@misc{vonWerderAubeleRegnathetal., author = {von Werder, Dina and Aubele, Maria and Regnath, Franziska and Tebbe, Elisabeth and Mladenov, Dejan and von Rheinbaben, Victoria and Hahn, Elisabeth and Sch{\"a}fer, Daniel and Biersack, Katharina and Adorjan, Kristina and Stubbe, Hans C. and Bogaerts, Katleen and J{\"o}rres, Rudolf A. and Nowak, Dennis and Van den Bergh, Omer and Glasauer, Stefan and Lehnen, Nadine}, title = {Increased breathlessness in post-COVID syndrome despite normal breathing patterns in a rebreathing challenge}, series = {Scientific reports}, volume = {15}, journal = {Scientific reports}, number = {1}, publisher = {Springer Nature}, address = {[London]}, issn = {2045-2322}, doi = {10.1038/s41598-025-11728-x}, pages = {1 -- 15}, abstract = {Severe symptoms in the absence of measurable body pathology are a frequent hallmark of post-COVID syndrome. From a Bayesian Brain perspective, such symptoms can be explained by incorrect internal models that the brain uses to interpret sensory signals. In this pre-registered study, we investigate whether induced breathlessness perception during a controlled CO2rebreathing challenge is reflected by altered respiratory measures (physiology and breathing patterns), and propose different computational mechanisms that could explain our findings in a Bayesian Brain framework. We analysed data from 40 patients with post-COVID syndrome and 40 healthy participants. Results from lung function, neurological and neurocognitive examination of all participants were within normal limits on the day of the experiment. Using a Bayesian repeated-measures ANOVA, we found that patients' breathlessness was strongly increased (BF10,baseline =8.029, BF10,rebreathing =11636, BF10,recovery =43662) compared to controls. When excluding patients who hyperventilated (N = 8, 20\%) during the experiment from the analysis, differences in breathlessness remained (BF10,baseline =1.283, BF10,rebreathing =126.812, BF10,recovery =751.282). For physiology and breathing patterns, all evidence pointed towards no difference between the two groups (0.307  BF10 \< 0.704). In summary, we found intact breathing patterns and physiology but increased symptom perception in patients with post-COVID syndrome.}, language = {en} } @misc{SchroederWerderRamaiolietal., author = {Schr{\"o}der, Lena and Werder, Dina von and Ramaioli, Cecilia and Wachtler, Thomas and Henningsen, Peter and Glasauer, Stefan and Lehnen, Nadine}, title = {Unstable Gaze in Functional Dizziness: A Contribution to Understanding the Pathophysiology of Functional Disorders}, series = {Frontiers in Neuroscience}, volume = {15}, journal = {Frontiers in Neuroscience}, issn = {1662-453X}, doi = {10.3389/fnins.2021.685590}, abstract = {Objective: We are still lacking a pathophysiological mechanism for functional disorders explaining the emergence and manifestation of characteristic, severely impairing bodily symptoms like chest pain or dizziness. A recent hypothesis based on the predictive coding theory of brain function suggests that in functional disorders, internal expectations do not match the actual sensory body states, leading to perceptual dysregulation and symptom perception. To test this hypothesis, we investigated the account of internal expectations and sensory input on gaze stabilization, a physiologically relevant parameter of gaze shifts, in functional dizziness. Methods: We assessed gaze stabilization in eight functional dizziness patients and 11 healthy controls during two distinct epochs of large gaze shifts: during a counter- rotation epoch (CR epoch), where the brain can use internal models, motor planning, and resulting internal expectations to achieve internally driven gaze stabilization; and during an oscillation epoch (OSC epoch), where, due to terminated motor planning, no movement expectations are present, and gaze is stabilized by sensory input alone. Results: Gaze stabilization differed between functional patients and healthy controls only when internal movement expectations were involved [F(1,17) = 14.63, p = 0.001, and partial η2 = 0.463]: functional dizziness patients showed reduced gaze stabilization during the CR (p = 0.036) but not OSC epoch (p = 0.26). Conclusion: While sensory-driven gaze stabilization is intact, there are marked, well- measurable deficits in internally-driven gaze stabilization in functional dizziness pointing at internal expectations that do not match actual body states. This experimental evidence supports the perceptual dysregulation hypothesis of functional disorders and is an important step toward understanding the underlying pathophysiology.}, language = {en} } @misc{WerderRegnathSchaeferetal., author = {Werder, Dina von and Regnath, Franziska and Sch{\"a}fer, Daniel and J{\"o}rres, Rudolf and Lehnen, Nadine and Glasauer, Stefan}, title = {Post-COVID breathlessness: a mathematical model of respiratory processing in the brain}, series = {European Archives of Psychiatry and Clinical Neuroscience}, journal = {European Archives of Psychiatry and Clinical Neuroscience}, issn = {0940-1334}, doi = {10.1007/s00406-023-01739-y}, abstract = {Breathlessness is among the most common post-COVID symptoms. In a considerable number of patients, severe breathlessness cannot be explained by peripheral organ impairment. Recent concepts have described how such persistent breathlessness could arise from dysfunctional processing of respiratory information in the brain. In this paper, we present a first quantitative and testable mathematical model of how processing of respiratory-related signals could lead to breathlessness perception. The model is based on recent theories that the brain holds an adaptive and dynamic internal representation of a respiratory state that is based on previous experiences and comprises gas exchange between environment, lung and tissue cells. Perceived breathlessness reflects the brain's estimate of this respiratory state signaling a potentially hazardous disequilibrium in gas exchange. The internal respiratory state evolves from the respiratory state of the last breath, is updated by a sensory measurement of CO2 concentration, and is dependent on the current activity context. To evaluate our model and thus test the assumed mechanism, we used data from an ongoing rebreathing experiment investigating breathlessness in patients with post-COVID without peripheral organ dysfunction (N = 5) and healthy control participants without complaints after COVID-19 (N = 5). Although the observed breathlessness patterns varied extensively between individual participants in the rebreathing experiment, our model shows good performance in replicating these individual, heterogeneous time courses. The model assumes the same underlying processes in the central nervous system in all individuals, i.e., also between patients and healthy control participants, and we hypothesize that differences in breathlessness are explained by different weighting and thus influence of these processes on the final percept. Our model could thus be applied in future studies to provide insight into where in the processing cascade of respiratory signals a deficit is located that leads to (post-COVID) breathlessness. A potential clinical application could be, e.g., the monitoring of effects of pulmonary rehabilitation on respiratory processing in the brain to improve the therapeutic strategies.}, language = {en} } @misc{SchaeferJoerresNowaketal., author = {Schaefer, Daniel and J{\"o}rres, Rudolf and Nowak, Dennis and Van Den Bergh, Omer and Bogaerts, Katleen and Glasauer, Stefan and Lehnen, Nadine and Von Werder, Dina}, title = {Late breaking abstract : replication and validation of a rebreathing experiment to investigate post-COVID symptoms}, series = {European Respiratory Journal}, volume = {62}, journal = {European Respiratory Journal}, number = {Suppl. 67}, publisher = {European Respiratory Society}, doi = {10.1183/13993003.congress-2023.PA5072}, language = {en} } @misc{HessvonWerderHarrisonetal., author = {Hess, Alexander J. and von Werder, Dina and Harrison, Olivia K. and Heinzle, Jakob and Stephan, Klaas Enno}, title = {Refining the allostatic self-efficacy theory of fatigue and depression using causal inference}, series = {Entropy}, volume = {26 (2024)}, journal = {Entropy}, number = {12}, publisher = {MDPI AG}, issn = {1099-4300}, doi = {10.3390/e26121127}, pages = {1 -- 18}, abstract = {Allostatic self-efficacy (ASE) represents a computational theory of fatigue and depression. In brief, it postulates that (i) fatigue is a feeling state triggered by a metacognitive diagnosis of loss of control over bodily states (persistently elevated interoceptive surprise); and that (ii) generalization of low self-efficacy beliefs beyond bodily control induces depression. Here, we converted ASE theory into a structural causal model (SCM). This allowed identification of empirically testable hypotheses regarding causal relationships between the variables of interest. Applying conditional independence tests to questionnaire data from healthy volunteers, we sought to identify contradictions to the proposed SCM. Moreover, we estimated two causal effects proposed by ASE theory using three different methods. Our analyses identified specific aspects of the proposed SCM that were inconsistent with the available data. This enabled formulation of an updated SCM that can be tested against future data. Second, we confirmed the predicted negative average causal effect from metacognition of allostatic control to fatigue across all three different methods of estimation. Our study represents an initial attempt to refine and formalize ASE theory using methods from causal inference. Our results confirm key predictions from ASE theory but also suggest revisions which require empirical verification in future studies.}, language = {en} } @misc{RegnathBiersackSchroederetal., author = {Regnath, Franziska and Biersack, Katharina and Schr{\"o}der, Lena and Stainer, Marie-Christin and von Werder, Dina and P{\"u}rner, Dominik and Haslinger, Bernhard and Lehnen, Nadine}, title = {Experimental evidence for a robust, transdiagnostic marker in functional disorders: Erroneous sensorimotor processing in functional dizziness and functional movement disorder}, series = {Journal of Psychosomatic Research}, volume = {183}, journal = {Journal of Psychosomatic Research}, editor = {Glasauer, Stefan}, publisher = {Elsevier BV}, issn = {0022-3999}, doi = {10.1016/j.jpsychores.2024.111694}, pages = {10}, language = {en} }