A longitudinal study of motor, oculomotor and cognitive function in progressive supranuclear palsy.

OBJECTIVE: We studied the annual change in measures of motor, oculomotor and cognitive function in progressive supranuclear palsy. This had twin objectives, to assess the potential for clinical parameters to monitor disease progression in clinical trials and to illuminate the progression of pathophysiology. METHODS: Twenty three patients with progressive supranuclear palsy (Richardson's syndrome) were compared to 22 matched controls at baseline and 16 of these patients compared at baseline and one year using: the progressive supranuclear palsy rating scale; the unified Parkinson's disease rating scale; the revised Addenbrooke's cognitive examination; the frontal assessment battery; the cubes section of the visual object and space perception battery; the Hayling and Brixton executive tests; and saccadic latencies. RESULTS: Patients were significantly impaired in all domains at baseline. However, cognitive performance was maintained over a year on the majority of tests. The unified Parkinson's disease rating scale, saccadic latency and progressive supranuclear palsy rating scale deteriorated over a year, with the latter showing the largest change. Power estimates indicate that using the progressive supranuclear palsy rating scale as an outcome measure in a clinical trial would require 45 patients per arm, to identify a 50% reduction in rate of decline with 80% power. CONCLUSIONS: Motor, oculomotor and cognitive domains deteriorate at different rates in progressive supranuclear palsy. This may be due to differential degeneration of their respective cortical-subcortical circuits, and has major implications for the selection of outcome measures in clinical trials due to wide variation in sensitivity to annual rates of decline.

Early saccades in amyotrophic lateral sclerosis.

Our objective was to correlate saccadic abnormalities, including early saccades, in patients with amyotrophic lateral sclerosis (ALS) with measures of motor and functional impairment. A portable saccadometer was used to record saccades in ALS patients and control subjects. The linear approach to threshold with ergodic rate model was used to characterize saccades, including sub-populations of early saccades. Patients with established cognitive impairment or frontotemporal dementia were excluded. Limb-onset (Limb ALS) and bulbar-onset (Bulbar ALS) patient groups were compared and saccadic abnormalities were correlated with measures of motor and functional impairment. In total, 48 participants were included in the study; 24 patients with ALS (15 males, 9 females; mean age 57.0 +/- 13.9 years; mean symptom duration 22.4 +/- 16.3 months, of whom 62.5% had Limb ALS) and 24 age-matched controls. Early saccades were increased in both Limb ALS and Bulbar ALS patients, but other saccadic parameters were normal in ALS. Saccadic abnormalities did not correlate with motor or functional impairment. In conclusion, ALS patients show increased early saccades, but exhibit no significant differences across ALS phenotypes.

Deep brain stimulation: eye movements reveal anomalous effects of electrode placement and stimulation.

One of the major difficulties in evaluating the efficacy of deep brain stimulation (DBS), or understanding its mechanism, is the need to distinguish the effects of stimulation itself from those of the lesion inevitably created during surgery. Recent work has shown that DBS of the subthalamic nucleus in Parkinson's disease greatly reduces the time it takes the eyes to make a saccade in response to a visual stimulus. Since this saccadic latency can be rapidly and objectively measured, we used it to compare the effects of surgery and of stimulation. We used a saccadometer to measure the saccadic latencies of 9 DBS patients (1) preoperatively, (2) the day after insertion of subthalamic nucleus electrodes, (3) three weeks later, prior to turning on the stimulator, and (4) after commencement of stimulation. Patients were on their anti-Parkinsonian medication throughout the study. It revealed an entirely unexpected and puzzling finding. As in previous studies an amelioration of symptoms is seen immediately after surgery, and then a further improvement when finally the stimulator is turned on, but in the case of saccadic latency the pattern is different: surgery produces a transient increase in latency, returning to baseline within three weeks, while subsequent stimulation reduced latency. Thus the differential effects of electrode placement and stimulation are completely different for saccades and for more general motor symptoms. This important finding rules out some over-simple interpretations of the mechanism of DBS, and needs to be taken into account in future attempts at modelling the neurophysiology of DBS.

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: similar improvements in saccadic and manual responses.

The purpose of this study was to determine whether the very large effects of saccadic latency distribution, generated by deep brain stimulation of the subthalamic nuclei are reflected in quantitatively corresponding changes for manual responses, rather than representing a reflection of the specific role of the subthalamus in controlling saccades. Saccadic and manual reaction times were measured under as nearly identical conditions as possible in six patients with implanted subthalamic electrodes and in six age-matched controls with the stimulation either on or off. Median latency was found to be reduced by stimulation in a similar way to saccadic latency; in neither case was there a significant change in the Linear Approach to Threshold with Ergotic Rate parameter σ. For both types of response, the effect is to move the responses proportionately in the direction of average of responses in the control group. We therefore conclude that the previously described effects of stimulation on latency are not a phenomenon peculiar to saccades, increasing confidence in using saccadic latency measurements as a surrogate for more general responses when determining the efficacy of deep brain stimulation.

Saccadic latency in Parkinson's disease correlates with executive function and brain atrophy, but not motor severity.

Brain regions related to saccadic control are affected by Parkinson's disease (PD) pathology and a relationship between abnormal saccades and cognitive features of PD has been suggested. We measured the latency of visually-evoked saccades, and correlated best-fit parameters in a LATER neuronal decision model µ and σ (mean and SD of the distribution of reciprocal latency, i.e. speed of response), and σ(E) (SD of the early component) with motor function, cognition and grey matter volume in 18 patients with PD and 17 controls. There was a negative correlation between verbal fluency and σ; no correlation was found between motor function and any of the latency parameters. Higher µ (shorter latency) positively correlated with grey matter volume in the prefrontal cortex, the cerebellar vermis, and the fusiform gyrus. There was a negative correlation between σ and grey matter volume in the frontal and parietal eye fields, the premotor cortex, and the lateral prefrontal cortex. σ(E) negatively correlated with grey matter volume in the frontal eye fields and the middle frontal gyrus. Our behavioural and imaging findings point to an association between saccade latency, executive function and the structural integrity within a well-defined oculomotor network.

Saccadic latency in deterministic environments: getting back on track after the unexpected happens.

Saccadic latencies are commonly used to study decision mechanisms. For instance, in a random sequence, saccadic latency to a target depends on how frequently it has recently appeared. However, frequency is not the only factor that determines probability. Here we presented targets to the left or right, either in random sequences or in repeating patterns. Although the frequency of appearing on a given side was identical in each case, latencies for the low-frequency side were significantly shorter for repeating patterns than in random sequences, showing that the system can respond to the deterministic probabilities in such patterns. We then disrupted our patterns episodically, recommencing at a random starting position in the sequence. This significantly increased the latency, which remained high until the low-frequency target in the sequence reappeared, implying that the oculomotor system makes strategic use of low-frequency--but high-information--events to determine the phase of repeating sequences. The deterministic sequences of events in our patterns represent a simple model for the habitual sequences of actions commonly performed in daily life, which, when disrupted, require the engagement of a higher level problem-solving strategy to return us to our previous automated sequence as quickly as possible.

Objective assessment of the hemisphere-specific neurological outcome of carotid endarterectomy: a quantitative saccadometric analysis.

BACKGROUND: Carotid endarterectomy (CEA) improves the cerebrovascular prognosis of patients with carotid stenosis but carries a risk of causing postoperative neurological deterioration. OBJECTIVE: We assessed hemisphere-specific changes in saccadic eye movements to determine the utility of saccadometry as a quantitative neurosurgical outcome measure. METHODS: Visually evoked saccades were recorded at the bedside before and 2 days after surgery from 30 patients undergoing CEA for symptomatic carotid stenosis. Hemisphere-specific latency distributions were compared using Kolmogorov-Smirnov statistics. Latency distributions were fitted using the Linear Approach to Threshold with Ergodic Rate model and compared with binomial logistic regression. RESULTS: There were 21 males and mean age at surgery was 71±7 years. Following CEA, the distribution of saccades initiated by the cerebral hemisphere distal to the operated artery significantly changed in 25 patients. By contrast, there were 14 significant contralateral-hemisphere saccadic changes (P<.001). Significant contralateral saccadic changes always co-occurred with significant ipsilateral changes and 10 of 14 patients with contralateral saccadic change had contralateral carotid stenosis. There was a significantly greater postoperative reduction in early saccades generated by the ipsilateral hemisphere than by the contralateral hemisphere (P<.02) CONCLUSION: CEA leads to significant hemisphere-specific subclinical changes in saccadic performance and, in particular, differentially affects the proportion of early saccades, a measure of the ability of the frontal cortex to successfully inhibit lower centers, generated by the 2 hemispheres. Saccadometry, a bedside test, provides data that can be statistically compared for individual and groups of patients. It could allow the neurological outcome of carotid surgery to be objectively quantified.

The effect of cognitive distraction on saccadic latency.

Saccadic initiation is increasingly being studied as a surrogate for more general neural mechanisms of decision-making. Visual 'decision-making' is thought to be controlled by higher cortical functions. Lower areas such as the superior colliculus are thought to be involved with more primitive optomotor reflexes that can generate short-latency saccades. It is now well established that imposition of fronto-executive load on subjects performing a saccadic task which, in particular, involves suppression of saccades (the no-go saccadic task), increases the number of errors made. It is theorised that a weakening of cortical control of the superior colliculus is responsible for the increase in error rate. One way to test this theory is to measure the latency of incorrect saccades made in a no-go saccadic task in relation to error rate under different conditions of fronto-executive load. A high error rate combined with an increased number of short-latency saccades in the range of express or early saccades would indicate that subjects have an inability to inhibit these short-latency more reflexive saccades, which seem to originate in the superior colliculus. Hence the normal cortical control of the superior colliculus is weakened. We used a saccadic go/no-go task under fronto-executive load and found that the proportion of short-latency saccades increased with audio-verbal interference, in conjunction with an increase in error rate. These findings provide strong empirical evidence to support the theory that maintenance of cortical functions is key to the control of saccadic responses. Under conditions of fronto-executive loading such cortical control is weakened, leaving subjects with a reduced ability to inhibit short-latency more reflexive saccades.

Saccadometry: a novel clinical tool for quantification of the motor effects of subthalamic nucleus stimulation in Parkinson's disease.

INTRODUCTION: High frequency stimulation of the subthalamic nucleus (STN HFS) is the therapy of choice in the surgical management of patients suffering from advanced Parkinson's disease (PD). Worldwide, more than 30,000 patients have undergone this procedure. At present, there is a need for a rapid method of assessing its therapeutic effect that is ideally also target-specific, objective, automated, quantitative, and with high overall reliability. Saccadic latency, that reflects the operation of central decision-making mechanisms, is increasingly being used as a way of obtaining quantitative, objective information about cerebral performance in general. OBJECTIVE: In this study we investigated the possible application of saccadic eye movements as a tool for assessing the therapeutic motor effects of STN HFS in patients with advanced PD. METHODS: Patients received bilateral STN HFS and were evaluated in stimulation and medication on and off conditions, together with conventional motor assessments under the same conditions. RESULTS: We found that saccadometry can provide a sensitive and objective measure of the effects of STN HFS in PD patients that correlates well with conventional, subjective, evaluation of motor impairment. The effect appears to be specific to the site of stimulation, and in terms of the LATER model appears to be due to an increase in the mean rate of rise of the underlying decision signal, combined with a degree of suppression of the mechanism responsible for the early component. INTERPRETATION: A possible interpretation of our findings is that electrical stimulation of the STN, which is known to have a powerful influence on substantia nigra pars reticulata, enhances both the descending facilitation that passes from the cortex to the colliculus via the basal ganglia, thus increasing the mean rate of rise of the decision signal, and also the tonic background inhibition that normally suppresses unwanted early responses.

Influence of history on saccade countermanding performance in humans and macaque monkeys.

The stop-signal or countermanding task probes the ability to control action by requiring subjects to withhold a planned movement in response to an infrequent stop signal which they do with variable success depending on the delay of the stop signal. We investigated whether performance of humans and macaque monkeys in a saccade countermanding task was influenced by stimulus and performance history. In spite of idiosyncrasies across subjects several trends were evident in both humans and monkeys. Response time decreased after successive trials with no stop signal. Response time increased after successive trials with a stop signal. However, post-error slowing was not observed. Increased response time was observed mainly or only after cancelled (signal inhibit) trials and not after noncancelled (signal respond) trials. These global trends were based on rapid adjustments of response time in response to momentary fluctuations in the fraction of stop signal trials. The effects of trial sequence on the probability of responding were weaker and more idiosyncratic across subjects when stop signal fraction was fixed. However, both response time and probability of responding were influenced strongly by variations in the fraction of stop signal trials. These results indicate that the race model of countermanding performance requires extension to account for these sequential dependencies and provide a basis for physiological studies of executive control of countermanding saccade performance.