Neuropsychological and neurophysiologic effects of carbamazepine and levetiracetam.

BACKGROUND: The relative effects of levetiracetam (LEV) and carbamazepine (CBZ) on cognitive and neurophysiologic measures are uncertain. METHODS: The effects of LEV and CBZ were compared in healthy adults using a randomized, double-blind, two-period crossover design. Outcome measures included 11 standard neuropsychological tests and the score from a cognitive-neurophysiologic test of attention and memory. Evaluations were conducted at screening, baseline pre-drug treatment, end of each maintenance phase (4 weeks), and end of each washout period after drug treatment. RESULTS: A total of 28 adults (17 women) with mean age of 33 years (range 18 to 51) completed the study. Mean maintenance doses (+/-SD) were CBZ = 564 mg/day (110) and LEV = 2,000 mg/day (0). CBZ was adjusted to mid-range therapeutic level. Mean serum levels (+/-SD) were CBZ = 7.5 mcg/mL (1.5) and LEV = 32.2 mcg/mL (11.2). An overall composite score including all measures revealed worse effects for CBZ compared to LEV (p

Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids.

This study investigated the contribution of different cannabinoids to the subjective, behavioral and neurophysiological effects of smoked marijuana. Healthy marijuana users (12 men, 11 women) participated in four sessions. They were randomly assigned to a low or a high delta9-tetrahydrocannabinol group (THC; 1.8% versus 3.6%). In the four sessions under blinded conditions subjects smoked marijuana cigarettes containing placebo (no active cannabinoids), or cigarettes containing THC with low or high levels of cannabichromene (CBC; 0.1% versus 0.5%) and low or high levels of cannabidiol (CBD; 0.2% versus 1.0%). Dependent measures included subjective reports, measures of cognitive task performance and neurophysiological measures [electroencephalographic (EEG) and event-related potential (ERP)]. Compared to placebo, active THC cigarettes produced expected effects on mood, behavior and brain activity. A decrease in performance, reduction in EEG power and attenuation of ERP components reflecting attentional processes were observed during tests of working memory and episodic memory. Most of these effects were not dose-dependent. Varying the concentrations of CBC and CBD did not change subjects' responses on any of the outcome measures. These findings are consistent with previous studies indicating that THC and its metabolites are the primary active constituents of marijuana. They also suggest that neurophysiological EEG and ERP measures are useful biomarkers of the effects of THC.

Neurophysiological signals of working memory in normal aging.

To examine how neurophysiological signals of working memory (WM) change with normal aging, we recorded EEGs from healthy groups (n=10 each) of young (mean age=21 years), middle-aged (mean=47 years), and older (mean=69 years) adults. EEGs were recorded while subjects performed easy and difficult versions of a spatial WM task. Groups were matched for IQ (mean=123; WAIS-R) and practiced in task performance. Responses slowed with age, particularly in the more difficult task. Advanced age was associated with decreased amplitude and increased latency of the parietal P300 component of the event-related potential and an increase in the amplitude of a frontal P200 component. Spectral features of the EEG also differed between groups. Younger subjects displayed an increase in the frontal midline θ rhythm with increased task difficulty, a result not observed in older subjects. Age-related changes were also observed in the task-related alpha signal, the amplitude of which decreases as more neurons become involved in task-related processing. Young adults showed a decrease in alpha power with increased task difficulty over parietal regions but not over frontal regions. Middle-aged and older adults showed decreased alpha power with increased task difficulty over both frontal and parietal regions. This suggests that normal aging may be associated with changes in the fronto-parietal networks involved with spatial WM processes. Younger subjects appear to use a strategy that relies on parietal areas involved with spatial processing, whereas older subjects appear to use a strategy that relies more on frontal areas.

Monitoring task loading with multivariate EEG measures during complex forms of human-computer interaction.

Electroencephalographic (EEG) recordings were made while 16 participants performed versions of a personal-computer-based flight simulation task of low, moderate, or high difficulty. As task difficulty increased, frontal midline theta EEG activity increased and alpha band activity decreased. A participant-specific function that combined multiple EEG features to create a single load index was derived from a sample of each participant's data and then applied to new test data from that participant. Index values were computed for every 4 s of task data. Across participants, mean task load index values increased systematically with increasing task difficulty and differed significantly between the different task versions. Actual or potential applications of this research include the use of multivariate EEG-based methods to monitor task loading during naturalistic computer-based work.

Prolonged neurophysiological effects of cumulative wine drinking.

The effects of a single, large dose of alcohol have been studied extensively, but how alcohol affects the brain under more realistic social drinking situations has received scant attention. The neurophysiological effects of a cumulative dose of alcohol were investigated as subjects drank three glasses of alcoholic or placebo red wine, 1 h apart. In a double-blind procedure, electroencephalographic (EEG) activity was recorded for social drinkers during rest and performance of a working memory task at two levels of difficulty. Background EEG power in the theta, slow alpha, and beta bands increased with alcohol consumption. Along with this systemic increase in background cortical resonant activity, event-related potential (ERP) amplitudes decreased between 200 and 350 ms poststimulus and P300 latency increased, effects that occurred while relevant stimulus factors were being evaluated. These neurophysiological effects endured 3 h after drinking, whereas blood/breath alcohol concentration had decreased considerably and cognitive performance returned to normal. These findings seem to indicate that moderate social alcohol consumption has cumulative effects on brain function that persist for hours after chemical and behavioral indicators of intoxication have diminished. The results seem to indicate that neuronal populations needed for stimulus processing were less available after wine consumption (as evidenced by reduced ERP amplitudes) because of increased background oscillatory activity (as evidenced by increased background EEG power).

Neurophysiological measures of working memory and individual differences in cognitive ability and cognitive style.

The capacity to deliberately control attention in order to hold and manipulate information in working memory is critical to higher cognitive functions. This suggests that between-subject differences in general cognitive ability might be related to observable differences in the activity of brain systems that support working memory and attention control. To test this notion, electroencephalograms were recorded from 80 healthy young adults during spatial working memory tasks. Measures of task-related neurophysiological and behavioral variables were derived from these data and compared to scores on a test battery commonly used to assess general cognitive ability (the WAIS-R). Subjects who scored high on the psychometric test also tended to respond faster in the experimental tasks without any loss of accuracy. The amplitude of the late positive component of the event-related potential was larger in high-ability subjects, and the frontal midline theta component of the EEG signal was also selectively enhanced in this group under conditions of sustained performance and high working memory load. These results suggest that subjects who scored high on the WAIS-R were better able to focus and sustain attention to task performance. Changes in the EEG alpha rhythm in response to manipulations of task practice and load were also examined and compared between frontal and parietal regions. The results indicated that high-ability subjects developed strategies that made relatively greater use of parietal regions, whereas low-ability subjects relied more exclusively on frontal regions. Other analyses indicated that hemispheric asymmetries in alpha band measures distinguish between individuals with relatively high verbal aptitude and those with relatively high nonverbal aptitude. In particular, subjects with a verbal cognitive style tended to make greater use of the left parietal region during task performance, and subjects with a nonverbal style tended to make greater use of the right parietal region. These results help clarify relationships between task-related brain activity and individual differences in cognitive ability and style.

Test-retest reliability of cognitive EEG.

OBJECTIVE: Task-related EEG is sensitive to changes in cognitive state produced by increased task difficulty and by transient impairment. If task-related EEG has high test-retest reliability, it could be used as part of a clinical test to assess changes in cognitive function. The aim of this study was to determine the reliability of the EEG recorded during the performance of a working memory (WM) task and a psychomotor vigilance task (PVT). METHODS: EEG was recorded while subjects rested quietly and while they performed the tasks. Within session (test-retest interval of approximately 1 h) and between session (test-retest interval of approximately 7 days) reliability was calculated for four EEG components: frontal midline theta at Fz, posterior theta at Pz, and slow and fast alpha at Pz. RESULTS: Task-related EEG was highly reliable within and between sessions (r0.9 for all components in WM task, and r0.8 for all components in the PVT). Resting EEG also showed high reliability, although the magnitude of the correlation was somewhat smaller than that of the task-related EEG (r0.7 for all 4 components). CONCLUSIONS: These results suggest that under appropriate conditions, task-related EEG has sufficient retest reliability for use in assessing clinical changes in cognitive status.

Detecting transient cognitive impairment with EEG pattern recognition methods.

This paper describes an initial evaluation of a new method for assessing transient states of cognitive impairment associated with intoxication or fatigue: neural network pattern recognition applied to features of the electroencephalogram (EEG) recorded from subjects performing a standardized task. Nine subjects performed a working memory task during an extended testing session occurring over the course of one night, and encompassing an alert baseline period, a state of mild acute intoxication, and a state of fatigue compounded by "hangover" or intoxication after-effects. Relative to the alert baseline, task performance was less accurate in the other test conditions, providing evidence of transient cognitive impairment. These states of impairment were associated with changes in spectral characteristics of the EEG. Neural network-based EEG pattern recognition techniques were used to develop and test detectors of these changes. Brief testing data samples originating from the alert baseline condition could be discriminated from those recorded during the state of acute intoxication with 98% accuracy (p < 0.0001), and from those recorded during the state of fatigue/hangover with 92% accuracy (p < 0.001). Furthermore, networks trained on data from a group of subjects were found to accurately classify data from test subjects who were not part of the training group. These results demonstrate the feasibility of using neurophysiological monitoring methods for detecting transient cognitive impairment.

Mental effort-related EEG modulation during video-game play: comparison between juvenile subjects with epilepsy and normal control subjects.

PURPOSE: This study investigated the effects of mental effort exerted during video-game play on features of the EEG in juvenile subjects diagnosed with seizure disorders and in age-matched clinically healthy subjects. METHODS: EEG was recorded from 14 children (9-15 years old) as they played a video game, watched another person playing a video-game, and sat quietly with their eyes open. Seven of the subjects had been clinically diagnosed with seizure disorders, three of whom had also exhibited photosensitivity. RESULTS: Three spectral components of the EEG showed cognitive load-related modulation. The amplitude of a frontal midline theta (6-7 Hz) signal increased with video-game play relative to the watching and eyes open resting conditions. A posterior alpha band (9-12 Hz) signal was attenuated during the playing and the watching conditions relative to the resting condition. A central mu (10-13 Hz) rhythm was attenuated during the game-playing condition. No significant differences were found between the patient and control groups for any of these features. Incidence of epileptiform events did not discriminate test conditions in the children with epilepsy. CONCLUSIONS: The results from this small sample suggest that video-game play tends to produce similar responses from children with epilepsy and in healthy control subjects. These responses in the juvenile population are similar to responses elicited by increased mental load in normal adult populations.

Electroencephalographic imaging of higher brain function.

High temporal resolution is necessary to resolve the rapidly changing patterns of brain activity that underlie mental function. Electroencephalography (EEG) provides temporal resolution in the millisecond range. However, traditional EEG technology and practice provide insufficient spatial detail to identify relationships between brain electrical events and structures and functions visualized by magnetic resonance imaging or positron emission tomography. Recent advances help to overcome this problem by recording EEGs from more electrodes, by registering EEG data with anatomical images, and by correcting the distortion caused by volume conduction of EEG signals through the skull and scalp. In addition, statistical measurements of sub-second interdependences between EEG time-series recorded from different locations can help to generate hypotheses about the instantaneous functional networks that form between different cortical regions during perception, thought and action. Example applications are presented from studies of language, attention and working memory. Along with its unique ability to monitor brain function as people perform everyday activities in the real world, these advances make modern EEG an invaluable complement to other functional neuroimaging modalities.

Deblurring.

In most instances, traditional EEG methodology provides insufficient spatial detail to identify relationships between brain electrical events and structures and functions visualized by magnetic resonance imaging or positron emission tomography. This article describes a method called Deblurring for increasing the spatial detail of the EEG and for fusing neurophysiologic and neuroanatomic data. Deblurring estimates potentials near the outer convexity of the cortex using a realistic finite element model of the structure of a subject's head determined from their magnetic resonance images. Deblurring is not a source localization technique and thus makes no assumptions about the number or type of generator sources. The validity of Deblurring has been initially tested by comparing deblurred data with potentials measured with subdural grid recordings. Results suggest that deblurred topographic maps, registered with a subject's magnetic resonance imaging and rendered in three dimensions, provide better spatial detail than has heretofore been obtained with scalp EEG recordings. Example results are presented from research studies of somatosensory stimulation, movement, language, attention and working memory. Deblurred ictal EEG data are also presented, indicating that this technique may have future clinical application as an aid to seizure localization and surgical planning.

Neurophysiological indices of strategy development and skill acquisition.

In order to examine neurophysiological changes associated with the development of cognitive and visuomotor strategies and skills, spectral features of the EEG were measured as participants learned to perform new tasks. In one experiment eight individuals practiced working memory tasks that required development of either spatial or verbal rehearsal and updating strategies. In a second experiment six individuals practiced a video game with a difficult visuomotor tracking component. The alpha rhythm, which is attenuated by functional cortical activation, was affected by task practice. In both experiments, a lower-frequency, centrally distributed alpha component increased between practice sessions in a task-independent fashion, reflecting an overall decrease in the extent of cortical activation after practice. A second, higher-frequency, posterior component of the alpha rhythm displayed task-specific practice effects. Practice in the verbal working memory task resulted in an increase of this signal over right posterior regions, an effect not seen after practice with the spatial working memory task or with the video game. This between-task difference presumably reflects a continued involvement of the posterior region of the right hemisphere in tasks that invoke visuospatial processes. This finding thus provides neurophysiological evidence for the formation of a task-specific neurocognitive strategy. In the second experiment a third component of the alpha rhythm, localized over somatomotor cortex, was enhanced in conjunction with acquisition of tracking skill. These alpha band results suggest that cortical regions not necessary for task performance become less active as skills develop. In both experiments the frontal midline (Fm) theta rhythm also displayed increases over the course of test sessions. This signal is associated with states of focused concentration, and its enhancement might reflect the conscious control over attention associated with maintenance of a task-appropriate mental set. Overall, the results suggest that the EEG can be used to monitor practice-related changes in the patterns of cortical activity that are associated with task processing. Additionally, these results highlight the importance of ensuring that subjects have developed stable strategies for performance before drawing inferences about the functional architecture underlying specific cognitive processes.

Dynamic cortical networks of verbal and spatial working memory: effects of memory load and task practice.

Working memory (WM), the ability to briefly retain and manipulate information in mind, is central to intelligent behavior. Here we take advantage of the high temporal resolution of electrophysiological measures to obtain a millisecond timescale view of the activity induced in distributed cortical networks by tasks that impose significant WM demands. We examined how these networks are affected by the type and amount of information to be remembered, and by the amount of task practice. Evoked potentials (EPs) were obtained from eight subjects performing spatial and verbal versions of a visual n-back WM task (n = 1, 2, 3) on each of three testing days. In well-trained subjects, WM tasks elicited transient responses reflecting different subcomponents of task processing, including transient (lasting 0.02-0.3 s) task-sensitive and load-sensitive EPs, as well as sustained responses (lasting 1-1.5 s), including the prestimulus Contingent Negative Variation (CNV), and post-stimulus frontal and parietal Slow Waves. The transient responses, with the exception of the P300, differed between the verbal and spatial task versions, and between trials with different response requirements. The P300 and the Slow Waves were not affected by task version but were affected by increased WM load. These results suggest that WM emerges from the formation of a dynamic cortical network linking task-specific processes with non-specific, capacity-limited, higher-order attentional processes. Practice effects on the EPs suggested that practice led to the development of a more effective cognitive strategy for dealing with lower-order aspects of task processing, but did not diminish demands made on higher order processes. Thus a simple WM task is shown to be composed of numerous elementary subsecond neural processes whose characteristics vary with type and amount of information being remembered, and amount of practice.

A rapid method for determining standard 10/10 electrode positions for high resolution EEG studies.

This report describes the basic principle and examines the comparative accuracy of a novel method for locating 3-D coordinates of electrode positions on the head. The method involves calculation of the 3-D coordinates for any array of 10/10 electrode positions from 14 straight-line distances between 11 10/10 electrodes. In 11 subjects the 3-D coordinates of 64 scalp electrodes embedded in an electrode cap were identified with the novel method, and also with a standard commercial magnetic field digitizer. The outcomes from the two methods were compared with directly measured coordinates of all 64 positions (cf. De Munck, J.C., Vijn, P.C.M. and Spekreijse, H. A practical method for determining electrode positions on the head. Electroenceph. clin. Neurophysiol., 1991, 89: 85-87). Coordinates in 3 dimensions obtained using the new method were significantly closer to the directly measured values than those from the magnetic field digitizer. The new method was also quicker and requires less specialized instrumentation than the magnetic field digitization method. The novel method appears to be a valid and convenient tool for use with EEG analysis techniques that require specific information about 10/10 electrode positions.

The future of electroencephalography in assessing neurocognitive functioning.

High temporal resolution is necessary to resolve the rapidly changing patterns of brain activity underlying mental function. Additionally, simple, non-intrusive equipment is needed to routinely measure such functions in doctors' offices, at home and work and in other naturalistic contexts as people perform normal everyday activities. When compared with all other modalities for measuring higher brain functions, EEG is unique in that it has both these attributes. Two factors are limiting the further development and application of EEG for measuring cognitive functioning: a technical one that is easy to overcome and a sociological one that is more problematic. The technical limitation is that traditional EEG technology and practice provides insufficient spatial detail to identify relationships between brain electrical events and structures and functions visualized by magnetic resonance imaging (MRI) or other modalities. Recent advances overcome this problem by recording EEGs from more electrodes, by registering EEG data with anatomical information from each subject's MRI, by correcting the distortion caused by volume conduction of EEG signals through the skull and scalp, and by computing hypotheses about the sources of signals recorded at the scalp. The sociological limitation is that clinical EEGs are mostly performed by neurologists with no particular special interest in cognitive brain function, while cognitive research using EEG is largely done by psychology professors and their graduate students with no clinical ambitions. The diminishing clinical role of traditional EEGs in localizing lesions in the brain, and the obvious and insistent medical need for inexpensive and accessible tests of cognitive brain functioning may serve to soon dissipate this sociological obstruction. This will lead to a golden age of EEG in which Hans Berger's vision of the EEG as a window on the mind will be realized. Rather than slowly fading into obsolescence, EEG will retain its role as the primary means of measuring higher brain function when the purpose is not 3D localization per se, and will serve as an invaluable complement to functional MRI in those instances when both high temporal and high spatial resolution are required.

Monitoring working memory load during computer-based tasks with EEG pattern recognition methods.

We assessed working memory load during computer use with neural network pattern recognition applied to EEG spectral features. Eight participants performed high-, moderate-, and low-load working memory tasks. Frontal theta EEG activity increased and alpha activity decreased with increasing load. These changes probably reflect task difficulty-related increases in mental effort and the proportion of cortical resources allocated to task performance. In network analyses, test data segments from high and low load levels were discriminated with better than 95% accuracy. More than 80% of test data segments associated with a moderate load could be discriminated from high- or low-load data segments. Statistically significant classification was also achieved when applying networks trained with data from one day to data from another day, when applying networks trained with data from one task to data from another task, and when applying networks trained with data from a group of participants to data from new participants. These results support the feasibility of using EEG-based methods for monitoring cognitive load during human-computer interaction.

High-resolution EEG mapping of cortical activation related to working memory: effects of task difficulty, type of processing, and practice.

Changes in cortical activity during working memory tasks were examined with electroencephalograms (EEGs) sampled from 115 channels and spatially sharpened with magnetic resonance imaging (MRI)-based finite element deblurring. Eight subjects performed tasks requiring comparison of each stimulus to a preceding one on verbal or spatial attributes. A frontal midline theta rhythm increased in magnitude with increased memory load. Dipole models localized this signal to the region of the anterior cingulate cortex. A slow (low-frequency), parietocentral, alpha signal decreased with increased working memory load. These signals were insensitive to the type of stimulus attribute being processed. A faster (higher-frequency), occipitoparietal, alpha signal was relatively attenuated in the spatial version of the task, especially over the posterior right hemisphere. Theta and alpha signals increased, and overt performance improved, after practice on the tasks. Increases in theta with both increased task difficulty and with practice suggests that focusing attention required more effort after an extended test session. Decreased alpha in the difficult tasks indicates that this signal is inversely related to the amount of cortical resources allocated to task performance. Practice-related increases in alpha suggest that fewer cortical resources are required after skill development. These results serve: (i) to dissociate the effects of task difficulty and practice; (ii) to differentiate the involvement of posterior cortex in spatial versus verbal tasks; (iii) to localize frontal midline theta to the anteromedial cortex; and (iv) to demonstrate the feasibility of using anatomical MRIs to remove the blurring effect of the skull and scalp from the ongoing EEG. The results are discussed with respect to those obtained in a prior study of transient evoked potentials during working memory.

Implications of electrolyte dispersion for high resolution EEG methods.

The effective recording area of an EEG electrode is its electrical contact area with the scalp. With techniques that employ wet electrolyte, this area is primarily determined by the extent of electrolyte dispersion rather than by the size of the electrode. The effective recording areas of 10 widely distributed EEG electrodes embedded in an elasticized stretch hat were measured on 7 subjects using a digital multimeter. On average, conventionally prepared electrodes were associated with an electrolyte (standard gel) spread of approximately 1 cm in each of four directions (above, below, right and left of the electrode's center). This implies that EEG electrodes prepared with wet electrolyte should not be spaced less than 2 cm apart unless special precautions are taken to prevent the spread of electrolyte, and that in most circumstances there is little advantage to methods for designating the 3-D coordinates of an electrode that have a measurement error of less than 1 cm.

High resolution evoked potential imaging of the cortical dynamics of human working memory.

High resolution evoked potentials (EPs), sampled from 115 channels and spatially sharpened with the finite element deblurring method, were recorded from 8 subjects during working memory (WM) and control tasks. The tasks required matching each stimulus with a preceding stimulus on either verbal or spatial attributes. All stimuli elicited a central P200 potential that was larger in the spatial tasks than in the verbal tasks, and larger in the WM tasks than in the control tasks. Frequent, non-matching stimuli elicited a frontal, positive peak at 305 msec that was larger in the spatial WM task relative to the other tasks. Irrespective of whether subjects attended to verbal or spatial stimulus attributes, non-matching stimuli in the WM tasks also elicited an enhanced P450 potential over the left frontal cortex, followed by a sustained potential over the superior parietal cortex. A posterior P390 potential elicited by infrequent, matching stimuli was smaller in amplitude for both spatial and verbal WM tasks compared to control tasks, as was a central prestimulus CNV. These results indicate that WM is a function of a distributed system with both task-specific and task-independent components. Lesion studies and course temporal resolution functional imaging methods, such as PET and fMRI, tend to paint a fairly static picture of the cortical regions which participate in the performance of WM tasks. In contrast, the fine-grain time resolution provided by imaging brain function with EP methods provides a dynamic picture of subsecond changes in the spatial distribution of WM effects over the course of individual trials, as well as evidence for differences in the activity elicited by matching and non-matching stimuli within sequences of trials. This information about the temporal dynamics of WM provides a critical complement to the fine-grain spatial resolution provided by other imaging modalities.

Spatio-temporal correlations in human gamma band electrocorticograms.

Animal electrocorticogram (ECoG) studies have shown that spatial patterns in the gamma band (>20 Hz) reflect perceptual categorization. Spatio-temporal correlations were investigated in the 20-50 Hz range in search for similar phenomena in human ECoG. ECoGs were recorded in a somatosensory discrimination task from 64-electrode subdural grid arrays, with inter-electrode spacing of 1 cm, overlying somatosensory, motor and superior temporal cortices in 2 patients with intractable epilepsy. Bootstrap techniques were devised to analyze the spatial and temporal characteristics of the correlations. Despite an extensive search, no evidence was found for globally correlated activity related to behavior either in narrow (1.e., 35-45 Hz) or broad (i.e., 20-50 Hz) bands. Spatial patterns, extracted using principal component analysis, could not be classified with respect to stimulus type in any time interval. Instead, spatially and temporally intermittent synchronization was observed between pairs of electrodes in 1 cm X 1 cm regions with high variability within and across trials. The distribution of correlation coefficients differed substantially from background levels at inter-electrode distances of 1 cm and 1.4 cm but not 2 cm or more. The minimum duration of correlation, the decorrelation time, of the ECoG was about 50 msec; the average correlation duration at 1 cm inter-electrode distance was about 150 msec; and the recurrence rate of significant correlation peaks was about 1.3/sec. The findings suggest that the surface diameters of domains of spatially correlated activity underlying perceptual categorization in human gamma band ECoG are limited to less than 2 cm and that the intermittent synchronization observed across separations of 1 cm and 1.4 cm is not solely due to volume conduction. Thus, if such gamma band spatial patterns exist in the human brain, no existing technology would be capable of measuring them at the scalp, and subdural electrode arrays for cortical surface recording would have to have spacings under 5 mm.