Local regulation of the threshold for calcium sparks in rat ventricular myocytes: role of sodium-calcium exchange.

1. To determine whether Na+-Ca2+ exchange modulates Ca2+ sparks, we studied enzymatically isolated patch clamped rat ventricular myocytes loaded with the Ca2+-sensitive indicator fluo-3, using confocal microscopy at 20-22 C. Two-dimensional images of Ca2+ sparks were recorded at 240 Hz using a laser scanning confocal microscope, allowing observation of a large area of the cell (820 microm2) at one time. 2. At a holding potential of -75 mV, spontaneous sparks were infrequent. Removal of extracellular Na+ for 520 ms, which in the absence of pipette Na+ should block Na+-Ca2+ exchange bidirectionally, was associated with a fourfold increase in spark frequency, without a significant change in cytoplasmic [Ca2+], sarcoplasmic reticulum (SR) Ca2+ content, or spark intensity, size or time course. 3. These findings are consistent with a model of excitation-contraction coupling in which Na+-Ca2+ exchange locally regulates the resting Ca2+ concentration in the diadic cleft (T-tubule-SR junction), thereby modulating the threshold for triggering Ca2+ sparks.

Prognostic value of dobutamine stress echocardiography in predicting cardiac events in patients with known or suspected coronary artery disease.

OBJECTIVES: The study sought to determine the utility of dobutamine stress echocardiography (DSE) in predicting cardiac events in the year after testing. BACKGROUND: Increasingly, DSE has been applied to risk stratification of patients. METHODS: Medical records of 1,183 consecutive patients who underwent DSE were reviewed. The cardiac events that occurred during the 12 months after DSE were tabulated: myocardial infarction (MI), cardiac death, percutaneous transluminal coronary angioplasty (PTCA), and coronary artery bypass surgery (CABG). Patient exclusions included organ transplant receipt or evaluation, recent PTCA, noncardiac death, and lack of follow-up. A positive stress echocardiogram (SE) was defined as new or worsened wall-motion abnormalities (WMAs) consistent with ischemia during DSE. Classification and regression tree (CART) analysis identified variables that best predicted future cardiac events. RESULTS: The average age was 68+/-12 years, with 338 women and 220 men. The overall cardiac event rate was 34% if SE was positive, and 10% if it was negative. The event rates for MI and death were 10% and 8%, respectively, if SE was positive, and 3% and 3%, respectively, if SE was negative. If an ischemic electrocardiogram (ECG) and a positive SE were present, the overall event rate was 42%, versus a 7% rate when ECG and SE were negative for ischemia. Rest WMA was the most useful variable in predicting future cardiac events using CART: 25% of patients with and 6% without a rest WMA had an event. Other important variables were a dobutamine EF <52.5%, a positive SE, an ischemic ECG response, history of hypertension and age. CONCLUSIONS: A positive SE provides useful prognostic information that is enhanced by also considering rest-wall motion, stress ECG response, and dobutamine EF.

Quasiperiodicity and chaos in cardiac fibrillation.

In cardiac fibrillation, disorganized waves of electrical activity meander through the heart, and coherent contractile function is lost. We studied fibrillation in three stationary forms: in human chronic atrial fibrillation, in a stabilized form of canine ventricular fibrillation, and in fibrillation-like activity in thin sheets of canine and human ventricular tissue in vitro. We also created a computer model of fibrillation. In all four studies, evidence indicated that fibrillation arose through a quasiperiodic stage of period and amplitude modulation, thus exemplifying the "quasiperiodic transition to chaos" first suggested by Ruelle and Takens. This suggests that fibrillation is a form of spatio-temporal chaos, a finding that implies new therapeutic approaches.

Dynamics of muscle sympathetic nerve activity in advanced heart failure patients.

Muscle sympathetic nerve activity (MSNA) is increased in patients with heart failure compared with healthy subjects. We applied spectral and correlation techniques to determine if qualitative as well as quantitative differences in MSNA differentiate heart failure patients from healthy subjects. We recorded MSNA, heart rate, and respiration in 11 heart failure patients and 10 healthy humans. Our results are as follows. 1) Statistically significant low-frequency modulation of MSNA at 0.029 +/- 0.002 Hz (mean +/- SE; range 0.026-0.038 Hz) was found in 10 of 11 heart failure patients but in only 2 of 10 healthy controls (differences between groups, P < 0.01; chi 2 test). 2) Heart rate and respiration also demonstrated significant low-frequency modulation in a similar range. 3) Spectral and correlation techniques revealed that low-frequency modulation of MSNA was highly correlated with low-frequency modulation of respiration in heart failure patients, but not in healthy subjects. In contrast, low-frequency modulation of MSNA did not correlate well with low-frequency modulation of heart rate. In summary, low-frequency modulation of respiration is coupled to low-frequency modulation of MSNA in heart failure patients, but not in normal subjects. We speculate that this low-frequency modulation of respiration may represent subclinical Cheyne-Stokes breathing, which has marked qualitative effects on MSNA in patients with heart failure.

Estimation of critical power with nonlinear and linear models.

Sixteen young, healthy males each performed five to seven randomly assigned, exhaustive exercise bouts on a cycle ergometer, with each bout on a separate day and at a different power, to compare estimates of critical power (PC) and anaerobic work capacity (W') among five different models: t = W'/(Pmax-PC) (two-parameter nonlinear); t = (W'/P-PC))-(W'/(Pmax-PC)) (three-parameter nonlinear); P.t = W' + (PC.t) (linear (P.t)); P = (W'/t) + PC (linear (P)); P = PC + (Pmax-PC)exp(-t/tau) (exponential). The data fit each of the models well (mean R2 = 0.96 through 1.00 for each model). However, significant differences among models were observed for both PC (mean +/- standard deviation (SD) for each model was 195 +/- 29 W through 242 +/- 21 W) and W' (18 +/- 5 kJ through 58 +/- 19 kJ). PC estimates among models were significantly correlated (r = 0.78 through 0.99). For W', between-model correlations ranged from 0.25 to 0.95. For a group of six subjects, the ventilatory threshold for long-term exercise (LTE Tvent; 189 +/- 34 W) was significantly lower than PC for all models except the three-parameter nonlinear (PC = 197 +/- 30 W); PC for each model was, however, positively correlated with LTE Tvent (r = 0.69 through 0.91).(ABSTRACT TRUNCATED AT 250 WORDS)

Electroencephalographic coherence in acquired immune deficiency syndrome.

We studied a quantitative electroencephalographic (EEG) measure, coherence, in 28 patients with acquired immune deficiency syndrome (AIDS) and 56 uninfected volunteers. Compared with uninfected subjects, AIDS patients had increased coherence in the 6- to 10-Hz band. The largest increases in coherence were between frontal and occipital regions and between temporal and frontal regions. Coherence within contiguous regions was less affected. Eight of the 28 AIDS patients (29%) had clinically abnormal EEG findings, compared with four of the 56 uninfected control subjects (7%). Among the AIDS patients, 12 had normal neuropsychological performance, nine had mild impairment, and six had moderate impairment. Coherence was increased in each subgroup of AIDS patients, including those with normal neuropsychologic performance and/or normal clinical EEG results. AIDS patients were then classified by quantitative EEG power in frontal head regions as "abnormal" (the upper third of patients) or "normal" (the remainder). Increased coherence was found among both groups. Because the development of abnormal neuropsychological performance or a clinically abnormal EEG examination indicates relatively advanced central nervous system disease, alterations in specific coherence measures may detect subclinical effects of the human immunodeficiency virus on brain function before other changes are evident.

Assessment of cerebral perfusion using quantitative EEG cordance.

Brain electrical activity is related to cerebral perfusion. The nature of this relationship is unclear, however, and surface-recorded activity has not been a reliable indicator of brain perfusion. We studied 27 subjects, all of whom were examined with single photon emission tomography (SPECT) and quantitative electroencephalography (QEEG), to assess associations between QEEG cordance and relative brain perfusion. Cordance has two indicator states: concordance, which may indicate high perfusion; and discordance, which may indicate low perfusion. We used multiple linear regression to assess the association between cordance and SPECT values, and found that cordance values were strongly associated with tissue perfusion. Concordance in the alpha band was associated both with mean tissue perfusion and the volume of normally perfused tissue, and it had a stronger association with perfusion than any other QEEG variable. Discordance in the beta 1 band was associated with mean perfusion, and it had a stronger association than did relative but not absolute power. These data suggest that cordance may be useful for the noninvasive assessment of brain perfusion.

Cordance: a new method for assessment of cerebral perfusion and metabolism using quantitative electroencephalography.

Increased slow-wave and decreased fast-wave activity on the electroencephalogram is common in brain dysfunction and may be caused by partial cortical deafferentation. No measure that is specific or sensitive for this deafferentation, however, has yet been reported. We studied a series of subjects with white-matter lesions undercutting the cortex and developed a method for analyzing electrical activity called "cordance" that has face validity as a measure of cortical deafferentation. Cordance is measured along a continuum of values: positive values denote "concordance," an indicator associated with normally functioning brain tissue; negative values denote "discordance," an indicator associated with undercutting lesions, low perfusion, and low metabolism. We present a series of subjects studied with magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography that demonstrate strong associations between cordance and other measures of brain structure and function.

Regional differences in brain electrical activity in dementia: use of spectral power and spectral ratio measures.

The pathologic changes in dementia of the Alzheimer's type (DAT) commonly affect selected brain regions. The cortical areas affected in multi-infarct dementia (MID) are less predictable and may be secondary to subcortical gray or white matter damage that is widespread in MID. We compared several types of quantitative EEG power measures (absolute and relative power, and ratios of power) to determine their regional distribution, and their association with changes in cognitive status and age. We examined 49 subjects with clinically diagnosed mild-to-moderate DAT, 29 with mild-to-moderate MID, and 38 elderly controls (CON). We used discriminant analysis to identify, for each parameter type, the brain region and frequency band where the parameter best distinguished between groups of subjects. The parameters showed regional differences in distinguishing between DAT and MID subjects, and in their association with age and cognitive status. All parameters were useful for detecting differences between normal and demented subjects and correctly identified comparable proportions of subjects as having dementia. Subjects who were abnormal on several parameters were much more likely to have dementia. The additive effects of these parameters in correct classification suggest that they may be monitoring different physiologic processes. Combinations of several types of parameters may be more useful than individual parameters for distinguishing demented from non-demented subjects.

Serial quantitative EEG among elderly subjects with delirium.

Serial quantitative electroencephalographic (QEEG) studies were performed in 33 elderly delirious, demented, and control subjects to determine which QEEG variables were associated with changes in clinical state as measured by the Folstein Mini-mental State Examination (MMSE). Conventional EEGs and brain maps were independently rated by two electroencephalographers without knowledge of clinical diagnoses. Correlational analyses were performed using these ratings, along with numerical data from QEEG. In the delirium group (n = 15), changes in scores for the relative power map and changes in relative power in the alpha band had significant associations with changes in MMSE. In the dementia group (n = 10), changes in score for absolute power maps and changes in absolute power in the delta band had significant associations with changes in MMSE. In the control group, changes in MMSE over time were negligible. These findings have potential clinical utility in diagnosing delirium, and in providing a quantitative measure of its severity, which can be used serially.

Conventional and quantitative EEG in the diagnosis of delirium among the elderly.

This study was performed to determine whether an admission quantitative EEG (QEEG) could assist in the differential diagnosis of encephalopathy among a group of elderly subjects with delirium, dementia, and delirium coexistent with dementia. Thirty four subjects from 57 to 93 years had standard 17-channel EEG and quantitative EEG studies, using a linked-ear reference. EEGs were independently rated by two electroencephalographers blind to clinical diagnosis, using conventional criteria to assess the degree of encephalopathy. Brain maps were scored by a scale developed by the authors. Numerical data examined included mean posterior dominant frequency, absolute and relative power in the delta, theta and alpha bands, and slow-wave ratios. The grouping of experimental subjects was by the discharge diagnosis, made using DSM-III-R criteria. Stepwise discriminant analysis was performed to determine which EEG and QEEG variables were best able to distinguish cases. Variables which collectively distinguished normal from encephalopathic records were Mini-Mental State Examination scores and relative power in the alpha frequency band. Variables which collectively distinguished delirium from dementia were EEG theta activity, relative power in delta, and brain map rating. The results suggest that cross-sectional QEEG study is potentially useful in the early differential diagnosis of encephalopathy, and that the variables which distinguish normal from encephalopathic patients might differ from the variables which distinguish delirium from dementia.

EEG coherence in men with AIDS: association with subcortical metabolic activity.

The authors studied the relationship between cerebral metabolism and brain electrical activity in patients with acquired immunodeficiency syndrome (AIDS), using positron-emission tomography and quantitative electroencephalography. Electroencephalographic coherence in the 6-to 10-Hz band correlated positively with thalamic metabolic activity. Coherence adjusted for background activity correlated strongly and positively with basal ganglia metabolic activity. Posterior interhemispheric coherence showed the highest correlations with measures of metabolic activity. These results suggest that changes in coherence may reflect AIDS-related subcortical disease. The high correlations between the two different measures of cerebral activity support the validity of electroencephalographic coherence measures in studies of AIDS-related neuropsychiatric dysfunction.

Changes in brain functional connectivity in Alzheimer-type and multi-infarct dementia.

Clinical and neuropathological evaluation of elderly subjects with dementia has traditionally concentrated upon the focal distribution of brain disease, ignoring changes in the complex connections that link brain areas and that are crucial for cognition. We examined subjects with the two most common forms of dementia in the elderly (dementia of the Alzheimer type or DAT, and multi-infarct dementia or MID); and used electroencephalographic (EEG) coherence to examine the effects of these illnesses on the functional connections between brain areas. We studied coherence between brain areas known to be linked by two different types of connections: (i) dense narrow bands of long corticocortical fibres; (ii) broad complex networks of corticocortical and corticosubcortical fibres. Areas that were linked by dense narrow bands of long corticocortical fibres showed greatly diminished coherence in subjects with DAT; among MID subjects, this coherence was not significantly affected. Areas that were linked by broad connective networks showed the largest decreases in coherence among MID subjects. These findings are consistent with neuropathological evidence that Alzheimer's disease is a neocortical 'disconnection syndrome' in which there is a loss of structural and functional integrity of long corticocortical tracts. The findings further suggest that the vascular disease of MID most prominently affects broad fibre networks that may be more vulnerable to diffuse subcortical vascular damage. A ratio of coherence from complex corticocortical-corticosubcortical networks divided by coherence from long corticocortical tracts correctly classified 76% of subjects into DAT and MID categories. Overall, these results indicate that EEG coherence detects basic pathophysiological differences between subjects with DAT and MID, and that these differences may be clinically useful.

Stable bimodal response to cholinomimetic drugs in Alzheimer's disease. Brain mapping correlates.

We investigated quantitative EEG brain mapping as a physiologic marker of drug response while studying the stability of intersubject variability in patients with Alzheimer's disease (AD) who were receiving bethanechol through intracerebroventricular (ICV) shunts. Two of the patients had previously demonstrated cognitive and behavioral improvements on medication; the third had cognitive deterioration complicated by agitated depression. All three patients were reexamined in a dose-response paradigm. Serial brain mapping examinations were performed along with brief cognitive testing. All patients showed drug responses that were comparable with responses during their initial dose-response phase. There were strong linear correlations between global decreases in 2 to 6 Hz slow-wave activity and cognitive improvement. Brain mapping demonstrated that slowing decreased in magnitude and field with increasing dose until optimal dose was reached; with supra-optimal doses, the magnitude and field of the slowing increased dramatically. These results suggest that the quality of cholinomimetic drug responses are stable over time in individual patients, and that magnitude and pattern of slow-wave activity as measured by brain mapping may be useful in monitoring treatment with cholinomimetic agents.

Non-linear dynamics of electrocardiographic waveforms following cocaine administration.

We examined dynamics of ECG waveforms preceding and following 10 mg/kg intravenous administration of cocaine in freely moving cats. Cocaine induced substantial variation in ECG waveforms, as demonstrated by non-linear procedures of phase-plane plots and Poincaré analyses. Phase-plane plots revealed that waveform variation following cocaine administration was not randomly or uniformly distributed, but instead followed patterns of clustered organization with unvisited regions. These patterns are characteristic of chaotic distributions, and support the hypothesis that ECG waveform variation following cocaine does not degenerate into random patterns; instead, the variation follows deterministic, though chaotic patterns.

Diagnosis and assessment of dementia using functional brain imaging.

Functional brain imaging using computer-analyzed electroencephalography was performed in 40 subjects: 15 with mild-to-moderate dementia of the Alzheimer's type (DAT), 13 with mild-to-moderate multi-infarct dementia (MID), and 12 age-matched controls. We examined three different parameters of brain electrical activity in these subjects: absolute slow-wave power, proportional power in all frequency bands, and ratios of high-frequency/low-frequency electrical activity (so-called "spectral ratios"). Spectral ratios were significantly more powerful in discriminating among groups than the other measures. Functional images using spectral ratios revealed that subjects with DAT have a characteristic left temporo-parietal defect which clearly distinguished them from subjects with MID and from control subjects. The severity of dementia was best assessed by examining absolute slow-wave power, which had the strongest linear correlation with mental status testing. Serial images from one subject with DAT over 3 years demonstrate both quantitative and qualitative shifts in slow-wave activity in the course of DAT. The study suggests that functional imaging may be more useful than either simple EEG or computer-analyzed EEG in assessing and diagnosing patients with suspected dementia.

Alexithymia and the split brain: VI. Electroencephalographic correlates of alexithymia.

Electroencephalographic recordings of eight corpus callosotomy patients and eight precision-matched control subjects were obtained as subjects watched a film symbolically depicting death. A content-analytic measure of alexithymia was regressed on eight auto-spectral alpha-band intensity averages and on subsets of alpha-band coherence averages. Results were interpreted on the basis of three possible mechanisms of alexithymia: (1) Alexithymic subjects had more right-temporal alpha-band intensity, suggesting inadequate understanding of the film. (2) A possible lack of inner speech in alexithymics was suggested by their relative alpha abundance of the left frontal and left temporal channels but left parietal alpha desynchronization, and by their lower left frontotemporal but higher left parietofrontal and left parietotemporal coherences. (3) Alexithymic subjects had higher right frontal-left parietal and left frontal-left parietal coherences, suggesting possible interhemispheric inhibition of expression. Expressive subjects had higher right frontal-left temporal (and homologous interhemispheric frontal, parietal, and frontal) coherences, suggesting interhemispheric facilitation of verbal expression.

Electroencephalographic spectra and coherence in the diagnosis of Alzheimer's-type and multi-infarct dementia. A pilot study.

The accurate diagnosis of dementia is difficult because there are no specific physiologic tests. Computer-analyzed electroencephalography (EEG) has shown promise as a tool for the differential diagnosis of dementia, but topographic methods for data collection and analysis have seldom been used. We used these methods to investigate EEG differences among three groups of elderly subjects: those with mild to moderate dementia of the Alzheimer's type (DAT), those with mild to moderate multi-infarct dementia (MID), and age- and sex-matched normal controls. The two groups of demented subjects were distinguished from the control group by a new criterion, the ratio of high-frequency to low-frequency electrical activity in the left temporal region, which was greatly diminished in demented subjects. Using this single variable, all control subjects and 15 of 18 demented subjects were correctly classified (sensitivity 83%, specificity 100%). The three misclassified subjects were among the least impaired subjects with DAT. Examination of coherence, or synchronization of the EEG signal, enabled us to distinguish subjects with DAT from those with MID. Using discriminant analysis of both EEG frequency and coherence, 92% (22/24) of subjects were accurately classified. These results justify further evaluation of topographic, computer-based EEG analysis as a test for the differential diagnosis of dementia.

Alexithymia and the split brain. V. EEG alpha-band interhemispheric coherence analysis.

Electroencephalographic (EEG) recordings were obtained while 6 completely commissurotomized patients, 2 partially commissurotomized patients, and 8 precision-matched normal control subjects watched 4 times a film symbolically depicting death. Our hypothesis was that alexithymia--a diminished capability to verbally express moods, symbols, and feelings--would be greater for patients because loss of cerebral commissures reduces interhemispheric communication, separating right-hemisphere-dependent affective understanding and left-hemisphere-dependent verbalization. Path and covariance structure analyses confirmed that callosotomy decreased alpha-band EEG coherences (after adjustment for mean intrahemispheric coherence) between pairs of scalp electrode channels placed homologously over frontal, parietal, and temporal lobes of the brain. This result occurred both for an index of interhemispheric coherence and for a latent variable indicated by the 3 adjusted coherences. Reduced levels of interhemispheric coherence in turn increased alexithymia, for an overall index and for a latent variable indicated by lexical-level content-analytic measures of verbal responses to the filmic stimulus.

Alexithymia: an experimental study of cerebral commissurotomy patients and normal control subjects.

This study assessed alexithymia in six patients with complete cerebral commissurotomy, two patients with partial commissurotomy, and eight matched control subjects. Comparisons were based on content-analytic measures of the subjects' spoken and written responses to a film that symbolically represented death and loss. The commissurotomized patients were more alexithymic on all four lexical-level variables, all six sentential-level variables, and all six global-level variables. Discriminant function analysis found a linear combination of four variables that effectively discriminated groups of fully commissurotomized, partially commissurotomized, and normal control subjects and correctly classified 15 of the 16 subjects.