Parkinson's disease deficits in time perception to auditory as well as visual stimuli - A large online study

Cognitive deficits are common in Parkinson’s disease (PD) and range from mild cognitive impairment to dementia, often dramatically reducing quality of life. Physiological models have shown that attention and memory are predicated on the brain’s ability to process time. Perception has been shown to be increased or decreased by activation or deactivation of dopaminergic neurons respectively. Here we investigate differences in time perception between patients with PD and healthy controls. We have measured differences in sub-second- and second-time intervals. Sensitivity and error in perception as well as the response times are calculated. Additionally, we investigated intra-individual response variability and the effect of participant devices on both reaction time and sensitivity. Patients with PD have impaired sensitivity in discriminating between durations of both visual and auditory stimuli compared to healthy controls. Though initially designed as an in-person study, because of the pandemic the experiment was adapted into an online study. This adaptation provided a unique opportunity to enroll a larger number of international participants and use this study to evaluate the feasibility of future virtual studies focused on cognitive impairment. To our knowledge this is the only time perception study, focusing on PD, which measures the differences in perception using both auditory and visual stimuli. The cohort involved is the largest to date, comprising over 800 participants

Learning and Recognition of a Non-conscious Sequence of Events in Human Primary Visual Cortex

Published Online: March 03, 2016Human primary visual cortex (V1) has long been associated with learning simple low-level visual discriminations [1] and is classically considered outside of neural systems that support high-level cognitive behavior in contexts that differ from the original conditions of learning, such as recognition memory [2, 3]. Here, we used a novel fMRI-based dichoptic masking protocol—designed to induce activity in V1, without modulation from visual awareness—to test whether human V1 is implicated in human observers rapidly learning and then later (15–20 min) recognizing a non-conscious and complex (secondorder) visuospatial sequence. Learning was associated with a change in V1 activity, as part of a temporo-occipital and basal ganglia network, which is at variance with the cortico-cerebellar network identified in prior studies of ‘‘implicit’’ sequence learning that involved motor responses and visible stimuli (e.g., [4]). Recognition memory was associated with V1 activity, as part of a temporo-occipital network involving the hippocampus, under conditions that were not imputable to mechanisms associated with conscious retrieval. Notably, the V1 responses during learning and recognition separately predicted non-conscious recognition memory, and functional coupling between V1 and the hippocampus was enhanced for old retrieval cues. The results provide a basis for novel hypotheses about the signals that can drive recognition memory, because these data (1) identify human V1 with a memory network that can code complex associative serial visuospatial information and support later nonconscious recognition memory-guided behavior (cf. [5]) and (2) align with mouse models of experiencedependent V1 plasticity in learning and memory [6].This work was supported by the Wellcome Trust (WT073735MA; C.R.R. and C.K.; http://www.wellcome.ac.uk/), the Medical Research Council (UK, 89631; D.S.; http://www.mrc.ac.uk/), the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford (C.R.R., C.A.A., and C.K.; http://oxfordbrc.nihr.ac.uk/), and the Dementias and Neurodegenerative Diseases Research Network (C.A.A.; https://www.crn.nihr.ac.uk/dementia)

Principal component analysis of the cytokine and chemokine response to human traumatic brain injury.

There is a growing realisation that neuro-inflammation plays a fundamental role in the pathology of Traumatic Brain Injury (TBI). This has led to the search for biomarkers that reflect these underlying inflammatory processes using techniques such as cerebral microdialysis. The interpretation of such biomarker data has been limited by the statistical methods used. When analysing data of this sort the multiple putative interactions between mediators need to be considered as well as the timing of production and high degree of statistical co-variance in levels of these mediators. Here we present a cytokine and chemokine dataset from human brain following human traumatic brain injury and use principal component analysis and partial least squares discriminant analysis to demonstrate the pattern of production following TBI, distinct phases of the humoral inflammatory response and the differing patterns of response in brain and in peripheral blood. This technique has the added advantage of making no assumptions about the Relative Recovery (RR) of microdialysis derived parameters. Taken together these techniques can be used in complex microdialysis datasets to summarise the data succinctly and generate hypotheses for future study

Statistical characteristics of finger-tapping data in Huntington’s disease

Measuring the rate of finger tapping is a technique commonly used as an indicator of impairment in degenerative neurological conditions, such as Huntington’s disease. The information it provides can be greatly enhanced by analysing not simply the overall tapping rate, but also the statistical characteristics of the individual times between each successive response. Recent technological improvements in the recording equipment allow the responses to be analysed extremely quickly, and permit modification of the task in the interest of greater clinical specificity. Here we illustrate its use with some pilot data from a group of manifest HD patients and age-matched controls. Even in this small cohort, differences in the responses are apparent that appear to relate to the severity of the disease as measured by conventional behavioural tests

Quantitative oculomotor assessment in hereditary ataxia: systematic review and consensus by the ataxia global initiative working group on digital-motor biomarkers

Oculomotor deficits are common in hereditary ataxia, but disproportionally neglected in clinical ataxia scales and as outcome measures for interventional trials. Quantitative assessment of oculomotor function has become increasingly available and thus applicable in multicenter trials and offers the opportunity to capture severity and progression of oculomotor impairment in a sensitive and reliable manner. In this consensus paper of the Ataxia Global Initiative Working Group On Digital Oculomotor Biomarkers, based on a systematic literature review, we propose harmonized methodology and measurement parameters for the quantitative assessment of oculomotor function in natural-history studies and clinical trials in hereditary ataxia. MEDLINE was searched for articles reporting on oculomotor/vestibular properties in ataxia patients and a study-tailored quality-assessment was performed. One-hundred-and-seventeen articles reporting on subjects with genetically confirmed (n=1134) or suspected hereditary ataxia (n=198), and degenerative ataxias with sporadic presentation (n=480) were included and subject to data extraction. Based on robust discrimination from controls, correlation with disease-severity, sensitivity to change, and feasibility in international multicenter settings as prerequisite for clinical trials, we prioritize a core-set of five eye-movement types: (i) pursuit eye movements, (ii) saccadic eye movements, (iii) fixation, (iv) eccentric gaze holding, and (v) rotational vestibulo-ocular reflex. We provide detailed guidelines for their acquisition, and recommendations on the quantitative parameters to extract. Limitations include low study quality, heterogeneity in patient populations, and lack of longitudinal studies. Standardization of quantitative oculomotor assessments will facilitate their implementation, interpretation, and validation in clinical trials, and ultimately advance our understanding of the evolution of oculomotor network dysfunction in hereditary ataxias

Retinal Optical Coherence Tomography Features Associated With Incident and Prevalent Parkinson Disease

Background and objectives: Cadaveric studies have shown disease-related neurodegeneration and other morphological abnormalities in the retina of individuals with Parkinson disease (PD), however it remains unclear whether this can be reliably detected with in vivo imaging. We investigated inner retinal anatomy, measured using optical coherence tomography (OCT), in prevalent PD and subsequently assessed the association of these markers with the development of PD using a prospective research cohort.// Methods: This cross-sectional analysis used data from two studies. For the detection of retinal markers in prevalent PD, we used data from AlzEye, a retrospective cohort of 154,830 patients aged 40 years and over attending secondary care ophthalmic hospitals in London, UK between 2008 and 2018. For the evaluation of retinal markers in incident PD, we used data from UK Biobank, a prospective population-based cohort where 67,311 volunteers aged 40-69 years were recruited between 2006 and 2010 and underwent retinal imaging. Macular retinal nerve fibre layer (mRNFL), ganglion cell-inner plexiform layer (GCIPL), and inner nuclear layer (INL) thicknesses were extracted from fovea--centred OCT. Linear mixed effects models were fitted to examine the association between prevalent PD and retinal thicknesses. Hazard ratios for the association between time to PD diagnosis and retinal thicknesses were estimated using frailty models.// Results: Within the AlzEye cohort, there were 700 individuals with prevalent PD and 105,770 controls (mean age 65.5 ± 13.5 years, 51.7% female). Individuals with prevalent PD had thinner GCIPL (-2.12 μm, 95% confidence interval: -3.17, -1.07, p = 8.2 × 10⁻⁵) and INL (-0.99 μm, 95% confidence interval: -1.52, -0.47, p = 2.1 × 10⁻⁴). The UK Biobank included 50,405 participants (mean age 56.1 ± 8.2 years, 54.7% female), of whom 53 developed PD at a mean of 2653 ± 851 days. Thinner GCIPL (hazard ratio: 0.62 per standard deviation increase, 95% confidence interval: 0.46, 0.84, p=0.002) and thinner INL (hazard ratio: 0.70, 95% confidence interval: 0.51, 0.96, p=0.026) were also associated with incident PD.// Discussion: Individuals with PD have reduced thickness of the INL and GCIPL of the retina. Involvement of these layers several years before clinical presentation highlight a potential role for retinal imaging for at-risk stratification of PD

Quantifying Motor Impairment in Movement Disorders

Until recently the assessment of many movement disorders has relied on clinical rating scales that despite careful design are inherently subjective and non-linear. This makes accurate and truly observer-independent quantification difficult and limits the use of sensitive parametric statistical methods. At last, devices capable of measuring neurological problems quantitatively are becoming readily available. Examples include the use of oculometers to measure eye movements and accelerometers to measure tremor. Many applications are being developed for use on smartphones. The benefits include not just more accurate disease quantification, but also consistency of data for longitudinal studies, accurate stratification of patients for entry into trials, and the possibility of automated data capture for remote follow-up. In this mini review, we will look at movement disorders with a particular focus on Parkinson's disease, describe some of the limitations of existing clinical evaluation tools, and illustrate the ways in which objective metrics have already been successful

Oculomotor deficits in Parkinson's disease: Increasing sensitivity using multivariate approaches

Parkinson's disease (PD) affects several domains of neurological function, from lower-level motor programs to higher cognitive processing. As certain types of eye movements (saccades) are fast, non-fatiguing, and can be measured objectively and non-invasively, they are a promising candidate for quantifying motor and cognitive dysfunction in PD, as well as other movement disorders. In this pilot study, we evaluate the latency (reaction time), damping (resistance to oscillation), and amplitude of saccadic movements in two tasks performed by 25 PD patients with mild to moderate disease and 26 age-matched healthy controls. As well as general increases in reaction time caused by PD, the damping of saccadic eye movements was found to be task-dependent and affected by disease. Finally, we introduce a proof-of-concept multivariate model to demonstrate how information from saccadometry can be combined to infer disease status