Abstract
Purpose.:
The purpose of the current research is to understand if the different eye movement abnormalities in patients with the same neurologic disease are related to varied disease processes or, alternately, do different patients adopt different strategies to overcome a singular brain deficiency.
Methods.:
Using a magnetic search coil, we measured saccade dynamics, that is position and velocity waveforms, for patients diagnosed with spinocerebellar ataxia type 3 (SCA-3), also known as Machado-Joseph disease (MJD).
Results.:
We observed that the saccadic waveform of the majority of the SCA-3 patients (7 of 10) exhibited dynamic overshoot, with the eye passing the desired endpoint and making a rapid correction before coming to rest. Patients with normal waveforms, that is with no dynamic overshoot, had saccades with relatively low peak velocity.
Conclusions.:
Velocity feedback in a closed loop control system is essential for providing a fast response without overshoot. Lack of a velocity feedback or an imbalance between position and velocity gains yields a tradeoff between response time and overshoot. While the goal of a saccade is to get to the desired position, models based on animal research suggest that the saccadic control also incorporates a velocity feedback. Results presented here indicated that all SCA-3 patients had deviations in the saccadic waveform, albeit of two types, either slow saccades or dynamic overshooting saccades. Using saccadic models based on animal research can explain how a single deficit, that is a mismatched velocity control of the motor error due to the disease, can yield these two different abnormalities in human patients.
The short duration of a saccade (tens of milliseconds) makes it impossible to achieve closed loop control using the relatively slow visual system. While saccades are triggered and programmed based on visual information, in-flight, saccades are controlled by an internal motor feedback control mechanism. This mechanism minimizes an error signal between the current gaze position and an efferent copy of the motor command. Supporting evidence for this model is based on experiments in primates in which saccades were interrupted mid-flight by electrical stimulation of the omnipause neuron region and still achieved accuracies similar to normal saccades even in the absence of visual input.
1 This led to a model in which the feedback control system uses motor velocity information in addition to position information. Generally, in control systems, using a velocity feedback, that is the rate of change, in addition to position enables the system to achieve a smoother dynamic, specifically minimizing the dynamic overshoot (DO) in systems where a fast reaction is required.
Comparing eye movement abnormalities observed in patients to given models can help differentiate between pathology in the ocular motor periphery and problems in higher level internal control mechanisms. Conversely, the validity of eye movement models based on electrical neurophysiology in primates can be tested against eye movement abnormalities found in humans.
Various saccadic abnormalities occur in many neurodegenerative diseases, including spinocerebellar ataxia type 3 (SCA-3), also known as Machado-Joseph disease (MJD). MJD, the most common form of autosomal dominant cerebellar ataxia, is an expanded repeat disease with “CAG” repeats in the
ATXN3 gene. Magnetic resonance imaging (MRI) studies reveal diffuse central nervous system (CNS) atrophic changes, particularly in the cerebellar vermis, superior cerebellar peduncle, pontine tegmentum, and frontal lobes.
2 Despite the common pathology of the disease, the clinical manifestations of MJD can be highly variable, even among affected persons in the same family.
The prevalence of the disease is highest among people of Portuguese/Azorean descent. Interestingly, in Israel the only population known to have MJD is a Yemenite Jewish subpopulation that has been found to have a genetic isolate of SCA-3 characterized by a relatively large number of homozygotes for the CAG trinucleotide repeat expansion at the
MJD1 gene.
3–5
Ocular motor functions were examined previously in patients with various spinocerebellar ataxias, including SCA-3. Gordon et al. found various degrees of gaze-evoked nystagmus and bilateral loss of the horizontal VOR in SCA-3.
5 Additional ocular-motor abnormalities, such as reduced smooth pursuit gain and VOR interactions, were documented in SCA-3 patients.
6 There is a discrepancy in the literature regarding abnormalities of saccades in SCA-3 patients. Gordon et al. reported amorphous “saccade abnormalities,” including “saccade accuracy” and “saccade velocity,”
5 Bürk et al. reported mild reduction of saccade velocity in approximately one-third of patients,
7,8 while Buttner et al.
9 and Rivuad-Pechoux et al.
10 didn't find any significant change in saccade velocity relative to healthy controls.
We examined the saccadic abnormalities found in MJD, and used them to propose a single ocular motor deficit that can explain the observed abnormalities and the discrepancy in the literature regarding the velocity of the saccades in patients with SCA-3. At the same time, our model buttresses the standard saccade generation model that includes velocity feedback.
All patients included in our study were examined in the neurologic outpatient clinic of Meir Medical Center, Kfar Saba, Israel, and were diagnosed clinically and genetically as having SCA-3 (MJD). Ataxia score of the MJD patients was evaluated according to the SARA scale.
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There were 10 SCA-3 (MJD) patients and 10 healthy controls. Among the 10 patients 7 were female and 3 male, with an average age of 48.6 (14.9). The average age of the healthy controls was 46.1 (14.4), which was a close match with the average age of the MJD patients.
The protocol of the experiment was approved by the Ethics Committee (Institutional Review Board) of Meir Medical Center, Kfar Saba, Israel, and followed the tenets of the Declaration of Helsinki. Before each testing session a written, informed consent was signed by the subject.
The statistical significance of the results was validated by performing a parametric test. Using a t-test, we examined the hypothesis that for each patient, there exists at least one saccadic parameter that differs significantly from the expected normal value. For peak velocity of the saccades, we tested the hypothesis that the peak velocity ratio was significantly smaller than 1.0. The peak velocity ratio was calculated for each saccade. The peak velocity ratio is the ratio between the measured peak velocity of the saccade and the expected peak velocity of a saccade, based on its amplitude and the main sequence of the controls. For DO, we used a t-test to test the hypothesis that the percentage of the overshoot relative to the amplitude of the saccade is significantly larger than 2.0%.
The nonparametric Kolmogorov–Smirnov test (K-S test) was used to compare the peak velocity ratio between the healthy control subjects and various groups of patients. The K-S test was used to check the significance of the prior assumption that those with MJD have lower peak velocities, that is slow saccades. Differences were considered significant at P < 0.05.
Position traces of saccades of some of the MJD patients showed DO, that is the eye passes the desired position endpoint and makes a rapid correction, with velocity in the opposite direction, before coming to rest. In DO, the corrective motion is an integral part of the motor process of the initial saccade. This differs from a hypermetric saccade in which there also is overshooting of the target, but in which the corrective saccade is initiated after the eye has come to a complete rest. In hypermetric saccades, the corrective motion is a result of a new motor process.
Figure 2 shows the overshoot as a percentage of saccade size for all patients and controls. The overshoot in percentage is the angular distance the eye moves past the endpoint relative to the desired saccade amplitude.
Table. Summary of Patient Characteristics for All 10 Patients
Table. Summary of Patient Characteristics for All 10 Patients
Patient ID | Age | Sex | Symptomatic, y | SARA | Saccade Peak Velocity Ratio | Slow Saccade | Overshoot, % | Significant Overshoot |
01 | 33 | Female | 1 | 4.0 | 0.88 | * | 0.7 | |
02 | 75 | Female | 7 | 25.0 | 0.90 | * | 11 | * |
03 | 29 | Female | 6 | 10.0 | 1.37 | | 17 | * |
04 | 50 | Female | 4 | 6.0 | 0.94 | * | 6.4 | * |
05 | 40 | Male | 14 | 11.5 | 0.80 | * | 0.3 | |
06 | 44 | Male | 3 | 5.0 | 1.36 | | 5.6 | * |
07 | 65 | Female | 12 | 10.0 | 0.90 | * | 8.8 | * |
08 | 52 | Female | 4 | 17.0 | 0.94 | | 20 | * |
09 | 61 | Female | 2 | 14.0 | 0.81 | * | 0.4 | |
10 | 37 | Male | 8 | 10.5 | 1.21 | | 14 | * |
A subset of 7 of 10 of the MJD patients had a significantly larger DO relative to the healthy controls. In contrast, none of the 10 healthy controls had an overshoot that is significantly larger than 2%. It is worth noting that due to the very short duration of this DO, it usually cannot be seen without recording eye movements at a relatively high temporal frequency and, thus, often is missed during a clinical examination.
Therefore, these patients can be divided into 2 subgroups: a group of patients with DO (7 of 10), and a group of patients without a significant overshoot (3 of 10). We were not able to correlate the presence of an overshoot with any other of the patients' clinical parameters listed in the Table.
The saccadic main sequence quantifies the peak velocity and duration of saccades versus the saccade amplitude. Saccades with larger amplitude have a higher peak velocity compared to saccades with smaller amplitudes. In addition, the duration of the saccade is longer for larger saccades. When evaluating saccadic peak velocity or duration, it is essential to relate the measured values to the amplitude of the saccade. This is done by plotting the measured peak velocity or the measured duration of the saccade as a function of saccadic amplitude. This function is referred to as the saccadic main sequence.
The peak velocity versus amplitude curves, that is the main sequences, of horizontal saccades for all MJD patients are shown in
Figure 3. As can be seen from the main sequence plots, only a subset of the MJD patients had slowness of saccades. To divide the patients into subgroups of those with slow saccades and those with normal peak velocity, we introduced the variable peak velocity ratio, which quantifies the slowness of the saccade. It is calculated for each saccade, and is the ratio between the measured peak velocity of the saccade and the expected peak velocity of a saccade with the same amplitude. The expected peak velocity of a saccade was estimated based on the measured main sequence of the healthy controls. The average and confidence interval of the peak velocity ratio for the ten MJD patients and ten healthy controls are given in
Figure 4. Slowness of saccadic eye movements, significantly lower than the nominal value of 1.0, was seen only for a subset of 7 of the 10 MJD patients. These 7 patients had a peak velocity ratio that was significantly lower than 1.0, although within the range of 2 SD of the healthy controls. For the age-matched healthy control subjects, we found that 3 of 10 had a peak velocity ratio significantly lower than 1.0. The observation that healthy controls had a peak velocity ratio not equal to 1.0 can be explained by the large peak velocity variation of saccades observed in healthy controls.
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The data in the Table indicate that there is a correlation between the slowness of the saccades and the DO. Slowness of the saccades was found for all 3 patients with no DO. Thus, each of the SCA-3 patients had a saccade flaw, either slowness and/or overshoot.
To examine the correlation between the velocity of the saccade and the overshoot further, we compared the mean peak velocity of the healthy controls to different subgroups of patients. According to the K–S test, the mean peak velocity ratio of the 3 MJD patients with no DO (patient IDs 1, 5, and 9 in the Table) was significantly lower (P < 0.005) relative to the mean peak velocity of the 10 healthy controls. In contrast, the mean of the peak velocity ratio of all MJD patients was not significantly different from the healthy controls.
Eye movements of patients with SCA-3 (MJD) have been examined in the past, with mixed reports about their saccadic velocity. Our results attempted to explain this disparity by dividing the MJD patients into two subgroups: those with significant DO and those with no DO. Patients with normal velocity saccades all had significant overshoot.
The earliest models of the saccadic system
14 from almost 40 years ago assumed a ballistic system lacking any feedback. Within a few years it was understood that there exists some form of feedback, and a feedback loop using an efference copy of the eye position was added to the saccadic model. This position signal was thought to be based on an efference copy of the eye velocity that passed through a resettable integrator. Subsequent models incorporated velocity feedback as well. These models were supported by computer simulations
15 and animal studies.
1
We propose that the data from our SCA-3 patients can bolster the contention that the saccadic system uses velocity feedback, and we suggest that all SCA-3 patients share a common deficit in the velocity feedback, despite the appearance of there being two types of saccadic abnormalities.