Martin Schmelz

Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany

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Publications (311)1164.4 Total impact

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    ABSTRACT: Objectives: Laser-evoked potentials (LEP) were assessed after peripheral nerve block of the lateral femoral cutaneous nerve (LFCN) in healthy volunteers from partially anesthetized skin areas to differentially stimulate mechano-insensitive nociceptors. Methods: An ultrasound-guided nerve block of the LFCN was performed in 12 healthy male subjects with Ropivacain 1%. After 30 min, the nerve block induced significantly larger anesthetic areas to mechanical stimuli than to electrical stimuli revealing an area of differential sensitivity. LEPs, reaction times and pain ratings were recorded in response to the laser stimuli of (1) completely anesthetic skin, (2) mechano-insensitive, but electrically excitable skin ('differential sensitivity'), (3) normal skin. Results: LEP latencies in the area of differential sensitivity were increased compared to unaffected skin (228 ± 8.5 ms, vs. 181 ± 3.6 ms, p < 0.01) and LEP amplitudes were reduced (14.8 ± 1.2 μV vs. 24.6 ± 1.7 μV, p < 0.01). Correspondingly, psychophysically assessed response latencies in the differentially anesthetic skin were increased (649 ms vs. 427 ms, p < 0.01) and pain ratings reduced (1.5/10 vs. 5/10 NRS, p < 0.01). Conclusion: The increase in LEP latency suggests that mechano-insensitive heat-sensitive Aδ nociceptors (MIA, type II) have a slower conduction velocity or higher utilization time than mechano-sensitive type II Aδ nociceptors. Moreover, widely branched, slowly conducting and mechano-insensitive branches of Aδ nociceptors can explain our finding. LEPs in the differentially anesthetized skin provide specific information about a mechanically insensitive but heat-sensitive subpopulation of Aδ nociceptors. These findings support the concept that A-fibre nociceptors exhibit a similar degree of modality specificity as C-fibre nociceptors.
    No preview · Article · Oct 2015 · European journal of pain (London, England)
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    ABSTRACT: Nine isoforms of voltage-gated sodium channels (NaV) have been characterized and in excitable tissues they are responsible for the initiation and conduction of action potentials. For primary afferent neurons residing in dorsal root ganglia (DRG), individual neurons may express multiple NaV isoforms extending the neuron's functional capabilities. Since expression of NaV isoforms can be differentially regulated by neurotrophic factors we have examined the functional consequences of exposure to either nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF) on action potential conduction in outgrowing cultured porcine neurites of DRG neurons. Calcium signals were recorded using the exogenous intensity based calcium indicator Fluo-8®, AM. In 94 neurons, calcium signals were conducted along neurites in response to electrical stimulation of the soma. At an image acquisition rate of 25 Hz it was possible to discern calcium transients in response to individual electrical stimuli. The peak amplitude of electrically-evoked calcium signals was limited by the ability of the neuron to follow the stimulus frequency. The stimulus frequency required to evoke a half-maximal calcium response was approximately 3 Hz at room temperature. In 13 of 14 (93%) NGF-responsive neurites, TTX-r NaV isoforms alone were sufficient to support propagated signals. In contrast, calcium signals mediated by TTX-r NaVs were evident in only 4 of 11 (36%) neurites from somata cultured in GDNF. This establishes a basis for assessing action potential signaling using calcium imaging techniques in individual cultured neurites and suggests that, in the pig, afferent nociceptor classes relying on the functional properties of TTX-r NaV isoforms, such as cold-nociceptors, most probably derive from NGF-responsive DRG neurons.
    Preview · Article · Sep 2015 · PLoS ONE
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    R W Carr · J E Coe · E Forsch · M Schmelz · D A Sandercock
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    ABSTRACT: Background and aims: Early postnatal tail docking (amputation of 2/3rds of the tail) in piglets is performed as a preventative measure to minimize potential trauma associated with tail biting in older animals. The aim of this study was to investigate caudal nerve axonal composition and the effects of tail docking on axonal function in neonatal pigs.
    Full-text · Conference Paper · Sep 2015
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    ABSTRACT: Objectives Mechano-insensitive (“silent”) nociceptors contribute to neuropathic pain. Their activation causes an axon-reflex erythema, but their high electrical excitation thresholds complicate their assessment, particularly in painful neuropathy. We therefore developed electrical stimulation paradigms for brief nociceptor activation and explored their sensitivity for clinical trials.Method The local ethics committee approved the study protocol, and 14 healthy subjects were enrolled. Electrical stimuli were administered to ventral forearm and dorsum of the foot via self-adhesive 3 × 10 mm electrodes and a pair of blunted 0.4-mm-diameter platinum/iridium pin electrodes. Pain thresholds were determined and nociceptors activated at 1.5-fold pain threshold by 5 blocks delivering 10 pulses each and at randomized frequencies of 5 to 10 to 20 to 50 to 100 Hz, respectively. Axon reflex erythema and pain were recorded.ResultsIncreased frequencies dose-dependently increased pain (P < 0.0001). Pin electrode stimulation was more painful than adhesive electrode stimulation (P < 0.04) particularly at the feet. Axon reflex erythema was significantly smaller at the feet than at the forearm (P < 0.0001). At both skin sites, pin electrode stimuli evoked significantly larger erythema (P < 0.05).Conclusions Electrical stimulation at high current density using pin electrodes is a sensitive method for investigating “silent” nociceptors, which might therefore preferably be applied in neuropathic pain conditions.
    No preview · Article · Sep 2015 · Pain Practice

  • No preview · Article · Sep 2015 · Free Radical Biology and Medicine
  • D Schwab · I Pahl · W Koppert · C Enk · R Sittl · S Mühldorfer · M Schmelz · EG Hahn

    No preview · Article · Aug 2015 · Zeitschrift für Gastroenterologie
  • A. Miclescu · M. Schmelz · T. Gordh
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    ABSTRACT: Both peripheral nerve injury and neuroma pain are the result of changes in sodium channel expression. Lidocaine selectively inhibits the spontaneous ectopic activity by binding to sodium channels. Subanesthetics concentrations of lidocaine are able to produce a differential block of the ectopic discharges, but not propagation of impulses, suppressing differentially the associated neuropathic pain symptoms. The aim of this study was to investigate the differences between the analgesic effects of lidocaine 0.5% and a control group of lidocaine 0.1% on several neuroma related pain modalities.
    No preview · Article · Jul 2015 · Scandinavian Journal of Pain
  • Martin Schmelz
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    ABSTRACT: Upon activation, nociceptors in the skin release neuropeptides that acutely cause a flare response in human skin that is also termed neurogenic vasodilation or neurogenic inflammation. In rodents, neurogenic inflammation also includes neurogenic protein extravasation. Positive feed-back loops of activation between skin nerve fibers and inflammatory cells exist that might pose the threat of self-sustained inflammation. However, an intricate pattern of stimulatory and inhibitory effects of the released neuropeptides provides a well-balanced regulation of skin inflammation. Yet, contrasting the aura linked to the term "neurogenic inflammation", the clinical implications of an erythema surrounding a mosquito bite appear rather limited. Apart from these acute effects of neuropeptides, there exist complex interactions between nerve fibers and skin cells that relate to trophic function, differentiation, skin barrier and modulation of immune responses. These operate on a longer time scale, but they are indeed of critical importance for skin homeostasis and impact on a variety of diseases. Conceptually, these longer term interactions cannot be subsumed under the term "neurogenic inflammation". Also on clinical grounds this separation makes sense as blocking of neuropeptide receptors can have a therapeutic effect on the longer term interactions for example on itch and inflammation in atopic dermatitis without changing the acute neurogenic inflammation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2015 · Experimental Dermatology
  • Hanns Ulrich Zeilhofer · Martin Schmelz

    No preview · Article · May 2015 · Pain
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    ABSTRACT: Seven patients diagnosed with erythromelalgia (EM) were investigated by microneurography to record from unmyelinated nerve fibers in the peroneal nerve. Two patients had characterized variants of sodium channel Nav1.7 (I848T, I228M) while no mutations of coding regions of Navs were found in 5 EM patients.Irrespective of NaV1.7 mutations, more than 50% of the silent nociceptors in the EM patients showed spontaneous activity. In the patient with mutation I848T all nociceptors, but not sympathetic efferents, displayed enhanced early subnormal conduction in the velocity recovery cycles and the expected late subnormality was reversed to supra-normal conduction. The larger hyperpolarizing shift of activation might explain the difference to the I228M mutation. Sympathetic fibers that lack Nav1.8 did not show supranormal conduction in the patient carrying the I848T mutation, confirming in human subjects that the presence of Nav1.8 crucially modulates conduction in cells expressing EM mutant channels. The characteristic pattern of changes in CV observed in the patient with the I848T gain-of function mutation in Nav1.7 could be explained by axonal depolarization and concomitant inactivation of Nav1.7. If this were true, activity-dependent hyperpolarization would reverse inactivation of Nav1.7 and account for the supranormal CV. This mechanism might explain normal pain thresholds under resting conditions.
    No preview · Article · May 2015 · Pain
  • R Jonas · A Klusch · R De Col · M Schmelz · M Petersen · R Carr

    No preview · Article · Apr 2015 · Diabetologie und Stoffwechsel
  • Martin Schmelz
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    ABSTRACT: As we all can easily differentiate the sensations of itch and pain, the most straightforward neurophysiologic concept would consist of two specific pathways that independently encode itch and pain. Indeed, a neuronal pathway for histamine-induced itch in the peripheral and central nervous system has been described in animals and humans, and recently several non-histaminergic pathways for itch have been discovered in rodents that support a dichotomous concept differentiated into a pain and an itch pathway, with both pathways being composed of different "flavors." Numerous markers and mediators have been found that are linked to itch processing pathways. Thus, the delineation of neuronal pathways for itch from pain pathways seemingly proves that all sensory aspects of itch are based on an itch-specific neuronal pathway. However, such a concept is incomplete as itch can also be induced by the activation of the pain pathway in particular when the stimulus is applied in a highly localized spatial pattern. These opposite views reflect the old dispute between specificity and pattern theories of itch. Rather than only being of theoretic interest, this conceptual problem has key implication for the strategy to treat chronic itch as key therapeutic targets would be either itch-specific pathways or unspecific nociceptive pathways.
    No preview · Article · Apr 2015 · Handbook of experimental pharmacology
  • Martin Schmelz
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    ABSTRACT: Pain and itch are generally regarded antagonistic as painful stimuli such as scratching suppresses itch. Moreover, inhibition of pain processing by opioids generates itch further supporting their opposing role. Separate specific pathways for itch and pain processing have been uncovered, and several molecular markers have been established in mice that identify neurons involved in the processing of histaminergic and non-histaminergic itch on primary afferent and spinal level. These results are in agreement with the specificity theory for itch and might suggest that pain and itch should be investigated separately on the level of neurons, mediators, and mechanisms. However, in addition to broadly overlapping mediators of itch and pain, there is also evidence for overlapping functions in primary afferents: nociceptive primary afferents can provoke itch when activated very locally in the epidermis, and sensitization of both nociceptors and pruriceptors has been found following local nerve growth factor application in volunteers. Thus, also mechanisms that underlie the development of chronic itch and pain including spontaneous activity and sensitization of primary afferents as well as spinal cord sensitization may well overlap to a great extent. Rather than separating itch and pain, research concepts should therefore address the common mechanisms. Such an approach appears most appropriate for clinical conditions of neuropathic itch and pain and also chronic inflammatory conditions. While itch researchers can benefit from the large body of information of the pain field, pain researchers will find behavioral readouts of spontaneous itch much simpler than those for spontaneous pain in animals and the skin as source of the pruritic activity much more accessible even in patients.
    No preview · Article · Apr 2015 · Handbook of experimental pharmacology
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    ABSTRACT: Background Mechano-sensitive and mechano-insensitive C-nociceptors in human skin differ in receptive field sizes and electrical excitation thresholds, but their distinct functional roles are yet unclear.Methods After blocking the lateral femoral cutaneous nerve (NCFL) in eight healthy male subjects (3-mL Naropin® 1%), we mapped the skin innervation territory being anaesthetic to mechanical pin prick but sensitive to painful transcutaneous electrical stimuli. Such ‘differentially anaesthetic zones’ indicated that the functional innervation with mechano-sensitive nociceptors was absent but the innervation with mechano-insensitive nociceptors remained intact. In these areas, we explored heat pain thresholds, low pH-induced pain, cowhage- and histamine-induced itch, and axon reflex flare.ResultsIn differentially anaesthetic skin, heat pain thresholds were above the cut-off of 50°C (non-anaesthetized skin 47 ± 0.4°C). Pain ratings to 30 μL pH 4 injections were reduced compared to non-anaesthetized skin (48 ± 9 vs. 79 ± 6 VAS; p < 0.01). The axon reflex flare area did not differ between these zones (7.8 ± 1.4 cm2 vs. 8.3 ± 0.5 cm2). Histamine iontophoresis still caused pruritus in differentially anaesthetized skin in five of eight subjects (VAS 26 ± 14), whereas itch upon cowhage spicules was absent (VAS 0 vs. 29 ± 11 in non-anaesthetized skin).Conclusions We conclude that activation of mechano-insensitive nociceptors is sufficient to provoke itch by histamine- and acid-induced pain. The mechano-sensitive nociceptors are crucial for cowhage-induced itch and for the assessment of heat pain thresholds.
    No preview · Article · Apr 2015 · European journal of pain (London, England)
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    ABSTRACT: Following each action potential, C-fiber nociceptors undergo cyclical changes in excitability, including a period of superexcitability, before recovering their basal excitability state. The increase in superexcitability during this recovery cycle depends upon their immediate firing history of the axon, but also determines the instantaneous firing frequency that encodes pain intensity. To explore the mechanistic underpinnings of the recovery cycle phenomenon a biophysical model of a C-fiber has been developed. The model represents the spatial extent of the axon including its passive properties as well as ion channels and the Na/K-ATPase ion pump. Ionic concentrations were represented inside and outside the membrane. The model was able to replicate the typical transitions in excitability from subnormal to supernormal observed empirically following a conducted action potential. In the model, supernormality depended on the degree of conduction slowing which in turn depends upon the frequency of stimulation, in accordance with experimental findings. In particular, we show that activity-dependent conduction slowing is produced by the accumulation of intraaxonal sodium. We further show that the supernormal phase results from a reduced potassium current Kdr as a result of accumulation of periaxonal potassium in concert with a reduced influx of sodium through Nav1.7 relative to Nav1.8 current. This theoretical prediction was supported by data from an in vitro preparation of small rat dorsal root ganglion somata showing a reduction in the magnitude of tetrodotoxin-sensitive relative to tetrodotoxin -resistant whole cell current. Furthermore, our studies provide support for the role of depolarization in supernormality, as previously suggested, but we suggest that the basic mechanism depends on changes in ionic concentrations inside and outside the axon. The understanding of the mechanisms underlying repetitive discharges in recovery cycles may provide insight into mechanisms of spontaneous activity, which recently has been shown to correlate to a perceived level of pain. Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Mar 2015 · Biophysical Journal
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    ABSTRACT: Excessive Ultraviolet (UV) exposure of the skin causes sunburn which is characterized by an acute cutaneous inflammatory response including skin tissue injury, dermal vasodilation, leukocyte infiltration and pain. Several studies have indicated that cytokines and chemokines are important mediators in UVB-induced skin damage (1,2). Besides their role in inducing and regulating the immune response, cytokines and chemokines have been implicated in modulating inflammatory pain perception (3). Recently, Dawes et al. reported the chemokine CXCL5, also known as epithelial-derived neutrophil-activating peptide 78 (ENA-78) in humans and liposaccharide-induced CXC chemokine (LIX) in rodents, as a novel mediator of UVB-induced mechanical hypersensitivity. Substantially increased CXCL5 mRNA expression was found in human and rodent skin punch biopsies after UV treatment (4). However, the regulation of CXCL5 in human non-immune skin cells after UV exposure has not been investigated in detail. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Feb 2015 · Experimental Dermatology
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    ABSTRACT: Background Inflammatory mediators activate and sensitize nociceptors. Tissue acidosis with low pH of 5.5 often accompanies inflammation and could enhance inflammatory pain and sensitization.Methods Action potentials from single mechano-responsive (CM) and mechano-insensitive (CMi) C-nociceptors of cutaneous fascicles of the peroneal nerve in healthy volunteers were recorded by microneurography. Low pH solutions with and without prostaglandin E2 (PGE2) were injected twice (with an interval of approximately 5 min) into two spots of the receptive fields of C-fibres. Heat thresholds of the C-fibres were obtained before and after each injection.ResultsInjections of the low pH solutions immediately induced phasic responses in CM nociceptors, whereas CMi fibres responded after a delay of several seconds with a sustained response. More CMi fibres than CM fibres showed ongoing discharge after low pH injection, but the duration and intensity of the responses to the first low pH injection did not differ between them. Upon repetition, duration and intensity of the pH responses increased more than twofold in CMi fibres only. Furthermore, combined application of pH and PGE2 sensitized the response in CMi fibres only. In contrast, heat activation thresholds were sensitized by the combination of low pH and PGE2 in both fibre classes.Conclusions Our results confirm nociceptor class independent heat sensitization by PGE2 which is probably mediated by transient receptor potential vanilloid 1 phosphorylation. However, prolonged and increased pain responses in humans upon low pH/PGE2 stimulation appear to be primarily dependent on CMi fibres, whereas CM nociceptors appear crucial for phasic responses.
    No preview · Article · Feb 2015 · European journal of pain (London, England)
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    ABSTRACT: Introduction: Nerve growth factor (NGF) induces profound hyperalgesia. In this study we explored patterns of NGF sensitization in muscle and fascia of distal and paraspinal sites. Methods: We injected 1 µg of NGF into human (n = 8) tibialis anterior and erector spinae muscles and their fasciae. The spatial extent of pressure sensitization, pressure pain threshold, and mechanical hyperalgesia (150 kPa, 10 s) was assessed at days 0.25, 1, 3, 7, 14, and 21. Chemical sensitization was explored by acidic buffer injections (pH 4, 100 µl) at days 7 and 14. Results: The mechanical hyperalgesia area was larger in tibial fascia than in muscle. Pressure pain thresholds were lower, tonic pressure pain ratings, and citrate buffer evoked pain higher in fascia than in muscle. Conclusions: Spatial mechanical sensitization differs between muscle and fascia. Thoracolumbar fasciae appear more sensitive than tibial fasciae and may be major contributors to low back pain, but the temporal sensitization profile is similar between paraspinal and distal sites. Muscle Nerve 52: 265-272, 2015.
    No preview · Article · Dec 2014 · Muscle & Nerve
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    ABSTRACT: Background and aims “Gain-of-function” mutations in voltage-gated sodium channel NaV1.7 have been linked to erythromelalgia (EM), characterized by painful hot and red hands and feet. We investigated the proportion of patients with EM that carry a mutation in NaV1.7 or in other pain-related genes and studied possible clinical differences. Methods In this study, 48 patients with EM were screened for mutations in a total of 29 candidate genes, including all sodium channel subunits, transient receptor potential channels (TRPA1, TRPV1, TRPM8), neurotrophic factors (NGF, NGFR, BDNF, GDNF, NTRK1 and WNK1) and other known pain-related genes (CACNG2, KCNS1, COMT, P2RX3, TAC1, TACR1), using a combination of next generation sequencing and classical Sanger sequencing. Results In 7/48 patients protein-modifying mutations of NaV1.7 (P187L, I228M, I848T (n = 4) and N1245S) were identified. Patients with the I848T mutation could be identified clinically based on early onset and severity of the disease. In contrast, there were no clinical characteristics that differentiated the other patients with NaV1.7 mutation from those patients without. We also found more than twenty rare protein-modifying genetic variants in the genes coding for sodium channels (NaV1.8, NaV1.9, NaV1.6, NaV1.5, NaV2.1, SCN1B, SCN3B), transient receptor potential channel (TRPA1, TRPV1), and other pain-related targets (WNK1 and NGFR). Conclusions We conclude that functionally characterized mutations of NaV1.7 (I848T) are present only in a minority of patient with EM. Albeit the majority of patients (27/48) carried rare protein-modifying mutations the vast majority of those will most probably not be causally linked to their disease. Implications The key question remaining to be solved is the possible role of rare variants of NaV1.8, NaV1.9, or beta-subunits in provoking chronic pain conditions or even EM.
    No preview · Article · Oct 2014 · Scandinavian Journal of Pain
  • B. Weinkauf · O. Obreja · M. Schmelz · R. Rukwied
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    ABSTRACT: Background Nerve growth factor (NGF) causes early heat and delayed mechanical hyperalgesia. Axonal transport might contribute to lasting responses. Temporal hyperalgesia development was investigated by administering NGF in paraspinal skin. Transient receptor potential ankyrin 1 (TRPA1) is up-regulated by NGF and chemical responsiveness to cinnamon aldehyde (TRPA1 agonist) was quantified.Methods Eight healthy volunteers received 1 μg human recombinant NGF (i.d. 50 μL) to L4/L5 processi spinosi skin. Mechanical, thermal and electrical sensitization was assessed at 3–6 h and at days 1, 2, 3, 5, 7, 10, 14 and 21, and pain upon cinnamon aldehyde (20%, 60 μL) recorded at days 3 and 21.ResultsHeat hyperalgesia developed with an initial maximum at 3 h [heat pain threshold −3.9°; peak pain ratings +22 visual analogue scale (VAS)] that decreased by day 1, subsequently increased to a maximum around day 5 (−5 ± 0.2 °C, +41 ± 4 VAS), and thereafter declined to ∼20% at day 21. Mechanical and electrical hyperexcitability developed within 3 days and gradually increased to peak between days 14 and 21. Pain intensity upon cinnamon aldehyde stimulation was doubled at the NGF site at day 3 and was still increased by about 50% at day 21.ConclusionsNGF causes immediate heat hyperalgesia probably linked to an up-regulation and sensitization of transient receptor potential vanilloid 1 and possibly other proteins involved in heat transduction. The delayed mechanical hyperalgesia is apparently independent of the time required for axonal transport of NGF receptor complexes. Local mRNA translation at axonal terminals and protein accumulation is hypothesized being involved in sustained NGF-evoked hyperalgesia.
    No preview · Article · Oct 2014 · European journal of pain (London, England)

Publication Stats

12k Citations
1,164.40 Total Impact Points


  • 2003-2015
    • Universität Heidelberg
      • • Faculty of Medicine Mannheim and Clinic Mannheim
      • • Department of Intensive Care Medicine
      Heidelburg, Baden-Württemberg, Germany
    • Wake Forest University
      • Department of Dermatology
      Winston-Salem, North Carolina, United States
    • University of Münster
      Muenster, North Rhine-Westphalia, Germany
  • 2006-2012
    • Universität Mannheim
      Mannheim, Baden-Württemberg, Germany
  • 1994-2005
    • Universitätsklinikum Erlangen
      • Department of Dermatology
      Erlangen, Bavaria, Germany
  • 2004
    • CUNY Graduate Center
      New York, New York, United States
  • 1994-2004
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • • Department of Neurology
      • • Department of Physiology and Pathophysiology
      • • Department of Anaesthesiology
      • • Institute of Physics
      Erlangen, Bavaria, Germany
  • 2002
    • Edel&weiss Clinic, Germany, Nuremberg
      Nuremberg, Bavaria, Germany
  • 2001
    • IT University of Copenhagen
      København, Capital Region, Denmark