The miR-17 family of microRNAs has recently been recognized for its importance during lung development. The transgenic overexpression of the entire miR-17-92 cluster in the lung epithelium led to elevated cellular proliferation and inhibition of differentiation, while targeted deletion of miR-17-92 and miR-106b-25 clusters showed embryonic or early post-natal lethality. Herein we demonstrate that miR-17 and its paralogs, miR-20a, and miR-106b, are highly expressed during the pseudoglandular stage and identify their critical functional role during embryonic lung development. Simultaneous downregulation of these three miRNAs in explants of isolated lung epithelium altered FGF10 induced budding morphogenesis, an effect that was rescued by synthetic miR-17. E-Cadherin levels were reduced, and its distribution was altered by miR-17, miR-20a and miR-106b downregulation, while conversely, beta-catenin activity was augmented, and expression of its downstream targets, including Bmp4 as well as Fgfr2b, increased. Finally, we identified Stat3 and Mapk14 as key direct targets of miR-17, miR-20a, and miR-106b and showed that simultaneous overexpression of Stat3 and Mapk14 mimics the alteration of E-Cadherin distribution observed after miR-17, miR-20a, and miR-106b downregulation. We conclude that the mir-17 family of miRNA modulates FGF10-FGFR2b downstream signaling by specifically targeting Stat3 and Mapk14, hence regulating E-Cadherin expression, which in turn modulates epithelial bud morphogenesis in response to FGF10 signaling.

Stroke is a leading cause of acquired disability resulting in distal upper extremity functional motor impairment. Stroke mortality rates continue to decline with advances in healthcare and medical technology. This has led to an increased demand for advanced, personalized rehabilitation. Survivors often experience some level of spontaneous recovery shortly after their stroke event; yet reach a functional plateau after which there is exiguous motor recovery. Nevertheless, studies have demonstrated the potential for recovery beyond this plateau. Non-traditional neurorehabilitation techniques, such as those incorporating the brain-computer interface (BCI), are being investigated for rehabilitation. BCIs may offer a gateway to the brain’s plasticity and revolutionize how humans interact with the world. Non-invasive BCIs work by closing the proprioceptive feedback loop with real-time, multi-sensory feedback allowing for volitional modulation of brain signals to assist hand function. BCI technology potentially promotes neuroplasticity and Hebbian-based motor recovery by rewarding cortical activity associated with sensory-motor rhythms through use with a variety of self-guided and assistive modalities.

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.

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.

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.

Loss of motor function is a common deficit following stroke insult and often manifests as persistent upper extremity (UE) disability which can affect a survivor’s ability to participate in activities of daily living. Recent research suggests the use of brain–computer interface (BCI) devices might improve UE function in stroke survivors at various times since stroke. This randomized crossover-controlled trial examines whether intervention with this BCI device design attenuates the effects of hemiparesis, encourages reorganization of motor related brain signals (EEG measured sensorimotor rhythm desynchronization), and improves movement, as measured by the Action Research Arm Test (ARAT). A sample of 21 stroke survivors, presenting with varied times since stroke and levels of UE impairment, received a maximum of 18–30 h of intervention with a novel electroencephalogram-based BCI-driven functional electrical stimulator (EEG-BCI-FES) device. Driven by spectral power recordings from contralateral EEG electrodes during cued attempted grasping of the hand, the user’s input to the EEG-BCI-FES device modulates horizontal movement of a virtual cursor and also facilitates concurrent stimulation of the impaired UE. Outcome measures of function and capacity were assessed at baseline, mid-therapy, and at completion of therapy while EEG was recorded only during intervention sessions. A significant increase in r-squared values [reflecting Mu rhythm (8–12 Hz) desynchronization as the result of attempted movements of the impaired hand] presented post-therapy compared to baseline. These findings suggest that intervention corresponds with greater desynchronization of Mu rhythm in the ipsilesional hemisphere during attempted movements of the impaired hand and this change is related to changes in behavior as a result of the intervention. BCI intervention may be an effective way of addressing the recovery of a stroke impaired UE and studying neuromechanical coupling with motor outputs.Clinical Trial Registration: ClinicalTrials.gov, identifier NCT02098265.

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.