The association between alterations of eye movement control and cerebral intrinsic functional connectivity in Parkinson’s disease

Abstract

Patients with Parkinson's disease (PD) present with eye movement disturbances that accompany the cardinal motor symptoms. Previous studies have consistently found evidence that large-scale functional networks are critically involved in eye movement control. We challenged the hypothesis that altered eye movement control in patients with PD is closely related to alterations of whole-brain functional connectivity in association with the neurodegenerative process. Saccadic and pursuit eye movements by video-oculography and 'resting-state' functional MRI (3 Tesla) were recorded from 53 subjects, i.e. 31 patients with PD and 22 matched healthy controls. Video-oculographically, a broad spectrum of eye movement impairments was demonstrated in PD patients vs. controls, including interrupted smooth pursuit, hypometric saccades, and a high distractibility in anti-saccades. Significant correlations between altered oculomotor parameters and functional connectivity measures were observed, i.e. the worse the oculomotor performance was, the more the regional functional connectivity in cortical, limbic, thalamic, cerebellar, and brainstem areas was decreased. Remarkably, decreased connectivity between major nodes of the default mode network was tightly correlated with the prevalence of saccadic intrusions as a measure for distractability. In conclusion, dysfunctional eye movement control in PD seems to be primarily associated with (cortical) executive deficits, rather than being related to the ponto-cerebellar circuits or the oculomotor brainstem nuclei. Worsened eye movement performance together with the potential pathophysiological substrate of decreased intrinsic functional connectivity in predominantly oculomotor-associated cerebral functional networks may constitute a behavioral marker in PD.

Patterns of Eye Movement Impairment Correlate with Regional Brain Atrophy in Neurodegenerative Parkinsonism

“…The reduced accuracy gain during the performance of reactive saccades indicated “hypometric saccades” - a characteristic oculomotor feature for PD which was accompanied by increased latencies. During fixation, PD patients presented a high incidence of abnormally large and frequent saccadic intrusions as characteristically observed in PD [7]. …”

“…This may indicate that oculomotor deficits in PD are not associated with disturbed pontocerebellar circuits or impaired oculomotor brainstem nuclei. PD patients presented pronounced difficulty suppressing unwanted gaze shifts by frequently moving their eyes away from the target in the absence of any distractor, but they almost instantaneously corrected these involuntary eye movements by refoveating the target [7]. This behavior was observed during a visually guided reactive saccade performance resulting in an increased rate of saccadic intrusions and correlated with overall brain atrophy and cerebral volumetric loss.…”

“…This behavior was observed during a visually guided reactive saccade performance resulting in an increased rate of saccadic intrusions and correlated with overall brain atrophy and cerebral volumetric loss. However, no correlations with a subdivision of brain areas could be demonstrated, suggesting that the executive dysfunctions as measured by the rate of saccadic intrusions can be attributed to a functional network disorder [7,24] rather than to regional brain atrophy. The volumetric value correlating with the oculomotor alterations in PD, i.e., the whole cerebral volume, is a measure of global atrophy and lacks specificity - this mirrors the limited diagnostic value of brain structural alterations in PD, especially in the early disease process.…”

“…The parameters of saccadic gain and peak eye velocity were computed for abducting and adducting primary saccades separately and they were then arithmetically averaged in order to obtain one value for horizontal and vertical saccades, respectively. Possible executive oculomotor deficits were measured by the rate of saccadic intrusions, i.e., involuntary gaze shifts bringing the gaze away and back onto the target, during a visually guided reactive saccade performance [7]. The rate of saccadic intrusions was computed according to Gorges et al [17] as the accumulated amplitude of saccades, excluding the primary saccades, divided by the trial time, excluding small saccades of <2° amplitude.…”

“…In other neurodegenerative parkinsonian syndromes, signs such as the eponymous gaze palsy in PSP presenting as slowed (vertical) saccades are highly specific in differential diagnosis at the single-patient level [3]. Recordings of eye movements could define cardinal oculomotor disturbances comprising executive dysfunctions in PD [7], a cerebellar type of saccadized smooth pursuit in MSA [8], and slowed vertical saccades in PSP [9]. …”