Time-Dependent Effects of Corticosteroids on Human Amygdala Processing

Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Centre for Cognitive Neuroimaging, 6500 HB Nijmegen, The Netherlands.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 09/2010; 30(38):12725-32. DOI: 10.1523/JNEUROSCI.3112-10.2010
Source: PubMed


Acute stress is associated with a sensitized amygdala. Corticosteroids, released in response to stress, are suggested to restore homeostasis by normalizing/desensitizing brain processing in the aftermath of stress. Here, we investigated the effects of corticosteroids on amygdala processing using functional magnetic resonance imaging. Since corticosteroids exert rapid nongenomic and slow genomic effects, we administered hydrocortisone either 75 min (rapid effects) or 285 min (slow effects) before scanning in a randomized, double-blind, placebo-controlled design. Seventy-two healthy males were scanned while viewing faces morphing from a neutral facial expression into fearful or happy expressions. Imaging results revealed that hydrocortisone desensitizes amygdala responsivity rapidly, while it selectively normalizes responses to negative stimuli slowly. Psychophysiological interaction analyses suggested that this slow normalization is related to an altered coupling of the amygdala with the medial prefrontal cortex. These results reveal a temporarily fine-tuned mechanism that is critical for avoiding amygdala overshoot during stress and enabling adequate recovery thereafter.

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    • "Firstly, the CAR may exert a slow effect on brain functional connectivity. Although a number of studies have revealed that stress and stress hormone have an acute effect on brain function and functional connectivity (Wang et al., 2005; Pruessner et al., 2008; Wager et al., 2009; Qin et al., 2009; Hermans et al., 2011; Ossewaarde et al., 2011; Veer et al., 2011), previous studies have also demonstrated that corticosteroids enhance PFC function (Henckens et al., 2011) and increase the coupling between the amygdala and the mPFC (Henckens et al., 2010) by slow, genomic changes that manifest themselves several hours after exogenous administration . These pharmacological studies, however, are not an exact copy of naturally occurring circumstances. "
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    ABSTRACT: Cortisol awakening response (CAR) is the cortisol secretory activity in the first 30-60 minutes immediately after awakening in the morning. Alterations in CAR as a trait have been associated with changes in the brain structure and function. CAR also fluctuates over days. Little, however, is known about the relationship between CAR as a state and brain activity. Using resting-state functional magnetic resonance imaging (fMRI), we investigated whether the CAR predicts intrinsic functional connectivity (FC) of the brain in the afternoon of the same day. Data from forty-nine healthy participants were analyzed. Salivary cortisol levels were assessed immediately after awakening and 15, 30 and 60 minutes after awakening, and resting-state fMRI data were obtained in the afternoon. Global FC strength (FCS) of each voxel was computed to provide a whole-brain characterization of intrinsic functional architecture. Correlation analysis was used to examine whether CAR predicts the intrinsic FC of core brain networks. We observed that the CAR was positively correlated with the FCS of the medial prefrontal cortex (mPFC). Further analysis revealed that higher CAR predicted stronger positive mPFC connectivity with regions in the default mode network. Our findings suggest that the HPA activity after awakening in the early morning may predict intrinsic functional connectivity of mPFC at rest in the afternoon of the same day. Copyright © 2015. Published by Elsevier Inc.
    NeuroImage 08/2015; 122. DOI:10.1016/j.neuroimage.2015.08.016 · 6.36 Impact Factor
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    • "Cortisol's effects on the human brain's threat systems have however only been studied using passive threat paradigms wherein no active escape was possible [Henckens et al., 2010; Merz et al., 2010]. The question therefore arises whether cortisol can exert dissociating effects on the brain's threat systems depending on active (escape) and passive (fear) threat conditions. "
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    ABSTRACT: Evolution has provided us with a highly flexible neuroendocrine threat system which, depending on threat imminence, switches between active escape and passive freezing. Cortisol, the "stress-hormone", is thought to play an important role in both fear behaviors, but the exact mechanisms are not understood. Using pharmacological functional magnetic resonance imaging we investigated how cortisol modulates the brain's fear systems when humans are under virtual-predator attack. We show dissociated neural effects of cortisol depending on whether escape from threat is possible. During inescapable threat cortisol reduces fear-related midbrain activity, whereas in anticipation of active escape cortisol boosts activity in the frontal salience network (insula and anterior cingulate cortex), which is involved in autonomic control, visceral perception and motivated action. Our findings suggest that cortisol adjusts the human neural threat system from passive fear to active escape, which illuminates the hormone's crucial role in the adaptive flexibility of fear behaviors. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Human Brain Mapping 08/2015; DOI:10.1002/hbm.22918 · 5.97 Impact Factor
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    • "However, the posterior hippocampus is also strongly connected to the anterior hippocampus, which is tightly linked to the amygdala [Fanselow and Dong, 2010]. These regions are all important targets of CORT, and although we did not find effects on these regions [in contrast to others, e.g., Henckens et al., 2010], we cannot exclude that CORT acted on the posterior hippocampus via these regions. Irrespective of drug condition, we did not find effects of the cry stimuli in the amygdala, which agrees with our findings using this crying paradigm in nonparental young women [Bos et al., 2010] and another finding with nonparental males [Seifritz et al., 2003]. "
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    ABSTRACT: Animal studies show that exposure to parental neglect alters stress regulation and can lead to neural hyposensitivity or hypersensitivity in response to cortisol, most pronounced in the hippocampus. Cortisol, the end product of the hypothalamic-pituitary-adrenal (HPA) axis, has also been related to parenting more directly, for example, in both sexes, cortisol levels increase when listening to infants crying, possibly to activate and facilitate effective care behavior. Severe trauma is known to negatively affect the HPA-axis in humans; however, it is unknown whether normal variation in parental care in the healthy population can alter sensitivity of the hippocampus to cortisol. Here, we investigate whether variation in experienced neglect changes neural sensitivity to cortisol when humans listen to infant crying, which is an unequivocal signal relevant for care behavior. In a placebo-controlled, within-subject neuroimaging study, we administered 40 mg cortisol to 21 healthy young males without children and used a validated task for measuring neural responses to infant crying. The Dutch version of the Childhood Trauma Questionnaire was used to index participants' early exposure to abuse and neglect. The data show that cortisol markedly increased hippocampal activation toward crying infants, and this effect varied significantly with parental neglect, even in our nonclinical subject sample. Without exposure to severe trauma or neglect, reduced self-experienced quality of parental care in the normal range already substantially increased hippocampal responsivity to cortisol. Altered hippocampal sensitivity to cortisol might be a cross-species marker for the risk of developing later life psychopathology. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc.
    Human Brain Mapping 10/2014; 35(10). DOI:10.1002/hbm.22537 · 5.97 Impact Factor
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