Colum D. MacKinnon, PhD - US grants

[unreadable] DESCRIPTION (provided by applicant): Parkinson's disease (PD) affects more than a million people in the United States. Voluntary movement in these patients is characterized by slowness and reduced movement amplitude (bradykinesia) and a lack of spontaneous volitional movement (akinesia). The severity of bradykinesia increases with disease progression and has a significant impact on quality of life. Bradykinesia is most evident during the performance of fast repetitive movements and worsened when external cues are removed. The purpose of this project is to examine the mechanisms contributing to impaired repetitive movement in patients with PD and the effects of the two most successful treatments for PD, levodopa and high frequency stimulation of the subthalamic nucleus (STN-DBS), on these mechanisms. The first specific aim will examine the effects of movement cueing (external vs. internal cues), frequency (0.8 Hz vs. 2 Hz) and levodopa on repetitive finger movement and movement-related cortical oscillations recorded using electroencephalography (EEC). The second specific aim will examine the effects of the same factors (cueing, movement frequency and levodopa) on the patterns of movement-related activity in the basal ganglia (a group of deep brain structures) of awake patients with PD. Basal ganglia activity will be recorded from electrodes implanted in the subthalamic nucleus (STN) of patients with PD. The third specific aim will compare the effects of levodopa versus STN-DBS on movement-related cortical oscillations. High-resolution EEC recordings of motor cortical activity will be used to examine how these treatments affect repetitive movement. These experiments will be the first to examine the neurophysiological basis for the deterioration of motor performance during repetitive movements in PD and the cortical mechanisms by which levodopa and STN-DBS improve the performance of these movements. The long-term goals of this project are twofold: to develop improved rehabilitation techniques that take advantage of factors that facilitate movement performance and to develop improved methods for the delivery of deep brain stimulation. Dysfunction of the basal ganglia is implicated in a variety of neurological disorders, including PD, that affect a large segment of the US population. This project is relevant to public health because the findings will provide a better understanding of the human basal ganglia and its role in the production of disordered movement and help to develop improved treatments. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): In advanced stages of Parkinson's disease (PD), the absence of spontaneous volitional movements (akinesia) often becomes the most debilitating aspect of the disease. In a subset of patients, akinesia manifests as an episodic impairment in the initiation of gait (start hesitation) in conjunction with freezing of gait (FOG). With disease progression, akinesia, start hesitation and FOG often becomes refractory to current treatments such as levodopa and deep brain stimulation. Currently there are no effective treatments for these symptoms. Yet, one of the paradoxes of PD is it that, under certain contexts, the provision of external cues can markedly facilitate movement initiation, even in those with profound akinesia in the off medication state. This observation demonstrates that patients with PD retain the capacity to initiate movement, but for reasons that are not understood, are unable to reliably access these pathways, particularly in self-initiated (non-cued) conditions. Despite the consensus that external cues can facilitate movement initiation in PD, clinical trials examining the efficacy of using external cues in the home environment have been disappointing. We propose that the utility of using external cues in clinical and home environments is currently limited by our lack of understanding of the conditions required to reliably facilitate initiation with cues and the mechanisms mediating the release of movement. The first Specific Aim of this project will examine the effects of cueing modality (acoustic, visual or somatosensory) and cue timing on the preparation and initiation of gait in patients with start hesitation. Information derived from these experiments can be used to establish stimulus presentation protocols that can be implemented in the clinical or home environments or via portable devices. Specific Aim 2 will use high- resolution EEG recordings and functional magnetic resonance imaging (fMRI) to examine the cortical and subcortical structures that mediate the preparation and release of movements by external cues. Specific Aim 3 will use transcranial direct current stimulation (tDCS) to examine the effects of transient suppression or facilitation of frontal cortical structures that are considered to a play role in the planning, preparation and initiation of gait and upper limb movements. These experiments will provide insight into the mechanisms and pathways that enable external cues to circumvent the impaired initiation of voluntary movements in patients with PD, such as start hesitation, and will provide an empirical rationale for the development of novel therapeutic interventions that facilitate these pathways.

? DESCRIPTION (provided by applicant): Postural instability and gait disturbances, including freezing of gait are common, disabling and poorly understood symptoms that afflict approximately half of all patients with Parkinson's disease. With disease progression these symptoms become resistant to treatment and are major causes of falls, immobility and increased morbidity. Currently there are no effective treatments. Degeneration of the pedunculopontine nucleus, a region in the brainstem that controls locomotor pattern generation and postural tone, has been hypothesized to mediate the pathogenesis of postural instability and gait dysfunction. The pedunculopontine nucleus also plays a role in suppressing muscle activity during rapid eye movement (REM) sleep. Thus, the loss of the pedunculopontine nucleus should manifest as disturbances in both sleep and gait. This project will conduct a series of experiments to establish that neurodegenerative processes that disrupt the control muscle activity during REM sleep are closely linked to the development and progression of treatment-resistant postural instability and gait dysfunction. Quantitative assessments of sleep and motor function (gait, gait initiation, postural stability), in conjunction with magnetic resonance imaging measures of structural (from diffusion- weighted imaging) and functional connectivity (from resting-state functional imaging) of the region of the pedunculopontine nucleus, will be obtained in a cohort of patients with early stage Parkinson's disease. These patients will be followed for three years to map the progression of changes in sleep, motor function and organization of brainstem locomotor pathways. We hypothesize that the loss of suppression of muscle activity during REM sleep will be predictive of the rate of progression of treatment-resistant motor features of disease and changes in structural and functional connectivity of the PPN region. Establishment of a link between REM sleep disorder and the development of treatment-resistant motor features of disease will help to identify individuals at risk of developing these symptoms. Since REM sleep disturbances can often be recognized years or decades before the emergence of parkinsonian motor symptoms, this may provide a critical period for early intervention to slow or prevent disease progression. Overall the study section was very enthusiastic about the focus of this application which addresses an area of high significance, but specific concerns reduced the overall level of enthusiasm.

Project Summary/Abstract Deep brain stimulation (DBS) in the region of the globus pallidus (GP) or subthalamic nucleus (STN) has been demonstrated to provide clinically meaningful improvements in motor function and improve patient quality of life in people with Parkinson?s disease (PD). While the STN is the typical target of choice at most neurosurgical centers, there has been a resurgence of interest in selecting the GP as a target. This interest is based on evidence that the overall clinical effects are comparable to those of STN DBS, but GP DBS may have fewer neuropsychological side-effects and affords greater flexibility for programming and adjustment of medications. Yet, there is considerable variability in response to GP DBS across patients, levodopa dose typically remains high, and, like STN DBS, is it ineffective for levodopa-resistant motor features such as postural instability, gait disturbances and freezing of gait. We argue that significant improvements in the efficacy of GP DBS can be gained through an increased understanding of the mechanisms, locations and pathways mediating the motor effects of DBS in the human pallidum. The premise of this project is that the motor effects of conventional GP DBS are compromised by a balance between the need to suppress levodopa-induced dyskinesias (akinetic) and reduce bradykinesia (prokinetic). We will test the hypothesis that the mechanisms and locations mediating these ?opposite effects? are in functionally and topographically separate regions of the GP. This hypothesis will be tested by conducting a systematic study of the effects of GP stimulation location on both levodopa- responsive (rigidity and bradykinesia) and levodopa-resistant (balance, gait, freezing) motor features of PD (Aim 2), and the topography of movement-related oscillatory activity within the pallidum (GPi and GPe) and STN by recording local field potentials in people with chronically implanted electrodes (Aim 3). State-of-the-art high-field MRI (7T) and patient-specific tractography-activation models will be used to focus stimulation to the region of interest (ventral GPi, dorsal GPi, ventral GPe) and estimate the pallidofugal pathways activated by stimulation (Aim 1). The results of these experiments will provide critical information about the stimulation location and axonal pathways mediating improvement or deterioration of motor signs with GP DBS, the neurophysiological biomarkers of disordered movement, and how these biomarkers are changed by medication and DBS. This knowledge can be translated to the next generation of DBS devices that provide current steering and closed-loop control to provide optimal therapeutic outcomes.

ABST RACT In current schemes of the pathophysiology of Parkinson?s disease (PD), neuronal activity changes in the sen- sorimotor region of the subthalamic nucleus (STN) play a central role in the development of parkinsonism. Until recently, the changes in STN activity were thought to result solely from reduced inhibition from the external globus pallidus (GPe). However, recent findings from animal models of advanced parkinsonism have suggested that a profound loss of glutamatergic cortico-subthalamic terminals and an increased strength of GABAergic pallidosubthalamic synapses may contribute to activity changes in the STN and to the development of parkin- sonism. Our preliminary data demonstrate that a loss of cortico-subthalamic terminals is also present in the sensorimotor STN territory of people with advanced PD. It remains unclear, however, how these anatomical and physiologic changes relate to the degree of nigrostriatal dopamine loss and to the expression of parkinsonism. Further, it is unknown if these changes also affect non-motor regions of the STN, perhaps contributing to cogni- tive or affective PD symptoms. We will examine these issues with neuropathological and electrophysiological studies in monkeys with different degrees of MPTP-induced dopamine loss (Aim 1), and with longitudinal 7T ultra-high field MRI studies in people with early PD (Aim 2). In Aim 1, we will record responses of STN neurons to optogenetic activation of cortical and pallidal inputs in monkeys that remained either asymptomatic after ex- posure to small dose of the dopamine-depleting neurotoxin MPTP or became parkinsonian after exposure to (larger doses of) MPTP. We will also assess changes in local field potentials (LFPs) and abnormal spiking activity in STN, and in the coherence between STN LFPs and motor cortical electrocorticograms. In postmortem studies of the same animals, we will use high resolution microscopic immunohistochemical studies and 3D-EM reconstructions to assess whether the number, localization, and morphology of glutamatergic and GABAergic synapses in the STN changes as a function of dopamine loss. We will also compare the number of cortico- subthalamic terminals and examine changes in GABAergic markers in STN tissue from patients with PD and age-matched controls. In Aim 2, we will use state-of-the-art diffusion and resting state functional MRI to test whether humans with early stage PD exhibit significant changes in the volume and microstructural organization of the STN and its cortical and pallidal afferents, and determine if these changes are related to the expression and progression of motor and non-motor impairments. The same patients will be studied at enrollment and 30 months later to examine changes in the MRI measures. The results of this project will increase our understanding of the temporal evolution of parkinsonism-associated plastic changes in the STN, and determine their potential relationships to the development and severity of motor and non-motor signs and symptoms of the disease. These studies may lead to novel interventions to control or prevent abnormal firing patterns in STN and may contribute to the development of imaging biomarkers to identify early stages of PD and predictors of disease progression.