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.
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