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Introduction: Nicotine and methylphenidate are putative cognitive enhancers in healthy and patient populations. Although they stimulate different neurotransmitter systems, they have been shown to enhance performance on overlapping measures of attention. So far, there has been no direct comparison of the effects of these two stimulants on behavioural performance or brain function in healthy humans. Here, we directly compare the two compounds using a well-established oculomotor biomarker in order to explore common and distinct behavioural and neural effects., Methods: Eighty-two healthy male non-smokers performed a smooth pursuit eye movement task while lying in an fMRI scanner. In a between-subjects, double-blind design, subjects either received placebo (placebo patch and capsule), nicotine (7mg nicotine patch and placebo capsule), or methylphenidate (placebo patch and 40mg methylphenidate capsule)., Results: There were no significant drug effects on behavioural measures. At the neural level, methylphenidate elicited higher activation in left frontal eye field compared to nicotine, with an intermediate response under placebo., Discussion: The reduced activation of task-related regions under nicotine could be associated with more efficient neural processing, while increased hemodynamic response under methylphenidate is interpretable as enhanced processing of task-relevant networks. Together, these findings suggest dissociable neural effects of these putative cognitive enhancers., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: In 3 previously published works (Brumback et al., 2007, Drug Alcohol Depend 91:10-17; King et al., 2011a, Arch Gen Psychiatry 68:389-399; Roche and King, 2010, Psychopharmacology (Berl) 212:33-44), our group characterized acute alcohol responses in a large group of young, heavy binge drinkers (n = 104) across a variety of subjective, eye-tracking, and psychometric performance measures., Methods: The primary goal of the current study was to directly replicate prior findings of alcohol response in heavy social drinkers (HD) in a second independent cohort (n = 104) using identical methodology. A secondary goal was to examine the effects of family history (FH) of alcohol use disorders (AUD) on acute alcohol response in both samples. Participants attended 2 randomized laboratory sessions in which they consumed 0.8 g/kg alcohol or a taste-masked placebo. At pre- and post-drink time points, participants completed subjective scales, psychomotor performance and eye-movement tasks, and provided salivary samples for cortisol determination., Results: Results showed that the second cohort of heavy drinkers exhibited a nearly identical pattern of alcohol responses to the original cohort, including sensitivity to alcohol's stimulating and hedonically rewarding effects during the rising breath alcohol content (BrAC) limb, increases in sedation during the declining BrAC limb, a lack of cortisol response, and psychomotor and eye-tracking impairment that was most evident at peak BrAC. The magnitude and temporal pattern of these acute effects of alcohol in the second cohort were similar to the first cohort across all measures, with the exception of 3 eye-movement measures: pro- and antisaccade accuracy and antisaccade velocity. FH of AUD did not affect alcohol response in the first cohort, and this was replicated in the second cohort., Conclusions: In sum, in 2 independent samples, we have demonstrated that HD display a consistent and reliable sensitivity to alcohol's subjective effects and impairment of eye-tracking and psychomotor performance, which is not affected by FH status. This acute alcohol response phenotype in heavy, frequent binge drinkers appears to be robust and reproducible., (Copyright © 2013 by the Research Society on Alcoholism.)

The frontal pursuit area (FPA) lies posterior to the frontal eye fields in the frontal cortex and contains neurons that are directionally selective for pursuit eye movements. Lesions of the FPA (alternately called "FEFsem") cause deficits in pursuit acceleration and velocity, which are largest for movements directed toward the lesioned side. Conversely, stimulation of the FPA evokes pursuit from fixation and increases the gain of the pursuit response. On the basis of these properties, it has been hypothesized that the FPA could underlie the selection of pursuit direction. To test this possibility, we manipulated FPA activity and measured the effect on target selection behavior in rhesus monkeys. First, we unilaterally inactivated the FPA with the GABA agonist muscimol. We then measured the monkeys' performance on a pursuit-choice task. Second, we applied microstimulation unilaterally to the FPA during pursuit initiation while monkeys performed the same pursuit-choice task. Both of these manipulations produced significant effects on pursuit metrics; the inactivation decreased pursuit velocity and acceleration, and microstimulation evoked pursuit directly. Despite these changes, both manipulations failed to significantly alter choice behavior. These results show that FPA activity is not necessary for pursuit target selection.

Background: Smooth pursuit deficits are an intermediate phenotype for schizophrenia that may result from disturbances in visual motion perception, sensorimotor transformation, predictive mechanisms, or alterations in basic oculomotor control. Which of these components are the primary causes of smooth pursuit impairments and whether they are impaired similarly across psychotic disorders remain to be established., Methods: First-episode psychotic patients with bipolar disorder (n = 34), unipolar depression (n = 24), or schizophrenia (n = 77) and matched healthy participants (n = 130) performed three smooth pursuit tasks designed to evaluate different components of pursuit tracking., Results: On ramp tasks, maintenance pursuit velocity was reduced in all three patients groups with psychotic bipolar patients exhibiting the most severe impairments. Open loop pursuit velocity was reduced in psychotic bipolar and schizophrenia patients. Motion perception during pursuit initiation, as indicated by the accuracy of saccades to moving targets, was not impaired in any patient group. Analyses in 138 participants followed for 6 weeks, during which patients were treated and psychotic symptom severity decreased, and no significant change in performance in any group was revealed., Conclusions: Sensorimotor transformation deficits in all patient groups suggest a common alteration in frontostriatal networks that dynamically regulate gain control of pursuit responses using sensory input and feedback about performance. Predictive mechanisms appear to be sufficiently intact to compensate for this deficit across psychotic disorders. The absence of significant changes after acute treatment and symptom reduction suggests that these deficits appear to be stable over time., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this paper was to determine whether antiretroviral medications, especially the nucleoside analogue reverse transcriptase inhibitors, lead to altered brain activation due to their potential neurotoxic effects in patients with human immunodeficiency virus (HIV) infection., Methods: Forty-two right-handed men were enrolled in three groups: seronegative controls (SN, n = 18), HIV subjects treated with antiretroviral medications (HIV+ARV, n = 12), or not treated with antiretroviral medications (HIV+NARV, n = 12). Each subject performed a set of visual attention tasks with increasing difficulty or load (tracking two, three or four balls) during functional magnetic resonance imaging., Results: HIV subjects, both groups combined, showed greater load-dependent increases in brain activation in the right frontal regions compared to SN (p-corrected = 0.006). HIV+ARV additionally showed greater load-dependent increases in activation compared to SN in bilateral superior frontal regions (p-corrected = 0.032) and a lower percent accuracy on the performance of the most difficult task (tracking four balls). Region of interest analyses further demonstrated that SN showed load-dependent decreases (with repeated trials despite increasing difficulty), while HIV subjects showed load-dependent increases in activation with the more difficult tasks, especially those on ARVs., Interpretation: These findings suggest that chronic ARV treatments may lead to greater requirement of the attentional network reserve and hence less efficient usage of the network and less practice effects in these HIV patients. As the brain has a limited reserve capacity, exhausting the reserve capacity in HIV+ARV would lead to declined performance with more difficult tasks that require more attention.

The contributions of the middle superior temporal area (MST) in the posterior parietal cortex of rhesus monkeys to the generation of smooth-pursuit eye movements as well as the contributions to motion perception are well established. Here, we present the first experimental evidence that this area also contributes to the generation of goal-directed hand movements toward a moving target. This evidence is based on the outcome of intracortical microstimulation experiments and transient lesions by small injections of muscimol at identified sites within the lateral part of area MST (MST-l). When microstimulation was applied during the execution of smooth-pursuit eye movements, postsaccadic eye velocity in the direction of the preferred direction of the stimulated site increased significantly (in 93 of 136 sites tested). When microstimulation was applied during a hand movement trial, the hand movement was displaced significantly in the same direction (in 28 of 39 sites tested). When we lesioned area MST-l transiently by injections of muscimol, steady-state eye velocity was exclusively reduced for ipsiversive smooth-pursuit eye movements. In contrast, hand movements were displaced toward the contralateral side, irrespective of the direction of the moving target. Our results provide evidence that area MST-l is involved in the processing of moving targets and plays a role in the execution of smooth-pursuit eye movements as well as visually guided hand movements.

Cannabis use has been associated with increased risk of becoming involved in traffic accidents; however, the relation between THC concentration and driver impairment is relatively obscure. The present study was designed to define performance impairment as a function of THC in serum and oral fluid in order to provide a scientific framework to the development of per se limits for driving under the influence of cannabis. Twenty recreational users of cannabis participated in a double-blind, placebo-controlled, three-way cross-over study. Subjects were administered single doses of 0, 250 and 500 microg/kg THC by smoking. Performance tests measuring skills related to driving were conducted at regular intervals between 15 min and 6h post smoking and included measures of perceptual-motor control (Critical tracking task), motor impulsivity (Stop signal task) and cognitive function (Tower of London). Blood and oral fluid were collected throughout testing. Results showed a strong and linear relation between THC in serum and oral fluid. Linear relations between magnitude of performance impairment and THC in oral fluid and serum, however, were low. A more promising way to define threshold levels of impairment was found by comparing the proportion of observations showing impairment or no impairment as a function of THC concentration. The proportion of observations showing impairment progressively increased as a function of serum THC in every task. Binomial tests showed an initial and significant shift toward impairment in the Critical tracking task for serum THC concentrations between 2 and 5 ng/ml. At concentrations between 5 and 10 ng/ml approximately 75-90% of the observations were indicative of significant impairment in every performance test. At THC concentrations >30 ng/ml the proportion of observations indicative of significant impairment increased to a full 100% in every performance tests. It is concluded that serum THC concentrations between 2 and 5 ng/ml establish the lower and upper range of a THC limit for impairment.

Nicotine and/or smoking have been shown to reduce various cognitive deficits associated with schizophrenia. Here, we examine the effects of nicotine gum on repeated performance on a simple eye movement task. Eight schizophrenic subjects and eight controls participated in three days of testing on saccade (S) and antisaccade (AS) tasks. On each testing day, subjects participated in four testing sessions and received both of two nicotine gum treatments (4 and 6 mg) and both of two control conditions (placebo gum and no gum), each followed by a recovery period. Overall, schizophrenics showed significant impairments on the AS task. However, upon individual examination only four schizophrenics showed significant differences in AS errors or reaction times (RTs) when compared to controls. The other four schizophrenic subjects showed control level performance. All schizophrenic subjects showed normal and better than control level performance on the simple S task. Furthermore, no effects of nicotine were seen on the simple S task. There were significant treatment effects on the AS task. Nicotine treatment significantly decreased errors in the task impaired schizophrenic group and this effect was most pronounced at the 6 mg level. No nicotine effects were demonstrated for non-impaired schizophrenic subjects or controls. This study demonstrates a benefit of short exposure to nicotine in cognitively impaired schizophrenic subjects. These results support previous findings of cognitive benefits of nicotine in schizophrenics.

Objective: The purpose of this study was to examine performance effects of alcohol in young adult heavy drinkers (HDs) and light drinkers (LDs). Prior research has shown that HDs have alterations in subjective alcohol response in comparison with LDs, with greater reported stimulant-like effects and reduced sedative-like effects. It is unclear whether these quantitative differences extend to performance and objective effects., Method: Thirty-four subjects participated (20 HDs and 14 LDs) in three early evening individual alcohol challenge sessions. Subjects were examined on eye movement and psychomotor performance tasks before and several times after consuming either 0.8 g/kg or 0.4 g/kg ethanol or placebo beverage., Results: Alcohol produced similar impairment for the groups in psychomotor performance and saccadic velocity measures, with blood alcohol concentration dependent group differences on the smooth pursuit task and a marginally lower threshold for impairment for HDs on the saccadic latency task. Covarying for personality differences (i.e., disinhibition and boredom susceptibility traits) and family history of alcoholism did not significantly alter the findings., Conclusions: Despite prior findings of differential subjective response to alcohol in HDs and LDs, alcohol-induced performance impairment was comparable between the groups. Our findings suggest HDs may be particularly at risk for alcohol-related consequences because their greater sensitivity to positive alcohol effects and/or tolerance to sedative effects may not be accompanied by a lesser degree of alcohol-induced performance impairment.

The effect of straight release carbamazepine monotherapy was studied in 12 well-controlled epileptic patients using adaptive tracking, smooth pursuit and saccadic eye movements, body sway, Digit Symbol Substitution Test (DSST) and Visual Analogue Scales. Patients were matched to healthy controls for age and gender. After patients had received their usual morning dose of carbamazepine, patient-control pairs were studied for 7 h. Compared to controls, the average DSST scores of patients were significant lower. No relationships were shown between DSST performance and plasma concentrations of carbamazepine and carbamazepine-epoxide. No significant differences were found for any of the other effect parameters. Variations in plasma concentrations were limited, contributing to the absence of systematic fluctuations in test results. Of the used tests, DSST is most clearly related to cognitive function. It is concluded that the difference in DSST performance appears to reflect a long-term small neurocognitive difference between subjects with and without epilepsy.

The contribution of the flocculus region of the cerebellum to horizontal gaze pursuit was studied in squirrel monkeys. When the head was free to move, the monkeys pursued targets with a combination of smooth eye and head movements; with the majority of the gaze velocity produced by smooth tracking head movements. In the accompanying study we reported that the flocculus region was necessary for cancellation of the vestibuloocular reflex (VOR) evoked by passive whole body rotation. The question addressed in this study was whether the flocculus region of the cerebellum also plays a role in canceling the VOR produced by active head movements during gaze pursuit. The firing behavior of 121 Purkinje (Pk) cells that were sensitive to horizontal smooth pursuit eye movements was studied. The sample included 66 eye velocity Pk cells and 55 gaze velocity Pk cells. All of the cells remained sensitive to smooth pursuit eye movements during combined eye and head tracking. Eye velocity Pk cells were insensitive to smooth pursuit head movements. Gaze velocity Pk cells were nearly as sensitive to active smooth pursuit head movements as they were passive whole body rotation; but they were less than half as sensitive ( approximately 43%) to smooth pursuit head movements as they were to smooth pursuit eye movements. Considered as a whole, the Pk cells in the flocculus region of the cerebellar cortex were <20% as sensitive to smooth pursuit head movements as they were to smooth pursuit eye movements, which suggests that this region does not produce signals sufficient to cancel the VOR during smooth head tracking. The comparative effect of injections of muscimol into the flocculus region on smooth pursuit eye and head movements was studied in two monkeys. Muscimol inactivation of the flocculus region profoundly affected smooth pursuit eye movements but had little effect on smooth pursuit head movements or on smooth tracking of visual targets when the head was free to move. We conclude that the signals produced by flocculus region Pk cells are neither necessary nor sufficient to cancel the VOR during gaze pursuit.

Marijuana continues to be the most commonly abused illicit drug in the United States. Because many people abuse marijuana during the evening and on weekends and then go to work or school the next day, more research is needed on the residual effects of marijuana. The current study sought to examine both acute and residual subjective. physiologic, and performance effects of smoking a single marijuana cigarette. Ten healthy male volunteers who reported recent use of marijuana resided on a residential research ward. On three separate days, subjects smoked one NIDA marijuana cigarette containing either 0%, 1.8%, or 3.6% delta9-tetrahydrocannabinol (THC) according to a paced puffing procedure. Subjective, physiologic, and performance measures were collected prior to smoking, five times following smoking on that day, and three times on the following morning. Subjects reported robust subjective effects following both active doses of marijuana, which returned to baseline levels within 3.5 h. Heart rate increased and the pupillary light reflex decreased following active dose administration with return to baseline on that day. A new finding was that marijuana smoking acutely produced decrements in smooth pursuit eye tracking. Although robust acute effects of marijuana were found on subjective and physiological measures, and on smooth pursuit eye tracking performance, no effects were evident the day following administration, indicating that the residual effects of smoking a single marijuana cigarette are minimal.

The effects of single doses of haloperidol (2, 4 and 6 mg) were compared with lorazepam 2.5 mg and placebo in 15 healthy subjects. Visual search strategy was measured, along with a range of psychomotor and eye movement tests. Patients with Parkinson's disease have been shown to exhibit a shift from parallel to serial processing in visual search, but we demonstrated that this does not occur following administration of either haloperidol or lorazepam. Haloperidol was detected by visual analogue rating scales and peak saccadic velocity, the latter being the more sensitive measure. Haloperidol had no statistically significant effect on smooth pursuit position error, velocity error or saccadic intrusions. Digit symbol substitution performance was clearly diminished by haloperidol, but there was no effect on the continuous attention test. Lorazepam decreased performance in all tests apart from saccadic latency.

A method was developed to determine the effects of pyridostigmine on sensory-motor control in baboons trained to perform visuo-oculo-manual tracking tasks. The performance was evaluated in terms of accuracy, maximum smooth pursuit velocity, and gain. Administration of pyridostigmine (0.4-0.7 mg/kg intramuscularly) induced a dose-related decrease in smooth pursuit performance which appeared 10 to 30 min after injection and lasted about 1 h. If the animal was allowed to track the target with its hand or to move the target itself, the smooth pursuit performance increased significantly, returning to near normal values. The movement of the hand was not altered. The effect of intramuscular injections of pyridostigmine (0.5 mg/kg) was studied on blood acetylcholinesterase activity in alert baboons. Maximum inhibition of about 60% of baseline activity was observed 10 min after pyridostigmine injection. Subsequently the activity slowly tended to return to control level. Three hours after drug administration, acetylcholinesterase activity inhibition was still 34.1% of control value. In the baboon, the time-course of acetylcholinesterase activity recovery after injection is similar to that recorded in human. The similarity of the time-course of blood acetylcholinesterase activity and changes in smooth pursuit performance suggests a causal relationship between the two factors. A further experiment showed that pyridostigmine administered per os at a dose normally used as a prophylactic against organophosphates does not significantly alter sensorimotor performance as evaluated at the oculomanual tracking system level. When compared to the literature, our results suggest that the baboon can be used as a human experimental analog for pharmacological studies such as the action of acetylcholinesterase inhibitors.

Effects of 6 and 12 mg bromazepam on reaction time, stimulus sensitivity and response bias in a 1-hour visual attention task, on smooth pursuit eye movements, and on performance in the digit symbol substitution test (DSST) were investigated in 12 healthy male volunteers. It was a placebo-controlled, double-blind, crossover study that used repeated measures. Three saliva samples and a blood sample were taken for correlating drug concentration and performance. Bromazepam lowered stimulus sensitivity dose-dependently. Response times for hits and response bias were affected by the 12-mg dose only. DSST performance decreased dose-dependently. Smooth pursuit was equally impaired by 6 and 12 mg. Concentrations in serum correlated with concentrations in saliva, but serum and saliva concentrations did not correlate with task performance.

Combinations of atropine (up to 4 mg.70 kg-1) and 2-PAM Cl (up to 1200 mg.70 kg-1) were studied for their effects on a pursuit tracking task, six visual functions, heart rate and blood pressure, and cognitive functions as measured by six psychological tests. Tracking performance in both bright light and dim light was significantly degraded up to 3.5 h after injection. High- and low-contrast near acuity was significantly altered up to 6 h after injection, whereas accommodation and pupil size remained altered for 24 h. Elevated pulse rates were observed for 4 h. Elevated systolic blood pressures were observed for 2 h while diastolic pressures remained elevated for 6 h. No drug effects were found for the psychological tests. Overall, the observed effects of these two drugs in combination are qualitatively similar to those of atropine alone although they are of greater magnitude. On two measures (accommodation and diastolic blood pressure), 2-PAM Cl was found to significantly potentiate the atropine effect.

The relation between performance on driving-related tasks and plasma levels of diphenhydramine was studied in eight male volunteers over 24 hours following oral administration. DPH plasma concentrations rose to peak levels in 1.5-2.5 hours varying with dose, declining to a nearly constant level by 12-24 hours. For all behavioral measures, the shape of performance curves over time was similar to that of plasma, reaching maximum decrements in 1-4 hours. The relation between plasma levels and performance was asynchronous varying with behavioral measure and dose. The use of plasma DPH values to predict performance decrements is limited due to the bivalued nature of these relationships in time. Nonetheless, it would appear that if DPH is administered in the therapeutic dosage range at the intervals typically recommended for cold symptoms and allergies, it appears some aspects of human performance may be impaired.

This work examined the effects of consuming relatively small amounts of caffeine, from 20 to 160 mg, on performance and self-reports of mood in a group of caffeine users. A group of non-caffeine users were studied after ingesting 160 mg of caffeine. At regular intervals after consumption subjects were tested on several behavioral measures and blood samples were taken for caffeine analysis. Results showed caffeine users had higher blood caffeine levels and lower blood pressure at some doses than did non-users. Regular caffeine users showed a tendency toward better performance on a rotary pursuit task than non-caffeine users given a placebo treatment. They also experienced a performance decrement, relative to users given placebo, when blood caffeine levels were relatively high. Caffeine users showed no sign of caffeine withdrawal when compared to non-users before caffeine treatment. Performance of non-users given caffeine was poorer than control performance, and they tended not to report altering effects of caffeine. However, in caffeine users, the ratio of alertness:tension self-ratings tended to roughly track plasma caffeine with the lowest ratios occurring when plasma caffeine peaked after 160 mg dose. Low ratios were also found after 0, 20, and 40 mg caffeine treatments. The ratio was highest after 80 mg caffeine, suggesting that an optimum caffeine dose might exist for peak alertness:tension, with higher or lower doses resulting in a decrease of that ratio. These data suggest that real or expected mood and perhaps performance benefits experienced by caffeine users contribute to the motivation for consumption.

23 Patients with multiple sclerosis were subjected to a visuomotor tracking test, consisting of subtests of different task difficulty, while being in a state of acute exacerbation and four weeks later, while exhibiting a more or less pronounced clinical remission (Kurtzke DSS 3.9 (+/- 1.4) vs. 3.3 (+/- 1.5); p less than 0.001). Corresponding to this the tracking test performances improved, the difference being significant only with the easiest test run. The tracking performances correlated with the Kurtzke scores, both for the acute state and for the remitted state, the highest correlation showing up for the easiest test run. Hence, the visuomotor tracking test seems to be suited to measure functional deficits and to evaluate the efficiency of therapeutic procedures.