biological responses to threat depend on activation of other brain areas, including the bed nucleus of the stria terminalis, which coordinates autonomic and motor responses to threat, and the periaqueductal gray, which coordinates stereotyped defensive reactions to threat, such as immobility and panic. Activity in this threat-related neural network is potentiated for individuals with anxiety disorders, as well as for persons exhibiting high levels of trait anxiety.

Fig. 3

Illustration of the pathways linking threat-related neural activity in the amygdala, medial prefrontal cortex and hippocampus with elevated inflammation. Threat perception leads to activation of the hypothalamic-pituitary-adrenal (HPA) axis leading to increased release of the glucocorticoid hormone cortisol from the adrenal glands (broken lines). Threat perception also activates the sympathetic arm and deactivates the parasympathetic arm of the autonomic nervous system (ANS), leading to increased release of the catecholamines epinephrine and norepinephrine (solid lines). This pattern of activation and deactivation is accompanied by increased synthesis and release of pro-inflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Binding of these factors to receptors on immune cells regulates gene expression, including expression of genes for pro-inflammatory cytokines. Thus, the effects of the HPA axis and ANS on the immune system depend on the expression of immune cell receptors for cortisol and catecholamines, as well as on the release of these hormones. The glucocorticoid receptor (GR) appears to be down-regulated in response to threat, limiting the anti-inflammatory effects of cortisol. Although there are complex bidirectional relationships between the various factors in this model, threat perception ultimately leads to elevated inflammation.

Fig. 4

Integrative neurobiological model showing the pathways mediating anxiety-related increased risk for diseases of aging. The model depicts how exaggerated neurobiological sensitivity to threat in anxious individuals leads to cognitive-behavioral threat responses characterized by a pattern of vigilance-avoidance, which ultimately results in sustained threat perception. Such sustained threat perception is accompanied by prolonged activation of threat-related neural circuitry and threat-responsive biological systems including the hypothalamic-pituitary-adrenal (HPA) axis, autonomic nervous system (ANS), and inflammatory response, ultimately leading to elevated inflammation. Over time, the effects on central and peripheral systems may become chronic through structural changes in the central nervous system (CNS), altered sensitivity of receptors on immune cells, and accelerated cellular aging. Finally, such chronic elevations in inflammation can increase risk for, and accelerate the progression of, diseases of aging.