Complicated grief, or persistent complex bereavement disorder, is a condition that affects approximately 10% of bereaved individuals and is marked by intense longing and yearning for the deceased. Little is known about the neurocognitive mechanisms contributing to this syndrome, but previous research suggests that reward pathways in the brain may play a role. The present study was designed with this theory in mind, aiming to understand reward processing in those experiencing complicated and non-complicated grief as well as to differentiate the "wanting" and "liking" phases of reward processing in bereavement. Twenty-five older adults were categorized based on grief severity into one of three groups: complicated grief (CG), non-complicated grief (NCG) and non-bereaved married controls (NB). Neural activation was examined using fMRI while participants viewed a countdown on the screen (anticipation) followed by a photo of their (living or deceased) spouse. There was no significantly differential activation between the three groups for the spouse v. stranger photo contrast, nor for anticipation period v. spouse photo. However, these two contrasts were also run separately in the three groups. Each group produced significant activation, in similar and distinct regions, primarily associated with emotion and visual processing. In addition, post-hoc analyses were conducted using self-reported yearning scores as a regressor across all bereaved participants, which revealed that greater symptoms of yearning predicted greater activation in the subgenual anterior cingulate cortex (sgACC). This region of the brain has been previously linked to depression and suggests that symptoms of yearning may present an opportune place to intervene to improve outcomes in CG.

The heterogeneity intrinsic to the ventromedial prefrontal cortex (vmPFC) is evidenced in both its anatomy and implicated function: vmPFC subregions have roles in positive affect, negative affect and autonomic/endocrine regulation. Whether different subregions serve fundamentally different functions, or whether they perform similar computations on different inputs, remains unclear. Nevertheless, the role of the vmPFC in psychopathology is widely appreciated - in mood and anxiety disorders, over-activity within constituent regions of the vmPFC is consistently implicated in symptomatology, together with its normalisation following successful treatment. However, the precise locus of change varies between studies. The work presented in this thesis investigates the causal contributions of over-activity within two key subregions of the vmPFC - the subgenual anterior cingulate cortex (sgACC, area 25) and perigenual anterior cingulate cortex (pgACC, area 32) - in discrete dimensions of behaviour and physiology affected in psychiatric disorders. Specifically, the impact of over-activity is assessed on (i) baseline physiological function; (ii) the regulation of anticipatory, motivational and consummatory aspects of reward-related behaviour; and (iii) negative affect including fear learning, stress recovery and the intolerance of uncertainty. To provide further insight into the mechanism of action of antidepressants, the efficacy of selected treatments is tested on changes induced by over-activity of these regions. Beyond the direct relevance of the results presented here to psychiatric disorders and their treatment, the thesis aims to emphasise the importance of broader themes associated with the measurement and quantification of emotion in preclinical animal studies. First, a multi-faceted approach is utilised enabling quantification of both the autonomic and behavioural aspects of emotion. In so doing, the experiments maintain relevance to studies which assess these correlates in isolation, both in humans (which typically measure subjective responses and physiology) and in rodents (which frequently assess behaviour in isolation). The assessment of more than one dimension of emotion confers these studies with improved power to detect maladaptive changes. Second, the experiments described were conducted in the marmoset, a new-world primate. The extensive anatomical homology between marmoset and human prefrontal cortex facilitates the forward-translation of functional results. In combination with the appropriate assays, this renders marmosets as an invaluable species to study the causal contributions of vmPFC subregions to symptoms of psychiatric disorders. I believe that the results of these experiments provide important insights into the causal role primate vmPFC has in relation to the behavioural and physiological aspects of psychiatric symptomatology. Most importantly, I hope that they serve as the foundation for future work to further elucidate the neuropathological processes underlying mental disorders.

Background: The aim of this thesis was to investigate the relationship of moral cognition and emotions to the pathophysiology of major depressive disorder (MDD). Patients with MDD may experience excessive guilt or self-blaming biases despite recovery from the depressed state. Since guilt is a moral emotion thought to motivate altruistic behaviours, it has been hypothesized that elevated self-blame in MDD may result in pathological increases to altruism in some patients. The relationship of self-blame to altruistic choices in individuals with remitted MDD (rMDD), however, has not been established. Guilt has been shown to activate the subgenual cingulate and adjacent septal region (SCSR) which is of known importance to the pathophysiology of MDD. Since MDD is thought to arise from network-level dysfunctions, and moral cognition and emotions are hypothesized to emerge from network-level binding, investigating resting-state SCSR functional connectivity in rMDD patients and healthy control (HC) participants could reveal networks of potential relevance both to MDD and to moral cognition and emotions. Chapter 2: We investigated whether melancholic rMDD patients could be distinguished from non-melancholic and HC groups on the basis of resting-state functional connectivity to an SCSR seed region. Lower SCSR-amygdala connectivity distinguished the melancholic rMDD group from non-melancholic and HC groups. Chapter 3: We investigated whether patients who remained resilient to recurring depressive episodes were distinguishable from recurring episode MDD and HC groups on the basis of resting-state connectivity to an SCSR seed region. Lower interhemispheric SCSR connectivity distinguished the resilient MDD patients from the recurring episode MDD and HC groups. Chapter 4: We measured explicit and implicit preferences for social options with and without altruistic motivations relative to selfish options in the rMDD and HC groups during emotion priming to modulate feelings of guilt. The rMDD patients explicitly preferred prosocial options (i.e., social options and altruism directed towards friends or colleagues) less than HC participants. Regardless of group, guilt priming increased explicit and implicit preferences for altruism towards strangers. Chapter 5: We investigated whether explicit and/or implicit preferences for prosocial options during guilt priming were correlated with resting-state connectivity to an SCSR seed region, and whether this relationship could distinguish the rMDD and HC groups. Across all participants, implicit prosocial choice preference negatively correlated with connectivity between the SCSR and right temporoparietal junction (TPJ). The relationship of SCSR-TPJ connectivity to implicit preferences for social options and for altruism towards friends and colleagues was weaker in the rMDD group compared to the HC group, particularly for implicit altruism. Conclusions: We identified resting-state SCSR networks associated with vulnerability to melancholia and with resilience to recurring depressive episodes. Patients with rMDD explicitly preferred options entailing social withdrawal, a symptom associated with MDD vulnerability. Irrespective of group, guilt motivated altruism towards strangers but not friends and colleagues. Implicit prosociality was negatively associated with connectivity in a social agency network, and the comparatively weak relationships between connectivity and implicit choice preferences in rMDD patients may reflect a vulnerability factor for MDD.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

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Women exhibit greater habituation to painful stimuli than men. The neural mechanism underlying this sex difference is unknown. However, pain habituation has been associated with pain-evoked activity of the subgenual anterior cingulate cortex (sgACC), implicating a connection between the sgACC and the descending pain antinociceptive system. Therefore, the thesis hypothesis was that women have stronger connectivity than men between the sgACC and the descending antinociceptive system. Healthy subjects provided informed consent. 3T MRI images included anatomical diffusion-weighted imaging for structural connectivity analyses (SC) with probabilistic tractography and resting-state functional images for functional connectivity (FC) analyses. Women had stronger sgACC FC with nodes of the descending pain modulation system (raphe, PAG) and the medial thalamus. In contrast, men had stronger sgACC FC with nodes of the salience/attention network (anterior insula, TPJ) and stronger sgACC SC with the hypothalamus. These findings implicate a mechanism for pain habituation and its associated sex differences.

Women exhibit greater habituation to painful stimuli than men. The neural mechanism underlying this sex difference is unknown. However, pain habituation has been associated with pain-evoked activity of the subgenual anterior cingulate cortex (sgACC), implicating a connection between the sgACC and the descending pain antinociceptive system. Therefore, the thesis hypothesis was that women have stronger connectivity than men between the sgACC and the descending antinociceptive system. Healthy subjects provided informed consent. 3T MRI images included anatomical diffusion-weighted imaging for structural connectivity analyses (SC) with probabilistic tractography and resting-state functional images for functional connectivity (FC) analyses. Women had stronger sgACC FC with nodes of the descending pain modulation system (raphe, PAG) and the medial thalamus. In contrast, men had stronger sgACC FC with nodes of the salience/attention network (anterior insula, TPJ) and stronger sgACC SC with the hypothalamus. These findings implicate a mechanism for pain habituation and its associated sex differences.