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The aim of this study was to apply recently developed mathematical tools of chaos theory to the analysis of event-related potentials (ERPs) recorded in paradigms in which the mismatch negativity (MMN) and the P3 component appeared. A new method, the point correlation dimension (PD2i), was used for data analysis, which is more accurate than other algorithms for the calculation of the correlation dimension (D2), which latter is a measure of the complexity of the generator(s) responsible for producing the analyzed time series, i.e., the EEG. ERPs were recorded from Fz, Cz and Pz in 6 subjects. With respect to baseline, the PD2i decreased significantly both during the event-related potentials in which the MMN and also in which the P3 was present, but the pattern and magnitude of this decrease was different between these two situations. The pattern of PD2i changes during the occurrence of deviant stimuli eliciting the MMN suggests the presence of a frontal MMN generator. The conspicuous PD2i decrease during the occurrence of the P3 wave may support the “context closure” hypothesis concerning its functional significance.

To understand the Electrocardiogram, one must understand both the origin of the waves (PQRST) and intervals between them (PQRST to PQRST or R-R). The waves are intrinsically generated within the heart, with some regulation by the cardiac nerves, but the intervals are extrinsically controlled primarily by the brain, through projections to both the auricular pacemakers and the ventricular tissues. That is, the intervals are regulated by the brain, as mediated through the autonomic effectors. To understand the R-R interval variations, one must understand the neural mechanism(s) that underlie changes in the T to P segments, which are lengthened and shortened in time to create the R-R variation. The Society for Neuroscience does not pay substantive attention to Cardiology, and the various societies of Cardiology do not pay much attention to Neuroscience. This two-way neglect has forced the formation of a new society devoted to both fields of inquiry. The Society for Heart-Brain Medicine was formed in 2007, and the plenary talks that established the field on its own foundation included two by the current authors (Skinner, 2007a; 2007b). A paradigm is a way of thinking, and a new one is a way of “thinking outside the box.” Two new paradigms were presented by us at the first SHBM Meeting and each was based on pivotal new discoveries. First, we showed that only nonlinear algorithms are appropriate for analysis of physiological data, because the data themselves are nonlinear--a nonlinear algorithm is thus a more sensitive measure of the heartbeat dynamics (e.g., of R-R variability) than all previous stochastic measures, such as the, mean, standard deviation, power spectrum, and so on. Secondly, small proteins and peptides are known to regulate physiology in parallel with the nervous system--that is, the “state” (behavioral / neural) determines the outputs of these two types of physiological effectors. Hibernation, for example, in which the cold eventually shuts off the nervous system, continues to be regulated by neuroendocrine molecules, some of which were indicated in a similar state (REM sleep) to have salutary effects on the ischemic heart (suppression of arrhythmogenesis in the electrocardiogram). This analogy between the similar states enabled conventional proteomics to be used in the other state (e.g., in hibernation) and thus formed the basis for a new way to discover drugs, “state-dependent proteomics.” With the method a new (antiinfarction) drug candidate was actually discovered (Skinner, 2007a). The realization that the heartbeat intervals in the electrocardiogram are primarily regulated by the brain provides us with an entirely new way to look at the electrocardiogram – the intervals are not intrinsically regulated by currents and pacemakers within the heart, as are the waves, but rather are under extrinsic control by the brain, mediated of course through the autonomic

Electrocardiograms were recorded in conscious pigs during psychological stress (touching), left anterior descending coronary artery occlusion, intracerebral levo-propranolol (0.05 mg/kg), and their respective controls. The R-R intervals were evaluated with both a deterministic measure (point correlation dimension) and a stochastic one (mean). Only the deterministic measure was sensitive to between-subject responses (P

In this review we examined the emerging science of deterministic chaos (nonlinear systems theory) and its application to selected physiological systems. Although many of the popular images of fractals represent fascination and beauty that by analogy corresponds to nature as we see it, the question remains as to its ultimate meaning for physiological processes. It was our intent to help clarify this somewhat popular, somewhat obscure area of nonlinear dynamics in the context of an ever-changing procedural base. We examined not only the basic concepts of chaos, but also its applications ranging from observations in single cells to the complexity of the EEG. We have not suggested that nonlinear dynamics will answer all of our questions; however, we did attempt to illustrate ways in which this approach may help us to answer new questions and to rearticulate old ones. Chaos is revolutionary in that the overall approach requires us to adopt a different frame of reference which, at times, may move us away from previous concerns and methods of data analysis. In sections I-IV, we summarized the nonlinear dynamics approach and described its application to physiology and neural systems. First, we presented a general overview of the application of nonlinear dynamical techniques to neural systems. We discussed the manner in which even apparently simple deterministic systems can behave in an unpredictable manner. Second, we described the principles of nonlinear dynamical systems including the derived analytical techniques. We now see a variety of procedures for delineating whether frenetic chaotic behavior results from a nonlinear dynamical system with a few degrees of freedom, or whether it is caused by an infinite number of variables, i.e., noise. Third, we approached the applications of nonlinear procedures to the cardiovascular systems and to the neurosciences. In terms of time series, we described initial studies which applied the now "traditional" measures of dimensionality (e.g., based on the algorithm by Grassberger and Procaccia) and information change (e.g., Lyapunov exponents). Examples include our own work and that of Pritchard et al., demonstrating that the dynamics of neural mass activity reflect psychopathological states. Today, however, the trend has expanded to include the use of surrogate data and statistical null hypotheses testing to examine whether a given time series can be considered different from that of white or colored noise (cf. Ref. 262). One of the most important potential applications is that of quantifying changes in nonlinear dynamics to predict future states of the system.(ABSTRACT TRUNCATED AT 400 WORDS)

Objectives. The purpose of this report was to study heart rate variability in Holter recordings of patients who experienced ventricular fibrillation during the recording.Background. Decreased heart rate variability is recognized as a long-term predictor of overall and arrhythmic death after myocardial infarction. It was therefore posttulated that heart rate variability would be lowest when measured immediately before ventricular fibrillation.Methods. Conventional indexes of heart rate variability were calculated from Holter recordings of 24 patients with structural heart disease who had ventricular fibrillation during monitoring. The control group consisted of 19 patients with coronary artery dipease, of comparable age and left ventricular ejection fraction, who had nonsustained ventricular tachycardia but no ventricular fibrillation.Results. Heart rate variability did not differ between the two groups, and no consistent trends in heart rate variability were observed before ventricular fibrillation occurred.Conclusions. Although conventional heart rate variability is an independent long-term predictor of adverse outcome after myocardial infarction, its clinical utility as a short-term predictor of life-threatening arrhythmias remains to be elucidated.

Chaos theory may have a widespread application in medicine, from the analysis of protein structure at one end of the spectrum to fetal monitoring and the measurement of aging on the other. This application is especially on firm ground in cardiology, where it is simple and precise for the experimenter, and a primer exists for the clinician. As just presented, the point-correlation-dimension analysis of heartbeat variability is able to characterize the patterns of low-dimensional chaos produced by the heartbeat generator, a mechanism that is a composite of the voltage-dependent, neurotransmitter-dependent, and circulation-dependent ionic conductances that are all located in the myocardium where the heartbeat is formed. Most importantly, this deterministic measure of heartbeat variability is able to predict imminent lethal arrhythmogenesis with an accuracy that the more familiar stochastic measures do not have. This may arise because the PD2 is sensitive to the net degrees of freedom of the heartbeat generator, which, under the influence of the nerves and the coronary circulation, can be shifted so the resulting dynamics cause the initiation of lethal arrhythmogenesis. Application of chaos theory in neurology may be equally fruitful because the deterministic measures can discriminate among neuronal firing patterns, reveal subtle changes in brain waves, and be related to higher cognitive processes. Psychiatry also seems quite likely to benefit more and more from the application because the algorithms can discriminate schizophrenic brain functions from normal ones. Thus it can be expected that future applications will enable observation of biologic processes all along the brain-heart axis by which lethal ventricular fibrillation is regulated and perhaps even caused by its determination of the heartbeat dynamics. The subfield of neurocardiology has come a long way since it was first positively identified as an important research area. It took a lot of experiments to show how lethal cardiac arrhythmogenesis is involved with cerebral activities delivered over autonomic pathways. Although we do not yet fully understand the causal mechanism of lethal arrhythmogenesis, we may be getting close. It will become increasingly imperative for the clinical neurologist, along with the cardiologist, to understand the importance of neurocardiology in medical therapy and for the neurologist, along with the cardiologist and psychiatrist, to understand its importance in preventive treatments.

Objective: The aim of this study was to test whether a new heart rate variability (HRV) complexity measure, the Point Correlation Dimension (PD2i), provides diagnostic information regarding early subclinical autonomic dysfunction in diabetes mellitus (DM). We tested the ability of PD2i to detect diabetic autonomic neuropathy (DAN) in asymptomatic young DM patients without overt neuropathy and compared them to age- and gender-matched controls. Methods: HRV in DM type 1 patients (n = 17, 10 female, 7 male) aged 12.9–31.5 years (duration of DM 12.4 ± 1.2 years) was compared to that in a control group of 17 healthy matched probands. The R–R intervals were measured over 1 h using a telemetric ECG system. Results: PD2i was able to detect ANS dysfunction with p = 0.0006, similar to the best discriminating MSE scale, with p = 0.0002. Discussion: The performance of PD2i to detect DAN in asymptomatic DM patients is similar to the best discriminative power of previously published complexity measures. Conclusions: The PD2i algorithm may prove to be an easy to perform and clinically useful tool for the early detection of autonomic neuropathy in DM type 1 patients, especially given its minimal data requirements.

Background: Traditional vital signs such as heart rate, blood pressure, and oxygen saturation are not ideal for timely and accurate assessment of physiologic status after trauma (TR) and hemorrhagic shock (HS). Analysis of the complex beat-to-beat variability present in the heart-rate time series has been proposed as a new vital sign in this setting. We determined the effect of chest TR and HS on heart-rate complexity (HRC) in a porcine model. Methods: Anesthetized swine in group II (n = 20) underwent blunt right chest TR with a modified captive-bolt stunner; then, 10 minutes later, hemorrhage of 12 mL/kg over 10 minutes, followed by resuscitation with lactated Ringer s solution, and reinfusion of blood. Group I (n = 15) served as time controls. Two hundred beat sections of EKG waveforms were analyzed at 7 time points: at baseline, after TR, immediately after hemorrhage (HS), and 1 hour, 2 hours, 4 hours, and 5 hours after HS. Several computationally different measures of HRC were calculated, including sample entropy, similarity of distribution, and point correlation dimension. Results: HRC was decreased after TR, HS, and at 1 hour, manifested by decreased sample entropy and point correlation dimension and increased similarity of distribution. These HRC measures were all restored by resuscitation. Conclusions: Several independent measures demonstrated decreased HRC after combined TR/HS and restored HRC with resuscitation. Complexity analysis may be useful for diagnosis of TR/HS and for monitoring resuscitation.

Quantification of a chaotic system can be made by calculating the correlation dimension (D2) of the data that the system generates (Packard et al., 1980). The D2 algorithm, however, requires stationarity of the generator, a feature that biological data rarely reflect (Mayer-Kress et al., 1988). So we developed the "point correlation dimension" (PD2), an algorithm that accurately tracks D2 in linked data of different dimensions (Carpeggiani et al., 1991). We now present a mathematical argument that, for stationary data, individual PD2s converge to D2 and we demonstrate that the algorithm rejects contributions made by bursts of noise. Data were obtained from the surface of the olfactory bulb of the conscious rabbit (64 electrodes, 640 Hz each, 1.3 sec epochs) before and after presentation of a novel or habituated odor. D2 could be calculated in only 1 of 10 novel-odor trials, whereas PD2 could be calculated in all. Both algorithms indicated that a novel odor evokes a spatially uniform dimensional increase. The PD2 uniquely exhibited the dimensional decreases that occur during inspiration and the gradients of mean dimension present during the nonstimulated control state. These control gradients remained unchanged without odor experience, but showed spatially specific PD2 increases following odor habituation. It is interpreted that, 1) the PD2 is sensitive, accurate, and appropriate for dimensional assessment of biological data, 2) that during analysis of unfamiliar information a single global process is transiently evoked in the neuropil, and 3) after experience multiple spatially specific processes tonically map the sites of learning.

The application of "chaos theory" to the physical and chemical sciences has resolved some long-standing problems, such as how to calculate a turbulent event in fluid dynamics or how to quantify the pathway of a molecule during Brownian motion. Biology and medicine also have unresolved problems, such as how to predict the occurrence of lethal arrhythmias or epileptic seizures. The quantification of a chaotic system, such as the nervous system, can occur by calculating the correlation dimension (D2) of a sample of the data that the system generates. For biological systems, the point correlation dimension (PD2) has an advantage in that it does not presume stationarity of the data, as the D2 algorithm must, and thus can track the transient non-stationarities that occur when the systems changes state. Such non-stationarities arise during normal functioning (e.g., during an event-related potential) or in pathology (e.g., in epilepsy or cardiac arrhythmogenesis). When stochastic analyses, such as the standard deviation or power spectrum, are performed on the same data they often have a reduced sensitivity and specificity compared to the dimensional measures. For example, a reduced standard deviation of heartbeat intervals can predict increased mortality in a group of cardiac subjects, each of which has a reduced standard deviation, but it cannot specify which individuals will or will not manifest lethal arrhythmogenesis; in contrast, the PD2 of the very same data can specify which patients will manifest sudden death. The explanation for the greater sensitivity and specificity of the dimensional measures is that they are deterministic, and thus are more accurate in quantifying the time-series. This accuracy appears to be significant in detecting pathology in biological systems, and thus the use of deterministic measures may lead to breakthroughs in the diagnosis and treatment of some medical disorders.

A reduced standard deviation of RR intervals (SDRR) predicts increased mortality in groups of survivors of myocardial infarction. Like SDRR, the correlation dimension (D2) describes variation within a sampled time series, but uniquely it reveals 1) the epoch's geometric structure and 2) the degrees of freedom of the generator. These unique features may be more sensitive predictors of mortality than SDRR. We developed a new algorithm for estimating D2 (i.e., the "point-D2"), tested it with known data, and found that it had greater accuracy for finite data than other published algorithms. Analysis of RR intervals from eight conscious pigs undergoing acute occlusion of the left anterior descending coronary artery revealed a drop in the point-D2 from a control mean and standard deviation of 2.50 +/- 0.81 to 1.58 +/- 0.64 during the first minute of ischemia (p less than 0.01) and to 1.07 +/- 0.18 during the last minute preceding ventricular fibrillation (p less than 0.01). Partial occlusions (50-90% reduction of coronary blood flow) evoked point-D2 reductions only 25-30% of control (p less than 0.01). The point-D2 means were correlated between pigs with the magnitude of the respiratory sinus arrhythmia (p less than 0.01), but during ischemia this correlation was replaced by one between the standard deviation of the point-D2s and SDRRs. Because the simultaneous reduction in the mean point-D2 and its standard deviation to 1.07 +/- 0.18 occurred in every case, was unique to the few minutes preceding ventricular fibrillation, and never reached these low values during other conditions in which it was reduced, we conclude that the point-D2 may be an accurate prospective predictor of mortality within the individual subject.

Neurocardiology emphasizes the role of the higher cerebral mechanisms in cardiovascular disorders. Several large clinical trials (BHAT, MIAMI, and ISIS) have consistently shown that treatment with a beta-receptor blocker (propranolol, metoprolol, or atenolol) will produce a 26% to 29% reduction in mortality in high-risk survivors of acute myocardial infarction. Because all beta-blockers cross the blood-brain barrier, it is not clear whether the salutary action is on the central or peripheral receptors. Therefore the effects of intracerebral versus intravenous propranolol were observed in 30 conscious pigs following complete occlusion of the left anterior descending coronary artery. Controls showed the propranolol to remain confined throughout the experiment to the central or peripheral compartment into which it was injected. To assure the occurrence of ventricular fibrillation (VF), each pig was psychologically stressed by being unconditioned to the laboratory. Intracerebral propranolol (0.05 mg/kg) prevented VF within a 20 min period of reversible ischemia in 6 of 9 pigs, whereas VF was prevented in 0 of 11 controls injected intravenously with either dextro-propranolol (2 pigs) or vehicle (9 pigs) (P less than .0006, binomial probability ratio). In some pigs in which VF was not manifested by 20 min, the ischemia was reversed and additional control observations were achieved; a total of 10 counter-balanced within-subjects experiments confirmed the between-subjects result (P less than .01, paired-t test). In contrast intravenous propranolol (0.2 to 2.0 mg/kg) in 7 pigs had no effect on VF latency compared to 7 vehicle controls. It is concluded that beta-receptor antagonists prevent VF in the ischemic myocardium by their effect on the brain and not the heart.

James E Skinner1, Michael Meyer2, William C Dalsey3, Brian A Nester4, George Ramalanjaona5, Brian J O’Neil6, Antoinette Mangione7, Carol Terregino8, Abel Moreyra9, Daniel N Weiss10, Jerry M Anchin1, Una Geary11, Pamela Taggart121Vicor Technologies, Inc, Boca Raton, FL, USA; 2Max Planck Institute for Experimental Physiology, Goettingen, Germany; 3Kimbal Medical Center, Lakewood, NJ, USA; 4Lehigh Valley Hospital and Health Network, Allentown, PA, USA; 5St. Michaels Hospital, Newark, NJ, USA; 6William Beaumont Hospital, Royal Oak, MI, USA; 7Luitpolb Pharmaceuticals, Inc., Norristown, PA, USA; 8Cooper Medical Center, Camden, NJ, USA; 9Robert Wood Johnson Medical School, New Brunswick, NJ, USA; 10Florida Arrhythmia Consultants, Ft. Lauderdale, FL, USA; 11St. James Hospital, Dublin, Ireland; 12Albert Einstein Medical Center, Philadelphia, PA, USAAbstract: Heart rate variability (HRV) reflects both cardiac autonomic function and risk of sudden arrhythmic death (AD). Indices of HRV based on linear stochastic models are independent risk factors for AD in postmyocardial infarction (MI) cohorts. Indices based on nonlinear deterministic models have a higher sensitivity and specificity for predicting AD in retrospective data. A new nonlinear deterministic model, the automated Point Correlation Dimension (PD2i), was prospectively evaluated for prediction of AD. Patients were enrolled (N = 918) in 6 emergency departments (EDs) upon presentation with chest pain and being determined to be at risk of acute MI (AMI) >7%. Brief digital ECGs (>1000 heartbeats, ∼15 min) were recorded and automated PD2i results obtained. Out-of-hospital AD was determined by modified Hinkle-Thaler criteria. All-cause mortality at 1 year was 6.2%, with 3.5% being ADs. Of the AD fatalities, 34% were without previous history of MI or diagnosis of AMI. The PD2i prediction of AD had sensitivity = 96%, specificity = 85%, negative predictive value = 99%, and relative risk >24.2 (p ≤ 0.001). HRV analysis by the time-dependent nonlinear PD2i algorithm can accurately predict risk of AD in an ED cohort and may have both life-saving and resource-saving implications for individual risk assessment.Keywords: heart rate variability, sudden death, ventricular arrhythmias, chaos, non-linear

James E Skinner, Jerry M Anchin, Daniel N WeissVicor Technologies, Inc., Bangor, PA, USAAbstract: Heart rate variability (HRV) reflects both cardiac autonomic function and risk of arrhythmic death (AD). Reduced indices of HRV based on linear stochastic models are independent risk factors for AD in post-myocardial infarct cohorts. Indices based on nonlinear deterministic models have a significantly higher sensitivity and specificity for predicting AD in retrospective data. A need exists for nonlinear analytic software easily used by a medical technician. In the current study, an automated nonlinear algorithm, the time-dependent point correlation dimension (PD2i), was evaluated. The electrocardiogram (ECG) data were provided through an National Institutes of Health-sponsored internet archive (PhysioBank) and consisted of all 22 malignant arrhythmia ECG files (VF/VT) and 22 randomly selected arrhythmia files as the controls. The results were blindly calculated by automated software (Vicor 2.0, Vicor Technologies, Inc., Boca Raton, FL) and showed all analyzable VF/VT files had PD2i < 1.4 and all analyzable controls had PD2i> 1.4. Five VF/VT and six controls were excluded because surrogate testing showed the RR-intervals to contain noise, possibly resulting from the low digitization rate of the ECGs. The sensitivity was 100%, specificity 85%, relative risk> 100; p < 0.01, power >90%. Thus, automated heartbeat analysis by the time-dependent nonlinear PD2i-algorithm can accurately stratify risk of AD in public data made available for competitive testing of algorithms.Keywords: heart rate variability, sudden death, ventricular arrhythmias, nonlinear, chaos

Mathematical “chaos” appears to occur in the heartbeat time-series. Low-dimensional chaos can be visualized as a geometric or spatial pattern in a temporal process. Several methods are available for representing these geometric patterns, including the mutual information content, the correlation dimension, and the type of pattern recurrences. Application of these methods to the heartbeat following coronary artery occlusion shows that prior to the initiation of lethal arrhythmogenesis the mutual information increases, the correlation dimension decreases, and the recurrence patterns shift from periodic clustering to local clustering. These observations not only have implications for new theoretical approaches to understanding how the heartbeat is generated and how arrhythmias occur, but also for the development of new biomedical tests and the manufacture of new devices for use in clinical cardiology.

A central noradrenergic process may permit expression of the stress-related increase in cardiac vulnerability to ventricular fibrillation (VF). Thus, the effect of central beta-adrenergic receptor blockade with L-propranolol (0.01 and 0.05 mg/kg) on ischemia-induced VF vulnerability was evaluated in the psychologically stressed pig model and compared with Ringer's solution and D-propranolol (0.05 mg/kg). The ischemia of a maximum 15-minute left anterior descending coronary artery occlusion was used since we previously determined that pigs surviving 15 minutes usually do not fibrillate. Time to the onset of VF was analyzed by time-to-event analysis and ranged from 0.75 to 13.8 minutes in vulnerable pigs. Intracerebroventricular administration of L-propranolol (0.05 mg/kg) prolonged the time to VF compared with Ringer's solution and D-propranolol (p less than 0.05). The high dose of L-propranolol also reduced the incidence of VF (7/15 fibrillated) compared with Ringer's solution (12/12 fibrillated) and D-propranolol (6/7 fibrillated). The lower dose of L-propranolol was without effect on VF vulnerability (7/9) fibrillated). The plasma concentration resulting from central administration of 0.05 mg/kg L-propranolol was found to be 9.05 +/- 3.25 ng/ml, which is significantly below therapeutic antiarrhythmic blood levels. We conclude that the reduced vulnerability to ischemia-induced VF after intracerebroventricular administration of propranolol is due to alteration of a central beta-adrenergic receptor-mediated phenomenon as opposed to an effect on the heart directly or to nonspecific membrane stabilization.

Indexes of heart rate variability (HRV) based on linear stochastic models are independent risk factors for arrhythmic death (AD). An index based on a nonlinear deterministic model, a reduction in the point correlation dimension (PD2 i), has been shown in both animal and human studies to have a higher sensitivity and specificity for predicting AD. Dimensional reduction subsequent to transient ischemia was examined previously in a simple model system, the intrinsic nervous system of the isolated rabbit heart. The present study presents a new model system in which the higher cerebral centers are blocked chemically (ketamine inhibition of N-methyl-d-aspartate receptors) and the system is perturbed over a longer 15-min interval by continuous hemorrhage. The hypothesis tested was that dimensional reduction would again be evoked, but in association with a more complex relationship between the system variables. The hypothesis was supported, and we interpret the greater response complexity to result from the larger autonomic superstructure attached to the heart. The complexities observed in the nonlinear heartbeat dynamics constitute a new genre of autonomic response, one clearly distinct from a hardwired reflex or a cerebrally determined defensive reaction.

The analytic algorithms derived from non-linear deterministic models may be more sensitive to differences in physiological data than those based on linear stochastic models. Among the non-linear algorithms the time-dependent dimensional ones appear to be the most sensitive discriminators. In the present study dimensional responses were examined in both electronically and mathematically generated data and in high-resolution physiological data. The latter were event-related potentials (ERPs) recorded from the primary auditory cortex of cats during classical conditioning. Two techniques were found to lengthen and stabilize the linear scaling region in the correlation integral of the dimensional algorithms: (1) linking trials to increase data length; and (2) gain reduction to lower integer-values of noise, combined with algorithmic setting of slopes

Reduced autonomic control of heartbeat intervals occurs with advanced heart disease and is an independent risk factor for mortality in cardiac patients. Such loss of control is manifested in the heartbeat intervals as a reduction in the total variability, including contributions made by oscillatory reflexes. Animal studies suggest that although the loss of autonomic control may arise following acute coronary artery obstruction, myocardial infarction, or other cardiological events, it may also arise periodically from psychological stress and other transient non-stationary influences mediated by the nervous system. Recent clinical studies of high-risk patients suggest that the deterministic measures of heartbeat dynamics may be more sensitive and specific predictors of risk of death than the more usual stochastic ones, such as the mean, standard deviation or power spectrum. In the present study, several new algorithms based in deterministic chaos theory were applied to a data set made from 20 high-risk patients, each of whom had documented nonsustained ventricular tachycardia (VT) and 10 of whom manifested lethal ventricular fibrillation (VF) within 24 hr. Only the algorithms which measured the time-dependent dimensional complexity (D2i, PD2i) in the data were able to discriminate those patients that later manifested VF. The algorithm which treated the problem of data nonstationarity (PD2i) had the highest sensitivity (100%) and specificity (100%) (P < 0.001, binomial test). Those algorithms which detected order in the data (stochastic-surrogates, determinism, largest Lyapunov exponent, entropy) clearly showed all data to contain low-dimensional chaos, but the order itself did not discriminate between VF and VT risk. It is concluded that among the nonlinear measures of heart rate variability, the ones that quantify the time-dependent complexity, as opposed to detecting the order, are best able to predict clinical risk of sudden cardiac death.

The conventional electrophysiological methods used for the analysis of the functional characteristics of the nervous system are not able to grasp its non-linear and random features. Of the methods based on the application of chaos-theory the correlation dimension analysis can be used to quantify the complexity of the analyzed signal, such as the electroencephalogram (EEG). The new version (point-correlation dimension, PD2) was used in this study, which is more accurate than the other, currently used algorithms. The purpose of the present investigation was to compare the sensitivity of the methods based on chaos-theory with the traditional electrophysiological ones in a case when no apparent abnormality was present as judged on the basis of this latter methodology. The PD2 was calculated from the EEG recorded in 13 healthy control subjects and in a patient who suffered a small subcortical stroke 2 years prior to the investigation and who was free of neurological symptoms at the time of recording. Compared to that seen in the control group, in the Z -score maps of the scalp distribution of the PD2, a marked asymmetry was seen and the absolute PD2 values showed a low-dimensional area in the parietal region, ipsilateral to the stroke. A relative decrease of the gamma band was found in the frequency power spectra in the same area. It is suggested that the additional information extracted from the EEG by non-linear analysis may increase the sensitivity of electrophysiological methods for detecting brain pathology. © 1997 Elsevier Science B.V.

During the past five years general rules have been developed for the application of chaos theory to biology and medicine, which enable investigators to avoid the pitfalls that invalidated and trivialized many earlier results. The importance of biological chaos is that the variables governing the spatial and temporal geometries of the system may be few in number, fractional in dimension, and thus enable low-energy control with complex deterministic consequences. The complexity of control inherent in chaotic systems may be important in the dynamics of gene expression and translation. Extending these ideas may lead to completely novel ways to modulate protein production by introducing simple pulses at critical times or places.

We conclude that the QT and RR intervals show independent responses to various types of stimuli. The spectral and dimension analyses of the RR and QT intervals show characteristic responses both to mental (stress interview) and physical (exercise) perturbations. Such analyses may probe the effects of the forebrain on the heart in such a way as to assess its potentially deleterious impact and thus to predict cardiac risk.

Reduced reflexive control of heartbeat intervals occurs with advanced heart disease and is an independent risk factor for mortality. Based on a previous study of experimental myocardial infarction in pigs, we hypothesized that a deterministic measure of heartbeat dynamics, the correlation dimension of R-R intervals (D2), may be a better predictor of risk than a stochastic measure, such as the standard deviation (SD). We determined the point estimates of the heartbeat D2 (i.e., PD2s) in Holter electrocardiographic recordings from 11 high-risk patients who manifested ventricular fibrillation (VF) during the recording and in high-risk controls having only nonsustained ventricular tachycardia (14 patients) or premature ventricular complexes (13 patients). We found that PD2 reduction (i.e., PD2s < 1.2) precedes lethal arrhythmias by hours, but is not reduced in high-risk controls (p < 0.001; sensitivity, 91%; specificity, 85%). Heartbeat SD did not discriminate among the patients. Thus PD2 of heartbeat intervals may provide an important diagnostic test and early warning sign of VF.

Neomammalian and paleomammalian (limbic) brain structures control different behaviors and the autonomic support specific to each. Both neural systems are involved in cardiovascular disorders. Our previous studies showed that bilateral cryoblockade of a neomammalian structure (the frontal lobes) reduces blood pressure elevations in experimental hypertension and prevents lethal arrhythmogenesis in experimental myocardial infarction. Other studies showed that bilateral lesions in a paleomammalian structure (amygdala) also reduce the blood pressure elevations. Thus, we hypothesized that cryoblockade of the amygdala would prevent lethal arrhythmogenesis. We found that cooling of cryoprobes implanted bilaterally in the amygdala prevented ventricular fibrillation in five of eight pigs during a 20-minute period of reversible myocardial ischemia, whereas cryoblockade in structures surrounding the amygdala (five pigs), unilateral cryoblockade in the amygdala (two pigs), or sham operations (three pigs) did not prevent ventricular fibrillation (p less than 0.003). In two of the five pigs with amygdaloid blockade, the cooling was reversed at 20 minutes while the coronary occlusion continued (24 hours), and still ventricular fibrillation did not occur. In all other cases, ischemia was reversed at 20 minutes so that the heart could recover; this enabled histochemical documentation that the heart was normal at the time(s) ischemia was induced, and it allowed within-subject control experiments. Amygdaloid cryoblockade produced a small but significant increase in heart rate (10 beats per minute) without a change in blood pressure. We conclude that the paleomammalian brain, like its neomammalian counterpart, mediates brain effects on fatal arrhythmogenesis.

Stressor-stimuli evoke a noradrenergic process in the frontal lobes, the amplitude of which depends on both the individual's experience with the stimulus and his or her genetic background. Novel and noxious stimuli evoke large frontocortical responses and benign ones evoke relatively larger reactions in persons with a family history of cardiovascular disease. Blockade of neural projections from the frontal cortex and amygdala to the brainstem cardiovascular centers will normalize blood-pressure elevations in experimental hypertension and prevent lethal arrhythmias in animals with a myocardial infarction. The anti-mortality effect of the cardiac drugs known as beta-blockers is exerted by inhibition of cerebral beta-receptors, not peripheral ones. A new putative neuropeptide, NLX, may have the same desirable cardiovascular effects, but without the side-effects that limit clinical usefulness. The neural regulation of the heart during stress can be detected by a new deterministic measure of low-dimensional chaos in heartbeat intervals. In both animals and humans undergoing myocardial infarction, this deterministic measure correctly predicts lethal arrhythmogenesis, minutes to hours prior to the event. Thus an approach combining both brain and heart studies (i.e., "neurocardiology") has led to an understanding of how stressor-stimuli evoke autonomic reactions. This, in turn, has led to new methods in the diagnosis and treatment of cardiovascular disorders.

Our laboratory has been interested in understanding the neural mechanisms involved in information processing in neocortex, especially in those structures that regulate the sensory and cardiovascular systems. Studies in comparative physiology suggest a theoretical basis for the regulation of the cardiovascular system by the brain. Following his life’s work, Cannon (1931) hypothesized the existence of a cerebral mechanism in which sensory input and autonomic output were simultaneously orchestrated; this orchestration, he suggested, became a focus for natural selection and evolved to enable the higher mammal to attend to its environment and simultaneously to prepare autonomic support in anticipation of the occurrence of certain survival behaviors that might be released.

— Fourteen animals each received 4 cutaneous shocks with an interval of 3–5 min between them. During a fifth trial 3–5 min later, eleven subjects received a fifth shock and then 3–30 s afterwards, as cerebral slow potentials developed in response to the stimulus, samples of parietal cortex were rapidly frozen and extracted by a cryoplate. Three baseline subjects received no shock at the time of the fifth trial and had their parietal tissue samples taken without the presence of slow potentials. A correlation coefficient of r=−0.77 (P < 0.01) was observed between the slow potential amplitude on the surface of the parietal cortex at the time of the sampling and the analyzed level of cyclic AMP in the underlying tissue. Five of the shocked animals whose samples were taken before the slow potentials increased significantly showed a tissue level of 11.1 ± 3.0 pmol cyclic AMP/mg protein. This level was significantly higher (P < 0.01) than that of the baseline animals (3.1 ± 2.0 pmol cyclic AMP/mg protein). The other six shocked animals who had developed large slow potentials manifested a cyclic AMP level that was not different from the baseline group. It is concluded that a reoccurring cutaneous shock results in the immediate increase in the level of cyclic AMP in the parietal cortex and that within 30 s this level decreases in proportion to the amplitude of the slow potential that develops in the same region.

Novel stimuli or electric stimulation of the mesencephalic reticular formation (MRF) produced large positive slow potentials (SPs) in rostral nucleus reticularis thalami (RVA) that accompanied the negative SPs known to occur in frontal cortex. SP durations (20-30 sec) were similar to the periods of unit inhibition that occur in RVA following MRF stimulation. Trains of 8 c/sec medial thalamic stimuli produced phasic negative SPs in RVA similar in duration to the intervals of unit excitation that follow each stimulus pulse. These results suggest that the polarity and duration of the SPs in RVA reflect changes in excitation of the underlying neurons. Direct activation of a specific region of RVA produced complete inhibition of visual cortex responses evoked by optic tract stimuli, a finding which suggests that RVA has an inhibitory action on the thalamus. A tone reinforced by electric shock also elicited SPs in frontal cortex (negative) and RVA (positive). In contrast to the long duration of the MRF- or novelty-elicited SPs, the durations of the conditioned SPs were phasic and were regulated by the tone--shock interval. Bilateral cryogenic blockade of the interconnections between the frontal cortex and medial thalamus abolished SPs of all origins in the frontal cortex. The blockade also abolished conditioned SPs in RVA, but did not affect the MRF-elicited ones. Thus, the subcortical SPs that accompany orienting to novel stimuli are distinct from those which occur during the higher cognitive process of conditioned expectancy and require the integrity of the mediothalamic-frontocortical system.

— Cryoplates were implanted on the surface of the cortex in 32 chronic rat preparations. These devices were used both to freeze and to extract small samples of tissue. Coolant was circulated through each device by small flexible polyethylene tubes. Two series of experiments were performed. In the first, the animals were unrestrained and showed no behavioral signs of stress during the freeze fixation. The temperature responses of the cryoplates were very rapid (−632°C/s), and samples more than 1 mm thick were frozen and extracted within a few hundred ms following the onset of cooling. Each sample was analyzed for 3′.5′-adenosine monophosphate (cyclic AMP) and protein content. The results from the cryoplate group (25.6 ± 15.6pmol cyclic AMP/mg protein) were compared to those obtained from two other groups in which freeze fixation was produced by immersion in liquid nitrogen (13.6 ± 4.6pmol/mg protein) or decapitation into liquid nitrogen (18.6 + 7.6pmol/mg protein). In the second series of experiments, three types of stress (limb restraint, non-adaptation to the experimental situation, and moderate cutaneous electric shock) were induced separately in order to determine the influence of each on cortical levels of cyclic AMP. Control animals were highly adapted to the experimental situation, freely moving and not shocked. The samples from each of the stressed groups showed a statistically significant (P≤. 0.01) reduction in cyclic AMP in comparison with the level in the controls (control: 29.3 pmol/mg protein; restrained: 14.2pmol/mg protein; unadapted: 9.6pmol/mg protein; shocked: 7.1 pmol/mg protein). Thus, psychological and physical stress reduced cyclic AMP content in parietal cortex. Results from the second series of experiments suggest that the significantly higher mean and larger standard deviation of the cryoplate group in the first series are due to less psychological and physical stress being evoked by our method; different types of stress appear to account for the two different lower levels found in the immersion and decapitation groups. We believe that our method of cryogenic tissue fixation offers an improved approach to study of the neurochemical correlates of behavioral and neuroelectric events in the conscious animal.

The present study uses a technique that enables the collection of multiple freeze-biopsy samples from the myocardium of the conscious pig (i.e., through a thoracic window). This technique enables sequential analysis of the metabolic state of the myocardium during different behavioral conditions. The results demonstrate that with daily adaptations to an unfamiliar environment (i.e., stress reduction), the phosphorylase activation ratio (phosphorylase a/total phosphorylase) in the quiescent pig declines steadily from approximately 80% to 30% (r = -0.91, P less than 0.01). This decline occurs with both the mean resting heart rate and left ventricular blood pressure remaining constant. The decline is seen within individual subjects during the whole adaptation sequence as well as between subjects whose samples were taken either early or late in the adaptation series. The dissociation of hemodynamic functional and metabolic activation in the unadapted, psychologically stressed pig may be associated with the occurrence of increased vulnerability of the ischemic heart to ventricular fibrillation, a phenomenon previously observed under the same behavioral conditions.

A thalamo-cortical system with origins in the midline nonspecific thalamic nuclei and projections to the orbitofrontal granular cortex has been identified with an electrocortical synchronizing function related to internal inhibition. 30 acute and 14 chronic cat preparations have been utilized in the study of the nonspecific thalamo-cortical system, including its origins, pathways and cortical projections. Its functional role has been assessed in terms of its effect upon spindle bursts, recruiting and augmenting responses, sensory evoked potentials and the performance of certain learned behavioral tasks. Interruption of this nonspecific thalamo-cortical system has been produced by lesions or reversible cryogenic blockade, and by cortical ablations at 3 principal sites: n. ventralis anterior, the inferior thalamic peduncle (ITP), and the orbitofrontal cortex. Blockade of this thalamo-cortical synchronizing mechanism has resulted in 3 effects: (1) Reduction or abolition of recruiting responses elicited by stimulation of the midline thalamic nuclei, and reduction or abolition of spontaneous spindle bursts produced by lesion of the mesencephalic reticular formation. These effects involving the nonspecific thalamo-cortical system are contrasted with the specific sensory and motor systems whose augmenting responses are not affected by blockade of the thalamo-cortical system. (2) Enhancement of visual cortical responses elicited by photic or optic tract stimulation. This effect upon specific sensory responses contrasts with the reduction or abolition of spindle bursts and recruiting responses mediated by a nonspecific system. (3) Deficits in performance of learned behavioral tasks involving bar-pressing and single alternation. Complete cryogenic blockade in ITP interrupted bar-pressing whereas partial blockade only slowed bar-pressing rate but interfered with single alternation performance due to perseveration. The nonspecific thalamo-cortical system has been discussed in terms of its synchronizing and regulating influences upon electrocortical activity, its inhibitory role, and as a possible mechanism mediating attention and inattention.

1. 1. The effect of various cortical ablations upon recruiting responses and spindle bursts in cats was studied in acute preparations immobilized with gallamine. 2. 2. Recruiting responses were induced by low frequency stimulation of the midline thalamic nuclear complex; spontaneous spindle bursts were produced by mesencephalic reticular formation lesions. 3. 3. Ablations of primary cortical areas (somato-sensory, auditory and visual), motor cortex and association areas, and orbito-frontal cortex were made in sequence and singly. Extensive ablations of the dorso-lateral convexity enhanced and modified both spindle bursts and recruiting responses. Only orbito-frontal cortex ablations abolished recruiting responses and spindle bursts recorded at the cortex, in the subcortical white matter, and in the thalamus. 4. 4. The results of these experiments suggest that the orbito-frontal cortex is an essential link in a thalamo-cortical synchronizing system responsible for spindle bursts and recruiting responses.

Reversible cryogenic blockade of neural systems in the brain may be accomplished by local cooling. A small cryoprobe is described which may be implanted in the brain of an unrestrained, behaving animal. Cooling may be restricted to the tip of the cryoprobe and the temperature of the tip and the shaft may be regulated and monitored independently by miniature thermocouples and appropriate control and indicator devices. Electrophysiological results are presented which show that the cryogenic blocking effect may be localized to within a few millimeters of the tip of the cryoprobe and that the size of the region blocked is proportional to the tip temperature. The system described has been shown to be effective in both electrophysiological and behavioral studies.

Intracerebral cannulas were implanted in both olfactory bulbs of 6 rabbits. A surface electrode-array (8 X 8) was implanted epidurally on the lateral surface of the left bulb. Each rabbit was conditioned to respond to sniffing to an odor paired with cutaneous shock while receiving continuous intrabulbar infusion of either vehicle or propranolol (100 microM at 1 microliter/hr) in vehicle. After two training sessions to the original odor, a response to a new odor was conditioned under the influence of the alternate infusate. Electroencephalographic (EEG) activity was sampled on inspirations before and during odor presentations. During vehicle infusion a transient alteration in the pattern of activity was acquired that occurred during the second and third inspirations following presentation of the reinforced odor. The acquisition did not occur when propranolol was infused. No significant pattern changes occurred with unreinforced odors in either condition. There was no local anesthetic effect of the racemic mixture of propranolol found for any type of electric activity, including antidromic spike activity observed in an independent control group. Intrabulbar norepinephrine injection (100 microM, 10 microL) resulted in an amplitude increase of the bulbar 40-80-Hz EEG and a potentiation of the transient spatial pattern change to a novel odor, when compared with those observed during vehicle infusion. It is concluded that norepinephrine released under centrifugal control may act to prevent or delay habituation that otherwise occurs rapidly to unreinforced odors.

Stimulation in the segment of nucleus reticularis thalami adjacent to the lateral geniculate body (RLG), abolished visual evoked potentials for up to 150 msec. Both photic stimulation in the contralateral visual field and electric stimulation in the ipsilateral optic tract elicited primary cortical responses that were markedly reduced or abolished by prior conditioning stimulation in RLG. Stimulation of the segments of nucleus reticularis thalami adjacent to the medial geniculate (RMG) or the ventrobasal complex (RVBC) had the effect of markedly reducing or abolishing unilaterally projected primary evoked responses in the auditory and cutaneous systems, respectively. Only the sensory evoked potentials mediated by the relay nucleus adjacent to the region of R stimulated were affected. The reduction of the cortical evoked potentials was not due to the processes underlying the cortical recovery cycle, because conditioning stimulation on either side of RLG stimulated the primary geniculocortical fibers, but had a minimal or no effect on the visual test evoked response. These results suggest that R functions as a topographically organized inhibitory gate which can regulate the patterns of sensory input from the thalamus to the cortex. The regulatory effects on R by the mesencephalic reticular formation and the mediothalamic-frontocortical system may mediate both generalized and selective control of cortical sensory evoked potentials.

Psychosocial stressors are risk factors for sudden cardiac death. A theoretical model of the brain mechanism that links defined environmental events (stressors) to cardiac vulnerability (initiation of ventricular fibrillation) has been developed. In the model, a stressor event evokes a set of electrochemical responses in the frontal cortex. Depending on the state of acquisition of these electrochemical responses to the stressor, activity will or will not be initiated in the frontocortical-brainstem pathway. Activity in this pathway, either alone or in combination with myocardial ischemia, triggers a state of increased vulnerability of the heart to the initiation of ventricular fibrillation. Three independent interventions have been shown to prevent the initiation of ventricular fibrillation after acute coronary artery occlusion in the psychologically stressed pig: 1) learned behavioral adaptation to the stressor, 2) cryogenic blockade of the frontocortical-brainstem pathway, and 3) intracerebral (but not intravenous) injection of a beta-receptor blocking agent (levo-propranolol).

Psychosocial stress is known to be a risk factor for sudden cardiac death. In animals, we have shown that operationally defined stressor-events must be present for coronary artery occlusion to result in ventricular fibrillation. Each type of stressor-event has been found to evoke the same pattern of electrochemical responses in the frontal granular cortex. These event-related responses include, negative-polarity slow potentials, extracellular potassium-reduction, and norepinephrine-release. The magnitudes of each of the cerebral responses is related to the animal’s level of acquisition and/or adaptation to the stressor-stimuli. The effect of stress on cardiac vulnerability is prevented by either the blockade of frontocortical projections to the brainstem cardiovascular nuclei or the intracerebral injection of 1-propranolol (0.01 mg/kg). We conclude that psychosocial stressors increase cardiac vulnerability through a learning-dependent noradrenergic process in frontocortical neurons.

Previous work in our laboratory showed that the mesencephalic reticular formation (MRF) and frontal granular cortex (FC) jointly regulate the activity in the thalamic reticular nucleus (R). The R neurons project specifically into relay nuclei and, when activated, inhibit the specific transmission of sensory information through the thalamus to primary receptive cortex. The MRF has a generalized inhibitory effect on the R cells and can produce generalized disinhibition of sensory channels, as is known to occur during orienting responses. The frontal cortex, on the other hand, provides specific and tonic excitation of individual R cells and can selectively turn off specific sensory channels, as is known to occur during selective attention. Our more recent work has focused on the cellular mechanisms in the frontal cortex that result in the specific sensory gating that occurs during operationally defined states of behavioral attention. The occurrence of the event-related potential (ERSP) in the FC seems to be the harbinger of both EEG desynchronization and sensory channel selection. Both of these latter event-related activities are explainable by FC effects on R cells. We have found that during an ERSP in the FC, in the underlying tissue: (a) norepinephrine (NE) is released, (b) cAMP is activated, (c) extracellular potassium ion activity is reduced, and (d) slow membrane potential shifts occur in some of the neurons. These results suggest that the same neuromodulatory mechanism exists in the cortex as is known to operate in a model preparation, the sympathetic ganglion.