Neurogenic and pericytic plasticity of conditionally immortalized cells derived from renal erythropoietin-producing cells.

In adult mammals, the kidney is the main source of circulating erythropoietin (Epo), the master regulator of erythropoiesis. In vivo data in mice demonstrated multiple subtypes of interstitial renal Epo-producing (REP) cells. To analyze the differentiation plasticity of fibroblastoid REP cells, we used a transgenic REP cell reporter mouse model to generate conditionally immortalized REP-derived (REPD) cell lines. Under nonpermissive conditions, REPD cells ceased from proliferation and acquired a stem cell-like state, with strongly enhanced hypoxia-inducible factor 2 (HIF-2α), stem cell antigen 1 (SCA-1), and CD133 expression, but also enhanced alpha-smooth muscle actin (αSMA) expression, indicating myofibroblastic signaling. These cells maintained the "on-off" nature of Epo expression observed in REP cells in vivo, whereas other HIF target genes showed a more permanent regulation. Like REP cells in vivo, REPD cells cultured in vitro generated long tunneling nanotubes (TNTs) that aligned with endothelial vascular structures, were densely packed with mitochondria and became more numerous under hypoxic conditions. Although inhibition of mitochondrial oxygen consumption blunted HIF signaling, removal of the TNTs did not affect or even enhance the expression of HIF target genes. Apart from pericytes, REPD cells readily differentiated into neuroglia but not adipogenic, chondrogenic, or osteogenic lineages, consistent with a neuronal origin of at least a subpopulation of REP cells. In summary, these results suggest an unprecedented combination of differentiation features of this unique cell type.

Different subpopulations of kidney interstitial cells produce erythropoietin and factors supporting tissue oxygenation in response to hypoxia in vivo.

Genetic induction of hypoxia signaling by deletion of the von Hippel-Lindau (Vhl) protein in mesenchymal PDGFR-ß+ cells leads to abundant HIF-2 dependent erythropoietin (EPO) expression in the cortex and outer medulla of the kidney. This rather unique feature of kidney PDGFR-ß+ cells promote questions about their special characteristics and general functional response to hypoxia. To address these issues, we characterized kidney PDGFR-ß+ EPO expressing cells based on additional cell markers and their gene expression profile in response to hypoxia signaling induced by targeted deletion of Vhl or exposure to low oxygen and carbon monoxide respectively, and after unilateral ureteral obstruction. CD73+, Gli1+, tenascin C+ and interstitial SMMHC+ cells were identified as zonally distributed subpopulations of PDGFR-ß+ cells. EPO expression could be induced by Vhl deletion in all PDGFR-ß+ subpopulations. Under hypoxemic conditions, recruited EPO+ cells were mostly part of the CD73+ subpopulation. Besides EPO production, expression of adrenomedullin and regulator of G-protein signaling 4 was upregulated in PDGFR-ß+ subpopulations in response to the different hypoxic stimuli. Thus, different kidney interstitial PDGFR-ß+ subpopulations exist, capable of producing EPO in response to different stimuli. Activation of hypoxia signaling in these cells also induces factors likely contributing to improved kidney interstitial tissue oxygenation.

The neuronal oxygen-sensing pathway controls postnatal vascularization of the murine brain.

The contribution of neurons to growth and refinement of the microvasculature during postnatal brain development is only partially understood. Tissue hypoxia is the physiologic stimulus for angiogenesis by enhancing angiogenic mediators partly through activation of hypoxia-inducible factors (HIFs). Hence, we investigated the HIF oxygen-sensing pathway in postmitotic neurons for physiologic angiogenesis in the murine forebrain during postnatal development by using mice lacking the HIF suppressing enzyme prolyl-4-hydroxylase domain (PHD)2 and/or HIF-1/2α in postmitotic neurons. Perinatal activation or inactivation of the HIF pathway in neurons inversely modulated brain vascularization, including endothelial cell number and proliferation, density of total and perfused microvessels, and vascular branching. Accordingly, several angiogenesis-related genes were up-regulated in vivo and in primary neurons derived from PHD2-deficient mice. Among them, only VEGF and adrenomedullin (Adm) promoted angiogenic sprouting of brain endothelial cells. VEGF and Adm additively enhanced endothelial sprouting through activation of multiple pathways. PHD2 deficiency in neurons caused HIF-α stabilization and increased VEGF mRNA levels not only in neurons but unexpectedly also in astrocytes, suggesting a new mechanism of neuron-to-astrocyte signaling. Collectively, our results identify the PHD-HIF pathway in neurons as an important determinant for vascularization of the brain during postnatal development.-Nasyrov, E., Nolan, K. A., Wenger, R. H., Marti, H. H., Kunze, R. The neuronal oxygen-sensing pathway controls postnatal vascularization of the murine brain.

The ReWalk ReStore™ soft robotic exosuit: a multi-site clinical trial of the safety, reliability, and feasibility of exosuit-augmented post-stroke gait rehabilitation.

BACKGROUND: Atypical walking in the months and years after stroke constrain community reintegration and reduce mobility, health, and quality of life. The ReWalk ReStore™ is a soft robotic exosuit designed to assist the propulsion and ground clearance subtasks of post-stroke walking by actively assisting paretic ankle plantarflexion and dorsiflexion. Previous proof-of-concept evaluations of the technology demonstrated improved gait mechanics and energetics and faster and farther walking in users with post-stroke hemiparesis. We sought to determine the safety, reliability, and feasibility of using the ReStore™ during post-stroke rehabilitation. METHODS: A multi-site clinical trial (NCT03499210) was conducted in preparation for an application to the United States Food and Drug Administration (FDA). The study included 44 users with post-stroke hemiparesis who completed up to 5 days of training with the ReStore™ on the treadmill and over ground. In addition to primary and secondary endpoints of safety and device reliability across all training activities, an exploratory evaluation of the effect of multiple exposures to using the device on users' maximum walking speeds with and without the device was conducted prior to and following the five training visits. RESULTS: All 44 study participants completed safety and reliability evaluations. Thirty-six study participants completed all five training days. No device-related falls or serious adverse events were reported. A low rate of device malfunctions was reported by clinician-operators. Regardless of their reliance on ancillary assistive devices, after only 5 days of walking practice with the device, study participants increased both their device-assisted (Δ: 0.10 ± 0.03 m/s) and unassisted (Δ: 0.07 ± 0.03 m/s) maximum walking speeds (P's < 0.05). CONCLUSIONS: When used under the direction of a licensed physical therapist, the ReStore™ soft exosuit is safe and reliable for use during post-stroke gait rehabilitation to provide targeted assistance of both paretic ankle plantarflexion and dorsiflexion during treadmill and overground walking. TRIAL REGISTRATION: NCT03499210. Prospectively registered on March 28, 2018.

Generation of renal Epo-producing cell lines by conditional gene tagging reveals rapid HIF-2 driven Epo kinetics, cell autonomous feedback regulation, and a telocyte phenotype.

Erythropoietin (Epo) is essential for erythropoiesis and is mainly produced by the fetal liver and the adult kidney following hypoxic stimulation. Epo regulation is commonly studied in hepatoma cell lines, but differences in Epo regulation between kidney and liver limit the understanding of Epo dysregulation in polycythaemia and anaemia. To overcome this limitation, we have generated a novel transgenic mouse model expressing Cre recombinase specifically in the active fraction of renal Epo-producing (REP) cells. Crossing with reporter mice confirmed the inducible and highly specific tagging of REP cells, located in the corticomedullary border region where there is a steep drop in oxygen bioavailability. A novel method was developed to selectively grow primary REP cells in culture and to generate immortalized clonal cell lines, called fibroblastoid atypical interstitial kidney (FAIK) cells. FAIK cells show very early hypoxia-inducible factor (HIF)-2α induction, which precedes Epo transcription. Epo induction in FAIK cells reverses rapidly despite ongoing hypoxia, suggesting a cell autonomous feedback mechanism. In contrast, HIF stabilizing drugs resulted in chronic Epo induction in FAIK cells. RNA sequencing of three FAIK cell lines derived from independent kidneys revealed a high degree of overlap and suggests that REP cells represent a unique cell type with properties of pericytes, fibroblasts, and neurons, known as telocytes. These novel cell lines may be helpful to investigate myofibroblast differentiation in chronic kidney disease and to elucidate the molecular mechanisms of HIF stabilizing drugs currently in phase III studies to treat anemia in end-stage kidney disease.

Negative Cooperativity in NAD(P)H Quinone Oxidoreductase 1 (NQO1).

NAD(P)H quinone oxidoreductase-1 (NQO1) is a homodimeric protein that acts as a detoxifying enzyme or as a chaperone protein. Dicourmarol interacts with NQO1 at the NAD(P)H binding site and can both inhibit enzyme activity and modulate the interaction of NQO1 with other proteins. We show that the binding of dicoumarol and related compounds to NQO1 generates negative cooperativity between the monomers. This does not occur in the presence of the reducing cofactor, NAD(P)H, alone. Alteration of Gly150 (but not Gly149 or Gly174) abolished the dicoumarol-induced negative cooperativity. Analysis of the dynamics of NQO1 with the Gaussian network model indicates a high degree of collective motion by monomers and domains within NQO1. Ligand binding is predicted to alter NQO1 dynamics both proximal to the ligand binding site and remotely, close to the second binding site. Thus, drug-induced modulation of protein motion might contribute to the biological effects of putative inhibitors of NQO1.

FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1.

The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1) is a substrate for hydroxylation by FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, in cultured cells, overexpression of N22A mutant OTUB1 impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. Additionally, we propose that our results provide new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit.

Source and microenvironmental regulation of erythropoietin in the kidney.

PURPOSE OF REVIEW: Historically, the identity of O2-sensing renal erythropoietin (Epo)-producing (REP) cells was a matter of debate. This review summarizes how recent breakthroughs in transgenic mouse and in-situ hybridization techniques have facilitated sensitive and specific detection of REP cells and accelerated advancements in the understanding of the regulation of renal Epo production in health and disease. RECENT FINDINGS: REP cells are a dynamically regulated unique subpopulation of tubulointerstitial cells with features of fibroblasts, pericytes and neurons. Under normal conditions, REP cells are located in the corticomedullary border region within a steep decrement in O2 availability. During the progression of chronic kidney disease (CKD), REP cells cease Epo production, dedifferentiate and contribute to the progression of renal fibrosis. However, CKD patients with renal anaemia still respond with elevated Epo production following treatment with hypoxia-mimicking agents. SUMMARY: We hypothesize that REP cells are neuron-like setpoint providers and controllers, which integrate information about blood O2 concentration and local O2 consumption via tissue pO2, and combine these inputs with intrinsic negative feedback loops and perhaps tubular cross-talk, converging in Epo regulation.

Cyclogram based Joint Symmetry Assessment after Utilization of a Foot Drop Stimulator during Post Stroke Hemiplegic Gait.

In the absence of standardized symmetry assessments, quantifying symmetry based on the kinematic evolution of lower extremity joints can elucidate gait irregularities. The objective was to develop a novel cyclogram based symmetry (CBS) method to quantify lower extremity joints' symmetry and assess the effect of 6-month utilization of foot drop stimulator (FDS) on CBS of the lower limbs during hemiplegic gait post stroke. Twenty-four participants (13 stroke and 11 healthy controls (HC)) performed 10 walking trials at a free cadence on level ground. Symmetry values were computed using geometric properties of bilateral cyclograms obtained from normalized sagittal ankle, knee and hip kinematics. CBS and traditional temporospatial symmetry values were compared between the two groups using independent sample t-test. Effect of FDS utilization on symmetry was assessed by paired sample t- test computed at baseline and 6-month follow up. The CBS method successfully showed that the HC group was significantly more symmetrical at the ankle (p=0.001), knee (p=0.001) and hip (p<0.005) compared with the stroke group. The stroke group showed significant increment in hip symmetry with FDS at baseline but did not show any significant CBS changes at follow up. Pearson correlations revealed that hip and knee CBS had a significant influence on overall walking speed. The CBS method presents a unique approach to calculate symmetry based on the kinematics of lower extremities during gait.

Neurophysiological Effects of Bitopertin in Schizophrenia.

PURPOSE/BACKGROUND: Deficits in N-methyl-D-aspartate receptor (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia and are associated with impaired generation of event-related potential measures including auditory mismatch negativity. Parallel studies of the NMDAR agonist D-serine have suggested that sensitivity of these measures to glutamate-based interventions is related to symptomatic and cognitive response. Bitopertin is a selective inhibitor of glycine transport. This study investigates effects of bitopertin on NMDAR-related event-related potential deficits in schizophrenia. METHODS/PROCEDURES: Patients with schizophrenia/schizoaffective disorder were treated with bitopertin (10 mg, n = 29), in a double-blind, parallel group investigation. Auditory mismatch negativity served as primary outcome measures. Secondary measures included clinical symptoms and neurocognitive performance. FINDINGS/RESULTS: No significant changes were seen with bitopertin for neurophysiological, clinical, or neurocognitive assessments. IMPLICATIONS/CONCLUSIONS: These findings represent the first assessment of the effect of bitopertin on neurophysiological biomarkers. Bitopertin did not significantly affect either symptoms or NMDAR-related biomarkers at the dose tested (10 mg). Mismatch negativity showed high test-retest reliability, supporting its use as a target engagement measure.

Erythropoietin production by PDGFR-ß(+) cells.

PDGFR-ß-expressing cells of the kidneys are considered as a relevant site of erythropoietin (EPO) production. The origin of these cells, their contribution to renal EPO production, and if PDGFR-ß-positive cells in other organs are also capable to express EPO are less clear. We addressed these questions in mice, in which hypoxia-inducible transcription factors were stabilized in PDGFR-ß(+) cells by inducible deletion of the von Hippel-Lindau (Vhl) protein. Vhl deletion led to a 600-fold increase of plasma EPO concentration, 170-fold increase of renal EPO messenger RNA (mRNA) levels, and an increase of hematocrit values up to 70 %. Intrarenal localization of EPO-expressing cells coincided with the zonal heterogeneity and distribution of cells expressing PDGFR-ß. Amongst a variety of extrarenal organs only adrenal glands showed significant EPO mRNA expression after Vhl deletion in PDGFR-ß(+) cells. EPO mRNA, plasma EPO, and hematocrit fell to subnormal values if HIF-2α, but not HIF-1α, was deleted either alone or in combination with Vhl in PDGFR-ß(+) cells. Treatment of mice with a prolyl-hydroxylase inhibitor caused an increase of EPO mRNA abundance and plasma EPO concentrations in wild-type mice and in mice lacking HIF-1α in PDGFR-ß(+) cells but exerted no effect in mice lacking HIF-2α in PDGFR-ß(+) cells. These findings suggest that PDGFR-ß(+) cells are the only relevant site of EPO expression in the kidney and that HIF-2 is the essential transcription factor triggering EPO expression therein. Moreover, our findings suggest that PDGFR-ß(+) cells elaborating EPO might arise from the metanephric mesenchyme, rather than from the neural crest.

Paricalcitol protects against TGF-ß1-induced fibrotic responses in hypoxia and stabilises HIF-α in renal epithelia.

Epithelial injury and tubulointerstitial fibrosis (TIF) within a hypoxic microenvironment are associated with progressive loss of renal function in chronic kidney disease [CKD]. Transforming growth factor beta-1 (TGF-ß1) is an important mediator of renal fibrosis. Growing evidence suggests that Vitamin D [1,25-(OH)2D] and its analogues may have a renoprotective effect in CKD. Here we examined the protective effect of the vitamin D analogue paricalcitol [PC; 19-nor-1α,3ß,25-trihydroxy-9,10-secoergosta-5(Z),7(E) 22(E)-triene] on the responses of human renal epithelial cells to TGF-ß1. PC attenuated TGF-ß1-induced Smad 2 phosphorylation and upregulation of the Notch ligand Jagged-1, α-smooth muscle actin and thrombospondin-1 and prevented the TGF-ß1-mediated loss of E-Cadherin. To mimic the hypoxic milieu of CKD we cultured renal epithelial cells in hypoxia [1% O2] and observed similar attenuation by PC of TGF-ß1-induced fibrotic responses. Furthermore, in cells cultured in normoxia [21% O2], PC induced an accumulation of hypoxia-inducible transcription factors (HIF) 1α and HIF-2α in a time and concentration [1 µM-2 µM] dependent manner. Here, PC-induced HIF stabilisation was dependent on activation of the PI-3Kinase pathway. This is the first study to demonstrate regulation of the HIF pathway by PC which may have importance in the mechanism underlying renoprotection by PC.

Lipoxins attenuate renal fibrosis by inducing let-7c and suppressing TGFßR1.

Lipoxins, which are endogenously produced lipid mediators, promote the resolution of inflammation, and may inhibit fibrosis, suggesting a possible role in modulating renal disease. Here, lipoxin A4 (LXA4) attenuated TGF-ß1-induced expression of fibronectin, N-cadherin, thrombospondin, and the notch ligand jagged-1 in cultured human proximal tubular epithelial (HK-2) cells through a mechanism involving upregulation of the microRNA let-7c. Conversely, TGF-ß1 suppressed expression of let-7c. In cells pretreated with LXA4, upregulation of let-7c persisted despite subsequent stimulation with TGF-ß1. In the unilateral ureteral obstruction model of renal fibrosis, let-7c upregulation was induced by administering an LXA4 analog. Bioinformatic analysis suggested that targets of let-7c include several members of the TGF-ß1 signaling pathway, including the TGF-ß receptor type 1. Consistent with this, LXA4-induced upregulation of let-7c inhibited both the expression of TGF-ß receptor type 1 and the response to TGF-ß1. Overexpression of let-7c mimicked the antifibrotic effects of LXA4 in renal epithelia; conversely, anti-miR directed against let-7c attenuated the effects of LXA4. Finally, we observed that several let-7c target genes were upregulated in fibrotic human renal biopsies compared with controls. In conclusion, these results suggest that LXA4-mediated upregulation of let-7c suppresses TGF-ß1-induced fibrosis and that expression of let-7c targets is dysregulated in human renal fibrosis.

Relationship between Timed Up and Go performance and quantitative biomechanical measures of balance.

Traumatic brain injury (TBI) impairs sensory-motor functions, with debilitating consequences on postural control and balance, which persist during the chronic stages of recovery. The Timed Up and Go (TUG) test is a reliable, safe, time-efficient, and one of the most widely used clinical measures to assess gait, balance, and fall risk in TBI patients and is extensively used in inpatient and outpatient settings. Although the TUG test has been used extensively due to its ease of performance and excellent reliability, limited research has been published that investigates the relationship between TUG performance and quantitative biomechanical measures of balance. The objective of this paper was to quantify the relationship between biomechanical variables of balance and the TUG scores in individuals with chronic TBI. Regression models were constructed using six biomechanical variables to predict TUG scores. The model that conservatively removed gait speed (i.e., TUG-1/GS) gave the best results, achieving a root-mean-square error of ∼±2 s and explaining over 69% of the variability.

Efficacy and safety of using auditory-motor entrainment to improve walking after stroke: a multi-site randomized controlled trial of InTandemTM.

Walking slowly after stroke reduces health and quality of life. This multi-site, prospective, interventional, 2-arm randomized controlled trial (NCT04121754) evaluated the safety and efficacy of an autonomous neurorehabilitation system (InTandemTM) designed to use auditory-motor entrainment to improve post-stroke walking. 87 individuals were randomized to 5-week walking interventions with InTandem or Active Control (i.e., walking without InTandem). The primary endpoints were change in walking speed, measured by the 10-meter walk test pre-vs-post each 5-week intervention, and safety, measured as the frequency of adverse events (AEs). Clinical responder rates were also compared. The trial met its primary endpoints. InTandem was associated with a 2x larger increase in speed (Δ: 0.14 ± 0.03 m/s versus Δ: 0.06 ± 0.02 m/s, F(1,49) = 6.58, p = 0.013), 3x more responders (40% versus 13%, χ2(1) ≥ 6.47, p = 0.01), and similar safety (both groups experienced the same number of AEs). The auditory-motor intervention autonomously delivered by InTandem is safe and effective in improving walking in the chronic phase of stroke.

EEG Based Cortico-Muscular Connectivity During Standing Early Post Stroke.

In this exploratory study we studied brain activation and corticomuscular connectivity during standing in healthy individuals and persons with stroke within 40 days of cerebrovascular accident (CVA). EEG and EMG data were acquired during standing and analysis showed a trend of higher EEG power (hyper activation) in the stroke group. Direct corticomuscular connectivity between sensorimotor cortices and contralateral lower extremity muscles showed lower connectivity between affected motor, premotor, and sensory cortices, and contralateral lower extremity peripheral muscles with moderate effect size. The preliminary data in this paper suggest re-organization in left sensorimotor cortex role in controlling contralateral lower extremity muscles during standing. Correlational analysis in stroke group within 40 days of CVA showed a relationship between higher corticomuscular connectivity and better scores on balance assessments.Clinical Relevance- This study evaluates corticomuscular connectivity during standing in healthy controls and individuals with subacute stroke (within 40 days of injury). Better understanding of cortical control of standing post stroke is important to improve strategies used in mobility rehabilitation.

Motor-Cognitive Virtual Reality Training to Improve Gait and Balance in Young Adults with TBI.

Traumatic Brain Injury (TBI) is one of the leading causes of motor and cognitive deficits in adults, and often results in motor control and balance impairments. Motor deficits include gait dysfunction and decreased postural control & coordination; leading to compromised functional ambulation and reduced quality of life. Research has shown that cognitive (attention and executive) function contributes to motor deficits and recovery. Hence, targeting the motor and the cognitive domains simultaneously by increasing cognitive and motor effort to perform the task may lead to improved ambulation recovery. The objective of this investigation was to evaluate the efficacy of simultaneous motor & cognitive training (MCT) using virtual reality to improve ambulation; assessed using biomechanical, cognitive, and functional outcomes. Preliminary data is presented for three participants with chronic TBI who received MCT. The results show improved cognition, speed, endurance, step length, gait cycle time, static & reactive balance, dual-task performance, and progression towards healthy ambulation. These preliminary results suggest that integrated cognitive motor training has the potential to induce functional recovery in young adults with TBI.Clinical Relevance - Preliminary data provides initial evidence for MCT as a therapeutic intervention for gait and balance rehabilitation in young adults with TBI.

Lower extremity robotic exoskeleton devices for overground ambulation recovery in acquired brain injury-A review.

Acquired brain injury (ABI) is a leading cause of ambulation deficits in the United States every year. ABI (stroke, traumatic brain injury and cerebral palsy) results in ambulation deficits with residual gait and balance deviations persisting even after 1 year. Current research is focused on evaluating the effect of robotic exoskeleton devices (RD) for overground gait and balance training. In order to understand the device effectiveness on neuroplasticity, it is important to understand RD effectiveness in the context of both downstream (functional, biomechanical and physiological) and upstream (cortical) metrics. The review identifies gaps in research areas and suggests recommendations for future research. We carefully delineate between the preliminary studies and randomized clinical trials in the interpretation of existing evidence. We present a comprehensive review of the clinical and pre-clinical research that evaluated therapeutic effects of RDs using various domains, diagnosis and stage of recovery.

Enhancing Anticipatory and Compensatory Postural Responses to Improve Balance in Individuals with TBI.

Traumatic Brain Injury (TBI) is one of the leading causes of sensorimotor deficits in adults and often results in balance impairments. Two types of postural mechanisms are employed to achieve balance during perturbations: Anticipatory Postural Adjustments (APA) and Compensatory Postural Adjustments (CPA). People with TBI have reduced APA/CPA responses due to sensory-motor deficits from the injury. The objective of this feasibility study was to evaluate a Perturbation-based Balance Training program with visual cues (PBTvc) to target both APA/CPA responses to improve balance. The evaluation included biomechanical (reactive balance during random perturbation) and functional (Berg Balance Scale, Timed Up and Go and Falls Efficacy Scale) metrics. Preliminary data is presented for two participants with chronic TBI who received 16 sessions of PBTvc. The results show an improved range of trunk oscillation and time to stability during random perturbation tasks with corresponding improvements in Berg Balance Scale, Timed Up & Go, and Falls Efficacy Scale. The results suggest that PBTvc has the potential to improve APA/CPA mechanisms for functional recovery.Clinical Relevance- Preliminary data provides initial evidence for PBTvc as a therapeutic intervention for balance rehabilitation in adults with TBI.

Intensity Modulated Exoskeleton Gait Training Post Stroke.

Stroke is a leading cause of long-term disability. While major advances have been made in early intervention for the treatment of patients post stroke, the majority of survivors have residual mobility challenges. Recovery of motor function is dependent on the interrelationship between dosing, intensity, and task specific practice applied during rehabilitation. Robotic exoskeleton (RE) based gait training utilizes progressive repetitive task-oriented movements to promote functional recovery. The purpose of this investigation was to demonstrate the utilization of intensity modulated exoskeleton gait training on functional outcomes and walking speed post stoke. Preliminary data is presented for individuals diagnosed with stroke who received RE gait training. The intensity modulated RE gait training was delivered by a physical therapist and participants trained at 75-85% of calculated max heart rates at each session, over 10 weeks (30 sessions). After 10 weeks of training participants increased walking speed (10 meter walk test) and functional measures (timed up and go, berg balance assessment, dynamic gait index and functional ambulation category). These preliminary results demonstrate the utilization of intensity modulated gait training for improved functional ambulation and motor recovery using a robotic exoskeleton overground gait training post stroke.Clinical Relevance- Preliminary data provides initial evidence for intensity modulated exoskeleton gait training as a therapeutic intervention post stroke. More research is needed to demonstrate the potential relationships between intensity based gait training, exoskeletons and improved functional ambulation in post stroke rehabilitation.