@article{KarlNandiniColacoSchulteetal.2019, author = {Karl, Franziska and Nandini Cola{\c{c}}o, Maria B. and Schulte, Annemarie and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Affective and cognitive behavior is not altered by chronic constriction injury in B7-H1 deficient and wildtype mice}, series = {BMC Neuroscience}, volume = {20}, journal = {BMC Neuroscience}, doi = {10.1186/s12868-019-0498-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200540}, pages = {16}, year = {2019}, abstract = {Background Chronic neuropathic pain is often associated with anxiety, depressive symptoms, and cognitive impairment with relevant impact on patients` health related quality of life. To investigate the influence of a pro-inflammatory phenotype on affective and cognitive behavior under neuropathic pain conditions, we assessed mice deficient of the B7 homolog 1 (B7-H1), a major inhibitor of inflammatory response. Results Adult B7-H1 ko mice and wildtype littermates (WT) received a chronic constriction injury (CCI) of the sciatic nerve, and we assessed mechanical and thermal sensitivity at selected time points. Both genotypes developed mechanical (p < 0.001) and heat hypersensitivity (p < 0.01) 7, 14, and 20 days after surgery. We performed three tests for anxiety-like behavior: the light-dark box, the elevated plus maze, and the open field. As supported by the results of these tests for anxiety-like behavior, no relevant differences were found between genotypes after CCI. Depression-like behavior was assessed using the forced swim test. Also, CCI had no effect on depression like behavior. For cognitive behavior, we applied the Morris water maze for spatial learning and memory and the novel object recognition test for object recognition, long-, and short-term memory. Learning and memory did not differ in B7-H1 ko and WT mice after CCI. Conclusions Our study reveals that the impact of B7-H1 on affective-, depression-like- and learning-behavior, and memory performance might play a subordinate role in mice after nerve lesion.}, language = {en} } @phdthesis{RamirezPasos2019, author = {Ramirez Pasos, Uri Eduardo}, title = {Subthalamic Nucleus Neural Synchronization and Connectivity during Limbic Processing of Emotional Pictures: Evidence from Invasive Recordings in Patients with Parkinson's Disease}, doi = {10.25972/OPUS-16985}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169850}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {In addition to bradykinesia and tremor, patients with Parkinson's disease (PD) are known to exhibit non-motor symptoms such as apathy and hypomimia but also impulsivity in response to dopaminergic replacement therapy. Moreover, a plethora of studies observe differences in electrocortical and autonomic responses to both visual and acoustic affective stimuli in PD subjects compared to healthy controls. This suggests that the basal ganglia (BG), as well as the hyperdirect pathway and BG thalamocortical circuits, are involved in affective processing. Recent studies have shown valence and dopamine-dependent changes in synchronization in the subthalamic nucleus (STN) in PD patients during affective tasks. This thesis investigates the role of dopamine, valence, and laterality in STN electrophysiology by analyzing event-related potentials (ERP), synchronization, and inter-hemispheric STN connectivity. STN recordings were obtained from PD patients with chronically implanted electrodes for deep brain stimulation during a passive affective picture presentation task. The STN exhibited valence-dependent ERP latencies and lateralized 'high beta' (28-40 Hz) event-related desynchronization. This thesis also examines the role of dopamine, valence, and laterality on STN functional connectivity with the anterior cingulate cortex (ACC) and the amygdala. The activity of these limbic structures was reconstructed using simultaneously recorded electroencephalographic signals. While the STN was found to establish early coupling with both structures, STN-ACC coupling in the 'alpha' range (7-11 Hz) and uncoupling in the 'low beta' range (14-21 Hz) were lateralized. Lateralization was also observed at the level of synchrony in both reconstructed sources and for ACC ERP amplitude, whereas dopamine modulated ERP latency in the amygdala. These results may deepen our current understanding of the STN as a limbic node within larger emotional-motor networks in the brain.
}, subject = {Nucleus subthalamicus}, language = {en} } @article{DopplerSchusterAppeltshauseretal.2019, author = {Doppler, Kathrin and Schuster, Yasmin and Appeltshauser, Luise and Biko, Lydia and Villmann, Carmen and Weishaupt, Andreas and Werner, Christian and Sommer, Claudia}, title = {Anti-CNTN1 IgG3 induces acute conduction block and motor deficits in a passive transfer rat model}, series = {Journal of Neuroinflammation}, volume = {16}, journal = {Journal of Neuroinflammation}, number = {73}, doi = {10.1186/s12974-019-1462-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200476}, year = {2019}, abstract = {Background: Autoantibodies against the paranodal protein contactin-1 have recently been described in patients with severe acute-onset autoimmune neuropathies and mainly belong to the IgG4 subclass that does not activate complement. IgG3 anti-contactin-1 autoantibodies are rare, but have been detected during the acute onset of disease in some cases. There is evidence that anti-contactin-1 prevents adhesive interaction, and chronic exposure to anti-contactin-1 IgG4 leads to structural changes at the nodes accompanied by neuropathic symptoms. However, the pathomechanism of acute onset of disease and the pathogenic role of IgG3 anti-contactin-1 is largely unknown. Methods: In the present study, we aimed to model acute autoantibody exposure by intraneural injection of IgG of patients with anti-contacin-1 autoantibodies to Lewis rats. Patient IgG obtained during acute onset of disease (IgG3 predominant) and IgG from the chronic phase of disease (IgG4 predominant) were studied in comparison. Results: Conduction blocks were measured in rats injected with the "acute" IgG more often than after injection of "chronic" IgG (83.3\% versus 35\%) and proved to be reversible within a week after injection. Impaired nerve conduction was accompanied by motor deficits in rats after injection of the "acute" IgG but only minor structural changes of the nodes. Paranodal complement deposition was detected after injection of the "acute IgG". We did not detect any inflammatory infiltrates, arguing against an inflammatory cascade as cause of damage to the nerve. We also did not observe dispersion of paranodal proteins or sodium channels to the juxtaparanodes as seen in patients after chronic exposure to anti-contactin-1. Conclusions: Our data suggest that anti-contactin-1 IgG3 induces an acute conduction block that is most probably mediated by autoantibody binding and subsequent complement deposition and may account for acute onset of disease in these patients. This supports the notion of anti-contactin-1-associated neuropathy as a paranodopathy with the nodes of Ranvier as the site of pathogenesis.}, language = {en} } @article{SchuhmannStollPappetal.2019, author = {Schuhmann, Michael K. and Stoll, Guido and Papp, Lena and Bohr, Arne and Volkmann, Jens and Fluri, Felix}, title = {Electrical stimulation of the mesencephalic locomotor region has no impact on blood-brain barrier alterations after cerebral photothrombosis in rats}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {16}, issn = {1422-0067}, doi = {10.3390/ijms20164036}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201284}, year = {2019}, abstract = {Blood-brain barrier (BBB) disruption is a critical event after ischemic stroke, which results in edema formation and hemorrhagic transformation of infarcted tissue. BBB dysfunction following stroke is partly mediated by proinflammatory agents. We recently have shown that high frequency stimulation of the mesencephalic locomotor region (MLR-HFS) exerts an antiapoptotic and anti-inflammatory effect in the border zone of cerebral photothrombotic stroke in rats. Whether MLR-HFS also has an impact on BBB dysfunction in the early stage of stroke is unknown. In this study, rats were subjected to photothrombotic stroke of the sensorimotor cortex and implantation of a stimulating microelectrode into the ipsilesional MLR. Thereafter, either HFS or sham stimulation of the MLR was applied for 24 h. After scarifying the rats, BBB disruption was assessed by determining albumin extravasation and tight junction integrity (claudin 3, claudin 5, and occludin) using Western blot analyses and immunohistochemistry. In addition, by applying zymography, expression of pro-metalloproteinase-9 (pro-MMP-9) was analyzed. No differences were found regarding infarct size and BBB dysfunction between stimulated and unstimulated animals 24 h after induction of stroke. Our results indicate that MLR-HFS neither improves nor worsens the damaged BBB after stroke. Attenuating cytokines/chemokines in the perilesional area, as mediated by MLR-HFS, tend to play a less significant role in preventing the BBB integrity.}, language = {en} } @article{SchuhmannStollBohretal.2019, author = {Schuhmann, Michael K. and Stoll, Guido and Bohr, Arne and Volkmann, Jens and Fluri, Felix}, title = {Electrical stimulation of the mesencephalic locomotor region attenuates neuronal loss and cytokine expression in the perifocal region of photothrombotic stroke in rats}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {9}, issn = {1422-0067}, doi = {10.3390/ijms20092341}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201355}, year = {2019}, abstract = {Deep brain stimulation of the mesencephalic locomotor region (MLR) improves the motor symptoms in Parkinson's disease and experimental stroke by intervening in the motor cerebral network. Whether high-frequency stimulation (HFS) of the MLR is involved in non-motor processes, such as neuroprotection and inflammation in the area surrounding the photothrombotic lesion, has not been elucidated. This study evaluates whether MLR-HFS exerts an anti-apoptotic and anti-inflammatory effect on the border zone of cerebral photothrombotic stroke. Rats underwent photothrombotic stroke of the right sensorimotor cortex and the implantation of a microelectrode into the ipsilesional MLR. After intervention, either HFS or sham stimulation of the MLR was applied for 24 h. The infarct volumes were calculated from consecutive brain sections. Neuronal apoptosis was analyzed by TUNEL staining. Flow cytometry and immunohistochemistry determined the perilesional inflammatory response. Neuronal apoptosis was significantly reduced in the ischemic penumbra after MLR-HFS, whereas the infarct volumes did not differ between the groups. MLR-HFS significantly reduced the release of cytokines and chemokines within the ischemic penumbra. MLR-HFS is neuroprotective and it reduces pro-inflammatory mediators in the area that surrounds the photothrombotic stroke without changing the number of immune cells, which indicates that MLR-HFS enables the function of inflammatory cells to be altered on a molecular level.}, language = {en} } @article{NeugebauerSchneiderKollmar2019, author = {Neugebauer, Hermann and Schneider, Hauke and Kollmar, Rainer}, title = {Letter by Neugebauer et al. regarding article "Hypothermia after decompressive hemicraniectomy in treatment of malignant middle cerebral artery stroke: comment on the randomized clinical trial"}, series = {Critical Care}, volume = {23}, journal = {Critical Care}, doi = {10.1186/s13054-019-2600-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232268}, year = {2019}, abstract = {No abstract available.}, language = {en} } @article{Gonzalez‐EscamillaMuthuramanReichetal.2019, author = {Gonzalez-Escamilla, Gabriel and Muthuraman, Muthuraman and Reich, Martin M. and Koirala, Nabin and Riedel, Christian and Glaser, Martin and Lange, Florian and Deuschl, G{\"u}nther and Volkmann, Jens and Groppa, Sergiu}, title = {Cortical network fingerprints predict deep brain stimulation outcome in dystonia}, series = {Movement Disorders}, volume = {34}, journal = {Movement Disorders}, number = {10}, doi = {10.1002/mds.27808}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213532}, pages = {1536 -- 1545}, year = {2019}, abstract = {Background Deep brain stimulation (DBS) is an effective evidence-based therapy for dystonia. However, no unequivocal predictors of therapy responses exist. We investigated whether patients optimally responding to DBS present distinct brain network organization and structural patterns. Methods From a German multicenter cohort of 82 dystonia patients with segmental and generalized dystonia who received DBS implantation in the globus pallidus internus, we classified patients based on the clinical response 3 years after DBS. Patients were assigned to the superior-outcome group or moderate-outcome group, depending on whether they had above or below 70\% motor improvement, respectively. Fifty-one patients met MRI-quality and treatment response requirements (mean age, 51.3 ± 13.2 years; 25 female) and were included in further analysis. From preoperative MRI we assessed cortical thickness and structural covariance, which were then fed into network analysis using graph theory. We designed a support vector machine to classify subjects for the clinical response based on individual gray-matter fingerprints. Results The moderate-outcome group showed cortical atrophy mainly in the sensorimotor and visuomotor areas and disturbed network topology in these regions. The structural integrity of the cortical mantle explained about 45\% of the DBS stimulation amplitude for optimal response in individual subjects. Classification analyses achieved up to 88\% of accuracy using individual gray-matter atrophy patterns to predict DBS outcomes. Conclusions The analysis of cortical integrity, informed by group-level network properties, could be developed into independent predictors to identify dystonia patients who benefit from DBS.}, language = {en} } @article{SilwedelHaarmannFehrholzetal.2019, author = {Silwedel, Christine and Haarmann, Axel and Fehrholz, Markus and Claus, Heike and Speer, Christian P. and Glaser, Kirsten}, title = {More than just inflammation: Ureaplasma species induce apoptosis in human brain microvascular endothelial cells}, series = {Journal of Neuroinflammation}, volume = {16}, journal = {Journal of Neuroinflammation}, doi = {10.1186/s12974-019-1413-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200711}, pages = {38}, year = {2019}, abstract = {Background Ureaplasma species (spp.) are commonly regarded as low-virulent commensals but may cause invasive diseases in immunocompromised adults and in neonates, including neonatal meningitis. The interactions of Ureaplasma spp. with host defense mechanisms are poorly understood. This study addressed Ureaplasma-driven cell death, concentrating on apoptosis as well as inflammatory cell death. Methods Human brain microvascular endothelial cells (HBMEC) were exposed to Ureaplasma (U.) urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). Resulting numbers of dead cells as well as mRNA levels and enzyme activity of key agents in programmed cell death were assessed by flow cytometry, RNA sequencing, and qRT-PCR, respectively. xCELLigence data were used for real-time monitoring of changes in cell adhesion properties. Results Both Ureaplasma isolates induced cell death (p < 0.05, vs. broth). Furthermore, Ureaplasma spp. enhanced mRNA levels for genes in apoptosis, including caspase 3 (Up3 p < 0.05, vs. broth), caspase 7 (p < 0.01), and caspase 9 (Up3 p < 0.01). Caspase 3 activity was increased upon Uu8 exposure (p < 0.01). Vice versa, Ureaplasma isolates downregulated mRNA levels for proteins involved in inflammatory cell death, namely caspase 1 (Uu8 p < 0.01, Up3 p < 0.001), caspase 4 (Uu8 p < 0.05, Up3 p < 0.01), NOD-like receptor pyrin domain-containing 3 (Uu8 p < 0.05), and receptor-interacting protein kinase 3 (p < 0.05). Conclusions By inducing apoptosis in HBMEC as main constituents of the blood-brain barrier, Ureaplasma spp. may provoke barrier breakdown. Simultaneous suppression of inflammatory cell death may additionally attenuate host defense strategies. Ultimate consequence could be invasive and long-term CNS infections by Ureaplasma spp.}, language = {en} } @phdthesis{Elhfnawy2019, author = {Elhfnawy, Ahmed}, title = {Relation between the length of the internal carotid stenotic segment and ischemic cerebrovascular events as well as white matter lesion load}, doi = {10.25972/OPUS-19161}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191616}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Background and Purpose: Internal carotid artery stenosis ≥70\% is a leading cause of ischemic cerebrovascular events. However, a considerable percentage of stroke survivors with symptomatic internal carotid artery stenosis have <70\% stenosis with a vulnerable plaque. Whether the length of internal carotid artery stenosis is associated with high risk of ischemic cerebrovascular events or with white matter lesions is poorly investigated. Our main aim was to investigate the relation between the length of internal carotid artery stenosis and the development of ischemic cerebrovascular events as well as ipsi-, contralateral as well as mean white matter lesion load. Methods: In a retrospective cross-sectional study, 168 patients with 208 internal carotid artery stenosis were identified. The degree and length of internal carotid artery stenosis as well as plaque morphology (hypoechoic, mixed or echogenic) were assessed on ultrasound scans. The white matter lesions were assessed in 4 areas separately, (periventricular and deep white matter lesions on each hemisphere), using the Fazekas scale. The mean white matter lesions load was calculated as the mean of these four values. Results: A statistically significant inverse correlation between the ultrasound-measured length and degree of internal carotid artery stenosis was detected for symptomatic internal carotid artery stenosis ≥70\% (Spearman correlation coefficient ρ = -0.57, p < 0.001, n = 51) but neither for symptomatic internal carotid artery stenosis <70\% (ρ = 0.15, p = 0.45, n = 27) nor for asymptomatic internal carotid artery stenosis (ρ = 0.07, p = 0.64, n = 54). The median (IQR) length for symptomatic internal carotid artery stenosis <70\% and ≥70\% was 17 (15-20) and 15 (12-19) mm (p = 0.06), respectively, while that for symptomatic internal carotid artery stenosis <90\% and symptomatic internal carotid artery stenosis 90\% was 18 (15-21) and 13 (10-16) mm, respectively (p < 0.001). Among patients with internal carotid artery stenosis <70\%, a cut-off length of ≥16 mm was found for symptomatic internal carotid artery stenosis rather than asymptomatic internal carotid artery stenosis with a sensitivity and specificity of 74.1\% and 51.1\%, respectively. Irrespective of the stenotic degree, plaques of the symptomatic internal carotid artery stenosis compared to asymptomatic internal carotid artery stenosis were significantly more often echolucent (43.2 vs. 24.6\%, p = 0.02). The length but not the degree of internal carotid artery stenosis showed a very slight trend toward association with ipsilateral white matter lesions and with mean white matter lesions load. Conclusion: We found a statistically insignificant tendency for the ultrasound-measured length of symptomatic internal carotid artery stenosis <70\% to be longer than that of symptomatic internal carotid artery stenosis ≥70\%. Moreover, the ultrasound-measured length of symptomatic internal carotid artery stenosis <90\% was significantly longer than that of symptomatic internal carotid artery stenosis 90\%. Among patients with symptomatic internal carotid artery stenosis ≥70\%, the degree and length of stenosis were inversely correlated. Furthermore, we have shown that a slight correlation exists between the length of stenosis and the presence of ipsilateral white matter lesions which might be due to microembolisation originating from the carotid plaque. Larger studies are needed before a clinical implication can be drawn from these results.}, subject = {Carotisstenose}, language = {en} } @article{ElhfnawyHeuschmannPhametal.2019, author = {Elhfnawy, Ahmed Mohamed and Heuschmann, Peter U. and Pham, Mirko and Volkmann, Jens and Fluri, Felix}, title = {Stenosis length and degree interact with the risk of cerebrovascular events related to internal carotid artery stenosis}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, number = {317}, issn = {1664-2295}, doi = {10.3389/fneur.2019.00317}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196225}, year = {2019}, abstract = {Background and Purpose: Internal carotid artery stenosis (ICAS)≥70\% is a leading cause of ischemic cerebrovascular events (ICVEs). However, a considerable percentage of stroke survivors with symptomatic ICAS (sICAS) have <70\% stenosis with a vulnerable plaque. Whether the length of ICAS is associated with high risk of ICVEs is poorly investigated. Our main aim was to investigate the relation between the length of ICAS and the development of ICVEs. Methods: In a retrospective cross-sectional study, we identified 95 arteries with sICAS and another 64 with asymptomatic internal carotid artery stenosis (aICAS) among 121 patients with ICVEs. The degree and length of ICAS as well as plaque echolucency were assessed on ultrasound scans. Results: A statistically significant inverse correlation between the ultrasound-measured length and degree of ICAS was detected for sICAS≥70\% (Spearman correlation coefficient ρ = -0.57, p < 0.001, n = 51) but neither for sICAS<70\% (ρ = 0.15, p = 0.45, n = 27) nor for aICAS (ρ = 0.07, p = 0.64, n = 54). The median (IQR) length for sICAS<70\% and ≥70\% was 17 (15-20) and 15 (12-19) mm (p = 0.06), respectively, while that for sICAS<90\% and sICAS 90\% was 18 (15-21) and 13 (10-16) mm, respectively (p < 0.001). Among patients with ICAS <70\%, a cut-off length of ≥16 mm was found for sICAS rather than aICAS with a sensitivity and specificity of 74.1\% and 51.1\%, respectively. Irrespective of the stenotic degree, plaques of the sICAS compared to aICAS were significantly more often echolucent (43.2 vs. 24.6\%, p = 0.02). Conclusion: We found a statistically insignificant tendency for the ultrasound-measured length of sICAS<70\% to be longer than that of sICAS≥70\%. Moreover, the ultrasound-measured length of sICAS<90\% was significantly longer than that of sICAS 90\%. Among patients with sICAS≥70\%, the degree and length of stenosis were inversely correlated. Larger studies are needed before a clinical implication can be drawn from these results.}, language = {en} } @article{StengelVuralBrunderetal.2019, author = {Stengel, Helena and Vural, Atay and Brunder, Anna-Michelle and Heinius, Annika and Appeltshauser, Luise and Fiebig, Bianca and Giese, Florian and Dresel, Christian and Papagianni, Aikaterini and Birklein, Frank and Weis, Joachim and Huchtemann, Tessa and Schmidt, Christian and K{\"o}rtvelyessy, Peter and Villmann, Carmen and Meinl, Edgar and Sommer, Claudia and Leypoldt, Frank and Doppler, Kathrin}, title = {Anti-pan-neurofascin IgG3 as a marker of fulminant autoimmune neuropathy}, series = {Neurology: Neuroimmunology \& Neuroinflammation}, volume = {6}, journal = {Neurology: Neuroimmunology \& Neuroinflammation}, number = {5}, doi = {10.1212/NXI.0000000000000603}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202462}, year = {2019}, abstract = {Objective To identify and characterize patients with autoantibodies against different neurofascin (NF) isoforms. Methods Screening of a large cohort of patient sera for anti-NF autoantibodies by ELISA and further characterization by cell-based assays, epitope mapping, and complement binding assays. Results Two different clinical phenotypes became apparent in this study: The well-known clinical picture of subacute-onset severe sensorimotor neuropathy with tremor that is known to be associated with IgG4 autoantibodies against the paranodal isoform NF-155 was found in 2 patients. The second phenotype with a dramatic course of disease with tetraplegia and almost locked-in syndrome was associated with IgG3 autoantibodies against nodal and paranodal isoforms of NF in 3 patients. The epitope against which these autoantibodies were directed in this second phenotype was the common Ig domain found in all 3 NF isoforms. In contrast, anti-NF-155 IgG4 were directed against the NF-155-specific Fn3Fn4 domain. The description of a second phenotype of anti-NF-associated neuropathy is in line with some case reports of similar patients that were published in the last year. Conclusions Our results indicate that anti-pan-NF-associated neuropathy differs from anti-NF-155-associated neuropathy, and epitope and subclass play a major role in the pathogenesis and severity of anti-NF-associated neuropathy and should be determined to correctly classify patients, also in respect to possible differences in therapeutic response.}, language = {en} } @article{EvdokimovFrankKlitschetal.2019, author = {Evdokimov, Dimitar and Frank, Johanna and Klitsch, Alexander and Unterecker, Stefan and Warrings, Bodo and Serra, Jordi and Papagianni, Aikaterini and Saffer, Nadine and Meyer zu Altenschildesche, Caren and Kampik, Daniel and Malik, Rayaz A. and Sommer, Claudia and {\"U}ceyler, Nurcan}, title = {Reduction of skin innervation is associated with a severe fibromyalgia phenotype}, series = {Annals of Neurology}, volume = {86}, journal = {Annals of Neurology}, number = {4}, doi = {10.1002/ana.25565}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206168}, pages = {504-516}, year = {2019}, abstract = {Objective: To assess patterns and impact of small nerve fiber dysfunction and pathology in patients with fibromyalgia syndrome (FMS). Methods: One hundred seventeen women with FMS underwent neurological examination, questionnaire assessment, neurophysiology assessment, and small fiber tests: skin punch biopsy, corneal confocal microscopy, microneurography, quantitative sensory testing including C-tactile afferents, and pain-related evoked potentials. Data were compared with those of women with major depressive disorder and chronic widespread pain (MD-P) and healthy women. Results: Intraepidermal nerve fiber density (IENFD) was reduced at different biopsy sites in 63\% of FMS patients (MDP: 10\%, controls: 18\%; p < 0.001 for each). We found 4 patterns of skin innervation in FMS: normal, distally reduced, proximally reduced, and both distally and proximally reduced (p < 0.01 for each compared to controls). Microneurography revealed initial activity-dependent acceleration of conduction velocity upon low frequencies of stimulation in 1A fibers, besides 1B fiber spontaneous activity and mechanical sensitization in FMS patients. FMS patients had elevated warm detection thresholds (p < 0.01), impaired C-tactile afferents (p < 0.05), and reduced amplitudes (p < 0.001) of pain-related evoked potentials compared to controls. Compared to FMS patients with normal skin innervation, those with generalized IENFD reduction had higher pain intensity and impairment due to pain, higher disease burden, more stabbing pain and paresthesias, and more anxiety (p < 0.05 for each). FMS patients with generalized IENFD reduction also had lower corneal nerve fiber density (p < 0.01) and length (p < 0.05). Interpretation: The extent of small fiber pathology is related to symptom severity in FMS. This knowledge may have implications for the diagnostic classification and treatment of patients with FMS.}, language = {en} } @article{OdorferWindZeller2019, author = {Odorfer, Thorsten M. and Wind, Teresa and Zeller, Daniel}, title = {Temporal discrimination thresholds and proprioceptive performance: impact of age and nerve conduction}, series = {Frontiers in Neuroscience}, volume = {13}, journal = {Frontiers in Neuroscience}, number = {1241}, issn = {1662-453X}, doi = {10.3389/fnins.2019.01241}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195648}, year = {2019}, abstract = {Background Increasing attention is payed to the contribution of somatosensory processing in motor control. In particular, temporal somatosensory discrimination has been found to be altered differentially in common movement disorders. To date, there have only been speculations as to how impaired temporal discrimination and clinical motor signs may relate to each other. Prior to disentangling this relationship, potential confounders of temporal discrimination, in particular age and peripheral nerve conduction, should be assessed, and a quantifiable measure of proprioceptive performance should be established. ObjectiveTo assess the influence of age and polyneuropathy (PNP) on somatosensory temporal discrimination threshold (STDT), temporal discrimination movement threshold (TDMT), and behavioral measures of proprioception of upper and lower limbs. Methods STDT and TDMT were assessed in 79 subjects (54 healthy, 25 with PNP; age 30-79 years). STDT was tested with surface electrodes over the thenar or dorsal foot region. TDMT was probed with needle electrodes in flexor carpi radialis (FCR) and tibialis anterior (TA) muscle. Goniometer-based devices were used to assess limb proprioception during (i) active pointing to LED markers, (ii) active movements in response to variable visual cues, and (iii) estimation of limb position following passive movements. Pointing (or estimation) error was taken as a measure of proprioceptive performance. Results In healthy subjects, higher age was associated with higher STDT and TDMT at upper and lower extremities, while age did not correlate with proprioceptive performance. Patients with PNP showed higher STDT and TDMT values and decreased proprioceptive performance in active pointing tasks compared to matched healthy subjects. As an additional finding, there was a significant correlation between performance in active pointing tasks and temporal discrimination thresholds. Conclusion Given their notable impact on measures of temporal discrimination, age and peripheral nerve conduction need to be accounted for if STDT and TDMT are applied in patients with movement disorders. As a side observation, the correlation between measures of proprioception and temporal discrimination may prompt further studies on the presumptive link between these two domains.}, language = {en} } @article{SchuhmannKraftBieberetal.2019, author = {Schuhmann, Michael K. and Kraft, Peter and Bieber, Michael and Kollikowski, Alexander M. and Schulze, Harald and Nieswandt, Bernhard and Pham, Mirko and Stegner, David and Stoll, Guido}, title = {Targeting platelet GPVI plus rt-PA administration but not α2β1-mediated collagen binding protects against ischemic brain damage in mice}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {8}, issn = {1422-0067}, doi = {10.3390/ijms20082019}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201700}, year = {2019}, abstract = {Platelet collagen interactions at sites of vascular injuries predominantly involve glycoprotein VI (GPVI) and the integrin α2β1. Both proteins are primarily expressed on platelets and megakaryocytes whereas GPVI expression is also shown on endothelial and integrin α2β1 expression on epithelial cells. We recently showed that depletion of GPVI improves stroke outcome without increasing the risk of cerebral hemorrhage. Genetic variants associated with higher platelet surface integrin α2 (ITGA2) receptor levels have frequently been found to correlate with an increased risk of ischemic stroke in patients. However until now, no preclinical stroke study has addressed whether platelet integrin α2β1 contributes to the pathophysiology of ischemia/reperfusion (I/R) injury. Focal cerebral ischemia was induced in C57BL/6 and Itga2\(^{-/-}\) mice by a 60 min transient middle cerebral artery occlusion (tMCAO). Additionally, wild-type animals were pretreated with anti-GPVI antibody (JAQ1) or Fab fragments of a function blocking antibody against integrin α2β1 (LEN/B). In anti-GPVI treated animals, intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment was applied immediately prior to reperfusion. Stroke outcome, including infarct size and neurological scoring was determined on day 1 after tMCAO. We demonstrate that targeting the integrin α2β1 (pharmacologic; genetic) did neither reduce stroke size nor improve functional outcome on day 1 after tMCAO. In contrast, depletion of platelet GPVI prior to stroke was safe and effective, even when combined with rt-PA treatment. Our results underscore that GPVI, but not ITGA2, is a promising and safe target in the setting of ischemic stroke.}, language = {en} } @article{KarlWussmannKressetal.2019, author = {Karl, Franziska and Wußmann, Maximiliane and Kreß, Luisa and Malzacher, Tobias and Fey, Phillip and Groeber-Becker, Florian and {\"U}{\c{c}}eyler, Nurcan}, title = {Patient-derived in vitro skin models for investigation of small fiber pathology}, series = {Annals of Clinical and Translational Neurology}, volume = {6}, journal = {Annals of Clinical and Translational Neurology}, number = {9}, doi = {10.1002/acn3.50871}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201649}, pages = {1797-1806}, year = {2019}, abstract = {Objective To establish individually expandable primary fibroblast and keratinocyte cultures from 3-mm skin punch biopsies for patient-derived in vitro skin models to investigate of small fiber pathology. Methods We obtained 6-mm skin punch biopsies from the calf of two patients with small fiber neuropathy (SFN) and two healthy controls. One half (3 mm) was used for diagnostic intraepidermal nerve fiber density (IENFD). From the second half, we isolated and cultured fibroblasts and keratinocytes. Cells were used to generate patient-derived full-thickness three-dimensional (3D) skin models containing a dermal and epidermal component. Cells and skin models were characterized morphologically, immunocyto- and -histochemically (vimentin, cytokeratin (CK)-10, CK 14, ki67, collagen1, and procollagen), and by electrical impedance. Results Distal IENFD was reduced in the SFN patients (2 fibers/mm each), while IENFD was normal in the controls (8 fibers/mm, 7 fibers/mm). Two-dimensional (2D) cultured skin cells showed normal morphology, adequate viability, and proliferation, and expressed cell-specific markers without relevant difference between SFN patient and healthy control. Using 2D cultured fibroblasts and keratinocytes, we obtained subject-derived 3D skin models. Morphology of the 3D model was analogous to the respective skin biopsy specimens. Both, the dermal and the epidermal layer carried cell-specific markers and showed a homogenous expression of extracellular matrix proteins. Interpretation Our protocol allows the generation of disease-specific 2D and 3D skin models, which can be used to investigate the cross-talk between skin cells and sensory neurons in small fiber pathology.}, language = {en} } @article{SilwedelSpeerHaarmannetal.2019, author = {Silwedel, Christine and Speer, Christian P. and Haarmann, Axel and Fehrholz, Markus and Claus, Heike and Schlegel, Nicolas and Glaser, Kirsten}, title = {Ureaplasma species modulate cytokine and chemokine responses in human brain microvascular endothelial cells}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {14}, issn = {1422-0067}, doi = {10.3390/ijms20143583}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201848}, year = {2019}, abstract = {Ureaplasma species are common colonizers of the adult genitourinary tract and often considered as low-virulence commensals. Intraamniotic Ureaplasma infections, however, facilitate chorioamnionitis and preterm birth, and cases of Ureaplasma-induced neonatal sepsis, pneumonia, and meningitis raise a growing awareness of their clinical relevance. In vitro studies are scarce but demonstrate distinct Ureaplasma-driven impacts on immune mechanisms. The current study addressed cytokine and chemokine responses upon exposure of native or lipopolysaccharide (LPS) co-stimulated human brain microvascular endothelial cells (HBMEC) to Ureaplasma urealyticum or U. parvum, using qRT-PCR, RNA sequencing, multi-analyte immunoassay, and flow cytometry. Ureaplasma exposure in native HBMEC reduced monocyte chemoattractant protein (MCP)-3 mRNA expression (p < 0.01, vs. broth). In co-stimulated HBMEC, Ureaplasma spp. attenuated LPS-evoked mRNA responses for C-X-C chemokine ligand 5, MCP-1, and MCP-3 (p < 0.05, vs. LPS) and mitigated LPS-driven interleukin (IL)-1α protein secretion, as well as IL-8 mRNA and protein responses (p < 0.05). Furthermore, Ureaplasma isolates increased C-X-C chemokine receptor 4 mRNA levels in native and LPS co-stimulated HBMEC (p < 0.05). The presented results may imply immunomodulatory capacities of Ureaplasma spp. which may ultimately promote chronic colonization and long-term neuroinflammation.}, language = {en} } @article{OdorferHomolaReichetal.2019, author = {Odorfer, Thorsten M. and Homola, Gy{\"o}rgy A. and Reich, Martin M. and Volkmann, Jens and Zeller, Daniel}, title = {Increased finger-tapping related cerebellar activation in cervical dystonia, enhanced by transcranial stimulation: an indicator of compensation?}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, number = {231}, issn = {1664-2295}, doi = {10.3389/fneur.2019.00231}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196249}, year = {2019}, abstract = {Background: Cervical dystonia is a movement disorder causing abnormal postures and movements of the head. While the exact pathophysiology of cervical dystonia has not yet been fully elucidated, a growing body of evidence points to the cerebellum as an important node. Methods: Here, we examined the impact of cerebellar interference by transcranial magnetic stimulation on finger-tapping related brain activation and neurophysiological measures of cortical excitability and inhibition in cervical dystonia and controls. Bilateral continuous theta-burst stimulation was used to modulate cerebellar cortical excitability in 16 patients and matched healthy controls. In a functional magnetic resonance imaging arm, data were acquired during simple finger tapping before and after cerebellar stimulation. In a neurophysiological arm, assessment comprised motor-evoked potentials amplitude and cortical silent period duration. Theta-burst stimulation over the dorsal premotor cortex and sham stimulation (neurophysiological arm only) served as control conditions. Results: At baseline, finger tapping was associated with increased activation in the ipsilateral cerebellum in patients compared to controls. Following cerebellar theta-burst stimulation, this pattern was even more pronounced, along with an additional movement-related activation in the contralateral somatosensory region and angular gyrus. Baseline motor-evoked potential amplitudes were higher and cortical silent period duration shorter in patients compared to controls. After cerebellar theta-burst stimulation, cortical silent period duration increased significantly in dystonia patients. Conclusion: We conclude that in cervical dystonia, finger movements—though clinically non-dystonic—are associated with increased activation of the lateral cerebellum, possibly pointing to general motor disorganization, which remains subclinical in most body regions. Enhancement of this activation together with an increase of silent period duration by cerebellar continuous theta-burst stimulation may indicate predominant disinhibitory effects on Purkinje cells, eventually resulting in an inhibition of cerebello-thalamocortical circuits.}, language = {en} } @article{WutzlerKrogiasGrauetal.2019, author = {Wutzler, Alexander and Krogias, Christos and Grau, Anna and Veltkamp, Roland and Heuschmann, Peter U. and Haeusler, Karl Georg}, title = {Stroke prevention in patients with acute ischemic stroke and atrial fibrillation in Germany - a cross sectional survey}, series = {BMC Neurology}, volume = {19}, journal = {BMC Neurology}, doi = {10.1186/s12883-019-1249-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201078}, pages = {25}, year = {2019}, abstract = {Background Atrial fibrillation (AF) is present in 15-20\% of patients with acute ischemic stroke. Oral anticoagulation reduces the risk of AF-related recurrent stroke but clinical guideline recommendations are rather vague regarding its use in the acute phase of stroke. We aimed to assess the current clinical practice of medical stroke prevention in AF patients during the acute phase of ischemic stroke. Methods In April 2017, a standardized anonymous questionnaire was sent to clinical leads of all 298 certified stroke units in Germany. Results Overall, 154 stroke unit leads participated (response rate 52\%). Anticoagulation in the acute phase of stroke is considered feasible in more than 90\% of AF patients with ischemic stroke. Clinicians assume that about two thirds of all AF patients (range 20-100\%) are discharged on oral anticoagulation. According to local preferences, acetylsalicylic acid is given orally in the majority of patients with delayed initiation of oral anticoagulation. A non-vitamin K-dependent oral anticoagulant (NOAC) is more often prescribed than a vitamin K-dependent oral anticoagulant (VKA). VKA is more often chosen in patients with previous VKA intake than in VKA naive patients. In the minority of patients, stroke unit leads discuss the prescription of a specific oral anticoagulant with the treating general practitioner. Adherence to medical stroke prevention after hospital discharge is not assessed on a regular basis in any patient by the majority of participating stroke centers. Conclusions Early secondary stroke prevention in AF patients in German stroke units is based on OAC use but prescription modalities vary in clinical practice.}, language = {en} } @article{ElhfnawyVolkmannSchliesseretal.2019, author = {Elhfnawy, Ahmed Mohamed and Volkmann, Jens and Schliesser, Mira and Fluri, Felix}, title = {Symptomatic vs. asymptomatic 20-40\% internal carotid artery stenosis: Does the plaque size matter?}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, number = {960}, doi = {10.3389/fneur.2019.00960}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201262}, year = {2019}, abstract = {Background: Around 9-15\% of ischemic strokes are related to internal carotid artery (ICA)-stenosis ≥50\%. However, the extent to which ICA-stenosis <50\% causes ischemic cerebrovascular events is uncertain. We examined the relation between plaque cross-sectional area and length and the risk of ischemic stroke or TIA among patients with ICA-stenosis of 20-40\%. Methods: We retrospectively identified patients admitted to the Department of Neurology, University Hospital of W{\"u}rzburg, from January 2011 until September 2016 with ischemic stroke or TIA and concomitant ICA-stenosis of 20-40\%, either symptomatic or asymptomatic. Plaque length and cross-sectional area were assessed on ultrasound scans. Results: We identified 41 patients with ischemic stroke or TIA and ICA-stenosis of 20-40\%; 14 symptomatic and 27 asymptomatic. The plaque cross-sectional area was significantly larger among symptomatic than asymptomatic ICA-stenosis; median values (IQR) were 0.45 (0.21-0.69) cm2 and 0.27 (0.21-0.38) cm2, p = 0.03, respectively. A plaque cross-sectional area ≥0.36 cm2 had a sensitivity of 71\% and a specificity of 76\% for symptomatic compared with asymptomatic ICA-stenosis. In a sex-adjusted multivariate logistic regression, a plaque cross-sectional area ≥0.36 cm2 and a plaque length ≥1.65 cm were associated with an OR (95\% CI) of 5.54 (1.2-25.6), p = 0.028 and 1.78 (0.36-8.73), p = 0.48, respectively, for symptomatic ICA-stenosis. Conclusion: Large plaques might increase the risk of ischemic stroke or TIA among patients with low-grade ICA-stenosis of 20-40\%. Sufficiently powered prospective longitudinal cohort studies are needed to definitively test the stroke risk stratification value of carotid plaque length and cross-sectional area in the setting of current optimal medical treatment.}, language = {en} } @article{PasosSteigerwaldReichetal.2019, author = {Pasos, Uri E. Ramirez and Steigerwald, Frank and Reich, Martin M. and Matthies, Cordula and Volkmann, Jens and Reese, Ren{\´e}}, title = {Levodopa modulates functional connectivity in the upper beta band between bubthalamic nucleus and muscle activity in tonic and phasic motor activity patterns in Parkinson's disease}, series = {Frontiers in Human Neuroscience}, volume = {13}, journal = {Frontiers in Human Neuroscience}, number = {223}, doi = {10.3389/fnhum.2019.00223}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201540}, year = {2019}, abstract = {Introduction: Striatal dopamine depletion disrupts basal ganglia function and causes Parkinson's disease (PD). The pathophysiology of the dopamine-dependent relationship between basal ganglia signaling and motor control, however, is not fully understood. We obtained simultaneous recordings of local field potentials (LFPs) from the subthalamic nucleus (STN) and electromyograms (EMGs) in patients with PD to investigate the impact of dopaminergic state and movement on long-range beta functional connectivity between basal ganglia and lower motor neurons. Methods: Eight PD patients were investigated 3 months after implantation of a deep brain stimulation (DBS)-system capable of recording LFPs via chronically-implanted leads (Medtronic, ACTIVA PC+S®). We analyzed STN spectral power and its coherence with EMG in the context of two different movement paradigms (tonic wrist extension vs. alternating wrist extension and flexion) and the effect of levodopa (L-Dopa) intake using an unbiased data-driven approach to determine regions of interest (ROI). Results: Two ROIs capturing prominent coherence within a grand average coherogram were identified. A trend of a dopamine effect was observed for the first ROI (50-150 ms after movement start) with higher STN-EMG coherence in medicated patients. Concerning the second ROI (300-500 ms after movement start), an interaction effect of L-Dopa medication and movement task was observed with higher coherence in the isometric contraction task compared to alternating movements in the medication ON state, a pattern which was reversed in L-Dopa OFF. Discussion: L-Dopa medication may normalize functional connectivity between remote structures of the motor system with increased upper beta coherence reflecting a physiological restriction of the amount of information conveyed between remote structures. This may be necessary to maintain simple movements like isometric contraction. Our study adds dynamic properties to the complex interplay between STN spectral beta power and the nucleus' functional connectivity to remote structures of the motor system as a function of movement and dopaminergic state. This may help to identify markers of neuronal activity relevant for more individualized programming of DBS therapy.}, language = {en} }