The Becker-DeGroot-Marschak method (BDM) is an auction-like mechanism widely used in behavioural economics, marketing research, and, more recently, in neuroimaging studies of human decision making. The BDM has never been used with animal subjects before, yet its application in monkeys would allow for comparison of studies across species while providing a direct measure of what a reward is worth to a monkey in a single experimental trial. In the BDM, a subject is given a budget with which they can place a bid for some reward, and a computer then randomly selects a competing bid. If the subject’s bid is higher than the computer’s bid then the subject pays an amount equal to the computer’s bid, receives the reward object, and gets to keep the remaining budget. If the subject’s bid is lower than the computer’s bid, the subject does not gain the reward object but retains the entire budget. To adapt the task for monkeys, two rhesus macaques were taught to use water as a budget, and to use a joystick to place a bid in terms of this budget for different volumes of fruit-juice reward. The BDM ensures that the subject’s optimal action is to place a bid equal to their value for the reward-object. This property of truthful value revelation is the BDM’s most important feature in the context of value-based decision making. Currently, the only method of eliciting a monkey’s value for one reward in terms of another depends upon inference of the magnitudes at which the two rewards are chosen with equal probability. Using this ‘binary-choice’ method, many trials are needed to infer a single value: pairwise comparisons of many different magnitudes must be made and choices of each pair must be repeated so that the probability of choosing a reward can be estimated. In contrast, the BDM provides a direct measure of the monkey’s value for the reward as they explicitly state this value on each trial by selecting an equivalent bid. Therefore, the BDM more efficiently utilises the limited time in which a monkey’s behaviour can be assessed in each experimental session, as animals lose the motivation to participate when they become sated. The thesis summarised here describes the training and performance of two rhesus macaques on a novel version of the BDM, specifically designed for a subject that cannot be instructed on the optimal strategy. The technical steps and intermediate tasks that are needed to train a monkey to flexibly place bids by operating a joystick are also detailed, as well as the development of different versions of the task over three years of testing. The results of the final version of the BDM are then presented for both monkeys, showing rational bidding behaviour consistent with an understanding of the method’s contingencies. Theoretical concerns and limitations of the BDM in such a setting are also discussed and the thesis outlines how future experiments can make use of and adapt this version of the BDM for neuronal recording experiments.

Tourette syndrome (TS) is a neurodevelopmental disorder characterised by vocal and motor tics. It is associated with cortical–striatal–thalamic–cortical (CSTC) circuit dysfunction and hyper-excitability of cortical motor regions. TS follows a developmental time course, in which tics often become increasingly more controlled during adolescence. Importantly, however, a substantial minority of patients continue to have debilitating tics into adulthood. This indicates that there may be important differences between adult TS patients and children and adolescents with the disorder. The first aim of my thesis was to explore the excitability of the primary motor cortex (PMC) at rest, during motor preparation, motor execution and the inhibition of action. In Chapters 3 and 4 I demonstrate that, in contrast to studies of adult patients, resting motor threshold (RMT) and the variability of motor-evoked potential (MEP) responses are increased in young people with TS, while the gain of motor excitability in reduced. Furthermore, these differences normalise with age over adolescence. I conclude that these effects are likely due to a developmental delay in the maturation of key brain networks in TS, consistent with recent brain imaging studies of structural and functional brain connectivity. Importantly, these findings suggest that the alterations in brain network structure and function associated with TS may be quite different in children and adult patients with the condition. In Chapter 4, I demonstrate that whilst there is evidence of reduced gain during motor execution in young people with TS relative to controls (Chapter 3), the reduction is likely driven by baseline differences and when corrected to baseline patients with TS show an increased ramping of motor excitability during motor execution. In fact, patients’ tic severity was inversely related to the modulation of motor excitability whereby those with the most severe tics were least able to increase excitability. Patients showed largely the same patterns of change in excitability during motor preparation and response inhibition. However, the extent to which patients could modulate excitability during motor preparation was related to phonic tic severity whereby those with the least severe tics had higher excitability change from baseline. In addition, those that were able to suppress motor excitability to a greater extent whilst inhibiting action had the least severe tics, likely engaging inhibitory mechanisms to a greater extent with the consequence of slower response times during the task. I conclude that the ability to modulate motor excitability is both related to pathology and adaptive compensatory mechanisms that may help in tic suppression. The second aim of this thesis was to explore effective connectivity, excitatory and inhibitory physiological mechanisms and the neurochemistry of PMC in young healthy adults. Subsequent experiments in Chapters 5 and 6 used various transcranial magnetic stimulation (TMS) techniques and proton magnetic resonance spectroscopy (1H-MRS) to investigate these issues. Chapter 5 explored interhemispheric facilitation and inhibition (IHI and IHF) in two directions between bilateral PMC. The results provided evidence for an asymmetry of interhemispheric interactions using dual site TMS (ds-TMS) whereby the left-to-right direction is more inhibitory than right-to-left. Furthermore, females appeared to show greater interhemispheric modulation than males and whilst there was robust evidence for IHI (in the left-to-right direction) IHF appeared to not be robust. Finally, Chapter 6 explored how TMS-induced measures of excitation and inhibition related to 1H-MRS measures of neurochemicals γ-aminobutyric acid (GABA), glutamate (Glu) and glutamine (Gln). GABA is the primary inhibitory neurotransmitter in the human brain and is critical for the regulation of neuronal excitability and the orchestration of neuronal networks and is critically important in neurodevelopmental disorders such as TS. GABA was not found to be related to measures of synaptic neurotransmission as assessed by TMS and neither was Gln. In contrast, Glu was found to be related to a hub of TMS measures, in particular, Glu was positively related to both intracortical facilitation (ICF) and long intracortical inhibition (LICI). Chapters 5 and 6 further uncovered relationships between ds-TMS, pp-TMS and 1H-MRS showing that these various measures likely have overlapping mechanisms. The final chapters extend our knowledge about the PMC and the methodologies used to assess its state. Chapter 5 extends our understanding of the communication between right and left PMC and highlights a normal asymmetry in communication. This is important for understanding neurodevelopmental disorders such as TS of which asymmetry in effective connectivity and brain volume have been implicated. Chapter 6 importantly shows that 1H-MRS measured GABA is likely irrelevant for assessing synaptic neurotransmission and thus its interpretations should be limited to non-synaptic levels of GABA. This is particularly important for TS research in which both changes in GABAA receptor activity is present in the PMC and abnormalities in GABA concentration have been shown.

A habilidade de se preparar para futuros eventos é essencial para o comportamento. No presente trabalho, investigamos como diferentes formas de expectativa temporal podem modular o processamento de estímulos sensoriais. Por meio de 4 experimentos psicofísicos, sendo 2 com registro eletroencefalográfico (EEG) concomitante, nós estudamos o efeito da ação motora voluntária e da expectativa temporal em diferentes estágios do processamento sensorial. Nossos resultados sugerem que mecanismos ligados à preparação motora influenciam a percepção temporal das consequências desta ação. Além disso, nossos resultados mostraram que a atenção temporal pode modular estágios motores e sensoriais do processamento. Em conjunto, nossos resultados sugerem que expectativas temporais podem influenciar diferentes estágios do processamento principalmente por meio do controle de excitabilidade cortical de regiões do sistema nervoso central ligadas àquela tarefa. / The ability to anticipate future events is essential for behavior. On the present work, we investigated how different forms of temporal expectations can modulate stimuli processing. In four psychophysical experiments (two of them with EEG) we studied how voluntary action and temporal attention can influence processing at different stages. Our results suggest that mechanisms related to motor preparation can bias the temporal perception of the consequences of this action. Moreover, we found that temporal attention can modulate perceptual and motor stages of stimulus processing. Altogether, our results suggest that temporal expectations can influence different levels of target processing, mainly by controlling cortical excitability of task-relevant regions of the central nervous system.

The use of neuropsychological tests with regards to language and culture is a relatively under researched area. Previous research has found that cultural familiarity with test-items is important for minimising differences between groups and that completing tests in a second language can increase differences between groups on both language- and performance-based tests. An exploratory mixed methods design was used for this study. Participants were 46 participants with English as a first language (L1) and 23 participants with English as a second language (L2). The L1 and L2 participants differed only on the Language index of the SPANS, with L1 participants scoring significantly higher. Participants whose first language is not English reported generally that the test experience was good and the language used in the testing was clear. They reported some anxiety and worry in relation to memory and numbers. The results of this study support previous research which suggests that language may influence performance on language based neuropsychological tests as well as support for a need for culturally familiar test-items. As there were minimal differences between the two groups this is support for the SPANS’s use with the tested population with caution given to interpretation of the language index.

Visual tracking is the task of repeatedly inferring the state (position, motion, etc.) of the desired target in an image sequence. It is an important scientific problem as humans can visually track targets in a broad range of settings. However, visual tracking algorithms struggle to robustly follow a target in unconstrained scenarios. Among the many challenges faced by visual trackers, two important ones are occlusions and abrupt motion variations. Occlusions take place when (an)other object(s) obscures the camera's view of the tracked target. A target may exhibit abrupt variations in apparent motion due to its own unexpected movement, camera movement, and low frame rate image acquisition. Each of these issues can cause a tracker to lose its target. This thesis introduces the idea of learning and propagation of tracking information over multiple temporal scales to overcome occlusions and abrupt motion variations. A temporal scale is a specific sequence of moments in time Models (describing appearance and/or motion of the target) can be learned from the target tracking history over multiple temporal scales and applied over multiple temporal scales in the future. With the rise of multiple motion model tracking frameworks, there is a need for a broad range of search methods and ways of selecting between the available motion models. The potential benefits of learning over multiple temporal scales are first assessed by studying both motion and appearance variations in the ground-truth data associated with several image sequences. A visual tracker operating over multiple temporal scales is then proposed that is capable of handling occlusions and abrupt motion variations. Experiments are performed to compare the performance of the tracker with competing methods, and to analyze the impact on performance of various elements of the proposed approach. Results reveal a simple, yet general framework for dealing with occlusions and abrupt motion variations. In refining the proposed framework, a search method is generalized for multiple competing hypotheses in visual tracking, and a new motion model selection criterion is proposed.

The ease at which individuals acquire a second language is astounding. Individuals are capable of learning a second language at any point through out their lifespan, although it is easier to learn a second language early in life. With increasing knowledge about linguistic neural processing and the brain’s capacity for plasticity, the research on bilingualism has increased substantially. Researchers have become increasingly more interested in the long-term effects of acquiring a second language, especially the enhancement of executive function (EF). This enhancement, also known as bilingual advantage, has been studied for a range of EFs, including inhibition, attention, problem solving, and reasoning. Although this effect was first demonstrated in bilingual children, researchers have extended the quest for understanding to young, middle, and older adults; however, the research findings are mixed for young adults. In order clarify these mixed results, the age of second language acquisition has been included as an experimental variable, producing three relevant groups: early bilinguals, late bilinguals, and monolinguals. There are several ways in which EFs can be measured, including behavioral rating scales, computerized cognitive tasks with behavioral outcomes (i.e., response times and accuracy), and computerized event-related potential cognitive tasks. A novel multi-level approach to measuring the bilingual advantage was developed and used as a framework for the current dissertation; i.e., the bilingual advantage was measured at three levels of measurement. This approach predicts that more complex levels of measurement (i.e., executive behaviors) would produce null findings between the three groups, while differences between early bilinguals and the other two groups would be predicted for less complex levels of measurement (i.e., neurophysiological markers). This approach predicts mixed results for levels of measurement that involve moderate complexity (e.g., computerized tasks of EF). Early bilinguals, late bilinguals, and monolinguals were compared across three hierarchical levels of measurement: (i) executive behaviors; (ii) information processing (i.e., computerized tasks of EF); and (iii) neurophysiology (i.e., event-related potential paradigm). Findings generally support the multi-level approach: no differences were found at the executive behavior level, limited and mixed differences were found at the information processing level, and differences between groups were found at the neurophysiological level. / Graduate

Tourette Syndrome (TS) is a developmental neurological disorder characterised by vocal and motor tics and is associated with cortical-striatal-thalamic-cortical circuit dysfunction and hyper-excitability within cortical motor areas. TS symptoms often become more controlled throughout adolescence until the individual is largely tic-free by early adulthood. It is likely that adaptive changes occur in the development of brain structure and function throughout the critical developmental period of adolescence in people with TS, which leads to tic remission in some individuals. To investigate this I used multiple brain-imaging approaches including diffusion tensor imaging to look at white matter microstructure, T1-weighted anatomical MR imaging to measure cortical grey matter thickness and MR-Spectroscopy (MRS) to measure neurotransmitters of interest (GABA and glutamate) in a group of young people with TS and a typically developing matched control group. Brain function (measures of excitation and inhibition in M1) was also considered by using transcranial magnetic stimulation. A significant positive relationship was found between white matter structural integrity (FA) measured from the body of the corpus callosum that contained projections to M1 or the SMA and motor tic severity. The TS group had increased levels of GABA in the SMA, as measured by MRS, compared to the control group. SMA- GABA levels had a significant positive relationship with FA from the SMA ROI but a negative relationship with TMS measures of cortical excitability during movement preparation. This suggests that those individuals with the least severe tic symptoms also have reduced callosal white matter from the SMA (an area implicated in the production and suppression of tics) in adolescents with TS, which relates to a reduction in task based cortical excitability and a reduction in SMA-GABA compared to those with more severe tics. The results from this thesis suggest that tic-suppression may occur through decreasing excitatory inputs to M1, either through increasing the inhibition (GABA levels) of the SMA, or by decreasing the number of excitatory interhemispheric inputs to sensorimotor regions.

Transcranial magnetic stimulation (TMS) is a non-invasive technique that can be used to assess the integrity neuronal circuits in the motor cortex, both at the intrahemispheric and interhemispheric level. In the present study, TMS was used to examine age-related modulation of corticospinal function. Participants underwent hand function testing to examine possible links between TMS measures and manual ability. Participants consisted of healthy young (n=13) and senior (n=17) right-handed individuals. Hand function testing consisted of a battery of tests administered bilaterally to assess each participant’s dexterity, strength, movement speed and reaction time. The following TMS measures were assessed bilaterally: resting motor threshold, recruitment curve and silent periods of the contralateral and ipsilateral hand. Both young and senior subjects showed significant intermanual differences in most behavioral measures, favoring their dominant right hand. There was an age-related difference in TMS measures indicating a decline in intrahemispheric excitability and interhemispheric inhibition. A general trend linking specific TMS measures in the active state with age-related changes in hand function on the dominant hand was found. Our results suggest that TMS markers of corticospinal excitability can be used to predict declining hand function with age and thus could provide an early diagnosis of pathological aging.

Rationale: Cardiac function is under exquisite intrinsic cardiac neural control. Neuroablative techniques to modulate control of cardiac function are currently being studied in patients, albeit with variable and sometimes deleterious results. Objective: Recognizing the major gaps in our understanding of cardiac neural control, we sought to evaluate neural regulation of impulse initiation in the sinoatrial node (SAN) as an initial discovery step. Methods and Results: We report an in-depth, multiscale structural and functional characterization of the innervation of the SAN by the right atrial ganglionated plexus (RAGP) in porcine and human hearts. Combining intersectional strategies, including tissue clearing, immunohistochemical, and ultrastructural techniques, we have delineated a comprehensive neuroanatomic atlas of the RAGP-SAN complex. The RAGP shows significant phenotypic diversity of neurons while maintaining predominant cholinergic innervation. Cellular and tissue-level electrophysiological mapping and ablation studies demonstrate interconnected ganglia with synaptic convergence within the RAGP to modulate SAN automaticity, atrioventricular conduction, and left ventricular contractility. Using this approach, we comprehensively demonstrate that intrinsic cardiac neurons influence the pacemaking site in the heart. Conclusions: This report provides an experimental demonstration of a discrete neuronal population controlling a specific geographic region of the heart (SAN) that can serve as a framework for further exploration of other parts of the intrinsic cardiac nervous system (ICNS) in mammalian hearts and for developing targeted therapies.

Cette thèse s'insère dans un projet plus vaste, dont le but est de s'attaquer aux fondements mathématiques du problème inverse en contrôle optimal afin de dégager une méthodologie générale utilisable en neurophysiologie. Les deux questions essentielles sont : (a) l'unicité d'un coût pour une synthèse optimale donnée (injectivité); (b) la reconstruction du coût à partir de la synthèse. Pour des classes de coût générales, le problème apparaît très difficile même avec une dynamique triviale. On a donc attaqué l'injectivité pour des classes de problèmes spéciales : avec un coût quadratique, la dynamique étant soit non-holonome, soit affine en le contrôle. Les résultats obtenus ont permis de traiter la reconstruction pour le problème linéaire-quadratique. / This PhD thesis is part of a larger project, whose aim is to address the mathematical foundations of the inverse problem in optimal control in order to reach a general methodology usable in neurophysiology. The two key questions are : (a) the uniqueness of a cost for a given optimal synthesis (injectivity) ; (b) the reconstruction of the cost from the synthesis. For general classes of costs, the problem seems very difficult even with a trivial dynamics. Therefore, the injectivity question was treated for special classes of problems, namely, the problems with quadratic cost and a dynamics, which is either non-holonomic (sub-Riemannian geometry) or control-affine. Based on the obtained results, we propose a reconstruction algorithm for the linear-quadratic problem.