Rozprawy doktorskie na temat „Psychobiology”

It has always been of great interest for scientists to study human performance and fatigue in order to better understand the limiting factors and determinants, which ultimately rule exercise tolerance in humans. In the last decades, the focus has moved to study fatigue and human performance not only from a physiological point of view but also to integrate it with psychophysiological mechanisms in order to reach a fuller understanding of fatigue processes and its implications on exercise performance. The aim of this thesis was to analyse the most prominent models of exercise tolerance and delineate psychological and physiological factors determining and/or limiting exercise performance. Moreover, the role of "effort" and its implications for exercise tolerance has been defined and elucidated. In chapter 2, it has been shown that maximal voluntary cycling power measured before and immediately after exhaustive cycling exercise does not decrease below the constant power at which participants were cycling at exhaustion. Such decrease in power, therefore, does not explain and challenge the traditional assumptions that in high intensity aerobic exercise muscle fatigue causes exhaustion, which occurs when the power generated from the muscles does not match any longer the power required by the task. Moreover, this study suggests the implication of other psychobiological variables such as rating of perceived exertion as important determinant and main limiting factor of exercise tolerance In chapter 3 has been tested the hypothesis that rating of perceived exertion and naturally occurring muscle pain, the two main perceptual determinants influencing physical performance have a different impact on physical performance. Muscle pain unpleasantness (Cook's scale) and rating of perceived exertion (RP E) (Borg's scale) were rated during a high intensity aerobic cycling test. During the cycling task, a constant increase in RPE was reported until subjects withdrew exercise while naturally occurring muscle pain rating increased at a moderate level without reaching the maximal rating. These findings suggest a high correlation between rating of perceived exertion and high intensity cycling at exhaustion and minimize the impact of naturally occurring muscle pain as limiting factor in aerobic performance. In chapter 4 it has been tested the validity and efficacy of a novel protocol to measure neural correlates of rating of perceived exertion using functional magnetic resonance imaging (fMRI). By comparing two different conditions: Fatigued leg vs. Non fatigued Leg, nine participants performed a series of leg extensions tasks alternating both legs. During this task, brain activation was measured using a 3 Tesla fMRI scanner and rating of perceived exertion has been recorded. Main results have shown an increase in rating of perceived exertion concomitantly to an increase in central motor command across the series of leg extension task performed and a significant activation of the cingulate gyrus and insular cortex has been detected when comparing higher ratings of effort compared to lower ones. These new findings may help the understanding of the neurobiology of perceived exertion and the brain areas and neural processes implicated with an increase of the rating of perceived exertion. Moreover, it elucidates the role of effort-based decisionmaking mechanisms related with perceived exertion. Overall, our findings showed the validity of a more psychophysiological approach to study complex processes of fatigue and to delineate main determinants involved in human performance with particular attention to the rating of perceived exertion. It redefined the role and the impact of exercise-related muscle pain in endurance performance. Finally, it proposes new neurophysiological insights into the origin and development of perceptions of effort in the brain. iii

Recent work in moral psychology emphasizes the role of immediate intuitive responses in shaping moral judgments, while at the same time questioning the causal role of more reflective reasoning processes. On this account (mainly due to Haidt, 2001), such reflective processes primarily provide post-hoc rationalizations for more immediate responses, and only appear to cause the associated judgments. This account poses a strong skeptical challenge to prior theories that focused on the role of reasoning in shaping moral judgments (most notably Kohlberg, 1969). In this dissertation, I attempt to address this challenge. I do so in Part I by reviewing the strengths and weaknesses of recent studies on moral reasoning and reflection. In Part II, I describe the results of six original studies that were designed to examine the roles of reasoning and reflection in moral judgment while accounting for skeptical interpretations. Part III concludes with a summary of the conditions under which reasoning and reflection were found to occur, along with a speculative account of the practical implications of this work and suggestions for future research on the cognitive mechanisms underlying reflective reasoning processes.
Psychology

Eating is one of the most important and essential behaviors that an animal can engage in (Ruiz-Mirazo, Pereto, & Moreno, 2002). For both humans and animals, energy acquisition is part of a complex system termed eating behavior that includes context, overt behaviors, and physiological processes (Morrison & Berthoud, 2007; Saper, Chou, & Elmquist, 2002; Schwartz, Woods, Porte, Seeley, & Baskin, 2000). Previous research suggests that a specific context, being socially ostracized, can increase consumption of palatable food via a decrease in motivation for self-control (e.g., Baumeister et al., 2005; Oten et al., 2008; Twenge et al., 2007; Twenge et al., 2003). Additionally, research has found that while normal weight adolescents will work harder for social reinforcements after ostracism, overweight adolescents will work harder for food reinforcements (Salvy et al., 2011b). Fortunately, there is research to suggest that the impact of ostracism may be protected against by simply having individuals write about things that they value (Brandon & Vohs, 2009). The current study explores whether or not a values writing intervention might be useful for buffering the impacts of social ostracism on the consumption of palatable foods. Specifically, whether or not weight interacted with these variables (i.e. social ostracism, values writing, and caloric consumption) was assessed. While participants did consume more after being ostracized verses being included, no other hypotheses were supported. The current research contributes implications and refinements for future research in the areas of values writing as an intervention and explorations of disordered eating.

Bariatric surgery has demonstrated efficacy as a strategy to address morbid obesity and the comorbidities associated with this issue. Beyond two years there is an increased risk for weight regain and increases in Body Mass Index. Excess weight loss may impact quality of life and mental health status initially. Post-surgically, social support healthcare professional utilization is believed to influence excess weight loss success. Social contagion theory provides a model to explain and predict the impact of social networks on self-management. The purpose of this quantitative correlational study was to examine the relationships between social support quality, health quality of life, mental health status, and healthcare team support utilization on the maintenance of excess weight loss and BMI in post-bariatric patients beyond two years after surgery. A total of 34 participants completed the Multidimensional Perceived Social Support Scale, SF-36, and Depression, Anxiety, Stress Scale. The electronic health records of these patients were analyzed to determine utilization of healthcare professional support. Health quality of life was the only construct that demonstrated a statistical relationship with weight and BMI maintenance after two years (r = .46, p <.05; r =.47, p <.05). A significant negative correlation between quality of life and mental health status was found with both weight maintenance and BMI maintenance (r = -.62, p <.01; r = -.62, p <.01). There is limited research on long-term maintenance, but these findings are inconsistent with research which has found that social support, support utilization and mental health status may influence initial post surgical weight maintenance. A regression model found that the study variables are not predictive of the maintenance of weight and BMI beyond two years. These finding may contribute to research on weight maintenance in post bariatric patients beyond two years. The results should be viewed cautiously due to the low participation rate, which may have influenced statistical significance. Future research should examine the possible impact of weight gain on study participation, and may benefit from qualitative research methodology to determine themes associated with excess weight maintenance beyond two years.

The intergenerational transmission of trauma has deleterious effects on families (Kestenburg, 1981; Yehuda, 2018). This study aims to examine the role of emotional regulation and parental reflective functioning (PRF) in the transmission of trauma to discover the underlying mechanisms of trauma so that clinicians are able to gain a deeper understanding of this phenomena in order to provide targeted interventions. An online sample of 219 participants who were over 18 years of age and who identified as being a mother completed the survey. The survey included the Adverse Childhood Experiences Questionnaire (ACE), Difficulties in Emotion Regulation Scale (DERS-18), and the Parental Reflective Functioning Questionnaire (PRFQ). What this study found are that the relationship between the ACE and PRFQ-IC was mediated by the DERS-18 (R = .273, R2 = .074, p = .000). These results indicate that clinicians may have success in treating the transmission of intergenerational trauma with interventions targeting emotional dysregulation.

The purpose of this study was to investigate imagery procedures used by visually impaired athletes prior to and during competition. Individual in depth interviews were conducted with 15 visually impaired goal ball players, competing at a national level. The results indicate that regardless of the degree of visual impairment, these athletes used imagery on a daily basis for functioning effectively within their handicap. Due to their lack of vision, a great deal of feeling and sound was incorporated into their imagery. Suggestions are made for the enhancement of "feeling oriented imagery" with sighted persons.

L'une des visions dans la recherche portant sur les émotions et les expressions faciales interprète les expressions comme le miroir des états intérieurs (Darwin, 1872/1965). Aujourd'hui, bien que plusieurs travaux aient mis en évidence qu'il existait effectivement une concordance entre l'émotion ressentie et l'expression faciale (Ekman, Friesen, & Ancoli, 1980, Roseberg & Ekman, 1994; Smith, McHugo, & Lanzetta, 1986), d'autres recherches ont démontré que l'activité du visage pouvait être trompeuse (Ekman & Friesen, 1974; Ekman, Friesen, & O'Sullivan, 1988). Certains indices faciaux favorisent la discrimination entre les expressions émotionnelles authentiques et non authentiques (i.e., dynamique temporelle de l'expression, temps de latence de la montée, certains mouvements faciaux, durée totale de l'expression). En dépit de ces indices, les êtres humains semblent avoir de la difficulté à distinguer entre ces deux types d'expression émotionnelle. L'objectif principal de la présente thèse est d'examiner la sensibilité des décodeurs à deux indices faciaux révélateurs de l'authenticité de l'expression faciale de la joie, soit la présence de la contraction de l'orbicularis oculi et la symétrie de l'expression. Le deuxième objectif est de vérifier si l'appréciation de l'authenticité varie selon le type de jugement (catégoriel vs intensité). Le troisième objectif est d'étudier le degré de confiance des décodeurs dans leurs jugements. Le quatrième objectif vise l'examen de la capacité des décodeurs à détecter ces deux caractéristiques de l'authenticité de la joie alors que le cinquième objectif est de mettre en relation la détection des indices et le jugement de l'authenticité. Trois études ont été effectuées afin d'atteindre ces objectifs. Les résultats des études suggèrent que, dans certaines circonstances, les décodeurs sont sensibles aux indices de l'authenticité de la joie et, ce, peu importe la modalité de jugement employée. Les résultats indiquent également que les décodeurs sont confiants dans leurs jugements, mais qu'il n'y a pas de relation entre la confiance et l'exactitude des jugements. De plus, il semble que les décodeurs soient capables de détecter les indices révélateurs de l'authenticité et que certains décodeurs sont plus habiles à repérer ces indices que d'autres. Toutefois, ceux-ci ne semblent pas interpréter la signification de ces indices aussi bien lorsqu'ils portent un jugement d'authenticité. Les forces, les limites et les applications pratiques de nos travaux sont également présentées.

In this study, the time courses of slow wave sleep (SWS) and EEG slow wave activity (SWA) were examined in relation to core body temperature (CBT) during extended sleep periods of 15 hours. This investigation examined the merits of a hypothetical 12-hour rhythm of SWS to: (1) confirm its existence; (2) see if it was reflected by the more objective measure of SWA (power spectral analysis); and (3) determine if there was any relationship between this 12-hour rhythm and the CBT rhythm. In Study 1, 7 subjects (age 18-22 years) slept in the laboratory for 3 consecutive nights (2 of 8 hours, then 1 of 15 hours). Rectal CBT was monitored during sleep periods. The main findings were that SWS and SWA both significantly increase in the final 3-hour block over the center 3-hour block, and that these late increases were not related to waking after sleep onset (WASO) or rapid eye movement (REM) sleep. Five of the 7 subjects showed a return of SWA, which was defined by the maximum 15 minute running average in the last 5 hours exceeding the same measure for the previous 4 hours (about 2 sleep cycles with lower SWA). With CBT phase defined as the delay from sleep onset to CBT minimum, it was found that late SWS (in the last 3 hours), and magnitude of the SWA return had significant positive relationships to CBT phase. In Study 2, 3 subjects (age 19, 21, and 29) were studied for 4 series of 4 consecutive nights, with bedtime at 23:30h on all nights. Two series served as baseline (8HBL, and 6HBL). During one series (ML) CBT rhythm was phase advanced using morning bright light (7000-11000 lux, 6:00h-9:00h), and during another series (EL) CBT was delayed using evening bright light (20:00h-23:00h). Subjects were kept in dim light (250 lux) during these morning and evening periods for the 8HBL and 6HBL. A range of CBT phase to sleep timing combinations resulted, with ML always phase advanced relative to EL. CBT phase plotted against late SWS and SWA measures showed a positive association between CBT phase and timing of SWA return (except in one subject (#3)), and a smaller positive association to SWA in the last 3 hours (except in one subject (#1)). When data from Study 1 and the equivalent 8HBL of Study 2 were combined, SWS and SWA late in the sleep period were not significantly related to WASO or REM, and magnitude of the SWA return was statistically significant. There was also a significant relationship between CBT phase and late SWS, magnitude of SWA return, and timing of the SWA return, but not with SWA in the last 3 hours. The data were consistent with a 12-hour rhythm of SWS and SWA, in which the minor pole does not depend solely on WASO or REM, and is related in timing and magnitude to the CBT rhythm. Magnitude of both poles are likely influenced by prior amounts of waking, but the special conditions of extended sleep illustrate the association of the minor pole to the CBT rhythm.

The hypothesis that individual differences in mental ability depend, in part, on the speed or efficiency of performing elementary cognitive tasks was examined. Performance and event-related potential measures were determined during the performance of a Sternberg memory scanning task with three levels of difficulty, a category matching task, and a synonym-antonym task. In each task two stimuli were presented sequentially on each trial. In the Sternberg task, the first stimulus was one, three, or five letters and is called the memory set. The second stimulus was a probe stimulus. A category name and a category exemplar were presented in each trial of the category matching task. The two stimulus words presented in each trial of the synonym-antonym task were either synonyms or antonyms. Reaction time, movement time, and reaction time standard deviation were all negatively correlated with intelligence at levels consistent with previous research. In the Sternberg task, P300 amplitude to the first stimulus increased as the number of items in the memory set increased, affirming that P300 amplitude is sensitive to demands for processing resources. P300 amplitude to the first stimulus was smaller for higher ability than lower ability subjects. This is consistent with the idea that lower ability subjects require greater processing resources than higher ability subjects. The ERP differences between higher and lower ability subjects to the first stimulus were greater at fronto-central electrode sites than at Pz where P300 is maximal. P300 amplitude to the target stimulus decreased as set size increased. This is consistent with the view that P300 amplitude is sensitive to changes in task difficulty. P300 amplitude to the second stimulus tended to be larger for the higher ability group, an effect that can be understood in terms of equivocation. P300 latency to both the first and second stimulus increased as the set size increased, affirming that P300 latency is a measure of the time required for stimulus evaluation and classification. Higher ability subjects displayed longer P300 latency to the first stimulus than lower ability subjects. The longer P300 latency to the first stimulus suggests that higher ability subjects devote more time to stimulus analysis and planning than lower ability subjects. The performance of higher ability subjects on these tasks was characterised by the more efficient deployment of processing resources and less equivocation than lower ability subjects. Speed of processing and speed of motor response were faster for higher ability than lower ability subjects.

Les resultats de plusieurs etudes appuient la notion d'une relation potentielle entre le sommeil paradoxal (SP) et le traitement de l'information. La presente recherche avait pour but d'examiner de plus pres cette relation en etudiant l'activite interhemispherique (EEG) en SP durant un apprentissage intensif de langue second. Huit etudiants droitiers unilingues anglophones, 5 femmes et 3 hommes (moyenne d'age = 24 ans), inscrits dans un cours d'immersion en francais d'une duree de six semaines, ont dormi en laboratoire pendant neuf nuits: 3 nuits avant le debut du cours, 2 nuits apres le cours. Nous avons mesure l'activite interhemispherique en SP a partir de deux sites: parieto-temporal (W1 et W2) ainsi que frontal (F3 et F4). En guise de comparaison, l'activite cerebrale a l'eveil a egalement ete enregistree pendant une serie de taches cognitives; soit la relaxation avec les yeux ouverts et fermes, l'ecoute de trois pieces musicales (classique, paroles francaises et paroles anglaises), et lors de la lecture d'un texte francais et anglais. Des analyses de la variance (ANOVAs) a mesures repetees ont revele des tendances lineaires significatives () au niveau du site parieto-temporal en SP pour les 7 frequences suivantes: delta, theta, alpha, beta, beta 1, beta 2, et totale. Cex memes analyses avec les donnees du site frontal ont decele des tendances lineaires significatives ($) dans deux frequences; theta et alpha. Il ressort de l'examen des resultats que la dominance de l'hemisphere gauche, apparente au debut du cours, s'est dirigee davantage vers une symetrie interhemispherique a mesure que le cours se deroulait. Des analyses identiques a partir des donnees enregistrees a l'eveil n'ont pas decele les tendances consistantes observees en SP. Ces donnees offrent donc un appui supplementaire au lien apparent entre le SP et le traitement de l'information, et suggerent que le sommeil serait une periode privilegiee pour mesurer le traitement hemispherique d'une langue seconde. Des analyses plus approfondies en utilisant des donnees provenant des autres stades de sommeil, nous permettrons de conclure si ce phenomene est reserve exclusivement au SP.

The Spontaneously Diabetic Wistar B.B. Rat (SDR) is considered to be a genetically determined animal model of human Type-1 diabetes. The overall objective of this thesis was to elucidate the behavioral and neurochemical profile of the SDR. This objective was attained using various pharmacological, behavioral and neurochemical approaches. The course of the changes was followed sequentially, at discretely defined time frames (0-2, 2-8 and 8-12 months duration of diabetes), to explore and characterize the contended dysfunctions. Overall, it was found that the insulin treated SDR exhibited a significantly attenuated locomotor and rearing response to the systemically administered dopamine agonists d-amphetamine and amfonelic acid. In the case of d-amphetamine, it was found that the attenuated response was robust and chronic as it persisted across all three time frames. The attenuated response of the insulin treated SDR to amfonelic acid demonstrated that the behavioral deficit could also be elicited by a dopamine agonist with a different mechanism of action from d-amphetamine. In a nonpharmacological experiment, it was found that the insulin treated SDR manifested a significantly attenuated nocturnal locomotor and rearing response, particularly to transitional photoperiodic cues. This deficit in responding was chronic and robust as it was observed across all three time frames. The possible neurochemical substrates of the aforementioned effects were investigated. A post-mortem neurochemical analysis of the region specific basal levels of CNS catecholamines and metabolites, in the insulin maintained and deprived SDR, was undertaken. There were no significant differences between the insulin maintained SDR and non-diabetic littermates or genetically distinct controls. The cessation of insulin administration to the SDR for four consecutive days resulted in significant increases in the levels of norepinephrine in the cortex and hypothalamus, dopamine in the hippocampus, and homovanillic acid in the striatum. The neurochemical response of the insulin treated SDR was assessed following a pharmacological challenge. The SDR was exposed to a single dose of (1.0 mg/kg, i.p.) amfonelic acid. The SDR exhibited a significantly greater reduction in the post-mortem levels of dopamine in the striatum, midbrain, and olfactory bulbs as well as striatal norepinephrine. The behavioral effects elicited by d-amphetamine and amfonelic acid are believed to be dopamine mediated. Thus, it was hypothesized that one source of the observed neurochemical and behavioral deficits may be related to an impairment of dopaminergic neurotransmission. Therefore, the concomitant measurement of spontaneous nocturnal locomotor activity and levels of interstitial dopamine from the ventral striatum was measured using in vivo microdialysis. No significant differences between the insulin treated SDR and controls were found. The SDR did exhibit significantly lower levels of locomotor activity. In a different vein, the behavioral response of the insulin treated SDR was assessed following exposure to environments varying in degree of novelty. It was found that the SDR exhibited a heightened behavioral response to novelty-stress. The insulin maintained SDR manifested a greater aversion to the anxiogenic regions of the open field and elevated plus maze whilst being treated with chlordiazepoxide. The anxiolytic effects of this drug were significantly attenuated in the SDR when compared to controls. In essence, it would appear that the SDR when treated with insulin and unchallenged by: (1) withdrawal of insulin treatment, (2) pharmacological stimulation or, (3) environmental stimulation, is able to maintain relatively stable baseline levels of brain catecholamines and behavior. (Abstract shortened by UMI.)

Children with Attention Deficit Hyperactivity Disorder (ADHD) have been reported to have electroencephalographic (EEG) abnormalities in the form of increased levels of theta band activity and lower than normal levels of beta band activity. The purpose of the present study was to determine if these abnormalities can also be observed in adults with ADHD. There were 32 control subjects, 25 subjects with ADHD of the primarily hyperactive type (ADHDhy), and 17 subjects with ADHD of the primarily inattentive type (ADHDpi). For the purposes of analysis, the ADHDhy and ADHDpi groups were combined to form a CLINICAL group. The subjects were right handed males and females between the ages of 20 and 50 years of age. During the study, EEG activity was recorded from 19 electrode sites while subjects sat with their eyes open and eyes closed, and while they performed a variety of tasks including: the Tests of Variability of Attention (TOVA), a reading task, a mental rotation task, a selective attention task, and a listening task. The results of the discriminant function analyses produced functions that correctly classified an average of 60 out of 74 of the control and ADHD subjects during the TOVA, listening, and selective attention tasks (p < .0005). An ANOVA of inter-hemispheric activity revealed that only the ADHDpi group were significantly different from the control group with more right than left hemispheric activity in the delta band during the mental rotation task (p < .006). A paired t-test analysis of inter-hemispheric activity showed that both the ADHDhy and ADHDpi groups had different percentage levels of right and left hemispheric activity (p < .005) during the performance of the eyes closed, T.O.V.A., mental rotation, and reading tasks; there were no significant differences in the control group in any of these comparisons. A MANOVA of regional (frontal, central, posterior, left temporal, and right temporal) activity revealed statistically significant differences in the theta/beta ratio during the eyes closed condition for the ADHDhy group with a higher ratio in the frontal region and right temporal area (p < .006). The results suggest that the differences between normal and ADHD children continues into adulthood but that the magnitude of the differences is reduced. A dysfunction in EEG activity caused by a maturational lag is supported by the results of this study. Based on the results of the analyses, recommendations are made as to which frequency bands and electrode sites should be targeted for use in neurotherapy.

This thesis examined changes in the brain's responses ("evoked potentials") during the transition from consciousness to unconsciousness. A negative wave, "N1", peaking at about 100 ms is affected by the subject's extent of attention/consciousness. Unfortunately, this same peak is also affected by manipulation of the physical parameters of the stimulus. The extent to which a component is affected by a physical or psychological parameter is often difficult to determine in the awake and alert subject. There are two principal reasons for this. Manipulation of the physical stimulus may inadvertently cause a change in the psychological state of the subject. Thus, subjects will attend to louder stimuli even if not asked to do so. Manipulation of the subject's level of attention also poses a dilemma. The change in the level of attention is always relative, not absolute. When subjects are asked to ignore stimuli, they are not able to do so. The sleep period provides a convenient means to resolve this dilemma. It is the period of time during which subjects are least attentive to, and thus least conscious of, their external environment. It can therefore be used to provide a baseline-near absolute level of attentiveness. Three experiments were run. In the first experiment, tones were presented to subjects at a rapid 600 ms interstimulus interval, during sleep onset (the transition period from Wakefulness through to Stage 2 of sleep). Subjects were not required to respond to the stimuli. In Experiment 2 stimuli were presented at a relatively slow rate (every 1000 msi. Again, subjects were not required to make an overt response. In Experiment 3 spatial resolution was enhanced by recording from 29 scalp electrode sites. Topographic changes to the P1-N1-P2 evoked potential complex during sleep onset were investigated. In addition, several novel methodological changes were implemented in this final study. Stimuli were presented in an oddball paradigm. Rare "target" tones were randomly presented within a train of frequently occurring standard stimuli. Subjects were required to press a hand held button whenever they detected a target stimulus. A radical interpretation of the present data is that a late negative wave, "N1", is entirely endogenous in nature. N1 may reflect the extent of the subject's conscious awareness of the external stimulus. As such, the N1 component of the auditory evoked potential provides a convenient and easy means to monitor the level of attention/consciousness in a number of applied settings. (Abstract shortened by UMI.)

This study was designed to gain a better understanding of the phenomenon of athletic excellence with regard to the mental aspects. The information was derived from the interviews with nine highly successful Japanese athletes. A thorough analysis of their experiences, feelings, and insights uncovered various mental factors underlying their athletic success. Content analyses of the interview data resulted in the identification of six main topic areas: (1) growth and development of exceptional athletes, (2) athletes' views on their sports and lives, (3) mental approaches to daily practice, (4) mental approaches to competitions, (5) psychological enhancement strategies, and (6) mental elements essential to athletic success. Based on the interview findings in these six main topic areas, a conceptual model of the mental path to athletic excellence was proposed from a holistic viewpoint. This model integrates five main components: personal qualities of the athlete, personal histories, mental strategies, nurturing experiences, and environmental variables.

Paired pulse stimulation is used to estimate the refractory period of the directly stimulated substrate of intracranial self stimulation. When the delay between the conditioning (C) pulse and the test (T) pulse is shorter than the refractory period, the T pulse elicits very little behaviour. The T pulse is ineffective because the substrate has not had time to recover from refractoriness. Conversely, when the C-T delay is longer than the refractory period, one would expect the T pulse to be fully effective. In practice, however, T pulses often fall 20% short of full effectiveness. This anomalous shortfall has received scant attention. The present study documented this anomaly, and tested a theory about its cause. Experiment 1 tested at very long C-T delays and at closely spaced C-T delays. It was found that T pulses always became fully effective, but often only at C-T delays of 30 ms. Experiment 2 determined that the shortfall is not an undersampling or scaling artifact. T pulse effectiveness was calculated using standard 0.1 log$\sb $ unit gradations, and then again with 0.05 log$\sb $ unit gradations, the finest practical scaling. The fine scaling had no effect on the shortfall. T pulse effectiveness is usually estimated with six replications per C-T delay. This limits statistical power, and estimates are necessarily approximate. Experiment 3 used an automated testing apparatus to generate very large numbers of replications: as many as 120 per C-T delay. The resulting effectiveness curves are extremely precise. They show that effectiveness usually rises to 80% within 5 ms. Effectiveness stays near that level until 25 ms. Then it gradually rises to 100% at 35 ms. Effectiveness remains steady near 100% until at least 50 ms, the longest C-T interval that was tested. Experiment 4 tested the theory that the shortfall is caused by a relative refractory period, a subnormal period, or a supernormal period by using T pulse currents that were 40% larger than the C pulse currents. Large T pulses eliminate relative refractory, subnormal, and supernormal effects, but they did not eliminate the shortfall. It follows that the shortfall is not caused by any of these factors.

A control group of normal readers and three subtypes of learning disability (LD) were compared in their visual event-related potentials (ERPs) to primed and unprimed words. The LD subtypes are characterized by deficient performance on tests of arithmetic skill (Group A), reading and spelling skills (Group RS), or both (Group RSA). The primed words were preceded by pictures or spoken words having a related meaning, while unprimed words were preceded by pictures or spoken words having a non-associated meaning. For normal readers, N400 amplitude was greater to unprimed words than to words primed by pictures and spoken words. For Group A, parietal N400 was reduced by spoken word primes, but not by picture primes. For Group RS and Group RSA, neither picture nor spoken word primes reduced N400 amplitude. These groups were differentiated by the amplitude of parietal N400. The normal readers displayed a greater left than right hemisphere frontal N400 amplitude to unprimed words. This asymmetry was absent in the ERPs of all the LD subtypes. The pattern of ERP results supports an LD typology that characterizes subtypes on the basis of difficulty with arithmetic or reading and spelling, or with a combination of both. The hemispheric asymmetry results suggest that left hemisphere dominance is associated with skilled reading.

The apparently simple decision to initiate or terminate a meal is extremely complex. However, the need to determine the physiological and psychological mechanisms regulating these processes has taken on an air of urgency due to escalating levels of eating disorders in our society. Ingestive patterns are influenced by a number of factors, including signaling circuits utilizing peptides, such as corticotropin-releasing hormone (CRH) and bombesin-like peptides (BN-LPs). As some of the peptidergic systems under study have also been implicated in the mediation of the stress response, some peptidergic linkages between 'stress' and 'satiety' responses are also explored. The overall objective of this thesis was to examine the pattern of utilization or release of BN-LPs and CRH at specific brain loci during (1) various phases of food ingestion, (2) the presentation of anticipatory cues paired with an appetitive event, and (3) exposure to stressors. Using in vivo microdialysis, we demonstrated that both CRH and BN-LPs are released from the central nucleus of the amygdala in response to both restraint stressor exposure and spontaneous food ingestion, an effect that was mirrored at the anterior pituitary. Furthermore, we demonstrated that CRH and BN-LPs were released at the medial prefrontal cortex in response to the "anticipation" of a palatable snack. These results raised the intriguing possibility that some aspects of both the feeding behavior and the organism's response to stressor exposure are being subserved by a common neurochemical mechanism(s). As such, it would be expected that variables that affect an organism's stress response would also have an impact on feeding behavior and related neurochemical processes. In fact we found that early life experience, gender and genetics variables (that appear to impact the stress response) also impact on the animal's neurochemical response(s) to ingestion as well as their propensity to consume a palatable snack. These experiments extend our current knowledge of the mechanism(s) underlying the control of food intake and support our contention that these systems may also serve to draw attention to events or cues of biological salience. Finally, these results also provide new insights into the potential mechanism(s) underlying various stress and eating dysfunctions, including anorexia nervosa, anorexia associated with AIDS, cancer, sickness or stress, bulimia nervosa, obesity and depression.

This study addresses recent ideas regarding the contribution of motor and frontal brain regions, traditionally engaged during speech production, to speech perception. Using an fMRI experiment concerned with word-level speech production and perception, the overlap between perception and production was investigated using a functional mask derived from a conjunction analysis of that experiment's word production tasks. This same mask was used to analyse activity during multi-modal sentence-level speech perception in another experiment. Common activity was found between word production and word perception, but not between word production and the more complex sentence-level speech perception tasks. Contrary to certain claims, visual speech perception did not lead to increased activation of speech production regions. Whole-brain analyses of the sentence-level experiment revealed complex differences between modality- and task-specific regions in frontal, temporal, and occipital regions. Activation in this experiment was clearly influenced by inherent demands of the speech level, task, and modality. Results are discussed in light of the task demands of both experiments, as well as their implication for current understanding of motor/frontal contributions to speech perception.
Cette étude s'appuie sur de récentes hypothèses concernant la contribution en perception de la parole des aires cérébrales motrices et frontales, traditionnellement recrutées lors de la production de la parole. La création d'un masque fonctionnel calculé à partir des données d'une étude en imagerie par résonance magnétique fonctionelle (IRMf) portant sur la perception et la production de mots nous a permis de rechercher une éventuelle superposition entre la perception et la production de la parole. Ce masque a été à nouveau utilisé pour analyser d'éventuelles activations pendant une tâche de perception de phrases multi-modales issue d'une autre expérience d'IRMf. Des activités communes à la production et à la perception de mots, mais pas entre la production de mots et la production plus complexe de phrases, ont été mises en évidence. Contrairement à certaines affirmations, la perception visuelle de la parole n'a pas entraîné d'augmentation des activations dans les régions dédiées à la production de la parole. Des analyses de l'ensemble du cerveau lors de la perception et de la production des phrases ont révélé des différences complexes entre les régions spécifiques de la tâche ou de la modalité dans des aires frontales, temporales et occipitales. La modalité, la tâche et le niveau de complexité de la parole ont clairement influencé les activations observées lors de cette expérience. Les résultats obtenus sont discutés en regard des demandes spécifiques dues aux tâches et aux expériences menées ainsi que de la compréhension actuelle des contributions motrices/frontales lors de la perception de la parole.

Introduction: Inbred strains of mice show heritable differences in their responses to drugs of abuse. Mice differ in their initial sensitivity to cocaine as measured by cocaine-induced locomotor activity. Genetic mapping studies using recombinant strains of mice confirmed a locus on mouse chromosome 18 which accounted for a large proportion of the variance in response to the psychostimulant effects of cocaine. A strong candidate gene, the deleted in colorectal cancer gene (Dcc), was identified using in silico bioinformatic techniques. In studies involving mice with a Dcc knockout, the mutant strain has been shown to exhibit a blunted behavioural response to amphetamine. Objectives: In light of these converging lines of evidence, the present study investigated the role of the Dcc gene in the initial sensitivity to cocaine, as measured by cocaine-induced locomotor activity in an open field apparatus. In addition, the reinforcing properties of the drug were assessed by examining intravenous cocaine self-administration in Dcc null mutants and wild-type littermates. Results: Dcc null mutants were shown to exhibit lower initial cocaine sensitivity. Under a fixed ratio 1 schedule of reinforcement, Dcc null mutants were no different in their operant responding. However, under a progressive ratio schedule of reinforcement, mice with a Dcc mutation reached higher break points and made more active lever responses at the 0.05mg/kg dose, indicating a greater motivation to acquire the drug. Conclusions: The Dcc gene plays a role in mediating the psychostimulant effects of cocaine. Dcc heterozygotes show a blunted cocaine-induced locomotor response, and an increased drive to self-administer the drug when drug contingencies are steadily increased under a progressive ratio schedule. The different effects of the gene knockout on cocaine-related behaviours may be mediated by the differential involvement of the motor and cortical brain areas subserving the two behavioural paradigms used. It is proposed that the increased responding under the progressive ratio of reinforcement may be related to an amplified motivational salience for cocaine and/or related cues, or an increase in response-outcome monitoring mediated by increased dopaminergic medial prefrontal cortex activity.
Introduction: Les souches consanguines de souris montrent des différences héréditaires dans leurs réponses aux drogues d'abus. En particulier, les souris diffèrent dans leur sensibilité initiale à la cocaïne tel que mesurée par l'activité locomotrice induite par la cocaïne. Des études de cartographie génétique utilisant des lignées recombinantes de souris ont confirmés un locus sur le chromosome 18, relié à une grande proportion de la variance phénotypique des effets psychostimulants de la cocaïne. Un gène candidat solide, le gène délété dans le cancer colorectal (Dcc), a été identifié en utilisant des techniques bio-informatiques « in silico. » Les études des souris avec un knock-out Dcc, ont montré que la lignée mutante présente une réponse comportementale émoussée à l'amphétamine. Objectifs: En raison des lignes convergentes de preuves d'un rôle du gène Dcc dans l'action de la cocaïne, la présente étude a évalué le rôle du gène Dcc dans la sensibilité initiale à la cocaïne, tel que mesuré par l'activité locomotrice induite par la cocaïne dans une boite à champ-ouvert. De plus, les propriétés renforçantes de la cocaïne ont été évaluées en examinant l'auto-administration intraveineuse de la drogue chez des souris knock-out Dcc hétérozygotes (Dcc KO) et des souris de type sauvage. Résultats: Les souris Dcc KO ont présentés une sensibilité initiale plus faible en réponse à une injection de cocaïne. Durant un programme de renforcement à proportion constante (FR1), les souris Dcc KO ne présentaient aucune différence dans leurs réponses opérantes. Cependant, lors d'un programme de renforcement proportion progressif, les souris Dcc KO ont atteint des points de rupture plus élevés et ont effectués plus de réponses sur le levier actif à la dose 0.05mg/kg, indiquant une plus grande motivation pour obtenir la drogue. Conclusions: Le gène candidat Dcc joue un rôle dans les effets psychostimulants de la cocaïne. Les hétérozygotes Dcc montrent une réponse locomotrice induite par la cocaïne diminuée, et une augmentation dans les réponses opérantes lorsque le nombre de réponses requises pour obtenir la drogue est régulièrement augmenté selon un programme de renforcement proportion progressif. L'effet différent du gène sur les comportements reliés à la cocaïne peut être expliqué par l'implication différentielle des zones cotices moteurs et préfrontaux activés par les deux paradigmes utilisés. Il est proposé que les réponses augmentées dans le rapport progressif de renforcement peuvent être liés à une amplification de la motivation d'obtenir la cocaïne et/ou des indices reliés à la drogue, ou une augmentation de la surveillance des réponses guidées par les conséquences médiée par l'activité dopaminergique du cortex préfrontal médial.

Background. Poor insight is primary symptom of psychosis that can be characterized along clinical and cognitive dimensions. Clinical insight describes ones awareness of illness, awareness of treatment need/efficacy, and ability to relabel unusual mental events, while cognitive insight reflects ones self-reflectiveness and self-certainty in beliefs. Purpose. Our overall aim was to map the psychopathological correlates and cognitive and neural systems underlying poor clinical and cognitive insight in FEP using behavioural analyses, and MRI-based cortical thickness, diffusion tensor imaging and functional imaging measurements.Methods. We carried out the following experiments: 1. Assessing the trajectory of clinical insight at multiple time points over the first year of a FEP 2–3. Mapping the extent of cortical thinning in FEP patients with poor clinical insight. 4. Analyzing the role of the hippocampus in cognitive insight in FEP 5. Analyzing the integrity of the fornix in relation to self-certainty in FEP. 6. Assessing the significance of delusional severity for cognitive insight in FEP. 7. Analyzing the role of source memory for cognitive insight in FEP using a virtual reality cognitive activation paradigm during fMRI data acquisition. Results. 1. Clinical insight improved concurrently with positive, negative and anxious symptoms between baseline and month 1. Five patient subgroups were discriminated: good, increasing, decreasing, moderate poor and very poor. 2–3. Cortical thinning was associated with clinical insight. 4. Verbal memory associated with self-reflectiveness, while hippocampal volume was associated with self-certainty. 5. Fornix integrity associated to self-certainty. 6. Delusions were associated with self-reflectiveness. 7. FES patients demonstrated statistically similar source memory performance to that of healthy controls. Despite this, within-group analyses revealed BOLD signal differences in frontal and parietal regions in correlation with higher self-reflectiveness and lower self-certainty in FES and controls during source memory recognition.Conclusions and significance. 1. Specific longitudinal insight trajectories appeared to be driving the observed associations between clinical insight and negative and depressive symptoms in the entire FEP cohort. 2–3. The findings suggest that the neural signature of clinical insight in FEP involves a network of semi-independent brain structures. 4–5. Structural deficits in the hippocampus and its circuitry, including fornix integrity, appear to be emerging as an intermediate phenotype for self-certainty in FEP. In individuals with a FEP, cognitive insight may rely on memory whereby current experiences are appraised based on previous ones. 6. Self-reflection may be important for delusion severity. 7. The disparate regional brain activity in FES might reflect the use of an alternate cognitive stratagem to achieve adaptive self-reflectiveness and self-certainty levels, or may reflect underlying neuropathology in frontal and parietal areas.
Contexte. Le manque d'auto-critique (insight) est un symptôme primaire de psychose qui peut être caractérisé sur les plans cliniques et cognitifs. L'insight clinique décrit la conscience qu'a une personne de sa maladie, la conscience du besoin ou de l'efficacité du traitement et l'habileté d'une personne à catégoriser des événements mentaux inhabituels, alors que l'insight cognitif représente la capacité de réflexion sur soi et le niveau de certitude par rapport à ses propres croyances. Objectif. Notre objectif général était de définir les corrélats psychopathologiques et cognitifs ainsi que les systèmes neuronaux impliqués dans le manque d'insight clinique et cognitif chez les premiers épisodes psychotiques (PEP) en utilisant des analyses comportementales ainsi que des mesures basées sur l'IRM comme l'épaisseur corticale, l'imagerie par tenseur de diffusion et l'imagerie fonctionnelle.Méthodes. Nous avons fait les expériences suivantes : 1. Évaluer la progression de l'insight clinique à plusieurs moments de la première année d'un PEP 2–3. Définir l'ampleur de l'amincissement cortical chez les patients PEP avec un manque d'insight clinique. 4. Analyser le rôle de l'hippocampe dans l'insight cognitif chez les PEP 5. Analyser l'intégrité du fornix en relation avec la certitude de soi chez les PEP. 6. Évaluer le rôle de la sévérité des délires par rapport à l'insight cognitif des PEP. 7. Analyser le rôle de la mémoire de la source dans l'insight cognitif chez les PEP en utilisant un paradigme d'activation cognitive en réalité virtuelle durant une acquisition de données d'IRMf.Résultats. 1. L'insight clinique s'est amélioré simultanément avec les symptômes positifs, négatifs et d'anxiété entre l'évaluation initiale et le premier mois. Cinq sous-groupes de patients ont été identifiés : bon, croissant, décroissant, modérément faible et très faible. 2–3. L'amincissement cortical était associé avec l'insight clinique 4. La mémoire verbale était associée avec la réflexion sur soi alors que le volume de l'hippocampe était associé avec la certitude de soi, indépendamment des effets de la mémoire verbale chez les PEP. 5. L'intégrité du fornix était associée à la certitude de soi. 6. Les délires étaient associés avec la réflexion sur soi. 7. Les patients PEP démontraient une performance de leur mémoire source similaire aux contrôles sains. Malgré ceci, les analyses à l'intérieur de chaque groupe ont révélé une différence du signal BOLD dans les régions frontales et pariétales en corrélation avec une plus grande réflexion de soi et une plus faible certitude de soi chez les PEP et les contrôles durant une tâche de reconnaissance de la mémoire source.Conclusions et importance. 1. La progression longitudinale spécifique de l'insight semble entraîner les associations entre l'insight clinique et les symptômes négatifs et dépressifs dans l'ensemble de la cohorte PEP. 2–3. Les résultats suggèrent que la signature neuronale de l'insight chez les PEP implique un réseau de structures cérébrales semi-indépendantes. 4–5. Les déficits structuraux de l'hippocampe et de ses circuits, incluant l'intégrité du fornix, semblent émerger en tant que phénotype de la certitude de soi chez les PEP. Chez les individus avec un PEP, l'insight cognitif pourrait reposer sur la mémoire puisque les expériences actuelles sont jugées sur la base des expériences précédentes. 6. La réflexion sur soi pourrait être importante pour la sévérité des délires. 7. L'hétérogénéité de l'activité des régions du cerveau chez les PEP peut refléter l'utilisation d'une stratégie cognitive alternative pour adapter la réflexion de soi ou la certitude de soi. Ceci pourrait aussi refléter une neuropathologie sous-jacente dans les régions frontales ou pariétales.

Psychological, Somatosensory and Autonomic functions in Women suffering from Eating Disorders.
General health and psychological, somatosensory and autonomic function were investigated in a sample of 23 eating disorder (ED) women currently in treatment and 16 controls. Somatosensory function in ED patients was generally similar to controls on cutaneous punctate sensitivity, pain sensitivity (i.e. pressure pain thresholds (PPT) on the hand or on soft tissues over the body, ischemic pain threshold and tolerance; pain distress and sensory ratings and reports of bodily aches and pains). The only differences were that bulimia nervosa (n= 6) was associated with elevated PPT on the hand and ED patient groups reported abdominal pain, and headaches for those with purging symptoms. Hand PPT correlated with BMIs (r = 0.34) and exercise frequency (r = 0.44). Self-reported general physical health and autonomic reactivity in ED patients (i.e., blood pressure, heart rate, heart rate variability, sympatico-vagal balance and sympathetically-driven stress-response) were similar to controls, with no major impairments of autonomic function in ED patients. Minor autonomic disturbances were lower blood pressure and slower heart rate in Anorexia Nervosa patients (AN), a slightly reduced stress-response in AN-Restrictive patients (n = 7) and a minor sympatico-vagal imbalance in AN-Binge/Purge patients (n = 10). On the other hand, ED patients, in particular AN Binge/Purge patients, suffered from various psychological impairments. Anxiety and Depression were related to autonomic function and to the inflammatory response to capsaicin across patients and controls. The results support the presence of clusters within ED subtypes which are associated with different profiles of general health, psychopathologies and somatosensory sensitivity, suggesting that treatment strategies also need to be specific.
Fonctionnement psychologique, somatosensoriel et autonomique chez des femmes souffrant de troubles alimentaires.
La santé générale et les fonctions psychologiques, somatosensorielles et autonomiques on été investiguées dans un échantillon de 23 femmes souffrant de troubles de l'alimentation (TA) sous traitement et 16 femmes sans TA. Les fonctions somatosensorielles des patients avec TA étaient, en général, similaires aux femmes sans TA pour la sensibilité ponctuée cutanée, la sensibilité à la douleur (i.e. seuil de douleur à la pression (SDP) sur la main ou sur les tissues mous du corps, seuil de douleur et tolérance ischémique, évaluation sensorielle et émotionnelle de la douleur et maux et douleurs allégués). Les seules différences étaient une association entre la Boulimie Nerveuse (BN) et une élévation du SDP sur la main, la présence de douleurs abdominales chez les patientes avec un TA, et de maux de tête chez les patients avec des symptômes purgatifs. L'indice de masse corporel (IMC) et la fréquence de l'activité physique étaient tous deux corrélés avec le SDP sur la main. L'autoévaluation de la santé physique générale et de la réactivité autonomique chez les patients souffrant d'un TA (i.e. Pression sanguine, pouls, variation des battements cardiaques, équilibre sympatico-vagual et réaction au stress induite par le système sympathique) étaient similaire à celles des femmes sans TA. Les troubles mineurs du système autonomique comprennent une baisse de la pression artérielle et des battements cardiaques chez les patients avec Anorexie Nerveuse (AN), une réduction mineure de la réponse au stress chez les patientes souffrant d'AN de type Restrictive (n =7) et un déséquilibre sympatico-vagual mineur chez les patientes souffrant d'AN de type boulimie/purgation (n =10). D'autre part, les patientes atteintes de TA, en particulier les patientes atteintes d'AN de type boulimie/purgation, souffrent d'une variété d'atteintes psychologiques. Les données indiquent une relation entre la dépression et l'anxiété et les fonctio

Studies have found pregnant women to be at higher risk of developing disorders of depression and anxiety than the general population. Oxytocin (OT), a neuropeptide hormone, has been linked to symptoms of psychological distress, such as depression and anxiety, in community and clinical samples. This study examined how peripheral OT levels related to symptoms of depression and anxiety in a community sample of pregnant women (N = 114). It was hypothesized that OT levels would be negatively correlated with symptoms of depression and anxiety. At the first and third trimester of pregnancy, participants completed two validated screening measures of depression and anxiety, the Edinburgh Postnatal Depression Scale (EPDS) and Generalized Anxiety Disorder scale (GAD-7), and provided a sample of blood. Blood samples were later analyzed for OT using enzyme immunoassay. Results from the study found that OT levels significantly increased from the first trimester to third trimester. While there was no direct association between peripheral OT levels and symptom scores on the EPDS or GAD-7, a profile of stable OT levels across pregnancy was associated with greater symptoms of depression and anxiety at the first and third trimester. A follow-up study using a larger sample size, and a comparative clinical population is recommended.
Des études ont révélé que les femmes enceintes étaient plus à risque que la population générale de développer des troubles de l'anxiété et de dépression. L'ocytocine (OT), une hormone neuropeptide, a été associée à des symptômes psychologiques de détresse, comme la dépression et l'anxiété, dans des populations cliniques ou issues de la communauté. Cette étude examine comment les niveaux périphériques d'ocytocine sont liés à des symptômes de dépression et d'anxiété, auprès d'un échantillon de femmes enceintes issues de la communauté (N = 114). Il a été émis comme hypothèse que les niveaux d'ocytocine seraient négativement corrélés aux symptômes de dépression et d'anxiété. Au premier et au troisième trimestre de grossesse, les participantes ont complété deux mesures de dépistage validé, telles que l'échelle de dépression postnatale Edinburgh (EPDS) et l'échelle d'anxiété généralisée (GAD-7). Elles ont aussi fourni un échantillon sanguin. Le sang a ensuite été analysé pour déterminer les niveaux d'ocytocine à l'aide de immunoassay. Les résultats de cette étude ont révélé que les niveaux d'ocytocine augmentaient considérablement entre le premier et le troisième trimestre de grossesse. Bien que l'étude n'ait pas démontré d'association directe entre les niveaux d'ocytocine périphérique et les résultats des symptômes compilés par les échelles EPDS ou GAD-7, un profil des niveaux stables d'ocytocine durant la grossesse a été associé à plus de symptômes de dépression et d'anxiété au premier et au troisième trimestre. Une étude de suivi utilisant un échantillon plus large, ainsi qu'un échantillon clinique de comparaison est recommandée.

Cognitive and mood changes during pregnancy and postpartum have been subjectively reported by women and have also been objectively measured. However, evidence relating to the relationship between hormone levels and these changes is sparse and contradictory. The studies presented in this thesis were undertaken to investigate the possible influence of estradiol (E2), progesterone (P), testosterone (T), cortisol (CORT) and prolactin (PRL) levels on cognitive functioning and mood during late pregnancy and the early postpartum period. In Study 1, pregnant women were tested on a battery of neuropsychological tests once during late pregnancy and once during the early postpartum period and their scores were compared to non-pregnant controls. Results showed that the pregnancy group had significantly lower scores than the controls on tasks of verbal recall and processing speed both during the pregnancy and the postpartum test times. CORT levels were significantly associated, in an inverted-U function, with verbal recall scores during pregnancy and postpartum and with spatial abilities at postpartum. During pregnancy, negative linear associations were observed between PRL and executive function and paragraph recall scores along with an inverted-U association with paragraph recall scores. At postpartum, E2 and CORT were negatively associated, in a linear fashion, with attention scores. In Study 2, linear and non-linear associations between hormones and mood during pregnancy and postpartum were investigated while taking into consideration psychosocial factors previously found to be related to mood changes during these reproductive periods. Perceived stress, social support from friends, social support from a significant other and sleep were found to be significant predictors of mood scores. During pregnancy, a small positive linear correlation was obtained between levels of PRL and lower mood scores. At the postpartum visit, moderate U-shaped correlations were found between mood disturbances and level of E2 and P while smaller increases in the Cortisol Awakening Response were associated with poorer mood. Collectively, the present studies provide new evidence that aspects of cognitive function and mood are altered during pregnancy and the postpartum periods and may be modulated, at least in part, by hormonal and psychosocial factors during these reproductive events.
Durant la grossesse et la période postpartum, plusieurs femmes ont constaté des changements cognitifs et des changements d'humeur, et des études ont évalué objectivement ces changements. Toutefois, les résultats démontrant les liens entre les hormones et les changements cognitifs et d'humeur durant ces périodes sont limités et contradictoires. Les études de recherche présentées dans cette thèse ont été entreprises afin d'examiner l'influence possible de l'estradiol (E2), de la progestérone (P), de la testostérone (T) du cortisol (CORT) et de la prolactine (PRL) sur le fonctionnement cognitif et l'humeur à la fin de la grossesse et le début de la période postpartum. Dans la première étude, une série de tests neuropsychologiques a été effectuée sur des femmes enceintes lors du troisième trimestre de leur grossesse et une autre fois au début de la période postpartum. Leurs résultats furent comparés aux résultats de femmes n'ayant jamais été enceintes. Durant la grossesse et la période postpartum, les femmes enceintes ont eu des résultats inférieurs aux tests de mémoire verbale et de raisonnement fluide. Les niveaux de CORT étaient liés, de façon significative et non-linéaire (c'est-à-dire en fonction U-inversé), avec les résultats de mémoire verbale durant la grossesse et la période postpartum ainsi qu'avec les habiletés spatiales durant la période postpartum. Durant la grossesse, des associations linéaires et négatives ont été observées entre les niveaux de PRL et les résultats de tests de fonctions exécutives et de mémoire de paragraphes. De plus, une fonction non-linéaire (U-inversé) était présente entre les niveaux de PRL et les résultats de tests de mémoire de paragraphes. Durant la période postpartum, les niveaux d'E2 et de CORT étaient associés, de façon linéaire et négative, avec les résultats d'attention. Dans la deuxième étude, les associations linéaires et non-linéaires entre les niveaux d'hormones et l'humeur durant la grossesse et la période postpartum ont été évaluées en prenant en considération certains facteurs psychosociaux reconnus pour influencer l'humeur durant ces périodes reproductives. Le stress perçu, le soutien social des ami(e)s, le soutien d'un(e) conjoint(e) et le sommeil étaient des variables explicatives des résultats liés aux changements d'humeur. Durant la grossesse, une faible corrélation linéaire positive a été observée entre les niveaux de PRL et les résultats d'humeur plus négative. Durant la période postpartum, des corrélations modérées non-linéaires (U-inversé) ont été observées entre les perturbations de l'humeur et les niveaux d'E2 et de P alors que de faibles augmentations de CORT au réveil matinal étaient associées à une humeur moindre. Dans son ensemble, les résultats de ces deux études apportent de nouveaux éléments démontrant que certains aspects du fonctionnement cognitif et de l'humeur sont influencés, au moins en partie, par des facteurs hormonaux et psychosociaux durant la grossesse et la période postpartum.

Fear and stress are two closely related psychological concepts. At the biological level, activity of the sympathetic nervous system (SNS) measured through galvanic skin response (GSR) is considered as a marker of fear in humans. In parallel, the secretion of cortisol consequent to the activation of the hypothalamic-pituitary-adrenal (HPA) axis has been identified as a reliable marker of stress. However, few human studies have investigated the interaction of endogenous cortisol and GSR in a pavlovian fear-conditioning design. Further, fear-conditioning has been used as a model for Post-Traumatic Stress Disorder (PTSD). This disorder is thought to be a failure to suppress exaggerated fearful reactions acquired at the time of trauma. Cortisol, as the main stress hormone, has been hypothesized as a potential modulator of the fearful reactions observed in PTSD. However, it remains unclear if PTSD is mostly a fear-based disorder or if symptoms may be associated to other factors, such as cortisol and brain structures, that are not part of the fear network.The work presented in this thesis followed two parallel lines. The two first chapters investigated the interaction between cortisol and GSR reactivity in healthy volunteers. We demonstrated that exposing subjects to a fear-conditioning paradigm was not enough to induce a cortisol response. Further, we observed a greater reactivity in women. In our second study, our results showed that an endogenous cortisol rise induced prior to extinction was associated with a faster decrease of the GSR response to the conditioned stimulus. Replicating our first study, we found that women reacted more to the conditioning paradigm compared to men. Lastly, while cortisol secretion was correlated with childhood adversity and anxiety trait, GSR reactivity did not correlate with personality measures.Our second line of investigation targeted civilians exposed to trauma. In our third study, we observed that increased levels of cortisol in response to awakening were associated with resilience to trauma. Furthermore, based on previous work investigating central nervous regulators of the HPA-axis and fear reactivity, our investigation of cortical thickness of individuals recently exposed to trauma confirmed the expected thinner ACC. We also highlighted the association between ventral temporal cortex and frontal pole with symptoms severity. These regions add a cognitive and social dimension to PTSD severity that may share more with stress than fear itself. These two studies argued for a more comprehensive model of PTSD that includes both fear-conditioning and stress reactivity to better account for the wide scope of symptoms.I conclude this thesis by re-examining the current proposed model for interaction between cortisol and peripheral measures of fear. I review the influence of sex as a mediator of fear acquisition, reactivity to stress and extinction of fear. Finally, I extend these findings to our PTSD studies to evaluate the use of pure fear-conditioning as a model for PTSD symptoms emergence and maintenance.
La peur et le stress sont deux concepts psychologiques intimement reliés. Au niveau biologique, l'activité du système nerveux sympathique (SNS), mesuré par la réponse électrodermale (RÉD), est considéré comme un marqueur de la peur chez l'être humain. Parallèlement, la sécrétion de cortisol suite à l'activation de l'axe hypothalamo-hypophyso-adrénergique (HHA) est le marqueur le plus commun du stress. Cependant, peu d'études se sont penchées sur l'interaction entre le cortisol et la RÉD lors d'un conditionnement de peur pavlovien chez l'être humain. De plus, le conditionnement de peur est utilisé comme modèle pour étudier le Trouble de Stress Post-Traumatique (TSPT). Ce trouble est considéré comme un échec de supprimer une réaction de peur exagérée acquise lors du traumatisme. Le cortisol, en tant qu'hormone de stress principale, est considéré comme un agent qui influencerait la force des réactions de peur dans le TSPT. Cependant, il demeure incertain si le TSPT est principalement un trouble relié à la peur ou si sa symptomatologie est relié à d'autres facteurs, tels le cortisol ou des structures neurologiques qui ne sont pas associées au système de la peur.Les travaux de cette thèse suivent deux lignes parallèles. Les deux premiers chapitres présentent les résultats de l'étude de l'interaction entre la peur et le stress chez des participants en santé. Nous illustrons que l'exposition à un conditionnement de peur n'est pas suffisant pour provoquer une réponse de cortisol. De plus, nous avons observé une plus forte réactivité au conditionnement chez les femmes. Les résultats de notre deuxième étude indiquent qu'une augmentation de cortisol endogène est associé à un déclin plus rapide de la réponse au stimulus conditionné lors de l'extinction. Cette étude confirme aussi une plus forte réactivité chez les femmes. Enfin, alors que la sécrétion de cortisol est associée à l'adversité durant l'enfance et l'anxiété, la RÉD n'était pas associée aux traits de personnalité.Parallèlement à ces études, nous avons étudiés des civils exposés à un événement traumatique. Notre troisième étude montre qu'une réponse accrue de cortisol en réaction au réveil est associée à la résilience face à un événement traumatique. De plus, notre étude de l'épaisseur corticale a confirmé que, chez des individus récemment exposés à un événement traumatique, le cortex cingulaire antérieur est correlé négativement à la sévérité des symptômes. Cette étude a aussi mis en lumière deux nouvelles structures, le cortex ventro-temporal et le pôle frontal, qui sont associées à la sévérité des symptômes. Ces deux structures ajoutent une dimension cognitive et sociale à la sévérité du TSPT et sont associés plus fortement au stress qu'à la peur en soi. Elles suggèrent donc un modèle d'étude qui va au-delà du conditionnement de peur et qui intègre l'importance du stress pour mieux décrire la symptômatologie.Je conclue cette thèse en réexaminant le modèle d'interaction entre le stress et les mesures périphériques de la peur. Suivant cela, j'examine le sexe comme médiateur possible dans l'apprentissage de peur, la réactivité au stress et l'extinction de la peur. Enfin, je fais le pont entre les premières études et celles sur le TSPT pour évaluer l'usage du pur conditionnement de peur comme modèle pour décrire l'émergence et le maintient des symptômes.

Different factors have been associated with changes in the regulation of the two major stress response systems of the human body, the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal(HPA) axis. These changes have been associated with various (psycho)pathologies across adulthood, and are thus frequently assessed within the context of allostatic load. Early Life Adversity (ELA) has been identified as one such factor. Individuals with histories of ELA show evidence of elevated basal and reactive salivary alpha amylase (sAA) levels (a marker of SNS activity), blunted cortisol levels (a marker of HPA axis activity), and an asymmetrical relationship between the two variables. However, different methods used in the past to measure each variable, and the relationship between the two systems, prevents us from drawing firm conclusions. The goal of this thesis was to propose a novel approach to improve the understanding of the relationship between SNS and HPA axis. We investigated whether the ratio of sAA and cortisol would be more a effective method to understand the relationship between SNS and HPAaxis, and if so whether this marker could be linked with indexes of chronic stress and depression. Using a social stress paradigm we studied this in individuals who experienced ELA and those who did not. Using a specific formula to determine the ratio of sAA over cortisol, we found a systematically stronger positive relationship with indexes of chronic stress and depression when compared to cortisol over sAA, or either marker alone. In order to enhance our understanding of stress as a construct, the specific associations between the systems must be taken into account. The ratio of sAA over cortisol combines the individual properties of each of the two stress markers into a single unit, and based on our findings appears to be a much more sensitive marker of the dysregulation between the two stress systems, as compared to the ratio of cortisol over sAA, sAA or cortisol alone. I conclude the thesis by discussing the implications of the findings and the usefulness of this marker for other chronic stress states as found in allostatic load.
Différents facteurs ont été associés à des changements dans la régulation des deux grands systèmes de réponse au stress chez l'humain, le système nerveux sympathique (SNS) et l'axe hypothalamo-hypophysosurrénalien(HHS). L'exposition à un milieu défavorable tôt dans le dévelopment (early life adversity, ELA) a été identifiée comme un de ces modulateurs de la réponse de stress. Ces changements ont été associés à diverses psychopathologies à l'âge adulte, et sont donc fréquemment quantifiés dans un contexte de stress chronique. Les individus exposés à des milieux défavorables pendant leur enfance présentent des niveaux élevés d'alpha-amylase salivaire(ASA), un marqueur de l'activité du SNS basale et réactif ainsi que des concentrations de cortisol réactives réduites (un marqueur de l'activité axeHHS), démontrant une relation asymétrique entre ces deux systèmes. Cependant, les différentes méthodes utilisées dans le passé pour mesurer chacun de ces système, et leurs interactions, présentaient certaines limites. L'objectif de cette thèse était de proposer une nouvelle approche pour améliorer la compréhension de la relation entre les SNS et l'axe HHS. Nous avons donc étudier si le ratio de l'ASA et du cortisol serait une mesure plus sensible pour quantifier la relation entre le SNS et l'axe HPA, et si oui, si ce marqueur pourrait être davantage lié à des indices de stress chronique et de symptômes dépressif. Nous avons donc exposé des individus ayant grandit dans un environnement défavorable et des sujets sains à un paradigme de stress psychosocial afin de mesurer leur réponse de stress. En utilisant une formule spécifique pour déterminer le ratio de SAA sur les niveaux de cortisol, nous avons démontrer une relation positive entre ce ratio et divers indices de stress chronique et de symptômes dépressifs comparativement aux marqueurs conventionnels de la réponse de stress. Nos résultats suggèrent que dans le but d'améliorer notre compréhension du stress, les associations spécifiques entre ces deux systèmes doivent être prises en considération. Le ratio des SAA sur le cortisol est une mesure unitaire qui combine les propriétés individuelles de chacun de ces deux systèmes et tel que démontré par nos résultats semble être un marqueur plus sensible de la dérégulation entre les deux systèmes de stress, comparativement au ratio de cortisol sur l'ASA ou aux mesures d'ASA ou de cortisol seules. Finalement, les implications des ces résultats sont discutées dans l'optique de l'utilisation d'un nouveau biomarqueur afin d'identifier des état de stress chronique.

Studies of sexual dimorphism in the corpus callosum (CC) have employed a variety of methodologies for measurement and normalization but have yielded disparate results. The present work demonstrates how in some cases different manipulations of the same raw data, corresponding to different commonly used methodologies, produce discordant results. Midsagittal CC area was measured from magnetic resonance images (MRIs) of 137 young normal volunteers. Three strategies intended to normalize for average differences in brain size between the sexes, as well as five different normalization variables, were contrasted and evaluated. The stereotaxic method normalizes for inter-subject differences in overall brain size by scaling MRIs into a standardized space. The ratio method uses one of five different indices of brain size and divides it into CC area. The covariate method uses one of these indices as a covariate in statistical analyses. Male subjects show significantly larger absolute total area, as well as anterior third and posterior midbody. However, in 2 of 3 normalization strategies, namely the stereotaxic and ratio methods, females show relatively larger total area, anterior midbody and splenium. The covariate method did not show any significant differences at the .05 level. Results suggest that different approaches to normalization and analysis are not necessarily equivalent and interchangeable.

Patients with unilateral temporal- or frontal-lobe excisions and normal control subjects were tested on four kinesthetic and two visual recall tasks. The first two studies required subjects to monitor peripheral feedback, in order to duplicate the distance or the end-position of examiner-defined arm movements. In the next two tasks, the subjects selected the movements to be recalled, and hence reliance on feedback was reduced. On the visual tests the subjects had to recall the distance traversed by a dot on a screen, or its end-position. Temporal lobectomy did not interfere with performance of the tasks, except for examiner-defined kinesthetic location. On this task, large left- or right-hippocampal resection produced an impairment following 30 s of counting. Patients with left frontal-lobe or small right frontal-lobe excisions performed normally on all tests, whereas those with large right frontal-lobe removals were impaired with both hands on the examiner-defined kinesthetic tasks. Patients with large right frontal-lobe lesions also demonstrated a delayed-recall deficit for visual distance. The results point to an important role played by the right frontal lobe in the monitoring of kinesthetic feedback both during the presentation of the movements and during the recall attempt.

This study investigates brain activity in male pathological gamblers (card gamblers) while gambling using a unique computerized card gambling paradigm that emulates actual gambling. The current study endeavored to concurrently explore group differences on factors such as mood states, cognitions, gambling behaviours, personality traits, and neural activity between a subset of pathological gamblers and control participants. A group of 14 predominately card playing male gamblers who met the DSM-IV-TR criteria for Pathological Gambling disorder and 15 infrequent or non-gambling control participants were screened and recruited. Personality characteristics were measured using the Arnett Inventory of Sensation Seeking (AISS), Tridimensional Personality Questionnaire (TPQ) and Conners' Adult Attention Deficit Hyperactivity Disorder Rating Scale-Long version (CAARS-L), while self-report mood and cognition questions were completed before, during, and after the gambling task. Pathological gamblers had significant increases in positive mood, urges to gamble, more irrational beliefs around luck and control, were more novelty-seeking and impulsive and were less likely to bet rationally using the information around risk presented at the time. The neurological findings revealed a complex interplay of activity in response to different aspects of the gambling task. Groups did not differ in regions of the striatum; however, overall group differences emerged in the medial and dorsolateral prefrontal cortex, subthalamic nucleus, insula, cerebellum, lentiform nucleus, and the posterior parietal cortex. Differences occurred in regions of the brain involved in conscious awareness of urges, decision-making in uncertain or risky situations, learning, as well as minimizing losses and ensuring future avoidance of penalties. The group differences that emerged across these factors suggest an intricate interplay of each of these variables in their contribution to the maintenance of
Cette étude en IRMf l'activité cérébrale chez des patients souffrant de jeu pathologique, en simulant pour la première fois par ordinateur un authentique jeu de pari. Le but de cette étude était de mesurer les différences potentielles d'activité cérébrale liées à des facteurs tel que les états d'humeur, les connaissances du jeu, le comportement, les traits de personnalité, entre un groupe d'homme souffrant d'un trouble de jeu pathologique (JP) et un groupe contrôle. Les 14 JP étaient principalement des joueurs de cartes, satisfaisants le critère DSM-IV-TR de Jeu Pathologique. Le groupe contrôle évalué et recruté pour cette étude était constitué de 15 participants, ne jouant que rarement aux cartes. Les caractères de personnalité ont été évalués avec l'Inventaire Arnett de Recherche de Sensations Fortes (AISS), le Questionnaire de Personnalité Tridimensionnel (TPQ) et la version longue de la Mesure de Troubles D'attention et D'hyperactivité Conners (CAARS). Les auto-évaluations de connaissances ont été recueillies avant, pendant et après la tâche expérimentale. Les joueurs pathologiques ont présenté une amélioration de leur état d'humeur, une plus grande envie de parier, une plus grande croyance en la chance et en son contrôle, étaient les plus ardents chercheurs de sensations fortes, étaient plus impulsifs et avaient moins tendance à parier rationnellement et à utiliser l'information disponible concernant le risque. Les résultats de neuro-imagerie ont révélé un pattern complexe d'activités en réponse aux différents aspects de la tâche de pari. Bien que les groupes n'aient présenté aucune différence au niveau du Striatum, des différences générales de groupe ont émergé au niveau du cortex préfrontal médial et dorsolatéral, du noyau sous-thalamique, de l'insula, du cervelet, du noyau lentiforme et du cortex pariétal postérieur. Ces différences sont localisées dans les régions connues$

Depression is associated with an increased risk of cardiovascular disease (CVD). One possible mechanism of this effect is dysregulation of the biological stress systems, the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis. The current thesis aimed to better understand the relationship between depression and these two systems. In the first study, the effect of major depression on heart rate recovery following exercise, a marker of ANS tone, was examined in cardiac patients. Depression was associated with poor early heart rate recovery, suggesting reduced post-exercise parasympathetic activation. The second study, which included healthy participants, examined the effect of cognitive and somatic depressive symptoms in relation to recovery of heart rate and heart rate variability, two markers of ANS tone, in response to interpersonal laboratory stressors. Both types of symptoms were found to predict post-stress recovery. The third study aimed to examine the relationship between major depression both ANS and HPA axis activity in response to a stressful diagnostic test. Furthermore, it aimed to determine whether antidepressant medication is effective in restoring a normal stress response in depressed individuals. Depressed cardiac patients exhibited elevated cortisol levels in response to the test but this effect was not seen among depressed individuals taking antidepressant medication. However, neither depression nor antidepressant use was associated with heart rate variability. As a whole, these studies suggest a modest and inconsistent relationship between depression and prolonged post-stress ANS activation. On the other hand, the relationship between depression and exaggerated HPA axis activity appears to be relatively strong. Finally, antidepressant medication may be effective in reversing the excessive HPA axis activation observed in depressed individuals.
La dépression est associée à un risque élevé de maladie cardiaque. Un mécanisme qui pourrait expliquer cette association est la dysfonction du système nerveux autonome (SNA) et l'axe hypothalamo-hypophyso-surrénalien (HHS), qui sont les deux systèmes impliqués dans la réaction physiologique au stress. Cette thèse avait comme but de mieux comprendre la relation entre la dépression et ces deux systèmes. Dans la première étude, l'effet de la dépression majeure sur le rétablissement de la fréquence cardiaque après l'exercice, un marqueur de la balance autonome, a été examiné chez des patients cardiaques. La dépression était associée à un pauvre rétablissement cardiaque immédiatement après l'exercice, ce qui suggère un délai dans l'activation du système parasympathique. Dans la deuxième étude, qui incluait des participants en santé, on examinait l'effet des symptômes dépressifs cognitifs et somatiques en relation avec le rétablissement de la fréquence cardiaque et la variabilité de la fréquence cardiaque, deux marqueurs de l'activation du SNA, en réaction à des stress interpersonnels de laboratoire. Les deux types de symptômes étaient associés avec un moins bon rétablissement cardiaque après les stress. Finalement, la troisième étude examinait la relation entre la dépression majeure et l'activité du SNA et de l'axe HHS en réaction à un test diagnostique stressant. De plus, l'étude a eu comme but de déterminer si les antidépresseurs sont efficaces dans le rétablissement d'une réponse normale au stress chez les dépressifs. Les patients cardiaques dépressifs avaient un niveau de cortisol plus élevé tout au long du test, ce qui indique une activation plus forte de l'axe HHS. Cet effet n'a pas été observé chez les dépressifs qui prenaient des antidépresseurs; par contre, ni la dépression ni l'utilisation des antidépresseurs étaient associées à la variabilité de la fréquence cardiaque. Ces études suggèrent une relation modeste et inconsistante entre la dépression et une activation altérée du SNA. Par contre, la relation entre la dépression et la suractivation de l'axe HHS apparait relativement forte. Finalement, les antidépresseurs semblent être efficaces en annulant la suractivation de l'axe HHS chez les dépressifs.

Individual differences in sex and trait anxiety (TA) have been suggested as important mediators of behavioural and neural responses to threat-related stimuli. In this study, the relationship between sex, TA and the processing of threat-related stimuli (fearful faces) was explored in healthy individuals. During fMRI scanning, 32 participants completed tasks probing two facets of emotional function: responses to unattended fearful faces and emotional memory. Interactions between TA and sex were observed in both behaviour and brain activity. In women, higher TA was associated with a stronger amygdala response to unattended fearful faces, whereas no such relationship was present in males. Also, in women only, high TA was associated with stronger anterior cingulate and left amygdala activity when fearful faces were successfully encoded. These findings may contribute to an understanding of the higher incidence of anxiety disorders in women than men.

The netrin-1 guidance cue and its receptors, DCC and UNC5H, contribute to the organization and function of mesocorticolimbic dopamine (mDA) circuitry during development. Interestingly, netrin-1 and its receptors continue to be expressed in mDA cell body and terminal regions throughout the lifespan, although there is a dramatic shift in the ratio of DCC: UNC5H receptor expression by mDA neurons in the ventral tegmental area (VTA), the mDA cell body region, during the adolescent period. This suggests that netrin-1 signaling may also play a role in the plasticity of MDA circuitry across the lifespan. Indeed, sensitizing regimens of the stimulant drug, amphetamine (AMPH), significantly upregulate DCC expression in adult rats. This upregulation, which is glutamate-dependent, is selective to the VTA, a site critical for the initiation of behavioral plasticity induced by stimulant drugs of abuse. Furthermore, adult dcc heterozygous (+/-) mice are "protected" against the sensitizing behavioral effects of repeated AMPH treatment. The aims of this Thesis were twofold: In the first instance, experiments were designed to determine whether netrin-1 signaling in the VTA plays a functional role in AMPH-induced sensitization during adulthood. Using a combination of behavioral and molecular techniques, it is demonstrated that the lack of AMPH-induced sensitization in adult dcc +/- mice is associated with a failure of AMPH to both upregulate DCC receptor expression and induce dendritic plasticity in the VTA. In parallel experiments conducted in adult rats, it is shown that VTA DCC receptor activation, at the time of AMPH pretreatment, is critical for sensitization to AMPH. These data implicate VTA DCC receptor signaling as a novel mechanism in the series of glutamate-dependent cellular processes that lead to enduring plasticity by stimulant drugs of abuse during adulthood. However, the effects of DCC/netrin-1 signaling on mDA system function have been shown to change across development, with the adolescent period being a crucial time in this netrin-1 /DA system interaction. Thus, the second aim of this Thesis was to begin to explore the role for netrin-1 receptor signaling in AMPH-induced sensitization during juvenile and adolescent periods. It is demonstrated that repeated exposure to AMPH during these early periods differentially regulates DCC expression in the VTA, in comparison to during adulthood. Significantly, it is also shown that the "protective" phenotype of adult dcc +/- mice is not present before adolescence, and in fact, is abolished when these mice are treated with AMPH during the juvenile, but not adolescent, period. Because DCC heterozygosity has recently been identified in the human population, these results may be relevant to the debate about stimulant use in children. Collectively, the findings reported in this Thesis are the first to demonstrate a function of DCC/netrin-1 signaling in the adult brain. DCC/netrin-1 receptor signaling may be a key factor in determining individual differences in vulnerability to drug abuse at different ages.
La nétrine-1, une molécule de guidage axonale, et ses récepteurs, DCC et UNC5H, contribuent à l'organisation et à la fonction des circuit dopaminergiques mésocorticolimbiques pendant le développement cérébral. Fait intéressant, la nétrine-1 et ses récepteurs continuent à s'exprimer dans les régions du corps cellulaire et des terminaisons nerveuses de la dopamine mésocorticolimbique tout au long de la vie, malgré un changement radical du ratio de l'expression des récepteurs DCC:UNC5H par les neurones de la dopamine mésocorticolimbique dans l'aire tegmentale ventrale (ATV), la région somato-dendritique de la dopamine mésocorticolimbique, à l'adolescence. Ceci suggère que la signalisation induite par la nétrine-1 est impliquée dans la plasticité du circuit dopaminergique mésocorticolimbique tout au long de la vie. En effet, la sensibilisation à l'amphétamine (AMPH), une drogue stimulante, provoque une augmentation considérable du niveau d'expression de DCC chez les rats d'âge adulte. Cette augmentation, qui depend de la « transmission » glutaminergique, est propre à l'ATV, une zone cruciale pour l'initiation de la plasticité comportementale en réponse à l'abus de drogues stimulantes. En outre, les souris adultes hétérozygotes (+/-) pour le gène encodant DCC sont « prémunies » contre les effets de la sensibilisation comportementale en réponse à l'administration répétée d'AMPH. Les objectifs de cette thèse comportaient deux volets : en premier lieu, le but était de déterminer si la signalisation induite par la nétrine-1 dans l'ATV joue un rôle fonctionnel dans la sensibilisation en réponse à l'AMPH à l'âge adulte. À l'aide d'une combinaison de techniques comportementales et moléculaires, il est démontré que le manque de sensibilisation en réponse à l'AMPH chez les souris adultes +/- pour le gène encodant dcc est lié à l'incapacité de l'AMPH d'augmenter le niveau d'expression du récepteur DCC et de provoquer la plasticité dendritique dans l'ATV. Dans des expériences parallèles menées chez des rats adultes, il est montré que l'activation du récepteur DCC dans l'ATV au moment du prétraitement à l'AMPH est cruciale pour la sensibilisation à l'AMPH. Ces données décrivent la signalisation par le récepteur DCC de l'AVT comme nouveau mécanisme dans les séries de processus cellulaires nécessitant la présence de glutamate qui mènent à une plasticité durable avec l'usage de drogues stimulantes à l'âge adulte. Toutefois, il a été démontré que les effets de la signalisation par DCC/nétrine-1 sur la fonction du système dopaminergique mésocorticolimbique changent durant le développement cérébral, et que l'adolescence est une période cruciale dans cette interaction entre la nétrine-1 et le système dopaminergique mésocorticolimbique. Par conséquent, le deuxième volet de cette thèse visait à commencer l'étude du rôle de la signalisation des récepteurs pour la nétrine-1 dans la sensibilisation en réponse à l'AMPH pendant les périodes juvéniles et adolescentes. Il est démontré que l'exposition répétée à l'AMPH lors de ces périodes d'âge précoce régule de manière différente l'expression du DCC dans l'ATV, comparativement à la période de l'âge adulte. De manière significative, il est également démontré que le phénotype « protecteur » des souris adultes +/- pour le gène encodant dcc est absent avant l'adolescence, et en fait, disparaît lorsque ces souris sont soumises à des traitements d'AMPH lors de la période juvénile, contrairement à la période adolescente. Étant donné que l'hétérozygosité DCC a été récemment identifiée chez l'être humain, ces résultats peuvent être pertinents au débat sur les implications de l'usage de stimulants chez les enfants. Globalement, les résultats présentés dans cette thèse démontrent pour la première fois que la signalisation par DCC/nétrine-1 joue un rôle dans le cerveau adulte.

Allostatic load (AL) refers to biological wear and tear caused by chronic psychosocial stress. The AL model proposes that by measuring the multi-systemic interactions among sub-clinically relevant biomarkers, biomedical advances can be made in the detection of individuals at high risk of developing stress-related diseases. By incorporating an AL index encompassing neuroendocrine, immune, metabolic, and cardiovascular biomarkers, a growing body of literature has demonstrated augmented prediction of numerous deleterious outcomes. As it stands, however, the AL index is a research tool that has not been standardized for use by healthcare providers. Using a new AL index based on clinical reference ranges, we investigated physical and psychological outcomes in two studies. In Study 1, 85 older adults were followed longitudinally over six years, while Study 2 included a separate cross-section of 30 younger workers. We hypothesized that increased AL indices based on 7 and 15 biomarkers respectively would relate to increased levels of psychological distress, dysregulated diurnal and reactive stress hormone levels, subjective memory and physical complaints, objective memory impairments, and finally symptoms of depression and burnout. Our results support our hypotheses at different ages. For older adults, higher AL predicted greater depressive symptoms three years in advance with subsequent cognitive complaints and impairments. For younger workers, higher AL was manifested physiologically and symptomatically as a pre-burnout condition without cognitive and physical complaints. These findings provide preliminary support for the utility of a new clinical AL index sensitive to specific stress-related problems throughout the life span that is easily accessible to healthcare providers.
La charge allostatique (CA) est la dégradation biologique causée par le stress chronique. Le modèle de la CA propose qu'en mesurant les interactions multi-systémiques de biomarqueurs qui sont sous-cliniquement significatifs, des avancées biomédicales seront possibles afin de détecter les individus à risque de développer différentes maladies. La littérature démontre qu'en utilisant un indice de CA qui inclut des biomarqueurs neuroendocriniens, immunitaires, métaboliques et cardiovasculaires, il est possible de mieux prédire de nombreuses conséquences négatives. Par contre, à ce jour, l'indice de la CA n'est qu'un outil de recherche et n'a pas encore été validé pour l'utilisation médicale. En utilisant un nouvel indice de la CA basé sur des distributions cliniques, nous avons investigué les conséquences physiques et psychologiques du stress chronique dans le cadre de deux études. Dans l'étude 1, 85 adultes âgés ont été suivis longitudinalement pendant six ans, alors que l'étude 2 a été réalisée à une reprise auprès de 30 travailleurs de divers domaines. Notre hypothèse était que des indices élevés de la CA seraient reliés à des niveaux plus élevés de stress psychologique, des niveaux dérégulés de cortisol basal et réactif, des plaintes subjectives de troubles de mémoire et de fonctionnement physique, des déficits de mémoire, et finalement des symptômes de dépression et d'épuisement professionnel. Nos résultats supportent nos hypothèses, mais diffèrent selon l'âge de l'échantillon étudié. Pour les adultes âgés, une CA plus élevée prédisait des symptômes de dépression trois ans en avance ainsi que des plaintes subjectives de mémoire et des déficits cognitifs. Pour les travailleurs plus jeunes, une CA plus élevée se manifestait physiologiquement et symptomatiquement par une condition ressemblant à l'épuisement professionnel sans trouble cognitif ou physique. Ces résultats sont une évidence p

Stress is a major health concern of the 21st century. It has been shown to be associated with a host of negative health outcomes, from a spectrum of several psychopathologies to cardiovascular disease. However, the exact mechanisms resulting in these disease states have not yet been identified. There are two main physiological systems solicited during an acute stress response: the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. Both the SNS and HPA have been hypothesized to interact, but the precise nature of their relationship is still under study. In addition to the biological response, there also is the subjective emotional experience of stress. As it is hypothesized to be the trigger of the endocrinological and physical responses, a relationship between these three variables is expected, though, literature on this topic has yielded inconsistent findings. The work in this thesis attempted to understand the relationship between the endocrinological, physiological and psychological responses during an acute stressor. To do so, we combined a pharmacological approach with the most widely used laboratory stress task - the Trier Social Stress Test (TSST). We suppressed these systems individually and together after which we exposed the participants to the TSST. Throughout the protocol a number of biomarkers of the SNS and HPA were assessed, including salivary cortisol and alpha-amylase, heart rate and blood pressure. State and trait subjective stress were also measured using questionnaires and visual analogue scales. Our first major finding suggested an inverse relationship between the biological systems, HPA and SNS. When one system was suppressed the other showed increased activity. Dysregulation of each of these systems have both been associated with adverse health consequences. Understanding how to keep an equilibrium between the HPA and SNS may thus be an important factor in the prevention of (psycho)pathologies like depression, or cardiovascular disease. We also observed a link between state subjective stress and the SNS. These findings were found to be in-line with the Two-Factor Theory of Emotion, which states that physiological arousal feeds back and contributes to the subjective emotion state. On the other hand, neuroticism was found to be associated with HPA axis activity. This may imply that neuroticism levels would be somewhat more of a threshold of threat detection. Logically it would not be associated with the SNS as it is a transient effect, but more with its biological analogue, the HPA axis. Future research in this field will surely yield interesting findings contributing to the understanding of its emotional component, inner workings and the etiology of its resulting disorders. Most importantly, it will broaden our understanding of this vast concept and hopefully contribute to the prevention of its associated negative health outcomes.
De nos jours, le stress est considéré comme un enjeu sociétal majeur qui continue de prendre de l'ampleur. Il a d'ailleurs été démontré qu'il a un impact néfaste considérable sur la santé et un lien direct avec plusieurs psychopathologies ainsi que les maladies cardiovasculaires. Cependant, les mécanismes par lesquels le stress cause un état pathologique n'ont pas encore été identifiés. Il y a principalement deux systèmes physiologiques sollicités au cours d'une réaction de stress : le système nerveux sympathique (SNS) et l'axe hypothalamo-pituito-surrénalien (HPS). Une hypothèse d'interaction entre les deux systèmes a été émise; par contre, la nature exacte de leur relation fait toujours l'objet d'études. En plus de la réponse biologique, il y a aussi l'expérience émotionnelle subjective du stress qui est considérée comme étant le déclencheur des réponses endocrines et physiques. Une relation entre ces trois variables semble donc logique, toutefois la littérature sur ce sujet récence plusieurs résultats contradictoires.Par conséquent, cette thèse tente de comprendre la relation entre les réponses endocrines, physiologiques et psychologiques lors d'une situation de stress.Pour ce faire, nous avons combiné une approche pharmacologique avec la tâche de stress psychologique la plus utilisée en laboratoire – le « Trier Social Stress Test » (TSST). Avant d'exposer les participants au TSST, nous avons inhibé les deux systèmes physiologiques, soit individuellement ou collectivement. Tout au long du protocole, plusieurs biomarqueurs des axes SNS et HPS, y compris le cortisol et l'alpha-amylase salivaires, la fréquence cardiaque et la pression artérielle ont été mesurés. Les différentes facettes du stress subjectif ont également été mesurées au moyen de questionnaires et d'échelles visuelles analogiques.Notre première constatation suggère une relation inverse entre les systèmes biologiques HPS et SNS. Lorsqu'un des systèmes est inhibé, l'autre montre une activité accrue. Le dérèglement de chacun de ces systèmes a été associé à des conséquences néfastes sur la santé. Le fait de mieux comprendre la façon de garder un équilibre entre les axes HPS et SNS peut donc être un facteur important dans la prévention des pathologies, comme la dépression et les maladies cardiovasculaires. Nous avons également observé un lien entre l'état subjectif du stress et le SNS. Ces résultats sont en accord avec la « Two-Factor Theory of Emotion » qui stipule que l'activité physiologique contribue à l'état subjectif du stress. D'autre part, l'inquiétude chronique a été associée à l'activité de l'axe HPS, ce qui suggère que le niveau de névrosisme pourrait agir comme seuil de détection du danger. Logiquement, il ne serait pas associé au SNS qui a un effet transitoire, mais plutôt à son analogue biologique, l'axe HPS.Les recherches futures dans ce domaine mèneront certainement à des résultats intéressants qui contribueront à la compréhension des composantes émotionnelles du stress, de son fonctionnement interne et de l'étiologie des troubles qui en résultent. Principalement, il permettra d'élargir notre compréhension de ce vaste concept et de contribuer à la prévention de ses effets néfastes sur la santé.

The guidance cue, netrin-1, and its receptors, deleted in colorectal cancer (DCC) and the UNC-5 homologues, are involved in the development and organization of mesocorticolimbic dopamine (DA) circuitry. We have previously demonstrated that mice heterozygous for the dcc gene have phenotypic alterations specific to medial prefrontal cortex (mPFC) circuitry, which only appear after adolescence. Currently, the role of UNC5C in the development and function of VTA DA projections remains poorly understood. The goal of this study was to determine whether UNC5H expression is selectively expressed by DA neurons which project to the mPFC or nucleus accumbens (NAcc). To this end, I used retrograde tract-tracing from the mPFC, and the core and shell of the NAcc. I combined this with immunolabeling of tyrosine hydroxylase (TH) and UNC5H in the ventral tegmental area (VTA) of adult wild type mice. Neurons with any combination of labels were visualized under a light microscope and counted using an optical fractionator stereological design. My analysis revealed that UNC5H expression by VTA DA neurons is not target-specific, whereas UNC5H expression by VTA non-DA neurons is selective for neurons projecting to the mPFC. These findings set the basis for future studies aimed at assessing the role of UNC5H in the organization of DA and non-DA VTA circuitry.
Le repère de guidage, la nétrine-1 et ses récepteurs, supprimé dans le cancer colorectal (DCC) et les homologues UNC-5, sont impliqués dans le développement et l'organisation des circuits mésocorticolimbique de la dopamine (DA). Nous avons précédemment démontré que les souris hétérozygotes pour le gène dcc ont altérations phénotypiques spécifiques du cortex préfrontal médiale (CPFm) circuits, ce qui n'apparaissent qu'après l'adolescence. Actuellement, le rôle de UNC5C dans le développement et la fonction des projections DA de l'aire tegmentale ventrale (ATV) reste mal comprise. Le but de cette étude était de déterminer si l'expression UNC5H est sélectivement exprimée par les neurones dopaminergiques qui se projettent à l'CPFm ou noyau accumbens (NAcc). À cette fin, j'ai utilisé un traceur des voies rétrograde du CPFm, et le centre et l'enveloppe du NAcc. J'ai combiné cela avec immunomarquage de la tyrosine hydroxylase (TH) et UNC5H dans l'ATV de souris adultes de type sauvage. Neurones avec n'importe quelle combinaison d'étiquettes ont été visualisées sous un microscope optique et comptées à l'aide d'une optique de conception de fractionnement stéréologique. Mon analyse a révélé que l'expression UNC5H par neurones DA de l'ATV n'est pas spécifique à la cible, tandis que l'expression UNC5H par l'ATV non-DA neurones est sélective pour les neurones se projetant vers le CPFm. Ces résultats jeté les bases de futures études visant à évaluer le rôle de UNC5H dans l'organisation de DA et non DA-circuits de l'ATV.

Drug addiction is a worldwide problem that imposes significant costs on society. Aggravating the problem is that we continue to have a poor understanding of vulnerability factors and treatment targets. To date the best implicated brain system is the ascending mesolimbic dopamine cell pathway and its regulation by descending cortical input. The present thesis first reviews the literature describing possible roles of dopamine in addiction, and the relationship between pre-frontal cortical function and striatal dopamine. The body of the thesis consists of three data chapters.In the first study we examined the possibility that young people at elevated risk for addiction based on a multi-generational family history (FH) of substance use problems might have perturbed mesolimbic dopamine responses. As a test, we used positron emission tomography (PET) with [11C]raclopride to measure d-amphetamine (0.3 mg/kg, p.o.) induced striatal dopamine responses in: (1) high-risk young adults with a multigenerational FH of substance use disorders (FH+exposed), (2) stimulant drug-naïve healthy controls with no known risk factors for addiction (Ctls_naive), and (3) subjects matched to the high-risk group on personal drug use but without a FH of substance use problems (Ctls_exposed). We found that compared to either control group, the FH+exposed subjects exhibited smaller [11C]raclopride responses, with the largest effect in the right ventral striatum. Together, the results suggest that young people at familial high-risk for substance use disorders have decreased dopamine responses to an amphetamine challenge, an effect that predates the onset of addiction. In the second study we examined the variability in the striatal dopamine response to d-amphetamine as a function of cortical thickness. Marked individual differences in these responses are seen in laboratory animals, related in part to input from the prefrontal cortex, and substance dependent individuals are reported to have significant cortical thinning. Based on these observations, we measured the relation between cortical morphology and drug-induced striatal dopamine release in healthy adults. As expected, d-amphetamine produced significant reductions in [11C]raclopride binding potential in the striatum. There was substantial individual variability in this response, which was correlated with cortical thickness in the frontal lobe as a whole. A thicker cortex correlated with a smaller dopamine response. While prefrontal regulation of striatal function has been well studied, it was unclear if the thickness of the prefrontal cortex was an acceptable proxy to the function of that region. These results suggest it is. In the third study we applied the analysis of cortical thickness to all three groups described in the first study. Of particular interest was whether the blunted amphetamine-induced dopamine response seen in the family history positive group was related to alterations in cortical thickness. The same methods described in the second study were applied to the data from the first. We found that 1) FH+exposed subjects had thicker cortex, 2) as in the Ctls_naive, cortical thickness correlated with the dopamine response in FH+exposed subjects.Together, the studies provide evidence of a pre-existing or rapidly developing neurobiological difference in individuals at high risk for addictions. If vulnerable individuals can be identified reliably, it might be possible to provide early preventative interventions.
La toxicomanie est un problème mondial qui impose des coûts importants à la société. De plus, nous continuons à mal comprendre les facteurs de vulnérabilité et les objectifs de traitement. Jusqu'à date, le système neural impliqué le plus connu est le réseau cellulaire ascendant méso-striatale et sa régulation par des voies corticales descendantes. Cette thèse examine d'abord la littérature décrivant les rôles possibles de la dopamine dans la toxicomanie, et la relation entre la fonction corticale préfrontale et la dopamine dans le striatum. Le corps de la thèse est composé de trois chapitres de données. Dans la première étude, nous avons examiné la possibilité que les jeunes à risque élevé de toxicomanie, le risque étant basé sur une histoire de famille (HF) multi-générationnelle de troubles de toxicomanie, peuvent avoir des réponses mésolimbiques de la dopamine perturbées. En guise de test, nous avons utilisé la tomographie par émission de positrons (TEP) avec le [11C]raclopride pour mesurer la réponse induite par la d-amphétamine (0,3 mg / kg, po) dans le striatum chez: (1) des jeunes adultes à haut risque avec une HF multigénérationnelle de troubles de toxicomanie (HF+expérimentation), (2) des sujets sains n'ayant jamais pris de drogues stimulants et ne présentant aucun facteur de risque connu pour la toxicomanie (Ctls_naïfs), et (3) des sujets appariés au groupe à haut risque sur l'usage personnel de drogues, mais sans HF de troubles de toxicomanie (Ctls_expérimentation). Nous avons constaté que par rapport aux deux groupes de contrôle, le groupe HF + expérimentation présentaient des réponses de [11C]raclopride plus petites, particulièrement dans le striatum ventral droit. Ensemble, ces résultats suggèrent que les jeunes à haut risque familial pour des troubles de toxicomanie ont des réponses dopaminergiques diminuées à un défi d'amphétamine, un effet présent avant l'apparition de la dépendance. Dans la seconde étude, nous avons examiné la variabilité de la réponse dopaminergique à la d-amphétamine dans le striatum en fonction de l'épaisseur corticale. Des différences individuelles marquées dans ces réponses peuvent être observées dans des animaux de laboratoire, associées en partie aux réseaux descendants du cortex préfrontal, et les toxicomanes démontrent un amincissement significatif du cortex. En se basant sur ces observations, nous avons enquêté sur la relation entre la morphologie corticale et la libération dopaminergique dans le striatum, induite par des médicaments, chez des adultes en bonne santé. En ligne avec nos prédictions, la d-amphétamine a engendré une réduction significative du potentiel de liaison du [11C] raclopride dans le striatum, qui était corrélée à l'épaisseur corticale du lobe frontal dans son ensemble. Un cortex plus épais était associé à une réponse dopaminergique plus petite. Bien que la régulation de la fonction préfrontale du striatum ait été bien étudiée, il n'était pas clair si l'épaisseur du cortex préfrontal était un substitut acceptable à la fonction de cette région. Ces résultats suggèrent que oui.Dans la troisième étude, nous avons appliqué l'analyse de l'épaisseur corticale aux trois groupes décrits dans la première étude. Un intérêt particulier était de savoir si la réponse dopaminergique induite par l'amphétamine diminuée observée dans le groupe avec une histoire familiale positive était associée à des altérations au niveau de l'épaisseur corticale. Nous avons constaté que 1) le groupe HF+expérimentation avait un cortex plus épais, 2) comme chez les Ctls_naïfs, l'épaisseur corticale était associée à la réponse dopaminergique dans le groupe FH+expérimentation. Ensemble, ces études fournissent des preuves d'une différence neurobiologique préexistante chez les individus à haut risque de toxicomanie. Si les personnes vulnérables peuvent être identifiées de façon fiable, il pourrait être possible d'offrir des interventions préventives précoces.

It is commonly believed that memory capacities decline with advanced age. Among various biological mechanisms investigated, the stress hormone (cortisol) has received much attention. When cortisol levels are elevated, they impair cognitive performance. Yet evidence shows that there is considerable variability in older adults' cortisol levels and cognitive performance, and the basis for this variability is not well understood. The work of the current thesis sought to investigate some factors that may explain some of the variability observed in stress reactivity and memory performance among older adults. Specifically, we investigated the roles of internalizing negative aging perceptions and stressful testing environments on cortisol levels and memory performance. The current work also aimed to determine whether differential reactivity to testing environments impacts the association between the hippocampus (brain structure involved in memory performance) and cortisol levels in older adults. Our results showed that while negative aging perceptions were not significantly associated with cortisol levels, they were associated with subjective memory complaints and depressive symptoms; two known risk factors for cognitive impairment and cortisol dysregulation. Our findings also showed that unfavourable (stressful) testing environments induce high cortisol levels and memory impairments in older adults. Yet, in a more favourable testing environment they showed lower cortisol levels and less forgetting. We also found that in both young and older adults, hippocampal volume is only correlated with cortisol levels when testing occurs in unfavourable testing environments for their respective age group. These results are important in showing that internalizing negative aging perceptions increases risk factors for cognitive impairment and dysregulation of cortisol levels. Moreover, stressful testing environments can increase cortisol levels, impair memory performance and modulate associations between hippocampal volume and cortisol.Finally, considering the important implications of the findings on stressful testing environments, we followed with a knowledge translation project to disseminate the findings to clinicians, researchers and health professionals who will use the knowledge to improve their practice and the validity of their findings, as well as the quality of life for older adults and their families.
Il est communément admis que les capacités de mémoire diminuent avec l'âge avancé. Parmi les différents mécanismes biologiques étudiés, les hormones du stress (cortisol) ont reçu beaucoup d'attention. Lorsque les niveaux de cortisol sont élevés, ils nuisent à la performance cognitive. Pourtant, la preuve montre qu'il existe une grande variabilité dans les niveaux de cortisol adultes plus âgés et la performance cognitive, et la base de cette variabilité n'est pas bien comprise. Le travail de la thèse actuelle visait à enquêter sur certains facteurs qui peuvent expliquer une partie de la variabilité observée dans la réactivité au stress et les performances de la mémoire chez les personnes âgées. Plus précisément, nous avons étudié le rôle de l'intériorisation des perceptions négatives du vieillissement et les environnements de tests de stress sur les niveaux de cortisol et les performances de la mémoire. Le travail actuel vise également à déterminer si la réactivité différentielle pour les environnements de test affecte l'association entre l'hippocampe (structure du cerveau impliquée dans la performance de mémoire) et les niveaux de cortisol. Nos résultats ont montré que, bien que les perceptions négatives du vieillissement n'aient pas été associées à des niveaux de cortisol, ils ont été associés à des plaintes de mémoire subjectives et des symptômes dépressifs, deux facteurs de risque connus pour la déficience cognitive et le dérèglement de cortisol. Nos résultats ont également montré qu'un environnement de test défavorable (stress) induit des niveaux élevés de cortisol et de troubles de la mémoire chez les personnes âgées. Par ailleurs, dans un environnement de test plus favorable, elles ont montré des niveaux de cortisol plus faibles et moins d'oubli. Nous avons également constaté chez les adultes jeunes et âgés, que le volume de l'hippocampe est uniquement associé à des niveaux de cortisol quand le test a lieu dans des environnements de test défavorables pour leurs groupes d'âge respectifs. Ces résultats sont importants, car ils démontrent que l'intériorisation des perceptions négatives du vieillissement augmente le risque de troubles cognitifs et de dérégulation du taux de cortisol. En outre, nous avons découvert que les environnements qui sont non-favorables peuvent mener à une augmentation des niveaux de cortisol, une altération des performances de la mémoire et la modulation d'associations entre volume de l'hippocampe et le cortisol. Enfin, considérant les importantes implications des données sur les environnements de test, nous avons lancé un projet de transfert des connaissances, afin de diffuser les résultats aux cliniciens, chercheurs et professionnels de la santé, qui utiliseront les connaissances nécessaires pour améliorer leur pratique et la validité de leurs résultats, ainsi que la qualité de vie des personnes âgées et de leurs familles.

The mammalian neocortex is highly dynamic, demonstrating incredible variability in size and complexity across species. This phenotypic diversity, however, evolved from an extinct common ancestor. By illuminating organization of this mammalian ancestor, we can better understand the common features and the constraints of the mammalian neocortex across all species. Brain organization is not preserved in fossilized tissue. Therefore, examinating the brain of extant species, such as the short-tailed opossum, and comparing it to the brains of other mammals, provides the best available data for understanding the brain organization of early mammals. We investigated both corticocortical and thalamocortical connections of parietal cortical areas as well as the visual acuity in the short-tailed opossum (Monodelphis domestica). This species was chosen because it is thought to share many features with early mammaliforms (including body morphology, ecological niche, and gross brain morphology). We also discuss the neocortical organization of the somatosensory and motor systems across small-brained mammals. This provides a more comprehensive understanding of similar features of organization, inherited from the common ancestor (homologous) as well as features of organization that are unique to this particular species. For studies of cortical connections of parietal cortex in Monodelphis domestica, injections of anatomical tracers were placed in four different cortical areas and both injection sites and retrogradely labeled cells were related to myeloarchitectonic boundaries of cortical fields. Using these techniques, we identified rostral and caudal somatosensory fields (SR and SC, respectively) on either side of primary somatosensory cortex (S1), as well as a multimodal region caudal to SC (termed MM). Together with the second somatosensory area (S2), these five areas compose an interconnected somatosensory/multisensory network in Monodelphis. Next, we investigated the thalamocortical connections of SR, S1, SC, and MM. In contrast with thalamocortical connections described in previous studies in the closely related Virginia opossum (Didelphis virginiana), Monodelphis domestica does not have strong projections from ventral lateral/ventral anterior nucleus to S1, suggesting a different pattern of motor organization in Monodelphis neocortex, and further complicating the hypothesized organization of the common mammalian ancestor. Finally, we provided the first behavioral measure of visual acuity in any American opossum. We discuss the significance of this finding, both in the context of future research on the visual system of Monodelphis as well as in the context of visual system organization across mammals.

N-methyl-D-aspartate receptor (NMDAR) hypofunction has been hypothesized as a pathological change accounting for many of the symptoms of schizophrenia, including cognitive deficits. Although the etiology of schizophrenia is still not known, prenatal infection has been identified as an early-life environmental risk factor. While the onset of psychosis commonly occurs in early adulthood, cognitive deficits can be present earlier. Exposure to risk factors during adolescence, such as stress, is hypothesized to precipitate the onset of psychosis. Recent findings suggest stress may impact cognition through the modulation of NMDAR function and plasticity in the hippocampus, a vulnerable structure in schizophrenia. Therefore, prenatal infection may increase vulnerability to schizophrenia through the modulation of hippocampal NMDAR function. In order to examine this we utilized a rodent model of prenatal immune activation and investigated hippocampal NMDAR function using behavioral, electrophysiological and molecular techniques in both adolescent and adult offspringFor all of the experiments in this thesis, we examined the male offspring from pregnant rats administered lipopolysaccharide (LPS), a bacterial endotoxin, or saline control on gestational days 15 and 16. In Chapter 2 we investigated the effects of prenatal LPS exposure on hippocampal and NMDAR associated learning and memory in adolescent and adult offspring. Using NMDAR associated behavioral tasks we found alterations in adolescent, but not adult offspring. Specifically, adolescent prenatal LPS offspring had subtle long-term spatial memory impairment and enhanced spatial reversal learning; both tasks which are associated with hippocampal NMDAR-dependent synaptic plasticity, long-term depression (LTD). Next, in Chapter 3 we used electrophysiological techniques to investigate the effects of prenatal LPS exposure on in vitro hippocampal NMDAR synaptic function and LTD in adolescent offspring and tested if this may be differentially affected by exposure to stress. We found NMDAR-dependent LTD was abolished in prenatal LPS offspring, which was supported by a significant decrease in both field and whole cell measures of NMDAR synaptic function. However, restraint stress repaired the abolished LTD in prenatal LPS offspring, and treatment with the stress hormone corticosterone (CORT) augmented LTD in prenatal LPS offspring but not in controls. In Chapter 4, similar experiments were performed in adult offspring. However, hippocampal NMDAR synaptic function was not significantly altered in either basal or CORT conditions in adult prenatal LPS offspring compared to controls, suggesting the effects observed in adolescence are transiently expressed. Finally, in Chapter 5 we investigated the effects of prenatal LPS exposure on hippocampal reelin and glutamic acid decarboxylase 67 (GAD67) expression in juvenile and adolescent offspring. Both reelin and GAD67 expression are reduced in schizophrenia and preclinical studies suggest they could modulate NMDAR-mediated synaptic plasticity. Using immunohistochemistry, we found a decrease in reelin+ cells at postnatal day (P)14 and decrease in GAD67+ cells at P14 and P28 in the hippocampus of prenatal LPS offspring compared to controls. The results from this thesis demonstrate that prenatal exposure to LPS transiently alters NMDAR function in the hippocampus of rat offspring during adolescence. Prenatal LPS causes NMDAR hypofunction under basal conditions, but increased NMDAR function in response to stress during adolescence. Also, the decreased hippocampal expression of reelin and GAD67 in juvenile prenatal LPS offspring could impact normal NMDAR development. Therefore, prenatal infection could be increasing vulnerability to schizophrenia during adolescence at the level of the NMDAR and interacting with a second risk factor, stress. These results may provide insight into how prenatal infection could increase risk for schizophrenia.
L'hypofonctionnement des récepteurs au N-methyl-D-aspartate (NMDA) est une des principales hypothèses pour expliquer les symptômes de la schizophrénie, en particulier les déficits cognitifs. Bien que les causes de la schizophrénie soient méconnues, une infection durant la grossesse est un des facteurs de risque qui a été identifié. Alors que la maladie ne se manifeste qu'à l'âge adulte, les déficits cognitifs peuvent apparaitre avant. Des études suggèrent que le stress affecte les capacités cognitives via les récepteurs NMDA et la plasticité synaptique dans l'hippocampe. Par conséquent, l'infection prénatale pourrait augmenter la vulnérabilité à la schizophrénie par une modulation des récepteurs NMDA dans l'hippocampe, dont les conséquences seraient observables à l'adolescence et à l'âge adulte. Afin d'étudier cette hypothèse nous avons évalué la fonction des récepteurs NMDA dans l'hippocampe de rats adultes et adolescents suite à une infection prénatale. Nous avons utilisé un modèle d'activation du système immunitaire chez la rate gestant : une dose de lipopolysaccharide (LPS) est injectée à des rates à 15 et 16 jours de gestation et les effets sur la progéniture ont été étudiés. Les effets de cette exposition au LPS sur les fonctions cognitives sont présentés dans le chapitre 2. Les rats adolescents exposés au LPS ont montré des déficits de mémoire spatiale à long terme et une augmentation de la réversion de l'apprentissage spatial. Les rats adultes n'ont présenté aucun déficit. Ces deux tâches étant associées à la fonction des récepteurs NMDA dans la plasticité synaptique et à la dépression synaptique à long terme (LTD) dans l'hippocampe, nous avons dans le troisième chapitre étudié l'effet de l'exposition au LPS sur la transmission synaptique liée aux récepteurs NMDA et sur la LTD dans l'hippocampe des rats adolescents. De plus, nous avons étudié la relation entre le stress et l'exposition au LPS. Nous avons montré que l'exposition au LPS abolit la LTD. Cet effet est associé à une diminution de la fonction des récepteurs NMDA puisque les potentiels de champ dépendant des récepteurs NMDA ainsi que les courants NMDA furent diminués. Un stress de contention permet de rétablir les déficits de LTD observés dans le groupe exposé au LPS alors qu'un traitement à la corticostérone augmente la LTD seulement chez les animaux du groupe LPS. Aucune altération de la fonction des récepteurs NMDA et de la plasticité synaptique n'a été observée chez l'animal adulte (chapitre 4). Par conséquent une exposition au LPS affecte les fonctions des récepteurs NMDA hippocampiques de façon transitoire pendant l'adolescence.Dans le chapitre 5, nous avons étudié l'effet de l'exposition au LPS sur l'expression de la reelin et de la GAD 67 chez le rat juvénile et adolescent. L'expression de ces deux protéines est réduite chez les schizophrènes et des études suggèrent que cela affecte la plasticité synaptique en modulant les récepteurs NMDA. Nous avons observé une diminution du nombre de cellules exprimant la reelin et la GAD67 dans l'hippocampe à 14 et 28 jours chez les rats du groupe LPS. L'ensemble de nos résultats montrent que l'exposition prénatale au LPS cause des altérations de la fonction des récepteurs NMDA de l'hippocampe de façon transitoire durant l'adolescence. Elle induit un hypofonctionnement des récepteurs NMDA et augmente l'effet du stress sur leur fonction ainsi que sur la LTD pendant l'adolescence. De plus, la diminution de l'expression de la reelin et de la GAD67 observée dans l'hippocampe chez les rats juvéniles et adolescents exposés au LPS suggère que ces changements pourraient avoir un impact sur le développement des récepteurs NMDA. En conclusion, nos résultats soutiennent l'hypothèse que l'infection prénatale augmente la vulnérabilité à la schizophrénie à l'adolescence et élucident une partie des mécanismes par lesquels l'infection prénatale augmente les risques de développer la schizophrénie.

Alternate day fasting (ADF) leads to weight loss in humans and rats. To examine the effects of ADF on diet preference, rats were assigned to alternate day or free food access and presented with chow and high-energy (HE) food. Satiety peptides CCK and exendin-4 were administered to determine if they altered the relationship between fasting and preference. Fasting decreased HE preference compared to controls. For males, this was driven by an increase in size and number of chow meals. For females, this was driven by an increase in chow meal number. ADF appeared to increase orosensory stimulation and/or decrease sensitivity to inhibitory cues for males; for females it appeared to decrease sensitivity to inhibitory cues. Peptides did not moderate the relationship between fasting and preference, but exendin-4 decreased HE preference across all groups. Shifts in diet preference may contribute to the effectiveness of using ADF as a dieting strategy.

This heuristic self-search inquiry (Sela-Smith, 2001, 2002) study reviews empirical and theoretical research on Autism Spectrum Disorder (Asperger, 1938, 1944; Bleuler, 1910, 1911a, 1911b; Kanner, 1943) and Turner Syndrome (Funke, 1902; Turner, 1938; Ullrich, 1930). It conjoins with existing literature on the main principles of existential-humanistic psychology and psychotherapy to prompt a heuristic investigation of the problem of the researcher-participant’s veridical reference as it pertains to her subjective experience. The purpose of the study was to elucidate the complementarity of what the existential-humanistic literature refers to as the intelligible responses of her equiprimordial I-who-feels encounter with biopsychological trauma as an initiator of chronic existential injury as an adult diagnosed with a conglomerate of associated clinical symptoms to sketch out their possible existential etiologies.

Stimuli precipitating heuristic data collection included psychotherapy sessions, childhood medical records, medical examinations and consultations conducted during the study, and prior academic work. The heuristic data collection adhered to Moustakas’ (1990) phases and processes of research. Schneider’s (2008/2015) expansion-constriction continuum model of consciousness of six-domains (physiological, environmental, cognitive, psychosexual, interpersonal, and experiential) was used to analyze the heuristic data and decipher whether tacit knowledge of the researcher-participant’s I-who-feels experience was discovered in the inquiry. A Heuristic-Expansion-Constriction Change scale was designed to subjectively measure degree of change in each domain. Bronfenbrenner’s (1979) biosystemic model of human development was employed to conceptualize the etiology of existential injury across four systems of being: the microsystem, mesosystem, ectosystem, and macrosystem.

The heuristic research findings indicated a high degree of meta-level abstraction in the researcher-participant paralleled by the review of the literature. Populations experiencing recalcitrant complications of similar ilk might gain insight into their psychological etiologies of by, through self-examination and change, acknowledging resistance to the I-who-feels . Additionally, ongoing interdisciplinary intervention by an established care team providing medical and psychotherapeutic support might prove satisfactorily beneficial. Data was distilled into a series of recommendations that existential-humanistic psychotherapists might adopt when working with clients exhibiting chronic existential injury due to multiplex medical symptoms. Implications for these populations were subsequently discussed, with special recommendations provided for medical providers on addressing existential concerns in patients.

Short-term longitudinal study of mother-infant feeding interactions is rare in the infant obesity, growth, eating disorder, and attachment research. Beginning at birth through 3 months of age, this case-study replication series utilized archival data of 12 mother-infant pairs videotaped during weekly bottle-feeding sessions in their homes. Measures included infant weight and length and amount of food ingested. Videotapes were scored according to five infant and nine maternal observed feeding behaviors scaled on the Interaction Rating Scale - Feeding Ratings, a global measure of mother-infant feeding interactions. Study hypotheses proposed that the more optimal the mothers’ or infants’ behaviors, the larger the weight or BMI of the infant or the more food the infant ingested at a feeding session. Spearman rank-order correlation time-point analyses on 69 feeding observations showed statistically significant relationships. All combined infant behavior ratings as well as specific infant behavior ratings of State Rating, Physical Activity, and Gaze Behavior were significantly related to larger infant weight or infant BMI. Regarding maternal behavior ratings, statistically significant negative correlations were found between Persistence in Feeding and infant weight, Contingent Vocalization and BMI, and Gaze Behavior and amount of food ingested. These results have implications for further theorizing about the early antecedents of pediatric obesity in particular, but also for the development of caregiver-infant attachment in general.

There is a long history in psychological science of studying the negative sequelae that follow exposure to traumatic or other adverse life events. A large body of evidence has accumulated showing that individuals who have experienced major adversity are at higher risk for both mental and physical illness. However, while it is certainly true that some individuals experience these deleterious outcomes following adversity, the majority of individuals appear to be resilient to adversity. Moreover, some people even demonstrate personal growth following the experience. These observations have given rise to an interest in understanding how people make meaning out of threatening experiences, as well as the mechanisms through which people display resilience and even growth following adversity.

Relevant to this, a mounting body of research coming out of personality and narrative psychology has argued that a person’s identity is formed by developing an autobiographical life narrative that reconstructs past experiences, acknowledges the present, and projects into the future. This is called “narrative identity.” These life stories are not objective recounts of past experiences; rather, they are insights into who individuals views themselves as now. As such, individuals have some ability to shape past adversities insofar as they are able to choose how they will ultimately narrate the experience and incorporate it into their own sense of identity.

There are two major types of scenes that come up in life stories that have importance to how one fares in the face of adversity. Some people develop stories of redemption, where negative experiences are transformed into something positive. Conversely, some people narrate stories of contamination, where positive experiences are subsequently ruined by something negative. The use of redemptive imagery in the life story is positively associated with indicators of psychological well-being, whereas the use of contamination sequences is negatively associated with well-being. However, whether redemption and contamination narrations are associated with physical health remains unknown.

To address this, I report on data drawn from a larger longitudinal study of midlife American adults. At the baseline visit, participants underwent an extensive life story interview and completed various questionnaires. Five years later they underwent the same procedure. Within a year of this second visit, they filled out additional questionnaires related to mood, well-being, and health, and also had their blood drawn to assess cardiometabolic health indicators. For metabolic properties, height, weight, waist circumference, blood pressure, total cholesterol, and glycosylated hemoglobin (a method of assessing average plasma glucose levels over the past 3 months) were assessed at the time of the study visit, and these variables were used to index metabolic syndrome related components and risk. At that time, serum was also frozen to allow for future batch testing of inflammatory proteins and markers. From this serum, C-reactive protein (CRP) and lipoprotein-associated phospholipase A₂ (Lp-PLA₂) were quantified in all participants to assess markers of general systemic inflammation (CRP) as well vasculature specific inflammation (Lp-PLA₂). Additionally, a panel of inflammatory chemical messengers – called cytokines – were assayed as broader indicators of peripheral inflammatory activity. These cytokines were interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interferon-γ (IFNγ), and tumor necrosis factor α (TNFα). Levels of the various inflammatory markers and cytokines (CRP, Lp-PLA2, IL-6, IL-8, IL-10, IFNγ, and TNFα) were z-scored and summed to create a composite inflammatory variable.

This study has three overarching sets of hypotheses, as well as one set of exploratory hypotheses. First, the usage of redemptive sequences in individuals’ life stories should be associated with better cardiometabolic health outcomes. This should be evidenced by better subjective self-reported health, fewer components related to metabolic syndrome as well as lower metabolic risk, lower levels of CRP, less risk of having a CRP value falling in the “high cardiovascular risk” category, and lower levels of composite inflammation. Second, the usage of contamination sequences in individuals’ life stories should be associated with poorer cardiometabolic health outcomes. This should be evidenced by worse subjective self-reported health, more components related to metabolic syndrome as well as higher metabolic risk, higher levels of CRP, more risk of having a CRP value falling in the “high cardiovascular risk” category, and higher levels of composite inflammation. Third, there should be an interaction between the presence of redemption sequences and the presence of contamination sequences in predicting the various cardiometabolic health outcomes. (Abstract shortened by ProQuest.)