Dissociable effects of age and Parkinson’s disease on instruction-based learning

The cognitive deficits associated with Parkinson’s disease vary across individuals and change across time, with implications for prognosis and treatment. Key outstanding challenges are to define the distinct behavioural characteristics of this disorder and develop diagnostic paradigms that can assess these sensitively in individuals. In a previous study, we measured different aspects of attentional control in Parkinson’s disease using an established fMRI switching paradigm. We observed no deficits for the aspects of attention the task was designed to examine; instead those with Parkinson’s disease learnt the operational requirements of the task more slowly. We hypothesized that a subset of people with early-to-mid stage Parkinson’s might be impaired when encoding rules for performing new tasks. Here, we directly test this hypothesis and investigate whether deficits in instruction-based learning represent a characteristic of Parkinson’s Disease. Seventeen participants with Parkinson’s disease (8 male; mean age: 61.2 years), 18 older adults (8 male; mean age: 61.3 years) and 20 younger adults (10 males; mean age: 26.7 years) undertook a simple instruction-based learning paradigm in the MRI scanner. They sorted sequences of coloured shapes according to binary discrimination rules that were updated at two-minute intervals. Unlike common reinforcement learning tasks, the rules were unambiguous, being explicitly presented; consequently, there was no requirement to monitor feedback or estimate contingencies. Despite its simplicity, a third of the Parkinson’s group, but only one older adult, showed marked increases in errors, 4 SD greater than the worst performing young adult. The pattern of errors was consistent, reflecting a tendency to misbind discrimination rules. The misbinding behaviour was coupled with reduced frontal, parietal and anterior caudate activity when rules were being encoded, but not when attention was initially oriented to the instruction slides or when discrimination trials were performed. Concomitantly, Magnetic Resonance Spectroscopy showed reduced gamma-Aminobutyric acid levels within the mid-dorsolateral prefrontal cortices of individuals who made misbinding errors. These results demonstrate, for the first time, that a subset of early-to-mid stage people with Parkinson’s show substantial deficits when binding new task rules in working memory. Given the ubiquity of instruction-based learning, these deficits are likely to impede daily living. They will also confound clinical assessment of other cognitive processes. Future work should determine the value of instruction-based learning as a sensitive early marker of cognitive decline and as a measure of responsiveness to therapy in Parkinson's disease

Fronto-striatal contributions to cognition and behaviour: Investigations in neurodegeneration

Alterations to fronto-striatal neural circuitry are the hallmark of many neurodegenerative conditions, giving rise to significant cognitive and behavioural symptoms. This thesis explores fronto-striatal atrophic change in two such conditions, Parkinson’s disease (PD) and behavioural variant frontotemporal dementia (bvFTD). This is a critical area of interest in PD where the role of atrophy in non-motor symptoms, as opposed to dopamine-mediated functional changes, is only beginning to be uncovered. In contrast, cognitive and behavioural decline in bvFTD has long been associated with cortical atrophy, but the contribution of striatal atrophic change is less established. Fronto-striatal atrophy in the conditions is investigated for its role in an array of cognitive and behavioural symptoms. In each study reported, patients have undergone either caregiver questionnaires, neuropsychological testing or novel experimental tasks, to assess 1) neuropsychiatric symptoms (Chapter 2, Publications I and II); 2) learning deficits (Chapter 3, Publication III); and 3) social decision-making (Chapter 4, Publication IV). Behavioural measures are related to fronto-striatal atrophy via voxel-based morphometry, a technique for neuroimaging analysis that enables quantification of local grey matter volume. This analysis was approached firstly at the group level to determine the extent of fronto-striatal grey matter loss in patients with respect to age-matched controls, before being correlated with specific cognitive/behavioural scores. Broadly, the results show that either distinct, or combined, regional fronto-striatal atrophy was related to cognition and behaviour in PD and bvFTD. More specially, these findings highlight a role for fronto-striatal atrophy in both the cognitive and everyday manifestations of neuropsychiatric dysfunction in PD, and in specific learning deficits. These findings have important implications for understanding the pathophysiology of those symptoms in PD, and represent a critical consideration in the future development of therapeutic interventions. In bvFTD these novel findings reveal a role for the striatum in complex cognition and behaviour, emphasising this as an important region for characterising symptoms in the disease, which may assist in diagnosis. Together, the findings provide important insights into the cognitive and behavioural symptoms in neurodegenerative disease, which at present remain incompletely understood and difficult to treat

Cortical and subcortical contributions to human cognitive flexibility

Cognitive flexibility enables individuals to respond adaptively to an ever-changing world. Neurally, flexibility is underpinned by involvement from across the cerebrum, and there is evidence from animal and human neuroscience suggesting that integration of cortical and thalamic signals in the striatum is necessary for appropriate behavioural control. A commonly used assay of flexibility is reversal learning, an associative learning task with high inter-species translatability. Evidence from animal literature has clearly defined the importance of the striatal cholinergic system in regulating striatal activity and output from the basal ganglia, and there is nascent evidence suggesting this system operates in a similar way in humans. However, there is a need to further disentangle the role of cortical, striatal, and thalamic regions during reversal learning in humans to better understand how the system works, and whether it has heterogeneous functionality in different contexts. Furthermore, as studying these processes is not trivial, further methodological work is required to enable us to understand the system. In chapter two we systematically assess an automated parcellation technique for identifying specific thalamic nuclei. Despite generally being treated as a homologous structure in neuroimaging work, nuclei within the thalamus have dissociable roles, and have diverse contributions to cognitive functioning, including reversal learning. We found mixed efficacy for segmentations across the thalamus, with some regions being more accurately defined relative to a “gold standard” atlas than others. Crucially, we find that the centromedian and parafascicular nuclei, which have an important role in reversal learning, are clearly defined and have little overlap with contiguous regions. These results show we can use this automated parcellation technique to identify specific thalamic nuclei that are relevant for cognitive flexibility and use these parcellations to study functionally relevant processes. Recent work has demonstrated that the functional relevance of the striatal cholinergic system can be studied in vivo using magnetic resonance spectroscopy by separating the peaks of different metabolites. But this non-conventional approach has not yet been widely adopted, and work is needed to determine its reliability. Chapter three presents test-retest reliability data on the use of magnetic resonance spectroscopy to study cholinergic activity in the striatum and cortex. We find measures of choline containing compounds are highly correlated when peaks are separated and when they are not. Across time we find that choline concentrations are relatively inconsistent, and that this was due to changes in the functionally relevant metabolite choline. Conversely, metabolites that we think are not functionally relevant were stable over time. We believe these differences may underly differences in acetylcholine function over time and may explain some intra-individual behavioural variability. In chapter four we use functional magnetic resonance imaging and psychophysiological interaction analysis to study corticostriatal and thalamostriatal connectivity during serial reversal learning. Functional connectivity between the centromedian-parafascicular nuclei of the thalamus and the associative dorsal striatum, and between the lateral-orbitofrontal cortex and the associative dorsal striatum was related to processing feedback during reversal learning. Specifically, thalamostriatal connectivity was found across the task, and may reflect a general error signal used to identify potential changes in context. Conversely, corticostriatal connectivity was found to be specific to when behaviour changed and suggests this may be a mechanism for the implementing adaptive change. We also show findings from exploratory work that may explain further how the cortex supports flexibility during reversal learning. Lastly, we used magnetic resonance spectroscopy to investigate whether the state of the cholinergic system at rest is related to reversal learning performance and latent measures of behaviour using computational modelling. Choline concentrations at rest showed significant functional relevance to our measures of reversal learning. More specifically, we found that errors during reversal learning, and learning rates for positive and negative prediction errors, explained significant variance in choline. However, the relationship between choline levels and task performance presented here differ from previous work which instead used a multi-alternative reversal learning task, and suggests that the striatal cholinergic system may have dissociable roles in different contexts. Overall, we show that the striatum, its cholinergic interneuron system, and its afferent projections from the cortex and thalamus, are associated with performance during serial reversal learning. Moreover, these findings suggest that the system may operate in separable ways in different contexts which may be dependent on internal representations of task structure

Performance of the odour span task is not impaired following inactivations of parietal cortex in rats

Peer Reviewe

Role Of The Dorsal Striatum In Learning and Decision Making

The striatum, the input region of the basal ganglia, has been shown to mediate many cognitive functions. The striatum itself can be functionally segregated into dorsal (DS) and ventral striatum (VS). For more than 60 years, DS has been reported to mediate stimulus-response learning, though evidence has been accruing pointing to a role in decision making. These literatures have been growing independently and an aim of this thesis was to bridge these two bodies of knowledge. We directly investigated the role of DS in stimulus-response learning versus decision making using functional magnetic resonance imaging (fMRI) in patients with Parkinson’s disease (Chapter 2) and obsessive compulsive disorder (Chapter 3). In Chapter 4, the role of DS in stimulus-response habit learning was tested in healthy individuals using fMRI. In three separate experiments (Chapters 2-4), all of the results strongly support the notion that DS mediates decision making and not learning. DS is implicated in many disorders ranging from Parkinson’s disease, obsessive compulsive disorder and addiction, and clarifying the role of DS in cognitive function is paramount for understanding substrates of disease and developing treatments

A mechanistic investigation of neuro-cognitive and experiential factors associated with psychiatric vulnerability following childhood maltreatment

Childhood maltreatment is one of the most potent predictors of future psychopathology. While progress has been made in documenting a number of cognitive and neurobiological mechanisms that might underpin this association, investigations to date have focused on a limited number of domains. The primary aim of this thesis was, therefore, to advance and extend our understanding of the neurocognitive domains that may contribute to increased psychiatric vulnerability following childhood maltreatment. In the first empirical chapter (Chapter Two), using a model-based fMRI analytic approach and a probabilistic passive-avoidance task, we showed that childhood maltreatment is associated with recalibrations in the neurocomputational processes that underlie reinforcement-based decision-making. These are expected-value representation and prediction-error signalling to reward and punishment cues. In Chapter Three we showed that altered brain responses to threat (in the form of heighted amygdala reactivity) and an increased propensity to experience stressful life events predict future internalising symptoms among individuals with a history of maltreatment. In Chapter Four we found that experiencing maltreatment during childhood is associated with difficulties in imagining specific and detailed possible future scenarios (‘Overgeneral Episodic Future Thinking’). In Chapter Five, a history of maltreatment was linked to deficits in interpersonal problem solving skills – this, in turn, contributed to the association between maltreatment and poor mental health. The findings of this thesis increase our understanding of how childhood maltreatment impacts neurobiological, cognitive and social functioning in ways that may potentiate subsequent risk of psychopathology. In the longer term, it is hoped that these findings will contribute to the development of screening tools and novel preventative clinical approaches that could foster a resilient outcome for those maltreated individuals at greatest psychiatric vulnerability

Brain Computations and Connectivity [2nd edition]

This is an open access title available under the terms of a CC BY-NC-ND 4.0 International licence. It is free to read on the Oxford Academic platform and offered as a free PDF download from OUP and selected open access locations. Brain Computations and Connectivity is about how the brain works. In order to understand this, it is essential to know what is computed by different brain systems; and how the computations are performed. The aim of this book is to elucidate what is computed in different brain systems; and to describe current biologically plausible computational approaches and models of how each of these brain systems computes. Understanding the brain in this way has enormous potential for understanding ourselves better in health and in disease. Potential applications of this understanding are to the treatment of the brain in disease; and to artificial intelligence which will benefit from knowledge of how the brain performs many of its extraordinarily impressive functions. This book is pioneering in taking this approach to brain function: to consider what is computed by many of our brain systems; and how it is computed, and updates by much new evidence including the connectivity of the human brain the earlier book: Rolls (2021) Brain Computations: What and How, Oxford University Press. Brain Computations and Connectivity will be of interest to all scientists interested in brain function and how the brain works, whether they are from neuroscience, or from medical sciences including neurology and psychiatry, or from the area of computational science including machine learning and artificial intelligence, or from areas such as theoretical physics

Psychological intervention with working memory training increases basal ganglia volume: A VBM study of inpatient treatment for methamphetamine use

Background: Protracted methamphetamine (MA) use is associated with decreased control over drug craving and altered brain volume in the frontostriatal network. However, the nature of volumetric changes following a course of psychological intervention for MA use is not yet known. Methods: 66 males (41 MA patients, 25 healthy controls, HC) between the ages of 18–50 were recruited, the MA patients from new admissions to an in-patient drug rehabilitation centre and the HC via public advertisement, both in Cape Town, South Africa. 17 MA patients received 4 weeks of treatment as usual (TAU), and 24 MA patients completed TAU plus daily 30-minute cognitive training (CT) using an N-back working memory task. Magnetic resonance imaging (MRI) at baseline and 4-week follow-up was acquired and voxel-based morphometry (VBM) was used for analysis. Results: TAU was associated with larger bilateral striatum (caudate/putamen) volume, whereas CT was associated with more widespread increases of the bilateral basal ganglia (incorporating the amygdala and hippocampus) and reduced bilateral cerebellum volume coinciding with improvements in impulsivity scores. Conclusions: While psychological intervention is associated with larger volume in mesolimbic reward regions, the utilisation of additional working memory training as an adjunct to treatment may further normalize frontostriatal structure and function