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Peripheral neuropathy (PN), the most common complication of diabetes, leads to sensory loss and associated health issues as pain and increased fall risk. However, present treatments do not counteract sensory loss, but only partially manage its consequences. Electrical neural stimulation holds promise to restore sensations, but its efficacy and benefits in PN damaged nerves are yet unknown. We designed a wearable sensory neuroprosthesis (NeuroStep) providing targeted neurostimulation of the undamaged nerve portion and assessed its functionality in 14 PN participants. Our system partially restored lost sensations in all participants through a purposely calibrated neurostimulation, despite PN nerves being less sensitive than healthy nerves (N = 22). Participants improved cadence and functional gait and reported a decrease of neuropathic pain after one day. Restored sensations activated cortical patterns resembling naturally located foot sensations. NeuroStep restores real-time intuitive sensations in PN participants, holding potential to enhance functional and health outcomes while advancing effective non-invasive neuromodulation. Neuropathy leads to sensory loss and increased risk of fall. Here, the authors design a wearable non-invasive neuroprosthesis that restores lost sensations and improves gait. [ABSTRACT FROM AUTHOR]

Motor fatigability emerges when challenging motor tasks must be maintained over an extended period of time. It is frequently observed in everyday life and affects patients as well as healthy individuals. Motor fatigability can be measured using simple tasks like finger tapping at maximum speed for 30 s. This typically results in a rapid decrease of tapping frequency, a phenomenon called motor slowing. In a previous study (Bächinger et al, eLife, 8 (September), https://doi.org/10.7554/eLife.46750, 2019), we showed that motor slowing goes hand in hand with a gradual increase in blood oxygen level dependent signal in the primary sensorimotor cortex (SM1), supplementary motor area (SMA), and dorsal premotor cortex (PMd). It is unclear what drives the activity increase in SM1 caused by motor slowing and whether motor fatigability affects the dynamic interactions between SM1, SMA, and PMd. Here, we performed dynamic causal modelling (DCM) on data of 24 healthy young participants collected during functional magnetic resonance imaging to answer this question. The regions of interest (ROI) were defined based on the peak activation within SM1, SMA, and PMd. The model space consisted of bilateral connections between all ROI, with intrinsic self-modulation as inhibitory, and driving inputs set to premotor areas. Our findings revealed that motor slowing was associated with a significant reduction in SM1 self-inhibition, as uncovered by testing the maximum à posteriori against 0 (t(23)=-4.51, p < 0.001). Additionally, the model revealed a significant decrease in the driving input to premotor areas (t(23) > 2.71, p < 0.05) suggesting that structures other than cortical motor areas may contribute to motor fatigability. [ABSTRACT FROM AUTHOR]

Anticipating the behaviour of moving objects in the physical environment is essential for a wide range of daily actions. This ability is thought to rely on mental simulations and has been shown to involve frontoparietal and early visual areas. Yet, the connectivity patterns between these regions during intuitive physical inference remain largely unknown. In this study, participants underwent fMRI while performing a task requiring them to infer the parabolic trajectory of an occluded ball falling under Newtonian physics, and a control task. Building on our previous research showing that when solving the physical inference task, early visual areas encode task-specific and perception-like information about the inferred trajectory, the present study aimed to (i) identify regions that are functionally coupled with early visual areas during the physical inference task, and (ii) investigate changes in effective connectivity within this network of regions. We found that early visual areas are functionally connected to a set of parietal and premotor regions when inferring occluded trajectories. Using dynamic causal modelling, we show that predicting occluded trajectories is associated with changes in effective connectivity within a parieto-premotor network, which may drive internally generated early visual activity in a top-down fashion. These findings offer new insights into the interaction between early visual and frontoparietal regions during physical inference, contributing to our understanding of the neural mechanisms underlying the ability to predict physical outcomes. [ABSTRACT FROM AUTHOR]

Single-pulse transcranial magnetic stimulation (spTMS) studies report that movement observation facilitates corticospinal excitability in primary motor cortex (M1) in a muscle-specific manner. However, motor evoked potentials (MEPs) elicited by spTMS are known to reflect the summation of several descending volleys in corticospinal neurons which are evoked via mono- and polysynaptic inputs (so-called indirect waves or I-waves). It is unclear which of these components contribute to the muscle-specific modulation of M1 during action observation. The interactions between different I-waves are reflected in the facilitatory peaks elicited with a short-intracortical facilitation (SICF) protocol when two pulses are sent to M1 at precise intervals (i.e., 1.3, 2.5 or 4.1 ms). Here, we explored the modulation of early and late SICF peaks during action observation by measuring highly specific MEP amplitude changes measured in two muscles (index, FDI and little finger, ADM) while participants observed two different actions (precision and whole-hand grip). Our results demonstrate that both early (1.3 ms) and late (2.5 and 4.1 ms) SICF peaks are modulated in the context of movement observation. However, only the second peak (ISI 2.5 ms) was significantly associated with the muscle-specific modulation of corticospinal excitability as measured with spTMS. This late SICF peak is believed to reflect the activity cortico-cortical pathways involved in the facilitation of muscle-specific representations in M1. Thus, our findings suggest that movement observation leads to widespread activation of different neural circuits within M1, including those mediating cortico-cortical communication. [ABSTRACT FROM AUTHOR]

This study explored the role of lesion timing (periventricular white matter versus cortical and deep grey matter lesions) and type of corticospinal tract (CST) wiring pattern (contralateral, bilateral, ipsilateral) on white matter characteristics of the CST, medial lemniscus, superior thalamic radiations and sensorimotor transcallosal fibers in children with unilateral cerebral palsy (CP), and examined the association with upper limb function. Thirty-four children (mean age 10 years 7 months ± 2 years 3 months) with unilateral CP underwent a comprehensive upper limb evaluation and diffusion weighted imaging (75 directions, b value 2800). Streamline count, fractional anisotropy and mean diffusivity were extracted from the targeted tracts and asymmetry indices were additionally calculated. Transcranial magnetic stimulation was applied to assess the CST wiring pattern. Results showed a more damaged CST in children with cortical and deep grey matter lesions (N = 10) and ipsilateral CST projections (N = 11) compared to children with periventricular white matter lesions (N = 24; p < 0.02) and contralateral CST projections (N = 9; p < 0.025), respectively. Moderate to high correlations were found between diffusion metrics of the targeted tracts and upper limb function (r = 0.45–0.72; p < 0.01). Asymmetry indices of the CST and sensory tracts could best explain bimanual performance (74%, p < 0.0001) and unimanual capacity (50%, p = 0.004). Adding lesion timing and CST wiring pattern did not further improve the model of bimanual performance, while for unimanual capacity lesion timing was additionally retained (58%, p = 0.0002). These results contribute to a better understanding of the underlying neuropathology of upper limb function in children with unilateral CP and point towards a clinical potential of tractography. [ABSTRACT FROM AUTHOR]

The ballistocardiographic (BCG) artifact is linked to cardiac activity and occurs in electroencephalographic (EEG) recordings acquired inside the magnetic resonance (MR) environment. Its variability in terms of amplitude, waveform shape and spatial distribution over subject’s scalp makes its attenuation a challenging task. In this study, we aimed to provide a detailed characterization of the BCG properties, including its temporal dependency on cardiac events and its spatio-temporal dynamics. To this end, we used high-density EEG data acquired during simultaneous functional MR imaging in six healthy volunteers. First, we investigated the relationship between cardiac activity and BCG occurrences in the EEG recordings. We observed large variability in the delay between ECG and subsequent BCG events (ECG-BCG delay) across subjects and non-negligible epoch-by-epoch variations at the single subject level. The inspection of spatial-temporal variations revealed a prominent non-stationarity of the BCG signal. We identified five main BCG waves, which were common across subjects. Principal component analysis revealed two spatially distinct patterns to explain most of the variance (85% in total). These components are possibly related to head rotation and pulse-driven scalp expansion, respectively. Our results may inspire the development of novel, more effective methods for the removal of the BCG, capable of isolating and attenuating artifact occurrences while preserving true neuronal activity. [ABSTRACT FROM AUTHOR]

The correction of intensity non-uniformity (INU) in magnetic resonance (MR) images is extremely important to ensure both within-subject and across-subject reliability. Here we tackled the problem of objectively comparing INU correction techniques for T1-weighted images, which are the most commonly used in structural brain imaging. We focused our investigations on the methods integrated in widely used software packages for MR data analysis: FreeSurfer, BrainVoyager, SPM and FSL. We used simulated data to assess the INU fields reconstructed by those methods for controlled inhomogeneity magnitudes and noise levels. For each method, we evaluated a wide range of input parameters and defined an enhanced configuration associated with best reconstruction performance. By comparing enhanced and default configurations, we found that the former often provide much more accurate results. Accordingly, we used enhanced configurations for a more objective comparison between methods. For different levels of INU magnitude and noise, SPM and FSL, which integrate INU correction with brain segmentation, generally outperformed FreeSurfer and BrainVoyager, whose methods are exclusively dedicated to INU correction. Nonetheless, accurate INU field reconstructions can be obtained with FreeSurfer on images with low noise and with BrainVoyager for slow and smooth inhomogeneity profiles. Our study may prove helpful for an accurate selection of the INU correction method to be used based on the characteristics of actual MR data. [ABSTRACT FROM AUTHOR]

Introduction: A workflow based on the ratio between standardized T1-weighted (T1-w) and T2-weighted (T2-w) MR images has been proposed as a new tool to study brain structure. This approach was previously used to map structural properties in the healthy brain. Here, we evaluate whether the T1-w/T2-w approach can support the assessment of structural impairments in the diseased brain. We use schizophrenia data to demonstrate the potential clinical utility of the technique. Methods: We analyzed T1-w and T2-w images of 36 schizophrenic patients and 35 age-matched controls. These were collected for the Function Biomedical Informatics Research Network (fBIRN) collaborative project, which had an IRB approval and followed the HIPAA guidelines. We computed T1-w/T2-w images for each individual and compared intensities in schizophrenic and control groups on a voxel-wise basis, as well as in regions of interest (ROIs). Results: Our results revealed that the T1-w/T2-w image permits to discriminate brain regions showing group-level differences between patients and controls with greater accuracy than conventional T1-w and T2-w images. Both the ROIs and the voxel-wise analysis showed globally reduced gray and white matter values in patients compared to controls. Significantly reduced values were found in regions such as insula, primary auditory cortex, hippocampus, inferior longitudinal fasciculus, and inferior fronto-occipital fasciculus. Conclusion: Our findings were consistent with previous meta-analyses in schizophrenia corroborating the hypothesis of a potential 'disconnection' syndrome in conjunction with structural alterations in local gray matter regions. Overall, our study suggested that the T1-w/T2-w technique permits to reliably map structural differences between the brains of patients and healthy individuals. [ABSTRACT FROM AUTHOR]

Fifty to 85 % of patients with sensorimotor hemiparesis following stroke encounter impaired tactile processing and proprioception. Sensory feedback is, however, paramount for motor recovery. Sensory feedback through passively guided somatosensory discrimination exercises has been used in therapy, but so far, no studies have investigated which brain areas are involved in this process. Therefore, we performed a study with functional magnetic resonance imaging (fMRI) to examine brain areas related to discriminating passively guided shape and length discrimination in stroke patients and evaluate whether they differed from healthy age-matched controls. Eight subcortical stroke patients discriminated different shapes or length based on passive finger movements provided by an fMRI compatible robot. The data were contrasted to a control condition whereby patients discriminated music fragments. Passively guided somatosensory discrimination versus music discrimination elicited activation in similar frontoparietal areas in stroke patients compared to the healthy control group. Still, patients had increased activation in the right angular gyrus, left superior lingual gyrus, and right cerebellar lobule VI compared to healthy volunteers. Conversely, healthy volunteers activated the right precentral gyrus to a greater extent than patients. In both groups, shape discrimination resulted in anterior intraparietal sulcus and premotor activation, while length discrimination elicited a more medially located parietal activation with mainly right-sided premotor activity. The current study is a first step in clarifying brain activations during passively guided shape and length discrimination in subcortical stroke patients. Research into the effects of the use of sensory discrimination exercises on brain reorganization and brain plasticity is encouraged. [ABSTRACT FROM AUTHOR]

During movement observation, corticomotor excitability of the observer's primary motor cortex (M1) is modulated according to the force requirements of the observed action. Here, we explored the time course of observation-induced force encoding. Force-related changes in M1-excitability were assessed by delivering transcranial magnetic stimulations at distinct temporal phases of an observed reach-grasp-lift action. Temporal changes in force-related electromyographic activity were also assessed during active movement execution. In observation conditions in which a heavy object was lifted, M1-excitability was higher compared to conditions in which a light object was lifted. Both during observation and execution, differential force encoding tended to gradually increase from the grasping phase until the late lift phase. Surprisingly, however, during observation, force encoding was already present at the early reach phase: a time point at which no visual cues on the object's weight were available to the observer. As the observer was aware that the same weight condition was presented repeatedly, this finding may indicate that prior predictions concerning the upcoming weight condition are reflected by M1 excitability. Overall, findings may provide indications that the observer's motor system represents motor predictions as well as muscular requirements to infer the observed movement goal. [ABSTRACT FROM AUTHOR]

Transcranial magnetic stimulation (TMS) is increasingly used to perturb targeted human brain sites non-invasively, to test for causal effects on performance of cognitive tasks. TMS might also be used in non-human primates to complement invasive work and compare with human studies. Here, we targeted the frontal eye fields (FEF) in two macaques with a continuous theta-burst (cTBS) protocol, testing the impact on visually guided saccades. After unilateral cTBS over the FEF in either hemisphere, a small (mean 7 ms) but highly consistent decrease in saccadic reaction times (RTs) was observed. Lower latencies arose for saccades both contra- and ipsilateral to the stimulated FEF after cTBS. These results provide the first demonstration that TMS can be used to affect saccadic behavior in non-human primates. The unexpectedly bilateral impact on RTs may reflect an impact on 'fixation' neurons in the FEF and/or transcallosal modulation of both FEFs induced by unilateral cTBS. In either case, this study demonstrates a clear behavioral effect induced by TMS in awake behaving monkeys performing a cognitive task. This opens new opportunities for investigating the causal roles of targeted brain areas in behavior, for measuring physiological consequences of TMS in the primate brain, and ultimately for human-monkey comparisons. [ABSTRACT FROM AUTHOR]

Current behavioural theories consider that during motor learning, an effector-independent memory representation of the acquired skill is built up. Using a transfer paradigm, we addressed the nature of the memory representation for a 2:1 multifrequency co-ordination task, requiring, for example, the left arm to cycle twice as fast as the right. After learning this 2:1 pattern, transfer to its converse pattern (i.e., the right arm cycles twice as fast as the left) revealed powerful evidence for negative transfer. The converse task arrangement revealed similar effects. These observations suggest a reconsideration of current viewpoints on movement representations, which emphasize effector independence. Based on the present findings, we propose a new model of motor memory, consisting of an abstract, effector-independent and an effector-specific layer. The abstract code is hypothesized to represent general spatiotemporal movement features, whereas the specific representation refers to effector-related movement commands. This concept is consistent with recent neuroscientific evidence in animal and human species, and invites a reconsideration of current behavioural theories of motor learning and memory. [ABSTRACT FROM AUTHOR]

In the present study, we investigated the influence of external force manipulations on movements in different directions, while keeping the amplitude invariant. Subjects (n=10) performed a series of cyclical anteroposterior, mediolateral, and oblique line-drawing movements (star drawing task) with their dominant limb in the horizontal plane. To dissociate kinematics from the underlying patterns of muscle activation, spring loading was applied to the forearm of the moving limb. Whereas spring loading of the arm resulted in considerable changes in the overall amount of muscle activation in the elbow and shoulder muscles, invariance was largely maintained at the kinematic level. Subjects produced the required movement directions and amplitudes of the star drawing largely successfully, irrespective of the force bias induced by the spring. These observations demonstrate motor equivalence and strengthen the notion that the spatial representation of drawing movements is encoded in the higher brain regions in a rather abstract form that is dissociated from the concrete muscle activation patterns underlying a particular movement direction. To achieve this goal, the central nervous system shifted between two or more muscle grouping strategies to overcome modulations in the interaction among posture-dependent (joint stiffness), dynamic (inertial), and elastic (spring) torque components in the joints. Spring loading induced general changes in the overall amount of EMG activity, which was largely muscle but not direction specific, presumably to represent the posture-dependent biasing force of the spring. Loading was mainly shown to increase muscle coactivation in the elbow joint. This indicates that the subjects tended to increase stiffness in the elbow to compensate for changes in the spring bias forces in order to minimize trajectory errors. Changes in muscle grouping of the shoulder antagonists were mainly a consequence of movement direction but were also affected partly by loading, presumably reflecting the influence of dynamic force components. Taken together, the results confirmed the hypothesis that changes of movement direction and direction of force in the end-effector generated specific sets of muscle grouping to overcome the dynamic requirements in the joints while keeping the kinematics largely unchanged. This suggests that directional tuning in muscle activity and changes in muscle grouping reflects the formation of appropriate internal models in the CNS that give rise to motor equivalence. [ABSTRACT FROM AUTHOR]

Abstract. Previous studies have argued that tremors of central versus peripheral origin can be distinguished based on their load dependence: the frequency of peripheral tremor decreases when a weight is added to the tremulous limb, while the frequency of central tremors remains unchanged. The present study scrutinizes the latter statement. We simulated central tremor using a simple network of coupled neural oscillators, which receives proprioceptive feedback from the motor periphery. The network produced a self-sustained, stable oscillation. When the gain of proprioceptive feedback was high, oscillation frequency decreased in the presence of an inertial load. When the gain was low, the oscillation frequency was load independent. We conclude that load dependence is not an exclusive property of peripheral tremors but may be found in tremors of central origin as well. Therefore, the load test is not sufficient to reject a central tremor origin. [ABSTRACT FROM AUTHOR]

Abstract. The present study scrutinizes the popular view that tremors of central origin but not those of peripheral origin are largely resistant to mechanical perturbations. We explore the effects of perturbations in a well-established model of peripheral tremor and document that (a) tremor frequency can remain unchanged when spring or weight loads are added, (b) entrainment by external drives can be limited to drives of similar frequency, and (c) resetting of tremor phase by torque pulses can remain fractional. This resistance to mechanical perturbations arises in the model because peripheral neuromuscular dynamics act as a limit-cycle oscillator which, by its very nature, will absorb moderate changes to signals and parameters. We conclude from our study that resistance to mechanical perturbations is not an exclusive property of central tremors, but rather may also be found in peripheral tremors. Other criteria are therefore needed to distinguish between different origins of tremor. [ABSTRACT FROM AUTHOR]

In children with unilateral cerebral palsy (uCP), the corticospinal tract (CST)-wiring patterns may differ (contralateral, ipsilateral or bilateral), partially determining motor deficits. However, the impact of such CST-wiring on functional connectivity remains unknown. Here, we explored resting-state sensorimotor functional connectivity in 26 uCP with periventricular white matter lesions (mean age (standard deviation): 12.87 m (±4.5), CST wiring: 9 contralateral, 9 ipsilateral, 6 bilateral) compared to 60 healthy controls (mean age (standard deviation): 14.54 (±4.8)), and between CST-wiring patterns. Functional connectivity from each M1 to three bilateral sensorimotor regions of interest (primary sensory cortex, dorsal and ventral premotor cortex) and the supplementary motor area was compared between groups (controls vs. uCP; and controls vs. each CST-wiring group). Seed-to-voxel analyses from bilateral M1 were compared between groups. Additionally, relations with upper limb motor deficits were explored. Aberrant sensorimotor functional connectivity seemed to be CST-dependent rather than specific from all the uCP population: in the dominant hemisphere, the contralateral CST group showed increased connectivity between M1 and premotor cortices, whereas the bilateral CST group showed higher connectivity between M1 and somatosensory association areas. These results suggest that functional connectivity of the sensorimotor network is CST-wiring-dependent, although the impact on upper limb function remains unclear. [ABSTRACT FROM AUTHOR]

It is hypothesized that deep sleep is essential for restoring the brain's capacity to learn efficiently, especially in regions heavily activated during the day. However, causal evidence in humans has been lacking due to the inability to sleep deprive one target area while keeping the natural sleep pattern intact. Here we introduce a novel approach to focally perturb deep sleep in motor cortex, and investigate the consequences on behavioural and neurophysiological markers of neuroplasticity arising from dedicated motor practice. We show that the capacity to undergo neuroplastic changes is reduced by wakefulness but restored during unperturbed sleep. This restorative process is markedly attenuated when slow waves are selectively perturbed in motor cortex, demonstrating that deep sleep is a requirement for maintaining sustainable learning efficiency. [ABSTRACT FROM AUTHOR]

(not available) [ABSTRACT FROM AUTHOR]