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.

Flurazepam effects on slow-wave sleep: stage 4 suppressed but number of delta waves constant.

Repeated administration of flurazepam reduced stage 4 sleep (high delta-wave concentration) but produced a greater increase in stage 2 duration so that total sleep time was increased. Computer analysis revealed that the increased amount of stage 2 (low delta-wave concentration) sleep provided a number and duration of delta waves sufficient to offset the loss of delta activity in stage 4. However, the amplitude of the average delta wave was reduced. These results demonstrate the value of direct quantification of delta-wave activity, the variable that underlies visual classification of slow-wave sleep into stages 2 to 4. They also give rise to new hypotheses regarding the relative absence of side effects in spite of profound stage 4 suppression by flurazepam and the mechanisms by which total sleep time is increased by this drug.

Flurazepam effects on sleep EEG. Visual, computer, and cycle analysis.

Analysis of sleep effects of flurazepam hydrochloride on four normal subjects confirmed that this drug substantially suppresses both REM and stage 4 sleep. Computer analysis disclosed that delta wave amplitude was greatly reduced by flurazepam. However, low density delta wave activity (ie, stage 2 sleep, which was increased in duration beyond the reduction in stage 4), permitted the number of delta waves and the time they occupied per night to remain at baseline levels. This finding suggests that sedative-hypnotics increase total sleep time by slowing the metabolic processes of sleep so that a longer sleep duration is required for the same biological effects. New observations on the induction times of REM and stage 4 effects are also presented. In general, the distortions in sleep EEG produced by flurazepam qualitatively resemble, but are quantitatively greater than, those produced by barbiturates in equivalent hypnotic doses.

Preservation of normal cognitive functioning in elderly subjects with extensive white-matter lesions of long duration.

Although deep white-matter brain lesions are seen on magnetic resonance imaging in about one third of elderly subjects, their clinical significance is not known. In 1984, we studied three retired teachers who had extensive deep white-matter brain lesions on magnetic resonance imaging, yet functioned cognitively at an above-average level. Blinded review of 1981 computed tomographic scans revealed patchy white-matter lucencies for two of the subjects. Repeated magnetic resonance imaging in 1987 showed that the deep white-matter brain lesions were at least as extensive as in the initial study. One subject had developed renal failure, while the other two continued to function at a high level with no evidence of cognitive decline or psychiatric or neurologic impairment. The presence of extensive deep white-matter brain lesions for up to 7 years in two subjects whose cognitive, behavioral, and neurologic functioning is unimpaired suggests that deep white-matter brain lesions do not necessarily indicate a clinically significant central nervous system disease process.

P50 suppression is not affected by attentional manipulations.

Auditory evoked potentials (EP) to high or moderate intensity, single or paired clicks were recorded from normal young adult subjects. A choice-reaction-time paradigm had two sets of instructions, for intensity discrimination and for number (single versus paired stimulus) discrimination. For intensity discrimination, the second click had no informative value and its N100 amplitude was markedly reduced relative to the first click. For number discrimination, the presence or absence of the second click provided the salient information, and N100 amplitude was actually slightly larger for the second compared to the first click. In contrast, the attentional manipulation had no effect on P50 amplitude, which showed over 50% suppression from the first to the second click for both tasks. Thus, suppression of P50 amplitude to the second of a pair of clicks is insensitive to attentional manipulations that have major effects on N100 amplitude. These findings suggest that abnormalities of schizophrenic P50 suppression reflect neuronal rather than psychological phenomena.

Cocaine abusers have reduced auditory P50 amplitude and suppression compared to both normal controls and alcoholics.

The auditory P50 evoked response to click stimuli was recorded from 10 2-week abstinent African-American chronic cocaine abusers and 10 African-American non-substance-abusing controls. Stimuli consisted of pairs of clicks with a 500-msec interval between clicks in a pair, and a 7-8 sec interval between pairs of clicks. After averaging responses to 100 pairs of clicks and digital bandpass filtering between 10 and 50 Hz, P50 amplitude to the first and the second click was measured. The conditioning/testing (C/T) ratio, an index of P50 suppression, was computed as the ratio of P50 amplitude to the second compared to the first click. Chronic cocaine abusers had markedly diminished P50 amplitudes and increased C/T ratios (indicating decreased P50 suppression) in comparison to the controls. These P50 abnormalities were not seen in additional Caucasian gay/bisexual comparison groups of active alcoholics (n = 15) and non-substance-abusing controls (n = 10). Thus, decrements in P50 amplitude and P50 suppression appear to be specific to cocaine abuse, and to differentiate cocaine abuse from alcohol abuse. A response analogous to P50 can be measured in animals, facilitating the development of animal models of this cocaine effect.

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.

Human P50 suppression is not affected by variations in wakeful alertness.

The amplitude and suppression of the auditory P50 event-related potential may be useful for studying schizophrenia and drug abuse; however, the low reliability of the P50 suppression measure limits its value for correlation with clinical measures. Reliability can be increased either by improving measurement methods or by reducing or eliminating sources of variance in the recordings. In this paper, the effect on P50 amplitude and suppression of variation in wakeful alertness within an experimental session was examined in 20 normal subjects. The percentage of beta power in the interval immediately prior to the P50 stimuli was used as an index of alertness. P50 amplitudes or C-T ratios were estimated using peak-picking and using the singular value decomposition (SVD) method. No effects of variation of wakeful alertness were observed on any P50 amplitude or suppression measure. Comparing the peak-picking vs SVD estimates replicated our prior results showing markedly higher reliabilities with SVD. We conclude: 1) that variation within an experimental session in wakeful alertness level as indexed by the percentage of beta power does not affect P50 amplitude or suppression, and 2) the SVD method brings the reliability of the C-T ratio up to levels where its usefulness in clinical studies can be examined.

Alcohol abuse and HIV infection have additive effects on frontal cortex function as measured by auditory evoked potential P3A latency.

Both alcohol and human immunodeficiency virus (HIV) infection have been shown to produce central nervous system (CNS) morbidity in frontal brain regions. The degree to which the CNS morbidity in HIV infection, as it affects frontal cortex function, may be preferentially increased by alcohol abuse was examined using the auditory P3A evoked potential. The P3A indexes an orienting response, maximal over frontal cortex that occurs when novel nontarget stimuli are presented in the midst of a target detection paradigm. Four groups of subjects were compared: HIV+ alcohol abusers, HIV+ light/nondrinkers, HIV- alcohol abusers, and HIV- light/nondrinkers. The alcohol abuser and light/nondrinker HIV+ groups were matched on percent CD4 lymphocytes, insuring that the results reflected specific CNS effects and were not a result of differences between the groups in the degree of systemic immune suppression. Alcohol abuse and HIV infection had at least additive effects on P3A latency, consistent with alcohol abuse worsening the effect of HIV disease on frontal cortex function. Post-hoc analyses suggested that concomitant alcohol abuse results in the effects of HIV infection on P3A latency becoming manifest earlier in the HIV disease process.

The reliability of P50 suppression as measured by the conditioning/testing ratio is vastly improved by dipole modeling.

Suppression of auditory P50 evoked potential amplitude to the second of a pair of clicks is potentially important in psychiatric research because it has been shown to be abnormal in both schizophrenics and their relatives. However, its clinical utility using the standard single-channel electroencephalographic (EEG) peak picking methodology is under question because of low test-retest reliability. Dipole Components Modeling of the P50 component was attempted as a method for increasing the reliability of the P50 suppression measure. It was hypothesized that this procedure might work because of pooling of noise from the two responses and because of the use of topographic information. Six replications of a P50 suppression paradigm in 12 subjects were analyzed. Reliability using peak picking was 0.27, and was significantly increased to 0.63 using dipole modeling. Dipole modeling was helpful not only for better modeling the P50 when it was present, but also for deciding that there was no P50 response in one subject.

Event-related potential evidence for frontal cortex effects of chronic cocaine dependence.

We examined the effects of cocaine dependence and cocaine and alcohol codependence on the P3A event-related potential component. Ten chronic cocaine-dependent subjects, 10 chronic cocaine and alcohol codependent subjects, and 20 controls were studied in an auditory paradigm that included target, nontarget, and novel rare nontarget conditions. Substance-dependent subjects were abstinent from cocaine and/or alcohol for 2-6 weeks. Eighteen of these subjects (4 chronic cocaine-dependent subjects, 4 chronic cocaine/alcohol codependent subjects, and 10 normal controls) were also studied in an analogous visual paradigm. In the auditory modality, the latency of the P3A response in the novel rare nontarget condition was delayed and its amplitude was reduced in both substance-dependent samples compared to controls. Comparable results were found for the smaller samples studied in the visual modality. These results suggest that chronic cocaine dependence produces deficits in frontal cortex functions.

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.

Asymmetry of temporal lobe phosphorous metabolism in schizophrenia: a 31phosphorous magnetic resonance spectroscopic imaging study.

In vivo 31Phosphorous magnetic resonance spectroscopic imaging (31P MRSI) was performed on 18 chronic schizophrenic patients and 14 normal controls to determine if there was asymmetry of high-energy phosphorous metabolism in the temporal lobes of schizophrenic patients. Temporal lobe phosphorous metabolites were also correlated with severity of psychiatric symptomatology as assessed by the Brief Psychiatric Rating Scale (BPRS). Schizophrenics demonstrated significantly higher right relative to left temporal phosphocreatine/adenosine triphosphate (PCr/ATP), phosphocreatine/inorganic phosphate (PCr/Pi), and PCr as well as significantly lower right relative to left temporal ATP. There were no asymmetries of temporal lobe phosphorous metabolites in the control group. In addition, both left temporal PCr and the degree of asymmetry of temporal lobe PCr were highly correlated with the thinking disturbance subscale of the BPRS. This study provides further support for temporal lobe metabolic asymmetry in schizophrenia and its possible association with clinical symptoms.

31Phosphorus magnetic resonance spectroscopy of the temporal lobes in schizophrenia.

Eleven schizophrenic patients and nine normal controls were studied using in vivo 31Phosphorous magnetic resonance spectroscopy (31P MRS) to test the hypothesis of metabolic asymmetry in the temporal lobes in schizophrenia. The controls did not demonstrate any asymmetry of phosphorous metabolite ratios, percentage of phosphorous metabolites, or pH. In the schizophrenics, however, phosphocreatine/beta-adenosine triphosphate (PCr/beta-ATP) and phosphocreatine/inorganic phosphate (PCr/Pi) effects appeared to primarily reflect higher ratios on the right side, while the percentage of beta-ATP appeared to primarily reflect higher relative concentrations in the left temporal lobe. Moreover, significant negative correlations were noted between total Brief Psychiatric Rating Scale scores and PCr/beta-ATP in both the right and left temporal lobes. These results support the hypothesis of an asymmetric distribution of 31P metabolites in the temporal lobe of schizophrenic patients, and also show an association between temporal lobe phosphorous metabolism and the severity of psychiatric symptomatology.

Hippocampal neuronal dysfunction in schizophrenia as measured by proton magnetic resonance spectroscopy.

BACKGROUND: Previous neuropathological and neuroimaging studies have documented neuronal loss in the hippocampal region in schizophrenia. N-acetylaspartate (NAA) is a neuronal/axonal marker that may be utilized to assess neuronal loss or dysfunction by proton magnetic resonance spectroscopy (1H MRS). This study measured NAA, choline, and creatine in the hippocampal region of patients with schizophrenia using in vivo proton magnetic resonance spectroscopic imaging (1H MRSI). METHODS: 1H MRSI was performed on the right and left hippocampal regions in 30 chronic schizophrenic patients and 18 control subjects. Concentration estimates of NAA, creatine, and choline were determined. RESULTS: Relative to the control group, the patients with schizophrenia demonstrated significantly lower NAA in both the right and left hippocampal regions. No group differences in choline were noted; however, there was a trend for creatine to be higher on the left than the right hippocampus in the schizophrenic group. There was also no association between NAA and duration of illness or medication dosage. CONCLUSIONS: This preliminary study provides support for neuronal dysfunction and/or decreased neuronal density in the hippocampal region. The absence of choline signal elevation does not support accelerated turnover of membrane phospholipids, which might be expected if there were ongoing neuronal atrophy or neuronal necrosis.

31phosphorus magnetic resonance spectroscopy of the frontal and parietal lobes in chronic schizophrenia.

In vivo 31Phosphorus magnetic resonance spectroscopic imaging (31P MRSI) was performed on 20 chronic schizophrenic patients and 16 normal controls to determine if there were specific changes in high energy phosphorus and phospholipid metabolism in the frontal lobes of schizophrenic patients. Phosphorous metabolites were assessed in each of the left and right frontal as well as the left and right parietal lobes. Frontal lobe phosphorous metabolites were also correlated with severity of psychiatric symptomatology as assessed by the Brief Psychiatric Rating Scale (BPRS). Schizophrenics demonstrated higher phosphodiesters (PDE) and lower phosphocreatine (PCr) in both the left and right frontal regions compared to controls. There was also lower left frontal inorganic phosphate (Pi) in the schizophrenic group. No group differences were noted in the left or right parietal regions. In addition, right frontal PDE and right frontal PCr were highly correlated with the hostility-suspiciousness and anxiety-depression subscales of the BPRS. This study provides further support for altered frontal lobe phosphorous metabolism in schizophrenia.

Sensory gating in chronic posttraumatic stress disorder: reduced auditory P50 suppression in combat veterans.

BACKGROUND: Posttraumatic stress disorder (PTSD) may be associated with a general impairment of cognitive function that extends beyond the processing of trauma-specific stimuli. Suppression of the auditory P50 response to repeated stimuli occurs in normal subjects and reflects the central nervous system's ability to screen out repetitive stimuli, a phenomenon referred to as sensory gating. This study examines P50 sensory gating to nonstartle auditory stimuli in PTSD subjects and normal controls. METHODS: P50 generation and gating were studied using a conditioning/testing paradigm in 15 male subjects with PTSD and 12 male controls. P50 test/conditioning (T/C) ratios were estimated using the Singular Value Decomposition method. RESULTS: The amplitude of the P50 response to the conditioning stimulus did not differ in subjects with PTSD compared to normal controls. The P50 T/C ratio is increased in PTSD subjects (mean = .408, SD = .275) as compared to the controls (mean = .213, SD = .126, two tailed t, p = .024). CONCLUSIONS: This study provides evidence that PTSD is associated with impaired gating to nonstartle trauma-neutral auditory stimuli.

Effect of photic stimulation on human visual cortex lactate and phosphates using 1H and 31P magnetic resonance spectroscopy.

Previous animal and human studies showed that photic stimulation (PS) increased cerebral blood flow and glucose uptake much more than oxygen consumption, suggesting selective activation of anaerobic glycolysis. In the present studies, image-guided 1H and 31P magnetic resonance spectroscopy (MRS) was used to monitor the changes in lactate and high-energy phosphate concentrations produced by PS of visual cortex in six normal volunteers. PS initially produced a significant rise (to 250% of control, p less than 0.01) in visual cortex lactate during the first 6.4 min of PS, followed by a significant decline (p = 0.01) as PS continued. The PCr/Pi ratios decreased significantly from control values during the first 12.8 min of PS (p less than 0.05), and the pH was slightly increased. The positive P100 deflection of the visual evoked potential recorded between 100 and 172 ms after the strobe was significantly decreased from control at 12.8 min of PS (p less than 0.05). The finding that PS caused decreased PCr/Pi is consistent with the view that increased brain activity stimulated ATPase, causing a rise in ADP that shifted the creatine kinase reaction in the direction of ATP synthesis. The rise in lactate together with an increase in pH suggest that intracellular alkalosis, caused by the shift of creatine kinase, selectively stimulated glycolysis.

Age-related metabolite changes and volume loss in the hippocampus by magnetic resonance spectroscopy and imaging.

Magnetic resonance imaging (MRI) studies have produced controversial results concerning the correlation of hippocampal volume loss with increasing age. The goals in this study were: 1) to test whether levels of N-acetyl aspartate (NAA, a neuron marker) change in the hippocampus during normal aging and 2) to determine the relationship between hippocampal NAA and volume changes. Proton magnetic resonance spectroscopic imaging (1H MRSI) and MRI were used to measure hippocampal metabolites and volumes in 24 healthy adults from 36 to 85 years of age. NAA/Cho decreased by 24% (r = 0.53, p = 0.01) and NAA/Cr by 26% (r = 0.61, p < 0.005) over the age range studied, whereas Cho/Cr remained stable, implying diminished NAA levels. Hippocampal volume shrank by 20% (r = 0.64, p < 0.05). In summary, aging effects must be considered in 1H MRSI brain studies. Furthermore, because NAA is considered a marker of neurons, these results provide stronger support for neuron loss in the aging hippocampus than volume measurements by MRI alone.

Abnormal frontal lobe phosphorous metabolism in bipolar disorder.

OBJECTIVE: Abnormalities in frontal lobe phosphorous metabolism in patients with bipolar disorder have been reported, but many of the patients studied were receiving lithium. In this study, medication-free bipolar patients were examined to determine abnormalities in frontal lobe high-energy phosphorous metabolism. METHOD: In vivo phosphorous-31 magnetic resonance spectroscopic imaging was performed on 12 unmedicated, euthymic bipolar patients and 16 healthy comparison subjects. The percentages of total phosphorous signal for phosphomonoesters, inorganic phosphate, phosphodiesters, phosphocreatine, and beta-ATP were calculated. RESULTS: In relation to the comparison group, the patients with bipolar disorder had significantly lower phosphomonoester values and higher phosphodiester values in both the left and right frontal lobes. The patients also had a significantly higher right-to-left ratio of frontal lobe phosphocreatine. No other differences in phosphorous metabolites or lateralized asymmetries were noted. CONCLUSIONS: This preliminary study provides support for abnormal frontal lobe phosphorous metabolism in bipolar disorder.