Hyper-acute effects of sub-concussive soccer headers on brain function and hemodynamics.

Introduction: Sub-concussive head impacts in soccer are drawing increasing research attention regarding their acute and long-term effects as players may experience thousands of headers in a single season. During these impacts, the head experiences rapid acceleration similar to what occurs during a concussion, but without the clinical implications. The physical mechanism and response to repetitive impacts are not completely understood. The objective of this work was to examine the immediate functional outcomes of sub-concussive level impacts from soccer heading in a natural, non-laboratory environment. Methods: Twenty university level soccer athletes were instrumented with sensor-mounted bite bars to record impacts from 10 consecutive soccer headers. Pre- and post-header measurements were collected to determine hyper-acute changes, i.e., within minutes after exposure. This included measuring blood flow velocity using transcranial Doppler (TCD) ultrasound, oxyhemoglobin concentration using functional near infrared spectroscopy imaging (fNIRS), and upper extremity dual-task (UEF) neurocognitive testing. Results: On average, the athletes experienced 30.7 ± 8.9 g peak linear acceleration and 7.2 ± 3.1 rad/s peak angular velocity, respectively. Results from fNIRS measurements showed an increase in the brain oxygenation for the left prefrontal cortex (PC) (p = 0.002), and the left motor cortex (MC) (p = 0.007) following the soccer headers. Additional analysis of the fNIRS time series demonstrates increased sample entropy of the signal after the headers in the right PC (p = 0.02), right MC (p = 0.004), and left MC (p = 0.04). Discussion: These combined results reveal some variations in brain oxygenation immediately detected after repetitive headers. Significant changes in balance and neurocognitive function were not observed in this study, indicating a mild level of head impacts. This is the first study to observe hemodynamic changes immediately after sub-concussive impacts using non-invasive portable imaging technology. In combination with head kinematic measurements, this information can give new insights and a framework for immediate monitoring of sub-concussive impacts on the head.

Neuroimaging, wearable sensors, and blood-based biomarkers reveal hyperacute changes in the brain after sub-concussive impacts.

Impacts in mixed martial arts (MMA) have been studied mainly in regard to the long-term effects of concussions. However, repetitive sub-concussive head impacts at the hyperacute phase (minutes after impact), are not understood. The head experiences rapid acceleration similar to a concussion, but without clinical symptoms. We utilize portable neuroimaging technology - transcranial Doppler (TCD) ultrasound and functional near infrared spectroscopy (fNIRS) - to estimate the extent of pre- and post-differences following contact and non-contact sparring sessions in nine MMA athletes. In addition, the extent of changes in neurofilament light (NfL) protein biomarker concentrations, and neurocognitive/balance parameters were determined following impacts. Athletes were instrumented with sensor-based mouth guards to record head kinematics. TCD and fNIRS results demonstrated significantly increased blood flow velocity (p = 0.01) as well as prefrontal (p = 0.01) and motor cortex (p = 0.04) oxygenation, only following the contact sparring sessions. This increase after contact was correlated with the cumulative angular acceleration experienced during impacts (p = 0.01). In addition, the NfL biomarker demonstrated positive correlations with angular acceleration (p = 0.03), and maximum principal and fiber strain (p = 0.01). On average athletes experienced 23.9 ± 2.9 g peak linear acceleration, 10.29 ± 1.1 rad/s peak angular velocity, and 1,502.3 ± 532.3 rad/s2 angular acceleration. Balance parameters were significantly increased following contact sparring for medial-lateral (ML) center of mass (COM) sway, and ML ankle angle (p = 0.01), illustrating worsened balance. These combined results reveal significant changes in brain hemodynamics and neurophysiological parameters that occur immediately after sub-concussive impacts and suggest that the physical impact to the head plays an important role in these changes.

Design and Comprehensive Characterization of Tetramethylpyrazine (TMP) for Targeted Lung Delivery as Inhalation Aerosols in Pulmonary Hypertension (PH): In Vitro Human Lung Cell Culture and In Vivo Efficacy.

This is the first study reporting on the design and development innovative inhaled formulations of the novel natural product antioxidant therapeutic, tetramethylpyrazine (TMP), also known as ligustrazine. TMP is obtained from Chinese herbs belonging to the class of Ligusticum. It is known to have antioxidant properties. It can act as a Nrf2/ARE activator and a Rho/ROCK inhibitor. The present study reports for the first time on the comprehensive characterization of raw TMP (non-spray dried) and spray dried TMP in a systematic manner using thermal analysis, electron microscopy, optical microscopy, and Raman spectroscopy. The in vitro aerosol dispersion performance of spray dried TMP was tested using three different FDA-approved unit-dose capsule-based human dry powder inhaler devices. In vitro human cellular studies were conducted on pulmonary cells from different regions of the human lung to examine the biocompatibility and non-cytotoxicity of TMP. Furthermore, the efficacy of inhaled TMP as both liquid and dry powder inhalation aerosols was tested in vivo using the monocrotaline (MCT)-induced PH rat model.

Dual-task performance is associated with brain MRI Morphometry in individuals with mild cognitive impairment.

BACKGROUND AND PURPOSE: Cognitive impairment is a critical health problem in the elderly population. Research has shown that patients with mild cognitive impairment (MCI) may develop dementia in later years. Therefore, early identification of MCI could allow for interventions to help delay the progression of this devastating disease. Our objective in this study was to detect the early presence of MCI in elderly patients via neuroimaging and dual-task performance. METHODS: Brain MRI scans from 21 older adult volunteers, including cognitively healthy adults (HA, n = 9, age = 68-79 years) and mild cognitively impaired (MCI, n = 12, age = 66-92 years) were analyzed using automatic segmentation techniques. Regional volume, surface area, and thickness measures were correlated with simultaneous performance of motor and cognitive tasks (dual-task) within a novel upper-extremity function (UEF) test, using multivariate analysis of variance models. RESULTS: We found significant associations of dual-task performance with volume of five cortical brain regions (P ≤ .048) and thickness of 13 regions (P ≤ .043) within the frontal, temporal, and parietal lobes. There was a significant interaction effect of cognitive group on dual-task score for the inferior temporal gyrus volume (P ≤ .034), and the inferior parietal lobule, inferior temporal gyrus, and middle temporal gyrus average thickness (P ≤ .037). CONCLUSIONS: This study highlighted the potential of dual-tasking and MRI morphometric changes as a simple and accurate tool for early detection of cognitive impairment among community-dwelling older adults. The strong interaction effects of cognitive group on UEF dual-task score suggest higher association between atrophy of these brain structures and compromised dual-task performance among the MCI group.

Advanced therapeutic inhalation aerosols of a Nrf2 activator and RhoA/Rho kinase (ROCK) inhibitor for targeted pulmonary drug delivery in pulmonary hypertension: design, characterization, aerosolization, in vitro 2D/3D human lung cell cultures, and in vivo efficacy.

Inhalable nanostructured microparticles of simvastatin, a Nrf2 activator and RhoA/Rho kinase (ROCK) inhibitor, were rationally designed for targeted pulmonary delivery as dry powder inhalers (DPIs) for the treatment of pulmonary hypertension (PH). Advanced particle engineering design technology was employed to develop inhalable dry powders using different dilute feed concentrations and spray drying pump rates. Several analytical techniques were used comprehensively to characterize the physicochemical properties of the resulting powders. Scanning electron microscopy (SEM) was used to visualize particle morphology (shape), surface structure, size, and size distribution. Karl Fischer titration (KFT) was employed to quantify the residual water content in the powders. X-ray powder diffraction (XRPD) was used to determine crystallinity. Hot-stage microscopy (HSM) under cross-polarizing lens was used to observe the presence or absence of birefringence characteristic of crystallinity. Differential scanning calorimetry (DSC) was employed to quantify thermotropic phase behavior. Attenuated total reflectance (ATR)-Fourier-transform infrared (FTIR) spectroscopy and Raman spectroscopy were used to determine the molecular fingerprint of simvastatin powders before and after particle engineering design. In vitro aerosol dispersion performance was performed with three different Food and Drug Administration (FDA)-approved human DPI devices. Cell viability and transepithelial electrical resistance (TEER) were demonstrated using different in vitro human pulmonary cell two and three-dimensional models at the air-liquid interface, and in vivo safety in healthy rats by inhalation. Efficacy was demonstrated in the in vivo lamb model of PH. Four different inhalable powders of simvastatin were successfully produced. They possessed nanostructured surfaces and were in the inhalable size range. Simvastatin retained its crystallinity following particle engineering design. The more dilute feed concentration spray dried at the lower pump rate produced the smallest particles. All powders successfully aerosolized with all three DPI human devices. Inhaled simvastatin as an aerosol restored the endothelial function in the shunt lamb model of PH, as demonstrated by the reduction of pulmonary vascular resistance (PVR) in response to the endothelium-dependent vasodilator acetylcholine.The reviews of this paper are available via the supplemental material section.

Comparison of l-Carnitine and l-Carnitine HCL salt for targeted lung treatment of pulmonary hypertension (PH) as inhalation aerosols: Design, comprehensive characterization, in vitro 2D/3D cell cultures, and in vivo MCT-Rat model of PH.

Disrupted l-Carnitine (L-Car) homeostasis has been implicated in the development of pulmonary hypertension (PH). L-Car has been administered orally and intravenously causing systemic side effects. To the authors' knowledge, there are no reports using L-Car or L-Car HCl as an inhaled aerosol through the respiratory route in a targeted manner either from dry powder inhaler (DPI) or liquid delivery system. The purpose of the comprehensive and systematic comparative study between L-Car and L-Car HCl salt was to design and develop dry powder inhalers (DPIs) of each. This was followed by comprehensive physicochemical characterization, in vitro cell viability as a function of dose on 2D human pulmonary cell lines from different lung regions and in vitro cell viability on 3D small airway epithelia human primary cells at the air-liquid interface (ALI). In addition in vitro transepithelial electrical resistance (TEER) in air-interface culture (AIC) conditions on 2D human pulmonary cell line and 3D small airway epithelia human primary cells was carried out. In vitro aerosol dispersion performance using three FDA-approved human DPI devices with different device properties was also examined. Following advanced spray drying under various conditions, two spray drying pump rates (low and medium) were found to successfully produce spray-dried L-Car powders while four spray drying pump rates (low, medium, medium-high, and high) all resulted in the production of spray-dried L-Car HCl powders. Raw L-Car and L-Car HCl were found to be crystalline. All SD powders retained crystallinity following spray drying and polymorphic interconversion in the solid-state was identified as the mechanism for retaining crystallinity after the advanced spray drying process. All SD powders aerosolized readily with all three human DPI devices. However, the in vitro dispersion parameters for the SD powders was not conducive for in vivo administration to rats in DPIs due to hygroscopicity and nanoaggreation. In vivo rat studies were successfully accomplished using inhaled liquid aerosols. Safety was successfully demonstrated in vivo in healthy Sprague Dawley rats. Furthermore, therapeutic efficacy was successfully demonstrated in vivo in the monocrotaline (MCT)-rat model of PH after two weeks of daily L-Car inhalation aerosol treatment.