The human postural coordination mechanism is an example of a complex closed-loop control system based on multisensory integration [9,10,13,14]. In models of this process, sensory data from vestibular, visual, tactile and proprioceptive systems are integrated as linearly additive inputs that drive multiple sensory-motor loops to provide effective coordination of body movement, posture and alignment [5-8, 10, 11]. In the absence of normal vestibular (such as from a toxic drug reaction) and other inputs, unstable posture occurs. This instability may be the result of noise in a functionally open-loop control system [9]. Nonetheless, after sensory loss the brain can utilize tactile information from a sensory substitution system for functional compensation [1-4, 12]. Here we have demonstrated that head-body postural coordination can be restored by means of vestibular substitution using a head-mounted accelerometer and a brain-machine interface that employs a unique pattern of electrotactile stimulation on the tongue. Moreover, postural stability persists for a period of time after removing the vestibular substitution, after which the open-loop instability reappears.
BackgroundVirus-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 FindingsPeptides 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/SignificanceWe 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.
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 (R2 = 0.21), 9-HPT (R2 = 0.41), SIS HF (R2 = 0.27), and SIS ADL (R2 = 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.
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.
Patients with bilateral vestibular loss (BVL) of both central and peripheral origin experience multiple problems with balance and posture control, movement, and abnormal gait.Wicab, Inc. has developed the BrainPort balance device to transmit head position/orientation information normally provided by the vestibular system to the brain through a substitute sensory channel: electrotactile stimulation of the tongue. Head-orientation data (artificially sensed) serves as the input signal for the BrainPort balance device to control the movement of a small pattern of stimulation on the tongue that relates to head position in real-time. With training, the brain learns to appropriately interpret the information from the device and utilize it to function as it would with data from a normal-functioning natural sense. Ina total of 40 subjects trained with the BrainPort, 18 have been tested using standardized quantitative measurements of the treatment effects. A specialized set of exercises, testing, and training procedures has been developed that may serve as the course of intensive physical therapy with the BrainPort balance device. Our results demonstrate consistent positive and statistically significant balance rehabilitation effects independent of aging and etiology of balance deficit.
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