The effects of pramipexole on motivational vigour during a saccade task: a placebo-controlled study in healthy adults.

Motivation allows us to energise actions when we expect reward and is reduced in depression. This effect, termed motivational vigour, has been proposed to rely on central dopamine, with dopaminergic agents showing promise in the treatment of depression. This suggests that dopaminergic agents might act to reduce depression by increasing the effects of reward or by helping energise actions. The aim of the current study was to investigate whether the dopamine agonist pramipexole enhanced motivational vigour during a rewarded saccade task. In addition, we asked whether the effects of pramipexole on vigour differ between reward contingent on performance and guaranteed reward. Healthy adult participants were randomised to receive either pramipexole (n = 19) or placebo (controls n = 18) for 18 days. The vigour of saccades was measured twice, once before the administration of study medication (Time 1) and after taking it for 12-15 days (Time 2). To separate motivation by contingency vs. reward, saccadic vigour was separately measured when (1) rewards were contingent on performance (2) delivered randomly with matched frequency, (3) when reward was guaranteed, (4) when reward was not present at all. Motivation increased response vigour, as expected. Relative to placebo, pramipexole also increased response vigour. However, there was no interaction, meaning that the effects of reward were not modulated by drug, and there was no differential drug effect on contingent vs. guaranteed rewards. The effect of pramipexole on vigour could not be explained by a speed/accuracy trade-off, nor by autonomic arousal as indexed by pupillary dilation. Chronic D2 stimulation increases general vigour, energising movements in healthy adults irrespective of extrinsic reward.

Ketamine disrupts gaze patterns during face viewing in the common marmoset.

Faces are stimuli of critical importance for primates. The common marmoset (Callithrix jacchus) is a promising model for investigations of face processing, as this species possesses oculomotor and face-processing networks resembling those of macaques and humans. Face processing is often disrupted in neuropsychiatric conditions such as schizophrenia (SZ), and thus, it is important to recapitulate underlying circuitry dysfunction preclinically. The N-methyl-d-aspartate (NMDA) noncompetitive antagonist ketamine has been used extensively to model the cognitive symptoms of SZ. Here, we investigated the effects of a subanesthetic dose of ketamine on oculomotor behavior in marmosets during face viewing. Four marmosets received systemic ketamine or saline injections while viewing phase-scrambled or intact videos of conspecifics' faces. To evaluate effects of ketamine on scan paths during face viewing, we identified regions of interest in each face video and classified locations of saccade onsets and landing positions within these areas. A preference for the snout over eye regions was observed following ketamine administration. In addition, regions in which saccades landed could be significantly predicted by saccade onset region in the saline but not the ketamine condition. Effects on saccade control were limited to an increase in saccade peak velocity in all conditions and a reduction in saccade amplitudes during viewing of scrambled videos. Thus, ketamine induced a significant disruption of scan paths during viewing of conspecific faces but limited effects on saccade motor control. These findings support the use of ketamine in marmosets for investigating changes in neural circuits underlying social cognition in neuropsychiatric disorders.NEW & NOTEWORTHY Face processing, an important social cognitive ability, is impaired in neuropsychiatric conditions such as schizophrenia. The highly social common marmoset model presents an opportunity to investigate these impairments. We administered subanesthetic doses of ketamine to marmosets to model the cognitive symptoms of schizophrenia. We observed a disruption of scan paths during viewing of conspecifics' faces. These findings support the use of ketamine in marmosets as a model for investigating social cognition in neuropsychiatric disorders.

Bilateral control of interceptive saccades: evidence from the ipsipulsion of vertical saccades after caudal fastigial inactivation.

The caudal fastigial nuclei (cFN) are the output nuclei by which the medio-posterior cerebellum influences the production of saccades toward a visual target. On the basis of the organization of their efferences to the premotor burst neurons and the bilateral control of saccades, the hypothesis was proposed that the same unbalanced activity accounts for the dysmetria of all saccades during cFN unilateral inactivation, regardless of whether the saccade is horizontal, oblique, or vertical. We further tested this hypothesis by studying, in two head-restrained macaques, the effects of unilaterally inactivating the caudal fastigial nucleus on saccades toward a target moving vertically with a constant, increasing or decreasing speed. After local muscimol injection, vertical saccades were deviated horizontally toward the injected side with a magnitude that increased with saccade size. The ipsipulsion indeed depended on the tested target speed but not its instantaneous value because it did not increase (decrease) when the target accelerated (decelerated). By subtracting the effect on contralesional horizontal saccades from the effect on ipsilesional ones, we found that the net bilateral effect on horizontal saccades was strongly correlated with the effect on vertical saccades. We explain how this correlation corroborates the bilateral hypothesis and provide arguments against the suggestion that the instantaneous saccade velocity would somehow be "encoded" by the discharge of Purkinje cells in the oculomotor vermis.NEW & NOTEWORTHY Besides causing dysmetric horizontal saccades, unilateral inactivation of caudal fastigial nucleus causes an ipsipulsion of vertical saccades. This study is the first to quantitatively describe this ipsipulsion during saccades toward a moving target. By subtracting the effects on contralesional (hypometric) and ipsilesional (hypermetric) horizontal saccades, we find that this net bilateral effect is strongly correlated with the ipsipulsion of vertical saccades, corroborating the suggestion that a common disorder affects all saccades.

Contribution of Ionotropic Glutamatergic Receptors to Excitability and Attentional Signals in Macaque Frontal Eye Field.

Top-down attention, controlled by frontal cortical areas, is a key component of cognitive operations. How different neurotransmitters and neuromodulators flexibly change the cellular and network interactions with attention demands remains poorly understood. While acetylcholine and dopamine are critically involved, glutamatergic receptors have been proposed to play important roles. To understand their contribution to attentional signals, we investigated how ionotropic glutamatergic receptors in the frontal eye field (FEF) of male macaques contribute to neuronal excitability and attentional control signals in different cell types. Broad-spiking and narrow-spiking cells both required N-methyl-D-aspartic acid and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation for normal excitability, thereby affecting ongoing or stimulus-driven activity. However, attentional control signals were not dependent on either glutamatergic receptor type in broad- or narrow-spiking cells. A further subdivision of cell types into different functional types using cluster-analysis based on spike waveforms and spiking characteristics did not change the conclusions. This can be explained by a model where local blockade of specific ionotropic receptors is compensated by cell embedding in large-scale networks. It sets the glutamatergic system apart from the cholinergic system in FEF and demonstrates that a reduction in excitability is not sufficient to induce a reduction in attentional control signals.

Environment-based object values learned by local network in the striatum tail.

Basal ganglia contribute to object-value learning, which is critical for survival. The underlying neuronal mechanism is the association of each object with its rewarding outcome. However, object values may change in different environments and we then need to choose different objects accordingly. The mechanism of this environment-based value learning is unknown. To address this question, we created an environment-based value task in which the value of each object was reversed depending on the two scene-environments (X and Y). After experiencing this task repeatedly, the monkeys became able to switch the choice of object when the scene-environment changed unexpectedly. When we blocked the inhibitory input from fast-spiking interneurons (FSIs) to medium spiny projection neurons (MSNs) in the striatum tail by locally injecting IEM-1460, the monkeys became unable to learn scene-selective object values. We then studied the mechanism of the FSI-MSN connection. Before and during this learning, FSIs responded to the scenes selectively, but were insensitive to object values. In contrast, MSNs became able to discriminate the objects (i.e., stronger response to good objects), but this occurred clearly in one of the two scenes (X or Y). This was caused by the scene-selective inhibition by FSI. As a whole, MSNs were divided into two groups that were sensitive to object values in scene X or in scene Y. These data indicate that the local network of striatum tail controls the learning of object values that are selective to the scene-environment. This mechanism may support our flexible switching behavior in various environments.

Ketamine reduces temporal expectation in the rhesus monkey.

RATIONALE: Ketamine, a well-known general dissociative anesthetic agent that is a non-competitive antagonist of the N-methyl-D-aspartate receptor, perturbs the perception of elapsed time and the expectation of upcoming events. OBJECTIVE: The objective of this study was to determine the influence of ketamine on temporal expectation in the rhesus monkey. METHODS: Two rhesus monkeys were trained to make a saccade between a central warning stimulus and an eccentric visual target that served as imperative stimulus. The delay between the warning and the imperative stimulus could take one of four different values randomly with the same probability (variable foreperiod paradigm). During experimental sessions, a subanesthetic low dose of ketamine (0.25-0.35 mg/kg) was injected i.m. and the influence of the drug on movement latency was measured. RESULTS: We found that in the control conditions, saccadic latencies strongly decreased with elapsed time before the appearance of the visual target showing that temporal expectation built up during the delay period between the warning and the imperative stimulus. However, after ketamine injection, temporal expectation was significantly reduced in both subjects. In addition, ketamine also increased average movement latency but this effect could be dissociated from the reduction of temporal expectation. CONCLUSION: In conclusion, a subanesthetic dose of ketamine could have two independent effects: increasing reaction time and decreasing temporal expectation. This alteration of temporal expectation could explain cognitive deficits observed during ketamine use.

Effects of lorazepam on prosaccades and saccadic adaptation.

BACKGROUND: Benzodiazepines have reliable adverse effects on saccadic eye movements, but the impact of sex as a potential modulator of these effects is less clear. A recent study reported stronger adverse effects on the spatial consistency of saccades in females, which may reflect sex differences in cerebellar mechanisms. AIMS: We aimed to further examine the role of sex as a potential modulator of benzodiazepine effects by employing the saccadic adaptation paradigm, which is known to be sensitive to cerebellar functioning. METHODS: A total of n=50 healthy adults performed a horizontal step prosaccade task and a saccadic adaptation task under 0.5 mg lorazepam, 1 mg lorazepam and placebo in a double-blind, within-subjects design. RESULTS: In the prosaccade task, lorazepam had adverse effects on measures of peak velocity, latency and spatial consistency. The administration of 0.5 mg lorazepam led to significant reductions in gain-decrease adaptation, while a dose of 1 mg did not impair adaptation learning. Gain-increase adaptation was generally less pronounced, and unaffected by the drug. There were no significant drug×sex interactions in either task. CONCLUSIONS: We conclude that a low dose of lorazepam impairs gain-decrease adaptation independent of sex. At higher doses, however, increasing fatigue may facilitate adaptation and thus counteract the adverse effects observed at lower doses. With regards to prosaccades, our findings confirm peak velocity as well as latency and spatial measures as sensitive biomarkers of GABAergic effects.

Dopamine promotes instrumental motivation, but reduces reward-related vigour.

We can be motivated when reward depends on performance, or merely by the prospect of a guaranteed reward. Performance-dependent (contingent) reward is instrumental, relying on an internal action-outcome model, whereas motivation by guaranteed reward may minimise opportunity cost in reward-rich environments. Competing theories propose that each type of motivation should be dependent on dopaminergic activity. We contrasted these two types of motivation with a rewarded saccade task, in patients with Parkinson's disease (PD). When PD patients were ON dopamine, they had greater response vigour (peak saccadic velocity residuals) for contingent rewards, whereas when PD patients were OFF medication, they had greater vigour for guaranteed rewards. These results support the view that reward expectation and contingency drive distinct motivational processes, and can be dissociated by manipulating dopaminergic activity. We posit that dopamine promotes goal-directed motivation, but dampens reward-driven vigour, contradictory to the prediction that increased tonic dopamine amplifies reward expectation.

The Contribution of AMPA and NMDA Receptors to Persistent Firing in the Dorsolateral Prefrontal Cortex in Working Memory.

Many tasks demand that information is kept online for a few seconds before it is used to guide behavior. The information is kept in working memory as the persistent firing of neurons encoding the memorized information. The neural mechanisms responsible for persistent activity are not yet well understood. Theories attribute an important role to ionotropic glutamate receptors, and it has been suggested that NMDARs are particularly important for persistent firing because they exhibit long time constants. Ionotropic AMPARs have shorter time constants and have been suggested to play a smaller role in working memory. Here we compared the contribution of AMPARs and NMDARs to persistent firing in the dlPFC of male macaque monkeys performing a delayed saccade to a memorized spatial location. We used iontophoresis to eject small amounts of glutamate receptor antagonists, aiming to perturb, but not abolish, neuronal activity. We found that both AMPARs and NMDARs contributed to persistent activity. Blockers of the NMDARs decreased persistent firing associated with the memory of the neuron's preferred spatial location but had comparatively little effect on the representation of the antipreferred location. They therefore decreased the information conveyed by persistent firing about the memorized location. In contrast, AMPAR blockers decreased activity elicited by the memory of both the preferred and antipreferred location, with a smaller effect on the information conveyed by persistent activity. Our results provide new insights into the contribution of AMPARs and NMDARs to persistent activity during working memory tasks.SIGNIFICANCE STATEMENT Working memory enables us to hold on to information that is no longer available to the senses. It relies on the persistent activity of neurons that code for the memorized information, but the detailed mechanisms are not yet well understood. Here we investigated the role of NMDARs and AMPARs in working memory using iontophoresis of antagonists in the PFC of monkeys remembering the location of a visual stimulus for an eye movement response. AMPARs and NMDARs both contributed to persistent activity. NMDAR blockers mostly decreased persistent firing associated with the memory of the neuron's preferred spatial location, whereas AMPAR blockers caused a more general suppression. These results provide new insight into the contribution of AMPARs and NMDARs to working memory.

Clinical pharmacology of the dual orexin receptor antagonist ACT-541468 in elderly subjects: Exploration of pharmacokinetics, pharmacodynamics and tolerability following single-dose morning and repeated-dose evening administration.

BACKGROUND: The dual orexin receptor antagonist ACT-541468 showed sedative pharmacodynamic effects during initial clinical testing in adult subjects. The present study explored pharmacokinetics, pharmacodynamics and tolerability in healthy elderly subjects. METHODS: Double-blind, placebo-controlled, randomised, single-ascending dose study in 24 male/female elderly (65-80 years, 5, 15 and 25 mg in the morning, 6/2 active/placebo per group). Additionally, 10 subjects (8/2 active/placebo) received 25 mg for 7 days in the evening. Pharmacokinetics, pharmacodynamics (saccadic peak velocity, adaptive tracking, body sway, visual analogue scales according to Bowdle and Bond and Lader, Karolinska Sleepiness Scale) and tolerability were assessed. In particular, pharmacodynamics results are to be interpreted exploratorily. RESULTS: Absorption was quick with a median time to maximum concentration of ∼ 1.0 h. The mean elimination half-life was 8.5-9.8 h, the area under the curve and the maximum plasma concentration increased proportionally with dose. Following repeated evening administration of 25 mg, minimal accumulation was observed. There were no pharmacodynamic effects at 5 mg. At 15 mg, saccadic peak velocity (degree/s; SD) was reduced (69; 38), while other variables showed no effects. At 25 mg, effects on all objective pharmacodynamic parameters were observed. At 8-12 h post-dose, there were no differences to placebo and no next-day effects on pharmacodynamic variables after evening administration. Elderly subjects reported fewer adverse events compared to adults in previous studies. CONCLUSION: ACT-541468 in elderly subjects was well tolerated and pharmacokinetics and pharmacodynamics are compatible with a drug for the treatment of insomnia. Clinicaltrials.gov: NCT02571855.

Rituximab improves not only back stiffness but also "stiff eyes" in stiff person syndrome: Implications for immune-mediated treatment.

OBJECTIVE: Stiff person syndrome (SPS) is usually characterized by truncal muscle rigidity and episodic painful spasms, but it sometimes appears with ocular symptoms called "stiff eyes". We recorded saccade movements in an SPS patient manifesting with "stiff eyes" conditions with slow saccade velocity and evaluated the effect of immunotherapy including rituximab on saccade parameters. METHODS: We repeatedly conducted saccade eye recordings using video-based eye tracking system on a 42-year-old male SPS patient with slow saccade. The velocity and onset latency of visual guided saccades (VGS) were measured at each recording. Because VGS velocity is affected by saccade amplitude, estimated peak velocity (Vmax) was also calculated by taking the relationship between the velocity and the amplitude of saccade into account. RESULTS: The mean VGS velocity improved significantly after two courses of rituximab administration compared with its lowest value. The estimated Vmax decreased as the clinical manifestations worsened, but it increased after rituximab administration. Other neurological symptoms in this patient such as muscle rigidity and gait instability also improved after the treatment. CONCLUSION: Slow saccade in a "stiff eyes" patient improved after rituximab administration. Our study also indicated that the saccade eye recording is useful for evaluating the clinical condition of SPS when it is complicated with ocular symptoms.

The effect of high vs. low dose lurasidone on eye movement biomarkers of prefrontal abilities in treatment-resistant schizophrenia.

OBJECTIVE: Eye movement (EM) measures can serve as biomarkers to evaluate pharmacological effects on brain systems involved in cognition. In recent onset schizophrenia, antipsychotic treatment can improve attentional control on the antisaccade task and exacerbate working memory impairment on the memory guided saccade task; effects in treatment-resistant schizophrenia (TRS) are less clear. This study evaluated the effects of high versus low dose lurasidone on EM performance in TRS. METHODS: TRS patients completed EM testing: 1) at baseline, on existing medication regimen (n = 42), 2) after 6 weeks of low dose (80 mg) lurasidone (n = 38), 3) after 12 weeks following randomization to low (80 mg) or high dose (240 mg) lurasidone (n = 27), and 4) after 24 weeks of treatment (n = 23). EM testing included prosaccade, antisaccade, and memory guided saccade tasks. RESULTS: Six weeks of lurasidone resulted in increased prosaccade saccade latency and reduced antisaccade errors, with no change in memory guided saccade accuracy. After randomization, prosaccade and antisaccade latencies increased in only the high dose group, with no change in antisaccade errors in both groups. Memory guided saccade error increased in the high dose group and remained stable in the low dose group. CONCLUSION: Among TRS, stabilization on low dose lurasidone was associated with improved executive control of attention reflected by reduced antisaccade errors. High dose lurasidone resulted in prolonged speed of reflexive and executive shifts of attention and reduced spatial working memory relative to low dose. These findings indicate that EM measures are helpful biomarkers of dose-dependent antipsychotic treatment effects on executive cognitive abilities in TRS.

Microinjectrode System for Combined Drug Infusion and Electrophysiology.

This microinjectrode system is designed for drug infusion, electrophysiology, and delivery and retrieval of experimental probes, such as microelectrodes and nanosensors, optimized for repeated use in awake, behaving animals. The microinjectrode system can be configured for multiple purposes: (1) simple arrangement of the cannula for placement of an experimental probe that would otherwise be too fragile to penetrate the dura mater, (2) microfluidic infusion of a drug, either independently or coupled to a cannula containing an experimental probe (i.e., microelectrode, nanosensor). In this protocol we explain the step by step construction of the microinjectrode, its coupling to microfluidic components, and the protocol for use of the system in vivo. The microfluidic components of this system allow for delivery of volumes on the nanoliter scale, with minimal penetration damage. Drug infusion can be performed independently or simultaneously with experimental probes such as microelectrodes or nanosensors in an awake, behaving animal. Applications of this system range from measuring the effects of a drug on cortical electrical activity and behavior, to understanding the function of a specific region of cortex in the context of behavioral performance based on probe or nanosensor measurements. To demonstrate some of the capabilities of this system, we present an example of muscimol infusion for reversible inactivation of the frontal eye field (FEF) in rhesus macaque during a working memory task.

The effect of levodopa on saccades - Oxford Quantification in Parkinsonism study.

OBJECTIVES: The evaluation of novel disease modifying drugs requires biomarkers that are simultaneously sensitive to disease state but resistant to the effects of background symptomatic treatment. Saccadic eye movement parameters have been proposed as a neurophysiological biomarker for Parkinson's disease (PD) and so it is important to know how they are affected by dopaminergic medication. Studies to date are conflicting: some have concluded that medication prolongs saccadic latencies while others suggest they are shortened. We aimed to characterise the effects of antiparkinsonian medication on prosaccadic and antisaccadic parameters in a large cohort of PD patients and age matched healthy controls and to survey the current literature in comparison to the study findings. METHODS: We studied saccades both off and on medication in 38 PD patients and 34 healthy controls (HC). Latencies, amplitudes, velocities, and directional errors were evaluated, using a published standardised protocol. We then combined this study and previously published literature in a meta-analysis of the effects of antiparkinsonian medication on prosaccadic latency (PSL). RESULTS: PSL is significantly prolonged by dopaminergic medication in PD, from a mean of 222.7 ms in the OFF medication state to a mean of 236.0 ms in the ON medication state (p = 0.028). This effect size is comparable to the difference between PD OFF medication and healthy control values. There was no statistically significant change in any other saccadic parameter with medication. Of particular note, antisaccadic latency was almost exactly the same on and off medication (means of 414.9 ms and 417.2 ms respectively, p = 0.97), while being almost 20% longer in PD patients compared to healthy controls (HC mean 357.2 ms; PD ON vs HC p = 0.015; PD OFF vs HC p = 0.0066). CONCLUSION: PSL is significantly affected by dopaminergic medication which may complicate its use as a biomarker in drug trials. Antisaccadic latency is particularly interesting in this regard because it shows a large disease effect with no medication effect.

Indirect pathway from caudate tail mediates rejection of bad objects in periphery.

The essential everyday task of making appropriate choices is a process controlled mainly by the basal ganglia. To this end, subjects need not only to find "good" objects in their environment but also to reject "bad" objects. To reveal this rejection mechanism, we created a sequential saccade choice task for monkeys and studied the role of the indirect pathway from the CDt (tail of the caudate nucleus) mediated by cvGPe (caudal-ventral globus pallidus externus). Neurons in cvGPe were typically inhibited by the appearance of bad objects; however, this inhibition was reduced on trials when the monkeys made undesired saccades to the bad objects. Moreover, disrupting the inhibitory influence of CDt on cvGPe by local injection of bicuculline (GABAA receptor antagonist) impaired the monkeys' ability to suppress saccades to bad objects. Thus, the indirect pathway mediates the rejection of bad choices, a crucial component of goal-directed behavior.

Oculomotor effects of medical and surgical treatments of Parkinson's disease.

Oculomotor abnormalities are fast becoming a proxy for disease diagnosis and progression. Saccades-ballistic eye movements-are known to be affected by dopaminergic cell loss in the basal ganglia, caused by Parkinson's disease. Pharmaceutical and neurosurgical interventions such as deep brain stimulation and functional neurosurgery have both been noted to have an effect on saccades. Comparing and contrasting these effects may yield insights into Parkinson's disease pathophysiology, and the mechanisms of pharmacological and neurosurgical treatments. Computational models of saccadic control, such as the LATER model, can help to interpret the distribution of saccadic latencies, providing a framework for objectively comparing the effects of pharmaceutical interventions and deep brain stimulation.

First-in-man study of ACT-709478, a novel selective triple T-type calcium channel blocker.

OBJECTIVE: Increased activity of T-type Ca2+ channels is linked to idiopathic generalized epilepsies, thus blocking these channels may be a new treatment option. ACT-709478 is an orally available triple T-type Ca2+ channel blocker. The aim of this first-in-man study was to investigate the pharmacokinetics, pharmacodynamics, tolerability, and safety of single doses of ACT-709478 in healthy subjects. METHODS: This double-blind, placebo-controlled, randomized study included 65 healthy male subjects. Ascending single oral doses of 1-400 mg ACT-709478 or placebo were administered to sequential groups of eight subjects (6 on active, 2 on placebo). Effect of food was tested in a crossover part at 60 mg. Blood and saliva sampling for pharmacokinetic evaluations and safety assessments was performed regularly. Effects on the central nervous system were assessed with a battery of pharmacodynamic tests. RESULTS: The maximum plasma concentration (Cmax ) was reached within 3 to 4 hours (≤60 mg) and within 20 to 28 hours (>60 mg), and across all dose levels the terminal half-life (95% confidence interval) ranged from 36 (29-45) to 43 (22-86) hours. Multiple peaks were observed and Cmax and area under the plasma concentration-time curve (AUC)0-∞ increased in a less than dose-proportional manner. A 1.6-fold increase in Cmax and no change in AUC0-∞ was observed in fed compared to fasted conditions. A significant correlation (P < 0.0001) between plasma and saliva concentrations was established using linear regression. All adverse events were transient and of mild or moderate intensity. No treatment-related effects on vital signs, clinical laboratory, telemetry, or electrocardiography were detected. The results of pharmacodynamic tests did not show relevant mean changes compared to baseline or placebo. SIGNIFICANCE: ACT-709478 exhibits good tolerability and safety after single-dose administration and its pharmacokinetic and pharmacodynamic properties warrant further investigations.

The computational pharmacology of oculomotion.

Many physiological and pathological changes in brain function manifest in eye-movement control. As such, assessment of oculomotion is an invaluable part of a clinical examination and affords a non-invasive window on several key aspects of neuronal computation. While oculomotion is often used to detect deficits of the sort associated with vascular or neoplastic events; subtler (e.g. pharmacological) effects on neuronal processing also induce oculomotor changes. We have previously framed oculomotor control as part of active vision, namely, a process of inference comprising two distinct but related challenges. The first is inferring where to look, and the second is inferring how to implement the selected action. In this paper, we draw from recent theoretical work on the neuromodulatory control of active inference. This allows us to simulate the sort of changes we would expect in oculomotor behaviour, following pharmacological enhancement or suppression of key neuromodulators-in terms of deciding where to look and the ensuing trajectory of the eye movement itself. We focus upon the influence of cholinergic and GABAergic agents on the speed of saccades, and consider dopaminergic and noradrenergic effects on more complex, memory-guided, behaviour. In principle, a computational approach to understanding the relationship between pharmacology and oculomotor behaviour affords the opportunity to estimate the influence of a given pharmaceutical upon neuronal function, and to use this to optimise therapeutic interventions on an individual basis.

Effects of nicotine on smooth pursuit eye movements in healthy non-smokers.

RATIONALE: The non-selective nicotinic acetylcholine receptor (nAChR) agonist nicotine has been argued to improve attention via enhanced filtering of irrelevant stimuli. Here, we tested this hypothesis in the context of smooth pursuit eye movements (SPEMs), an oculomotor function previously shown to improve with nicotine in some but not all studies. OBJECTIVES: In order to test whether nicotine improves performance particularly when the inhibition of distracting stimuli is required, SPEM was elicited in conditions with or without peripheral distractors. Additionally, different target frequencies were employed in order to parametrically vary general processing demands on the SPEM system. METHODS: Healthy adult non-smokers (N = 18 females, N = 13 males) completed a horizontal sinusoidal SPEM task at different target frequencies (0.2 Hz, 0.4 Hz, 0.6 Hz) in the presence or absence of peripheral distractors in a double-blind, placebo-controlled, cross-over design using a 2 mg nicotine gum. RESULTS: Nicotine increased peak pursuit gain relative to placebo (p < .001), but an interaction with distractor condition (p = .001) indicated that this effect was most pronounced in the presence of distractors. Catch-up saccade frequency was reduced by nicotine (p = .01), particularly at higher target frequencies (two-way interaction, p = .04). However, a three-way interaction (p = .006) indicated that the reduction with nicotine was strongest at the highest target frequency (0.6 Hz) only without distractors, whereas in the presence of distractors, it was strongest at 0.4-Hz target frequency. There were no effects of nicotine on subjective state measures. CONCLUSIONS: Together, these findings support a role of both distractor inhibition and general processing load in the effects of nicotine on smooth pursuit.

Treatment of internuclear ophthalmoparesis in multiple sclerosis with fampridine: A randomized double-blind, placebo-controlled cross-over trial.

AIM: To examine whether the velocity of saccadic eye movements in internuclear ophthalmoparesis (INO) improves with fampridine treatment in patients with multiple sclerosis (MS). METHODS: Randomized, double-blind, placebo-controlled, cross-over trial with fampridine in patients with MS and INO. Horizontal saccades were recorded at baseline and at multiple time points post-dose. Main outcome measures were the change of peak velocity versional dysconjugacy index (PV-VDI) and first-pass amplitude VDI (FPA-VDI). Both parameters were compared between fampridine and placebo using a mixed model analysis of variance taking patients as their own control. Pharmacokinetics was determined by serial blood sampling. RESULTS: Thirteen patients had a bilateral and 10 had a unilateral INO. One patient had an INO of abduction (posterior INO of Lutz) and was excluded. Fampridine significantly reduced both PV-VDI (-17.4%, 95% CI: -22.4%, -12.1%; P < 0.0001) and FPA-VDI (-12.5%, 95% CI: -18.9%, -5.5%; P < 0.01). Pharmacokinetics demonstrated that testing coincided with the average tmax at 2.08 hours (SD 45 minutes). The main adverse event reported after administration of fampridine was dizziness (61%). CONCLUSION: Fampridine improves saccadic eye movements due to INO in MS. Treatment response to fampridine may gauge patient selection for inclusion to remyelination strategies in MS using saccadic eye movements as primary outcome measure.