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Publication Open Access A new method to determine reflex latency induced by high rate stimulation of the nervous system(Frontiers, 2014) Karacan, İlhan; Çakar, Halil İ.; Cidem, Muharrem; Kara, Sadık; N/A; Yılmaz, Gizem; Sebik, Oğuz; Türker, Kemal Sıtkı; PhD Student; Researcher; Faculty Member; School of Medicine; N/A; N/A; 6741High rate stimulations of the neuromuscular system, such as continuous whole body vibration, tonic vibration reflex and high frequency electrical stimulation, are used in the physiological research with an increasing interest. In these studies, the neuronal circuitries underlying the reflex responses remain unclear due to the problem of determining the exact reflex latencies. We present a novel 'cumulated average method" to determine the reflex latency during high rate stimulation of the nervous system which was proven to be significantly more accurate than the classical method. The classical method, cumulant density analysis, reveals the relationship between the two synchronously recorded signals as a function of the lag between the signals. The comparison of new method with the classical technique and their relative accuracy was tested using a computer simulation. In the simulated signals the EMG response latency was constructed to be exactly 40 ms. The new method accurately indicated the value of the simulated reflex latency (40 ms). However, the classical method showed that the lag time between the simulated triggers and the simulated signals was 49 ms. Simulation results illustrated that the cumulated average method is a reliable and more accurate method compared with the classical method. We therefore suggest that the new cumulated average method is able to determine the high rate stimulation induced reflex latencies more accurately than the classical method.Publication Open Access A possible role of prolonged whirling episodes on structural plasticity of the cortical networks and altered vertigo perception: the cortex of sufi whirling dervishes(Frontiers, 2017) Çakmak, Yusuf Ö.; Ekinci, Gazanfer; Heinecke, Armin; N/A; Çavdar, Safiye; Faculty Member; School of MedicineAlthough minutes of a spinning episode may induce vertigo in the healthy human, as a result of a possible perceptional plasticity, Sufi Whirling Dervishes (SWDs) can spin continuously for an hour without a vertigo perception.This unique long term vestibular system stimulation presents a potential human model to clarify the cortical networks underlying the resistance against vertigo. This study, therefore, aimed to investigate the potential structural cortical plasticity in SWDs. Magnetic resonance imaging (MRI) of 10 SWDs and 10 controls were obtained, using a 3T scanner. Cortical thickness in the whole cortex was calculated. Results demonstrated significantly thinner cortical areas for SWD subjects compared with the control group in the hubs of the default mode network (DMN), as well as in the motion perception and discrimination areas including the right dorsolateral prefrontal cortex (DLPFC), the right lingual gyrus and the left visual area 5 (V5)/middle temporal (MT) and the left fusiform gyrus. In conclusion, this is the first report that warrants the potential relationship of the motion/body perception related cortical networks and the prolonged term of whirling ability without vertigo or dizziness.Publication Open Access Anti-inflammatory modulation of microglia via CD163-targeted glucocorticoids protects dopaminergic neurons in the 6-OHDA Parkinson's disease model(Society for Neuroscience, 2016) Tentillier, Noemie; Etzerodt, Anders; Olesen, Mads N.; Jacobsen, Jan; Bender, Dirk; Moestrup, Soren K.; Romero-Ramos, Marina; Department of Molecular Biology and Genetics; Department of Molecular Biology and Genetics; Rızalar, F. Sıla; Graduate School of Sciences and EngineeringIncreasing evidence supports a decisive role for inflammation in the neurodegenerative process of Parkinson's disease (PD). The immune response in PD seems to involve, not only microglia, but also other immune cells infiltrated into the brain. Indeed, we observed here the infiltration of macrophages, specifically CD163+ macrophages, into the area of neurodegeneration in the 6-hydroxydopamine (6-OHDA) PD model. Therefore, we investigated the therapeutic potential of the infiltrated CD163+ macrophages to modulate local microglia in the brain to achieve neuroprotection. To do so, we designed liposomes targeted for the CD163 receptor to deliver dexamethasone (Dexa) into the CD163+ macrophages in the 6-OHDA PD model. Our data show that a fraction of the CD163-targeted liposomes were carried into the brain after peripheral intravenous injection. The 6-OHDA-lesioned rats that received repeated intravenous CD163-targeted liposomes with Dexa for 3 weeks exhibited better motor performance than the control groups and had minimal glucocorticoid-driven side effects. Furthermore, these animals showed better survival of dopaminergic neurons in substantia nigra and an increased number of microglia expressing major histocompatibility complex II. Therefore, rats receiving CD163-targeted liposomes with Dexa were partially protected against 6-OHDA-induced dopaminergic neurodegeneration, which correlated with a distinctive microglia response. Altogether, our data support the use of macrophages for the modulation of brain neurodegeneration and specifically highlight the potential of CD163-targeted liposomes as a therapeutic tool in PD.Publication Open Access Anti-pan-neurofascin IgG3 as a marker of fulminant autoimmune neuropathy(Lippincott Williams and Wilkins (LWW), 2019) Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM)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.Publication Open Access Antimuscarinic-induced convulsions in fasted rats after food intake: EEG patterns of fasting, scopolamine treatment, and convulsions(Galenos Yayınevi, 2022) Türkmen, Aslı Zengin; Nurten, Asiye; Edis, Bilge Özerman; Özen, İlknur; Kara, İhsan; Karamürsel, Sacit; Faculty Member; School of Medicine; 19597Objective: antimuscarinic treatment in fasted mice and rats causes clonic convulsion soon after food intake. This study was designed to evaluate the electrophysiological markers of these convulsions and fasting in electrocorticograms in rats. Methods: Male Wistar albino rats were stereotaxically implanted with 10 cortical electrodes, and baseline electroencephalogram recordings were taken for 10 minutes. After weighing, rats were deprived of food for 52 hours. At the 24th and 52nd hours of deprivation, continuous electroencephalogram recordings were repeated. After the deprivation period, animals were treated with saline or scopolamine (3 mg/kg). Twenty minutes after injections, animals were given food pellets. After eating food, electroencephalogram recordings were taken for 60 minutes and all animals were observed simultaneously to determine the incidence and onset of convulsions. Results: these results show that food deprivation for 52 hours decreased the amplitude of the gamma band when compared to basal (P <.05) and 24 hours (P <.008) food deprivation. And the amplitude of the beta band in the 52nd hour decreased when compared to the 24th hour of food deprivation (P <.05). The treatment with scopolamine changes the effects of food deprivation on the electroencephalogram. As a typical epileptiform manifestation, refeeding after scopolamine treatment caused a series of high-voltage polyspikes and synchronized spikes with a predominant frequency in the 1-3 Hz range. Conclusions: it was revealed that the behavioral patterns of rats and the electroencephalogram properties in these convulsions are in accordance with each other.Publication Open Access Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking(Oxford University Press (OUP), 2021) Sanderson, L.E.; Lanko, K.; Alsagob, M.; Almass, R.; Al-Ahmadi, N.; Najafi, M.; Al-Muhaizea, M.A.; Alzaidan, H.; AlDhalaan, H.; Perenthaler, E.; van der Linde, H.C.; Nikoncuk, A.; Kühn, N. A.; Antony, D.; Owaidah, T.M.; Raskin, S.; Vieira, L. G. D. R.; Mombach, R.; Ahangari, N.; Silveira, T. R. D.; Ameziane, N.; Rolfs, A.; Alharbi, A.; Sabbagh, R. M.; AlAhmadi, K.; Alawam, B.; Ghebeh, H.; AlHargan, A.; Albader, A. A.; Binhumaid, F. S.; Goljan, E.; Monies, D.; Mustafa, O. M.; Aldosary, M.; AlBakheet, A.; Alyounes, B.; Almutairi, F.; Al-Odaib, A; Aksoy, D. B.; Trabzuni, D.; Rosenfeld, J. A.; Karimiani, E. G.; Meyer, B. F.; Karakaş, B.; Al-Mohanna, F.; Arold, S. T.; Çolak, D.; Maroofian, R.; Houlden, H.; Bertoli-Avella, A. M.; Schmidts, M.; Barakat, T. S.; van Ham, T. J.; Kaya, N.; Başak, Ayşe Nazlı; Palvadeau, Robin Jerome; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 1512; N/AMembrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.Publication Open Access Brain atrophy and lesion burden are associated with disability progression in a multiple sclerosis real-world dataset using only T2-FLAIR: the NeuroSTREAM MSBase study(Elsevier, 2021) Barnett, M.; Bergsland, N.; Weinstock Guttman, B.; Butzkueven, H.; Kalıncık, T.; Desmond, P.; Gaillard, F.; van Pesch, V.; Özakbaş, S.; Rojas, JI.; Boz, C.; Wang, C.; Dwyer, MG.; Yang, S.; Jakimovski, D.; Kyle, K.; Ramasamy, DP.; Zivadinov, R.; Altıntaş, Ayşe; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 11611Background: methodological challenges limit the use of brain atrophy and lesion burden measures in the followup of multiple sclerosis (MS) patients on clinical routine datasets. Objective: to determine the feasibility of T2-FLAIR-only measures of lateral ventricular volume (LVV) and salient central lesion volume (SCLV), as markers of disability progression (DP) in MS. Methods: a total of 3,228 MS patients from 9 MSBase centers in 5 countries were enrolled. Of those, 2,875 (218 with clinically isolated syndrome, 2,231 with relapsing-remitting and 426 with progressive disease subtype) fulfilled inclusion and exclusion criteria. Patients were scanned on either 1.5 T or 3 T MRI scanners, and 5,750 brain scans were collected at index and on average after 42.3 months at post-index. Demographic and clinical data were collected from the MSBase registry. LVV and SCLV were measured on clinical routine T2-FLAIR images. Results: longitudinal LVV and SCLV analyses were successful in 96% of the scans. 57% of patients had scanner related changes over the follow-up. After correcting for age, sex, disease duration, disability, disease-modifying therapy and LVV at index, and follow-up time, MS patients with DP (n = 671) had significantly greater absolute LVV change compared to stable (n = 1,501) or disability improved (DI, n = 248) MS patients (2.0 mL vs. 1.4 mL vs. 1.1 mL, respectively, ANCOVA p < 0.001, post-hoc pair-wise DP vs. Stable p = 0.003; and DP vs. DI, p = 0.002). Similar ANCOVA model was also significant for SCLV (p = 0.03). Conclusions: LVV-based atrophy and SCLV-based lesion outcomes are feasible on clinically acquired T2-FLAIR scans in a multicenter fashion and are associated with DP over mid-term.Publication Open Access Can COVID-19 related mental health issues be measured?(Elsevier, 2020) Ransing, Ramdas; Ramalho, Rodrigo; Orsolini, Laura; Adiukwu, Frances; Gonzalez-Diaz, Jairo M.; Larnaout, Amine; da Costa, Mariana Pinto; Grandinetti, Paolo; Bytyci, Drita Gashi; Shalbafan, Mohammadreza; Patil, Ishwar; Nofal, Marwa; Pereira-Sanchez, Victor; Kılıç, Özge; Doctor; Koç University HospitalPublication Open Access Censoring distances based on labeled cortical distance maps in cortical morphometry(Frontiers, 2013) Nishino, Tomoyuki; Alexopolous, Dimitrios; Todd, Richard D.; Botteron, Kelly N.; Miller, Michael I.; Ratnanather, J. Tilak; Department of Mathematics; Department of Mathematics; Ceyhan, Elvan; Undergraduate Student; Faculty Member; College of SciencesIt has been demonstrated that shape differences in cortical structures may be manifested in neuropsychiatric disorders. Such morphometric differences can be measured by labeled cortical distance mapping (LCDM) which characterizes the morphometry of the laminar cortical mantle of cortical structures. LCDM data consist of signed/labeled distances of gray matter (GM) voxels with respect to GM/white matter (VW) surface. Volumes and other summary measures for each subject and the pooled distances can help determine the morphometric differences between diagnostic groups, however they do not reveal all the morphometric information contained in LCDM distances. To extract more information from LCDM data, censoring of the pooled distances is introduced for each diagnostic group where the range of LCDM distances is partitioned at a fixed increment size; and at each censoring step, the distances not exceeding the censoring distance are kept. Censored LCDM distances inherit the advantages of the pooled distances but also provide information about the location of morphometric differences which cannot be obtained from the pooled distances. However, at each step, the censored distances aggregate, which might confound the results. The influence of data aggregation is investigated with an extensive Monte Carlo simulation analysis and it is demonstrated that this influence is negligible. As an illustrative example, GM of ventral medial prefrontal cortices (VMPFCs) of subjects with major depressive disorder (MDD), subjects at high risk (HR) of MDD, and healthy control (Ctrl) subjects are used. A significant reduction in laminar thickness of the VMPFC in MDD and HR subjects is observed compared to Ctrl subjects. Moreover, the GM LCDM distances (i.e., locations with respect to the GM/WM surface) for which these differences start to occur are determined. The methodology is also applicable to LCDM-based morphometric measures of other cortical structures affected by disease.Publication Open Access Changes in the expression of c-fos and AQP4 in the hippocampus and amygdala regions of rats with kainic acid-induced temporal lobe epilepsy and their role in the pathogenesis of disease(Galenos Yayınevi, 2022) Taşkıran, Emine; Yılmaz, Canan Uğur; Orhan, Nurcan; Kaya, Mehmet; Arıcan, Nadir; Bahçeci, Metin Berkant; Kaya, Mehmet; Gürses, Rabia Candan; Ahıshalı, Bülent; Faculty Member; Faculty Member; Faculty Member; School of Medicine; 10486; 110149; N/AObjective: aquaporin4 is the main water channel in the brain that is associated with neurological disorders. The role and the expressive changes of aquaporin4 in epilepsy are still limited and controversial. The study aims to evaluate the expression of c-fos and aquaporin4 during epileptogenesis after systemic kainic acid-induced status epilepticus in the temporal lobe epilepsy animal model and to investigate their alterations in both hippocampus and amygdala. Methods: intraperitoneal injections of kainic acid (5-15 mg/kg) by repeated low kainic acid protocol were given to young adult 32 Wistar albino rats for status epilepticus. Aquaporin4 and c-fos were investigated in the hippocampus and amygdala on days 1 and 60 after status epilepticus by immunostaining methods in brain slices. Results: the intensity of c-fos immunostaining rose considerably in the hippocampus CA1 area of rats during the acute period (P < 0.05) and in the amygdala during the chronic period. The immunostaining intensity of aquaporin4in the hippocampus of rats with acute kainic acid increased significantly (P <.05). It was also raised in the hippocampal region of the rats in the acute sham and chronic kainic acid groups. Discussion: the results of this study support a link between aquaporin4 and epilepsy. It can be speculated that aquaporin4 change is primarily a defense mechanism immediately after status epilepticus, and then, it can evolve into a causal factor with exhaustion as a result of overuse.