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PNEC-1550; No of Pages 13
Please cite this article in press as: Pruessner, J.C., et al., Stress regulation in the central nervous system: Evidence from structural andfunctional neuroimaging studies in human populations. Psychoneuroendocrinology (2009), doi:10.1016/j.psyneuen.2009.02.016
REVIEW
Stress regulation in the central nervous system:Evidence from structural and functionalneuroimaging studies in human populations
Jens C. Pruessner
a,c,
*, KatarinaDedovic
a
, Marita Pruessner
a
,Catherine Lord
a
, Claudia Buss
b
,Louis Collins
c
,Alain Dagher
c
, Sonia J. Lupien
a
a
Douglas Mental Health Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada
b
Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA
c
Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
Received 30 September 2008; received in revised form 19 February 2009; accepted 20 February 2009
Psychoneuroendocrinology (2009)
xxx
, xxx—xxx
KEYWORDS
Stress;Cortisol;Hippocampus;Personality;Structural magneticresonance imaging;Functional magneticresonance imaging
Summary
The metabolic effects of stress are known to have significant health effects in bothhumans and animals. Most of these effects are mediated by the major stress hormonal axis in thebody, the hypothalamic—pituitary—adrenal (HPA) axis. Within the central nervous system (CNS),the hippocampus, the amygdala and the prefrontal cortex as part of the limbic system arebelieved to play important roles in the regulation of the HPA axis. With the advent of structuraland functional neuroimaging techniques, the role of different CNS structures in the regulation of the HPA axis can be investigated more directly. In the current paper, we summarize the findingsobtained in our laboratory in the context of stress and HPA axis regulation.Our laboratory has developed and contributed to the development of manual and automatedsegmentationprotocolsfromstructuralmagneticresonanceimaging(MRI)scansforassessmentof hippocampus, amygdala, medial temporal lobe and frontal lobe structures. Employing theseprotocols, we could show significant age-related changes in HC volumes, which were differentbetween men and women, with pre-menopausal women showing smaller age-related volumedecline compared to men. We could recently extent these findings by showing how estrogentherapy after menopause leads to higher volumes in the HC.Investigating possible neurotoxicity effects of steroids, we showed effects of long-termsteroid exposure on HC volumes, and investigated variability of HC volumes in relation to HPAaxis regulation in young and elderly populations. Here, we were able to follow-up from non-
 Abbreviations:
HPA, hypothalamic—pituitary—adrenal; CRF, corticotropin releasing hormone; ACTH, adrenocorticotropic hormone; CNS,central nervous system; HC, hippocampus; PFC, prefrontal cortex; AG, amygdala; MR, mineralcorticoid receptor; GR, glucocorticoid receptor;PET, positron emission tomography; MRI, magnetic resonance imaging; ET, estrogen therapy; HT, hormonal therapy; PTSD, Posttraumatic StressDisorder; PVN, paraventricular nucleus; VBM, voxel-based morphometry; ACC, anterior cingulate cortex; fMRI, functional magnetic resonanceimaging; MIST, Montreal Imaging Stress Task; TSST, Trier Social Stress Test.* Corresponding author at: FBC 3146, Douglas Mental Health Institute, Verdun, QC H4H 1R3, Canada. Tel.: +1 514 761 6131x3370;fax: +1 514 888 4099.
E-mail address:
jens.pruessner@mcgill.ca(J.C. Pruessner).available at www.sciencedirect.comjournal homepage: www.elsevier.com/locate/psyneuen0306-4530/$ — see front matter
#
2009 Elsevier Ltd. All rights reserved.doi:10.1016/j.psyneuen.2009.02.016
 
Contents
1. Limbic system regulation of the HPA axis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0001.1. Overview of HPA axis function and regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0001.2. Target points for functional and structural neuroimaging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0002. Structural neuroimaging in association with HPA axis regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0002.1. Medial temporal lobes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0002.1.1. Manual segmentation protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0002.1.2. Automated segmentation protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0002.2. Hippocampus and HPA axis regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0002.2.1. Estrogen-related differences in HC volumes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0002.2.2. HC atrophy after transplant surgery and steroid treatment . . . . . . . . . . . . . . . . . . . . . . . . . 0002.2.3. Self-esteem and HC volume in relation to HPA axis regulation . . . . . . . . . . . . . . . . . . . . . . . 0002.2.4. Volume variability of HC in both young and elderly adults . . . . . . . . . . . . . . . . . . . . . . . . . . 0002.2.5. Maternal care and HC volume. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0002.3. Prefrontal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0002.3.1. Semi-automated frontal lobe segmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0002.3.2. Frontal lobe interaction with HPA axis regulation: the role of the anterior cingulate in PosttraumaticStress Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0003. Functional neuroimaging in association with HPA axis regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0003.1. Induction of acute stress during functional imaging: the Montreal Imaging Stress Task . . . . . . . . . . . . . 0003.2. Dopamine and cortisol regulation investigated using PET. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0003.3. Brain activation changes in stress responders and non-responders using functional magneticresonance imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0004. Outlook and conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
1. Limbic system regulation of the HPA axis
1.1. Overview of HPA axis function andregulation
Psychological stress is known to trigger activation of thehypothalamic—pituitary—adrenal (HPA) axis, leading to asecretion of corticotropin releasing hormone (CRF) from thehypothalamus, adrenocorticotropichormone(ACTH) from theanterior pituitary, and glucocorticoids (corticosterone in ani-mals, cortisol in humans) from the adrenal cortex. In humans,the glucocorticoid hormone cortisol affects a wide range of physiological functions, e.g. immune responses and metabo-lismchanges,generallyunderstoodasimportantforthebody’sadaptationtoincreasedenergydemandsduringtimesofstress(Sapolsky et al., 2000; Sapolsky, 1996, 1999).
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PNEC-1550; No of Pages 13
Please cite this article in press as: Pruessner, J.C., et al., Stress regulation in the central nervous system: Evidence from structural andfunctional neuroimaging studies in human populations. Psychoneuroendocrinology (2009), doi:10.1016/j.psyneuen.2009.02.016
imaging studies showing that subjects low in self-esteem have higher cortisol stress responses,and the HC emerged as the critical link between these variables. Recently, we have made twomore important discoveries with regard to HC volume: we could show that HC volume is asvariable in young as it is in older adults, in subjects ranging in age from 18 to 80 years. Also, wehave linked birth weight and maternal care to HC volumes in young adults, demonstrating theeffects of variations in maternal care on the integrity of the CNS.Besides structural assessments, there is increasing interest in functional techniques toinvestigate possible links between CNS activity and HPA axis regulation. These two approachescomplement each other; some aspects of HPA axis regulation might be linked to the integrity of aspecific CNS structure, while other aspects might be linked to the function of a specific structurewithnoinvolvement ofCNSmorphology.Thus,wehavedevelopedamentalarithmeticstresstaskthat can be employed in functional neuroimaging studies, and have used it in a number of functionalneuroimagingstudies.Employingpositronemissiontomography(PET),wewereabletodemonstrate that stress causes dopamine release if subjects reported low maternal care early inlife. Finally, employing the task in functional magnetic resonance imaging (fMRI), we could showhow exposure to stress and activation of the HPA axis are associated with decreased activity inmajor portions of the limbic system, a result that allows to speculate on the effects of stress oncognitive and emotional regulation in the brain. Taken together, the use of neuroimagingtechniques in Psychoneuroendocrinology opens exciting new possibilities for the investigationof stress effects in the central nervous system.
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2009 Elsevier Ltd. All rights reserved.
2 J.C. Pruessner et al.
 
Within the central nervous system (CNS), limbic systemcomponents involved in processing of emotion and stress arethe top regulators of the HPA axis. Most of our current knowl-edge on CNS involvement in endocrine regulation originatesfrom animal studies. Commonly, such studies revealed that30—60 min after the onset of a stressor, molecular markers of neuralactivity(e.g.cFos,NGFI-A)inmultiplelimbicstructuresare increased, indicating a stimulating effect of stress onneuralactivity(Pacaketal.,1995;Kovacs,1998).Investigatingstressors like social defeat in animals (Herman et al., 2003),the hippocampus (HC) has been identified as a limbic systemstructure that can have an inhibitory effect on HPA axisactivity. The HC lies in the medial parts of the temporal lobe,next to the entorhinal and perirhinal cortex, and the para-hippocampal cortex. The inhibition of the HC is usually dis-cussedinthecontextofglucocorticoidfeedbackarrivinginthecentral nervous system in the aftermath of stress to suppressfurther HPA axis activity (‘negative feedback loop’), but it isalso acknowledged that the hippocampus can exert a tonicinhibitory influence on HPA axis regulation (Herman et al.,2005; Jacobson, 2005). Besides the HC, the prefrontal cortex(PFC) with the anterior cingulate as a neocortical regulatorystructure(MacLullichetal.,2006),andtheamygdala(AG;Urry etal.,2006),dominantlyinvolvedintheregulationoffear,arediscussed as limbic system structures implicated in HPA reg-ulation. While the amygdala is predominantly excitatory, thePFC can be both inhibitory and excitatory, depending on theexact substructure, and the neurotransmitter involved (Her-man et al., 2005).Although animal studies have contributed extensively toour knowledge of CNS involvement in endocrine regulation,whereas animal models using molecular markers present aclear description of the consequences of stress on neuralsystems, comparability with human anatomy and with reg-ulatory mechanisms of endocrine systems is limited. Also,animal studies usuallylack the necessary temporal resolutionto show which brain activation changes are associated withthe initiation of the hormonal stress response. Here, struc-tural and functional neuroimaging studies possess clearadvantages since markers of HPA axis activity in humanscan be associated with volume and shape of a person’sCNS structures and even simultaneous blood flow changes.
1.2. Target points for functional and structuralneuroimaging
One ofthemost interesting aspects ofinvestigatingstress andtheregulationoftheHPAaxisareinter-individualdifferences–—whyaresomepeoplemorevulnerabletotheeffectsofstressand develop stress-related diseases like Burnout, ChronicFatigue Syndrome, depression, cardiovascular disease, whileothers seem to show remarkable resilience even in the pre-sence of extreme adversity? Investigating this question hasbeen at the core of this laboratory’s research efforts for thepast seven years, and we have focused on the central nervoussystem (CNS) and the specific brain structures involved inregulating the HPA to find some of the answers.Given the dominant involvement of HC, PFC and AG in theregulation of the HPA and the stress response (Herman et al.,2005), these structures together with their immediate affer-ents and efferents provide the key targets for investigationsusing functional and structural neuroimaging. The hippocam-pus has a high number of both mineralocorticoid (MR) andglucocorticoid (GR) receptors, is known to exert a negativefeedback on HPA axis activity after stress, and is discussed toplay a tonic inhibitory role on HPA axis activity (Hermanet al., 2005). A number of studies have shown results indicat-ing that prolonged exposure to glucocorticoids alters themorphology and the functional integrity of hippocampalneurons (Joels and de Kloet, 1989; McEwen, 2001). Inhumans, a number of neuroimaging studies have providedevidence for an association between HPA function and HCmorphology (Starkman et al., 1992; Magarinos et al., 1996;Bremner et al., 2000).The HC also plays an important role in memory consolida-tion and retrieval (Squire et al., 1993). Studies investigatingthe effects of varying cortisol levels on cognitive perfor-mance demonstrate how cortisol can have an impact oncognitive aspects of HC function as well (Lupien and Lepage,2001). In detail, several studies have shown that administra-tion of glucocorticoids after learning and before retrievalnegatively affects hippocampal-dependent declarativememory (Newcomer et al., 1994; Lupien et al., 2002; deQuervain et al., 2003). As well, increased levels of endogen-ous glucocorticoids in young and elderly populations afterexposure to psychological stress tests have been shown toimpair memory retrieval (Kirschbaum et al., 1996; Lupienet al., 1997; Elzinga et al., 2005). When glucocorticoids areadministered before learning, however, the picture is morecomplex; here, it seems to depend on the time of daywhether the impact on learning is detrimental (Het et al.,2005). Recently, anatomical neuroimaging studies haverevealed a link between HC volume, cognitive performanceand HPA axis function in pathological and normal humanpopulations (Wolf et al., 2002; Pruessner et al., 2005, 2007).Thus far, two studies had investigated the effects of glucocorticoids on hippocampal function and memory inneuroimaging paradigms: in a CMRglu-positron emissiontomography (PET) study with Alzheimer’s disease patientsand normal controls,de Leon et al. (1997)have shown thatadministration of synthetic cortisol led to decreased neuro-nal excitation in the HC only in the normal controls. In asimilar study, another group could show a reduction of regio-nal cerebral blood flow (indicative of reduced neuronalexcitation) in association with 25 mg dose of cortisoneadministration, as well as impairment of declarative memory(de Quervain et al., 2003).Taken together, the available literature points to a signifi-cant involvement of the HC, amygdala and PFC in the regula-tion of the HPA, with the HC also being strongly implicated inthe regulation of memory. In the following, we will presentneuroimaging studies we have conducted or contributed tothat investigated the variations in structure and function of these areas, and their effects on HPA axis regulation.
2. Structural neuroimaging in associationwith HPA axis regulation
2.1. Medial temporal lobes
To allow assessment of the HC and surrounding medial tem-poral lobe structures, we have developed and contributed to
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PNEC-1550; No of Pages 13
Please cite this article in press as: Pruessner, J.C., et al., Stress regulation in the central nervous system: Evidence from structural andfunctional neuroimaging studies in human populations. Psychoneuroendocrinology (2009), doi:10.1016/j.psyneuen.2009.02.016
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