Evaluation of Neuromuscular Diseases and Complaints by Quantitative Muscle MRI.

Background: Quantitative muscle MRI (qMRI) is a promising tool for evaluating and monitoring neuromuscular disorders (NMD). However, the application of different imaging protocols and processing pipelines restricts comparison between patient cohorts and disorders. In this qMRI study, we aim to compare dystrophic (limb-girdle muscular dystrophy), inflammatory (inclusion body myositis), and metabolic myopathy (Pompe disease) as well as patients with post-COVID-19 conditions suffering from myalgia to healthy controls. Methods: Ten subjects of each group underwent a 3T lower extremity muscle MRI, including a multi-echo, gradient-echo, Dixon-based sequence, a multi-echo, spin-echo (MESE) T2 mapping sequence, and a spin-echo EPI diffusion-weighted sequence. Furthermore, the following clinical assessments were performed: Quick Motor Function Measure, patient questionnaires for daily life activities, and 6-min walking distance. Results: Different involvement patterns of conspicuous qMRI parameters for different NMDs were observed. qMRI metrics correlated significantly with clinical assessments. Conclusions: qMRI metrics are suitable for evaluating patients with NMD since they show differences in muscular involvement in different NMDs and correlate with clinical assessments. Still, standardisation of acquisition and processing is needed for broad clinical use.

Cortical excitability in human somatosensory and visual cortex: implications for plasticity and learning - a minireview.

The balance of excitation and inhibition plays a key role in plasticity and learning. A frequently used, reliable approach to assess intracortical inhibition relies on measuring paired-pulse behavior. Moreover, recent developments of magnetic resonance spectroscopy allows measuring GABA and glutamate concentrations. We give an overview about approaches employed to obtain information about excitatory states in human participants and discuss their putative relation. We summarize paired-pulse techniques and basic findings characterizing paired-pulse suppression in somatosensory (SI) and (VI) visual areas. Paired-pulse suppression describes the effect of paired sensory stimulation at short interstimulus intervals where the cortical response to the second stimulus is significantly suppressed. Simultaneous assessments of paired-pulse suppression in SI and VI indicated that cortical excitability is not a global phenomenon, but instead reflects the properties of local sensory processing. We review studies using non-invasive brain stimulation and perceptual learning experiments that assessed both perceptual changes and accompanying changes of cortical excitability in parallel. Independent of the nature of the excitation/inhibition marker used these data imply a close relationship between altered excitability and altered performance. These results suggest a framework where increased or decreased excitability is linked with improved or impaired perceptual performance. Recent findings have expanded the potential role of cortical excitability by demonstrating that inhibition markers such as GABA concentrations, paired-pulse suppression or alpha power predict to a substantial degree subsequent perceptual learning outcome. This opens the door for a targeted intervention where subsequent plasticity and learning processes are enhanced by altering prior baseline states of excitability.

Hypnotic suggestions cognitively penetrate tactile perception through top-down modulation of semantic contents.

Perception is subject to ongoing alterations by learning and top-down influences. Although abundant studies have shown modulation of perception by attention, motivation, content and context, there is an unresolved controversy whether these examples provide true evidence that perception is penetrable by cognition. Here we show that tactile perception assessed as spatial discrimination can be instantaneously and systematically altered merely by the semantic content during hypnotic suggestions. To study neurophysiological correlates, we recorded EEG and SEPs. We found that the suggestion "your index finger becomes bigger" led to improved tactile discrimination, while the suggestion "your index finger becomes smaller" led to impaired discrimination. A hypnosis without semantic suggestions had no effect but caused a reduction of phase-locking synchronization of the beta frequency band between medial frontal cortex and the finger representation in somatosensory cortex. Late SEP components (P80-N140 complex) implicated in attentional processes were altered by the semantic contents, but processing of afferent inputs in SI remained unaltered. These data provide evidence that the psychophysically observed modifiability of tactile perception by semantic contents is not simply due to altered perception-based judgments, but instead is a consequence of modified perceptual processes which change the perceptual experience.

Developmental neuroscience: Boosting inhibition boosts learning.

Compared to adults, children learn differently and more efficiently. A new study shows that in children a rapid boost of inhibition evoked during learning leads to better stabilization of learned items due to reduced retrograde interference.

Low test-retest reliability of a protocol for assessing somatosensory cortex excitability generated from sensory nerves of the lower back.

In people with chronic low back pain (CLBP), maladaptive structural and functional changes on a cortical level have been identified. On a functional level, somatosensory cortical excitability has been shown to be reduced in chronic pain conditions, resulting in cortical disinhibition. The occurrence of structural and/or functional maladaptive cortical changes in people with CLBP could play a role in maintaining the pain. There is currently no measurement protocol for cortical excitability that employs stimulation directly to the lower back. We developed a protocol for the measurement of single pulse somatosensory evoked potential (SEP) waveforms and paired-pulse behavior (PPB) generated from sensory nerves of the lower back and quantified its test-retest reliability in a sample of 30 healthy individuals to gain insights into the normal variability of cortical responses, which could then be compared to results from people with CLBP. We investigated cortical excitability by measuring SEPs and PPB. PPB was defined as the ratio of the amplitude of the second cortical response (A2s) divided by the first cortical response (A1). A2s was determined by subtracting the response to single-pulse stimuli from the paired pulse stimuli response to account for linear superposition effects. The test-retest reliability of the protocol was very poor with no evidence of systematic bias but a high amount of random variability between sessions. There was no significant difference in the right side PPB for session 1 (Mean ratio A2s/A1 = 0.66, SD = 0.54) and session 2 (Mean ratio A2s/A1 = 0.94, SD = 1.56); mean session difference [(95% CI) = -0.44 (-1.23 to 0.34); t (22) = -1.17, p = 0.26]. The ICC3.1 (absolute agreement) for the outlier-removed right side PPB were 0.19 (95% CI: -0.84 to 0.66) and 0.43 for left side PPB (95% CI: -0.37 to 0.76). This finding potentially has wider implications for PPB protocols. If these findings were replicated in other groups and other nerves, it would question the validity of this measure more generally. However, these findings are restricted to healthy people and sensory nerves of the lower back and may not be generalizable.

Visual and Tactile Sensory Systems Share Common Features in Object Recognition.

Although we use our visual and tactile sensory systems interchangeably for object recognition on a daily basis, little is known about the mechanism underlying this ability. This study examined how 3D shape features of objects form two congruent and interchangeable visual and tactile perceptual spaces in healthy male and female participants. Since active exploration plays an important role in shape processing, a virtual reality environment was used to visually explore 3D objects called digital embryos without using the tactile sense. In addition, during the tactile procedure, blindfolded participants actively palpated a 3D-printed version of the same objects with both hands. We first demonstrated that the visual and tactile perceptual spaces were highly similar. We then extracted a series of 3D shape features to investigate how visual and tactile exploration can lead to the correct identification of the relationships between objects. The results indicate that both modalities share the same shape features to form highly similar veridical spaces. This finding suggests that visual and tactile systems might apply similar cognitive processes to sensory inputs that enable humans to rely merely on one modality in the absence of another to recognize surrounding objects.

Parallel modulation of intracortical excitability of somatosensory and visual cortex by the gonadal hormones estradiol and progesterone.

The levels of the gonadal hormones estradiol and progesterone vary throughout the menstrual cycle thereby affecting cognition, emotion, mood, and social behaviour. However, how these hormones modulate the balance of neural excitation and inhibition, which crucially regulate processing and plasticity, is not fully understood. We here used paired-pulse stimulation to investigate in healthy humans the action of low and high estradiol and progesterone on intracortical inhibition in somatosensory (SI) and visual cortex (V1). We found that paired-pulse suppression in both SI and VI depended on estradiol. During high estradiol levels, paired-pulse suppression was significantly reduced. No comparable effects were found for progesterone, presumably due to a confounding effect of estradiol. Also, no hormone level-depending effects were observed for single-pulse evoked SEPs (somatosensory evoked potentials) and VEPs (visual evoked potentials) indicating a specific hormonal action on intracortical processing. The results demonstrate that estradiol globally modulates the balance of excitation and inhibition of SI and VI cortex.

20 Hz Steady-State Response in Somatosensory Cortex During Induction of Tactile Perceptual Learning Through LTP-Like Sensory Stimulation.

The induction of synaptic plasticity requires the presence of temporally patterned neural activity. Numerous cellular studies in animals and brain slices have demonstrated that long-term potentiation (LTP) enhances synaptic transmission, which can be evoked by high-frequency intermittent stimulation. In humans, plasticity processes underlying perceptual learning can be reliably induced by repetitive, LTP-like sensory stimulation. These protocols lead to improvement of perceptual abilities parallel to widespread remodeling of cortical processing. However, whether maintained rhythmic cortical activation induced by the LTP-like stimulation is also present during human perceptual learning experiments, remains elusive. To address this question, we here applied a 20 Hz intermittent stimulation protocol for 40 min to the index-, middle- and ring-fingers of the right hand, while continuously recording EEG over the hand representation in primary somatosensory cortex in young adult participants. We find that each train of stimulation initiates a transient series of sensory-evoked potentials which accumulate after about 500 ms into a 20 Hz steady-state response persisting over the entire period of the 2-s-train. During the inter-train interval, no consistent evoked activity can be detected. This response behavior is maintained over the whole 40 min of stimulation without any indication of habituation. However, the early stimulation evoked potentials (SEPs) and the event-related desynchronization (ERD) during the steady-state response change over the 40 min of stimulation. In a second experiment, we demonstrate in a separate cohort of participants that the here-applied pneumatic type of stimulation results in improvement of tactile acuity as typically observed for electrically applied 20 Hz intermittent stimulation. Our data demonstrate that repetitive stimulation using a 20 Hz protocol drives rhythmic activation in the hand representation of somatosensory cortex, which is sustained during the entire stimulation period. At the same time, cortical excitability increases as indicated by altered ERD and SEP amplitudes. Our results, together with previous data underlining the dependence of repetitive sensory stimulation effects on NMDA-receptor activation, support the view that repetitive sensory stimulation elicits LTP-like processes in the cortex, thereby facilitating perceptual learning processes.

Differential effects of the temporal and spatial distribution of audiovisual stimuli on cross-modal spatial recalibration.

Visual input constantly recalibrates auditory spatial representations. Exposure to isochronous audiovisual stimuli with a fixed spatial disparity typically results in a subsequent auditory localization bias (ventriloquism aftereffect, VAE), whereas exposure to spatially congruent audiovisual stimuli improves subsequent auditory localization (multisensory enhancement, ME). Here, we tested whether cross-modal recalibration is affected by the stimulation rate and/or the distribution of audiovisual spatial disparities during training. Auditory localization was tested before and after participants were exposed either to audiovisual stimuli with a constant spatial disparity of 13.5° (VAE) or to spatially congruent audiovisual stimulation (ME). In a between-subjects design, audiovisual stimuli were presented either at a low frequency of 2 Hz, as used in previous studies of VAE and ME, or intermittently at a high frequency of 10 Hz, which mimics long-term potentiation (LTP) protocols and which was found superior in eliciting unisensory perceptual learning. Compared to low-frequency stimulation, VAE was reduced after high-frequency stimulation, whereas ME occurred regardless of the stimulation protocol. In two additional groups, we manipulated the spatial distribution of audiovisual stimuli in the low-frequency condition. Stimuli were presented with varying audiovisual disparities centered around 13.5° (VAE) or 0° (ME). Both VAE and ME were equally strong compared to a fixed spatial relationship of 13.5° or 0°, respectively. Taken together, our results suggest (a) that VAE and ME represent partly dissociable forms of learning and (b) that auditory representations adjust to the overall stimulus statistics rather than to a specific audiovisual spatial relationship.

Perceptual Learning: Sharing and Keeping Learned Improvements within a Category.

Perceptual learning is highly specific for the trained feature with limited generalization. A new study shows broad transfer of perceptual learning for features belonging to the same category, but no transfer for features of different categories.

Somatosensory alpha oscillations gate perceptual learning efficiency.

Cognition and perception are closely coupled to alpha power, but whether there is a link between alpha power and perceptual learning efficacy is unknown. Here we show that somatosensory alpha power can be successfully up- and down-regulated with short-term neurofeedback training, which in turn controls subsequent tactile perceptual learning. We find that neurofeedback-induced increases in alpha power lead to enhanced learning, whereas reductions in alpha power impede learning. As a consequence, interindividual learning variability is substantially reduced. No comparable impact is observed for oscillatory power in theta, beta, and lower gamma frequency bands. Our results demonstrate that high pre-learning alpha levels are a requirement for reaching high learning efficiency. These data provide further evidence that alpha oscillations shape the functional architecture of the brain network by gating neural resources and thereby modulating levels of preparedness for upcoming processing.

The effect of LTP- and LTD-like visual stimulation on modulation of human orientation discrimination.

Studies showing that repetitive visual stimulation protocols alter perception and induce cortical reorganization, as well-reported for the tactile domain, have been sparse. In this study, we investigated how "long-term potentiation [LTP]-like" and "long-term depression [LTD]-like" repetitive visual stimulation affects orientation discrimination ability in human observers. LTP-like stimulation with features most closely resembling the stimuli used during behavioral assessment evoked the largest improvement, while the effects were smaller in protocols that differed in shape or orientation features. This gradient suggests lower learning specificity than classical perceptual learning experiments, possibly because of an interplay of task- and feature-based factors. All modulatory effects of repetitive stimulation were superimposed on top of spontaneous task learning. Moreover, blockwise analysis revealed that LTP-like stimulation, in contrast to LTD-like or sham stimulation, prevented a loss of practice-related gain of orientation discrimination thresholds. This observation highlights a critical role of LTP-like stimulation for consolidation, typically observed during sleep.

Tactile learning transfer from the hand to the face but not to the forearm implies a special hand-face relationship.

In the primary somatosensory cortex, large-scale cortical and perceptual changes have been demonstrated following input deprivation. Recently, we found that the cortical and perceptual changes induced by repetitive somatosensory stimulation (RSS) at a finger transfer to the face. However, whether such cross-border changes are specific to the face remains elusive. Here, we investigated whether RSS-induced acuity changes at the finger can also transfer to the forearm, which is the body part represented on the other side of the hand representation. Our results confirmed the transfer of tactile learning from the stimulated finger to the lip, but no significant changes were observed at the forearm. A second experiment revealed that the same regions on the forearm exhibited improved tactile acuity when RSS was applied there, excluding the possibility of low plastic ability at the arm representation. This provides also the first evidence that RSS can be efficient on body parts other than the hand. These results suggest that RSS-induced tactile learning transfers preferentially from the hand to the face rather than to the forearm. This specificity could arise from a stronger functional connectivity between the cortical hand and face representations, reflecting a fundamental coupling between these body parts.

Daily repetitive sensory stimulation of the paretic hand for the treatment of sensorimotor deficits in patients with subacute stroke: RESET, a randomized, sham-controlled trial.

BACKGROUND: Repetitive sensory stimulation (RSS) adapts the timing of stimulation protocols used in cellular studies to induce synaptic plasticity. In healthy subjects, RSS leads to widespread sensorimotor cortical reorganization paralleled by improved sensorimotor behavior. Here, we investigated whether RSS reduces sensorimotor upper limb impairment in patients with subacute stroke more effectively than conventional therapy. METHODS: A single-blinded sham-controlled clinical trial assessed the effectiveness of RSS in treating sensorimotor deficits of the upper limbs. Patients with subacute unilateral ischemic stroke were randomly assigned to receive standard therapy in combination with RSS or with sham RSS. Patients were masked to treatment allocation. RSS consisted of intermittent 20 Hz electrical stimulation applied on the affected hand for 45 min/day, 5 days per week, for 2 weeks, and was transmitted using custom-made stimulation-gloves with built-in electrodes contacting each fingertip separately. Before and after the intervention, we assessed light-touch and tactile discrimination, proprioception, dexterity, grip force, and subtasks of the Jebsen Taylor hand-function test for the non-affected and the affected hand. Data from these quantitative tests were combined into a total performance index serving as primary outcome measure. In addition, tolerability and side effects of RSS intervention were recorded. RESULTS: Seventy one eligible patients were enrolled and randomly assigned to receive RSS treatment (n = 35) or sham RSS (n = 36). Data of 25 patients were not completed because they were transferred to another hospital, resulting in n = 23 for each group. Before treatment, sensorimotor performance between groups was balanced (p = 0.237). After 2 weeks of the intervention, patients in the group receiving standard therapy with RSS showed significantly better restored sensorimotor function than the control group (standardized mean difference 0.57; 95% CI -0.013-1.16; p = 0.027) RSS treatment was superior in all domains tested. Repetitive sensory stimulation was well tolerated and accepted, and no adverse events were observed. CONCLUSIONS: Rehabilitation including RSS enhanced sensorimotor recovery more effectively than standard therapy alone. Rehabilitation outcome between the effects of RSS and standard therapy was largest for sensory and motor improvement; however, the results for proprioception and everyday tasks were encouraging warranting further studies in more severe patients. TRIAL REGISTRATION: The trial was retrospectively registered January 31, 2012 under DRKS00003515 ( https://www.drks.de/drks_web/navigate.do;jsessionid=AEE2585CCB82A22A2B285470B37C47C8?navigationId=results ).

Regionally Specific Regulation of Sensorimotor Network Connectivity Following Tactile Improvement.

Correlations between inherent, task-free low-frequency fluctuations in the blood oxygenation level-dependent (BOLD) signals of the brain provide a potent tool to delineate its functional architecture in terms of intrinsic functional connectivity (iFC). Still, it remains unclear how iFC is modulated during learning. We employed whole-brain resting-state magnetic resonance imaging prior to and after training-independent repetitive sensory stimulation (rSS), which is known to induce somatosensory cortical reorganization. We investigated which areas in the sensorimotor network are susceptible to neural plasticity (i.e., where changes in functional connectivity occurred) and where iFC might be indicative of enhanced tactile performance. We hypothesized iFC to increase in those brain regions primarily receiving the afferent tactile input. Strengthened intrinsic connectivity within the sensorimotor network after rSS was found not only in the postcentral gyrus contralateral to the stimulated hand, but also in associative brain regions, where iFC correlated positively with tactile performance or learning. We also observed that rSS led to attenuation of the network at higher cortical levels, which possibly promotes facilitation of tactile discrimination. We found that resting-state BOLD fluctuations are linked to behavioral performance and sensory learning, indicating that network fluctuations at rest are predictive of behavioral changes and neuroplasticity.

Priming Hand Motor Training with Repetitive Stimulation of the Fingertips; Performance Gain and Functional Imaging of Training Effects.

BACKGROUND: Application of repetitive electrical stimulation (rES) of the fingers has been shown to improve tactile perception and sensorimotor performance in healthy individuals. OBJECTIVE: To increase motor performance by priming the effects of active motor training (arm ability training; AAT) using rES. METHODS: We compared the performance gain for the training increase of the averaged AAT tasks of both hands in two groups of strongly right-handed healthy volunteers. Functional Magnetic Resonance Imaging (fMRI) before and after AAT was assessed using three tasks for each hand separately: finger sequence tapping, visually guided grip force modulation, and writing. Performance during fMRI was controlled for preciseness and frequency. A total of 30 participants underwent a two-week unilateral left hand AAT, 15 participants with 20 minutes of rES priming of all fingertips of the trained hand, and 15 participants without rES priming. RESULTS: rES-primed AAT improved the trained left-hand performance across all training tasks on average by 32.9%, non-primed AAT improved by 29.5%. This gain in AAT performance with rES priming was predominantly driven by an increased finger tapping velocity. Functional imaging showed comparable changes for both training groups over time. Across all participants, improved AAT performance was associated with a higher contralateral primary somatosensory cortex (S1) fMRI activation magnitude during the grip force modulation task. CONCLUSIONS: This study highlights the importance of S1 for hand motor training gain. In addition, it suggests the usage of rES of the fingertips for priming active hand motor training.

The stress hormone cortisol blocks perceptual learning in humans.

Cortisol, the primary glucocorticoid (GC) in humans, influences neuronal excitability and plasticity by acting on mineralocorticoid and glucocorticoid receptors. Cellular studies demonstrated that elevated GC levels affect neuronal plasticity, for example through a reduction of hippocampal long-term potentiation (LTP). At the behavioural level, after treatment with GCs, numerous studies have reported impaired hippocampal function, such as impaired memory retrieval. In contrast, relatively little is known about the impact of GCs on cortical plasticity and perceptual learning in adult humans. Therefore, in this study, we explored the impact of elevated GC levels on human perceptual learning. To this aim, we used a training-independent learning approach, where lasting changes in human perception can be induced by applying passive repetitive sensory stimulation (rss), the timing of which was determined from cellular LTP studies. In our placebo-controlled double-blind study, we used tactile LTP-like stimulation to induce improvements in tactile acuity (spatial two-point discrimination). Our results show that a single administration of hydrocortisone (30mg) completely blocked rss-induced changes in two-point discrimination. In contrast, the placebo group showed the expected rss-induced increase in two-point discrimination of over 14%. Our data demonstrate that high GC levels inhibit rss-induced perceptual learning. We suggest that the suppression of LTP, as previously reported in cellular studies, may explain the perceptual learning impairments observed here.

Repetitive Transcranial Direct Current Stimulation Induced Excitability Changes of Primary Visual Cortex and Visual Learning Effects-A Pilot Study.

Studies on noninvasive motor cortex stimulation and motor learning demonstrated cortical excitability as a marker for a learning effect. Transcranial direct current stimulation (tDCS) is a non-invasive tool to modulate cortical excitability. It is as yet unknown how tDCS-induced excitability changes and perceptual learning in visual cortex correlate. Our study aimed to examine the influence of tDCS on visual perceptual learning in healthy humans. Additionally, we measured excitability in primary visual cortex (V1). We hypothesized that anodal tDCS would improve and cathodal tDCS would have minor or no effects on visual learning. Anodal, cathodal or sham tDCS were applied over V1 in a randomized, double-blinded design over four consecutive days (n = 30). During 20 min of tDCS, subjects had to learn a visual orientation-discrimination task (ODT). Excitability parameters were measured by analyzing paired-stimulation behavior of visual-evoked potentials (ps-VEP) and by measuring phosphene thresholds (PTs) before and after the stimulation period of 4 days. Compared with sham-tDCS, anodal tDCS led to an improvement of visual discrimination learning (p < 0.003). We found reduced PTs and increased ps-VEP ratios indicating increased cortical excitability after anodal tDCS (PT: p = 0.002, ps-VEP: p = 0.003). Correlation analysis within the anodal tDCS group revealed no significant correlation between PTs and learning effect. For cathodal tDCS, no significant effects on learning or on excitability could be seen. Our results showed that anodal tDCS over V1 resulted in improved visual perceptual learning and increased cortical excitability. tDCS is a promising tool to alter V1 excitability and, hence, perceptual visual learning.

A complementary role of intracortical inhibition in age-related tactile degradation and its remodelling in humans.

Many attempts are currently underway to restore age-related degraded perception, however, the link between restored perception and remodeled brain function remains elusive. To understand remodeling of age-related cortical reorganization we combined functional magnetic resonance imaging (fMRI) with assessments of tactile acuity, perceptual learning, and computational modeling. We show that aging leads to tactile degradation parallel to enhanced activity in somatosensory cortex. Using a neural field model we reconciled the empirical age-effects by weakening of cortical lateral inhibition. Using perceptual learning, we were able to partially restore tactile acuity, which however was not accompanied by the expected attenuation of cortical activity, but by a further enhancement. The neural field model reproduced these learning effects solely through a weakening of the amplitude of inhibition. These findings suggest that the restoration of age-related degraded tactile acuity on the cortical level is not achieved by re-strengthening lateral inhibition but by further weakening intracortical inhibition.

Neuromagnetic correlates of adaptive plasticity across the hand-face border in human primary somatosensory cortex.

It is well established that permanent or transient reduction of somatosensory inputs, following hand deafferentation or anesthesia, induces plastic changes across the hand-face border, supposedly responsible for some altered perceptual phenomena such as tactile sensations being referred from the face to the phantom hand. It is also known that transient increase of hand somatosensory inputs, via repetitive somatosensory stimulation (RSS) at a fingertip, induces local somatosensory discriminative improvement accompanied by cortical representational changes in the primary somatosensory cortex (SI). We recently demonstrated that RSS at the tip of the right index finger induces similar training-independent perceptual learning across the hand-face border, improving somatosensory perception at the lips (Muret D, Dinse HR, Macchione S, Urquizar C, Farnè A, Reilly KT.Curr Biol24: R736-R737, 2014). Whether neural plastic changes across the hand-face border accompany such remote and adaptive perceptual plasticity remains unknown. Here we used magnetoencephalography to investigate the electrophysiological correlates underlying RSS-induced behavioral changes across the hand-face border. The results highlight significant changes in dipole location after RSS both for the stimulated finger and for the lips. These findings reveal plastic changes that cross the hand-face border after an increase, instead of a decrease, in somatosensory inputs.