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.

Long-Term Neurophysiologic Impact of Childhood Sleep Disordered Breathing on Neurocognitive Performance.

STUDY OBJECTIVE: To determine the impact of sleep disordered breathing (SDB) in children on neurocognitive function 5 years later. DESIGN SETTING AND PARTICIPANTS: A subgroup of 43 children from the Tucson Children's Assessment of Sleep Apnea Study (TuCASA) who had SDB (RDI ≥ 6 events/hour) at their initial exam (ages 6-11 years) were matched on the basis of age (within 1 year), gender and ethnicity (Anglo/Hispanic) to 43 children without SDB (Control, RDI ≤ 4 events/hour). The Sustained Working Memory Task (SWMT) which combines tests of working memory (1-Back Task), reaction time (Simple Reaction Time) and attention (Multiplexing Task) with concurrent electroencephalographic monitoring was administered approximately 5 years later. RESULTS: There were no differences in performance on the working memory, reaction time and attention tests between the SDB and Control groups. However, the SDB group exhibited lower P300 evoked potential amplitudes during the Simple Reaction Time and Multiplexing Tasks. Additionally, peak alpha power during the Multiplexing Task was lower in the SDB Group with a similar trend in the Simple Reaction Time Task (p=0.08). CONCLUSIONS: SDB in children may cause subtle long-term changes in executive function that are not detectable with conventional neurocognitive testing and are only evident during neuroelectrophysiologic monitoring.

Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES).

STUDY OBJECTIVE: To determine the neurocognitive effects of continuous positive airway pressure (CPAP) therapy on patients with obstructive sleep apnea (OSA). DESIGN, SETTING, AND PARTICIPANTS: The Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, randomized, double-blind, 2-arm, sham-controlled, multicenter trial conducted at 5 U.S. university, hospital, or private practices. Of 1,516 participants enrolled, 1,105 were randomized, and 1,098 participants diagnosed with OSA contributed to the analysis of the primary outcome measures. INTERVENTION: Active or sham CPAP MEASUREMENTS: THREE NEUROCOGNITIVE VARIABLES, EACH REPRESENTING A NEUROCOGNITIVE DOMAIN: Pathfinder Number Test-Total Time (attention and psychomotor function [A/P]), Buschke Selective Reminding Test-Sum Recall (learning and memory [L/M]), and Sustained Working Memory Test-Overall Mid-Day Score (executive and frontal-lobe function [E/F]) RESULTS: The primary neurocognitive analyses showed a difference between groups for only the E/F variable at the 2 month CPAP visit, but no difference at the 6 month CPAP visit or for the A/P or L/M variables at either the 2 or 6 month visits. When stratified by measures of OSA severity (AHI or oxygen saturation parameters), the primary E/F variable and one secondary E/F neurocognitive variable revealed transient differences between study arms for those with the most severe OSA. Participants in the active CPAP group had a significantly greater ability to remain awake whether measured subjectively by the Epworth Sleepiness Scale or objectively by the maintenance of wakefulness test. CONCLUSIONS: CPAP treatment improved both subjectively and objectively measured sleepiness, especially in individuals with severe OSA (AHI > 30). CPAP use resulted in mild, transient improvement in the most sensitive measures of executive and frontal-lobe function for those with severe disease, which suggests the existence of a complex OSA-neurocognitive relationship. CLINICAL TRIAL INFORMATION: Registered at clinicaltrials.gov. Identifier: NCT00051363. CITATION: Kushida CA; Nichols DA; Holmes TH; Quan SF; Walsh JK; Gottlieb DJ; Simon RD; Guilleminault C; White DP; Goodwin JL; Schweitzer PK; Leary EB; Hyde PR; Hirshkowitz M; Green S; McEvoy LK; Chan C; Gevins A; Kay GG; Bloch DA; Crabtree T; Demen WC. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: the Apnea Positive Pressure Long-term Efficacy Study (APPLES). SLEEP 2012;35(12):1593-1602.

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.

Neurocognitive effects of brivaracetam, levetiracetam, and lorazepam.

PURPOSE: Brivaracetam (BRV) is a new anticonvulsant under development. Although BRV is an analog of levetiracetam (LEV), in addition to being an SV2A ligand, it also inhibits sodium channels in a voltage-dependent manner. The cognitive effects of BRV are uncertain. METHODS: A randomized, double-blind, placebo-controlled, four-way cross-over design was employed in 16 healthy volunteers comparing acute dosing (i.e., two doses) of BRV 10 mg, LEV 500 mg, lorazepam (LZP) 2 mg, and placebo. The primary outcome was the summary score from the cognitive neurophysiologic test (CNT), which combines electrophysiologic and performance measures. Secondary outcomes included CNT cognitive and electrophysiologic subscores, traditional neuropsychological measures, and treatment-emergent adverse events (TEAEs). RESULTS: Compared to BRV, LEV, and placebo, LZP adversely affected the CNT summary score and the majority of CNT subscores and neuropsychological measures. In contrast, BRV did not differ from placebo or LEV on any measure. More TEAEs occurred with LZP compared to each of the other treatment conditions. DISCUSSION: The differential pattern of drug effects was consistent across multiple electrophysiologic, cognitive, and subjective measures. The profile of cognitive, subjective, and electrophysiologic effects for BRV was similar to the analog compound LEV and to placebo. The findings suggest that BRV should be tolerated well from a neuropsychological perspective, but additional studies are needed.

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.

Neurophysiological and cognitive effects of smoked marijuana in frequent users.

RATIONALE: Previously, we reported that acute marijuana intoxication minimally affected complex cognitive performance of daily marijuana smokers. It is possible that the cognitive tests used were insensitive to marijuana-related cognitive effects. OBJECTIVES: In the current study, electroencephalographic (EEG) signals were recorded as daily marijuana users performed additional tests of immediate working memory and delayed episodic memory, before and after smoking marijuana. METHODS: Research volunteers (N=24), who reported smoking approximately 24 marijuana cigarettes/week, completed this study. Participants completed baseline computerized cognitive tasks, smoked a single marijuana cigarette (0%, 1.8%, or 3.9% (9)-THC w/w), and completed additional cognitive tasks; sessions were separated by at least 72-hours. Cardiovascular and subjective effects were also assessed throughout sessions. RESULTS: Overall performance accuracy was not significantly altered by marijuana, although the drug increased response times during task performance and induced a response bias towards labeling "new" words as having been previously seen in the verbal episodic memory task. Marijuana reduced slow wave evoked potential amplitude in the episodic memory task and decreased P300 amplitude and EEG power in the alpha band in the spatial working memory task. Heart rate and "positive" subjective-effect ratings were increased in a (9)-THC concentration-dependent manner. CONCLUSIONS: Relative to previous findings with infrequent marijuana users, the frequent users in the current study exhibited similar neurophysiological effects but more subtle performance effects. These data emphasize the importance of taking into account the drug-use histories of research participants and examining multiple measures when investigating marijuana-related effects on cognitive functioning.

Characterizing impaired functional alertness from diphenhydramine in the elderly with performance and neurophysiologic measures.

STUDY OBJECTIVES: Psychometric task performance measures can be highly sensitive to manipulations that impair functional alertness in young adults; such measures have been shown to be less sensitive to reduced alertness in older adults. The purpose of this study is to determine whether neurophysiologic measures can aid in the detection and characterization of impairments in functional alertness in the elderly. DESIGN: Double-blind, placebo-controlled, counter-balanced, crossover study. SETTING: Research laboratory. PARTICIPANTS: Twelve healthy older adults (62-75 years of age). INTERVENTIONS: Diphenhydramine, 50 mg. MEASUREMENTS AND RESULTS: Behavioral performance and electroencephalogram measures were obtained while participants completed spatial working memory and word recognition episodic memory tasks in a baseline interval before drug ingestion and in 4 hourly test intervals following drug ingestion. Relative to placebo, diphenhydramine had marginal effects on task performance yet was effective in reducing alertness, as evidenced by subjective ratings and objective neurophysiologic (electroencephalogram) markers. Diphenhydramine significantly reduced the amplitude of alertness-sensitive event-related potentials recorded during working memory task performance, including the N160 and P300. It also affected neurophysiologic processes underlying episodic memory, as evidenced by a reduction in the difference in event-related potentials between old and new words in the word recognition task. Discriminant analyses incorporating neurophysiologic measures showed that the time course of the central effects of diphenhydramine in older subjects was similar to that previously observed in young adults. CONCLUSIONS: These results demonstrate that diphenhydramine has adverse neurocognitive effects in elderly individuals and highlights the utility of incorporating direct measures of brain function into assessments of functional alertness.

Distinct cognitive neurophysiologic profiles for lamotrigine and topiramate.

PURPOSE: To contrast the effects of lamotrigine (LTG) and topiramate (TPM) on cognitive task-related and resting-state EEG and evoked potential (EP) measures. METHODS: We used a double-blind, randomized, crossover design. Healthy adults (N = 29) had two 8-week periods of dose escalation, 4 weeks of drug maintenance (300 mg daily), and 4 weeks of washout. EEG was recorded during working memory (WM) tasks and resting conditions at baseline, at the end of each maintenance phase, and after final washout. RESULTS. LTG did not affect overt performance on the tasks, although it reduced EEG power in both resting and WM task conditions, most prominently in the 6- to 12-Hz frequency range, and attenuated P300 evoked-potential amplitude equally in both WM task loads. TPM slowed responses and increased errors. It also increased EEG power below 6 Hz in all conditions, and reduced the amplitude of a slow wave observed in a difficult version of the WM task. CONCLUSIONS: The drugs produced both task-independent and task-related alterations in neurophysiologic measures. The EEG and EP changes produced by TPM are consistent with an impairment of WM, as evidenced by overt performance deficits on the behavioral tasks. By contrast, the reduction in synchronous cortical activity produced by LTG was not accompanied by cognitive impairment. It is unknown whether such effects would also be observed at lower doses, such as those that often are used in monotherapy for newly diagnosed patients.

The Apnea Positive Pressure Long-term Efficacy Study (APPLES): rationale, design, methods, and procedures.

STUDY OBJECTIVE: To assess the size, time course, and durability of the effects of long-term continuous positive airway pressure (CPAP) therapy on neurocognitive function, mood, sleepiness, and quality of life in patients with obstructive sleep apnea. DESIGN: Randomized, double-blinded, 2-arm, sham-controlled, multicenter, long-term, intention-to-treat trial of CPAP therapy. SETTING: Sleep clinics and laboratories at 5 university medical centers and community-based hospitals. PATIENTS OR PARTICIPANTS: Target enrollment is 1100 randomly assigned subjects across 5 clinical centers. INTERVENTIONS: Active versus sham (subtherapeutic) CPAP. MEASUREMENTS AND RESULTS: A battery of conventional and novel tests designed to evaluate neurocognitive function, mood, sleepiness, and quality of life. CONCLUSIONS: The Apnea Positive Pressure Long-term Efficacy Study (APPLES) is designed to study obstructive sleep apnea and test the effects of CPAP through a comprehensive, controlled, and long-term trial in a large sample of subjects with obstructive sleep apnea.

Effects of marijuana on neurophysiological signals of working and episodic memory.

RATIONALE: The primary psychoactive constituent of marijuana, Delta9-THC, activates cannabinoid receptors, which are especially abundant in the frontal cortex and hippocampus. Acute marijuana smoking can disrupt working memory (WM) and episodic memory (EM) functions that are known to rely on these regions. However, the effects of marijuana on the brain activity accompanying such cognitive processes remain largely unexplored. OBJECTIVES: To examine such effects on performance and neurophysiological signals of these functions, EEG recordings were obtained from ten subjects (5M, 5F) performing cognitive tasks before and after smoking marijuana (3.45% Delta9-THC) or a placebo. WM was assessed with a spatial N-back task, and EM was evaluated with a test requiring recognition of words after a 5-10 min delay between study and test. RESULTS: Marijuana increased heart rate and decreased global theta band EEG power, consistent with increased autonomic arousal. Responses in the WM task were slower and less accurate after smoking marijuana, accompanied by reduced alpha band EEG reactivity in response to increased task difficulty. In the EM task, marijuana was associated with an increased tendency to erroneously identify distracter words as having been previously studied. In both tasks, marijuana attenuated stimulus-locked event-related potentials (ERPs). CONCLUSIONS: The results suggest that marijuana disrupted both sustained and transient attention processes resulting in impaired memory task performance. In subjects most affected by marijuana a pronounced ERP difference between previously studied words and new distracter words was also reduced, suggesting disruption of neural mechanisms underlying memory for recent study episodes.

The impact of moderate sleep loss on neurophysiologic signals during working-memory task performance.

STUDY OBJECTIVES: This study examined how sleep loss affects neurophysiologic signals related to attention and working memory. DESIGN: Subjective sleepiness, resting-state electroencephalogram, and behavior and electroencephalogram during performance of working-memory tasks were recorded in a within-subject, repeated-measures design. SETTING: Data collection occurred in a computerized laboratory setting. PARTICIPANTS: Sixteen healthy adults (mean age, 26 years; 8 female) INTERVENTIONS: Data from alert daytime baseline tests were compared with data from tests during a late-night, extended-wakefulness session that spanned up to 21 hours of sleep deprivation. MEASUREMENTS AND RESULTS: Alertness measured both subjectively and electrophysiologically decreased monotonically with increasing sleep deprivation. A lack of alertness-related changes in electroencephalographic measures of the overall mental effort exerted during task execution indicated that participants attempted to maintain high levels of performance throughout the late-night tests. Despite such continued effort, responses became slower, more variable, and more error prone within 1 hour after participants' normal time of sleep onset. This behavior failure was accompanied by significant degradation of event-related brain potentials related to the transient focusing of attention. CONCLUSIONS: Moderate sleep loss compromises the function of neural circuits critical to subsecond attention allocation during working-memory tasks, even when an effort is made to maintain wakefulness and performance. Multivariate analyses indicate that combinations of working-memory-related behavior and neurophysiologic measures can be sensitive enough to permit reliable detection of such effects of sleep loss in individuals. Similar methods might prove useful for assessment of functional alertness in patients with sleep disorders.

Task-related EEG and ERP changes without performance impairment following a single dose of phenytoin.

OBJECTIVES: The acute effects of a single, low dose of phenytoin on behavioral and neurophysiological measures of cognitive function were examined in healthy adults. METHODS: Electroencephalograms (EEGs) were recorded from 7 healthy volunteers while they performed spatial working memory tasks and while they rested quietly. Behavioral measures, EEG power spectra, and event-related potentials (ERPs) were compared between separate sessions in which subjects ingested either 10mg/kg of phenytoin or placebo. RESULTS: Peak serum levels of phenytoin were in the low therapeutic range. Although participants reported subjective effects of the drug, task accuracy and response time were not affected. In the resting EEG, phenytoin decreased power in the alpha band. In the task-related EEG, the frontal midline theta signal was enhanced in response to increased task difficulty following placebo but not following phenytoin. An attention-related augmentation of the N160 ERP to matching stimuli was also reduced by phenytoin. CONCLUSIONS: Neurophysiological measures displayed sensitivity to subtle alterations in attentional processing even in response to a dose of phenytoin too low to produce behavioral impairment. Such results indicate that EEG and ERP measures can provide information about the neurocognitive side effects of medications that cannot be inferred from cognitive task performance measures alone.

Tracking the cognitive pharmacodynamics of psychoactive substances with combinations of behavioral and neurophysiological measures.

Many common pharmacological treatments have effects on cognitive ability. Psychometric task batteries used to characterize such effects do not provide direct information about treatment-related changes in brain function. Since overt task performance reflects motivation and effort as well as ability, behavioral measures alone may overestimate or underestimate the impact of a pharmacological intervention on brain function. Here we present a method that combines behavioral and neurophysiological measures in an attempt to detect the psychoactive effects of pharmacological treatments with greater sensitivity than that provided by behavioral measures alone. Initial application of the method is made to the data from a double blind, placebo-controlled, crossover study in which caffeine, diphenhydramine, and alcohol were used to alter the mental state of 16 healthy subjects at rest and while they performed low load and high load versions of a working memory task. For each intervention, more sensitive detection of drug or alcohol effects over a four hour period was obtained when EEG variables were included in multivariate analyses than when only behavioral variables were used. These initial results suggest that it can be useful to incorporate neurophysiological measures of brain activity into inferences concerning the acute impact of drugs on mental function, and demonstrate the feasibility of using multivariate combinations of behavioral and neurophysiological measures to sensitively characterize the pharmacodynamics of drug-induced changes in cognition.