Bipolar disorder (BD) and unipolar depression (UD) are two severe mood disorders, with BD often misdiagnosed as UD. Given their severity and high rates of misdiagnosis, it is of paramount importance to understand the psychological and neurobiological mechanisms underlying these disorders to enhance our ability to diagnose, treat, and prevent them effectively. Many neuroimaging studies have shown that mood disorders are associated with abnormal reward-related responses, particularly in the ventral striatum (VS). Yet, the link between mood disorders and reward-related responses in other regions remains inconclusive, thus limiting our understanding of the pathophysiology of mood disorders. To provide insights into the neurobiological underpinnings of reward processing dysfunction in mood disorders, two studies were conducted. Study 1 (Chapter 2) is a coordinate-based meta-analysis of 41 whole-brain neuroimaging studies encompassing reward-related responses from a total of 794 patients with major depressive disorder (MDD), and 803 healthy controls (HC). It aims to address inconsistencies in the literature by synthesizing the literature quantitatively. The findings of Study 1 indicate that MDD is associated with opposing abnormalities in the reward circuit: hypo-responses in the VS and hyper-responses in the orbitofrontal cortex (OFC). These findings provide a foundation for Study 2 (Chapter 3) and help to reconceptualize our understanding of reward processing abnormalities in UD by suggesting a role for dysregulated corticostriatal connectivity. Study 2 is the first fMRI study to employ region-of-interest (VS and OFC), whole-brain, activation, connectivity, and network analyses to examine the similarities and differences in reward-related brain activation patterns between 46 children with remitted bipolar I disorder, 48 children with remitted MDD, and 46 HC. The results of Study 2 revealed differential connectivity in corticostriatal circuitry during reward processing among BD, UD, and HC in pre-adolescence. Specifically, BD exhibited increases in OFC-VS connectivity during anticipation of larger reward, whereas UD and HC showed no changes in OFC-VS connectivity across anticipation conditions ranging from large loss to large reward. Furthermore, BD and UD generally showed more abnormal whole-brain responses to reward anticipation in accordance with the valence of the stimuli than HC. These findings suggest that pre-adolescents with BD and UD exhibit reward processing dysfunction during reward anticipation relative to HC even outside of acute periods of illness. Taken together, the dissertation provides novel insight into the nature of reward processing abnormalities in mood disorders in pre-adolescence. As early onset BD or UD often is associated with long treatment delays and a persistently pernicious illness course, this dissertation may aid efforts to ensure early accurate diagnosis, which may improve our ability to intervene with appropriate treatments and result in a more benign prognosis and course of illness over the lifespan. / Psychology

The brain has the capacity to modify itself structurally and functionally, to adapt to novel circumstances. Adaptive changes in neural circuitry that become intransigent, such as continued hypervigilance after resolution of a threat situation, become maladaptive and may facilitate development of psychiatric disorders such as Major Depressive Disorder (MDD). Although MDD pathogenesis is unclear, hypothalamic-pituitary-adrenal axis dysregulation may facilitate the neuroplastic changes observed in MDD. Whether these neuroplastic changes facilitate the development of MDD or develop due to MDD remains unclear. The characterization of neuroplastic changes in MDD has resulted in sometimes contradictory findings. There are gaps in understanding the timing of neuroplastic changes in MDD, and how and when they are affected by antidepressant treatment. Characterization of neuroplasticity in MDD may uncover different phenotypes and aid in the discovery of a predictive biomarker of antidepressant treatment response. This dissertation presents the results of a series of neuroimaging studies. Chapter 1 provides an introduction to neuroplasticity and MDD. In Chapter 2 results of a study examining hippocampal memory function in treatment naïve patients with MDD are presented. Chapter 3 exhibits findings from a study examining effects of an acute tryptophan depletion paradigm in midlife women receiving estrogen-based treatment on an emotional conflict task. Chapter 4 discusses results from an examination of unmedicated patients with MDD and healthy control participants on an emotional conflict task. Chapter 5 presents longitudinal data of the sample from Chapter 4, and the effect of 8 weeks of treatment with antidepressant escitalopram on performance on an emotional conflict task. In Chapter 6 a case study is presented of a patient with long-standing overt ventriculomegaly, whose chief complaint was of mood and cognitive impairments. Chapter 7 summarizes the findings and contributions of this body of research and discusses clinical implications and future directions. / Dissertation / Doctor of Philosophy (PhD) / The characterization of brain changes in Major Depressive Disorder (MDD) has resulted in contradictory findings, and gaps in understanding how the brain changes in response to antidepressant treatment. This dissertation aims to characterize brain changes in MDD through a series of neuroimaging studies. Chapter 1 provides an introduction to MDD and brain changes in MDD. Chapter 2 presents an examination of memory in treatment naïve patients with MDD. Chapter 3 presents a study of acute tryptophan depletion in midlife women receiving estrogen-based treatment on an emotional conflict task. Chapter 4 examines unmedicated patients with MDD and healthy control participants on an emotional conflict task. Chapter 5 examines the effects of antidepressant treatment on performance on an emotional conflict task. Chapter 6 presents a case study of a patient with ventriculomegaly with mood and cognitive impairments. Chapter 7 summarizes the contributions of this research and discusses implications and future directions.

Risky decision-making and social influence are associated with many health-risk behaviors. However, more work is necessary to understand risky decision-making and social influence. Additionally, to begin identifying ways to change individuals' engagement in health-risk behaviors, more work is necessary to understand whether and how risky decision-making and social influence can be modulated. Using computational modeling in conjunction with other techniques, this dissertation 1) explores mechanisms underlying risky decision-making under social influence (Study 1) and 2) examines how individuals could modulate risky decision-making and social influence (Studies 2 and 3). Study 1 identifies a novel social heuristic decision-making process whereby individuals who are more uncertain about risky decisions follow others and proposes dorsolateral prefrontal cortex (dlPFC) as a 'controller' of this heuristic. Study 2 finds that giving individuals agency in viewing social information increases the utility of that information. Study 3 finds that some individuals can modulate brain patterns associated with risky decision-making using a real-time fMRI (rt-fMRI) neurofeedback paradigm, and preliminarily shows that this leads to behavior change in risky decision-making. In sum, these studies expand on previous work elucidating mechanisms of risky decision-making under social influence and suggest two possible avenues (agency and real-time fMRI neurofeedback) by which individuals can be taught to change their behavior when making risky decisions under social influence. / Doctor of Philosophy / Risky decision-making and social influence are associated with many health-risk behaviors such as smoking and alcohol use. However, more work is necessary to understand risky decision-making and social influence. Additionally, to identify ways to change individuals' engagement in health-risk behaviors, more work is necessary to understand how risky decision-making and social influence can be changed. Here, computational modeling, a way to quantify individual's behavior, is used in a series of studies to 1) understand how individuals make risky decisions under social influence (Study 1) and 2) test ways in which individuals can be guided to change the way they respond to social influence (Study 2) and make risky decisions (Study 3). Study 1 shows that individuals who do not have strong preferences respond to social information in a different way than those who do and utilizes neuroimaging to identify a particular brain region which may be responsible for this process. Study 2 shows that individuals are more influenced by others when they ask to see their choices, as compared to passively viewing others' choices. Study 3 shows that a brain–computer interface can be used to guide individuals to change their brain activity related to risky decision-making and preliminarily demonstrates that following this training individuals change their risky decisions. Together, these studies further the field's understanding of how individuals make risky decisions under social influence and suggest avenues for behavior change in risky decision-making under social influence.

Episodic memories are neurally coded records of personally experienced events across a lifetime. These records are encoded via medial temporal lobe structures in the brain, including the hippocampus, and are commonly called "representations" or "memory traces". Existing studies indicate that information about the neural signal corresponding to a memory representation can be found in functional magnetic resonance imaging (fMRI) data when the pattern across its smallest units (voxels, often 3mm3 sections of the brain) is measured. Many prior studies have measured these voxel patterns in response to stimuli as if they are a spontaneous brain function, regardless of cognitive factors. These studies sometimes find that similarity in the voxel patterns across repetition of a to-be-remembered event predicts later memory retrieval, but the results are inconsistent. The current fMRI study investigated the possibility that cognitive goals during encoding affect the type of neural representation (voxel pattern) that will later support memory retrieval. This seems likely because prior behavioral studies indicate that cognitive variability across repetitions of an event benefits later memory retrieval, which is difficult to reconcile with the common finding that voxel pattern variability across repetitions of an event harms later memory. We tested this hypothesis by comparing voxel patterns that support later memory retrieval to those associated with forgotten items in the medial temporal lobe, including the hippocampus, and lateral occipital cortex. Overall, as previously demonstrated, the behavioral results showed that exposure to variable cognitive goals across repetition of events during encoding benefited subsequent memory retrieval. Voxel patterns in the hippocampus indicated a significant interaction between cognitive goals (variable vs. consistent) and memory (remembered vs. forgotten) such that less voxel pattern similarity for the repeated events with variable cognitive goals, but not consistent cognitive goals, supported later memory success. In other words, variable hippocampal neural activations for the same events under different cognitive goals predicted better later memory performance. However, there was no significant interaction in neural pattern similarity between cognitive goals and memory success in medial temporal cortices or lateral occipital lobe. Instead, higher similarity in voxel patterns in right medial temporal cortices was associated with later memory retrieval, regardless of cognitive goals. In the lateral occipital lobe, the main effects of cognitive goals, hemisphere, and memory success were found but no interactions. In conclusion, we found that the relationship between pattern similarity and memory success in the hippocampus (but not the medial temporal lobe cortex) changes when the cognitive goal during encoding does or does not vary across repetitions of the event. / Master of Science / Episodic memory is a long-term memory of personal experiences which are encoded via the medial temporal lobe in the brain, primarily in the hippocampus. The records of personal experiences in these areas are commonly called "patterns", "representations", or "memory traces". Prior investigations indicate that the way of measuring the neural signals corresponding to personal events is functional magnetic resonance imaging (fMRI). The brain images taken by an fMRI scanner represent the patterns of the smallest unit (voxels, often 3mm3 sections of the brain). Many prior investigations of episodic memory used the voxel patterns but showed mixed results in whether similarity in the voxel patterns across repetition of a repeated event leads to subsequent memory retrieval. One of the possible explanations for mixed results is that the cognitive factors during encoding were neglected. Therefore, the current fMRI study examined how cognitive goals during encoding influence the voxel patterns that later support memory retrieval. During encoding, participants were shown an image repeated with the same or different questions and answered the question on the screen in an fMRI scanner. After 10 days, they were invited to the item memory test on the images that they were given during the encoding phase. The voxel patterns in the medial temporal lobe, including the hippocampus, and the lateral occipital lobe were compared across the repetitions of each image. The behavioral results showed that variable cognitive goals across repeated events during encoding benefited later memory retrieval. Furthermore, less similar voxel patterns in the hippocampus for the images repeated with different questions, but not the same questions, during encoding predicted better later memory success. In the right medial temporal cortices, higher similarity in voxel patterns was significantly associated with later memory retrieval, regardless of cognitive goals. In the lateral occipital lobe, higher voxel pattern similarity was found in the right hemisphere, for images repeated with the same question, and for images successfully retrieved later. In conclusion, we found that the relationship between voxel pattern similarity and memory success in the hippocampus (but not the medial temporal lobe cortex) changes when the cognitive goal during encoding does or does not vary across repetitions of the event.

This systematic review explores the complex relationship between depression, dorsolateral prefrontal cortex (DLPFC) activity as measured by functional magnetic resonance imaging (fMRI), and working memory (WM) performance. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a search was conducted on Medline EBSCO and Web of Science databases, specifically targeting peer-reviewed, published papers in English that utilised fMRI. Three studies meeting the inclusion criteria were included. Findings from the included studies yielded conflicting results. Some studies reported hyperactivation in the DLPFC among depressed individuals, suggesting a potential compensatory mechanism to address impairments during WM tasks. Conversely, other studies found no significant differences in DLPFC activity between depressed individuals and healthy controls. Regarding WM performance, studies revealed heterogeneity among depressed individuals compared to controls. While some indicated no significant differences between groups, others highlighted slower performance and decreased accuracy in depressed individuals. This review underscores the necessity for cohesive methodologies to advance understanding of depression-related cognitive impairments. While deficits in WM were observed in individuals with depression, the precise neural correlates of these impairments remain unclear, pointing to possibilities for further research and potential implications for clinical practice.

Background Obesity and associated metabolic dysregulation are linked to impaired cognitive function and alterations in brain structure, which increases the risk of age-related dementia. Increased glucocorticoid (GC) exposure may be a potential mediator of these negative effects on the brain. Methods and results In paper 1, we tested the relationship between cortisol levels, brain morphology and cognitive function in 200 women and men. Salivary cortisol levels were negatively related to cortical surface areas in prefrontal brain regions in both sexes. In participants with type 2 diabetes, high salivary cortisol levels were associated with lower memory performance. In paper 2, we tested in 70 overweight women the effects on tissue-specific GC metabolism of a Paleolithic diet or a diet following the Nordic nutrition recommendations. The 24-month interventions led to decreased expression of the GC-activating enzyme 11βHSD1 in adipose tissue, interpreted as a normalization of an obesity-related disturbance in GC metabolism. Furthermore, GC metabolism by 5α-reductase increased substantially after 2 years, an unexpected and novel result. The outcomes did not differ by diet. In paper 3, 20 women included in paper 2 were examined with functional magnetic resonance imaging (fMRI) while performing a memory task at baseline and after 6 months. Memory performance improved and functional brain responses increased in the hippocampus. Once again, the results were similar in both diet groups. In paper 4, 24 overweight participants with type 2 diabetes were examined with fMRI, using the same memory test as in paper 3, at baseline and after 12 weeks of intervention with a Paleolithic diet with or without exercise training. Functional brain response increased in the hippocampus, but memory was not improved. The addition of physical exercise did not alter the results. Conclusion Cortisol levels are linked to prefrontal brain structure and, at least in type 2 diabetes, lower memory performance. Furthermore, the dysregulated GC metabolism in obesity can be reversed by long-term diet- induced weight loss. Finally, dietary interventions with associated metabolic improvements alter functional brain responses during memory testing, including increased activation of the hippocampus. Whether these changes are linked to alterations in GC exposure and mediate improved cognition requires further study.

<p>Neuronal current MRI (ncMRI) is a field of study to directly map electrical activity in the brain using MRI, which has many benefits over functional MRI. One potential ncMRI method, Lorentz effect imaging (LEI), has shown promise but needs a better theoretical understanding to improve its use.</p><p>We develop three computational models to simulate the LEI experiments of an electrolyte filled phantom subject to a current dipole based on: ion flow, particle drift, and electromagnetohydrodynamics (EMHD). With comparative experimental results, we use the EMHD model to better understand the Lorentz effect over a range of current strengths. We also quantify the LEI experimental images and assess ways to measure the underlying current strength, which would greatly benefit comparative brain mapping.</p><p>EMHD is a good predictor of LEI signal loss. We can measure the underlying current strength and polarity in the phantom using LEI images. We can also use trends from the EMHD model results to predict the required current density for signal detection in future LEI experiments. We can also infer the electric field strength, flow velocity, displacement, and pressure from the predicted current magnitude in an LEI experiment.</p><p>The EMHD model provides information that greatly improves the utility and understanding of LEI. Future study with our EMHD model should be performed using shorter dipole lengths, higher density and lower strength of current sources, and varying current source frequencies to understand LEI in the setting of mapping brain activity.</p> / Dissertation

Background: Despite our distinct impression to the contrary, we are only conscious of a fraction of all the neural activity underlying our thoughts and behavior. Most neural processes occur non-consciously, and in parallel with our conscious experience. However, it is still unclear what the limits of non-conscious processes are in terms of higher cognitive functions. Many recent studies have shown that increasingly more advanced functions can operate non-consciously, but non-conscious information is still thought to be fleeting and undetectable within 500 milliseconds. Here we used various techniques to render information non-conscious, together with functional magnetic resonance imaging (fMRI), to investigate if non-consciously presented information can be retained for several seconds, what the neural substrates of such retention are, and if it is consistent with working memory maintenance. Results: In Study I we used an attentional blink paradigm to render stimuli (single letters) non-conscious, and a variable delay period (5 – 15 s) prior to memory test. It was found that non-conscious memory performance was above chance after all delay durations, and showed no signs of decline over time. Univariate fMRI analysis showed that the durable retention was associated with sustained BOLD signal change in the prefrontal cortex and cerebellum during the delay period. In Study II we used continuous flash suppression (CFS) to render stimuli (faces and tools) non-conscious, and a variable delay period (5 or 15 s) prior to memory test. The durable retention of up to 15 s was replicated, and it was found that stimuli identity and spatial position was retained until prospective use. In Study III we used CFS to render tools non-conscious, and a variable delay period (5 – 15 s) prior to memory test. It was found that memory performance was not better than chance. However, by using multi-voxel pattern analysis it was nonetheless possible to detect the presence vs. absence of non-conscious stimuli in the frontal cortex,and their spatial position (left vs. right) in the occipital cortex during the delay. Conclusions: Overall these findings suggest that non-consciously presented information (identity and/or position) can be retained for several seconds,and is associated with BOLD signal in frontal and posterior regions. These findings are consistent with working memory maintenance of non-consciously presented information, and thereby constrain models of working memory and theories of consciousness.

Behaviour is guided by accumulated experience, valuation and comparison. While many aspects associated with these functions are mediated by the frontal lobes, the precise contribution from particular regions remains debated. This thesis will deal with how an organism comes to select an option and will specifically focus on the role of the orbitofrontal cortex (OFC) in two mechanisms in this process: learning of outcome specificities and selecting between multiple options based on their expected values. Despite evidence emphasizing anatomical and connective heterogeneity within this structure, the OFC is often regarded as a uniform region. This thesis aims to resolve some of this uncertainty by assuming that the medial and lateral regions of the OFC contribute differentially to learning and decision-making. Two distinct methodologies were used in these investigations. First, the contribution of the medial OFC to social and emotional processing was examined. The findings from this study disprove previously held beliefs that the medial regions of the OFC guide social and emotional behaviours, but indicted a role for this region in value-guided decision-making. The second study examined functional differences between the lateral and medial OFC by making circumscribed lesions to either region in macaque monkeys. The animals performed a number of 3-armed bandit tasks which were designed to investigate different aspects of value assignment and comparison. The results show that while lateral OFC was required for "credit assignment" – the correct assignment of values to visual cues – medial OFC was critical for comparison of the cues' values during decision-making. In unchanging probabilistic environments, mOFC lesions induced decision-making impairments when value comparison was difficult without affecting credit assignment and associative learning. By contrast, lateral OFC lesions caused the opposite pattern of impairment. The final study used human-neuroimaging techniques to investigate the differential representation of outcome-specific contingency learning and found not only that the expectation of a unique outcome facilitated learning and memory recall but that this was supported by a neural network which included the lateral regions of the OFC and the anterior cingulate cortex. Activity in the mOFC did not correlate with outcome-specific contingency learning but instead reflected both the value associated with the receipt and expectation of a reward. Taken together, the results from this thesis suggest that specific parts of the OFC make markedly different contributions to these very different cognitive functions.

Balance of motor network activity between the two brain hemispheres after stroke is crucial for functional recovery. Several studies have extensively studied the role of the affected brain hemisphere to better understand changes in motor network activity following stroke. Very few studies have examined the role of the unaffected brain hemisphere and confirmed the testretest reliability of connectivity measures on unaffected hemisphere. We recorded blood oxygenation level dependent functional magnetic resonance imaging (fMRI) signals from nine stroke survivors with hemiparesis of the left or right hand. Participants performed a motor execution task with affected hand, unaffected hand, and both hands simultaneously. Participants returned for a repeat fMRI scan 1 week later. Using dynamic causal modeling (DCM), we evaluated effective connectivity among three motor areas: the primary motor area (M1), the premotor cortex (PMC) and the supplementary motor area for the affected and unaffected hemispheres separately. Five participants manual motor ability was assessed by Fugl-Meyer Motor Assessment scores and root-mean square error of participants tracking ability during a robot-assisted game. We found (i) that the task performance with the affected hand resulted in strengthening of the connectivity pattern for unaffected hemisphere, (ii) an identical network of the unaffected hemisphere when participants performed the task with their unaffected hand, and (iii) the pattern of directional connectivity observed in the affected hemisphere was identical for tasks using the affected hand only or both hands. Furthermore, paired t-test comparison found no significant differences in connectivity strength for any path when compared with one-week follow-up. Brain-behavior linear correlation analysis showed that the connectivity patterns in the unaffected hemisphere more accurately reflected the behavioral conditions than the connectivity patterns in the affected hemisphere. Above findings enrich our knowledge of unaffected brain hemisphere following stroke, which further strengthens our neurobiological understanding of stroke-affected brain and can help to effectively identify and apply stroke-treatments.