Neurobiologische und behaviorale Marker der Verarbeitung stressbezogener und affektiv negativer Stimuli bei Multipler Sklerose und deren Zusammenhang mit dem Erkrankungsschweregrad

Psychologischer Stress kann den Schweregrad von Multipler Sklerose (MS) beeinflussen. Die peripher-physiologische Stresssystemaktivität ist bei PatientInnen mit MS (PmMS) verändert, was mit einer abweichenden Verarbeitung allgemeiner affektiver negativer Reize einhergehen kann. Wenig ist über die neurobiologischen Faktoren von Entspannung bei PmMS bzw. die Verarbeitung allgemeiner affektiver Reize und über den Zusammenhang zwischen neuronalen Stress-Mechanismen und Krankheitsparametern bekannt. In drei Experimenten untersuchten wir (i) Zusammenhänge von stressinduzierter neuronaler Aktivität und neurologischen Erkrankungsschwereparametern, (ii) neurobiologische Korrelate von Entspannung nach Stress und (iii) evaluierten, ob es Hinweise auf abweichende Verarbeitungen affektiv negativer Stimuli gibt. Methodik: Experiment I: Der Zusammenhang zwischen Stress und Hirnaktivität wurde bei 36 PmMS und 21 gesunde KontrollprobandInnen (GK) mittels eines stresserzeugenden funktionellen Magnetresonanztomographie(fMRT)-Paradigmas untersucht, in dem Kopfrechenaufgaben gelöst und die Leistung bewertet wurde. Die erfassten fMRT-Signale korrelierten wir mit Krankheitsparametern. Experiment II: Innerhalb desselben Paradigmas erfassten wir psychologische Stress- und Entspannungsreaktionen durch Selbstbeurteilungsdaten. Als eine physiologische Stress-Reaktion wurde die Herzfrequenz (HF) gemessen. Das regionale Graue Substanz (GS)-Volumen wurde für die Untersuchung von neurobiologischen Korrelaten von Entspannung nach Stress bei MS über das gesamte Gehirn zu psychologischer Entspannung in Beziehung gesetzt. Experiment III: Zur affektiven Stimulusverarbeitungstestung (als Teilaspekt der belohnungsbezogenen Entscheidungsfindung) bei MS, nutzten wir eine fMRT-Version der Iowa-Gambling-Task (IGT). ProbandInnen sollten lernen, durch das Identifizieren und Auswählen gewinnbringender und das Vermeiden verlustbehafteter (affektiv positiv/negativ besetzter) Kartenstapel möglichst viel Gewinn zu erspielen. Wir untersuchten die zugrunde liegende neuronale Aktivität in den Entscheidungsfindungsprozessphasen. Ergebnisse: Experiment I: Neuronale Stressantworten im insulären Cortex korrelierten bei PmMS mit pyramidaler und cerebraler Funktionsbeeinträchtigung. Die cerebelläre Aktivität korrelierte negativ mit GS-Atrophie in beiden Gruppen. Experiment II: Anders als bei GK, war die Entspannungsbeurteilung innerhalb von PmMS signifikant schwächer an den HF-Rückgang und das ventromediale-präfrontale-Cortex (VMPFC)-Volumen gekoppelt. Experiment III: Schwerer betroffene PmMS zeigten im Vergleich mit GK einen weniger stark ausgeprägten Lerneffekt und erzielten weniger Gewinne bei höheren Verlusten. Die VMPFC-Aktivität spiegelte die Performanz über Personen beider Gruppen wider. Fazit: Stressinduzierte neuronale Aktivität spiegelt den Erkrankungsschweregrad wider und war mit GS-Volumenverlust in deckungsgleichen Arealen bei PmMS und GK assoziiert. Dies suggeriert, dass die Assoziation innerhalb von PmMS keinem ausschließlich reaktiven Mechanismus folgen kann. PmMS scheinen den Rückgang peripherer Stresssignale weniger gut in die Entspannungswahrnehmung integrieren zu können, was an Veränderungen in der Reizverarbeitung in zentralen Belohnungsarealen des Gehirns (VMPFC) gekoppelt zu sein scheint. Die Leistung in Aufgaben, die das Erlernen affektiver Reizeigenschaften erfordern, scheint bei PmMS reduziert. Das legt Verarbeitungsdefizit belohnungs- bzw. bestrafungsrelevanter Prozesse bei MS nahe.Psychological stress can influence the severity of Multiple Sclerosis (MS). Peripheral stress system activity alters in patients with MS (PwMS) compared to healthy controls (HC). This can be paired with an impaired processing of negative affective stimuli. Little is known about the underlying neurobiological factors of relaxation, the processing of affective stimuli and the association of neural stress-mechanisms and disease parameters in PwMS. We aimed to (i) investigate associations of stress-induced neural activity and neurological disease parameters, (ii) test neurobiological correlates of relaxation after stress-exposure and (iii) evaluate if the processing of negative affective stimuli in PwMS is impaired. Methods: Experiment I: We investigated the connection between stress and brain activity in 36 PwMS and 21 HC by using a stress-inducing arithmetical fMRI paradigm and correlated results with disease parameters. Experiment II: Psychological stress- and relaxation-responses were conducted by self- assessment in the same paradigm. Heart rate (HR) was determined as physiological stress response. We investigated regional gray-matter (GM)-volume throughout the brain as central nervous correlate of relaxation after stress exposure. Experiment III: To investigate the processing of affective stimuli (as part of reward-related decision making) in PwMS we used an fMRI-version of the Iowa-Gambling-Task (IGT). Subjects should learn to distinguish between reward- and loss-related card decks to win as much money as possible. We investigated the underlying brain-activity during different stages of decision making. Results: Experiment I: Neural stress-responses in the insular cortex correlated with pyramidal and cerebral impairment in PwMS. Cerebellar activity showed a negative association with GM- atrophy in both groups. Experiment II: In PwMS relaxation-perception showed a significantly lower association with a decline in HR and ventromedial-prefrontal-cortex (VMPFC)-volume compared to HC. Experiment III: VMPFC-activity during IGT correlated positively with performance in all subjects, with more severely affected PwMS showing a worse learning effect resulting in winning less money than HC. Conclusion: Stress-induced neural activity depicts disease-severity and was associated with GM-volume-loss in overlapping areas in both groups. This suggests that this association can not be caused by MS alone. It looks like PwMS were not able to integrate the decline of peripherical stress-signals in their perception of relaxation, which seems to be related to alterations in stimuli-processing in central reward-areas of the brain (VMPFC). The relevance of reward (or punishment)-related stimuli-processing in PwMS is supported by the correlation of performance in reward-related tasks and the activity in reward-related brain-areas (VMPFC) by simultaneously showing a worse IGT-performance compared to HC

Assessment of Parotid Gland Tumors by Means of Quantitative Multiparametric Ultrasound (mpUS)

Objective: The preoperative diagnostical differentiation of parotid gland tumor (PGT) is not always simple due to several different entities. B-mode-ultrasound (US) remains the imaging modality of choice, while histopathology serves as the gold standard for finalizing the diagnosis. We aimed to evaluate the use of multiparametric US (mpUS) in the assessment of PGT. Methods: We included 97 PGTs from 96 patients. A standardized mpUS protocol using B-mode-US, shear-wave elastography (SWE), and standardized contrast-enhanced ultrasound (CEUS) was performed prior to surgical intervention. SWE was assessed by real-time measurement conducting a minimum of five measurements, while quantitative CEUS parameters were assessed with a post-processing perfusion software. Results: SWE allowed differentiation between benign PGT (Warthin's Tumor (WT) paired with lymph nodes (LN) and pleomorphic adenoma (PA)), and WT and LN were softer compared to PA. WT showed lower velocities than squamous cell carcinoma (SCC): the most common malignant PGT. CEUS parameters showed significant group differences between WT and PA, WT and malignant lesions, WT and SCC, WT paired with LN versus PA, and WT paired with LN versus SCC. Conclusion: MpUS seems to be beneficial in the assessment of PGT characterization, with benign PGT appearing to be softer in SWE than tumors with malignant tendencies. The quantitative CEUS parameter shows higher perfusion in WT than in PA, and malignant PGTs are less vascularized than WTs

Altered Coupling of Psychological Relaxation and Regional Volume of Brain Reward Areas in Multiple Sclerosis

Background:Psychological stress can influence the severity of multiple sclerosis (MS), but little is known about neurobiological factors potentially counteracting these effects. Objective:To identify gray matter (GM) brain regions related to relaxation after stress exposure in persons with MS (PwMS). Methods:36 PwMS and 21 healthy controls (HCs) reported their feeling of relaxation during a mild stress task. These markers were related to regional GM volumes, heart rate, and depressive symptoms. Results:Relaxation was differentially linked to heart rate in both groups (t= 2.20,p= 0.017), i.e., both markers were only related in HCs. Relaxation was positively linked to depressive symptoms across all participants (t= 1.99,p= 0.045) although this link differed weakly between groups (t= 1.62,p= 0.108). Primarily, the volume in medial temporal gyrus was negatively linked to relaxation in PwMS (t= -5.55, p(family-wise-error(FWE)corrected)= 0.018). A group-specific coupling of relaxation and GM volume was found in ventromedial prefrontal cortex (VMPFC) (t= -4.89, p(FWE)= 0.039). Conclusion:PwMS appear unable to integrate peripheral stress signals into their perception of relaxation. Together with the group-specific coupling of relaxation and VMPFC volume, a key area of the brain reward system for valuation of affectively relevant stimuli, this finding suggests a clinically relevant misinterpretation of stress-related affective stimuli in MS

Analysis of Lymphocytic DNA Damage in Early Multiple Sclerosis by Automated Gamma-H2AX and 53BP1 Foci Detection: A Case Control Study

Background In response to DNA double-strand breaks, the histone protein H2AX becomes phosphorylated at its C-terminal serine 139 residue, referred to as γ-H2AX. Formation of γ-H2AX foci is associated with recruitment of p53-binding protein 1 (53BP1), a regulator of the cellular response to DNA double-strand breaks. γ-H2AX expression in peripheral blood mononuclear cells (PBMCs) was recently proposed as a diagnostic and disease activity marker for multiple sclerosis (MS). Objective To evaluate the significance of γ-H2AX and 53BP1 foci in PBMCs as diagnostic and disease activity markers in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS) using automated γ-H2AX and 53BP1 foci detection. Methods Immunocytochemistry was performed on freshly isolated PBMCs of patients with CIS/early RRMS (n = 25) and healthy controls (n = 27) with γ-H2AX and 53BP1 specific antibodies. Nuclear γ-H2AX and 53BP1 foci were determined using a fully automated reading system, assessing the numbers of γ-H2AX and 53BP1 foci per total number of cells and the percentage of cells with foci. Patients underwent contrast enhanced 3 Tesla magnetic resonance imaging (MRI) and clinical examination including expanded disability status scale (EDSS) score. γ-H2AX and 53BP1 were also compared in previously frozen PBMCs of each 10 CIS/early RRMS patients with and without contrast enhancing lesions (CEL) and 10 healthy controls. Results The median (range) number of γ-H2AX (0.04 [0–0.5]) and 53BP1 (0.005 [0–0.2]) foci per cell in freshly isolated PBMCs across all study participants was low and similar to previously reported values of healthy individuals. For both, γ-H2AX and 53BP1, the cellular focus number as well as the percentage of positive cells did not differ between patients with CIS/RRMS and healthy controls. γ-H2AX and 53BP1 levels neither correlated with number nor volume of T2-weighted lesions on MRI, nor with the EDSS. Although γ-H2AX, but not 53BP1, levels were higher in previously frozen PBMCs of patients with than without CEL, γ-H2AX values of both groups overlapped and γ-H2AX did not correlate with the number or volume of CEL. Conclusion γ-H2AX and 53BP1 foci do not seem to be promising diagnostic or disease activity biomarkers in patients with early MS. Lymphocytic DNA double-strand breaks are unlikely to play a major role in the pathophysiology of MS

Quantitative Multiparametric Ultrasound (mpUS) in the Assessment of Inconclusive Cervical Lymph Nodes

Background: Enlarged cervical lymph nodes (CLN) are preferably examined by ultrasound (US) by using criteria such as size and echogenicity to assess benign and suspicious CLN, which should be histologically evaluated. This study aims to assess the differentiation of malign and benign CLN by using multiparametric US applications (mpUS). Methods: 101 patients received a standardized US protocol prior to surgical intervention using B-mode–US, shear-wave elastography (SWE) and contrast-enhanced ultrasound (CEUS). SWE was assessed by 2D real-time SWE conducting a minimum of five measurements, CEUS parameters were assessed with post-processing perfusion software. Histopathological confirmation served as the gold standard. Results: B-mode–US and SWE analysis of 104 CLN (36 benign, 68 malignant) showed a significant difference between benign and malignant lesions, presenting a larger long axis and higher tissue stiffness (both p < 0.001). Moreover, tissue stiffness assessed by SWE was significantly higher in CLN with regular B-mode–US criteria (Solbiati Index > 2 and short-axis < 1 cm, p < 0.001). No perfusion parameter on CEUS showed a significant differentiation between benign and malignant CLN. Discussion: As the only multiparametric parameter, SWE showed higher tissue stiffness in malignant CLN, also in subgroups with regular B-mode criteria. This fast and easy application may be a promising noninvasive tool to US examination to ameliorate the sonographic differentiation of inconclusive CLN

Assessment of Parotid Gland Tumors by Means of Quantitative Multiparametric Ultrasound (mpUS)

Objective: The preoperative diagnostical differentiation of parotid gland tumor (PGT) is not always simple due to several different entities. B-mode-ultrasound (US) remains the imaging modality of choice, while histopathology serves as the gold standard for finalizing the diagnosis. We aimed to evaluate the use of multiparametric US (mpUS) in the assessment of PGT. Methods: We included 97 PGTs from 96 patients. A standardized mpUS protocol using B-mode-US, shear-wave elastography (SWE), and standardized contrast-enhanced ultrasound (CEUS) was performed prior to surgical intervention. SWE was assessed by real-time measurement conducting a minimum of five measurements, while quantitative CEUS parameters were assessed with a post-processing perfusion software. Results: SWE allowed differentiation between benign PGT (Warthin’s Tumor (WT) paired with lymph nodes (LN) and pleomorphic adenoma (PA)), and WT and LN were softer compared to PA. WT showed lower velocities than squamous cell carcinoma (SCC): the most common malignant PGT. CEUS parameters showed significant group differences between WT and PA, WT and malignant lesions, WT and SCC, WT paired with LN versus PA, and WT paired with LN versus SCC. Conclusion: MpUS seems to be beneficial in the assessment of PGT characterization, with benign PGT appearing to be softer in SWE than tumors with malignant tendencies. The quantitative CEUS parameter shows higher perfusion in WT than in PA, and malignant PGTs are less vascularized than WTs

Assessment of Parotid Gland Tumors by Means of Quantitative Multiparametric Ultrasound (mpUS)

Objective: The preoperative diagnostical differentiation of parotid gland tumor (PGT) is not always simple due to several different entities. B-mode-ultrasound (US) remains the imaging modality of choice, while histopathology serves as the gold standard for finalizing the diagnosis. We aimed to evaluate the use of multiparametric US (mpUS) in the assessment of PGT. Methods: We included 97 PGTs from 96 patients. A standardized mpUS protocol using B-mode-US, shear-wave elastography (SWE), and standardized contrast-enhanced ultrasound (CEUS) was performed prior to surgical intervention. SWE was assessed by real-time measurement conducting a minimum of five measurements, while quantitative CEUS parameters were assessed with a post-processing perfusion software. Results: SWE allowed differentiation between benign PGT (Warthin’s Tumor (WT) paired with lymph nodes (LN) and pleomorphic adenoma (PA)), and WT and LN were softer compared to PA. WT showed lower velocities than squamous cell carcinoma (SCC): the most common malignant PGT. CEUS parameters showed significant group differences between WT and PA, WT and malignant lesions, WT and SCC, WT paired with LN versus PA, and WT paired with LN versus SCC. Conclusion: MpUS seems to be beneficial in the assessment of PGT characterization, with benign PGT appearing to be softer in SWE than tumors with malignant tendencies. The quantitative CEUS parameter shows higher perfusion in WT than in PA, and malignant PGTs are less vascularized than WTs

Stress-induced brain activity, brain atrophy, and clinical disability in multiple sclerosis

Prospective clinical studies support a link between psychological stress and multiple sclerosis (MS) disease severity, and peripheral stress systems are frequently dysregulated in MS patients. However, the exact link between neurobiological stress systems and MS symptoms is unknown. To evaluate the link between neural stress responses and disease parameters, we used an arterial-spin–labeling functional MRI stress paradigm in 36 MS patients and 21 healthy controls. Specifically, we measured brain activity during a mental arithmetic paradigm with performance-adaptive task frequency and performance feedback and related this activity to disease parameters. Across all participants, stress increased heart rate, perceived stress, and neural activity in the visual, cerebellar and insular cortex areas compared with a resting condition. None of these responses was related to cognitive load (task frequency). Consistently, although performance and cognitive load were lower in patients than in controls, stress responses did not differ between groups. Insula activity elevated during stress compared with rest was negatively linked to impairment of pyramidal and cerebral functions in patients. Cerebellar activation was related negatively to gray matter (GM) atrophy (i.e., positively to GM volume) in patients. Interestingly, this link was also observed in overlapping areas in controls. Cognitive load did not contribute to these associations. The results show that our task induced psychological stress independent of cognitive load. Moreover, stress-induced brain activity reflects clinical disability in MS. Finally, the link between stress-induced activity and GM volume in patients and controls in overlapping areas suggests that this link cannot be caused by the disease alone

A description of visual structure: Relations with human information processing mechanisms

Industrial Design Engineerin

Demographic and clinical data of patients and healthy controls of which freshly isolated PBMCs were analyzed in this study.

<p>Demographic and clinical data of patients and healthy controls of which freshly isolated PBMCs were analyzed in this study.</p