Skip to main content

Advertisement

SpringerLink
Log in

Sex-specific effects of low-dose hydrocortisone on threat detection in HIV

  • Published:
Journal of NeuroVirology Aims and scope Submit manuscript

Abstract

One sex differences in the perception of emotion is that females, particularly those with high anxiety, often show heightened identification of fearful faces. To better understand the causal role of glucocorticoids in this sex difference, we examine these associations in people with HIV(PWH) where emotion perception is impaired and mental health disorders are frequent. In a double-blind, placebo-controlled, cross-over study, we used a single low-dose of hydrocortisone (10 mg; LDH) as a mechanistic probe of the effects of elevated glucocorticoids on negative emotion perception in 65 PWH (31 women). The primary outcome was accuracy in identifying emotional expressions on the Facial Emotion Perception Test (FEPT). Salivary cortisol, self-reported stress/anxiety, and childhood trauma were also assessed. LDH increased salivary cortisol levels versus placebo. The effect of LDH versus placebo on FEPT accuracy depended on the combined influence of facial expression and sex (P = 0.03). LDH influenced accuracy only for women (P = 0.03), specifically for fearful faces (Cohen’s d = 0.44, P = 0.04). Women’s enhanced threat detection varied with psychological burden (mood, anxiety, and post-traumatic stress symptoms), more pronounced among those with lower burden and trauma (P < 0.05). This result suggests a role of the HPA axis in sex differences for perception of fearful faces in women with HIV, potentially due to changes in glucocorticoid receptor availability/activity, or improved integration of signals from facial recognition and emotion processing regions. The blunting of this effect in men and in individuals with more severe trauma suggests that the mechanisms underlying threat detection differ by sex and trauma history and warrant further investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Aerni A, Traber R, Hock C, Roozendaal B, Schelling G, Papassotiropoulos A, Nitsch RM, Schnyder U, de Quervain DJ (2004) Low-dose cortisol for symptoms of posttraumatic stress disorder. Am J Psychiatry 161:1488–1490

    Article  PubMed  Google Scholar 

  • Baldonero E, Ciccarelli N, Fabbiani M, Colafigli M, Improta E, D’Avino A, Mondi A, Cauda R, Di Giambenedetto S, Silveri MC (2013) Evaluation of emotion processing in HIV-infected patients and correlation with cognitive performance. BMC Psychology 1:3–3

    Article  PubMed  PubMed Central  Google Scholar 

  • Barbot A, Carrasco M (2018) Emotion and anxiety potentiate the way attention alters visual appearance. Sci Rep 8:5938

    Article  PubMed  PubMed Central  Google Scholar 

  • Benedict RHB, Schretlen D, Groninger L, Brandt J (1998) Hopkins Verbal Learning Test - Revised: normative data and analysis of inter-form and test-retest relability. Clin Neuropsychol 12(1):43-55

  • Benton AL, Hamsher K, Varney NR, Spreen O (1983) Judgment of line orientation. Oxford University Press, Inc.

  • Bernstein D, Fink L (1998) Childhood trauma questionnaire: a retrospective self-report. The Psychological Coorporation: San Antonio, TX

  • Bieliauskas L, Counte M, Glandon G (1995) Inventorying stressing life events as related to health change in the elderly. Stress Med 11(1):93-103

  • Brooks SJ, Savov V, Allzen E, Benedict C, Fredriksson R, Schioth HB (2012) Exposure to subliminal arousing stimuli induces robust activation in the amygdala, hippocampus, anterior cingulate, insular cortex and primary visual cortex: a systematic meta-analysis of fMRI studies. Neuroimage 59:2962–2973

    Article  CAS  PubMed  Google Scholar 

  • Buysse DJ, Reynolds CF 3rd, Monk TH, Hoch CC, Yeager AL, Kupfer DJ (1991) Quantification of subjective sleep quality in healthy elderly men and women using the Pittsburgh Sleep Quality Index (PSQI). Sleep 14:331–338

    CAS  PubMed  Google Scholar 

  • Cahill L, Haier RJ, White NS, Fallon J, Kilpatrick L, Lawrence C, Potkin SG, Alkire MT (2001) Sex-related difference in amygdala activity during emotionally influenced memory storage. Neurobiol Learn Mem 75:1–9

    Article  CAS  PubMed  Google Scholar 

  • Campbell R, Elgar K, Kuntsi J, Akers R, Terstegge J, Coleman M, Skuse D (2002) The classification of “fear” from faces is associated with face recognition skill in women. Neuropsychologia 40:575–584

    Article  PubMed  Google Scholar 

  • Clark US, Cohen RA, Westbrook ML, Devlin KN, Tashima KT (2010) Facial emotion recognition impairments in individuals with HIV. J Int Neuropsychol Soc: JINS 16:1127–1137

    Article  PubMed  Google Scholar 

  • Clark US, Walker KA, Cohen RA, Devlin KN, Folkers AM, Pina MJ, Tashima KT (2015) Facial emotion recognition impairments are associated with brain volume abnormalities in individuals with HIV. Neuropsychologia 70:263–271

    Article  PubMed  PubMed Central  Google Scholar 

  • Cohen S, Kamarck T, Mermelstein R (1983) A global measure of perceived stress. J Health Soc Behav 24:385–396

    Article  CAS  Google Scholar 

  • Cruess DG, Leserman J, Petitto JM, Golden RN, Szuba MP, Morrison MF, Evans DL (2001) Psychosocial-immune relationships in HIV disease. Semin Clin Neuropsychiatry 6:241–251

    Article  CAS  PubMed  Google Scholar 

  • Cservenka A, Lahanas S, Dotson-Bossert J (2018) Marijuana use and hypothalamic-pituitary-adrenal axis functioning in humans. Front Psychiatry 9:472

    Article  PubMed  PubMed Central  Google Scholar 

  • Ferrini MG, Grillo CA, Piroli G, de Kloet ER, De Nicola AF (1997) Sex difference in glucocorticoid regulation of vasopressin mRNA in the paraventricular hypothalamic nucleus. Cell Mol Neurobiol 17:671–686

    Article  CAS  PubMed  Google Scholar 

  • Fusar-Poli P, Placentino A, Carletti F, Landi P, Allen P, Surguladze S, Benedetti F, Abbamonte M, Gasparotti R, Barale F, Perez J, McGuire P, Politi P (2009) Functional atlas of emotional faces processing: a voxel-based meta-analysis of 105 functional magnetic resonance imaging studies. J Psychiatry Neurosci: JPN 34:418–432

    Google Scholar 

  • Goel N, Workman JL, Lee TT, Innala L, Viau V (2014) Sex differences in the HPA axis. Compr Physiol 4:1121–1155

    Article  PubMed  Google Scholar 

  • Grill-Spector K, Knouf N, Kanwisher N (2004) The fusiform face area subserves face perception, not generic within-category identification. NatNeurosci 7:555–562

    CAS  Google Scholar 

  • Im HY, Adams RB Jr, Cushing CA, Boshyan J, Ward N, Kveraga K (2018) Sex-related differences in behavioral and amygdalar responses to compound facial threat cues. Hum Brain Mapp 39:2725–2741

    Article  PubMed  PubMed Central  Google Scholar 

  • Kajantie E, Phillips DI (2006) The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendocrinology 31:151–178

    Article  CAS  PubMed  Google Scholar 

  • Katz S, Nevid JS (2005) Risk factors associated with posttraumatic stress disorder symptomatology in HIV-infected women. AIDS Patient Care STDS 19:110–120

    Article  PubMed  Google Scholar 

  • Kirschbaum C, Kudielka BM, Gaab J, Schommer NC, Hellhammer DH (1999) Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus-pituitary-adrenal axis. Psychosom Med 61:154–162

    Article  CAS  PubMed  Google Scholar 

  • Kitada R, Johnsrude IS, Kochiyama T, Lederman SJ (2010) Brain networks involved in haptic and visual identification of facial expressions of emotion: an fMRI study. Neuroimage 49:1677–1689

    Article  PubMed  Google Scholar 

  • Knorr U, Vinberg M, Kessing LV, Wetterslev J (2010) Salivary cortisol in depressed patients versus control persons: a systematic review and meta-analysis. Psychoneuroendocrinology 35:1275–1286

    Article  CAS  PubMed  Google Scholar 

  • Kogler L, Müller VI, Seidel E-M, Boubela R, Kalcher K, Moser E, Habel U, Gur RC, Eickhoff SB, Derntl B (2016) Sex differences in the functional connectivity of the amygdalae in association with cortisol. Neuroimage 134:410–423

    Article  CAS  PubMed  Google Scholar 

  • Langenecker SA, Bieliauskas LA, Rapport LJ, Zubieta JK, Wilde EA, Berent S (2005) Face emotion perception and executive functioning deficits in depression. J Clin Exp Neuropsychol 27:320–333

    Article  PubMed  Google Scholar 

  • Leserman J (2003) The effects of stressful life events, coping, and cortisol on HIV infection. CNS Spectr 8:25–30

    Article  PubMed  Google Scholar 

  • Lok A, Mocking RJ, Ruhe HG, Visser I, Koeter MW, Assies J, Bockting CL, Olff M, Schene AH (2012) Longitudinal hypothalamic-pituitary-adrenal axis trait and state effects in recurrent depression. Psychoneuroendocrinology 37:892–902

    Article  CAS  PubMed  Google Scholar 

  • Ma ST, Abelson JL, Okada G, Taylor SF, Liberzon I (2017) Neural circuitry of emotion regulation: effects of appraisal, attention, and cortisol administration. Cogn Affect Behav Neurosci 17:437–451

    Article  PubMed  Google Scholar 

  • MacLeod CM (1991) Half a century of research on the stroop effect: an integrative review. Psychol Bull 109:163–203

    Article  CAS  PubMed  Google Scholar 

  • Marteau TM, Bekker H (1992) The development of a six-item short-form of the state scale of the Spielberger state-trait anxiety inventory (STAI). Br J Clin Psychol 31(Pt 3):301–306

    Article  CAS  PubMed  Google Scholar 

  • Mattavelli G, Sormaz M, Flack T, Asghar AUR, Fan S, Frey J, Manssuer L, Usten D, Young AW, Andrews TJ (2014) Neural responses to facial expressions support the role of the amygdala in processing threat. Soc Cogn Affect Neurosci 9:1684–1689

    Article  PubMed  Google Scholar 

  • Merz CJ, Tabbert K, Schweckendiek J, Klucken T, Vaitl D, Stark R, Wolf OT (2010) Investigating the impact of sex and cortisol on implicit fear conditioning with fMRI. Psychoneuroendocrinology 35:33–46

    Article  CAS  PubMed  Google Scholar 

  • Milders M, Sahraie A, Logan S, Donnellon N (2006) Awareness of faces is modulated by their emotional meaning. Emotion 6:10–17

    Article  PubMed  Google Scholar 

  • Nasr S, Tootell RBH (2012) Role of fusiform and anterior temporal cortical areas in facial recognition. Neuroimage 63:1743–1753

    Article  PubMed  Google Scholar 

  • Neigh GN, Rhodes ST, Valdez A, Jovanovic T (2016) PTSD co-morbid with HIV: Separate but equal, or two parts of a whole? Neurobiol Dis 92:116–123

    Article  Google Scholar 

  • Orozco S, Ehlers CL (1998) Gender differences in electrophysiological responses to facial stimuli. Biol Psychiatry 44:281–289

    Article  CAS  PubMed  Google Scholar 

  • Oyola MG, Handa RJ (2017) Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity. Stress (amsterdam, Netherlands) 20:476–494

    Article  CAS  Google Scholar 

  • Panagiotakopoulos L, Neigh GN (2014) Development of the HPA axis: where and when do sex differences manifest? Front Neuroendocrinol 35:285–302

    Article  CAS  PubMed  Google Scholar 

  • Petrowski K, Wintermann GB, Siepmann M (2012) Cortisol response to repeated psychosocial stress. Appl Psychophysiol Biofeedback 37:103–107

    Article  PubMed  Google Scholar 

  • Pooley AE, Benjamin RC, Sreedhar S, Eagle AL, Robison AJ, Mazei-Robison MS, Breedlove SM, Jordan CL (2018) Sex differences in the traumatic stress response: the role of adult gonadal hormones. Biol Sex Differ 9:32

    Article  PubMed  PubMed Central  Google Scholar 

  • Pruessner JC, Kirschbaum C, Meinlschmid G, Hellhammer DH (2003) Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology 28:916–931

    Article  CAS  PubMed  Google Scholar 

  • Radloff LS (1977) The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1:385–401

    Article  Google Scholar 

  • Rampp C, Eichelkraut A, Best J, Czamara D, Rex-Haffner M, Uhr M, Binder EB, Menke A (2018) Sex-related differential response to dexamethasone in endocrine and immune measures in depressed in-patients and healthy controls. J Psychiatr Res 98:107–115

    Article  PubMed  Google Scholar 

  • Reif S, Mugavero M, Raper J, Thielman N, Leserman J, Whetten K, Pence BW (2011) Highly stressed: stressful and traumatic experiences among individuals with HIV/AIDS in the Deep South. AIDS Care 23:152–162

    Article  PubMed  PubMed Central  Google Scholar 

  • Reitan R (1978) Manual for administration of neuropsychological test batteries for adults and children. Neuropsychology Laboratories Inc, Tuscon, AZ

    Google Scholar 

  • Roca CA, Schmidt PJ, Deuster PA, Danaceau MA, Altemus M, Putnam K, Chrousos GP, Nieman LK, Rubinow DR (2005) Sex-related differences in stimulated hypothalamic-pituitary-adrenal axis during induced gonadal suppression. J Clin Endocrinol Metab 90:4224–4231

    Article  PubMed  Google Scholar 

  • Rohleder N, Schommer NC, Hellhammer DH, Engel R, Kirschbaum C (2001) Sex differences in glucocorticoid sensitivity of proinflammatory cytokine production after psychosocial stress. Psychosom Med 63:966–972

    Article  CAS  PubMed  Google Scholar 

  • Rohleder N, Wolf JM, Kirschbaum C (2003) Glucocorticoid sensitivity in humans-interindividual differences and acute stress effects. Stress 6:207–222

    Article  CAS  PubMed  Google Scholar 

  • Rubin LH, Phan KL, Keating SM, Maki PM (2018) A single low-dose of hydrocortisone enhances cognitive functioning in HIV-infected women. AIDS 32:1983–1993

    Article  CAS  PubMed  Google Scholar 

  • Rubin LH, Phan KL, Keating SM, Weber KM, Maki PM (2017) Brief report: low-dose hydrocortisone has acute enhancing effects on verbal learning in HIV-infected men. J Acquir Immune Defic Syndr 75:e65–e70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruggiero KJ, Del Ben K, Scotti JR, Rabalais AE (2003) Psychometric properties of the PTSD Checklist-Civilian Version. J Trauma Stress 16:495–502

    Article  PubMed  Google Scholar 

  • Spies G, Fennema-Notestine C, Cherner M, Seedat S (2017) Changes in cognitive function in women with HIV infection and early life stress. AIDS Care 29:14–23

    Article  PubMed  Google Scholar 

  • Stein T, Peelen MV, Funk J, Seidl KN (2010) The fearful-face advantage is modulated by task demands: evidence from the attentional blink. Emotion 10:136–140

    Article  PubMed  Google Scholar 

  • Stein T, Zwickel J, Ritter J, Kitzmantel M, Schneider WX (2009) The effect of fearful faces on the attentional blink is task dependent. Psychon Bull Rev 16:104–109

    Article  PubMed  Google Scholar 

  • Stienen BMC, de Gelder B (2011) Fear modulates visual awareness similarly for facial and bodily expressions. Front Hum Neurosci 5:132–132

    Article  PubMed  PubMed Central  Google Scholar 

  • Swaab DF, Bao A-M (2020) Chapter 21 - Sex differences in stress-related disorders: major depressive disorder, bipolar disorder, and posttraumatic stress disorder. In: Handb Clin Neurol. Lanzenberger R, Kranz GS, Savic I, (eds). Elsevier, pp 335–358

  • Szymkowicz SM, Persson J, Lin T, Fischer H, Ebner NC (2016) Hippocampal brain volume is associated with faster facial emotion identification in older adults: preliminary results. Front Aging Neurosci 8:203–203

    Article  PubMed  PubMed Central  Google Scholar 

  • Vreeburg SA, Hoogendijk WJ, van Pelt J, Derijk RH, Verhagen JC, van Dyck R, Smit JH, Zitman FG, Penninx BW (2009) Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study. Arch Gen Psychiatry 66:617–626

    Article  CAS  PubMed  Google Scholar 

  • Vuilleumier P, Armony JL, Driver J, Dolan RJ (2003) Distinct spatial frequency sensitivities for processing faces and emotional expressions. Nat Neurosci 6:624–631

    Article  CAS  PubMed  Google Scholar 

  • Walsh JC, Mandalia S, Gazzard BG (2002) Responses to a 1 month self-report on adherence to antiretroviral therapy are consistent with electronic data and virological treatment outcome. AIDS 16:269–277

    Article  PubMed  Google Scholar 

  • Wang Y, Guo N, Zhao L, Huang H, Yao X, Sang N, Hou X, Mao Y, Bi T, Qiu J (2017) The structural and functional correlates of the efficiency in fearful face detection. Neuropsychologia 100:1–9

    Article  CAS  PubMed  Google Scholar 

  • Wechsler D (2008) Wechsler adult intelligence scale. 4. Pearson: San Antonio, TX

  • Wright SL, Langenecker SA, Deldin PJ, Rapport LJ, Nielson KA, Kade AM, Own LS, Akil H, Young EA, Zubieta JK (2009) Gender-specific disruptions in emotion processing in younger adults with depression. Depress Anxiety 26:182–189

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank Bruni Hirsch, Alana Aziz-Bradley, Jacob Ellis, Sheila D’Sa, Shannon Dowty, Lauren Drogos, Lacey Wisslead, Aleksa Anderson, and Preet Dhillon for their assistance with this study. We would also like to thank all of our participants, for without you this work would not be possible.

Funding

Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health under Award Numbers Award Numbers K01MH098798 (Rubin), R21MH099978 (Rubin), R01MH113512 (Rubin), and U54 AG062334. The project described was also supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR000050. This project was also supported in part by a University of Illinois at Chicago Campus Review Board (CRB) Grant (Rubin) and a Chicago Developmental Center for AIDS Research pilot grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Meyer 6-113a, Baltimore, MD, 21287, USA

    Asante R. Kamkwalala & Leah H. Rubin

  2. Departments of Psychiatry, Psychology, and OB/GYN University of Illinois At Chicago, IL, Chicago, USA

    Pauline M. Maki

  3. Department of Psychiatry, University of Utah, Salt Lake City, UT, USA

    Scott A. Langenecker

  4. Department of Psychiatry, The Ohio State University, Wexner Medical Center, Columbus, OH, USA

    K. Luan Phan

  5. CORE Center, Cook County Health and Hektoen Institute of Medicine, Chicago, IL, USA

    Kathleen M. Weber

  6. Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Leah H. Rubin

  7. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA

    Leah H. Rubin

Authors
  1. Asante R. Kamkwalala
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pauline M. Maki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Scott A. Langenecker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K. Luan Phan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kathleen M. Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Leah H. Rubin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leah H. Rubin.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kamkwalala, A.R., Maki, P.M., Langenecker, S.A. et al. Sex-specific effects of low-dose hydrocortisone on threat detection in HIV. J. Neurovirol. 27, 716–726 (2021). https://doi.org/10.1007/s13365-021-01007-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13365-021-01007-6

Keywords

Search

Navigation