Publications by authors named "Miklos Palotai"

33 Publications

The effects of CRF and the urocortins on the hippocampal acetylcholine release in rats.

Neuropeptides 2021 Apr 20;88:102147. Epub 2021 Apr 20.

Department of Pathophysiology, Faculty of Medicine, University of Szeged, Hungary.

Corticotropin-releasing factor (CRF) and the urocortins (Ucn1, Ucn2 and Ucn3) are structurally related neuropeptides which act via two distinct CRF receptors, CRF1 and CRF2, with putatively antagonistic effects in the brain. CRF and Ucn1 activate both CRF1 and CRF2, while Ucn2 and Ucn3 activate selectively CRF2. The aim of the present study was to investigate the effects of CRF, Ucn1, Ucn2 and Ucn3 on the hippocampal acetylcholine release through which they may modulate cognitive functions, including attention, learning and memory. In this purpose male Wistar rats were used, their hippocampus was isolated, dissected, incubated, superfused and stimulated electrically. The hippocampal slices were first pretreated with selective CRF1 antagonist antalarmin or selective CRF2 antagonist astressinB, and then treated with non-selective CRF1 agonists, CRF or Ucn1, and selective CRF2 agonists, Ucn2 or Ucn3. The hippocampal acetylcholine release was increased significantly by CRF and Ucn1 and decreased significantly by Ucn2 and Ucn3. The increasing effect of CRF and Ucn1 was reduced significantly by antalarmin, but not astressinB. In contrast, the decreasing effect of Ucn2 and Ucn3 was reversed significantly by the selective CRF2, but not the selective CRF1 antagonist. Our results demonstrate that CRF and Ucn1 stimulate the hippocampal acetylcholine release through CRF1, whereas Ucn2 and Ucn3 inhibit the hippocampal acetylcholine release through CRF2. Therefore, the present study suggests the existence of two apparently opposing CRF systems in the hippocampus, through which CRF and the urocortins might modulate cholinergic activity and thereby cognitive functions.
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http://dx.doi.org/10.1016/j.npep.2021.102147DOI Listing
April 2021

Development and evaluation of a manual segmentation protocol for deep grey matter in multiple sclerosis: Towards accelerated semi-automated references.

Neuroimage Clin 2021 Apr 6;30:102659. Epub 2021 Apr 6.

Radiology and Nuclear Medicine, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Location VUmc, Amsterdam, NL, Netherlands.

Background: Deep grey matter (dGM) structures, particularly the thalamus, are clinically relevant in multiple sclerosis (MS). However, segmentation of dGM in MS is challenging; labeled MS-specific reference sets are needed for objective evaluation and training of new methods.

Objectives: This study aimed to (i) create a standardized protocol for manual delineations of dGM; (ii) evaluate the reliability of the protocol with multiple raters; and (iii) evaluate the accuracy of a fast-semi-automated segmentation approach (FASTSURF).

Methods: A standardized manual segmentation protocol for caudate nucleus, putamen, and thalamus was created, and applied by three raters on multi-center 3D T1-weighted MRI scans of 23 MS patients and 12 controls. Intra- and inter-rater agreement was assessed through intra-class correlation coefficient (ICC); spatial overlap through Jaccard Index (JI) and generalized conformity index (CIgen). From sparse delineations, FASTSURF reconstructed full segmentations; accuracy was assessed both volumetrically and spatially.

Results: All structures showed excellent agreement on expert manual outlines: intra-rater JI > 0.83; inter-rater ICC ≥ 0.76 and CIgen ≥ 0.74. FASTSURF reproduced manual references excellently, with ICC ≥ 0.97 and JI ≥ 0.92.

Conclusions: The manual dGM segmentation protocol showed excellent reproducibility within and between raters. Moreover, combined with FASTSURF a reliable reference set of dGM segmentations can be produced with lower workload.
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http://dx.doi.org/10.1016/j.nicl.2021.102659DOI Listing
April 2021

Usability of a Mobile App for Real-Time Assessment of Fatigue and Related Symptoms in Patients With Multiple Sclerosis: Observational Study.

JMIR Mhealth Uhealth 2021 Apr 16;9(4):e19564. Epub 2021 Apr 16.

Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

Background: Although fatigue is one of the most debilitating symptoms in patients with multiple sclerosis (MS), its pathogenesis is not well understood. Neurogenic, inflammatory, endocrine, and metabolic mechanisms have been proposed. Taking into account the temporal dynamics and comorbid mood symptoms of fatigue may help differentiate fatigue phenotypes. These phenotypes may reflect different pathogeneses and may respond to different mechanism-specific treatments. Although several tools have been developed to assess various symptoms (including fatigue), monitor clinical status, or improve the perceived level of fatigue in patients with MS, options for a detailed, real-time assessment of MS-related fatigue and relevant comorbidities are still limited.

Objective: This study aims to present a novel mobile app specifically designed to differentiate fatigue phenotypes using circadian symptom monitoring and state-of-the-art characterization of MS-related fatigue and its related symptoms. We also aim to report the first findings regarding patient compliance and the relationship between compliance and patient characteristics, including MS disease severity.

Methods: After developing the app, we used it in a prospective study designed to investigate the brain magnetic resonance imaging correlates of MS-related fatigue. In total, 64 patients with MS were recruited into this study and asked to use the app over a 2-week period. The app features the following modules: Visual Analogue Scales (VASs) to assess circadian changes in fatigue, depression, anxiety, and pain; daily sleep diaries (SLDs) to assess sleep habits and quality; and 10 one-time questionnaires to assess fatigue, depression, anxiety, sleepiness, physical activity, and motivation, as well as several other one-time questionnaires that were created to assess those relevant aspects of fatigue that were not captured by existing fatigue questionnaires. The app prompts subjects to assess their symptoms multiple times a day and enables real-time symptom monitoring through a web-accessible portal.

Results: Of 64 patients, 56 (88%) used the app, of which 51 (91%) completed all one-time questionnaires and 47 (84%) completed all one-time questionnaires, VASs, and SLDs. Patients reported no issues with the usage of the app, and there were no technical issues with our web-based data collection system. The relapsing-remitting MS to secondary-progressive MS ratio was significantly higher in patients who completed all one-time questionnaires, VASs, and SLDs than in those who completed all one-time questionnaires but not all VASs and SLDs (P=.01). No other significant differences in demographics, fatigue, or disease severity were observed between the degrees of compliance.

Conclusions: The app can be used with reasonable compliance across patients with relapsing-remitting and secondary-progressive MS irrespective of demographics, fatigue, or disease severity.
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http://dx.doi.org/10.2196/19564DOI Listing
April 2021

Microstructural Changes in the Left Mesocorticolimbic Pathway are Associated with the Comorbid Development of Fatigue and Depression in Multiple Sclerosis.

J Neuroimaging 2021 Feb 1. Epub 2021 Feb 1.

Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Background And Purpose: Lower reward responsiveness has been associated with fatigue in multiple sclerosis (MS). However, association of MS-related fatigue with damage to the mesocorticolimbic reward pathway (superolateral medial forebrain bundle [slMFB]) has not been assessed. We investigated the association of fatigue and depression with slMFB damage in MS patients stratified based on longitudinal fatigue patterns.

Methods: Patient stratification: 1. Sustained Fatigue (SF): latest two Modified Fatigue Impact Scale (MFIS) ≥ 38 (n = 26); 2. Reversible Fatigue (RF): latest MFIS < 38, and at least one previous MFIS ≥ 38 (n = 25); 3. Never Fatigued (NF): ≥ 5 consecutive MFIS < 38 (n = 42); 4. Healthy Controls (n = 6). Diffusion MRI-derived measures of fractional anisotropy (FA), axial (AD), mean (MD), and radial diffusivity (RD) of the slMFB were compared between the groups. Depression was assessed using the Center for Epidemiologic Studies-Depression Scale (CES-D).

Results: Depressed (CES-D ≥ 16) SF patients showed significantly higher MD and RD than nondepressed SF and RF, and depressed RF patients, and significantly lower FA than nondepressed SF and depressed RF patients in their left slMFB. Depressed SF patients showed significantly higher left slMFB MD and AD than healthy controls.

Conclusion: Microstructural changes to the left slMFB may play a role in the comorbid development of fatigue and depression in MS.
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http://dx.doi.org/10.1111/jon.12832DOI Listing
February 2021

Identification and Characterization of Leptomeningeal Metastases Using SPINE, A Web-Based Collaborative Platform.

J Neuroimaging 2021 Mar 17;31(2):324-333. Epub 2020 Dec 17.

Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Background And Purpose: Leptomeningeal metastases (LMs) carry a poor prognosis. Existing LM scoring systems show limited reproducibility. We assessed the contribution of education level on the reproducibility of LM scoring using structured planning and implementation of new experiments (SPINE), a novel web-based platform.

Methods: Stringent radiological definitions of LM and a customized interactive scoring system were implemented in SPINE. Five patients with brain LM and 3 patients with spine, but no brain LM, were selected. Each patient's baseline post-contrast T1-weighted brain MRI was analyzed by three attending neuroradiologists, two neuroradiology fellows, and two radiology residents. Raters identified and characterized all LMs based on: (1) location (cerebrum, cerebellum, brainstem, ventricle, and/or cranial nerves); (2) shape (nodular and/or linear/curvilinear); (3) size (≥ or <5mm in two orthogonal diameters); (4) spatial extension (focal or diffuse). Inter-rater agreement and association of LM with patient survival were investigated.

Results: On average, 6.5 LMs per case were detected. Forty-nine percent of LMs were cerebral, 77.7% were nodular, 86.6% were focal, and 66% were <5 × 5 mm. Agreement on the total number of LMs and the above-mentioned common LM characteristics was higher between attendings (intra-class correlation [ICC] = 0.8-0.94) than fellows (ICC = 0.6-0.82) or residents (ICC = 0.43-0.73). Agreement on ventricular, cranial nerve, and nodular + linear LM was low even between attendings. The number of brainstem LMs showed significant correlation with survival.

Conclusion: Structured education using SPINE may improve consistency in LM reporting. Future work should address the impact of the presented approach on the reproducibility of longitudinal analyses directly relevant to the assessment of treatment-response.
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http://dx.doi.org/10.1111/jon.12820DOI Listing
March 2021

Corrigendum: Perivascular Unit: This Must Be the Place. The Anatomical Crossroad Between the Immune, Vascular and Nervous System.

Front Neuroanat 2020 15;14:51. Epub 2020 Sep 15.

Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

[This corrects the article DOI: 10.3389/fnana.2020.00017.].
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http://dx.doi.org/10.3389/fnana.2020.00051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522475PMC
September 2020

Reduced accuracy of MRI deep grey matter segmentation in multiple sclerosis: an evaluation of four automated methods against manual reference segmentations in a multi-center cohort.

J Neurol 2020 Dec 3;267(12):3541-3554. Epub 2020 Jul 3.

Department of Radiology and Nuclear Medicine, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Location VUmc, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.

Background: Deep grey matter (DGM) atrophy in multiple sclerosis (MS) and its relation to cognitive and clinical decline requires accurate measurements. MS pathology may deteriorate the performance of automated segmentation methods. Accuracy of DGM segmentation methods is compared between MS and controls, and the relation of performance with lesions and atrophy is studied.

Methods: On images of 21 MS subjects and 11 controls, three raters manually outlined caudate nucleus, putamen and thalamus; outlines were combined by majority voting. FSL-FIRST, FreeSurfer, Geodesic Information Flow and volBrain were evaluated. Performance was evaluated volumetrically (intra-class correlation coefficient (ICC)) and spatially (Dice similarity coefficient (DSC)). Spearman's correlations of DSC with global and local lesion volume, structure of interest volume (ROIV), and normalized brain volume (NBV) were assessed.

Results: ICC with manual volumes was mostly good and spatial agreement was high. MS exhibited significantly lower DSC than controls for thalamus and putamen. For some combinations of structure and method, DSC correlated negatively with lesion volume or positively with NBV or ROIV. Lesion-filling did not substantially change segmentations.

Conclusions: Automated methods have impaired performance in patients. Performance generally deteriorated with higher lesion volume and lower NBV and ROIV, suggesting that these may contribute to the impaired performance.
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http://dx.doi.org/10.1007/s00415-020-10023-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674567PMC
December 2020

Magnetic Resonance Elastography reveals effects of anti-angiogenic glioblastoma treatment on tumor stiffness and captures progression in an orthotopic mouse model.

Cancer Imaging 2020 May 12;20(1):35. Epub 2020 May 12.

Department of Radiology, Brigham and Women's Hospital, Boston, MA, USA.

Background: Anti-angiogenic treatment of glioblastoma (GBM) complicates radiologic monitoring. We evaluated magnetic resonance elastography (MRE) as an imaging tool for monitoring the efficacy of anti-VEGF treatment of GBM.

Methods: Longitudinal studies were performed in an orthotopic GBM xenograft mouse model. Animals treated with B20 anti-VEGF antibody were compared to untreated controls regarding survival (n = 13), classical MRI-contrasts and biomechanics as quantified via MRE (n = 15). Imaging was performed on a 7 T small animal horizontal bore MRI scanner. MRI and MRE parameters were compared to histopathology.

Results: Anti-VEGF-treated animals survived longer than untreated controls (p = 0.0011) with progressively increased tumor volume in controls (p = 0.0001). MRE parameters viscoelasticity |G*| and phase angle Y significantly decreased in controls (p = 0.02 for |G*| and p = 0.0071 for Y). This indicates that untreated tumors became softer and more elastic than viscous with progression. Tumor volume in treated animals increased more slowly than in controls, indicating efficacy of the therapy, reaching significance only at the last time point (p = 0.02). Viscoelasticity and phase angle Y tended to decrease throughout therapy, similar as for control animals. However, in treated animals, the decrease in phase angle Y was significantly attenuated and reached statistical significance at the last time point (p = 0.04). Histopathologically, control tumors were larger and more heterogeneous than treated tumors. Vasculature was normalized in treated tumors compared with controls, which showed abnormal vasculature and necrosis. In treated tumors, a higher amount of myelin was observed within the tumor area (p = 0.03), likely due to increased tumor invasion. Stiffness of the contralateral hemisphere was influenced by tumor mass effect and edema.

Conclusions: Anti-angiogenic GBM treatment prolonged animal survival, slowed tumor growth and softening, but did not prevent progression. MRE detected treatment effects on tumor stiffness; the decrease of viscoelasticity and phase angle in GBM was attenuated in treated animals, which might be explained by normalized vasculature and greater myelin preservation within treated tumors. Thus, further investigation of MRE is warranted to understand the potential for MRE in monitoring treatment in GBM patients by complementing existing MRI techniques.
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http://dx.doi.org/10.1186/s40644-020-00314-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218549PMC
May 2020

Perivascular Unit: This Must Be the Place. The Anatomical Crossroad Between the Immune, Vascular and Nervous System.

Front Neuroanat 2020 16;14:17. Epub 2020 Apr 16.

Harvard Medical School, Center for Neurological Imaging, Brigham and Women's Hospital, Boston, MA, United States.

Most neurological disorders seemingly have heterogenous pathogenesis, with overlapping contribution of neuronal, immune and vascular mechanisms of brain injury. The perivascular space in the brain represents a crossroad where those mechanisms interact, as well as a key anatomical component of the recently discovered glymphatic pathway, which is considered to play a crucial role in the clearance of brain waste linked to neurodegenerative diseases. The pathological interplay between neuronal, immune and vascular factors can create an environment that promotes self-perpetration of mechanisms of brain injury across different neurological diseases, including those that are primarily thought of as neurodegenerative, neuroinflammatory or cerebrovascular. Changes of the perivascular space can be monitored in humans using magnetic resonance imaging (MRI). In the context of glymphatic clearance, MRI-visible enlarged perivascular spaces (EPVS) are considered to reflect glymphatic stasis secondary to the perivascular accumulation of brain debris, although they may also represent an adaptive mechanism of the glymphatic system to clear them. EPVS are also established correlates of dementia and cerebral small vessel disease (SVD) and are considered to reflect brain inflammatory activity. In this review, we describe the "perivascular unit" as a key anatomical and functional substrate for the interaction between neuronal, immune and vascular mechanisms of brain injury, which are shared across different neurological diseases. We will describe the main anatomical, physiological and pathological features of the perivascular unit, highlight potential substrates for the interplay between different noxae and summarize MRI studies of EPVS in cerebrovascular, neuroinflammatory and neurodegenerative disorders.
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http://dx.doi.org/10.3389/fnana.2020.00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177187PMC
April 2020

A novel classification of fatigue in multiple sclerosis based on longitudinal assessments.

Mult Scler 2020 05 23;26(6):725-734. Epub 2020 Jan 23.

Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Background: Magnetic resonance imaging (MRI) studies of multiple sclerosis-related fatigue had limited reproducibility. Temporal fatigue fluctuations have not been considered.

Objective: To investigate whether a novel group allocation that reflects temporal dynamics of fatigue improves our ability to detect fatigue-associated structural brain abnormalities.

Methods: Patient stratification based on biennial fatigue assessments: sustained fatigue (SF,  = 29, fatigued at the latest ⩾2 assessments), one time-point fatigue (1F,  = 15, fatigued at the latest, but non-fatigued at the penultimate assessment), reversible fatigue (RF,  = 31, non-fatigued at the latest assessment, but reported fatigue previously), and never fatigued (NF,  = 54). Brain parenchymal fraction (BPF) and T2 lesion volume (T2LV) were compared between these groups and were derived using a conventional, single time-point fatigued versus non-fatigued stratification.

Results: The SF versus NF stratification yielded improved power. SF ( = 0.005) and RF ( = 0.043) showed significantly higher T2LV than NF. T2LV showed no significant differences in SF versus 1F, SF versus RF, or 1F versus RF. Fatigued versus non-fatigued patients showed significantly higher T2LV ( = 0.030). We found no significant differences in BPF between the groups.

Conclusion: Taking into account temporal fatigue dynamics increases the statistical power with respect to T2LV and may improve characterization of brain pathological correlates of MS-related fatigue.
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http://dx.doi.org/10.1177/1352458519898112DOI Listing
May 2020

History of fatigue in multiple sclerosis is associated with grey matter atrophy.

Sci Rep 2019 10 14;9(1):14781. Epub 2019 Oct 14.

Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Fatigue in multiple sclerosis (MS) has been associated with brain damage with low replicability. Temporal fatigue fluctuations have not been considered. We assessed whether sustained fatigue (SF) associates more strongly with grey matter (GM) changes than reversible fatigue (RF). Patients were stratified into three groups according to historical fatigue levels: SF (n = 30, i.e. patients who reported fatigue at the latest ≥2 assessments), RF (n = 31, i.e. patients not fatigued at the latest assessment, but reported fatigue previously), and never fatigued (NF, n = 37). Groups were compared for brain GM volume using cross-sectional voxel-based and volumetric analyses of 3T T1-weighted MRI. Confounding effects of depression and related medications were also investigated. SF and RF patients showed similar anatomical distribution of GM atrophy. While we robustly replicated the anatomical patterns of GM atrophy described in previous work, we also found an association between hippocampal atrophy and fatigue. Depression showed confounding effects in frontal, parietal, occipital, accumbal and thalamic regions. Assessed treatments showed confounding effects in frontal, parietal and striatal areas. Our results suggest that history of clinically-relevant fatigue in currently non-fatigued patients is associated with GM atrophy, potentially explaining inconsistent findings of previous studies that stratified patients using a single fatigue assessment.
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http://dx.doi.org/10.1038/s41598-019-51110-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791855PMC
October 2019

Brain anatomical correlates of fatigue in multiple sclerosis.

Mult Scler 2020 06 19;26(7):751-764. Epub 2019 Sep 19.

Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Fatigue is one of the most debilitating symptoms in patients with multiple sclerosis (MS). Despite its clinical significance, the aetiology and pathophysiology of MS-related fatigue are not well understood. Current evidence and understanding of the neuroanatomical underpinnings of MS-related fatigue are reviewed in this article. The aims of this paper are to (1) review the findings of previous structural neuroimaging studies on MS-related fatigue and summarize consistent findings regarding brain circuitry associated with fatigue in MS, (2) contextualize these findings with the neurochemistry of the relevant circuits and (3) discuss future perspectives with regard to impact on fatigue management of MS patients and methodological challenges towards improved understanding of fatigue pathogenesis. The detailed understanding of the neuroanatomical underpinnings of fatigue might contribute to the identification of novel treatment targets and factors determining treatment resistance to drugs used in current clinical practice.
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http://dx.doi.org/10.1177/1352458519876032DOI Listing
June 2020

Microstructural fronto-striatal and temporo-insular alterations are associated with fatigue in patients with multiple sclerosis independent of white matter lesion load and depression.

Mult Scler 2020 11 16;26(13):1708-1718. Epub 2019 Aug 16.

Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Background: Fatigue in multiple sclerosis (MS) has been inconsistently associated with disruption of specific brain circuitries. Temporal fluctuations of fatigue have not been considered.

Objective: The aim of this study was to investigate the association of fatigue with brain diffusion abnormalities, using robust criteria for patient stratification based on longitudinal patterns of fatigue.

Methods: Patient stratification: (1) sustained fatigue (SF, = 26): latest two Modified Fatigue Impact Scale (MFIS) ⩾ 38; (2) reversible fatigue (RF, = 25): latest MFIS < 38 and minimum one previous MFIS ⩾ 38; and (3) never fatigued (NF, = 42): MFIS always < 38 (five assessments minimum). 3T brain magnetic resonance imaging (MRI) was used to perform voxel-wise comparison of fractional anisotropy (FA) between the groups controlling for age, sex, disease duration, physical disability, white matter lesion load (T2LV), and depression.

Results: SF and, to a lesser extent, RF patients showed lower FA in multiple brain regions compared to NF patients, independent of age, sex, disease duration, and physical disability. In cingulo-postcommissural-striato-thalamic regions, the differences in FA between SF and NF (but not between RF and NF or SF) patients were independent of T2LV, and in ventromedial prefronto-precommissuro-striatal and temporo-insular areas, independent of T2LV and depression.

Conclusion: Damage to ventromedial prefronto-precommissuro-striatal and temporo-insular pathways appears to be a specific substrate of SF in MS.
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http://dx.doi.org/10.1177/1352458519869185DOI Listing
November 2020

Imaging localized neuronal activity at fast time scales through biomechanics.

Sci Adv 2019 04 17;5(4):eaav3816. Epub 2019 Apr 17.

School of Biomedical Engineering and Imaging Sciences, Kings College London, London, UK.

Mapping neuronal activity noninvasively is a key requirement for in vivo human neuroscience. Traditional functional magnetic resonance (MR) imaging, with a temporal response of seconds, cannot measure high-level cognitive processes evolving in tens of milliseconds. To advance neuroscience, imaging of fast neuronal processes is required. Here, we show in vivo imaging of fast neuronal processes at 100-ms time scales by quantifying brain biomechanics noninvasively with MR elastography. We show brain stiffness changes of ~10% in response to repetitive electric stimulation of a mouse hind paw over two orders of frequency from 0.1 to 10 Hz. We demonstrate in mice that regional patterns of stiffness modulation are synchronous with stimulus switching and evolve with frequency. For very fast stimuli (100 ms), mechanical changes are mainly located in the thalamus, the relay location for afferent cortical input. Our results demonstrate a new methodology for noninvasively tracking brain functional activity at high speed.
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http://dx.doi.org/10.1126/sciadv.aav3816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469937PMC
April 2019

Aquaporin 4 distribution in the brain and its relevance for the radiological appearance of neuromyelitis optica spectrum disease.

J Neuroradiol 2019 Apr 11. Epub 2019 Apr 11.

Université Lyon 1, Laboratoire d'Anatomie de Rockefeller,Centre Hospitalier Lyon Sud, Service de Radiologie, Pierre Bénite, CREATIS-LRMN, CNRS/UMR/5220-INSERM U630, Villeurbanne, France.

Background And Purpose: To determine the precise incidence of lesions at sites of high Aquaporin-4 expression (hAQP4) and their possible association with known neuromyelitis optica spectrum disease (NMOSD) lesions patterns.

Materials And Methods: A retrospective analysis of brain and, when available, spinal cord MRI scans of 54 NMOSD patients recruited among the French NMOSD cohort was performed. Brain lesions were annotated as MS-like, non-specific, or evocative of NMOSD. The topography of hAQP4 was reassessed by human brain atlas. The incidence of lesions in hAQP4 and their association with lesions evocative of NMOSD was estimated.

Results: Among those included (41/54 female, mean age:45 years) 47/54(87%) presented brain lesions. Twenty-six/47(55%) had lesions in hAQP4. Thirty-two/54 patients(60%) had lesions considered evocative of NMOSD. The majority of them also presented lesions in hAQP4 (65%, 21/32). Patients with lesions in hAQP4 and lesions evocative of NMOSD demonstrated more extensive myelitis compared to the other patients (7[6-10] versus 4[3-5] vertebral segments, P = 0.009).

Conclusion: The coexistence of lesions evocative of NMOSD and in hAQP4 is associated with significantly more extensive myelitis, and might have pathophysiological and clinical significance.
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http://dx.doi.org/10.1016/j.neurad.2019.03.015DOI Listing
April 2019

Changes in striatal dopamine release and locomotor activity following acute withdrawal from chronic nicotine are mediated by CRF1, but not CRF2, receptors.

Brain Res 2019 03 26;1706:41-47. Epub 2018 Oct 26.

Department of Pathophysiology, Faculty of Medicine, University of Szeged, Hungary. Electronic address:

The aim of the present study was to investigate the participation of corticotropin-releasing factor (CRF) receptors (CRF1 and CRF2) in the alterations of the dorsal and ventral striatal dopamine release and the vertical and horizontal locomotor activity observed in rats following chronic nicotine treatment and consequent acute withdrawal. In this purpose, male Wistar rats were exposed to repeated intraperitoneal (ip) injection with nicotine or saline solution for 7 days. On the 8th day or the 9th day the rats were injected intracerebroventricularly (icv) with selective CRF1 antagonist antalarmin or selective CRF2 antagonist astressin or saline solution. Thirty minutes after the icv injection the changes of the horizontal and vertical locomotor activity were recorded in an in vivo conducta system. Immediately after the behavioral recordings the changes of the dorsal and ventral striatal dopamine release were determined in an in vitro superfusion system. On the 8th day, the horizontal and vertical locomotor activities and the dorsal and ventral striatal dopamine releases increased significantly in nicotine-treated rats, compared to the saline-treated ones. On the 9th day, the horizontal locomotor activity and the dorsal striatal dopamine release increased significantly, whereas the vertical locomotor activity and the ventral striatal dopamine release decreased significantly in nicotine-treated rats, compared to the saline-treated ones. All the changes observed were attenuated significantly by antalarmin, but not astressin. The present study demonstrates that the changes of striatal dopamine release and locomotor activity observed following chronic nicotine treatment and consequent acute withdrawal are mediated by CRF1, but not CRF2, receptor.
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http://dx.doi.org/10.1016/j.brainres.2018.10.028DOI Listing
March 2019

Evaluating the Association between Enlarged Perivascular Spaces and Disease Worsening in Multiple Sclerosis.

J Neuroimaging 2018 05 11;28(3):273-277. Epub 2017 Dec 11.

Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Background And Purpose: Enlarged perivascular spaces (EPVSs) have been associated with relapses and brain atrophy in multiple sclerosis (MS). We investigated the association of EPVS with clinical and MRI features of disease worsening in a well-characterized cohort of relapsing-remitting MS patients prospectively followed for up to 10 years.

Methods: Baseline EPVSs were scored on 1.5T MRI in 30 converters to moderate-severe disability, and 30 nonconverters matched for baseline characteristics.

Results: EPVS scores were not significantly different between converters and nonconverters, nor associated with accrual of lesions or brain atrophy.

Conclusions: Our preliminary findings from a relatively small study sample argue against a potential use of EPVS as early indicator of risk for disease worsening in relapsing-remitting MS patients in a clinical setting. Although the small sample size and clinical 1.5T MRI may have limited our ability to detect a significant effect, we provided estimates of the association of EPVS with clinical and MRI indicators of disease worsening in a well-characterized cohort of MS patients.
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http://dx.doi.org/10.1111/jon.12490DOI Listing
May 2018

Characterization of glioblastoma in an orthotopic mouse model with magnetic resonance elastography.

NMR Biomed 2018 10 29;31(10):e3840. Epub 2017 Nov 29.

Department of Radiology, Brigham and Women's Hospital, Boston, MA, USA.

Glioblastoma (GBM) is the most common primary brain tumor. It is highly malignant and has a correspondingly poor prognosis. Diagnosis and monitoring are mainly accomplished with MRI, but remain challenging in some cases. Therefore, complementary methods for tumor detection and characterization would be beneficial. Using magnetic resonance elastography (MRE), we performed a longitudinal study of the biomechanical properties of intracranially implanted GBM in mice and compared the results to histopathology. The biomechanical parameters of viscoelastic modulus, shear wave speed and phase angle were significantly lower in tumors compared with healthy brain tissue and decreased over time with tumor progression. Moreover, some MRE parameters revealed sub-regions at later tumor stages, which were not easily detectable on anatomical MRI images. Comparison with histopathology showed that softer tumor regions contained necrosis and patches of viable tumor cells. In contrast, areas of densely packed tumor cells and blood vessels identified with histology coincided with higher values of viscoelastic modulus and shear wave speed. Interestingly, the phase angle was independent from these anatomical variations. In summary, MRE depicted longitudinal and morphological changes in GBM and may prove valuable for tumor characterization in patients.
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http://dx.doi.org/10.1002/nbm.3840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538416PMC
October 2018

Changes to the septo-fornical area might play a role in the pathogenesis of anxiety in multiple sclerosis.

Mult Scler 2018 07 26;24(8):1105-1114. Epub 2017 May 26.

Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Background: Reports on the relationships between white matter lesion load (WMLL) and fatigue and anxiety in multiple sclerosis (MS) are inconsistent.

Objective: To investigate the association of total and tract-specific WMLL with fatigue and anxiety.

Methods: Total and regional T2 WMLL was assessed for 19 tracts in 48 MS patients (30 females). ICBM-DTI-81 Atlas-based parcellation was combined with WMLL segmentation of T2-weighted magnetic resonance imaging (MRI). Fatigue, anxiety, and depression were assessed using Fatigue Impact Scale, State Trait Anxiety Inventory, and Beck Depression Inventory, respectively.

Results: Fatigue, anxiety, and depression showed significant inter-correlation. We found no association between fatigue and total or regional WMLLs, whereas anxiety was associated with total and regional WMLLs in nine tracts. After adjusting for total WMLL, age, and depression, only the column and body of the fornix (CBF) remained significantly associated with anxiety. Post hoc analyses showed no CBF lesions on T1-weighted MRI and suggested, but could not confirm, that the septum pellucidum might play a role in the pathogenesis of anxiety.

Conclusion: Our results suggest that anxiety in MS patients may have a neuropathological substrate in the septo-fornical area, which requires further validation using larger sample size and ultra-high-field MRI in targeted prospective studies.
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http://dx.doi.org/10.1177/1352458517711273DOI Listing
July 2018

Selective CRF2 receptor agonists ameliorate the anxiety- and depression-like state developed during chronic nicotine treatment and consequent acute withdrawal in mice.

Brain Res 2016 12 29;1652:21-29. Epub 2016 Sep 29.

Department of Pathophysiology, Faculty of Medicine, University of Szeged, Hungary.

The aim of the present study was to investigate the effects of the selective agonists of the corticotropin-releasing factor (CRF) 2 receptor, urocortin 2 (UCN 2) and urocortin 3 (UCN 3), on the anxiety- and depression-like signs induced by acute nicotine withdrawal in mice. In order to do so, male CFLP mice were exposed for 7 days to repeated intraperitoneal (IP) injection with nicotine or saline solution and 1day of acute withdrawal and then a single intracerebroventricular (ICV) injection with UCN 2, UCN 3 or saline solution. After 30min the mice were observed in an elevated plus-maze test or a forced swim test, for anxiety- and depression-like behavior. After 5min of testing, the plasma corticosterone concentration reflecting the activity of the hypothalamic-pituitary-adrenal (HPA) axis was also determined by a chemo-fluorescent method. Half of the animals were treated ICV and evaluated on the 8th day, the other half on the 9th day. On the 8th day, nicotine-treated mice presented signs of anxiolysis and depression, but no significant elevation of the plasma corticosterone concentration. On the 9th day, nicotine-treated mice exhibited signs of anxiety and depression and a significant increase of the plasma corticosterone levels. Central administration of UCN 2 or UCN 3 ameliorated the anxiety- and depression-like state including the hyperactivity of the HPA axis, developed during acute withdrawal following chronic nicotine treatment. The present study suggests that selective CRF2 receptor agonists could be used as a therapy in nicotine addiction.
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http://dx.doi.org/10.1016/j.brainres.2016.09.044DOI Listing
December 2016

Anxiolytic effect of the GPR103 receptor agonist peptide P550 (homolog of neuropeptide 26RFa) in mice. Involvement of neurotransmitters.

Peptides 2016 08 17;82:20-25. Epub 2016 May 17.

Department of Pathophysiology, Faculty of Medicine, University of Szeged, Hungary; Neuroscience Research Group of the Hungarian Academy of Sciences, Szeged, Hungary.

The GPR103 receptor is a G protein-coupled receptor, which plays a role in several physiological functions. However, the role of the GPR103 receptor in anxiety has not been clarified. The first aim of our study was to elucidate the involvement of the GPR103 receptor in anxious behavior. Mice were treated with peptide P550, which is the mouse homolog of neuropeptide 26RFa and has similar activity for the GPR103 receptor as neuropeptide 26RFa. The anxious behavior was investigated using an elevated plus-maze paradigm. The second aim of our study was to investigate the underlying neurotransmissions. Accordingly, mice were pretreated with a nonselective muscarinic acetylcholine receptor antagonist, atropine, a γ-aminobutyric acid subunit A (GABAA) receptor antagonist, bicuculline, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a D2, D3, D4 dopamine receptor antagonist, haloperidol, a nonselective α-adrenergic receptor antagonist, phenoxybenzamine and a nonselective β-adrenergic receptor antagonist, propranolol. Our results demonstrated that peptide P550 reduces anxious behavior in elevated plus maze test in mice. Our study shows also that GABAA-ergic, α- and β-adrenergic transmissions are all involved in this action, whereas 5-HT1 and 5-HT2 serotonergic, muscarinic cholinergic and D2, D3, D4 dopaminergic mechanisms may not be implicated.
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http://dx.doi.org/10.1016/j.peptides.2016.05.004DOI Listing
August 2016

Fatigue predicts disease worsening in relapsing-remitting multiple sclerosis patients.

Mult Scler 2016 12 26;22(14):1841-1849. Epub 2016 Feb 26.

Partners Multiple Sclerosis Center, Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Background: It is unclear whether fatigue is a consequence or a predictive trait of disease worsening.

Objective: To investigate the predictive value of fatigue toward conversion to confirmed moderate-severe disability in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: We retrospectively selected from the Comprehensive Longitudinal Investigations in MS at the Brigham and Women's Hospital (CLIMB) study cohort RRMS patients who converted to confirmed (⩾2 years) Expanded Disability Status Scale (EDSS) score ⩾3 within a follow-up period ⩾3 years. We contrasted the Modified Fatigue Impact Scale (MFIS) score of 33 converters, obtained at least 1 year before conversion to EDSS ⩾3, with that of 33 non-converter RRMS patients matched for baseline characteristics.

Results: Total MFIS score was higher in converter versus non-converter MS patients (median 37 vs 13; p < 0.0001). EDSS and Center for Epidemiological Studies Depression scale (CES-D) scores were also higher in the converters (median EDSS 1.5 vs 0, p < 0.0001; median CES-D 30 vs 24, p < 0.0001) and were both associated with MFIS score (EDSS: rho = 0.42, p = 0.0005; CES-D: rho = 0.72, p < 0.0001). After adjusting for EDSS and CES-D in multivariate analysis, MFIS remained a significant predictor of subsequent conversion to confirmed EDSS ⩾3.

Conclusion: Fatigue is a promising indicator of risk for conversion to confirmed moderate-severe disability in RRMS patients.
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http://dx.doi.org/10.1177/1352458516635874DOI Listing
December 2016

The action of neuropeptide AF on passive avoidance learning. Involvement of neurotransmitters.

Neurobiol Learn Mem 2016 Jan 28;127:34-41. Epub 2015 Nov 28.

Department of Pathophysiology, Faculty of Medicine, University of Szeged, Hungary.

Neuropeptide AF (NPAF) is an amidated octadecapeptide, which is member of the RFamide peptide family. NPAF is encoded by the farp-1 gene and acts through the G protein coupled NPFF-1 and NPFF-2 receptors. NPAF is involved in several physiological functions of the central nervous system, however we have little evidence about the involvement of NPAF in learning and memory. Therefore, the aim of the present study was to investigate the action of NPAF on consolidation of memory in a passive avoidance learning paradigm in mice. We have also investigated the underlying neurotransmissions and the action of NPAF on β-amyloid-induced memory impairment. Accordingly, mice were pretreated with a nonselective muscarinic acetylcholine receptor antagonist, atropine, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a D2, D3, D4 dopamine receptor antagonist, haloperidol, a non-selective opioid receptor antagonist, naloxone, a nitric oxide synthase inhibitor, nitro-l-arginine, a α1/α2β-adrenergic receptor antagonist, prazosin, a nonselective β-adrenergic receptor antagonist, propranolol or β-amyloid 25-35 in combination with NPAF administration. Our results demonstrate for the first time that NPAF improves the consolidation of passive avoidance learning. This effect is mediated through muscarinic cholinergic, 5HT1- and 5HT2-serotoninergic, dopaminergic, nitrergic and α- and β-adrenergic neurotransmissions, but not by opioid transmission, since atropine, cyproheptadine, methysergide, haloperidol, nitro-l-arginine, prazosin and propranolol reversed the action of NPAF, whereas naloxone was ineffective. The present study also shows that NPAF reverses the β-amyloid 25-35-induced memory impairment.
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http://dx.doi.org/10.1016/j.nlm.2015.11.011DOI Listing
January 2016

Neuropeptide AF induces anxiety-like and antidepressant-like behavior in mice.

Behav Brain Res 2014 Nov 10;274:264-9. Epub 2014 Aug 10.

Department of Pathophysiology, Faculty of Medicine, University of Szeged, Hungary.

Little is known about the action of neuropeptide AF (NPAF) on anxiety and depression. Only our previous study provides evidence that NPAF induces anxiety-like behavior in rats. Therefore, the aim of the present study was to investigate the action of NPAF on depression-like behavior and the underlying neurotransmissions in mice. In order to determine whether there are species differences between rats and mice, we have investigated the action of NPAF on anxiety-like behavior in mice as well. A modified forced swimming test (mFST) and an elevated plus maze test (EPMT) were used to investigate the depression and anxiety-related behaviors, respectively. Mice were treated with NPAF 30min prior to the tests. In the mFST, the animals were pretreated with a non-selective muscarinic acetylcholine receptor antagonist, atropine, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a D2/D3/D4 dopamine receptor antagonist, haloperidol, a α1/α2β-adrenergic receptor antagonist, prazosin or a non-selective β-adrenergic receptor antagonist, propranolol 30min before the NPAF administration. In the mFST, NPAF decreased the immobility time and increased the climbing and swimming times. This action was reversed completely by methysergide and partially by atropine, whereas cyproheptadine, haloperidol, prazosin and propranolol were ineffective. In the EPMT, NPAF decreased the time spent in the arms (open/open+closed). Our results demonstrate that NPAF induces anti-depressant-like behavior in mice, which is mediated, at least in part, through 5HT2-serotonergic and muscarinic cholinergic neurotransmissions. In addition, the NPAF-induced anxiety is species-independent, since it develops also in mice.
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http://dx.doi.org/10.1016/j.bbr.2014.08.007DOI Listing
November 2014

The action of orexin B on passive avoidance learning. Involvement of neurotransmitters.

Behav Brain Res 2014 Oct 13;272:1-7. Epub 2014 Jun 13.

Department of Pathophysiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.

The extensive projection of orexigenic neurons and the diffuse expression of orexin receptors suggest that endogenous orexins are involved in several physiological functions of the central nervous system, including learning and memory. Our previous study demonstrated that orexin A improves learning, consolidation and retrieval processes, which involves α- and β-adrenergic, cholinergic, dopaminergic, GABA-A-ergic, opiate and nitrergic neurotransmissions. However, we have little evidence about the action of orexin B on memory processes and the underlying neuromodulation. Therefore, the aim of the present study was to investigate the action of orexin B on passive avoidance learning and the involvement of neurotransmitters in this action in rats. Accordingly, rats were pretreated with the selective orexin 2 receptor (OX2R) antagonist, EMPA; the γ-aminobutyric acid subunit A (GABA-A) receptor antagonist, the bicuculline; a D2, D3, D4 dopamine receptor antagonist, haloperidol; the nonselective opioid receptor antagonist, naloxone; the non-specific nitric oxide synthase (NOS) inhibitor, nitro-l-arginine; the nonselective α-adrenergic receptor antagonist, phenoxybenzamine and the β-adrenergic receptor antagonist, propranolol. Our results demonstrate that orexin B can improve learning, consolidation of memory and retrieval. EMPA reversed completely the action of orexin B on memory consolidation. Bicuculline blocked fully; naloxone, nitro-l-arginine, phenoxybenzamine and propranolol attenuated the orexin B-induced memory consolidation, whereas haloperidol was ineffective. These data suggest that orexin B improves memory functions through OX2R and GABA-ergic, opiate, nitrergic, α- and β-adrenergic neurotransmissions are also involved in this action.
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http://dx.doi.org/10.1016/j.bbr.2014.06.016DOI Listing
October 2014

Involvement of neurotransmitters in the action of the nociceptin/orphanin FQ peptide-receptor system on passive avoidance learning in rats.

Neurochem Res 2014 Aug 4;39(8):1477-83. Epub 2014 Jun 4.

Department of Pathophysiology, Faculty of Medicine, University of Szeged, Semmelweis Str. 1, Szeged, 6701, Hungary.

The nociceptin/orphanin FQ peptide (NOP) receptor and its endogenous ligand plays role in several physiologic functions of the central nervous system, including pain, locomotion, anxiety and depression, reward and drug addiction, learning and memory. Previous studies demonstrated that the NOP-receptor system induces impairment in memory and learning. However, we have little evidence about the underlying neuromodulation. The aim of the present study was to investigate the involvement of distinct neurotransmitters in the action of the selective NOP receptor agonist orphan G protein-coupled receptor (GPCR) SP9155 P550 on memory consolidation in a passive avoidance learning test in rats. Accordingly, rats were pretreated with a nonselective muscarinic acetylcholine receptor antagonist, atropine, a γ-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline, a D2, D3, D4 dopamine receptor antagonist, haloperidol, a nonselective opioid receptor antagonist, naloxone, a non-specific nitric oxide synthase inhibitor, nitro-L-arginine, a nonselective α-adrenergic receptor antagonist, phenoxybenzamine and a β-adrenergic receptor antagonist, propranolol. Atropine, bicuculline, naloxone and phenoxybenzamine reversed the orphan GPCR SP9155 P550-induced memory impairment, whereas propranolol, haloperidol and nitro-L-arginine were ineffective. Our results suggest that the NOP system-induced impairment of memory consolidation is mediated through muscarinic cholinergic, GABA-A-ergic, opioid and α-adrenergic receptors, whereas β-adrenergic, D2, D3, D4-dopaminergic and nitrergic mechanisms are not be implicated.
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http://dx.doi.org/10.1007/s11064-014-1337-8DOI Listing
August 2014

Orexin A-induced anxiety-like behavior is mediated through GABA-ergic, α- and β-adrenergic neurotransmissions in mice.

Peptides 2014 Jul 27;57:129-34. Epub 2014 May 27.

Department of Pathophysiology, Faculty of Medicine, University of Szeged, Hungary.

Orexins are hypothalamic neuropeptides, which are involved in several physiological functions of the central nervous system, including anxiety and stress. Several studies provide biochemical and behavioral evidence about the anxiogenic action of orexin A. However, we have little evidence about the underlying neuromodulation. Therefore, the aim of the present study was to investigate the involvement of neurotransmitters in the orexin A-induced anxiety-like behavior in elevated plus maze (EPM) test in mice. Accordingly, mice were pretreated with a non-selective muscarinic cholinergic antagonist, atropine; a γ-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline; a D2, D3, D4 dopamine receptor antagonist, haloperidol; a non-specific nitric oxide synthase (NOS) inhibitor, nitro-l-arginine; a nonselective α-adrenergic receptor antagonist, phenoxybenzamine and a β-adrenergic receptor antagonist, propranolol 30min prior to the intracerebroventricular administration of orexin A. The EPM test started 30min after the i.c.v. injection of the neuropeptide. Our results show that orexin A decreases significantly the time spent in the arms (open/open+closed) and this action is reversed by bicuculline, phenoxybenzamine and propranolol, but not by atropine, haloperidol or nitro-l-arginine. Our results provide evidence for the first time that the orexin A-induced anxiety-like behavior is mediated through GABA-A-ergic, α- and β-adrenergic neurotransmissions, whereas muscarinic cholinergic, dopaminergic and nitrergic neurotransmissions may not be implicated.
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http://dx.doi.org/10.1016/j.peptides.2014.05.003DOI Listing
July 2014

Interleukin-1β (187-207)-induced hyperthermia is inhibited by interleukin-1β (193-195) in rats.

Neurochem Res 2014 Feb 13;39(2):254-8. Epub 2013 Dec 13.

Department of Pathophysiology, Faculty of Medicine, University of Szeged, 6725, Semmelweis Str. 1, Szeged, Hungary.

Interleukin-1β (IL-1β) is a pro-inflammatory cytokine, which plays an important role in the immune response and signal transduction both in the periphery and the central nervous system (CNS). Various diseases of the CNS, including neurodegenerative disorders, vascular lesions, meningo-encephalitis or status epilepticus are accompanied by elevated levels of IL-1β. Different domains within the IL-lβ protein are responsible for distinct functions. The IL-lβ domain in position 208-240 has pyrogenic properties, while the domain in position 193-195 exerts anti-inflammatory effects. Previous studies provide little evidence about the effect of the domain in position 187-207 on the body temperature. Therefore, the aim of the present study was to investigate the action of IL-1β (187-207) and its interaction with IL-1β (193-195) on the body temperature. IL fragments were administered intracerebroventricularly and the body temperature was measured rectally in male Wistar rats. IL-1β (187-207) induced hyperthermia, while IL-1β (193-195) did not influence the core temperature considerably. In co-administration, IL-1β (193-195) completely abolished the IL-1β (187-207)-induced hyperthermia. The non-steroid anti-inflammatory drug metamizole also reversed completely the action of IL-1β (187-207). Our results provide evidence that the IL-lβ domain in position 187-207 has hyperthermic effect. This effect is mediated through prostaglandin E2 stimulation and other mechanisms may also be involved in the action of IL-1β (187-207). It also suggests that IL-lβ domain in position 187-207 and IL-1β (193-195) fragment may serve as novel target for treatment of disorders accompanied with hyperthermia.
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http://dx.doi.org/10.1007/s11064-013-1215-9DOI Listing
February 2014

The effect of urocortin I on the hypothalamic ACTH secretagogues and its impact on the hypothalamic-pituitary-adrenal axis.

Neuropeptides 2014 Feb 21;48(1):15-20. Epub 2013 Nov 21.

Department of Pathophysiology, Faculty of Medicine, University of Szeged, Hungary; Neuroscience Research Group of the Hungarian Academy of Sciences, Szeged, Hungary.

Urocortin I (UCN I) is a structural analogue of corticotropin-releasing factor (CRF), which, together with arginine-vasopressin (AVP), are the principle adrenocorticotropic hormone (ACTH) secretagogues in mammals. The aim of the present study was to investigate the effects of UCN I on the hypothalamic CRF and AVP concentration and its impact on the hypothalamic-pituitary-adrenal (HPA) axis. First, male Wistar rats were injected intracerebroventricularly (ICV) with 0.5, 1, 2 and 5 μg of UCN I. After 30 min hypothalamic CRF and AVP concentrations were determined by immunoassays. In parallel, the trunk blood was collected and plasma ACTH and corticosterone concentration was determined by ELISA and chemofluorescent assay, respectively. Second, rats were pretreated ICV with selective antagonists of receptors being implicated in the regulation of the HPA axis (0.1 μg antalarmin for CRFR1, 1 μg astressin 2B for CRFR2 or 0.1 μg deamino-Pen1,Tyr2,Arg8-vasopressin for AVPR3) and treated ICV with the most effective dose of UCN I (5 μg). After 30 min plasma corticosterone concentration was determined by chemofluorescent assay. UCN I induced dose-dependent augmentation of the hypothalamic CRF and AVP concentration, associated with dose-dependent elevation of the plasma ACTH and corticosterone concentration. The most significant effect of UCN I on the plasma corticosterone concentration was inhibited by antalarmin, but was not influenced by astressin 2B or deamino-Pen1,Tyr2,Arg8-vasopressin. The present study demonstrates that UCN I modulates the concentration of the hypothalamic ACTH secretagogues in parallel with the concentration of the plasma ACTH and corticosterone. Our results suggest that UCN I may activate the HPA axis by stimulation of the hypothalamic CRF production, and this process is mediated by CRFR1, and not by CRFR2. UCN I may stimulate the AVP production, as well, but, based on the results with AVPR3 antagonist, this effect is not involved in the regulation of the HPA axis.
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http://dx.doi.org/10.1016/j.npep.2013.11.002DOI Listing
February 2014

The actions of neuropeptide SF on the hypothalamic-pituitary-adrenal axis and behavior in rats.

Regul Pept 2014 Jan 5;188:46-51. Epub 2013 Dec 5.

Department of Pathophysiology, University of Szeged, Szeged, Hungary; MTA-SZTE Neuroscience Research Group of the Hungarian Academy of Sciences Szeged, Szeged, Hungary. Electronic address:

Present experiments focused on measuring the effect of neuropeptide SF (NPSF) on the hypothalamus-pituitary-adrenal (HPA) axis and behavior. The peptide was administered in different doses (0.25, 0.5, 1, 2 μg) intracerebroventricularly to rats, and the behavior of which was then observed by telemetry and open-field test. Effect of NPSF on core temperature was also measured via telemetry. Plasma ACTH and corticosterone concentrations were measured to assess the influence of NPSF on the HPA activation. In addition, the changes in corticotrophin-releasing hormone (CRH) level in the hypothalamic paraventricular nucleus were continuously monitored by means of intracerebral microdialysis. Our results showed that NPSF augmented paraventricular CRH release and increased ACTH and corticosterone levels in the plasma. The release of corticosterone was successfully blocked by the pre-treatment of the CRH antagonist α-helical CRH9-41. Spontaneous and exploratory locomotor activity was also stimulated according to the telemetric and open-field studies. However, NPSF only tended to alter stereotyped behavior in the open-field experiments. These results demonstrate that NPSF may play a physiologic role in the regulation of such circadian functions as the activity of motor centers and the HPA axis, through the release of CRH.
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http://dx.doi.org/10.1016/j.regpep.2013.11.004DOI Listing
January 2014