Integrating Brain and Biomechanical Models—A New Paradigm for Understanding Neuro-muscular Control

To date, realistic models of how the central nervous system governs behavior have been restricted in scope to the brain, brainstem or spinal column, as if these existed as disembodied organs. Further, the model is often exercised in relation to an in vivo physiological experiment with input comprising an impulse, a periodic signal or constant activation, and output as a pattern of neural activity in one or more neural populations. Any link to behavior is inferred only indirectly via these activity patterns. We argue that to discover the principles of operation of neural systems, it is necessary to express their behavior in terms of physical movements of a realistic motor system, and to supply inputs that mimic sensory experience. To do this with confidence, we must connect our brain models to neuro-muscular models and provide relevant visual and proprioceptive feedback signals, thereby closing the loop of the simulation. This paper describes an effort to develop just such an integrated brain and biomechanical system using a number of pre-existing models. It describes a model of the saccadic oculomotor system incorporating a neuromuscular model of the eye and its six extraocular muscles. The position of the eye determines how illumination of a retinotopic input population projects information about the location of a saccade target into the system. A pre-existing saccadic burst generator model was incorporated into the system, which generated motoneuron activity patterns suitable for driving the biomechanical eye. The model was demonstrated to make accurate saccades to a target luminance under a set of environmental constraints. Challenges encountered in the development of this model showed the importance of this integrated modeling approach. Thus, we exposed shortcomings in individual model components which were only apparent when these were supplied with the more plausible inputs available in a closed loop design. Consequently we were able to suggest missing functionality which the system would require to reproduce more realistic behavior. The construction of such closed-loop animal models constitutes a new paradigm of computational neurobehavior and promises a more thoroughgoing approach to our understanding of the brain’s function as a controller for movement and behavior

Investigating the effects of psychosocial stress on cerebellar function

Differences in cerebellar structure and function are consistently reported in individuals exposed to early-life stress and individuals with diagnosed stress-related psychopathology. Despite this, current neurobiological models of stress have not considered the role of the cerebellum in the regulation of the stress response. Furthermore, it is unclear the mechanism by which stress may affect cerebellar function. The studies presented in this thesis set out to address these questions by exploring the relationship between acute psychosocial stress and the cerebellum. To achieve this, two putative cerebellar functions were investigated: saccadic adaptation and postural balance control. Chapters 4 and 5 present two studies, which evaluated the effectiveness of each task, as well as individual differences in task performance. Chapter 4 presents evidence demonstrating a linear effect of saccadic adaptation across participants. Chapter 5 revealed improved postural balance control under perturbed balancing conditions. Individual differences in task performance were inconclusive. Each study was followed by an investigation on the effects of acute psychosocial stress on task performance. Particularly, Chapter 6 demonstrated that stress impaired the rate of saccadic adaptation, and that this impairment was associated with the stress-related endocrine response. The study presented in Chapter 7 showed no effect of psychosocial stress on postural balance control. Finally, Chapter 8 explored the effects of non-invasive cerebellar stimulation on saccadic adaptation and cortisol output, revealing that a decrease in cerebellar excitability yielded adaptation rates that were similar to those observed after stress. These findings suggest that psychosocial stress impairs error-driven feedforward computations specifically, via glucocorticoid signalling, thus contributing to the current neurobiological models of stress

Motor Control of Rapid Eye Movements in Larval Zebrafish

Animals move the same body parts in diverse ways. How the central nervous system executes one action over related ones is poorly understood. To investigate this, I assessed the behavioural manifestation and neural control of saccadic eye rotations made by larval zebrafish, since these movements are simple and easy to investigate at a circuit level. I first classified the larva’s saccadic repertoire into 5 types, of which hunting specific convergent saccades and exploratory conjugate saccades were the main types used to orient vision. Convergent and conjugate saccades shared a nasal eye rotation, which had kinematic differences and similarities that suggested the rotation was made by overlapping but distinct populations of neurons between saccade types. I investigated this further, using two-photon Ca2+ imaging and selective circuit interventions to identify a circuit from rhombomere 5/6 to abducens internuclear neurons to motoneurons that was crucial to nasal eye rotations. Motoneurons had distinct activity patterns for convergent and conjugate saccades that were consistent with my behavioural observations and were explained largely by motoneuron kinematic tuning preferences. Surprisingly, some motoneurons also modulated activity according to saccade type independent of movement kinematics. In contrast, pre-synaptic internuclear neuron activity profiles were almost entirely explained by movement kinematics, but not neurons in rhombomere 5/6, which had mixed saccade type and kinematic encoding, like motoneurons. Regions exerting descending control on this circuit from the optic tectum and anterior pretectal nucleus had few neurons tuned to saccade kinematics compared to neurons selective for convergent saccades. My results suggest a transformation from encoding action type to encoding movement kinematics at successive circuit levels. This transformation was not monotonic or complete, and suggests that control of even simple, highly comparable, movements cannot be entirely described by a shared kinematic encoding scheme at a motor or premotor level

Compensatory strategies in humans performing active and passive gaze fixation and re-fixation tasks after unilateral vestibular deafferentation

The human vestibulo-ocular reflex (VOR) stabilizes gaze during head movement. The reflex is typically tested in a clinic or laboratory using passive rotations or artificial stimuli which measure the amount of damage the vestibular apparatus has suffered. However, during everyday activities the vestibular system is stimulated by active, self generated head movements. Head movements are often rapid and associated with the goal of achieving either gaze-fixation or re-fixation. Patients who complain of on-going symptoms will typically identify a particular position or movement that aggravates their symptoms in their everyday life. There is a need to identify objective parameters which correlate with the subjective complaints of patients whose symptoms persist after vestibular damage. In the first study, a gaze-refixation task, patients who complain of ongoing symptoms (poorly-compensated), during rapid head turns, after unilateral vestibular de-afferentation (uVD) were compared with those who did not have the same complaints (well-compensated) and normal subjects. Well- and poorly-compensated groups were sorted according to responses on a standardized questionnaire. All subjects were then located in a real-world, non-laboratory environment in which poorly-compensated subjects reported experiencing symptoms. Each subject’s head, eye and gaze displacement and velocity, head rotation frequency and blink or eye-lid closure were measured and analysed and compared between ipsi- and contra-lesional head rotations within and between subject groups. When subjects are able to generate their own active head rotations it has been suggested that a number of vestibular and extra-vestibular strategies might be employed to compensate for an impaired VOR. In subsequent studies, high resolution scleral search coils were used to identify the compensatory mechanisms used during active head rotations during a gaze-fixation task. A corrective saccade is typically observed during passive ipsilesional head rotations or “impulses” and might be potentiated during rapid, active or self-generated head rotations. The conditions which predict or contribute to the generation of the rapid, corrective eye movement were investigated. The results were compared with responses to passive head impulses of matched velocity and acceleration to determine if active head impulses could be used to identify a lesioned vestibular apparatus as is routinely clinically achieved with passive head impulses

NOCH: A framework for biologically plausible models of neural motor control

This thesis examines the neurobiological components of the motor control system and relates it to current control theory in order to develop a novel framework for models of motor control in the brain. The presented framework is called the Neural Optimal Control Hierarchy (NOCH). A method of accounting for low level system dynamics with a Linear Bellman Controller (LBC) on top of a hierarchy is presented, as well as a dynamic scaling technique for LBCs that drastically reduces the computational power and storage requirements of the system. These contributions to LBC theory allow for low cost, high-precision control of movements in large environments without exceeding the biological constraints of the motor control system

Diagnosis of Neurogenetic Disorders: Contribution of Next Generation Sequencing and Deep Phenotyping

The contribution of genomic variants to the aetiopathogenesis of both paediatric and adult neurological disease is being increasingly recognized. The use of next-generation sequencing has led to the discovery of novel neurodevelopmental disorders, as exemplified by the deciphering developmental disorders (DDD) study, and provided insight into the aetiopathogenesis of common adult neurological diseases. Despite these advances, many challenges remain. Correctly classifying the pathogenicity of genomic variants from amongst the large number of variants identified by next-generation sequencing is recognized as perhaps the major challenge facing the field. Deep phenotyping (e.g., imaging, movement analysis) techniques can aid variant interpretation by correctly classifying individuals as affected or unaffected for segregation studies. The lack of information on the clinical phenotype of novel genetic subtypes of neurological disease creates limitations for genetic counselling. Both deep phenotyping and qualitative studies can capture the clinical and patient’s perspective on a disease and provide valuable information. This Special Issue aims to highlight how next-generation sequencing techniques have revolutionised our understanding of the aetiology of brain disease and describe the contribution of deep phenotyping studies to a variant interpretation and understanding of natural history

The role of error-based learning in movement and stillness

When people and other animals perform a movement that produces an unexpected outcome, they learn from the resulting error and retain a portion of this learning over time. Curiously, for reaching movements of the arm, errors that occur solely during periods of movement cause changes to both the way we move and also the way we hold the arm still. Here, we explore the way the brain corrects for error after a single occurrence, how this response to error changes with experience, and finally, how these responses to error change the way we maintain stillness of the arm. In Chapter 2, we consider mechanisms that guide learning after a single error. Here we provide evidence that the brain uses its past corrections as a model for its future movement plans. This learning response does not remain fixed over time, but is augmented with experience. In Chapter 3, we describe a new algorithm that can be used to extract mathematical properties of adaptation. With this tool, we show that savings (faster rate of re-learning) is caused by an increase in the brain’s sensitivity to error, specifically within fast motor learning processes. Next, we show that reemergence of earlier memories is caused by the decay of fast learning processes. In Chapter 4, we show that anterograde interference (slower rate of re-learning) is caused by a reduction in one’s sensitivity to error, that recovers over time. Finally, in Chapter 5, we demonstrate that modulation of error sensitivity not only changes the rate at which we acquire motor memories, but also the point at which the learning process saturates. Lastly, in Chapter 6, we revisit our initial observation, that adaptation changes not only the way we move, but also the way we hold still. In a series of experiments in human and non-human primates, we report a surprising relationship between movement and posture: on a within-trial basis, the commands that hold the arm and finger at a target location depend in part on the mathematical integration of the commands that moved the limb to that location

Contributions of Spatial Working Memory to Visuomotor Adaptation.

Previous studies of motor learning have described the importance of cognitive processes during the early stages of learning. However, it remains unclear which cognitive processes contribute. In this dissertation, I test the role of one particular cognitive subsystem in the motor learning process, spatial working memory (SWM). This was tested through i) behavioral correlations between the rate of learning on a visuomotor adaptation task and SWM measures, and ii) confirming overlapping neural substrates between the two types of tasks using functional magnetic resonance imaging (fMRI). In the first study, I found that young adults’ performance on a behavioral test of SWM involving mental rotation correlated with the rate of early, but not late, visuomotor adaptation. In addition, participants showed overlapping brain activation during a SWM task and the early adaptation period in regions previously identified in other SWM and visuomotor adaptation studies. A similar analysis performed with the late phase of adaptation produced no commonly activated regions. These findings suggest that the early phase of visuomotor adaptation engages SWM processes related to mental rotation. It is well documented that both cognitive and motor learning abilities decline with normative aging. However, it is unclear whether age-related declines in SWM can partially explain age-related deficits in visuomotor adaptation. A group of older adults were tested using the same methodologies as in the first study, with their results then compared to the young adults’ findings. Older adults showed a less steep learning curve for the visuomotor adaptation task than young adults, and were also less accurate on each SWM task. Unlike the young adults, older adults’ early rate of adaptation did not correlate with SWM performance. Both groups showed very similar activation for the SWM task; however, older adults did not show neural activation overlap at the early (or late) visuomotor adaptation period. A pooled group partial correlation controlling for age revealed that a steeper early rate of adaptation was associated with increased activation in a brain region associated with SWM. These findings suggest that the effective engagement of SWM processes helps explain age-related differences in visuomotor adaptation.Ph.D.KinesiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/61757/1/janguera_1.pd

Life Sciences Program Tasks and Bibliography

This document includes information on all peer reviewed projects funded by the Office of Life and Microgravity Sciences and Applications, Life Sciences Division during fiscal year 1995. Additionally, this inaugural edition of the Task Book includes information for FY 1994 programs. This document will be published annually and made available to scientists in the space life sciences field both as a hard copy and as an interactive Internet web pag