The role of subcortical pathology in altered cognition is increasingly recognised. However, measu... more The role of subcortical pathology in altered cognition is increasingly recognised. However, measurement and monitoring of impairments in motivation and behaviour due to subcortical disease is challenging. Basal ganglia – cortico-thalamo-cortical loops and the neurotransmitter, dopamine, are recognised to be important in modulating both reward learning and oculomotor performance. This thesis considers the use of novel and adapted oculomotor (saccadic) tasks as a means of interrogating these dynamic circuits as measures of rewarded decision-making under risk and time pressure. I first describe a novel rewarded oculomotor task, the Traffic Light Task, which provokes two distributions of saccades – one anticipatory, and one reactive. The balance of these distributions, the number of errors and the reward obtained are used to index oculomotor decision-making. Demonstrated effects of healthy aging include a significant reduction in anticipatory responding and consequent reduction in reward. I then compare behavioural oculomotor task responses in healthy controls with established “self-report” measures of impulsivity, finding significant correlations. Next, I consider a patient with focal lesions of the basal ganglia causing profound apathy. I demonstrate reduced oculomotor anticipatory responding and reward sensitivity. I then show the positive effects of dopaminergic medications (levodopa and ropinirole) upon his oculomotor decision-making in tandem with a clinical improvement in his motivational state. To further qualify this dopaminergic effect, I then assess the effects of two dopaminergic drugs (levodopa and methylphenidate) upon healthy volunteers. Finally, I use oculomotor tasks to compare patients with Parkinson’s Disease, with and without impulse control disorders, with both healthy volunteers and pathological gamblers without neurological disease. The results of these experiments raise questions regarding the development of models of basal ganglia – cortico-thalamo-cortical loops and how best to understand them.
Introduction: Autoimmune encephalitis is a disorder associated with antibodies directed against c... more Introduction: Autoimmune encephalitis is a disorder associated with antibodies directed against central nervous system proteins with variable clinical features. This study aims to add to knowledge of the disease by reporting the details of a cohort of patients with autoimmune encephalitis in Queensland, Australia.Methodology: We surveyed patients with autoimmune encephalitis diagnosed and managed through public hospitals in Queensland, Australia between 2010 and the end of 2019. Cases were identified via case detection through a centralized diagnostic neuroimmunology laboratory (Division of Immunology, HSQ Pathology Queensland Central Laboratory, Brisbane, Queensland, Australia) and a survey of neurologists. Data including demographic details, clinical presentation, investigation results, treatments including immune therapy and outcomes was collected.Results: Sixty cases of antibody positive autoimmune encephalitis were identified. Twenty-eight were of anti-NMDA-receptor encephaliti...
Impulsivity is a feature of many brain disorders. Although often defined as the predisposi-tion t... more Impulsivity is a feature of many brain disorders. Although often defined as the predisposi-tion to act with an inadequate degree of deliberation, forethought, or control, it has proven difficult to measure. This may in part be due to the fact that it is a multifaceted construct, with impulsive decisions potentially arising as a result of a number of underlying mecha-nisms. Indeed, a “functional ” degree of impulsivity may even promote effective behavior in healthy participants in a way that can be advantageous under certain circumstances. Although many tasks have been developed to study impulsivity, few examine decisions made rapidly, for time-sensitive rewards. In the current study we examine behavior in 59 adults on a manual “Traffic Light ” task which requires participants to take risks under time pressure, if they are to maximize reward. We show that behavioral variables that index rapid anticipatory responding in this paradigm are correlated with one, specific self-report measu...
This prospective cohort study, Prospective Imaging Study of Ageing: "Genes, Brain and Behavi... more This prospective cohort study, Prospective Imaging Study of Ageing: "Genes, Brain and Behaviour" (PISA) seeks to characterise the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer's disease (AD). In particular, we are recruiting mid-life Australians with high and low genetic risk of dementia to discover biological markers of early neuropathology, identify modifiable risk factors, and establish the very earliest phenotypic and neuronal signs of disease onset. PISA utilises genetic prediction to recruit and enrich a prospective cohort and follow them longitudinally. Online surveys and cognitive testing are used to characterise an Australia-wide sample currently totalling nearly 3,000 participants. Participants from a defined at-risk cohort and positive controls (clinical cohort of patients with mild cognitive impairment or early AD) are invited for onsite visits for lifestyle monitoring, detailed neurocognitive testing, blood sam...
OVERVIEWWe report on the evolution of the rapid access neurology clinic (established in 1995) at ... more OVERVIEWWe report on the evolution of the rapid access neurology clinic (established in 1995) at Addenbrooke's Hospital, Cambridge. Annualised attendance data demonstrate an ever increasing demand, with primary headache disorders now accounting for more than 40% of referrals. Secondary causes of headache (including intracranial tumours, idiopathic intracranial hypertension, carotid or vertebral artery dissection and subdural haematomas) remain infrequent. In all such cases, there were additional diagnostic clues. The number of patients referred with problems related to chronic neurological diseases has fallen considerably, reflecting the roles of specialist nurses and clinics. Imaging investigation of choice shifted from computerised tomography scan (45 to 16%) towards magnetic resonance imaging (17 to 47%). Management is increasingly on an outpatient basis, often without the need for a follow-up appointment. The experience presented here should inform further development of rap...
OVERVIEWWe report on the evolution of the rapid access neurology clinic (established in 1995) at ... more OVERVIEWWe report on the evolution of the rapid access neurology clinic (established in 1995) at Addenbrooke's Hospital, Cambridge. Annualised attendance data demonstrate an ever increasing demand, with primary headache disorders now accounting for more than 40% of referrals. Secondary causes of headache (including intracranial tumours, idiopathic intracranial hypertension, carotid or vertebral artery dissection and subdural haematomas) remain infrequent. In all such cases, there were additional diagnostic clues. The number of patients referred with problems related to chronic neurological diseases has fallen considerably, reflecting the roles of specialist nurses and clinics. Imaging investigation of choice shifted from computerised tomography scan (45 to 16%) towards magnetic resonance imaging (17 to 47%). Management is increasingly on an outpatient basis, often without the need for a follow-up appointment. The experience presented here should inform further development of rap...
Energization is the process of initiating and sustaining a response over time. It has been descri... more Energization is the process of initiating and sustaining a response over time. It has been described as one of three key "supervisory" attentional control processes associated with the frontal lobes. Attentional mechanisms, such as energization, are critical for a range of cognitive functions, such as spontaneous speech and other higher-order tasks. We aimed to investigate the process of energization in a case series of patients with progressive supranuclear palsy (PSP). Patients with a diagnosis of PSP (N = 5), patient controls with a neurodegenerative condition (Alzheimer's disease N = 3, frontotemporal dementia N = 2) and healthy older adult controls (N = 30) were assessed on a standard neuropsychological battery, including executive tasks and standard attention and language tests. Energization was investigated using word fluency tasks, samples of spontaneous speech and an experimental button-pressing concentration task. Response rates for the word fluency, spontane...
Impulsivity is a feature of many brain disorders. Although often defined as the predisposition to... more Impulsivity is a feature of many brain disorders. Although often defined as the predisposition to act with an inadequate degree of deliberation, forethought, or control, it has proven difficult to measure. This may in part be due to the fact that it is a multifaceted construct, with impulsive decisions potentially arising as a result of a number of underlying mechanisms. Indeed, a “functional” degree of impulsivity may even promote effective behavior in healthy participants in a way that can be advantageous under certain circumstances. Although many tasks have been developed to study impulsivity, few examine decisions made rapidly, for time-sensitive rewards. In the current study we examine behavior in 59 adults on a manual “Traffic Light” task which requires participants to take risks under time pressure, if they are to maximize reward. We show that behavioral variables that index rapid anticipatory responding in this paradigm are correlated with one, specific self-report measure of impulsivity: “lack of premeditation” on the UPPS Impulsive Behavior Scale. Participants who scored more highly on this subscale performed better on the task. Moreover, anticipatory behavior reduced significantly with age (18–79years), an effect that continued to be upheld after correction for potential age differences in the ability to judge the timing of responses. Based on these findings, we argue that the Traffic Light task provides a parametric method to study one aspect of impulsivity in health and disease: namely, rapid decision-making in pursuit of risky, time-sensitive rewards.
The role of subcortical pathology in altered cognition is increasingly recognised. However, measu... more The role of subcortical pathology in altered cognition is increasingly recognised. However, measurement and monitoring of impairments in motivation and behaviour due to subcortical disease is challenging. Basal ganglia – cortico-thalamo-cortical loops and the neurotransmitter, dopamine, are recognised to be important in modulating both reward learning and oculomotor performance. This thesis considers the use of novel and adapted oculomotor (saccadic) tasks as a means of interrogating these dynamic circuits as measures of rewarded decision-making under risk and time pressure. I first describe a novel rewarded oculomotor task, the Traffic Light Task, which provokes two distributions of saccades – one anticipatory, and one reactive. The balance of these distributions, the number of errors and the reward obtained are used to index oculomotor decision-making. Demonstrated effects of healthy aging include a significant reduction in anticipatory responding and consequent reduction in reward. I then compare behavioural oculomotor task responses in healthy controls with established “self-report” measures of impulsivity, finding significant correlations. Next, I consider a patient with focal lesions of the basal ganglia causing profound apathy. I demonstrate reduced oculomotor anticipatory responding and reward sensitivity. I then show the positive effects of dopaminergic medications (levodopa and ropinirole) upon his oculomotor decision-making in tandem with a clinical improvement in his motivational state. To further qualify this dopaminergic effect, I then assess the effects of two dopaminergic drugs (levodopa and methylphenidate) upon healthy volunteers. Finally, I use oculomotor tasks to compare patients with Parkinson’s Disease, with and without impulse control disorders, with both healthy volunteers and pathological gamblers without neurological disease. The results of these experiments raise questions regarding the development of models of basal ganglia – cortico-thalamo-cortical loops and how best to understand them.
Introduction: Autoimmune encephalitis is a disorder associated with antibodies directed against c... more Introduction: Autoimmune encephalitis is a disorder associated with antibodies directed against central nervous system proteins with variable clinical features. This study aims to add to knowledge of the disease by reporting the details of a cohort of patients with autoimmune encephalitis in Queensland, Australia.Methodology: We surveyed patients with autoimmune encephalitis diagnosed and managed through public hospitals in Queensland, Australia between 2010 and the end of 2019. Cases were identified via case detection through a centralized diagnostic neuroimmunology laboratory (Division of Immunology, HSQ Pathology Queensland Central Laboratory, Brisbane, Queensland, Australia) and a survey of neurologists. Data including demographic details, clinical presentation, investigation results, treatments including immune therapy and outcomes was collected.Results: Sixty cases of antibody positive autoimmune encephalitis were identified. Twenty-eight were of anti-NMDA-receptor encephaliti...
Impulsivity is a feature of many brain disorders. Although often defined as the predisposi-tion t... more Impulsivity is a feature of many brain disorders. Although often defined as the predisposi-tion to act with an inadequate degree of deliberation, forethought, or control, it has proven difficult to measure. This may in part be due to the fact that it is a multifaceted construct, with impulsive decisions potentially arising as a result of a number of underlying mecha-nisms. Indeed, a “functional ” degree of impulsivity may even promote effective behavior in healthy participants in a way that can be advantageous under certain circumstances. Although many tasks have been developed to study impulsivity, few examine decisions made rapidly, for time-sensitive rewards. In the current study we examine behavior in 59 adults on a manual “Traffic Light ” task which requires participants to take risks under time pressure, if they are to maximize reward. We show that behavioral variables that index rapid anticipatory responding in this paradigm are correlated with one, specific self-report measu...
This prospective cohort study, Prospective Imaging Study of Ageing: "Genes, Brain and Behavi... more This prospective cohort study, Prospective Imaging Study of Ageing: "Genes, Brain and Behaviour" (PISA) seeks to characterise the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer's disease (AD). In particular, we are recruiting mid-life Australians with high and low genetic risk of dementia to discover biological markers of early neuropathology, identify modifiable risk factors, and establish the very earliest phenotypic and neuronal signs of disease onset. PISA utilises genetic prediction to recruit and enrich a prospective cohort and follow them longitudinally. Online surveys and cognitive testing are used to characterise an Australia-wide sample currently totalling nearly 3,000 participants. Participants from a defined at-risk cohort and positive controls (clinical cohort of patients with mild cognitive impairment or early AD) are invited for onsite visits for lifestyle monitoring, detailed neurocognitive testing, blood sam...
OVERVIEWWe report on the evolution of the rapid access neurology clinic (established in 1995) at ... more OVERVIEWWe report on the evolution of the rapid access neurology clinic (established in 1995) at Addenbrooke's Hospital, Cambridge. Annualised attendance data demonstrate an ever increasing demand, with primary headache disorders now accounting for more than 40% of referrals. Secondary causes of headache (including intracranial tumours, idiopathic intracranial hypertension, carotid or vertebral artery dissection and subdural haematomas) remain infrequent. In all such cases, there were additional diagnostic clues. The number of patients referred with problems related to chronic neurological diseases has fallen considerably, reflecting the roles of specialist nurses and clinics. Imaging investigation of choice shifted from computerised tomography scan (45 to 16%) towards magnetic resonance imaging (17 to 47%). Management is increasingly on an outpatient basis, often without the need for a follow-up appointment. The experience presented here should inform further development of rap...
OVERVIEWWe report on the evolution of the rapid access neurology clinic (established in 1995) at ... more OVERVIEWWe report on the evolution of the rapid access neurology clinic (established in 1995) at Addenbrooke's Hospital, Cambridge. Annualised attendance data demonstrate an ever increasing demand, with primary headache disorders now accounting for more than 40% of referrals. Secondary causes of headache (including intracranial tumours, idiopathic intracranial hypertension, carotid or vertebral artery dissection and subdural haematomas) remain infrequent. In all such cases, there were additional diagnostic clues. The number of patients referred with problems related to chronic neurological diseases has fallen considerably, reflecting the roles of specialist nurses and clinics. Imaging investigation of choice shifted from computerised tomography scan (45 to 16%) towards magnetic resonance imaging (17 to 47%). Management is increasingly on an outpatient basis, often without the need for a follow-up appointment. The experience presented here should inform further development of rap...
Energization is the process of initiating and sustaining a response over time. It has been descri... more Energization is the process of initiating and sustaining a response over time. It has been described as one of three key "supervisory" attentional control processes associated with the frontal lobes. Attentional mechanisms, such as energization, are critical for a range of cognitive functions, such as spontaneous speech and other higher-order tasks. We aimed to investigate the process of energization in a case series of patients with progressive supranuclear palsy (PSP). Patients with a diagnosis of PSP (N = 5), patient controls with a neurodegenerative condition (Alzheimer's disease N = 3, frontotemporal dementia N = 2) and healthy older adult controls (N = 30) were assessed on a standard neuropsychological battery, including executive tasks and standard attention and language tests. Energization was investigated using word fluency tasks, samples of spontaneous speech and an experimental button-pressing concentration task. Response rates for the word fluency, spontane...
Impulsivity is a feature of many brain disorders. Although often defined as the predisposition to... more Impulsivity is a feature of many brain disorders. Although often defined as the predisposition to act with an inadequate degree of deliberation, forethought, or control, it has proven difficult to measure. This may in part be due to the fact that it is a multifaceted construct, with impulsive decisions potentially arising as a result of a number of underlying mechanisms. Indeed, a “functional” degree of impulsivity may even promote effective behavior in healthy participants in a way that can be advantageous under certain circumstances. Although many tasks have been developed to study impulsivity, few examine decisions made rapidly, for time-sensitive rewards. In the current study we examine behavior in 59 adults on a manual “Traffic Light” task which requires participants to take risks under time pressure, if they are to maximize reward. We show that behavioral variables that index rapid anticipatory responding in this paradigm are correlated with one, specific self-report measure of impulsivity: “lack of premeditation” on the UPPS Impulsive Behavior Scale. Participants who scored more highly on this subscale performed better on the task. Moreover, anticipatory behavior reduced significantly with age (18–79years), an effect that continued to be upheld after correction for potential age differences in the ability to judge the timing of responses. Based on these findings, we argue that the Traffic Light task provides a parametric method to study one aspect of impulsivity in health and disease: namely, rapid decision-making in pursuit of risky, time-sensitive rewards.
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