Background: Subtle and inconsistent differences in hypothalamic-pituitary-adrenal (HPA) axis activity have been reported for patients with panic disorder. While these patients show little or no alterations in basal ACTH and cortisol levels, it has been hypothesized that HPA hyperresponsivity was a trait in panic patients when exposed to novel and uncontrollable stimulation. Methods: Thirty-four patients (23 females, mean age 35 yrs) diagnosed with panic disorder were compared to 34 healthy controls matched for age, gender, smoking status, and use of oral contraceptives. Both groups were exposed twice to a potent laboratory stress protocol, the Trier Social Stress Test (TSST) on consecutive days. Free salivary cortisol levels and heart rate responses were repeatedly measured before and following the TSST. In addition, the cortisol awakening response (CAR) was assessed to further investigate HPA reactivity in PD patients. Results: While the TSST induced similar heart rate stress responses in both groups, cortisol responses were clearly absent in the panic patients with normal responses in the controls (F(1.96, 66) = 20.16; p < 0.001). No differences in basal cortisol levels were observed in the extended baseline period. The same cortisol stress non-response patterns were observed when patients with/without comorbid depression, or with/without psychotropic medication were compared. In contrast to their non-response to the psychosocial stressor, panic patients showed a significant CAR. Conclusion: These findings provide strong evidence to suggest that PD patients present with a striking lack of cortisol responsivity to acute uncontrollable psychosocial stress under laboratory conditions. This unresponsiveness of the HPA axis appears to be rather specific, since a normal CAR in the morning could be documented in these patients. Thus, the present results do not support the hypothesis that PD patients show a trait HPA hyperresponsiveness to novel and uncontrollable stimulation. In contrast, the data provide support for a hyporesponsive HPA axis under emotional stress in PD patients.

Transdisciplinary research in general, and stress research in particular, requires an efficient integration of methodological knowledge of all involved academic disciplines, in order to obtain conclusions of incremental value about the investigated constructs. From a psychologist’s point of view, biochemistry and quantitative neuroendocrinology are of particular importance for the investigation of endocrine stress systems (i.e., the HPA axis, and the SNS). Despite of their fundamental role for the adequate assessment of endocrine activity, both topics are rarely covered by conventional psychological curriculae. Consequently, the transfer of the respective knowledge has to rely on other, less efficient channels of scientific exchange. The present thesis sets out to contribute to this exchange, by highlighting methodological issues that are repeatedly encountered in research on stress-related endocrine activity, and providing solutions to these issues. As outlined within this thesis, modern stress research tends to fall short of an adequate quantification of the kinetics and dynamics of bioactive cortisol. Cortisol has gained considerable popularity during the last decades, as its bioactive fraction is supposed to be reliably determinable from saliva and is therefore the most conveniently obtainable marker of HPA activity. However, a substantial fraction of salivary cortisol is metabolized to its inactivated form cortisone by the enzyme 11β-HSD2 in the parotid glands, which is likely to restrict its utility. Although the commonly used antibody-based quantification methods (i.e. immunoassays) might “involuntarily” qualify this issue to some degree (due to their inherent cross-reactivity with matrix components that are structurally-related to cortisol; e.g., cortisone), they also cause differential within-immunoassay measurement bias: Salivary cortisone has (as compared to salivary cortisol) a substantially longer half-life, which leads to an overestimation of cortisol levels the more time has passed since the onset of the prior HPA secretory episode, and thus tends to distort any inference on the kinetics of bioactive cortisol. Furthermore, absolute cortisol levels also depend on the between-immunoassay variation of antibodies. Consequently, raw signal comparisons between laboratories and studies, which are favorable as compared to effect comparisons, can hardly be performed. This finding also highlights the need for the long-sought standardization of biochemical measurement procedures. The presumably only way to circumvent both issues is to rely on quantification of ultrafiltrated blood cortisol by mass-spectrometric methods. Being partly related to biochemical considerations with research on HPA activity, a second topic arises concerning the operationalization of the construct itself: In contrast to the simple outcome measures like averaged reaction times, inclined stress researchers can only indirectly infer on the sub-processes being involved in HPA activity from longitudinally sampled hormone concentrations. HPA activity can be quantified either by (a) discrete-time, or by (b) continuous-time models. Although the former is the most popular and more convenient approach (as indicated by the overly frequent encounter of ANOVAs and trapezoidal AUC calculations in the field of psychobiological stress research), most discrete time models form rather data-driven, descriptive approaches to quantify HPA activity, that assume the existence of some endocrine resting-state (i.e., a baseline) at the first sampling point and disregard any mechanistic hormonal change occurring in between all following sampling points. Even if one ignores the fact, that such properties are unlikely to pertain to endocrine systems in general, many generic discrete time models fail to account for the specific structure of endocrine data that results from biochemical hormone measurement, as well as from the dynamics of the investigated system. More precisely speaking, cortisol time series violate homoscedasticity, residual normality, and sphericity, which need to be present in order to enable (mixed effects) GLM-based analyses. Neglecting these prerequisites may lead to inference bias unless counter-measures are taken. Such counter-measures usually involve alteration of the scale of hormone concentrations via transformation techniques. As such, a fourth-root transformation of salivary cortisol (being determined by a widely used, commercially available immunoassay) is shown to yield the optimal tradeoff for generating homoscedasticity and residual normality simultaneously. Although the violation of sphericity could be partly accounted for by several correction techniques, many modern software packages for structural equation modeling (e.g., Mplus, OpenMX, Lavaan) also offer the opportunity to easily specify more appropriate moment structures via path notation and therefore to relax the modeling assumptions of GLM approaches to the analysis of longitudinal hormone data. Proceeding from this reasoning, this thesis illustrates how one can additionally incorporate hypotheses about HPA functioning, and thus model all relevant sub-processes that give rise to HPA kinetics and dynamics. The ALT modeling framework being advocated within this thesis, is shown to serve well for this purpose: ALT modeling can recover HPA activity parameters, which are directly interpretable within a physiological framework, that is, distinct growth factors representing the amount of secreted cortisol and velocity of cortisol elimination can serve to interpret HPA reactivity and regulation in a more unambiguous way, as compared to GLM effect measures. For illustration of these advantages on a content level, cortisol elimination after stress induction was found to be elevated as compared to its known pharmacokinetics. While the mechanism behind this effect requires further investigation, its detection would obviously have been more difficult upon application of conventional GLM methods. Further extension of the ALT framework allowed to address a methodological question, which had previously been dealt with by a mere rule of thumb; what’s the optimal threshold criterion, that enables a convenient but comparably accurate classification of individuals whose HPA axis is or is not activated upon encountering a stressful situation? While a rather arbitrarily chosen baseline-to-peak threshold of 2.5 nmol/L was commonly used to identify episodes of secretory HPA activity in time series of salivary cortisol concentrations, a reanalysis of a TSST meta- dataset by means of ALT mixture modeling suggested that this 2.5 nmol/L criterion is overly conservative with modern biochemical measurement tools and should be lowered according to the precision of the utilized assay (i.e., 1.5 nmol/L). In sum, parametric ALT modeling of endocrine activity can provide a convenient alternative to the commonly utilized GLM-based approaches that enables the inference on and quantification of distinct HPA components on a theoretical foundation, and thus to bridge the gap between discrete- and continuous-time modeling frameworks. The implementation of the outlined modeling approaches by the respective statistical syntaxes and practical guidelines being derived from the comparison of cortisol assays mentioned above, are provided in the appendix of the present thesis, which will hopefully help stress researchers to directly quantify the construct they actually intend to assess.

Summary: Salivary alpha-amylase: More than an enzyme - Investigating confounders of stress-induced and basal amylase activity (Dipl.-Psych. Jana Strahler) The hypothalamus-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS) are two of the major systems playing a role in the adaptation of organisms to developmental changes that threaten homeostasis. The HPA system involves the secretion of glucocorticoids, including cortisol, into the circulatory system. Numerous studies have been published that introduced salivary cortisol to assess HPA axis activity and therefore strengthens its role as an easy obtainable biomarker in stress research that can be monitored easily and frequently. Recent findings suggest a possible surrogate marker of autonomic activity due to autonomic innervation of salivary glands: salivary alpha-amylase (sAA). Up to date, additional methodological research is needed for a better understanding of the advantages and disadvantages of sAA activity in comparison to already established markers of ANS activity. The aim of the present thesis is to further our knowledge of confounders of sAA activity under basal and acute stress conditions and to strengthen the validity of this enzyme as an easy obtainable alternative for ANS testing. After introducing classical and modern stress concepts and stress system physiology (chapter 2), the reader is acquainted with anatomical basics of salivary gland innervation and secretion of salivary proteins, including sAA, due to autonomic innervation (chapter 3 and 4). Afterwards, a more nuanced review of methodological considerations of sAA determination shows gaps of knowledge concerning its usefulness as a marker of ANS activity (chapter 5). Given the fact that the integration of sAA into developmental and aging research is a relative recent phenomenon, several issues have to be addressed before a final conclusion could be drawn. Therefore, we conducted a series of studies incorporating these considerations regarding behavioral correlates of inter- and intraindividual differences in sAA activity with a special emphasis on older adults. Chapter 7 deals with sAA activity under psychological stress conditions in different age groups. Since vulnerability to disease and disease prevalence patterns change with age, it is important to investigate stress reactivity of people in different age groups. We therefore investigated children between 6 and 10 years, because childhood is a sensitive period of growth and development, and thus plays an important role for later life health. Young adults were included to represent the most studied human age group as a reference. Older adults between 59 and 61 years were investigated, because at this age the course is set for the further development of a person’s health in later life, and because autonomic stress responses in older age might be important determinants of cardiovascular and inflammatory aging. Our goal is to test for associations of sAA with more established stress system markers, i.e., salivary cortisol as outcome measurement of HPA reactivity, heart rate (HR) and heart rate variability (HRV) as markers for autonomic reactivity, and to directly compare these responses between different age groups across the life span. Secretion of sAA and cortisol was repeatedly assessed in 62 children, 78 young adults, and 74 older adults after exposure to a standardized psychosocial stressor, the Trier Social Stress Test. In addition, cardiovascular activity was measured in both adult groups. Older adults showed attenuated sAA, HR, and HRV responses. Furthermore, we found higher sAA but lower cortisol at baseline as well as lower sAA and cortisol responses in children. Age by sex interactions were observed only for cortisol with higher responses in older male participants. No associations between the parameters were found. Results in children and young adults confirm previous results. Overall, findings implicate sAA as an alternative or additional autonomic stress marker throughout the life span, with marked and rapid responsiveness to stress in three relevant age groups. The impact of age and chronic stress on basal sAA activity is the center of interest in chapter 8. We therefore assessed diurnal profiles of sAA and salivary cortisol in 27 younger and 31 older competitive ballroom dancers as well as 26 younger and 33 older age- and sex-matched controls. According to the Allostatic Load concept, repeated, non-habituating responses to social-evaluative conditions, which characterize the lives of competitive ballroom dancers, should be associated with stress system dysregulations. Furthermore, we expect to see an increased sympathetic drive associated higher overall alpha-amylase activity in older adults. Analyses revealed an elevated daily overall output of sAA in older adults while there was no effect of age on mean cortisol levels. Alterations of diurnal rhythms were only seen in younger male dancers showing a flattened diurnal profile of sAA and younger dancers and female older dancers showing a blunted diurnal rhythmicity of cortisol. Furthermore, we found a negative correlation between summary indices of basal sAA and the amount of physical activity. In conclusion, higher overall output of sAA in older adults was in line with the phenomenon of a “sympathetic overdrive” with increasing age. Furthermore, a lower output of sAA in people who are more physical active was in line with the hypothesis of an exercise-induced decrease of sympathetic activity. Taken together, results of chapter 7 and 8 show a clear impact of age on sAA activity, either under acute stress or basal conditions. One problem when integrating sAA into developmental and aging research is the use of adrenergic agonists and antagonists what is very common in older adults, i.e. antihypertensive drugs (AD). As well, the previously shown sympathetic overactivity that occurs with normal aging is associated with higher blood pressure (BP). Therefore, chapter 9 deals with a possible impact of high BP and AD on diurnal sAA activity in 79 older adults (33 normotensive adults, 16 medicated vs. 45 hypertensive adults, 34 medicated). Results showed a pronounced rhythm of sAA in all groups. Diurnal profiles differed significantly between men and women with men lacking the typical decrease of sAA in the morning and showing more pronounced alterations throughout the day. An effect of AD on sAA profiles and area under the curve values indicates that subjects not using AD´s show a heightened diurnal profile and a higher total output of sAA. Descriptively, this was also true for hypertensive older adults. Hypertensive subjects and those not using AD showed the highest diurnal output of sAA and the steepest slope. In sum, our results show an impact of antihypertensive medication and a difference between normotensive and hypertensive subjects on characteristics of diurnal sAA activity. Hence, findings are of particular interest in research using sAA as a prognostic indicator of pathological states and processes. Given the fact that hypertension was also shown to be associated with substantial changes of transmitters within the suprachiasmatic nucleus (SCN) - the “biological clock” that receives photic input from retinal glands via the retinohypothalamic pathway - and an altered output from the SCN to the sympathetic nervous system, we broaden the idea of a possible effect of different lighting conditions on morning sAA profiles in chapter 10. In a counterbalanced within-subjects design six men and 16 women of different ages collected sAA morning profiles on two consecutive days with leaving their shutters closed on the one day (= dark) and open their shutters on the other day (= bright). We were able to replicate earlier findings of light-induced changes of salivary cortisol with higher responses during the bright condition. On either day, women showed larger cortisol increases than men. Despite multisynaptic autonomic connections arising from the SCN projecting to multiple organs of the body, we could not find an effect of sunlight on sAA morning profiles. Evidence for circadian clock gene expression in human oral mucosa might account for this result and indicates that peripheral oscillators may act more like integrators of multiple different time cues, e.g. light, food intake, instead of a “master” oscillator (SCN). Results of chapter 7 to 10 provide clear evidence that sAA is heightened in states of autonomic arousal, i.e. stress, aging and hypertension, and that its circadian rhythmicity seems to be regulated rather integrative than directly via efferent input from hypothalamic SCN neurons. In chapter 11 this thesis tries to approach one central question: What is the biological meaning of the findings made? According to this enzyme´s anti-bacterial and digestive action short term changes might not have a biological meaning itself but rather reflect just a small part of multiple coordinated body responses to stressful stimuli. While the sympathetic branch of the ANS mainly stimulates protein secretion, the parasympathetic branch stimulates saliva flow. Acute stress responses might therefore be interpreted as reflecting predominant sympathetic activity together with parasympathetic withdrawal. The same mechanism could also be suitable for the finding of higher diurnal levels of sAA in older adults or hypertensive subjects reflecting a higher peripheral sympathetic tone in these groups. Diurnal profiles of sAA itself may reflect circadian changes in autonomic balance. Circadian rhythms are of great advantage since they enable individuals to anticipate. This pre-adaptation enables the individual to cope with upcoming demands and challenges. Our finding of a relationship between sAA and salivary cortisol what strengthens the relevance of glucocorticoids that were previously shown to be able to phase shift circadian rhythms in cells and tissue. Within a food-related context there is evidence that decreasing levels of sAA in the morning could reflect increases of feeling hungry since sAA systematically increases during food consumption and with the subjective state of satiety. So far, much more research is needed to identify underlying physiological mechanisms of circadian sAA rhythmicity. Taking the next step, future studies will have to focus on the integration of sAA assessment into longitudinal studies and different disease states to prove its applicability as a marker of sympathetic neural functioning in the genesis and prognosis of disease.

Die Dissertation beschäftigt sich mit der Frage, ob und wie Feedback-basiertes Lernen durch Stress moduliert wird. Der Zusammenhang zwischen Stress und Kognition sowie die zugrunde liegenden biologischen Mechanismen sind Gegenstand der kognitiven Stressforschung. Während der Einfluss von Stress und Stresshormonen auf andere Lernformen bereits gut etabliert ist, gibt es bisher kaum Studien, die Feedback-basiertes Lernen unter Stress bei Menschen betrachtet haben. In der vorliegenden Arbeit werden daher die Auswirkungen akuten Stresses auf diese Lernform untersucht. Es werden gezielt Auswirkungen auf die generelle Akquisition einer Lernaufgabe mittels Feedback, auf die Nutzung sowohl positiven als auch negativen Feedbacks beim Lernen sowie auf die Fähigkeit der flexiblen Anpassung an sich änderndes Feedback betrachtet. Dafür werden in den experimentellen Untersuchungen der Arbeit Feedback-basierte Aufgaben mit einer vorangestellten Induktion akuten psychosozialen Stresses kombiniert. Die Ergebnisse der vorliegenden Arbeit deuten darauf hin, dass akuter psychosozialer Stress das generelle Erlernen Feedback-basierter Aufgaben nicht beeinflusst, jedoch die Nutzung positiven und negativen Feedbacks beim Lernen verändert. Im Speziellen wird negatives Feedback nach einer Stressinduktion weniger genutzt, während über eine möglicherweise stärkere Nutzung positiven Feedbacks aufgrund der vorliegenden Ergebnisse keine fundierte Aussage getroffen werden kann. Zudem finden sich in der vorliegenden Arbeit Hinweise auf einen positiven Zusammenhang zwischen Cortisolwerten und der Flexibilität in Feedback-basierten Lernaufgaben. Als Erklärungsansätze werden veränderte Aufmerksamkeitsprozesse nach einer Stressinduktion sowie andere psychologische Faktoren wie eine kognitive Nachbeschäftigung mit dem Stresstest und eine geringere Involviertheit in die kognitiven Aufgaben diskutiert. Die berichteten Korrelationen zwischen Cortisolwerten und kognitiven Parametern werden dahingehend interpretiert, dass Cortisol ein vermittelnder Faktor des Stresseffekts auf die Nutzung und neuronale Verarbeitung negativen Feedbacks sein könnte. Zur Integration der Ergebnisse aller Studien wird eine Modulation der dopaminergen Signalübertragung durch Stress und erhöhte Cortisolspiegel und damit verbundene Auswirkung auf Feedback-basiertes Lernen vorgeschlagen. Die vorliegende Arbeit gibt zum ersten Mal Hinweise auf eine veränderte Nutzung und Verarbeitung von Feedback nach psychosozialem Stress und bestätigt frühere Befunde eines Zusammenhangs zwischen Cortisol und der Flexibilität beim Lernen.

L’objectif de ce projet de recherche était de vérifier la présence de changements de sensibilité de la rétine et du système circadien suite à deux semaines d'exposition à un milieu faiblement ou fortement éclairé, dans des conditions contrôlées en laboratoire. De plus, comme un changement de sensibilité peut modifier l'ajustement du système circadien au cycle jour-nuit extérieur, nous voulions également vérifier si la phase circadienne serait modifiée par le traitement et si la vigilance et l’humeur seraient affectées. Dix sujets ont été exposés à de la lumière tamisée (70 lux [LT]) et 10 ont été exposés à de la lumière vive (3000 lux [LV]) pendant 12 jours consécutifs en laboratoire de 8h45 à 19h00 tous les jours. L’exposition à la lumière a été mesurée 5 jours avant l’entrée au laboratoire dans l’habitat naturel du sujet et pendant la période en laboratoire à l’aide de l’Actiwatch-L®. La sensibilité rétinienne a été mesurée avant et après le traitement lumineux, par un électrorétinogramme (ERG) et la sensibilité circadienne, par le test de suppression de mélatonine salivaire. Tout au long du protocole, la vigilance, la somnolence et l'humeur ont été évaluées à plusieurs moments de la journée à intervalles prédéterminés. Après 12 jours d’exposition en lumière contrôlée, l’amplitude de l’onde-a au Vmax à l’ERG photopique a diminué en LV alors qu’elle a augmenté en LT. À l’ERG scotopique, une différence de sensibilité rétinienne (log K) entre les groupes avant le traitement expérimental s’est amenuisée à la fin du traitement (p=.053). La suppression de mélatonine après 90 minutes d’exposition au test de suppression a diminué en LV alors qu’il n’y a pas eu de modification en LT, cependant cette interaction n’était pas significative (p=.16). La phase circadienne des sujets exposés à LV a été devancée de 58 minutes (p=.04) alors qu’elle a été retardée de 26 minutes en LT (p=.32). Les mesures de vigilance subjective (EVA) ont indiqué que les sujets LV se considéraient plus éveillés que les sujets LT après le traitement (p=.02). Par contre, aucune différence n’est apparue quant aux mesures de performance psychomotrice ni de l’humeur. L’histoire lumineuse n’a pas modifié la sensibilité rétinienne dans le sens prévu par les hypothèses alors qu’il y a eu une tendance vers une augmentation de la sensibilité circadienne en condition de lumière tamisée. L’amélioration de la vigilance subjective après l’exposition en LV n’a pas été soutenue par les résultats de la performance psychomotrice. L’histoire lumineuse n’a eu aucun effet sur l’humeur des sujets. Cette étude souligne l’importance d’utiliser des mesures permettant de départager les effets immédiats d’un traitement lumineux des effets à long terme autant sur le plan rétinien que circadien. Il reste également complexe d’étudier en laboratoire des changements adaptatifs qui se produisent dans le milieu naturel en raison du confinement et des modifications physiologiques et psychologiques pouvant y être associées. / The purpose of this study was to evaluate the impact of two weeks exposure in a dim or bright light environment on retinal and circadian sensitivity to light in a controlled laboratory setting. Given that a change in sensitivity to light could modify the circadian adjustment to the external light-dark cycle, it was expected that the circadian phase would be modified with the light treatment and have an effect on alertness and mood. Ten participants were exposed to a dim light (DL) environment (70 lux) and 10 participants to a bright light (BL) environment (3000 lux) 10 hours per day for 12 consecutive days. Light exposure was measured 5 days prior to the onset of the experiment in the subject’s natural environment and during the entire laboratory experiment with an Actiwatch-L®. Retinal function was assessed with the electroretinogram (ERG). Circadian light sensitivity was evaluated with a salivary melatonin suppression test. Retinal and circadian sensitivity measures were taken before and after the experimental condition. Alertness, sleepiness and mood were measured several times per day at fixed intervals. After 12 days of controlled light exposure, the amplitude of amax of the photopic ERG was decreased in BL whereas it was increased in DL. In scotopic ERG, there was a difference in the retinal sensitivity (log K) between the two groups before light treatment that disappeared at the end of light exposure (p=.053). The percentage of melatonin suppression after 90 minutes exposure to the melatonin suppression test was decreased in BL while it did not changed in DL condition. This interaction, however, did not reach significance (p=.16). We measured a 58 minutes phase advance in the BL condition (p=.04) and a 26 minutes phase delay in DL (p=.32). Measures of subjective vigilance (EVA) suggested that BL subjects were more alert after the light treatment than DL subject (p=.02). However, there was no difference in the psychomotor vigilance task or mood. Light history did not modify the retinal sensitivity as predicted by the hypotheses. However, there was a trend toward an increased circadian sensitivity in the dim light condition. The improvement of subjective vigilance in the BL condition was not supported by the results at the psychomotor vigilance task. Light history had no effect on the mood of the subjects. Long-term effects of a light treatment are difficult to isolate from shorter direct effects of light. Moreover, the study of adaptative environmental changes that spontaneously appeared in the field are possibly masked in a laboratory setting where confinement could induce physiological and psychological changes.

RÉSUMÉ L’étiologie de la schizophrénie est complexe et le modèle de vulnérabilité-stress (Nuechterlein & Dawson, 1984) propose que des facteurs de vulnérabilité d’ordre génétique combinés à une histoire environnementale de stress particulier pousseraient l’individu vers un état clinique de psychose. L’objectif principal de cette thèse est de mieux comprendre la réaction physiologique des personnes schizophrènes face à un stress psychologique, tout en conceptualisant les symptômes psychotiques comme faisant partie d’un continuum, plutôt que de les restreindre sur un plan catégoriel. Afin de faire la différence entre les patients schizophrènes et les individus de la population générale, au-delà de la sévérité de leurs symptômes psychotiques, leur réaction au stress est comparée et le phénomène de seuil critique dans la réaction de cortisol est exploré en tant que point décisif pouvant distinguer entre les deux groupes. La première étude de cette thèse (Brenner et al., 2007) examine la fiabilité, la validité et la structure factorielle du Community Assessment of Psychic Experiences (CAPE) (Stefanis et al., 2002), avec un échantillon francophone et anglophone de la population nord américaine, un questionnaire auto-administré de 42 items qui évalue les expériences quasi-psychotiques présentes dans la population générale : des symptômes positifs (ou psychotiques), négatifs (ou végétatifs) et dépressifs. Ce questionnaire a été complété par un échantillon de 2 275 personnes de la population montréalaise. Les résultats appuient la consistance interne des 3 sous-échelles originales. De plus, l’analyse factorielle exploratoire suggère des solutions de 3-5 facteurs, où les solutions à 4 et 5 facteurs proposent de séparer les symptômes positifs en sous-catégories plus spécifiques. Finalement, cette étude suggère une version plus courte du CAPE, avec seulement 23 items, tout en préservant les mêmes trois échelles originales. La toile de fond de cet article confirme l’existence du phénomène du continuum de la psychose, où une variation de symptômes psychotiques peut se retrouver aussi bien dans la population générale que dans la population clinique. Dans une deuxième étude (Brenner et al., 2009), cette thèse examine à quel point la réponse de l’hormone de stress, le cortisol, à un test de stress psychosocial nommé le Trier Social Stress Test (TSST) (Kirschbaum, Pirke, & Hellhammer, 1993), peut établir une différence entre les sujets témoins et les patients schizophrènes, tout en contrôlant des variables importantes. Un groupe de 30 personnes schizophrènes et un groupe de 30 sujets de la population générale, recrutés lors de la première étude de cette thèse, ont participé à cette recherche qui est construite selon un plan expérimental. Le groupe témoin inclut des personnes légèrement symptomatiques et un chevauchement des scores psychotiques existe entre les deux groupes. Suite au stresseur, les deux groupes démontrent une augmentation significative de leur rythme cardiaque et de leur pression artérielle. Cependant, leur réponse de cortisol a tendance à différer : les patients schizophrènes présentent une réponse de cortisol plus petite que celle des témoins, mais en atteignant un seuil statistique significatif seulement à la mesure qui suit immédiatement le stresseur. Ces résultats significatifs sont obtenus en contrôlant pour la sévérité des symptômes positifs, un facteur discriminant significatif entre les deux groupes. Ainsi, le niveau de cortisol mesuré immédiatement après le stresseur se révèle être un marqueur de seuil critique pouvant établir une distinction entre les deux groupes. Aussi, leur réponse de cortisol maximale a tendance à apparaître plus tard que chez les sujets témoins. De façon générale, la réaction au stress des deux groupes étudiés est un autre moyen d’observer la continuité d’un comportement présent chez les individus, jusqu’à ce qu’un seuil critique soit atteint. Ainsi, il est possible de trancher, à un moment donné, entre psychose clinique ou absence de diagnostic. / ABSTRACT The aetiology of schizophrenia seems to be complex and the Vulnerability-Stress model (Nuechterlein & Dawson, 1984) proposes that genetic vulnerability factors, in conjunction with a particular history of environmental stress, would act together to drive the individual into a clinical state of psychosis. The principal objective of this thesis is to better understand the physiological reaction to a psychological stressor in people with schizophrenia, while conceptualizing psychotic symptoms along a continuum, rather than as a restrictive dichotomy. In order to distinguish between schizophrenia patients and controls from the general community, beyond the severity of their psychotic symptoms, they are compared on their stress reaction, and the phenomenon of critical threshold is explored within the cortisol reaction for its ability to distinguish between the two groups. The first study of this thesis (Brenner et al., 2007) examines the reliability, validity and factor structure of the Community Assessment of Psychic Experiences (CAPE) (Stefanis et al., 2002), with a French and English speaking sample form the north American population, a 42-item self-report questionnaire assessing psychotic-like symptoms in the general community: positive (or psychotic), negative (or vegetative) and depressive symptoms. This questionnaire was completed by 2 275 individuals from the Montreal area and the results support the internal consistencies of the original three subscales. Further, the exploratory factor analysis suggests 3-5 factor solutions, where the 4- and 5-factor solutions propose separating the positive symptoms into more specific subcategories. Finally, this study suggests a shorter version of the CAPE with 23 items, representing the same three original scales. These results support the existence of the continuum of psychosis, in which variation of psychotic symptoms can be found in the clinical population as well as in the general community. The second study of this thesis (Brenner et al., 2009) examines the extent to which cortisol reaction to a psychosocial stress test, the Trier Social Stress Test (TSST) (Kirschbaum et al., 1993), can discriminate between controls and schizophrenia patients while controlling for important variables. A group of 30 schizophrenia patients and a group of 30 individuals from the general community, recruited from the first study of this thesis, participated in this study designed as a case-control experiment. The control group includes people with subclinical symptoms, and an overlap in the severity of psychotic symptoms exists between the two groups. Following the stressor, both groups have significant increases in heart rate and mean arterial pressure. However, their cortisol responses diverge, with schizophrenia patients exhibiting a smaller response than the controls, but with statistically significant group differences at only one time point, immediately after the stressor. These significant results are obtained after controlling for the severity of positive symptoms, which is a discriminating factor between the two groups. The level of cortisol measured immediately after the stressor is actually a marker of the critical threshold capable of discriminating between the groups. Cortisol levels in patients have a tendency to peak later than that of the controls. As a general conclusion, the two groups’ reactions to stress are another way to observe the continuity of a certain behaviour, up until it reaches a critical threshold, which allows the differentiation between clinical psychosis and absence of illness.

Objectives: Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis has frequently been reported in multiple sclerosis (MS). So far, HPA axis function in MS has predominantly been studied under pharmacological stimulation which is associated with a series of methodological caveats. Knowledge of circadian cortisol patterns and cortisol awakening response (CAR) is still limited. Methods: A total of 77 MS patients (55 relapsing-remitting MS (RRMS)/22 secondary-progressive MS (SPMS)) as well as 34 healthy control (HC) subjects were enrolled. Diurnal cortisol release was assessed by repeated salivary cortisol sampling. Neurological disability was rated by the Kurtzke’s Expanded Disability Status Scale (EDSS). Depressive symptoms and perceived stress were assessed by self-report measures. Results: RRMS but not SPMS patients differed in circadian cortisol release from HC subjects. Differences in cortisol release were restricted to CAR. Treated and treatment naïve RRMS patients did not differ in CAR. In a RRMS follow-up cohort (nine months follow-up), RRMS patients with EDSS progression (≥0.5) expressed a significantly greater CAR compared to HC subjects. RRMS patients with a stable EDSS did not differ from HC subjects. Neither depressive symptoms nor perceived stress ratings were associated with CAR in RRMS patients. In a step-wise regression analysis, EDSS at baseline and CAR were predictive of EDSS at follow-up (R2 = 67%) for RRMS patients. Conclusions: Circadian cortisol release, in particular CAR, shows a course specific pattern with most pronounced release in RRMS. There is also some evidence for greater CAR in RRMS patients with EDSS progression. As a consequence, CAR might be of predictive value in terms of neurological disability in RRMS patients. The possible role of neuroendocrine-immune interactions in MS pathogenesis is further discussed.

In part one, betulinic acid (1) was isolated from the American Sycamore (Platanus occidentalis) in 1.6% yield, while ursolic acid (3) was isolated from Fuji and McIntosh apple peels in 1.0% and 0.8% crude yields, respectively. Oleanolic (4) and dehydrocanophyllic (6) acids were previously available, along with several analogs. Additional analogs of 1, 3 and 4 were prepared, including 9 new compounds, for a total of 51 compounds. Compounds were initially screened for cortisol lowering properties in vitro using a fish head kidney cell assay. Platanic acid (43) was selected for in vivo study in rats, along with 1 and a blend of Platanus occidentalis and Souroubea sympetela. No significant cortisol lowering was observed in vivo. In part two, β-ionone-d6 (75) was synthesized in 6.5% yield from ethyl 2-oxo-cyclohexane carboxylate (77). Total deuterium incorporation was 99.85%, with 0.03% d0 analog. 75 was converted to retinoic acid-d6 (93) in 2.2% yield.

Allergic manifestations are increasingly common in infants and children. Accumulating evidence suggests that the ‘epidemic’ increase of childhood allergy may be associated with environmental factors such as stress. Although the impact of stress on the manifestation and exacerbation of allergy has been demonstrated, the underlying mechanisms of stress-induced exacerbation are still obscure. A growing number of studies have suggested an altered hypothalamus-pituitary-adrenal (HPA) axis function to stress in allergic children. It is speculated that a dysfunctional HPA axis in response to stress may facilitate and/or consolidate immunological aberrations and thus, may increase the risk for allergic sensitization and exacerbation especially under stressful conditions. In the present review the potential impact of a hyporesponsive as well as a hyperresponsive HPA axis on the onset and chronification of childhood allergy is summarized. Moreover, potential factors that may contribute to the development of an aberrant HPA axis responsiveness in allergy are discussed. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Il a été suggéré que lorsqu’une trace de mémoire consolidée est rappelée (réactivée), elle devient instable et sujette aux modifications avant de se stabiliser à nouveau en mémoire à long terme. Nous avons récemment démontré que lorsque la réactivation d’un souvenir négatif est couplée à l’exposition à un stress psychosocial, le souvenir de l’évènement négatif est augmenté de façon durable. En se basant sur ces résultats, le but de cette thèse est de préciser le rôle du stress psychologique et physiologique (hormones de stress) sur la modulation de souvenirs réactivés. Plus précisément, la première étude visait à déterminer si le cortisol, hormone de stress majeure, est un joueur clé dans la modulation des souvenirs réactivés. Pour ce faire, nous avons inhibé pharmacologiquement les niveaux de cortisol au moment de la réactivation d’un souvenir contenant des segments neutres et négatifs. Les résultats démontrent que la réactivation du matériel négatif est amoindrie lorsque les niveaux de cortisol sont inhibés, et cet effet est toujours présent quatre jours plus tard. Étant donné que les stimuli utilisés jusqu’à maintenant ont une faible validité écologique, nous avons voulu déterminer si d’autres types de mémoires pouvaient également être modulables lors de leur réactivation. L’objectif de la deuxième étude était donc de déterminer si les mémoires autobiographiques collectives sont modulables par le stress au moment de leur réactivation. Pour ce faire, nous avons exposé les participants à de vrais extraits de journaux, neutres ou négatifs, afin de réactiver les mémoires collectives associées à ces évènements. Par la suite, tous les participants ont été exposés à un stress psychosocial et leur mémoire des extraits a été évaluée la journée suivante. Les résultats démontrent que les femmes ayant lu les nouvelles négatives avaient une réactivité physiologique accrue face au stresseur et une mémoire augmentée de ces mêmes nouvelles le jour suivant. Ce phénomène n’était cependant pas observable chez les hommes. Le but de la troisième étude était de déterminer si les mémoires autobiographiques personnelles sont modulables par le stress au moment de leur réactivation. Nous avons demandé aux participants de se remémorer deux évènements de leur passé, négatifs ou neutres. Par la suite, ils ont été exposés à un stress psychosocial et leur mémoire pour ces mêmes évènements a été évaluée à nouveau la journée suivante. Les résultats démontrent que les mémoires autobiographiques personnelles réactivées ne semblent pas être modulables par l’exposition à un stresseur. Globalement, les résultats de cette thèse démontrent que le cortisol a la capacité de moduler des souvenirs négatifs réactivés, mais que la nature (extrinsèque vs. intrinsèque) et l'intensité des souvenirs réactivés sont des facteurs déterminants pour que ce phénomène prenne place. / It has been suggested that when a consolidated memory trace is recalled (reactivated), it becomes active and sensitive to modifications before stabilizing again in the long-term memory system. We have recently demonstrated that when the reactivation of a negative memory is followed by exposition to a psychosocial stressor, the memory for the negative material is enhanced in a long-lasting manner. Based on these results, the goal of this thesis is to clarify the role of physiological (stress hormones) and psychological stress on the modulation of reactivated memories. More precisely, the first study aimed to determine whether cortisol, a major stress hormone, is a key player in the modulation of reactivated memories. To do so, we have pharmacologically inhibited cortisol levels at the time of reactivating a memory composed of neutral and negative segments. Results showed that the reactivation of the negative material is decreased when cortisol levels are inhibited and this effect is still present four days later. Given that the stimuli used so far have a weak ecological validity, we wanted to determine whether other types of memories could also be modified upon their reactivation. The goal of the second study was to examine whether collective autobiographical memories were sensitive to the effects of stress at the time of reactivation. To do so, we have exposed participants to real newspaper excerpts, either neutral or negative, in order to reactivate the collective memories associated to these events. We have then exposed all the participants to a psychosocial stressor and their memory for the excerpts was assessed the following day. Results showed that women who have read negative news excerpts had a more pronounced physiological reactivity to the stressor and an increased memory for these news the following day. This phenomenon, however, was not observed in men. The goal of the third study was to determine whether personal autobiographical memories were sensitive to the effects of stress at the time of their reactivation. We have asked participants to recall two personal events, either negative or neutral. We then exposed them to a stressor and their memory for these events was tested the following day. The results showed that reactivated personal autobiographical memories were not sensitive to stress. Globally, the results of this thesis show that cortisol has the capacity to modulate reactivated negative memories, but that the nature (extrinsic vs. intrinsic) and the intensity of the memories are determining factors for this phenomenon to occur.