Impact of chronic hypercortisolemia on affective processing☆
Highlights
► We demonstrate the impact of chronic hypercortisolemia upon affective processing using functional MRI. ► The study includes a Cushings Disorder group, where the disease results in excessive release of high levels of cortisol. ► The Cushings Disorder group shows excessive activation in frontal and subcortical regions, primarily on the left.
Introduction
Excessive, chronic, exposure to high levels of glucocorticoids (GC) has multiple adverse effects on brain biology in animals and humans (Abercrombie et al., 2011, Akil et al., 1993, Axelson et al., 1993, Erickson et al., 2003, Lupien et al., 1998, Starkman et al., 1992, Tessner et al., 2007), most clearly in animal studies (Magarinos and McEwen, 1995, Roozendaal et al., 2009). Specifically, GC administration and/or threat challenges that increase GC concentrations in animals result in increased depressive and anxiety-like symptoms as well as enhancement of aversive/avoidance memories linked to limbic function (McEwen, 1997, Mitra and Sapolsky, 2008, Mitra et al., 2006, Vyas et al., 2003). These animal studies strengthen the hypothesis that GC exposure results in morphologic/functional changes in brain structures supporting memory and affective processing.
There is increasing interest in possible effects of chronic GC exposure on cognitive and affective processing in humans (Brown et al., 2007, Sapolsky, 2000, Seeman et al., 1997). While the animal studies are highly informative, there are difficulties in creating parallels between animal behaviors and human medical and psychiatric illnesses. Behaviors elicited in animals are not the same as those observed in humans, nor can they be clarified absent self-report of symptoms (Starkman et al., 1981). Investigation of in vivo brain changes in humans secondary to chronic GC exposure are needed in order to clarify translation of animal studies to humans and to better understand cognitive and affective outcomes in humans.
A useful human illustration of the pathophysiologic effects of chronic, excessive GC exposure is Cushings Syndrome (CS). In CS, chronic, stress-level concentrations of cortisol lead to depressed mood in over 60% of patients (Starkman et al., 1981), vegetative symptoms, abnormal sleep profiles (Shipley et al., 1992) and cognitive dysfunction, especially in memory (Forget et al., 2000, Starkman et al., 2001, Starkman et al., 1986a). In addition, there is evidence of reduced regional brain volumes in the hippocampus, as well as decreased glucose utilization during active hypercortisolism (Khiat et al., 1999, Starkman et al., 1992).
With normalization in cortisol levels following treatment, we have shown reductions in mood and anxiety symptoms (Starkman et al., 1986b), increase in memory and hippocampal volume (Starkman et al., 1999, Starkman et al., 2003), and improvements in fluency and processing speed (Hook et al., 2007). We have also observed a post-treatment decrease in depressed/anxious mood related to an increase in caudate head, but not hippocampal volume in this study (Starkman et al., 2007). In summary, the human work with CS, as well as the animal work with GC administration or manipulation suggest that chronic GC exposure has direct effects upon cognitive and affective functioning and supportive brain regions in medial temporal, limbic, and frontal areas.
Affective functioning and its neural correlates is an important, yet understudied area in humans that is also related to medial temporal function and disruption secondary to GC exposure. In human studies, a few functional neuroimaging studies of emotion processing and regulation in volunteers using observational, normal levels of GC have been conducted. Using naturalistic measurement of normal-range cortisol levels in healthy adults during fMRI, these studies demonstrate positive relationships of medial temporal and frontal activation with GC concentrations (Pruessner et al., 2008, Tessner et al., 2007, Urry et al., 2006, van Stegeren et al., 2007). In a PET study with a mixed bipolar and major depression (MDD) group, there was a positive association between left amygdala glucose metabolism and plasma cortisol concentrations (Drevets et al., 2002). In contrast, the study of acute GC administration in humans is now being explored more extensively with current imaging technologies, including in psychiatric groups (Abercrombie et al., 2011, Scheel et al., 2009).
In the present study, we extend our investigations of the impact of chronic GC exposure to sensitive brain regions with high GR/MR receptor concentrations. We expand our prior work with mood and cognition in CS to now use an affective identification task during fMRI. The goal of the present study was to examine the relationship between excessive GC exposure and disruption of affective networks and processing, by studying individuals with CS prior to treatment. We tested the following hypotheses: 1) CS patients would demonstrate decreased ability to identify facial expressions of emotion; 2) CS patients would exhibit dysfunction in frontal and limbic regions, regions that also mediate successful and efficient identification of facial emotional expressions; and 3) Decrements in emotional identification ability and markers of severity of HPA axis dysfunction and duration of hypercortisolemia would be related to abnormal activation in regions within the affective processing circuits.
Section snippets
Participants
Twenty-one patients with CS and 21 healthy control subjects participated in the study after giving informed consent. The study was approved by the University of Michigan Institutional Review Board for Medical Experimentation, with protocols consistent with the Declaration of Helsinki. Demographic and select clinical data are reported in Table 1.
Patients with CS were recruited after the diagnosis was confirmed using diagnostic criteria which involved confirmation of elevated serum and urine free
Decreased accuracy in classification of emotions in faces for CS compared to controls
The healthy control group outperformed the CS group in accuracy of classification of emotion in human faces in a repeated measures ANCOVA (with age and sex as covariates) including both practice and in-scanner performance (F(1,35) = 7.67, P < .05). There was no difference between performance inside the scanner and practice (F(1,35) = 0.79, P > .05) and the interaction between setting (practice versus in-scanner) and group was not significant (F(1,35) = 1.77, P > .05).
In a similar repeated measures ANCOVA
Discussion
The present results extend our previous observations linking a dysregulated HPA axis with alterations in central nervous system structure and cognitive performance, especially memory, and depressed mood (Hook et al., 2007, Starkman et al., 1992, Starkman et al., 2003, Starkman et al., 2007, Starkman et al., 1981, Starkman et al., 1986b). The present study is the first report of alterations in emotion perception and processing as measured by fMRI in adult patients with untreated CS. Chronic
Acknowledgments
This project was supported by a General Clinical Research Center pilot grant to MNS and SAL (for some control and all Cushing’s fMRI scans, from # MO1 RR00042), KL2 Career Development Award (RR024987, SAL), K23 Award (MH074459, SAL), NIMH grant (# MH 43372, MNS), a Rachel Upjohn Clinical Scholars Award for screening of control subjects (SAL), and some pilot (control) fMRI scans from the University of Michigan functional MRI lab (SAL,SLW). Allison M. Kade, Kathleen E. Hazlett, Michael L.
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Precis: The present study shows for the first time a link between chronic HPA dysregulation, dysfunctional emotion processing, and activation abnormalities.