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.

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.