Imprecise perception of hand position during early motor adaptation.

Localizing one's body parts is important for movement control and motor learning. Recent studies have shown that the precision with which people localize their hand places constraints on motor adaptation. Although these studies have assumed that hand localization remains equally precise across learning, we show that precision decreases rapidly during early motor learning. In three experiments, healthy young participants (n = 92) repeatedly adapted to a 45° visuomotor rotation for a cycle of two to four reaches, followed by a cycle of two to four reaches with veridical feedback. Participants either used an aiming strategy that fully compensated for the rotation (experiment 1), or always aimed directly at the target, so that adaptation was implicit (experiment 2). We omitted visual feedback for the last reach of each cycle, after which participants localized their unseen hand. We observed an increase in the variability of angular localization errors when subjects used a strategy to counter the visuomotor rotation (experiment 1). This decrease in precision was less pronounced in the absence of reaiming (experiment 2), and when subjects knew that they would have to localize their hand on the upcoming trial, and could thus focus on hand position (experiment 3). We propose that strategic reaiming decreases the precision of perceived hand position, possibly due to attention to vision rather than proprioception. We discuss how these dynamics in precision during early motor learning could impact on motor control and shape the interplay between implicit and strategy-based motor adaptation.NEW & NOTEWORTHY Recent studies indicate that the precision with which people localize their hand limits implicit visuomotor learning. We found that localization precision is not static, but decreases early during learning. This decrease is pronounced when people apply a reaiming strategy to compensate for a visuomotor perturbation and is partly resistant to allocation of attention to the hand. We propose that these dynamics in position sense during learning may influence how implicit and strategy-based motor adaption interact.

The P3 event-related potential increases when humans learn a strategy for motor adaptation.

Human motor learning involves cognitive strategies in addition to implicit adaptation. Differences in systems-level neurophysiology between strategy-based and implicit learning remain poorly understood. We asked how the P3 event-related potential, an electroencephalography signal known to increase during early motor learning, relates to strategy-based learning and implicit adaptation. We re-analysed data from two experiments, in which participants (n = 64) reached towards a visual target, with online visual feedback replacing vision of their moving hand. We induced learning by rotating the visual feedback. In the first experiment, feedback rotations were turned on during pairs of two consecutive trials, interspersed between non-rotated trials. In one condition, feedback was rotated relative to the actual movement, allowing participants to develop a re-aiming strategy on the second trial of each pair, while it was rotated relative to the target in the other condition, rendering re-aiming futile. P3 amplitude increased in the first rotated trial in both conditions, but this increase was more pronounced in the re-aiming condition. In the second experiment, a constant visuomotor rotation was turned on for many consecutive trials. We instructed one group beforehand how to re-aim successfully, while the other group had to develop a strategy by themselves. P3 amplitude increased during early adaptation only in the latter group. These findings collectively suggest that in the context of motor learning, the P3 ERP is associated with a need to develop, or adjust, a cognitive strategy.

Rapid Compensation for Noisy Voluntary Movements in Adults with Primary Tic Disorders.

BACKGROUND: It has been proposed that tics and premonitory urges in primary tic disorders (PTD), like Tourette syndrome, are a manifestation of sensorimotor noise. However, patients with tics show no obvious movement imprecision in everyday life. One reason could be that patients have strategies to compensate for noise that disrupts performance (ie, noise that is task-relevant). OBJECTIVES: Our goal was to unmask effects of elevated sensorimotor noise on the variability of voluntary movements in patients with PTD. METHODS: We tested 30 adult patients with PTD (23 male) and 30 matched controls in a reaching task designed to unmask latent noise. Subjects reached to targets whose shape allowed for variability either in movement direction or extent. This enabled us to decompose variability into task-relevant versus less task-relevant components, where the latter should be less affected by compensatory strategies than the former. In alternating blocks, the task-relevant target dimension switched, allowing us to explore the temporal dynamics with which participants adjusted movement variability to changes in task demands. RESULTS: Both groups accurately reached to targets, and adjusted movement precision based on target shape. However, when task-relevant dimensions of the target changed, patients initially produced movements that were more variable than controls, before regaining precision after several reaches. This effect persisted across repeated changes in the task-relevant dimension across the experiment, and therefore did not reflect an effect of novelty, or differences in learning. CONCLUSIONS: Our results suggest that patients with PTD generate noisier voluntary movements compared with controls, but rapidly compensate according to current task demands. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Non-invasive recording of high-frequency signals from the human spinal cord.

Throughout the somatosensory system, neuronal ensembles generate high-frequency signals in the range of several hundred Hertz in response to sensory input. High-frequency signals have been related to neuronal spiking, and could thus help clarify the functional architecture of sensory processing. Recording high-frequency signals from subcortical regions, however, has been limited to clinical pathology whose treatment allows for invasive recordings. Here, we demonstrate the feasibility to record 200-1200 Hz signals from the human spinal cord non-invasively, and in healthy individuals. Using standard electroencephalography equipment in a cervical electrode montage, we observed high-frequency signals between 200 and 1200 Hz in a time window between 8 and 16 ms after electric median nerve stimulation (n = 15). These signals overlapped in latency, and, partly, in frequency, with signals obtained via invasive, epidural recordings from the spinal cord in a patient with neuropathic pain. Importantly, the observed high-frequency signals were dissociable from classic spinal evoked responses. A spatial filter that optimized the signal-to-noise ratio of high-frequency signals led to submaximal amplitudes of the evoked response, and vice versa, ruling out the possibility that high-frequency signals are merely a spectral representation of the evoked response. Furthermore, we observed spontaneous fluctuations in the amplitude of high-frequency signals over time, in the absence of any concurrent, systematic change to the evoked response. High-frequency, "spike-like" signals from the human spinal cord thus carry information that is complementary to the evoked response. The possibility to assess these signals non-invasively provides a novel window onto the neurophysiology of the human spinal cord, both in a context of top-down control over perception, as well as in pathology.

Can moving in a redundant workspace accelerate motor adaptation?

Variability in behavior can be a manifestation of unwanted noise. However, variability can also reflect exploration and benefit learning. For example, it has been shown that interindividual differences in motor learning can be partly explained by differences in movement variability at baseline. Here, we examined whether permitting versus constraining movement variability via target shape alters motor learning rate in one and the same individual. Healthy young subjects made reaching movements to visual targets in two-dimensional space with their unseen hand. During an initial priming phase, the shape of targets allowed for movement variability either in direction (arc-shaped targets), or, in a separate session, in extent (radially oriented line-shaped targets), while requiring highly precise movements in the other spatial dimension, respectively. In subsequent test phases in each session, we quantified the rate of (single-trial) motor adaptation to visuomotor perturbations along these two spatial dimensions (rotation and gain). During priming, we observed higher variability in movement direction for arc-shaped targets, compared with radial line-shaped targets, and vice versa for variability in movement extent. As predicted, participants adapted more to a visuomotor rotation following priming with arc-shaped targets, compared with radial line-shaped targets, and vice versa for adaptation to a change in visuomotor gain. This effect was prominent in the part of the examined workspace where variability in initial movement trajectories was highest, suggesting high planning noise. Our results suggest that workspace redundancy can modulate motor adaptation in a spatially specific manner, however, this modulation may depend on the level of planning noise.NEW & NOTEWORTHY Interindividual differences in motor adaptation are partly explained by differences in movement variability. Movement variability is higher in a redundant workspace. Can workspace redundancy increase adaptation? In a within-subject experiment, we show that moving in a workspace that permits versus constrains movement variability in a given spatial dimension modulates adaptation rate in that dimension, at least in part of the workspace where initial movement trajectories vary most, indicating planning noise. Redundant workspaces might aid rehabilitation.

Spatial Filtering of Electroencephalography Reduces Artifacts and Enhances Signals Related to Spinal Cord Stimulation (SCS).

OBJECTIVES: How spinal cord stimulation (SCS) in its different modes suppresses pain is poorly understood. Mechanisms of action may reside locally in the spinal cord, but also involve a larger network including subcortical and cortical brain structures. Tonic, burst, and high-frequency modes of SCS can, in principle, entrain distinct temporal activity patterns in this network, but finally have to yield specific effects on pain suppression. Here, we employ high-density electroencephalography (EEG) and recently developed spatial filtering techniques to reduce SCS artifacts and to enhance EEG signals specifically related to neuromodulation by SCS. MATERIALS AND METHODS: We recorded high-density resting-state EEGs in patients suffering from pain of various etiologies under different modes of SCS. We established a pipeline for the robust spectral analysis of oscillatory brain activity during SCS, which includes spatial filtering for attenuation of pulse artifacts and enhancement of brain activity potentially modulated by SCS. RESULTS: In sensor regions responsive to SCS, neuromodulation strongly reduced activity in the theta and low alpha range (6-10 Hz) in all SCS modes. Results were consistent in all patients, and in accordance with thalamocortical dysrhythmia hypothesis of pain. Only in the tonic mode showing paresthesia as side effect, SCS also consistently and strongly reduced high-gamma activity (>84 Hz). CONCLUSIONS: EEG spectral analysis combined with spatial filtering allows for a spatially and temporally specific assessment of SCS-related, neuromodulatory EEG activity, and may help to disentangle therapeutic and side effects of SCS.

Intact automatic motor inhibition in patients with tourette syndrome.

BACKGROUND: Behavioral disinhibition has been proposed as a key mechanism in Tourette syndrome. Yet classic inhibition tasks have yielded inconsistent results, likely reflecting interference by strategies compensating for tic release. METHODS: We examined a core inhibitory function that is immune to such interference because it suppresses movements automatically. We measured automatic motor inhibition behaviorally in 21 adults with Tourette syndrome and 21 healthy controls via the negative compatibility effect. When a motor response is activated, for example, by a subliminal prime stimulus, but execution is delayed, activation turns into inhibition, increasing reaction time and error. Diminished automatic inhibition could underlie tic release. RESULTS: Both controls and patients showed strong automatic motor inhibition with no significant group difference. Bayesian statistics, allowing inference on the absence of effects, favored intact inhibition in patients. Our study was well powered. CONCLUSIONS: Automatic motor inhibition in Tourette syndrome is neither impaired nor harnessed by compensation. © 2018 International Parkinson and Movement Disorder Society.

Perimovement decrease of alpha/beta oscillations in the human nucleus accumbens.

The human nucleus accumbens is thought to play an important role in guiding future action selection via an evaluation of current action outcomes. Here we provide electrophysiological evidence for a more direct, i.e., online, role during action preparation. We recorded local field potentials from the nucleus accumbens in patients with epilepsy undergoing surgery for deep brain stimulation. We found a consistent decrease in the power of alpha/beta oscillations (10-30 Hz) before and around the time of movements. This perimovement alpha/beta desynchronization was observed in seven of eight patients and was present both before instructed movements in a serial reaction time task as well as before self-paced, deliberate choices in a decision making task. A similar beta decrease over sensorimotor cortex and in the subthalamic nucleus has been directly related to movement preparation and execution. Our results support the idea of a direct role of the human nucleus accumbens in action preparation and execution.

Attentional modulation of alpha/beta and gamma oscillations reflect functionally distinct processes.

The brain adapts to dynamic environments by adjusting the attentional gain or precision afforded to salient and predictable sensory input. Previous research suggests that this involves the regulation of cortical excitability (reflected in prestimulus alpha oscillations) before stimulus onset that modulates subsequent stimulus processing (reflected in stimulus-bound gamma oscillations). We present two spatial attention experiments in humans, where we first replicate the classic finding of prestimulus attentional alpha modulation and poststimulus gamma modulation. In the second experiment, the task-relevant target was a stimulus change that occurred after stimulus onset. This enabled us to show that attentional alpha modulation reflects the predictability (precision) of an upcoming sensory target, rather than an attenuation of alpha activity induced by neuronal excitation related to stimulus onset. In particular, we show that the strength of attentional alpha modulations increases with the predictability of the anticipated sensory target, regardless of current afferent drive. By contrast, we show that the poststimulus attentional gamma enhancement is stimulus-bound and decreases when the subsequent target becomes more predictable. Hence, this pattern suggests that the strength of gamma oscillations is not merely a function of cortical excitability, but also depends on the relative mismatch of predictions and sensory evidence. Together, these findings support recent theoretical proposals for distinct roles of alpha/beta and gamma oscillations in hierarchical perceptual inference and predictive coding.

Parallel processing streams for motor output and sensory prediction during action preparation.

Sensory consequences of one's own actions are perceived as less intense than identical, externally generated stimuli. This is generally taken as evidence for sensory prediction of action consequences. Accordingly, recent theoretical models explain this attenuation by an anticipatory modulation of sensory processing prior to stimulus onset (Roussel et al. 2013) or even action execution (Brown et al. 2013). Experimentally, prestimulus changes that occur in anticipation of self-generated sensations are difficult to disentangle from more general effects of stimulus expectation, attention and task load (performing an action). Here, we show that an established manipulation of subjective agency over a stimulus leads to a predictive modulation in sensory cortex that is independent of these factors. We recorded magnetoencephalography while subjects performed a simple action with either hand and judged the loudness of a tone caused by the action. Effector selection was manipulated by subliminal motor priming. Compatible priming is known to enhance a subjective experience of agency over a consequent stimulus (Chambon and Haggard 2012). In line with this effect on subjective agency, we found stronger sensory attenuation when the action that caused the tone was compatibly primed. This perceptual effect was reflected in a transient phase-locked signal in auditory cortex before stimulus onset and motor execution. Interestingly, this sensory signal emerged at a time when the hemispheric lateralization of motor signals in M1 indicated ongoing effector selection. Our findings confirm theoretical predictions of a sensory modulation prior to self-generated sensations and support the idea that a sensory prediction is generated in parallel to motor output (Walsh and Haggard 2010), before an efference copy becomes available.

No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients.

Functional magnetic resonance imaging (fMRI), cyclic voltammetry, and single-unit electrophysiology studies suggest that signals measured in the nucleus accumbens (Nacc) during value-based decision making represent reward prediction errors (RPEs), the difference between actual and predicted rewards. Here, we studied the precise temporal and spectral pattern of reward-related signals in the human Nacc. We recorded local field potentials (LFPs) from the Nacc of six epilepsy patients during an economic decision-making task. On each trial, patients decided whether to accept or reject a gamble with equal probabilities of a monetary gain or loss. The behavior of four patients was consistent with choices being guided by value expectations. Expected value signals before outcome onset were observed in three of those patients, at varying latencies and with nonoverlapping spectral patterns. Signals after outcome onset were correlated with RPE regressors in all subjects. However, further analysis revealed that these signals were better explained as outcome valence rather than RPE signals, with gamble gains and losses differing in the power of beta oscillations and in evoked response amplitudes. Taken together, our results do not support the idea that postsynaptic potentials in the Nacc represent a RPE that unifies outcome magnitude and prior value expectation. We discuss the generalizability of our findings to healthy individuals and the relation of our results to measurements of RPE signals obtained from the Nacc with other methods.

Cortical drive of low-frequency oscillations in the human nucleus accumbens during action selection.

The nucleus accumbens is thought to contribute to action selection by integrating behaviorally relevant information from multiple regions, including prefrontal cortex. Studies in rodents suggest that information flow to the nucleus accumbens may be regulated via task-dependent oscillatory coupling between regions. During instrumental behavior, local field potentials (LFP) in the rat nucleus accumbens and prefrontal cortex are coupled at delta frequencies (Gruber AJ, Hussain RJ, O'Donnell P. PLoS One 4: e5062, 2009), possibly mediating suppression of afferent input from other areas and thereby supporting cortical control (Calhoon GG, O'Donnell P. Neuron 78: 181-190, 2013). In this report, we demonstrate low-frequency cortico-accumbens coupling in humans, both at rest and during a decision-making task. We recorded LFP from the nucleus accumbens in six epilepsy patients who underwent implantation of deep brain stimulation electrodes. All patients showed significant coherence and phase-synchronization between LFP and surface EEG at delta and low theta frequencies. Although the direction of this coupling as indexed by Granger causality varied between subjects in the resting-state data, all patients showed a cortical drive of the nucleus accumbens during action selection in a decision-making task. In three patients this was accompanied by a significant coherence increase over baseline. Our results suggest that low-frequency cortico-accumbens coupling represents a highly conserved regulatory mechanism for action selection.

Enhanced alpha-oscillations in visual cortex during anticipation of self-generated visual stimulation.

The perceived intensity of sensory stimuli is reduced when these stimuli are caused by the observer's actions. This phenomenon is traditionally explained by forward models of sensory action-outcome, which arise from motor processing. Although these forward models critically predict anticipatory modulation of sensory neural processing, neurophysiological evidence for anticipatory modulation is sparse and has not been linked to perceptual data showing sensory attenuation. By combining a psychophysical task involving contrast discrimination with source-level time-frequency analysis of MEG data, we demonstrate that the amplitude of alpha-oscillations in visual cortex is enhanced before the onset of a visual stimulus when the identity and onset of the stimulus are controlled by participants' motor actions. Critically, this prestimulus enhancement of alpha-amplitude is paralleled by psychophysical judgments of a reduced contrast for this stimulus. We suggest that alpha-oscillations in visual cortex preceding self-generated visual stimulation are a likely neurophysiological signature of motor-induced sensory anticipation and mediate sensory attenuation. We discuss our results in relation to proposals that attribute generic inhibitory functions to alpha-oscillations in prioritizing and gating sensory information via top-down control.

Re-construction of action awareness depends on an internal model of action-outcome timing.

The subjective time of an instrumental action is shifted towards its outcome. This temporal binding effect is partially retrospective, i.e., occurs upon outcome perception. Retrospective binding is thought to reflect post-hoc inference on agency based on sensory evidence of the action - outcome association. However, many previous binding paradigms cannot exclude the possibility that retrospective binding results from bottom-up interference of sensory outcome processing with action awareness and is functionally unrelated to the processing of the action - outcome association. Here, we keep bottom-up interference constant and use a contextual manipulation instead. We demonstrate a shift of subjective action time by its outcome in a context of variable outcome timing. Crucially, this shift is absent when there is no such variability. Thus, retrospective action binding reflects a context-dependent, model-based phenomenon. Such top-down re-construction of action awareness seems to bias agency attribution when outcome predictability is low.

Strategy-based motor learning decreases the post-movement ß power.

Motor learning depends on the joint contribution of several processes including cognitive strategies aiming at goal achievement and prediction error-driven implicit adaptation. Understanding this functional interplay and its clinical implications requires insight into the individual learning processes, including at a neural level. Here, we set out to examine the impact of learning a cognitive strategy, over and above implicit adaptation, on the oscillatory post-movement ß rebound (PMBR), which typically decreases in power following (visuo)motor perturbations. Healthy participants performed reaching movements towards a target, with online visual feedback replacing the view of their moving hand. The feedback was sometimes rotated, either relative to their movements (visuomotor rotation) or invariant to their movements (and relative to the target; clamped feedback), always for two consecutive trials interspersed between non-rotated trials. In both conditions, the first trial with a rotation was unpredictable. On the second trial, the task was either to re-aim, and thereby compensate for the rotation experienced in the first trial (visuomotor rotation; Compensate condition), or to ignore the rotation and keep on aiming at the target (clamped feedback; Ignore condition). After-effects did not differ between conditions, indicating that the amount of implicit learning was similar, while large differences in movement direction in the second rotated trial between conditions indicated that participants successfully acquired re-aiming strategies. Importantly, PMBR power following the first rotated trial was modulated differently in the two conditions. Specifically, it decreased in both conditions, but this effect was larger when participants had to acquire a cognitive strategy and prepare to re-aim. Our results therefore suggest that the PMBR is modulated by cognitive demands of motor learning, possibly reflecting the evaluation of a behaviourally significant goal achievement error.

Immunological and clinical consequences of treating a patient with natalizumab.

BACKGROUND: Long-term therapy with natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML). OBJECTIVES: We present a patient study through therapy, the diagnosis of PML (after 29 infusions), plasma exchange (PE) and development of immune reconstitution inflammatory syndrome (IRIS). METHODS: Routine diagnostics, magnetic resonance imaging (MRI), immunological status (flow cytometry, T-cell migration assays and T-cell repertoire analysis), and brain biopsy with immunohistological analysis. RESULTS: CD49d decreased after 12 months of treatment. At PML diagnosis, CD49d expression and migratory capacity of T cells was low and peripheral T-cell receptor (TCR) complexity showed severe perturbations. The distribution of peripheral monocytes changed from CCR5+ to CCR7+. After PE some changes reverted: CD49d increased and overshot earliest levels, migratory capacities of T cells recovered and peripheral TCR complexity increased. With no clinical, routine laboratory or cerebrospinal fluid (CSF) changes, MRI 2 months after PE demonstrated progressive lesion development. Brain histopathology confirmed the presence of infiltrates indicative of IRIS without clinical signs, immunologically accompanied by CCR7/CCR5 recovery of peripheral monocytes. CONCLUSION: Natalizumab-associated immunological changes accompanying PML were reversible after PE; IRIS can occur very late, remain asymptomatic and be elusive to CSF analysis. Our study may provide insights into the changes under treatment with natalizumab associated with JC virus control.

Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis.

Migration of immune cells characterizes inflammation and plays a key role in autoimmune diseases such as MS. CD4(+)Foxp3(+) regulatory T cells (Treg) have the potential to dampen immune responses but show functional impairment in patients with MS. We here show that murine Treg exhibit higher constitutive cell motility in horizontal migration on laminin, surpass non-Treg in transwell assays through microporous membranes as well as across primary brain endothelium and are present in the naïve CNS to a significantly higher extent compared to spleen, lymph nodes and blood. Likewise, human Treg from healthy donors significantly exceed non-Treg in migratory rates across primary human brain endothelium. Finally, we investigated whether the propensity to migrate is impaired as a feature of autoimmunity and therefore tested patients with MS. Treg from patients with stable relapsing-remitting MS show significantly impaired migratory capacity under non-inflammatory conditions compared to healthy donors. We hypothesize that the enhanced propensity to migrate is a feature of Treg that allows for an equilibrium in parenchymal immune surveillance, e.g. of the CNS. Impaired Treg migration across the intact blood-brain barrier, as observed for Treg from patients with MS, indicates a broader functional deficiency hypothetically contributing to early CNS lesion development or phases of MS remissions.

Glatiramer acetate attenuates pro-inflammatory T cell responses but does not directly protect neurons from inflammatory cell death.

Glatiramer acetate (GA) is a synthetic, random, basic copolymer capable of modulating adaptive T cell responses. In animal models of various inflammatory and degenerative central nervous system disorders, GA-induced T cells cross the blood-brain barrier, secrete high levels of anti-inflammatory cytokines and neurotrophins, and thus both reduce neuronal damage and promote neurogenesis. Recently, it has been suggested that GA itself may permeate the (impaired) blood-brain-barrier and directly protect neurons under conditions of inflammation-mediated neurodegeneration. To test this hypothesis, we examined the direct effects of GA on neuronal functionality and T cell-mediated neuronal apoptosis in culture, acute brain slices, and focal experimental autoimmune encephalomyelitis. GA caused a depolarization of the resting membrane potential and led to an immediate impairment of action potential generation in neurons. Moreover, GA-incubated neurons underwent dose-dependent apoptosis. Apoptosis of ovalbumin peptide-loaded major histocompatibility complex class I-expressing neurons induced by ovalbumin-specific effector T cells could be reduced by pre-incubation of T cells, but not neurons with GA. Similar results could be found using acute brain slices. In focal experimental autoimmune encephalomyelitis, lesion size and neuronal apoptosis could be limited by pretreating rats with GA, whereas intracerebral GA application into the inflammatory lesion had no effect on neuronal survival. Our data suggest that GA attenuates adaptive pro-inflammatory T cell responses, but does not exert direct neuroprotective effects.

Upregulation of K2P5.1 potassium channels in multiple sclerosis.

OBJECTIVE: Activation of T cells critically depends on potassium channels. We here characterize the impact of K(2P)5.1 (KCNK5; TASK2), a member of the 2-pore domain family of potassium channels, on T-cell function and demonstrate its putative relevance in a T-cell-mediated autoimmune disorder, multiple sclerosis (MS). METHODS: Expression of K(2P)5.1 was investigated on RNA and protein level in different immune cells and in MS patients' biospecimens (peripheral blood mononuclear cells, cerebrospinal fluid cells, brain tissue specimen). Functional consequences of K(2P)5.1 expression were analyzed using pharmacological modulation, small interfering RNA (siRNA), overexpression, electrophysiological recordings, and computer modeling. RESULTS: Human T cells constitutively express K(2P)5.1. After T-cell activation, a significant and time-dependent upregulation of K(2P)5.1 channel expression was observed. Pharmacological blockade of K(2P)5.1 or knockdown with siRNA resulted in reduced T-cell functions, whereas overexpression of K(2P)5.1 had the opposite effect. Electrophysiological recordings of T cells clearly dissected K(2P)5.1-mediated effects from other potassium channels. The pathophysiological relevance of these findings was demonstrated by a significant K(2P)5.1 upregulation in CD4(+) and CD8(+) T cells in relapsing/remitting MS (RRMS) patients during acute relapses as well as higher levels on CD8(+) T cells of clinically isolated syndrome, RRMS, and secondary progressive multiple sclerosis patients during clinically stable disease. T cells in the cerebrospinal fluid from MS patients exhibit significantly elevated K(2P)5.1 levels. Furthermore, K(2P)5.1-positive T cells can be found in inflammatory lesions in MS tissue specimens. INTERPRETATION: Selective targeting of K(2P)5.1 may hold therapeutic promise for MS and putatively other T-cell-mediated disorders.