Skip to main content
    • Aa
    • Aa
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 18
  • Cited by
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.

    Bogdan, Ryan Pagliaccio, David Baranger, David AA and Hariri, Ahmad R 2016. Genetic Moderation of Stress Effects on Corticolimbic Circuitry. Neuropsychopharmacology, Vol. 41, Issue. 1, p. 275.

    Van Sandwijk, Marit S. Ten Berge, Ineke J. M. Majoie, Charles B.L.M. Caan, Matthan W.A. De Sonneville, Leo M. J. Van Gool, Willem A. and Bemelman, Frederike J. 2016. Cognitive Changes in Chronic Kidney Disease and After Transplantation. Transplantation, Vol. 100, Issue. 4, p. 734.

    Andela, C. D. van Haalen, F. M. Ragnarsson, O. Papakokkinou, E. Johannsson, G. Santos, A. Webb, S. M. Biermasz, N. R. van der Wee, N. J. A. and Pereira, A. M. 2015. MECHANISMS IN ENDOCRINOLOGY: Cushing's syndrome causes irreversible effects on the human brain: a systematic review of structural and functional magnetic resonance imaging studies. European Journal of Endocrinology, Vol. 173, Issue. 1, p. R1.

    Bas-Hoogendam, Janna Marie Andela, Cornelie D. van der Werff, Steven J.A. Pannekoek, J. Nienke van Steenbergen, Henk Meijer, Onno C. van Buchem, Mark A. Rombouts, Serge A.R.B. van der Mast, Roos C. Biermasz, Nienke R. van der Wee, Nic J.A. and Pereira, Alberto M. 2015. Altered neural processing of emotional faces in remitted Cushing's disease. Psychoneuroendocrinology, Vol. 59, p. 134.

    Goldstein, J.M. Handa, R.J. and Tobet, S.A. 2014. Disruption of fetal hormonal programming (prenatal stress) implicates shared risk for sex differences in depression and cardiovascular disease. Frontiers in Neuroendocrinology, Vol. 35, Issue. 1, p. 140.

    Manetti, L. Cavagnini, F. Martino, E. and Ambrogio, A. 2014. Effects of cocaine on the hypothalamic–pituitary–adrenal axis. Journal of Endocrinological Investigation, Vol. 37, Issue. 8, p. 701.

    Resmini, Eugenia 2014. Persistent Comorbidities in Cushing’s Syndrome after Endocrine Cure. Advances in Endocrinology, Vol. 2014, p. 1.

    Keil, M.F. Briassoulis, G. Nesterova, M. Miraftab, N. Gokarn, N. Wu, T.J. and Stratakis, C.A. 2013. Threat bias in mice with inactivating mutations of Prkar1a. Neuroscience, Vol. 241, p. 206.

    Malik, Osman and Westphal, Birgit 2013. A Role for Selective Serotonin Reuptake Inhibitors in the Management of Residual Cognitive Dysfunction in Pediatric Cushing's Disease. Journal of Child and Adolescent Psychopharmacology, Vol. 23, Issue. 1, p. 65.

    Starkman, Monica N. 2013. Neuropsychiatric Findings in Cushing Syndrome and Exogenous Glucocorticoid Administration. Endocrinology and Metabolism Clinics of North America, Vol. 42, Issue. 3, p. 477.

    Thomason, Moriah E. Tocco, Maria A. Quednau, Kelly A. Bedway, Andrea R. and Carré, Justin M. 2013. Idle Behaviors of the Hippocampus Reflect Endogenous Cortisol Levels in Youth. Journal of the American Academy of Child & Adolescent Psychiatry, Vol. 52, Issue. 6, p. 642.

    Arnaldi, G. Mancini, T. Tirabassi, G. Trementino, L. and Boscaro, M. 2012. Advances in the epidemiology, pathogenesis, and management of Cushing’s syndrome complications. Journal of Endocrinological Investigation, Vol. 35, Issue. 4, p. 434.

    Wheeler, Sarah M. McAndrews, Mary Pat Sheard, Erin D. and Rovet, Joanne 2012. Visuospatial Associative Memory and Hippocampal Functioning in Congenital Hypothyroidism. Journal of the International Neuropsychological Society, Vol. 18, Issue. 01, p. 49.

    White, M. G. Bogdan, R. Fisher, P. M. Muñoz, K. E. Williamson, D. E. and Hariri, A. R. 2012. FKBP5and emotional neglect interact to predict individual differences in amygdala reactivity. Genes, Brain and Behavior, Vol. 11, Issue. 7, p. 869.

    Mazzone, Luigi Mueller, Sven C. Maheu, Francoise VanRyzin, Carol Merke, Deborah P. and Ernst, Monique 2011. Emotional Memory in Early Steroid Abnormalities: An fMRI Study of Adolescents With Congenital Adrenal Hyperplasia. Developmental Neuropsychology, Vol. 36, Issue. 4, p. 473.

    Pilhatsch, Maximilian Marxen, Michael Winter, Christine Smolka, Michael N and Bauer, Michael 2011. Hypothyroidism and mood disorders: integrating novel insights from brain imaging techniques. Thyroid Research, Vol. 4, Issue. Suppl 1, p. S3.

    Sonino, Nicoletta Fallo, Francesco and Fava, Giovanni A. 2010. Psychosomatic aspects of Cushing’s syndrome. Reviews in Endocrine and Metabolic Disorders, Vol. 11, Issue. 2, p. 95.

    2010. Biological Psychiatry.


Altered amygdala and hippocampus function in adolescents with hypercortisolemia: A functional magnetic resonance imaging study of Cushing syndrome

  • Françoise S. Maheu (a1), Luigi Mazzone (a1), Deborah P. Merke (a2), Margaret F. Keil (a2), Constantine A. Stratakis (a2), Daniel S. Pine (a1) and Monique Ernst (a1)
  • DOI:
  • Published online: 01 October 2008

Chronic elevations of endogenous cortisol levels have been shown to alter medial temporal cortical structures and to be accompanied by declarative memory impairments and depressive symptoms in human adults. These effects of elevated endogenous levels of cortisol have not been directly studied in adolescents. Because adolescents with Cushing syndrome show endogenous elevations in cortisol, they represent a unique natural model to study the effects of prolonged hypercortisolemia on brain function, and memory and affective processes during this developmental stage. Using functional magnetic resonance imaging (fMRI), we compared 12 adolescents with Cushing syndrome with 22 healthy control adolescents on amygdala and anterior hippocampus activation during an emotional faces encoding task. None of these adolescents manifested depressive symptoms. Encoding success was assessed using a memory recognition test performed after the scan. The fMRI analyses followed an event-related design and were conducted using the SPM99 platform. Compared to healthy adolescents, patients with Cushing syndrome showed greater left amygdala and right anterior hippocampus activation during successful face encoding. Memory performance for faces recognition did not differ between groups. This first study of cerebral function in adolescents with chronic endogeneous hypercortisolemia due to Cushing syndrome demonstrates the presence of functional alterations in amygdala and hippocampus, which are not associated with affective or memory impairments. Such findings need to be followed by work examining the role of age and related brain maturational stage on these effects, as well as the identification of possible protective factors conferring resilience to affective and cognitive consequences in this disease and/or during this stage of cerebral development.

Corresponding author
Address correspondence and reprint requests to: Monique Ernst, Emotional Development and Affective Neuroscience Branch, Mood and Anxiety Disorders Program, National Institute of Mental Health (NIMH), 15K North Drive, Room 118, Bethesda, MD, 20892-2670; E-mail:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

H. C. Abercrombie , N. H. Kalin , M. E. Thurow , M. A. Rosenkranz , & R. J. Davidson (2003). Cortisol variation in humans affects memory for emotionally-laden and neutral information. Behavioral Neuroscience, 117, 505516.

R. Adolphs (2003). Cognitive neuroscience of human social behaviour. Nature Reviews in Neuroscience, 4, 165167.

D. Bannerman , J. Rawlins , S. McHugh , R. Deacon , B. Yee , T. Bast , (2004). Regional dissociations within the hippocampus—Memory and anxiety. Neuroscience and Biobehavioral Reviews, 28, 273283.

B. Birmaher , R. E. Dahl , J. Perel , D. E. Williamson , B. Nelson , S. Stull , (1996). Corticotropin-releasing hormone challenge in prepubertal major depression. Biological Psychiatry, 39, 267277.

I. Bourdeau , C. Bard , H. Forget , Y. Boulanger , H. Cohen , & A. Lacroix (2005). Cognitive function and cerebral assessment in patients who have Cushing's syndrome. Endocrinology and Metabolism Clinics of North America, 34, 357369.

T. W. Buchanan , & W. R. Lovallo (2001). Enhanced memory for emotional material following stress-level cortisol treatment in humans. Psychoneuroendocrinology, 26, 307317.

L. Cahill , L. Gorski , & K. Le (2003). Enhanced human memory consolidation with post-learning stress: Interaction with the degree of arousal at encoding. Learning and Memory, 10, 270274.

D. S. Charney (2004). Psychobiological mechanisms of resilience and vulnerability: Implications for successful adaptation to extreme stress. American Journal of Psychiatry, 161, 195216.

D. Cicchetti (2003). Experiments of nature: Contributions to developmental theory [Editorial]. Development and Psychopathology, 15, 833835.

R. Dahl , J. Puig-Antich , N. Ryan , B. Nelson , H. Novacenko , J. Twomey , (1989). Cortisol secretion in adolescents with major depressive disorder. Acta Psychiatrica Scandinavica, 80, 1826.

R. E. Dahl , N. D. Ryan , J. Puig-Antich , N. A. Nguyen , M. al-Shabbout , V. A. Meyer , (1991). 24-hour cortisol measures in adolescents with major depression: A controlled study. Biological Psychiatry, 30, 2536.

E. de Kloet , M. Joels , & F. Holsboer (2005). Stress and the brain: From adaptation to disease. Nature Reviews in Neuroscience, 6, 463475.

F. Dolcos , K. LaBar , & R. Cabeza (2004). Interaction between the amygdala and the medial temporal lobe memory system predicts better memory for emotional events. Neuron, 42, 855863.

E. E. Forbes , D. E. Williamson , N. D. Ryan , B. Birmaher , D. A. Axelson , & R. E. Dahl (2006). Peri-sleep-onset cortisol levels in children and adolescents with affective disorders. Biological Psychiatry, 59, 2430.

K. Friston , A. Mechelli , R. Turner , & C. Price (2000). Nonlinear responses in fMRI: The balloon model, Volterra kernels, and other hemodynamics. NeuroImage, 12, 466477.

C. C. Gispen-de Wied , L. M. Jansen , J. H. Duyx , J. H. Thijssen , & H. van Engeland (2000). Pituitary–adrenal function in adolescent psychiatric patients: Impact of depressive symptoms. Journal of Affective Disorders, 59, 7176.

S. Greenhouse , & S. Geisser (1959). On methods in the analysis of profile data. Psychometrika, 24, 95112.

N. Gogtay , J. N. Giedd , L. Lusk , K. M. Hayashi , D. Greenstein , A. C. Vaituzis , (2004). Dynamic mapping of the human cortical development during childhood through early adulthood. Proceedings of the National Academy of Science of the United States of America, 101, 81748179.

I. M. Goodyer , R. J. Park , & J. Herbert (2001). Psychosocial and endocrine features of chronic first-episode major depression in 8–16 year olds. Biological Psychiatry, 50, 351357.

I. M. Goodyer , R. J. Park , C. M. Netherton , & J. Herbert (2001). Possible role of cortisol and dehydroepiandrosterone in human development and psychopathology. British Journal of Psychiatry, 179, 243249.

A. Hariri , A. Tessitore , V. Mattay , F. Fera , & D. Weinberger (2002). The amygdala response to emotional stimuli: A comparison of faces and scenes. NeuroImage, 17, 317323.

C. Isgor , M. Kabbaj , H. Akil , & S. J. Watson (2004). Delayed effects of chronic variable stress during peripubertal–juvenile period of hippocampal morphology and on cognitive and stress axis function in rats. Hippocampus, 14, 636648.

J. Kaufman , B. Birmaher , D. Brent , U. Rao , C. Flynn , P. Moreci , (1997). Schedule for affective disorders and schizophrenia for school-age children—Present and life-time version (K-SADS-PL): Initial reliability and validity data. Journal of the American Academy of Child & Adolescent Psychiatry, 36, 980988.

S. J. Lupien , A. Fiocco , N. Wan , F. S. Maheu , C. Lord , T. E. Schramek , (2005). Stress hormones and human memory function across the lifespan. Psychoneuroendocrinology, 30, 225242.

S. J. Lupien , & M. Lepage (2001). Stress, memory, and the hippocampus: Can't live with it, can't live without it. Behavioral Brain Research, 127, 137158.

M. A. Magiakou , & G. P. Chrousos (2002). Cushing's syndrome in children and adolescents: Current diagnostic and therapeutic strategies. Journal of Endocrinological Investigation, 25, 181194.

D. P. Merke , J. N. Giedd , M. F. Keil , S. L. Mehlinger , E. A. Wiggs , S. Holzer , (2005). Children experience cognitive decline despite reversal of brain atrophy one year after resolution of Cushing syndrome. Journal of Clinical Endocrinology and Metabolism, 90, 25312536.

R. Mitra , S. Jadhav , B. S. McEwen , A. Vyas , & S. Chattarji (2005). Stress duration modualtes the spatiotemporal patterns of spine formation in the basolateral amygdala. Proceedings of the National Academy of Sciences of the United States of America, 102, 93719376.

E. E. Nelson , E. B. McClure , C. S. Monk , E. Zarahn , E. Leibenluft , D. S. Pine , (2003). Developmental differences in neuronal engagement during implicit encoding of emotional faces: An event-related fMRI study. Journal of Child Psychology and Psychiatry, 44, 10151024.

T. G. O'Connor (2003). Natural experiments to study the effects of early experience: Progress and limitations. Development and Psychopathology, 15, 837852.

C. M. Pariante (2006). The glucocorticoid receptor: Part of the solution or part of the problem ? Journal of Psychopharmacology, 20(Suppl.), 7984.

C. M. Pariante , & A. H. Miller (2001). Glucocorticoid receptors in major depression: Relevance to pathophysiology and treatment. Biological Psychiatry, 49, 391404.

E. A. Phelps , & J. E. LeDoux (2005). Contributions of the amygdala to emotion processing: From animal models to human behavior. Neuron, 48, 175187.

M. Phillips , W. Drevets , S. Rauch , & R. Lane (2003). Neurobiology of emotion perception I: The neural basis of normal emotion perception. Biological Psychiatry, 54, 504514.

D. S. Pine , S. Lissek , R. Klein , S. Mannuzza , J. Moulton III, M. Guardino , (2004). Face-memory and emotion: Associations with major depression in children and adolescents. Journal of Child Psychology and Psychiatry, 45, 11991208.

G. Poeggel , C. Helmeke , A. Abraham , T. Schwabe , P. Friedrich , & K. Braun (2003). Juvenile emotional experience alters synaptic composition in the rodent cortex, hippocampus, and lateral amygdala. Proceedings of the National Academy of Science of the United Sates of America, 100, 1613716142.

R. Roberson-Nay , E. B. McClure , C. S. Monk , E. E. Nelson , A. E. Guyer , S. Froom , (2006). Increased amygdala activity during successful memory encoding in adolescent major depressive disorder: An fMRI study. Biological Psychiatry, 60, 966973.

B. Roozendaal (2003). Systems mediating acute glucocorticoid effects on memory consolidation and retrieval. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 27, 12131223.

J. G. Snodgrass , & J. Corwin (1988). Pragmatics of measuring recognition memory: Applications to dementia and amnesia. Journal of Experimental Psychology, General, 117, 3450.

L. P. Spear (2000). The adolescent brain development and animal models. Annals of the New York Academy of Sciences, 1021, 2326.

P. Szeszko , D. Robinson , J. Alvir , R. Bilder , T. Lencz , M. Ashtari , (1999). Orbital frontal and amygdala volume reductions in obsessive–compulsive disorder. Archives of General Psychiatry, 56, 913919.

P. Szeszko , R. Strous , R. Goldman , M Ashtari , K. Knuth , J. Lieberman , (2002). Neuropsychological correlates of hippocampal volumes in patients experiencing a first episode of schizophrenia. American Journal of Psychiatry, 159, 217226.

J. Winston , B. Strange , J. O'Doherty , & R. Dolan (2002). Automatic and intentional brain responses during evaluation of trustworthiness of faces. Nature Neuroscience, 5, 277283.

K. Worsley , S. Marrett , P. Neelin , A. Vandal , K. Friston , & A. Evans (1996). A unified statistical approach for determining significant signals in images of cerebral activation. Human Brain Mapping, 4, 873.

E. Zarahn , G. Aguirre , & M. D'Esposito (1997). Empirical analyses of BOLD fMRI statistics. I. Spatially unsmoothed data collected under null-hypothesis conditions. NeuroImage, 5, 179197.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Development and Psychopathology
  • ISSN: 0954-5794
  • EISSN: 1469-2198
  • URL: /core/journals/development-and-psychopathology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *