Saccadic Peak Velocity Research Articles

Oculomotor assessment of diurnal arousal variations

Saccadic and pupillary responses are reliable indices of arousal decrement (e.g. fatigue), that might be exploited to improve work schedule guidelines. In this study, we tested the sensitivity of a short 30-s oculomotor test to detect diurnal arousal variations. Twelve participants (5 females, 7 males, 37.7+-11.9 years) volunteered to be assessed every hour (66+-20 min) for three consecutive working days, during their regular office-hours. We used a fully automated testing system, the FIT 2000 Fitness Impairment Tester (Pulse Medical Instruments Inc., Rockville, MD, USA), to measure and record saccadic peak velocity, pupil diameter, and latency and amplitude of the pupillary light reflex. In addition, we collected subjective levels of arousal using the Stanford Sleepiness Scale, and body core temperature. We analyzed the data using a linear mixed model approach for longitudinal data. Both saccadic velocity and subjective alertness decreased over the course of a day, while body core temperature increased (all p-values.05). The data also weakly suggested an increase of the pupil diameter (p 07). The findings support the use of oculomotor indices in the assessment of arousal and fatigue in applied settings.

O2-6-06. The role of gaze in performing the trail making test

We studied the role of gaze in performing the trail-making test (TMT) in eight normal subjects, a task frequently used to assess frontal executive function in neurological patients. TMT was presented on a touch-panel monitor placed in front of the subjects, on which they were asked to connect the presented numbers with their fingers in an ascending order (version A), or with the added task of alternately connecting between the numbers and letters in ascending and alphabetical orders (version B), respectively. The subjects’ gaze position on the monitor was recorded by a video-based eye tracking system (Eyelink 1000), as was the hand (finger) position on the touch-panel. The completion time and the total number of saccades made during the task, the amplitude, peak velocity of saccades and the interval between consecutive saccades (i.e., fixation duration) were measured. Multiple regression analysis showed that the task completion time correlated with the total number of saccades and, less prominently, with the mean fixation duration, suggesting that gaze plays an important role in performing TMT, and should be considered when using this task to assess executive function in neurological patients with eye movement disorders.

A nonlinear generalization of the Savitzky-Golay filter and the quantitative analysis of saccades.

The Savitzky-Golay (SG) filter is widely used to smooth and differentiate time series, especially biomedical data. However, time series that exhibit abrupt departures from their typical trends, such as sharp waves or steps, which are of physiological interest, tend to be oversmoothed by the SG filter. Hence, the SG filter tends to systematically underestimate physiological parameters in certain situations. This article proposes a generalization of the SG filter to more accurately track abrupt deviations in time series, leading to more accurate parameter estimates (e.g., peak velocity of saccadic eye movements). The proposed filtering methodology models a time series as the sum of two component time series: a low-frequency time series for which the conventional SG filter is well suited, and a second time series that exhibits instantaneous deviations (e.g., sharp waves, steps, or more generally, discontinuities in a higher order derivative). The generalized SG filter is then applied to the quantitative analysis of saccadic eye movements. It is demonstrated that (a) the conventional SG filter underestimates the peak velocity of saccades, especially those of small amplitude, and (b) the generalized SG filter estimates peak saccadic velocity more accurately than the conventional filter.

Attention holding elicited by direct-gaze faces is reflected in saccadic peak velocity.

Manual response times to peripherally presented targets have been reported to be greater in the presence of task-irrelevant pictorial faces at fixation which establish an eye contact with the observer. This effect is interpreted as evidence that direct-gaze faces hold attention. In three experiments, we investigated whether this attention-holding effect is also reflected in saccadic response times. Participants were asked to make a saccade towards a symbolic target that could appear rightwards or leftwards, in the presence of a task-irrelevant centrally placed face with either direct gaze or closed eyes. Unexpectedly, saccadic response times did not show any consistent response pattern as a function of whether the faces were presented with direct gaze vs. closed eyes. Interestingly, saccadic peak velocities were found to be lower in the presence of faces with direct gaze rather than closed eyes (Experiment 1). This effect emerged even in the presence of non-human primate faces (Experiment 2), and no differences between direct gaze and closed eyes emerged when the faces were presented inverted rather than upright (Experiment 3). Overall, these findings suggest that eye contact can have an impact on the saccadic generation system.

Eye tracking measures of uncertainty during perceptual decision making

Perceptual decision making involves gathering and interpreting sensory information to effectively categorize the world and inform behavior. For instance, a radiologist distinguishing the presence versus absence of a tumor, or a luggage screener categorizing objects as threatening or non-threatening. In many cases, sensory information is not sufficient to reliably disambiguate the nature of a stimulus, and resulting decisions are done under conditions of uncertainty. The present study asked whether several oculomotor metrics might prove sensitive to transient states of uncertainty during perceptual decision making. Participants viewed images with varying visual clarity and were asked to categorize them as faces or houses, and rate the certainty of their decisions, while we used eye tracking to monitor fixations, saccades, blinks, and pupil diameter. Results demonstrated that decision certainty influenced several oculomotor variables, including fixation frequency and duration, the frequency, peak velocity, and amplitude of saccades, and phasic pupil diameter. Whereas most measures tended to change linearly along with decision certainty, pupil diameter revealed more nuanced and dynamic information about the time course of perceptual decision making. Together, results demonstrate robust alterations in eye movement behavior as a function of decision certainty and attention demands, and suggest that monitoring oculomotor variables during applied task performance may prove valuable for identifying and remediating transient states of uncertainty.

Saccadic Impairments in Patients with the Norrbottnian Form of Gaucher's Disease Type 3.

Chronic neuronopathic Gaucher's disease type 3 (GD3) is relatively frequent in northern Sweden. Besides multiple other neurological symptoms, horizontal gaze palsy or oculomotor apraxia is common in GD3. To characterize the saccades in patients with Norrbottnian GD3 with respect to their neurological and cognitive status using a computer-based eye-tracking technique. Horizontal and vertical reflexive saccades as well as antisaccades of nine GD3 patients [4M/5F; 41.1 ± 11.0 years; modified severity scoring tool (mSST): 9.3 ± 5.4; Montreal Cognitive Assessment (MoCA): 24.0 ± 4.2] and age-matched controls were analyzed using EyeBrain T2, a head-mounted binocular eye tracker. Systematic clinical assessment included the mSST, a valid tool for monitoring the neurological progression in GD3 and MoCA. In Norrbottnian GD3 patients, gain, peak, and average velocity (107.5°/s ± 41.8 vs. 283.9°/s ± 17.0; p = 0.0009) of horizontal saccades were reduced compared to healthy controls (HCs). Regarding vertical saccades, only the average velocity of downward saccades was decreased (128.6°/s ± 63.4 vs. 244.1°/s ± 50.8; p = 0.004). Vertical and horizontal saccadic latencies were increased (294.3 ms ± 37.0 vs. 236.5 ms ± 22.4; p = 0.005) and the latency of horizontal reflexive saccades was correlated with the mSST score (R2 = 0.80; p = 0.003). The latency of antisaccades showed association to MoCA score (R2 = 0.70; p = 0.009). GD3 patients made more errors in the antisaccade task (41.5 ± 27.6% vs. 5.2 ± 5.8%; p = 0.005), and the error rate tended to correlate with the cognitive function measured in MoCA score (p = 0.06). The mean age of 41 years of our GD3 cohort reflects the increased life expectancy of patients in the Norrbottnian area compared to other GD3 cohorts. Marked impairment of horizontal saccades was evident in all patients, whereas vertical saccades showed distinct impairment of downward velocity. Latency of reflexive saccades was associated with the severity of neurological symptoms. Increased latency and error rate in the antisaccade task were linked to cognitive impairment. The assessment of saccades provides markers for neurological and neuropsychological involvement in Norrbottnian GD3.

Caffeine increases the velocity of rapid eye movements in unfatigued humans.

Caffeine is a widely used dietary stimulant that can reverse the effects of fatigue on cognitive, motor and oculomotor function. However, few studies have examined the effect of caffeine on the oculomotor system when homeostasis has not been disrupted by physical fatigue. This study examined the influence of a moderate dose of caffeine on oculomotor control and visual perception in participants who were not fatigued. Within a placebo-controlled crossover design, 13 healthy adults ingested caffeine (5mg·kg-1 body mass) and were tested over 3h. Eye movements, including saccades, smooth pursuit and optokinetic nystagmus, were measured using infrared oculography. Caffeine was associated with higher peak saccade velocities (472±60° s-1) compared to placebo (455±62° s-1). Quick phases of optokinetic nystagmus were also significantly faster with caffeine, whereas pursuit eye movements were unchanged. Non-oculomotor perceptual tasks (global motion and global orientation processing) were unaffected by caffeine. These results show that oculomotor control is modulated by a moderate dose of caffeine in unfatigued humans. These effects are detectable in the kinematics of rapid eye movements, whereas pursuit eye movements and visual perception are unaffected. Oculomotor functions may be sensitive to changes in central catecholamines mediated via caffeine's action as an adenosine antagonist, even when participants are not fatigued.

Using endogenous saccades to characterize fatigue in multiple sclerosis

PurposeMultiple Sclerosis (MS) is likely to cause dysfunction of neural circuits between brain regions increasing brain working load or a subjective overestimation of such working load leading to fatigue symptoms. The aim of this study was to investigate if saccades can reveal the effect of fatigue in patients with MS. MethodsPatients diagnosed with MS (EDSS<=3) and age matched controls were recruited. Eye movements were monitored using an infrared eyetracker. Each participant performed 40 trials in an endogenous generated saccade paradigm (valid and invalid trials). The fatigue severity scale (FSS) was used to assess the severity of fatigue. FSS scores were used to define two subgroups, the MS fatigue group (score above normal range) and the MS non-fatigue. Differences between groups were tested using linear mixed models. ResultsThirty-one MS patients and equal number of controls participated in this study. FSS scores were above the normal range in 11 patients. Differences in saccade latency were found according to group (p<0.001) and trial validity (p=0.023). Differences were 16.9ms, between MS fatigue and MS non-fatigue, 15.5ms between MS fatigue and control. The mean difference between valid and invalid trials was 7.5ms. Differences in saccade peak velocity were found according to group (p<0.001), the difference between MS fatigue and control was 22.3°/s and between MS fatigue and non-fatigue was 12.3°/s. Group was a statistically significant predictor for amplitude (p<0.001). FSS scores were correlated with peak velocity (p=0.028) and amplitude (p=0.019). ConclusionConsistent with the initial hypothesis, our study revealed altered saccade latency, peak velocity and amplitude in patients with fatigue symptoms. Eye movement testing can complement the standard inventories when investigating fatigue because they do not share similar limitations. Our findings contribute to the understanding of functional changes induced by MS and might be useful for clinical trials and treatment decisions.

The effect of sampling rate and lowpass filters on saccades - A modeling approach.

The study of eye movements has become popular in many fields of science. However, using the preprocessed output of an eye tracker without scrutiny can lead to low-quality or even erroneous data. For example, the sampling rate of the eye tracker influences saccadic peak velocity, while inadequate filters fail to suppress noise or introduce artifacts. Despite previously published guiding values, most filter choices still seem motivated by a trial-and-error approach, and a thorough analysis of filter effects is missing. Therefore, we developed a simple and easy-to-use saccade model that incorporates measured amplitude-velocity main sequences and produces saccades with a similar frequency content to real saccades. We also derived a velocity divergence measure to rate deviations between velocity profiles. In total, we simulated 155 saccades ranging from 0.5° to 60° and subjected them to different sampling rates, noise compositions, and various filter settings. The final goal was to compile a list with the best filter settings for each of these conditions. Replicating previous findings, we observed reduced peak velocities at lower sampling rates. However, this effect was highly non-linear over amplitudes and increasingly stronger for smaller saccades. Interpolating the data to a higher sampling rate significantly reduced this effect. We hope that our model and the velocity divergence measure will be used to provide a quickly accessible ground truth without the need for recording and manually labeling saccades. The comprehensive list of filters allows one to choose the correct filter for analyzing saccade data without resorting to trial-and-error methods.

Asymmetry in visual information processing depends on the strength of eye dominance

Unlike handedness, sighting eye dominance, defined as the eye unconsciously chosen when performing monocular tasks, is very rarely considered in studies investigating cerebral asymmetries. We previously showed that sighting eye dominance has an influence on visually triggered manual action with shorter reaction time (RT) when the stimulus appears in the contralateral visual hemifield with respect to the dominant eye (Chaumillon et al. 2014). We also suggested that eye dominance may be more or less pronounced depending on individuals and that this eye dominance strength could be evaluated through saccadic peak velocity analysis in binocular recordings (Vergilino-Perez et al. 2012). Based on these two previous studies, we further examine here whether the strength of the eye dominance can modulate the influence of this lateralization on manual reaction time. Results revealed that participants categorized as having a strong eye dominance, but not those categorized as having a weak eye dominance, exhibited the difference in RT between the two visual hemifields. This present study reinforces that the analysis of saccade peak velocity in binocular recordings provides an effective tool to better categorize the eye dominance. It also shows that the influence of eye dominance in visuo-motor tasks depends on its strength. Our study also highlights the importance of considering the strength of eye dominance in future studies dealing with brain lateralization.

Pharmacokinetics and pharmacodynamics of a new highly concentrated intranasal midazolam formulation for conscious sedation.

To evaluate the pharmacokinetics, pharmacodynamics, nasal tolerance and effects on sedation of a highly concentrated aqueous intranasal midazolam formulation (Nazolam) and to compare these to intravenous midazolam. In this four-way crossover, double-blind, double-dummy, randomized, placebo-controlled study, 16 subjects received 2.5mg Nazolam, 5.0mg Nazolam, 2.5mg intravenous midazolam or placebo on different occasions. Pharmacokinetics of midazolam and α-hydroxy-midazolam were characterized and related to outcome variables for sedation (saccadic peak velocity, the Bond and Lader visual analogue scale for sedation, the simple reaction time task and the observer's assessment of alertness/sedation). Nasal tolerance was evaluated through subject reporting, and ear, nose and throat examination. Nazolam bioavailability was 75%. Maximal plasma concentrations of 31ngml-1 (CV, 42.3%) were reached after 11min (2.5mg Nazolam), and of 66ngml-1 (coefficient of variability, 31.5%) after 14min (5.0mg Nazolam). Nazolam displayed a significant effect on OAA/S scores. Sedation onset (based on SPV change) occurred 1±0.7min after administration of 2.5mg intravenous midazolam, 7±4.4min after 2.5mg Nazolam, and 4±1.8min after 5mg Nazolam. Sedation duration was 118±95.6min for 2.5mg intravenous midazolam, 76±80.4min for 2.5mg Nazolam, and 145±104.9min for 5.0mg Nazolam. Nazolam did not lead to nasal mucosa damage. This study demonstrates the nasal tolerance, safety and efficacy of Nazolam. When considering the preparation time needed for obtaining venous access, conscious sedation can be achieved in the same time span as needed for intravenous midazolam. Nazolam may offer important advantages in conscious sedation.

Saccadic and Postsaccadic Disconjugacy in Zebrafish Larvae Suggests Independent Eye Movement Control.

Spontaneous eye movements of zebrafish larvae in the dark consist of centrifugal saccades that move the eyes from a central to an eccentric position and postsaccadic centripetal drifts. In a previous study, we showed that the fitted single-exponential time constants of the postsaccadic drifts are longer in the temporal-to-nasal (T->N) direction than in the nasal-to-temporal (N->T) direction. In the present study, we further report that saccadic peak velocities are higher and saccadic amplitudes are larger in the N->T direction than in the T->N direction. We investigated the underlying mechanism of this ocular disconjugacy in the dark with a top-down approach. A mathematic ocular motor model, including an eye plant, a set of burst neurons and a velocity-to-position neural integrator (VPNI), was built to simulate the typical larval eye movements in the dark. The modeling parameters, such as VPNI time constants, neural impulse signals generated by the burst neurons and time constants of the eye plant, were iteratively adjusted to fit the average saccadic eye movement. These simulations suggest that four pools of burst neurons and four pools of VPNIs are needed to explain the disconjugate eye movements in our results. A premotor mechanism controls the synchronous timing of binocular saccades, but the pools of burst and integrator neurons in zebrafish larvae seem to be different (and maybe separate) for both eyes and horizontal directions, which leads to the observed ocular disconjugacies during saccades and postsaccadic drifts in the dark.

Effects of a single, oral 60 mg caffeine dose on attention in healthy adult subjects.

Caffeine induces positive effects on sustained attention, although studies assessing the acute effects of low caffeine dose (<75 mg) on sustained attention are limited and use short-term tests. Therefore, we investigated the acute effects of a 60 mg dose of caffeine on sustained attention in tests lasting up to 45 minutes using 82 low or non-caffeine-consuming healthy male ( n=41) and female ( n=41) adults aged between 40 and 60 years. Vigilance was measured using Mackworth Clock test, Rapid Visual Information Processing Test, adaptive tracking test, saccadic eye movement and attention switch test. Effects on mood and fatigue were analysed using Bond and Lader and Caffeine Research visual analogue scales, and Samn-Perelli questionnaire. Saliva sampling was performed for both compliance and caffeine pharmacokinetic analysis. Administration of a 60 mg caffeine dose resulted in a significant improvement in sustained attention compared with the placebo. Also a significantly improved peak saccadic velocity and reaction time performance was found, and decreased error rate. Significantly increased feelings of alertness, contentment and overall mood after caffeine treatment compared with placebo were observed. This study demonstrated that in healthy adult subjects oral administration of a single 60 mg caffeine dose elicited a clear enhancement of sustained attention and alertness, measured both in multiple objective performances and in subjective scales.

Saccadic Velocity in the New Suppression Head Impulse Test: A New Indicator of Horizontal Vestibular Canal Paresis and of Vestibular Compensation.

To determine whether saccadic velocity in the suppression head impulse paradigm (SHIMP) test is a reliable indicator of vestibular loss at the acute and at the chronic stage in patients suffering from different vestibular pathologies. Thirty-five normal subjects and 57 patients suffering from different vestibular pathologies associated with unilateral vestibular loss (UVL) or bilateral vestibular loss (BVL) were tested in the SHIMPs paradigm. SHIMPs were performed by turning the head 10 times at high velocities to the left or right side, respectively. The patients were instructed to fixate on a red spot generated by a head-fixed laser projected on the wall. In this SHIMPs paradigm, healthy subjects made a large anti-compensatory saccade at the end of the head turn (a SHIMP saccade). The peak saccadic velocity, the percentage of the trials completed with saccades in 10 trials, and the latency of the saccades were quantified in each group. A video-head impulse test (v-HIT) was systematically performed in all of our subjects as well as a caloric test. The dizziness handicap inventory questionnaire was also given to chronic UVL and BVL patients. At the acute stage after a complete UVL, patients had zero or a few anti-compensatory saccades for low velocity head turns toward the lesioned side. These saccades had lower velocity than the anti-compensatory saccades recorded during head rotation toward the intact side and/or compared with the saccades measured in control subjects. At the chronic stage, some of the patients recovered the ability to perform SHIMP saccades at each head turn toward the lesioned side, but very often these saccades were of significantly lower velocity. In BVL patients, no anti-compensatory saccades, or only significantly smaller ones, could be detected for head turns to both sides. SHIMP is a specific and sensitive test to detect a complete horizontal canal loss at the acute stage. In addition, it reflects the ability of patients with moderate horizontal vestibulo-ocular reflex gain decrease to generate anti-compensatory saccades in the chronic stage. In association with v-HIT, it allows determination of the residual vestibular function and to detect anti-compensatory saccades.

The pupil is faster than the corneal reflection (CR): Are video based pupil-CR eye trackers suitable for studying detailed dynamics of eye movements?

Most modern video eye trackers use the p-CR (pupil minus CR) technique to deal with small relative movements between the eye tracker camera and the eye. We question whether the p-CR technique is appropriate to investigate saccade dynamics. In two experiments we investigated the dynamics of pupil, CR and gaze signals obtained from a standard SMI Hi-Speed eye tracker. We found many differences between the pupil and the CR signals. Differences concern timing of the saccade onset, saccade peak velocity and post-saccadic oscillation (PSO). We also obtained that pupil peak velocities were higher than CR peak velocities. Saccades in the eye trackers’ gaze signal (that is constructed from p-CR) appear to be excessive versions of saccades in the pupil signal. We conclude that the pupil-CR technique is not suitable for studying detailed dynamics of eye movements.

Pharmacological interactions between brivaracetam and ethanol in healthy males.

This double-blind, randomized, three-way crossover study explored the potential pharmacokinetic and pharmacodynamic interactions between ethanol and brivaracetam in 18 healthy males, as required for the development of CNS-active drugs. Subjects received (A) ethanol+brivaracetam, (B) ethanol placebo+brivaracetam and (C) ethanol+brivaracetam placebo. Ethanol was infused as a 5.5-hour intravenous clamp with the first 0.5-hour as loading phase to a target level of 0.6 g/L, and brivaracetam was orally administered as a single 200 mg dose. No relevant pharmacokinetic interactions were observed. Co-administration of brivaracetam and ethanol resulted in decreased saccadic peak velocity, smooth pursuit, adaptive tracking and VAS alertness, and increased body sway, saccadic reaction time and VAS score for ethanol effect compared with brivaracetam alone or ethanol alone. Additionally, the immediate word recall scores were generally lower when brivaracetam was co-administered with ethanol, whereas the delayed word test did not show clear additional effects. A post-hoc exploratory analysis for supra-additivity suggested that most pharmacodynamic effects were likely to be additive in nature, except for adaptive tracking, which appeared to be slightly supra-additive. In conclusion, brivaracetam increased ethanol effects on psychomotor function, attention and memory in healthy males. Intake of brivaracetam with alcohol is not recommended.

Correlation Between Peak Velocity of Saccades and Susceptibility to Motion Blur

A major problem in the subjective evaluation of TV image quality is individual variability among viewers. If observers are not carefully selected for viewing studies, large individual differences in the susceptibility to image blurring result in imprecise evaluations and loss of power to detect statistically significant differences between experimental conditions. In assessments of the picture quality of traditional television, which has a narrow field of view (FOV), observers’ visual acuity (VA) should be screened before the subjective evaluations. For emerging TV systems with wide FOV (Ultra-High-Definition TV: UHDTV), in which objects move quickly relative to the display frame, it is unclear whether screening viewers’ VA is sufficient for selecting viewers to subjectively evaluate moving picture quality or sharpness. Here, we evaluated saccadic eye movement parameters to identify adequate methods to screen participants for studies evaluating UHDTV motion image quality. Each participant's evaluation of two moving pictures were highly correlated, suggesting that participants evaluated sharpness consistently. A significant correlation was observed between the average subjective evaluation score and the peak saccade velocity, but not the VA of each participant. We conclude that each participant has a certain susceptibility to image blur when evaluating moving pictures, and that this susceptibility correlates with the participant's peak saccade velocity. Thus, the objective measure of peak saccade velocity can be used to screen participants for motion picture evaluation studies.

Rapid number naming in chronic concussion: eye movements in the King-Devick test.

ObjectiveThe King–Devick (KD) test, which is based on rapid number naming speed, is a performance measure that adds vision and eye movement assessments to sideline concussion testing. We performed a laboratory‐based study to characterize ocular motor behavior during the KD test in a patient cohort with chronic concussion to identify features associated with prolonged KD reading times.MethodsTwenty‐five patients with a concussion history (mean age: 31) were compared to control participants with no concussion history (n = 42, mean age: 32). Participants performed a computerized KD test under infrared‐based video‐oculography.ResultsAverage intersaccadic intervals for task‐specific saccades were significantly longer among concussed patients compared to controls (324.4 ± 85.6 msec vs. 286.1 ± 49.7 msec, P = 0.027). Digitized KD reading times were prolonged in concussed participants versus controls (53.43 ± 14.04 sec vs. 43.80 ± 8.55 sec, P = 0.004) and were highly correlated with intersaccadic intervals. Concussion was also associated with a greater number of saccades during number reading and larger average deviations of saccade endpoint distances from the centers of the to‐be‐read numbers (1.22 ± 0.29° vs. 0.98 ± 0.27°, P = 0.002). There were no differences in saccade peak velocity, duration, or amplitude.InterpretationProlonged intersaccadic intervals, greater numbers of saccades, and larger deviations of saccade endpoints underlie prolonged KD reading times in chronic concussion. The KD test relies upon a diffuse neurocognitive network that mediates the fine control of efferent visual function. One sequela of chronic concussion may be disruption of this system, which may produce deficits in spatial target selection and planning of eye movements.

Reward sensitivity deficits modulated by dopamine are associated with apathy in Parkinson's disease.

Apathy is a debilitating and under-recognized condition that has a significant impact in many neurodegenerative disorders. In Parkinson's disease, it is now known to contribute to worse outcomes and a reduced quality of life for patients and carers, adding to health costs and extending disease burden. However, despite its clinical importance, there remains limited understanding of mechanisms underlying apathy. Here we investigated if insensitivity to reward might be a contributory factor and examined how this relates to severity of clinical symptoms. To do this we created novel ocular measures that indexed motivation level using pupillary and saccadic response to monetary incentives, allowing reward sensitivity to be evaluated objectively. This approach was tested in 40 patients with Parkinson's disease, 31 elderly age-matched control participants and 20 young healthy volunteers. Thirty patients were examined ON and OFF their dopaminergic medication in two counterbalanced sessions, so that the effect of dopamine on reward sensitivity could be assessed. Pupillary dilation to increasing levels of monetary reward on offer provided quantifiable metrics of motivation in healthy subjects as well as patients. Moreover, pupillary reward sensitivity declined with age. In Parkinson's disease, reduced pupillary modulation by incentives was predictive of apathy severity, and independent of motor impairment and autonomic dysfunction as assessed using overnight heart rate variability measures. Reward sensitivity was further modulated by dopaminergic state, with blunted sensitivity when patients were OFF dopaminergic drugs, both in pupillary response and saccadic peak velocity response to reward. These findings suggest that reward insensitivity may be a contributory mechanism to apathy and provide potential new clinical measures for improved diagnosis and monitoring of apathy.media-1vid110.1093/brain/aww188_video_abstractaww188_video_abstract.

Model-based exposure-response analysis to quantify age related differences in the response to scopolamine in healthy subjects.

Subjects with increasing age are more sensitive to the effects of the anti-muscarinic agent scopolamine, which is used (among other indications) to induce temporary cognitive dysfunction in early phase drug studies with cognition enhancing compounds. The enhanced sensitivity has always been attributed to incipient cholinergic neuronal dysfunction, as a part of the normal aging process. The aim of the study was to correlate age-dependent pharmacodynamic neuro-physiologic effects of scopolamine after correcting for differences in individual exposure. We applied a pharmacokinetic and pharmacodynamic modelling approach to describe individual exposure and neurocognitive effects of intravenous scopolamine administration in healthy subjects. A two-compartment linear kinetics model best described the plasma concentrations of scopolamine. The estimated scopolamine population mean apparent central and peripheral volume of distribution was 2.66 ± 1.050l and 62.10 ± 10.100l, respectively and the clearance was 1.09 ± 0.096lmin(-1) . Age was not related to a decrease of performance in the tests following scopolamine administration in older subjects. Only the saccadic peak velocity showed a positive correlation between age and sensitivity to scopolamine. Age was, however, correlated at baseline with an estimated slower reaction time while performing the cognitive tests and to higher global δ and frontal θ frequency bands measured with the surface EEG. Most of the differences in response to scopolamine administration between young and older subjects could be explained by pharmacokinetic differences (lower clearance) and not to an enhanced sensitivity when corrected for exposure levels.