Abstracts

RATIONALE: The purpose of this study is to determine whether electrophysiological measures, in conjunction with behavioral measures and subjective reports, could be used as a sensitive and reliable method in the evaluation of medication-induced cognitive side effects.
METHODS: We recorded multi-channel EEGs from seven healthy young volunteers while they performed easy and difficult versions of a spatial working memory (WM) task, and while they rested quietly. After training, all subjects participated in two sessions separated by at least one week. In one session subjects were given 10 mg/kg of phenytoin in gelatin capsules, and in the other they were given similar placebo capsules. We compared resting and task-related EEG, event-related potentials (ERP), and behavioral performance between placebo and phenytoin conditions.
RESULTS: Average serum phenytoin levels were 7.2 and 9.0 mgm/ml at 3 and 5 hours after ingestion respectively. Task accuracy and response time were not affected by phenytoin even when subjects had reported a significant drug effect. In the resting EEG, phenytoin increased EEG spectral power in the theta (4-7 Hz) band and decreased power in the alpha band (8-12) relative to placebo. In the task-related EEG, the typical task difficulty-related enhancement of the frontal midline theta signal was significantly attenuated by phenytoin (p [lt] 0.01), with the peak effect occurring when the subjective reports of drug effects were maximal. In addition, the expected augmentation of the N160 response to matching stimuli (in comparison to non-matching stimuli) was significantly reduced by phenytoin (p [lt] 0.05). No significant differences were observed in the P300 responses.
CONCLUSIONS: The results of this study show that phenytoin was associated with subjective effects and alterations in neurophysiological signals of attention, even though subjects did not show behavioral impairments. This suggests that subjects were able to muster the resources necessary to compensate for the effects of the drug and maintain accurate performance. However, the electrophysiological measures showed alterations in attention-related neurophysiological signals thus revealing that phenytoin, even at low and therapeutic levels, interfere with cognitive processing, a finding that was consistent with subjective complaints. This suggests that neurophysiological signals may provide a sensitive and reliable index to assess cognitive side effects of anticonvulsants, even under conditions in which behavioral measures are relatively insensitive.
Support: The American Academy of Neurology Education & Research Foundation, National Epifellows Foundation, and the National Institute of Neurological Disorders and Stroke.