Post-COVID breathlessness: a mathematical model of respiratory processing in the brain.

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.

Individual differences do matter.

The integrative experiment design proposal currently only relates to group results, but downplays individual differences between participants, which may nevertheless be substantial enough to constitute a relevant dimension in the design space. Excluding the individual participant in the integrative design will not solve all problems mentioned in the target article, because averaging results may obscure the underlying mechanisms.

Neural mechanisms of sequential dependence in time perception: the impact of prior task and memory processing.

Our perception and decision-making are susceptible to prior context. Such sequential dependence has been extensively studied in the visual domain, but less is known about its impact on time perception. Moreover, there are ongoing debates about whether these sequential biases occur at the perceptual stage or during subsequent post-perceptual processing. Using functional magnetic resonance imaging, we investigated neural mechanisms underlying temporal sequential dependence and the role of action in time judgments across trials. Participants performed a timing task where they had to remember the duration of green coherent motion and were cued to either actively reproduce its duration or simply view it passively. We found that sequential biases in time perception were only evident when the preceding task involved active duration reproduction. Merely encoding a prior duration without reproduction failed to induce such biases. Neurally, we observed activation in networks associated with timing, such as striato-thalamo-cortical circuits, and performance monitoring networks, particularly when a "Response" trial was anticipated. Importantly, the hippocampus showed sensitivity to these sequential biases, and its activation negatively correlated with the individual's sequential bias following active reproduction trials. These findings highlight the significant role of memory networks in shaping time-related sequential biases at the post-perceptual stages.

Accounting for endogenous effects in decision-making with a non-linear diffusion decision model.

The Drift-Diffusion Model (DDM) is widely accepted for two-alternative forced-choice decision paradigms thanks to its simple formalism and close fit to behavioral and neurophysiological data. However, this formalism presents strong limitations in capturing inter-trial dynamics at the single-trial level and endogenous influences. We propose a novel model, the non-linear Drift-Diffusion Model (nl-DDM), that addresses these issues by allowing the existence of several trajectories to the decision boundary. We show that the non-linear model performs better than the drift-diffusion model for an equivalent complexity. To give better intuition on the meaning of nl-DDM parameters, we compare the DDM and the nl-DDM through correlation analysis. This paper provides evidence of the functioning of our model as an extension of the DDM. Moreover, we show that the nl-DDM captures time effects better than the DDM. Our model paves the way toward more accurately analyzing across-trial variability for perceptual decisions and accounts for peri-stimulus influences.

The precuneus as a central node in declarative memory retrieval.

Both, the hippocampal formation and the neocortex are contributing to declarative memory, but their functional specialization remains unclear. We investigated the differential contribution of both memory systems during free recall of word lists. In total, 21 women and 17 men studied the same list but with the help of different encoding associations. Participants associated the words either sequentially with the previous word on the list, with spatial locations on a well-known path, or with unique autobiographical events. After intensive rehearsal, subjects recalled the words during functional magnetic resonance imaging (fMRI). Common activity to all three types of encoding associations was identified in the posterior parietal cortex, in particular in the precuneus. Additionally, when associating spatial or autobiographical material, retrosplenial cortex activity was elicited during word list recall, while hippocampal activity emerged only for autobiographically associated words. These findings support a general, critical function of the precuneus in episodic memory storage and retrieval. The encoding-retrieval repetitions during learning seem to have accelerated hippocampus-independence and lead to direct neocortical integration in the sequentially associated and spatially associated word list tasks. During recall of words associated with autobiographical memories, the hippocampus might add spatiotemporal information supporting detailed scenic and contextual memories.

Not a general, symptom-unspecific, transdiagnostic marker for functional symptoms: sensorimotor processing of head control is intact in chronic pain.

Introduction: Functional disorders are prevalent in all medical fields and pose a tremendous public health problem, with pain being one of the most common functional symptoms. Understanding the underlying, potentially unifying mechanism in functional (pain) disorders is instrumental in facilitating timely diagnosis, stigma reduction, and adequate treatment options. Neuroscientific models of perception suggest that functional symptoms arise due to dysregulated sensorimotor processing in the central nervous system, with brain-based predictions dominating the eventual percept. Experimental evidence for this transdiagnostic mechanism has been established in various functional symptoms. The goal of the current study was to investigate whether erroneous sensorimotor processing is an underlying transdiagnostic mechanism in chronic (functional) pain. Method: A total of 13 patients with chronic (functional) pain [three patients with chronic (functional) pain disorder, F45.40, ICD-10; 10 patients with chronic pain disorder with somatic and psychological factors, F45.41, ICD-10]; and 15 healthy controls performed large combined eye-head gaze shifts toward visual targets, naturally and with increased head moment of inertia. We simultaneously measured participants' eye and head movements to assess head oscillations at the end of the gaze shift, which are an established indicator of (transdiagnostic) sensorimotor processing deficits of head control. Results: Using a Bayesian analysis protocol, we found that patients with chronic (functional) pain and control participants stabilized their heads equally well (Bayes Factor 01 = 3.7, Bayes Factor exclusion = 5.23; corresponding to substantial evidence) during all sessions of the experiment. Conclusion: Our results suggest that patients with chronic (functional) pain do not show measurable symptom-unspecific sensorimotor processing deficits. We discuss outcome parameter choice, organ system specificity, and selection of patient diagnoses as possible reasons for this result and recommend future avenues for research.

Altered sensorimotor processing in irritable bowel syndrome: Evidence for a transdiagnostic pathomechanism in functional somatic disorders.

Objective: A recent hypothesis suggests that functional somatic symptoms are due to altered information processing in the brain, with rigid expectations biasing sensorimotor signal processing. First experimental results confirmed such altered processing within the affected symptom modality, e.g., deficient eye-head coordination in patients with functional dizziness. Studies in patients with functional somatic symptoms looking at general, trans-symptomatic processing deficits are sparse. Here, we investigate sensorimotor processing during eye-head gaze shifts in irritable bowel syndrome (IBS) to test whether processing deficits exist across symptom modalities. Methods: Study participants were seven patients suffering from IBS and seven age- and gender-matched healthy controls who performed large gaze shifts toward visual targets. Participants performed combined eye-head gaze shifts in the natural condition and with experimentally increased head moment of inertia. Head oscillations as a marker for sensorimotor processing deficits were assessed. Bayes statistics was used to assess evidence for the presence or absence of processing differences between IBS patients and healthy controls. Results: With the head moment of inertia increased, IBS patients displayed more pronounced head oscillations than healthy controls (Bayes Factor 10 = 56.4, corresponding to strong evidence). Conclusion: Patients with IBS show sensorimotor processing deficits, reflected by increased head oscillations during large gaze shifts to visual targets. In particular, patients with IBS have difficulties to adapt to the context of altered head moment of inertia. Our results suggest general transdiagnostic processing deficits in functional somatic disorders.

Low Gain Values of the Vestibulo-Ocular Reflex Can Optimize Retinal Image Slip.

The angular vestibulo-ocular reflex (aVOR) stabilizes retinal images by counter-rotating the eyes during head rotations. Perfect compensatory movements would thus rotate the eyes exactly opposite to the head, that is, eyes vs. head would exhibit a unity gain. However, in many species, but also in elderly humans or patients with a history of vestibular damage, the aVOR is far from compensatory with gains that are in part considerably lower than unity. The reason for this apparent suboptimality is unknown. Here, we propose that low VOR gain values reflect an optimal adaptation to sensory and motor signal variability. According to this hypothesis, gaze stabilization mechanisms that aim at minimizing the overall retinal image slip must consider the effects of (1) sensory and motor noise and (2) dynamic constraints of peripheral and central nervous processing. We demonstrate that a computational model for optimizing retinal image slip in the presence of such constraints of signal processing in fact predicts gain values smaller than unity. We further show specifically for tadpoles of the clawed toad, Xenopus laevis with particularly low gain values that previously reported VOR gains quantitatively correspond to the observed variability of eye movements and thus constitute an optimal adaptation mechanism. We thus hypothesize that lower VOR gain values in elderly human subjects or recovered patients with a history of vestibular damage may be the sign of an optimization given higher noise levels rather than a direct consequence of the damage, such as an inability of executing fast compensatory eye movements.

Individual beliefs about temporal continuity explain variation of perceptual biases.

Perception of magnitudes such as duration or distance is often found to be systematically biased. The biases, which result from incorporating prior knowledge in the perceptual process, can vary considerably between individuals. The variations are commonly attributed to differences in sensory precision and reliance on priors. However, another factor not considered so far is the implicit belief about how successive sensory stimuli are generated: independently from each other or with certain temporal continuity. The main types of explanatory models proposed so far-static or iterative-mirror this distinction but cannot adequately explain individual biases. Here we propose a new unifying model that explains individual variation as combination of sensory precision and beliefs about temporal continuity and predicts the experimentally found changes in biases when altering temporal continuity. Thus, according to the model, individual differences in perception depend on beliefs about how stimuli are generated in the world.

Unstable Gaze in Functional Dizziness: A Contribution to Understanding the Pathophysiology of Functional Disorders.

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.

The origin of Vierordt's law: The experimental protocol matters.

In 1868, Karl Vierordt discovered one type of errors in time perception-an overestimation of short duration and underestimation of long durations, known as Vierordt's law. Here we reviewed the original study in its historical context and asked whether Vierordt's law is a result of an unnatural experimental randomization protocol. Using iterative Bayesian updating, we simulated the original results with high accuracy. Importantly, the model also predicted that a slowly changing random-walk sequence produces less central tendency than a random sequence with the same durations. This was validated by a duration reproduction experiment from two sequences (random and random walk) with the same sampled distribution. The results showed that trial-wise variation influenced the magnitude of Vierordt's law. We concluded that Vierordt's law is caused by an unnatural yet widely used experimental protocol.

Image motion with color contrast suffices to elicit an optokinetic reflex in Xenopus laevis tadpoles.

The optokinetic reflex is a closed-loop gaze-stabilizing ocular motor reaction that minimizes residual retinal image slip during vestibulo-ocular reflexes. In experimental isolation, the reflex is usually activated by motion of an achromatic large-field visual background with strong influence of radiance contrast on visual motion estimation and behavioral performance. The presence of color in natural environments, however, suggests that chromatic cues of visual scenes provide additional parameters for image motion detection. Here, we employed Xenopus laevis tadpoles to study the influence of color cues on the performance of the optokinetic reflex and multi-unit optic nerve discharge during motion of a large-field visual scene. Even though the amplitude of the optokinetic reflex decreases with smaller radiance contrast, considerable residual eye movements persist at the 'point of equiluminance' of the colored stimuli. Given the color motion preferences of individual optic nerve fibers, the underlying computation potentially originates in retinal circuits. Differential retinal ganglion cell projections and associated ocular motor signal transformation might further reinforce the color dependency in conceptual correspondence with head/body optomotor signaling. Optokinetic reflex performance under natural light conditions is accordingly influenced by radiance contrast as well as by the color composition of the moving visual scene.

Somatosensory Influence on Platform-Induced Translational Vestibulo-Ocular Reflex in Vertical Direction in Humans.

The vestibulo-ocular reflex (VOR) consists of two components, the rotational VOR (rVOR) elicited by semicircular canal signals and the translational VOR (tVOR) elicited by otolith signals. Given the relevant role of the vertical tVOR in human walking, this study aimed at measuring the time delay of eye movements in relation to whole-body vertical translations in natural standing position. Twenty (13 females and 7 males) healthy, young subjects (mean 25 years) stood upright on a motor-driven platform and were exposed to sinusoidal movements while fixating a LED, positioned at a distance of 50 cm in front of the eyes. The platform motion induced a vertical translation of 2.6 cm that provoked counteracting eye movements similar to self-paced walking. The time differences between platform and eye movements indicated that the subject's timing of the extraocular motor reaction depended on stimulus frequency and number of repetitions. At low stimulus frequencies (<0.8 Hz) and small numbers of repetitions (<3), eye movements were phase advanced or in synchrony with platform movements. At higher stimulus frequencies or continuous stimulation, eye movements were phase lagged by ~40 ms. Interestingly, the timing of eye movements depended on the initial platform inclination. Starting with both feet in dorsiflexion, eye movements preceded platform movements by 137 ms, whereas starting with both feet in plantar flexion eye movement precession was only 19 ms. This suggests a remarkable influence of foot proprioceptive signals on the timing of eye movements, indicating that the dynamics of the vertical tVOR is controlled by somatosensory signals.

Synchronization between instructor and observer when learning a complex bimanual skill.

While learning from an instructor by watching a 'how-to' video has become common practice, we know surprisingly little about the relation between brain activities in instructor and observers. In this fMRI study we investigated the temporal synchronization between instructor and observers using intersubject correlation in the naturalistic setting of learning to fold origami. Brain activity of the blindfolded instructor during action production was compared to the observers while they viewed the instructor's video-taped actions. We demonstrate for the first time that the BOLD activity in the instructor's and observer's brain are synchronized while observing and learning a manual complex task with the goal of reproducing it. We can rule out that this synchrony originates from visual feedback. Observers exhibiting higher synchrony with the instructor in the ventral premotor cortex, while viewing the video for the first time, were more successful in reproducing the origami afterwards. Furthermore, changes in instructor-observer synchrony across observational learning sessions occur in cerebellar areas, as well as differences in instructor-observer synchrony between learning and the counting folds, our non-learning control. Not only known cerebellar motor production areas show synchrony, shedding new light on the involvement of the cerebellum in action observation and learning.

Sequential Bayesian updating as a model for human perception.

Sequential Bayesian updating has been proposed as model for explaining various systematic biases in human perception, such as the central tendency, range effects, and serial dependence. The present chapter introduces to the principal ideas behind Bayesian updating for the random-change model introduced previously and shows how to implement sequential updating using the exact method via probability distributions, the Kalman filter for Gaussian distributions, and a particle filter for approximate sequential updating. Finally, it is demonstrated how to couple perception to action by selecting an appropriate action based on the posterior distribution that results from sequential updating.

Deficient head motor control in functional dizziness: Experimental evidence of central sensory-motor dysfunction in persistent physical symptoms.

Understanding the mechanisms of symptoms that are insufficiently explained by organic dysfunction remains challenging. Recently, it has been proposed that such "functional symptoms" are based on erroneous sensory processing in the central nervous system (CNS), with internal expectations dominating sensory inputs. In a pilot study, we used a head motor control set-up to assess the interplay between sensory input and expectation on the example of patients with functional dizziness. Eight patients and 11 age-matched healthy controls performed large active eye-head gaze shifts towards visual targets in the natural situation and with the head moment of inertia 3.3-fold increased. The latter induces head oscillations and the expected sensory outcome of the movement, estimated in the CNS, does not match the actual sensory input. Head oscillations were assessed in patients and in healthy subjects and compared to prior results from patients with organic disease (vestibular loss and cerebellar ataxia). Head oscillations in patients with functional dizziness were different from those of healthy subjects (F(1,17)=27.26, P<0.001, partial η2=0.62), and similar to those of patients with cerebellar ataxia, and with vestibular loss (F(2,19)=0.56, P=0.58). Even in the natural, unweighted, condition, head oscillations were higher in functional dizziness patients than in healthy subjects (P=0.001). Since an extensive work-up failed to demonstrate any explanatory peripheral vestibular, motor, or cerebellar organic dysfunction, these motor control deficits are a first indication of erroneous interplay between expectations and sensory input in the CNS that could account for persistent physical symptoms.

Ecological Momentary Assessment of Head Motion: Toward Normative Data of Head Stabilization.

Head stabilization is fundamental for balance during locomotion but can be impaired in elderly or diseased populations. Previous studies have identified several parameters of head stability with possible diagnostic value in a laboratory setting. Recently, the ecological validity of measures obtained in such controlled contexts has been called into question. The aim of this study was to investigate the ecological validity of previously described parameters of head stabilization in a real-world setting. Ten healthy subjects participated in the study. Head and trunk movements of each subject were recorded with inertial measurement units (IMUs) for a period of at least 10 h. Periods of locomotion were extracted from the measurements and predominant frequencies, root mean squares (RMSs) and bout lengths were estimated. As parameters of head stabilization, attenuation coefficients (ACs), harmonic ratios (HRs), coherences, and phase differences were computed. Predominant frequencies were distributed tightly around 2 Hz and ACs, HRs, and coherences exhibited the highest values in this frequency range. All head stability parameters exhibited characteristics consistent with previous reports, although higher variances were observed. These results suggest that head stabilization is tuned to the 2 Hz fundamental frequency of locomotion and that previously described measures of head stability could generalize to a real-world setting. This is the first study to address the ecological validity of these measures, highlighting the potential use of head stability parameters as diagnostic tools or outcome measures for clinical trials. The low cost and ease of use of the IMU technology used in this study could additionally be of benefit for a clinical application.

Computational neurology of gravity perception involving semicircular canal dysfunction in unilateral vestibular lesions.

Unilateral peripheral vestibular lesions not only lead to vertigo, nystagmus and imbalance, but also to a bias in the perception of verticality, which can be measured as tilt of the subjective visual vertical (SVV). Previously, this tilt has been assumed to be caused by a residual otolith bias, for example, because unequal numbers of active haircells on both sides of the utricular striola might result in an imbalance of the firing rates of central otolith neurons. Here we propose that a tilt of the subjective visual vertical might as well be caused by a vertical semicircular canal bias in the roll axis after unilateral peripheral lesions. The canal bias, acting similar to angular velocity stimuli, influences the SVV via the central gravity estimator, which under normal circumstances resolves a perceptual tilt-translation ambiguity. To illustrate our hypothesis, we compare model predictions to data on SVV measurements in patients with unilateral vestibular lesions while being tilted or being rotated eccentrically. We further embed the model of peripheral processing in a neural network that implements the idiotropic bias and represents the direction of gravity as population code in a three dimensional spherical topography.