Apart from the impairments in classical vertical eye movements that characterize progressive supranuclear palsy (PSP), a second ocular motor dysfunction was described early on: PSP patients exhibit frequent square-wave jerks (SWJs) whose presence—at least in quantitative eye-movement recordings—is practically universal.1 Nonetheless, the genesis of SWJs is still uncertain and clear evidence of structural brain abnormalities that are causally linked to SWJs is lacking.

Clinical data favor either the “cerebellar hypothesis” or the “brainstem hypothesis” of SWJ generation. The former is based on numerous observations in neurological conditions such as Friedreich ataxia, X-linked ataxia, spinocerebellar ataxia 3, spinocerebellar ataxia 6, and oculomotor apraxia type 2.2345678 Frequent SWJs have also been noted in structural cerebellar disorders such as Arnold-Chiari malformation, Langerhans cell histiocytosis, anti-GAD ataxia, and multiple sclerosis.9101112 On the other hand, the brainstem hypothesis provides a morestraightforward explanation for the increased frequency of SWJs in PSP. This theory stems mainly from the elegant model of Otero-Millan et al.13 that assumes the presence of a disturbance in the brainstem ocular motor network. The latter includes the excitatory burst neurons (EBNs), inhibitory burst neurons (IBNs), omnipause neurons (OPNs), and their connections with the superior colliculus (SC). At the core of the model is the emergence of enhanced random fluctuations of neural activity within the SC that leads to increased input to burst neurons and decreased input to OPNs. When the inhibition exerted by the IBNs on the OPNs overcomes the inhibition of the OPNs on the IBNs, a short burst of activity appears in the EBNs that produces a small saccade. In turn, this produces a small retinal error that is detected in the SC network and results in a second saccade in the opposite direction, completing a SWJ. Given that the SC receives input from the basal ganglia, this model offers an explanation for the increased occurrence of SWJs and microsaccades in parkinsonian syndromes. Nonetheless, the cerebellar and brainstem hypotheses are not necessarily mutually exclusive: through its direct projections to IBN, the cerebellar fastigial nucleus directly modifies the brainstem ocular motor network.1415 Hence, cerebellar (fastigial) damage would ultimately result in a disinhibition of EBNs and motoneurons leading to an increased SWJ occurrence.11

In the present study we aimed to determine the characteristics of SWJs in PSP and Parkinson's disease (PD) and, more importantly, to relate various SWJ features to findings in volumetric brain imaging. Our main goal was to map the brain structures responsible for the increased prevalence of SWJ in patients with PSP.

Two patient groups were studied: 1) those with PSP (the Richardson subtype) and 2) those with PD. All participants underwent standardized clinical-neurological examinations performed by two movement disorder specialists (V.C., C.P.), and were diagnosed according to the current standardized consensus criteria for PSP and PD.1617 Eye-movement data were also compared to recordings from matched healthy controls.

All subjects gave written informed consent for participation in the study, which was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Department of Neurology of the University of Athens (IRB No. 165-20/03/2017).

This study included 12 PSP patients (the Richardson subtype), 12 PD patients, and 12 age-matched healthy controls. The clinical features and demographics of all subjects are summarized in Supplementary Table 1 (in the online-only Data Supplement).

Various oculomotor abnormalities in parkinsonian syndromes have long been known and have been described in detail using quantitative eye-movement recordings.293031 However, the search for the causative brain alterations in living patients has only been possible following recent advancements in structural and functional neuroimaging techniques. Indeed, combined studies of eye movements and morphometry- or connectivity-based MRI analyses have confirmed the traditional hypotheses regarding oculomotor deficits in parkinsonian syndromes: decreased peak eye velocities of saccades in PSP (the Richardson subtype) are significantly correlated with midbrain atrophy, hypometric (“staircase”) saccades to visual targets in PD are linked to functional connectivity changes in cortical areas, and saccadic smooth pursuit in multiple-system atrophy is related to cerebellar and pontine volume reductions.323334 Nonetheless, common oculomotor findings such as the increased latency of reactive saccades in PD—traditionally considered a dysexecutive syndrome—did not show any significant correlation with regional brain volume changes.34

In PSP, SWJs—which are the second-most-obvious eye-movement abnormality after the slowed vertical saccadic eye movements—have not been investigated in the context of the underlying reduction in brain volume. It is possible that the only oculomotor parameter with a conceptual proximity to SWJs is the accumulated intrusion index examined by Vintonyak et al.,34 which was not correlated with volumetric changes in any of the investigated brain structures. However, the accumulated intrusion index differs fundamentally from classic saccadic intrusions such as SWJs, in that it is obtained during an active saccadic task (i.e., not during fixation) and, more importantly, it excludes all saccades smaller than 2° while keeping all macrosaccades without an upper amplitude limit. Thus, the findings of such combined oculomotor-MRI analyses are not directly comparable with those in the present study.

As expected, we found that the SWJ rate was markedly higher in the PSP group than in both the PD patients and controls. This increase was more than threefold in the fixation-on condition, whereas the effect was more moderate in the fixation-off condition, although it was still highly statistically significant. The PD patients also showed a tendency toward more SWJs compared to controls, but this difference was not significant. The mean SWJ amplitude, particularly in the fixation-off condition, showed a nonsignificant tendency toward higher values in PSP patients, while the SWJ velocity (expressed by the velocity-to-amplitude ratio) did not differ among the three patient groups. On the other hand, voluntary (macro) saccades had much slower velocities in the PSP group than in both the PD patients and controls. Thus, the present data replicated the well-known hallmark of fixational abnormality in PSP, namely the increased SWJ rate.1

Not surprisingly, voxel-based morphometry demonstrated that the midbrain volume was lower in our PSP patients than in the PD patients. A particularly interesting finding was that the midbrain volume loss was not associated with SWJ parameters.1 Focused MRI analysis of the SC using dedicated ROI calculations also did not reveal any correlation with SWJs. Thus, although reductions in the midbrain volume have been previously shown to be related to impairments in vertical eye-movement performance in PSP,34 it appears that they do not play a major role in SWJ generation.

Instead, our morphometric-oculographic correlation analysis using a stringent statistical significance threshold (p<0.001) indicated that supratentorial rather than infratentorial structures are involved in SWJ generation in PSP. In particular, atrophy in the middle and inferior temporal gyri was correlated with increased SWJ rates in the fixation-on condition, while volume losses in the inferior temporal, superior temporal, and superior occipital gyri were associated with higher SWJ rates in the fixation-off condition. Although of less importance due to the absence of significant SWJ abnormalities in PD patients, the SWJ rates in that group were correlated with volume reductions in the pallidum and putamen in the fixation-on condition, while no correlations were evident in the fixation-off condition. Also, our analyses of the MRI data set with regard to other SWJ parameters, such as the SWJ amplitude and velocity, proved to have a rather questionable heuristic value, since these oculomotor parameters did not differ significantly in PSP patients. It is perhaps worth noting that cortical rather than infratentorial sites displayed correlations with the SWJ amplitude and velocity in both PSP and PD patients, with the exception of a significant association of a volume reduction in cerebellar crus I and an increased mean SWJ amplitude in PSP.

Thus, gyri of the temporal lobe appear to play a crucial role in SWJ generation in PSP. Neuropathological studies of PSP brains have traditionally focused on changes in the brainstem, basal ganglia, and frontal lobe, providing straightforward correlations with the cardinal signs of the disease, namely supranuclear saccade slowing, parkinsonism, and frontal-type dementia.3536 However, recent cross-sectional and longitudinal neuroimaging studies have found small but significant amounts of atrophy in the temporal lobe of PSP patients, whereas most researchers tend to associate these changes with behavioral deficits.37383940 Unfortunately, no previous study has attempted to link any parts of the temporal lobe with SWJs.

A completely different line of evidence provides indirect support for an association of the temporal cortex with SWJ generation. Although less extensively investigated in the context of ocular motility, patients with Alzheimer's disease—which perhaps is the prototype of degenerative temporal-lobe atrophy—reportedly show abnormally high SWJ rates. Jones et al.41 described the first series of Alzheimer patients with a high prevalence of SWJs, demonstrating SWJ rates ranging from 51 to 74 per minute. Additional oculomotor deficits such as saccadic smooth pursuit were subsequently shown to cooccur with SWJs in Alzheimer's disease.42 More recently, a comparison of typical Alzheimer's patients with patients with posterior cortical atrophy revealed that the former show significantly higher SWJ rates, whereas the latter exhibit more macrosaccade intrusions.43 Few studies have investigated SWJs in focal hemispheric lesions. The systematic study of Sharpe et al.44 analyzed 17 patients with pathological SWJs due to solitary brain tumors or infarctions, and measured the highest SWJ rate (65 per minute) in a patient with parietotemporal astrocytoma. There were no pure temporal or parietal lesions in this cohort to allow more precise comparisons, but patients with lesions in the frontal or occipital lobe exhibited fewer SWJs.

It is worthwhile to consider how temporal cortical areas could influence the generation of SWJs. There is only indirect neuroanatomical evidence linking the temporal neocortex to pontine neurons (EBN and OPN), which are presumably responsible for SWJ generation. With regard to the brainstem SWJ hypothesis,13 several anatomical staining and anterograde degeneration studies have demonstrated connections of neocortical areas of the temporal lobe to parts of the SC.454647 It could be hypothesized that reduced control on SC neurons due to temporal cortex atrophy would lead to an enhancement of random fluctuations of neural activity within the SC, ultimately leading to increased input to EBNs and decreased input to OPNs. Alternatively, older neuroanatomical investigations indicated the presence of direct connections of the temporal neocortex to the vestibulocerebellum, presumably via cortico-ponto-cerebellar mossy fiber projections.484950 These pathways could play a role in fastigial-nucleus-mediated disinhibition of EBNs that is presumably consistent with the cerebellar hypothesis of SWJ triggering (see the Introduction).

The present study was subject to some limitations. First, a larger sample might have revealed more SWJ-related brain volume changes. Second, the availability of MRI data for the control subjects, who were included only for oculomotor comparisons, might have revealed interesting correlations between voxel-based morphometry and SWJs in healthy individuals, at least in those who exhibited some SWJs. Third, it is worth noting that SWJs are linked to temporal cortex volume loss in PSP but not in PD, and the SWJ rate was correlated with reduced putamen and pallidum volumes in the latter patients. Although this association should be interpreted with caution since the PD patients did not show significantly increased SWJs compared to controls, this difference in voxel-based morphometric correlations between PSP and PD with regard to SWJs remains an open issue that requires further investigations. Nonetheless, it is not unusual for the same ocular motor phenomenon to be associated with different regional brain atrophies in different diseases. For instance, the increased latency of voluntary saccades that is observed to the same degree in PD, PSP, and multiple-system atrophy seems to be mediated by different brain structures in each syndrome.34 Another example is the disturbances of smooth-pursuit eye movements being very similar in PSP and multiple system atrophy, which shows a correlation with cerebellar and pontine atrophy in the latter but not in the former syndrome.34 With respect to the present findings, we speculate that the core neural circuit responsible for SWJ generation in the brainstem becomes hyperexcitable by damage or atrophy of multiple upstream brain regions.

In summary, this study is the first to use voxel-based morphometry and quantitative oculography to demonstrate that SWJs (a universal fixation abnormality) are not mediated by midbrain atrophy. Instead, supratentorial cortical structures located mainly in the temporal lobe appear to be deeply involved in the generation of abnormally high SWJ rates. A focused, multidisciplinary research approach that aligns precise eye-movement recordings with advanced structural and functional neuroimaging has the potential to elucidate the origin of saccadic intrusions in various movement disorders and might ultimately contribute to the understanding of the neural mechanisms underlying visual fixation.