Dopamine depletion impairs gait automaticity by altering cortico-striatal and cerebellar processing in Parkinson's disease

Impairments in motor automaticity cause patients with Parkinson's disease to rely on attentional resources during gait, resulting in greater motor variability and a higher risk of falls. Although dopaminergic circuitry is known to play an important role in motor automaticity, little evidence exists on the neural mechanisms underlying the breakdown of locomotor automaticity in Parkinson's disease. This impedes clinical management and is in great part due to mobility restrictions that accompany the neuroimaging of gait. This study therefore utilized a virtual reality gait paradigm in conjunction with functional MRI to investigate the role of dopaminergic medication on lower limb motor automaticity in 23 patients with Parkinson's disease that were measured both on and off dopaminergic medication. Participants either operated foot pedals to navigate a corridor (‘walk’ condition) or watched the screen while a researcher operated the paradigm from outside the scanner (‘watch’ condition), a setting that controlled for the non-motor aspects of the task. Step time variability during walk was used as a surrogate measure for motor automaticity (where higher variability equates to reduced automaticity), and patients demonstrated a predicted increase in step time variability during the dopaminergic “off” state. During the “off” state, subjects showed an increased blood oxygen level-dependent response in the bilateral orbitofrontal cortices (walk>watch). To estimate step time variability, a parametric modulator was designed that allowed for the examination of brain regions associated with periods of decreased automaticity. This analysis showed that patients on dopaminergic medication recruited the cerebellum during periods of increasing variability, whereas patients off medication instead relied upon cortical regions implicated in cognitive control. Finally, a task-based functional connectivity analysis was conducted to examine the manner in which dopamine modulates large-scale network interactions during gait. A main effect of medication was found for functional connectivity within an attentional motor network and a significant condition by medication interaction for functional connectivity was found within the striatum. Furthermore, functional connectivity within the striatum correlated strongly with increasing step time variability during walk in the off state (r=0.616, p=0.002), but not in the on state (r=−0.233, p=0.284). Post-hoc analyses revealed that functional connectivity in the dopamine depleted state within an orbitofrontal-striatal limbic circuit was correlated with worse step time variability (r=0.653,

Motor and cognitive abilities in Parkinson’s disease with a brain activity perspective : performance at baseline and the effects of a balance training program

Background: Around one per cent of the population over 60 years of age have Parkinson’s disease (PD). PD is a progressive and complicated disease presenting a wide range of symptoms. More knowledge of the common impairments in balance, gait, cognition, and motor learning is needed. There is also a need for more studies of physical exercise as a complement to pharmacological treatment for people with PD. Our research group has previously observed positive effects of a highly challenging balance training program (HiBalance) for people with PD in comparison to a passive control group. It is of considerable interest to further investigate the effects of the HiBalance program using an enhanced design quality such as an active control group, blinded assessors as well as by the inclusion of measures of brain activity and neuroprotective factors (BDNF). Aims: The first aim of this thesis was to develop feasible methods of investigating motor and cognitive abilities in people with PD as well as the effects of the HiBalance program. The second aim was to investigate motor and cognitive abilities as well as the effects of the HiBalance program for people with PD. This also included investigating the neural correlates of motor and cognitive baseline performances as well as the effects of the HiBalance program. Methods: In Paper I, feasibility aspects relating to the recruitment process, measurement methods, and the participants’ experience of the assessments and the two interventions to be used in Paper IV were investigated. In Paper II, feasibility aspects of two computer-based tasks created to measure implicit motor sequence learning and dual-task ability were investigated. These tasks were to be used in Paper III and IV for task-induced functional magnetic resonance imaging data. Feasibility aspects investigated included task fatigue, difficulty level and possible ceiling effects. In Paper III, people with PD and healthy individuals performed the implicit motor sequence learning task during the acquisition of functional magnetic resonance imaging data. In Paper IV, we investigated a wide range of outcomes of the HiBalance program for people with mild to moderate PD. Our primary outcome was balance and secondary outcomes included gait speed, executive functions, and measures of brain activity during implicit motor sequence learning as well as measures of the brain-derived neurotrophic factor. We used a double-blinded randomised controlled design with an active control group. Results: In Paper I, we found the feasibility of the randomised controlled design for investigating the HiBalance program to be overall acceptable but with some important modifications needed. In Paper II, we found the feasibility of the two computer-based tasks to be overall acceptable. In Paper III, we found support for the hypothesis that implicit motor sequence learning is impaired in people with PD. Exploratory analyses suggested that this impairment may be due to a lower learning rate. We found no statistically significant group changes in the task-induced brain activity. The results of Paper IV did not support the hypothesis of beneficial effects of the HiBalance program in comparison to our control group, for people with mild to moderate PD. Discussion: The two feasibility studies guided us in design aspects that needed improvement before use in Paper III and Paper IV. We hope that our feasibility studies can also help other researchers in their study designs and thereby decrease unnecessary efforts for study participants and increase the value of research investments. As for paper III, impaired motor sequence learning in people with PD is an interesting finding as motor learning ability is of crucial importance for motor performance. If implicit motor sequence learning has a lower learning rate in people with PD than healthy individuals, this could mean that people with PD need more time to practice and repeat when learning and doing motor tasks and physical exercise. As for paper IV, the lack of support for the HiBalance program in its investigated form is discouraging. This is however an important finding that we hope will spark future rigorous projects aiming to find interventions of physical exercise with robust, replicable positive effects for people with PD

Is Online Motor Control Really Impaired In Parkinson\u27s Disease?

Patients with Parkinson’s disease (PD) are thought to be selectively impaired in consciously-mediated online automatic motor control, whereas the ability to perform subconscious online adjustments remains intact. This present study evaluates the hypothesis that the previously alleged deficits in online motor control in PD are not due to the consciousness of the correction, but rather are attributable to aspects of the prior experimental designs disproportionately penalizing patients for PD-related bradykinesia. Here, we implemented a modified traditional double-step paradigm to investigate consciously-mediated online motor control in PD, in a manner that would be unconfounded by disease-related bradykinesia. Further, we investigated the effects of dopamine-replacement therapy on performance. We found that PD patients (n=12) and healthy-matched controls (n=12) were equal in performing automatic online corrections whether or not these corrections were consciously perceived, and their performance was unaffected by dopaminergic therapy. These findings inform our understanding of automatic motor control in PD

Executive control of walking in people with Parkinson’s disease with freezing of gait

Background: Walking abnormalities in people with Parkinson’s disease (PD) are characterized by a shift in locomotor control from healthy automaticity to compensatory prefrontal executive control. Indirect measures of automaticity of walking (e.g., step-to-step variability and dual-task cost) suggest that freezing of gait (FoG) may be associated with reduced automaticity of walking. However, the influence of FoG status on actual prefrontal cortex (PFC) activity during walking remains unclear. Objective: To investigate the influence of FoG status on automaticity of walking in people with PD. Methods: Forty-seven people with PD were distributed into two groups based on FoG status, which was assessed by the New Freezing of Gait Questionnaire: PD-FoG (n=23; UPDRS-III=35) and PD+FoG (n=24; UPDRS-III=43.1). Participants walked over a 9m straight path (with a 180° turn at each end) for 80s. Two conditions were tested Off medication: single- and dual-task walking (i.e., with a concomitant cognitive task). A portable functional near-infrared spectroscopy system recorded PFC activity while walking (including turns). Wearable inertial sensors were used to calculate spatiotemporal gait parameters. Results: PD+FoG had greater PFC activation during both single and dual-task walking than PD-FoG (p=0.031). There were no differences in gait between PD-FoG and PD+FoG. Both groups decreased gait speed (p=0.029) and stride length (p<0.001) during dual-task walking compared to single-task walking. Conclusions: These findings suggest that PD+FoG have reduced automaticity of walking, even in absence of FoG episodes. PFC activity while walking seems to be more sensitive than gait measures in identifying reduction in automaticity of walking in PD+FoG

Exploring the effects of spinal cord stimulation for freezing of gait in parkinsonian patients

Dopaminergic replacement therapies (e.g. levodopa) provide limited to no response for axial motor symptoms including gait dysfunction and freezing of gait (FOG) in Parkinson’s disease (PD) and Richardson’s syndrome progressive supranuclear palsy (PSP-RS) patients. Dopaminergic-resistant FOG may be a sensorimotor processing issue that does not involve basal ganglia (nigrostriatal) impairment. Recent studies suggest that spinal cord stimulation (SCS) has positive yet variable effects for dopaminergic-resistant gait and FOG in parkinsonian patients. Further studies investigating the mechanism of SCS, optimal stimulation parameters, and longevity of effects for alleviating FOG are warranted. The hypothesis of the research described in this thesis is that mid-thoracic, dorsal SCS effectively reduces FOG by modulating the sensory processing system in gait and may have a dopaminergic effect in individuals with FOG. The primary objective was to understand the relationship between FOG reduction, improvements in upper limb visual-motor performance, modulation of cortical activity and striatal dopaminergic innervation in 7 PD participants. FOG reduction was associated with changes in upper limb reaction time, speed and accuracy measured using robotic target reaching choice tasks. Modulation of resting-state, sensorimotor cortical activity, recorded using electroencephalography, was significantly associated with FOG reduction while participants were OFF-levodopa. Thus, SCS may alleviate FOG by modulating cortical activity associated with motor planning and sensory perception. Changes to striatal dopaminergic innervation, measured using a dopamine transporter marker, were associated with visual-motor performance improvements. Axial and appendicular motor features may be mediated by non-dopaminergic and dopaminergic pathways, respectively. The secondary objective was to demonstrate the short- and long-term effects of SCS for alleviating dopaminergic-resistant FOG and gait dysfunction in 5 PD and 3 PSP-RS participants without back/leg pain. SCS programming was individualized based on which setting best improved gait and/or FOG responses per participant using objective gait analysis. Significant improvements in stride velocity, step length and reduced FOG frequency were observed in all PD participants with up to 3-years of SCS. Similar gait and FOG improvements were observed in all PSP-RS participants up to 6-months. SCS is a promising therapeutic option for parkinsonian patients with FOG by possibly influencing cortical and subcortical structures involved in locomotion physiology

Relationship between Anxiety and Freezing of Gait

Parkinson’s disease (PD) is the second most common neurodegenerative and a large percentage of PD patients develop freezing of gait (FOG) leading to an overall reduced quality of life. The overarching aim of the thesis is to investigate the relationship between anxiety and freezing of gait, to extend current research on this topic and produce findings that could facilitate more adequate treatment methods for this symptom. The first study validated the seated functional MRI-compatible version of the walking threat paradigm that was previously found to induce anxiety and FOG. This would enable future studies to examine the neural correlates behind anxiety-induced freezing of gait. The second study investigated the effect of anxiety on the utilisation of body-related visual feedback in the form of an avatar in the virtual environment to improve FOG. The third study investigated the effects of Levodopa on the fronto-striato-limbic circuitry in PD Freezers at rest in their ‘ON’ and ‘OFF’ dopaminergic state. Findings suggest that the VR seated threat paradigm is an adequate behavioural surrogate for the VR walking threat paradigm, eliciting comparable amounts of anxiety and freezing of gait as the walking version. Anxiety was also found to interfere with the utilisation of sensory feedback to improve FOG, where in highly threatening situations Freezers lack the capacity to process visual feedback for gait. Finally, dopaminergic medication was also found to partially modulate the frontoparietal-limbic-striatal circuitry in PD Freezers, where baseline anxiety levels influence the impact of Levodopa on the frontoparietal (FPN)- limbic connectivity, and the FPN-putamen connectivity. In conclusion, the current thesis suggests that anxiety contributes to freezing of gait, which may present a barrier to treatment and could be a key factor in the heterogeneity observed in response to medication and sensory cueing

The alteration of dopamine receptors in L-DOPA (L-3,4-dihydroxyphenylalanine) induced dyskinesias.

Masters Degree. University of KwaZulu-Natal, Durban.L-3,4-dihydroxyphenylalanine (L-DOPA) can ease symptoms of Parkinson’s disease (PD), butextended use of L-DOPA causes abnormal involuntary movements (AIMs) called L-DOPA induced dyskinesias (LIDs). The present study aims to investigate alterations in HPA axis stimulation, neuroinflammation, DA signalling, and cholinergic signalling using molecular markers in a rat model of LIDs. A unilateral 6-hydroxydopamine (6-OHDA) lesion in the medial forebrain bundle of male Sprague-Dawley rats was used to model Parkinsonism. The PD rat model was treated with L-DOPA to further model LIDs. L-DOPA treated groups included rodents treated for 14 days and rats that developed AIMs during 28 days of treatment. LIDs severity was rated using the AIMs score. Motor skills were assessed using the elevated beam walking test. Cognitive functions were assessed using the Morris water maze test and the novel object recognition test. The concentrations of tumour necrosis factor-alpha (TNF-α), corticosterone, acetylcholinesterase (AChE), and dopamine (DA), and the expressions of D1 receptor (D1R) and D2 receptor (D2R) were quantified. L-DOPA treatment for 14 days improved the 6-OHDA-induced hypokinesia, incoordination, spatial learning, and spatial memory but did not improve recognition memory impairment. Prolonged (28 days) L-DOPA treatment led to AIMs development and failed to improve 6-OHDA-induced spatial memory impairment. L-DOPA treatment significantly increased striatal TNF-α and striatal DA concentration, cerebellar TNF-α and DA concentration, prefrontal cortex (PFC) DA and AChE concentration, but significantly reduced striatal AChE concentration, the concentration of TNF-α and D1R expression in the PFC, plasma corticosterone, and hippocampal AChE concentration. When treatment was prolonged for 28 days, striatal D2R expression significantly increased, while cerebellar TNF-α and DA concentration significantly decreased. Increased striatal D2R signalling increases motor output since the direct basal ganglia (BG) pathway is activated in LIDs. The present study showed significantly increased cerebellar DA concentration in response to BG hypoactivity; however, as striatal D2R increased cerebellar DA decreased. The connectivity between the BG and cerebellum in PD increases off L-DOPA and lowers On L-DOPA. The cognitive decline in the 6-OHDA lesioned rodents and those treated with L-DOPA results from increased AChE concentration. High AChE concentration leads to increased ACh catabolism which impairs cognitive function

Sensorimotor Inhibition and Mobility in Genetic Subgroups of Parkinson's Disease

Background: Mobility and sensorimotor inhibition impairments are heterogeneous in Parkinson's disease (PD). Genetics may contribute to this heterogeneity since the apolipoprotein (APOE) ε4 allele and glucocerebrosidase (GBA) gene variants have been related to mobility impairments in otherwise healthy older adult (OA) and PD cohorts. The purpose of this study is to determine if APOE or GBA genetic status affects sensorimotor inhibition and whether the relationship between sensorimotor inhibition and mobility differs in genetic sub-groups of PD. Methods: Ninety-three participants with idiopathic PD (53 non-carriers; 23 ε4 carriers; 17 GBA variants) and 72 OA (45 non-carriers; 27 ε4 carriers) had sensorimotor inhibition characterized by short-latency afferent inhibition. Mobility was assessed in four gait domains (pace/turning, rhythm, trunk, variability) and two postural sway domains (area/jerkiness and velocity) using inertial sensors. Results: Sensorimotor inhibition was worse in the PD than OA group, with no effect of genetic status. Gait pace/turning was slower and variability was higher (p &lt; 0.01) in PD compared to OA. Postural sway area/jerkiness (p &lt; 0.01) and velocity (p &lt; 0.01) were also worse in the PD than OA group. Genetic status was not significantly related to any gait or postural sway domain. Sensorimotor inhibition was significantly correlated with gait variability (r = 0.27; p = 0.02) and trunk movement (r = 0.23; p = 0.045) in the PD group. In PD non-carriers, sensorimotor inhibition related to variability (r = 0.35; p = 0.010) and trunk movement (r = 0.31; p = 0.025). In the PD ε4 group, sensorimotor inhibition only related to rhythm (r = 0.47; p = 0.024), while sensorimotor inhibition related to pace/turning (r = -0.49; p = 0.046) and rhythm (r = 0.59; p = 0.013) in the PD GBA group. Sensorimotor inhibition was significantly correlated with gait pace/turning (r = -0.27; p = 0.04) in the OA group. There was no relationship between sensorimotor inhibition and postural sway. Conclusion: ε4 and GBA genetic status did not affect sensorimotor inhibition or mobility impairments in this PD cohort. However, worse sensorimotor inhibition was associated with gait variability in PD non-carriers, but with gait rhythm in PD ε4 carriers and with gait rhythm and pace in PD with GBA variants. Impaired sensorimotor inhibition had a larger effect on mobility in people with PD than OA and affected different domains of mobility depending on genetic status

Gait Performance in People with Symptomatic, Chronic Mild Traumatic Brain Injury

There is a dearth of knowledge about how symptom severity affects gait in the chronic (>3 months) mild traumatic brain injury (mTBI) population despite up to 53% of people reporting persisting symptoms following mTBI. The purpose of this investigation was to determine if gait is affected in a symptomatic, chronic mTBI group and to assess the relationship between gait performance and symptom severity on the Neurobehavioral Symptom Inventory (NSI). Gait was assessed under single- and dual-task conditions using five inertial sensors in 57 control subjects and 65 people with chronic mTBI (1.1 year from mTBI). The single- and dual-task gait domains of Pace, Rhythm, Variability, and Turning were calculated from individual gait characteristics. Dual-task cost (DTC) was calculated for each domain. The mTBI group walked (domain z-score mean difference: single-task = 0.70; dual-task = 0.71) and turned (z-score mean difference: single-task = 0.69; dual-task = 0.70) slower (p<0.001) under both gait conditions, with less rhythm under dual-task gait (z-score difference = 0.21, p=0.001). DTC was not different between groups. Higher NSI somatic sub-score was related to higher single- and dual-task gait variability as well as slower dual-task pace and turning (p<0.01). People with chronic mTBI and persistent symptoms exhibited altered gait, particularly under dual-task, and worse gait performance related to greater symptom severity. Future gait research in chronic mTBI should assess the possible underlying physiological mechanisms for persistent symptoms and gait deficits