Experimental evidence for a robust, transdiagnostic marker in functional disorders: Erroneous sensorimotor processing in functional dizziness and functional movement disorder.

OBJECTIVE: Recent neuroscientific models suggest that functional bodily symptoms can be attributed to perceptual dysregulation in the central nervous system. Evidence for this hypothesis comes from patients with functional dizziness, who exhibit marked sensorimotor processing deficits during eye-head movement planning and execution. Similar findings in eye-head movement planning in patients with irritable bowel syndrome confirmed that these sensorimotor processing deficits represent a shared, transdiagnostic mechanism. We now examine whether erroneous sensorimotor processing is also at play in functional movement disorder. METHODS: We measured head movements of 10 patients with functional movement disorder (F44.4, ICD-10), 10 patients with functional dizziness (F45.8, ICD-10), and (respectively) 10 healthy controls during an eye-head experiment, where participants performed large gaze shifts under normal, increased, and again normal head moment of inertia. Head oscillations at the end of the gaze shift served as a well-established marker for sensorimotor processing problems. We calculated Bayesian statistics for comparison. RESULTS: Patients with functional movement disorder (Bayes Factor (BF)10 = 5.36, BFincl = 11.16; substantial to strong evidence) as well as patients with functional dizziness (BF10 = 2.27, BFincl = 3.56; anecdotal to substantial evidence) showed increased head oscillations compared to healthy controls, indicating marked deficits in planning and executing movement. CONCLUSION: We replicate earlier experimental findings on erroneous sensorimotor processing in patients with functional dizziness, and show that patients with functional movement disorder show a similar impairment of sensorimotor processing during large gaze shifts. This provides an objectively measurable, transdiagnostic marker for functional disorders, highlighting important implications for diagnosis, treatment, and de-stigmatization.

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.

Distributed coding of duration in rodent prefrontal cortex during time reproduction.

As we interact with the external world, we judge magnitudes from sensory information. The estimation of magnitudes has been characterized in primates, yet it is largely unexplored in nonprimate species. Here, we use time interval reproduction to study rodent behavior and its neural correlates in the context of magnitude estimation. We show that gerbils display primate-like magnitude estimation characteristics in time reproduction. Most prominently their behavioral responses show a systematic overestimation of small stimuli and an underestimation of large stimuli, often referred to as regression effect. We investigated the underlying neural mechanisms by recording from medial prefrontal cortex and show that the majority of neurons respond either during the measurement or the reproduction of a time interval. Cells that are active during both phases display distinct response patterns. We categorize the neural responses into multiple types and demonstrate that only populations with mixed responses can encode the bias of the regression effect. These results help unveil the organizing neural principles of time reproduction and perhaps magnitude estimation in general.

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.