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.

Individuals with Chronic Mild-to-Moderate Traumatic Brain Injury Exhibit Decreased Neuromuscular Complexity During Gait.

BACKGROUND: Synergy analysis provides a means of quantifying the complexity of neuromuscular control during gait. Prior studies have shown evidence of reduced neuromuscular complexity during gait in individuals with neurological disorders associated with stroke, cerebral palsy, and Parkinson's disease. OBJECTIVE: The purpose of this study was to investigate neuromuscular complexity during gait in individuals who experienced a prior traumatic brain injury (TBI) that resulted in chronic balance deficits. METHODS: We measured and analyzed lower extremity electromyographic data during treadmill and overground walking for 44 individuals with residual balance deficits from a mild-to-moderate TBI at least 1 year prior. We also tested 20 unimpaired controls as a comparison. Muscle synergies were calculated for each limb using non-negative matrix factorization of the activation patterns for 6 leg muscles. We quantified neuromuscular complexity using Walk-DMC, a normalized metric of the total variance accounted for by a single synergy, in which a Walk-DMC score of 100 represents normal variance accounted for. We compared group average synergy structures and inter-limb similarity using cosine similarity. We also quantified each individual's gait and balance using the Sensory Organization Test, the Dynamic Gait Index, and the Six-Minute Walk Test. RESULTS: Neuromuscular complexity was diminished for individuals with a prior TBI. Walk-DMC averaged 92.8 ± 12.3 for the TBI group during overground walking, which was significantly less than seen in controls (100.0 ± 10.0). Individuals with a prior TBI exhibited 13% slower overground walking speeds than controls and reduced performance on the Dynamic Gait Index (18.5 ± 4.7 out of 24). However, Walk-DMC measures were insufficient to stratify variations in assessments of gait and balance performance. Group average synergy structures were similar between groups, although there were considerable between-group differences in the inter-limb similarity of the synergy activation vectors. CONCLUSIONS: Individuals with gait and balance deficits due to a prior TBI exhibit evidence of decreased neuromuscular complexity during gait. Our results suggest that individuals with TBI exhibit similar muscle synergy weightings as controls, but altered control of the temporal activation of these muscle weightings.

The Effect of Reactive Balance Training on Falls in Daily Life: An Updated Systematic Review and Meta-Analysis.

OBJECTIVE: Reactive balance training (RBT) is an emerging approach to reducing falls risk in people with balance impairments. The purpose of this study was to determine the effect of RBT on falls in daily life among individuals at increased risk of falls and to document associated adverse events. METHODS: Databases searched were Ovid MEDLINE (1946 to March 2022), Embase Classic and Embase (1947 to March 2022), Cochrane Central Register of Controlled Trials (2014 to March 2022), and Physiotherapy Evidence Database (PEDro; searched on 22 March 2022). Randomized controlled trials of RBT were included. The literature search was limited to the English language. Records were screened by 2 investigators separately. Outcome measures were number of participants who reported falls after training, number of falls reported after training, and the nature, frequency, and severity of adverse events. Authors of included studies were contacted to obtain additional information. RESULTS: Twenty-nine trials were included, of which 17 reported falls and 21 monitored adverse events. Participants assigned to RBT groups were less likely to fall compared with control groups (fall risk ratio = 0.76; 95% CI = 0.63-0.92; I2 = 32%) and reported fewer falls than control groups (rate ratio = 0.61; 95% CI = 0.45-0.83; I2 = 81%). Prevalence of adverse events was higher in RBT (29%) compared with control groups (20%). CONCLUSION: RBT reduced the likelihood of falls in daily life for older adults and people with balance impairments. More adverse events were reported in RBT than control groups. IMPACT: Balance training that evokes balance reactions can reduce falls among people at increased risk of falls. Older adults and individuals with balance problems were less likely to fall in daily life after participating in RBT compared with traditional balance training. LAY SUMMARY: If you are an older adult and/or have balance problems, your physical therapist may prescribe reactive balance training rather than traditional balance training in order to reduce your likelihood of falling in daily life.

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.

Abnormal muscle activation patterns are associated with chronic gait deficits following traumatic brain injury.

BACKGROUND: Gait and balance disorders are common among individuals who have experienced a mild to moderate traumatic brain injury (TBI). However, little is known about how the neuromuscular control of gait is altered following a TBI. RESEARCH QUESTION: Investigate the relationship between lower limb muscle activation patterns and chronic gait deficits in individuals who previously experienced a mild to moderate TBI. METHODS: Lower extremity electromyographic (EMG) signals were collected bilaterally during treadmill and overground walking in 44 ambulatory individuals with a TBI >1 year prior and 20 unimpaired controls. Activation patterns of TBI muscles were cross-correlated with normative data from control subjects to assess temporal phasing of muscle recruitment. Clinical assessments of gait and balance were performed using dynamic posturography, the dynamic gait index, six-minute walk test, and preferred walking speed. RESULTS: TBI subjects exhibited abnormal activation patterns in the tibialis anterior, medial gastrocnemius, and rectus femoris muscles during both overground and treadmill walking. Activation patterns of the vastus lateralis and soleus muscles did not differ from normal. There was considerable heterogeneity in performance on clinical balance and gait assessments. Abnormal muscle activation patterns were significantly correlated with variations in the dynamic gait index among the TBI subjects. SIGNIFICANCE: Individuals who have experienced a prior TBI do exhibit characteristic changes in the temporal coordination of select lower extremity muscles, which may contribute to impairments during challenging walking tasks.

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.

Brain-Computer Interface Training after Stroke Affects Patterns of Brain-Behavior Relationships in Corticospinal Motor Fibers.

Background: Brain-computer interface (BCI) devices are being investigated for their application in stroke rehabilitation, but little is known about how structural changes in the motor system relate to behavioral measures with the use of these systems. Objective: This study examined relationships among diffusion tensor imaging (DTI)-derived metrics and with behavioral changes in stroke patients with and without BCI training. Methods: Stroke patients (n = 19) with upper extremity motor impairment were assessed using Stroke Impact Scale (SIS), Action Research Arm Test (ARAT), Nine-Hole Peg Test (9-HPT), and DTI scans. Ten subjects completed four assessments over a control period during which no training was administered. Seventeen subjects, including eight who completed the control period, completed four assessments over an experimental period during which subjects received interventional BCI training. Fractional anisotropy (FA) values were extracted from each corticospinal tract (CST) and transcallosal motor fibers for each scan. Results: No significant group by time interactions were identified at the group level in DTI or behavioral measures. During the control period, increases in contralesional CST FA and in asymmetric FA (aFA) correlated with poorer scores on SIS and 9-HPT. During the experimental period (with BCI training), increases in contralesional CST FA were correlated with improvements in 9-HPT while increases in aFA correlated with improvements in ARAT but with worsening 9-HPT performance; changes in transcallosal motor fibers positively correlated with those in the contralesional CST. All correlations p < 0.05 corrected. Conclusion: These findings suggest that the integrity of the contralesional CST may be used to track individual behavioral changes observed with BCI training after stroke.

Dose-response relationships using brain-computer interface technology impact stroke rehabilitation.

Brain-computer interfaces (BCIs) are an emerging novel technology for stroke rehabilitation. Little is known about how dose-response relationships for BCI therapies affect brain and behavior changes. We report preliminary results on stroke patients (n = 16, 11 M) with persistent upper extremity motor impairment who received therapy using a BCI system with functional electrical stimulation of the hand and tongue stimulation. We collected MRI scans and behavioral data using the Action Research Arm Test (ARAT), 9-Hole Peg Test (9-HPT), and Stroke Impact Scale (SIS) before, during, and after the therapy period. Using anatomical and functional MRI, we computed Laterality Index (LI) for brain activity in the motor network during impaired hand finger tapping. Changes from baseline LI and behavioral scores were assessed for relationships with dose, intensity, and frequency of BCI therapy. We found that gains in SIS Strength were directly responsive to BCI therapy: therapy dose and intensity correlated positively with increased SIS Strength (p ≤ 0.05), although no direct relationships were identified with ARAT or 9-HPT scores. We found behavioral measures that were not directly sensitive to differences in BCI therapy administration but were associated with concurrent brain changes correlated with BCI therapy administration parameters: therapy dose and intensity showed significant (p ≤ 0.05) or trending (0.05 < p < 0.1) negative correlations with LI changes, while therapy frequency did not affect LI. Reductions in LI were then correlated (p ≤ 0.05) with increased SIS Activities of Daily Living scores and improved 9-HPT performance. Therefore, some behavioral changes may be reflected by brain changes sensitive to differences in BCI therapy administration, while others such as SIS Strength may be directly responsive to BCI therapy administration. Data preliminarily suggest that when using BCI in stroke rehabilitation, therapy frequency may be less important than dose and intensity.

DTI measures track and predict motor function outcomes in stroke rehabilitation utilizing BCI technology.

Tracking and predicting motor outcomes is important in determining effective stroke rehabilitation strategies. Diffusion tensor imaging (DTI) allows for evaluation of the underlying structural integrity of brain white matter tracts and may serve as a potential biomarker for tracking and predicting motor recovery. In this study, we examined the longitudinal relationship between DTI measures of the posterior limb of the internal capsule (PLIC) and upper-limb motor outcomes in 13 stroke patients (median 20-month post-stroke) who completed up to 15 sessions of intervention using brain-computer interface (BCI) technology. Patients' upper-limb motor outcomes and PLIC DTI measures including fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were assessed longitudinally at four time points: pre-, mid-, immediately post- and 1-month-post intervention. DTI measures and ratios of each DTI measure comparing the ipsilesional and contralesional PLIC were correlated with patients' motor outcomes to examine the relationship between structural integrity of the PLIC and patients' motor recovery. We found that lower diffusivity and higher FA values of the ipsilesional PLIC were significantly correlated with better upper-limb motor function. Baseline DTI ratios were significantly correlated with motor outcomes measured immediately post and 1-month-post BCI interventions. A few patients achieved improvements in motor recovery meeting the minimum clinically important difference (MCID). These findings suggest that upper-limb motor recovery in stroke patients receiving BCI interventions relates to the microstructural status of the PLIC. Lower diffusivity and higher FA measures of the ipsilesional PLIC contribute toward better motor recovery in the stroke-affected upper-limb. DTI-derived measures may be a clinically useful biomarker in tracking and predicting motor recovery in stroke patients receiving BCI interventions.

Changes in functional brain organization and behavioral correlations after rehabilitative therapy using a brain-computer interface.

This study aims to examine the changes in task-related brain activity induced by rehabilitative therapy using brain-computer interface (BCI) technologies and whether these changes are relevant to functional gains achieved through the use of these therapies. Stroke patients with persistent upper-extremity motor deficits received interventional rehabilitation therapy using a closed-loop neurofeedback BCI device (n = 8) or no therapy (n = 6). Behavioral assessments using the Stroke Impact Scale, the Action Research Arm Test (ARAT), and the Nine-Hole Peg Test (9-HPT) as well as task-based fMRI scans were conducted before, during, after, and 1 month after therapy administration or at analogous intervals in the absence of therapy. Laterality Index (LI) values during finger tapping of each hand were calculated for each time point and assessed for correlation with behavioral outcomes. Brain activity during finger tapping of each hand shifted over the course of BCI therapy, but not in the absence of therapy, to greater involvement of the non-lesioned hemisphere (and lesser involvement of the stroke-lesioned hemisphere) as measured by LI. Moreover, changes from baseline LI values during finger tapping of the impaired hand were correlated with gains in both objective and subjective behavioral measures. These findings suggest that the administration of interventional BCI therapy can induce differential changes in brain activity patterns between the lesioned and non-lesioned hemispheres and that these brain changes are associated with changes in specific motor functions.

Characterizing relationships of DTI, fMRI, and motor recovery in stroke rehabilitation utilizing brain-computer interface technology.

The relationship of the structural integrity of white matter tracts and cortical activity to motor functional outcomes in stroke patients is of particular interest in understanding mechanisms of brain structural and functional changes while recovering from stroke. This study aims to probe these underlying mechanisms using diffusion tensor imaging (DTI) and fMRI measures. We examined the structural integrity of the posterior limb of the internal capsule (PLIC) using DTI and corticomotor activity using motor-task fMRI in stroke patients who completed up to 15 sessions of rehabilitation therapy using Brain-Computer Interface (BCI) technology. We hypothesized that (1) the structural integrity of PLIC and corticomotor activity are affected by stroke; (2) changes in structural integrity and corticomotor activity following BCI intervention are related to motor recovery; (3) there is a potential relationship between structural integrity and corticomotor activity. We found that (1) the ipsilesional PLIC showed significantly decreased fractional anisotropy (FA) values when compared to the contralesional PLIC; (2) lower ipsilesional PLIC-FA values were significantly associated with worse motor outcomes (i.e., ipsilesional PLIC-FA and motor outcomes were positively correlated.); (3) lower ipsilesional PLIC-FA values were significantly associated with greater ipsilesional corticomotor activity during impaired-finger-tapping-task fMRI (i.e., ipsilesional PLIC-FA and ipsilesional corticomotor activity were negatively correlated), with an overall bilateral pattern of corticomotor activity observed; and (4) baseline FA values predicted motor recovery assessed after BCI intervention. These findings suggest that (1) greater vs. lesser microstructural integrity of the ipsilesional PLIC may contribute toward better vs. poor motor recovery respectively in the stroke-affected limb and demand lesser vs. greater cortical activity respectively from the ipsilesional motor cortex; and that (2) PLIC-FA is a promising biomarker in tracking and predicting motor functional recovery in stroke patients receiving BCI intervention.

Case report: post-stroke interventional BCI rehabilitation in an individual with preexisting sensorineural disability.

Therapies involving new technologies such as brain-computer interfaces (BCI) are being studied to determine their potential for interventional rehabilitation after acute events such as stroke produce lasting impairments. While studies have examined the use of BCI devices by individuals with disabilities, many such devices are intended to address a specific limitation and have been studied when this limitation or disability is present in isolation. Little is known about the therapeutic potential of these devices for individuals with multiple disabilities with an acquired impairment overlaid on a secondary long-standing disability. We describe a case in which a male patient with congenital deafness suffered a right pontine ischemic stroke, resulting in persistent weakness of his left hand and arm. This patient volunteer completed four baseline assessments beginning at 4 months after stroke onset and subsequently underwent 6 weeks of interventional rehabilitation therapy using a closed-loop neurofeedback BCI device with visual, functional electrical stimulation, and tongue stimulation feedback modalities. Additional assessments were conducted at the midpoint of therapy, upon completion of therapy, and 1 month after completing all BCI therapy. Anatomical and functional MRI scans were obtained at each assessment, along with behavioral measures including the Stroke Impact Scale (SIS) and the Action Research Arm Test (ARAT). Clinically significant improvements in behavioral measures were noted over the course of BCI therapy, with more than 10 point gains in both the ARAT scores and scores for the SIS hand function domain. Neuroimaging during finger tapping of the impaired hand also showed changes in brain activation patterns associated with BCI therapy. This case study demonstrates the potential for individuals who have preexisting disability or possible atypical brain organization to learn to use a BCI system that may confer some rehabilitative benefit.

Changes in functional connectivity correlate with behavioral gains in stroke patients after therapy using a brain-computer interface device.

Brain-computer interface (BCI) technology is being incorporated into new stroke rehabilitation devices, but little is known about brain changes associated with its use. We collected anatomical and functional MRI of nine stroke patients with persistent upper extremity motor impairment before, during, and after therapy using a BCI system. Subjects were asked to perform finger tapping of the impaired hand during fMRI. Action Research Arm Test (ARAT), 9-Hole Peg Test (9-HPT), and Stroke Impact Scale (SIS) domains of Hand Function (HF) and Activities of Daily Living (ADL) were also assessed. Group-level analyses examined changes in whole-brain task-based functional connectivity (FC) to seed regions in the motor network observed during and after BCI therapy. Whole-brain FC analyses seeded in each thalamus showed FC increases from baseline at mid-therapy and post-therapy (p < 0.05). Changes in FC between seeds at both the network and the connection levels were examined for correlations with changes in behavioral measures. Average motor network FC was increased post-therapy, and changes in average network FC correlated (p < 0.05) with changes in performance on ARAT (R (2) = 0.21), 9-HPT (R (2) = 0.41), SIS HF (R (2) = 0.27), and SIS ADL (R (2) = 0.40). Multiple individual connections within the motor network were found to correlate in change from baseline with changes in behavioral measures. Many of these connections involved the thalamus, with change in each of four behavioral measures significantly correlating with change from baseline FC of at least one thalamic connection. These preliminary results show changes in FC that occur with the administration of rehabilitative therapy using a BCI system. The correlations noted between changes in FC measures and changes in behavioral outcomes indicate that both adaptive and maladaptive changes in FC may develop with this therapy and also suggest a brain-behavior relationship that may be stimulated by the neuromodulatory component of BCI therapy.

The use of hybrid virus-like particles to enhance the immunogenicity of a broadly protective HPV vaccine.

Virus-like particles (VLPs) can serve as a highly immunogenic vaccine platform for the multivalent display of epitopes from pathogens. We have used bacteriophage VLPs to develop vaccines that target a highly conserved epitope from the human papillomavirus (HPV) minor capsid protein, L2.VLPs displaying an L2-peptide from HPV16 elicit antibodies that broadly neutralize infection by HPV types associated with the development of cervical cancer. To broaden the cross-neutralization further, we have developed a strategy to display two different peptides on a single, hybrid VLP in a multivalent, highly immunogenic fashion. In general, hybrid VLPs elicited high-titer antibody responses against both targets, although in one case we observed an immunodominant response against only one of the displayed epitopes. Immunization with hybrid particles elicited antibodies that were able to neutralize heterologous HPV types at higher titers than those elicited by particles displaying one epitope alone, indicating that the hybrid VLP approach may be an effective technique to target epitopes that undergo antigenic variation.

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.

Immunization with a consensus epitope from human papillomavirus L2 induces antibodies that are broadly neutralizing.

Vaccines targeting conserved epitopes in the HPV minor capsid protein, L2, can elicit antibodies that can protect against a broad spectrum of HPV types that are associated with cervical cancer and other HPV malignancies. Thus, L2 vaccines have been explored as alternatives to the current HPV vaccines, which are largely type-specific. In this study we assessed the immunogenicity of peptides spanning the N-terminal domain of L2 linked to the surface of a highly immunogenic bacteriophage virus-like particle (VLP) platform. Although all of the HPV16 L2 peptide-displaying VLPs elicited high-titer anti-peptide antibody responses, only a subset of the immunogens elicited antibody responses that were strongly protective from HPV16 pseudovirus (PsV) infection in a mouse genital challenge model. One of these peptides, mapping to HPV16 L2 amino acids 65-85, strongly neutralized HPV16 PsV but showed little ability to cross-neutralize other high-risk HPV types. In an attempt to broaden the protection generated through vaccination with this peptide, we immunized mice with VLPs displaying a peptide that represented a consensus sequence from high-risk and other HPV types. Vaccinated mice produced antibodies with broad, high-titer neutralizing activity against all of the HPV types that we tested. Therefore, immunization with virus-like particles displaying a consensus HPV sequence is an effective method to broaden neutralizing antibody responses against a type-specific epitope.

Miniature ambulatory skin conductance monitor and algorithm for investigating hot flash events.

A skin conductance monitoring system was developed and shown to reliably acquire and record hot flash events in both supervised laboratory and unsupervised ambulatory conditions. The 7.2 × 3.8 × 1.2 cm(3) monitor consists of a disposable adhesive patch supporting two hydrogel electrodes and a reusable, miniaturized, enclosed electronic circuit board that snaps onto the electrodes. The monitor measures and records the skin conductance for seven days without external wires or telemetry and has an event marker that the subject can press whenever a hot flash is experienced. The accuracy of the system was demonstrated by comparing the number of hot flashes detected by algorithms developed during this research with the number identified by experts in hot flash studies. Three methods of detecting hot flash events were evaluated, but only two were fully developed. The two that were developed were an artificial neural network and a matched filter technique with multiple kernels implemented as a sliding form of the Pearson product-moment correlation coefficient. Both algorithms were trained on a 'development' cohort of 17 women and then validated using a second similar 'validation' cohort of 20. All subjects were between the ages of 40 and 60 and self-reported ten or more hot flashes per day over a three day period. The matched filter was the most accurate with a mean sensitivity of 0.92 and a mean specificity of 0.90 using the data from the development cohort and a mean sensitivity of 0.92 and a mean specificity of 0.87 using the data from the validation cohort. The matched filter was the method implemented in our processing software.

Second-generation prophylactic HPV vaccines: successes and challenges.

The role of HPV as the causative factor in cervical cancer has led to the development of the HPV vaccines Gardasil and Cervarix. These vaccines effectively protect against two HPV types associated with 70% of cervical cancer cases. Despite this success, researchers continue to develop second-generation HPV vaccines to protect against more HPV types and allow increased uptake in developing countries. While a reformulated vaccine based on the current technology is currently in clinical trials, another strategy consists of targeting highly conserved epitopes in the minor capsid protein of HPV, L2. Vaccines targeting L2 induce broadly neutralizing antibodies, capable of blocking infection by a wide range of HPV types. Several vaccine designs have been developed to optimize the display of L2 epitopes to the immune system and to reduce the cost of manufacture and distribution. L2-based vaccines show considerable promise as a potential next-generation HPV vaccine.

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.

VLPs displaying a single L2 epitope induce broadly cross-neutralizing antibodies against human papillomavirus.

BACKGROUND: Virus-like Particles (VLPs) display can be used to increase the immunogenicity of heterologous antigens. Here, we report the use of a bacteriophage MS2-based VLP display platform to develop a monovalent vaccine targeting a broadly neutralizing epitope in the minor capsid protein human papillomavirus (HPV) that provides broad protection from diverse HPV types in a mouse pseudovirus infection model. METHODOLOGY/PRINCIPAL FINDINGS: Peptides spanning a previously described cross-neutralizing epitope from HPV type 16 were genetically inserted at the N-terminus of MS2 bacteriophage coat protein. Three of the four recombinant L2-coat proteins assembled into VLPs. L2-VLPs elicited high-titer anti-L2 antibodies in mice, similar to recombinant VLPs that we had previously made in which the L2 peptide was displayed on a surface-exposed loop on VLPs of a related bacteriophage, PP7. Somewhat surprisingly, L2-MS2 VLPs elicited antibodies that were much more broadly cross-reactive with L2 peptides from diverse HPV isolates than L2-PP7 VLPs. Similarly, mice immunized with L2-MS2 VLPs were protected from genital and cutaneous infection by highly diverse HPV pseudovirus types. CONCLUSION/SIGNIFICANCE: We show that peptides can be displayed in a highly immunogenic fashion at the N-terminus of MS2 coat protein VLPs. A VLP-based vaccine targeting HPV L2 elicits broadly cross-reactive and cross-protective antibodies to heterologous HPV types. L2-VLPs could serve as the basis of a broadly protective second generation HPV vaccine.