Dynamic Visual Tests to Identify and Quantify Visual Damage and Repair Following Demyelination in Optic Neuritis Patients

Podsumowanie

Object From Motion (OFM) and Time-constrained stereo protocols are sensitive tools to identify monocular and binocular dynamic visual function deficits, which are uniquely affected in optic neuritis patients. Furthermore, these tests may be used as quantitative noninvasive tools to assess the extent of myelination along visual pathways.

Streszczenie

In order to follow optic neuritis patients and evaluate the effectiveness of their treatment, a handy, accurate and quantifiable tool is required to assess changes in myelination at the central nervous system (CNS). However, standard measurements, including routine visual tests and MRI scans, are not sensitive enough for this purpose. We present two visual tests addressing dynamic monocular and binocular functions which may closely associate with the extent of myelination along visual pathways. These include Object From Motion (OFM) extraction and Time-constrained stereo protocols. In the OFM test, an array of dots compose an object, by moving the dots within the image rightward while moving the dots outside the image leftward or vice versa. The dot pattern generates a camouflaged object that cannot be detected when the dots are stationary or moving as a whole. Importantly, object recognition is critically dependent on motion perception. In the Time-constrained Stereo protocol, spatially disparate images are presented for a limited length of time, challenging binocular 3-dimensional integration in time. Both tests are appropriate for clinical usage and provide a simple, yet powerful, way to identify and quantify processes of demyelination and remyelination along visual pathways. These protocols may be efficient to diagnose and follow optic neuritis and multiple sclerosis patients.

In the diagnostic process, these protocols may reveal visual deficits that cannot be identified via current standard visual measurements. Moreover, these protocols sensitively identify the basis of the currently unexplained continued visual complaints of patients following recovery of visual acuity. In the longitudinal follow up course, the protocols can be used as a sensitive marker of demyelinating and remyelinating processes along time. These protocols may therefore be used to evaluate the efficacy of current and evolving therapeutic strategies, targeting myelination of the CNS.

Wprowadzenie

Optic neuritis as a model for tracking tissue degeneration and repair

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system (CNS) and is the leading cause of nontraumatic neurological disability in young adults in developed countries. Demyelination is considered the most characteristic histopathological feature of MS. Recent studies, however, revealed that MS is also a neurodegenerative disease with early neuroaxonal damage^1-3.

Optic neuritis (ON), inflammation of the optic nerve, is the presenting symptom in 20% of MS patients and at least 50% of those suffering from MS experience at least one episode of ON during their lifetime⁴. Unlike other locations of MS lesions that do not always correlate to the clinical manifestations, demyelinating episode of the optic nerve typically results in distinctive manifestation of acute visual loss. Given its comorbidity with MS and its prominent clinical features, ON offers a unique opportunity for tracking tissue degeneration and repair and their consequences in a single MS lesion.

The need for improved methods for tracking tissue degeneration and repair in vivo

Pathologic studies in MS implicate demyelination as a principal cause of axonal transection and subsequent axonal degeneration. Remyelination may prevent demyelinated axons from degenerating; however, effective remyelination may be limited as a result of repeated attacks. Therefore, current and evolving neuroprotective and regenerative therapeutic strategies in MS are aimed to prevent new attacks and promote remyelination processes in the CNS⁵.

In order to follow up optic neuritis patients and evaluate the efficacy of their treatment, a fine tool to quantify changes in myelination at the CNS is required. However, the standard measurements, including routine visual tests and MRI scans, are not sensitive enough for this purpose. Routine visual tests (i.e. visual acuity, contrast sensitivity, visual fields, and color perception) may reveal cases of reduced input projection along the visual pathways but are insensitive to identify delayed projection rates, which is the role of the demyelinated fibers^6,7. T2 hyperintense lesions, which are the hallmark of the disease, result from residual mixture of edema, inflammation, demyelination, axonal loss and gliosis and thus cannot differentiate between demyelination and other brain pathologies. Furthermore, standard MRI is designed to reveal qualitative tissue contrast. While these are adequate for identifying the location of unusual tissue, they are insufficient to quantitatively assess tissue properties.

Dynamic visual tests may be used as markers of demyelination and remyelination

We argue that dynamic visual functions are more appropriate than static functions to identify and quantify changes in projection latencies along the visual pathways. While accomplishment of both static and dynamic visual functions requires sufficient amount of visual input projection, only dynamic visual functions depend on projection rates. Optic nerve demyelination may thus affect dynamic rather than static visual functions, implicating the need for rapid transmission of visual input in order to perceive motion.

We have developed two behavioral tasks to assess monocular and binocular visual functions which may closely associate with projection latencies along the visual pathways. These include Object From Motion (OFM) extraction and Time-constrained stereo protocols.

In the OFM test, an array of dots compose an object, by moving the dots within the image rightward while moving the dots outside the image leftward or vice versa. The dot pattern generates a camouflaged object that cannot be detected when the dots are stationary or moving as a whole. Importantly, object recognition is dependent on motion perception. Using the OFM protocol, we have demonstrated a sustained deficit in the affected eyes of ON patients, evident even 12 months following the optic neuritis attack, while standard visual functions had recovered⁸. Furthermore, impaired performance was associated with delayed conductions (delayed P100, reflecting demyelination) and improvement in motion perception was correlated with shortening of conduction rates (reflecting remyelination; linear least squares regression with calculation of the correlation coefficient F=27.3; p=0.0005; r=-0.87)⁹.

The currently presented OFM protocol was updated in order to fit the test for clinical usage, including test shortening, adjusting the test software to result in an automatic output file, and to result in a motion sensitivity score.

To assess the effect of projection latencies on binocular vision, the Time-constrained Stereo protocol was developed. In this protocol, spatially disparate images are presented for a limited length of time, challenging binocular integration in time. This test was designed to test the hypothesis that due to demyelination at the affected nerve, information from the two eyes will reach the cortex at different time points impairing binocular integration in time. Testing a group of recovered ON patients (1-2.5 years following the attack), we have shown that while most patients had intact performance levels in a standard static stereo task; performance on the time-constrained stereo task was impaired in most cases¹⁰.

The OFM and the time-constrained stereo protocols provide a simple, yet powerful, way to identify and quantify processes of demyelination and remyelination along the visual pathways. These protocols may be efficient to diagnose and follow up ON and MS patients in a cost effective manner using an easy to use computer based protocol.

Protokół

The protocol follows the Hadassah Hebrew University Ethics Committee guidelines for studies in human subjects. To avoid the effect of myopia or refractive errors on test results, the protocols should be performed while patients wear their eyeglasses (corrected vision).

Object From Motion (OFM) protocol:

1. Test Initiation and Instructing Subjects

1. Seat the subject 50 cm in front of the computer screen.
2. Open the OFM software.
3. Instruct the subject that he will be presented with motion defined objects. Instruct him to respond as correct and as fast as possible by pressing the "A" keyboard and then verbally naming the perceived object.
4. Following response, a screen indicating "press the space bar" will appear. Instruct the subject to press the space bar when ready to identify the next stimulus.
5. Explain to the subject that stimuli may appear at very hard to-perceive velocities or at some easier to perceive ones.

2. Learning Phase

Enter "learning OFM" at the command line. Subject will now be presented with 4 example stimuli. This phase is conducted when subject's both eyes are open.

3. Testing Phase

In general, each OFM test includes 20 stimuli. All are first presented at the lowest velocity of 4 pixels/sec. Those not recognized will be then presented at the next velocity of 5.5 pixels/sec. Those not recognized, will be then presented at the next velocity of 7.5 pixels/sec and so on, going through 10 pixels/sec, 13.5 pixels/sec, 18 pixels/sec, and till the fastest velocity of 24.5 pixels/sec. Velocities were defined based on the exponent y=3*e^0.3. If five consecutive stimuli in a certain velocity were not recognized, the next stimuli will be presented at the next faster velocity to avoid frustration in the patients. This will result in shortening test length which generally is longer as recognition is worse (necessitating the passage through larger number of velocities per stimulus).

1. Cover subject's one eye with an eye patch. Every eye patch may be adequate as long as it supplies full coverage.
2. Enter "OFM objects" at the command line.
3. Choose one stimuli set (software includes 4 stimuli sets. Each set includes 20 different objects. Selection may be random. However, make sure that you apply different stimuli sets for each of the tested eyes; Apply different stimuli sets for subsequent learning time points in case of longitudinal assessment).
4. A prompt asking you to enter subject's name, tested eye and testing date will appear. Complete required information.
5. Carefully monitor the subject and respond to the subject while she/he completes the task as follows:
   1. When a stimulus appears the subject must press the "A" button on the keyboard and name the identity of the presented stimulus.
   2. Press the left mouse button for a correct answer or the right mouse button for a wrong answer.
   3. Subject presses the "space bar" on the keyboard for initiation of the next stimulus.
   4. This procedure (steps 3.5.1-3.1.5.3) continues until all 20 stimuli in the set are either recognized or presented at the fastest velocity.
6. Repeat the whole procedure (from step 3.1) for the subject's second eye using a different set of stimuli.

Time-constrained Stereo Protocol:

1. Test Initiation and Instructing Subjects

1. Seat the subject 50 cm in front of the computer screen.
2. Open the Stereo software.
3. Instruct the subject that he will be presented with 3 dimensional (3D) shapes and will have to name the perceived shape as correct and fast as possible. Shapes will be one of the following: a circle, a square, a triangle, or a star.
4. Explain to the subject that stimuli may appear at very hard to perceive conditions or at some easier to perceive ones.
5. Instruct the subject to wear the 3D glasses.
6. Turn off the room lightening.

2. Learning Phase

Enter "learning Stereo" at the command line. Subject will be now presented with 4 repetitions of each shape, presented at the longest stimuli duration (500 msec) and at the easiest disparity (840 sec of arc) conditions. Following the 3D presentation condition, a 2D presentation will follow for each shape. In the latter, a line marking shapes contours will be added, to make sure subject perceived the dimensions of the presented shape. Subjects, who did not succeed at this easy condition, will not be tested at the next phase.

3. Testing Phase: Stereopsis Perception as a Function of Binocular Disparity

The 4 shapes will be presented for 500 msec at 4 different disparity conditions: 120, 300, 540, and 840 sec of arc.

1. Enter "Stereo Disparity" at the command line.
2. A prompt asking you to enter subject's name and testing date will appear. Complete required information.
3. Stimulus appears
4. Subject names the presented shape. Responses are coded by the examiner at key buttons 1-4 (i.e. press the 1, 2, 3, or 4 key buttons for subject's verbal responses of "a circle", "a square", "a triangle", or "a star", respectively). Due to lighting conditions and the fact that the subject wears 3D glasses, he cannot code the responses by himself).
5. Subject presses any key to continue to the next stimulus. The order of stimuli presentation is random.

4. Testing Phase

Stereopsis perception as a function of stimulus presentation time. The 4 shapes will be presented for disparities of 540 and 840 sec of arc at either 40, 60, or 100 msec durations.

1. Enter "Stereo Duration" at the command line.
2. Repeat steps 3.2-3.5.

Wyniki

OFM protocol

The protocol results in a text file, automatically summarizing subject's responses. Outcome can be analyzed in two ways:

Total score: Each stimulus presented is assigned with a stimulus weight, and the sum of weights of all identified stimuli is set as the subject's response score. The weight of a particular stimulus is set based on the speed of the stimulus, with higher weights to lower speeds. Unidentified stimuli are assigned with a zero weight. General...

Dyskusje

Optic neuritis is a demyelinative disease of the optic nerve, causing acute visual loss. Though considered transient when using standard visual testing¹, patients continue to perceive difficulties in performing everyday visual tasks. We argue that dynamic visual tests are adequate to identify and quantify these sustained deficits. This is since dynamic but not static visual functions depend on projection rates, and may be more vulnerable to delayed projection following demyelination.

T...

Materiały

Name	Company	Catalog Number	Comments
Personal computer, including laptops			The OFM software runs best on Mac or on Windows 7 (or higher) PC. The Stereo software runs on every personal computer.
Monitor  specification			Size: at least 15inch,  Color: at least 16 bit
The OFM and the Stereo softwares	These are self-developed softwares		Researchers & physicians who are interested in these softwares may contact us at: fmri-hadassah.org
Red/Cyan 3D glasses (We had tested the Stereo software on the two following 3D glasses):	Nvidia & American Paper Optics	3D Vision Ultimate Anaglyph 3D Glasses & Pro X Style Red/Cyan 3D Glasses for Movies and Games on Flat Screens
Performance on our stereo task was compared to performance on the standard Randot stereo test	Stereo Optical Co.	Randot SO-002