B Heppelmann

University of Wuerzburg, Würzburg, Bavaria, Germany

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Publications (53)140.46 Total impact

  • Bernd Heppelmann, Jason J McDougall
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    ABSTRACT: Synovial joints are complex sensory organs which provide continuous feedback regarding position sense and degree of limb movement. The transduction mechanisms which convert mechanical forces acting on the joint into an electrochemical signal which can then be transmitted to the central nervous system are not well understood. The present investigation examined the effect of the mechanogated ion channel blockers amiloride and gadolinium on knee joint mechanosensitivity. In deeply anaesthetised rats (sodium thiopental: 100-120 mg/kg, i.p.), single unit extracellular recordings were made from knee joint group III (Adelta) and group IV (C) primary afferents in response to mechanical rotation of the joint. Afferent firing rate was measured before and after topical application of either amiloride (0.1 mM, 1 mM) or gadolinium (250 microM) onto the receptive field of the sensory unit and recording was continued every 10 min up to a total of 50 min. With normal rotation of the knee, joint mechanosensitivity was significantly reduced by both amiloride (P<0.0001; n=10-21) and gadolinium (P=0.001; n=12) and this effect was sustained throughout the recording period. This investigation provides the first in vivo electrophysiological evidence that joint mechanotransduction involves the activation of amiloride and gadolinium-sensitive mechanogated ion channels. Future studies to determine the mechanogated ion channel subtypes present in joints and the modulation of their gating properties during inflammation may yield novel approaches for the control of arthritis pain.
    Experimental Brain Research 11/2005; 167(1):114-8. · 2.22 Impact Factor
  • Stefan Just, Bernd Heppelmann
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    ABSTRACT: Voltage-gated Ca(2+) channels play an important role in the central processing of nociceptive information. Recently, it has been shown that L- and N-type voltage-gated Ca(2+) channels are also present on peptidergic, fine afferent nerve fibers in the knee joint capsule. Therefore, the influence of specific blockers for L-type (verapamil) or N-type (omega-conotoxin GVIA) Ca(2+) channels on the mechanosensitivity of slowly conducting afferents was tested in the rat knee joint. Topical application of 100 microM verapamil onto the receptive field reduced the mean response to knee joint rotation to 67+/-8% (SEM, n=12), obtained by outward rotations with a torque of 10 mNm above the mechanical threshold and compared with control movements. In the presence of 50 microM omega-conotoxin GVIA, the mean response decreased to 44+/-5% ( n=12), a reduction that was also observed during rotations of other intensities. Simultaneous application of both substances further reduced the response to 25+/-11% ( n=6). In additional experiments it was shown that L- and N-type voltage-gated Ca(2+) channels do not influence activity-dependent changes of the mechanical excitability. In conclusion, the data of the present study indicate that voltage-gated Ca(2+) channels may also be involved in the regulation of the mechanosensitivity of nociceptive nerve fiber endings.
    Experimental Brain Research 07/2003; 150(3):379-84. · 2.22 Impact Factor
  • S Just, B Heppelmann
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    ABSTRACT: The aim of the present study was to examine the effect of electrical saphenous nerve stimulation (14 V, 1-10 Hz) on the mechanosensitivity of rat knee joint afferents. The responses to passive joint rotations at defined torque were recorded from slowly conducting knee joint afferent nerve fibres (0.6-20.0 m/s). After repeated nerve stimulation with 1 Hz, the mechanosensitivity of about 79% of the units was significantly affected. The effects were most prominent at a torque close to the mechanical threshold. In about 46% of the examined nerve fibres a significant increase was obtained, whereas about 33% reduced their mechanosensitivity. The sensitisation was prevented by an application of 5 microM phentolamine, an alpha-adrenergic receptor blocker, together with a neuropeptide Y receptor blocker. An inhibition of N-type Ca(2+) channels by an application of 1 microM omega-conotoxin GVIA caused comparable changes of the mechanosensitivity during the electrical stimulation. Electrical nerve stimulation with higher frequencies resulted in a further reduction of the mean response to joint rotations. After stimulation with 10 Hz, there was a nearly complete loss of mechanosensitivity.In conclusion, antidromic electrical nerve stimulation leads to a frequency dependent transient decrease of the mechanosensitivity. A sensitisation was only obtained at 1 Hz, but this effect may be based on the influence of sympathetic nerve fibres.
    Neuroscience 02/2002; 112(4):783-9. · 3.12 Impact Factor
  • Bernd Heppelmann
    Pharmazie in unserer Zeit 02/2002; 31(1):96-100.
  • International Review of Neurobiology 02/2002; 47:173-201. · 1.65 Impact Factor
  • B Heppelmann, M Pawlak, S Just, R F Schmidt
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    ABSTRACT: In recent years the rat knee joint has become an important model for the study of nociception of deep tissues. In contrast to the cortical processing of superficial pain, the knowledge about the processing of deep pain evoked by noxious stimuli in tissues such as tendons, bone, and joint is sparse. To obtain a basis for further functional studies, the projections of the knee joint in the cerebral cortex were determined. Cortical surface potentials evoked by electrical stimulation of the posterior articular nerve were recorded by a platinum ball electrode. Evoked activity was found in the primary somatosensory area SI in an area of about 3 x 3 mm on the contralateral side. Its center was located about 3 mm caudal to the bregma and about 3 mm lateral to the superior sagittal sinus. A small projection in SII was found on the lateral side of the cortex about 6 mm lateral from SI. This area had a size of about 1 x 1 mm, and the amplitudes of the potentials were smaller but had similar latencies to those in SI. An additional projection with small potentials and longer latencies was observed in SI on the ipsilateral side. Cooling of the contralateral SI revealed deprivation of the ipsilateral evoked potentials in SI whereas the potentials in SII remained unchanged. These data indicate that information from the knee joint is processed in parallel in SI and SII on the contralateral side and that there is an additional serial processing in SI on the ipsilateral side.
    Experimental Brain Research 01/2002; 141(4):501-6. · 2.22 Impact Factor
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    ABSTRACT: Sensory endings that respond to local cooling were identified electrophysiologically in the cat's sclera. Functionally identified scleral thermal fibers were then used to analyze the structural characteristics of cold receptor endings. Four Adelta units sensitive to controlled cooling of their scleral receptive fields were recorded. The receptive areas were mapped, demarcated with pins and examined electron microscopically using extensive three-dimensional reconstructions. The supporting tissue within the receptive areas of cold units consisted of dense collageneous tissue with a small number of blood vessels that were either veins or capillaries. Adelta nerve fibers were found within these tissue blocks presumably corresponding with cold sensitive fibers. Small nerves and single nerve fibers devoid of a perineurium were found in all parts of the tissue, only occasionally passing a blood vessel. The terminal portions showed axonal swellings all along the unmyelinated segment filled with mitochondria, glycogen particles, and some vesicles. About 30% of the terminal axonal membrane is not covered by Schwann cells. In the unmyelinated distal portion, the mitochondrial content ranged from 0.012 to 0.038 microm(3) mitochondrial volume per microm(2) nerve fiber membrane. In comparison with sensory endings in the cat's knee joint, cold receptors in the cat sclera showed many similarities in their three-dimensional structure with polymodal nociceptor endings of the knee joint but contain less mitochondria. This suggests that cold sensory endings do not require specialized cellular processes for the transduction of cold stimuli, as is the case for multimodal transduction and sensitization in the terminal portion of polymodal nociceptors.
    The Journal of Comparative Neurology 01/2002; 441(2):148-54. · 3.66 Impact Factor
  • Bernd Heppelmann
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    ABSTRACT: Vergleichbar mit den Verhältnissen im peripheren Gewebe, wo eine Vielzahl an Substanzen die Erregbarkeit von Nozizeptoren beeinflusst, sind auch im Rückenmark verschiedene Transmitter, Peptide und Rezeptoren an der Verarbeitung nozizeptiver Informationen beteiligt. Für die spinale Analgesie beim Menschen können inzwischen einige spezifische Agonisten bzw. Antagonisten eingesetzt werden. Da bestimmte Transmitter und Neuropeptide nicht nur bei der Nozizeption sondern auch bei verschiedenen anderen physiologischen Vorgängen eine Rolle spielen, sind entsprechende Nebenwirkungen unausweichlich. Eine Möglichkeit, diese zu reduzieren oder sogar zu verhindern, könnte darin bestehen, mehrere Pharmaka mit einer jeweils geringeren Konzentration zu kombinieren und somit eine multimodale Analgesie einzusetzen.
    Pharmazie in unserer Zeit 01/2002; 31(1):96-100.
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    ABSTRACT: Sensory endings that respond to local cooling were identified electrophysiologically in the cat's sclera. Functionally identified scleral thermal fibers were then used to analyze the structural characteristics of cold receptor endings. Four Aδ units sensitive to controlled cooling of their scleral receptive fields were recorded. The receptive areas were mapped, demarcated with pins and examined electron microscopically using extensive three-dimensional reconstructions. The supporting tissue within the receptive areas of cold units consisted of dense collageneous tissue with a small number of blood vessels that were either veins or capillaries. Aδ nerve fibers were found within these tissue blocks presumably corresponding with cold sensitive fibers. Small nerves and single nerve fibers devoid of a perineurium were found in all parts of the tissue, only occasionally passing a blood vessel. The terminal portions showed axonal swellings all along the unmyelinated segment filled with mitochondria, glycogen particles, and some vesicles. About 30% of the terminal axonal membrane is not covered by Schwann cells. In the unmyelinated distal portion, the mitochondrial content ranged from 0.012 to 0.038 μm3 mitochondrial volume per μm2 nerve fiber membrane. In comparison with sensory endings in the cat's knee joint, cold receptors in the cat sclera showed many similarities in their three-dimensional structure with polymodal nociceptor endings of the knee joint but contain less mitochondria. This suggests that cold sensory endings do not require specialized cellular processes for the transduction of cold stimuli, as is the case for multimodal transduction and sensitization in the terminal portion of polymodal nociceptors. J. Comp. Neurol. 441:148–154, 2001. © 2001 Wiley-Liss, Inc.
    The Journal of Comparative Neurology 12/2001; 441(2):148 - 154. · 3.66 Impact Factor
  • Source
    B. Heppelmann, M. Pawlak, S. Just, R. Schmidt
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    ABSTRACT: In recent years the rat knee joint has become an important model for the study of nociception of deep tissues. In contrast to the cortical processing of superficial pain, the knowledge about the processing of deep pain evoked by noxious stimuli in tissues such as tendons, bone, and joint is sparse. To obtain a basis for further functional studies, the projections of the knee joint in the cerebral cortex were determined. Cortical surface potentials evoked by electrical stimulation of the posterior articular nerve were recorded by a platinum ball electrode. Evoked activity was found in the primary somatosensory area SI in an area of about 3×3mm on the contralateral side. Its center was located about 3mm caudal to the bregma and about 3mm lateral to the superior sagittal sinus. A small projection in SII was found on the lateral side of the cortex about 6mm lateral from SI. This area had a size of about 1×1mm, and the amplitudes of the potentials were smaller but had similar latencies to those in SI. An additional projection with small potentials and longer latencies was observed in SI on the ipsilateral side. Cooling of the contralateral SI revealed deprivation of the ipsilateral evoked potentials in SI whereas the potentials in SII remained unchanged. These data indicate that information from the knee joint is processed in parallel in SI and SII on the contralateral side and that there is an additional serial processing in SI on the ipsilateral side.
    Experimental Brain Research 11/2001; 141(4):501-506. · 2.22 Impact Factor
  • S Just, C Leipold-Büttner, B Heppelmann
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    ABSTRACT: The afferent (excitability) and efferent functions (release of neuropeptides) of primary afferent nerve fibres are based on Ca(2+)-influx. The aim of the present study was to examine the presence of L- and N-type Ca(2+)-channels at sensory nerve fibres in the mouse knee joint capsule. Specific fluorescent labelled channel blockers and antisera against these channel subtypes were combined with an immunohistochemical staining for calcitonin gene-related peptide (CGRP), a neuropeptide that is widely distributed in primary afferents. There was a nearly complete colocalisation of CGRP immunoreactivity and the binding of omega-conotoxin GVIA (toxin VIA of Conus geographus or BODIPY-verapamil (BODIPY(R) FL verapamil, hydrochloride) demonstrating the presence of N-type and L-type Ca(2+)-channels, respectively. These data were further confirmed by identical results obtained after an immunohistochemical demonstration of the two channel subtypes at the peptidergic nerve fibres.
    Neuroscience Letters 11/2001; 312(3):133-6. · 2.03 Impact Factor
  • M Pawlak, R F Schmidt, B Heppelmann, U Hanesch
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    ABSTRACT: The inflammatory mediator substance P (SP) produces a variety of biological effects in several tissues by binding to the tachykinin receptor neurokinin 1 (NK1) and, to a lesser extent, by binding to the neurokinin 2 receptor (NK2). To assess the sensitizing effect of SP on articular afferent fibres the NK1receptor antagonist RP 67580 was applied in normal and acutely inflamed rat knee joints. Altogether 38 fine afferent nerve fibres from the rat knee with conduction velocities of 0.71-13.5 m/s were recorded as single units, during non-noxious and noxious joint rotations. SP, injected i.a. as a bolus close to the knee joint, was able to sensitize 45.5% (10 of 22) of the units recorded from normal joints and 33.3% (five of 15) of afferents from inflamed joints. The following i.a. application of RP 67580 in a range of 20-200 nmol antagonized in a dose-dependent manner the sensitizing effect of SP in a large proportion of slowly conducting articular afferents from normal (66.7%) and inflamed (46.2%) knee joints. Subsequent SP application enhanced the afferent sensitivity further. The electrophysiological results presented here further support the suggestion that the sensitization of afferents by SP in the rat knee joint is mediated mainly by the NK1 receptor, which is probably located on the primary afferents.
    European Journal of Pain 02/2001; 5(1):69-79. · 3.07 Impact Factor
  • M Ebinger, R F Schmidt, B Heppelmann
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    ABSTRACT: The number and the distribution of fiber size in the medial (MAN) and posterior (PAN) articular nerves of the mouse knee joint were studied by electron microscopy. The MAN contained 75 +/- 28 nerve fibers consisting of 63 +/- 24 unmyelinated and 12 +/- 6 myelinated fibers. The PAN was composed of 195 +/- 50 nerve fibers, namely 129 +/- 28 unmyelinated and 66 +/- 24 myelinated fibers. A skewed unimodal distribution of the unmyelinated nerve fiber diameters was seen in both nerves ranging from 0.1 to 1.2 microm with a maximum between 0.3 and 0.6 microm. The myelinated nerve fibers in the MAN ranged from 1 to 8 microm with a peak between 2 and 5 microm. In the PAN, their diameters ranged from 1 to 12 microm with a clearly visible peak at 4-5 microm and a plateau at 8-9 microm that may represent a second maximum. These data show that the knee joint innervation of the mouse is comparable to those of the cat and rat concerning the types of nerve fibers and the composition of the two nerves. However, in relation to the much smaller area of tissue to be innervated the total number of primary afferents is considerable smaller in the mouse.
    Somatosensory and Motor Research 02/2001; 18(1):62-5. · 0.93 Impact Factor
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    Stefan Just, Bernd Heppelmann
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    ABSTRACT: The aim of the present study was to examine the effects of the sympathetic co-transmitter Neuropeotide Y on primary afferent nerve fibres of the rat knee joint. The responses to passive joint rotations at defined torque were recorded from 41 slowly conducting afferent nerve fibres (0.9 – 18.8 m s−1) innervating the knee joint capsule.About 70% of the joint afferents were significantly affected in their mechanosensitivity by topical application of Neuropeptide Y. Significant effects occurred at a concentration of 10 nM.Decreased mechanosensitivity was observed in about 40% of nerve fibres, whereas 30% of the units increased the mechanosensitivity. In addition, in about 35% of the fibres resting activity was induced or increased. Neither the conduction velocity nor the mechanical threshold of the units correlated with the described effects of Neuropeptide Y.NPY(13 – 36), a specific Y2-receptor agonist, only modulated the mechanosensitivity, with no effect on the resting activity. The effects on the mechanosensitivity were similar to Neuropeptide Y, i.e. increase and decrease of the response.Studies with the Y1-agonist (Leu31, Pro34)-NPY showed that activation of the Y1-receptor predominantly resulted in an enhanced mechanosensitivity and an induction or increase of a resting activity. The opposite effect was observed by application of BIBP 3226 BS, a Y1-receptor antagonist.In conclusion, these data indicate that Neuropeptide Y affects the excitability of sensory nerve fibre endings.British Journal of Pharmacology (2001) 132, 703–708; doi:10.1038/sj.bjp.0703871
    British Journal of Pharmacology 01/2001; 132(3):703 - 708. · 5.07 Impact Factor
  • S Just, M Pawlak, B Heppelmann
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    ABSTRACT: In total 23 rat knee joint afferent units with conduction velocities of 1.2-17 m/s were recorded extracellularly during inward and outward joint rotations of defined torque using a newly developed torque-meter. There was not a linear relation between the torque and the obtained angle of the joint. The mechanical thresholds of the units ranged from 10 to 60 mNm. During 10 s of stimulation with 60 mNm they responded with 12-300 action potentials. Two mechanosensitive nerve fibres could not be activated via knee joint rotation at any torque at all. The units could be classified according to their response pattern during stimulation: (1) phasic-tonic response behaviour; (2) constant discharge rate; (3) delayed onset of activity. In conclusion, the novel torque-meter allows a precise characterisation of the mechanical threshold and the corresponding response of fine afferent joint units during knee joint rotation.
    Journal of Neuroscience Methods 12/2000; 103(2):157-62. · 2.11 Impact Factor
  • B Heppelmann, S Just, M Pawlak
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    ABSTRACT: The aim of the present study was to examine the effect of galanin on group III and IV afferent nerve fibres (n = 53) innervating normal and acutely inflamed knee joints in rats. They responded to local mechanical stimulation, movements of the joint and i.a. injections of KCl close to the joint. Single i.a. bolus injections of galanin (0.1 mM, 0.2 mL) caused no direct responses of the units. In normal and acutely inflamed joints, about half of the units did not change the responses to knee joint rotation. A significant reduction of the responses to noxious movements was found in approximately 40% of the units reaching a mean value of 57% in normal joints and 70% in inflamed joints compared with control movements. In approximately 10% the responses increased to 143% in normal joints and 120% in inflamed joints. Injection of a galanin receptor antagonist (M35) doubled the responses to noxious movements in 36% of the units in normal joints and reduced it in 18% to 86% of the control movements, indicating a tonic release and influence on the mechanosensitivity of a proportion of primary afferents by galanin. In conclusion, these data further support the hypothesis that the mechanosensitivity of fine afferent nerve fibres is regulated by a mixture of different substances being released into the innervated tissue. Besides the action of several pro-inflammatory peptides there seems to exist a tonic inhibitory system.
    European Journal of Neuroscience 06/2000; 12(5):1567-72. · 3.75 Impact Factor
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    ABSTRACT: Recently we presented a method to label the neuropeptide substance P with a 1.4-nm gold particle covalently bound at the N-terminus that can be used for demonstrating its binding sites in histological sections. In this study we examined whether the peptides neuropeptide Y, somatostatin, calcitonin gene-related peptide and bradykinin can be labelled in the same way. Polyacrylamide gel electrophoresis revealed a reduction in mobility for peptide-gold conjugates over gold particles alone consistent with peptide binding. In cryostat sections of the rat lumbar spinal cord, the peptides showed a distinct binding pattern in the grey matter corresponding to data of studies using autoradiographic methods. Therefore, we conclude that this simple and fast method can be used for labelling peptides in general to demonstrate their binding sites in histological sections, provided the peptide binds by its C-terminus.
    Journal of Neuroscience Methods 04/1999; 87(2):195-200. · 2.11 Impact Factor
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    ABSTRACT: Using gold-labelled somatostatin, somatostatin binding sites were predominantly found in laminae I-III, X and on motorneurones of the rat lumbar spinal cord. A comparison with immunohistochemical staining using antisera against somatostatin receptor sequences revealed that the marked binding in laminae I-III coincided with the presence of somatostatin receptor-like immunoreactivity for the receptor subtypes 1, 2 and 3. Binding sites on motorneurones were only paralleled by an immunoreaction for subtype 3. In lamina X, however, the lack of a positive immunoreaction indicates that in this part other subtypes may be present.
    Brain Research 02/1999; 816(1):254-7. · 2.88 Impact Factor
  • B Heppelmann, M Pawlak
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    ABSTRACT: Recently it has been shown that neuropeptides may be involved in the regulation of the mechanosensitivity of fine afferent nerve fibres. Somatostatin seems to provide a tonic inhibition of the sensitivity of sensory endings in normal tissue. In the present study cyclo-somatostatin, a somatostatin antagonist, was used to test this hypothesis. In a normal joint, 50% (8/16) of the examined primary afferents significantly increased their responses to noxious joint movements after the cyclo-somatostatin application. In an acutely inflamed joint, however, only 9% (1/11) of the nerve fibres significantly increased the response to noxious movements. These data further support the hypothesis that the mechanosensitivity of articular afferents in a normal joint is also regulated by a balance of pro-inflammatory peptides and anti-inflammatory peptides such as somatostatin. In an inflamed joint, pro-inflammatory peptides predominate and together with other mediators, they may be involved in the sensitization of the peripheral nerve fibres.
    Neuroscience Letters 02/1999; 259(1):62-4. · 2.03 Impact Factor
  • F Gohlke, E Janssen, J Leidel, B Heppelmann, J Eulert
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    ABSTRACT: Purpose of this study was the evaluation of distribution and morphology of mechanoreceptors in the glenohumeral joint capsule and rotator cuff in comparison to the coracoacromial ligament by means of specific immunfluorescence microscopy. The complemente joint capsules, rotator cuffs and coracoacromial ligaments of three fresh cadaver shoulder were harvesed. Serial cryostate sections were taken and alternately incubated with antiserum against neurofilament, lamin or myelin of peripheral nerves. The antibody-reaction was visualized with fluorescin lg-G. The nerve endings were photographed and computer-aided 3-dimensional reconstructions were performed. Three types of corpuscular and free nerve endings of different morphology were found in different distributions: whereas the Ruffini corpuscles were much more frequent in the coracoacromial ligament and rotator cuff, Pacini endings were predominantly found in the joint capsule. Generally corpuscular nerve endings were more frequent in the coracoacromial ligament and the rotator cuff than in the antero-inferior capsule and the number of corpuscles increased from medial to lateral within the anterior and inferior parts of the capsule. The dense ligamentous tissue was almost aneural whereas the periarticular fatty or loose connective tissue contained nerve fibres and nerve endings. In view of the results of other experimental and clinical studies the high frequency of Ruffini and Pacini endings in the rotator cuff and coracoacromial ligament suggest, that both are involved in the neurosensory control of glenohumeral stability and subacromial impingement. In contrast our findings in the joint capsule do not clearly prove, that those joint receptors predominantly maintain joint stability.
    Der Orthopäde 09/1998; 27(8):510-7. · 0.51 Impact Factor

Publication Stats

855 Citations
140.46 Total Impact Points

Institutions

  • 1988–2005
    • University of Wuerzburg
      • Institute for Physiology
      Würzburg, Bavaria, Germany
    • Barrow Neurological Institute
      • Division of Neurobiology
      Phoenix, AZ, United States
  • 2002
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 1999
    • Universitätsklinikum Jena
      Jena, Thuringia, Germany
  • 1994
    • Babraham Institute
      Cambridge, England, United Kingdom