Sebastian Ivens

Charité Universitätsmedizin Berlin, Berlin, Land Berlin, Germany

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Publications (16)67.74 Total impact

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    ABSTRACT: The 28-item General Health Questionnaire (GHQ-28) is a scaled version of the General Health Questionnaire that has been used internationally to screen for mental disorders in nonpsychiatric populations. There is great need to validate international screening instruments in the Russian language for their use in post-Soviet countries. 200 persons were surveyed in a deprived area of Almaty, Kazakhstan using the Russian version of the GHQ-28 and socioeconomic measures (income level, employment situation and education). We calculated the median and the mean GHQ-28 scores for different socioeconomic subgroups. The internal reliability was tested using Cronbach's α coefficient and intersubscale correlations. We conducted an exploratory factor analysis using varimax rotation. The median score of the GHQ-28 was 2 (mean = 3.56; SD = 5.09) for the total sample. Higher age, unemployment and female gender were significantly associated with high mean GHQ-28 scores. Cronbach's α coefficient was 0.92 for the total scale. Exploratory factor analysis revealed four factors explaining 50.07% of the variance. The factor Anxiety/Insomnia accounted for 14.87%, Severe Depression for 13.74%, Social Dysfunction for 13.47% and Somatic Symptoms for 8.81% of the variance. The test showed good internal consistency. The median GHQ-28 score was relatively low compared to other countries. The subscale Severe Depression including items on suicidal ideation may have a lower acceptance than the other subscales Somatic Symptoms, Anxiety/Insomnia and Social Dysfunction.
    Psychopathology 05/2012; 45(4):252-8. · 1.62 Impact Factor
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    ABSTRACT: Little is known about psychopharmacological prescription practice in low-income countries. The present study aimed for an analysis of pharmacological treatment strategies for inpatients with schizophrenia in Tashkent, the capital city of Uzbekistan, facing a low-income situation as compared with four German cities in a high-income Western situation. We conducted a cross-sectional quantitative survey of age, gender, diagnoses, and psychotropic medication of 845 urban psychiatric inpatients of the Tashkent psychiatric hospital and of 922 urban psychiatric inpatients in four German cities on 1 day in October 2008. We compared the current treatment strategies for specific diagnostic categories between the two settings. In Tashkent, patients diagnosed with schizophrenia were treated with clozapine (66%), haloperidol (62%), or both (44%). More than one-third of the patients treated for schizophrenia were prescribed amitriptyline. The usual treatment strategy for schizophrenia was the combination of two or more antipsychotics (67%). In German cities, the preferred antipsychotics for the treatment of schizophrenia were olanzapine (21%), clozapine (20%), quetiapine (17%), risperidone (17%), and haloperidol (14%); the most common treatment strategy for patients with schizophrenia was the combination of antipsychotics and benzodiazepines; 44% of the patients were treated with two or more antipsychotics at a time. In both settings, psychotropic combination treatments are common for the treatment of schizophrenia contrasting current guideline recommendations. Its rationale and effectiveness needs to be tested in further studies.
    Pharmacoepidemiology and Drug Safety 07/2011; 21(2):145-51. · 2.90 Impact Factor
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    ABSTRACT: Clinical and experimental data suggest that stress contributes to the pathology of epilepsy. We review mechanisms by which stress, primarily via stress hormones, may exacerbate epilepsy, focusing on the intersection between stress-induced pathways and the progression of pathological events that occur before, during, and after the onset of epileptogenesis. In addition to this temporal nuance, we discuss other complexities in stress-epilepsy interactions, including the role of blood-brain barrier dysfunction, neuron-glia interactions, and inflammatory/cytokine pathways that may be protective or damaging depending on context. We advocate the use of global analytical tools, such as microarray, in support of a shift away from a narrow focus on seizures and towards profiling the complex, early process of epileptogenesis, in which multiple pathways may interact to dictate the ultimate onset of chronic, recurring seizures.
    Cardiovascular Psychiatry and Neurology 01/2011; 2011:461263.
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    ABSTRACT: The present study shows a comparison of diagnoses used for the treatment of urban psychiatric inpatients in Tashkent/Uzbekistan and Berlin/Germany. Differential diagnostic practices related to different traditions in psychopathology between the two settings are analysed to explain part of the difference in relative frequencies of the diagnoses. We conducted a cross-sectional survey of diagnoses used for the treatment of 845 inpatients including 17 out of 18 wards of the Tashkent psychiatric hospital and of all 2,260 psychiatric and psychotherapeutic inpatients in Berlin in October 2008. Relative frequencies of diagnostic categories were calculated for each setting and compared between the two settings using the Chi-square test. A descriptive analysis of differential diagnostic practice is used to explain differences in relative frequencies. Patients diagnosed with schizophrenia (59.3 vs. 21.0%), with organic mental disorders (20.5 vs. 8.3%), with mental retardation (6.9 vs. 0.2%) and with neurasthenia (1.4 vs. 0.0%) had larger relative frequencies of the psychiatric inpatient population in Tashkent than in Berlin. Patients diagnosed with unipolar depression (24.1 vs. 0.9%), substance use disorder (17.4 vs. 6.4%), adjustment disorder (6.0 vs. 0.4%), schizoaffective disorder (4.9 vs. 0.0%), mania and bipolar disorder (5.3 vs. 0.4%), personality disorder (3.2 vs. 2.0%) and anxiety disorder (3.1 vs. 0.1%) had larger relative frequencies in Berlin than in Tashkent. The diagnostic concept of schizophrenia in Tashkent includes patients with affective psychoses, schizoaffective psychoses and delusional disorders. In Tashkent, mental disorders are more readily associated with organic brain disease such as head trauma or vascular disease than in Berlin. In Tashkent, most of the psychiatric inpatient capacities are used for the treatment of schizophrenia and organic mental disorders, whereas in Berlin patients with affective disorders, schizophrenia and substance use disorders are most commonly treated as inpatients. The differences can in part be explained by differential diagnostic traditions between the Russian/post-Soviet nosology and the use of the ICD.
    Social Psychiatry 10/2010; 46(12):1295-302. · 2.05 Impact Factor
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    ABSTRACT: Cerebral hyperperfusion syndrome (CHS) may occur as a severe complication following surgical treatment of carotid stenosis. However, the mechanism inducing neurological symptoms in CHS remains unknown. We describe a patient with CHS presenting with seizures 24 h following carotid endarterectomy. Imaging demonstrated early ipsilateral blood-brain barrier (BBB) breakdown with electroencephalographic evidence of cortical dysfunction preceding brain edema. Using in vitro experiments on rat cortical tissue, we show that direct exposure of isolated brain slices to a serum-like medium induces spontaneous epileptiform activity, and that neuronal dysfunction is triggered by albumin. We propose BBB breakdown and subsequent albumin extravasation as a novel pathogenic mechanism underlying CHS and a potential target for therapy.
    Journal of Neurology 04/2010; 257(4):615-20. · 3.58 Impact Factor
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    ABSTRACT: Focal epilepsy often develops following traumatic, ischemic, or infectious brain injury. While the electrical activity of the epileptic brain is well characterized, the mechanisms underlying epileptogenesis are poorly understood. We have recently shown that in the rat neocortex, long-lasting breakdown of the blood-brain barrier (BBB) or direct exposure of the neocortex to serum-derived albumin leads to rapid upregulation of the astrocytic marker GFAP (glial fibrillary acidic protein), followed by delayed (within 4-7 d) development of an epileptic focus. We investigated the role of astrocytes in epileptogenesis in the BBB-breakdown and albumin models of epileptogenesis. We found similar, robust changes in astrocytic gene expression in the neocortex within hours following treatment with deoxycholic acid (BBB breakdown) or albumin. These changes predict reduced clearance capacity for both extracellular glutamate and potassium. Electrophysiological recordings in vitro confirmed the reduced clearance of activity-dependent accumulation of both potassium and glutamate 24 h following exposure to albumin. We used a NEURON model to simulate the consequences of reduced astrocytic uptake of potassium and glutamate on EPSPs. The model predicted that the accumulation of glutamate is associated with frequency-dependent (>100 Hz) decreased facilitation of EPSPs, while potassium accumulation leads to frequency-dependent (10-50 Hz) and NMDA-dependent synaptic facilitation. In vitro electrophysiological recordings during epileptogenesis confirmed frequency-dependent synaptic facilitation leading to seizure-like activity. Our data indicate a transcription-mediated astrocytic transformation early during epileptogenesis. We suggest that the resulting reduction in the clearance of extracellular potassium underlies frequency-dependent neuronal hyperexcitability and network synchronization.
    Journal of Neuroscience 09/2009; 29(34):10588-99. · 6.91 Impact Factor
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    ABSTRACT: Brain injury may result in the development of epilepsy, one of the most common neurological disorders. We previously demonstrated that albumin is critical in the generation of epilepsy after blood-brain barrier (BBB) compromise. Here, we identify TGF-beta pathway activation as the underlying mechanism. We demonstrate that direct activation of the TGF-beta pathway by TGF-beta1 results in epileptiform activity similar to that after exposure to albumin. Coimmunoprecipitation revealed binding of albumin to TGF-beta receptor II, and Smad2 phosphorylation confirmed downstream activation of this pathway. Transcriptome profiling demonstrated similar expression patterns after BBB breakdown, albumin, and TGF-beta1 exposure, including modulation of genes associated with the TGF-beta pathway, early astrocytic activation, inflammation, and reduced inhibitory transmission. Importantly, TGF-beta pathway blockers suppressed most albumin-induced transcriptional changes and prevented the generation of epileptiform activity. Our present data identifies the TGF-beta pathway as a novel putative epileptogenic signaling cascade and therapeutic target for the prevention of injury-induced epilepsy.
    Journal of Neuroscience 08/2009; 29(28):8927-35. · 6.91 Impact Factor
  • Journal of Neuroscience - J NEUROSCI. 01/2009; 29(28):8927-8935.
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    ABSTRACT: The entorhinal cortex (EC) plays an important role in temporal lobe epilepsy. Under normal conditions, the enriched cholinergic innervation of the EC modulates local synchronized oscillatory activity; however, its role in epilepsy is unknown. Enhanced neuronal activation has been shown to induce transcriptional changes of key cholinergic genes and thus alter cholinergic responses. To examine cholinergic modulations in epileptic tissue we studied molecular and electrophysiological cholinergic responses in the EC of chronically epileptic rats following exposure to pilocarpine or kainic acid. We confirmed that while the total activity of the acetylcholine (ACh)-hydrolysing enzyme, acetylcholinesterase (AChE) was not altered, epileptic rats showed alternative splicing of AChE pre-mRNA transcripts, accompanied by a shift from membrane-bound AChE tetramers to soluble monomers. This was associated with increased sensitivity to ACh application: thus, in control rats, ACh (10–100 µm) induced slow (< 1Hz), periodic events confined to the EC; however, in epileptic rats, ACh evoked seconds-long seizure-like events with initial appearance in the EC, and frequent propagation to neighbouring cortical regions. ACh-induced seizure-like events could be completely blocked by the non-specific muscarinic antagonist, atropine, and were partially blocked by the muscarinic-1 receptor antagonist, pirenzepine; but were not affected by the non-specific nicotinic antagonist, mecamylamine. Epileptic rats presented reduced transcript levels of muscarinic receptors with no evidence of mRNA editing or altered mRNA levels for nicotinic ACh receptors. Our findings suggest that altered cholinergic modulation may initiate seizure events in the epileptic temporal cortex.
    European Journal of Neuroscience 08/2008; 28(2):418. · 3.75 Impact Factor
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    ABSTRACT: The entorhinal cortex (EC) plays an important role in temporal lobe epilepsy. Under normal conditions, the enriched cholinergic innervation of the EC modulates local synchronized oscillatory activity; however, its role in epilepsy is unknown. Enhanced neuronal activation has been shown to induce transcriptional changes of key cholinergic genes and thus alter cholinergic responses. To examine cholinergic modulations in epileptic tissue we studied molecular and electrophysiological cholinergic responses in the EC of chronically epileptic rats following exposure to pilocarpine or kainic acid. We confirmed that while the total activity of the acetylcholine (ACh)-hydrolysing enzyme, acetylcholinesterase (AChE) was not altered, epileptic rats showed alternative splicing of AChE pre-mRNA transcripts, accompanied by a shift from membrane-bound AChE tetramers to soluble monomers. This was associated with increased sensitivity to ACh application: thus, in control rats, ACh (10-100 microm) induced slow (< 1Hz), periodic events confined to the EC; however, in epileptic rats, ACh evoked seconds-long seizure-like events with initial appearance in the EC, and frequent propagation to neighbouring cortical regions. ACh-induced seizure-like events could be completely blocked by the non-specific muscarinic antagonist, atropine, and were partially blocked by the muscarinic-1 receptor antagonist, pirenzepine; but were not affected by the non-specific nicotinic antagonist, mecamylamine. Epileptic rats presented reduced transcript levels of muscarinic receptors with no evidence of mRNA editing or altered mRNA levels for nicotinic ACh receptors. Our findings suggest that altered cholinergic modulation may initiate seizure events in the epileptic temporal cortex.
    European Journal of Neuroscience 02/2008; 27(4):965-75. · 3.75 Impact Factor
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    ABSTRACT: Disruption of the blood-brain barrier (BBB) is a characteristic finding in common neurological disorders. Human data suggest BBB disruption may underlie cerebral dysfunction. Animal experiments show the development of epileptiform activity following BBB breakdown. In the present study we investigated the neurophysiological, structural and functional consequences of BBB disruption. Adult rats underwent focal BBB disruption in the rat sensory-motor cortex using the bile salt sodium deoxycholate (DOC). Magnetic resonance imaging in-vivo showed an early BBB disruption with delayed reduction in cortical volume. This was associated with a reduced number of neurons and an increased number of astrocytes. In-vitro experiments showed that the threshold for spreading depression and the propagation velocity of the evoked epileptic potentials were increased 1 month after treatment. Furthermore, animals' motor functions deteriorated during the first few weeks following BBB disruption. Treatment with serum albumin resulted in a similar cell loss confirming that the effect of DOC was due to opening of the BBB. Our findings suggest that delayed neurodegeneration and functional impairment occur following the development of the epileptic focus in the BBB-permeable cerebral cortex.
    Neurobiology of Disease 03/2007; 25(2):367-77. · 5.62 Impact Factor
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    ABSTRACT: It has long been recognized that insults to the cerebral cortex, such as trauma, ischaemia or infections, may result in the development of epilepsy, one of the most common neurological disorders. Human and animal studies have suggested that perturbations in neurovascular integrity and breakdown of the blood-brain barrier (BBB) lead to neuronal hypersynchronization and epileptiform activity, but the mechanisms underlying these processes are not known. In this study, we reveal a novel mechanism for epileptogenesis in the injured brain. We used focal neocortical, long-lasting BBB disruption or direct exposure to serum albumin in rats (51 and 13 animals, respectively, and 26 controls) as well as albumin exposure in brain slices in vitro. Most treated slices (72%, n = 189) displayed hypersynchronous propagating epileptiform field potentials when examined 5-49 days after treatment, but only 14% (n = 71) of control slices showed similar responses. We demonstrate that direct brain exposure to serum albumin is associated with albumin uptake into astrocytes, which is mediated by transforming growth factor beta receptors (TGF-betaRs). This uptake is followed by down regulation of inward-rectifying potassium (Kir 4.1) channels in astrocytes, resulting in reduced buffering of extracellular potassium. This, in turn, leads to activity-dependent increased accumulation of extracellular potassium, resulting in facilitated N-methyl-d-aspartate-receptor-mediated neuronal hyperexcitability and eventually epileptiform activity. Blocking TGF-betaR in vivo reduces the likelihood of epileptogenesis in albumin-exposed brains to 29.3% (n = 41 slices, P < 0.05). We propose that the above-described cascade of events following common brain insults leads to brain dysfunction and eventually epilepsy and suggest TGF-betaRs as a possible therapeutic target.
    Brain 02/2007; 130(Pt 2):535-47. · 9.92 Impact Factor
  • Brain 01/2007; 130(2):535-547. · 9.92 Impact Factor
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    ABSTRACT: 031NEUROGENESIS IN EPILEPTIC BRAIN: AFFERENT SYNAPSES TO NEWBORN CELLS ATTENUATE NETWORK EXCITABILITY 1M.Kokaia ( Wallenberg Neuroscience Center, Lund University Hospital, Sweden ) Purpose: Neural stem cells in the adult mammalian brain (including humans) continue to produce new functional granule cells in the dentate gyrus subgranular zone and new olfactory bulb neurons in the subventricular zone during an entire life. In the hippocampus, neurogenesis has been proposed to play a role in learning and memory and mood regulation. The new cells develop electrophysiological characteristics and synaptic inputs very similar to those of the rest of the cell population. The purpose of the study was to explore whether tissue environment in an epileptic brain influences properties of afferent synapses formed on newborn granule cells. Method: Rats were exposed to either a physiological stimulus, i.e., running, or status epilepticus, which gives rise to neuronal death, inflammation, increased network excitability and recurrent spontaneous seizures. Both treatments increase neurogenesis in the dentate gyrus. We labelled newborn cells by GFP-retroviral vector injections right after these treatments to identify the cells and apply whole-cell patch-clamp recordings in live hippocampal slices. Results: Granule cells formed after running and status epilepticus exhibited similar intrinsic membrane properties. However, new neurons born into the epileptic environment differed with respect to tonic drive and short-term plasticity of both excitatory and inhibitory afferent synapses. The new granule cells formed after status epilepticus exhibited functional connectivity consistent with reduced synaptic network excitability of the dentate gyrus, i.e., decreased excitatory and increased inhibitory input activity. Conclusion: We demonstrate for the first time a high degree of plasticity in synaptic inputs to the new neurons, which could mitigate pathological activity in the epileptic brain.
    Epilepsia 01/2006; 47. · 3.91 Impact Factor
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    ABSTRACT: Perturbations in the integrity of the blood-brain barrier have been reported in both humans and animals under numerous pathological conditions. Although the blood-brain barrier prevents the penetration of many blood constituents into the brain extracellular space, the effect of such perturbations on the brain function and their roles in the pathogenesis of cortical diseases are unknown. In this study we established a model for focal disruption of the blood-brain barrier in the rat cortex by direct application of bile salts. Exposure of the cerebral cortex in vivo to bile salts resulted in long-lasting extravasation of serum albumin to the brain extracellular space and was associated with a prominent activation of astrocytes with no inflammatory response or marked cell loss. Using electrophysiological recordings in brain slices we found that a focus of epileptiform discharges developed within 4-7 d after treatment and could be recorded up to 49 d postoperatively in >60% of slices from treated animals but only rarely (10%) in sham-operated controls. Epileptiform activity involved both glutamatergic and GABAergic neurotransmission. Epileptiform activity was also induced by direct cortical application of native serum, denatured serum, or albumin-containing solution. In contrast, perfusion with serum-adapted electrolyte solution did not induce abnormal activity, thereby suggesting that the exposure of the serum-devoid brain environment to serum proteins underlies epileptogenesis in the blood-brain barrier-disrupted cortex. Although many neuropathologies entail a compromised blood-brain barrier, this is the first direct evidence that it may have a role in the pathogenesis of focal cortical epilepsy, a common neurological disease.
    Journal of Neuroscience 10/2004; 24(36):7829-36. · 6.91 Impact Factor
  • Journal of Neuroscience. 01/2004;

Publication Stats

662 Citations
67.74 Total Impact Points

Institutions

  • 2007–2010
    • Charité Universitätsmedizin Berlin
      • Institute of Neurophysiology
      Berlin, Land Berlin, Germany
  • 2007–2009
    • Ben-Gurion University of the Negev
      Be'er Sheva`, Southern District, Israel
  • 2008
    • Hebrew University of Jerusalem
      • Interdisciplinary Center for Neural Computation
      Jerusalem, Jerusalem District, Israel