Increased preparation time reduces, but does not abolish, action history bias of saccadic eye movements.

The characteristics of movements are strongly history-dependent. Marinovic et al. (Marinovic W, Poh E, de Rugy A, Carroll TJ. eLife 6: e26713, 2017) showed that past experience influences the execution of limb movements through a combination of temporally stable processes that are strictly use dependent and dynamically evolving and context-dependent processes that reflect prediction of future actions. Here we tested the basis of history-dependent biases for multiple spatiotemporal features of saccadic eye movements under two preparation time conditions (long and short). Twenty people performed saccades to visual targets. To prompt context-specific expectations of most likely target locations, 1 of 12 potential target locations was specified on ~85% of the trials and each remaining target was presented on ~1% trials. In long preparation trials participants were shown the location of the next target 1 s before its presentation onset, whereas in short preparation trials each target was first specified as the cue to move. Saccade reaction times and direction were biased by recent saccade history but according to distinct spatial tuning profiles. Biases were purely expectation related for saccadic reaction times, which increased linearly as the distance from the repeated target location increased when preparation time was short but were similar to all targets when preparation time was long. By contrast, the directions of saccades were biased toward the repeated target in both preparation time conditions, although to a lesser extent when the target location was precued (long preparation). The results suggest that saccade history affects saccade dynamics via both use- and expectation-dependent mechanisms and that movement history has dissociable effects on reaction time and saccadic direction. NEW & NOTEWORTHY The characteristics of our movements are influenced not only by concurrent sensory inputs but also by how we have moved in the past. For limb movements, history effects involve both use-dependent processes due strictly to movement repetition and processes that reflect prediction of future actions. Here we show that saccade history also affects saccade dynamics via use- and expectation-dependent mechanisms but that movement history has dissociable effects on saccade reaction time and direction.

Pushing attention to one side: Force field adaptation alters neural correlates of orienting and disengagement of spatial attention.

Sensorimotor adaptation to wedge prisms can alter the balance of attention between left and right space in healthy adults, and improve symptoms of spatial neglect after stroke. Here we asked whether the orienting of spatial attention to visual stimuli is affected by a different form of sensorimotor adaptation that involves physical perturbations of arm movement, rather than distortion of visual feedback. Healthy participants performed a cued discrimination task before and after they made reaching movements to a central target. A velocity-dependent force field pushed the hand aside during each reach, and required participants to apply compensatory forces toward the opposite side. We used event-related potentials (ERPs) to determine whether electroencephalography (EEG) responses reflecting orienting (cue-locked N1) and disengagement (target-locked P1) of spatial attention are affected by adaptation to force fields. After adaptation, the cue-locked N1 was relatively larger for stimuli presented in the hemispace corresponding to the direction of compensatory hand force. P1 amplitudes evoked by invalidly cued targets presented on the opposite side were reduced. This suggests that force field adaptation boosted attentional orienting responses toward the side of hand forces, and impeded attentional disengagement from that side, mimicking previously reported effects of prism adaptation. Thus, remapping between motor commands and intended movement direction is sufficient to bias ERPs, reflecting changes in the orienting of spatial attention in the absence of visuo-spatial distortion or visuo-proprioceptive mismatch. Findings are relevant to theories of how sensorimotor adaptation can modulate attention, and may open new avenues for treatment of spatial neglect.

Dynamical signatures of isometric force control as a function of age, expertise, and task constraints.

From the conceptual and methodological framework of the dynamical systems approach, force control results from complex interactions of various subsystems yielding observable behavioral fluctuations, which comprise both deterministic (predictable) and stochastic (noise-like) dynamical components. Here, we investigated these components contributing to the observed variability in force control in groups of participants differing in age and expertise level. To this aim, young (18-25 yr) as well as late middle-aged (55-65 yr) novices and experts (precision mechanics) performed a force maintenance and a force modulation task. Results showed that whereas the amplitude of force variability did not differ across groups in the maintenance tasks, in the modulation task it was higher for late middle-aged novices than for experts and higher for both these groups than for young participants. Within both tasks and for all groups, stochastic fluctuations were lowest where the deterministic influence was smallest. However, although all groups showed similar dynamics underlying force control in the maintenance task, a group effect was found for deterministic and stochastic fluctuations in the modulation task. The latter findings imply that both components were involved in the observed group differences in the variability of force fluctuations in the modulation task. These findings suggest that between groups the general characteristics of the dynamics do not differ in either task and that force control is more affected by age than by expertise. However, expertise seems to counteract some of the age effects.NEW & NOTEWORTHY Stochastic and deterministic dynamical components contribute to force production. Dynamical signatures differ between force maintenance and cyclic force modulation tasks but hardly between age and expertise groups. Differences in both stochastic and deterministic components are associated with group differences in behavioral variability, and observed behavioral variability is more strongly task dependent than person dependent.

Dendritic cells tip the balance towards induction of regulatory T cells upon priming in experimental autoimmune encephalomyelitis.

Counter-balancing regulatory mechanisms, such as the induction of regulatory T cells (Treg), limit the effects of autoimmune attack in neuroinflammation. However, the role of dendritic cells (DCs) as the most powerful antigen-presenting cells, which are intriguing therapeutic targets in this context, is not fully understood. Here, we demonstrate that conditional ablation of DCs during the priming phase of myelin-specific T cells in experimental autoimmune encephalomyelitis (EAE) selectively aborts inducible Treg (iTreg) induction, whereas generation of T helper (Th)1/17 cells is unaltered. DCs facilitate iTreg induction by creating a milieu with high levels of interleukin (IL)-2 due to a strong proliferative response. In the absence of DCs, B220+ B cells take over priming of Th17 cells in the place of antigen-presenting cells (APCs), but not the induction of iTreg, thus leading to unregulated, severe autoimmunity.

Increased structural white and grey matter network connectivity compensates for functional decline in early multiple sclerosis.

BACKGROUND: The pathology of multiple sclerosis (MS) consists of demyelination and neuronal injury, which occur early in the disease; yet, remission phases indicate repair. Whether and how the central nervous system (CNS) maintains homeostasis to counteract clinical impairment is not known. OBJECTIVE: We analyse the structural connectivity of white matter (WM) and grey matter (GM) networks to understand the absence of clinical decline as the disease progresses. METHODS: A total of 138 relapsing-remitting MS patients (classified into six groups by disease duration) and 32 healthy controls were investigated using 3-Tesla magnetic resonance imaging (MRI). Networks were analysed using graph theoretical approaches based on connectivity patterns derived from diffusion-tensor imaging with probabilistic tractography for WM and voxel-based morphometry and regional-volume-correlation matrix for GM. RESULTS: In the first year after disease onset, WM networks evolved to a structure of increased modularity, strengthened local connectivity and increased local clustering while no clinical decline occurred. GM networks showed a similar dynamic of increasing modularity. This modified connectivity pattern mainly involved the cerebellum, cingulum and temporo-parietal regions. Clinical impairment was associated at later disease stages with a divergence of the network patterns. CONCLUSION: Our findings suggest that network functionality in MS is maintained through structural adaptation towards increased local and modular connectivity, patterns linked to adaptability and homeostasis.

Role of Sortilin in Models of Autoimmune Neuroinflammation.

The proneurotrophin receptor sortilin is a protein with dual functions, being involved in intracellular protein transport, as well as cellular signal transduction. The relevance of the receptor for various neuronal disorders, such as dementia, seizures, and brain injury, is well established. In contrast, little is known about the role of sortilin in immune cells and inflammatory diseases. The aim of our study was to elucidate the distribution of sortilin in different immune cell types in mice and humans and to analyze its function in autoimmune CNS inflammation. Sortilin was expressed most profoundly in murine and human macrophages and dendritic cells and to a much lesser extent in B and T cells. In dendritic cells, sortilin had an impact on Ag processing. Accordingly, sortilin was highly expressed by infiltrated perivascular myeloid cells, mainly in vessel cuffs, in the CNS of patients suffering from multiple sclerosis, the most common inflammatory autoimmune disease of the CNS. Yet, sortilin gene-targeted mice (Sort1(-/-)) and chimeras deficient in sortilin in the immune system were as susceptible as wild-type littermates to T cell-dependent experimental autoimmune encephalomyelitis. Considering our results and recent data from other investigators, we conclude that the proneurotrophin receptor sortilin plays a role in innate, rather than in adaptive, immune processes and, thus, not in autoimmune neuroinflammation.

Cross-recognition of a myelin peptide by CD8+ T cells in the CNS is not sufficient to promote neuronal damage.

Multiple sclerosis (MS) is an inflammatory disease of the CNS thought to be driven by CNS-specific T lymphocytes. Although CD8(+) T cells are frequently found in multiple sclerosis lesions, their distinct role remains controversial because direct signs of cytotoxicity have not been confirmed in vivo. In the present work, we determined that murine ovalbumin-transgenic (OT-1) CD8(+) T cells recognize the myelin peptide myelin oligodendrocyte glycoprotein 40-54 (MOG40-54) both in vitro and in vivo. The aim of this study was to investigate whether such cross-recognizing CD8(+) T cells are capable of inducing CNS damage in vivo. Using intravital two-photon microscopy in the mouse model of multiple sclerosis, we detected antigen recognition motility of the OT-1 CD8(+) T cells within the CNS leading to a selective enrichment in inflammatory lesions. However, this cross-reactivity of OT-1 CD8(+) T cells with MOG peptide in the CNS did not result in clinically or subclinically significant damage, which is different from myelin-specific CD4(+) Th17-mediated autoimmune pathology. Therefore, intravital imaging demonstrates that local myelin recognition by autoreactive CD8(+) T cells in inflammatory CNS lesions alone is not sufficient to induce disability or increase axonal injury.

Feedforward compensation for novel dynamics depends on force field orientation but is similar for the left and right arms.

There are well-documented differences in the way that people typically perform identical motor tasks with their dominant and the nondominant arms. According to Yadav and Sainburg's (Neuroscience 196: 153-167, 2011) hybrid-control model, this is because the two arms rely to different degrees on impedance control versus predictive control processes. Here, we assessed whether differences in limb control mechanisms influence the rate of feedforward compensation to a novel dynamic environment. Seventy-five healthy, right-handed participants, divided into four subsamples depending on the arm (left, right) and direction of the force field (ipsilateral, contralateral), reached to central targets in velocity-dependent curl force fields. We assessed the rate at which participants developed predictive compensation for the force field using intermittent error-clamp trials and assessed both kinematic errors and initial aiming angles in the field trials. Participants who were exposed to fields that pushed the limb toward ipsilateral space reduced kinematic errors more slowly, built up less predictive field compensation, and relied more on strategic reaiming than those exposed to contralateral fields. However, there were no significant differences in predictive field compensation or kinematic errors between limbs, suggesting that participants using either the left or the right arm could adapt equally well to novel dynamics. It therefore appears that the distinct preferences in control mechanisms typically observed for the dominant and nondominant arms reflect a default mode that is based on habitual functional requirements rather than an absolute limit in capacity to access the controller specialized for the opposite limb.

Putaminal alteration in multiple sclerosis patients with spinal cord lesions.

Typical multiple sclerosis (MS) lesions occur in the brain as well as in the spinal cord. However, two extreme magnetic resonance imaging phenotypes appear occasionally: those with predominantly spinal cord lesions (MS + SL) and those with cerebral lesions and no detectable spinal lesions (MS + CL). We assessed whether morphological differences can be found between these two extreme phenotypes. We examined 19 patients with MS + SL, 18 with MS + CL and 20 controls. All subjects were examined using magnetic resonance imaging, including anatomical and diffusion tensor imaging sequences. Voxel-based morphologic and regions of interest-based analyses and tract-based spatial statistics were performed. Patients also underwent neuropsychological testing. Demographic, clinical and neuropsychological characteristics did not differ between MS + SL and MS + CL patients. Patients with MS + SL showed significantly larger putamen volumes than those with MS + CL which correlated negatively with disability. Compared to controls, only MS + CL revealed clear cortical and deep gray matter atrophy, which correlated with cerebral lesion volume. Additionally, extensive white matter microstructural damage was found only in MS + CL compared to MS + SL and controls in the tract-based spatial statistics. Higher putamen volumes in MS + SL could suggest compensatory mechanisms in this area responsible for motor control. Widely reduced fractional anisotropy values in MS + CL were caused by higher cerebral lesion volume and thus presumably stronger demyelination, which subsequently leads to higher global gray matter atrophy.

Reliance on visual attention during visuomotor adaptation: an SSVEP study.

Visuomotor adaptation involves the learning of a new mapping between a spatial goal and well-learned movements. In order to learn a new visuomotor transformation, visual attention is needed to monitor movements and their visual consequences. Once a transformation is learnt, it can be executed automatically without attentional control. Using steady-state visual evoked potentials (SSVEPs) measured from EEG activity, we examined how visual attention changes during the early phase of visuomotor adaptation. SSVEPs were elicited by a green disc flickering at 15 Hz which was either the movement target or the cursor that participants controlled. Participants performed an adapted continuous visuomotor adaptation task with either 60° or 120° screen cursor rotation, and changes in 15-Hz SSVEP power were examined. Participants' performance improved over time in all conditions, with the rate of learning significantly influenced by the degree of rotation. SSVEPs at 15 Hz showed a significant change over time with adaptation for 60° rotations, but not for 120° rotations, such that SSVEPs elicited by the stimuli were significantly lower for 60° compared with 120° rotation conditions over the last adaptation blocks. This suggests that visual attention to the movement target and feedback reduces over time as performance improves during visuomotor adaptation for easier rotations, but must be maintained throughout the task for more difficult 120° rotations that might require more strategic control.

The role of CD8+ T cells and their local interaction with CD4+ T cells in myelin oligodendrocyte glycoprotein35-55-induced experimental autoimmune encephalomyelitis.

T cells have an essential role in the induction of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Although for CD4(+) T cells it is well established that they contribute to the disease, less is known about the role of CD8(+) T cells. Our aim was to determine the individual contribution of CD4(+) and CD8(+) T cells in myelin oligodendrocyte glycoprotein (MOG)35-55-induced EAE. We investigated MOG35-55-activated CD8(+) T cells to clarify their potential to induce or attenuate EAE. We monitored the behavior of CD8(+) T cells and their interaction with CD4(+) T cells directly at the site of inflammation in the CNS using intravital imaging of the brainstem of EAE-affected living anesthetized mice. We found that mice without CD4(+) T cells did not develop relevant clinical signs of disease, although CD8(+) T cells were present in the CNS of these mice. These CD8(+) T cells displayed reduced motility compared with those in the presence of CD4(+) T cells. In mice that harbored CD4(+) and CD8(+) T cells, we saw a similar extent of clinical signs of EAE as in mice with only CD4(+) T cells. Furthermore, the dynamic motility and viability of CD4(+) T cells were not disturbed by CD8(+) T cells in the lesions of these mice. Therefore, we conclude that in MOG35-55-induced EAE, CD8(+) T cell accumulation in the CNS represents instead an epiphenomenon with no impact on clinical disease or on the effects of CD4(+) T cells, the latter being the true inducers of the disease.

Effects of age and expertise on tactile learning in humans.

Repetitive tactile stimulation is a well-established tool for inducing somatosensory cortical plasticity and changes in tactile perception. Previous studies have suggested that baseline performance determines the amount of stimulation-induced learning differently in specific populations. Older adults with lower baseline performance than young adults, but also experts, with higher baseline performance than non-experts of the same age, have been found to profit most from such interventions. This begs the question of how age-related and expertise-related differences in tactile learning are reflected in neurophysiological correlates. In two experiments, we investigated how tactile learning depends on age (experiment 1) and expertise (experiment 2). We assessed tactile spatial and temporal discrimination accuracy and event-related potentials (ERPs) in 57 persons of different age and expertise groups before and after a 30-min tactile stimulation intervention. The intervention increased accuracy in temporal (found in experiment 1) and spatial (found in experiment 2) discrimination. Experts improved more than non-experts in spatial discrimination. Lower baseline performance was associated with higher learning gain in experts and non-experts. After the intervention, P300 latencies were reduced in young adults and amplitudes were increased in late middle-aged adults in the temporal discrimination task. Experts showed a steeper P300 parietal-to-frontal gradient after the stimulation. We demonstrated that tactile stimulation partially reverses the age-related decline in late middle-aged adults and increases processing speed in young adults. We further showed that learning gain depends on baseline performance in both non-experts and experts. In experts, however, the upper limit for learning seems to be shifted to a higher level.

Age-related differences in finger force control are characterized by reduced force production.

It has been repeatedly shown that precise finger force control declines with age. The tasks and evaluation parameters used to reveal age-related differences vary between studies. In order to examine effects of task characteristics, young adults (18-25 years) and late middle-aged adults (55-65 years) performed precision grip tasks with varying speed and force requirements. Different outcome variables were used to evaluate age-related differences. Age-related differences were confirmed for performance accuracy (TWR) and variability (relative root mean square error, rRMSE). The task characteristics, however, influenced accuracy and variability in both age groups: Force modulation performance at higher speed was poorer than at lower speed and at fixed force levels than at force levels adjusted to the individual maximum forces. This effect tended to be stronger for older participants for the rRMSE. A curve fit confirmed the age-related differences for both spatial force tracking parameters (amplitude and intercept) and for one temporal parameter (phase shift), but not for the temporal parameter frequency. Additionally, matching the timing parameters of the sine wave seemed to be more important than matching the spatial parameters in both young adults and late middle-aged adults. However, the effect was stronger for the group of late middle-aged, even though maximum voluntary contraction was not significantly different between groups. Our data indicate that changes in the processing of fine motor control tasks with increasing age are caused by difficulties of late middle-aged adults to produce a predefined amount of force in a short time.

Effects of age and fine motor expertise on the bilateral deficit in force initiation.

Performance of a task carried out with two hands separately is better than the performance of the same task done with both hands at the same time. This so-called bilateral deficit may be reduced or counteracted by long-term practice. Little is known about age-related changes. We examined age- and expertise-related differences in the bilateral deficit in force initiation. Participants performed static and dynamic force modulation tasks either with the right and left hand separately or both hands simultaneously. In order to examine age-related differences, we compared novices of fine motor control (service employees) from three age groups, covering the working age (young n = 13, early middle-aged n = 10 and late middle-aged n = 12). To assess the influence of expertise, we considered precision mechanics as experts in fine motor control. To ensure the acquisition of expertise, only early middle-aged (n = 10) and late middle-aged (n = 14) experts were recruited. Regardless of the task, bimanual force initiation was slower than unimanual force initiation. This bilateral deficit was (1) more pronounced in the static than in the dynamic task, (2) higher in early and late middle-aged than in younger novices, and (3) lower in experts as compared to novices. Based on our results, we assume both interhemispheric inhibition and division of attention to contribute to the bilateral deficit and the expertise- and age-related differences, respectively. The results are promising for the possibility to overcome constraints of bilateral hand movements by long-term practice.

Classification of age groups and task conditions provides additional evidence for differences in electrophysiological correlates of inhibitory control across the lifespan.

The aim of this study was to extend previous findings on selective attention over a lifetime using machine learning procedures. By decoding group membership and stimulus type, we aimed to study differences in the neural representation of inhibitory control across age groups at a single-trial level. We re-analyzed data from 211 subjects from six age groups between 8 and 83 years of age. Based on single-trial EEG recordings during a flanker task, we used support vector machines to predict the age group as well as to determine the presented stimulus type (i.e., congruent, or incongruent stimulus). The classification of group membership was highly above chance level (accuracy: 55%, chance level: 17%). Early EEG responses were found to play an important role, and a grouped pattern of classification performance emerged corresponding to age structure. There was a clear cluster of individuals after retirement, i.e., misclassifications mostly occurred within this cluster. The stimulus type could be classified above chance level in ~ 95% of subjects. We identified time windows relevant for classification performance that are discussed in the context of early visual attention and conflict processing. In children and older adults, a high variability and latency of these time windows were found. We were able to demonstrate differences in neuronal dynamics at the level of individual trials. Our analysis was sensitive to mapping gross changes, e.g., at retirement age, and to differentiating components of visual attention across age groups, adding value for the diagnosis of cognitive status across the lifespan. Overall, the results highlight the use of machine learning in the study of brain activity over a lifetime.

Shaping a suitable EU HTA dossier template: why the German template is not fit for purpose.

From 2025, Health Technology Developers (HTDs) have to submit EU HTA dossiers. The joint clinical assessment (JCA) aims to streamline HTA processes and access to medicinal products across Europe. Currently, German HTA bodies IQWiG and G-BA actively shape the JCA methodology. Here we examine if German HTA dossier requirements are suitable for the JCA. We compare the number of safety endpoint and subgroup analyses in German dossiers with analyses considered in IQWIG's benefit assessment and evaluate if these analyses were considered by the G-BA. We further investigated how the number of analyses was affected by the latest change in the German dossier template. With the current template, HTDs report in median 2.6 times more analyses on adverse events (AE) and 1.1 times more subgroup categories than in the previous template. IQWiG does not consider 33% of AE analyses and 73% of the subgroup categories presented by the HTD under the current template. G-BA considered the same AE as IQWiG in 76% of cases. Subgroups were uncommented by G-BA in most cases, independent of the template (previous: 93%, current 85%) and unconsidered in the conclusion on additional benefit (previous: 77%, current 69%). Thus, changes in the dossier template drastically increased HTD workload, but additional analyses seem unconsidered by the HTA bodies. With a broader scope in JCA, this effect could be amplified. To mitigate duplicative efforts and ensure prompt availability of medicinal products as envisioned by the HTAR, we suggest well-chosen and precise dossier requirements, early consultations, and early HTD engagement.

Touch perception throughout working life: effects of age and expertise.

Fine motor skills including precise tactile and haptic perception are essential to the manipulation of objects. With increasing age, one's perception decreases; however, little is known about the state of touch perception in middle-aged adults. This study investigated the extent to which the decline in touch perception affects adults throughout their working life. In addition, the influence of work-related expertise on tactile and haptic perception was examined in an attempt to determine whether expertise, in the form of the frequent use of the fingers, affects perception and counters age-related losses. The study was conducted with subjects from three age groups (18-25, 34-46, and 54-65 years) with two levels of expertise. Expertise was classified by the subjects' occupations. Five sensory tasks of touch perception were conducted. The results confirmed age-related changes in tactile perception over the span of one's working life. Older workers were proven to have lower tactile performance than younger adults. However, middle-aged workers were hardly affected by the perception losses and did not differ significantly from younger adults. Work-related expertise was not proven to either affect tactile and haptic perception or counteract age-related declines. We conclude that the age-related decline gets steeper in the late working life and that specific work-related expertise does not lead to generally improved touch perception that would result in lower thresholds and improved performance in non-expertise specific tasks.

Using EEG to study sensorimotor adaptation.

Sensorimotor adaptation, or the capacity to flexibly adapt movements to changes in the body or the environment, is crucial to our ability to move efficiently in a dynamic world. The field of sensorimotor adaptation is replete with rigorous behavioural and computational methods, which support strong conceptual frameworks. An increasing number of studies have combined these methods with electroencephalography (EEG) to unveil insights into the neural mechanisms of adaptation. We review these studies: discussing EEG markers of adaptation in the frequency and the temporal domain, EEG predictors for successful adaptation and how EEG can be used to unmask latent processes resulting from adaptation, such as the modulation of spatial attention. With its high temporal resolution, EEG can be further exploited to deepen our understanding of sensorimotor adaptation.

Task Feedback Processing Differs Between Young and Older Adults in Visuomotor Rotation Learning Despite Similar Initial Adaptation and Savings.

Ageing has been suggested to affect sensorimotor adaptation by impairing explicit strategy use. Here we recorded electrophysiological (EEG) responses during visuomotor rotation in both young (n = 24) and older adults (n = 25), to investigate the neural processes that underpin putative age-related effects on adaptation. We measured the feedback related negativity (FRN) and the P3 in response to task-feedback, as electrophysiological markers of task error processing and outcome evaluation. The two age groups adapted similarly and showed comparable after effects and savings when re-exposed to the same perturbation several days after the initial session. Older adults, however, had less distinct EEG responses (i.e., reduced FRN amplitudes) to negative and positive task feedback. The P3 did not differ between age groups. Both young and older adults also showed a sustained late positivity following task feedback. Measured at the frontal electrode Fz, this sustained activity was negatively associated with both the amount of voluntary disengagement of explicit strategy and savings. In conclusion, despite preserved task performance, we find clear differences in neural responses to errors in older people, which suggests that there is a fundamental decline in this aspect of sensorimotor brain function with age.