Steffen Schulz

Methods derived from nonlinear dynamics for analysing heart rate variability

Methods from nonlinear dynamics (NLD) have shown new insights into heart rate (HR) variability changes under various physiological and pathological conditions, providing additional prognostic information and complementing traditional time- and frequency-domain analyses. In this review, some of the most prominent indices of nonlinear and fractal dynamics are summarized and their algorithmic implementations and applications in clinical trials are discussed. Several of those indices have been proven to be of diagnostic relevance or have contributed to risk stratification. In particular, techniques based on mono- and multifractal analyses and symbolic dynamics have been successfully applied to clinical studies. Further advances in HR variability analysis are expected through multidimensional and multivariate assessments. Today, the question is no longer about whether or not methods from NLD should be applied; however, it is relevant to ask which of the methods should be selected and under which basic and standardized conditions should they be applied.

Non-linear complexity measures of heart rate variability in acute schizophrenia

OBJECTIVE Cardiovascular mortality is significantly increased in patients suffering from schizophrenia. The mechanisms currently discussed contain unhealthy lifestyle with obesity and smoking, increased incidence of diabetes, adverse pro-arrhythmic effects of antipsychotic medication and altered autonomic function. It is therefore likely that the adaptation of the heart rate to different requirements is faulty in schizophrenia. One way to detect adaptive capabilities and thus stability of regulation is to measure complexity of heart rate fluctuations, with more complex heart rate fluctuations indicating better adaptability of the underlying system. METHODS We calculated novel non-linear measures for beat-to-beat interval complexity from short-term ECG recordings in 20 unmedicated patients suffering from acute schizophrenia and compared them to those obtained from matched controls. RESULTS Data from all mathematical models applied, i.e. joint symbolic dynamics, compression entropy, fractal dimension and approximate entropy, revealed significantly reduced complexity of heart rate time series in acute schizophrenia. When using heart rate as a covariate, only fractal dimension remained significantly altered, thus appearing to be a relatively more important heart rate independent parameter. CONCLUSIONS Complexity of heart rate modulation is significantly reduced in acute, untreated schizophrenia, thus indicating an increased risk for cardiovascular events in these patients. SIGNIFICANCE These data might eventually add to the currently discussed monitoring of physical health in patients with schizophrenia, possibly providing a promising tool for cardio-arrhythmic risk stratification.

Autonomy of Autonomic Dysfunction in Major Depression

Objective: To investigate cardiac autonomic dysfunction in patients with major depressive disorder (MDD). Research in this area has faced several limitations because of the heterogeneity of the disease, the influence of medication, and methodological shortcomings. Methods: Participants were 75 patients suffering from an acute recurrent episode of MDD and 75 matched controls. All participants were assessed at baseline for linear and nonlinear parameters of heart rate variability, QT variability and baroreflex sensitivity. Participants with MDD were reassessed after 7 to 9 days of treatment with either a selective serotonin reuptake inhibitor (SSRI) or a serotonin and noradrenaline selective reuptake inhibitor (SNRI) antidepressant. Results: In the initial examination, patients showed an overall shift of autonomic balance toward sympathetic predominance as compared with matched controls, with a decrease in parasympathetic parameters and baroreflex sensitivity, and an increase in sympathetically influenced QT variability. Overall, antidepressant treatment exacerbated this imbalance, with differential effects observed for SSRI and SNRI treatment. In contrast to autonomic dysfunction in other disorders, such as schizophrenia, autonomic dysfunction in MDD appeared to be independent of disease severity. Conclusions: Patients suffering from MDD show profound autonomic dysfunction, which is exacerbated by SNRI and to a lesser degree by SSRI treatment. This information could prove important when selecting antidepressant medication for patients at risk for cardiac arrhythmias. ANOVA = analysis of variance; BBI = beat-to-beat interval; BMI = body mass index; BRS = baroreflex sensitivity; bslope = bradycardic slope; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; HAMD = Hamilton Depression Rating Scale; Hc = compression entropy; HF = high frequency of the heart rate variability power spectrum; HRV = heart rate variability; LF = low frequency of the heart rate variability power spectrum; LF/HF = ratio between the low and high frequency of the heart rate variability power spectrum; MANOVA = multivariate analysis of variance; MDD = major depressive disorder; QTV = QT variability; QTvi = QT variability index; SNRI = serotonin and noradrenaline selective reuptake inhibitor; PHVAR = probability of high variability sequences; PLVAR = probability of low variability sequences; RMSSD = square root of the mean squared differences of successive normal-to-normal intervals; RR-interval = interval between consecutive R waves in the electrocardiogram; SBP = systolic blood pressure; SPSS = statistical package for the social sciences; SSRI = selective serotonin reuptake inhibitor; tslope = tachycardic slope.

The altered complexity of cardiovascular regulation in depressed patients

Major depressive disorders (MDD) are associated with an increased risk for cardiovascular morbidity and mortality. Even if it is known that MDD are accompanied by an autonomic dysbalance with increased sympathetic and/or reduced parasympathetic activity, to date only limited information is available about the degree and complexity of cardiovascular regulation. The aim of this study was to investigate the influence of MDD on the autonomous nervous system and cardiovascular complexity by means of linear and nonlinear indices from heart rate and blood pressure variability (HRV, BPV). From 57 non-medicated patients and 57 matched healthy controls with respect to age and gender HRV and BPV in time and frequency domain, symbolic dynamics, compression entropy, multiscale entropy, detrended fluctuation analysis, Poincaré plot analysis and baroreflex sensitivity were analysed from 30 min short-term recordings. Complexity indices from nonlinear dynamics demonstrated considerable changes in autonomous regulation due to MDD. For the first time we could show that non-medicated depressed patients who were matched with respect to age and gender reveal a significantly changed short-term as well as long-term complexity of cardiovascular regulation. These results suggest substantial changes in autonomic control probably due to a change of interactions between different physiological control loops in MDD.

Spinal tumor necrosis factor α neutralization reduces peripheral inflammation and hyperalgesia and suppresses autonomic responses in experimental arthritis: A role for spinal tumor necrosis factor α during induction and maintenance of peripheral inflammation

OBJECTIVE In addition to the sensitization of pain fibers in inflamed tissues, the increased excitability of the spinal cord is an important mechanism of inflammatory pain. Furthermore, spinal neuronal excitability has been suggested to play a role in modulating peripheral inflammation. This study was undertaken to test the hypothesis that spinal actions of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) add significantly to both hyperalgesia and maintenance of peripheral inflammation. METHODS Rats with antigen-induced arthritis (AIA) were treated intrathecally with the TNFalpha-neutralizing compound etanercept continuously during the complete time course of AIA, which was 3 days for the acute phase and 21 days for the chronic phase. During this time, inflammation and pain-related behavior were monitored. Since a role for autonomic control of inflammation was proposed, measures from heart rate time series were obtained in the acute phase. Findings were compared with those in vehicle-treated animals and in animals receiving etanercept intraperitoneally. RESULTS Spinally administered etanercept acutely reduced pain-related behavior, attenuated both the development and the maintenance of inflammation, and was superior to systemic administration. Parameters indicating autonomic modulation showed a shift toward a sympathetically dominated state in vehicle-treated animals, which was prevented by intrathecal etanercept. CONCLUSION Our findings indicate that spinal TNFalpha plays an important role in both pain signaling and modulation of peripheral inflammation. Thus, neutralizing this cytokine at the spinal site not only represents a putative therapeutic option for different pain syndromes, but may be directly used to attenuate peripheral inflammation.

Cardiovascular and cardiorespiratory coupling analyses: a review.

Recently, methods have been developed to analyse couplings in dynamic systems. In the field of medical analysis of complex cardiovascular and cardiorespiratory systems, there is growing interest in how insights may be gained into the interaction between regulatory mechanisms in healthy and diseased persons. The couplings within and between these systems can be linear or nonlinear. However, the complex mechanisms involved in cardiovascular and cardiorespiratory regulation very likely interact with each other in a nonlinear way. Recent advances in nonlinear dynamics and information theory have allowed the multivariate study of information transfer between time series. They therefore might be able to provide additional diagnostic and prognostic information in medicine and might, in particular, be able to complement traditional linear coupling analysis techniques. In this review, we describe the approaches (Granger causality, nonlinear prediction, entropy, symbolization, phase synchronization) most commonly applied to detect direct and indirect couplings between time series, especially focusing on nonlinear approaches. We will discuss their capacity to quantify direct and indirect couplings and the direction (driver–response relationship) of the considered interaction between different biological time series. We also give their basic theoretical background, their basic requirements for application, their main features and demonstrate their usefulness in different applications in the field of cardiovascular and cardiorespiratory coupling analyses.

The interaction between pupil function and cardiovascular regulation in patients with acute schizophrenia

OBJECTIVE Cardiac autonomic dysregulation has been reported in patients with schizophrenia. However, there are no definite data examining whether other branches of the autonomic nervous system are compromised as well and how they interrelate with cardiac function. In this study, we tested the hypothesis that the autonomic dysregulation at the heart is reflected in the regulation of the pupillary light reflex. METHODS We assessed heart rate variability and baroreflex sensitivity parameters as well as pupillographic measures in 28 unmedicated patients with schizophrenia and compared these measures to those of 28 controls. In addition, cardiovascular and pupillographic parameters were correlated in both groups. RESULTS The obtained cardiovascular parameters indicated decreased parasympathetic modulation. Patients showed a significantly increased resting pupil diameter as well as reduced relative amplitude, suggesting a dominance of sympathetic control and a lack of parasympathetic modulation at the pupil. Intriguingly, the parasympathetic latency of the pupil constriction was similar in both groups and correlated with several cardiovascular parameters. These correlations were in the opposite direction in patients compared to controls. Furthermore, shorter latencies of the pupil constriction were associated with symptom severity in patients. CONCLUSIONS Overall, we found evidence for an autonomic dysregulation at the pupil and heart in patients with schizophrenia. Future studies are warranted to describe this complex interaction at different levels of the autonomic system. SIGNIFICANCE The interrelationship of both the systems indicates that the autonomic dysfunction affects the regulation in different branches of the autonomic network as well as their interaction in schizophrenia.

Influence of olanzapine on QT variability and complexity measures of heart rate in patients with schizophrenia.

Previous studies have shown that untreated patients with acute schizophrenia present with reduced heart rate variability and complexity as well as increased QT variability. This autonomic dysregulation might contribute to increased cardiac morbidity and mortality in these patients. However, the additional effects of newer antipsychotics on autonomic dysfunction have not been investigated, applying these new cardiac parameters to gain information about the regulation at sinus node level as well as the susceptibility to arrhythmias. We have investigated 15 patients with acute schizophrenia before and after established olanzapine treatment and compared them with matched controls. New nonlinear parameters (approximate entropy, compression entropy, fractal dimension) of heart rate variability and also the QT-variability index were calculated. In accordance with previous results, we have observed reduced complexity of heart rate regulation in untreated patients. Furthermore, the QT-variability index was significantly increased in unmedicated patients, indicating increased repolarization lability. Reduction of the heart rate regulation complexity after olanzapine treatment was seen, as measured by compression entropy of heart rate. No change in QT variability was observed after treatment. This study shows that unmedicated patients with acute schizophrenia experience autonomic dysfunction. Olanzapine treatment seems to have very little additional impact in regard to the QT variability. However, the decrease in heart rate complexity after olanzapine treatment suggests decreased cardiac vagal function, which may increase the risk for cardiac mortality. Further studies are warranted to gain more insight into cardiac regulation in schizophrenia and the effect of novel antipsychotics.

Exercise Reveals the Interrelation of Physical Fitness, Inflammatory Response, Psychopathology, and Autonomic Function in Patients With Schizophrenia

Maintaining and improving fitness are associated with a lower risk of premature death from cardiovascular disease. Patients with schizophrenia are known to exercise less and have poorer health behaviors than average. Physical fitness and physiological regulation during exercise tasks have not been investigated to date among patients with schizophrenia. We studied autonomic modulation in a stepwise exhaustion protocol in 23 patients with schizophrenia and in matched controls, using spirometry and lactate diagnostics. Parameters of physical capacity were determined at the aerobic, anaerobic, and vagal thresholds (VT), as well as for peak output. VT was correlated with psychopathology, as assessed by the Positive and Negative Syndrome Scale, with the inflammatory markers IL-1β, IL-6, and TNF-α and with peak output. The MANOVA for heart and breathing rates, as well as for vagal modulation and complexity behavior of heart rate, indicated a profound lack of vagal modulation at all intensity levels, even after the covariate carbon monoxide concentration was introduced as a measure of smoking behavior. Significantly decreased physical capacity was demonstrated at the aerobic, anaerobic, and VT in patients. After the exercise task, reduced vagal modulation in patients correlated negatively with positive symptoms and with levels of IL-6 and TNF-α. This study shows decreased physical capacity in patients with schizophrenia. Upcoming intervention studies need to take into account the autonomic imbalance, which might predispose patients to arrhythmias during exercise. Results of inflammatory parameters are suggestive of a reduced activity of the anti-inflammatory cholinergic pathway in patients, leading to a pro-inflammatory state.

Influence of age on linear and nonlinear measures of autonomic cardiovascular modulation.

Background: Age has been identified as an independent risk factor for cardiovascular diseases. In addition, autonomic imbalance toward sympathetic preponderance has been shown to facilitate the occurrence of heart disease. Here, we aimed to assess autonomic modulation of cardiovascular parameters during normal ageing applying well‐established linear and novel nonlinear parameters.