Clinical symptoms of schizophrenia affect reference-independent measures of task-induced EEG alpha asymmetry.

Differential patterns of EEG alpha asymmetry during verbal and spatial cognitive activity are commonly described and are thought to reflect predominance of left- vs. right-sided cortical activation. Although these patterns have been difficult to elicit reliably in schizophrenics, the authors have previously suggested that clinical status may have confounded results. Therefore, EEG data from 17 additional schizophrenic patients, 16 mood disorder patient controls, and 17 normal controls were used to examine the relationship between severity of schizophrenic symptoms and task induced alpha asymmetry. Subjects performed verbal and spatial tasks during recording of 16-channel EEG. After transformation to the average reference, log alpha power from central and temporal leads was analyzed by MANOVA and MANCOVA. The expected task-side interaction (P < 0.02) was present for the total sample and for each control group when analyzed alone. However, it was only present in schizophrenics when the BPRS score was entered as a covariable. Patterns of correlations between BPRS scores, left temporal alpha power, right/left temporal alpha ratios, and task differences in ratios suggested that higher symptom levels were associated with excessive left-sided activation during spatial activity. This is consistent with other evidence of left hemisphere overactivity in schizophrenics.

Negative symptoms and EEG alpha in schizophrenia: a replication.

The authors previously reported that negative symptoms were associated with reduced EEG alpha power and coherence in medication-free schizophrenic inpatients. These post-hoc findings were based on resting EEG data in an eyes open condition. This report describes the replication of these results in a new sample of 17 male veterans (aged 38 +/- 8) recently hospitalized with DSM-III-R schizophrenia. All patients had been free of neuroleptic medication at least 12-14 days. The relationships between resting alpha (7.5-12.5 Hz) power and coherence and symptom ratings (as measured by subscales derived from the Brief Psychiatric Rating Scale) were examined with multivariate repeated measure analyses of covariance. Results were similar to those obtained earlier, with a main effect of negative symptoms (p = 0.05) on log alpha power, a localized effect on right frontal-parietal alpha coherence (p < 0.02), and a main effect (p < 0.03) on between-hemisphere alpha coherence. There was also a trend for an asymmetrical effect on power favoring the right side in parietal leads. Negative symptoms were associated with reduced alpha power and less alpha coherence between hemispheres and between right parietal and frontal regions. The authors discuss the implications of these results on neurodevelopmental, genetic, and attentional aspects of schizophrenia.

Correlation between left frontal phospholipids and Wisconsin Card Sort Test performance in schizophrenia.

The relationship between frontal lobe phospholipid measures as measured by in vivo 31phosphorus magnetic resonance spectroscopic imaging and performance on the Wisconsin Card Sort Test was examined in 16 chronic schizophrenic patients and 13 normal controls. Lower left frontal phosphomonoester levels in the schizophrenics were associated with fewer categories achieved, lower percent conceptual level, and greater total errors. No significant correlations between frontal phospholipid measures and performance on the WCST were noted in the controls. The results suggest a relationship between altered left frontal phospholipid metabolism and a specific measure of frontal lobe neuropsychological functioning.

P300 responses to novel auditory stimuli in hospitalized schizophrenic patients.

The authors studied the scalp topography of P300 responses to novel auditory stimuli and its relationship to negative symptoms in medication-free hospitalized schizophrenic patients. Schizophrenics (n = 12), patients with major mood disorders (n = 13), and 17 non-ill controls (all men) responded to rare target tones while ignoring background tones and rare novel stimuli. P300 responses were identified from plots of global field power (GFP), a measure of potential variability over the entire electrode set. Multivariate analysis revealed that P300 responses to novel stimuli were faster (p < 0.003), larger (p < 0.001), and distributed more centrally than parietally (p < 0.001) than those to targets, but this central augmentation was significantly (p < 0.04) less in schizophrenics. Compared to controls, P300 amplitude (p < 0.05) and GFP (p < 0.02) after novel stimuli were reduced relative to target responses in schizophrenics. Negative symptoms were inversely correlated with P300 amplitude (P = 0.013) and GFP (p < 0.04) across conditions and with P300 GFP in the novel condition (p = 0.01), but did not predict topography of responses to novel stimuli. The findings were consistent with but not conclusive evidence of prefrontal impairment in the schizophrenics subjects. Methodological issues and conflicts with other reports are discussed.

Negative symptoms and EEG alpha activity in schizophrenic patients.

Quantitative analyses of electroencephalographic (EEG) recordings in schizophrenic patients have often demonstrated reduced alpha band (8-13 Hz) activity. However, this finding is not universal and there is some evidence that subgroups of schizophrenics may differ in overall or lateralized levels of EEG alpha activity. To investigate this issue, the authors examined relationships between clinical ratings performed at the time of EEG recording and resting alpha power and coherence in 14 medication free schizophrenic patients. Nine channels of previously recorded resting (eyes open) EEG were transformed to average reference prior to spectral analysis and transformed to source derivation prior to calculation of inter-electrode coherences. Patients were rated with the Brief Psychiatric Rating Scale (BPRS), from which subscales corresponding to negative symptoms, positive symptoms, paranoia, and anxiety/depression were derived. Ratings and EEG measures were also obtained on 10 of the schizophrenic patients after neuroleptic treatment. Multiple regression with repeated measures was used to examine the influence of the subscale scores on bilateral log alpha power and both within- and between-hemisphere alpha coherence at selected locations. Prior to treatment, negative symptoms varied inversely with alpha power (p < 0.02), within-hemisphere alpha coherence (p < 0.03), and between-hemisphere coherence (p = 0.053). The effect of negative symptoms on alpha power was bilateral, but the effect on within-hemisphere coherence tended (p = 0.053) to be right-sided. After treatment these relationships were no longer present. The possible implications of and the effects of drug treatment on an association between negative symptoms and reduced alpha activity are discussed.

Acute deprivation of the terminal 3.5 hours of sleep does not increase delta (0-3-Hz) electroencephalograms in recovery sleep.

Sleep electroencephalograms (EEG) and electrooculograms were recorded in nine young adult males on a baseline night, a night in which they were deprived of an average of 3 hr 27 min of sleep by early awakening, and on a recovery night. Records were analyzed by visual sleep stage scoring and period-amplitude analysis; the results of both were tabulated by successive nonrapid eye movement periods (NREMPs) and rapid eye movement (REM) periods. Neither visually scored delta nor REM measures were affected by this substitution of waking for sleep. Although there was a significant increase in the 0-3-Hz time/epoch on the recovery night, this finding was not confirmed in the accompanying report. These results, taken in association with data from previous studies, are consistent with the hypothesis that, in an acute experiment, visually scored delta and computer-measured 0-3-Hz EEGs increase above the baseline levels only if there has been loss of stage 3/4 EEG (or of sleep) from the first two NREMPs. The findings here are inconsistent with older reports and indicate that further parametric data are required to construct a quantitative model of the relation of sleep EEG waveforms to the duration of prior waking.

Average reference EEG lateralization in schizophrenic patients.

The authors transformed 9 channels of electroencephalogram (EEG) to 10 channels of average reference data and compared EEG asymmetry between medication-free (for 2 weeks) schizophrenic male patients (n = 14), male patients with affective disorder (n = 9), and normal males (n = 13). Multivariate analyses failed to find lateralized differences between groups in resting and task EEG. Neuroleptic treatment (n = 11) was associated with asymmetrical changes in beta power rather than in alpha and theta, as previously reported. There were no relationships between clinical ratings (based on the Brief Psychiatric Rating Scale and subscales) and alpha asymmetry. The authors discuss conflicts with previous findings and the advantages of minimizing reference bias when studying EEG topography.

Topographic segmentation of waking EEG in medication-free schizophrenic patients.

Lehmann has demonstrated that EEG topography can be used to segment EEG map series into a sequence of spatially stationary segments characterized by location of potential maxima and minima. We employed topographic segmentation techniques to study 9 channel EEGs recorded from 11 medication-free schizophrenic patients and 10 normal controls during resting and active task conditions, retesting 8 patients after neuroleptic treatment. To define EEG segments, average reference potential maps corresponding to global field power peaks in theta, alpha, and low beta activity were classified according to locations of extreme minimum and maximum values. Normals and schizophrenics did not differ in the number or types of switches between segments, or the frequency of hemisphere crossing of potential extrema. However, EEGs of normal subjects were characterized by significantly more (P less than 0.003) unused theta segment types (of a theoretically possible 36). Moreover, medication significantly (P less than 0.02) increased the number of unused theta segment types in EEGs of schizophrenics. We interpret these findings as evidence of increased spatial variability of brain electrical activity in schizophrenics and discuss their functional implications.

EEG coherence in unmedicated schizophrenic patients.

We have recently shown that electroencephalogram (EEG) coherence data recorded with common reference methods, including those obtained from schizophrenics, are confounded by power and phase effects. Three published reports using bipolar recordings found that EEG coherence was higher in schizophrenics; however, only medicated patients were studied. To extend these findings, we measured EEG coherence from bipolar EEG recordings in unmedicated schizophrenics (n = 10), affective disorder patients (n = 8), and normal controls (n = 13) during resting and task conditions. Seven schizophrenics were restudied after a period of neuroleptic treatment. Schizophrenics had higher across-task interhemispheric (p less than 0.05) and intrahemispheric (p less than 0.04) coherence in the theta band and tended to have higher intrahemispheric alpha coherence (p less than 0.08). Medication treatment was associated with clinical improvement and increases in spectral power, but not with changes in coherence values. These results confirm those obtained by earlier investigations and suggest that increased coherence reflects the presence of anomalous cortical organization in schizophrenics rather than medication effects or transient states related to acute clinical disturbance.

Task-related EEG alpha asymmetry in schizophrenic patients prior to and after neuroleptic treatment.

EEG was recorded from bilateral frontal, central, temporal, and parietal leads (referenced to or transformed to a vertex reference) during cognitive activity in 13 normal controls, ten schizophrenics, and eight patients with affective disorders. All subjects were male and right-handed, and patients had been free of psychotropic medications for at least 2 weeks. A verbal (copying text) and spatial (copying shapes) task were matched for stimulus presentation and motor output. The number and rate of correct responses were recorded for each normal subject and 11 of the patients. As reported by others, normal subjects manifested a significant difference in alpha asymmetry between the tasks, reflecting relatively greater alpha suppression over the left hemisphere during the verbal task compared to the spatial task (P less than 0.05). This effect was not significant in either patient group. However, analysis of seven schizophrenics after neuroleptic treatment revealed robust effects of task on alpha asymmetry similar to that present in the normal control group (P less than 0.02). The results suggest that abnormal task-related brain lateralization may be present in untreated schizophrenic patients, but it is state dependent and does not reflect permanent patterns of brain organization.

Effects of sleep loss on delta (0.3-3 Hz) EEG and eye movement density: new observations and hypotheses.

One night's sleep loss in young adults increased delta (0.3-3 Hz) EEG only in the first non-REM period of recovery sleep. The delta increase was limited to frequencies 0.3-4 Hz; within this range, the effects on wave form periods and amplitudes differed by frequency band. These results illustrate the value of computer analysis applied to the physiological units of sleep (the successive non-REM and REM periods of each sleep cycle). The finding that all of the delta increase occurred in the first sleep cycle appears inconsistent with the exponential decline of delta across cycles predicted by 'recovery' models of sleep. The fact that wave periods and amplitudes are differentially affected by sleep loss indicates that it is premature to adopt any single wave form characteristic (e.g., power spectral density) to index delta sleep. Our data also confirm a recent report that eye movement density decreases after sleep loss; we hypothesize that this change results from greater depth of sleep; an inverse relation of depth of sleep to eye movement density provides a coherent explanation for a range of otherwise disparate observations. Lastly, we propose a new hypothesis to account for the presence of eye movement during REM sleep.

Sleep spindles in normal elderly: comparison with young adult patterns and relation to nocturnal awakening, cognitive function and brain atrophy.

Visual measurements of sleep spindles were carried out in 48 elderly and 20 young normal adults. Computed tomography brain scans and psychometric testing were also performed. Earlier findings of reduced spindle abundance, amplitude and duration in the elderly were confirmed. In addition, we demonstrated a linear increase in spindle density and duration across NREMPs in young adults that was absent in the elderly, indicating that age affects the temporal pattern as well as the quantity of spindles. Contrary to what seemed a highly plausible hypothesis, the amount of waking in the elderly was not inversely correlated with spindle abundance, confirming earlier observations (Feinberg et al. 1967) but in a much larger group. This finding suggests that spindle abundance does not reflect the integrity of the systems that maintain the brain in NREM sleep. We also were unable to show any clear evidence that relative preservation of spindles in the elderly is associated with relative preservation of cognitive skills: psychometric performance and spindle measures were, in most instances, not significantly correlated. However, the test of this hypothesis was limited by the high level of function and the narrow range of impairment of these Ss. One intriguing positive finding was the significant inverse relation between ratings of sulcal atrophy and spindle amplitude. This observation suggests an etiology for the reduced amplitude of the sleep EEG in old age. This change is one of the most striking effects of age on brain electrophysiology.

EEG asymmetry in schizophrenic patients before and during neuroleptic treatment.

Lateral asymmetry of electroencephalographic (EEG) spectra was assessed in schizophrenic patients compared to normal controls. Ten predominantly unmedicated schizophrenic inpatients and nine normal controls performed monitored cognitive tasks during bilateral recording of EEG from parietal and temporal sites. Lateralization of EEG power in five frequency bands was compared between the groups; separate analyses were performed for linked ears and vertex references. A subsample of schizophrenic patients was restudied after a period of neuroleptic treatment. All significant group differences were obtained with the linked ears reference only. Pretreatment schizophrenics manifested relatively less alpha power over the right hemisphere during all conditions than controls, particularly in the parietal leads. After treatment, there was a significant shift in alpha lateralization toward the control values. These latter effects were also present in the theta frequency band to a lesser extent.

Further evidence of abnormal non-rapid-eye-movement sleep in schizophrenia.

Very low levels of visually scored stage 4 sleep are found in 40% to 50% of acute and chronic schizophrenics. Stage 4 is a visual estimate of high-amplitude delta (0.5 to 3 Hz) electroencephalographic waves; these waves can now be measured directly and reliably by computer. In this pilot study, we carried out such measurement in the successive non-rapid-eye-movement periods (NREMPs). We also sampled and measured visually sleep spindles by NREMP; spindles constitute a second distinctive feature of the NREM electroencephalogram. In five unmedicated, recently rehospitalized schizophrenic patients we found reduced delta amplitude and abundance (and increased spindle density) in NREMP1 (also called "REM latency") as compared with ambulatory normal controls. NREMP1 was also abnormally short with an average length similar to that reported for major depression. These striking abnormalities of NREM sleep may underlie the abnormal rapid eye movement distributions sometimes found in schizophrenic and depressed patients. Further studies are required to evaluate the relation of these NREM abnormalities to psychopathology (and hence their utility as biological "markers") and to rule out confounding effects of hospitalization or undetected napping.

Homeostatic changes during post-nap sleep maintain baseline levels of delta EEG.

It has been hypothesized that visually scored stage 4 EEG (dense, high amplitude 0.5-3 Hz (delta) waves) is a correlate of a metabolic process that reverses some of the effects of waking on the brain. The results of nap studies appear inconsistent with this hypothesis since late naps produce a disproportionate loss of stage 4 during subsequent sleep. We show here with direct computer measurement that the integrated amplitude (and other measures) of 0.5-3 Hz EEG waves are conserved across a nap and post-nap sleep. Thus, the metabolic model remains tenable. However, the homeostatic adjustments involve changes in the periods, durations and distributions of delta waves that are not predictable by any existing model. This study also demonstrates the limitations inherent in visual estimates (sleep stage scoring) of delta wave amplitude and abundance.

Computer-detected patterns of electroencephalographic delta activity during and after extended sleep.

Delta (0.5 to 3 hertz) waves are the electroencephalographic hallmark of human sleep. We measured their rate of production during and following an extended night of sleep. On the extended night, we confirmed previous observations of a linear decline in delta wave production across the first four periods of non-rapid-eye-movement (non-REM) sleep. An asymptote was reached in the fifth non-REM period, perhaps signifying that sleep processes reached completion. On the day after the extended night, subjects were allowed to remain awake 3.6 hours less than normal. During the next sleep session, amplitude and number of delta waves in non-REM periods 1 and 3 were significantly reduced. These findings illustrate the value of computer analysis of electroencephalographic waveforms in sleep. Systematic measurement of the amount and distribution of these waveforms as a function of preceding waking duration should provide clues to the kinetics of the metabolic processes underlying sleep.