Herbert Budka

University Hospital Zürich, Zürich, Zurich, Switzerland

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Publications (448)2321.79 Total impact

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    PLoS ONE 04/2015; 10(4):e0123654. DOI:10.1371/journal.pone.0123654 · 3.53 Impact Factor
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    ABSTRACT: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS with severe involvement of the optic nerve and spinal cord. Highly specific serum IgG autoantibodies (NMO-IgG) that react with aquaporin-4 (AQP4), the most abundant CNS water channel protein, are found in patients with NMO. However, in vivo evidence combining the results of AQP4 antibody serum levels and brain pathology is lacking. We report a patient with NMO whose AQP4 antibody levels decreased simultaneously with clinical deterioration caused by the development of a tumor-like brain lesion. In the seminecrotic biopsied brain lesion, there was activated complement complex, whereas only very scattered immunoreactivity to AQP4 protein was detectable. The decrease in serum AQP4 antibody levels and the loss of AQP4 in the tumor-like lesion could represent a "serum antibody-consuming effect" during lesion formation.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
    Journal of Neuropathology and Experimental Neurology 02/2015; 74(3). DOI:10.1097/NEN.0000000000000173 · 4.37 Impact Factor
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    Journal of Neurology Neurosurgery & Psychiatry 01/2015; DOI:10.1136/jnnp-2014-309871 · 5.58 Impact Factor
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    ABSTRACT: Prion infections cause neurodegeneration, which often goes along with oxidative stress. However, the cellular source of reactive oxygen species (ROS) and their pathogenetic significance are unclear. Here we analyzed the contribution of NOX2, a prominent NADPH oxidase, to prion diseases. We found that NOX2 is markedly upregulated in microglia within affected brain regions of patients with Creutzfeldt-Jakob disease (CJD). Similarly, NOX2 expression was upregulated in prion-inoculated mouse brains and in murine cerebellar organotypic cultured slices (COCS). We then removed microglia from COCS using a ganciclovir-dependent lineage ablation strategy. NOX2 became undetectable in ganciclovir-treated COCS, confirming its microglial origin. Upon challenge with prions, NOX2-deficient mice showed delayed onset of motor deficits and a modest, but significant prolongation of survival. Dihydroethidium assays demonstrated a conspicuous ROS burst at the terminal stage of disease in wild-type mice, but not in NOX2-ablated mice. Interestingly, the improved motor performance in NOX2 deficient mice was already measurable at earlier stages of the disease, between 13 and 16 weeks post-inoculation. We conclude that NOX2 is a major source of ROS in prion diseases and can affect prion pathogenesis.
    PLoS Pathogens 12/2014; 10(12):e1004531. DOI:10.1371/journal.ppat.1004531 · 8.14 Impact Factor
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    ABSTRACT: Objective To identify the prevalence of MRI features of Binswanger's disease (BD), specifically MRI with diffuse white matter lesions and scattered multiple lacunes (BD-MRI), and to describe neurological features and pathological outcomes of a community-based cohort study.Methods Of 697 participants (all 75 years old), 503 completed neurological examinations at baseline and were followed-up every 30 months thereafter with MRIs, the mini-mental state examination (MMSE) and the Unified Parkinson Disease Rating Scale-Motor Section (UPDRSM). Data from participants with BD-MRI were compared with those from participants with predominant white matter lesions (WML-MRI), scattered multiple lacunes (ML-MRI), or normal MRIs.ResultsFourteen BD-MRI patients (2.8%) were detected at baseline. The mean MMSE scores in the BD-MRI, WML-MRI, ML-MRI, and normal MRIs groups were 26.4, 28.2, 28.4, and 28.5, respectively, and the mean UPDRSM scores were 9.1, 1.3, 3.1, and 1.7, respectively. At the 30-month follow-up, mortality rates in the normal MRIs, WML-MRI and ML-MRI were 4%, 9.1%, and 22.2%, respectively, and follow-up MRIs were available for 80%, 82%, and 61% of the participants, respectively. In the BD-MRI, however, five patients were deceased, and only five follow-up individual MRIs were available (33.3%). Autopsies were performed on six of eight BD-MRI brains, and these brains fulfilled the pathological criteria for BD independent of Alzheimer disease pathology. All these six individuals also showed systemic atherosclerosis and renal arterio-arteriolosclerosis.InterpretationThe BD-MRI participants had poor prognoses and showed pure BD pathology with advanced systemic vascular disease. BD-MRI appears to be a predictor of vascular neurocognitive impairment.
    10/2014; DOI:10.1002/acn3.123
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    ABSTRACT: Dementia with Lewy bodies (DLB), Parkinson’s disease (PD) and multiple system atrophy are characterized by the deposition of disease-associated α-synuclein. In the present study we 1) examined the molecular specificity of the novel anti-α-synuclein 5G4 antibody; 2) evaluated immunoreactivity patterns and their correlation in human brain tissue with micro- and astrogliosis in 57 cases with PD or DLB; and 3) performed a systematic immunoelectron microscopical mapping of subcellular localizations. 5G4 strongly binds to the high molecular weight fraction of β-sheet rich oligomers, while no binding to primarily disordered oligomers or monomers was observed. We show novel localizations of disease-associated α-synuclein including perivascular macrophages, ependyma and cranial nerves. α-Synuclein immunoreactive neuropil dots and thin threads associate more with glial reaction than Lewy bodies alone. Astrocytic α-synuclein is an important component of the pathology. Furthermore, we document ultrastructurally the pathway of processing of disease-associated α-synuclein within neurons and astroglial cells. Interaction of mitochondria and disease-associated α-synuclein plays a key role in the molecular–structural cytopathogenesis of disorders with Lewy bodies. We conclude that 1) the 5G4 antibody has strong selectivity for β-sheet rich α-synuclein oligomers; 2) Lewy bodies themselves are not the most relevant morphological substrate that evokes tissue lesioning; 3) both neurons and astrocytes internalize disease-associated α-synuclein in the human brain, suggesting prion-like cell-to-cell spread of α-synuclein by uptake from surrounding structures, as shown previously in experimental observations.
    Neurobiology of Disease 09/2014; 69:76–92. DOI:10.1016/j.nbd.2014.05.020 · 5.20 Impact Factor
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    ABSTRACT: Objective We sought to identify the prevalence of MRI features of disproportionately enlarged subarachnoid space hydrocephalus in possible idiopathic normal pressure hydrocephalus (DESH-iNPH) and to describe the clinico-radiological features and outcomes of a community-based investigation (The Vienna Trans-Danube Aging study).Methods Of the 697 inhabitants (all 75 years old), 503 completed extensive neurological examinations at baseline and were followed up every 30 months thereafter with MRIs, mini-mental state examination (MMSE), and the Unified Parkinson Disease Rating Scale-Motor Section (UPDRSM). The DESH-iNPH participant data were compared with the data from participants with Evans index ratios >0.3 (ex vacuo hydrocephalus), cerebral small-vessel diseases, and normal MRIs. The widening of perivascular space was also evaluated by MRI in these groups.ResultsEight participants with DESH-iNPH (1.6%) and 76 with ex vacuo hydrocephalus (16.1%) at baseline were identified. The mean MMSE in DESH-iNPH, ex vacuo hydrocephalus, and normal MRIs was 26.4, 27.9, and 28.3, respectively, and the mean UPDRSM was 9.75, 2.96, and 1.87, respectively. After a 90-month follow-up, the mortality rates for DESH-iNPH, ex vacuo hydrocephalus, and normal MRIs were 25.0%, 21.3%, and 10.9%, respectively. The perivascular-space widening scores were significantly smaller in the DESH-iNPH cases, particularly at the centrum semiovale, compared to cerebral small-vessel disease and ex vacuo hydrocephalus cases.InterpretationThe prevalence of DESH-iNPH was 1.6% for participants aged 75 years and revealed significantly lower MMSE and higher UPDRSM scores compared to the ex vacuo hydrocephalus and controls. Moreover, it is suggested that perivascular-space narrowing is a morphological and pathophysiological marker of DESH-iNPH.
    08/2014; 1(8). DOI:10.1002/acn3.87
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    ABSTRACT: Human prion diseases are a group of rare fatal neurodegenerative conditions with well-developed clinical and neuropathological diagnostic criteria. Recent observations have expanded the spectrum of prion diseases beyond the classically recognized forms. In the present study we report six patients with a novel, apparently sporadic disease characterised by thalamic degeneration and rapidly progressive dementia (duration of illness 2¿12 months; age at death: 55¿81 years). Light and electron microscopic immunostaining for the prion protein (PrP) revealed a peculiar intraneuritic distribution in neocortical regions. Proteinase K resistant PrP (PrPres) was undetectable by Western blotting in frontal cortex from the three cases with frozen tissue, even after enrichment for PrPres by centrifugation or by phosphotungstic acid precipitation. Conformation-dependent immunoassay analysis using a range of PK digestion conditions (and no PK digestion) produced only very limited evidence of meaningful D-N (denatured/native) values, indicative of the presence of disease-associated PrP (PrPSc) in these cases, when the results were compared with appropriate negative control groups. Our observation expands the spectrum of conditions associated with rapidly progressive dementia and may have implications for the understanding of the pathogenesis of prion diseases.
    11/2013; 1(1):72. DOI:10.1186/2051-5960-1-72
  • Journal of the Neurological Sciences 10/2013; 333:e613. DOI:10.1016/j.jns.2013.07.2137 · 2.26 Impact Factor
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    ABSTRACT: Recent studies have highlighted a group of 4-repeat (4R) tauopathies that are characterised neuropathologically by widespread, globular glial inclusions (GGIs). Tau immunohistochemistry reveals 4R immunoreactive globular oligodendroglial and astrocytic inclusions and the latter are predominantly negative for Gallyas silver staining. These cases are associated with a range of clinical presentations, which correlate with the severity and distribution of underlying tau pathology and neurodegeneration. Their heterogeneous clinicopathological features combined with their rarity and under-recognition have led to cases characterised by GGIs being described in the literature using various and redundant terminologies. In this report, a group of neuropathologists form a consensus on the terminology and classification of cases with GGIs. After studying microscopic images from previously reported cases with suspected GGIs (n = 22), this panel of neuropathologists with extensive experience in the diagnosis of neurodegenerative diseases and a documented record of previous experience with at least one case with GGIs, agreed that (1) GGIs were present in all the cases reviewed; (2) the morphology of globular astrocytic inclusions was different to tufted astrocytes and finally that (3) the cases represented a number of different neuropathological subtypes. They also agreed that the different morphological subtypes are likely to be part of a spectrum of a distinct disease entity, for which they recommend that the overarching term globular glial tauopathy (GGT) should be used. Type I cases typically present with frontotemporal dementia, which correlates with the fronto-temporal distribution of pathology. Type II cases are characterised by pyramidal features reflecting motor cortex involvement and corticospinal tract degeneration. Type III cases can present with a combination of frontotemporal dementia and motor neuron disease with fronto-temporal cortex, motor cortex and corticospinal tract being severely affected. Extrapyramidal features can be present in Type II and III cases and significant degeneration of the white matter is a feature of all GGT subtypes. Improved detection and classification will be necessary for the establishment of neuropathological and clinical diagnostic research criteria in the future.
    Acta Neuropathologica 08/2013; DOI:10.1007/s00401-013-1171-0 · 9.78 Impact Factor
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    ABSTRACT: Prospective national screening and surveillance programmes serve a range of public health functions. Objectively determining their adequacy and impact on disease may be problematic for rare disorders. We undertook to assess whether objective measures of disease surveillance intensity could be developed for the rare disorder sporadic Creutzfeldt-Jakob disease (CJD) and whether such measures correlate with disease incidence. From 10 countries with national human prion disease surveillance centres, the annual number of suspected prion disease cases notified to each national unit (n=17 610), referrals for cerebrospinal fluid (CSF) 14-3-3 protein diagnostic testing (n=28 780) and the number of suspect cases undergoing diagnostic neuropathological examination (n=4885) from 1993 to 2006 were collected. Age and survey year adjusted incidence rate ratios with 95% CIs were estimated using Poisson regression models to assess risk factors for sporadic, non-sporadic and all prion disease cases. Age and survey year adjusted analysis showed all three surveillance intensity measures (suspected human prion disease notifications, 14-3-3 protein diagnostic test referrals and neuropathological examinations of suspect cases) significantly predicted the incidence of sporadic CJD, non-sporadic CJD and all prion disease. Routine national surveillance methods adjusted as population rates allow objective determination of surveillance intensity, which correlates positively with reported incidence for human prion disease, especially sporadic CJD, largely independent of national context. The predictive relationship between surveillance intensity and disease incidence should facilitate more rapid delineation of aberrations in disease occurrence and assessment of the adequacy of disease monitoring by national registries.
    Journal of neurology, neurosurgery, and psychiatry 08/2013; 84(12). DOI:10.1136/jnnp-2012-304820 · 5.58 Impact Factor
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    ABSTRACT: Neurodegenerative diseases are characterised by neuronal loss and cerebral deposition of proteins with altered physicochemical properties. The major proteins are amyloid-β (Aβ), tau, α-synuclein, and TDP-43. Although neuropathological studies on elderly individuals have emphasised the importance of mixed pathologies, there have been few observations on the full spectrum of proteinopathies in the ageing brain. During a community-based study we performed comprehensive mapping of neurodegeneration-related proteins and vascular pathology in the brains of 233 individuals (age at death 77-87; 73 examined clinically in detail). While all brains (from individuals with and without dementia) showed some degree of neurofibrillary degeneration, Aβ deposits were observed only in 160 (68.7 %). Further pathologies included α-synucleinopathies (24.9 %), non-Alzheimer tauopathies (23.2 %; including novel forms), TDP-43 proteinopathy (13.3 %), vascular lesions (48.9 %), and others (15.1 %; inflammation, metabolic encephalopathy, and tumours). TDP-43 proteinopathy correlated with hippocampal sclerosis (p < 0.001) and Alzheimer-related pathology (CERAD score and Braak and Braak stages, p = 0.001). The presence of one specific variable (cerebral amyloid angiopathy, Aβ parenchymal deposits, TDP-43 proteinopathy, α-synucleinopathy, vascular lesions, non-Alzheimer type tauopathy) did not increase the probability of the co-occurrence of others (p = 0.24). The number of observed pathologies correlated with AD-neuropathologic change (p < 0.0001). In addition to AD-neuropathologic change, tauopathies associated well with dementia, while TDP-43 pathology and α-synucleinopathy showed strong effects but lost significance when evaluated together with AD-neuropathologic change. Non-AD neurodegenerative pathologies and their combinations have been underestimated, but are frequent in reality as demonstrated here. This should be considered in diagnostic evaluation of biomarkers, and for better clinical stratification of patients.
    Acta Neuropathologica 07/2013; DOI:10.1007/s00401-013-1157-y · 9.78 Impact Factor
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    ABSTRACT: Presenile dementia may be caused by a variety of different genetic conditions such as familial Alzheimer's disease, prion disease as well as several hereditary metabolic disorders including adult onset neuronal ceroid lipofuscinosis. We report a multigenerational family with autosomal dominant presenile dementia harboring a cerebellar phenotype. Longitudinal clinical work-up in affected family members revealed ataxia accompanied by progressive cognitive decline, rapid loss of global cognition, memory, visuospatial and frontal-executive functions accompanied by progressive motor deterioration and early death. Linkage analysis and exome sequencing identified the p.S170F mutation of Presenilin 1 in all affected individuals, which is known to be associated with very early onset Alzheimer's disease. Additional search for potentially modifying variants revealed in all affected individuals of the third generation a paternally inherited variant p.A58V (rs17571) of Cathepsin D which is considered an independent risk factor for Alzheimer's disease. Involvement of cerebellar and brainstem structures leading to functional decortication in addition to rapid progressive presenile dementia in this PSEN1 family may therefore indicate an epistatic effect of the p.A58V Cathepsin D variant on the deleterious course of this disease.
    Journal of the neurological sciences 03/2013; 326(1-2):75-82. DOI:10.1016/j.jns.2013.01.017 · 2.26 Impact Factor
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    ABSTRACT: Muscle repair relies on coordinated activation and differentiation of satellite cells, a process that is unable to counterbalance progressive degeneration in sporadic inclusion body myositis (s-IBM). To explore features of myo regeneration, the expression of myogenic regulatory factors Pax7, MyoD and Myogenin and markers of regenerating fibers was analyzed by immunohistochemistry in s-IBM muscle compared with polymyositis, dermatomyositis, muscular dystrophy and age-matched controls. In addition, the capillary density and number of interstitial CD34(+) hematopoietic progenitor cells was determined by double-immunoflourescence staining. Satellite cells and regenerating fibers were significantly increased in s-IBM similar to other inflammatory myopathies and correlated with the intensity of inflammation (R>0.428). Expression of MyoD, visualizing activated satellite cells and proliferating myoblasts, was lower in s-IBM compared to polymyosits. In contrast, Myogenin a marker of myogenic cell differentiation was strongly up-regulated in s-IBM muscle. The microvascular architecture in s-IBM was distorted, although the capillary density was normal. Notably, CD34(+) hematopoietic cells were significantly increased in the interstitial compartment. Our findings indicate profound myo-endothelial remodeling of s-IBM muscle concomitant to inflammation. An altered expression of myogenic regulatory factors involved in satellite cell activation and differentiation, however, might reflect perturbations of muscle repair in s-IBM.
    Neuromuscular Disorders 10/2012; 23(1). DOI:10.1016/j.nmd.2012.09.003 · 3.13 Impact Factor
  • Ellen Gelpi, Herbert Budka, Matthias Preusser
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    ABSTRACT: Introduction: The external granular layer (EGL) of the developing human cerebellum is detectable until an age of ~ 1 year. It has been described as a thin, evenly calibrated layer of germinal cells. We have repeatedly observed a distinct discontinuous bobbled configuration of the EGL (external granular layer bobbling = EGLB) in human infantile autopsy brains. Aim, materials and methods: We investigated 106 human fetal and infantile postmortem brains (range of gestational week at birth: 14 - term; range of postpartal age: 0 - 500 days) for presence of EGLB and correlated it with gestational/postpartal age, gender, developmental stage of cerebellar cortex, medical history and neuropathological findings. Results: EGLB was detectable in 38/106 (35.8%) cases. EGLB presents as focal series of uniform knob-like protrusions of the EGL. In the notches between individual knobs, capillaries penetrate from the primitive leptomeningeal vascular plexus into the molecular layer. We found EGLB predominantly in depths of fissures of cerebellar hemispheres, vermis and/or tonsils. Presence of EGLB was statistically significantly more common in liveborn cases who died after gestational week 25 and cases with higher maturity grade of the cerebellar cortex, respectively. There was no gender difference. EGLB was not associated with medical history or neuropathological findings. Conclusions: EGLB is a distinct histomorphological feature of the developing cerebellum, which is predominantly found in infants. Our data indicate that EGLB is a physiological phenomenon occuring during cerebellar development at a certain gestational age, although we cannot exclude that it represents an artifact related to tissue fixation. In any case, recognition of this recurring feature is relevant for the practicing neuropathologist and should not be interpreted as a cerebellar migration disorder.
    Clinical neuropathology 09/2012; 32(01). DOI:10.5414/NP300518 · 1.31 Impact Factor
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    ABSTRACT: Transmission of prions to a new host is frequently accompanied by strain adaptation, a phenomenon that involves reduction of the incubation period, a change in neuropathological features and, sometimes, tissue tropism. Here we show that a strain of synthetic origin (SSLOW), although serially transmitted within the same species, displayed the key attributes of the strain adaptation process. At least four serial passages were required to stabilize the strain-specific SSLOW phenotype. The biological titration of SSLOW revealed a correlation between clinical signs and accumulation of PrP(Sc) in brains of animals inoculated with high doses (10(-1)-10(-5) diluted brain material), but dissociation between the two processes at low dose inocula (10(-6)-10(-8) diluted brain material). At low doses, several asymptomatic animals harbored large amounts of PrP(Sc) comparable with those seen in the brains of terminally ill animals, whereas one clinically ill animal had very little, if any, PrP(Sc). In summary, the current study illustrates that the phenomenon of prion strain adaptation is more common than generally thought and could be observed upon serial transmission without changing the host species. When PrP(Sc) is seeded by recombinant PrP structures different from that of authentic PrP(Sc), PrP(Sc) properties continued to evolve for as long as four serial passages.
    Journal of Biological Chemistry 07/2012; 287(36):30205-14. DOI:10.1074/jbc.M112.392985 · 4.60 Impact Factor
  • Alzheimer's and Dementia 07/2012; 8(4):P173. DOI:10.1016/j.jalz.2012.05.467 · 17.47 Impact Factor

Publication Stats

12k Citations
2,321.79 Total Impact Points

Institutions

  • 2013–2015
    • University Hospital Zürich
      Zürich, Zurich, Switzerland
    • University of Melbourne
      • Department of Pathology
      Melbourne, Victoria, Australia
  • 2004–2015
    • Medical University of Vienna
      • Clinical Department of Virology
      Wien, Vienna, Austria
  • 2014
    • University of Zurich
      • Institut für Neuropathologie
      Zürich, Zurich, Switzerland
  • 2010–2014
    • IST Austria
      Klosterneuberg, Lower Austria, Austria
  • 2006–2013
    • University College London
      • • Department of Molecular Neuroscience
      • • Institute of Neurology
      London, ENG, United Kingdom
    • Ludwig-Maximilians-University of Munich
      München, Bavaria, Germany
  • 2012
    • University of Maryland, Baltimore
      • Department of Anatomy and Neurobiology
      Baltimore, Maryland, United States
  • 2009
    • Boston University
      Boston, Massachusetts, United States
  • 1976–2009
    • University of Vienna
      • • Institute of Neurophysiology
      • • Institute of Clinical Neurobiology
      Vienna, Vienna, Austria
  • 2008
    • University of Kuopio
      Kuopio, Eastern Finland Province, Finland
  • 2007
    • University of Cologne
      Köln, North Rhine-Westphalia, Germany
    • Hospital Universitari de Bellvitge
      l'Hospitalet de Llobregat, Catalonia, Spain
    • Hadassah Medical Center
      • Department of Neurology
      Jerusalem, Jerusalem District, Israel
    • Friedrich Loeffler Institute
      Griefswald, Mecklenburg-Vorpommern, Germany
  • 1995–2007
    • Institute of Neurology
      Moskva, Moscow, Russia
  • 2004–2006
    • Vienna General Hospital
      Wien, Vienna, Austria
  • 1997–2006
    • Kyoto University
      • Department of Neurology
      Kyoto, Kyoto-fu, Japan
    • University of Veterinary Medicine in Vienna
      • Institute of Pathology and Forensic Veterinary Medicine
      Wien, Vienna, Austria
  • 2005
    • University of Lodz
      Łódź, Łódź Voivodeship, Poland
  • 2003
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 2002
    • Krankenhaus der Barmherzige Schwestern
      Linz, Upper Austria, Austria
  • 2001
    • University of Innsbruck
      Innsbruck, Tyrol, Austria
  • 1999
    • Robert Koch Institut
      Berlín, Berlin, Germany
  • 1994–1997
    • Markusovszky University Teaching Hospital, Szombathely
      Olad, Vas, Hungary
  • 1993
    • Barrow Neurological Institute
      Phoenix, Arizona, United States
  • 1990
    • University of Milan
      Milano, Lombardy, Italy
  • 1985
    • TNO
      Delft, South Holland, Netherlands