Julie M. Hall

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.

The major impact of freezing of gait on quality of life in Parkinson’s disease

Freezing of gait (FOG) is a disabling motor symptom experienced by a large proportion of patients with Parkinson’s disease (PD). While it is known that FOG contributes to lower health-related quality of life (HRQoL), previous studies have not accounted for other important factors when measuring the specific impact of this symptom. The aim of this study was to examine FOG and HRQoL while controlling for other factors that are known to impact patient well-being, including cognition, motor severity, sleep disturbance and mood. Two hundred and three patients with idiopathic PD (86 with FOG) were included in the study. All patients were between Hoehn and Yahr stages I–III. A forced entry multiple regression model evaluating the relative contribution of all symptoms was conducted, controlling for time since diagnosis and current dopaminergic treatment. Entering all significantly correlated variables into the regression model accounted for the majority of variance exploring HRQoL. Self-reported sleep–wake disturbances, depressive and anxious symptoms and FOG were individually significant predictors. FOG accounted for the highest amount of unique variance. While sleep–wake disturbance and mood have a significant negative impact on HRQoL in PD, the emergence of FOG represents the most substantial predictor among patients in the earlier clinical stages of disease. This finding presumably reflects the disabling loss of independence and fear of injury associated with FOG and underlines the importance of efforts to reduce this common symptom.

Impaired cognitive control in Parkinson's disease patients with freezing of gait in response to cognitive load.

Freezing of gait is a frequent and disabling symptom experienced by many patients with Parkinson’s disease. A number of executive deficits have been shown to be associated with the phenomenon suggesting a common underlying pathophysiology, which as of yet remains unclear. Neuroimaging studies have also implicated the role of the cognitive control network in patients with freezing. To explore this concept, the current study examined error-monitoring as a measure of cognitive control. Thirty-four patients with and 38 without freezing of gait, who were otherwise well matched on disease severity, completed a colour-word interference task that allowed the specific assessment of error monitoring during conflict. Whilst both groups performed colour-naming and word-reading tasks equally well, those patients with freezing showed a pattern between conditions whereby they were better able to monitor performance and self-correct errors in the pure inhibition task but not after a switching rule was introduced. The novel results shown here provide insight into possible pathophysiological mechanisms involved in cognitive load and error monitoring in patients with freezing of gait. These results provide further evidence for the role of functional frontostriatal circuitry impairments in patients with freezing of gait and have implications for future studies and possible therapeutic interventions.

Brain activation underlying turning in Parkinson’s disease patients with and without freezing of gait: a virtual reality fMRI study

Background:Freezing of gait is a debilitating symptom affecting many patients with Parkinson’s disease (PD), causing severe immobility and decreased quality of life. Turning is known to be the most common trigger for freezing and also causes the highest rates of falls. However, the pathophysiological basis for these effects is not well understood.Methods:This study used a virtual reality paradigm in combination with functional magnetic resonance imaging to explore the neural correlates underlying turning in 17 PD patients with freezing of gait (FOG) and 10 PD patients without FOG while off their dopaminergic medication. Participants used foot pedals to navigate a virtual environment, which allowed for blood oxygen level-dependent (BOLD) responses and footstep latencies to be compared between periods of straight “walking” and periods of turning through 90°. BOLD data were then analyzed using a mixed effects analysis.Results:Within group similarities revealed that overall, PD patients with freezing relied heavily on cortical control to enable effective stepping with increased visual cortex activation during turning. Between groups differences showed that when turning, patients with freezing preferentially activated inferior frontal regions that have been implicated in the recruitment of a putative stopping network. In addition, freezers failed to activate premotor and superior parietal cortices. Finally, increased task-based functional connectivity was found in subcortical regions associated with gait and stopping within the freezers group during turning.Conclusions:These findings suggest that an increased propensity towards stopping in combination with reduced sensorimotor integration may underlie the neurobiology of freezing of gait during turning.

Early phenotypic differences between Parkinson's disease patients with and without freezing of gait.

BACKGROUND Previous studies have associated freezing of gait in Parkinsons disease with the presence of specific phenotypic features such as mood disturbances, REM sleep behavior disorder and selective cognitive impairments. However, it is not clear whether these features are present in the earlier stages of disease or simply represent a more general pattern of progression. To investigate this issue, the current study evaluated motor, cognitive, affective and autonomic features as well as REM sleep behavior disorder in Parkinsons disease patients in the early stages of the condition. METHODS Thirty-eight freezers and fifty-three non-freezers with disease duration of less than five years and a Hoehn and Yahr stage of less than three were included in this study. The groups were matched on a number of key disease features including age, disease duration, motor severity and dopamine dose equivalence. Furthermore, patients were assessed on measures of motor, cognitive, affective and autonomic features, as well as REM sleep behavior disorder. RESULTS Compared to non-freezers, patients with freezing of gait had significantly more non-tremor symptoms and a selective impairment on executive functions, such as set-shifting ability and working memory. Freezers and non-freezers did not differ on measures of tremor, autonomic function, REM sleep behavior disorder, mood or more general cognition. CONCLUSION These results suggest the pathophysiological mechanisms underlying freezing of gait in the early clinical stages of Parkinsons disease are likely to be related to specific changes in the frontostriatal pathways rather than being due to brainstem or more diffuse neuropathology.

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.

Dysfunction in attentional processing in patients with Parkinson’s disease and visual hallucinations

Mechanistic insights into visual hallucinations (VH) in Parkinson’s disease (PD) have suggested a role for impaired attentional processes. The current study tested 25 PD patients with and 28 PD patients without VH on the attentional network test. Hallucinators had significantly lower accuracy rates compared to non-hallucinators, but no differences were found in reaction times. This suggests that hallucinators show deficits in attentional processes and conflict monitoring. Our findings provide novel behavioural insights that dovetail with current neurobiological frameworks of VH.

Anxiety is associated with freezing of gait and attentional set-shifting in Parkinson’s disease: A new perspective for early intervention

Previous research has shown that anxiety in Parkinsons disease (PD) is associated with freezing of gait (FOG), and may even contribute to the underlying mechanism. However, limited research has investigated whether PD patients with FOG (PD+FOG) have higher anxiety levels when compared directly to non-freezing PD patients (PD-NF) and moreover, how anxiety might contribute to FOG. The current study evaluated whether: (i) PD+FOG have greater anxiety compared to PD-NF, and (ii) anxiety in PD is related to attentional set-shifting, in order to better understand how anxiety might be contributing to FOG. In addition, we explored whether anxiety levels differed between those PD patients with mild FOG (PD+MildFOG) compared to PD-NF. Four hundred and sixty-one patients with PD (231 PD-NF, 180 PD+FOG, 50 PD+MildFOG) were assessed using the Freezing of Gait Questionnaire item 3 (FOG-Q3), Hospital Anxiety and Depression Scale (HADS), Digit Span Test, Logical Memory Retention Test and Trail Making Tests. Compared to PD-NF, PD+FOG had significantly greater anxiety (p<0.001). PD+MildFOG, however, demonstrated similar levels of anxiety as the PD+FOG. In all patients, the severity of anxiety symptoms was significantly correlated to their degree of self-reported FOG on FOG-Q3 (p<0.001) and TMT B-A (p=0.039). Similar results were found for depression. In conclusion, these results confirm the key role played by anxiety in FOG and also suggest that anxiety might be a promising biomarker for FOG. Future research should consider whether treating anxiety with pharmacological and/or cognitive behavioural therapies at early stages of gait impairment in PD may alleviate troublesome FOG.

Freezing of Gait and its Associations in the Early and Advanced Clinical Motor Stages of Parkinson’s Disease: A Cross-Sectional Study

BACKGROUND Freezing of gait is a common disabling symptom of Parkinsons disease (PD) with limited treatment options. The pathophysiological mechanisms of freezing behaviour are still contentious. OBJECTIVE To investigate the prevalence of freezing of gait and its associations with increasing disease severity to gain a better understanding of the underlying pathophysiology. METHODS This exploratory study included 389 idiopathic PD patients, divided into four groups; early and advanced PD with freezing of gait, and early and advanced PD without freezing of gait. Motor, cognitive and affective symptoms, REM sleep behaviour disorder and autonomic function were assessed. RESULTS Regardless of disease stage, patients with freezing of gait had more severe motor symptoms and a predominant non-tremor phenotype. In the early stages, freezers had a selective impairment in executive function and had more marked REM sleep behaviour disorder. Autonomic disturbances were not associated with freezing of gait across early or advanced disease stages. CONCLUSION These findings support the notion that impairments across the frontostriatal pathways are intricately linked to the pathophysiology underlying freezing of gait across all stages of PD. Features of REM sleep behaviour disorder suggest a contribution to freezing from brainstem pathology but this does not extend to more general autonomic dysfunction.

Interrelations between cognitive dysfunction and motor symptoms of Parkinson's disease: behavioral and neural studies.

Abstract Parkinson’s disease (PD) is characterized by a range of motor symptoms. Besides the cardinal symptoms (tremor, bradykinesia/akinesia, and rigidity), PD patients also show other motor deficits, including gait disturbance, speech deficits, and impaired handwriting. However, along with these key motor symptoms, PD patients also experience cognitive deficits in attention, executive function, working memory, and learning. Recent evidence suggests that these motor and cognitive deficits of PD are not completely dissociable, as aspects of cognitive dysfunction can impact motor performance in PD. In this article, we provide a review of behavioral and neural studies on the associations between motor symptoms and cognitive deficits in PD, specifically akinesia/bradykinesia, tremor, gait, handwriting, precision grip, and speech production. This review paves the way for providing a framework for understanding how treatment of cognitive dysfunction, for example cognitive rehabilitation programs, may in turn influence the motor symptoms of PD.