Hypothalamic–pituitary–adrenal axis tonus is associated with hippocampal microstructural asymmetry Kathrine Skak Madsen a, b, ⁎, Terry L. Jernigan a, b, c , Pernille Iversen a, b , Vibe G. Frokjaer b, d , Gitte M. Knudsen b, d, e , Hartwig R. Siebner a, b, e , William F.C. Baaré a, b a Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital, Hvidovre, Denmark b Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark c Veterans Affairs Center of Excellence for Stress and Mental Health, San Diego, La Jolla, CA, USA d Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark e Faculty of Health Sciences, University of Copenhagen, Denmark abstract article info Article history: Accepted 30 June 2012 Available online 6 July 2012 Keywords: Diffusion tensor imaging Cortisol Grey matter microstructure Hippocampus MRI Laterality It is well-established that prolonged high levels of cortisol have adverse effects on hippocampal neurons and glial cells. Morphometric studies linking hippocampus volume to basal HPA-axis activity, however, have yielded less consistent results. Asymmetry may also be considered, since there is growing evidence for hemi- spheric lateralization in brain systems regulating arousal and emotion. Here we tested the hypotheses that individual variations in basal morning and afternoon/evening cortisol levels would be associated with the de- gree of hemispheric asymmetry in hippocampal microstructure. Fifty healthy adults aged 19 to 86 years were included in the analyses. Diffusion-weighted imaging was acquired from all subjects. Hippocampal mean diffusivity (MD) and volume was extracted. Cortisol measures were based on 5 morning and 3 afternoon/evening saliva samples. Higher left relative to right hippocampus MD was associated with higher basal cortisol levels. Associations were anatomically specific and not attributable to hippocampal volume asymmetry. No correlation between hippocampal volume and MD was observed, suggesting that MD and volume index distinct biological properties of the hippocampus. Observed associations raise a number of possibilities, among them an asymmetric role of the hippocampus on HPA-axis regulation, or conversely, that individual variations in secreted cortisol, perhaps associated with stress, may have lateralized effects on hippocampal microstructure. Our results point to an important relationship between the limbic system and neuroendocrine function in terms of left–right asymmetries, raising additional questions about how the limbic system is related to neuroendocrine functions. © 2012 Elsevier Inc. All rights reserved. Introduction The hypothalamic–pituitary–adrenal (HPA)-axis regulates the secretion of cortisol in response to stress and is critically involved in coping with bodily and environmental challenges (Fries et al., 2009). Prolonged increases in cortisol level, for instance induced by chronic stress, have adverse effects on hippocampal neurons and glial cells (Jauregui-Huerta et al., 2010; Rajkowska and Miguel-Hidalgo, 2007; Sapolsky, 2000; Starkman et al., 1992). Moreover, the hippocampus is involved in stress regulation by modulating the HPA-axis (Dedovic et al., 2009; Jankord and Herman, 2008). Under normal conditions, basal HPA-axis activity follows a distinct diurnal profile with plasma cortisol levels peaking approximately 30 min after morning awakening, com- monly referred to as cortisol awakening response (CAR), followed by a gradual decrease in cortisol levels during the rest of the day (Clow et al., 2009; Fries et al., 2009; Pruessner et al., 1997). Disruption of the normal diurnal profile of the HPA-axis has been found in several psychi- atric disorders. Although not consistently, lower basal cortisol levels and lower CAR have been associated with fatigue, burnout, and post-traumatic stress disorder (Chida and Steptoe, 2009; Handwerger, 2009), while higher morning cortisol levels have been associated with anxiety disorder (Vreeburg et al., 2010) and major depression (Chida and Steptoe, 2009; Handwerger, 2009; Vreeburg et al., 2009). Previous research on the relationship between human brain struc- ture and cortisol measures as an index of HPA-axis function has typical- ly focused on the hippocampus in healthy subjects and pathological conditions (Buchanan et al., 2004; Knoops et al., 2010; Pruessner et al., 2007; Wolf et al., 2002). Bilateral and unilateral hippocampal dam- age in humans has been reported to abolish the morning response, while preserving overall cortisol levels throughout the day (Buchanan et al., 2004). In patients with elevated cortisol levels due to Cushing's syndrome, hippocampal volume was negatively correlated with mean plasma cortisol levels (Starkman et al., 1992), and following treatment NeuroImage 63 (2012) 95–103 ⁎ Corresponding author at: Danish Research Centre for Magnetic Resonance, MR-department, section 340, Copenhagen University Hospital, Hvidovre, Kettegaard Allé 30, 2650 Hvidovre, Denmark. Fax: +45 3647 0302. E-mail address: kathrine@drcmr.dk (K.S. Madsen). 1053-8119/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2012.06.071 Contents lists available at SciVerse ScienceDirect NeuroImage journal homepage: www.elsevier.com/locate/ynimg