Fifty Percent of the Time, Tones Come Every Time: Stronger Prediction Error Effects on Neurophysiological Sensory Attenuation for Self-generated Tones.

The N1/P2 amplitude reduction for self-generated tones in comparison to external tones in EEG, which has recently also been described for action observation, is an example of the so-called sensory attenuation. Whether this effect is dependent on motor-based or general predictive mechanisms is unclear. Using a paradigm, in which actions (button presses) elicited tones in only half the trials, this study examined how the processing of the tones is modulated by the prediction error in each trial in a self-performed action compared with action observation. In addition, we considered the effect of temporal predictability by adding a third condition, in which visual cues were followed by external tones in half the trials. The attenuation result patterns differed for N1 and P2 amplitudes, but neither showed an attenuation effect beyond temporal predictability. Interestingly, we found that both N1 and P2 amplitudes reflected prediction errors derived from a reinforcement learning model, in that larger errors coincided with larger amplitudes. This effect was stronger for tones following button presses compared with cued external tones, but only for self-performed and not for observed actions. Taken together, our results suggest that attenuation effects are partially driven by general predictive mechanisms irrespective of self-performed actions. However, the stronger prediction-error effects for self-generated tones suggest that distinct motor-related factors beyond temporal predictability, potentially linked to reinforcement learning, play a role in the underlying mechanisms. Further research is needed to validate these initial findings as the calculation of the prediction errors was limited by the design of the experiment.

Patients' and caregivers' perception of multidimensional and palliative care in amyotrophic lateral sclerosis - protocol of a German multicentre study.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an inevitably fatal condition that leads to a progressive loss of physical functioning, which results in a high psychosocial burden and organizational challenges related to medical care. Multidimensional and multiprofessional care is advised to meet the complex needs of patients and their families. Many healthcare systems, including Germany, may not be able to meet these needs because non-medical services such as psychological support or social counselling are not regularly included in the care of patients with ALS (pwALS). Specialised neuropalliative care is not routinely implemented nor widely available. Caregivers of pwALS are also highly burdened, but there is still a lack of support services for them. METHODS: This project aims to assess the perceptions and satisfaction with ALS care in Germany in pwALS and their caregivers. This will be achieved by means of a cross-sectional, multicentre survey. The examination will assess, to which extend the patients' needs in the six domains of physical, psychological, social, spiritual, practical and informational are being met by current care structures. This assessment will be linked to mental well-being, subjective quality of life, attitudes toward life-sustaining measures and physician-assisted suicide, and caregiver burden. The study aims to recruit 500 participants from nationwide ALS centres in order to draw comprehensive conclusions for Germany. A total of 29 centres, mostly acquired via the clinical and scientific German Network for Motor Neuron Diseases (MND-NET), will take part in the project, 25 of which have already started recruitment. PERSPECTIVE: It is intended to provide data-based starting points on how current practice of care in Germany is perceived pwALS and their caregivers and how it can be improved according to their needs. Planning and initiation of the study has been completed. TRIAL REGISTRATION: The study is registered at ClinicalTrails.gov; NCT06418646.

Prediction-error-dependent processing of immediate and delayed positive feedback.

Learning often involves trial-and-error, i.e. repeating behaviours that lead to desired outcomes, and adjusting behaviour when outcomes do not meet our expectations and thus lead to prediction errors (PEs). PEs have been shown to be reflected in the reward positivity (RewP), an event-related potential (ERP) component between 200 and 350 ms after performance feedback which is linked to striatal processing and assessed via electroencephalography (EEG). Here we show that this is also true for delayed feedback processing, for which a critical role of the hippocampus has been suggested. We found a general reduction of the RewP for delayed feedback, but the PE was similarly reflected in the RewP and the later P300 for immediate and delayed positive feedback, while no effect was found for negative feedback. Our results suggest that, despite processing differences between immediate and delayed feedback, positive PEs drive feedback processing and learning irrespective of delay.

'Reading the palm' - A pilot study of grip and finger flexion strength as an outcome measure in 5q spinal muscular atrophy.

BACKGROUND: Innovative RNA modifying and gene replacement therapies are currently revolutionizing the therapeutic landscape in 5q-associated spinal muscular atrophy (SMA). In order to provide individual recommendations for choice of treatment and therapy (dis-) continuation, objective outcome measures are needed. The purpose of this study was to determine whether maximum isometric voluntary grip and finger flexion strength is a useful sensitive outcome measure in children and adult patients with SMA. METHODS: In this non-interventional, longitudinal pilot study, we assessed grip and finger flexion strength on 39 patients with SMA II and III (n = 16 children, mean age = 10.0; n = 23 adults, mean age = 38.4) using the Weber hand and finger dynamometer HFD 200. Grip and finger flexion strength, clinical examinations and motor function scores (Revised Upper Limb Module, Hammersmith Functional Motor Scale Expanded) were assessed over a 12-month treatment period concurrent with the nusinersen treatment. RESULTS: Grip and finger flexion strength was highly associated with motor function and disease severity, SMA type and SMN2 copy number. During nusinersen treatment, grip and finger flexion strength significantly increased in children and adults with SMA. CONCLUSION: Grip and finger flexion strength measured with the HFD 200 is a promising sensitive outcome measure for SMA.

My view on your actions: Dynamic changes in viewpoint-dependent auditory ERP attenuation during action observation.

It has been suggested that during action observation, a sensory representation of the observed action is mapped onto one's own motor system. However, it is largely unexplored what this may imply for the early processing of the action's sensory consequences, whether the observational viewpoint exerts influence on this and how such a modulatory effect might change over time. We tested whether the event-related potential of auditory effects of actions observed from a first- versus third-person perspective show amplitude reductions compared with externally generated sounds, as revealed for self-generated sounds. Multilevel modeling on trial-level data showed distinct dynamic patterns for the two viewpoints on reductions of the N1, P2, and N2 components. For both viewpoints, an N1 reduction for sounds generated by observed actions versus externally generated sounds was observed. However, only during first-person observation, we found a temporal dynamic within experimental runs (i.e., the N1 reduction only emerged with increasing trial number), indicating time-variant, viewpoint-dependent processes involved in sensorimotor prediction during action observation. For the P2, only a viewpoint-independent reduction was found for sounds elicited by observed actions, which disappeared in the second half of the experiment. The opposite pattern was found in an exploratory analysis concerning the N2, revealing a reduction that increased in the second half of the experiment, and, moreover, a temporal dynamic within experimental runs for the first-person perspective, possibly reflecting an agency-related process. Overall, these results suggested that the processing of auditory outcomes of observed actions is dynamically modulated by the viewpoint over time.

T cell epitope: friend or foe? Immunogenicity of biologics in context.

Like vaccines, biologic proteins can be very immunogenic for reasons including route of administration, dose frequency and the underlying antigenicity of the therapeutic protein. Because the impact of immunogenicity can be quite severe, regulatory agencies are developing risk-based guidelines for immunogenicity screening. T cell epitopes are at the root of the immunogenicity issue. Through their presentation to T cells, they activate the process of anti-drug antibody development. Preclinical screening for T cell epitopes can be performed in silico, followed by in vitro and in vivo validation. Importantly, screening for immunogenicity is complicated by the discovery of regulatory T cell epitopes, which suggests that immunogenicity testing must now take regulatory T cells into consideration. In this review, we address the application of computational tools for preclinical immunogenicity assessment, the implication of the discovery of regulatory T cell epitopes, and experimental validation of those assessments.