Comparing the effects of oxazepam and diazepam in actual highway driving and neurocognitive test performance: a validation study.

OBJECTIVE: Screening of drug-induced performance impairment is needed to provide meaningful information for users and prescribers regarding the impact of drugs on driving. The main objective was to assess the effects of oxazepam 10 mg (OXA10), oxazepam 30 mg (OXA30), and diazepam 10 mg (DIA10) on standard deviation of lateral position (SDLP) in a highway driving test in actual traffic and to determine the ability of eight neurocognitive tests to detect comparable effects. METHODS: Twenty-three healthy volunteers participated in a four-way double-blind, placebo-controlled, crossover study. The highway driving test was conducted between 4 and 5 h after drug intake. A range of neurocognitive tests was conducted before and after driving, 2 and 6 h post-treatment, respectively. RESULTS: Mean SDLP increased by 1.83, 3.03, and 7.57 cm after OXA10, DIA10, and OXA30, respectively. At 2 h post-treatment, all neurocognitive tests, except the useful field of view, showed performance impairment in all active treatments. Effect sizes (ES) were moderate for OXA10, large ES for DIA10, and largest ES for OXA30. Modest correlations were found between changes in SDLP and performance in the attention network test (ANT), the divided attention test (DAT), and the psychomotor vigilance test (PVT). CONCLUSION: OXA10 caused minor, DIA10 moderate, and OXA30 severe driving impairment. No neurocognitive test was both dose dependently sensitive and able to be associated with driving impairment. No neurocognitive test can replace the on-the-road highway driving test.

A pooled analysis of on-the-road highway driving studies in actual traffic measuring standard deviation of lateral position (i.e., "weaving") while driving at a blood alcohol concentration of 0.5 g/L.

INTRODUCTION: The on-the-road highway driving test is generally regarded as a gold standard for assessing drug-induced driving impairment. The primary outcome measure is the standard deviation of lateral position (SDLP), a measure of road tracking error or "weaving". The test has been calibrated for incremental doses of alcohol almost 30 years ago in order to define the impact of drug-induced impairment in terms of blood alcohol concentration (BAC) equivalents. Drug-induced changes in SDLP exceeding 2.4 cm have been evaluated as clinically relevant ever since. The present analysis was conducted to assess the robustness of the alcohol effect in a range of on-the-road driving studies which have been conducted since the initial alcohol calibration study. METHODS: The present study pooled data of 182 participants from nine placebo-controlled crossover studies who performed the highway driving test, while their BAC was at or just below the legal limit for drivers (i.e., 0.5 g/L). RESULTS: Overall, mean SDLP increased with 2.5 cm (95% CI 2.0-2.9 cm). Equivalence testing showed that the clinical relevance criterion value of 2.4 cm fell well within the 95% CI in each individual study. Gender did not affect alcohol-induced changes in SDLP. DISCUSSION: These results demonstrate the robustness and validity of the clinical relevance criterion for SDLP as measured during on-the-road driving.

The sensitivity of laboratory tests assessing driving related skills to dose-related impairment of alcohol: A literature review.

Laboratory tests assessing driving related skills can be useful as initial screening tools to assess potential drug induced impairment as part of a standardized behavioural assessment. Unfortunately, consensus about which laboratory tests should be included to reliably assess drug induced impairment has not yet been reached. The aim of the present review was to evaluate the sensitivity of laboratory tests to the dose dependent effects of alcohol, as a benchmark, on performance parameters. In total, 179 experimental studies were included. Results show that a cued go/no-go task and a divided attention test with primary tracking and secondary visual search were consistently sensitive to the impairing effects at medium and high blood alcohol concentrations. Driving performance assessed in a simulator was less sensitive to the effects of alcohol as compared to naturalistic, on-the-road driving. In conclusion, replicating results of several potentially useful tests and their predictive validity of actual driving impairment should deserve further research. In addition, driving simulators should be validated and compared head to head to naturalistic driving in order to increase construct validity.

Allergic rhinitis is a risk factor for traffic safety.

BACKGROUND: Allergic rhinitis (AR) affects up to 30% of the adult population and symptomatic patients continue to engage in daily life activities, including car driving. Previous studies have shown that AR can impair cognitive functions, especially during longer-lasting tasks. Other reports suggest negative effects on psychomotor functions such as driving, but no clear evidence has been presented yet. OBJECTIVES: Primary objective was to determine the effect of AR per se on actual driving performance and compare it with the effects of treated AR. METHODS: Nineteen patients with documented AR history underwent a unique and validated 1-h on-the-road driving test outside the pollen season. In a 4-leg repeated measures design, patients underwent a nasal provocation test with either pollen or inactive control prior to the driving test. In the three conditions with pollen provocation, patients were pretreated with either cetirizine 10 mg, fluticasone furoate 27.5 µg, or placebo to alleviate the provoked AR symptoms. RESULTS: The driving performance of patients when symptomatic and not treated was significantly impaired compared to the placebo condition. When engaging in a secondary memory task during driving, their performance deteriorated further. The magnitude of impairment was relevant and comparable to that seen at a blood alcohol level of 0.05%, the legal limit in many countries. Treatment of AR symptoms partially counteracted the effect of AR on driving. CONCLUSIONS: Untreated AR can impair driving ability and put patients at risk. Drug therapy reduces this impairment, and AR patients should therefore be advised to always treat their condition.

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.

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.

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.

Age differences in speed of processing are partially mediated by differences in axonal integrity.

Advanced age is associated with declines in brain structure and in cognitive performance, but it is unclear which aspects of brain aging mediate cognitive declines. We inquired if individual differences in white matter integrity contribute to age differences in two cognitive domains with established vulnerability to aging: executive functioning and speed of processing. The participants were healthy volunteers aged 50-81, some of whom had elevated blood pressure, a known vascular risk factor. Using latent variable analyses, we examined whether age differences in regional white matter integrity mediated age-related differences in executive functions and speed of processing. Although diffusion-related latent variables showed stronger age differences than white matter volumes and white matter hyperintensity volumes, only one of them was significantly associated with cognitive performance. Smaller linear anisotropy partially mediated age-related reduction in speed of processing. The effect was significant in posterior (temporal-parietal-occipital) but not anterior (frontal) region, and appeared stronger for cognitive rather than reaction time measures of processing speed. The presence of hypertensive participants did not affect the results. We conclude that in healthy adults, deterioration of axonal integrity and ensuing breech of connectivity may underpin age-related slowing of information processing.

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.

Increased neural activation during picture encoding and retrieval in 60-year-olds compared to 20-year-olds.

Brain aging has been associated with both reduced and increased neural activity during task execution. The purpose of the present study was to investigate whether increased neural activation during memory encoding and retrieval is already present at the age of 60 as well as to obtain more insight into the mechanism behind increased activity. Eighteen young (mean age 21.3) and 18 older (mean age 59.9) right-handed male participants were administered two picture memory tasks in an fMRI environment. Neural activation was measured during encoding and retrieval of pictures of natural scenes (landscapes) and physical objects. Results indicated reduced medial temporal activity during encoding in older participants and increased activity during both encoding and retrieval in several other areas in the brain, including the inferior and dorsolateral prefrontal cortices. This increased activation was not related to better memory performance. The present findings indicate that increased neural activation during memory tasks is present in individuals near the age of 60 compared to individuals near the age of 20, which extends findings from studies of more-advanced age groups. Also, increased activation was present even though cognitive performance at 60 was not as impaired as is generally found in more-advanced age groups. Although compensation is a plausible explanation of the increased activation at this age, we suggest that other mechanisms like disinhibition, dedifferentiation, or the recruitment of less-efficient cognitive strategies may be more likely.

Acute tryptophan depletion selectively attenuates cardiac slowing in an Eriksen flanker task.

In the present study, the effects of transiently lowering central serotonin levels by means of acute tryptophan depletion on measures of cognitive flexibility were examined. Flexible behaviour was measured in an Eriksen flanker task, and cardiac and electro-cortical responses to errors and congruent and incongruent stimuli were measured. The depletion was successful in lowering tryptophan levels and, as expected, it did not affect subjective mood. Depletion did not affect performance and electro-cortical measures and selectively affected cardiac measures. Depletion attenuated cardiac slowing to incongruent flanker stimuli but did not affect cardiac responses to congruent stimuli and errors. The selective effect on cardiac responses as compared to performance and electro-cortical measures was in accordance with earlier findings, as well as the attenuation of cardiac slowing. The selective effect on the cardiac response to incongruent stimuli was unexpected. Detailed analyses showed a close connection to the earlier reported attenuation of the cardiac response to negative feedback, and the effect is explained in terms of reduced anticipation of the feedback stimulus due to enhanced punishment prediction.

Multiple indicators of age-related differences in cerebral white matter and the modifying effects of hypertension.

We investigated differences associated with age and hypertension, a common risk factor for vascular disease, in three aspects of white matter integrity--gross regional volumes of the white matter, volume of the white matter hyperintensities (WMH) and diffusion properties. We acquired MRI scans on 93 adult volunteers (age 50-77 years; 36 with diagnosis of hypertension or elevated blood pressure), and obtained all measures in seven brain regions: frontal, temporal, parietal and occipital white matter, and the genu, body and splenium of the corpus callosum. The results demonstrated robust age-related differences in diffusion-based indices of cerebral white matter integrity and age-related increase in the WMH volume, but no age differences in the gross regional volumes of the white matter. Hypertension was associated with decline in fractional anisotropy, and exacerbated age differences in fractional anisotropy more than those in the volume of WMH. These findings indicate that of all examined measures, diffusion-based indices of white matter integrity may be the most sensitive indicators of global and regional declines and vascular damage in the aging brain.

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.

Prefrontal cortex atrophy predicts dementia over a six-year period.

The present study investigated prefrontal cortex (PFC) atrophy as a possible predictor of dementia. Eighty-eight older participants of the Maastricht Aging Study (MAAS) were administered for neuropsychological tests at baseline and after three years (t(3)). Magnetic resonance images were acquired at t(3) and nine years after baseline all participants were screened for dementia. Three groups were distinguished: (1) participants who did not develop dementia or cognitive decline, (2) participants who did not develop dementia but did show significant cognitive decline, and (3) participants who developed dementia. Gray matter volume of structures in the PFC and medial temporal lobe (MTL) was measured. Prefrontal volume was significantly smaller in group 3 than in the other two groups, and PFC volume was significantly better than MTL volume in distinguishing between groups 2 and 3. These findings suggest that PFC atrophy is highly associated with dementia and can be considered an important predictor of the disease. It may even be a better predictor than the MTL atrophy that has been found in earlier studies.

Increased EEG gamma band activity in Alzheimer's disease and mild cognitive impairment.

High frequency (30-70 Hz) gamma band oscillations in the human electro-encephalogram (EEG) are thought to reflect perceptual and cognitive processes. It is therefore interesting to study these measures in cognitive impairment and dementia. To evaluate gamma band oscillations as a diagnostic biomarker in Alzheimer's disease (AD) and mild cognitive impairment (MCI), 15 psychoactive drug naïve AD patients, 20 MCI patients and 20 healthy controls participated in this study. Gamma band power (GBP) was measured in four conditions viz. resting state, music listening, story listening and visual stimulation. To evaluate test-retest reliability (TRR), subjects underwent a similar assessment one week after the first. The overall TRR was high. Elevated GBP was observed in AD when compared to MCI and control subjects in all conditions. The results suggest that elevated GBP is a reproducible and sensitive measure for cognitive dysfunction in AD in comparison with MCI and controls.

Differences in cognitive performance during pregnancy and early motherhood.

BACKGROUND: Pregnancy has often been associated with cognitive deficits, but results are equivocal and little is known about how these deficits progress with time. METHOD: In the present study, the cognitive performance of 57 pregnant women was compared with that of 50 non-pregnant women matched for age and education, using a well-validated neurocognitive test battery at weeks 14, 17, 29, and 36 of pregnancy, and 32 weeks postpartum in the pregnant group and at comparable times in the non-pregnant group. RESULTS: Memory encoding and retrieval, as assessed with a word learning task, were significantly lower in the pregnant group than in the control group. This difference was still present at 32 weeks after delivery. The two groups did not differ in complex speed of information processing at any of the test moments; however, general speed of information processing was significantly compromised during early motherhood (week 32 postpartum). CONCLUSION: Thus, memory performance is poorer during pregnancy and early motherhood, and general speed of information processing is slower during early motherhood.

Effects of desloratadine, diphenhydramine, and placebo on driving performance and psychomotor performance measurements.

INTRODUCTION: First-generation antihistamines taken for relief of allergic rhinitis are sedating and pose potential risks for those driving a car or operating machinery. Desloratadine is a potent, selective, histamine H(1)-receptor antagonist that does not easily cross the blood-brain barrier. It is nonsedating at therapeutic doses and should not affect driving or psychomotor performance. OBJECTIVE: This study compared the acute effects of desloratadine with diphenhydramine (active control) and placebo on the performance of healthy subjects evaluated with standard over-the-road driving tests (primary objective). The subjects' performances were also evaluated (secondary objective) with the use of conventional performance tests. METHODS: Eighteen men and women received a single dose of desloratadine 5 mg, diphenhydramine 50 mg, or placebo during each period of this randomized, double-blind, three-way, crossover study. Two hours post-dosing, subjects operated a specially instrumented vehicle in a 90-min test designed to measure their ability (1) to maintain constant speed and lateral position while following another vehicle at a constant distance and (2) to respond to brake signals. Additionally, a full battery of performance tests was administered. RESULTS: No significant differences were noted between desloratadine and placebo in standard deviation of lateral position (SDLP), whereas diphenhydramine treatment significantly increased SDLP ( P< 0.001 for both comparisons). Brake reaction time was significantly faster following treatment with desloratadine than diphenhydramine (473.72 ms vs 541.22 ms; P< 0.001) or placebo (512.06 ms; P=0.033). No differences were seen among treatments in deviation of speed or distance to the lead car. The majority of performance tests showed no significant differences among groups. CONCLUSION: Desloratadine at a therapeutic dose does not impair driving performance.

Memory functions and focussed attention in middle-aged and elderly subjects are unaffected by a low, acute dose of caffeine.

The putative beneficial effects of caffeine on cognitive performance may vary between ages. The acute cognitive effects of 100 g caffeine on memory functions and focussed attention were investigated in sixteen middle-aged (45-60 years) and fourteen elderly (60-75 years) healthy men and women according to a cross-over design. Caffeine did not affect short-term memory span or speed, long-term memory retrieval functions or focussed attention. It is proposed that in middle-aged and elderly subjects cognitive effects may occur predominantly at higher caffeine dosages.

Event-related potentials and white matter lesions in bipolar disorder.

OBJECTIVES: To investigate neurophysiological parameters which possibly distinguish subtypes I and II of patients with a bipolar disorder, and contrast the findings with observations from a group of schizophrenic patients and a group of healthy controls. METHODS: Sixty-six volunteers underwent a MRI scan to determine the number and location of white matter lesions (WSL). A electrophysiological registration was made while all volunteers performed a auditory 'oddball' task, and the amplitude of the resulting P300 wave was compared. RESULTS: Earlier reports of higher numbers of WSL in bipolar disorder were not replicated in this study. Subtypes I and II showed a different P300 amplitude and subtype I resembled the results of the schizophrenia group. CONCLUSION: Bipolar patients in remission have a functional brain disorder that is expressed by a change in physiological response to external stimuli.