Elie Matar

Freezing of gait in Parkinson’s disease is associated with functional decoupling between the cognitive control network and the basal ganglia

Recent neuroimaging evidence has led to the proposal that freezing of gait in Parkinsons disease is due to dysfunctional interactions between frontoparietal cortical regions and subcortical structures, such as the striatum. However, to date, no study has employed task-based functional connectivity analyses to explore this hypothesis. In this study, we used a data-driven multivariate approach to explore the impaired communication between distributed neuronal networks in 10 patients with Parkinsons disease and freezing of gait, and 10 matched patients with no clinical history of freezing behaviour. Patients performed a virtual reality gait task on two separate occasions (once ON and once OFF their regular dopaminergic medication) while functional magnetic resonance imaging data were collected. Group-level independent component analysis was used to extract the subject-specific time courses associated with five well-known neuronal networks: the motor network, the right- and left cognitive control networks, the ventral attention network and the basal ganglia network. We subsequently analysed both the activation and connectivity of these neuronal networks between the two groups with respect to dopaminergic state and cognitive load while performing the virtual reality gait task. During task performance, all patients used the left cognitive control network and the ventral attention network and in addition, showed increased connectivity between the bilateral cognitive control networks. However, patients with freezing demonstrated functional decoupling between the basal ganglia network and the cognitive control network in each hemisphere. This decoupling was also associated with paroxysmal motor arrests. These results support the hypothesis that freezing behaviour in Parkinsons disease is because of impaired communication between complimentary yet competing neural networks.

Differential Neural Activation Patterns in Patients with Parkinson's Disease and Freezing of Gait in Response to Concurrent Cognitive and Motor Load

Freezing of gait is a devastating symptom of Parkinsons disease (PD) that is exacerbated by the processing of cognitive information whilst walking. To date, no studies have explored the neural correlates associated with increases in cognitive load whilst performing a motor task in patients with freezing. In this experiment, 14 PD patients with and 15 PD patients without freezing of gait underwent 3T fMRI while performing a virtual reality gait task. Directions to walk and stop were presented on the viewing screen as either direct cues or as more cognitively indirect pre-learned cues. Both groups showed a consistent pattern of BOLD response within the Cognitive Control Network during performance of the paradigm. However, a between group comparison revealed that those PD patients with freezing of gait were less able to recruit the bilateral anterior insula, ventral striatum and the pre-supplementary motor area, as well as the left subthalamic nucleus when responding to indirect cognitive cues whilst maintaining a motor output. These results suggest that PD patients with freezing of gait are unable to properly recruit specific cortical and subcortical regions within the Cognitive Control Network during the performance of simultaneous motor and cognitive functions.

The role of frontostriatal impairment in freezing of gait in Parkinson's disease

Freezing of gait (FOG) is a disabling symptom of advanced Parkinsons disease (PD) that leads to an increased risk of falls and nursing home placement. Interestingly, multiple lines of evidence suggest that the manifestation of FOG is related to specific deficits in cognition, such as set shifting and the ability to process conflict-related signals. These findings are consistent with the specific patterns of abnormal cortical processing seen during functional neuroimaging experiments of FOG, implicating increased neural activation within cortical structures underlying cognition, such as the Cognitive Control Network. In addition, these studies show that freezing episodes are associated with abnormalities in the BOLD response within key structures of the basal ganglia, such as the striatum and the subthalamic nucleus. In this article, we discuss the implications of these findings on current models of freezing behavior and propose an updated model of basal ganglia impairment during FOG episodes that integrates the neural substrates of freezing from the cortex and the basal ganglia to the cognitive dysfunctions inherent in the condition.

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.

Post-contrast enhancement as a clinical indicator of prognosis in patients with anaplastic astrocytoma

Diagnosis of an anaplastic astrocytoma (World Health Organization grade III) is associated with a highly variable prognosis. The identification of clinical markers that allow a more careful delineation of this prognostic spectrum is urgently needed. In this study, we analysed 48 patients with a histological diagnosis of anaplastic astrocytoma and found peritumoral post-gadolinium contrast enhancement to be a clear prognostic marker of poor prognosis. Multivariate analysis also confirmed surgery type, Karnofsky Performance Status score (<70) and increasing age as independent adverse predictors of survival. The survival differences observed in the enhancing and non-enhancing lesions in patients diagnosed with anaplastic astrocytoma supports the existence of a broad anaplastic spectrum of disease, with enhancement being a clinical marker of tumour progression along this spectrum.

Dopamine Depletion Alters Macroscopic Network Dynamics in Parkinsons Disease

Abstract Parkinson’s disease is primarily characterised by diminished dopaminergic function, however the impact of these impairments on large-scale brain dynamics remains unclear. It has been difficult to disentangle the direct effects of Parkinson’s disease from compensatory changes that reconfigure the functional signature of the whole brain network. To examine the causal role of dopamine depletion in network-level topology, we investigated time-varying network structure in 37 individuals with idiopathic Parkinson’s disease, both ‘On’ and ‘Off’ dopamine replacement therapy, along with 50 age-matched, healthy control subjects using resting-state functional MRI. By tracking dynamic network-level topology, we found that the Parkinson’s disease ‘Off’ state was associated with greater network-level integration than in the ‘On’ state. The extent of integration in the ‘Off’ state inversely correlated with motor symptom severity, suggesting that a shift toward a more integrated network topology may be a compensatory mechanism associated with preserved motor function in the dopamine depleted ‘Off’ state. Furthermore, we were able to demonstrate that measures of both cognitive and brain reserve (i.e., premorbid intelligence and whole brain grey matter volume) had a positive relationship with the relative increase in network integration observed in the dopaminergic ‘Off’ state. This suggests that each of these factors plays an important role in promoting network integration in the dopaminergic ‘Off’ state. Our findings provide a mechanistic basis for understanding the PD ‘Off’ state and provide a further conceptual link with network-level reconfiguration. Together, our results highlight the mechanisms responsible for pathological and compensatory change in Parkinson’s disease.

025 The neural correlates of doorway freezing in parkinson’s disease

Introduction Freezing of gait (FOG) in Parkinson’s disease (PD) is a disabling symptom of advanced PD and is frequently triggered upon passing through narrow spaces such as doorways. 1 Despite being common, the mechanisms underlying this phenomenon are poorly understood. We have previously shown that increased footstep latency in a virtual reality (VR) environment is a surrogate measure of FOG. 2 In this study we aimed to model doorway freezing utilising the VR paradigm in conjunction with functional magnetic resonance imaging (fMRI) to determine the neural correlates of this phenomenon. Methods In our study, nineteen patients who routinely experience FOG performed a previously validated VR gait paradigm 3 where they used foot-pedals to navigate a series of doorways. Patients underwent testing randomised between both their ‘ON’ and ‘OFF’ medication states. Task performance in conjunction with blood oxygenation level dependent signal changes were compared within each patient. Results We were able to reproduce the finding that patients in the OFF state demonstrated significantly longer ‘footstep’ latencies as they passed through a doorway in the VR environment compared to the ON state. As seen clinically with FOG this locomotive delay was primarily triggered by narrow doorways rather than wide doorways. fMRI analysis revealed that doorway-provoked footstep delay was associated with selective hypoactivation in the pre-supplementary motor area (pSMA) bilaterally. Task-based functional connectivity analyses showed that this delay was inversely correlated with the degree of functional connectivity between the pSMA and the subthalamic nucleus (STN) across both hemispheres. Furthermore, increased frequency of prolonged footstep latency was associated with increased connectivity between the bilateral STN. Conclusion These findings suggest that the effect of environmental cues on triggering FOG reflects a degree of impaired processing within the pSMA and disrupted signalling between the pSMA and STN, thus implicating the ‘hyperdirect’ pathway in the generation of this phenomenon. References . Giladi N, Treves TA, Simon ES, Shabtai H, Orlov Y, Kandinov B, Paleacu D, Korczyn AD. Freezing of gait in patients with advanced Parkinson’s disease. J Neural Transm (Vienna)2001;108:53–61. . Matar E, Shine JM, Naismith SL, Lewis SJ.Virtual realitywalking and dopamine: opening new doorways to understanding freezing of gait in Parkinson’s disease. J Neurol Sci 2014;344:182–5. . Shine JM, Matar E, Bolitho SJ, Dilda V, Morris TR, Naismith SL, Moore ST, Lewis SJ. Modelling freezing of gait in Parkinson’s disease with a virtual reality paradigm. Gait Posture2013;38:104–8.

Complicated silicosis resulting from occupational exposure to engineered stone products

The biopsy specimen (A) shows the whorled appearance of a silicotic lung nodule, consisting of concentric laminated collagen fibres (haematoxylineeosin stain, magnification 10 ). A higher magnification image (B) highlights clefts containing faintly visible silicate particles surrounded by macrophages and giant cells (magnification 20 ). u A 54-year-old man, formerly a smoker, presented with a 6-year history of chronic coughandexertionalbreathlessnesswithout previous respiratory illnesses. Born in Vietnam,hecametoAustraliaasa refugeeat the age of 20 years. A screening chest x-ray was performed on his arrival in Australia; as the patient was not informed about any abnormality, thiswas assumed tobenormal. He commenced work as a labourer; he denied exposure to silica-containing materials and did not participate in activities typically associated with silica exposure (such as jack-hammering) during this period. About 15 years later, the patient started a job manufacturing stone benchtops. He cut, ground,finishedand installed thebenchtops, using a popular brand of engineered stone comprising > 85% crystalline silica. Occasionally, he made benchtops from granite andmarble. During the first 7 years of this work, the patient did not use any respiratory protective equipment, but later used a simple paper mask. Despite some dust extraction facilities in the factory, he reported that the environment was visibly dusty and that dust suppression with water was hardly ever used.

REM sleep behaviour disorder: not just a bad dream

Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia characterised by the loss of the normal atonia during the REM stage of sleep, resulting in overt motor behaviours that usually represent the enactment of dreams. Patients will seek medical attention due to sleep-related injuries or unpleasant dream content. Idiopathic RBD which occurs independently of any other disease occurs in up to 2% of the older population. Meanwhile, secondary RBD is very common in association with certain neurodegenerative conditions. RBD can also occur in the context of antidepressant use, obstructive sleep apnoea and narcolepsy. RBD can be diagnosed with a simple screening question followed by confirmation with polysomnography to exclude potential mimics. Treatment for RBD is effective and involves treatment of underlying causes, modification of the sleep environment, and pharmacotherapy with either clonazepam or melatonin. An important finding in the past decade is the recognition that almost all patients with idiopathic RBD will ultimately go on to develop Parkinson disease or dementia with Lewy bodies. This suggests that idiopathic RBD represents a prodromal phase of these conditions. Physicians should be aware of the risk of phenoconversion. They should educate idiopathic RBD patients to recognise the symptoms of these conditions and refer as appropriate for further testing and enrolment into research trials focused on neuroprotective measures.