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Freezing of Gait (FoG) is a common symptom of Parkinson’s disease (PD), manifesting as a brief, episodic absence, or marked reduction in walking, despite a patient’s intention to move. Clinical assessment of FoG events from manual observations by experts is both time-consuming and highly subjective. Therefore, machine learning-based FoG identification methods would be desirable. In this article, we address this task as a fine-grained human action recognition problem based on vision inputs. A novel deep learning architecture, namely, higher order polynomial transformer (HP-Transformer), is proposed to incorporate pose and appearance feature sequences to formulate fine-grained FoG patterns. In particular, a higher order self-attention mechanism is proposed based on higher order polynomials. To this end, linear, bilinear, and trilinear transformers are formulated in pursuit of discriminative fine-grained representations. These representations are treated as multiple streams and further fused by a cross-order fusion strategy for FoG detection. Comprehensive experiments on a large in-house dataset collected during clinical assessments demonstrate the effectiveness of the proposed method, and an area under the receiver operating characteristic (ROC) curve (AUC) of 0.92 is achieved for detecting FoG.

Background: Although prior research has established that freezing of gait (FOG) in Parkinson’s disease (PD) is associated with anxiety, only one study to date has directly manipulated anxiety levels to induce FOG.Objective: The current study aimed to replicate these previous findings and evaluate whether a seated version of a ‘threat’ virtual reality (VR) paradigm could induce anxiety and provoke FOG.Methods: Twenty-four PD patients with FOG were assessed across various threat conditions in both a walking VR paradigm (Experiment 1) and a seated VR paradigm (Experiment 2). Both paradigms manipulated the height (i.e., elevated vs ground) and width (wide vs narrow) of the planks participants were instructed to walk across.Results: Across both experiments, the Elevated + Narrow condition provoked significantly greater number of freezing episodes compared to all other conditions. Higher levels of self-reported anxiety were reported during the Elevated+Narrow condition compared to all other conditions in Experiment 1, and compared to the Ground condition in Experiment 2.Conclusion: These findings confirm that anxiety contributes to FOG and validates the use of a seated VR threat paradigm for provoking anxiety-related freezing. This enables future studies to combine this paradigm with functional MRI to explore the neural correlates underlying the role of anxiety in FOG.

Background: Freezing of gait (FOG) in Parkinson’s disease (PD) has been shown to be more frequent in stressful situations, implicating anxiety. Heart rate (HR) has been shown to increase prior to a FOG episode supporting the notion that elevated stress levels may trigger FOG. However, no studies to date have investigated whether elevated HR precedes all subtypes of FOG or only those episodes that are driven by anxiety.Objective: The present study sought to investigate whether 1) HR increases prior to FOG episodes in nonspecific environments (Experiment 1), and if 2) HR increases prior to FOG when provoked in high but not low threat environments using a virtual reality paradigm (Experiment 2).Methods: In Experiment 1, 10 of 19 participants with PD and FOG (PD + FOG) experienced FOG during a series of walking trials. In Experiment 2, 12 of 23 participants with PD + FOG experienced FOG while walking across an elevated and ground level narrow plank in virtual reality. HR was collected throughout the duration of both experiments, while FOG was quantified by experts using video review and tagging.Results: HR significantly increased 2–3 seconds prior to a FOG episode during Experiment 1. In Experiment 2, HR significantly increased 4–6 seconds prior to a FOG episode, specifically while navigating the elevated plank. However, there were no significant increases in HR prior to FOG episodes when participants navigated the ground plank.Conclusion: This study extends previous work further demonstrating that increases in HR prior to FOG episodes appear linked to elevated anxiety levels.

Freezing of gait (FOG) in Parkinson’s disease (PD) has been shown to be more frequent in stressful situations, implicating anxiety. Heart rate (HR) has been shown to increase prior to a FOG episode supporting the notion that elevated stress levels may trigger FOG. However, no studies to date have investigated whether elevated HR precedes all subtypes of FOG or only those episodes that are driven by anxiety. The present study sought to investigate whether 1) HR increases prior to FOG episodes in nonspecific environments (Experiment 1), and if 2) HR increases prior to FOG when provoked in high but not low threat environments using a virtual reality paradigm (Experiment 2). In Experiment 1, 10 of 19 participants with PD and FOG (PD + FOG) experienced FOG during a series of walking trials. In Experiment 2, 12 of 23 participants with PD + FOG experienced FOG while walking across an elevated and ground level narrow plank in virtual reality. HR was collected throughout the duration of both experiments, while FOG was quantified by experts using video review and tagging. HR significantly increased 2–3 seconds prior to a FOG episode during Experiment 1. In Experiment 2, HR significantly increased 4–6 seconds prior to a FOG episode, specifically while navigating the elevated plank. However, there were no significant increases in HR prior to FOG episodes when participants navigated the ground plank. This study extends previous work further demonstrating that increases in HR prior to FOG episodes appear linked to elevated anxiety levels.

Although prior research has established that freezing of gait (FOG) in Parkinson’s disease (PD) is associated with anxiety, only one study to date has directly manipulated anxiety levels to induce FOG. The current study aimed to replicate these previous findings and evaluate whether a seated version of a ‘threat’ virtual reality (VR) paradigm could induce anxiety and provoke FOG. Twenty-four PD patients with FOG were assessed across various threat conditions in both a walking VR paradigm (Experiment 1) and a seated VR paradigm (Experiment 2). Both paradigms manipulated the height (i.e., elevated vs ground) and width (wide vs narrow) of the planks participants were instructed to walk across. Across both experiments, the Elevated + Narrow condition provoked significantly greater number of freezing episodes compared to all other conditions. Higher levels of self-reported anxiety were reported during the Elevated+Narrow condition compared to all other conditions in Experiment 1, and compared to the Ground condition in Experiment 2. These findings confirm that anxiety contributes to FOG and validates the use of a seated VR threat paradigm for provoking anxiety-related freezing. This enables future studies to combine this paradigm with functional MRI to explore the neural correlates underlying the role of anxiety in FOG.

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 investigated the spatial, dynamic, and molecular signatures of system-wide neural activity across a range of cognitive tasks. We found that neuronal activity converged onto a low-dimensional manifold that facilitates the execution of diverse task states. Flow within this attractor space was associated with dissociable cognitive functions, unique patterns of network-level topology, and individual differences in fluid intelligence. The axes of the low-dimensional neurocognitive architecture aligned 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 neural activity, neuromodulatory systems, and cognitive function.

Threatening situations lead to observable gait deficits in individuals with Parkinson’s disease (PD) who suffer from high trait anxiety levels. The specific characteristics of gait that are affected appear to be similar to behaviors observed while walking during a dual-task (DT) condition. Yet, it remains unclear whether anxiety is similar to a cognitive load. If it were, then those with PD who have high trait anxiety might be expected to be more susceptible to DT interference during walking. Thus, the overall aim of this study was to evaluate whether trait anxiety influences gait during single-task (ST) and DT walking. Seventy participants (high-anxiety PD [HA-PD], N=26; low-anxiety PD [LA-PD], N=26; healthy control [HC], N=18) completed three ST and three DT walking trials on a data-collecting carpet. The secondary task consisted of digit monitoring while walking. Results showed that during both ST and DT gait, the HA-PD group demonstrated significant reductions in walking speed and step length, as well as increased step length variability and step time variability compared with healthy controls and the LA-PD group. Notably, ST walking in the HA-PD group resembled (i.e., it was not significantly different from) the gait behaviors seen during a DT in the LA-PD and HC groups. These results suggest that trait anxiety may consume processing resources and limit the ability to compensate for gait impairments in PD.

The aim of this study was to evaluate the utility of the Bistable Percept Paradigm (BPP), a computerised behavioural task that has previously been utilised for the assessment of visual hallucinations in Parkinson’s Disease, in a Dementia with Lewy bodies (DLB) cohort. Dementia with Lewy bodies patients demonstrated poorer performance than healthy controls (HC) on the BPP with significantly more misperceptions and a greater failure to detect bistable percepts correctly compared to HC. Further, the number of misperceptions was also correlated with the severity of hallucinations. The findings from this study demonstrate that the BPP is a viable tool to measure misperceptions in DLB patients.

IntroductionIdiopathic REM sleep behaviour(iRBD) disorder represents the most specific prodromal marker of an impending synucleinopathy with over 90% developing either Parkinson’s disease(PD), Dementia with Lewy Bodies(DLB) or Multiple System Atrophy(MSA) after 15 years. This finding has stimulated efforts to actively register and track progression of such patients. Here we present experience of a biobanking program established with the aim of identifying prodromal synucleinopathies to facilitate recruitment to neuroprotective trials as they become available.MethodsPatients with iRBD were prospectively and sequentially recruited. Cross-sectional comparator groups consisting of healthy controls, idiopathic PD (within 5 years of diagnosis) and DLB were also recruited. Patients underwent a standardized assessment protocol including clinical phenotyping, neuropsychometric testing, multimodal MRI, polysomnography, quantitative electroencephalography, chronobiology (melatonin and clock gene expression profiling) and gait testing. Subjects were invited for annual and biennial review.Results102 patients have been recruited into the study since July 2016 including 35 patients with iRBD, 26 DLB, 19 early PD and 16 controls. 15 patients have returned for follow-up with 3 converting to a synucleinopathy(2 DLB, 1 PD). 75% of participants were able to complete all elements of assessment protocol. Preliminary evaluation of iRBD participants reveals early changes in clock gene expression(BMAL1) and subtle changes in patterns of gait compared to older controls.ConclusionsOur preliminary findings demonstrate utility and feasibility of a prodromal biobanking program within the Australian context aimed at identifying prodromal synucleinopathies. Similar models can be applied to other centers to improve access and create an extended national collaborative network.

IntroductionEmerging evidence indicates that color discrimination impairments can predict the development of dementia across a range of prodromal Lewy body conditions. However, color vision deficits are not seen uniformly in patients with Dementia with Lewy Bodies (DLB), suggesting a more nuanced association. Visual hallucinations(VH) represent a discriminating feature of DLB, and recent evidence implicates visual pathway dysfunction as a significant contributor to this phenomenon. We therefore hypothesized that color impairment will more closely associate with VH in DLB rather than general cognition.MethodsIn this study, we examined the relationship between color vision impairment and VH, along with other clinical and neuropsychological features in 24 patients with DLB alongside 25 age-matched controls. Color discrimination was assessed using the Farnsworth-Munsell-100 Hue (FM-100) test.ResultsColor discrimination impairment was seen in 16/24 DLB participants (67%) with a higher error score relative to controls(p=0.001). We demonstrate for the first time a strong association between color discrimination errors and both the presence and severity of VH in DLB based on clinician-derived(p=0.008) and questionnaire-derived(p=0.03) measures. Correlation with clinical and neuropsychological variables revealed that color discrimination is significantly related to visuospatial impairment(p=0.02) but not to global measures of cognition, motor severity, age or disease duration. Factor analysis confirmed a unique relationship between color discrimination, visual hallucinations and visuospatial function.ConclusionOur results suggest that color impairments may be a specific biomarker of visual hallucinations and associated visuoperceptual deficits in evolving Lewy body disorders rather than dementia per se and thus providing insight into a shared pathophysiological substrate.

IntroductionFreezing 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.1Despite 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.2In 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.MethodsIn our study, nineteen patients who routinely experience FOG performed a previously validated VR gait paradigm3where 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.ResultsWe 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.ConclusionThese 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.

In the version of this article initially published, Kaylena A. Ehgoetz Martens’ name was misspelled as Kayla. The error has been corrected in the HTML and PDF versions of the article.

IntroductionDespite its importance for management, prognostication and selection of patients for clinical trials, the diagnosis of Dementia with Lewy Bodies (DLB) remains challenging. Complicating this is a recent change in the diagnostic criteria which has arguably shifted the expected phenotype of DLB patients. In this study we aimed to characterize and examine the relationship between cognitive and clinical diagnostic variables in DLB patients to uncover latent symptom clusters that may streamline future diagnostic approaches in the clinic.MethodsThe clinical and neuropsychological profile of 27 prospectively recruited participants diagnosed with probableDLB and 25 age-matched controls was characterized according to the most recent consensus criteria.Symptoms were scored using a novel combination of established clinical and research instruments.ResultsWe demonstrate comparable sensitivity of formal neuropsychological testing and bedside screening tools (MOCA/MMSE) for identifying domain-specific differences between controls and patients(p<0.001). Optimal sensitivity thresholds for diagnosis of Parkinsonism (88.9%) were explored yielding a prevalence range of 50%-90% within our cohort.Factor analysis using all core and supportive features of the diagnostic criteria identified 6 independent factors accounting for 81% of the total variance. Unique relationships identified included between hallucinations and fluctuations and excessive daytime somnolence; between REM sleep behavior disorder and orthostatic hypotension; and Parkinsonism and urinary disturbance. ‘Prodromal’ symptoms including autonomic and early neuropsychiatric features are represented in the remaining factors.ConclusionParsimonious delineation of clinical variables using identified symptom clusters can aid DLB diagnosis.Clusters are also used to highlight latent pathological relationships. Appropriate instruments and thresholds for detecting dementia and core and suggestive features are presented.