Background: The present study was designed to examine prefrontal cortical processes in anxious children that mediate cognitive regulation in response to emotion-eliciting stimuli, and the changes that occur after anxious children participate in a cognitive behavioral therapy treatment program. Methods: Electroencephalographic activity was recorded from clinically anxious children and typically developing children at pre- and post-treatment sessions. Event-related potential components were recorded while children performed a go/no-go task using facial stimuli depicting angry, calm, and happy expressions. Results: At pre-treatment, anxious children had significantly greater posterior P1 and frontal N2 amplitudes than typically developing children, components associated with attention/arousal and cognitive control, respectively. For the anxious group only, there were no differences in neural activation between face (emotion) types or trial (Go vs. No-go) types. Anxious children who did not improve with treatment showed increased cortical activation within the time window of the P1 at pre-treatment relative to comparison and improver children. From pre- to post-treatment, only anxious children who improved with treatment showed increased cortical activation within the time window of the N2. Conclusions: At pre-treatment, anxious children appeared to show increased cortical activation regardless of the emotional content of the stimuli. Anxious children also showed greater medial-frontal activity regardless of task demands and response accuracy. These findings suggest indiscriminate cortical processes that may underlie the hypervigilant regulatory style seen in clinically anxious individuals. Neural activation patterns following treatment suggest that heightened perceptual vigilance, as represented by increased P1 amplitudes for non-improvers, may have prevented these anxious children from learning the treatment strategies, leading to poorer outcomes. Increased cognitive control, as represented by increased N2 amplitudes for improvers, may have enabled these anxious children to implement treatment strategies more effectively, leading to improved treatment outcomes. Hence, P1 activation may serve as a predictor of treatment outcome, while N2 activation may serve as an indicator of treatment-related outcome. These findings point to the cortical processes that maintain maladaptive functioning versus the cortical processes that underlie successful intervention in clinically anxious children.

The current thesis directly investigated whether changes in the neural correlates of self-regulation (SR) are associated with the effectiveness of treatment for children’s externalizing problems. In order to test this, seventy-one children 8–12 years of age with clinical levels of externalizing behaviour and their parents completed a 12-week cognitive behavioural therapy program (12 sessions) with a parent management training component that was aimed at improving SR. Electroencephalogram (EEG) correlates of SR were evaluated before and after treatment with a go/no-go task requiring inhibitory control on the children. Results showed that event-related potential (ERP) correlates of SR, such as the frontal N2 and frontal P3 event-related potential magnitudes, differed between the clinical sample and a matched comparison group before treatment: the clinical sample had larger N2 magnitudes and smaller frontal P3 magnitudes. Children who showed improvement (45%) with treatment demonstrated a decrease in the magnitude of the N2 in comparison with children who did not improve. For improvers only, source analysis during the time period of the N2 modeled activation decreases in dorsomedial and ventromedial prefrontal cortex as well as the anterior medial temporal lobe. A decrease in N2 magnitudes and corresponding reductions in source activation, in children who improved with treatment, might reflect improved efficiency in the neural mechanisms of SR. These findings may be important steps toward a better identification of neural markers of SR and a better understanding of the mechanisms of treatment efficacy.

There is a paucity of research examining the neurobiological functioning of new mothers who have experienced parental loss during development. The current study investigated the relationship between inconsistent (IC) versus consistent (CC) care and brain activity in regions that comprise a putative neurobiological model of mothering. Mothers were shown positive and negative pictures of their own and an unfamiliar infant. Through repeated measures ANOVAs, it was found that BOLD activity was greater for own infant in the nucleus accumbens (NAC) and amygdala (AMY) and that positive pictures elicited greater BOLD response in the NAC, AMY and anterior cingulate cortex. Interestingly, IC mothers show an even greater response own infant in the NAC and left hypothalamus (HYPO). In the left dorsolateral prefrontal cortex, IC mothers showed greater BOLD response to other infant. Thus, functioning of the maternal circuit, which includes areas strongly implicated in reward, may be altered by early experiences.

Doctor of Philosophy / Department of Psychology / Mary E. Cain / Glutamate contributes to the neurological and behavioral changes that occur during differential rearing, and those that occur during conditioned hyperactivity and sensitization. Metabotropic glutamate receptor 5 (mGluR5) in particular contributes to the psychostimulant reward pathway, plasticity, and differential rearing. The present study examined the role of mGluR5 in conditioning and sensitization in differentially reared rats. Rats were reared in an enriched (EC), impoverished (IC), or social (SC) condition for 30 days, after which they received repeated amphetamine (0.3 mg/kg) or saline injections. Following training, rats received an injection of the mGluR5 antagonist MTEP or saline prior to undergoing conditioned hyperactivity and sensitization tests. Results showed that MTEP attenuated conditioned hyperactivity and sensitization in IC but not EC and SC rats, suggesting that glutamatergic changes occur during differential rearing that alter the effects of MTEP on amphetamine conditioning and sensitization. Additionally, results demonstrated that enrichment rearing has a protective effect against conditioned hyperactivity at low doses of amphetamine.

Master of Science / Department of Psychology / Mary E. Cain / Previous research has shown that both the environment and psychostimulant use influence dopamine levels via the mesolimbic dopamine pathway. C-fos expression has also been observed following exposure to novel environments and psychostimulants. The present study looked to determine the effects of acute amphetamine exposure on locomotor activity and c-fos expression in the basolateral and central nucleus of the amygdala, for rats raised in either an enriched condition (EC), impoverished condition (IC), or social condition (SC). Rats were reared in either the EC, IC, or SC for 30 days, after which they received an acute amphetamine injection (1.0 mg/kg) and locomotor activity was measured. Following the locomotor test rats were perfused and immunohistochemistry was used to measure c-fos levels in the basolateral and central nucleus of the amygdala. Results showed that EC amphetamine rats had significantly greater locomotor activity compared to EC saline rats. There were no significant group or treatment differences in c-fos expression in the ACe. In the BLA SC amphetamine rats had significantly greater c-fos expression than EC amphetamine rats. Overall, the current study revealed that environmental enrichment and amphetamine do significantly alter locomotor activity and c-fos expression in the BLA.

Background: Traumatic musculoskeletal injury (TMsI) often leads to chronic pain and post-traumatic stress disorder (PTSD). This study examined factors of a modified diathesis-stress model in the development of PTSD symptoms following TMsI. Methods: 205 patients were recruited in this prospective, observational study. Within 14 days of injury, participants completed an in-hospital questionnaire investigating acute symptoms of anxiety, depression, pain, and PTSD. Results: Logistic regression identified multiple factors associated with symptoms of PSTD (p<.0001). Neuropathic pain (odds ratio[OR]=1.091, 95% confidence interval[CI] 1.020-1.168), general anxiety (OR=1.176, 95%CI 1.046-1.318), pain anxiety (OR=1.056, 95%CI 1.018-1.094), and pain catastrophizing (OR=1.168, 95%CI 1.016-1.348) were associated with acute symptoms of PTSD. Conclusions: The results support the modified diathesis-stress model indicating that neuropathic pain, general anxiety, pain anxiety, and pain catastrophizing are associated with symptoms of PTSD. Future studies should examine the influence of these acute factors on the development of chronic pain and PTSD following TMsI.

Plusieurs études antérieures ont proposé que la ménarche pouvait représenter une vulnérabilité accrue au développement de la dépression en augmentant la réactivité au stress chez les filles ayant atteint leur cycle menstruel. Dans la présente étude, les symptômes dépressifs et les niveaux de cortisol salivaire ont été mesurés chez 198 garçons et 142 filles (11 - 13 ans), et ce, à quatre reprises au cours de leur première année de transition vers l’école secondaire, une période de stress chez les adolescents. Les résultats ont montré que les filles qui avaient atteint la ménarche au moment de la transition vers le secondaire avait des niveaux significativement plus élevés de symptômes dépressifs et de cortisol salivaire entre l’automne et le printemps, comparativement aux filles qui n'avaient pas encore atteint la ménarche. Ces dernières présentaient des niveaux plus élevés de symptômes dépressifs que les filles sans et les garçons. Les filles sans ménarche présentaient d’avantages des niveaux de symptômes dépressives plus élevés que les garçons. En utilisant l’âge de ménarche comme variable catégorique, les résultats démontrent que les filles ayant eu leur ménarche plus jeunes présentent des symptômes dépressifs plus élevés tout au long de l'année scolaire, alors que les filles qui ont commencé leur cycle menstruel à l’âge dit ‘normal’ présentent des symptômes dépressifs transitoires. Globalement, ces résultats suggèrent que la ménarche est un indice significatif d’une vulnérabilité accrue pour les symptômes dépressifs et les niveaux de cortisol plus élevés chez les adolescentes qui font leur entrée au secondaire. Également, ces résultats suggèrent qu’un âge précoce de ménarche peut exposer à long-terme le cerveau en développement à des niveaux élévés de cortisol, rendant ainsi ce groupe d’adolescentes plus vulnérables à la dépression. / It has been proposed that the onset and/or earlier age at menarche confer greater vulnerability to depressive symptoms by increasing the reactivity of menarcheal girls to stressors associated with adolescence. In the present study, we measured depressive symptoms and salivary cortisol levels in 198 boys and 142 girls (11 -13 years) tested four times during their first year of transition into high school, a period known to be associated with stress among adolescents. Results showed that girls who had reached menarche before the transition to high school transit presented significantly higher depressive symptoms and salivary cortisol levels across the school year, when compared to girls who had not reached menarche and boys. Girls who had reached menarche presented significantly higher depressive scores than girls who had not reached menarche and boys. Girls who did had not reached menarche also scored significantly higher on depressive symptoms when compared to boys. When we divided the menarcheal girls as a function of age of onset, we found that girls with early age at menarche presented consistently higher scores for depressive symptoms from the start of the school year to early spring. Girls with on-time menarche scored higher for symptoms of depression, but these were more transitory. Altogether, these results show that onset of menarche is associated with greater depressive symptoms and higher cortisol levels in adolescent girls going through the stress of high school transition. These findings also suggest that early menarche may confer greater vulnerability to depression due to long-term exposure of the developing brain to high cortisol levels.

La recherche montre que l’insula est impliquée dans le traitement d’informations intéroceptives, émotionnelles et relevant de fonctions exécutives de haut niveau. L’hypothèse des marqueurs somatiques propose que ces fonctions vraisemblablement séparées travaillent plutôt de concert au sein d’un système neural dont le rôle consiste à extraire les messages émotionnels des signaux corporels. Si l’insula exerce effectivement un rôle de modulateur des sensations corporelles et des processus cognitifs découlant de ceux-ci, des lésions au cortex insulaire risquent d’occasionner des altérations au niveau de l’expérience émotionnelle, des fonctions exécutives et de la personnalité. La présente étude a pour but de mesurer ces changements chez 19 patients ayant subi une insulectomie unilatérale dans le cadre de leur traitement de l’épilepsie. Ces patients ont été comparés à un groupe contrôle composé de 19 patients épileptiques ayant subi une résection du lobe temporal. Les participants ont été évalués par l’entremise du Iowa Scales of Personality Change (ISPC), rempli par un proche du patient. Les résultats montrent que les patients du groupe insulaire exhibent des changements qui dénotent une dérégulation émotionnelle à long terme, caractérisée par une augmentation modérée de l’irritabilité, de la labilité émotionnelle, de l’anxiété et de la frugalité, tous des changements qui, outre l’anxiété, n’ont pas été observés chez les patients temporaux. Cependant, pour ce qui est des fonctions exécutives, aucun changement significatif n’a été noté. De plus, la comparaison pré- et post opératoire des scores des deux groupes aux items de l’ISPC ne s’est pas avérée significative. Globalement, les résultats suggèrent que l’insula joue probablement un rôle accessoire au sein du modèle proposé par l’hypothèse des marqueurs somatiques et que les résections unilatérales partielles ou complètes de l’insula ne risquent pas d’occasionner de changements prononcés de la personnalité. / Research has shown that the insula is involved in the processing of information relating to interoceptive, emotional and executive functions. It was proposed that these two seemingly separate functions may work conjointly as part of a large neural circuit tasked with the extraction of emotional information from bodily signals. It was hypothesized that, if the insula does indeed modulate feelings and the cognitive processes which derive from them, insular damage would result in alterations of emotional experience, executive functions and personality. To that effect, we examined such changes in a group of patients (n = 19) who underwent epilepsy surgery involving partial or complete resection of the insula, and compared them to a group of patients who underwent temporal lobe epilepsy surgery (n = 19) as a lesion-control group. Participants were assessed on the Iowa Scales of Personality Change, filled by a close relative at least six months after surgery. While pre- vs. post-surgery changes did not significantly differ between groups on any of the outcome variables, insular resections were associated with mild but significant increases in irritability, emotional lability, anxiety, and frugality postoperatively, which, with the exception of increased anxiety, were not found among temporal patients. Against our initial prediction, the surgery did not lead to executive functioning deficits. Overall, our results support the notion that the insula most likely holds an accessorial role in the model proposed by the somatic marker hypothesis, and that there isn’t a risk of dramatic personality change as a result of the partial or complete unilateral surgical removal of the insula.

Certains gènes, modulant la sérotonine (5-hydroxytryptamine, 5-HT), ont été associés aux tempéraments liés à l'anxiété. Une limitation dans la plupart de ces études est que les études sont de nature transversale et l'anxiété a été évaluée à un seul point dans le temps. De plus, seules quelques études ont été réalisées chez les enfants. Le but de la présente étude était d'étudier le rôle des gènes HTR2A et TPH2 dans le développement des trajectoires d’anxiété durant l’enfance. Les associations entre ces gènes, ces trajectoires, le diagnostic d’anxiété à l'âge adulte et les différences entre les sexes ont été examinées dans l'Étude Longitudinale des Enfants de Maternelle au Québec, composée de 3185 enfants recrutés en 1986-1987. Leur anxiété a été cotée par leur professeur annuellement entre 6 et 12 ans. Ces cotes ont été modélisées en trajectoires comportementales. Les données genotypées de 5-HT, disponibles pour 1068 personnes, ont été analysées en utilisant les statistiques du Chi-carré, des régressions logistiques et des analyses de variance. Sur les 37 polymorphismes étudiés, plusieurs ont été associés à la trajectoire de forte anxiété, tels le 5-HTR2A (rs1328684, rs95534511, rs1745837, rs7984966, 7330636) et TPH2 (rs11179050, rs11179052, rs1386498). Bien que les trajectoires d’anxiété en enfance n’aient pas prédit le diagnostic d'anxiété à 21 ans, les relations ont été trouvées entre ce diagnostic, HTR2A et les polymorphismes du nucléotide simple (PNS) de TPH2. On remarque que les PNS associés à l’anxiété durant l’enfance et l’âge adulte ne sont pas les mêmes. La force d'association entre les gènes étudiés et l'anxiété diffère entre les garçons et les filles. Cette étude est la première à identifier une association entre les variantes TPH2, 5-HTR2A et les trajectoires d’anxiété en enfance. Les études futures devraient reproduire les résultats dans d'autres échantillons, enquêter sur l'interaction avec les facteurs de stress, et étudier la pertinence fonctionnelle de la PNS. / A number of genes known to modulate serotonin (5-hydroxytryptamine, 5-HT) have been associated with anxiety-related temperaments. A limitation in most of these studies is that the studies are cross-sectional and anxiety has been measured at a single point in time. Furthermore, only a few studies have been done in children. The aim of the present study was to investigate the role of the HTR2A and TPH2 gene in the development of trajectories of anxiety in childhood/ adolescence. Associations between these genes, anxiety trajectories in childhood and anxiety diagnoses in adulthood were also investigated. Finally, gender differences were explored. Research questions were investigated in the Quebec Longitudinal Study of Kindergarten Children, consisting of 3185 boys and girls, selected in 1986-1987. Children`s anxiety was rated by their teacher every year between the age of 6 and 12 years. The ratings were modeled into behavioral trajectories. 5-HT genotyping data were available for 1068 cohort members. Data were analyzed using Chi-square statistics, logistic regressions and ANOVAs. Out of 37 investigated polymorphisms, several polymorphisms, such as 5-HTR2A (rs1328684, rs95534511, rs1745837, rs7984966, 7330636) and TPH2 (rs11179050, rs11179052, rs1386498) were associated with a high anxiety trajectory. Though trajectories of high anxiety in childhood did not predict an anxiety diagnosis at age 21, relationships were found between HTR2A and TPH2 SNPs and anxiety diagnosis at age 21. We note that the SNPs associated with anxiety were different between adults and children. The strength of association between the investigated genes and anxiety differed between boys and girls. This is the first study reporting an association with some HTR2A and TPH2 variants and trajectories of anxiety in children. Future studies should replicate the findings in other samples, investigate the interaction with stressors, and study the functional relevance of the SNPs

Feature binding refers to the fundamental challenge of the brain to integrate sensory information registered by distinct brain regions to form a unified neural representation of a stimulus. While the human cognitive literature has established that attentional processes in a frontoparietal cortical network support feature binding, the neurochemical contributions to this attentional process remain unknown. Using systemic administration of the cholinergic muscarinic receptor antagonist scopolamine and a digging-based rat feature binding task that used both odor and texture stimuli, it was demonstrated that blockade of acetylcholine (ACh) at the muscarinic receptors impaired rats’ ability to feature bind at encoding, and it was proposed that ACh may support the attentional processes necessary for feature binding (Botly & De Rosa, 2007). This series of experiments further investigated a role for ACh and the cholinergic basal forebrain (BF) in feature binding. In Experiment 1, a cross-species experimental design was employed in which rats under the systemic influence of scopolamine and human participants under divided-attention performed comparable feature binding tasks using odor stimuli for rats and coloured-shape visual stimuli for humans. Given the comparable performance impairments demonstrated by both species, Experiment 1 suggested that ACh acting at muscarinic receptors supports the attentional processes necessary for feature binding at encoding. Experiments 2-4 investigated the functional neuroanatomy of feature binding using bilateral quisqualic acid excitotoxic (Experiment 2) and 192 IgG-saporin cholinergic immunotoxic (Experiments 3 and 4) brain lesions that were assessed for completeness using histological and immunohistological analyses. Using the crossmodal digging-based rat feature binding task, Experiment 2 revealed that the nucleus basalis magnocellularis (NBM) of the BF is critically involved in feature binding, and Experiment 3 revealed that cholinergic neurons in the NBM are necessary for feature binding at encoding. Lastly, in Experiment 4, rats performed visual search, the standard test of feature binding in humans, with touchscreen-equipped operant chambers. Here it was also revealed that cholinergic neurons in the NBM of the BF are critical for efficient visual search. Taken together, these behavioural, pharmacological, and brain-lesion findings have provided insights into the neurochemical contributions to the fundamental attentional process of feature binding.