Moran Gilat

The role of dysfunctional attentional control networks in visual misperceptions in Parkinson's disease

Visual misperceptions and hallucinations represent a problematic symptom of Parkinsons disease. The pathophysiological mechanisms underlying these symptoms remain poorly understood, however, a recent hypothesis has suggested that visual misperceptions and hallucinations may arise from disrupted processing across attentional networks. To test the specific predictions of this hypothesis, 22 patients with Parkinsons disease underwent 3T fMRI while performing the Bistable Percept Paradigm, a task that has previously been shown to identify patients with hallucinations. Subjects are required to study a battery of randomly assigned “monostable” and “bistable” monochromatic images for the presence or absence of a bistable percept. Those patients who scored a high percentage of misperceptions and missed images on the task were less able to activate frontal and parietal hubs of the putative Dorsal Attention Network. Furthermore, poor performance on the task was significantly correlated with the degree of decreased activation in a number of these hubs. At the group level, the difference between processing a bistable versus a monostable cue was associated with increased recruitment of the anterior insula. In addition, those patients with impaired performance on the paradigm displayed decreased resting state functional connectivity between hubs of the Ventral and Dorsal Attention Networks. These same patients had significantly decreased gray matter in the insula bilaterally. In addition, a combined analysis of the separate neuroimaging approaches revealed significant relationships across the impaired networks. These findings are consistent with specific predictions from a recently proposed hypothesis that implicates dysfunction within attentional networks in Parkinsonian hallucinations. Hum Brain Mapp 35:2206–2219, 2014.

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.

Dopaminergic basis for impairments in functional connectivity across subdivisions of the striatum in Parkinson's disease.

The pathological hallmark of Parkinsons disease is the degeneration of dopaminergic nigrostriatal neurons, leading to depletion of striatal dopamine. Recent neuroanatomical work has identified pathways for communication across striatal subdivisions, suggesting that the striatum provides a platform for integration of information across parallel corticostriatal circuits. The aim of this study was to investigate whether dopaminergic dysfunction in Parkinsons disease was associated with impairments in functional connectivity across striatal subdivisions, which could potentially reflect reduced integration across corticostriatal circuits. Utilizing resting‐state functional magnetic resonance imaging (fMRI), we analyzed functional connectivity in 39 patients with Parkinsons disease, both “on” and “off” their regular dopaminergic medications, along with 40 age‐matched healthy controls. Our results demonstrate widespread impairments in connectivity across subdivisions of the striatum in patients with Parkinsons disease in the “off” state. The administration of dopaminergic medication significantly improved connectivity across striatal subdivisions in Parkinsons disease, implicating dopaminergic deficits in the pathogenesis of impaired striatal interconnectivity. In addition, impaired striatal interconnectivity in the Parkinsons disease “off” state was associated with pathological decoupling of the striatum from the thalamic and sensorimotor (SM) networks. Specifically, we found that although the strength of striatal interconnectivity was positively correlated with both (i) the strength of internal thalamic connectivity, and (ii) the strength of internal SM connectivity, in both healthy controls and the Parkinsons disease “on” state, these relationships were absent in Parkinsons disease when in the “off” state. Taken together our findings emphasize the central role of dopamine in integrated striatal function and the pathological consequences of striatal dopamine denervation in Parkinsons disease. Hum Brain Mapp 36:1278–1291, 2015.

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.

Investigating rapid eye movement sleep without atonia in Parkinson's disease using the rapid eye movement sleep behavior disorder screening questionnaire.

Rapid eye movement (REM) sleep behavior disorder (RBD) is frequently observed in patients with Parkinsons disease (PD). Accurate diagnosis is essential for managing this condition. Furthermore, the emergence of idiopathic RBD in later life can represent a premotor feature, heralding the development of PD. Reliable, accurate methods for identifying RBD may offer a window for early intervention. This study sought to identify whether the RBD screening questionnaire (RBDSQ) and three questionnaires focused on dream enactment were able to correctly identify patients with REM without atonia (RWA), the neurophysiological hallmark of RBD. Forty‐six patients with PD underwent neurological and sleep assessment in addition to completing the RBDSQ, the RBD single question (RBD1Q), and the Mayo Sleep Questionnaire (MSQ). The REM atonia index was derived for all participants as an objective measure of RWA. Patients identified to be RBD positive on the RBDSQ did not show increased RWA on polysomnography (80% sensitivity and 55% specificity). However, patients positive for RBD on questionnaires specific to dream enactment correctly identified higher degrees of RWA and improved the diagnostic accuracy of these questionnaires. This study suggests that the RBDSQ does not accurately identify RWA, essential for diagnosing RBD in PD. Furthermore, the results suggest that self‐report measures of RBD need to focus questions on dream enactment behavior to better identify RWA and RBD. Further studies are needed to develop accurate determination and quantification of RWA in RBD to improve management of patients with PD in the future.

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.

Assessing the utility of the Movement Disorder Society Task Force Level 1 diagnostic criteria for mild cognitive impairment in Parkinson's disease

BACKGROUND Using the Movement Disorder Society (MDS) Task Force Level 1 criteria, this study examined the classification of mild cognitive impairment in Parkinsons Disease (PD-MCI) derived from a range of cut-off scores that have previously been suggested by the MDS Task Force. Furthermore, differences in PD-MCI frequencies were examined when comparing performance on current neuropsychological testing to the normative sample, as opposed to decline from premorbid functioning, as evidence of cognitive impairment. METHOD Two hundred and thirty-four non-demented PD patients underwent neurological and neuropsychological assessment at the Parkinsons Disease Research Clinic at the Brain and Mind Research Institute, University of Sydney. RESULTS When cognitive impairment was defined as 1SD and 1.5SD below premorbid intellect, 109 patients (47%) and 76 (32%) patients met criteria for PD-MCI respectively. This proportion dropped considerably to 50 patients (21%) with a 2SD cut-off score. However, when calculating impairment based on comparisons with normative data, only 68 patients (29%) and 41 patients (18%) met PD-MCI criteria when a cut-off score of 1 and 1.5SD was employed. This proportion dropped to just 22 patients (9%) with a 2SD cut-off score. CONCLUSION Results from the present study suggest that the MDS PD-MCI criteria may be too broad, as substantial differences in frequencies of PD-MCI were observed with the application of differing criteria. We propose that a 1.5SD cut-off score below premorbid functioning may provide greater utility in characterizing PD-MCI than a 1.5SD cut-off below normative data, which has been widely applied in previous studies examining the MDS PD-MCI criteria.

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.

Variability of Stepping during a Virtual Reality Paradigm in Parkinson's Disease Patients with and without Freezing of Gait

Background Freezing of gait is a common and debilitating symptom affecting many patients with advanced Parkinson’s disease. Although the pathophysiology of freezing of gait is not fully understood, a number of observations regarding the pattern of gait in patients with this symptom have been made. Increased ‘Stride Time Variability’ has been one of the most robust of these features. In this study we sought to identify whether patients with freezing of gait demonstrated similar fluctuations in their stepping rhythm whilst performing a seated virtual reality gait task that has recently been used to demonstrate the neural correlate of the freezing phenomenon. Methods Seventeen patients with freezing and eleven non-freezers performed the virtual reality task twice, once whilst ‘On’ their regular Parkinsonian medication and once in their practically defined ‘Off’ state. Results All patients displayed greater step time variability during their ‘Off’ state assessment compared to when medicated. Additionally, in the ‘Off’ state, patients with freezing of gait had greater step time variability compared to non-freezers. The five steps leading up to a freezing episode in the virtual reality environment showed a significant increase in step time variability although the final three steps preceding the freeze were not characterized by a progressive shortening of latency. Conclusions The results of this study suggest that characteristic features of gait disturbance observed in patients with freezing of gait can also be demonstrated with a virtual reality paradigm. These findings suggest that virtual reality may offer the potential to further explore the freezing phenomenon in Parkinson’s disease.

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.