Transcranial Blood-Brain Barrier Opening in Alzheimer's Disease Patients Using a Portable Focused Ultrasound System with Real-Time 2-D Cavitation Mapping.

Background: Focused ultrasound (FUS) in combination with microbubbles has recently shown great promise in facilitating blood-brain barrier (BBB) opening for drug delivery and immunotherapy in Alzheimer's disease (AD). However, it is currently limited to systems integrated within the MRI suites or requiring post-surgical implants, thus restricting its widespread clinical adoption. In this pilot study, we investigate the clinical safety and feasibility of a portable, non-invasive neuronavigation-guided FUS (NgFUS) system with integrated real-time 2-D microbubble cavitation mapping. Methods: A phase 1 clinical study with mild to moderate AD patients (N=6) underwent a single session of microbubble-mediated NgFUS to induce transient BBB opening (BBBO). Microbubble activity under FUS was monitored with real-time 2-D cavitation maps and dosing to ensure the efficacy and safety of the NgFUS treatment. Post-operative MRI was used for BBB opening and closure confirmation as well as safety assessment. Changes in AD biomarker levels in both blood serum and extracellular vesicles (EVs) were evaluated, while changes in amyloid-beta (Aß) load in the brain were assessed through 18 F-Florbetapir PET. Results: BBBO was achieved in 5 out of 6 subjects with an average volume of 983±626 mm 3 following FUS at the right frontal lobe both in white and gray matter regions. The outpatient treatment was completed within 34.8±10.7 min. Cavitation dose significantly correlated with the BBBO volume ( R 2 >0.9, N =4), demonstrating the portable NgFUS system's capability of predicting opening volumes. The cavitation maps co-localized closely with the BBBO location, representing the first report of real-time transcranial 2-D cavitation mapping in the human brain. Larger opening volumes correlated with increased levels of AD biomarkers, including Aß42 ( R 2 =0.74), Tau ( R 2 =0.95), and P-Tau181 ( R 2 =0.86), assayed in serum-derived EVs sampled 3 days after FUS ( N =5). From PET scans, subjects showed a lower Aß load increase in the treated frontal lobe region compared to the contralateral region. Reduction in asymmetry standardized uptake value ratios (SUVR) correlated with the cavitation dose ( R 2 >0.9, N =3). Clinical changes in the mini-mental state examination over 6 months were within the expected range of cognitive decline with no additional changes observed as a result of FUS. Conclusion: We showed the safety and feasibility of this cost-effective and time-efficient portable NgFUS treatment for BBBO in AD patients with the first demonstration of real-time 2-D cavitation mapping. The cavitation dose correlated with BBBO volume, a slowed increase in pathology, and serum detection of AD proteins. Our study highlights the potential for accessible FUS treatment in AD, with or without drug delivery.

Frequency-dependent analysis of ultrasound apparent absorption coefficient in multiple scattering porous media: application to cortical bone.

The effect of matrix viscoelastic absorption on frequency-dependent attenuation in porous structures mimicking simplified cortical bone is addressed in this numerical study. An apparent absorption is defined to quantify the difference between total attenuation (resulting from both absorption and scattering) and attenuation exclusively due to scattering. A power-law model is then used to describe the frequency-dependent apparent absorption as a function of pore diameter and density. The frequency response of the porous structures to a Gaussian pulse is studied to determine the frequency range over which the system can be considered linear. The results show that for low scattering regimes (normalized frequency [Formula: see text]0.80), the system and its apparent absorption can be considered linear. Hence, the total attenuation coefficient results from the summation of scattering and absorption coefficients. However, for highly scattering regimes, the system can no longer be considered linear, as the apparent absorption vs. frequency deviates from a linear trend. As the pore density increases, the apparent absorption coefficient increases as well.

Evaluation of Structural Anisotropy in a Porous Titanium Medium Mimicking Trabecular Bone Structure Using Mode-Converted Ultrasonic Scattering.

The mode-converted (longitudinal to transverse, L-T) ultrasonic scattering method was utilized to characterize the structural anisotropy of a phantom mimicking the structural properties of trabecular bone. The sample was fabricated using metal additive manufacturing from high-resolution computed tomography (CT) images of a sample of trabecular horse bone with strong anisotropy. Two focused transducers were used to perform the L-T ultrasonic measurements. A normal incidence transducer was used to transmit longitudinal ultrasonic waves into the sample, while the scattered transverse signals were received by an oblique incidence transducer. At multiple locations on the sample, four L-T measurements were performed by collecting ultrasonic scattering from four directions. The amplitude of the root mean square (rms) of the collected ultrasonic scattering signals was calculated for each L-T measurement. The ratios of rms amplitudes for L-T measurements in different directions were calculated to characterize the anisotropy of sample. The results show that the amplitude of L-T converted scattering is highly dependent on the direction of microstructural anisotropy. A strong anisotropy of the microstructure was observed, which coincides with simulation results previously published on the same structure as well as with the anisotropy estimated from the CT images. These results suggest the potential of mode-converted ultrasonic scattering methods to assess the anisotropy of materials with porous, complex structures, including trabecular bone.

Artificial neural network to estimate micro-architectural properties of cortical bone using ultrasonic attenuation: A 2-D numerical study.

The goal of this study is to estimate micro-architectural parameters of cortical porosity such as pore diameter (φ), pore density (ρ) and porosity (ν) of cortical bone from ultrasound frequency dependent attenuation using an artificial neural network (ANN). First, heterogeneous structures with controlled pore diameters and pore densities (mono-disperse) were generated, to mimic simplified structure of cortical bone. Then, more realistic structures were obtained from high resolution CT scans of human cortical bone. 2-D finite-difference time-domain simulations were conducted to calculate the frequency-dependent attenuation in the 1-8 MHz range. An ANN was then trained with the ultrasonic attenuation at different frequencies as the input feature vectors while the output was set as the micro-architectural parameters (pore diameter, pore density and porosity). The ANN is composed of three fully connected dense layers with 24, 12 and 6 neurons, connected to the output layer. The dataset was trained over 6000 epochs with a batch size of 16. The trained ANN exhibits the ability to predict the micro-architectural parameters with high accuracy and low losses. ANN approaches could potentially be used as a tool to help inform physics-based modelling of ultrasound propagation in complex media such as cortical bone. This will lead to the solution of inverse-problems to retrieve bone micro-architectural parameters from ultrasound measurements for the non-invasive diagnosis and monitoring osteoporosis.

Acoustic diffusion constant of cortical bone: Numerical simulation study of the effect of pore size and pore density on multiple scattering.

While osteoporosis assessment has long focused on the characterization of trabecular bone, the cortical bone micro-structure also provides relevant information on bone strength. This numerical study takes advantage of ultrasound multiple scattering in cortical bone to investigate the effect of pore size and pore density on the acoustic diffusion constant. Finite-difference time-domain simulations were conducted in cortical microstructures that were derived from acoustic microscopy images of human proximal femur cross sections and modified by controlling the density (Ct.Po.Dn) ∈[5-25] pore/mm2 and size (Ct.Po.Dm) ∈[30-100] µm of the pores. Gaussian pulses were transmitted through the medium and the backscattered signals were recorded to obtain the backscattered intensity. The incoherent contribution of the backscattered intensity was extracted to give access to the diffusion constant D. At 8 MHz, significant differences in the diffusion constant were observed in media with different porous micro-architectures. The diffusion constant was monotonously influenced by either pore diameter or pore density. An increase in pore size and pore density resulted in a decrease in the diffusion constant (D =285.9Ct.Po.Dm-1.49, R2=0.989 , p=4.96×10-5,RMSE=0.06; D=6.91Ct.Po.Dn-1.01, R2=0.94, p=2.8×10-3 , RMSE=0.09), suggesting the potential of the proposed technique for the characterization of the cortical microarchitecture.

A Systems-Based Analysis of the CardioMEMS HF Sensor for Chronic Heart Failure Management.

BACKGROUND: Hemodynamic-guided therapy using the CardioMEMS™ system has been shown to reduce heart failure hospitalization (HFH) in both clinical trials and real-world settings. However, the CardioMEMS system requires input from multiple independent elements to achieve its effect, and no studies have been done to investigate those elements. Consistent patient participation and health care provider participation are two of those key elements, and this study sought to assess how they affect HFHs. METHODS: This was a single-center, retrospective cohort study of patients with the CardioMEMS sensor. The primary outcome was the number of HFH days patients experienced in the 1 year following CardioMEMS sensor implant. The primary independent variables were the average number of days between patient transmissions of data and the average number of days between health care provider reviews of those data. Covariates included patient demographics, medical comorbidities, history of HFHs, and initial pressure response to hemodynamic-guided therapy at 28 days after implant. Data were fit to a zero-inflated negative binomial regression. RESULTS: Seventy-eight patients were included in the study. The mean age was 64 ± 15 years, 52 (67%) were male, and 58 (76%) had heart failure with reduced ejection fraction. During the study period, there were 538 cumulative HFH patient-days. Based on the regression model, there was an exponential relationship between HFH days and the mean number of days between patient transmissions (IRR = 1.74, 95% CI: 1.09-2.75, p=0.019). There was also an exponential relationship between HFH days and the mean number of days between health care provider reviews (IRR = 1.03, 95% CI: 1.01-1.05, p=0.013). CONCLUSIONS: This single-center study suggests that more frequent patient transmissions and health care provider reviews of the CardioMEMS system are associated with a decreased number of HFH days, but larger multicentered studies are required. Further systems-based analyses of the CardioMEMS system may be a useful approach to guiding effective use of the CardioMEMS device.

Modeling ultrasound attenuation in porous structures with mono-disperse random pore distributions using the independent scattering approximation: a 2D simulation study.

The validity of the independent scattering approximation (ISA) to predict the frequency dependent attenuation in 2D models of simplified structures of cortical bone is studied. Attenuation of plane waves at central frequencies ranging from 1 to 8 MHz propagating in structures with mono-disperse random pore distributions with pore diameter and pore density in the range of those of cortical bone are evaluated by finite difference time domain numerical simulations. An approach to assess the multiple scattering of waves in random media is discussed to determine the pore diameter ranges at which the ISA is applicable. A modified version of the ISA is proposed to more accurately predict the attenuation in porosity ranges where it would traditionally fail. The results show that the modified ISA can model the frequency-dependent attenuation of ultrasonic wave with pore diameter and density ranges comparable to those of cortical bone.

Predicting Structural Properties of Cortical Bone by Combining Ultrasonic Attenuation and an Artificial Neural Network (ANN): 2-D FDTD Study.

The goal of this paper is to predict the micro-architectural parameters of cortical bone such as pore diameter (ϕ) and porosity (v) from ultrasound attenuation measurements using an artificial neural network (ANN). Slices from a 3-D CT scan of human femur are obtained. The micro-architectural parameters of porosity such as average pore size and porosity are calculated using image processing. When ultrasound waves propagate in porous structures, attenuation is observed due to scattering. Two-dimensional finite-difference time-domain simulations are carried out to obtain frequency dependent attenuation in those 2D structures. An artificial neural network (ANN) is then trained with the input feature vector as the frequency dependent attenuation and output as pore diameter (ϕ) and porosity (v). The ANN is composed of one input layer, 3 hidden layers and one output layer, all of which are fully connected. 340 attenuation data sets were acquired and trained over 2000 epochs with a batch size of 32. Data was split into train, validation and test. It was observed that the ANN predicted the micro-architectural parameters of the cortical bone with high accuracies and low losses with a minimum R2 (goodness of fit) value of 0.95. ANN approaches could potentially help inform the solution of inverse-problems to retrieve bone porosity from ultrasound measurements. Ultimately, those inverse-problems could be used for the non-invasive diagnosis and monitoring of osteoporosis.

The effect of pore size and density on ultrasonic attenuation in porous structures with mono-disperse random pore distribution: A two-dimensional in-silico study.

This work proposes a power law model to describe the attenuation of ultrasonic waves in non-absorbing heterogeneous media with randomly distributed scatterers, mimicking a simplified structure of cortical bone. This paper models the propagation in heterogeneous structures with controlled porosity using a two-dimensional finite-difference time domain numerical simulation in order to measure the frequency dependent attenuation. The paper then fits a phenomenological model to the simulated frequency dependent attenuation by optimizing parameters under an ordinary least squares framework. Local sensitivity analysis is then performed on the resulting parameter estimates in order to determine to which estimates the model is most sensitive. This paper finds that the sensitivity of the model to various parameter estimates depends on the micro-architectural parameters, pore diameter (ϕ) and pore density (ρ). In order to get a sense for how confidently model parameters are able to be estimated, 95% confidence intervals for these estimates are calculated. In doing so, the ability to estimate model-sensitive parameters with a high degree of confidence is established. In the future, being able to accurately estimate model parameters from which micro-architectural ones could be inferred will allow pore density and diameter to be estimated via an inverse problem given real or simulated ultrasonic data to be determined.

Rotors exhibit greater surface ECG variation during ventricular fibrillation than focal sources due to wavebreak, secondary rotors, and meander.

INTRODUCTION: Ventricular fibrillation is a common life-threatening arrhythmia. The ECG of VF appears chaotic but may allow identification of sustaining mechanisms to guide therapy. HYPOTHESIS: We hypothesized that rotors and focal sources manifest distinct features on the ECG, and computational modeling may identify mechanisms of such features. METHODS: VF induction was attempted in 31 patients referred for ventricular arrhythmia ablation. Simultaneous surface ECG and intracardiac electrograms were recorded using biventricular basket catheters. Endocardial phase maps were used to mechanistically classify each VF cycle as rotor or focally driven. ECGs were analyzed from patients demonstrating both mechanisms in the primary analysis and from all patients with induced VF in the secondary analysis. The ECG voltage variation during each mechanism was compared. Biventricular computer simulations of VF driven by focal sources or rotors were created and resulting ECGs of each VF mechanism were compared. RESULTS: Rotor-based VF exhibited greater voltage variation than focal source-based VF in both the primary analysis (n = 8, 110 ± 24% vs. 55 ± 32%, P = 0.02) and the secondary analysis (n = 18, 103 ± 30% vs. 67 ± 34%, P = 0.009). Computational VF simulations also revealed greater voltage variation in rotors compared to focal sources (110 ± 19% vs. 33 ± 16%, P = 0.001), and demonstrated that this variation was due to wavebreak, secondary rotor initiation, and rotor meander. CONCLUSION: Clinical and computational studies reveal that quantitative criteria of ECG voltage variation differ significantly between VF-sustaining rotors and focal sources, and provide insight into the mechanisms of such variation. Future studies should prospectively evaluate if these criteria can separate clinical VF mechanisms and guide therapy.

Effects of pressure variation and atrial fibrillation on CardioMEMS™ HF measured pulmonary artery diastolic pressure: comparison of device-averaged and visually inspected waveforms.

OBJECTIVE: Heart failure (HF) management guided by implantable hemodynamic monitoring reduces hospitalization rates. Hemodynamic data from the CardioMEMS™ HF system includes device-averaged pulmonary artery pressures (PAP) and heart rate. Agreement of device-averaged values compared to the standard method of visual inspection of pressure waveforms at end-expiration is unknown. We evaluated the agreement between device-averaged and visually inspected end-expiratory PAP. APPROACH: Twenty-one patients implanted with the CardioMEMS™ HF system were evaluated. Eight-hundred twenty-three PAP waveforms from the Merlin remote monitoring website were visually inspected and pulmonary artery systolic pressure (PASP) and pulmonary artery diastolic pressure (PADP) at end-expiration were recorded. Waveforms were evaluated for pressure variation (PV), defined as the difference between highest and lowest PASP measurement of ⩾20 mmHg. Bland-Altman analysis quantified differences between device-averaged and visually inspected waveforms. MAIN RESULTS: All patients were NYHA functional class III, mean age was 67 ± 15 years and 15 (71%) had AF. Bland-Altman analysis of all waveforms revealed a mean-difference in PADP of -1.4 mmHg, indicating that visually inspected values were higher than device-averaged values. For PV ⩾20 mmHg, this value increased to -2.8 mmHg. The mean-difference comparing waveforms from patients with or without AF was -1.3 and -1.6 mmHg, respectively. The 95% limits of agreement were >50% wider for waveforms from patients with versus without AF (10.3 versus 6.7 mmHg). SIGNIFICANCE: There is good agreement between device-averaged and visually inspected waveforms when pressure variation is <20 mmHg and for patients without atrial fibrillation.

Outcomes of lead extraction without subsequent device reimplantation.

AIMS: Outcomes among patients who do not receive device reimplantation after cardiovascular implantable electronic device (CIED) extraction have not been well studied. The present study aims to investigate the outcomes of patients without device reimplantation after lead extraction and device removal. METHODS AND RESULTS: We retrospectively searched for consecutive patients who underwent CIED extraction at Mayo Clinic, Rochester, MN and University of California San Diego Medical Center from 2001 through 2012. Among the patients identified, we compared characteristics of those who did and did not have device reimplantation. The Kaplan-Meier survival was analysed. Among 678 patients, 97 patients had their device extracted without reimplantation during 1-year follow-up ('no-reimplant group'). Median age was younger in the no-reimplant group (60.7 vs. 70.6 years; P < 0.001). The reasons for no reimplantation were as follows: no longer meeting criteria for CIED (48%), inappropriate device indication at initial implantation (23%), patient preference (17%), and unresolved device complications (12%). Three major arrhythmias were reported in the no-reimplant group. Overall survival in the no-reimplant group was significantly lower than in the reimplant group (60 vs. 93%; P < 0.001). Ongoing device-related complications [hazard ratio (HR), 3.91; 95% CI, 1.74-8.81; P = 0.001], infection (HR, 3.06; 95% CI, 1.24-7.52; P = 0.02), and concurrent dialysis (HR, 2.74; 95% CI, 1.12-6.71; P = 0.03) were associated with increased mortality. Of 31 deaths in the no-reimplant group, 1 was secondary to cardiac arrhythmia. CONCLUSION: Fourteen per cent of patients who had device extraction did not undergo reimplantation mainly because they no longer met CIED indications. The high mortality in these patients is related to device complications and comorbid conditions, whereas mortality associated with arrhythmia is rare.

Clock drawing in children with perinatal stroke.

BACKGROUND: Children with perinatal stroke may show evidence of contralateral spatial neglect. The goal of this study was to determine whether the Clock Drawing Test commonly used in adults to identify neglect would be effective in detecting neglect in children with perinatal stroke. METHODS: Thirty-eight individuals (age range 6-21 years) with left hemisphere or right hemisphere perinatal onset unilateral lesions and 179 age-matched controls were given a free-drawn Clock Drawing Test in a cross-sectional design. An adapted scoring system that evaluated right- and left-sided errors separately was developed as part of the investigation. RESULTS: Children with right hemisphere lesions made a greater number of errors on both the right and left sides of the clock drawings in all age subgroups (6-8 years, 9-14 years, and 15-21 years) compared with controls. Children with right hemisphere lesions showed greater left and right errors in the younger groups compared with controls, with significantly poorer performance on the left at 6-8 years, suggestive of contralateral neglect. However, by ages 15-21 years, the right hemisphere lesion subjects no longer differed from controls. CONCLUSIONS: Clock drawing can identify spatial neglect in children with early hemispheric damage. However, brain development is a dynamic process, and as children age, spatial neglect may no longer be evident. These findings demonstrate the limitations of predicting long-term outcome after perinatal stroke from early neurocognitive data. Children with perinatal stroke may require different neural pathways to accomplish specific skills or to overcome deficits, but ultimately they may have "typical" outcomes.