Michael Karl Boettger

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.

Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition

Synaptic inhibition is a central factor in the fine tuning of neuronal activity in the central nervous system. Symptoms consistent with reduced inhibition such as stiffness, spasms and anxiety occur in paraneoplastic stiff person syndrome with autoantibodies against the intracellular synaptic protein amphiphysin. Here we show that intrathecal application of purified anti-amphiphysin immunoglobulin G antibodies induces stiff person syndrome-like symptoms in rats, including stiffness and muscle spasms. Using in vivo recordings of Hoffmann reflexes and dorsal root potentials, we identified reduced presynaptic GABAergic inhibition as an underlying mechanism. Anti-amphiphysin immunoglobulin G was internalized into neurons by an epitope-specific mechanism and colocalized in vivo with presynaptic vesicular proteins, as shown by stimulation emission depletion microscopy. Neurons from amphiphysin deficient mice that did not internalize the immunoglobulin provided additional evidence of the specificity in antibody uptake. GABAergic synapses appeared more vulnerable than glutamatergic synapses to defective endocytosis induced by anti-amphiphysin immunoglobulin G, as shown by increased clustering of the endocytic protein AP180 and by defective loading of FM 1-43, a styryl dye used to label cell membranes. Incubation of cultured neurons with anti-amphiphysin immunoglobulin G reduced basal and stimulated release of γ-aminobutyric acid substantially more than that of glutamate. By whole-cell patch-clamp analysis of GABAergic inhibitory transmission in hippocampus granule cells we showed a faster, activity-dependent decrease of the amplitude of evoked inhibitory postsynaptic currents in brain slices treated with antibodies against amphiphysin. We suggest that these findings may explain the pathophysiology of the core signs of stiff person syndrome at the molecular level and show that autoantibodies can alter the function of inhibitory synapses in vivo upon binding to an intraneuronal key protein by disturbing vesicular endocytosis.

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.

The role of proinflammatory cytokines in the generation and maintenance of joint pain

The proinflammatory cytokines tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) not only promote and maintain inflammation, they also contribute to the generation and maintenance of inflammatory pain by acting at nociceptive nerve cells. A large proportion of dorsal root ganglion (DRG) neurons express TNF receptors and receptor units for stimulation with IL‐6. In the rat model of antigen‐induced arthritis (AIA), neutralization of TNF‐α by etanercept and infliximab reduced inflammation‐evoked mechanical hyperalgesia at the inflamed knee joint. This treatment also attenuated the infiltration of macrophages into the DRGs usually observed during the acute phase of AIA. Intra‐articular application of etanercept reduced the responses of C‐fibers to mechanical stimulation of the inflamed joint but did not influence responses to stimulation of the normal joint. Finally, in cultured DRG neurons TNF‐α increased the proportion of neurons that express the TRPV1 receptor and may thus contribute to the generation of inflammation‐evoked thermal hyperalgesia.

Antinociceptive effects of tumor necrosis factor α neutralization in a rat model of antigen-induced arthritis: Evidence of a neuronal target

OBJECTIVE The reduction of pain in the course of antiinflammatory therapy can result from an attenuation of the inflammatory process and/or from the neutralization of endogenous mediators of inflammation that act directly on nociceptive neurons. The purpose of this study was to investigate whether analgesic effects of the neutralization of tumor necrosis factor alpha (TNFalpha) are due to an attenuation of inflammation or whether direct neuronal effects significantly contribute to pain relief in the course of therapy. METHODS Locomotor and pain-related behavior and histology were assessed in rats with chronic antigen-induced arthritis (AIA) in the knee joint, and the rats were treated with systemic saline, etanercept, or infliximab. The expression of TNF receptors (TNFRs) in dorsal root ganglia was measured using immunohistochemical analysis and polymerase chain reaction. Action potentials were recorded from afferent Adelta fibers and C fibers of the medial knee joint nerve, and etanercept and infliximab were injected intraarticularly into normal or inflamed knee joints (AIA or kaolin/carrageenan-induced inflammation). RESULTS In rats with AIA, both etanercept and infliximab significantly decreased inflammation-induced locomotor and pain-related behavior, while joint swelling was only weakly attenuated and histomorphology still revealed pronounced inflammation. A large proportion of dorsal root ganglion neurons showed TNFRI- and TNFRII-like immunoreactivity. Intraarticular injection of etanercept reduced the responses of joint afferents to mechanical stimulation of the inflamed joint starting 30 minutes after injection, but had no effect on responses to mechanical stimulation of the uninflamed joint. CONCLUSION Overall, these data show the pronounced antinociceptive effects of TNFalpha neutralization, thus suggesting that reduction of the effects of TNFalpha on pain fibers themselves significantly contributes to pain relief.

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.

Differences in inflammatory pain in nNOS-, iNOS- and eNOS-deficient mice

To assess the relative importance of the isoforms of nitric oxide synthase (NOS) in inflammatory pain, we directly compared pain behaviour and paw thickness after intraplantar injection of complete Freunds adjuvant (CFA) in wild‐type (WT) mice and in mice lacking either inducible (iNOS), endothelial (eNOS) or neuronal NOS (nNOS). In mice deficient for nNOS, thermal hyperalgesia was reduced by approximately 50% compared to wild type mice at 4 and 8h after CFA injection, and mechanical hypersensitivity was absent. The only change in pain behaviour in iNOS and eNOS deficient mice compared to WT mice was a more rapid recovery from thermal hyperalgesia. A compensatory up‐regulation of nNOS in dorsal root ganglia (DRG) and spinal cords of iNOS and eNOS knockout mice was excluded using RT‐PCR. However, an increase of iNOS gene expression was found in spinal cords of eNOS and nNOS deficient mice. To study the downstream effects of nNOS deficiency on DRG neurones, we assessed their immunoreactivity for calcitonin gene‐related peptide (CGRP) and cytokines. We found a significant reduction in the CFA induced increase in CGRP immunoreactive neurones as well as in CGRP gene expression in nNOS deficient mice, whereas the percentage of cells immunopositive for tumour necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) was unchanged. These results support the proposed role of nNOS in sensitization of DRG neurones, and might indicate that CGRP is involved in this process.

Experimental arthritis causes tumor necrosis factor-α-dependent infiltration of macrophages into rat dorsal root ganglia which correlates with pain-related behavior

ABSTRACT After peripheral nerve damage macrophages infiltrate the dorsal root ganglia (DRG) in which cell bodies of lesioned neurons are located. However, infiltration of macrophages into the DRGs was also reported in complete Freunds adjuvant (CFA)‐induced inflammation raising the question whether CFA inflammation induces nerve cell damage or whether peripheral inflammation may also trigger macrophage infiltration into DRGs. Related questions are, first, which signals trigger macrophage infiltration into DRGs and, second, is macrophage infiltration correlated with pain‐related behavior. Using the rat model of unilateral antigen‐induced arthritis (AIA) in the knee we found a massive infiltration of ED1+ macrophages into the ipsi‐ and contralateral lumbar DRGs but not into thoracic DRGs. At no time point of AIA DRG neurons showed expression of activating transcription factor‐3 (ATF3) indicating that macrophage infiltration is not explainable by nerve cell lesions in this model. During AIA, lumbar but not thoracic DRGs exhibited a bilateral de novo expression of vascular cell adhesion molecule‐1 (VCAM‐1) which is known to be involved in macrophage infiltration. Tumor necrosis factor‐&agr; (TNF‐&agr;) neutralization with etanercept or infliximab treatment after induction of AIA significantly reduced both macrophage infiltration and VCAM‐1 expression. It also decreased mechanical hyperalgesia at the inflamed joint although the joint inflammation itself was barely attenuated, and it reduced mechanical hyperalgesia at the non‐inflamed contralateral knee joint. Thus, bilateral segment‐specific infiltration of macrophages into DRGs is part of an unilateral inflammatory process in peripheral tissue and it may be involved in the generation of hyperalgesia in particular on the non‐inflamed side.