A Multiple-Plasticity Spiking Neural Network Embedded in a Closed-Loop Control System to Model Cerebellar Pathologies

The cerebellum plays a crucial role in sensorimotor control and cerebellar disorders compromise adaptation and learning of motor responses. However, the link between alterations at network level and cerebellar dysfunction is still unclear. In principle, this understanding would benefit of the development of an artificial system embedding the salient neuronal and plastic properties of the cerebellum and operating in closed-loop. To this aim, we have exploited a realistic spiking computational model of the cerebellum to analyze the network correlates of cerebellar impairment. The model was modified to reproduce three different damages of the cerebellar cortex: (i) a loss of the main output neurons (Purkinje Cells), (ii) a lesion to the main cerebellar afferents (Mossy Fibers), and (iii) a damage to a major mechanism of synaptic plasticity (Long Term Depression). The modified network models were challenged with an Eye-Blink Classical Conditioning test, a standard learning paradigm used to evaluate cerebellar impairment, in which the outcome was compared to reference results obtained in human or animal experiments. In all cases, the model reproduced the partial and delayed conditioning typical of the pathologies, indicating that an intact cerebellar cortex functionality is required to accelerate learning by transferring acquired information to the cerebellar nuclei. Interestingly, depending on the type of lesion, the redistribution of synaptic plasticity and response timing varied greatly generating specific adaptation patterns. Thus, not only the present work extends the generalization capabilities of the cerebellar spiking model to pathological cases, but also predicts how changes at the neuronal level are distributed across the network, making it usable to infer cerebellar circuit alterations occurring in cerebellar pathologies

Cerebellar Codings for Control of Compensatory Eye Movements

This thesis focuses on the control of the cerebellum on motor behaviour, and more specifically on the role of the cerebellar Purkinje cells in exerting this control. As the cerebellum is an online control system, we look at both motor performance and learning, trying to identify components involved at the molecular, cellular and network level. To study the cerebellum we used the vestibulocerebellum, with visual and vestibular stimulation as input and eye movements as recorded output. The advantage of the vestibulocerebellum over other parts is that the input given is highly controllable, while the output can be reliably measured, and performance and learning can be easily studied. In addition, we conducted electrophysiological recordings from the vestibulocerebellum, in particular of Purkinje cells in the flocculus. Combining the spiking behaviour of Purkinje cells with visual input and eye movement output allowed us to study how the cerebellum functions and using genetically modified animals we could determine the role of different elements in this system. To provide some insights in the techniques used and the theory behind them, we will discuss the following topics in this introduction: compensatory eye movements, the anatomy of pathways to, within and out of the flocculus, the cellular physiology of Purkinje cells in relation to performance and the plasticity mechanisms related to motor learning

The Intrinsic Plasticity Of Medial Vestibular Nucleus Neurons During Vestibular Compensation: A Systematic Review And Meta-Analysis

The diversity of activity displayed by neurons of the central nervous system is unmatched by any other cell in the body. Each neuron displays a characteristic, stereotypic pattern of firing which often defines its functional role (Llinas, 1988). Some neurons are spontaneously active at rest, displaying pacemaker-like properties, while others are very quiescent until stimulated by synaptic inputs. Some neurons fire rapid, regular action potential trains which show little deterioration in frequency over time. Others fire only short bursts of action potentials and reduce their rate of firing quickly, producing very little response to even large inputs (Bean, 2007). These discharge characteristics are fundamentally determined by two main features: the intrinsic membrane properties of the neuron and the nature of the synaptic inputs the neuron receives. Intrinsic properties are those relating to the architecture of the neuronal membrane, intracellular ionic buffers that regular electrolyte concentrations and the types of ion channels expressed on the membrane and their pattern of distribution (Wijesinghe & Camp, 2011). Meanwhile, synaptic properties are determined by the types of transmitters arriving at the neuronal surface, the distribution of these synapses and their density over various functionally specialised regions of the neuron (Spruston, 2008). From the various permutations of these different properties emerges the vast array of different firing characteristics observed of individual neurons from different regions of the brain (Llinas, 2014). Despite the prevalent stereotypy observed across different subtypes of neurons, alterations in the local environment and external stimuli can induce changes in these basic properties. This phenomenon, known as neuronal plasticity, has been observed in normal physiological states and is believed to underlie experience-dependent changes in neural activity such as learning and memory (Mayford, Siegelbaum & Kandel, 2012; Sweatt, 2016). It has also been observed in various disease states and may act as a homeostatic mechanism to downregulate excitotoxicity or restore lost functional capacities (Beck & Yaari, 2008; Camp, 2012; Vitureira, Letellier & Goda, 2012; Yin & Yuan, 2014). These changes were first observed to occur in synapses, where high intensity stimuli induced changes that altered the likelihood of signal transmission at a particular synapse. Since then, the stimuli that induce synaptic plasticity and the cellular mechanisms that maintain these changes have been widely investigated (Bailey, Kandel & Harris, 2015; Kandel, 2001). However, it has now been recognised that intrinsic neuronal properties themselves are plastic and may contribute to some of the processes previously attributed to synaptic mechanisms alone (Desai, 2003; Hanse, 2008; Mozzachiodi & Byrne, 2010; Titley, Brunel & Hansel, 2017). A number of studies in the past 30 years have demonstrated important activity-dependent changes in firing dynamics that appear to be act along multiple timescales and influence network activity in a variety of ways. These changes, termed intrinsic plasticity, are manifest in the patterns and frequency of action potential discharge of individual neurons. This dynamism is primarily driven by alterations in ion channel expression, excitatory neurotransmitter receptor expression and intracellular buffering protein concentrations (Beraneck & Idoux, 2012; Camp & Wijesinghe, 2009). I am interested in the studying the basic intrinsic properties of individual neurons, how they determine discharge dynamics in networks, and the conditions that modulate these properties (for example see previous work in Camp & Wijesinghe, 2009; Wijesinghe & Camp, 2011; Wijesinghe, Solomon & Camp, 2013; Wijesinghe et al., 2015). In particular, I am interested in how pathological changes might influence the firing properties of downstream neurons. Typically, animal models with a simple neuronal circuit, an easily lesioned peripheral sensory organ and observable behaviours have been chosen for such studies. One such model system is the vestibular system, which maintains our sense of equilibrium. It is composed of an easily accessible neuronal circuit within the brainstem which is homologous between a number of species (Goldberg et al., 2012). It mediates basic reflexes that maintain gaze stability during head movement and stabilises dynamic posture (Bronstein, Patel & Arshad, 2015). This sensory modality also has a unique property of near immediate recovery following damage to the components that mediate it, a process known as vestibular compensation (Curthoys & Halmagyi, 1995). This process occurs in humans and can be reliably reproduced experimentally, making it a convenient model to bridge in vitro findings to clinical observations (Straka, Zwergal & Cullen, 2016). Recent studies have suggested that vestibular compensation may be behavioural correlate of a form of experience-dependent plasticity occurring within the vestibular nuclei of the brainstem (Dutia, 2010; Lacour & Tighilet, 2010; Macdougall & Curthoys, 2012). More interestingly, part of the recovery may be mediated by changes in the intrinsic properties of vestibular nucleus neurons in a way that is necessary for the process to occur. In the thesis that follows, I present the first comprehensive systematic review of the scientific literature searching for evidence to investigate the following hypothesis: intrinsic plasticity mediates changes observed during the acute phase of vestibular compensation. To determine the methodological quality of studies discovered through searches of electronic databases, I independently developed tools to assess the precision, validity and bias of each study. Based on a total of 17 studies which met pre-determined inclusion and exclusion criteria, I conclude that there is evidence in favour of the hypothesis. Then, pooling quantitative data from this evidence, I performed a meta-analysis which demonstrates a moderate, statistically significant increase in the intrinsic excitability of medial vestibular nucleus neurons following unilateral vestibular deafferentation. Specifically, their spontaneous discharge rate increases by 4 spikes/sec on average and their sensitivity (or gain) in response to current stimuli increases. Using this novel approach, I demonstrate that the methodology of systematic review and meta-analysis is a useful tool in the summation of data across experimental studies with similar aims. I also identify a number of areas in which the reporting of experimentation in field of vestibular research can be improved to strengthen the quality and validity of future work. Despite the prevalent stereotypy observed different subtypes of neurons, alterations in the local environment and external stimuli can induce changes in these basic properties. This phenomenon, known as neuronal plasticity, has been observed in normal physiological states and is believed to underlie experience-dependent changes in neural activity such as learning and memory (Mayford, Siegelbaum et al. 2012, Sweatt 2016). It has also been observed in various disease states and may act as a homeostatic mechanism to downregulate excitotoxicity or restore lost functional capacities (Beck and Yaari 2008, Camp 2012, Vitureira, Letellier et al. 2012, Yin and Yuan 2014). These changes were first observed to occur in synapses, where high intensity stimuli induced changes that altered the likelihood of signal transmission at a particular synapse. Since then, the stimuli that induce synaptic plasticity and the cellular mechanisms that maintain these changes have been widely investigated (Kandel 2001, Bailey, Kandel et al. 2015). However, it has now been recognised that intrinsic neuronal properties themselves are plastic and may contribute to some of the processes previously solely attributed to synaptic mechanisms (Desai 2003, Hanse 2008, Mozzachiodi and Byrne 2010, Titley, Brunel et al. 2017). A number of studies in the past 20 years have demonstrated important activity dependent changes in firing dynamics that appear to be act along multiple timescales and influence network activity in a variety of ways. These changes, termed intrinsic plasticity, are manifest in the patterns and frequency of action potential discharge of individual neurons. This dynamism is primarily driven by alterations in ion channel expression, excitatory neurotransmitter receptor expression and intracellular buffering protein concentrations (Camp and Wijesinghe 2009, Beraneck and Idoux 2012). I am interested in the studying the basic intrinsic properties of individual neurons, how they determine discharge dynamics in networks, and the conditions that modulate these properties. In particular, I am interested in how pathological changes might influence the firing properties of downstream neurons. Typically, animal models with a simple neuronal circuit, an easily lesioned peripheral sensory organ and observable behaviours have been chosen for such studies. One such model system is the vestibular system, which maintains an animal’s sense of equilibrium. It is composed of an easily accessible neuronal circuit within the brainstem which is homologous between a number of species (Goldberg, Wilson et al. 2012). It mediates basic reflexes that maintain gaze stability during head movement (vestibuloocular reflex) and stabilises posture (vestibulospinal reflex) (Bronstein, Patel et al. 2015). This sensory modality also has a unique property of near immediate and complete recovery following damage to the components that mediate it, a process known as vestibular compensation (Curthoys and Halmagyi 1995). For example, following unilateral peripheral vestibular lesions, the acute symptom of vertigo and its behavioural effects abate spontaneously within days (Fetter 2016). This process occurs in humans and can be reliably reproduced experimentally, making it a convenient and ideal model to bridge in vitro findings to clinical observations (Straka, Zwergal et al. 2016). Recent studies have suggested that vestibular compensation may be a form of experience dependent plasticity which occurs within the brainstem vestibular reflex arc, most clearly in the vestibular nuclei (Dutia 2010, Lacour and Tighilet 2010, Macdougall and Curthoys 2012). More interestingly, part of the recovery may be mediated by changes in the intrinsic properties of vestibular nucleus neurons. Many of these changes are of the firing patterns and sensitivity to external stimuli, reflecting changes in the intrinsic properties of these. In the thesis that follows, I present a systematic review of the scientific literature looking for evidence to investigate the following hypothesis: intrinsic plasticity mediates changes observed during vestibular compensation. To determine the quality of studies revealed through searches of electronic databases, I independently developed tools to assess the precision, validity and bias of each study. Based on a total of 16 studies which met pre-determined inclusion and exclusion criteria, I conclude that there is moderate amount of moderate quality evidence, and a small amount of high quality evidence, in favour of the hypothesis. Further, using quantitative data from rodent models of compensation, I performed a meta-analysis which demonstrates strong, statistically significant evidence in favour of the hypothesis. In summary, published evidence to date supports the notion that unilateral vestibular lesions induce changes in the intrinsic membrane properties of medial vestibular nucleus neurons such that their spontaneous discharge rate increases and their sensitivity (or gain) in response to current stimuli increases

A multi-layer mean-field model of the cerebellum embedding microstructure and population-specific dynamics

Mean-field (MF) models are computational formalism used to summarize in a few statistical parameters the salient biophysical properties of an inter-wired neuronal network. Their formalism normally incorporates different types of neurons and synapses along with their topological organization. MFs are crucial to efficiently implement the computational modules of large-scale models of brain function, maintaining the specificity of local cortical microcircuits. While MFs have been generated for the isocortex, they are still missing for other parts of the brain. Here we have designed and simulated a multi-layer MF of the cerebellar microcircuit (including Granule Cells, Golgi Cells, Molecular Layer Interneurons, and Purkinje Cells) and validated it against experimental data and the corresponding spiking neural network (SNN) microcircuit model. The cerebellar MF was built using a system of equations, where properties of neuronal populations and topological parameters are embedded in inter-dependent transfer functions. The model time constant was optimised using local field potentials recorded experimentally from acute mouse cerebellar slices as a template. The MF reproduced the average dynamics of different neuronal populations in response to various input patterns and predicted the modulation of the Purkinje Cells firing depending on cortical plasticity, which drives learning in associative tasks, and the level of feedforward inhibition. The cerebellar MF provides a computationally efficient tool for future investigations of the causal relationship between microscopic neuronal properties and ensemble brain activity in virtual brain models addressing both physiological and pathological conditions

Cerebellar Nonmotor Functions – Approaches and Significance

The cerebellum is involved in the control of motor and nonmotor functions. Refined and innovative experimental and clinical approaches, starting from anatomy and including functional magnetic resonance imaging (fMRI), have allowed researchers to store extensive information on the cerebellar contributions to motor control and also helped them to understanding cerebellar nonmotor functions. Does the cerebellum process exclusively cerebral information related to certain specific actions, or does it also process some forms of information independent of such relation? At present, researchers are close to evaluating how the cerebellum is active during resolution of cognitive tasks. Various therapy lines in perspective, from cerebellar stimulation to cerbellar grafts and artificial cerebellum, are of particular significance, as they can restore lost brain functions in animal models and repair insufficient brain processes in patients.Мозочок залучений у контроль моторних та немоторних функцій. Вдосконалені та інноваційні експериментальні та клінічні підходи, починаючи від врахування даних анатомічних досліджень та аж до використання результатів функціональної магніто-резонансної томографії (fMRT), дозволили дослідникам отримати великий обсяг інформації щодо внесків мозочка в керування рухами і допомогли усвідомити, що мозочок також виконує функції немоторного контролю. Виникає питання: чи оброблює мозочок виключно церебральну інформацію щодо контролю певних специфічних дій, або він також має відношення до обробки деяких форм інформації, незалежних від таких відношень. Зараз дослідники вже підійшли до визначення того, яким чином мозочок є активним протягом вирішення когнітивних задач. Різні перспективні підходи в терапії (від стимуляції мозочка до використання імплантів мозочка та «штучного» мозочка) виглядають досить важливими, оскільки вони дозволяють відновити втрачені мозкові функції в модельних експериментах на тваринах та коригувати певні процеси мозкової недостатності у пацієнтів

The role of non-invasive camera technology for gait analysis in patients with vestibular disorders

Purpose of the study Current balance assessments performed in clinical settings do not provide objective measurements of gait. Further, objective gait analysis typically requires expensive, large and dedicated laboratory facilities. The aim of this pilot study was to develop and assess a low-cost, non-invasive camera technology for gait analysis, to assist the clinical assessment of patients with vestibular disorders. Materials and methods used This is a prospective, case-controlled study that was developed jointly by the local Neurotology Department and the Centre for Sports Engineering Research. Eligible participants were approached and recruited at the local Neurotology Clinic. The gait assessment included two repetitions of a straight 7-metre walk. The gait analysis system, comprised of a camera (P3215-V, Axis Communications, Sweden) and analysis software was installed in an appropriately sized clinic room. Parameters extruded were walking velocity, step velocity, step length, cadence and step count per meter. The effect sizes (ESB) were calculated using the MatLab and were considered large, medium or small if >0.8, 0.5 and 0.2 respectively. This study was granted ethical approval by the Coventry and Warwickshire Research Ethics Committee (15/WM/0448). Results Six patients with vestibular dysfunction (P group) and six age-matched healthy volunteers (V group) were recruited in this study. The average velocity of gait for P group was 1189.1 ± 69.0 mm·s-1 whereas for V group it was 1351.4 ± 179.2 mm·s-1, (ESB: -0.91). The mean step velocities were 1353.1 ± 591.8 mm·s-1 and 1434.0 ± 396.5 mm·s-1 for P and V groups respectively (ESB: -0.20). The average cadence was 2.3 ± 0.9 Hz and 2.0 ± 0.5 Hz for P and V groups respectively (ESB: 0.60). The mean step length was 620.5 ± 150.7 mm for the P group and 728.5 ± 86.0 mm for the V group (ESB = -1.26). The average step count per meter was 1.7 ± 0.3 and 1.4 ± 0.1 for P and V groups respectively (ESB = 3.38). Conclusion This pilot study used a low-cost, non-invasive camera technology to identify changes in gait characteristics. Further, gait measurements were obtained without the application of markers or sensors to patients (i.e. non-invasive), thus allowing current, clinical practice to be supplemented by objective measurement, with minimal procedural impact. Further work needs to be undertaken to refine the device and produce normative data. In the future, similar technologies could be used in the community setting, providing an excellent diagnostic and monitoring tool for balance patients