Elsevier

Psychoneuroendocrinology

Volume 59, September 2015, Pages 134-146
Psychoneuroendocrinology

Altered neural processing of emotional faces in remitted Cushing's disease

https://doi.org/10.1016/j.psyneuen.2015.05.001Get rights and content

Highlights

  • Long-term remission of Cushing's disease (CD) still leaves psychological complaints.

  • We investigated processing of emotional faces in remitted CD-patients using fMRI.

  • CD-patients (n = 21) showed hypoactivation of the vmPFC relative to controls (n = 21).

  • Functional coupling of vmPFC with posterior cingulate cortex was decreased in CD.

  • We report functional brain alterations after cure of endogenous hypercortisolism.

Summary

Patients with long-term remission of Cushing's disease (CD) demonstrate residual psychological complaints. At present, it is not known how previous exposure to hypercortisolism affects psychological functioning in the long-term. Earlier magnetic resonance imaging (MRI) studies demonstrated abnormalities of brain structure and resting-state connectivity in patients with long-term remission of CD, but no data are available on functional alterations in the brain during the performance of emotional or cognitive tasks in these patients.

We performed a cross-sectional functional MRI study, investigating brain activation during emotion processing in patients with long-term remission of CD. Processing of emotional faces versus a non-emotional control condition was examined in 21 patients and 21 matched healthy controls. Analyses focused on activation and connectivity of two a priori determined regions of interest: the amygdala and the medial prefrontal–orbitofrontal cortex (mPFC–OFC). We also assessed psychological functioning, cognitive failure, and clinical disease severity.

Patients showed less mPFC activation during processing of emotional faces compared to controls, whereas no differences were found in amygdala activation. An exploratory psychophysiological interaction analysis demonstrated decreased functional coupling between the ventromedial PFC and posterior cingulate cortex (a region structurally connected to the PFC) in CD-patients.

The present study is the first to show alterations in brain function and task-related functional coupling in patients with long-term remission of CD relative to matched healthy controls. These alterations may, together with abnormalities in brain structure, be related to the persisting psychological morbidity in patients with CD after long-term remission.

Introduction

Cushing's disease (CD) is characterized by elevated endogenous cortisol levels and is related to physical and psychological morbidity in more than 70% of the patients (Newell-Price et al., 2006). After correction of hypercortisolism, physical and psychological symptoms improve substantially. However, patients with long-term remission of CD still demonstrate residual physical and psychopathological morbidity (Resmini, 2014, Tiemensma et al., 2010a), impairments in cognitive functioning (Hook et al., 2007, Ragnarsson et al., 2012, Resmini et al., 2012, Tiemensma et al., 2010b) and reduced quality of life (Van Aken et al., 2005). A recent study provided evidence for a role of specific genetic polymorphisms in the etiology of cognitive impairments in these patients (Ragnarsson et al., 2014), but the persistent symptoms in patients with long-term remission of CD are still ill-understood. Cortisol acts in the central nervous system by stimulation of mineralocorticoid receptors and glucocorticoid receptors. An appropriate balance in activation of these two receptor systems is required for adequate stress responses. Hyperactivation of the hypothalamic–pituitary–adrenal (HPA)-axis during active CD not only induces overactivation of the receptors, but also an imbalance in mineralocorticoid- and glucocorticoid receptor activation, both of which might result in inadequate stress responses and enhanced vulnerability to psychopathology (De Kloet et al., 2005). The residual psychological and cognitive morbidity after long-term remission of CD suggests that exposure to hypercortisolism not only has acute effects, but might also be related to persistent changes in the brain.

Several neuroimaging studies have observed changes in morphology and function of the brain during the active phase of CD (Andela et al., 2015). Using functional magnetic resonance imaging (fMRI), less activation in the left anterior superior temporal gyrus and higher activation in frontal, medial, and subcortical regions during the identification of emotional faces was measured, indicating altered activity of brain structures relevant to the perception, processing and regulation of emotion (Langenecker et al., 2012). In addition, adolescents with active CD demonstrated increased activation in the left amygdala and right anterior hippocampus during a memory task involving emotional faces (Maheu et al., 2008). Moreover, patients with active CD showed structural brain abnormalities, including hippocampal volume reduction and cerebral atrophy (Bourdeau et al., 2002, Starkman et al., 1992). Mainly short term follow-up studies (duration of follow-up: 6–40 months) demonstrated at least partly reversibility of these structural brain abnormalities (Bourdeau et al., 2002, Starkman et al., 1999), although no firm conclusions can be drawn about the completeness of reversibility since long-term follow-up studies are lacking. Recently, we and others have shown that patients with long-term remission of CD (mean duration of remission: 11.2 years) still have abnormalities in brain structure, as evidenced by smaller gray matter volumes in the anterior cingulate cortex, larger gray matter volumes in the left lobe of the cerebellum (Andela et al., 2013) and widespread reductions in white matter integrity (Van der Werff et al., 2014). In addition, these patients showed increased resting-state functional connectivity of the anterior cingulate cortex (Van der Werff et al., 2015). Furthermore, a spectroscopy study by Resmini and colleagues demonstrated persistent biochemical alterations in both the left and right hippocampus in cured CD patients (Resmini et al., 2013). Taken together, these findings indicate that patients with long-term remission of CD have persisting structural and biochemical brain abnormalities, as well as changes in functional connectivity at rest, after cure of previous hypercortisolism (Andela et al., 2015). However, it is presently unknown whether these alterations appear in conjunction with altered brain activity patterns during the performance of cognitive or emotional tasks.

Given the link between hypercortisolism and disturbances in the stress response (De Kloet et al., 2005), and the irritability, anxiety, and depressive symptoms reported by patients with long-term remission of CD (Tiemensma et al., 2010a), we decided to examine brain activity during the processing of emotional faces in these patients. Patients were part of the sample described previously (Andela et al., 2013, Van der Werff et al., 2015, Van der Werff et al., 2014). Focus was on two regions of interest (ROIs): the amygdala and the medial prefrontal–orbitofrontal cortex (mPFC–OFC) (Shin and Liberzon, 2010). The amygdala and the mPFC, including the orbitofrontal cortex, are both part of the limbic system and involved in the regulation of the HPA-axis (Kim et al., 2011). Previous neuroimaging studies in patients with stress-related psychiatric disorders demonstrated hyperactivation of the amygdala and hypoactivation of the mPFC in response to emotional stimuli (Etkin and Wager, 2007, Shin and Wright, 2005), and it has been suggested that disturbances in the amygdala–mPFC circuitry lead to symptoms of anxiety (Kim et al., 2011). Considering the similarity in psychopathology between patients with CD and patients suffering from stress-related psychiatric disorders, we hypothesized that patients with long-term remission of CD would also show hypoactivaton of the mPFC combined with hyperactivation of the amygdala, relative to matched controls.

In addition to the ROI analyses, we performed a whole-brain analysis to examine task-related activation in other brain regions. Furthermore, we investigated potential associations between brain activity and psychological and cognitive measures, and several clinical characteristics (e.g. hydrocortisone dependency and disease severity). In addition, we used psychophysiological interaction analyses (Friston et al., 1997) to explore group differences in functional connectivity during processing of emotional faces.

Section snippets

Participants

Patients with long-term remission of CD of pituitary origin, monitored yearly at our institute, were invited by letter to participate in this study (n = 49; age 18–60 years). Patients who did not respond to the invitation letter were contacted by phone. Thirty-one CD-patients were willing to participate and were screened for eligibility. Exclusion criteria were past or present drug- or alcohol abuse, neurological disorders, general contraindications for undergoing a magnetic resonance imaging

Participants

Characteristics of CD-patients and matched healthy controls are presented in Table 1. Patients had a mean estimated duration of disease of 8.2 years (standard deviation (SD): 8.5; range 0.8–37.0 y), while the mean duration of remission at the time of evaluation was 10.8 years (SD: 7.9; range 1.9–10.8 y). CSI scores during active disease and at the time of evaluation were 8.3 (SD: 2.0, range 5.0–12.0) and 2.5 (SD: 1.6, range 0.0–5.0), respectively. Eleven patients (55%) received hydrocortisone

Discussion

The present study is the first to demonstrate task-related functional brain abnormalities in patients with long-term remission of CD relative to matched healthy control participants. We found hypoactivation of the ventromedial prefrontal cortex (vmPFC) during processing of facial expressions (vs. scrambled faces), without alterations in amygdala activation. This vmPFC hypoactivation was not elicited by a specific facial expression. The post-hoc exploratory psychophysiological interaction (PPI)

Role of funding source

The authors declare that the funding sources did not have any influence on the design of the study, the interpretation of the data, nor in the writing or submission of this manuscript.

Conflict of interest

The authors have no conflict of interest to report.

Acknowledgements

S.J.A. van der Werff was supported through the Netherlands Organization for Scientific Research – National Initiative Brain and Cognition project (NWO-NIHC, project no. 056-25-010). N.R. Biermasz was supported through the Netherlands Organization for Scientific Research – (NWO-VENI, project no. 016136125). S.A.R.B. Rombouts was supported through the Netherlands Organization for Scientific Research – (NWO-VICI, project no. 016.130.677). Furthermore, we thank the participants for their time and

References (52)

  • M.N. Starkman et al.

    Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing's disease

    Biol. Psychiatry

    (1999)
  • C.M. Sylvester et al.

    Functional network dysfunction in anxiety and anxiety disorders

    Trends Neurosci.

    (2012)
  • S.J.A. Van der Werff et al.

    Widespread reductions of white matter integrity in patients with long-term remission of Cushing's disease

    NeuroImage. Clin.

    (2014)
  • S.P.A. Wolfensberger et al.

    Amygdala responses to emotional faces in twins discordant or concordant for the risk for anxiety and depression

    Neuroimage

    (2008)
  • C.D. Andela et al.

    Smaller grey matter volumes in the anterior cingulate cortex and greater cerebellar volumes in patients with long-term remission of Cushing's disease: a case–control study

    Eur. J. Endocrinol.

    (2013)
  • C.D. Andela et al.

    Mechanisms in endocrinology: Cushing's syndrome causes irreversible effects on the human brain: a systematic review of structural and functional MRI studies

    Eur. J. Endocrinol.

    (2015)
  • R.L. Bluhm et al.

    Alterations in default network connectivity in posttraumatic stress disorder related to early-life trauma

    J. Psychiatry Neurosci.

    (2009)
  • I. Bourdeau et al.

    Loss of brain volume in endogenous Cushing's syndrome and its reversibility after correction of hypercortisolism

    J. Clin. Endocrinol. Metab.

    (2002)
  • D.E. Broadbent et al.

    The Cognitive Failures Questionnaire (CFQ) and its correlates

    Br. J. Clin. Psychol.

    (1982)
  • A. Chatterjee et al.

    A comparison of self-report and caregiver assessment of depression, apathy, and irritability in Huntington's disease

    J. Neuropsychiatry Clin. Neurosci.

    (2005)
  • E.R. De Kloet et al.

    Stress and the brain: from adaptation to disease

    Nat. Rev. Neurosci.

    (2005)
  • L.R. Demenescu et al.

    Neural correlates of perception of emotional facial expressions in out-patients with mild-to-moderate depression and anxiety. A multicenter fMRI study

    Psychol. Med.

    (2011)
  • A. Etkin et al.

    Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia

    Am. J. Psychiatry

    (2007)
  • J.N. Hook et al.

    Patterns of cognitive change over time and relationship to age following successful treatment of Cushing's disease

    J. Int. Neuropsychol. Soc.

    (2007)
  • S. Khalsa et al.

    The structural and functional connectivity of the posterior cingulate cortex: comparison between deterministic and probabilistic tractography for the investigation of structure–function relationships

    Neuroimage

    (2013)
  • W.D.S. Killgore et al.

    Cortico-limbic responses to masked affective faces across PTSD, panic disorder, and specific phobia

    Depress. Anxiety

    (2014)
  • Cited by (0)

    1

    Janna Marie Bas-Hoogendam and Cornelie D. Andela share first authorship.

    View full text