Bipolar affective disorder and schizophrenia are highly heritable psychiatric illnesses and the leading causes of worldwide disability. The orbitofrontal cortex (OFC) is a region of the frontal lobe with wide spread connectivity with other brain areas involved in reward, motivation and emotion. Evidence from various neuroimaging, genetic, post-mortem and brain lesion studies suggest that orbitofrontal cortex may play a role in pathophysiology of mental illnesses. This thesis sought to investigate the pathogenesis of major psychiatric illnesses through the investigation of orbitofrontal morphology in schizophrenia and bipolar disorder and through its associations with brain structure and function. Orbitofrontal morphology and its structural and functional associations were examined in healthy controls, patients with schizophrenia or bipolar affective disorder, and those at high genetic risk using functional and structural MRI. In the first study we found that the orbitofrontal type III is more frequent and the orbitofrontal type I is less common in the right hemisphere in patients with schizophrenia while in patients with bipolar disorder type III appears more often in both left and right hemispheres. We then sought to examine the relationship of orbitofrontal morphology to disease risk in a study of 146 people at high risk of developing schizophrenia and 110 people at high risk of developing bipolar disorder. We discovered that in the unaffected high risk groups the orbitofrontal type III predicted the development of later psychiatric illnesses, when combined with anterior cingulate morphology. Finally we showed, in a further study, that OFC morphology was associated with measures of schizotypy, brain structure, brain function and cognition. In conclusion, orbitofrontal morphology is linked to major psychiatric disorder and has significant structural and functional associations. As orbitofrontal sulcogyral patterns are formed in early life a fuller awareness of their relevance to brain function holds out the prospect that we could use such measures as an indicator of vulnerability to the development of illness later in life. This work points to the potential for the foundation of a theory of predictive associations between morphological patterns and the development of psychosis.

Indiana University-Purdue University Indianapolis (IUPUI) / Social processing is the reception, interpretation, and reciprocation of social information and is critical for mental health. The neural structures, circuits, and substrates regulating these complex mechanisms are not well understood. Social processing in the form of social safety learning, as measured by a rat model of social familiarity-induced anxiolysis (SoFiA), was impaired following mild blast traumatic brain injury (mbTBI). Initial findings indicated that mbTBI altered resting state network activity in the orbitofrontal cortex (OFC) and was associated with accumulation of neurotoxin marker, acrolein, in lateral prefrontal cortex (PFC) (including OFC), indicating OFC as a brain region of interest that may contribute to social processing. Measuring GABA and Glutamate-related gene expression in OFC of mbTBI or sham-exposed rat brain revealed specific elevations of metabotropic glutamate receptor type 1 and 5 (mGluR1/5) expression in mbTBI but not sham OFC. Exposure-naïve rats intracranially injected with mGluR1/5 agonist demonstrated attenuated SoFiA, and this coincided with an impairment of social recognition (SR) behavior. Additionally, inactivation of OFC by local intracranial injection of GABAA agonist, muscimol, impaired two different measures of SR in which two conspecifics, or members of the same species, one novel and one familiar, were presented and required discrimination. Novelty seeking, decision-making, memory, and gregariousness were tested in isolation to determine OFC contributions to these specific behavioral contributions to SR test performance. OFC inactivation did not impair novelty seeking, non-social decision-making, or non-social memory as measured by novel object recognition (NOR) test, or gregariousness or social decision-making as measure by social preference (SP) test. When measuring SR behavior via consecutive presentation of two different conspecifics, OFC inactivation did not impact SR. Therefore, OFC is not directly responsible for social recognition, but rather the discrimination or ability to act upon discrimination of two simultaneously present conspecifics. These data suggest a novel role for OFC in high order processing or execution of action based on social information. / 2 years (2021-05-24)

In recent years Social Neuroscience has started to investigate how mood and culture influence social and emotional situations. In the present study differences in elicited emotion and neural activation were investigated when participants viewed films depicting social interactions. Film clips are preferred stimuli for elicitation of emotion in laboratory studies, but given the lack of standardised film sets in the literature, two behavioural studies were conducted prior to imaging. The first study (147 females, 30 males; 98.8% 18 to 24 years) identified a set of clips that elicited emotion profiles in which the target emotion (happy, sad) was strongest, as well as neutral clips, and demonstrated an effect of participants’ stable mood. The second study (143 females, 19 males; mean age 19.2 years) optimised the stimulus set and demonstrated effects of self-reported ethnic origin, mood and interest on profiles of elicited emotion. In the fMRI investigation 33 female and 8 male participants (mean age 19.2 years) viewed film clips in a block design experiment with loose and tight t-contrasts and retrospective ratings of elicited emotion. Across all-participants, social interaction depicting sadness activated key emotion-related structures such as left amygdala and insula, and medial frontal cortex that were not significantly activated with social interaction depicting happiness. However, greater activation was observed for Europeans than for non-Europeans in orbitofrontal cortex, anterior and posterior cingulate for happy social interaction and in hippocampus, precuneus and retrosplenial cortex for sad social interaction. Individual differences in trait emotions and stable mood were measured with PANAS-X. For high fatigue participants greater activation was observed in the left amgydala for happy social interaction. For participants with high positive stable mood greater activation was observed in the insula for happy and sad social interaction. The research described here indicates that self-reported ethnic origin and mood are potentially significant influences on elicited emotion and brain reactivity to positive and negative social and emotional situations.

The amygdala and hippocampus interact with thalamocortical systems to regulate cognitive-emotional learning, and lesions of amygdala, hippocampus, thalamus, and cortex have different effects depending on the phase of learning when they occur. In examining eyeblink conditioning data, several questions arise: Why is the hippocampus needed for trace conditioning where there is a temporal gap between the conditioned stimulus offset and the onset of the unconditioned stimulus, but not needed for delay conditioning where stimuli temporally overlap and co-terminate? Why do amygdala lesions made before or immediately after training decelerate conditioning while those made later have no impact on conditioned behavior? Why do thalamic lesions degrade trace conditioning more than delay conditioning? Why do hippocampal lesions degrade recent learning but not temporally remote learning? Why do cortical lesions degrade temporally remote learning, and cause amnesia, but not recent or post-lesion learning? How is temporally graded amnesia caused by ablation of medial prefrontal cortex? How are mechanisms of motivated attention and the emergent state of consciousness linked during conditioning? How do neurotrophins, notably Brain Derived Neurotrophic Factor (BDNF), influence memory formation and consolidation? A neural model, called neurotrophic START, or nSTART, proposes answers to these questions. The nSTART model synthesizes and extends key principles, mechanisms, and properties of three previously published brain models of normal behavior. These three models describe aspects of how the brain can learn to categorize objects and events in the world; how the brain can learn the emotional meanings of such events, notably rewarding and punishing events, through cognitive-emotional interactions; and how the brain can learn to adaptively time attention paid to motivationally important events, and when to respond to these events, in a context-appropriate manner. The model clarifies how hippocampal adaptive timing mechanisms and BDNF may bridge the gap between stimuli during trace conditioning and thereby allow thalamocortical and corticocortical learning to take place and be consolidated. The simulated data arise as emergent properties of several brain regions interacting together. The model overcomes problems of alternative memory models, notably models wherein memories that are initially stored in hippocampus move to the neocortex during consolidation.

Early life stress is a prevalent problem affecting many worldwide and can be experienced in a variety of ways, including limited access to resources as in many low socioeconomic status households. In humans, exposure to stress early in life is linked to various psychiatric conditions such as substance use disorder, attention-deficit/hyperactivity disorder, and gambling. One characteristic that these disorders share is elevated impulsivity. Impulsivity is a multifaceted construct and often behaviors are classified as either an impulsive choice (e.g., inability to delay gratification) or an impulsive action (e.g., inability to inhibit premature responses). In the first set of experiments presented here, we characterize the limited bedding and nesting model (LBN) of early life adversity in rodents, in which rat dams and their pups are housed in a limited resource environment from postnatal day (PND) 2 through 9. This model works by inducing stress in the dams, which alters their maternal care behaviors towards pups. As a result, this altered care can be stressful for the developing pups. We have found that LBN exposure promoted resilience to addiction-related phenotypes in adult male, but not female rats. Specifically, LBN reduced impulsive choice, morphine self-administration, and nucleus accumbens (NAc) glutamate transmission in males, effects not seen in females. Additionally, changes in NAc gene transcription unique to LBN males may contribute to resilience. We build on these findings in the second set of experiments, which explores whether LBN alters impulsive action, risky decision-making, and the gene transcriptome of the orbitofrontal cortex (OFC). We found that LBN increased impulsive action in males. Additionally, we found LBN exposure in rats across sex reduces risky choice. These changes in behavior were accompanied by highly specific changes in gene transcription in the OFC, which is a brain region that mediates both impulsive and risky decision-making behaviors. The identification of genes and signaling pathways that are altered by LBN in the male OFC lays the groundwork for future studies investigating the mechanisms by which early life stress alters addiction-related phenotypes. / Psychology

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Previous research has suggested that viewing of another’s averted eye gaze causes automatic orienting of attention and eye movements in observers due to the importance of eye gaze for effective social interaction. Other types of visual cues with no social or biological relevance, such as arrows, are claimed not to produce such a direct effect on orienting behaviour. The finding that processing of eye gaze is reduced in individuals with Autistic Spectrum Disorders as well as following damage to the orbitofrontal cortex of the brain, suggests that gaze processing is indeed critical for effective social behaviour and therefore eye gaze may constitute a “special” directional cue. This thesis tested these ideas by examining the influence of socio-biological (eye gaze and finger pointing) and non-social cues (arrows and words) on eye movement responses in both healthy control participants and those with damage to the frontal lobes of the brain. It further investigated the relationship between orienting to gaze and arrow cues and autistic traits in a healthy population. Important differences between the effects of socio-biological and non-social cues were found on saccadic eye movements. Although in the pro-saccade tasks, arrow cues caused a similar facilitation of responses in the cued direction as eye gaze and pointing cues, in the anti-saccade tasks (in which participants have to respond away from the location of a peripheral onset), arrows had a greatly reduced effect on oculomotor programming relative to the biologically relevant cues. Importantly, although the socio-biological cues continued to influence saccadic responses, the facilitation was in the opposite direction to the cues. This finding suggests that the cues were being processed within the same "anti-response" task set (i.e. "go opposite") as the target stimulus. Word cues had almost no effects on saccadic orienting in either pro- or anti-saccade tasks. Schematicised eye gaze cues had a smaller magnitude effect than photographic gaze cues suggesting that ecological validity ("biological-ness") is an important factor in influencing oculomotor responses to social cues. No relationship was found between autistic traits and orienting to gaze or arrow cues in a large sample of males. However, findings from the neurological patients point to a possible double-dissociation between the neural mechanisms subserving processing of socio-biological and non-social cues, with the former reliant on the orbitofrontal cortex, and the latter on lateral frontal cortex. Taken together, these results suggest that biologically relevant cues have privileged access to the oculomotor system. The findings are interpreted in terms of a neurocognitive model of saccadic orienting to socio-biological and non-social cues, and an extension to an existing model of saccade generation is proposed. Finally, limitations of the research, its wider impact and directions for future work are discussed.

Previous research indicates that many important changes in executive functions, or higher cognitive capacities, occur between the ages of three and five years. Additionally, a distinction can be made between the cognitive functions associated with two different cortical regions. The functions of the dorsolateral prefrontal cortex (DL-PFC) are assessed using 'cool' tasks that are abstract and decontextualised. In contrast, the functions of the orbitofrontal cortex (OFC) are assessed using 'hot' tasks that require flexible appraisal of the affective significance of stimuli (Zelazo & Müller, 2002). Different clinical populations have been hypothesized to differ in terms of their impairment on tasks associated with each area of functioning. Current research conclusions regarding the primacy of hot versus cool executive function impairments are limited, however, as they have not taken complexity into account. That is, tasks currently used in investigations of hot and cool executive functions might differ in terms of the complexity of the cognitive processes that the tasks require. Therefore, comparisons across tasks may be misleading because these tasks vary in terms of the demands they place on participants as well as their hot versus cool status. While complexity theories have been applied to a number of cool tasks, only one hot task, those measuring theory-of-mind abilities, have been analysed in terms of complexity. One aim of the current research was to modify several tasks presumed to measure OFC performance to include a complexity manipulation. Tasks from three hot domains (conditional discrimination, the Children's Gambling Task, and future-oriented decision-making) were analysed in terms of their relational complexity, that is, the number of related entities or arguments inherent in a task or concept (Halford, 1993). Based on these complexity analyses, binary-relational and ternary-relational items of each of these tasks were developed or existing tasks were selected and/or modified. The binary-relational items were closely matched to the ternary-relational items in terms of stimuli and procedure, however, they were lower in complexity. After pilot testing, the three new measures of hot executive functioning were included in a larger test battery that was administered to a sample of 120 normally developing 3-, 4-, 5- and 6-year-old children. Existing binary- and ternary-relational items assessing theory-of-mind (a hot task) and three cool measures (transitivity, class inclusion and the Dimensional Change Card Sort test) were also included. The inclusion of measures of both hot and cool executive functions, each with complexity manipulated, allowed for the examination of a possible differential age of emergence of executive abilities associated with the DL-PFC versus the OFC. In support of the relational complexity approach, significant complexity effects were found across all seven tasks. Items at a higher level of complexity were experienced as relatively more difficult by children of all ages. Significant effects of age were also observed, with performance across all tasks increasing with age. The age effects were strongest on the ternary-relational items. The pass-fail data indicated that the majority of children in all age groups succeeded on the binary-relational items. However, it was not until a median of five years of age that children were able to process ternary relations. Consequently, the ternary-relational items produce the greatest differences in performance between the four age groups. The overall pattern of the results also suggested that a distinction can be made between the ages of emergence of abilities associated with the OFC versus the DL-PFC. The results of the pass-fail percentages, patterns of age-related change and age effects on domain factor scores all suggested that while hot executive functions may begin to develop around four years of age, similar levels of improvement are not seen in cool executive functions until five years of age. Thus, the ability to succeed on ternary-relational items of hot executive function tasks appeared to emerge slightly earlier than the cool executive function tasks. Complexity appears to be a critical factor underlying children's performance on executive function tasks, and future assessment regarding the development of executive abilities will benefit from keeping this in mind. While some refinement of new task items may be beneficial, the current test battery may have utility in further examinations of the executive profiles underlying clinical groups, such as children with autism and ADHD.

Drug addiction is a complex behavioral disorder that has been extensively studied in an attempt to uncover its underlying biological mechanisms. This paper contributes to the literature on addiction by demonstrating that addiction is a result of an improperly functioning decision making process. The areas of the brain that are most implicated in decision making demonstrate significant overlap with those areas most affected by addiction. Specifically, the limbic structures of the brain (amygdala, basal ganglia, and mesolimbic reward pathway) and the prefrontal cortices (orbitofrontal cortex, dorsolateral prefrontal cortex, and ventromedial prefrontal cortex) are discussed in relation to their involvement in prominent theories of decision making such as Prospect Theory and the Somatic Marker Hypothesis. This paper will then use the above knowledge regarding the specific brain mechanisms that control decision making and apply it to neurobiological theories of addiction. The view that addiction is a behavioral disorder that results primarily from a degradation of the brain mechanisms involved in decision making processes is important to consider because it can help provide a concrete approach to developing more individualized and effective treatment programs in the future.

Decades of research have demonstrated that people sometimes provide self-evaluations that emphasize their most flattering qualities. Different theoretical accounts have been offered to explain the mechanisms underlying positively-biased self-evaluation. Some researchers theorize that positively-biased self-evaluations arise from a self-protection motivation because positivity biases increase in situations of heightened self-esteem threat. Alternative views question whether self-protection motivation is a necessary or even dominant source of positivity bias by demonstrating that positively-biased self-evaluations occur even when threat is not heightened, and that a general judgment approach leads to positivity biases in some domains but also to negativity biases in other domains. One reason for this gap in knowledge is that behavioral measures are limited in their ability to resolve whether the processes underlying positively-biased self-evaluation are the same or different depending on contextual motivators. Neuroimaging methods are well suited to examine whether different mechanisms underlie similar behaviors, specifically similar positively-biased responses in different contexts. The four studies presented here explore the neural mechanisms of positively-biased self-evaluation by first identifying a core set of neural regions associated with positivity bias (Study 1A and 1sB), examining whether a heightened self-protection motivation changes the engagement of those neural systems (Study 2), and specifying the precise mechanisms supported by those regions (Study 3). Studies 1A and 1B revealed evidence for a neural system comprised of medial and lateral orbitofrontal cortex (OFC) and, to a lesser extent dorsal anterior cingulate (dACC) that was modulated by positivity bias. Study 2 found that a heightened self-protection motivation changes the engagement of medial OFC in positively-biased self-evaluation. Finally, Study 3 found evidence that medial OFC may support a common mechanism in positively-biased judgment that is implemented differently as a function of the motivational context. Taken together, these studies represent a first step toward developing a neural model of positively-biased self-evaluation. The findings provide some preliminary evidence that positivity biases may represent distinct processes in different motivational contexts. This dissertation sets the stage for future work to examine how specific positively-biased cognitive mechanisms may be supported by specific neural systems and computations as a function of motivational contexts. / text