Mandy Koschke

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.

Increased Prefrontal Activation During Pain Perception in Major Depression

BACKGROUND To further elucidate the close interrelation of pain and depression, we investigated cerebral responses to parametrically varied thermal pain intensities in female patients suffering from major depressive disorder (MDD) (n = 13) and matched control subjects (n = 13) by means of functional magnetic resonance imaging (fMRI). METHODS After the assessment of the individual thermal pain threshold, an fMRI-compatible thermode was used to deliver thermal painful stimuli to the right arm. All stimuli were initiated for 10 sec from a baseline resting temperature (32 degrees C) in three different conditions (37 degrees C, 42 degrees C, 45 degrees C). Statistical Parametric Mapping 2 (SPM2) software was used for image processing and statistical analyses. RESULTS Patients displayed significantly increased thermal pain thresholds. A comparable increase in blood oxygenation level-dependent (BOLD) signal was observed in key structures of the pain matrix in patients and control subjects. Patients displayed hyperactivation in comparison with control subjects for the painful 45 degrees C condition in the left ventrolateral thalamus, in the right ventrolateral prefrontal cortex (VLPFC) and dorsolateral prefrontal cortex (DLPFC), as well as a stronger parametric BOLD signal increase in the right VLPFC, DLPFC, and in the contralateral insula. Symptom severity correlated positively with the BOLD signal in the left ventrolateral nucleus of the thalamus. CONCLUSIONS We present evidence that cortical structures of the pain matrix are similarly activated in depressed patients and healthy subjects. We report increased prefrontal and lateral thalamic activation during the presentation of painful stimuli, which might explain reduced thermal pain perception on the skin in depressed patients.

Acute psychosis leads to increased QT variability in patients suffering from schizophrenia

Patients with schizophrenia have been reported to experience sudden cardiac death 3 times more likely than individuals from the general population. One important factor related to an increased risk of cardiac arrhythmias and sudden death is the prolongation of the QTc interval. This study examined whether acute psychosis might influence the beat-to-beat variability of the QT interval, which reflects effectively cardiac repolarization lability. High resolution electrocardiographic recordings were performed in 25 unmedicated patients suffering from acute schizophrenia and matched controls. From these, parameters of beat-to-beat heart rate and QT variability measures such as approximate entropy and QT variability index (QTvi) were calculated. Measures were correlated with the scale for the assessment of positive symptoms (SAPS) and negative symptoms (SANS). QTvi was significantly higher in patients with schizophrenia compared to controls. While QTvi correlated with the degree of delusions and hallucinations, no correlation with electrolyte concentrations was found. Approximate entropy of heart rate was decreased indicating reduced complexity and decreased vagal tone. In conclusion, increased QT variability in patients with schizophrenia indicates abnormal cardiac repolarization lability, which can result in serious cardiac arrhythmias. The correlation of positive symptoms with QT variability might indicate high sympathetic cardiac activity in these patients, which might be associated with increased cardiovascular mortality.

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.

Reduced heat pain thresholds after sad-mood induction are associated with changes in thalamic activity

Negative affective states influence pain processing in healthy subjects in terms of augmented pain experience. Furthermore, our previous studies revealed that patients with major depressive disorder showed increased heat pain thresholds on the skin. Potential neurofunctional correlates of this finding were located within the fronto-thalamic network. The aim of the present study was to investigate the neurofunctional underpinnings of the influence of sad mood upon heat pain processing in healthy subjects. For this purpose, we used a combination of the Velten Mood Induction procedure and a piece of music to induce sad affect. Initially we assessed heat pain threshold after successful induction of sad mood outside the MR scanner in Experiment 1. We found a highly significant reduction in heat pain threshold on the left hand and a trend for the right. In Experiment 2, we applied thermal pain stimuli on the left hand (37, 42, and 45 degrees C) in an MRI scanner. Subjects were scanned twice, one group before and after sad-mood induction and another group before and after neutral-mood induction, respectively. Our main finding was a significant group x mood-induction interaction bilaterally in the ventrolateral nucleus of the thalamus indicating a BOLD signal increase after sad-mood induction and a BOLD signal decrease in the control group. We present evidence that induced sad affect leads to reduced heat pain thresholds in healthy subjects. This is probably due to altered lateral thalamic activity, which is potentially associated with changed attentional processes.

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.

Correlations between the autonomic modulation of heart rate, blood pressure and the pupillary light reflex in healthy subjects

Information on autonomic modulation can be derived from different organs that are innervated by the sympathetic and the parasympathetic nervous system, when assessing e.g. heart rate or blood pressure fluctuations or the pupils reaction to light. Correlations between parameters from different target organs might reveal information on hierarchically higher centres of autonomic integration. Here, we obtained parameters of heart rate variability, blood pressure variability, baroreflex function and light reaction pupillography from 50 individuals and tested the hypothesis that these are associated. Pupil diameter and constriction latency significantly correlated with parameters of heart rate variability, but not with those of blood pressure variability. In contrast, relative amplitude significantly correlated with blood pressure variability only. In conclusion, the different branches of the autonomic nervous system examined here are not associated unequivocally but show a distinct pattern of interrelations in healthy subjects. Examinations as described here might add to the diagnosis of autonomic dysfunction and reveal differential patterns in certain disease states.

Increased QT variability in patients with anorexia nervosa - an indicator for increased cardiac mortality?

OBJECTIVE Increased mortality in anorexia nervosa is associated with autonomic dysfunction and prolongation of the QT interval. In this study, we examined the relative importance of repolarization abnormalities and vagal modulation of heart rate. In particular, we hypothesized that patients with anorexia nervosa show increased QT interval variability, particularly since this measure has been shown to correlate with serious cardiac arrhythmias. METHOD We assessed linear and nonlinear heart rate variability (HRV) parameters as well as measures of QT variability in 20 female patients with anorexia nervosa and 20 controls. In patients, parameters were correlated with serum electrolytes. RESULTS QT variability was significantly increased in the patient group and correlated negatively with serum potassium concentrations. HRV measures showed a shift of autonomic balance towards vagal predominance. DISCUSSION The increase in QT variability might at least in part account for the higher risk of cardiac arrhythmias in patients with anorexia nervosa. Once validated in a prospective study design, parameters of QT variability might serve as surrogate markers for arrhythmia risk stratification in anorexia nervosa. Supplementation with potassium might normalize QT variability abnormalities.

Entwicklung des „Mannheimer Multikomponenten-Stress-Test” (MMST)

The aim of the present study was to develop and evaluate an economical stress paradigm, which can be used for the investigation of stress reactions in a laboratory setting. Different stressors were combined to investigate the changes of heart frequency and subjective stress levels as response to stressful stimulation. A combination of mental stress, noise and emotional pictures presented in the background during performing a mental arithmetic task showed significant increases in heart rate and subjective stress levels. Furthermore we tested the stress combination in 32 healthy subjects to evaluate the physiological response. We found significant changes in the cardiovascular parameters such as heart rate variability, baroreflex sensitivity and cardiac output. We conclude that the Mannheim Multicomponent Stress Test (MMST) induces high levels of physiological and psychological stress and can serve as an economical method to investigate stress reactions in a laboratory setting.