Tag Archives: saccades

Down and sideways

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Eye movement was the topic of the fourth of the five papers on PSP to be published on a single day last week and is the topic of the fifth as well.  It’s altogether fitting and proper that on this dies mirabilis for PSP, disproportionate attention should go to the most specific single feature of PSP and the source of its name. 

One of the most important early symptoms of PSP is difficulty reading that many patients describe as difficulty shifting from the end of one line to the start of the next.  The problem isn’t the long leftward horizontal movement to pick up the next line, but the short downward component, and patients may report that they can’t avoid re-reading the same line.  This can happen long before the neurologist’s exam can detect any loss of downward eye movement on a simple pursuit (“follow my finger”) or voluntary saccade (“look left”) test.

A group of scientists in Yonago, Japan have studied this phenomenon in a new way.  Yasuhiro Watanabe, Suzuha Takeuchi, Kazutake Uehara, Haruka Takeda and Ritsuko Hanajima tracked patients’ eye movements as they read a paragraph aloud.  In Japan, people are almost equally skilled at reading horizontally and vertically.  Computer screen text and most books use horizontal text, while newspapers and official, formal and traditional publications are vertical.  This makes Japanese people excellent subjects in an experiment comparing horizontal with vertical reading skills. 

The participants included groups with PSP, Parkinson’s disease, multiple system atrophy (MSA) and spinocerebellar atrophy (SCA) as well as a group of healthy controls.  For the analysis. the MSA and SCA participants were combined into one group called “spinocerebellar degeneration” (SCD). 

Shown below are the tracings of their eye movement during reading.  The first and third rows show superimposed tracings of all 19 to 29 participants in each group.  It’s obvious that the group with PSP did reasonably well with horizontal movements but had difficulty finding the start of the next line.  When attempting to read vertically, those with PSP had extreme difficulty, as expected.

The second and fourth rows show eye movements over time (horizontal axis) while reading, with horizontal movements in blue and vertical movement in orange.  The vertical axis shows the size of the movement.  Again, for horizontal text, the horizontal movements are nearly normal in PSP, while the vertical movement is impaired.  For vertical text, horizontal movement to pick up each subsequent line is moderately impaired, but the main, vertical movement down each line of characters is severely so.

The analysis used a “machine learning” procedure, a form of artificial intelligence, to create a statistical profile of the measurements for each disease group.  It showed that the main difficulty distinguishing each group were downward movements in PSP, general slowness and a “stickiness” of ocular fixation in PD and poorly aimed horizontal movement with rhythmic horizontal overlying movement (“nystagmus”) in SCD.  The accuracy in distinguishing controls from the patients as a combined group was 87.5%. (Accuracy combines sensitivity and specificity.)  In this analysis combining the three disease groups, horizontal reading was more useful than vertical reading.  Using vertical reading, PSP was readily distinguished from SCD (accuracy 91.4%) but not as well from controls.  Nor did it do well in distinguishing PSP from PD despite appearances in the tracings shown above.

The authors feel that this technique could be improved in various ways.  They did correct the results for overall cognitive performance using the Montreal Cognitive Assessment (MoCA), but perhaps a correction for overall neurological disability, or at least dysarthria (in this reading aloud task) could be added.  I’d further suggest that to remove most of the cognitive and speech components of reading, the task could be reduced to reading a series of single digits rather than text sentences.  This could also allow the test to be used in populations not as skilled as the Japanese in reading text vertically.

A major virtue of this test is that after the one-time, initial software development, it’s very inexpensive, convenient and non-invasive.  It could be implemented on a desktop computer screen or perhaps on a tablet (a phone screen might be too small).  If we’re trying to detect people with PSP in a very early stage to test a new drug — and eventually to receive a prescription for it — a widely applicable, remotely administered screening test like this could be just the ticket. 

We don’t yet know the sensitivity of this test to PSP progression over time, but if it proves useful in that regard, perhaps it can be used as an outcome measure in treatment trials or as a way for neurologists to monitor their patients’ illness and offer prognostic advice.

Squares and jerks

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The fourth of the five PSP-related research papers to land in PubMed on a single day this week is from Ulm, Germany.   It compared PSP with ALS with regard “small involuntary fixation saccades” or SIFSs.  Here’s what that means and why it’s important: (Red alert: serious, nerdy neuroscience is coming.)

When we stare at a small visual target, we all have small, fast, irregular, eye movements away from the target.  Each is rapidly corrected by an equal and opposite movement and their size ranges from 0.01 degrees to 2 degrees.  (The normal full range of voluntary eye movement in each of the four directions is about 50 degrees.)  In PSP, these SIFSs become larger and more frequent in the horizontal plane (i.e., left and right), ranging up to 3 degrees and occurring up to twice per second.  The largest of these are called “square wave jerks.” They are so common in PSP, even in the earliest stages, that a neurologist finding signs of PSP but no square wave jerks must strongly consider some other diagnosis.  As you’d imagine, SWJs degrade vision by making it difficult to aim the most sensitive, central part of the retina at a target.

Square wave jerks and milder forms of SIFSs also occur in amyotrophic lateral sclerosis (ALS or Lou Gehrig disease).  ALS and PSP both include frontal cognitive loss and affect overall body movement, especially speech and swallowing, have frontal cognitive loss and have a similarly rapid course, but are otherwise not at all similar.  In ALS, the average age of onset is 10 years younger; the cognitive loss is a late occurrence; it affects the spinal cord worst; and the protein aggregating in the cells is TDP-43 rather than tau.  As eye movement are controlled, in part by the frontal lobes, it seems reasonable that the frontal damage is the source of SWJs in both diseases. 

Now, Drs. Wolfgang Becker, Anna Behler, Olga Vintonyak and Jan Kassubek have compared people with PSP and ALS with regard to the details of their SIFSs, including their square wave jerks.  In addition to making some new observations about SIFSs in general, they found that in ALS, the size and frequency of SIFSs are correlated, while such a relationship is absent in PSP. 

The researchers explain this result by suggesting that the basal ganglia, where the substantia nigra, globus pallidus and subthalamic nucleus are the first three nuclei affected in PSP, are the most likely source of SWJs in that disease, while in ALS, the SWJs probably arise from damage to the frontal cortex.  They suggest that in PSP, the amplitude and frequency of the SWJs are regulated by different sites in the basal ganglia, explaining their observed lack of correlation.  More work will be needed to confirm that suspicion, but some support comes from the observation in this paper that the severity of vertical eye movement loss, the cardinal feature of PSP, correlates closely with the amplitude of the (horizontal!) square wave jerks.

Why should anyone care?  First of all, a general point: One never knows when a “basic science” observation may lead to broader insights that could allow treatments to be developed.  More specifically, finding that a feature of PSP arises from multiple parts of the basal ganglia reduces the appeal of targeting just one allegedly critical or rate-limiting area of basal ganglia damage with a preventative or restorative treatment.  Such approaches have been proposed using injection of viral vectors to deliver gene therapy or growth factors.  Non-invasive targeting of the basal ganglia has been proposed using focused ultrasound.  This new paper suggests that a more general approach reaching the whole brain, or at least all the basal ganglia, might work better.