Name: characterizing the relationship between eye movement parameters and cognitive functions in non-demented parkinson's disease patients with eye tracking
Uploaded: 2019-09-26T14:30:00
Description: Watch this Scientific Journal Video about Characterizing the Relationship Between Eye Movement Parameters and Cognitive Functions in Non-demented Parkinson's Disease Patients with Eye Tracking at JoVE

The authors would like to thank Dr. Harvey Hung for his advice&#160;on the manuscript.

This research project was approved by the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (CREC Ref. No.: 2015.263).
1. Participants Recruitment and Baseline Assessment
<ol>
	<li>Recruit Parkinson&#39;s disease patients aged less than or equal to 70 from a neurology specialist clinic with the diagnosis made based on the United Kingdom Parkinson&#39;s Disease Society (UKPDS) Brain Bank Diagnostic Criteria12....

<ol>
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F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+modified+Fuld+Verbal+Fluency+Test:+a+validation+study+in+Hong+Kong.">The modified Fuld Verbal Fluency Test: a validation study in Hong Kong.</a> The journals of gerontology. Series B, Psychological sciences and social sciences. 52 (5), 247-250 (1997).</li><li>Chan, A. S., Kwok, I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hong+Kong+list+learning+test:+manual+and+preliminary+norm.">Hong Kong list learning test: manual and preliminary norm.</a> Hong Kong: Department of Psychological and Clinical Psychology Center. , (1999).</li><li>Robbins, T. W., James, M., Owen, A. M., Sahakian, B. 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The protocol presented above was designed as the first part of a longitudinal study in exploring the potential clinical utility of eye movement parameters as surrogate markers for cognitive functions in Parkinson&#39;s disease. While there are studies that examine more classical eye tracking paradigms such as self-paced saccade, reflexive saccade, and anti-saccade25,26,27, a visual search task was used in this study to measure e...

Parkinson&#8217;s disease is classically a motor disorder; yet, the disease is also associated with cognitive deficits, and progression into dementia is common1. The pathophysiology of cognitive impairment in Parkinson&#39;s disease is not well understood. It is thought to be related to alpha-synuclein deposition in the cortical area based on Braak&#39;s staging2. It was also proposed that a dual syndrome of degeneration of the dopaminergic and the cholinergic system leads to different cognitive deficits with prognostic implication3. More research is needed to further elucidate the exact mechanisms involved in cognitive impairment in Parkinson&#39;s disease. On the clinical aspect, the presence of cognitive impairment has a significant impact on prognosis4,5. Assessment of cognitive function in clinical practice is, therefore, essential. However, a lengthy cognitive assessment is limited by patients&#8217; mental and motor conditions. Therefore, a noninvasive and simple measurement that can reflect the disease&#39;s burden on cognitive function is needed.
The eye movement abnormalities are widely described detectable signs of Parkinson&#39;s disease from its early stages6, yet the pathophysiology is even less well-characterized than that of cognitive impairment. The generation of eye movement is through a transformation of the visual sensory input, subserved by an intertwined cortical and subcortical network, into signals to the oculomotor nuclei in the brainstem for effect7. Involvement of Parkinson&#39;s disease pathologies in these networks may lead to observable eye movement abnormalities. There is, perhaps overlapping of neuroanatomical structures that govern the control of eye movement and cognitive function. Furthermore, there have been studies examining the relationship between saccadic eye movement and cognitive function in other neurodegenerative disorders8. On such grounds, it is worthwhile to explore the use of eye movement parameters as a proxy marker of cognitive functions in Parkinson&#39;s disease. One cross-sectional study9 showed that reduced saccadic amplitude and longer fixation duration was associated with the severity of global cognitive impairment in Parkinson&#39;s disease. However, there is a lack of data on the correlation between eye movement parameters and specific cognitive domains. The significance and need of measurement of specific cognitive domains, rather than a general cognitive state, is that individual cognitive domain informs differential prognostic information in Parkinson&#39;s disease3 and they are subserved by different neural networks. The aim of this study is to explore the specific relationship between eye movement metrics and different cognitive functions. This is the first step to establish a foundation on which the development of biomarkers of cognitive decline in Parkinson&#39;s disease using eye tracking technology could be built.
The experimental paradigm presented is composed of 2 major parts: the cognitive assessment and the eye tracking task. The cognitive assessment battery encompassed a range of cognitive functions, including attention and working memory, executive function, language, verbal memory and visuospatial function. The choice of these 5 cognitive domains is based on the Movement Disorder Society Task Force Guidelines for the mild cognitive impairment in Parkinson&#39;s disease10, and a set of locally available cognitive tests were selected to build the assessment battery. In a previous similar eye tracking study on Parkinson&#39;s disease cognition mentioned9, the author extracted the eye movement parameters while the subjects were engaged in visual cognitive tasks, where the parameters may potentially be influenced by the subject&#39;s cognitive ability. As this study aimed to assess the correlation between the eye movement parameters and different cognitive domains, the potential confounding effect of cognitive abilities on the eye parameters must be addressed. In this regards, a visual search task, adapted from another eye tracking study on Alzheimer&#8217;s disease11, was employed to capture the eye movement parameters of the subjects. During the task, subjects had to search for a single number on a computer screen among multiple alphabet distracters. This task would elicit the alternate use of saccadic eye movement and visual fixation, the abnormalities of which are described widely in Parkinson&#39;s disease. The identification and differentiation of number and alphabet is an overlearned task where the demand for cognitive functions is only minimal and would, therefore, be suitable to answer the research question of this study. A computer program was developed based on the specifications and design as stated by R&#246;sler et al.11. in their original study to be run within the in-built software of our eye tracker. An in-house algorithm for classification and analysis of the eye tracking data was also developed for this study.

<table border="0" cellpadding="0" cellspacing="0" style="width:1008px;" width="1007">
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		<col />
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	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Computer&#160;</td>
			<td style="width:121px;">Intel</td>
			<td style="width:505px;"></td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:215px;">Computerized cognitive assessment tool</td>
			<td style="width:121px;">CANTAB</td>
			<td style="width:505px;">CANTAB Research Suite</td>
			<td>Contains Pattern Recognition Memory, Spatial Span, and Stockings of Cambridge</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Eye Movement Analyzer</td>
			<td style="width:121px;">Lab Viso Limited</td>
			<td style="width:505px;"></td>
			<td>https://github.com/lab-viso-limited/visual-search-analyzer</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Eye tracker</td>
			<td style="width:121px;">Tobii</td>
			<td style="width:505px;">Tx300</td>
			<td>23 inch computer screen with resolution of 1920x1080, Sampling rate at 300Hz</td>
		</tr>
		<tr height="105">
			<td height="105" style="height:105px;width:215px;">Hong Kong List Leanrning Test</td>
			<td style="width:121px;">Department of Psychology, The Chinese University of Hong Kong</td>
			<td style="width:505px;">The Hong Kong List Learning Test (HKLLT) 2nd Edition</td>
			<td></td>
		</tr>
		<tr height="84">
			<td height="84" style="height:84px;width:215px;">Stroop test</td>
			<td style="width:121px;">Laboratory of Neuropsychology, The University of Hong Kong</td>
			<td style="width:505px;">Neuropsychological Measures: Normative Data for Chinese, Second Edition (Revised)</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Tobii Studio</td>
			<td style="width:121px;">Tobii</td>
			<td style="width:505px;">Tobii Studio version 3.2.2</td>
			<td>Computer programme for running the visual search task</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Visual Search Task</td>
			<td style="width:121px;">Lab Viso Limited</td>
			<td style="width:505px;"></td>
			<td>https://www.labviso.com/#products</td>
		</tr>
	</tbody>
</table>

characterizing the relationship between eye movement parameters and cognitive functions in non-demented parkinson's disease patients with eye tracking

Cognitive impairment is a common phenomenon in Parkinson&#8217;s disease that has implications on the prognosis. A simple, noninvasive and objective proxy measurement of cognitive function in Parkinson&#8217;s disease will be helpful in detecting early cognitive decline. As a physiological metric, eye movement parameter is not confounded by the subject&#39;s attributes and intelligence and can function as a proxy marker if it correlates with cognitive functions. To this end, this study explored the relationship between the eye movement parameters and performance in cognitive tests in multiple domains. In the experiment, a visual search task with eye tracking was set up, where subjects were asked to look for a number embedded in an array of alphabets scattered randomly on a computer screen. The differentiation between the number and the alphabet is an overlearned task such that the confounding effect of cognitive ability on the eye movement parameters is minimized. The average saccadic amplitude and fixation duration were captured and calculated during the visual search task. The cognitive assessment battery covered domains of frontal-executive functions, attention, verbal and visual memory. It was found that prolonged fixation duration was associated with poorer performance in verbal fluency, visual and verbal memory, allowing further exploration on the use of eye movement parameters as proxy markers for cognitive function in Parkinson&#8217;s disease patients. The experimental paradigm has been found to be highly tolerable in our group of Parkinson&#39;s disease patients and could be applied transdiagnostically to other disease entities for similar research questions.

The full result of this study is available in the original paper published23. Parkinson&#8217;s disease subjects (n = 67) were recruited and completed the assessment. However, 5 cases failed to complete the visual search task as they wore progressive lens incompatible with the eye tracker and their data was discarded. The mean age of the subjects was 58.9 years (SD = 7.5 years) with a male to female ratio of 1.7:1. 62 healthy age-, sex-, and education-matched controls were recruited for comparison...

Watch this Scientific Journal Video about Characterizing the Relationship Between Eye Movement Parameters and Cognitive Functions in Non-demented Parkinson's Disease Patients with Eye Tracking at JoVE

Characterizing the Relationship Between Eye Movement Parameters and Cognitive Functions in Non-demented Parkinson's Disease Patients with Eye Tracking

Here, we present a protocol to study the relationship between the eye movement parameters and cognitive functions in non-demented Parkinson&#39;s disease patients. The experiment used an eye tracker to measure the saccadic amplitude and fixation duration in a visual search task. The correlation with performance in multi-domain cognitive tasks was subsequently measured.

Cognitive impairment is a common phenomenon in Parkinson&#8217;s disease that has implications on the prognosis. A simple, noninvasive and objective proxy ...

Our protocol aims to study the relationship between eye-movement metrics and cognitive functions in a group of non-demented Parkinson's Disease patients that suffer from both occular-motor and cognitive dysfunction. To design the trial images for the visual search task, use the numbers four, six, seven, and nine exclusively. Ensure that the location of the target number is randomized from trial to trial with the rule that each number can not be in the same visual quadrant for more than three successive trials.Do not use ambiguous letters such as I and O, and set the size of the fixation cross, letters, and numbers at a 0.85 degree visual angle. Set the program to allow a time lapse of 1.5 seconds after Enter is pressed, before the display of the central fixation cross is switched to a trial image to begin a trial. Ensure that the screen will go blank with the fixation cross reappearing as the mouse is clicked or after 10 seconds have elapsed from the beginning of a trial, whichever is earlier.Then set the program to generate a csv file that contains the time stamps of the beginning and end of each trial. After conducting a clinical diagnostic interview with the subject and if available, their relatives to exclude dementia and to screen for cognitive impairment using the Mini-Mental State Examination and Montreal Cognitive Assessment, evaluate the subject's visual acuity with a Snellen chart. Then, in a quiet room with an adequate light source, set up a screen based eye-tracker with a sampling rate of at least 300 Hertz, a computer, a mouse, and a standard keyboard.A chin rest placed 60 centimeters in front of the eye checker screen and the appropriate cognitive assessment tools. To set up for a visual search task, position the subject on a chair with their chin on the chin rest and their forehead against a bar to minimize any head movement. Align the subject's eyes to approximately the center of the computer screen and click the start button in the eye tracking program.Click start to calibrate the eye tracker with the built-in calibration program. And ask the subject to gaze at the red dot moving across the screen with nine fixation points while keeping their head still. View the calibration plot to check the quality of the calibration, making sure that the length of the green lines, which represent the error vectors fall within the gray circles.Then click Accept to proceed to the visual search task. To initiate a practice trial, instruct the subject to fix their gaze on the central fixation cross and press Enter on the keyboard to begin the trial. The computer screen will display a single number and 79 randomly scattered distractor letters.Instruct the subject to look as quickly as possible for the number and to simultaneously click on the mouse while stating the number aloud as soon as the number is located. Then cross check whether the stated number is correct and repeat the practice trial four more times. For eye tracking data processing and analysis in the replay section of the computer program, check the sample's percentage of the eyes during the visual search task.Click play for the recording, to check the quality of the data by eyeballing the visualized scan path video generated. Discard all of the subject's data if it is grossly erroneous. And discard any trials in which the subject clicked the mouse accidentally or prematurely.In the data export section of the program, select GazePointX and GazePointY Click export data to export the subject's data and save the data as a csv file. In the interface of the visual search analyzer, select the exported data as the input of the eye data and the generated csv file as the input of the action data. Select ST DB Scan as the classification algorithm and click run.Then click summary to generate a spreadsheet file containing the main saccade amplitude and the mean fixation duration of the subject. To design the visual search analyzer, program the analyzer such that it extracts and analyzes only the data from the beginning to the end of the trial using the generated csv file. To program the analyzer such that it fills in the data lost due to eye blinking, average the x and y coordinates of the gaze point immediately before and after the blinking.Then use the algorithm based on the ST DB scan to program the analyzer such that it classifies the raw data into either saccade or fixation. Consistent with previous studies, in this analysis, the Parkinson's disease group showed a poorer performance in multiple cognitive tasks, compared to the control group. Using the in-house algorithm for classification of the visual search task data, fixations and saccades can be identified and extracted for calculation and analysis.Indeed, the disease group had a smaller mean saccadic amplitude compared to the control group, and the mean fixation duration was not significantly different between the groups. In this evaluation, after adjusting for covariates, negative correlations were found between the mean fixation duration, the performance in the verbal recognition memory and discrimination score, in the pattern recognition memory, and in the categorical verbal fluency test within the fruit and vegetable categories. However, there was no significant interactions found in these correlations between the disease and control groups, suggesting that the correlations are not specific to the disease group.The design of the visual search task is important as the aim is to minimize the interference of the cognitive ability of the distractor eye movement parameters. If this research task is highly tolerable it can be applied to trans-diagnostically to other new degenerative disorder to answer similar research questions.

Research

JoVE Journal

Neuroscience

Eye Movement Monitoring of Memory

Explicit (often verbal) reports are typically used to investigate memory (e.g. "Tell me what you remember about the person you saw at the bank ...

A Fully Automated and Highly Versatile System for Testing Multi-cognitive Functions and Recording Neuronal Activities in Rodents

We have developed a fully automated system for operant behavior testing and neuronal activity recording by which multiple cognitive brain functions can be ...

Semi-Quantitative Determination of Dopaminergic Neuron Density in the Substantia Nigra of Rodent Models using Automated Image Analysis

Estimation of the number of dopaminergic neurons in the substantia nigra is a key method in pre-clinical Parkinson's disease research. Currently, unbiased ...

Immunostaining of Whole-Mount Retinas with the CLARITY Tissue Clearing Method

The tissue hydrogel delipidation method (CLARITY), originally developed by the Deisseroth laboratory, has been modified and widely used for immunostaining ...

Optimizing the Setup and Conditions for Ex Vivo Electroretinogram to Study Retina Function in Small and Large Eyes

Optimizing the Setup and Conditions for Ex Vivo Electroretinogram to Study Retina Function in Small and Large Eyes

Measurements of retinal neuronal light responses are critical to investigating the physiology of the healthy retina, determining pathological changes in ...

In Vivo Methods to Assess Retinal Ganglion Cell and Optic Nerve Function and Structure in Large Animals

In Vivo Methods to Assess Retinal Ganglion Cell and Optic Nerve Function and Structure in Large Animals

The optic nerve collects axons signals from the retinal ganglion cells and transmits visual signal to the brain. Large animal models of optic nerve injury ...

The 6-hydroxydopamine Rat Model of Parkinson's Disease

Motor symptoms of Parkinson's disease (PD)-bradykinesia, akinesia, and tremor at rest-are consequences of the neurodegeneration of dopaminergic neurons in ...

Organotypic Retinal Explant Cultures from Macaque Monkey

Hereditary retinal degeneration (RD) is characterized by progressive photoreceptor cell death. Overactivation of the cyclic guanosine monophosphate ...

Dual-Task Stroop Paradigm for Detecting Cognitive Deficits in High-Functioning Stroke Patients

General clinical cognitive assessment scales are not sensitive enough to cognitive impairment in high-functioning stroke patients. The dual-task ...

An In Situ Immunostaining Protocol for Parkinson's Disease Study

Histological Examination of Mitochondrial Morphology in a Parkinson's Disease Model

Author Spotlight: Establishing a New Fluorescence-Based Protocol for In Vivo Mitochondrial Morphology Analysis in Parkinson's Disease

Mitochondria play a central role in the energy metabolism of cells, and their function is especially important for neurons due to their high energy ...