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1.
Horm Behav ; 165: 105633, 2024 Sep 07.
Article in English | MEDLINE | ID: mdl-39244875

ABSTRACT

Time of day can alter memory performance in general. Its influence on memory recognition performance for faces, which is important for daily encounters with new persons or testimonies, has not been investigated yet. Importantly, high levels of the stress hormone cortisol impair memory recognition, in particular for emotional material. However, some studies also reported high cortisol levels to enhance memory recognition. Since cortisol levels in the morning are usually higher than in the evening, time of day might also influence recognition performance. In this pre-registered study with a two-day design, 51 healthy men encoded pictures of male and female faces with distinct emotional expressions on day one around noon. Memory for the faces was retrieved two days later at two consecutive testing times either in the morning (high and moderately increased endogenous cortisol levels) or in the evening (low endogenous cortisol levels). Additionally, alertness as well as salivary cortisol levels at the different timepoints was assessed. Cortisol levels were significantly higher in the morning compared to the evening group as expected, while both groups did not differ in alertness. Familiarity ratings for female stimuli were significantly better when participants were tested during moderately increased endogenous cortisol levels in the morning than during low endogenous cortisol levels in the evening, a pattern which was previously also observed for stressed versus non-stressed participants. In addition, cortisol levels during that time in the morning were positively correlated with the recollection of face stimuli in general. Thus, recognition memory performance may depend on the time of day and as well as on stimulus type, such as the difference of male and female faces. Most importantly, the results suggest that cortisol may be meaningful and worth investigating when studying the effects of time of day on memory performance. This research offers both, insights into daily encounters as well as legally relevant domains as for instance testimonies.

2.
Sci Rep ; 14(1): 20826, 2024 09 06.
Article in English | MEDLINE | ID: mdl-39242764

ABSTRACT

How stress affects functional hemispheric asymmetries is relevant because stress represents a risk factor for the development of mental disorders and various mental disorders are associated with atypical lateralization. Using three lateralization tasks, we investigated whether functional hemispheric asymmetries in the form of hemispheric dominance for language (verbal dichotic listening task), emotion processing (emotional dichotic listening task), and visuo-spatial attention (line bisection task) were affected by acute stress in healthy adults. One hundred twenty right-handed men and women performed these lateralization tasks in randomized order after exposure to a mild online stressor (i.e., an online variant of the Trier Social Stress Test (TSST), TSST-OL) and a non-stressful online control task (friendly TSST-OL, fTSST-OL) in a within-subjects design. Importantly, the verbal and the emotional dichotic listening tasks were presented online whereas the line bisection task was completed in paper-pencil form. During these tasks, we found the expected hemispheric asymmetries, indicating that online versions of both the verbal and the emotional dichotic listening task can be used to measure functional hemispheric asymmetries in language and emotion processing remotely. Even though subjective and physiological markers confirmed the success of the online stress manipulation, replicating previous studies, we found no stress-induced effect on functional hemispheric asymmetries. Thus, in healthy participants, functional hemispheric asymmetries do not seem to change flexibly in response to acute stress.


Subject(s)
Emotions , Functional Laterality , Stress, Psychological , Humans , Male , Female , Stress, Psychological/physiopathology , Adult , Young Adult , Functional Laterality/physiology , Emotions/physiology , Language , Attention/physiology , Dichotic Listening Tests
3.
Stress ; 27(1): 2361237, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38946453

ABSTRACT

Compared to the in-person Trier Social Stress Test (TSST), virtual reality (VR) variants reduce resource-intensity and improve standardization but induce stress with smaller effect sizes. However, higher cortisol reactivity is given for more immersive TSST-VRs. Immersivity depends on the VR-system, but perceived immersion may be targeted by exposure to, or interaction with the VR. We investigated whether stress reactivity towards the openly accessible OpenTSST VR can be enhanced by prior exposure to a sensorimotor game completed in VR as mediated by increased immersion. Therefore, N = 58 healthy participants underwent the OpenTSST VR or its inbuilt control condition (placebo TSST-VR, pTSST-VR). Beforehand, participants completed a sensorimotor game either in VR or in real life. Stress was measured by means of self-reports, salivary cortisol concentrations, and salivary alpha-amylase (sAA) activity. Perceived immersion was assessed with the Igroup Presence Questionnaire (IPQ). The TSST-VR-group showed higher subjective stress than the pTSST-VR-group. Even though area under the curve measures indicated significant differences in cortisol levels between TSST-VR and pTSST-VR, this effect was not replicated in omnibus-analyses. Likewise, sAA was not responsive to stress. Our data suggests the OpenTSST VR does not reliably trigger physiological stress reactivity. Likewise, participants playing the VR-game before exposure to the TSST-VR did not show enhanced stress reactivity. Importantly, playing the VR-game did not lead to increased immersion (indicated by the IPQ), either. The key question resulting from our study is which manipulation may be fruitful to obtain a comparable stress response toward the TSST-VR compared to the in-person TSST.


Subject(s)
Hydrocortisone , Saliva , Stress, Psychological , Virtual Reality , Humans , Hydrocortisone/metabolism , Male , Female , Adult , Saliva/chemistry , Saliva/metabolism , Young Adult , Video Games , Salivary alpha-Amylases/metabolism
4.
BMC Psychol ; 12(1): 324, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38831468

ABSTRACT

Cognitive functions, such as learning and memory processes, depend on effective communication between brain regions which is facilitated by white matter tracts (WMT). We investigated the microstructural properties and the contribution of WMT to extinction learning and memory in a predictive learning task. Forty-two healthy participants completed an extinction learning paradigm without a fear component. We examined differences in microstructural properties using diffusion tensor imaging to identify underlying neural connectivity and structural correlates of extinction learning and their potential implications for the renewal effect. Participants with good acquisition performance exhibited higher fractional anisotropy (FA) in WMT including the bilateral inferior longitudinal fasciculus (ILF) and the right temporal part of the cingulum (CNG). This indicates enhanced connectivity and communication between brain regions relevant to learning and memory resulting in better learning performance. Our results suggest that successful acquisition and extinction performance were linked to enhanced structural connectivity. Lower radial diffusivity (RD) in the right ILF and right temporal part of the CNG was observed for participants with good acquisition learning performance. This observation suggests that learning difficulties associated with increased RD may potentially be due to less myelinated axons in relevant WMT. Also, participants with good acquisition performance were more likely to show a renewal effect. The results point towards a potential role of structural integrity in extinction-relevant WMT for acquisition and extinction.


Subject(s)
Diffusion Tensor Imaging , Extinction, Psychological , White Matter , Humans , Male , Female , Diffusion Tensor Imaging/methods , White Matter/diagnostic imaging , Adult , Young Adult , Extinction, Psychological/physiology , Learning/physiology , Neural Pathways/diagnostic imaging , Gyrus Cinguli/diagnostic imaging , Gyrus Cinguli/anatomy & histology , Anisotropy
5.
Brain Topogr ; 37(5): 834-848, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38635017

ABSTRACT

The post-retrieval extinction paradigm, rooted in reconsolidation theory, holds promise for enhancing extinction learning and addressing anxiety and trauma-related disorders. This study investigates the impact of two reminder types, mild US-reminder (US-R) and CS-reminder (CS-R), along with a no-reminder extinction, on fear recovery prevention in a categorical fear conditioning paradigm. Scalp EEG recordings during reminder and extinction processes were conducted in a three-day design. Results show that the US-R group exhibits a distinctive extinction learning pattern, characterized by a slowed-down yet successful process and pronounced theta-alpha desynchronization (source-located in the prefrontal cortex) during CS processing, followed by enhanced synchronization (source-located in the anterior cingulate) after shock cancellation in extinction trials. These neural dynamics correlate with the subtle advantage of US-R in the Day 3 recovery test, presenting faster spontaneous recovery fading and generally lower fear reinstatement responses. Conversely, the CS reminder elicits CS-specific effects in later episodic tests. The unique neural features of the US-R group suggest a larger prediction error and subsequent effortful conflict learning processes, warranting further exploration.


Subject(s)
Conditioning, Classical , Electroencephalography , Extinction, Psychological , Fear , Galvanic Skin Response , Humans , Extinction, Psychological/physiology , Galvanic Skin Response/physiology , Electroencephalography/methods , Male , Female , Fear/physiology , Young Adult , Conditioning, Classical/physiology , Adult , Brain/physiology , Mental Recall/physiology , Conflict, Psychological
6.
Stress ; 27(1): 2330704, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38528793

ABSTRACT

Acute stress has been demonstrated to affect a diverse array of attentional processes, one of which is selective attention. Selective attention refers to the cognitive process of deliberately allocating attentional resources to a specific stimulus, while ignoring other, distracting stimuli. While catecholamines have been shown to narrow attention, investigations on the influence of the stress hormone cortisol have yielded ambiguous results. We conducted two separate studies utilizing different laboratory stress induction paradigms to examine if cortisol influences the ability to selectively attend to local or global elements of a visual stimulus. In Study 1, 72 healthy young men took part either in the stressful Socially Evaluated Cold Pressor Test (SECPT) or a non-stressful (warm water) control, before being exposed to a composite letter task (CLT). Study 2 comprised a sample of 72 healthy young men and women and made use of a modified version of the Trier Social Stress Test (TSST) as well as a non-stressful control version, the friendly-TSST (f-TSST). Via endocrine, physiological, and subjective markers, we confirmed a successful stress induction. As verified with Bayesian statistics, stress did not affect selective attention in neither of the two studies. Furthermore, we were able to replicate the previously demonstrated absence of global precedence for composite figures composed of letters. Our results offer novel insights into the temporal dynamics of the effects of acute stress on attentional processes. Future studies should manipulate the timing of stress induction and investigate the effects of stress on letter vs. non-letter composite figures to shed further light on the underlying mechanisms.


Subject(s)
Hydrocortisone , Stress, Psychological , Male , Humans , Female , Bayes Theorem , Stress, Psychological/psychology , Psychological Tests , Attention/physiology , Saliva
7.
Ann Hematol ; 103(4): 1221-1233, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38413410

ABSTRACT

In low-risk Myelodysplastic Neoplasms (MDS), increased activity of apoptosis-promoting factors such as tumor necrosis factor (TNFα) and pro-apoptotic Fas ligand (CD95L) have been described as possible pathomechanisms leading to impaired erythropoiesis. Asunercept (APG101) is a novel therapeutic fusion protein blocking CD95, which has previously shown partial efficacy in reducing transfusion requirement in a clinical phase I trial for low-risk MDS patients (NCT01736436; 2012-11-26). In the current study we aimed to evaluate the effect of Asunercept therapy on the clonal bone marrow composition to identify potential biomarkers to predict response. Bone marrow samples of n = 12 low-risk MDS patients from the above referenced clinical trial were analyzed by serial deep whole exome sequencing in a total of n = 58 time points. We could distinguish a mean of 3.5 molecularly defined subclones per patient (range 2-6). We observed a molecular response defined as reductions of dominant clone sizes by a variant allele frequency (VAF) decrease of at least 10% (mean 20%, range: 10.5-39.2%) in dependency of Asunercept treatment in 9 of 12 (75%) patients. Most of this decline in clonal populations was observed after completion of 12 weeks treatment. Particularly early and pronounced reductions of clone sizes were found in subclones driven by mutations in genes involved in regulation of methylation (n = 1 DNMT3A, n = 1 IDH2, n = 1 TET2). Our results suggest that APG101 could be efficacious in reducing clone sizes of mutated hematopoietic cells in the bone marrow of Myelodysplastic Neoplasms, which warrants further investigation.


Subject(s)
Myelodysplastic Syndromes , Neoplasms , Humans , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathology , Clone Cells/pathology , Bone Marrow/pathology , Apoptosis , Mutation
8.
eNeuro ; 11(2)2024 Feb.
Article in English | MEDLINE | ID: mdl-38176906

ABSTRACT

Functional brain imaging studies in humans suggest involvement of the cerebellum in fear conditioning but do not allow conclusions about the functional significance. The main aim of the present study was to examine whether patients with cerebellar degeneration show impaired fear conditioning and whether this is accompanied by alterations in cerebellar cortical activations. To this end, a 2 d differential fear conditioning study was conducted in 20 cerebellar patients and 21 control subjects using a 7 tesla (7 T) MRI system. Fear acquisition and extinction training were performed on day 1, followed by recall on day 2. Cerebellar patients learned to differentiate between the CS+ and CS-. Acquisition and consolidation of learned fear, however, was slowed. Additionally, extinction learning appeared to be delayed. The fMRI signal was reduced in relation to the prediction of the aversive stimulus and altered in relation to its unexpected omission. Similarly, mice with cerebellar cortical degeneration (spinocerebellar ataxia type 6, SCA6) were able to learn the fear association, but retrieval of fear memory was reduced. In sum, cerebellar cortical degeneration led to mild abnormalities in the acquisition of learned fear responses in both humans and mice, particularly manifesting postacquisition training. Future research is warranted to investigate the basis of altered fMRI signals related to fear learning.


Subject(s)
Brain Mapping , Conditioning, Classical , Humans , Animals , Mice , Conditioning, Classical/physiology , Extinction, Psychological/physiology , Fear/physiology , Learning , Magnetic Resonance Imaging
9.
J Pain ; 25(4): 1082-1093, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37956744

ABSTRACT

Despite the crucial role of effective and sustained extinction of conditioned pain-related fear in cognitive-behavioral treatment approaches for chronic pain, experimental research on extinction memory retrieval in chronic pain remains scarce. In healthy populations, extinction efficacy of fear memory is affected by stress. Therefore, we investigated the effects of oral hydrocortisone administration on the reinstatement of pain-related associations in 57 patients with non-specific chronic back pain (CBP) and 59 healthy control (HC) participants in a differential pain-related conditioning paradigm within a placebo-controlled, randomized, and double-blind design. Participants' skin conductance responses indicate hydrocortisone-induced reinstatement effects in HCs but no observable reinstatement in HCs receiving placebo treatment. Interestingly, these effects were reversed in patients with CBP, that is, reinstatement responses were only observed in the placebo and not in the hydrocortisone group. Our findings corroborate previous evidence of stress-induced effects on extinction efficacy and reinstatement of fear memory in HCs, extending them into the pain context, and call for more research to clarify the role of stress in fear extinction and return of fear phenomena possibly contributing to treatment failure in chronic pain treatment. PERSPECTIVE: Opposing effects in HCs and patients with non-specific CBP may be associated with changes in the patients' stress systems. These findings could be of relevance to optimizing psychological, extinction-based treatment approaches.


Subject(s)
Chronic Pain , Fear , Phobic Disorders , Humans , Fear/physiology , Hydrocortisone , Extinction, Psychological/physiology , Healthy Volunteers , Chronic Pain/drug therapy , Conditioning, Classical/physiology , Back Pain/drug therapy , Galvanic Skin Response
10.
Neurobiol Learn Mem ; 205: 107844, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37866754

ABSTRACT

Conditioned responding gradually stops during successful extinction learning. The renewal effect is defined as the recovery of a extinguished conditioned response when the context of extinction is different from acquisition. The stress hormone cortisol is known to have an influence on extinction memory and associative learning. Different effects of cortisol on behaviour and brain activity have been observed with respect to stress timing, duration, and intensity. However, the influence of cortisol prior to the initial encoding of stimulus-outcome associations on extinction learning, renewal and its behavioural and neurobiological correlates is still largely unknown. In our study, 60 human participants received 20 mg cortisol or placebo and then learned, extinguished, and recalled the associations between food stimuli presented in distinct contexts and different outcomes in three subsequent task phases. Learning performance during acquisition and extinction phases was equally good for both treatment groups. In the cortisol group, significantly more participants showed renewal compared to placebo. In the subgroup of participants with renewal, cortisol treated participants showed significantly better extinction learning performance compared to placebo. Participants showing renewal had in general difficulties with recalling extinction memory, but in contrast to placebo, the cortisol group exhibited a context-dependent impairment of extinction memory recall. Imaging analyses revealed that cortisol decreased activation in the hippocampus during acquisition. The cortisol group also showed reduced dorsolateral prefrontal cortex activation when extinction learning took place in a different context, but enhanced activation in inferior frontal gyrus during extinction learning without context change. During recall, cortisol decreased ventromedial prefrontal cortex activation. Taken together, our findings illustrate cortisol as a potent modulator of extinction learning and recall of extinction memory which also promotes renewal.


Subject(s)
Extinction, Psychological , Hydrocortisone , Humans , Hydrocortisone/pharmacology , Extinction, Psychological/physiology , Brain/diagnostic imaging , Mental Recall/physiology , Prefrontal Cortex/physiology , Magnetic Resonance Imaging
11.
Elife ; 122023 08 09.
Article in English | MEDLINE | ID: mdl-37555830

ABSTRACT

Human neuroscience has always been pushing the boundary of what is measurable. During the last decade, concerns about statistical power and replicability - in science in general, but also specifically in human neuroscience - have fueled an extensive debate. One important insight from this discourse is the need for larger samples, which naturally increases statistical power. An alternative is to increase the precision of measurements, which is the focus of this review. This option is often overlooked, even though statistical power benefits from increasing precision as much as from increasing sample size. Nonetheless, precision has always been at the heart of good scientific practice in human neuroscience, with researchers relying on lab traditions or rules of thumb to ensure sufficient precision for their studies. In this review, we encourage a more systematic approach to precision. We start by introducing measurement precision and its importance for well-powered studies in human neuroscience. Then, determinants for precision in a range of neuroscientific methods (MRI, M/EEG, EDA, Eye-Tracking, and Endocrinology) are elaborated. We end by discussing how a more systematic evaluation of precision and the application of respective insights can lead to an increase in reproducibility in human neuroscience.


Subject(s)
Neurosciences , Humans , Reproducibility of Results , Sample Size , Magnetic Resonance Imaging
12.
Curr Top Behav Neurosci ; 64: 179-191, 2023.
Article in English | MEDLINE | ID: mdl-37455303

ABSTRACT

Effects of a specific factor on fear extinction or exposure therapy have revealed promising results, for example how sex or stress hormones exert the capability to critically change extinction learning and consolidation processes. However, we must acknowledge that in real life these factors do not operate in isolation, they go hand in hand. In this chapter, the available evidence regarding interactions of sex and stress hormones on extinction processes and exposure therapy will be integrated and discussed. First hints exist that these factors in combination critically target extinction learning and consolidation processes, calling for more detailed research on the exact underlying mechanisms. In addition to experiments with high sample sizes, we must aim for a collaborative effort of laboratories across the whole world to be able to identify critical combinations of factors associated with improved, but also impaired extinction processes and exposure therapy success. We expect that the revelation of further relevant factors will not only be limited to the interplay between sex and stress hormones but will include factors such as sleep and exercise as well. In the long run, uncovering the most important interaction effects will give us critical hints for differential treatment options to be realized in the sense of a personalized medicine approach.


Subject(s)
Extinction, Psychological , Fear , Learning , Sex Characteristics , Hormones/pharmacology
13.
Psychophysiology ; 60(11): e14373, 2023 11.
Article in English | MEDLINE | ID: mdl-37350416

ABSTRACT

Based on the mechanisms of fear extinction, exposure therapy is the most common treatment for anxiety disorders. However, extinguished fear responses can reemerge even after successful treatment. Novel interventions enhancing exposure therapy efficacy are therefore critically needed. Physical exercise improves learning and memory and was also shown to enhance extinction processes. This study tested whether physical exercise following fear extinction training improves the consolidation of extinction memories. Sixty healthy men underwent a differential fearconditioning paradigm with fear acquisition training on day 1 and fear extinction training followed by an exercise or resting control intervention on day 2. On day 3, retrieval and reinstatement were tested including two additional but perceptually similar stimuli to explore the generalization of exercise effects. Exercise significantly increased heart rate, salivary alpha amylase, and cortisol, indicating successful exercise manipulation. Contrary to our expectations, exercise did not enhance but rather impaired extinction memory retrieval on the next day, evidenced by significantly stronger differential skin conductance responses (SCRs) and pupil dilation (PD). Importantly, although conditioned fear responses were successfully acquired, they did not fully extinguish, explaining why exercise might have boosted the consolidation of the original fear memory trace instead. Additionally, stronger differential SCRs and PD toward the novel stimuli suggest that the memory enhancing effects of exercise also generalized to perceptually similar stimuli. Together, these findings indicate that physical exercise can facilitate both the long-term retrievability and generalization of extinction memories, but presumably only when extinction was successful in the first place.


Subject(s)
Extinction, Psychological , Fear , Male , Humans , Fear/physiology , Extinction, Psychological/physiology , Memory/physiology , Conditioning, Classical/physiology , Exercise
14.
Front Psychiatry ; 14: 1204136, 2023.
Article in English | MEDLINE | ID: mdl-37275987

ABSTRACT

Visceral pain and stress are tightly intertwined bodily and emotional phenomena, which enable a flexible adaptation to environmental challenges by activating a response repertoire to restore homeostasis along the gut-brain axis. However, visceral pain and stress can persist widely independent of the initial cause, acquiring independent disease values and posing major health burdens as predominant features in disorders of gut-brain interaction (DGBI). Epidemiological data consistently documents an increased prevalence for women to suffer from chronic visceral pain, possibly shaped by sex hormones and modulated by stress and its biological and psychosocial correlates. Yet, mechanisms underlying the complex interactions between altered visceroception, stress and sex remain widely elusive, especially in clinical populations with DGBI. We herein selectively review mechanisms of interactions between stress and sex in the complex pathophysiology of DGBI. A particular emphasis is laid on visceral pain, in which stress constitutes a major risk factor as well as mediator, and sex-related differences are particularly pronounced. Building on the neurobiology of stress and mechanisms of gut-brain interactions, we highlight putative target mechanisms via which visceral pain and stress may converge with sex effects into a triad. Accommodating a global demographic shift, we propose a lifespan perspective in future research, which may enable a more fine-tuned evaluation of this complex interplay exerting distinct challenges during vulnerable developmental phases. This viewpoint may advance our understanding of pathophysiological processes and can ultimately inspire novel tailored prevention strategies and therapeutic approaches in the treatment of chronic visceral pain and DGBI across the lifespan.

15.
Neurobiol Stress ; 25: 100544, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37275340

ABSTRACT

The ability of emotion regulation under stress is of crucial importance to psychosocial health. Yet, the dynamic function of stress hormones for the cognitive control of emotions over time via non-genomic and genomic cortisol effects remains to be elucidated. In this randomized, double-blind, placebo-controlled neuroimaging experiment, 105 participants (54 men, 51 women) received 20 mg hydrocortisone (cortisol) or a placebo either 30min (rapid, non-genomic cortisol effects) or 90min (slow, genomic cortisol effects) prior to a cognitive reappraisal task including different regulatory goals (i.e., downregulate vs. upregulate negative emotions). On the behavioral level, cortisol rapidly reduced and slowly enhanced emotional responsivity to negative pictures. However, only slow cortisol effects improved downregulation of negative emotions. On the neural level, cortisol rapidly enhanced, but slowly reduced amygdala and dorsolateral prefrontal activation as well as functional connectivity between both structures in the down- minus upregulate contrast. This interaction speaks for an effortful but ineffective regulation of negative emotions during rapid cortisol effects and improved emotion regulation capacities during slow cortisol effects. Taken together, these results indicate a functional shift of cortisol effects on emotion regulation processes over time which may foster successful adaptation to and recovery from stressful life events.

16.
Front Immunol ; 14: 1160116, 2023.
Article in English | MEDLINE | ID: mdl-37304285

ABSTRACT

Introduction: The ability to modulate and enhance the anti-tumor immune responses is critical in developing novel therapies in cancer. The Tumor Necrosis Factor (TNF) Receptor Super Family (TNFRSF) are potentially excellent targets for modulation which result in specific anti-tumor immune responses. CD40 is a member of the TNFRSF and several clinical therapies are under development. CD40 signaling plays a pivotal role in regulating the immune system from B cell responses to myeloid cell driven activation of T cells. The CD40 signaling axis is well characterized and here we compare next generation HERA-Ligands to conventional monoclonal antibody based immune modulation for the treatment of cancer. Methods & results: HERA-CD40L is a novel molecule that targets CD40 mediated signal transduction and demonstrates a clear mode of action in generating an activated receptor complex via recruitment of TRAFs, cIAP1, and HOIP, leading to TRAF2 phosphorylation and ultimately resulting in the enhanced activation of key inflammatory/survival pathway and transcription factors such asNFkB, AKT, p38, ERK1/2, JNK, and STAT1 in dendritic cells. Furthermore, HERA-CD40L demonstrated a strong modulation of the tumor microenvironment (TME) via the increase in intratumoral CD8+ T cells and the functional switch from pro-tumor macrophages (TAMs) to anti-tumor macrophages that together results in a significant reduction of tumor growth in a CT26 mouse model. Furthermore, radiotherapy which may have an immunosuppressive modulation of the TME, was shown to have an immunostimulatory effect in combination with HERA-CD40L. Radiotherapy in combination with HERA-CD40L treatment resulted in an increase in detected intratumoral CD4+/8+ T cells compared to RT alone and, additionally, the repolarization of TAMs was also observed, resulting in an inhibition of tumor growth in a TRAMP-C1 mouse model. Discussion: Taken together, HERA-CD40L resulted in activating signal transduction mechanisms in dendritic cells, resulting in an increase in intratumoral T cells and manipulation of the TME to be pro-inflammatory, repolarizing M2 macrophages to M1, enhancing tumor control.


Subject(s)
CD40 Ligand , Neoplasms , Animals , Mice , CD40 Antigens , Antigen-Presenting Cells , Macrophages , Neoplasms/radiotherapy , Disease Models, Animal , Tumor Microenvironment
17.
Psychopharmacology (Berl) ; 240(5): 1075-1089, 2023 May.
Article in English | MEDLINE | ID: mdl-36894736

ABSTRACT

RATIONALE: The administration of glucocorticoids (GC) as an adjunct to exposure represents a promising strategy to improve one-session exposure outcome in anxiety disorders. It remains to be determined whether similar effects can be induced with the use of acute stress. Furthermore, the possible modulation of exposure effects by hormonal factors (e.g., use of oral contraceptives (OCs)) was not explored so far. OBJECTIVES: We investigated whether acute stress prior to one-session exposure for spider fear affects its efficacy in women using oral contraceptives (OC) relative to free-cycling (FC) women. In addition, effects of stress on generalization of exposure therapy effects towards untreated stimuli were examined. METHODS: Women with fears of spiders and cockroaches were randomly assigned to a Stress (n = 24) or No-Stress (n = 24) condition prior to one-session exposure. Of these 48 participants, 19 women used OC (n = 9 in the Stress, and n = 10 in the No-Stress group). All FC women had a regular menstrual cycle and were tested only in the follicular phase of their menstrual cycle. Pre-exposure stress induction was realized with the socially evaluated cold-pressor test. Exposure-induced changes towards treated and untreated fear stimuli were tested with behavioral approach tests for spiders and cockroaches and subjective fear and self-report measures. RESULTS: Acute stress did not influence exposure-induced reduction in fear and avoidance of the treated stimuli (spiders). Similarly, stress had no effect on the generalization of exposure-therapy effects towards untreated stimuli (cockroaches). Exposure-induced reduction in subjective fear and self-report measures for treated stimuli was less evident in women using OC specifically after pre-exposure stress. Women using OC had higher levels of subjective fear and scored higher in self-report measures at post-treatment (24 h after exposure) and follow-up (4 weeks after exposure). CONCLUSIONS: OC intake may represent an important confounding factor in augmentation studies using stress or GC.


Subject(s)
Implosive Therapy , Phobic Disorders , Spiders , Humans , Animals , Female , Contraceptives, Oral/pharmacology , Phobic Disorders/therapy , Fear , Anxiety Disorders , Glucocorticoids/pharmacology
18.
Neurosci Biobehav Rev ; 148: 105146, 2023 05.
Article in English | MEDLINE | ID: mdl-36990370

ABSTRACT

Fear conditioning is a widely used laboratory model to investigate learning, memory, and psychopathology across species. The quantification of learning in this paradigm is heterogeneous in humans and psychometric properties of different quantification methods can be difficult to establish. To overcome this obstacle, calibration is a standard metrological procedure in which well-defined values of a latent variable are generated in an established experimental paradigm. These intended values then serve as validity criterion to rank methods. Here, we develop a calibration protocol for human fear conditioning. Based on a literature review, series of workshops, and survey of N = 96 experts, we propose a calibration experiment and settings for 25 design variables to calibrate the measurement of fear conditioning. Design variables were chosen to be as theory-free as possible and allow wide applicability in different experimental contexts. Besides establishing a specific calibration procedure, the general calibration process we outline may serve as a blueprint for calibration efforts in other subfields of behavioral neuroscience that need measurement refinement.


Subject(s)
Fear , Learning , Humans , Calibration
19.
Psychoneuroendocrinology ; 150: 106043, 2023 Apr.
Article in English | MEDLINE | ID: mdl-36731350

ABSTRACT

Stress and the stress hormone cortisol typically impair memory recognition, especially for emotional words, scenes or objects. However, prior research almost exclusively focused on rapid non-genomic cortisol effects. Additionally, findings for stress hormone effects on face stimuli are contradictory and rare, although very relevant for everyday life. In this preregistered study, we investigated the rapid and delayed stress effects on memory recognition for faces. In a two-day design, 52 healthy men first encoded pictures of male and female faces with distinct emotional expressions. One day later, participants were exposed to a psychophysiological stress (Socially Evaluated Cold-Pressor Test) or a (warm water) control procedure. Memory for the faces was tested at two time points: 25 min after stress onset at the peak of the cortisol increase for stressed participants (rapid non-genomic cortisol effects, which presumably operate within minutes through membrane bound receptors), as well as 90 min after stress onset when cortisol concentrations were back to baseline (delayed genomic cortisol effects, which describe an altered gene transcription resulting in modified neural functions, acting supposedly via intracellular receptors). Rapid stress effects led to enhanced memory recognition for female faces selectively, whereas delayed stress effects led to enhanced memory recognition across male and female faces. Altogether, we observed a beneficial rather than detrimental impact of stress on face recognition with a differential impact on recognition of male and female faces over time. It remains to be determined if this beneficial stress effect relies on the interaction of participants' sex and the sex of facial stimuli. Future research should also more closely look at the underlying mechanisms of how stress exactly influences face recognition, which is for example critically relevant for testimonies.


Subject(s)
Facial Recognition , Hydrocortisone , Humans , Male , Female , Hydrocortisone/physiology , Recognition, Psychology/physiology , Emotions/physiology , Facial Recognition/physiology , Psychophysiology , Stress, Psychological/psychology
20.
Sports Biomech ; : 1-15, 2023 Feb 28.
Article in English | MEDLINE | ID: mdl-36854680

ABSTRACT

Swing to strength hold elements are important for a top ranking on still rings, require a high level of upper body strength of the gymnasts and have not yet been scientifically investigated. Therefore, the aim of this study was to determine force requirement profiles for these elements using a dynamometric measuring system. Two force sensors attached to the cables of each ring and synchronised with video recorded the forces exerted by the gymnast. For eight swing to strength hold elements (Uprise backward to support scale straddled, Uprise backward to swallow, Uprise backward to cross, Honma to cross, Uprise backward to support scale, Kip to cross, Back kip to swallow and Uprise backward to inverted cross), the variables maximal force (Fmax), minimal force (Fmin), time over Fhold (t1-3), rate of maximal force development (RFD) and impulse (p) were analysed. Honma to cross shows the highest force requirements (Median: Fmax = 120.4% BW, Fmin = 109.8% BW, t1-3 = 882 ms, RFD = 143.93% BW/s, p = 9.85% BWs) whereas back kip to swallow shows the least (Fmax = 102.3% BW, RFD = 34.99% BW/s and p = 0.84% BW/s). The biomechanical demand profiles can be used to provide feedback to coaches and gymnasts. In future research, they should be extended with kinematic and electromyographic data.

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