Translingual neural stimulation affects resting-state functional connectivity in mild-moderate traumatic brain injury.

BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) can lead to movement and balance deficits. In addition to physical therapy, brain-based neurorehabilitation efforts have begun to show promise in improving these deficits. The present study investigated the effectiveness of translingual neural stimulation (TLNS) on patients with mild-to-moderate TBI (mmTBI) and related brain connectivity using a resting-state functional connectivity (RSFC) approach. METHODS: Resting-state images with 5-min on GE750 3T scanner were acquired from nine participants with mmTBI. Paired t-test was used for calculating changes in RSFC and behavioral scores before and after the TLNS intervention. The balance and movement performances related to mmTBI were evaluated by Sensory Organization Test (SOT) and Dynamic Gait Index (DGI). RESULTS: Compared to pre-TLNS intervention, significant behavioral changes in SOT and DGI were observed. The analysis revealed increased RSFC between the left postcentral gyrus and left inferior parietal lobule and left Brodmann Area 40, as well as the increased RSFC between the right culmen and right declive, indicating changes due to TLNS treatment. However, there were no correlations between the sensory/somatomotor (or visual or cerebellar) network and SOT/DGI behavioral performance. CONCLUSIONS: Although the limited sample size may have led to lack of significant correlations with functional assessments, these results provide preliminary evidence that TLNS in conjunction with physical therapy can induce brain plasticity in TBI patients with balance and movement deficits.

Translingual Neurostimulation for the Treatment of Chronic Symptoms Due to Mild-to-Moderate Traumatic Brain Injury.

OBJECTIVE: To compare the efficacy of high- and low-frequency noninvasive translingual neurostimulation (TLNS) plus targeted physical therapy (PT) for treating chronic balance and gait deficits due to mild-to-moderate traumatic brain injury (mmTBI). DESIGN: Participants were randomized 1:1 in a 26-week double-blind phase 1/2 study (NCT02158494) with 3 consecutive treatment stages: in-clinic, at-home, and no treatment. Arms were high-frequency pulse (HFP) and low-frequency pulse (LFP) TLNS. SETTING: TLNS plus PT training was initiated in-clinic and then continued at home. PARTICIPANTS: Participants (N=44; 18-65y) from across the United States were randomized into the HFP and LFP (each plus PT) arms. Forty-three participants (28 women, 15 men) completed at least 1 stage of the study. Enrollment requirements included an mmTBI ≥1 year prior to screening, balance disorder due to mmTBI, a plateau in recovery with current PT, and a Sensory Organization Test (SOT) score ≥16 points below normal. INTERVENTIONS: Participants received TLNS (HFP or LFP) plus PT for a total of 14 weeks (2 in-clinic and 12 at home), twice daily, followed by 12 weeks without treatment. MAIN OUTCOME MEASURES: The primary endpoint was change in SOT composite score from baseline to week 14. Secondary variables (eg, Dynamic Gait Index [DGI], 6-minute walk test [6MWT]) were also collected. RESULTS: Both arms had a significant (P<.0001) improvement in SOT scores from baseline at weeks 2, 5, 14 (primary endpoint), and 26. DGI scores had significant improvement (P<.001-.01) from baseline at the same test points; 6MWT evaluations after 2 weeks were significant. The SOT, DGI, and 6MWT scores did not significantly differ between arms at any test point. There were no treatment-related serious adverse events. CONCLUSIONS: Both the HFP+PT and LFP+PT groups had significantly improved balance scores, and outcomes were sustained for 12 weeks after discontinuing TLNS treatment. Results between arms did not significantly differ from each other. Whether the 2 dosages are equally effective or whether improvements are because of provision of PT cannot be conclusively established at this time.

Interaction of Perceived Frequency and Intensity in Fingertip Electrotactile Stimulation: Dissimilarity Ratings and Multidimensional Scaling.

Sensations elicited by electrical stimulation of touch are multidimensional, varying in perceived intensity and quality in response to changes in stimulus current or waveform timing. This paper manipulated both current and frequency, while volunteer participants estimated the dissimilarity of all non-identical pairs of 16 stimulus conditions. Multidimensional scaling analysis revealed that a model having two perceptual dimensions was adequate in representing the electrotactile (electrocutaneous) sensations. The two dimensions were identified as perceptual frequency and intensity, and were strongly correlated with the two stimulus variables, frequency and current, although not in a 1:1 correspondence. Perception of frequency differences increased monotonically with stimulus intensity, which is consistent with other human sensory systems, such as hearing and vision. Our results are consistent with previously-reported research using a different methodology and cutaneous locus. Congruence across different methods and laboratories suggests similar underlying perceptual mechanisms.

Non-invasive neuromodulation to improve gait in chronic multiple sclerosis: a randomized double blind controlled pilot trial.

BACKGROUND: This study sought to examine the effect of targeted physical therapy with and without cranial nerve non-invasive neuromodulation (CN-NINM), on the walking ability of people with MS who exhibited a dysfunctional gait. We hypothesized that subjects who received electrical stimulation would have greater improvement than those who had a control device after a 14-week intervention. Gait disturbance is a common problem for people with multiple sclerosis (MS). Current management may include exercise, pharmacology, functional electrical stimulation, compensatory strategies, use of assistive devices, and implanted electrical devices. We have developed an effective rehabilitative strategy using neuromodulation of the cranial nerves via electrical stimulation of the tongue to enhance the plasticity of the brain. METHODS: The study is a within-subject blinded randomized control design. Twenty chronic MS subjects with an identified gait disturbance were assigned to either an active or control group. Both groups completed a 14-week intervention program using a standardized combination of exercise and a device that provided electrical stimulation to the tongue. Those in the active group received electrical stimulation on the tongue that they could perceive. Those in the control group used a device that did not provide a physiologically significant stimulus and was not perceivable. Subjects were assessed with the Dynamic Gait Index (DGI). RESULTS: The DGI scores improved for both groups. There were significant between-group differences, with the active group showing statistically greater improvement than the control group mean. CONCLUSION: People with MS demonstrated improved gait with CN-NINM training in a pilot randomized controlled trial. This study suggests that tongue-based neurostimulation may amplify the benefits of exercise for improving gait in people with chronic MS.

Altered connectivity of the balance processing network after tongue stimulation in balance-impaired individuals.

Some individuals with balance impairment have hypersensitivity of the motion-sensitive visual cortices (hMT+) compared to healthy controls. Previous work showed that electrical tongue stimulation can reduce the exaggerated postural sway induced by optic flow in this subject population and decrease the hypersensitive response of hMT+. Additionally, a region within the brainstem (BS), likely containing the vestibular and trigeminal nuclei, showed increased optic flow-induced activity after tongue stimulation. The aim of this study was to understand how the modulation induced by tongue stimulation affects the balance-processing network as a whole and how modulation of BS structures can influence cortical activity. Four volumes of interest, discovered in a general linear model analysis, constitute major contributors to the balance-processing network. These regions were entered into a dynamic causal modeling analysis to map the network and measure any connection or topology changes due to the stimulation. Balance-impaired individuals had downregulated response of the primary visual cortex (V1) to visual stimuli but upregulated modulation of the connection between V1 and hMT+ by visual motion compared to healthy controls (p ≤ 1E-5). This upregulation was decreased to near-normal levels after stimulation. Additionally, the region within the BS showed increased response to visual motion after stimulation compared to both prestimulation and controls. Stimulation to the tongue enters the central nervous system at the BS but likely propagates to the cortex through supramodal information transfer. We present a model to explain these brain responses that utilizes an anatomically present, but functionally dormant pathway of information flow within the processing network.

High-resolution fMRI detects neuromodulation of individual brainstem nuclei by electrical tongue stimulation in balance-impaired individuals.

High-resolution functional magnetic resonance imaging (fMRI) can be used to precisely identify blood oxygen level dependent (BOLD) activation of small structures within the brainstem not accessible with standard fMRI. A previous study identified a region within the pons exhibiting sustained neuromodulation due to electrical tongue stimulation, but was unable to precisely identify the neuronal structure involved. For this study, high-resolution images of neural activity induced by optic flow were acquired in nine healthy controls and nine individuals with balance dysfunction before and after information-free tongue stimulation. Subjects viewed optic flow videos to activate the structures of interest. Sub-millimeter in-plane voxels of structures within the posterior fossa were acquired using a restricted field of view. Whole-brain functional imaging verified that global activation patterns due to optic flow were consistent with previous studies. Optic flow activated the visual association cortices, the vestibular nuclei, and the superior colliculus, as well as multiple regions within the cerebellum. The anterior cingulate cortex showed decreased activity after stimulation, while a region within the pons had increased post-stimulation activity. These observations suggest the pontine region is the trigeminal nucleus and that tongue stimulation interfaces with the balance-processing network within the pons. This high-resolution imaging allows detection of activity within individual brainstem nuclei not possible using standard resolution imaging.

Electrical tongue stimulation normalizes activity within the motion-sensitive brain network in balance-impaired subjects as revealed by group independent component analysis.

Multivariate analysis of functional magnetic resonance imaging (fMRI) data allows investigations into network behavior beyond simple activations of individual regions. We apply group independent component analysis to fMRI data collected in a previous study looking at the sustained neuromodulatory effects of electrical tongue stimulation in balance-impaired individuals. Twelve subjects with balance disorders viewed optic flow in an fMRI scanner before and after 5 days of electrical tongue stimulation. Nine healthy controls also viewed the visual stimuli but did not receive any stimulation. Multiple regression of the 47 estimated components found two that were modulated by the visual stimuli. Component 7, comprised primarily of the primary visual cortex (V1), responded to all visual stimuli and showed no difference in task-related activity between the healthy controls and the balance-impaired subjects before or after stimulation. Component 11 responded only to motion in the visual field and contained multiple cortical and subcortical regions involved in processing information pertinent to balance. Two-sample t-tests of the calculated signal change revealed that the task-related activity of this network is greater in balance-impaired subjects compared with controls before stimulation (p=0.02), but that this network hypersensitivity decreases after electrical tongue stimulation (p=0.001).

Sustained cortical and subcortical neuromodulation induced by electrical tongue stimulation.

This pilot study aimed to show that information-free stimulation of the tongue can improve behavioral measures and induce sustained neuromodulation of the balance-processing network in individuals with balance dysfunction. Twelve balance-impaired subjects received one week of cranial nerve non-invasive neuromodulation (CN-NINM). Before and after the week of stimulation, postural sway and fMRI activation were measured to monitor susceptibility to optic flow. Nine normal controls also underwent the postural sway and fMRI tests but did not receive CN-NINM. Results showed that before CN-NINM balance-impaired subjects swayed more than normal controls as expected (p ≤ 0.05), and that overall sway and susceptibility to optic flow decreased after CN-NINM (p ≤ 0.005 & p ≤ 0.05). fMRI showed upregulation of visual sensitivity to optic flow in balance-impaired subjects that decreased after CN-NINM. A region of interest analysis indicated that CN-NINM may induce neuromodulation by increasing activity within the dorsal pons (p ≤ 0.01).

Electrotactile stimulation on the tongue: Intensity perception, discrimination, and cross-modality estimation.

Due to its high sensitivity and conductivity, electrotactile stimulation (ETS) on the tongue has proven to be a useful and technically convenient tool to substitute and/or augment sensory capabilities. However, most of its applications have only provided spatial attributes and little is known about (a) the ability of the tongue's sensory system to process electrical stimuli of varying magnitudes and (b) how modulation of ETS intensity affects subjects' ability to decode stimulus intensity. We addressed these questions by quantifying: (1) the magnitude of the dynamic range (DR; maximal comfortable intensity/perception threshold) and its sensitivity to prolonged exposure; (2) subjects' ability to perceive intensity changes; and (3) subjects' ability to associate intensity with angular excursions of a protractor's handle. We found that the average DR (17 dB) was generally large in comparison with other tactile loci and of a relatively constant magnitude among subjects, even after prolonged exposure, despite a slight but significant upward drift (p < 0.001). Additionally, our results showed that as stimulus intensity increased, subjects' ability to discriminate ETS stimuli of different intensities improved (p < 0.05) while estimation accuracy, in general, slightly decreased (increasing underestimation). These results suggest that higher ETS intensity may increase recruitment of rapidly adapting mechanoreceptor fibers, as these are specialized for coding stimulus differences rather than absolute intensities. Furthermore, our study revealed that the tongue's sensory system can effectively convey electrical stimuli despite minimal practice and when information transfer is limited by memory and DR drift.

A high-voltage bipolar transconductance amplifier for electrotactile stimulation.

This paper describes a high-performance transconductance amplifier specifically designed for electrotactile (electrocutaneous) stimulation. It enables voltages up to +/-600 V to be produced at the output that will allow the psychophysiological performance associated with stimulation of the fingertip using various stimulation waveforms to be studied more thoroughly. The design has a transconductance of up to 20 mA/V, an 8.8-Momega output resistance, and can provide output currents up to +/-20 mA. A complete schematic diagram is presented along with a discussion of theory of operation and safety issues as well as performance and derating plots from the implemented design.

Polarity effect in electrovibration for tactile display.

Electrovibration is the tactile sensation of an alternating potential between the human body and a smooth conducing surface when the skin slides over the surface and where the current is too small to stimulate sensory nerves directly. It has been proposed as a high-density tactile display method, for example to display pictographic information to persons who are blind. Previous models for the electrovibration transduction mechanism are based on a parallel-plate capacitor in which the electrostatic force is insensitive to polarity. We present experimental data showing that electrovibratory perceptual sensitivity to positive pulses is less than that for negative or biphasic pulses and propose that this disparity may be due to the asymmetric electrical properties of human skin. We furthermore propose using negative pulses for insulated tactile displays based on electrovibration because their sensory thresholds were found to be more stable than for waveforms incorporating positive pulses.

Pattern identification as a function of stimulation current on a fingertip-scanned electrotactile display.

Two studies were conducted to determine the effect of stimulation current on pattern perception on a 49-point fingertip-scanned electrotactile (electrocutaneous) display. Performance increased monotonically from near chance levels at the lowest sub-threshold current levels tested to approximately 90% at the highest comfortable current levels. This suggests the existence of a tradeoff between spatial performance and usable "gray scale" range in electrotactile presentation of graphical information.

Pattern identification and perceived stimulus quality as a function of stimulation waveform on a fingertip-scanned electrotactile display.

The effect of stimulation waveform on pattern perception was investigated on a 49-point fingertip-scanned electrotactile (electrocutaneous) display. Waveform variables burst frequency (F), number of pulses per burst (NPB), and pulse repetition rate (PRR) were varied in a factorial design. Contrast reduction was used to limit performance of perceiving a 1-tactor gap defined within a 3 x 3 tactor outline square. All three variables accounted for significant variations in performance with higher levels of F and NPB and lower levels of PRR, leading to better performance. In addition, we collected qualitative data on each waveform, and the qualitative differences were related to performance (e.g., waveforms perceived as having a more localized sensation were correlated with better pattern identification performance than those waveforms perceived as more broad). We also investigated the effect of stimulation contrast on pattern perception.