Kaylena A. Ehgoetz Martens

Diffusion alterations associated with Parkinson's disease symptomatology: A review of the literature

Parkinsons disease (PD) is a heterogeneous neurological disorder with a variety of motor and non-motor symptoms. The underlying mechanisms of these symptoms are not fully understood. An increased interest in structural connectivity analyses using diffusion tensor imaging (DTI) in PD has led to an expansion of our understanding of the impact of abnormalities in diffusivity on phenotype. This review outlines the contribution of these abnormalities to symptoms of PD including bradykinesia, tremor and non-tremor phenotypes, freezing of gait, cognitive impairment, mood, sleep disturbances, visual hallucinations and olfactory dysfunction. Studies have shown that impairments in cognitive functioning are related to diffusion abnormalities in frontal and parietal regions, as well as in the corpus callosum and major fibres connecting midbrain and subcortical structures with the neocortex. However, the impact of diffusion alterations on motor, mood and other symptoms of PD are less well understood. The findings presented here highlight the challenges faced and the potential areas of future research avenues where DTI may be beneficial. Larger cohort studies and standardized imaging protocols are required to investigate current promising preliminary findings.

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

ABSTRACT Impairments in motor automaticity cause patients with Parkinsons 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 Parkinsons 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 Parkinsons 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, p<0.001). Overall, this study demonstrates that dopamine ameliorates gait automaticity in Parkinsons disease by altering striatal, limbic and cerebellar processing, thereby informing future therapeutic avenues for gait and falls prevention. HighlightsParkinsons disease patients performed a virtual reality gait task during fMRI.The role of dopamine on gait automaticity impairments was investigated.Limbic interference and poor striatal and cerebellar processing impair automaticity.Dopamine ameliorates gait automaticity impairments in Parkinsons disease.

Pathology of behavior in PD: What is known and what is not?

Abnormal behavior in Parkinsons disease (PD) stems from a complex orchestration of impaired neural networks that result from PD-related neurodegeneration across multiple levels. Typically, cellular and tissue abnormalities generate neurochemical changes and disrupt specific regions of the brain, in turn creating impaired neural circuits and dysfunctional global networks. The objective of this chapter is to provide an overview of the array of pathological changes that have been linked to different behavioral symptoms of PD such as depression, anxiety, apathy, fatigue, impulse control disorders, psychosis, sleep disorders and dementia.

Investigating motor initiation and inhibition deficits in patients with Parkinson’s disease and freezing of gait using a virtual reality paradigm

Freezing of gait (FOG) is a common, disabling symptom of Parkinsons disease (PD) that is associated with deficits in motor initiation and inhibition. Understanding of underlying neurobiological mechanisms has been limited by difficulties in eliciting and objectively characterizing such gait phenomena in the clinical setting. However, recent work suggests that virtual reality (VR) techniques might offer the potential to study motor control. This study utilized a VR paradigm to explore deficits in motor initiation and stopping performance, including stop failure in PD patients with (Freezers, 31) and without (Non-Freezers, 23) FOG, and healthy age-matched Controls (15). The VR task required subjects to respond to a series of start and stop cues while navigating a corridor using ankle flexion/extension movements on foot pedals. We found that Freezers experienced slower motor output initiation and more frequent start hesitations (SHs) (initiations greater than twice a subjects usual initiation latency) compared to Non-Freezers and Controls. Freezers also showed more marked inhibitory impairments, taking significantly longer to execute motor inhibition, and experiencing an increased frequency of failed stopping in response to stop cues compared to Non-Freezers and Controls. Stopping impairments were exacerbated by stop cues requiring additional cognitive processing. These results suggest that PD patients with FOG have marked impairments in motor initiation and inhibition that are not prominent in patients without FOG, nor healthy controls. Future work combining such VR paradigms with neuroimaging techniques and intra-operative deep brain recordings may increase our understanding of these phenomena, promoting the development of novel technologies and therapeutic approaches.

Cognitive training for freezing of gait in Parkinson’s disease: a randomized controlled trial

The pathophysiological mechanism of freezing of gait (FoG) has been linked to executive dysfunction. Cognitive training (CT) is a non-pharmacological intervention which has been shown to improve executive functioning in Parkinson’s disease (PD). This study aimed to explore whether targeted CT can reduce the severity of FoG in PD. Patients with PD who self-reported FoG and were free from dementia were randomly allocated to receive either a CT intervention or an active control. Both groups were clinician-facilitated and conducted twice-weekly for seven weeks. The primary outcome was percentage of time spent frozen during a Timed Up and Go task, assessed both on and off dopaminergic medications. Secondary outcomes included multiple neuropsychological and psychosocial measures. A full analysis was first conducted on all participants randomized, followed by a sample of interest including only those who had objective FoG at baseline, and completed the intervention. Sixty-five patients were randomized into the study. The sample of interest included 20 in the CT group and 18 in the active control group. The primary outcome of percentage time spent frozen during a gait task was significantly improved in the CT group compared to active controls in the on-state. There were no differences in the off-state. Patients who received CT also demonstrated improved processing speed and reduced daytime sleepiness compared to those in the active control. The findings suggest that CT can reduce the severity of FoG in the on-state, however replication in a larger sample is required.Freezing of gait: a non-pharmacological approachCognitive training can reduce the severity of gait freezing in Parkinson’s disease (PD) patients on dopaminergic medication. The inability to move forwards despite the intention to walk is one of the most debilitating symptoms in patients with PD and has been linked to cognitive dysfunction. Simon Lewis at the University of Sydney, Australia, and colleagues examined the effects of cognitive training in patients with self-reported freezing of gait and without dementia. Patients receiving cognitive therapy twice a week for seven weeks showed a significant reduction in gait freezing compared to the control group. Interestingly, the effect was observed when patients had maximum benefit from their PD medication (on-state) but not in the off-state. Cognitive training also improved patients’ processing speed and reduced their daytime sleepiness highlighting the usefulness of non-pharmacological interventions in the treatment of PD.

Using Virtual Reality to Advance the Understanding and Rehabilitation of Gait Impairments in Parkinson’s Disease

Virtual reality (VR) provides a unique platform to study the complex interactions between an individual’s movement and their environment. Although this innovative technology has not yet been widely used in Parkinson’s disease (PD) research, it has tremendous potential to advance both our understanding and treatment of gait impairments. In this chapter, we will first outline the variety of virtual reality systems available and contrast the associated advantages and disadvantages that warrant consideration for using virtual reality in experimental and/or therapeutic settings. We will then discuss the utility of VR in the scientific exploration of mechanisms that underlie gait impairments in PD. Finally, we will examine the effectiveness of using VR in a therapeutic setting based on the current research, and provide future directions for therapeutic interventions for gait in PD utilizing virtual reality.

The low dimensional dynamic and integrative core of cognition in the human brain

The human brain seamlessly integrates innumerable cognitive functions into a coherent whole, shifting with fluidity between changing task demands. To test the hypothesis that the brain contains a core dynamic network that integrates specialized regions across a range of unique task demands, we investigated whether brain activity across multiple cognitive tasks could be embedded within a relatively low dimensional, dynamic manifold. Analysis of task-related fMRI data from the Human Connectome Project revealed a core brain system that fluctuates in accordance with cognitive demands, bringing new brain systems on-line in accordance with changing task demands, while maximizing temporal information processing complexity. Regional differences in noradrenergic neurotransmitter receptor density align with this integrative core, providing a biologically plausible mechanism for the control of global brain dynamics. Our results advance a unique window into functional brain organization that emphasizes the confluence between low dimensional neural activity, network topology, neuromodulator systems and cognitive function.The human brain integrates diverse cognitive processes into a coherent whole, shifting fluidly as a function of changing environmental demands. Despite recent progress, the neurobiological mechanisms responsible for this dynamic system-level integration remain poorly understood. Here, we used multi-task fMRI data from the Human Connectome Project to examine the spatiotemporal architecture of cognition in the human brain. By investigating the spatial, dynamic and molecular signatures of system-wide neural activity across a range of cognitive tasks, we show that large-scale neuronal activity converges onto a low dimensional manifold that facilitates the dynamic execution of diverse task states. Flow within this attractor space is associated with dissociable cognitive functions, and with unique patterns of network-level topology and information processing complexity. The axes of the low-dimensional neurocognitive architecture align with regional differences in the density of neuromodulatory receptors, which in turn relate to distinct signatures of network controllability estimated from the structural connectome. These results advance our understanding of functional brain organization by emphasizing the interface between low dimensional neural activity, network topology, neuromodulatory systems and cognitive function. One Sentence Summary A diverse set of neuromodulators facilitates the formation of a dynamic, low-dimensional integrative core in the brain that is recruited by diverse cognitive demands

Changes in structural network topology correlate with severity of hallucinatory behaviour in Parkinson's disease

An inefficient integration between bottom-up visual input and higher-order visual processing regions is implicated in the manifestation of visual hallucinations (VH) in Parkinson’s disease (PD). Using graph theory, the current study aimed to investigate white matter contributions to this perceptual imbalance hypothesis. Twenty-nine PD patients reported their hallucinatory behaviour on a questionnaire and performed a behavioural test that has been shown to elicit misperceptions. A composite score derived from these measures was used as a proxy for hallucinations severity and was correlated to connectivity strength of the network using the Network Based Statistic approach. The results showed that the severity of VH was associated with reduced connectivity within a large sub-network. This network included the majority of the diverse club and showed overall greater between- and within-module scores, compared to nodes not associated with hallucination severity. Furthermore, a reduction in between-module connectivity in the lateral occipital cortex, insula and pars orbitalis, as well as decreased within-module connectivity in the prefrontal, somatosensory and primary visual cortices were associated with VH severity. In contrast, the severity of VH was associated with an increase in between- and within-module connectivity in the orbitofrontal and temporal cortex, as well as regions comprising the dorsal attentional and DMN. These results suggest that the severity of VHs is associated with marked alterations in structural network topology, highlighted by a reduction in connectivity strength across a large sub-network, as well as changes in participation across top-down visual processing centres, visual and attentional networks. Therefore, impaired integration across the perceptual hierarchy may result in the inefficient transfer of information that gives rise to VHs in PD.

Evidence for subtypes of freezing of gait in Parkinson's disease: Investigating Subtypes Of Freezing

Background: The purpose of this study is to identify and characterize subtypes of freezing of gait by using a novel questionnaire designed to delineate freezing patterns based on self‐reported and behavioral gait assessment.

The interactions between non-motor symptoms of Parkinson’s disease

Non-motor symptoms (NMS) are an important, yet underappreciated, feature of Parkinson’s disease (PD). Many of these varied symptoms are central determinants of quality of life. This burden is in large part due to the ineffective management strategies that are rooted in our limited understanding of the pathophysiological mechanisms which underlie the many NMS that manifest in PD. Here, we highlight several common NMS, their respective assessment methods and evidence that they are often inter-related. We then suggest several strategies that may help to interrogate the complexities of NMS interactions. We end by concluding that future research should focus on the relationships between NMS – how they interact, coexist, and/or amplify one another – and whether NMS may also have phenotypic profiles that are useful to clinicians and researchers for future clinical trial selection, prodromal biomarkers profiles, or determining different pathological progression.