Simultane Erfassung von Verhaltensdaten, evozierten Potentialen und funktioneller MRT bei einer Aufgabe zur Verhaltenskontrolle

Ziel der Arbeit war die Untersuchung exekutiver Funktionen, in diesem Fall der Inhibition und der Volition, also der freien Entscheidung mittels simultaner EEG- und fMRT-Datenerhebung. Mit dem EEG lassen sich Datensätze mit einer hohen zeitlichen Auflösung generieren. Als neurophysiologisches Korrelat auf einen Stimulus erhält man sog. Ereignis korrelierte Potentiale (EKPs), die nach einer bestimmten Zeitdauer nach Stimuluspräsentation auftreten. Die räumliche Auflösung dieser Methode ist jedoch stark limitiert. Andererseits erhält man mit der fMRT Datensätze mit einer hohen räumlichen, jedoch geringen zeitlichen Auflösung. Mittels einer neuen Methode, der sog. Single-Trial-Koppelung können Datensätze generiert werden, die beide Modalitäten miteinander vereinen. Somit können Rückschlüsse über die zeitliche Aktivierung von Hirnarealen gezogen werden.15 gesunde Probanden nahmen an einem adaptierten, auditiven Go/NoGo-Paradigma teil, welches um eine Volitionsbedingung erweitert wurde. Es wurden Töne mit unterschiedlich hoher Frequenz demonstriert. Bei der Go-Bedingung (mittelhoch-hoch) mussten die Probanden so schnell wie möglich eine Reaktionstaste betätigen. Bei der NoGo-Bedingung (mittelhoch-tief) musssten sie dies unterlassen und bei der Volitionsbedingung (2x mittelhoch) mussten sie sich entscheiden, ob sie die Reaktionstaste drücken wollten oder nicht. Die fMRT-Auswertung erfolte mit dem Programm Brain Voyager, die EEG-Daten wurden zunächst mit EEGlab vorverarbeitet und dann mit dem Programm Brain Vision Analyzer analysiert. Bei der Single-Trial-Analyse wurden die EEG-Daten jedes einzelnen Durchgangs mit den BOLD-Veränderungen im fMRT korreliert. Technisch wurden dabei bei der Berechnung des sog. Allgemeinen Linearen Modells die Signaländerungen im EEG für bestimmte Zeiträume berücksichtigt. Auf diese Weise kann man Hirnregionen darstellen, bei denen die in der fMRT gemessenen Signaländerungen am stärksten mit der Signaländerung im EEG korrelieren. Die Single-Trial-Analyse wurde für das N2-Potential bei Volition und NoGo an der Elektrode Fz durchgeführt, für die P300 bei NoGo an Cz und für Volition und Go an Pz.Bei der Auswertung der hämodynamischen Daten zeigten sich für die Bedingung Volition gegen eine Kontrollbedingung Aktivierungen im Bereich der prä-SMA und des dorsolateralen präfrontalen Kortex (DLPFC). Elektrophysiologisch zeigte sich ein negatives Potential nach ca. 200ms (N2) und ein positives Potential nach ca. 300ms (P300). In der Single-Trial-Analyse zeigte sich, dass das N2-Potential während der Volitionsbedingung vornehmlich mit medio-frontalen Hirnregionen wie der SMA und lateral-frontalen Arealen assoziiert war. Das P300-Potential bot ebenfalls Aktiveriungen in lateral-frontalen Arealen und in der temporoparietalen Übergangszone. Bei der Inhibition von Verhalten zeigten sich bei Analyse der fMRT-Daten Aktiveriungen im Bereich des Gyrus frontalis superior und des DLPFC. Das N2-Potential war hier vornehmlich mit frontalen Bereichen wie dem DLPFC und dem ventro-lateralen präfrontalen Kortex (VLPFC) assoziiert. Das NoGo-P300-Potential hingegen lieferte Minderaktivierungen in allen für Motorik wichtigen Bereiche.Durch die direkte Korrelation von hämodynamischen und elektrophysiologischen Daten ist es uns gelungen, nicht nur diejenigen Hirnareale darzustellen, die bei den einzelnen Versuchsbedingungen aktiviert waren, sondern auch zu zeigen, wie es sich mit der zeitlichen Organisation innerhalb dieses neuronalen Netzwerkes verhält. Darüber hinaus konnten wir zeigen, dass die EKPs je nach Versuchsbedingung von unterschiedlichen Hirngeneratoren erzeugt wurden, was den Schluss zulässt, dass die EKPs abhängig von den jeweiligen Versuchsbedingungen sind und somit auch stets eine andere Funktion repräsentieren. Zudem konnten wir bei der Single-Trial-Analyse eine Beteiligung jener Hirnareale zeigen, welche auch bei der isolierten Auswertung der hämodynamischen Daten identifiziert werden konnten, was den Schluss zulässt, dass die Signale, die in beiden Modalitäten erzeugt wurden, zu einem großen Teil von denselben neuronalen Generatoren in Abhängigkeit der Versuchsbedingung erzeugt wurden

Effects of parabolic flight and spaceflight on the endocannabinoid system in humans

The endocannabinoid system (ECS) plays an important role in the regulation of physiological functions, from stress and memory regulation to vegetative control and immunity. The ECS is considered a central and peripheral stress response system to emotional or physical challenges and acts through endocannabinoids (ECs), which bind to their receptors inducing subsequent effecting mechanisms. In our studies, the ECS responses have been assessed through blood concentrations of the ECs anandamide and 2-arachidonoylglycerol. In parallel, saliva cortisol was determined and the degree of perceived stress was quantified by questionnaires. This report summarizes the reactivity of the ECS in humans subjected to brief periods of kinetic stress and weightlessness during parabolic flights and to prolonged stress exposure during life onboard the International Space Station (ISS). Both conditions resulted in a significant increase in circulating ECs. Under the acute stress during parabolic flights, individuals who showed no evidence of motion sickness were in low-stress conditions and had a significant increase of plasma ECs. In contrast, highly stressed individuals with severe motion sickness had an absent EC response and a massive increase in hypothalamic-pituitary-adrenal axis activity. Likewise, chronic but well-tolerated exposure to weightlessness and emotional and environmental stressors on the ISS for 6 months resulted in a sustained increase in EC blood concentrations, which returned to baseline values after the cosmonauts' return. These preliminary results suggest that complex environmental stressors result in an increase of circulating ECs and that enhanced EC signaling is probably required for adaptation and tolerance under stressful conditions

Motion sickness, stress and the endocannabinoid system

A substantial number of individuals are at risk for the development of motion sickness induced nausea and vomiting (N&V) during road, air or sea travel. Motion sickness can be extremely stressful but the neurobiologic mechanisms leading to motion sickness are not clear. The endocannabinoid system (ECS) represents an important neuromodulator of stress and N&V. Inhibitory effects of the ECS on N&V are mediated by endocannabinoid-receptor activation

Predictive Capability of an iPad-Based Medical Device (medx) for the Diagnosis of Vertigo and Dizziness

Background:Making the correct diagnosis of patients presenting with vertigo and dizziness in clinical practice is often challenging. Objective:In this study we analyzed the usage of the iPad based program medx in the prediction of different clinical vertigo and dizziness diagnoses . We examined the power of medx to distinguish between different vertigo diagnoses. Patients and methods:The data collection was done in the outpatient clinic of the German Center of Vertigo and Balance Disorders. The “gold standard diagnosis” was defined as the clinical diagnosis of the specialist during the visit of the patient standardized history and clinical examination. Another independent and blinded physician finalized each patient’s case in constellatory diagnostic of medx by entering all available clinical information in the system. The accuracy, sensitivity, specificity as well as positive and negative predictive values for the most common diagnoses were determined. Sixteen possible different vertigo and dizziness diagnoses could be provided by medx constellatory diagnostic system. These diagnoses were compared to the “gold standard” by retrospective review of the charts of the patients over the study period. Results:610 patients (mean age58.1±16.3 years, 51.2 female) were included. The accuracy for the most common diagnoses was between 82.1- 96.6 with a sensitivity from 40- 80.5 and a specificity of more than 80. When analyzing the quality of medx in a multiclass-problem for the six most common clinical diagnoses the sensitivity, specificity, positive and negative predictive value were as follows: Bilateral vestibulopathy (81.6, 97.1, 71.1, 97.5), Menière's disease (77.8, 97.6, 87., 95.3), benign paroxysmal positional vertigo (61.7, 98.3, 86.6, 93.4), downbeat nystagmus syndrome (69.6, 97.7, 71.1, 97.5), vestibular migraine (34.7, 97.8, 76.1, 88.3) and phobic postural vertigo (80.5, 82,5, 52.5, 94.6), Conclusions:This study demonstrates that medx is a new and easy approach to screen for different diagnoses. With the high specificity and high negative predictive value the system helps to rule out differential diagnoses and can therefore also lead to a cost reduction in health care system. However, the sensitivity was unexpectedly low, especially for vestibular migraine. All in all, this device can only be a complementary tool, in particular for non-experts in the field

SARS-CoV-2 pneumonia and bacterial pneumonia patients differ in a second hit immune response model

Secondary infections have been shown to complicate the clinical course and worsen the outcome of critically ill patients. Severe Coronavirus Disease 2019 (COVID-19) may be accompanied by a pronounced cytokine release, and immune competence of these patients towards most pathogenic antigens remains uncompromised early in the disease. Patients with bacterial sepsis also exhibit excessive cytokine release with systemic hyper-inflammation, however, typically followed by an anti-inflammatory phase, causing immune paralysis. In a second hit immune response model, leukocyte activation capacity of severely ill patients with pneumonia caused by SARS-CoV-2 or by bacteria were compared upon ICU admission and at days 4 and 7 of the ICU stay. Blood cell count and release of the pro-inflammatory cytokines IL-2, IFNγ and TNF were assessed after whole-blood incubation with the potent immune stimulus pokeweed mitogen (PWM). For comparison, patients with bacterial sepsis not originating from pneumonia, and healthy volunteers were included. Lymphopenia and granulocytosis were less pronounced in COVID-19 patients compared to bacterial sepsis patients. After PWM stimulation, COVID-19 patients showed a reduced release of IFNγ, while IL-2 levels were found similar and TNF levels were increased compared to healthy controls. Interestingly, concentrations of all three cytokines were significantly higher in samples from COVID-19 patients compared to samples from patients with bacterial infection. This fundamental difference in immune competence during a second hit between COVID-19 and sepsis patients may have implications for the selection of immune suppressive or enhancing therapies in personalized medicine

Psychiatric comorbidity and psychosocial impairment among patients with vertigo and dizziness

Background: Vertigo and dizziness are often not fully explained by an organic illness, but instead are related to psychiatric disorders. This study aimed to evaluate psychiatric comorbidity and assess psychosocial impairment in a large sample of patients with a wide range of unselected organic and non-organic (ie, medically unexplained) vertigo/dizziness syndromes. Methods: This cross-sectional study involved a sample of 547 patients recruited from a specialised interdisciplinary treatment centre for vertigo/dizziness. Diagnostic evaluation included standardised neurological examinations, structured clinical interview for major mental disorders (SCID-I) and self-report questionnaires regarding dizziness, depression, anxiety, somatisation and quality of life. Results: Neurological diagnostic workup revealed organic and non-organic vertigo/dizziness in 80.8% and 19.2% of patients, respectively. In 48.8% of patients, SCID-I led to the diagnosis of a current psychiatric disorder, most frequently anxiety/phobic, somatoform and affective disorders. In the organic vertigo/dizziness group, 42.5% of patients, particularly those with vestibular paroxysmia or vestibular migraine, had a current psychiatric comorbidity. Patients with psychiatric comorbidity reported more vertigo-related handicaps, more depressive, anxiety and somatisation symptoms, and lower psychological quality of life compared with patients without psychiatric comorbidity. Conclusions: Almost half of patients with vertigo/dizziness suffer from a psychiatric comorbidity. These patients show more severe psychosocial impairment compared with patients without psychiatric disorders. The worst combination, in terms of vertigo-related handicaps, is having non-organic vertigo/dizziness and psychiatric comorbidity. This phenomenon should be considered when diagnosing and treating vertigo/dizziness in the early stages of the disease

Influences of large sets of environmental exposures on immune responses in healthy adult men

Environmental factors have long been known to influence immune responses. In particular, clinical studies about the association between migration and increased risk of atopy/asthma have provided important information on the role of migration associated large sets of environmental exposures in the development of allergic diseases. However, investigations about environmental effects on immune responses are mostly limited in candidate environmental exposures, such as air pollution. The influences of large sets of environmental exposures on immune responses are still largely unknown. A simulated 520-d Mars mission provided an opportunity to investigate this topic. Six healthy males lived in a closed habitat simulating a spacecraft for 520 days. When they exited their "spacecraft" after the mission, the scenario was similar to that of migration, involving exposure to a new set of environmental pollutants and allergens. We measured multiple immune parameters with blood samples at chosen time points after the mission. At the early adaptation stage, highly enhanced cytokine responses were observed upon ex vivo antigen stimulations. For cell population frequencies, we found the subjects displayed increased neutrophils. These results may presumably represent the immune changes occurred in healthy humans when migrating, indicating that large sets of environmental exposures may trigger aberrant immune activity

Early immune anergy towards recall antigens and mitogens in patients at onset of septic shock

The pathology of sepsis is typically characterized by an infection and excessive initial inflammation including a cytokine storm, followed by a state of immune suppression or paralysis. This classical view of a two peak kinetic immune response is currently controversially discussed. This study was a sub-study of the randomized clinical Trial SISPCT registered with www. clinicaltrials. gov (NCT00832039, Registration date: 29/01/2009). Blood samples from 76 patients with severe sepsis and septic shock were incubated for 48 h at 37 degrees C in vitro with bacterial or fungal recall-antigens or specific mitogen antigens within 24 hours of sepsis onset. Recall-antigen stimulation led to a severe dampening of normal cytokine release. This immunologic anergy was similarly observed after mitogen stimulation. Moreover, patients under hydrocortisone therapy or with lowered arterial oxygen tension had further reductions in cytokine levels upon B- and T-cell mitogen stimulation. This investigation reveals an early onset of immunoparalysis during sepsis. This immune incompetence in mounting an adequate response to further infections includes previously sensitized pathogens, as seen with recall- antigens. Also, the immune-suppressive role of hydrocortisone and low PaO2 is highlighted. Aside from early broad-spectrum antimicrobial therapy, our findings reinforce the need for maximal immunological support and protection against further infections at the onset of sepsis

Stress Induced Immune Dysregulation: A Continuum Spanning Antarctica Winterover, Spaceflight, and Terrestrial Patients

Spaceflight is a unique environment characterized by stress, microgravity, isolation, circadian misalignment, and radiation exposure and impacts immune health. Planned long duration missions to Mars are a top priority for NASA and mitigating the negative health consequences of spaceflight is particularly important. Terrestrial analogs are a vital aspect of spaceflight research since data from astronauts is limited and it is costly to receive samples from ISS. The most relevant ground analog would include station lifestyle, stress, disrupted circadian rhythms and isolation. This analysis compares various aspects of immune dysregulation in astronauts during long-duration orbital spaceflight to groundanalogs. Astronaut data were also compared to a clinical immunodeficiency population, shingles patients, to help interpret clinical risks during deep space missions. A comprehensive evaluation was performed across hypoxic interior Antarctica, normoxic coastal Antarctica, HERA, and astronauts which included plasma and mitogen stimulated cytokine profiles, T-cell function, and peripheral leukocyte distribution. A cross platform analysis was then performed to define in-flight immune alterations, determine analog appropriateness, and interpret clinical risk