Efficacy of biologically-directed daylight therapy on sleep and circadian rhythm in Parkinson's disease: a randomised, double-blind, parallel-group, active-controlled, phase 2 clinical trial.

Background: New non-pharmacological treatments for improving non-motor symptoms in Parkinson's disease (PD) are urgently needed. Previous light therapies for modifying sleep behaviour lacked standardised protocols and were not personalised for an individual patient chronotype. We aimed to assess the efficacy of a biologically-directed light therapy in PD that targets retinal inputs to the circadian system on sleep, as well as other non-motor and motor functions. Methods: In this randomised, double-blind, parallel-group, active-controlled trial at the Queensland University of Technology, Australia, participants with mild to moderate PD were computer randomised (1:1) to receive one of two light therapies that had the same photometric luminance and visual appearance to allow blinding of investigators and participants to the intervention. One of these biologically-directed lights matched natural daylight (Day Mel), which is known to stimulate melanopsin cells. The light therapy of the other treatment arm of the study, specifically supplemented the stimulation of retinal melanopsin cells (Enhanced Mel), targeting deficits to the circadian system. Both lights were administered 30 min per day over 4-weeks and personalised to an individual patient's chronotype, while monitoring environmental light exposure with actigraphy. Co-primary endpoints were a change from baseline in mean sleep macrostructure (polysomnography, PSG) and an endocrine biomarker of circadian phase (dim light melatonin secretion onset, DLMO) at weeks 4 and 6. Participants data were analysed using an intention to treat principle. All endpoints were evaluated by applying a mixed model analysis. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12621000077864. Findings: Between February 4, 2021 and August 8, 2022, 144 participants with PD were consecutively screened, 60 enrolled and randomly assigned to a light intervention. There was no significant difference in co-primary outcomes between randomised groups overall or at any individual timepoint during follow-up. The mean (95% CI) for PSG, N3% was 24.15 (19.82-28.48) for Day Mel (n = 23) and 19.34 (15.20-23.47) for the Enhanced Mel group (n = 25) in week 4 (p = 0.12); and 21.13 (16.99-25.28) for Day Mel (n = 26) and 18.48 (14.34-22.62) for the Enhanced Mel group (n = 25) in week 6, (p = 0.37). The mean (95% CI) DLMO (decimal time) was 19.82 (19.20-20.44) for Day Mel (n = 22) and 19.44 (18.85-20.04) for the Enhanced Mel group (n = 24) in week 4 (p = 0.38); and 19.90 (19.27-20.53) for Day Mel (n = 23) and 19.04 (18.44-19.64) for the Enhanced Mel group (n = 25) in week 6 (p = 0.05). However, both the controlled daylight (Day Mel) and the enhanced melanopsin (Enhanced Mel) interventions demonstrated significant improvement in primary PSG sleep macrostructure. The restorative deep sleep phase (PSG, N3) significantly improved at week 6 in both groups [model-based mean difference to baseline (95% CI): -3.87 (-6.91 to -0.83), p = 0.04]. There was a phase-advance in DLMO in both groups which did not reach statistical significance between groups at any time-point. There were no safety concerns or severe adverse events related to the intervention. Interpretation: Both the controlled daylight and melanopsin booster light showed efficacy in improving measures of restorative deep sleep in people with mild to moderate PD. That there was no significant difference between the two intervention groups may be due to the early disease stage. The findings suggest that controlled indoor daylight that is personalised to the individuals' chronotype could be effective for improving sleep in early to moderate PD, and further studies evaluating controlled daylight interventions are now required utilising this standardised approach, including in advanced PD. Funding: The Michael J Fox Foundation for Parkinson's Research, Shake IT Up Australia, National Health and Medical Research Council, and Australian Research Council.

Limbic thalamus atrophy is associated with visual hallucinations in Lewy body disorders.

Recent models of hallucinations in Lewy body disorders implicate dysfunction in 'higher order' thalamic regions involved in perceptual integration and cognitive processing. However, the degree of pathology and degeneration in these regions has not been assessed. We sought to assess atrophy, neuronal size, and neuronal numbers in the Mediodorsal (MDn) and Anterior Principal (APn) nuclei of the thalamus across Lewy body disorders comparing between patients with and without hallucinations. Postmortem tissue was acquired from 24 patients with Lewy body disease and 10 age-matched controls and analyzed using standard stereological and quantitative neuropathological techniques. Atrophy in MDn was significantly greater in patients with well-formed visual hallucinations and did not correlate significantly with neuronal size or number. Atrophy in APn was seen across all Lewy body disorders but was not significantly associated with hallucinations. α-synuclein immunoreactivity was found to be low in both the APn and MDn across all groups. These results suggest that MDn atrophy may be a marker of hallucinations and plays a role in their pathophysiology.

A critical review of the pharmacological treatment of REM sleep behavior disorder in adults: time for more and larger randomized placebo-controlled trials.

Rapid Eye Movement sleep behavior disorder (RBD) is a parasomnia causing sufferers to physically act out their dreams. These behaviors can disrupt sleep and sometimes lead to injuries in patients and their bed-partners. Clonazepam and melatonin are the first-line pharmacological treatment options for RBD based on direct uncontrolled clinical observations and very limited double-blind placebo-controlled trials. Given the risk for adverse outcomes, especially in older adults, it is of great importance to assess the existing level of evidence for the use of these treatments. In this update, we therefore critically review the clinical and scientific evidence on the pharmacological management of RBD in people aged over 50. We focus on the first-line treatments, and provide an overview of all other alternative pharmacological agents trialed for RBD we could locate as supplementary materials. By amalgamating all clinical observations, our update shows that 66.7% of 1,026 RBD patients reported improvements from clonazepam and 32.9% of 137 RBD patients reported improvements from melatonin treatment on various outcome measures in published accounts. Recently, however, three relatively small randomized placebo-controlled trials did not find these agents to be superior to placebo. Given clonazepam and melatonin are clinically assumed to majorly modify or eliminate RBD in nearly all patients-there is an urgent need to test whether this magnitude of treatment effect remains intact in larger placebo-controlled trials.

Validating a Seated Virtual Reality Threat Paradigm for Inducing Anxiety and Freezing of Gait in Parkinson's Disease.

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.

Feasibility of 3-month melatonin supplementation for brain oxidative stress and sleep in mild cognitive impairment: protocol for a randomised, placebo-controlled study.

INTRODUCTION: Melatonin has multiple proposed therapeutic benefits including antioxidant properties, synchronisation of the circadian system and lowering of blood pressure. In this protocol, we outline a randomised controlled trial to assess the feasibility, acceptability and tolerability of higher dose (25 mg) melatonin to target brain oxidative stress and sleep disturbance in older adults with mild cognitive impairment (MCI). METHODS AND ANALYSIS: The study design is a randomised double-blind, placebo-controlled, parallel group trial. Forty individuals with MCI will be recruited from the Healthy Brain Ageing Clinic, University of Sydney and from the community, and randomised to receive either 25 mg oral melatonin or placebo nightly for 12 weeks. The primary outcomes are feasibility of recruitment, acceptability of intervention and adherence to trial medication at 12 weeks. Secondary outcomes will include the effect of melatonin on brain oxidative stress as measured by magnetic resonance spectroscopy, blood pressure, blood biomarkers, mood, cognition and sleep. Outcomes will be collected at 6 and 12 weeks. The results of this feasibility trial will inform a future conclusive randomised controlled trial to specifically test the efficacy of melatonin on modifiable risk factors of dementia, as well as cognition and brain function. This will be the first trial to investigate the effect of melatonin in the population with MCI in this way, with the future aim of using this approach to reduce progression to dementia. ETHICS AND DISSEMINATION: This protocol has been approved by the Sydney Local Health District Ethics Committee (X18-0077). This randomised controlled trial will be conducted in compliance with the protocol published in the registry, the International Conference for Harmonisation on Good Clinical Practice and all other applicable regulatory requirements. The findings of the trial will be disseminated via conferences, publications and media, as applicable. Participants will be informed of results of the study at the conclusion of the trial. Eligible authors will include investigators who are involved in the conception and design of the study, the conduct of the trial, the analysis of the results, and reporting and presentation of study findings. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ANZCTRN 12619000876190). PROTOCOL VERSION: V.8 15 October 2020.

Functional MRI to Study Gait Impairment in Parkinson's Disease: a Systematic Review and Exploratory ALE Meta-Analysis.

PURPOSE OF REVIEW: Whilst gait impairment is a main cause for disability in Parkinson's disease (PD), its neural control remains poorly understood. We performed a systematic review and meta-analysis of neuroimaging studies of surrogate features of gait in PD. FINDINGS: Assessing the results from PET or SPECT scans after a period of actual walking as well as fMRI during mental imagery or virtual reality (VR) gait paradigms, we found a varying pattern of gait-related brain activity. Overall, a decrease in activation of the SMA during gait was found in PD compared to elderly controls. In addition, the meta-analysis showed that the most consistent gait-related activation was situated in the cerebellar locomotor region (CLR) in PD. Despite methodological heterogeneity, the combined neuroimaging studies of gait provide new insights into its neural control in PD, suggesting that CLR activation likely serves a compensatory role in locomotion.

The role of high-field magnetic resonance imaging in parkinsonian disorders: Pushing the boundaries forward.

Historically, magnetic resonance imaging (MRI) has contributed little to the study of Parkinson's disease (PD), but modern MRI approaches have unveiled several complementary markers that are useful for research and clinical applications. Iron- and neuromelanin-sensitive MRI detect qualitative changes in the substantia nigra. Quantitative MRI markers can be derived from diffusion weighted and iron-sensitive imaging or volumetry. Functional brain alterations at rest or during task performance have been captured with functional and arterial spin labeling perfusion MRI. These markers are useful for the diagnosis of PD and atypical parkinsonism, to track disease progression from the premotor stages of these diseases and to better understand the neurobiological basis of clinical deficits. A current research goal using MRI is to generate time-dependent models of the evolution of PD biomarkers that can help understand neurodegeneration and provide reliable markers for therapeutic trials. This article reviews recent advances in MRI biomarker research at high-field (3T) and ultra high field-imaging (7T) in PD and atypical parkinsonism. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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 Parkinson's 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 subject's 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.

The effect of 12-wk ω-3 fatty acid supplementation on in vivo thalamus glutathione concentration in patients "at risk" for major depression.

OBJECTIVES: As life expectancy increases, the need to prevent major health disorders is clear. Depressive symptoms are common in older adults and are associated with cognitive decline and greater risk for transitioning to major depression. Oxidative stress may be implicated in the pathophysiology of major depression and can be measured in vivo using proton magnetic resonance spectroscopy via the neurometabolite glutathione (GSH). Evidence suggests ω-3 fatty acid (FA) supplementation may prevent depression and directly affect GSH concentration. The aim of this study was to examine the effect of ω-3 FA supplementation on in vivo GSH concentration in older adults at risk for depression. METHODS: Fifty-one older adults at risk for depression were randomized to receive either four 1000-mg ω-3 FA supplements daily (containing eicosapentaenoic acid 1200 mg plus docosahexaenoic acid 800 mg) or placebo (four 1000-mg paraffin oil placebo capsules daily) for 12 wk. Participants underwent magnetic resonance spectroscopy, as well as medical, neuropsychological, and self-report assessments at baseline and after 12 wk of supplementation. GSH was measured in the thalamus and calculated as a ratio to creatine. Depressive symptoms were measured using the Patient Health Questionnaire. RESULTS: Compared with the group given the ω-3 FA supplements, the placebo group had greater change in the GSH-to-creatine ratio in the thalamus (t = 2.00; P = 0.049) after the 12 wk intervention. This increase was in turn associated with a worsening of depressive symptoms (r = 0.43; P = 0.043). CONCLUSIONS: Depressive symptom severity in older adults appears to be associated with increased brain levels of GSH, a key marker of oxidative stress. Importantly, ω-3 FA supplementation may attenuate oxidative stress mechanisms, thereby offering benefits for depression prevention.

Imagine that: elevated sensory strength of mental imagery in individuals with Parkinson's disease and visual hallucinations.

Visual hallucinations occur when our conscious experience does not accurately reflect external reality. However, these dissociations also regularly occur when we imagine the world around us in the absence of visual stimulation. We used two novel behavioural paradigms to objectively measure visual hallucinations and voluntary mental imagery in 19 individuals with Parkinson's disease (ten with visual hallucinations; nine without) and ten healthy, age-matched controls. We then used this behavioural overlap to interrogate the connectivity both within and between the major attentional control networks using resting-state functional magnetic resonance imaging. Patients with visual hallucinations had elevated mental imagery strength compared with patients without hallucinations and controls. Specifically, the sensory strength of imagery predicted the frequency of visual hallucinations. Together, hallucinations and mental imagery predicted multiple abnormalities in functional connectivity both within and between the attentional control networks, as measured with resting-state functional magnetic resonance imaging. However, the two phenomena were also dissociable at the neural level, with both mental imagery and visual misperceptions associated with specific abnormalities in attentional network connectivity. Our results provide the first evidence of both the shared and unique neural correlates of these two similar, yet distinct phenomena.

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

The pathological hallmark of Parkinson's 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 Parkinson's 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 Parkinson's 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 Parkinson's disease in the "off" state. The administration of dopaminergic medication significantly improved connectivity across striatal subdivisions in Parkinson's disease, implicating dopaminergic deficits in the pathogenesis of impaired striatal interconnectivity. In addition, impaired striatal interconnectivity in the Parkinson's 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 Parkinson's disease "on" state, these relationships were absent in Parkinson's 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 Parkinson's disease.

Sleep quality in healthy older people: relationship with ¹H magnetic resonance spectroscopy markers of glial and neuronal integrity.

The hippocampus and thalamus assume a significant role in the overnight consolidation of memories, a process that is negatively impacted by sleep disruption. Emerging evidence suggests that disturbances of sleep in older people may co-occur with underlying neurobiological changes. This study sought to assess glial and neuronal integrity in these regions in relation to subjective sleep disturbance in a healthy older sample. Forty-three healthy older people (mean age = 70, SD = 5.0) were assessed clinically and medically and screened for cognitive and depressive symptoms, as well as sleep disturbance. Single voxel hippocampal and thalamus metabolite ratios of N-acetyl aspartate (NAA) and myo-inositol (mI) with total creatine (Cr + PCr) were measured using magnetic resonance spectroscopy at 3-Tesla. Higher hippocampal mI/Cr + PCr ratios were significantly correlated with poorer self-reported sleep quality (r = .42, p < .01) and less sleep efficiency (r = -0.42, p < .01) as recorded by the Pittsburgh Sleep Quality Index (Buysse, Reynolds, Monk, Berman, & Kupfer, 1989). No other significant correlations were observed within the hippocampus or within the thalamus. These results indicate that in healthy older people, subjective sleep disturbance may be associated with glial alterations in the hippocampus. Future research is now needed to examine these associations with respect to objective sleep measures and overnight memory consolidation.

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.

Investigating visual misperceptions in Parkinson's disease: a novel behavioral paradigm.

Visual misperception and hallucinations represent a major problem in advanced PD. The pathophysiological mechanisms underlying these symptoms remain poorly understood, with limited tests for their assessment. A recent hypothesis has suggested that visual misperception and hallucinations may arise from disrupted processing in the attentional networks. To assess and quantify visual misperceptions, we developed the novel bistable percept paradigm (BPP), which consists of a battery of "single" and "hidden" monochromatic images that subjects are required to study until they are satisfied that they have recognized everything that the image may represent. In this experiment, 45 patients and 18 age-matched controls performed the BPP. Using an error score value derived from the control group, 23 patients were identified as having significant deficits on the task. Compared to patients who were unimpaired on the task, this group of patients had significantly higher levels of self-reported hallucinations on the SCales for Outcomes in PArkinson's Disease-Psychiatric Complications and also symptoms of rapid eye movement sleep behavior disorder (RBD). Furthermore, impairment on the BPP was associated with significantly reduced performance on an attentional set-shifting task. Patients with impaired performance on the BPP had higher rates of hallucinations, increased symptoms of RBD, and poorer performance on set shifting, suggesting disrupted processing within the attentional control networks. We propose that the BPP may offer a novel approach for exploring the neural correlates underlying visual hallucinations and misperceptions in PD.

A novel paradigm for modelling freezing of gait in Parkinson's disease.

Freezing of gait (FOG) is a common cause of disability in Parkinson's disease (PD) but its underlying pathophysiology is poorly understood. A recent hypothesis has proposed that FOG is related to a problem of set-shifting between motor, cognitive and limbic pathways. In this model, the functional convergence of these pathways on the output nuclei of the basal ganglia is believed to result in paroxysmal excessive inhibition of the thalamus and brainstem nuclei leading to freezing episodes. This hypothesis could be assessed with functional neuroimaging but would require a behavioural paradigm capable of modelling FOG. In this experiment, 12 patients with PD underwent assessment on a novel computer-based paradigm where they navigated a realistic three-dimensional environment in which cognitive and limbic load could be manipulated. Performance on this paradigm was significantly correlated with self-reported FOG symptoms assessed by a validated questionnaire. We believe this paradigm is capable of accurately modelling FOG and will have validity in future functional neuroimaging and therapeutic intervention studies.