Neuropsychology of reinforcement processes in the rat

This thesis investigated the role played by regions of the prefrontal cortex and ventral striatum in the control of rats’ behaviour by Pavlovian conditioned stimuli, and in their capacity to choose delayed reinforcement. First, the function of the anterior cingulate cortex (ACC) in simple Pavlovian conditioning tasks was addressed. The ACC is a subdivision of prefrontal cortex that has previously been suggested to be critical for the formation of stimulus–reward associations. It was found that lesions of the ACC did not prevent rats from learning a simple conditioned approach response to a conditioned stimulus (CS) predictive of food reward, or from utilizing that CS as a conditioned reinforcer subsequently. Additionally, these subjects successfully acquired a conditioned freezing response to a CS predicting footshock. However, the same animals were impaired at the acquisition of autoshaped behaviour, an impairment that has been demonstrated previously. An autoshaping deficit was also observed when lesions were made following training. The phenomenon of Pavlovian–instrumental transfer was intact in these subjects. The hypothesis was developed that the ACC is not critical for the formation of stimulus–reward associations per se, but is critical when multiple stimuli must be discriminated on the basis of their differential association with reward. In support of this hypothesis, animals with lesions of the ACC were impaired on a version of the conditioned approach task in which a second, neutral stimulus, perceptually similar to the CS, was added; the lesioned subjects exhibited reduced discrimination. Second, the role of the nucleus accumbens (Acb) in Pavlovian–instrumental transfer was investigated. The nucleus accumbens core, together with a larger amygdalar–striatal network of which it is a component, has previously been shown to be necessary for the expression of ‘simple’ Pavlovian–instrumental transfer. Rats with lesions of the nucleus accumbens core (AcbC) and shell (AcbSh) were tested on a ‘response-specific’ Pavlovian–instrumental transfer task, in which a Pavlovian CS selectively enhances instrumental responding for the outcome with which the CS was originally paired. AcbC lesions impaired the response specificity of this effect, while AcbSh lesions abolished Pavlovian–instrumental transfer entirely. These results are consistent with some — but not all — previous results in suggesting that the shell provides ‘vigour’ and the core provides ‘direction’ for the potentiation of behaviour by Pavlovian CSs. Third, an attempt was made to train rats on a task for assessing preference for delayed reinforcement, using the ‘adjusting-delay’ paradigm. It was not immediately apparent that the rats reacted to the contingencies operative in this task, and mathematical analysis of their behaviour was conducted to establish whether their behaviour was sensitive to the delay, and what ‘molar’ features of performance on this task could be explained by delay-independent processes. Fourth, a different delayed reinforcement choice task was developed, modifying a previously published task in which the subject is repeatedly offered a choice, in discrete trials, of a small reward delivered immediately, and a large reward delivered after a delay, with the delays systematically varied by the experimenter. Rats were trained on versions of this task in which the large, delayed reinforcer was or was not explicitly signalled by a cue present during the delay. The behavioural basis of performance on this task was examined, and d-amphetamine, chlordiazepoxide, and alpha-flupenthixol were administered systemically. It was found that the effects of d-amphetamine depended on whether the delayed reinforcer was signalled or unsignalled, increasing preference for signalled delayed reinforcement at some doses, but decreasing preference for unsignalled delayed reinforcement. These results may resolve contradictions in the literature, and are suggested to reflect the known effect of amphetamine to potentiate responding for conditioned reinforcers. Fifth, rats that had been trained on this task (with no explicit signals present during the delay) were given lesions of the ACC, AcbC, or medial prefrontal cortex (mPFC). ACC-lesioned rats were no different from sham-operated controls in their ability to choose a large, delayed reinforcer. Lesions of mPFC reduced the tendency of subjects to shift from one lever to the other during the course of a session, but mPFC-lesioned subjects responded normally to removal of the delays, suggesting a loss of stimulus control. However, rats with lesions of the AcbC were severely impaired on this task, preferring the small, immediate reward, even though they discriminated the reinforcers. Additionally, the effects of intra-Acb amphetamine were assessed using a different version of the delayed reinforcement choice task, and found to have slight but inconsistent effects to reduce preference for the delayed reinforcer, though this effect did not depend on whether the delayed reward was signalled or unsignalled. These results suggest that the AcbC contributes significantly to the rat’s ability to choose a delayed reward, a finding that has important implications for the understanding of Acb function. It is suggested that dysfunction of the AcbC may be a key element in the pathology of impulsivity.Supported by a UK Medical Research Council (MRC) research studentship, 1997–2000, and a James Baird award, University of Cambridge School of Clinical Medicine, 1997–2000

Neural basis of genetic vulnerability to bipolar disorder

Abnormalities of reward processing, decision-making and emotion processing are core features of bipolar I disorder (BD). These processes are closely linked with fronto-striatal and midbrain circuitry. I sought to test whether dysfunctions of these pathways were present in BD and whether they related to genetic vulnerability to illness or resilience. I recruited twenty-five BD I patients each with their unaffected sibling, and compared them to 24 healthy age- and gender-matched controls. In chapter 1, I provide a research background and literature review. Chapter 2 describes the neuropsychological assessments which demonstrated trait-related deficits in working memory with slower processing speed representing an endophenotype. Chapter 3 describes the implicit/ explicit facial emotion processing task performed during event-related functional MRI (erfMRI). Pairwise comparisons demonstrated implicit processing was associated with increases in lingual gyrus and insula activations and explicit processing elicited reduced fusiform activations in patients compared with controls. Increased posterior cingulate activations and reductions in putamen and cerebellar activity were found in siblings compared to controls, and reductions in parietal activations were noted in siblings compared to their ill relatives. These findings suggest over-activations in regions involved in facial expression recognition and attentional shifting (lingual and insula respectively) and deactivations in a region important for the perception and recognition of faces (fusiform) represent correlates of disease expression. Additionally regional deactivations associated with category learning and attentional processing (parietal, putamen and cerebellar) and increased activations in a region involved in emotional salience (posterior cingulate) may represent adaptive responses associated with resilience. Chapter 4 describes an instrumental reward-learning task performed during erfMRI. Data were analysed at whole brain level and using a priori region of interest analyses in ventral striatum/midbrain and prefrontal cortex (PFC). Results included increased ventral striatum activation in association with the difference between observed and expected rewarding outcomes (the prediction error (PE)) in patients compared to controls. Decreased prefrontal activations were seen in the patient and sibling groups compared to controls in association with the learning of the value of the conditioned stimulus. These findings suggest that i) PE associated circuitry (striatal) overactivation, and ii) prefrontal deactivations underlie the genetic vulnerability to BD

The Multi-Dimensional Contributions of Prefrontal Circuits to Emotion Regulation during Adulthood and Critical Stages of Development

The prefrontal cortex (PFC) plays a pivotal role in regulating our emotions. The importance of ventromedial regions in emotion regulation, including the ventral sector of the medial PFC, the medial sector of the orbital cortex and subgenual cingulate cortex, have been recognized for a long time. However, it is increasingly apparent that lateral and dorsal regions of the PFC, as well as neighbouring dorsal anterior cingulate cortex, also play a role. Defining the underlying psychological mechanisms by which these functionally distinct regions modulate emotions and the nature and extent of their interactions is a critical step towards better stratification of the symptoms of mood and anxiety disorders. It is also important to extend our understanding of these prefrontal circuits in development. Specifically, it is important to determine whether they exhibit differential sensitivity to perturbations by known risk factors such as stress and inflammation at distinct developmental epochs. This Special Issue brings together the most recent research in humans and other animals that addresses these important issues, and in doing so, highlights the value of the translational approach

Neural Signals of Video Advertisement Liking:Insights into Psychological Processes and their Temporal Dynamics

What drives the liking of video advertisements? The authors analyzed neural signals during ad exposure from three functional magnetic resonance imaging (fMRI) data sets (113 participants from two countries watching 85 video ads) with automated meta-analytic decoding (Neurosynth). These brain-based measures of psychological processes—including perception and language (information processing), executive function and memory (cognitive functions), and social cognition and emotion (social-affective response)—predicted subsequent self-report ad liking, with emotion and memory being the earliest predictorsafter the first three seconds. Over the span of ad exposure, while the predictiveness of emotion peaked early and fell, that of social cognition had a peak-and-stable pattern, followed by a late peak of predictiveness in perception and executive function.At the aggregate level, neural signals—especially those associated with social-affective response—improved the prediction of out-of-sample ad liking compared with traditional anatomically based neuroimaging analysis and self-report liking. Finally, earlyonset social-affective response predicted population ad liking in a behavioral replication. Overall, this study helps delineate the psychological mechanisms underlying ad processing and ad liking and proposes a novel neuroscience-based approach for generating psychological insights and improving out-of-sample predictions

The Role of Amygdala Subregions in the Neurobiology of Social Anxiety Disorder

Social anxiety is characterised by fear and/or avoidance of social situations in which an individual may be scrutinised by others. Social anxiety is thought to exist as a spectrum, with individuals on the high-end experiencing frequent and severe anxiety in the context of social situations. When severe social anxiety is accompanied by distress and functional impairment, a diagnosis of social anxiety disorder (SAD) can be made. SAD is a prevalent and debilitating disorder that can be unremitting and pervasive in the absence of intervention. Current psychotherapeutic and pharmacotherapeutic treatments for SAD demonstrate limited efficacy in remitting symptoms. Therefore, it is important to achieve a better understanding of the neurobiological mechanisms implicated in this disorder and identify potential neural treatment targets to develop more efficacious treatments. This thesis aimed to further investigate the neurobiological mechanisms implicated in SAD (vs. controls) and the associations between neural functioning and social anxiety as a dimensional symptom, with a focus on the amygdala and four of its subregions (the amygdalostriatal, basolateral, centromedial, and superficial subregions). This was due to previous findings in the neuroimaging literature in SAD having consistently implicated the amygdala, albeit with mixed findings of both increased and decreased functioning in those with SAD compared to controls. In the literature to date, however, most studies had examined the amygdala as a singular homogenous region due to methodological limitations in being able to examine the functionally and structurally distinct subnuclei that make up this region. By examining the amygdala subregions through the use of multiband functional magnetic resonance imaging (fMRI), this thesis additionally sought to determine whether the mixed findings in the literature to date may be a result of amygdala subregion-specific activity and connectivity patterns. This was achieved through three research studies. Firstly, Study 1 involved a comprehensive systematic review that summarised the literature on resting-state neuroimaging in SAD with a focus on fMRI studies and findings specific to the amygdala and its subregions (Chapter 3). This was followed by two empirical studies which investigated the role of the amygdala and its subregions during resting-state (Study 2) and emotion processing (Study 3) fMRI paradigms (Chapters 5 and 6, respectively). Findings from the systematic review (Study 1) highlighted the mixed findings in the resting-state neuroimaging literature in SAD to date, along with methodological limitations relating to neuroimaging acquisition and analysis. The empirical studies sought to address these limitations and demonstrated differing amygdala subregion activity and connectivity patterns at rest and during emotion processing. In the resting-state fMRI study (Study 2), there were no statistically significant differences in functional connectivity of the amygdala and its subregions in those with SAD compared to controls. However, social anxiety severity was found to be positively associated with connectivity between the superficial subregion and the supramarginal gyrus. The superficial subregion, along with the basolateral and centromedial subregions, were also implicated in the task-based emotion processing fMRI study (Study 3). In response to happy, angry, and fearful faces, those with SAD (vs. controls) had hyperactivation of the superficial subregion, hypoconnectivity between the superficial subregion and the precuneus, and hyperconnectivity between the basolateral subregion and broader brain regions (i.e., the pre/postcentral gyrus and the supramarginal gyrus). Additionally, social anxiety severity was positively associated with superficial and centromedial activation. Overall, the findings from this thesis provide novel information to the current understanding of the neurobiology of SAD by demonstrating amygdala subregion-specific alterations. This has important implications for research, theory, and clinical practice that are detailed in the thesis discussion (Chapter 7). Briefly, in terms of research, findings from the thesis provide support for the continuing investigation of SAD using both dimensional and categorical approaches. This was evident by the findings from the two empirical papers which demonstrated positive associations between subregional activity and connectivity patterns and social anxiety severity. With regards to theory, differences in neural patterns that were observed at rest (Study 2) and during emotion processing (Study 3) provide support for distinct neurobiological models to be constructed based on whether those with SAD are in the absence or presence of social stimuli. This is in contrast to the most recently proposed neurobiological model of SAD which was informed by a combination of resting-state and task-based fMRI data. Finally, with regards to clinical practice, the findings from this thesis provide preliminary evidence of the superficial, basolateral, and centromedial subregions of the amygdala as being potential treatment targets that can be used to inform the development of more efficacious treatments for SAD

Behavioural disinhibition in the syndromes associated with frontotemporal lobar degeneration

The different clinical syndromes caused by frontotemporal lobar degeneration (FTLD) have highly heterogenous and overlapping features which complicate clinical and research practice. Behavioural impairments are associated with all FTLD syndromes, cause high morbidity and lack proven symptomatic treatments. Treatments for cognitive and behavioural impairment in other neurodegenerative diseases include restoration of neurotransmitter deficits. Deficits in the neurotransmitters glutamate and GABA occur in FTLD syndromes and are associated with behavioural disinhibition in other diseases. I propose that these neurotransmitter deficits contribute to behavioural change in FTLD syndromes. This thesis has two main aims. First, to develop a transdiagnostic approach to FTLD syndromes to facilitate a better understanding of aetiology, pathophysiology and in due course their symptomatic treatment. Second, to use this approach to test the hypothesis that glutamate and GABA deficits are associated with behavioural disinhibition in FTLD syndromes. In a cross-sectional epidemiological study, I examined 310 of 365 regional patients with a FTLD-associated syndrome, including behavioural variant frontotemporal dementia, the nonfluent and semantic variants of primary progressive aphasia, progressive supranuclear palsy and corticobasal syndrome. Multivariate analyses of clinical features and brain morphometry identified components that showed considerable overlap across the diagnostic groups. The transdiagnostic components of clinical features predicted neuropathology better than the current FTLD diagnostic labels. Behavioural disturbance, including disinhibition, was associated with reduced functionally independent survival, irrespective of diagnosis. Next, I investigated the role of glutamate and GABA in behavioural disinhibition. Ultrahigh-field magnetic resonance spectroscopy was used to measure glutamate and GABA in the frontal cortex of 44 patients with a FTLD syndrome and 20 healthy controls. Bayesian modelling of a response inhibition task was used to quantify behavioural disinhibition. Both neurotransmitters were reduced in the frontal cortex, but not occipital cortex, of patients compared to controls. Glutamate and GABA concentrations in the frontal cortex were inversely associated with behavioural disinhibition. In summary, the transdiagnostic approach provided new insights into the phenotypic heterogeneity in FTLD syndromes. Behavioural disinhibition, which can occur to a variable degree in all FTLD syndromes, was associated with reduced functionally independent survival. GABA and glutamate deficits in the frontal cortex are associated with behavioural disinhibition and are a potential target for future treatments.Holt Fellowshi

Early Experience And The Development Of Dopaminergic Circuitry

The developing brain is highly malleable, meaning that children are acutely sensitive to their early experiences, for better or for worse. Early adversity significantly increases the risk for psychopathology and learning challenges. Recent work in animal models powerfully suggests that the ventral tegmental area (VTA), a major source of dopaminergic projections to the rest of the brain, is a key mediator for how early stressful experiences can become biologically embedded: in mice, absent or disrupted caregiving results in latent vulnerability of the dopaminergic system to stress well into adulthood. Thus, it may be that early adversity causes a shift in the developmental trajectory of the VTA, with cascading effects on later motivational and socioemotional processes. However, little is known about whether similar disruptions in VTA circuitry are detectable in children. Thus, I leveraged fMRI methods in 4- to 10-year-old children, to examine the functional integrity of dopaminergic circuitry early in development. In Chapter 2, I tested whether stress exposure relates to VTA resting-state functional connectivity. I found an age x stress exposure interaction, such that only children with lower stress exposure showed a positive relationship between age and VTA-mPFC connectivity, consistent with an interpretation that high stress exposure is related to blunted VTA maturation. Chapter 3 examined children’s neural responses to naturalistic emotional content using movie fMRI, and linked to parenting behaviors observed in the lab. I found that children who experienced more negative parenting showed reduced VTA activity during positive emotion scenes. Finally, Chapter 4 examined curiosity, a behavior that is supported by dopaminergic circuitry, and that encourages greater learning by engaging positive interest and intrinsic motivation. I tested whether individual differences in curiosity are reflected in resting-state connectivity patterns, and can be predicted by environmental experiences. Together, this work suggests that early experiences play a critical role in tuning dopaminergic neurocircuitry in children, with potentially enduring consequences for reward and socioemotional processing. This has implications both for education and for policy: how can we protect children in negative environments, and provide positive support that will allow them to best thrive as learners