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.

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 ).

Local GABA Concentration Predicts Perceptual Improvements After Repetitive Sensory Stimulation in Humans.

Learning mechanisms are based on synaptic plasticity processes. Numerous studies on synaptic plasticity suggest that the regulation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays a central role maintaining the delicate balance of inhibition and excitation. However, in humans, a link between learning outcome and GABA levels has not been shown so far. Using magnetic resonance spectroscopy of GABA prior to and after repetitive tactile stimulation, we show here that baseline GABA+ levels predict changes in perceptual outcome. Although no net changes in GABA+ are observed, the GABA+ concentration prior to intervention explains almost 60% of the variance in learning outcome. Our data suggest that behavioral effects can be predicted by baseline GABA+ levels, which provide new insights into the role of inhibitory mechanisms during perceptual learning.

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.

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.

Cortical topography of intracortical inhibition influences the speed of decision making.

The neocortex contains orderly topographic maps; however, their functional role remains controversial. Theoretical studies have suggested a role in minimizing computational costs, whereas empirical studies have focused on spatial localization. Using a tactile multiple-choice reaction time (RT) task before and after the induction of perceptual learning through repetitive sensory stimulation, we extend the framework of cortical topographies by demonstrating that the topographic arrangement of intracortical inhibition contributes to the speed of human perceptual decision-making processes. RTs differ among fingers, displaying an inverted U-shaped function. Simulations using neural fields show the inverted U-shaped RT distribution as an emergent consequence of lateral inhibition. Weakening inhibition through learning shortens RTs, which is modeled through topographically reorganized inhibition. Whereas changes in decision making are often regarded as an outcome of higher cortical areas, our data show that the spatial layout of interaction processes within representational maps contributes to selection and decision-making processes.

State-dependent perceptual learning.

Learning constitutes a fundamental property of the human brain-yet an unresolved puzzle is the profound variability of the learning success between individuals. Here we highlight the relevance of individual ongoing brain states as sources of the learning variability in exposure-based somatosensory perceptual learning. Electroencephalogram recordings of ongoing rhythmic brain activity before and during learning revealed that prelearning parietal alpha oscillations as well as during-learning stimulus-induced contralateral central alpha changes are predictive for the learning outcome. These two distinct alpha rhythm sources predicted up to 64% of the observed learning variability, one source representing an idling state with posteroparietal focus and a potential link to the default mode network, the other representing the sensorimotor mu rhythm, whose desynchronization is indicative for the degree of engagement of sensorimotor neuronal populations during application of the learning stimuli. Unspecific effects due to global shifts of attention or vigilance do not explain our observations. Our study thus suggests a brain state-dependency of perceptual learning success in humans opening new avenues for supportive learning tools in the clinical and educational realms.

Synergistic effects of noradrenergic modulation with atomoxetine and 10 Hz repetitive transcranial magnetic stimulation on motor learning in healthy humans.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is able to induce changes in neuronal activity that outlast stimulation. The underlying mechanisms are not completely understood. They might be analogous to long-term potentiation or depression, as the duration of the effects seems to implicate changes in synaptic plasticity. Norepinephrine (NE) has been shown to play a crucial role in neuronal plasticity in the healthy and injured human brain. Atomoxetine (ATX) and other NE reuptake inhibitors have been shown to increase excitability in different systems and to influence learning processes. Thus, the combination of two facilitative interventions may lead to further increase in excitability and motor learning. But in some cases homeostatic metaplasticity might protect the brain from harmful hyperexcitability. In this study, the combination of 60 mg ATX and 10 Hz rTMS over the primary motor cortex was used to examine changes in cortical excitability and motor learning and to investigate their influence on synaptic plasticity mechanisms. RESULTS: The results of this double-blind placebo-controlled study showed that ATX facilitated corticospinal and intracortical excitability in motor cortex. 10 Hertz rTMS applied during a motor task was able to further increase intracortical excitability only in combination with ATX. In addition, only the combination of 10 Hz rTMS and ATX was capable of enhancing the total number of correct responses and reaction time significantly, indicating an interaction effect between rTMS and ATX without signs of homeostatic metaplasticity. CONCLUSION: These results suggest that pharmacologically enhanced NE transmission and 10 Hz rTMS exert a synergistic effect on motor cortex excitability and motor learning in healthy humans.

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.

Increased excitability of somatosensory cortex in aged humans is associated with impaired tactile acuity.

Aging affects all levels of neural processing, including changes of intracortical inhibition and cortical excitability. Paired-pulse stimulation, the application of two stimuli in close succession, is a useful tool to investigate cortical excitability in humans. The paired-pulse behavior is characterized by the second response being significantly suppressed at short stimulus onset asynchronies. While in rat somatosensory cortex, intracortical inhibition has been demonstrated to decline with increasing age, data from human motor cortex of elderly subjects are controversial and there are no data for the human somatosensory cortex (SI). Moreover, behavioral implications of age-related changes of cortical excitability remain elusive. We therefore assessed SI excitability by combining paired-pulse median nerve stimulation with recording somatosensory evoked potentials in 138 healthy subjects aged 17-86 years. We found that paired-pulse suppression was characterized by substantial interindividual variability, but declined significantly with age, confirming reduced intracortical inhibition in elderly subjects. To link the age-related increase of cortical excitability to perceptual changes, we measured tactile two-point discrimination in a subsample of 26 aged participants who showed either low or high paired-pulse suppression. We found that tactile performance was particularly impaired in subjects showing markedly enhanced cortical excitability. Our data demonstrate that paired-pulse suppression of human SI is significantly reduced in older adults, and that age-related enhancement of cortical excitability correlates with degradation of tactile perception. These findings indicate that cortical excitability constitutes an important mechanism that links age-related neurophysiological changes to behavioral alterations in humans.

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.

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.

Improved acuity and dexterity but unchanged touch and pain thresholds following repetitive sensory stimulation of the fingers.

Neuroplasticity underlies the brain's ability to alter perception and behavior through training, practice, or simply exposure to sensory stimulation. Improvement of tactile discrimination has been repeatedly demonstrated after repetitive sensory stimulation (rSS) of the fingers; however, it remains unknown if such protocols also affect hand dexterity or pain thresholds. We therefore stimulated the thumb and index finger of young adults to investigate, besides testing tactile discrimination, the impact of rSS on dexterity, pain, and touch thresholds. We observed an improvement in the pegboard task where subjects used the thumb and index finger only. Accordingly, stimulating 2 fingers simultaneously potentiates the efficacy of rSS. In fact, we observed a higher gain of discrimination performance as compared to a single-finger rSS. In contrast, pain and touch thresholds remained unaffected. Our data suggest that selecting particular fingers modulates the efficacy of rSS, thereby affecting processes controlling sensorimotor integration.

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.

Striatal functional connectivity networks are modulated by fMRI resting state conditions.

Resting state fluctuations in blood oxygenation level dependent functional connectivity magnetic resonance imaging (BOLD fcMRI) time-series have been increasingly employed to study functional connectivity networks in healthy and diseased brain. FcMRI studies have been conducted under a number of different conditions, including resting eyes open, visual fixation and finger tapping. BOLD fcMRI networks are believed to reflect both anatomically constrained spontaneous fluctuations and state-dependent activity. In this study, state-dependence of functional connectivity to dorsal and ventral striatum was assessed with fcMRI during an eyes open resting state condition (REST) and during continuous 3 Hz transcutaneous electrical nerve stimulation (TENS), with the a priori hypotheses: (1) dorsal striatum connectivity with sensorimotor/attention networks will be stronger during TENS compared to REST, (2) ventral striatum connectivity with limbic system emotion-processing network will be weaker during TENS compared to REST and (3) ventral striatum connectivity with sensorimotor/attention networks will be stronger during TENS compared to REST. These hypotheses were confirmed by the results obtained, indicating that resting state BOLD fMRI networks reflect, in substantial measure, state-dependent activity.

Effects of aging on paired-pulse behavior of rat somatosensory cortical neurons.

Aging affects all levels of neural processing including changes of intracortical inhibition and cortical excitability. The paired-pulse stimulation protocol, the application of 2 stimuli in close succession, is used to investigate cortical excitability. The paired-pulse behavior is characterized by the fact that the second response is significantly suppressed at short interstimulus intervals (ISIs) but approaches the first response with increasing ISIs. However, there are controversial reports about the influence of age on paired-pulse behavior. We therefore used pairs of tactile stimuli (ISIs from tens to hundreds of milliseconds) to record extracellular responses of somatosensory cortical neurons of young and aged rats. Paired-pulse behavior was quantified as the ratio of the amplitude of the second response divided by the first. For all ISIs, we found significantly higher ratios in the old animals indicating reduced paired-pulse suppression (PPS). Evaluation of the single response components revealed a significant reduction of the response to the first stimulus for old animals but no age-dependent decrement to the second. Changes in PPS are usually mediated by modulating the second response characteristics. Thus, our data demonstrate reduced PPS due to an overall reduction of the first response as a form of modified PPS developing at old age.

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.

Impaired tactile acuity in old age is accompanied by enlarged hand representations in somatosensory cortex.

The representations of the human hand in primary somatosensory cortex (SI) undergo continuous adaptational plastic processes, which arise from learning, altered use, or injury. The resulting reorganization affects size, extent, and position of the cortical maps, which parallels alterations of tactile behavior indicating a close relationship between map changes and perception. Here we investigate the influence of healthy aging on the cortical hand representation and on age-related changes of tactile performance. Using somatosensory evoked potential mapping in combination with electric source localization, we found that in elderly subjects aged 60-85 years the distance between the dipoles of the index and the little fingers increased indicating an expansion of the representations within SI by approximately 40%. Assessment of tactile spatial 2-point discrimination thresholds in the same subjects showed a strong decline with age. These results indicate that healthy aging strongly affects the homuncular structures of the hand representations within SI. Map expansion typically observed in young and adult subjects during learning is associated with a gain in performance. Whereas learning-related map changes are assumed to result from specific strengthening of synaptic connections, we suggest that the age-related map changes are related to the reduction of intracortical inhibition developing with age.

Repetitive electric stimulation elicits enduring improvement of sensorimotor performance in seniors.

Age-related changes occur on all stages of the human somatosensory pathway, thereby deteriorating tactile, haptic, and sensorimotor performance. However, recent studies show that age-related changes are not irreversible but treatable through peripheral stimulation paradigms based on neuroplasticity mechanisms. We here applied repetitive electric stimulation (rES) to the fingers on a bi-weekly basis for 4 weeks to induce enduring amelioration of age-related changes in healthy individuals aged 60-85 years. Tactile, haptic, and motor performance gradually improved over time of intervention. After termination of rES, tactile acuity recovered to baseline within 2 weeks, while the gains in haptic and motor performance were preserved for 2 weeks. Sham stimulation showed no comparable changes. Our data indicate that age-related decline of sensorimotor performance can be ameliorated by rES and can be stabilized by the repeated application. Thus, long-term application of rES appears as a prime candidate for maintaining sensorimotor functions in elderly individuals.