The authors would like to thank Ralf K&#252;hne for technical support. This work was funded by the Deutsche Forschungsgemeinschaft (DFG) and the Bundesministerium f&#252;r Bildung und Forschung (BMBF #01GM1103A). This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following organizations under the aegis of JPND-e.g., Germany, Bundesministerium f&#252;r Bildung und Forschung (BMBF, FKZ), Sweden, Vetenskapr&#229;det Sverige, Poland, Narodowe Centrum Bada&#324; i Rozwoju (NCBR).

The study was approved by the Ethics Committee of the University of Ulm (Statement No. 19/12) and the protocol described therefore follows their guidelines. All participants gave written informed consent.
1. Stimuli and Testing Environment
<ol>
	<li>To keep distractions to a minimum perform the research in a dark or a very dimly lit and quiet room.</li>
	<li>Use an appropriate eye tracking device. 
	NOTE: There are a wide variety of devices available to perform eye movement studies. In ...

<ol>
	<li>Kiernan, M. C., 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=Amyotrophic+lateral+sclerosis.">Amyotrophic lateral sclerosis.</a> Lancet. 377 (9769), 942-955 (2011).</li><li>Neumann, M., 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=Ubiquitinated+TDP-43+in+frontotemporal+lobar+degeneration+and+amyotrophic+lateral+sclerosis.">Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.</a> Science. 314 (5796), 130-133 (2006).</li><li>Beeldman, E., Raaphorst, J., Klein Twennaar, ., de Visser, M., Schmand, B. A., de Haan, R. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+cognitive+profile+of+ALS:+a+systematic+review+and+meta-analysis+update.">The cognitive profile of ALS: a systematic review and meta-analysis update.</a> J. Neurol. Neurosurg. Psychiatry. , (2015).</li><li>Phukan, J., 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+syndrome+of+cognitive+impairment+in+amyotrophic+lateral+sclerosis:+a+population-based+study.">The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study.</a> J. Neurol. Neurosurg. Psychiatry. 83 (1), 102-108 (2012).</li><li>Elamin, M., 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=Executive+dysfunction+is+a+negative+prognostic+indicator+in+patients+with+ALS+without+dementia.">Executive dysfunction is a negative prognostic indicator in patients with ALS without dementia.</a> Neurology. 76 (14), 1263-1269 (2011).</li><li>Martin, N. A., 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=Psychological+as+well+as+illness+factors+influence+acceptance+of+non-invasive+ventilation+(NIV)+and+gastrostomy+in+amyotrophic+lateral+sclerosis+(ALS):+a+prospective+population+study.">Psychological as well as illness factors influence acceptance of non-invasive ventilation (NIV) and gastrostomy in amyotrophic lateral sclerosis (ALS): a prospective population study.</a> Amyotroph. Lateral. Scler. Frontotemporal. Degener. 15 (5-6), 376-387 (2014).</li><li>Chi&#242;, A., 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=Neurobehavioral+symptoms+in+ALS+are+negatively+related+to+caregivers'+burden+and+quality+of+life.">Neurobehavioral symptoms in ALS are negatively related to caregivers' burden and quality of life.</a> Eur. J. Neurol. 17 (10), 1298-1303 (2010).</li><li>Lakerveld, J., Kotchoubey, B., K&#252;bler, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cognitive+function+in+patients+with+late+stage+amyotrophic+lateral+sclerosis.">Cognitive function in patients with late stage amyotrophic lateral sclerosis.</a> J. Neurol. Neurosurg. Psychiatry. 79 (1), 25-29 (2008).</li><li>Sharma, R., Hicks, S., Berna, C. M., Kennard, C., Talbot, K., Turner, M. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Oculomotor+dysfunction+in+amyotrophic+lateral+sclerosis:+a+comprehensive+review.">Oculomotor dysfunction in amyotrophic lateral sclerosis: a comprehensive review.</a> Arch. Neurol. 68 (7), 857-861 (2011).</li><li>Witiuk, K., Fernandez-Ruiz, J., McKee, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cognitive+Deterioration+and+Functional+Compensation+in+ALS+Measured+with+fMRI+Using+an+Inhibitory+Task.">Cognitive Deterioration and Functional Compensation in ALS Measured with fMRI Using an Inhibitory Task.</a> J. Neurosci. 34 (43), 14260-14271 (2014).</li><li>Gorges, M., 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=Eye+Movement+Deficits+Are+Consistent+with+a+Staging+Model+of+pTDP-43+Pathology+in+Amyotrophic+Lateral+Sclerosis.">Eye Movement Deficits Are Consistent with a Staging Model of pTDP-43 Pathology in Amyotrophic Lateral Sclerosis.</a> PLoS One. 10 (11), 0142546 (2015).</li><li>Hicks, S. L., 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=An+eye-tracking+version+of+the+trail-making+test.">An eye-tracking version of the trail-making test.</a> PLoS One. 8 (12), 84061 (2013).</li><li>Keller, J., 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=Eye-tracking+controlled+cognitive+function+tests+in+patients+with+amyotrophic+lateral+sclerosis:+a+controlled+proof-of-principle+study.">Eye-tracking controlled cognitive function tests in patients with amyotrophic lateral sclerosis: a controlled proof-of-principle study.</a> J. Neurol. 262 (8), 1918-1926 (2015).</li><li>Raven, J. C., Court, J. H., Raven, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Manual for Raven's progressive matrices and vocabulary scales. Section 2, the coloured progressive matrices. , (1998).</li><li>Brickenkamp, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Aufmerksamkeits-Belastungs-Test (Test d2), 8th edn. , (1994).</li><li>Elamin, M., 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=Cognitive+changes+predict+functional+decline+in+ALS.">Cognitive changes predict functional decline in ALS.</a> Neurology. 80 (17), 1590-1597 (2013).</li><li>Ludolph, A. C., 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=Frontal+lobe+function+in+amyotrophic+lateral+sclerosis:+a+neuropsychologic+and+positron+emission+tomography+study.">Frontal lobe function in amyotrophic lateral sclerosis: a neuropsychologic and positron emission tomography study.</a> Acta. Neurol. Scand. 85 (2), 81-89 (1992).</li><li>Schneider, E., 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=Eye-SeeCam:+an+eye+movement-driven+head+camera+for+the+examination+of+natural+visual+exploration.">Eye-SeeCam: an eye movement-driven head camera for the examination of natural visual exploration.</a> Ann. N. Y. Acad. Sci. 1164, 461-467 (2009).</li><li>Lul&#233;, D., 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+Edinburgh+Cognitive+and+Behavioural+Amyotrophic+Lateral+Sclerosis+Screen:+a+cross-sectional+comparison+of+established+screening+tools+in+a+German-Swiss+population.">The Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen: a cross-sectional comparison of established screening tools in a German-Swiss population.</a> Amyotroph. Lateral. Scler. Frontotemporal. Degener. 16 (1-2), 16-23 (2015).</li><li>Olney, R. K., 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+effects+of+executive+and+behavioral+dysfunction+in+the+course+of+ALS.">The effects of executive and behavioral dysfunction in the course of ALS.</a> Neurology. 65 (11), 1774-1777 (2005).</li><li>Donaghy, C., Thurtell, M. J., Pioro, E. P., Gibson, J. M., Leigh, R. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Eye+movements+in+amyotrophic+lateral+sclerosis+and+its+mimics:+a+review+with+illustrative+cases.">Eye movements in amyotrophic lateral sclerosis and its mimics: a review with illustrative cases.</a> J. Neurol. Neurosurg. Psychiatry. 82 (1), 110-116 (2011).</li><li>Mizutani, T., 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=Development+of+ophthalmoplegia+in+amyotrophic+lateral+sclerosis+during+long-term+use+of+respirators.">Development of ophthalmoplegia in amyotrophic lateral sclerosis during long-term use of respirators.</a> J. Neurol. Sci. 99 (2-3), 311-319 (1990).</li><li>Khin Khin, E., Minor, D., Holloway, A., Pelleg, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Decisional+Capacity+in+Amyotrophic+Lateral+Sclerosis.">Decisional Capacity in Amyotrophic Lateral Sclerosis.</a> J. Am. Acad. Psychiatry Law. 43 (2), 210-217 (2015).</li><li>K&#252;bler, A., 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=Patients+with+ALS+can+use+sensorimotor+rhythms+to+operate+a+brain-computer+interface.">Patients with ALS can use sensorimotor rhythms to operate a brain-computer interface.</a> Neurology. 64 (10), 1775-1777 (2005).</li><li>Connolly, S., Galvin, M., Hardiman, O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=End-of-life+management+in+patients+with+amyotrophic+lateral+sclerosis.">End-of-life management in patients with amyotrophic lateral sclerosis.</a> Lancet Neurol. 14 (4), 435-442 (2015).</li></ol>

It is a challenging task to successfully assess the cognitive status of patients with ALS who are unable to speak and write. The use of videooculography systems provides a promising approach. The hereby presented technique is reliable in detecting cognitive deficits, which play a pivotal role in the context of carer burden and disease management20 in ALS patients. Also, the oculomotor versions of the CPM and the D2-test correlate significantly with their respective standard paper-pencil versions, but further s...

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder usually leading to death within 3 to 5 years. In the course of the pathology, patients present with progressive loss of respiratory and bulbar functioning as well as impairments in movement abilities1. It shares some clinical, pathological, and genetic features with frontotemporal dementia2 and it is well documented that about 30% of ALS patients exhibit cognitive deficits3. These deficits are most prominent in the domains of executive function, verbal fluency and language4 and have an influence on survival5, compliance6 and carer burden7. Thus, reliable neuropsychological assessment is crucial in this disease.
Advancing impairments in motor and speech abilities are, however, a limiting factor for thorough evaluation of cognitive abilities in later stages of the disease8. Here, oculomotor based approaches seem to be very promising, as basic eye movement control remains intact for a comparably long time during the course of ALS for the majority of patients9. Eye-tracking parameters itself have been used to gain information about the cognitive status of patients with ALS10 and also correlate with the sequential spreading pattern of ALS11. Eye movement as a means to control cognitive tests in the context of ALS has also been studied in previous works. One study has successfully demonstrated its usability in healthy controls using an oculomotor based version of the Trail-Making Test12, whereas another found it suitable to distinguish between healthy controls and ALS patients based on cognitive performance and to discriminate between cognitively more and less impaired patients13.
The research described here used an oculomotor based methodology to study cognitive impairments in ALS patients, specifically in the domain of executive functioning. Two well validated and commonly used neuropsychological tests were adapted to eye movement control: the Raven&#39;s coloured progressive matrices (CPM)14 and the D2-test15. The CPM is a non-verbal instrument used to measure executive and visuospatial abilities as well as fluid intelligence. The D2-test is also a non-verbal tool used to uncover executive dysfunction in the domains of selective and sustained attention and visual processing speed. Both are widely used clinical tools which have been successfully employed in previous studies assessing potential cognitive decline during the course of the disease16 and the neuropsychological status of ALS patients compared to healthy controls17.
The goal of this work was to show the requirements for successful evaluation of cognitive deficits in ALS independent of movement and speech disabilities using a reliable, eye-tracking based version of the CPM and the D2-test. Importantly, the method described here has the potential to be expanded to study other populations of patients with severe motor impairments.

<table border="0" cellpadding="0" cellspacing="0" width="1081">
	<tbody>
		<tr height="21">
			<td>EyeSeeCam</td>
			<td>EyeSeeTec GmbH; 82256 F&#252;rstenfeldbruck, Germany</td>
			<td></td>
			<td>Videooculography device</td>
		</tr>
	</tbody>
</table>

eye-tracking control to assess cognitive functions in patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with pathological involvement of upper and lower motoneurons, subsequently leading to progressive loss of motor and speech abilities. In addition, cognitive functions are impaired in a subset of patients. To evaluate these potential deficits in severely physically impaired ALS patients, eye-tracking is a promising means to conduct cognitive tests. The present article focuses on how eye movements, an indirect means of communication for physically disabled patients, can be utilized to allow for detailed neuropsychological assessment. The requirements, in terms of oculomotor parameters that have to be met for sufficient eye-tracking in ALS patients are presented. The properties of stimuli, including type of neuropsychological tests and style of presentation, best suited to successfully assess cognitive functioning, are also described. Furthermore, recommendations regarding procedural requirements are provided. Overall, this methodology provides a reliable, easy to administer and fast approach for assessing cognitive deficits in patients who are unable to speak or write such as patients with severe ALS. The only confounding factor might be deficits in voluntary eye movement control in a subset of ALS patients.

For the purpose of the research presented here, i.e.,&#160;the development of a reliable oculomotor based neuropsychological assessment for ALS patients, in-house developed software stores the subject&#39;s choices of the CPM in a separate file, allowing for manual computation of the percentage of correct answers. For the D2-test, a record of the vertical eye movements is manually analyzed using a threshold of + 5&#176; for detection of a relevant response. Recordings are assigne...

Watch this Scientific Journal Video about Eye-Tracking Control to Assess Cognitive Functions in Patients with Amyotrophic Lateral Sclerosis at JoVE.com

Eye-Tracking Control to Assess Cognitive Functions in Patients with Amyotrophic Lateral Sclerosis

Cognitive deficits are common in about one third of patients with amyotrophic lateral sclerosis, a neurological condition leading to progressive impairments in speech and movement abilities. To conduct cognitive tests in patients unable to speak or write a reliable and easy to administer eye-tracking paradigm was developed.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with pathological involvement of upper and lower motoneurons, subsequently leading to ...

The overall goal of this eye-tracking paradigm is to use an oculomotor based technique to assess cognitive functions in patients with Amyotrophic Lateral Sclerosis or ALS who are unable to speak and write. This method can help answer key questions in the field of potential cognitive deficits in patients with severe physical impairments, such as ALS. The main advantage of this technique is that it uses eye movement to conduct neuropsychological testing in ALS patients, and therefore is suited for patients who are unable to speak or write.Though this method was developed for patients with ALS it can also be applied to other patient samples unable to speak and write but within intact oculomotor control. For this experiment, use a portable eye movement recording device with goggles. Optimize eye movement detection by adjusting the cameras in all six degrees of freedom.Next, set up a standardized oculomotor testing paradigm such as a series of saccadic tasks in order to detect deficits in eye movement control. Use software to present these tasks on a hemicylindrical screen via a projector that is mounted above where the participant will sit. Finally, in preparation for the second part of the experiment, check that a red laser spot, which will be used for the eye-tracking based version of the D2 test, appears correctly on the screen.Begin by asking the participant to turn off all potentially disturbing devices, such as mobile phones or pagers. Bring a participant who does not have substantial visual impairments into the testing room. Seat them on an elevated chair in front of an adjustable chin rest that is 150 centimeters from the computer screen.Ask the participant to place their head on the chin rest. And then place the video-oculography goggles on their head. Adjust the goggles to properly fit the head shape and size.Ensure that both eyes are visible on the experimenter's screen, and focus the cameras within the goggles so that the images of each eye are centered on the screen. Next, check that the system is continuously recording eye movements at all times by instructing the participant to look in each corner of the hemicylindrical screen. Start the standardized oculomotor testing paradigm and have the participant complete a second calibration.Ask the participant to track a single spot on the screen oscillating horizontally and then vertically with a frequency of 0.125 hertz in order to map the non-calibrated orthogonalized raw data from the eye movement recording device with respect to the true orthoganlized eye position. Finally, check if the calibration is acceptable, meaning the true eye movement and the raw data are spatially and temporally synchronized. If so, instruct the participant to keep their head as still as possible.For the first part of the experiment the Raven's colored progressive matrices, or CPM test, displays a series of matrices 22 degrees long and 15 degrees high on the screen with a blank space cut out. Instruct the participant to identify the missing piece below each matrix. After making a choice, have the subject close their eyes for at least 250 milliseconds to start off a green frame outlining the six possible alternatives of missing pieces for 1500 milliseconds each.Ask the participant to designate the alternative they think is correct by closing their eyes for at least 250 milliseconds while their choice is within the green frame. Project the participant's choice separately on the hemicylindrical screen, in order to confirm, instruct them to close their eyes again for at least 250 milliseconds. Have the participant complete further training by selecting the missing piece in the next three matrices.Answer any questions the participant may have about the procedure. Then have the participant complete the full CPM task. For the second part of the experiment, the D2 test, ask the participant to direct their gaze to the center of the screen.Tell them to observe each of the 47 letters with a height of 11 degrees and a width of 2.5 degrees, one after the other in the middle of the screen in which each stimulus lasts for 2000 milliseconds. Whenever the letter d with two dashes is presented instruct the participant to look at the red laser spot positioned above the letter until the next stimulus appears. Finally, after the training is complete, have the participant complete the full D2 test, consisting of five blocks of 47 stimuli each.In a sample of patients with Amyotrophic Lateral Sclerosis, or ALS, there was a good congruency between the eye-tracking and standard version of the CPM test. Furthermore, there's significant group differences in the CPM test and the D2 test, indicating that this technique reliably distinguishes between more and less cognitively impaired ALS patients. Once mastered this technique can be completed in 25 minutes if it is performed properly.For ALS patients with insufficient oculomotor control other methods, such as the brain-computer interface can be utilized in order to assess their cognitive functioning. After watching this video, you should have good understanding of how to perform eye movement based neural psychological testing with ALS patients.

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8.0K vistas.  Ulm University. The overall goal of this eye-tracking paradigm is to use an oculomotor based technique to assess cognitive functions in patients with Amyotrophic Lateral Sclerosis or ALS who are unable to speak and write. This method can help answer key questions in the field of potential cognitive deficits in patients with severe physical impairments, such as ALS. The main advantage of this technique is that it uses eye movement to conduct neuropsychological testing in ALS patients, and therefore is suited ...