Vagus nerve stimulation ameliorated deficits in one-way active avoidance learning and stimulated hippocampal neurogenesis in bulbectomized rats

BackgroundVagus nerve stimulation (VNS) has been introduced as a therapeutic option for treatment-resistant depression. The neural and chemical mechanisms responsible for the effects of VNS are largely unclear.MethodsBilateral removal of the olfactory bulbs (OBX) is a validated animal model in depression research. We studied the effects of vagus nerve stimulation (VNS) on disturbed one-way active avoidance learning and neurogenesis in the hippocampal dentate gyrus of rats.ResultsAfter a stimulation period of 3 weeks, OBX rats acquired the learning task as controls. In addition, the OBX-related decrease of neuronal differentiated BrdU positive cells in the dentate gyrus was prevented by VNS.ConclusionsThis suggests that chronic VNS and changes in hippocampal neurogenesis induced by VNS may also account for the amelioration of behavioral deficits in OBX rats. To the best of our knowledge, this is the first report on the restorative effects of VNS on behavioral function in an animal model of depression that can be compared with the effects of antidepressants.     

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.Key words: heart rate, physical exercise, respiration, schizophrenia, vagal threshold, cardiac death, inflammation, physical fitness     

Transient activation of a somatosensory area in painful hallucinations shown by fMRI

The disturbance of somatosensory perception and bodily experiences, including somatosensory hallucinations, are main features of the coenaesthesia sub-syndrome of schizophrenia. We used functional MRI to study a coenaesthesia patient with rapidly fluctuating painful somatosensory hallucinatory perceptions. Transient brain activations accompanying hallucinations were similar to the pattern elicited in a control experiment (non-painful tactile stimulation). However, an area in the medial parietal cortex, including parts of the precuneus and previously characterised as a supplementary sensory area, was activated significantly stronger during hallucinations than the control condition. This finding demonstrates elevated brain activity in a somatosensory area accompanying painful somatic hallucinations.     

A technical triade for proteomic identification and characterization of cancer biomarkers

Biomarkers are needed to elucidate the biological background and to improve the detection of cancer. Therefore, we have analyzed laser-microdissected cryostat sections from head and neck tumors and adjacent mucosa on ProteinChip arrays. Two differentially expressed proteins (P = 3.34 x 10(-5) and 4.6 x 10(-5)) were isolated by two-dimensional gel electrophoresis and identified as S100A8 (calgranulin A) and S100A9 (calgranulin B) by in-gel proteolytic digestion, peptide mapping, tandem mass spectrometry analysis, and immunodepletion assay. The relevance of these single marker proteins was evaluated by immunohistochemistry. Positive tissue areas were reanalyzed on ProteinChip arrays to confirm the identity of these proteins. As a control, a peak with low P was identified as calgizzarin (S100A11) and characterized in the same way. This technical triade of tissue microdissection, ProteinChip technology, and immunohistochemistry opens up the possibility to find, identify, and characterize tumor relevant biomarkers, which will allow the movement toward the clonal heterogeneity of malignant tumors. Taking this approach, proteins were identified that might be responsible for invasion and metastasis.     

Neurobrucellosis with thalamic infarction: a case report

Brucellosis is prevalent in North and East Africa, the Middle East, South and Central Asia, South and Central America and the Mediterranean countries of Europe. In 5% of cases it may lead to central nervous system manifestation presenting most often as a meningitis or meningoencephalitis. Here we report and discuss a case of neurobrucellosis with meningitis with cranial nerves neuritis. A 56-year-old German male was admitted with bilateral abducens nerve palsy, amblyacousia and intractable headaches. An enzyme-linked immunosorbent assay (ELISA) revealed antibodies against Brucella in serum and cerebrospinal fluid (CSF). Additionally, our patient suffered from an infarction of the left thalamus. In conclusion, in cases of unresponsive meningitis or meningoencephalitis and history of travel in endemic regions, neurobrucellosis should be considered. If initial microbiological tests fail, complementary investigations such as ELISA are indicated to detect Brucella species in serum and/or CSF.     

Is hyperlipasemia in critically ill patients of clinical importance? An observational CT study

Objective To assess morphological alterations of the pancreas by contrast-enhanced computed tomography (cCT) and subclinical cellular damage of the pancreas by measuring pancreatitis-associated protein (PAP) in critically ill patients without prior pancreatic disorder who presented with raised serum lipase levels. Design Prospective, observational study Setting Mixed surgical/neurosurgical intensive care unit of a German university hospital. Patients One hundred and thirty consecutive critically ill patients without prior damage or disease of the pancreas and an expected length of stay of more than 5 days. Interventions Daily serum lipase measurements and daily serum PAP measurements. Contrast-enhanced upper abdominal cCT study in patients with triple increase of serum lipase. Measurements and results Thirty-eight patients showed raised serum lipase levels and qualified for the cCT scan study. In 20 patients cCT scans were performed. Morphological alterations of the pancreas were found in 7 out these 20 patients while serum PAP levels were raised in all patients. Conclusion Hyperlipasemia is a common finding in critically ill patients without prior pancreatic disorder. While elevated serum PAP levels indicate pancreatic cellular stress morphological alterations of the pancreas are rare and of little clinical importance. C. Denz and L. Siegel contributed equally to this study. Results were presented in part and published as an abstract at the 18th ESICM Annual Congress, 25–28 September 2005, Amsterdam, Netherlands.     

Perception to laser heat stimuli in depressed patients is reduced to Aδ- and selective C-fiber stimulation

Depression and clinical pain have been shown being strongly associated with each other. However, recent studies have demonstrated that depressed patients are less sensitive to experimental pain than healthy individuals. Reasons for this phenomenon are still elusive. The study investigates whether cutaneous C- and/or Aδ-fibers might contribute to this phenomenon. C- and Aδ-fiber systems were assessed in 12 depressed patients and 12 sex- and age-matched healthy controls using stimulation of tiny skin areas by laser heat stimuli. Detection and pain thresholds as well as proportions of trials associated with C- and Aδ-fiber stimulation as well as of non-perceived trials were compared between groups. Patients showed elevated pain thresholds and significantly less C-fiber responses. They also failed significantly more often to recognize the noxious laser-heat stimuli. Thus, higher pain thresholds to experimental stimuli in depressed patients are not only associated with reduced perception of cutaneous Aδ-, but also with decreased perception of selective C-fiber input. The physiological underpinnings of the phenomenon remain elusive and should be examined in the future to understand whether it is based on changes in the periphery or in central processing or both.     

Dynamic microvascular blood flow analysis during post-occlusive reactive hyperemia test in patients with schizophrenia

Patients suffering from schizophrenia have an increased mortality risk due to cardiovascular events. Recently the analysis of peripheral circulation has revealed interesting results in the study of vascular pathological conditions assuming that the state of microcirculation of the skin is at least partly representative for the constitution of other vascular beds including those of the cardiac muscle and arteries. The objective of this study was to investigate the microcirculation in patients with acute schizophrenia (PAT, n = 15, mean age 33.0 years, 7 male, 8 female) to identify whether spectral features from blood flow signals derived through laser Doppler spectrometry are significantly altered compared to healthy subjects (CON, n = 15, mean age 32.4 years, 7 male, 8 female) by means of the post-occlusive reactive hyperemia test. It was also explored if a segmentation of the post-ischemic stage can disclose more detailed and additional information about the dynamic behavior of the blood flow during hyperemic response. For this reason, time–frequency analyses were performed to observe the course of the blood flow frequency components over time. Our results indicate significant differences in the patients group, already detectable under baseline conditions but also in the hyperemic phase. The main modifications affect the respiratory (p = 0.006) as well as the cardiac (p = 0.001) activity. It was further shown that the application of a segmented analysis of the post-ischemic state considerably improves the differentiation between both groups. Only with the introduced segmentation algorithm using a window length of 2048 samples and a shift of 128 and 256 samples we could demonstrate influences of the disease on the endothelial (p = 0.029), the sympathetic (p = 0.019) and the myogenic (p = 0.029) mechanisms. These information provide further insights into the appearance of schizophrenia and could lead to an improvement of the patients’ treatment to avoid the occurrence of cardiovascular events.     

Decreased sensitivity to thermal pain in rats bred for high anxiety-related behaviour is attenuated by citalopram or diazepam treatment

Complex interactions between pain perception, anxiety and depressive symptoms have repeatedly been described. However, pathophysiological or biochemical mechanisms underlying the alterations of pain perception in patients suffering from anxiety or depression still remain a matter of debate. Thus, we aimed to perform an investigation on pain perception in an animal model of extremes in anxiety-related behaviour, which might provide a tool for future studies. Here, thermal pain thresholds were obtained from rats with a genetic predisposition to high anxiety-related behaviour (HAB), including signs of comorbid depression-like behaviour and from controls (low-anxiety rats (LAB); cross-bred HAB and LAB rats; Wistar rats). Furthermore, the effect of eight-week antidepressive treatment using citalopram and of short-term anxiolytic treatment with diazepam on pain-related behaviour was assessed. Simultaneously, anxiety-related behaviour was monitored. At baseline, HAB animals showed 35% higher thresholds for thermal pain than controls. These were normalized to control levels after eight weeks of continuous citalopram treatment paralleled by a reduction of anxiety-related behaviour, but also acutely after diazepam administration. Overall, thermal pain thresholds in HAB animals are shifted in a similar fashion as seen in patients suffering from major depressive disorder. Antidepressive, as well as anxiolytic treatments, attenuated these differences. As the relative importance of the factors anxiety and depression cannot be derived from this study with certainty, extending these investigations to additional animal models might represent a valuable tool for future investigations concerning the interrelations between anxiety, depression, and pain at a molecular level.