Neuroimaging techniques are likely to continue to improve our understanding of the brain in health and disease, but studies tend to be small, based in one imaging centre and of uncertain generalisability. Multicentre imaging studies therefore have great appeal but it is not yet clear under which circumstances data from different scanners can be combined. The successful harmonisation of multiple Magnetic Resonance Imaging (MRI) machines will increase study power, flexibility and generalisability. I have conducted a detailed study of the performance of three research MRI scanners in Scotland under the name CaliBrain, with the aims of developing reliable, valid image acquisition and analysis techniques that will facilitate multicentre MRI studies in Scotland and beyond. Fourteen healthy volunteers had two brain scans on each of three 1.5T MRI research machines in Aberdeen, Edinburgh and Glasgow. The scans usually took place 2-3 weeks apart. Each scan was performed using an identical scanning protocol consisting of a detailed structural MRI (sMRI) and a range of functional MRI (fMRI) paradigms. The quality assurance (QA) of scanner performance was monitored in all three sites over the duration of the study using a three-part protocol comprising a baseline assessment, regular measures and session specific measures. The analyses have demonstrated that the data are comparable but also that within- and between-scanner variances are evident and that harmonisation work could enhance the level of agreement. The QA data suggest that scanner performance was similar between and within machines over the course of the study. For the structural MRI scans an optimised methodology was utilised to minimise variation in brain geometry between scanners and fit all the scanned brains into a common stereotactic space, such that repeated measures analyses yielded no significant differences over time for any of the three scanners. I examined the reproducibility of the fMRI motor task within and between the three sites. Similar results were obtained in all analyses; areas consistently activated by the task include the premotor, primary motor and supplementary motor areas, the striatum and the cerebellum. Reproducibility of statistical parametric maps was evaluated within and between sites comparing the activation extent and spatial agreement of maps at both the subject and the group level. The results were within the range reported by studies examining the reproducibility of similar tasks on one scanner and reproducibility was found to be comparable within and between sites, with between site comparisons often exceeding the within site measures. A components of variance analysis showed a relatively small contribution of the factor site with subject being the main source of variation. Similar results were obtained for the working memory task. The analysis of the emotional face processing task showed poor reproducibility both within and between sites. These findings suggest that multicentre structural and functional MRI studies are feasible, at least on similar machines, when a consistent protocol is followed in all participating scanning sites, a suitable fMRI task is employed and appropriate analysis methods are used.

Introduction Social and emotional functions play a key role in schizophrenia. Both positive symptoms, such as hallucinations and persecutory delusions, as well as negative symptoms such as social withdrawal, and flattened affect impact socioemotional function. These functions involve distributed brain networks. The ‘Disconnection Hypothesis’, a plausible unifying theory of schizophrenia, proposes connectivity within such networks as a core pathological feature of schizophrenia. Connectivity is also related to specific genetic risk factors. Therefore the present project addresses the hypothesis that individuals with schizophrenia might show disconnection within socio-emotional brain networks, and examines the effects of a functional polymorphism of the BDNF gene on connectivity within these networks. Methods Here I examined the brain activation and connectivity for implicit emotional reaction and social judgment in schizophrenia, as well as with variation in the val66met polymorphism of BDNF. Brain activation was examined with functional magnetic resonance imaging, and effective connectivity was estimated using psycho-physiological interactions, from the bilateral amygdala to the whole brain (using a facial image paradigm for explicit approachability judgement and implicit fear response respectively). Results Individuals with schizophrenia showed reduced activation in the right lingual gyrus, right superior temporal gyrus and left amygdala during fear processing, as well as reduced connectivity from the left amygdala to the right temporo-parietal junction and precuneus. During approachability judgments, patients overactivated the right inferior frontal gyrus and right precuneus and showed reduced connectivity from the bilateral amygdala to the right inferior frontal gyrus. Met allele carriers of the BDNF val66met polymorphism showed overactivation in the medial anterior cingulate cortex, and bilateral insula, as well as reduced connectivity between the anterior cingulate cortex and hippocampus. For approachability judgment, met carriers overactivated the middle occipital gyrus, and showed reduced connectivity from the left amygdala to the right parahippocampal gyrus and medial frontal gyrus, as well as the left posterior cingulate gyrus, pre and post central gyrus, middle temporal gyrus and cerebellum. Conclusion In conclusion, connectivity between the amygdala and brain regions associated with a range of socially relevant functions were found to be reduced in both patients, and met allele carriers of the BDNF val66met SNP. Given the key role of the amygdala in affective processing this diffuse disconnection in networks for socio-emotional functions might mediate the aberrant emotional and social behavior seen in individuals with schizophrenia.

<p>Moral cognition represents a foundational faculty of the human species. Our sense of morality develops beginning at a very young age, and its dysfunction can lead to devastating mental disorders. Given its central importance, it has fittingly garnered the attention of thinkers throughout the ages. For millennia, philosophers have pondered what it is to be right or wrong, good or bad, virtuous or vicious. For centuries, psychologists have elucidated how people acquire and act upon a sense of morality. More recently in the last decade, neuroscientists have embarked on a project to study how morality arises from computations in the brain. However, this latest project has been fragmented: researchers have largely studied various neural components of morality - including emotion, value, and mentalizing - in isolation. This has resulted in an informal and disjointed model for the neural mechanisms of morality. This dissertation is concerned with more formally identifying neural components and their influences on each other in the context of moral cognition.</p><p>In Chapter 2, I study how the component neural networks of moral cognition may be involved in distinct aspects of a single decision by employing a complex clinical decision making task involving the disclosure of conflicts of interest. I show that for a given decision, the magnitude of conflict of interest is tracked by mentalizing networks, while the degree of disclosure-induced behavioral change exhibited by participants is predicted by value networks. In Chapter 3, I move beyond the informal model of morality used in Chapter 2 and previous literature by devising a methodology to identify hierarchical ontologies of neural circuits; such an approach can have implications on further discussions of morality, and more generally, on other aspects of cognitive neuroscience. From this, I present the 50 elemental neural circuits that are fundamental to human cognition and explore how these elements can differentially combine to form emergent neural circuits. In Chapter 4, I use these advances to address morality, uncovering its relevant component neural networks in a data-driven way. I show that neural circuits important in supporting higher-level moral computations include mentalizing and taste. In Chapter 5, I demonstrate an important complexity in a compositional model of morality. I show that one of the components of moral cognition, mentalizing, can paradoxically be influenced by moral judgments themselves. To conclude, I highlight the implications of both theoretical and methodological advances. The hierarchical ontologies of neural circuits may be a profitable framework for the future characterization and study of mental disorders; and to effectively study these circuits, the use of moral judgment and decision-making paradigms will be effective experimental tasks, considering the centrality of moral cognition to who we are, whether in health or illness.</p> / Dissertation

In the present set of experiments, we investigated the effects of age and COMT genotypes on traditional measures of executive functions, e.g., Wisconsin Card Sorting Test (WCST; Hart et al., 1988), a battery of executive functions based on the 3 factor model (shifting, updating, inhibition) described by Miyake et al. (2000) and developed at the University of Arizona (Alexander et al., 2012), and two fMRI tasks of executive functions (shifting, updating). The results of experiment 1 showed that COMT influenced performance on several traditional measures of executive functions, with Met homozygotes outperforming Val homozygotes. However, on the WCST we did not observe less perseverative errors in Met carriers as reported previously (Barnett, Jones, Robbins, & Muller, 2007; Bruder et al., 2005; Malhotra et al., 2002; Nagel et al., 2008). According to Miyake et al. (2000), however, such tasks as the WCST may actually involve multiple executive processes, making it difficult to tease apart the different types of executive functions being measured. Furthermore, COMT may be sensitive to some aspects of executive functions and not others. To this end, in experiment 2 we investigated associations between COMT and measures of executive functions from each of the 3 domains described in Miyake et al. (2000). According to the models proposed by Bilder et al. (2004) and Cools and D’Esposito (2011), the Val allele promotes cognitive flexibility, while the Met allele promotes cognitive stability. Contrary to what we expected, Met homozygotes actually performed better than Met/Val heterozygotes but no better than Val homozygotes on one measure of updating (flexibility). Upon closer examination of the processes involved in the updating task, however, the results may not necessarily be contradictory as the task may have required greater stability than previously thought. In the fMRI experiment, although behavioral performance was largely similar between age groups and COMT genotypes on the fMRI tasks, we observed differences in activation such that younger adults and Met homozygotes showed higher levels of activation relative to older adults and Val carriers, respectively. Our results suggest that these higher levels of activation may have been relied upon to maintain similar levels of performance. Additionally, across the 3 experiments the effects of COMT indicate that an overall Met advantage cannot be assumed. Rather, the benefits of one allele compared to the other should be investigated in terms of the specific cognitive processes involved in the task at hand. Thus, it is important for future studies to continue characterizing the unity and diversity of executive functions and investigate factors that may influence these patterns behaviorally and neurally, such as age and genetics.

Thesis advisor: Elizabeth A. Kensinger / Research in three parts investigated sleep’s preferential consolidation of memories for experiences that are prioritized at encoding due to intrinsic characteristics (e.g., emotion), extrinsic characteristics (e.g., instructed learning, reward), or both. Results showed that sleep broadly strengthens memory for future-relevant information, with these prioritization cues at encoding aiding in the selection process for what is subsequently strengthened during sleep. Part I investigated the effects of sleep on the consolidation of information that was prioritized at encoding due to the intrinsic cue of emotion. Results showed that even once the emotionally salient aspect of the stimuli was removed (i.e., when memory was tested using a neutral cue), residual effects of emotion were reflected in enhanced visual activity following sleep, with this visual activity correlating with the percentage of rapid eye movement sleep obtained during consolidation and likely driven by enhanced occipital-hippocampal connectivity following sleep. This suggests that sleep prioritizes information that was salient due to the intrinsic cue of emotion at encoding, leading to changes in neural activity during retrieval even once that intrinsic cue is no longer present. As in Part I, most prior research has examined how sleep preferentially consolidates memory for information that is salient due to a single cue for future relevance. Part II investigated whether future relevance can be assigned to stimuli via top-down manipulations (i.e., extrinsic prioritization cues), as well as how sleep prioritizes memory for information when intrinsic and extrinsic cues for future relevance co-occur within the same stimuli. Results suggest that when multiple dimensions of future relevance co-occur, sleep prioritizes extrinsic cues (i.e., instructed learning, and to a lesser degree, reward) over intrinsic cues (i.e., emotion). Further, results suggest that additional cues for future relevance do not have additive effects on consolidation, but rather that sleep may binarize information based on whether it is future-relevant or not, preferentially consolidating memory for the former category. Lastly, Part III focused on a manipulation of extrinsic prioritization at encoding to investigate both how the effects of prioritization on memory differ minutes after encoding relative to after long-term consolidation processes take place, and also whether these effects depend on if a healthy versus restricted amount of nocturnal sleep is obtained during the consolidation interval. Results showed that a top-down manipulation of prioritization (i.e., typographical cueing) was effective in enhancing memory; highlighted relative to non-highlighted content was better remembered at multiple time points, with evidence suggesting that N3 (slow-wave) sleep may contribute to these memorial benefits. Together, findings across Parts I-III suggest that sleep selectively strengthens future-relevant information, elucidating which cues for future relevance at the time of encoding lead to enhanced consolidation following sleep, as well as how sleep acts on intrinsic and extrinsic prioritization cues when they co-occur. In identifying intrinsic targets of sleep’s selective consolidation effects, as well as extrinsic manipulations that can be applied to use sleep as a tool to enhance consolidation, these three studies have important implications for optimizing memory that are relevant across domains. / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology.

Various topics on functional magnetic resonance imaging (fMRI) analyses have been in study through the last 30 years. This work delineates the pathways required for resting-state functional connectivity analyses, which illuminates the correlations between different rat brain regions and can be presented in a functional connectivity matrix. The matrix is built based on the category nomenclature system of Swanson Rat Atlas 1998. From which a structural connectivity matrix is also built. This work developed the complete functional connectivity counterpart to the physical connections and explored the relationships between the functional and structural connectivity matrices. The functional connectivity matrices developed in this work map the entire rat brain. The results demonstrate that where structural connectivities exist, functional connectivities exist as well. The methodologies used to create the functional and structural analyses were completely independent.

A key feature of many psychiatric disorders, including schizophrenia and bipolar disorder, are pervasive deficits in several domains of cognition. Episodic memory is one of the most consistently observed cognitive deficits exhibited by patients with schizophrenia, and can be a predictor of overall functional outcome. Several neuroimaging studies have assessed episodic memory in psychosis, however the neural mechanisms underlying this deficit remain somewhat unclear. Studying the impact of rare genetic variants of large effect can offer a powerful method to further our understanding of the pathophysiology of psychiatric disorders. One such gene, DISC1 (Disrupted in Schizophrenia 1) is a putative susceptibility gene for a spectrum of major psychiatric disorders such as schizophrenia, bipolar disorder and major depression. DISC1 was originally identified in a large Scottish pedigree, in which it is disrupted by a balanced translocation between chromosomes 1 and 11, and this translocation confers a dramatically increased risk of major psychiatric disorder. However, the impact of this translocation on brain imaging measures is largely unknown. The rarity of this variation results in small group numbers for analysis, however rare variants are likely to have large neural effects. This thesis offers a unique investigation into the effects of the t(1;11) translocation, by examining fMRI of members of the original Scottish pedigree. Four groups of participants; 19 family members (8 with the translocation, 11 without), 30 patients with schizophrenia, 11 patients with bipolar disorder and 40 healthy controls underwent a functional MRI episodic memory encoding and recognition paradigm. Data processing and statistical analyses were performed using the standard approach in SPM8. The primary aim of this work was to investigate functional activation during episodic memory in individuals with and without the translocation, to examine the impact of the t(1;11) translocation. Analyses were also performed to examine differences between controls and patients with schizophrenia and bipolar disorder, to compare the effects of the translocation to the effects of a having a psychotic illness. During encoding of neutral scenes, translocation carriers showed greater activation of the left posterior cingulate, right fusiform gyrus and right superior frontal gyrus compared to non-carriers. During recognition, carriers showed greater activation in the right fusiform gyrus, left posterior cerebellum, right superior temporal gyrus, left anterior cingulate, right ventrolateral prefrontal cortex (VLPFC) and right dorsolateral prefrontal cortex (DLPFC). For both contrasts, no regions were found to be more active in family members without the translocation when compared to carriers. There were no significant differences between the groups in terms of their performance or reaction time on encoding and recognition conditions. Compared to healthy controls, patients with schizophrenia demonstrated increased activation during encoding in the inferior parietal lobe bilaterally, and decreased activation during recognition in a region encompassing the caudate nucleus and anterior cingulate cortex. Patients with bipolar disorder showed no difference in activation compared to controls during encoding, and increased activation during recognition in a region encompassing the caudate and anterior cingulate, extending to the inferior frontal lobe and insula. There was also a significant difference between patients with schizophrenia and bipolar disorder during recognition, with patients with bipolar disorder again showing increased activation in the caudate extending to the anterior cingulate cortex. These findings support previous research suggesting overactivation of fronto-limbic and striatal structures including the anterior cingulate and caudate in bipolar disorder, with a relative underactivation in schizophrenia. This thesis presents the first evidence of functional alterations during episodic memory in association with the translocation, primarily in fronto-temporal regions. Brain regions that were over activated in translocation carriers have been shown to be involved in memory encoding and recognition, and are known to be affected in patients with major psychiatric disorders and unaffected relatives. Family members with the translocation demonstrated a more similar pattern of activation during recognition to patients with bipolar disorder compared to schizophrenia, perhaps due to the fact that most diagnoses in the carriers were of an affective disorder rather than a schizophrenia-related psychosis. Based on these findings it can be argued that the translocation has an influence on brain activations in areas associated with episodic memory processes. These findings begin to provide a better understanding of the neural effects of the t(1;11) translocation, and highlight the significance of rare but biologically informative genetic variants in understanding psychosis.

Driving is a cognitively complex task, yet the areas of the brain involved in driving are not well understood. This thesis investigates the neural correlates of driving using functional magnetic resonance imaging and driving simulations with custom built driving hardware (steering wheel and foot pedals). The feasibility of driving in fMRI is first investigated, and a methodology is described to minimize head motions. Next, the functional neuroanatomical correlates of driving tasks of varying complexity are explored. Simple tasks such as straight driving activate areas of the brain related to motion, spatial navigation and coordination. Complex tasks are found to recruit additional areas of the brain, including areas of higher cognitive function such as the prefrontal cortex. Developing a better understanding of the areas involved in different driving tasks is an important first step in understanding the neural basis of driving skill and safe driving.

Driving is a cognitively complex task, yet the areas of the brain involved in driving are not well understood. This thesis investigates the neural correlates of driving using functional magnetic resonance imaging and driving simulations with custom built driving hardware (steering wheel and foot pedals). The feasibility of driving in fMRI is first investigated, and a methodology is described to minimize head motions. Next, the functional neuroanatomical correlates of driving tasks of varying complexity are explored. Simple tasks such as straight driving activate areas of the brain related to motion, spatial navigation and coordination. Complex tasks are found to recruit additional areas of the brain, including areas of higher cognitive function such as the prefrontal cortex. Developing a better understanding of the areas involved in different driving tasks is an important first step in understanding the neural basis of driving skill and safe driving.

Priming refers to a change in the ability to identify, produce, or classify a stimulus as a result of a previous encounter with the same or a related stimulus. Recent neuroimaging studies often found behavioral priming to co-occur with a reduction in neural activations in various cortical regions, which is called repetition suppression. It is thought that repetition suppression is closely related to behavioral priming, and may even be the underlying neural mechanism that supports priming. However, current literature still has several unsolved questions about the relationship between repetition suppression and priming. The present dissertation set out to further elucidate their relationship. In Study 1, a mirror-word identification task was used to limit overlap between study and test to a primarily perceptual level with little or no conceptual overlap nor top-down modulation. Repetition suppression was found in visual perceptual and frontal phonological regions involved at both study and test, supporting a "component process" view that repetition suppression and priming can occur at a perceptual level with limited conceptual or top-down processes involved. In Study 2, three perceptual priming tasks and one conceptual priming task were used to directly examine component process view's prediction that perceptual priming would be correlated with posterior repetition suppression and conceptual priming would be correlated with frontal repetition suppression. The results showed that both perceptual and conceptual priming involved repetition suppression in both frontal and posterior perceptual regions, at least when measured with our paradigm and tasks, and both frontal and posterior repetition suppression effects were correlated with behavioral priming in all four perceptual and conceptual priming tasks. This finding suggests that both frontal and posterior perceptual regions are involved in perceptual and conceptual priming, and that they are most likely working in concert with one another during priming, as exemplified by an interactive view of priming. Taken together, our data suggest that priming may be supported by several different underlying mechanisms, such as bottom-up processes (component process view of priming), top-down modulation and frontal-posterior interaction/synchrony.