Karl-Jürgen Bär

The Autonomic Brain: An Activation Likelihood Estimation Meta-Analysis for Central Processing of Autonomic Function

The autonomic nervous system (ANS) is of paramount importance for daily life. Its regulatory action on respiratory, cardiovascular, digestive, endocrine, and many other systems is controlled by a number of structures in the CNS. While the majority of these nuclei and cortices have been identified in animal models, neuroimaging studies have recently begun to shed light on central autonomic processing in humans. In this study, we used activation likelihood estimation to conduct a meta-analysis of human neuroimaging experiments evaluating central autonomic processing to localize (1) cortical and subcortical areas involved in autonomic processing, (2) potential subsystems for the sympathetic and parasympathetic divisions of the ANS, and (3) potential subsystems for specific ANS responses to different stimuli/tasks. Across all tasks, we identified a set of consistently activated brain regions, comprising left amygdala, right anterior and left posterior insula and midcingulate cortices that form the core of the central autonomic network. While sympathetic-associated regions predominate in executive- and salience-processing networks, parasympathetic regions predominate in the default mode network. Hence, central processing of autonomic function does not simply involve a monolithic network of brain regions, instead showing elements of task and division specificity.

Pain perception in major depression depends on pain modality.

&NA; One frequently described feature of depression is an increased vulnerability to pain complaints, and chronic pain is frequently accompanied by symptoms of depression. In contrast to this, a decreased sensitivity to experimental pain has been described in major depression. The physiological basis of this phenomenon is yet elusive. We investigated 30 patients suffering from a major depressive disorder and matched controls. Pain testing (threshold and tolerance) was performed on both sides of the body and included assessment of thermal, electrical and ischemic pain. While confirming hypoalgesia to heat and electrical pain in comparison to controls, we found hyperalgesia to ischemic muscle pain. Furthermore, thermal pain tolerance and electrical pain tolerance were significantly increased on the right hand side confirming previous results of a lateralized perception of pain in depression. Our main finding suggests that painful stimuli are processed differentially depending on the localization of pain induction in depression. This knowledge may enable us to understand and ultimately treat pain complaints more appropriately in depressed patients.

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.

Altered diurnal autonomic variation and reduced vagal information flow in acute schizophrenia

OBJECTIVE This study aimed to further investigate autonomic function in schizophrenic patients using long-term electrocardiographic (ECG) recordings. METHODS Twenty unmedicated patients suffering from an acute episode of paranoid schizophrenia and 20 matched control subjects were recruited and 24-h ambulatory electrocardiograms were recorded. In order to investigate complexity of heart rate fluctuations related to different physiological time scales, linear heart rate variability (HRV) as well as autonomic information flow (AIF) parameters were calculated from day and night time intervals. RESULTS While heart rates were increased, root mean successive square difference (RMSSD), a measure for vagal function as well as standard deviation of 5-min mean NN-intervals (SDANN), reflecting parasympathetic and sympathetic tone, were decreased in schizophrenia. Furthermore, a decrease of vagal information flow was apparent during night time (decreased mean high frequency peak decay (PD(mHF))). In addition, increased INT(NN) (area under the AIF curve) as well as decreased beat decay (BD(NN)) and mean very low frequency PD (PD(mVLF)) indicated reduced complexity in patients during day and night time. CONCLUSIONS HRV and AIF parameters indicate altered diurnal autonomic variation in schizophrenia. SIGNIFICANCE Reduced vagal modulation and loss of complexity might both contribute to the increased risk for sudden cardiac death in schizophrenia.

Influence of gender and hemispheric lateralization on heat pain perception in major depression

Increased incidence of clinical pain complaints from patients with major depression, as well as increased experimental pain thresholds have been reported. The basis of this phenomenon remains unclear, as well as its relation to medication, clinical recovery, gender and lateralization of hemispheric function. We aimed to further elucidate heat pain perception in depression applying a testing battery including assessment (on both arms) of warmth perception, heat pain perception and heat pain tolerance, and the jaw opening reflex (duration of ES2 component) as a putative indicator of descending pain inhibition. The battery was applied to 20 patients and 20 age- and sex-matched controls. Patients were assessed: on admission (acutely depressed, off-medication), few days after admission (depressed, on medication), and after clinical recovery (mostly on medication), and controls at corresponding intervals. Significant elevated heat pain thresholds were found off and on medication in the acute stage (mainly in women) and after recovery on the right arm only. Elevated heat pain tolerance (on the right arm only) was seen in medicated patients in the acute and recovered stage. Significant prolongation of ES2 duration was only found in acutely depressed patients off medication. While confirming hypalgesia to heat pain in major depression, our findings demonstrate a close relation to gender and strong influence of lateralization after recovery. Altered pain processing at brain stem level might only partially be responsible for the observed finding.

Motor cortex disinhibition in Alzheimer's disease

OBJECTIVES To explore subclinical disturbances in the motor cortex of patients with Alzheimers disease (AD). METHODS We used transcranial magnetic stimulation in a paired pulse technique to test intracortical inhibition (ICI) and intracortical facilitation in mildly to moderately demented AD patients with a normal neurological examination. Patients were studied before and during treatment with the cholinesterase inhibitor donepezil. RESULTS AD patients had a reduced ICI compared to an age-matched control group. The amount of disinhibition correlated with the severity of dementia. Treatment with 10 mg donepezil daily was associated with an increase of ICI. CONCLUSIONS The subclinical motor cortex disinhibition in AD patients indicates a functional disturbance, and is probably associated with a cholinergic deficit.

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.

Relationship between cardiovagal modulation and psychotic state in patients with paranoid schizophrenia.

Disturbed autonomic nervous system (ANS) function in schizophrenia might contribute to increased cardiovascular mortality. We obtained heart rate variability indices from 40 unmedicated schizophrenic patients and 58 matched controls. Mainly we found that patients displaying stronger psychotic symptoms as assessed by the Brief Psychiatric Rating Scale exhibit more severe cardiac ANS disturbances compared with controls.