Neurophysiological pharmacodynamic measures of groups and individuals extended from simple cognitive tasks to more "lifelike" activities.

OBJECTIVE: Extend a method to track neurophysiological pharmacodynamics during repetitive cognitive testing to a more complex "lifelike" task. METHODS: Alcohol was used as an exemplar psychoactive substance. An equation, derived in an exploratory analysis to detect alcohol's EEGs effects during repetitive cognitive testing, was validated in a Confirmatory Study on a new group whose EEGs after alcohol and placebo were recorded during working memory testing and while operating an automobile driving simulator. RESULTS: The equation recognized alcohol by combining five times beta plus theta power. It worked well (p < .0001) when applied to both tasks in the confirmatory group. The maximum EEG effect occurred 2-2.5 h after drinking (>1 h after peak BAC) and remained at 90% at 3.5-4 h (BAC < 50% of peak). Individuals varied in the magnitude and timing of the EEG effect. CONCLUSION: The equation tracked the EEG response to alcohol in the Confirmatory Study during both repetitive cognitive testing and a more complex "lifelike" task. The EEG metric was more sensitive to alcohol than several autonomic physiological measures, task performance measures or self-reports. SIGNIFICANCE: Using EEG as a biomarker to track neurophysiological pharmacodynamics during complex "lifelike" activities may prove useful for assessing how drugs affect integrated brain functioning.

Towards measuring brain function on groups of people in the real world.

In three studies, EEGs from three groups of participants were recorded during progressively more real world situations after drinking alcoholic beverages that brought breath alcohol contents near the limit for driving in California 30 minutes after drinking. A simple equation that measured neurophysiological effects of alcohol in the first group of 15 participants performing repetitive cognitive tasks was applied to a second group of 15 operating an automobile driving simulator, and to a third group of 10 ambulatory people recorded simultaneously during a cocktail party. The equation derived from the first group quantified alcohol's effect by combining measures of higher frequency (beta) and lower frequency (theta) power into a single score. It produced an Area Under the Receiver Operator Characteristic Curve of .73 (p<.05; 67% sensitivity in recognizing alcohol and 87% specificity in recognizing placebo). Applying the same equation to the second group operating the driving simulator, AUC was .95, (p<.0001; 93% sensitivity and 73% specificity), while for the cocktail party group AUC was .87 (p<.01; 80% sensitivity and 80% specificity). EEG scores were significantly related to breath alcohol content in all studies. Some individuals differed markedly from the overall response evident in their respective groups. The feasibility of measuring the neurophysiological effect of a psychoactive substance from an entire group of ambulatory people at a cocktail party suggests that future studies may be able to fruitfully apply brain function measures derived under rigorously controlled laboratory conditions to assess drug effects on groups of people interacting in real world situations.

Long-term and within-day variability of working memory performance and EEG in individuals.

OBJECTIVE: Assess individual-subject long-term and within-day variability of a combined behavioral and EEG test of working memory. METHODS: EEGs were recorded from 16 adults performing n-back working memory tasks, with 10 tested in morning and afternoon sessions over several years. Participants were also tested after ingesting non-prescription medications or recreational substances. Performance and EEG measures were analyzed to derive an Overall score and three constituent sub-scores characterizing changes in performance, cortical activation, and alertness from each individual's baseline. Long-term and within-day variability were determined for each score; medication effects were assessed by reference to each individual's normal day-to-day variability. RESULTS: Over the several year period, the mean Overall score and sub-scores were approximately zero with standard deviations less than one. Overall scores were lower and their variability higher in afternoon relative to morning sessions. At the group level, alcohol, diphenhydramine and marijuana produced significant effects, but there were large individual differences. CONCLUSIONS: Objective working memory measures incorporating performance and EEG are stable over time and sensitive at the level of individual subjects to interventions that affect neurocognitive function. SIGNIFICANCE: With further research these measures may be suitable for use in individualized medical care by providing a sensitive assessment of incipient illness and response to treatment.

The association between obstructive sleep apnea and neurocognitive performance--the Apnea Positive Pressure Long-term Efficacy Study (APPLES).

STUDY OBJECTIVES: To determine associations between obstructive sleep apnea (OSA) and neurocognitive performance in a large cohort of adults. STUDY DESIGN: Cross-sectional analyses of polysomnographic and neurocognitive data from 1204 adult participants with a clinical diagnosis of obstructive sleep apnea (OSA) in the Apnea Positive Pressure Long-term Efficacy Study (APPLES), assessed at baseline before randomization to either continuous positive airway pressure (CPAP) or sham CPAP. MEASUREMENTS: Sleep and respiratory indices obtained by laboratory polysomnography and several measures of neurocognitive performance. RESULTS: Weak correlations were found for both the apnea hypopnea index (AHI) and several indices of oxygen desaturation and neurocognitive performance in unadjusted analyses. After adjustment for level of education, ethnicity, and gender, there was no association between the AHI and neurocognitive performance. However, severity of oxygen desaturation was weakly associated with worse neurocognitive performance on some measures of intelligence, attention, and processing speed. CONCLUSIONS: The impact of OSA on neurocognitive performance is small for many individuals with this condition and is most related to the severity of hypoxemia.

A method to combine cognitive and neurophysiological assessments of the elderly.

BACKGROUND: The development of better treatments for brain diseases of the elderly will necessitate more sensitive and efficient means of repeatedly assessing an individual's neurocognitive status. AIM: To illustrate the development of an assessment combining episodic memory and working memory tasks with simultaneous electroencephalography and evoked potential (EP) brain function measures. METHODS: Data from matched groups of elderly subjects with mildly impaired episodic verbal memory on neuropsychological tests and those with no objective signs of impairment were used for scale development. An exploratory multivariate divergence analysis selected task performance and neurophysiological variables that best recognized impairment. Discriminant validity was then initially assessed on separate impaired and unimpaired groups. RESULTS: Decreased response accuracy and parietal late positive component EP amplitude in the episodic memory task best characterized impaired subjects. Sensitivity in recognizing impairment in the validation analysis was 89% with 79% specificity (area under the curve = 0.94). Retest reliability was 0.89 for the unimpaired and 0.74 for the impaired validation groups. CONCLUSION: These promising initial results suggest that with further refinement and testing, an assessment combining cognitive task performance with simultaneous neurofunctional measures could eventually provide an important benefit for clinicians and researchers.

Combined neuropsychological and neurophysiological assessment of drug effects on groups and individuals.

An initial standardized approach for combining neuropsychological and neurophysiological measures in order to assess the neurocognitive effects of drugs in groups and individuals is introduced. Its application is illustrated with sedatives, antiepileptic drugs, psychostimulants, antihistamines, and intoxicants. Task performance, electroencephalography, and evoked potential measures during computerized attention and memory testing that are most sensitive to drug effects are identified in a sample population and then applied to individuals. In six example exploratory studies, drug effects were detected with an average area under curve (AUC) of 0.97 (p < 0.0001; 95% sensitivity, 96% specificity). In 10 example validation studies with other drugs and/or different subjects and populations, detection was strong in the eight studies with drugs and doses known to have significant neurocognitive effects (AUC 0.83, p < 0.0001; 82% sensitivity, 89% specificity), whereas no effect was detected in the two studies with drugs known to have faint neurocognitive effects (AUC 0.56, p > 0.10). Individual differences in response to different drugs with similar clinical uses, to varying doses of the same drug, and in pharmacodynamic response were then demonstrated. The significant (p < 0.01) increase in sensitivity and specificity of combined neuropsychological and neurophysiological measures compared with the former alone suggests that fewer subjects may be needed to assess the neurocognitive effects of drugs in future studies. The findings suggest that the concept of combining neuropsychological testing with simultaneous measures of neurophysiological function is worth further exploration.

A cognitive and neurophysiological test of change from an individual's baseline.

OBJECTIVE: An automated cognitive neurophysiological test is presented that characterizes how an individual was affected by a drug or treatment. The test calculates sub-scores for working memory task performance, cortical activation, and alertness, and combines the sub-scores into an overall score. METHODS: The test was applied in a double-blind, placebo-controlled study of alcohol, caffeine, diphenhydramine, and sleep deprivation in 16 healthy adults. RESULTS: The between- and within-day variability of the sub-scores and overall scores for placebo were all near zero, suggesting that the scores are stable. All treatments affected the overall score, while differential effects on sub-scores highlighted the added value of EEG measures. CONCLUSIONS: The test is sensitive to relatively mild alterations in cognitive function. Its automation makes it suitable for use in large-scale clinical trials. SIGNIFICANCE: By combining task performance with EEG brain function measures, the test may prove to have better sensitivity and specificity in detecting changes due to drugs or other treatments than comparable neuropsychological test batteries that do not directly measure brain function signals.

Validation of an instrument to assess patient attitudes towards prescribing of pharmaceuticals by doctors.

OBJECTIVES: To establish the reliability and validity of a questionnaire designed to assess Chinese patients' attitudes towards pharmaceuticals that may influence the prescribing behaviours of their doctors. STUDY DESIGN: A draft questionnaire of 48 items was designed in English, translated into Chinese, and then back-translated into English. After establishing for content and face validity, it was administered to a convenience sample of patients. Responses were factor analysed to establish construct validity and to reduce the questionnaire's length. POPULATION: Hong Kong Chinese patients (n = 387) who visited one of 24 primary care doctors. OUTCOMES MEASURED: Derived factor score means were compared among various age, gender and education groupings. RESULTS: A final 21-item questionnaire was produced. Spearman's rank correlations indicated the instrument was relatively stable over repeated applications. Patients' attitudes were found to be multidimensional. The three-factor solution achieved a simple structure and accounted for 40% of the variance among the 21 items. Items loading heavily on each construct were internally consistent. Nine items measured patients' attitudes towards careful use of medications. Six questions measured a preference for information exchanges between patients and doctors. Six items measured patients' scepticism concerning the need for pharmaceuticals to hasten recovery from most illnesses. The three factors yielded factor score means that discriminated among the patients as expected. CONCLUSIONS: The questionnaire met adequate standards for reliability and validity. It is suitable for further use in investigating Chinese patients' attitudes concerning pharmaceuticals and how these attitudes might influence their physicians' prescribing behaviours.

Eradication of Helicobacter pylori and risk of peptic ulcers in patients starting long-term treatment with non-steroidal anti-inflammatory drugs: a randomised trial.

BACKGROUND: Whether Helicobacter pylori increases the risk of ulcers in patients taking non-steroidal anti-inflammatory drugs (NSAIDs) is controversial. We hypothesised that eradication of H pylori infection would reduce the risk of ulcers for patients starting long-term NSAID treatment. METHODS: Patients were enrolled if they were NSAID naïve, had a positive urea breath test, had dyspepsia or an ulcer history, and required long-term NSAID treatment. They were randomly assigned omeprazole triple therapy (eradication group) or omeprazole with placebo antibiotics (placebo group) for 1 week. All patients were given diclofenac slow release 100 mg daily for 6 months from randomisation. Endoscopy was done at 6 months or if severe dyspepsia or gastrointestinal bleeding occurred. The primary endpoint was the probability of ulcers within 6 months. Analyses were by intention to treat. FINDINGS: Of 210 arthritis patients screened, 128 (61%) were positive for H pylori. 102 patients were enrolled, and 100 were included in the intention-to-treat analysis. H pylori was eradicated in 90% of the eradication group and 6% of the placebo group. Five of 51 eradication-group patients and 15 of 49 placebo-group patients had ulcers. The 6-month probability of ulcers was 12.1% (95% CI 3.1-21.1) in the eradication group and 34.4% (21.1-47.7) in the placebo group (p=0.0085). The corresponding 6-month probabilities of complicated ulcers were 4.2% (1.3-9.7) and 27.1% (14.7-39.5; p=0.0026). INTERPRETATION: Screening and treatment for H pylori infection significantly reduces the risk of ulcers for patients starting long-term NSAID treatment.