David S. Zee

The neuro-ophthalmology of multiple sclerosis

Multiple sclerosis (MS) is the most common disabling neurological disease in young people. Most CNS lesions involve neuroanatomically non-eloquent zones that often do not result in symptomatic complaints. By contrast, tissue-injury mechanisms involving inflammatory demyelination can involve more eloquent sites, such as the optic nerve and brainstem, which can correspondingly produce the development of well recognised syndromes such as optic neuritis and internuclear ophthalmoplegia, respectively. In this review we discuss the broad landscape of abnormalities that affect the afferent visual system and the ocular motor apparatus, and emphasise relevant features, the recognition and treatment of which are of importance to general neurological practice. The commonness of visual sensory and eye movement abnormalities in MS highlights the importance of understanding the principles addressed in this review.

Saccades in Huntington's disease: Initiation defects and distractibility

We recorded saccadic eye movements in patients mildly affected with Huntingtons disease. Most showed an increase in saccade latencies that was greater for saccades made on command than to the sudden appearance of a visual target. All patients showed excessive distractibility during attempted fixation. They had particular difficulty suppressing a saccade to a suddenly appearing visual target when simultaneously trying to initiate a saccade in the opposite direction. Our results are compatible with a posited role of the basal ganglia in both the initiation of volitional saccades and in the maintenance of fixation. Saccade abnormalitie—especially distractibility—are sensitive but probably not specific indicators of Huntingtons disease.

Adaptive Control of Saccades via Internal Feedback

Ballistic movements like saccades require the brain to generate motor commands without the benefit of sensory feedback. Despite this, saccades are remarkably accurate. Theory suggests that this accuracy arises because the brain relies on an internal forward model that monitors the motor commands, predicts their sensory consequences, and corrects eye trajectory midflight. If control of saccades relies on a forward model, then the forward model should adapt whenever its predictions fail to match sensory feedback at the end of the movement. Using optimal feedback control theory, we predicted how this adaptation should alter saccade trajectories. We trained subjects on a paradigm in which the horizontal target jumped vertically during the saccade. With training, the final position of the saccade moved toward the second target. However, saccades became increasingly curved, i.e., suboptimal, as oculomotor commands were corrected on-line to steer the eye toward the second target. The adaptive response had two components: (1) the motor commands that initiated the saccades changed slowly, aiming the saccade closer to the jumped target. The adaptation of these earliest motor commands displayed little forgetting during the rest periods. (2) Late in saccade trajectory, another adaptive response steered it still closer to the jumped target, producing curvature. Adaptation of these late motor commands showed near-complete forgetting during the rest periods. The two components adapted at different timescales, with the late-acting component displaying much faster rates. It appears that in controlling saccades, the brain relies on an internal feedback that has the characteristics of a fast-adapting forward model.

Transient torsion during and after saccades.

In five normal subjects, we analyzed uncalled for torsion (blips) during and after horizontal and vertical saccades. Torsion was defined as movement out of Listings plane. During horizontal saccades in downward gaze the abducting eye extorted and the adducting eye intorted. The direction of the blips reversed in upward gaze. Peak torsional amplitudes (up to 1-2 deg) were always reached during saccades; drifts back to Listings plane outlasted the saccades. Torsion of the extorting eye was larger than that of the intorting eye, producing a transient positive cyclovergence. Torsion and cyclovergence evoked by vertical saccades were also stereotyped in each eye, but showed idiosyncratic differences among subjects. We conclude that Listings law is violated during saccades. Transient saccade-evoked torsion might reflect properties of the three-dimensional velocity-to-position integrator and/or the ocular plant.

Ocular motor abnormalities in Huntington's disease

We review here the eye movements in patients with Huntingtons disease (HD), concentrating upon saccades as they show the most prominent abnormalities. Inability to suppress reflexive glances to suddenly appearing novel visual stimuli and delayed initiation of voluntary saccades, including predictive saccades, are early and consistent findings. These two abnormalities can be interpreted in the context of a model, based upon the idea that the frontal lobes and basal ganglia contribute more to the control of voluntary than to reflexive types of saccades. Most patients eventually also show slow saccades but they are most prominent when the disease is early-onset. Slowing of saccades may reflect involvement of both the higher-level cerebral centers that trigger saccades and the areas in the brain stem that produce premotor saccade commands. The study of eye movements in HD has led to a fruitful interaction between basic science and clinical investigation, and has served as a paradigm for examining higher-level defects in saccadic eye movement control in patients with various degenerative, neurological diseases or with focal cerebral hemispheral lesions.

Cerebellar Contributions to Adaptive Control of Saccades in Humans

The cerebellum may monitor motor commands and through internal feedback correct for anticipated errors. Saccades provide a test of this idea because these movements are completed too quickly for sensory feedback to be useful. Earlier, we reported that motor commands that accelerate the eyes toward a constant amplitude target showed variability. Here, we demonstrate that this variability is not random noise, but is due to the cognitive state of the subject. Healthy people showed within-saccade compensation for this variability with commands that arrived later in the same saccade. However, in people with cerebellar damage, the same variability resulted in dysmetria. This ability to correct for variability in the motor commands that initiated a saccade was a predictor of each subjects ability to learn from endpoint errors. In a paradigm in which a target on the horizontal meridian jumped vertically during the saccade (resulting in an endpoint error), the adaptive response exhibited two timescales: a fast timescale that learned quickly from endpoint error but had poor retention, and a slow timescale that learned slowly but had strong retention. With cortical cerebellar damage, the fast timescale of adaptation was effectively absent, but the slow timescale was less impaired. Therefore, the cerebellum corrects for variability in the motor commands that initiate saccades within the same movement via an adaptive response that not only exhibits strong sensitivity to previous endpoint errors, but also rapid forgetting.

Deficits in the initiation of eye movements in the absence of a visual target in adolescents with high functioning autism

BACKGROUND We used ocular motor paradigms to examine whether or not saccades are impaired in individuals with high functioning autism (HFA). METHODS We recorded eye movements in patients with HFA (n=11), and in normal adolescents (n=11) on anti-saccade, memory-guided saccade (MGS), predictive saccade and gap/overlap tasks. RESULTS Compared with the normal subjects, patients with HFA had (1) a significantly higher percentage of directional errors on the anti-saccade task (63.2% versus 26.6%), (2) a significantly higher percentage of response suppression errors on a MGS task (60.3% versus 29.5%) and (3) a significantly lower percentage of predictive eye movements on a predictive saccade task. They also showed longer latencies on a MGS task and for all conditions tested on a gap/null/overlap task (fixation target extinguished before, simultaneously, or after the new peripheral target appeared). When the latencies during the gap condition were subtracted from the latencies in the overlap condition, there was no difference between patients and normals. CONCLUSIONS Abnormalities in ocular motor function in patients with HFA provide preliminary evidence for involvement of a number of brain regions in HFA including the dorsolateral prefrontal cortex (dlPFC) and the frontal eye fields (FEFs) and possibly the basal ganglia and parietal lobes.

Oculomotor abnormalities in attention deficit hyperactivity disorder: A preliminary study

Background: Prevailing hypotheses suggest that attention deficit hyperactivity disorder (ADHD) is secondary to dysfunction of motor intentional systems mediated by prefrontal circuitry. Oculomotor paradigms provide a mechanism for examining and localizing dysfunction at the interface between movement and cognition. Objective: Three different saccade tasks (reflexive or prosaccades, antisaccades, and memory-guided saccades) were used to examine functions necessary for the planning and the execution of eye movements, including motor response preparation, response inhibition, and working memory. Methods: The study included 19 children with ADHD, divided into two groups: a group of 8 children on methylphenidate at the time of testing and a group of 11 children not taking any psychoactive medication. Results from the two groups were compared with those from 25 age- and gender-matched normal control children. Results: Both groups of children with ADHD made significantly more directional errors than did controls on the antisaccade task and significantly more anticipatory errors than did controls on the memory-guided saccade task, findings that are consistent with deficits in response inhibition. There were no significant differences in prosaccade latency, although unmedicated children with ADHD showed significantly greater variability in latency on the prosaccade task than did controls. On the memory-guided saccade task there were no significant differences in saccade accuracy; however, unmedicated children with ADHD showed longer saccade latency than did either controls or medicated children with ADHD. Conclusions: Oculomotor findings suggest that deficits in prefrontal functions, in particular response inhibition, contribute to behavioral abnormalities observed in ADHD. Findings also suggest that the administration of methylphenidate is associated with improvements in the consistency of motor response. Although there were no observed improvements in response inhibition with methylphenidate, conclusions await a design in which subjects complete testing both on and off medication.

A hypothetical explanation of congenital nystagmus

Congenital nystagmus (CN) is a conjugate, rhythmic, eye movement disorder characterized by a wide variety of waveforms ranging from jerk to pendular types. No detailed mechanisms have been proposed to explain the generation of the CN wave-form This paper proposes a hypothetical mechanism for CN, and shows with computer simulations that a model based on this hypothesis can account for a variety of disparate waveforms. The basis of this model is a gaze-holding network, or neural integrator, that has both position and velocity feedback loops. The signals carried in these loops could arise from either afference or efference. In normal subjects, the position feedback would be positive and the velocity feedback would be negative. Both would help to increase the time constant of an imperfect neural integrator in the brain stem. We propose that in patients with CN the sign of the velocity pathway is reversed, making the neural integrator unstable. This instability could manifest as many different CN waveforms, depending on the direction and velocity of post-saccadic ocular drift and actions of nonlinearities within the position and velocity feedback loops. Thus a single underlying abnormality may be responsible for a variety of CN waveforms.

Saccades in Huntington's disease: Slowing and dysmetria

Eye movements were recorded from 20 mildly affected patients with Huntingtons disease (HD) who were divided into two groups, 10 patients with onset of symptoms before age 30 and 10 with onset of symptoms after age 30. In the younger onset group (HD < 30), peak saccade velocities were low (<255 deg/sec for 20-deg saccades) in six of the 10 patients, whereas none of the 10 patients in the older onset group (HD > 30) had peak saccade velocities lower than 300 deg/sec. Latencies for volitional saccades were greater than normal in the HD > 30 group, but were normal for the HD < 30 group. The ability to maintain steady fixation in the face of a distracting visual stimulus was decreased, to the same degree, in both groups of HD patients. In addition, 70% of the HD < 30 group had an affected father, while 70% of the HD > 30 group had an affected mother. These findings suggest that the pathophysiology of the slow saccades, initiation deficit, and excessive distractibility in HD are different.