On-the-road driving performance and driving-related skills in older untreated insomnia patients and chronic users of hypnotics.

RATIONALE: Many older adults report sleep problems and use of hypnotics. Several studies have shown that hypnotics can have acute adverse effects on driving the next morning. It is unclear however whether driving of chronic hypnotic users is impaired. Therapeutic effects on insomnia and development of tolerance may reduce the residual effects on driving. OBJECTIVES: The present study aimed to compare actual driving performance and driving-related skills of chronic hypnotic users to good sleepers. To determine whether insomnia itself affects driving performance, driving and driving-related skills were compared between insomnia patients who do not or infrequently use hypnotics and good sleepers. METHODS: Twenty-two frequent users of hypnotics (using hypnotics ≥ 4 nights per week for more than 3 months), 20 infrequent users (using hypnotics ≤ 3 nights per week), and 21 healthy, age-matched controls participated in this study. On the night before testing, all subjects were hospitalized for an 8-h sleep recorded by polysomnography. Frequent hypnotic users used their regular medication at bedtime (2330 hours), while infrequent users and controls received no medication. Cognitive performance (word learning, digit span, tracking, divided attention, vigilance, and inhibitory control) was assessed 8.5 h and driving performance between 10 and 11 h after bedtime and dosing. RESULTS: Polysomnographic recordings did not significantly differ between the groups, but the insomnia patients, treated or untreated, still reported subjective sleep complaints. Results show no differences in driving performance and driving-related skills between both groups of insomnia patients and controls. CONCLUSIONS: Driving performance in chronic users of hypnotics and untreated insomnia patients is not impaired. For chronic users, this may be due to prescription of relatively safe drugs and low doses. For untreated insomniacs, this corroborates previous findings showing an absence of neuropsychological deficits in this group of patients.

Cognitive effects of methylphenidate in healthy volunteers: a review of single dose studies.

Methylphenidate (MPH), a stimulant drug with dopamine and noradrenaline reuptake inhibition properties, is mainly prescribed in attention deficit hyperactivity disorder, is increasingly used by the general population, intending to enhance their cognitive function. In this literature review, we aim to answer whether this is effective. We present a novel way to determine the extent to which MPH enhances cognitive performance in a certain domain. Namely, we quantify this by a percentage that reflects the number of studies showing performance enhancing effects of MPH. To evaluate whether the dose-response relationship follows an inverted-U-shaped curve, MPH effects on cognition are also quantified for low, medium and high doses, respectively. The studies reviewed here show that single doses of MPH improve cognitive performance in the healthy population in the domains of working memory (65% of included studies) and speed of processing (48%), and to a lesser extent may also improve verbal learning and memory (31%), attention and vigilance (29%) and reasoning and problem solving (18%), but does not have an effect on visual learning and memory. MPH effects are dose-dependent and the dose-response relationship differs between cognitive domains. MPH use is associated with side effects and other adverse consequences, such as potential abuse. Future studies should focus on MPH specifically to adequately asses its benefits in relation to the risks specific to this drug.

Residual effects of zopiclone 7.5 mg on highway driving performance in insomnia patients and healthy controls: a placebo controlled crossover study.

RATIONALE: Residual effects of hypnotics on driving performance have been mainly determined in studies using a standardized driving test with healthy good sleepers. Responses to effects may differ, however, between insomniacs and healthy volunteers due to the underlying sleep disorder. In addition, a majority of insomniacs uses hypnotics chronically resulting in the development of tolerance to impairing effects. Impaired driving performance in healthy volunteers may then be an overestimation of the actual effects in insomniacs. OBJECTIVES: The present study aims to compare the residual effects of zopiclone 7.5 mg on on-the-road driving performance of 16 middle-aged insomniacs chronically using hypnotics (chronic users), 16 middle-aged insomniacs not or infrequently using hypnotics (infrequent users), and 16 healthy, age matched, good sleepers (controls). METHODS: The study was conducted according to a 3 × 2 double-blind, placebo controlled crossover design, with three groups and two treatment conditions. Treatments were single oral doses of zopiclone 7.5 mg and placebo administered at bedtime (2330 hours). Between 10 and 11 h after administration subjects performed a standardized highway driving test. RESULTS: Zopiclone 7.5 mg significantly impaired on-the-road driving performance in both insomnia groups and healthy controls. The magnitude of impairment was significantly less in the chronic users group as compared with the controls. CONCLUSIONS: The smaller magnitude of effects suggests that investigating residual effects of hypnotics in healthy volunteers may yield a minor overestimation of the actual effects in insomnia patients.

Cognitive effects of methylphenidate and levodopa in healthy volunteers.

Our previous study showed enhanced declarative memory consolidation after acute methylphenidate (MPH) administration. The primary aim of the current study was to investigate the duration of this effect. Secondary, the dopaminergic contribution of MPH effects, the electrophysiological correlates of declarative memory, and the specificity of memory enhancing effects of MPH to declarative memory were assessed. Effects of 40 mg of MPH on memory performance were compared to 100mg of levodopa (LEV) in a placebo-controlled crossover study with 30 healthy volunteers. Memory performance testing included a word learning test, the Sternberg memory scanning task, a paired associates learning task, and a spatial working memory task. During the word learning test, event-related brain potentials (ERPs) were measured. MPH failed to enhance retention of words at a 30 min delay, but it improved 24 h delayed memory recall relative to PLA and LEV. Furthermore, during encoding, the P3b and P600 ERP latencies were prolonged and the P600 amplitude was larger after LEV compared to PLA and MPH. MPH speeded response times on the Sternberg Memory Scanning task and improved performance on the Paired Associates Learning task, relative to LEV, but not PLA. Performance on the Spatial working memory task was not affected by the treatments. These findings suggest that MPH and LEV might have opposite effects on memory.

Cognitive impairment in depression: a systematic review and meta-analysis.

BACKGROUND: This review aimed to address the question of whether cognitive impairment should be considered a core feature of depression that may be a valuable target for treatment. METHOD: We conducted a systematic review and meta-analysis of cognitive function, assessed with a single neuropsychological test battery, the Cambridge Neuropsychological Test Automated Battery (CANTAB), in patients with depression during symptomatic and remitted states. Inclusion of studies comparing patients remitted from depression and controls enabled us to investigate whether cognitive impairment persists beyond episodes of low mood in depression. RESULTS: Our meta-analysis revealed significant moderate cognitive deficits in executive function, memory and attention in patients with depression relative to controls (Cohen's d effect sizes ranging from -0.34 to -0.65). Significant moderate deficits in executive function and attention (Cohen's d ranging from -0.52 to -0.61) and non-significant small/moderate deficits in memory (Cohen's d ranging from -0.22 to -0.54) were found to persist in patients whose depressive symptoms had remitted, indicating that cognitive impairment occurs separately from episodes of low mood in depression. CONCLUSIONS: Both low mood and cognitive impairment are associated with poor psychosocial functioning. Therefore, we argue that remediation of cognitive impairment and alleviation of depressive symptoms each play an important role in improving outcome for patients with depression. In conclusion, this systematic review and meta-analysis demonstrates that cognitive impairment represents a core feature of depression that cannot be considered an epiphenomenon that is entirely secondary to symptoms of low mood and that may be a valuable target for future interventions.

Higher, faster, stronger: the effect of dynamic stimuli on response preparation and CNV amplitude.

The contingent negative variation (CNV) is a slow negative shift in the electroencephalogram (EEG), observed during response preparation. To optimalize the CNV paradigm, this study developed a task using dynamic stimuli and next combined this task with a Go/No-go test. In the first experiment, 19 healthy volunteers were subjected to the classic Traffic light (TL) task and the new dynamic Lines task. In the Lines task, response time was faster and CNV amplitude was larger compared to the TL task. In the second experiment, 20 healthy participants were tested on a Go/No-go version of the Lines task. Response times increased as the probability of response requirement decreased. CNV amplitude was larger when probability of response requirement was higher. In conclusion, the dynamic task promotes response preparation. The new tasks may be especially valuable in groups with attention difficulties (i.e. elderly or ADHD patients).

Methylphenidate produces selective enhancement of declarative memory consolidation in healthy volunteers.

RATIONALE: Methylphenidate inhibits the reuptake of dopamine and noradrenaline and is used to treat children with attention deficit hyperactivity disorder (ADHD). Besides reducing behavioral symptoms, it improves their cognitive function. There are also observations of methylphenidate-induced cognition enhancement in healthy adults, although studies in this area are relatively sparse. We assessed the possible memory-enhancing properties of methylphenidate. OBJECTIVE: In the current study, the possible enhancing effects of three doses of methylphenidate on declarative and working memory, attention, response inhibition and planning were investigated in healthy volunteers. METHODS: In a double blind placebo-controlled crossover study, 19 healthy young male volunteers were tested after a single dose of placebo or 10, 20 or 40 mg of methylphenidate. Cognitive performance testing included a word learning test as a measure of declarative memory, a spatial working memory test, a set-shifting test, a stop signal test and a computerized version of the Tower of London planning test. RESULTS: Declarative memory consolidation was significantly improved relative to placebo after 20 and 40 mg of methylphenidate. Methylphenidate also improved set shifting and stopped signal task performance but did not affect spatial working memory or planning. CONCLUSIONS: To the best of our knowledge, this is the first study reporting enhanced declarative memory consolidation after methylphenidate in a dose-related fashion over a dose range that is presumed to reflect a wide range of dopamine reuptake inhibition.

40-Hz steady state response in Alzheimer's disease and mild cognitive impairment.

The 40-Hz steady state response (SSR) reflects early sensory processing and can be measured with electroencephalography (EEG). The current study compared the 40-Hz SSR in groups consisting of mild Alzheimer's disease patients (AD) (n=15), subjects with mild cognitive impairment (MCI) (n=20) and healthy elderly control subjects (n=20). All participants were naïve for psychoactive drugs. Auditory click trains at a frequency of 40-Hz evoked the 40-Hz SSR. To evaluate test-retest reliability (TRR), subjects underwent a similar assessment 1 week after the first. The results showed a high TRR and a significant increase of 40-Hz SSR power in the AD group compared to MCI and controls. Furthermore a moderate correlation between 40-Hz SSR power and cognitive performance as measured by ADAS-cog was shown. The results suggest that 40-Hz SSR might be an interesting candidate marker of disease progression.

Histamine H1 receptor antagonist cetirizine impairs working memory processing speed, but not episodic memory.

BACKGROUND AND PURPOSE: The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders. The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction, for example, as associated with the use of centrally active antihistamines. Of the selective second generation antihistamines, cetirizine has been found to have central nervous system effects. The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction. EXPERIMENTAL APPROACH: The study was conducted according to a three-way, double-blind, cross-over design. Treatments were single oral doses of cetirizine 10 and 20 mg and placebo. Effects on cognition were assessed using tests of word learning, memory scanning, vigilance, divided attention, tracking and visual information processing speed. KEY RESULTS: Cetirizine 10 mg impaired tracking performance and both doses impaired memory scanning speed. None of the other measures indicated impaired performance. CONCLUSION AND IMPLICATIONS: Cetirizine affects information processing speed, but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders.

Cognitive domains affected by histamine H(1)-antagonism in humans: a literature review.

The neurotransmitter histamine has been suggested to be involved in cognitive functioning. Generally, studies in animals have shown a decrease in performance after decreasing histamine neurotransmission and improved performance after increasing histamine neurotransmission. It is unclear, however, what role histamine plays in cognition in humans. Up until now, most data are derived from studies and reviews that aimed to assess the sedative potential of H(1)-antagonists and not the effects on cognition in particular. The objective of this paper is specifically to review which cognitive domains are affected by H(1)-antagonists. Taken together, 90 experimental studies on the performance effects of sedative H(1)-antagonists published between 1973 and 2009 were reviewed. Results showed that psychomotor skills and attention are most frequently impaired and memory the least. Tasks assessing memory that were affected usually required rapid responses. It was concluded that both the complexity of the task as well as the demand for information processing speed determines the sensitivity to the effects of central H(1)-antagonism. The importance of the sensitive cognitive domains to histaminergic dysfunction, as well as the relation between histamine related decrease in arousal and task performance deserve further research.

Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the living human brain.

Studies in vitro suggest that the expression of the serotonin transporter (5-HTT) is regulated by polymorphic variation in the promoter region of the 5-HTT gene (5-HTTLPR); however, results from human brain imaging studies examining the relation between 5-HTT genotype and 5-HTT radioligand binding in vivo have been inconsistent. This inconsistency could reflect small participant numbers or the use of sub-optimal radiotracer for measuring the 5-HTT. We used positron emission tomography in conjunction with the selective 5-HTT ligand [(11)C] DASB to examine the availability of the 5-HTT in seven brain regions in 63 healthy European caucasian volunteers who were genotyped for short (S) and long (L) variants (SLC6A4 and rs25531) of the 5-HTTLPR. [(11)C] DASB binding potential was not influenced by the allelic status of participants whether classified on a biallelic or triallelic basis in any of the regions studied. Our PET findings, in a relatively large sample with a near optimal radiotracer, suggest that 5-HTTLPR polymorphic variation does not affect the availability of 5-HTT to [(11)C] DASB binding in adult human brain. The reported impact of 5-HTTLPR polymorphic variation on emotional processing and vulnerability to depression are more likely therefore to be expressed through effects exerted during neurodevelopment.

The effects of acute tryptophan depletion on brain activation during cognition and emotional processing in healthy volunteers.

Acute tryptophan depletion (ATD), a method to temporarily lower central serotonin levels, has been used to study the functioning of the serotonergic system. Relatively recent studies that examined the effects of ATD on brain activation associated with cognitive and emotional processing in healthy volunteers are reviewed. An overview of the findings in healthy volunteers is important for the interpretation of the effect of ATD on brain activation in patients with an affective disorder, such as major depression. These studies show that during response control and negative feedback processing ATD modulates the BOLD response in the inferior/orbitofrontal cortex, the anterior cingulate cortex and the dorsomedial prefrontal cortex. During emotional processing, it is consistently found that ATD modulates the BOLD response in the amygdala. These brain regions also show abnormal activation in depressed patients. However, at the moment it remains unclear if the changes induced by ATD are related to decreased basal serotonin (5-HT) release or the result of other biochemical changes that are mediated by ATD. Future studies should implement methodological improvements, explore the possibilities of new promising imaging techniques and expand investigations into the effects of ATD on basal 5-HT release and other biochemical mechanisms that might be modulated by ATD.

Memory in humans is unaffected by central H1-antagonism, while objectively and subjectively measured sedation is increased.

Animal literature suggests an important role for histamine in memory. In humans, this hypothesis has been scarcely tested and results from studies that have addressed this are conflicting. Second, impaired memory performance may be secondary to sedation. This study aimed to determine whether a centrally active antihistamine impairs memory performance and to dissociate such effects from sedation. Eighteen healthy volunteers received single oral doses of dexchlorpheniramine 4 mg, lorazepam 1mg and placebo in a 3-way, double blind, crossover designed study. The active control lorazepam impaired episodic- and working memory performance and increased sedation, while dexchlorpheniramine only increased sedation.

Method development studies for repeatedly measuring anxiolytic drug effects in healthy humans.

Human experimental models for anxiety may serve as translational tools for translating preclinical psychopharmacological investigations into human studies. For the evaluation of drugs of which pharmacokinetics and pharmacodynamics are unidentified, repeating measurements after drug administration is necessary for characterising the time course of drug effects. In experiment 1, a threat-of-shock paradigm and adaptations of the Trier mental arithmetic test and the Stroop colour naming test were repeated four times within a day to evaluate whether anxiety responses to this test battery remain stable after repeated testing. This procedure was repeated on 4 days in a second experiment to evaluate suitability of the paradigm for a crossover design with multiple sessions. Results indicate no reductions or changes in fear potentiated startle, the main outcome measure for the threat paradigm, over test sessions or days. Skin conductance responses and subjective ratings under threat-of-shock showed significant fluctuations but also no systematic decline over time. Finally, the threat paradigm and Stroop test resulted in small increases in reported state anxiety while mental arithmetic produced larger effects that diminished after the first test day. It is concluded that especially the startle paradigm could be a useful new instrument for screening new anxiolytic drugs.

Effects of L-histidine depletion and L-tyrosine/L-phenylalanine depletion on sensory and motor processes in healthy volunteers.

BACKGROUND AND PURPOSE: Animal studies show that histamine plays a role in cognitive functioning and that histamine H3-receptor antagonists, which increase histaminergic function through presynaptic receptors, improve cognitive performance in models of clinical cognitive deficits. In order to test such new drugs in humans, a model for cognitive impairments induced by low histaminergic functions would be useful. Studies with histamine H1-receptor antagonists have shown limitations as a model. Here we evaluated whether depletion of L-histidine, the precursor of histamine, was effective in altering measures associated with histamine in humans and the behavioural and electrophysiological (event-related-potentials) effects. EXPERIMENTAL APPROACH: Seventeen healthy volunteers completed a three-way, double-blind, crossover study with L-histidine depletion, L-tyrosine/L-phenylalanine depletion (active control) and placebo as treatments. Interactions with task manipulations in a choice reaction time task were studied. Task demands were increased using visual stimulus degradation and increased response complexity. In addition, subjective and objective measures of sedation and critical tracking task performance were assessed. KEY RESULTS: Measures of sedation and critical tracking task performance were not affected by treatment. L-histidine depletion was effective and enlarged the effect of response complexity as measured with the response-locked lateralized readiness potential onset latency. CONCLUSIONS AND IMPLICATIONS: L-histidine depletion affected response- but not stimulus-related processes, in contrast to the effects of H1-receptor antagonists which were previously found to affect primarily stimulus-related processes. L-histidine depletion is promising as a model for histamine-based cognitive impairment. However, these effects need to be confirmed by further studies.

Response speed, contingent negative variation and P300 in Alzheimer's disease and MCI.

BACKGROUND: Decreased speed of information processing is a hallmark of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Recent studies suggest that response speed (RS) measures are very sensitive indicators of changes in longitudinal follow-up studies. Insight into the psycho-physiological underpinnings of slowed RS can be provided by measuring the associated event-related potentials (ERP). AIMS: The current study aims to investigate the relation between RS and its psycho-physiological correlates in AD and MCI. METHODS: Fifteen psychoactive drug-naïve AD patients, 20 MCI patients and twenty age-matched, healthy control subjects participated. Response speed was measured during a simple (SRT) and choice reaction time task (CRT). An oddball and contingent negative variation (CNV) paradigm were used to elicit ERP. To evaluate test-retest reliability (TRR), subjects underwent a similar assessment one week after the first. RESULTS: The SRT and CRT distinguished the patient groups significantly. The P300 amplitude and latency also distinguished the groups and showed a significant correlation with response speed. The CNV amplitude did not reveal a significant difference between groups and also showed a low TRR. The TRR of the SRT, CRT and P300 amplitude and latency in general was moderate to high. The current study suggests that response speed measures on a behavioural and psycho-physiological level deserve attention as a possible marker in the diagnosis and follow-up of AD.

Histamine H1 receptor blockade predominantly impairs sensory processes in human sensorimotor performance.

BACKGROUND AND PURPOSE: Centrally active antihistamines impair cognitive performance, particularly sensorimotor performance. The aim of the present study was to further elucidate the scarcely studied subprocesses involved in sensorimotor performance, which may be affected by H1 receptor blockade. Better knowledge about the cognitive deficits associated with histamine dysfunction can contribute to better treatment of clinical disorders in which histamine hypofunction may be a contributing factor, such as in schizophrenia. EXPERIMENTAL APPROACH: Interactions of dexchlorpheniramine with specific task manipulations in a choice reaction time task were studied. Task demands were increased at the level of sensory subprocesses by decreasing stimulus quality, and at the level of motor subprocesses by increasing response complexity. A total of 18 healthy volunteers (9 female) aged between 18 and 45 years participated in a three-way, double-blind, crossover design. Treatments were single oral doses of 4 mg dexchlorpheniramine, 1 mg lorazepam and placebo. Behavioural effects were assessed by measuring reaction times and effects on brain activity by event-related potentials. KEY RESULTS: Dexchlorpheniramine significantly slowed reaction times, but did not significantly interact with task manipulations. However, it did significantly interact with stimulus quality, as measured by event-related potentials. Lorazepam slowed reaction times and interacted with perceptual manipulations, as shown by effects on reaction times. CONCLUSIONS AND IMPLICATIONS: The results confirm that the histamine system is involved in sensory information processing and show that H1 blockade does not affect motoric information processing. Histamine hypofunction in clinical disorders may cause impaired sensory processing, which may be a drug target.

Memory impairments in humans after acute tryptophan depletion using a novel gelatin-based protein drink.

Acute tryptophan depletion (ATD) can be used to decrease serotonin levels in the brain. Traditionally, ATD has been established by administering amino acid (AA) mixtures and studies using this method showed that serotonin is involved in learning and memory processes. This study used a recently developed gelatin-based protein drink to examine whether it 1) is superior to the traditional AA method in controlling the tryptophan levels in the placebo condition, 2) impairs long-term memory and 3) differentially affects episodic and spatial memory. Sixteen healthy subjects participated in a double-blind, placebo-controlled study. Memory was assessed using a visual verbal learning test and an object relocation task (spatial memory). Tryptophan ratio significantly decreased after ATD and did not significantly increase in the placebo condition. Delayed recall in the verbal learning test and delayed relocation of objects to positions in the spatial task were impaired after ATD. Spatial short-term memory, however, improved. The current results indicate that the tryptophan levels were essentially neutral in the placebo condition compared with those in the traditional AA mixture. Our study provides further evidence that impairment in long-term episodic and elementary spatial memory after ATD is related to lowered tryptophan levels in plasma.