Neural effects of methylphenidate and nicotine during smooth pursuit eye movements.

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.

Effects of ketamine on brain function during smooth pursuit eye movements.

The uncompetitive NMDA receptor antagonist ketamine has been proposed to model symptoms of psychosis. Smooth pursuit eye movements (SPEM) are an established biomarker of schizophrenia. SPEM performance has been shown to be impaired in the schizophrenia spectrum and during ketamine administration in healthy volunteers. However, the neural mechanisms mediating SPEM impairments during ketamine administration are unknown. In a counter-balanced, placebo-controlled, double-blind, within-subjects design, 27 healthy participants received intravenous racemic ketamine (100 ng/mL target plasma concentration) on one of two assessment days and placebo (intravenous saline) on the other. Participants performed a block-design SPEM task during functional magnetic resonance imaging (fMRI) at 3 Tesla field strength. Self-ratings of psychosis-like experiences were obtained using the Psychotomimetic States Inventory (PSI). Ketamine administration induced psychosis-like symptoms, during ketamine infusion, participants showed increased ratings on the PSI dimensions cognitive disorganization, delusional thinking, perceptual distortion and mania. Ketamine led to robust deficits in SPEM performance, which were accompanied by reduced blood oxygen level dependent (BOLD) signal in the SPEM network including primary visual cortex, area V5 and the right frontal eye field (FEF), compared to placebo. A measure of connectivity with V5 and FEF as seed regions, however, was not significantly affected by ketamine. These results are similar to the deviations found in schizophrenia patients. Our findings support the role of glutamate dysfunction in impaired smooth pursuit performance and the use of ketamine as a pharmacological model of psychosis, especially when combined with oculomotor biomarkers. Hum Brain Mapp 37:4047-4060, 2016. © 2016 Wiley Periodicals, Inc.

Acute alcohol response phenotype in heavy social drinkers is robust and reproducible.

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.

Eye movement impairments in Parkinson's disease: possible role of extradopaminergic mechanisms.

BACKGROUND: The basal ganglia (BG) are thought to play an important role in the control of eye movements. Accordingly, the broad variety of subtle oculomotor alterations that has been described in Parkinson's disease (PD) are generally attributed to the dysfunction of the BG dopaminergic system. However, the present study suggest that dopamine substitution is much less effective in improving oculomotor performance than it is in restoring skeletomotor abilities. METHODS: We investigated reactive, visually guided saccades (RS), smooth pursuit eye movements (SPEM), and rapidly left-right alternating voluntary gaze shifts (AVGS) by video-oculography in 34 PD patients receiving oral dopaminergic medication (PD-DA), 14 patients with deep brain stimulation of the nucleus subthalamicus (DBS-STN), and 23 control subjects (CTL);In addition, we performed a thorough review of recent literature according therapeuthic effects on oculomotor performance in PD by switching deep brain stimulation off and on in the PD-DBS patients, we achieved swift changes between their therapeutic states without the delays of dopamine withdrawal. In addition, participants underwent neuropsychological testing. RESULTS: Patients exhibited the well known deficits such as increased saccade latency, reduced SPEM gain, and reduced frequency and amplitude of AVGS. Across patients none of the investigated oculomotor parameters correlated with UPDRS III whereas there was a negative correlation between SPEM gain and susceptibility to interference (Stroop score). Of the observed deficiencies, DBS-STN slightly improved AVGS frequency but neither AVGS amplitude nor SPEM or RS performance. CONCLUSIONS: We conclude that the impairment of SPEM in PD results from a cortical, conceivably non-dopaminergic dysfunction, whereas patients' difficulty to rapidly execute AVGS might be related to their BG dysfunction.

Inactivation and stimulation of the frontal pursuit area change pursuit metrics without affecting pursuit target selection.

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.

Vestibular and balance findings in nonsymptomatic workers exposed to styrene and dichloromethane.

OBJECTIVE: The aim of our study was to assess the vestibular and balance system in non-symptomatic workers exposed to styrene and dichloromethane at the workplace. DESIGN: Subjects underwent videonystagmography including saccades, smooth pursuit (SP), optokinetic test (OKN), gaze nystagmus assessment, bithermal caloric test, and static posturography. STUDY SAMPLE: Study groups included 74 workers in plastics manufacturing, aged 40 (SD 8) years, exposed to styrene and dichloromethane, and the reference group of 49 non-exposed subjects, aged 36 (SD 10) years. RESULTS: More than 60% of exposed and non-symptomatic workers revealed abnormal results of vestibular tests. Saccadic latency elongation (p = 0.0098), lower gain in SP (p = 0.0037) and OKN (p = 0.0000) were more common in the exposed group, as well as lower reactivity (p = 0.0337) and mean slow phase velocity of caloric nystagmus. Static posturography revealed higher sway velocities in the test with eyes closed, on foam and worse results of three from five limit of stability tests. No relationship between chemicals exposure and vestibular and balance test results was found. CONCLUSIONS: In principle, our findings indicate the possibility of high-level deficits in the central part of vestibular system. Lower vestibular reactivity may suggest that bilateral vestibular hypofunction might also be the possible consequence of solvent exposure.

The effect of L-Dopa administration on pursuit ocular movements in suspected Parkinson's disease.

The objective of this study is to evaluate pursuit ocular movements (POM) by using a vision-based non-intrusive eye tracker, in patients with suspected Parkinson's disease (PD), before and after L: -Dopa administration. We studied ten patients with suspected diagnosis of idiopathic PD. We compared POM values to those of a group of normal controls (NC), and evaluated them before and after L: -Dopa administration. Unified Parkinson's Disease Rating Scale (UPDRS) motor subscores improved significantly (p = 0.001). At baseline, values of POM were lower in suspected PD patients than in NC (p = 0.01). One hour after L: -Dopa administration, POM values correlated with UPDRS motor subscore (p = 0.01). We used a recent method, a new vision-based non-intrusive eye tracker, previously described, which can be proposed as a possible tool for supporting the diagnosis of PD in association with levodopa test, as an add-on to the UPDRS score.

Superior colliculus inactivation causes stable offsets in eye position during tracking.

The primate superior colliculus (SC) is often viewed as composed of two distinct motor zones with complementary functions: a peripheral region that helps generate saccades to eccentric targets and a central one that maintains fixation by suppressing saccades. Here, we directly tested the alternative interpretation that topography in the SC is not strictly motor, nor does it form two distinct zones, but instead forms a single map of behaviorally relevant goal locations. Primates tracked the invisible midpoint between two moving stimuli, such that the stimuli guiding tracking were peripheral whereas the inferred movement goal was foveal and parafoveal. Temporary inactivation of neurons in the central portion of the topographic map of the SC, representing the invisible goal, caused stable offsets in eye position during tracking that were directed away from the retinotopic position encoded by the inactivated SC site. Critically, these offsets were not accompanied by a systematic inability to generate or suppress saccades, and they were not fully explained by motor deficits in saccades, smooth pursuit, or fixation. In addition, the magnitude of the offset depended on the eccentricity of the inactivated site as well as the degree of spatial uncertainty associated with the behavioral goal. These results indicate that gaze control depends on the balance of activity across a map of goal locations in the SC, and that by silencing some of the neurons in the normally active population representing the behavioral goal, focal inactivation causes a biased estimate of where to look.

The pharmacokinetic and pharmacodynamic effects of SL65.1498, a GABA-A alpha2,3 selective agonist, in comparison with lorazepam in healthy volunteers.

Benzodiazepines are effective short-term treatments for anxiety disorders, but their use is limited by undesirable side effects related to Central Nervous System impairment and tolerance development. SL65.1498 is a new compound that acts in vitro as a full agonist at the gamma-aminobutyric acid(A) 2 and 3 receptor and as a partial agonist at the 1 and 5 receptor subtypes. It is thought that the compound could be anxiolytic by its activation at the alpha2 and alpha3 receptor subtypes, without causing unfavourable side effects, which are believed to be mediated by the alpha1 and alpha5 subtypes. This study was a double-blind, five-way cross-over study to investigate the effects of three doses of SL65.1498 in comparison with placebo and lorazepam 2 mg in healthy volunteers. The objective was to select a dose level (expected to be therapeutically active), free of any significant deleterious effect. Psychomotor and cognitive effects were measured using a validated battery of measurements, including eye movements, body sway, memory tests, reaction-time assessments, and visual analogue scales. The highest dose of SL65.1498 showed slight effects on saccadic peak velocity and smooth pursuit performance, although to a much lesser extent than lorazepam. In contrast to lorazepam, none of the SL65.1498 doses affected body sway, visual analogue scale alertness, attention, or memory tests. This study showed that the three doses of SL65.1498 were well tolerated and induced no impairments on memory, sedation, psychomotor, and cognitive functions.

Involvement of the cerebellar dorsal vermis in vergence eye movements in monkeys.

Frontal-eyed primates use both smooth pursuit in frontoparallel planes (frontal pursuit) and pursuit-in-depth (vergence pursuit) to track objects moving slowly in 3-dimensional (3D) space. To understand how 3D-pursuit signals represented in frontal eye fields are processed further by downstream pathways, monkeys were trained to pursue a spot moving in 3D virtual space. We characterized pursuit signals in Purkinje (P) cells in the cerebellar dorsal vermis and their discharge during vergence pursuit. In 41% of pursuit P-cells, 3D-pursuit signals were observed. However, the majority of vermal-pursuit P-cells (59%) discharged either for vergence pursuit (43%) or for frontal pursuit (16%). Moreover, the majority (74%) of vergence-related P-cells carried convergence signals, displaying both vergence eye position and velocity sensitivity during sinusoidal and step vergence eye movements. Preferred frontal-pursuit directions of vergence + frontal-pursuit P-cells were distributed in all directions. Most pursuit P-cells (73%) discharged before the onset of vergence eye movements; the median lead time was 16 ms. Muscimol infusion into the sites where convergence P-cells were recorded resulted in a reduction of peak convergence eye velocity, of initial convergence eye acceleration, and of frontal-pursuit eye velocity. These results suggest involvement of the dorsal vermis in conversion of 3D-pursuit signals and in convergence eye movements.

The effect of change in clinical state on eye movement dysfunction in schizophrenia.

Measures of eye movement dysfunction have been considered as candidate endophenotypes for the study of genetic liability in schizophrenia. In this respect it is crucial to confirm a clinical state independentce of these measures. Twenty people with DSM-IV schizophrenia were assessed using a battery of oculomotor tasks in the acute phase of their disorder without being treated with antipsychotic medication and then again in the remission phase under treatment with antipsychotic medication. The saccade latency in the saccade task, the error rate and antisaccade latency in the antisaccade task, and the frequency of unwanted saccades in the active fixation task were stable in time both at the group level and within each individual, showing no relation to the significant improvement in different psychopathological dimensions of these patients. The root mean square error, gain and saccade frequency in the pursuit task were not stable over time, although again this instability was not related to the changes in psychopathological status of these patients. Finally, the saccade frequency in the active fixation task with distracters was not stable in time and was correlated with changes in specific dimensions of psychopathology. These results provide further evidence that saccade and smooth eye pursuit dysfunction measures are not affected by the substantial change in the clinical state of schizophrenia from the acute phase to remission, and strengthen the current view that they can be used as endophenotypes. On the other hand, active fixation might be state-dependent adding to the evidence against its use as a candidate endophenotype in schizophrenia.

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.

Stress-induced dopamine release in humans at risk of psychosis: a [11C]raclopride PET study.

Drugs that increase dopamine levels in the brain can cause psychotic symptoms in healthy individuals and worsen them in schizophrenic patients. Psychological stress also increases dopamine release and is thought to play a role in susceptibility to psychotic illness. We hypothesized that healthy individuals at elevated risk of developing psychosis would show greater striatal dopamine release than controls in response to stress. Using positron emission tomography and [(11)C]raclopride, we measured changes in synaptic dopamine concentrations in 10 controls and 16 psychometric schizotypes; 9 with perceptual aberrations (PerAb, ie positive schizotypy) and 7 with physical anhedonia (PhysAn, ie negative schizotypy). [(11)C]Raclopride binding potential was measured during a psychological stress task and a sensory-motor control. All three groups showed significant increases in self-reported stress and cortisol levels between the stress and control conditions. However, only the PhysAn group showed significant stress-induced dopamine release. Dopamine release in the entire sample was significantly negatively correlated with smooth pursuit gain, an endophenotype linked to frontal lobe function. Our findings suggest the presence of abnormalities in the dopamine response to stress in negative symptom schizotypy, and provide indirect evidence of a link to frontal function.

Modelling of the concentration--effect relationship of THC on central nervous system parameters and heart rate -- insight into its mechanisms of action and a tool for clinical research and development of cannabinoids.

Pharmacokinetics after pulmonary administration of delta-9-tetrahydrocannabinol (THC) and its major metabolites 11-OH-THC and 11-nor-9-COOH-THC was quantified. Additionally, the relationship between THC and its effects on heart rate, body sway and several visual analogue scales was investigated using pharmacokinetic-pharmacodynamic (PK-PD) modelling. This provided insights useful for the research and development of novel cannabinoids and the physiology and pharmacology of cannabinoid systems. First, the PK-PD model gave information reflecting various aspects of cannabinoid systems. The delay between THC concentration and effect was quantified in equilibration half-lives of 7.68 min for heart rate and from 39.2 to 84.8 min for the CNS responses. This suggests that the effect of THC on the different responses could be due to different sites of action or different physiological mechanisms. Differences in the shape of the concentration-effect relationship could indicate various underlying mechanisms. Second, the PK-PD model can be used for prediction of THC concentration and effect profiles. It is illustrated how this can be used to optimise studies with entirely different trial designs. Third, many new cannabinoid agonists and antagonists are in development. PK-PD models for THC can be used as a reference for new agonists or as tools to quantitate the pharmacological properties of cannabinoid antagonists.

Effect of intrapulmonary tetrahydrocannabinol administration in humans.

This randomised, double-blind, placebo-controlled, cross-over study was designed to identify which pharmacodynamic parameters most accurately quantify the effects of delta-9-Tetrahydrocannabinol (THC), the predominantly psychoactive component of cannabis. In addition, we investigated the acceptability and usefulness of a novel mode of intrapulmonary THC administration using a Volcano vaporizer and pure THC instead of cannabis. Rising doses of THC (2, 4, 6 and 8 mg) or vehicle were administered with 90 minutes intervals to twelve healthy males using a Volcano vaporizer. Very low between-subject variability was observed in THC plasma concentrations, characterising the Volcano vaporizer as a suitable method for the administration of THC. Heart rate showed a sharp increase and rapid decline after each THC administration (8 mg: 19.4 bpm: 95% CI 13.2, 25.5). By contrast, dose dependent effects of body sway (8 mg: 108.5%: 95% CI 72.2%, 152.4%) and different subjective parameters did not return to baseline between doses (Visual Analogue Scales of 'alertness' (8 mg: -33.6 mm: 95% CI -41.6, -25.7), 'feeling high' (8 mg: 1.09 U: 95% CI 0.85, 1.33), 'external perception' (8 mg: 0.62 U: 95% CI 0.37, 0.86)). PK/PD-modeling of heart rate displayed a relatively short equilibration half-life of 7.68 min. CNS parameters showed equilibration half-lives ranging between 39.4 - 84.2 min. Some EEG-frequency bands, and pupil size showed small changes following the highest dose of THC. No changes were seen in saccadic eye movements, smooth pursuit and adaptive tracking performance. These results may be applicable in the development of novel cannabinoid agonists and antagonists, and in studies of the pharmacology and physiology of cannabinoid systems in humans.

Medications influencing central cholinergic neurotransmission affect saccadic and smooth pursuit eye movements in healthy young adults.

RATIONALE: Acetylcholine is an important neuromodulator in the central nervous system, where it plays a significant role in central functions such as the regulation of movement. OBJECTIVE: This study investigated the pharmacological effects of over-the-counter anticholinergic medications on saccadic and smooth pursuit eye movements, in order to establish the significance of central cholinergic pathways in the control of these centrally regulated oculomotor processes. METHODS: Sixteen subjects (mean age 23 ± 3 years, 9 females) performed pro-saccadic, anti-saccadic and smooth pursuit eye movement tests, while an eye tracker collected eye movement data. Oculomotor assessments were performed pre-ingestion, 0.5 and 2 h post-ingestion of drugs with varying degrees of central anticholinergic properties. The drugs tested were promethazine, hyoscine hydrobromide, hyoscine butylbromide and placebo. RESULTS: The drug intervention with stronger central anticholinergic properties, promethazine, decreased amplitude and increased velocity in the pro-saccadic task and increased duration in the anti-saccadic task. Promethazine, once again, was the only drug to decrease eye velocity in the smooth pursuit test. CONCLUSION: The prominent effects of the stronger central anticholinergic promethazine, on saccadic and smooth pursuit eye movements, potentially conveys the significance of central cholinergic pathways in the control of these centrally regulated oculomotor processes.

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

BACKGROUND: 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. METHODS: Within a placebo-controlled crossover design, 13 healthy adults ingested caffeine (5 mg·kg-1 body mass) and were tested over 3 h. Eye movements, including saccades, smooth pursuit and optokinetic nystagmus, were measured using infrared oculography. RESULTS: 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. CONCLUSIONS: 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.

Sleep deprivation as an experimental model system for psychosis: Effects on smooth pursuit, prosaccades, and antisaccades.

Current antipsychotic medications fail to satisfactorily reduce negative and cognitive symptoms and produce many unwanted side effects, necessitating the development of new compounds. Cross-species, experimental behavioural model systems can be valuable to inform the development of such drugs. The aim of the current study was to further test the hypothesis that controlled sleep deprivation is a safe and effective model system for psychosis when combined with oculomotor biomarkers of schizophrenia. Using a randomized counterbalanced within-subjects design, we investigated the effects of 1 night of total sleep deprivation in 32 healthy participants on smooth pursuit eye movements (SPEM), prosaccades (PS), antisaccades (AS), and self-ratings of psychosis-like states. Compared with a normal sleep control night, sleep deprivation was associated with reduced SPEM velocity gain, higher saccadic frequency at 0.2 Hz, elevated PS spatial error, and an increase in AS direction errors. Sleep deprivation also increased intra-individual variability of SPEM, PS, and AS measures. In addition, sleep deprivation induced psychosis-like experiences mimicking hallucinations, cognitive disorganization, and negative symptoms, which in turn had moderate associations with AS direction errors. Taken together, sleep deprivation resulted in psychosis-like impairments in SPEM and AS performance. However, diverging somewhat from the schizophrenia literature, sleep deprivation additionally disrupted PS control. Sleep deprivation thus represents a promising but possibly unspecific experimental model that may be helpful to further improve our understanding of the underlying mechanisms in the pathophysiology of psychosis and aid the development of antipsychotic and pro-cognitive drugs.

Effects of nicotine on hippocampal and cingulate activity during smooth pursuit eye movement in schizophrenia.

BACKGROUND: Abnormal smooth pursuit eye movement (SPEM) in schizophrenic patients is a well known phenomenon, but the neurophysiological mechanisms underlying the deficit are unknown. Nicotine temporarily improves SPEM and has been associated with reduced hippocampal hemodynamic activity in schizophrenics. Nicotine's effect on brain activity in control subjects performing SPEM has not been studied. The purpose of this work was to determine if nicotine differentially affects brain activity in schizophrenic and control subjects during pursuit eye tracking. METHODS: 16 subjects with schizophrenia and 16 control subjects underwent functional MR imaging during SPEM after receiving placebo or nicotine gum. Four brain regions were analyzed for main effects of group, drug, and interactions: hippocampus, cingulate gyrus, frontal eye fields, and area MT. RESULTS: Nicotine reduced hippocampal activity in both groups, but the effect was greater in control subjects. A group by drug interaction was observed in the anterior cingulate gyrus, where nicotine decreased activity in control subjects and increased activity in schizophrenic subjects. There were no significant effects of group, drug, or interactions in frontal eye fields or area MT. CONCLUSIONS: Nicotine may improve SPEM performance in people with schizophrenia through cholinergic stimulation of the hippocampus and cingulate gyrus. Potential mechanisms include improved inhibitory function and attention.

Cognition and motor control as a function of Delta9-THC concentration in serum and oral fluid: limits of impairment.

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.