Search

Early life adversity (ELA) has been associated with inflammation and immunosenescence, as well as hyporeactivity of the HPA-axis. As the immune system and HPA-axis are tightly intertwined around the glucocorticoid receptor (GR) we examined peripheral GR functionality in the EpiPath cohort, where participants had either been exposed to ELA (separation from parents and/or institutionalization followed by adoption) (n=40) or had been reared by their biological parents (n=72). Expression of the strict GR target genes FKBP5 and GILZ as well as total and 1F and 1H GR transcripts were similar between groups. Furthermore, there were no differences in GR sensitivity, examined by the effects of dexamethasone on IL6 production in LPS-stimulated whole blood. Although we did not find differences in methylation at the GR 1F exon or promoter region, we identified a region of the GR 1H promoter (CpG 1-9) that showed lower methylation levels in ELA. Peripheral GR signaling was unperturbed in our cohort and the observed immune phenotype does not appear to be secondary to an altered glucocorticoid receptor response to glucocorticoids. To identify signaling pathways that may underlie the ELA immune phenotype, future research should focus on unbiased approaches, such as investigating whole genome methylation profiles.

Nach dem Perception-Filter-Modell der somatoformen Störungen (Rief & Barsky, 2005) könnte verstärkte Signalübermittlung von Körperorganen zur Symptomentstehung beitragen. Dabei wurden insbesondere das sympathische Nervensystem und die HPA-Achse als primäre physiologische Stressachsen diskutiert. Aufgrund hoher Heterogenität somatoformer Störungen ist die Befundlage zu beiden Achsen jedoch gemischt, was dafürspricht, größere Populationen ohne Multi-Komorbidität zu untersuchen. Bei einer studentischen Stichprobe (N=217; 113 w; Alter: 18-33 [M=23.0; SD=2.9] Jahre; BMI=22.2 [SD=2.8]) wurden selbstberichteter chronischer Stress (Trierer Inventar für Chronischen Stress/TICS) und somatoforme Symptome (Screening für Somatoforme Störungen/SOMS-2) erhoben. Alle Probanden lieferten Cortisol- Aufwachreaktionen (Erwachen, +15,+30,+45,+60 Min.) an zwei aufeinanderfolgenden Tagen, sowie ein Cortisol-Tagesprofil. Zusätzlich wurde im Labor in einer 10-minütigen Ruhemessung EKG zur Bestimmung der Ruhe-Herzratenvariabilität (RMSSD, pNN50, SDNN; Low- und High-Frequency) als Indikatoren des zentralen sympathischen und parasympathischen Tonus erfasst. Diejenigen TICS-Skalen, die psychosozialen Stress reflektieren, sowie „Chronische Besorgnis“ waren zwischen r=.16 und .26 mit somatoformen Symptomen korreliert. Die Skala „Chronische Besorgnis“ korrelierte außerdem positiv mit dem Tagescortisolspiegel (r=.19), sowie negativ mit SDNN (r=-.20), RMSSD (r=-.17), pNN50 (r=-.17), LF-Power (r=-.19) und HF-Power (r=-.16; alle ps < .05). Somatoforme Symptome korrelierten hingegen nicht mit Indikatoren der physiologischen Stressachsen. In einem Regressionsmodell mit Somatisierungsindex als Kriterium zeigte sich nur für die TICS-Skalen „Mangel an sozialer Anerkennung“ (b=.19) und „Chronische Besorgnis“ (b=.25), sowie LF-HRV (b=.20) signifikante Vorhersagekraft. Die Annahmen des Perception-Filter-Modells konnten nur hinsichtlich des sympathischen Nervensystems bestätigt werden, was daher als Frühindika

The negative health effects of early life adversity (ELA) continue long into adulthood. Changes in the physiological response to psychosocial stressors have been proposed to mediate this effect. However, many previous studies have come to contradicting conclusions as to whether ELA induces a long-term increase or decrease in stress reactivity. Therefore, we tested the association of ELA exposure and adult stress reactivity in a sample of early life adoptees and controls.Two previously validated stressful elements (bilateral feet CPT and the Paced Auditory Serial Addition Task (PASAT)) were combined in an extended Cold Pressor Test (CPT). This test was performed on 22 participants who had experienced severe ELA (separation from biological parents, institutionalization, and adoption in early childhood), and in 22 age-matched control participants.A prior history of ELA was associated with blunted reactivity of the hypothalamic-pituitary-adrenal (HPA) axis (Cohen´s d = 0.680). Cardiovascular reactivity remained unchanged, and affective reactivity (self-report ratings) were increased in participants exposed to ELA compared to the control group (range Cohen´s d: 0.642–0.879).Our results suggest that the activity of the HPA axis reactivity was inhibited in ELA participants. Importantly, cardiovascular stress responsiveness was not affected by ELA. This separation of the HPA axis and cardiovascular stress responses may best be explained by ELA selectively enhancing central feedback-sensitivity to glucocorticoids, but preserving cardiovascular/ autonomic stress reactivity.

Early life adversity (ELA) increases the risk for multiple age-related diseases, such as diabetes type 2 and cardiovascular disease. As prevalence is high, ELA poses a major and global public health problem. Immunosenescence, or aging of the immune system, has been proposed to underlie the association between ELA and long-term health consequences. However, it is unclear what drives ELA-associated immunosenescence and which cells are primarily affected. We investigated different biomarkers of immunosenescence in a healthy subset of the EpiPath cohort. Participants were either parent-reared (Ctrl, n = 59) or had experienced separation from their parents in early childhood and were subsequently adopted (ELA, n = 18). No difference was observed in telomere length or in methylation levels of age-related CpGs in whole blood, containing a heterogeneous mixture of immune cells. However, when specifically investigating T cells, we found a higher expression of senescence markers (CD57) in ELA. In addition, senescent T cells (CD57+) in ELA had an increased cytolytic potential compared to senescent cells in controls. With a mediation analysis we demonstrated that cytomegalovirus (CMV) infection, which is an important driving force of immunosenescence, largely accounted for elevated CD57 expression observed in ELA. Leukocyte telomere length may obscure cell-specific immunosenescence; here, we demonstrated that the use of cell surface markers of senescence can be more informative. Our data suggest that ELA may increase the risk of CMV infection in early childhood, thereby mediating the effect of ELA on T cell-specific immunosenescence. Thus, future studies should include CMV as a confounder or selectively investigate CMV seronegative cohorts.

Early life adversity (ELA) has been associated with an increased risk for diseases in which the immune system plays a critical role. The ELA immune phenotype is characterized by inflammation, impaired cellular immunity, and immunosenescence. However, data on cell-specific immune effects are largely absent. Additionally, stress systems and health behaviors are altered in ELA, which may contribute to the generation of the ELA immune phenotype. The present investigation tested cell-specific immune differences in relationship to the ELA immune phenotype, altered stress parameters, and health behaviors in individuals with ELA (n = 42) and those without a history of ELA (control, n = 73). Relative number and activation status (CD25, CD69, HLA-DR, CD11a, CD11b) of monocytes, NK cells, B cells, T cells, and their main subsets were assessed by flow cytometry. ELA was associated with significantly reduced numbers of CD69+CD8+ T cells (p = 0.022), increased numbers of HLA-DR+ CD4 and HLA-DR+ CD8 T cells (p < 0.001), as well as increased numbers of CD25+CD8+ T cells (p = 0.036). ELA also showed a trend toward higher numbers of CCR4+CXCR3−CCR6+ CD4 T cells. Taken together, our data suggest an elevated state of immune activation in ELA, in which particularly T cells are affected. Although several aspects of the ELA immune phenotype were related to increased activation markers, neither stress nor health-risk behaviors explained the observed group differences. Thus, the state of immune activation in ELA does not seem to be secondary to alterations in the stress system or health-risk behaviors, but rather a primary effect of early life programming on immune cells.

Arterial pressure (AP) and inter-beat interval (IBI) length are under autonomic nervous system control. The control mechanisms can be investigated by transfer function analysis. It is not known if this type of analysis may be helpful in monitoring depth of sedation. In an open-label, uncontrolled investigation, the effect of midazolam on the transfer function between AP and IBI, and on spectral indices of AP and heart rate (HR) variability (APV, HRV) were assessed in the absence and presence of the benzodiazepine antagonist flumazenil. We studied 11 healthy male volunteers. After an initial control period of 60 min, we studied three consecutive periods, each of 60 min duration, with progressively increasing concentrations of midazolam (0.02, 0.06, 0.14 mg kg-1 h-1). A final 60-min period during administration of flumazenil 0.004 mg kg-1 h-1 and while the agonist was still present was also studied. To confirm midazolam-induced central nervous system effects, electroencephalography was performed and Ramsay sedation scores were determined. With increasing dose of midazolam, the high frequency (0.15-0.4 Hz) component of the transfer function between AP and IBI decreased progressively (mean 26.5 (SEM 3.7), 19.2 (2.9), 12.8 (1.7), 8.4 (1.6) ms mm Hg-1). This effect was antagonized by flumazenil (21.5 (3.2) ms mm Hg-1). Other indices (e.g. HRV, APV) did not reveal such a clear response to midazolam dose and flumazenil application. Thus in healthy male volunteers, the transfer function between AP and IBI in the parasympathetically dominated high frequency range varies according to benzodiazepine agonism and antagonism. This finding has potential implications for monitoring the effects of benzodiazepines

Item does not contain fulltext, The stress hormone cortisol is assumed to influence cognitive functions. While cortisol-induced alterations of declarative memory in particular are well-investigated, considerably less is known about its influence on executive functions. Moreover, most research has been focused on slow effects, and rapid non-genomic effects have not been studied. The present study sought to investigate the impact of acute cortisol administration as well as basal cortisol levels on cognitive flexibility, a core executive function, within the non-genomic time frame. Thirty-eight healthy male participants were randomly assigned to intravenously receive either cortisol or a placebo before performing a task switching paradigm with happy and angry faces as stimuli. Cortisol levels were measured at six points during the experiment. Additionally, before the experiment, basal cortisol measures for the cortisol awakening response were collected on three consecutive weekdays immediately following awakening and 30, 45, and 60 min after. First and foremost, results showed a pronounced impact of acute and basal cortisol on reaction time switch costs, particularly for angry faces. In the placebo group, low basal cortisol was associated with minimal switch costs, whereas high basal cortisol was related to maximal switch costs. In contrast, after cortisol injection, basal cortisol levels showed no impact. These results show that cognitive flexibility-enhancing effects of acute cortisol administration are only seen in men with high basal cortisol levels. This result supports the context dependency of cortisol administration and shows the relevance of taking basal cortisol levels into account.

Im positiven Feedback-Modell zu Interozeption und Stress (Schulz & Vögele, 2015) wird postuliert, dass chronischer Stress zu einer Dysregulation der beiden physiologischen Stressachsen (HPA-Achse, ANS) führt, was wiederum durch veränderte Interozeption zur Entstehung körperlicherSymptome beitragen kann. Dieser postulierte Zusammenhang basiert jedoch bislang auf einer Integration von Einzelbefunden und wurde bisher noch nicht an einer gemeinsamen Stichprobe überprüft. Bei einer studentischen Stichprobe (N=217; 113 w; Alter: 18-33 [M=23.0; SD=2.9] Jahre; BMI=22.2 [SD=2.8]) wurden selbstberichteter chronischer Stress (Trierer Inventar für Chronischen Stress/TICS) und somatoforme Symptome (Screening für Somatoforme Störungen/SOMS-2) erhoben. Alle Probanden lieferten Cortisol-Aufwachreaktionen (Erwachen,+15,+30,+45,+60 Min.) an zwei aufeinanderfolgenden Tagen, sowie ein Cortisol-Tagesprofil. Zusätzlich wurde im Labor in einer 10-minütigen Ruhemessung EKG zur Bestimmung der Ruhe-Herzratenvariabilität (RMSSD, pNN50, SDNN; Low- [0.06-0.14 Hz] und High-Frequency [0.15-0.4 Hz]) als Indikatoren des zentralen sympathischen und parasympathischen Tonus erfasst. Diejenigen TICS-Skalen, die psychosozialen Stress reflektieren, sowie „Chronische Besorgnis“ waren zwischen r=.16 und .26 mit somatoformen Symptomen korreliert. Die Skala „Chronische Besorgnis“ korrelierte außerdem positiv mit dem Tagescortisolspiegel (r=.19), sowie negativ mit SDNN (r=-.20), RMSSD (r=-.17), pNN50 (r=-.17), LF-Power (r=-.19) und HF-Power (r=-.16; alle ps < .05). Somatoforme Symptome korrelierten hingegen nicht mit Indikatoren der physiologischen Stressachsen. In einem Regressionsmodell mit Somatisierungsindex als Kriterium zeigte sich nur für die TICS-Skalen „Mangel an sozialer Anerkennung“ (b=.19) und „chronische Besorgnis“ (b=.25), sowie LF-HRV (b=.20) signifikante Vorhersagekraft. Die Annahmen des Modells zu Interozeption und Stress konnten nur teilweise bestätigt werden. Selbstberichteter Stress, vor a

Current approaches to assess interoception of respiratory functions cannot differentiate between the physiological basis of interoception, i.e. visceral-afferent signal processing, and the psychological process of attention focusing. Furthermore, they typically involve invasive procedures, e.g. induction of respiratory occlusions or the inhalation of CO2 enriched air. The aim of the current study was to test the capacity of startle methodology to reflect respiratory-related afferent signal processing, independent of invasive procedures. Forty-two healthy participants were tested in a spontaneous breathing and in a 0.25 Hz paced breathing condition. Acoustic startle noises of 105 dB(A) intensity (50 ms white noise) were presented with identical trial frequency at peak and on-going inspiration and expiration, based on a new pattern detection method, involving the online processing of the respiratory belt signal. The results show the highest startle magnitudes during on-going expiration compared to any other measurement points during the respiratory cycle, independent of whether breathing was spontaneous or paced. Afferent signals from slow adapting phasic pulmonary stretch receptors may be responsible for this effect. The current study is the first to demonstrate startle modulation by respiration. These results offer the potential to apply startle methodology in the non-invasive testing of interoception-related aspects in respiratory psychophysiology.

Die Depersonalisations-/Derealisationsstörung (DPD) ist durch eine subjektiv erlebte Distanz von Emotionen, sowie von Empfindungen des eigenen Körpers charakterisiert. Während viele neurophysiologische Befunde ein verändertes Emotionserleben stützen, gibt es bislang keine neurophysiologischen Korrelate für eine veränderte Interozeption bei DPD. 27 Patienten mit DPD, sowie 27 gesunde Kontrollprobanden absolvierten zwei Herzschlagwahrnehmungstests: eine Herzschlagzählaufgabe (Schandry) und einen Test, bei dem zwischen Herzschlägen und exterozeptiven Signalen diskriminiert werden musste (Whitehead). Außerdem absolvierten die Probanden zwei psychophysiologische Verfahren, die interozeptive Signalübermittlung reflektieren: (1.) Herzschlag- evozierte Potenziale (HEPs), Indikatoren für die kortikale Verarbeitung afferenter Signale vom kardiovaskulären System und (2.) die kardiale Modulation der Schreckreaktion (CMS), welche als Index für die Verarbeitung kardio-afferenter Signale auf Ebene des Hirnstamms gilt. In den Herzschlagwahrnehmungstests gab es keine Gruppenunterschiede zwischen Patienten mit DPD und gesunden Kontrollprobanden, jedoch eine gegenläufige Tendenz beider Gruppen hinsichtlich der Genauigkeit über den Zeitverlauf (negative Lernkurve bei DPD). Bei der Kontrollgruppe zeigte sich ein intakter CMS-Effekt (geringere Schreckreaktionen während der frühen kardialen Phase), während sich bei den DPD-Patienten überhaupt kein CMS-Effekt beobachten ließ (Interaktion: p=.041). Ebenso wurden Gruppenunterschiede im HEP-Pattern beobachtet: gesunde Kontrollprobanden zeigten höhere HEP-Amplituden während der Aufmerksamkeitslenkung auf Körpersignale als während Ruhe. Dieser Effekt konnte bei DPD-Patienten nicht gefunden werden (Interaktion: p=.027). Die gegenläufigen Trends über den Zeitverlauf in verhaltensbasierten Indikatoren für Interozeption (Herzschlagwahrnehmung) bei DPD-Patienten gegenüber Kontrollprobanden impliziert, dass es Patienten weniger gut gelingt, ihre Aufm

The hypothalamus-pituitary-adrenal (HPA) axis is a crucial endocrine system for coping with stress. A reliable and stable marker for the basal state of that system is the cortisol awakening response (CAR). We examined the influence of variants of four relevant candidate genes; the mineralocorticoid receptor gene (MR), the glucocorticoid receptor gene (GR), the serotonin transporter gene (5-HTT) and the gene encoding the brain-derived neurotrophic factor (BDNF) on CAR and self-perceived stress in 217 healthy subjects. We found that polymorphisms of GR influenced both, the basal state of the HPA axis as well as self-perceived stress. MR only associated with self-perceived stress and 5-HTT only with CAR. BDNF did not affected any of the investigated indices. In summary, we suggest that GR variants together with the CAR and supplemented with self reports on perceived stress might be useful indicators for the basal HPA axis activity.

Patients with depersonalization-/derealization disorder (DPD) show altered heartbeat-evoked brain potentials, which are considered psychophysiological indicators of cortical representation of visceral-afferent neural signals. The aim of the current investigation was to clarify whether the impaired CNS representation of visceral-afferent neural signals in DPD is restricted to the cortical level or is also present in sub-cortical structures. We used cardiac modulation of startle (CMS) to assess baro-afferent signal transmission at brainstem level in 22 DPD and 23 healthy control individuals. The CMS paradigm involved acoustic startle stimuli (105 dB(A), 50 ms) elicited 0, 100, 200, 300, 400 and 500 ms after a cardiac R-wave. In healthy control individuals, we observed lower startle responses at 100 and 300 ms than at 0 and 400 ms after an R-wave. In DPD patients, no effect of the cardiac cycle on startle response magnitude was found. We conclude that the representation of visceral-afferent neural signals at brainstem level may be deficient in DPD. This effect may be due to increased peripheral sympathetic tone or to dysregulated signal processing at brainstem level.

Nutritional state, i.e. fasting or non-fasting, may affect the processing of interoceptive signals, but mechanisms underlying this effect remain unclear. We investigated 16 healthy women on two separate days: when satiated (standardized food intake) and after an 18 h food deprivation period. On both days, heartbeat-evoked potentials (HEPs) and cardiac and ANS activation indices (heart rate, nLF HRV) were assessed. The HEP is an EEG pattern that is considered an index of cortical representation of afferent cardiovascular signals. Average HEP activity (R-wave +455-595 ms) was enhanced during food deprivation compared to normal food intake. Cardiac activation did not differ between nutritional conditions. Our results indicate that short-term food deprivation amplifies an electrophysiological correlate of the cortical representation of visceral-afferent signals originating from the cardiovascular system. This effect could not be attributed to increased cardiac activation, as estimated by heart rate and nLF HRV, after food deprivation.

OBJECTIVE: Core features of depersonalization-/derealization disorder (DPD) are emotional numbing and feelings of disembodiment. While there are several neurophysiological findings supporting subjective emotional numbing, the psychobiology of disembodiment remains unclear. METHODS: Heartbeat-evoked potentials (HEPs), which are considered psychophysiological indicators for the cortical representation of afferent signals originating from the cardiovascular system, were assessed in 23 patients with DPD and 24 healthy control individuals during rest and while performing a heartbeat perception task. RESULTS: Absolute HEP amplitudes did not differ between groups. Nevertheless, healthy individuals showed higher HEPs during the heartbeat perception task than during rest, while no such effect was found in DPD patients (p = .031). DPD patients had higher total levels of salivary alpha-amylase than healthy individuals (9626.6±8200.0 vs. 5344.3±3745.8 kUmin/l; p = .029), but there were no group differences in cardiovascular measures (heart rate: 76.2±10.1 vs. 74.3 ±7.5 bpm, p = .60; nLF HRV: .63±.15 vs. .56 ±.15 n.u., p = .099; LF/HF ratio: 249.3±242.7 vs. 164.8 ±108.8, p = .10), salivary cortisol (57.5±46.7 vs. 55.1±43.6 nmolmin/l, p = .86) or cortisone levels (593.2±260.3 vs. 543.8±257.1 nmolmin/l, p = .52). CONCLUSION: These results suggest altered cortical representation of afferent signals originating from the cardiovascular system in DPD patients, which may be associated with higher sympathetic tone. These findings may reflect difficulties of DPD patients to attend to their actual bodily experiences.

BACKGROUND: Disembodiment is a core feature of depersonalization disorder (DPD). Given the narratives of DPD patients about their disembodiment and emotional numbing and neurobiological findings of an inhibition of insular activity, DPD may be considered as a mental disorder with specific impairments of interoceptive awareness and body perception. METHODS: We investigated cardioceptive accuracy (CA) of DPD patients (n = 24) as compared to healthy controls (n = 26) with two different heartbeat detection tasks ("Schandry heartbeat counting task" and "Whitehead heartbeat discrimination task"). Self-rated clearness of body perception was measured by questionnaire. RESULTS: Contrary to our hypothesis, DPD patients performed similarly to healthy controls on the two different heartbeat detection tasks, and they had equal scores regarding their self-rated clearness of body perception. There was no correlation of the severity of "anomalous body experiences" and depersonalization with measures of interoceptive accuracy. Only among healthy controls CA in the Schandry task was positively correlated with self-rated clearness of body perception. Depersonalization was unrelated to severity of depression or anxiety, while depression and anxiety were highly correlated. Anxiety and depression did not modify the associations of depersonalization with interoceptive accuracy. CONCLUSIONS: Our main findings highlight a striking discrepancy of normal interoception with overwhelming experiences of disembodiment in DPD. This may reflect difficulties of DPD patients to integrate their visceral and bodily perceptions into a sense of their selves. This problem may be considered an important target for psychotherapeutic treatment approaches.

Stress glucocorticoids and insulin are important endocrine regulators of energy homeostasis, but little is known about their central interaction on the reward-related processing of food cues. According to a balanced group design, healthy food deprived men received either 40 IU intranasal insulin (n=13), 30 mg oral cortisol (n=12), both (n=15), or placebo (n=14). Acoustic startle responsiveness was assessed during presentation of food and non-food pictures. Cortisol enhanced startle responsiveness during visual presentation of "high glycemic" food, but not during presentation of neutral and pleasant non-food pictures. Insulin had no effect. Based on the "frustrative non-reward" model these results suggest that the reward value of high glycemic food items is specifically increased by cortisol.

Little is known about the impact of stress and stress hormones on the processing of visceral-afferent signals. Clinical data suggest that cortisol may lower the threshold for interoceptive stimuli, while a pharmacological administration of cortisol decreases the sensitivity for physical symptoms. To clarify the role of cortisol for the processing of interoceptive signals, we investigated 16 healthy men on two occasions, once during the infusion of 4mg of cortisol and once during the infusion of a placebo substance. Heartbeat-evoked potentials (HEP; derived from resting EEG and ECG, during open and closed eyes), which are psychophysiological indicators for the cortical processing of cardioceptive signals, were measured over 6-min periods once before, and four times after the infusion (1-7, 11-17, 21-27 and 31-37min). We found that HEP amplitudes were higher during open than during closed eyes between 1 and 17min after cortisol infusion. There was no effect of cortisol on heart rate. We conclude that cortisol may rapidly modulate the cortical processing of cardioceptive neural signals. These results may have relevance for the effects of stress on the development and maintenance of psychosomatic symptoms.