905 research outputs found

    Use of functional neuroimaging and optogenetics to explore deep brain stimulation targets for the treatment of Parkinson's disease and epilepsy

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    Deep brain stimulation (DBS) is a neurosurgical therapy for Parkinson’s disease and epilepsy. In DBS, an electrode is stereotactically implanted in a specific region of the brain and electrical pulses are delivered using a subcutaneous pacemaker-like stimulator. DBS-therapy has proven to effectively suppress tremor or seizures in pharmaco-resistant Parkinson’s disease and epilepsy patients respectively. It is most commonly applied in the subthalamic nucleus for Parkinson’s disease, or in the anterior thalamic nucleus for epilepsy. Despite the rapidly growing use of DBS at these classic brain structures, there are still non-responders to the treatment. This creates a need to explore other brain structures as potential DBS-targets. However, research in patients is restricted mainly because of ethical reasons. Therefore, in order to search for potential new DBS targets, animal research is indispensable. Previous animal studies of DBS-relevant circuitry largely relied on electrophysiological recordings at predefined brain areas with assumed relevance to DBS therapy. Due to their inherent regional biases, such experimental techniques prevent the identification of less recognized brain structures that might be suitable DBS targets. Therefore, functional neuroimaging techniques, such as functional Magnetic Resonance Imaging and Positron Emission Tomography, were used in this thesis because they allow to visualize and to analyze the whole brain during DBS. Additionally, optogenetics, a new technique that uses light instead of electricity, was employed to manipulate brain cells with unprecedented selectivity

    Functional Connectivity of the Rodent Striatum

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    The striatum serves as the major input nucleus of the basal ganglia circuitry, important for its varied roles in cognition, motivation, and sensorimotor function. Despite decades of study, fundamental features of the striatum’s functional organization and broader role(s) within the basal ganglia circuitry remain contentious and/or poorly defined. Given the diverse and critical roles of striatal activity in normal brain function and a multitude of disease states (including neurodegenerative and psychiatric disorders), a better understanding of this nucleus’ functional organization is imperative. The use of electrophysiological tools, which predominate the field, allow for in-depth characterizations of discrete, pre-selected brain regions, but are not appropriate for delineating functional neural circuit interactions on large spatial scales in an unbiased manner. A complementary approach to these studies is the use of functional magnetic resonance imaging (fMRI), which provides global, unbiased measures of functional neural circuit and network connectivity. In the first two studies described herein (Chapters 2 and 3), we used fMRI to map the functional response patterns to electrical DBS of the rat nucleus accumbens (NAc; ventral striatum), as well as the dual striatal outputs: external globus pallidus (GPe), and substantia nigra pars reticulata. Notable findings included the presence of negative fMRI signals in striatum during stimulation of each nuclei, robust prefrontal cortical modulation by NAc- and GPe-DBS, and marked functional connectivity changes by high frequency DBS. We next used optogenetic tools to more selectively map the brain-wide responses to stimulation of GPe neurons in healthy and Parkinson’s disease model rats (Chapter 4), as well as dorsal striatal neurons and their motor cortical inputs (Chapter 5). Optogenetic stimulation of each nuclei elicited an intriguing dorsal striatal negative fMRI signal, observed during direct striatal stimulation as well as putative recruitment of both excitatory both inhibitory striatal inputs, and thus suggestive of neurovascular uncoupling. Additionally, results from our GPe experiments revealed that this signal may be compromised in certain neurological disease states (e.g., Parkinson’s disease). Collectively, the studies described in this dissertation have exploited fMRI tools to reveal novel features of striatal connectivity, which may shed light on striatal function in health and disease.Doctor of Philosoph

    Frequency-selective control of cortical and subcortical networks by central thalamus

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    Central thalamus plays a critical role in forebrain arousal and organized behavior. However, network-level mechanisms that link its activity to brain state remain enigmatic. Here, we combined optogenetics, fMRI, electrophysiology, and video-EEG monitoring to characterize the central thalamus-driven global brain networks responsible for switching brain state. 40 and 100 Hz stimulations of central thalamus caused widespread activation of forebrain, including frontal cortex, sensorimotor cortex, and striatum, and transitioned the brain to a state of arousal in asleep rats. In contrast, 10 Hz stimulation evoked significantly less activation of forebrain, inhibition of sensory cortex, and behavioral arrest. To investigate possible mechanisms underlying the frequency-dependent cortical inhibition, we performed recordings in zona incerta, where 10, but not 40, Hz stimulation evoked spindle-like oscillations. Importantly, suppressing incertal activity during 10 Hz central thalamus stimulation reduced the evoked cortical inhibition. These findings identify key brain-wide dynamics underlying central thalamus arousal regulation

    Investigating the mechanism of action of Deep Brain Stimulation using functional magnetic resonance imaging

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    Depleted of dopamine, the dynamics of the Parkinsonian brain impact on both “action” and “resting” motor behaviour. Subthalamic nucleus deep brain stimulation (STN DBS) has become an established means of managing these symptoms, although its mechanisms of action remain unclear. Functional magnetic resonance imaging (fMRI) using the blood oxygen level dependent (BOLD) contrast provides the opportunity to study the human brain in vivo, collecting indirect measures of neural activity across the whole brain. To date, technical difficulties and safety concerns have precluded the use of fMRI in DBS patients. Previous work from this department has demonstrated that scanning patients with certain DBS systems and MRI equipment is both safe and feasible. This thesis explores the neuromodulatory actions of STN DBS on both action and resting motor behaviours in patients with Parkinson’s disease (PD) using fMRI. In brief, I present two fMRI studies conducted on STN DBS patients, one task-based, and one resting, collected under a previously approved protocol. I then present experiments exploring the safety of scanning DBS patients using an improved protocol, and then detail two further experiments collected under this new protocol, again one task-based, and one resting. Specifically, I employ statistical parametric mapping to determine DBS-induced changes in motor evoked responses. Using dynamic causal modelling (DCM) and Bayesian model selection, I compare generative models of cortico-subcortical interactions to explain the observed data, inferring which connections DBS may be affecting, and which modulations predict efficacy. I proceed to use stochastic DCM to model the modulatory effects of DBS on endogenous (resting-state) dynamics. Abstract | 4 4 This work casts DBS in terms of modulating effective connectivity within the cortico-basal ganglia motor loops. I discuss how this may explain its current usage in PD, as well as exploratory uses to treat other pathological brain states

    Dopaminergic dysfunction in neurodevelopmental disorders: recent advances and synergistic technologies to aid basic research

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    Neurodevelopmental disorders (NDDs) represent a diverse group of syndromes characterized by abnormal development of the central nervous system and whose symptomatology includes cognitive, emotional, sensory, and motor impairments. The identification of causative genetic defects has allowed for creation of transgenic NDD mouse models that have revealed pathophysiological mechanisms of disease phenotypes in a neural circuit- and cell type-specific manner. Mouse models of several syndromes, including Rett syndrome, Fragile X syndrome, Angelman syndrome, Neurofibromatosis type 1, etc., exhibit abnormalities in the structure and function of dopaminergic circuitry, which regulates motivation, motor behavior, sociability, attention, and executive function. Recent advances in technologies for functional circuit mapping, including tissue clearing, viral vector-based tracing methods, and optical readouts of neural activity, have refined our knowledge of dopaminergic circuits in unperturbed states, yet these tools have not been widely applied to NDD research. Here, we will review recent findings exploring dopaminergic function in NDD models and discuss the promise of new tools to probe NDD pathophysiology in these circuits

    Cerebellum

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    A role for the cerebellum in causing ataxia, a disorder characterized by uncoordinated movement, is widely accepted. Recent work has suggested that alterations in activity, connectivity, and structure of the cerebellum are also associated with dystonia, a neurological disorder characterized by abnormal and sustained muscle contractions often leading to abnormal maintained postures. In this manuscript, the authors discuss their views on how the cerebellum may play a role in dystonia. The following topics are discussed: The relationships between neuronal/network dysfunctions and motor abnormalities in rodent models of dystonia. Data about brain structure, cerebellar metabolism, cerebellar connections, and noninvasive cerebellar stimulation that support (or not) a role for the cerebellum in human dystonia. Connections between the cerebellum and motor cortical and sub-cortical structures that could support a role for the cerebellum in dystonia. Overall points of consensus include: Neuronal dysfunction originating in the cerebellum can drive dystonic movements in rodent model systems. Imaging and neurophysiological studies in humans suggest that the cerebellum plays a role in the pathophysiology of dystonia, but do not provide conclusive evidence that the cerebellum is the primary or sole neuroanatomical site of origin.P40 OD010996/ODCDC CDC HHS/Office of the Director/United StatesR01 NS079750/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesP51 OD011132/ODCDC CDC HHS/Office of the Director/United StatesR25 MH086466/NIMH NIH HHS/National Institute of Mental Health/United StatesR01 NS024328/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesR01 NS082296/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesP30 NS076405/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesR01 NS085054/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesR01 NS050808/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesU54 TR001456/NCATS NIH HHS/National Center for Advancing Translational Sciences/United StatesR01 NS069936/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesU54 NS065701/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesR01 NS088528/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesK08 NS072158/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United States2018-04-01T00:00:00Z27734238PMC53365116542vault:3362

    Dopaminergic dysfunction in neurodevelopmental disorders: recent advances and synergistic technologies to aid basic research

    Get PDF
    Neurodevelopmental disorders (NDDs) represent a diverse group of syndromes characterized by abnormal development of the central nervous system and whose symptomatology includes cognitive, emotional, sensory, and motor impairments. The identification of causative genetic defects has allowed for creation of transgenic NDD mouse models that have revealed pathophysiological mechanisms of disease phenotypes in a neural circuit- and cell type-specific manner. Mouse models of several syndromes, including Rett syndrome, Fragile X syndrome, Angelman syndrome, Neurofibromatosis type 1, etc., exhibit abnormalities in the structure and function of dopaminergic circuitry, which regulates motivation, motor behavior, sociability, attention, and executive function. Recent advances in technologies for functional circuit mapping, including tissue clearing, viral vector-based tracing methods, and optical readouts of neural activity, have refined our knowledge of dopaminergic circuits in unperturbed states, yet these tools have not been widely applied to NDD research. Here, we will review recent findings exploring dopaminergic function in NDD models and discuss the promise of new tools to probe NDD pathophysiology in these circuits
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