Action control in uncertain environments

A long-standing dichotomy in neuroscience pits automatic or reflexive drivers of behaviour against deliberate or reflective processes. In this thesis I explore how this concept applies to two stages of action control: decision-making and response inhibition. The first part of this thesis examines the decision-making process itself during which actions need to be selected that maximise rewards. Decisions arise through influences from model-free stimulus-response associations as well as model-based, goal-directed thought. Using a task that quantifies their respective contributions, I describe three studies that manipulate the balance of control between these two systems. I find that a pharmacological manipulation with levodopa increases model-based control without affecting model-free function; disruption of dorsolateral prefrontal cortex via magnetic stimulation disrupts model-based control; and direct current stimulation to the same prefrontal region has no effect on decision-making. I then examine how the intricate anatomy of frontostriatal circuits subserves reinforcement learning using functional, structural and diffusion magnetic resonance imaging (MRI). A second stage of action control discussed in this thesis is post-decision monitoring and adjustment of action. Specifically, I develop a response inhibition task that dissociates reactive, bottom-up inhibitory control from proactive, top-down forms of inhibition. Using functional MRI I show that, unlike the strong neural segregation in decision-making systems, neural mechanisms of reactive and proactive response inhibition overlap to a great extent in their frontostriatal circuitry. This leads to the hypothesis that neural decline, for 4 example in the context of ageing, might affect reactive and proactive control similarly. I test this in a large population study administered through a smartphone app. This shows that, against my prediction, reactive control reliably declines with age but proactive control shows no such decline. Furthermore, in line with data on gender differences in age-related neural degradation, reactive control in men declines faster with age than that of women

Single neuron computations of cognition in the human brain

Understanding how information is encoded, processed, and decoded to produce behavior is a fundamental goal of neuroscience. In this dissertation, we aim to expand our understanding of our human decision-making processes at the single-neuronal level. We describe three studies exploring the neural substrate of decision-making in three separate brain regions. First, we describe a method for recording the activity of individual neurons in human subjects. The unique combination of behavioral and neurophysiological data will allow us to better understand the neural substrate of cognitive functions in humans. Second, we explored how decisions are represented in the brain. We recorded single neuronal responses in the human nucleus accumbens while subjects engaged in a financial decision-making task. We found that neurons in the nucleus accumbens predicted upcoming decisions well before the behavior was manifested. In addition, these neurons encoded a positive and negative prediction error signal, signaling the difference between expected and realized outcome. Third, we explored how the brain represents decision conflict and how it adapts to prime future decisions allowing tradeoff between speed and accuracy. We found that individual neurons in the human dorsal anterior cingulate cortex encode the level of decision conflict in a dose-dependent manner. In addition, these neurons encode historical conflict information, priming the neural circuit to future trials of the same or varying conflict levels. Following selective ablation of the dorsal anterior cingulate cortex, we found this signal was selectively abolished. Lastly, we explored how the brain represents decisions under conflict and if these decisions are malleable to external intervention. We found that neurons in the human subthalamic nucleus are selectively activated and encode the upcoming decision during situations of high decision conflict. Based on the physiological findings, we then applied intermittent stimulation through the implanted deep brain stimulation electrode during the same task, to demonstrate a causal interaction between the physiology and behavior. In conclusion, we describe a set of experiments that systematically explore human decision-making processes at the single-neuronal level

Controlling for non-inhibitory processes in response inhibition research

Central to human adaptive behaviour is the ability to update one’s motor actions in the face of environmental changes, for which a key component is the ability to inhibit ongoing actions that are no longer appropriate. A substantial body of previous research has implicated the right inferior frontal gyrus (rIFG) and the pre-supplementary motor area (pre-SMA) as plausible sources of inhibitory control, but it remains unclear whether these regions host a specialised inhibitory control mechanism or instead support a more general system of action updating. This uncertainty stems from the limited number of studies that have controlled for non-inhibitory processes in response inhibition research. The overarching aim of this thesis was to resolve this ambiguity by studying behaviour, neurophysiology and neurochemistry during action updating in the presence and absence of inhibition. For the key experiments, detailed methods and hypotheses were pre-registered prior to data collection to minimise research bias and ensure transparent discrimination of confirmatory and exploratory inferences

The effects of dopamine and dopamine precursor medication on impairments to high-level vision in Parkinson\u27s disease

The goal of this study was to examine how dopamine (DA) and dopaminergic medications affect the performance of high-level visual tasks in individuals with Parkinson’s disease (PD). Various studies have reported that PD is associated with impairments on visual tasks known to depend on processing in the ventral visual pathway of the brain. Because most behavioral symptoms in PD arise from chronic dopamine deficiency, the author sought to investigate the role that DA played in cognitive vision. Accordingly, five complex visual tasks were chosen that were known to recruit processing from different constellations of brain areas, either in the ventral pathway or to which the ventral pathway was known to send projections. The tasks included discrimination of abstract objects and three-dimensional face stimuli, visual working memory for these same stimuli, and mental rotation of three-dimensional wire-frame objects. An additional task, in which participants were required to discriminate between pairs of lines with varying orientations, was included as a control. Individuals with PD, as well as healthy age- and sex-matched control participants, completed all five of these tasks twice, and individuals with PD, in particular, were asked to complete them once on and once off of their prescribed dopaminergic medications. The PD group performed significantly worse than the group of healthy control participants across all five tasks. Strikingly, the performance of individuals in the PD group did not differ significantly depending on their medication state. This finding indicates either that dopamine deficiency is not responsible for cognitive visual impairments in PD, or that the dopaminergic circuitry responsible for these impairments is incapable of responding to the administration of dopaminergic medication. Further, since all tasks, including the line orientation discrimination task, showed an effect of group, the results of this study are insufficient to rule out the possibility that impairments that have been reported elsewhere as cognitive visual deficits in PD are simply the result of deficits in more basic visual processing. Finally, the results of this study provide preliminary evidence that impairments of mental rotation in PD are the result of impaired processing in brain regions traditionally associated with motor functioning

Characterisation of genetic risk factors for mental illness in rodent models, impact of Map2k7+/- and Fxyd6-/- mice on neural systems and working memory

Even in wealthy and seemingly prosperous countries like the United Kingdom, the spectre of mental illness and psychiatric disorders remains highly prevalent. These disorders present a huge economic burden to societies, where in the UK alone, mental disorders cost the economy an estimated €134 billion a year; along with the unmeasurable societal and human costs. This has led to an intense debate over the past few decades just as to what factors contribute to these illnesses. It is now understood that a number of biological and non-biological factors contribute. These include socio-economic pressures, early-life trauma, gestational and peri-natal infections; genetic and familial factors, and molecular and cellular factors. However, while the definitions and diagnostic criteria of mental disorders remain based in the subjective realms of the DSM and ICD, treatment and understanding of psychiatric illness has had little chance to progress over the last fifty years. As a result, neuroscientists are starting to direct psychiatric disorder research from the bottom-up; where genetic, cognitive and neuroconnectivity factors are being investigated to serve as a future basis for diagnosis and treatment. One of the most complex and debilitating psychiatric disorders, schizophrenia, exhibits a complex array of genetic, cognitive and neuroconnectivity abnormalities. Current challenges in schizophrenia research is to understand how identified genetic abnormalities contribute to neuroconnectivity and cognitive impairments which are prominent in schizophrenia. Recently, genetic association studies have implicated two genes as risk factors for schizophrenia - FXYD6 and MAP2K7. Currently it is unclear exactly how these genes contribute to schizophrenia pathology, particularly cognitive symptoms and neural circuitry.;This thesis investigates these two genes by utilising two mouse models, first a heterozygous mouse line of Map2k7+/- and second, a gene knock-out line of Fxyd6-/-. MAP2K7 is a gene that expresses a kinase that is involved in the c-Jun N-terminal kinase (JNK) pathway, which is implicated in neuronal activity, receptor function, and cortical and hippocampal plasticity. Recent studies have found a decreased expression of MA2PK7 in the PFC, ACC and hippocampal regions in schizophrenia patients; regions associated with memory and decision making. A component of the cognitive profile of MAP2K7 was therefore investigated using Map2k7+/- mouse lines in a working memory paradigm in the radial arm maze. This test is known as the n-back test or the retention interval test. For the first time this investigation reveals that Map2k7+/- mice exhibit a subtle yet significant spatial working memory deficit compared to WT mice; as judged by their average performance over the whole experiment. WT mice exhibited an overall average performance of 70% and MAP2K7+/- mice 66% (p<0.001). This indicates that MAP2K7 may play a subtle role in working memory function in rodents, and may represent a component of the aberrations in the genetic architecture that gives rise to working memory impairments in psychiatric disorders, particularly schizophrenia. This experiment also backs up previous evidence for this radial arm maze paradigm as a robust behavioural test for testing rodent working memory.;FXYD6 belongs to a group of proteins that are known to be involved in modulating NaKATPase activity. Previously, NaKATPase has been associated with bipolar disorder and depression, but has now also been implicated in schizophrenia. Previous studies have found that FXYD6 is also abnormally expressed in the PFC of schizophrenia patients, and therefore may contribute to the cognate symptoms of the disorder. This experiment, therefore, investigated how Fxyd6 contributes to local brain activation, particularly in neural systems relevant to cognition, using gene knockout Fxyd6-/- mouse models and semi quantitative 2DG autoradiographic imaging. Three regions showed a significant deviation in activity in Fxyd6-/- mice compared to WT mice. The subiculum, medial septum and lateral septum all exhibited significant reductions in activity in Fxyd6-/- mice compared to WT mice. Notably the subiculum is heavily implicated with memory functions, particularly working memory and disambiguation of previously learned memory. Indicating a possible role for FXYD6 and NaKATPase in working memory processing and memory disambiguation in the subiculum. Finally, the role of glutamate in relation to FXYD6 function and brain activity was assessed by administering the NMDA receptor antagonist ketamine and analysing regional brain activity using semi quantitative 2DG autoradiographic imaging. Generally, regions which were affected by ketamine in WT mice including PFC, thalamic and septal regions, were not affected in Fxyd6-/- mice. It is hypothesized that this may be down to a compensatory effect that knocking-out Fxyd6 may have on glutamate reuptake. Because NaKATPase is involved in glutamate reuptake into glia and neurons, the blockage of NMDA receptors may have less effect due to a reduction in glutamate reuptake, and therefore higher than normal postsynaptic glutamate concentrations. In conclusion, this investigation highlights two genes which may have roles in working memory functioning and neural circuitry that contribute to cognitive processes. While the evidence from this investigation does not explicitly associate these genes with symptoms of schizophrenia and other psychiatric disorders; the evidence does provide indication that they are involved in cognitive processes in rodents, and possibly humans. This investigation provides an interesting path of investigation for the potential roles of these genes regardless of their relationship to psychiatric disorders and will inform future research into the genetic architecture of neural circuits and cognition.Even in wealthy and seemingly prosperous countries like the United Kingdom, the spectre of mental illness and psychiatric disorders remains highly prevalent. These disorders present a huge economic burden to societies, where in the UK alone, mental disorders cost the economy an estimated €134 billion a year; along with the unmeasurable societal and human costs. This has led to an intense debate over the past few decades just as to what factors contribute to these illnesses. It is now understood that a number of biological and non-biological factors contribute. These include socio-economic pressures, early-life trauma, gestational and peri-natal infections; genetic and familial factors, and molecular and cellular factors. However, while the definitions and diagnostic criteria of mental disorders remain based in the subjective realms of the DSM and ICD, treatment and understanding of psychiatric illness has had little chance to progress over the last fifty years. As a result, neuroscientists are starting to direct psychiatric disorder research from the bottom-up; where genetic, cognitive and neuroconnectivity factors are being investigated to serve as a future basis for diagnosis and treatment. One of the most complex and debilitating psychiatric disorders, schizophrenia, exhibits a complex array of genetic, cognitive and neuroconnectivity abnormalities. Current challenges in schizophrenia research is to understand how identified genetic abnormalities contribute to neuroconnectivity and cognitive impairments which are prominent in schizophrenia. Recently, genetic association studies have implicated two genes as risk factors for schizophrenia - FXYD6 and MAP2K7. Currently it is unclear exactly how these genes contribute to schizophrenia pathology, particularly cognitive symptoms and neural circuitry.;This thesis investigates these two genes by utilising two mouse models, first a heterozygous mouse line of Map2k7+/- and second, a gene knock-out line of Fxyd6-/-. MAP2K7 is a gene that expresses a kinase that is involved in the c-Jun N-terminal kinase (JNK) pathway, which is implicated in neuronal activity, receptor function, and cortical and hippocampal plasticity. Recent studies have found a decreased expression of MA2PK7 in the PFC, ACC and hippocampal regions in schizophrenia patients; regions associated with memory and decision making. A component of the cognitive profile of MAP2K7 was therefore investigated using Map2k7+/- mouse lines in a working memory paradigm in the radial arm maze. This test is known as the n-back test or the retention interval test. For the first time this investigation reveals that Map2k7+/- mice exhibit a subtle yet significant spatial working memory deficit compared to WT mice; as judged by their average performance over the whole experiment. WT mice exhibited an overall average performance of 70% and MAP2K7+/- mice 66% (p<0.001). This indicates that MAP2K7 may play a subtle role in working memory function in rodents, and may represent a component of the aberrations in the genetic architecture that gives rise to working memory impairments in psychiatric disorders, particularly schizophrenia. This experiment also backs up previous evidence for this radial arm maze paradigm as a robust behavioural test for testing rodent working memory.;FXYD6 belongs to a group of proteins that are known to be involved in modulating NaKATPase activity. Previously, NaKATPase has been associated with bipolar disorder and depression, but has now also been implicated in schizophrenia. Previous studies have found that FXYD6 is also abnormally expressed in the PFC of schizophrenia patients, and therefore may contribute to the cognate symptoms of the disorder. This experiment, therefore, investigated how Fxyd6 contributes to local brain activation, particularly in neural systems relevant to cognition, using gene knockout Fxyd6-/- mouse models and semi quantitative 2DG autoradiographic imaging. Three regions showed a significant deviation in activity in Fxyd6-/- mice compared to WT mice. The subiculum, medial septum and lateral septum all exhibited significant reductions in activity in Fxyd6-/- mice compared to WT mice. Notably the subiculum is heavily implicated with memory functions, particularly working memory and disambiguation of previously learned memory. Indicating a possible role for FXYD6 and NaKATPase in working memory processing and memory disambiguation in the subiculum. Finally, the role of glutamate in relation to FXYD6 function and brain activity was assessed by administering the NMDA receptor antagonist ketamine and analysing regional brain activity using semi quantitative 2DG autoradiographic imaging. Generally, regions which were affected by ketamine in WT mice including PFC, thalamic and septal regions, were not affected in Fxyd6-/- mice. It is hypothesized that this may be down to a compensatory effect that knocking-out Fxyd6 may have on glutamate reuptake. Because NaKATPase is involved in glutamate reuptake into glia and neurons, the blockage of NMDA receptors may have less effect due to a reduction in glutamate reuptake, and therefore higher than normal postsynaptic glutamate concentrations. In conclusion, this investigation highlights two genes which may have roles in working memory functioning and neural circuitry that contribute to cognitive processes. While the evidence from this investigation does not explicitly associate these genes with symptoms of schizophrenia and other psychiatric disorders; the evidence does provide indication that they are involved in cognitive processes in rodents, and possibly humans. This investigation provides an interesting path of investigation for the potential roles of these genes regardless of their relationship to psychiatric disorders and will inform future research into the genetic architecture of neural circuits and cognition

Investigating basal ganglia function using ultra-high field MRI

The basal ganglia (BG) are a group of highly interconnected nuclei that are located deep at the base of the cerebral cortex. They participate in multiple neural circuits or 'loops' with cognitive and motor areas of the cerebral cortex. The basal ganglia has primarily been thought to be involved in motor control and learning, but more recently a number of brain imaging studies have shown that the basal ganglia are involved also in cognitive function. The aim of this work is to investigate the role of the basal ganglia in cognitive control and motor learning by examining its involvement in GO/WAIT and GO/NO-GO tasks, and Motor Prediction task, respectively. Ultra-high field (7 Tesla) fMRI is used to provide higher BOLD contrast and thus higher achievable spatial resolution. A dual echo gradient echo EPI method is used to obtain high quality images from both cortical and sub-cortical regions. A common neural basis across different forms of response inhibition using GO/WAIT and GO/NO-GO cognitive paradigms is observed in the experiments of Chapter 4, as well as distinct brain regions involved in withholding and cancelling of motor responses. Using the GO/WAIT cognitive paradigm in Chapter 5 individuals with Tourette syndrome (TS) are compared to age and gender-matched control healthy subjects (CS), and it is shown that TS subjects are unable to recruit critical cortical and sub-cortical nodes that are typically involved in mediating behavioural inhibition. Furthermore, in Chapter 6, the role of the basal ganglia in motor learning is investigated using the Motor Prediction task. The findings show that the basal ganglia and midbrain regions (i.e., habenula) are involved in motor prediction and enhancing the reinforcement learning process. This thesis aims to investigate the basal ganglia function in cognitive and motor tasks, and concludes with suggested further studies to advance our understanding of the role of the basal ganglia nuclei in cognitive function

Investigating basal ganglia function using ultra-high field MRI

The basal ganglia (BG) are a group of highly interconnected nuclei that are located deep at the base of the cerebral cortex. They participate in multiple neural circuits or 'loops' with cognitive and motor areas of the cerebral cortex. The basal ganglia has primarily been thought to be involved in motor control and learning, but more recently a number of brain imaging studies have shown that the basal ganglia are involved also in cognitive function. The aim of this work is to investigate the role of the basal ganglia in cognitive control and motor learning by examining its involvement in GO/WAIT and GO/NO-GO tasks, and Motor Prediction task, respectively. Ultra-high field (7 Tesla) fMRI is used to provide higher BOLD contrast and thus higher achievable spatial resolution. A dual echo gradient echo EPI method is used to obtain high quality images from both cortical and sub-cortical regions. A common neural basis across different forms of response inhibition using GO/WAIT and GO/NO-GO cognitive paradigms is observed in the experiments of Chapter 4, as well as distinct brain regions involved in withholding and cancelling of motor responses. Using the GO/WAIT cognitive paradigm in Chapter 5 individuals with Tourette syndrome (TS) are compared to age and gender-matched control healthy subjects (CS), and it is shown that TS subjects are unable to recruit critical cortical and sub-cortical nodes that are typically involved in mediating behavioural inhibition. Furthermore, in Chapter 6, the role of the basal ganglia in motor learning is investigated using the Motor Prediction task. The findings show that the basal ganglia and midbrain regions (i.e., habenula) are involved in motor prediction and enhancing the reinforcement learning process. This thesis aims to investigate the basal ganglia function in cognitive and motor tasks, and concludes with suggested further studies to advance our understanding of the role of the basal ganglia nuclei in cognitive function