Differential dose responses of transcranial focused ultrasound at brain regions indicate causal interactions.

We have previously shown that focused ultrasound (FUS) pulses in low pressure range exerted bidirectional and brain state-dependent neuromodulation in the nonhuman primate somatosensory cortices by fMRI. Here we aim to gain insights about the proposed neuron selective modulation of FUS and probe feedforward versus feedback interactions by simultaneously quantifying the stimulus (FUS pressures: 925, 425, 250 kPa) and response (% BOLD fMRI changes) function at the targeted area 3a/3b and off-target cortical areas at 7T. In resting-state, lowered intensities of FUS resulted in decreased fMRI signal changes at the target area 3a/3b and off-target area 1/2, S2, MCC, insula and auditory cortex, and no signal difference in thalamic VPL and MD nuclei. In activated states, concurrent high-intensity FUS significantly enhanced touch-evoked signals in area 1/2. Medium- and low-intensity FUS significantly suppressed touch-evoked BOLD signals in all areas except in the auditory cortex, VPL and MD thalamic nuclei. Distinct state dependent and dose-response curves led us to hypothesize that FUS's neuromodulatory effects may be mediated through preferential activation of different populations of neurons. Area 3a/3b may have distinct causal feedforward and feedback interactions with Area 1/2, S2, MCC, insula, and VPL. FUS offers a noninvasive neural stimulation tool for dissecting brain circuits and probing causal functional connections.

A reduced aperture allows for transcranial focus localization at lower pressure.

Localizing the focus during transcranial focused ultrasound procedures is important to ensure accurate targeting of specific brain regions and interpretation of results. Magnetic resonance acoustic radiation force imaging uses the displacement induced by the ultrasound focus in the brain to localize the beam, but the high pressure required to displace brain tissue may cause damage or confounds during subsequent neuromodulatory experiments. Here, reduced apertures were applied to a phased array transducer to generate comparable displacement to the full aperture but with 20% lower free field pressure.

Conditional Vasospasm-Free Survival Following Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Following aneurysmal subarachnoid hemorrhage (SAH), patients are monitored closely for vasospasm in the intensive care unit. Conditional vasospasm-free survival describes the risk of future vasospasm as a function of time elapsed without vasospasm. Conditional survival has not been applied to this clinical scenario but could improve patient counseling and intensive care unit use. The objective of this study was to characterize conditional vasospasm-free survival following SAH. METHODS: This was a single institution, retrospective cohort study of patients treated for aneurysmal SAH between 1/1/2000-6/1/2020. The primary outcome was the development of vasospasm defined by the first instance of either radiographic vasospasm on computed tomography angiography, Lindegaard Index > 3.0 by transcranial doppler ultrasonography, or vasospasm-specific intraarterial therapy. Multivariable Cox regression was performed, and conditional vasospasm-free survival curves were constructed. RESULTS: A total of 528 patients were treated for aneurysmal SAH and 309 (58.5%) developed vasospasm. Conditional survival curves suggest patients who survive to postbleed day 10 without vasospasm have a nearly 90% chance of being discharged without vasospasm. The median onset of vasospasm was postbleed day 6. Age more than 50 years was associated with a lower risk (hazard ratio [HR] = .76; 95% confidence interval [CI] 0.64-0.91; p < 0.001). Higher initial systolic blood pressure (HR = 1.18; 95% CI 1.046-1.350; p = .008), Hunt-Hess grades 4 or 5 (HR = 1.304; 95% CI 1.014-1.676), and modified Fisher scale score of 4 (HR = 1.808; 95% CI 1.198-2.728) were associated with higher vasospasm than the respective lower grades. CONCLUSION: Conditional survival provides a useful framework for counseling patients and making decisions around vasospasm risk for patients with aneurysmal SAH, while risk factor-stratified plots facilitate a patient-centric, evidence-based approach to these conversations and decisions.

Impact of postoperative dexamethasone on survival, steroid dependency, and infections in newly diagnosed glioblastoma patients.

BACKGROUND: We examined the effect of dexamethasone prescribed in the initial 3 postoperative weeks on survival, steroid dependency, and infection in glioblastoma patients. METHODS: In this single-center retrospective cohort analysis, we electronically retrieved inpatient administration and outpatient prescriptions of dexamethasone and laboratory values from the medical record of 360 glioblastoma patients. We correlated total dexamethasone prescribed from postoperative day (POD) 0 to 21 with survival, dexamethasone prescription from POD30 to POD90, and diagnosis of an infection by POD90. These analyses were adjusted for age, Karnofsky performance status score, tumor volume, extent of resection, IDH1/2 tumor mutation, tumor MGMT promoter methylation, temozolomide and radiotherapy initiation, and maximum blood glucose level. RESULTS: Patients were prescribed a median of 159 mg [109-190] of dexamethasone cumulatively by POD21. Every 16-mg increment (4 mg every 6 hours/day) of total dexamethasone associated with a 4% increase in mortality (95% confidence interval [CI] 1%-7%, P < .01), 12% increase in the odds of being prescribed dexamethasone from POD30 to POD90 (95% CI 6%-19%, P < .01), and 10% increase in the odds of being diagnosed with an infection (95% CI, 4%-17%, P < .01). Of the 175 patients who had their absolute lymphocyte count measured in the preoperative week, 80 (45.7%) had a value indicative of lymphopenia. In the POD1-POD28 period, this proportion was 82/167 (49.1%). CONCLUSIONS: Lower survival, steroid dependency, and higher infection rate in glioblastoma patients associated with higher dexamethasone administration in the initial 3 postoperative weeks. Nearly half of the glioblastoma patients are lymphopenic preoperatively and up to 1 month postoperatively.

Bidirectional and state-dependent modulation of brain activity by transcranial focused ultrasound in non-human primates.

Transcranial focused ultrasound (FUS) stimulation under MRI guidance, coupled with functional MRI (fMRI) monitoring of effects, offers a precise, noninvasive technology to dissect functional brain circuits and to modulate altered brain functional networks in neurological and psychiatric disorders. Here we show that ultrasound at moderate intensities modulated neural activity bi-directionally. Concurrent sonication of somatosensory areas 3a/3b with 250 kHz FUS suppressed the fMRI signals produced there by peripheral tactile stimulation, while at the same time eliciting fMRI activation at inter-connected, off-target brain regions. Direct FUS stimulation of the cortex resulted in different degrees of BOLD signal changes across all five off-target regions, indicating that its modulatory effects on active and resting neurons differed. This is the first demonstration of the dual suppressive and excitative modulations of FUS on a specific functional circuit and of ability of concurrent FUS and MRI to evaluate causal interactions between functional circuits with neuron-class selectivity.

Hyperoxemia and Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Cerebral vasospasm is a major contributor to disability and mortality after aneurysmal subarachnoid hemorrhage. Oxidation of cell-free hemoglobin plays an integral role in neuroinflammation and is a suggested source of tissue injury after aneurysm rupture. This study sought to determine whether patients with subarachnoid hemorrhage and cerebral vasospasm were more likely to have been exposed to early hyperoxemia than those without vasospasm. METHODS: This single-center retrospective cohort study included adult patients presenting with aneurysmal subarachnoid hemorrhage to Vanderbilt University Medical Center between January 2007 and December 2017. Patients with an ICD-9/10 diagnosis of aneurysmal subarachnoid hemorrhage were initially identified (N = 441) and subsequently excluded if they did not have intracranial imaging, arterial PaO2 values or died within 96 h post-rupture (N = 96). The final cohort was 345 subjects. The degree of hyperoxemia was defined by the highest PaO2 measured within 72 h after aneurysmal rupture. The primary outcome was development of cerebral vasospasm, which included asymptomatic vasospasm and delayed cerebral ischemia (DCI). Secondary outcomes were mortality and modified Rankin Scale. RESULTS: Three hundred and forty five patients met inclusion criteria; 218 patients (63%) developed vasospasm. Of those that developed vasospasm, 85 were diagnosed with delayed cerebral ischemia (DCI, 39%). The average patient age of the cohort was 55 ± 13 years, and 68% were female. Ninety percent presented with Fisher grade 3 or 4 hemorrhage (N = 310), while 42% presented as Hunt-Hess grade 4 or 5 (N = 146). In univariable analysis, patients exposed to higher levels of PaO2 by quintile of exposure had a higher mortality rate and were more likely to develop vasospasm in a dose-dependent fashion (P = 0.015 and P = 0.019, respectively). There were no statistically significant predictors that differentiated asymptomatic vasospasm from DCI and no significant difference in maximum PaO2 between these two groups. In multivariable analysis, early hyperoxemia was independently associated with vasospasm (OR = 1.15 per 50 mmHg increase in PaO2 [1.03, 1.28]; P = 0.013), but not mortality (OR = 1.10 [0.97, 1.25]; P = 0.147) following subarachnoid hemorrhage. CONCLUSIONS: Hyperoxemia within 72 h post-aneurysmal rupture is an independent predictor of cerebral vasospasm, but not mortality in subarachnoid hemorrhage. Hyperoxemia is a variable that can be readily controlled by adjusting the delivered FiO2 and may represent a modifiable risk factor for vasospasm.

Considerations for ultrasound exposure during transcranial MR acoustic radiation force imaging.

The aim of this study was to improve the sensitivity of magnetic resonance-acoustic radiation force imaging (MR-ARFI) to minimize pressures required to localize focused ultrasound (FUS) beams, and to establish safe FUS localization parameters for ongoing ultrasound neuromodulation experiments in living non-human primates. We developed an optical tracking method to ensure that the MR-ARFI motion-encoding gradients (MEGs) were aligned with a single-element FUS transducer and that the imaged slice was prescribed at the optically tracked location of the acoustic focus. This method was validated in phantoms, which showed that MR-ARFI-derived displacement sensitivity is maximized when the MR-ARFI MEGs were maximally aligned with the FUS propagation direction. The method was then applied in vivo to acquire displacement images in two healthy macaque monkeys (M fascicularis) which showed the FUS beam within the brain. Temperature images were acquired using MR thermometry to provide an estimate of in vivo brain temperature changes during MR-ARFI, and pressure and thermal simulations of the acoustic pulses were performed using the k-Wave package which showed no significant heating at the focus of the FUS beam. The methods presented here will benefit the multitude of transcranial FUS applications as well as future human applications.

Volumetric MRI thermometry using a three-dimensional stack-of-stars echo-planar imaging pulse sequence.

PURPOSE: To measure temperature over a large brain volume with fine spatiotemporal resolution. METHODS: A three-dimensional stack-of-stars echo-planar imaging sequence combining echo-planar imaging and radial sampling with golden angle spacing was implemented at 3T for proton resonance frequency-shift temperature imaging. The sequence acquires a 188x188x43 image matrix with 1.5x1.5x2.75 mm3 spatial resolution. Temperature maps were reconstructed using sensitivity encoding (SENSE) image reconstruction followed by the image domain hybrid method, and using the k-space hybrid method. In vivo temperature maps were acquired without heating to measure temperature precision in the brain, and in a phantom during high-intensity focused ultrasound sonication. RESULTS: In vivo temperature standard deviation was less than 1°C at dynamic scan times down to 0.75 s. For a given frame rate, scanning at a minimum repetition time (TR) with minimum acceleration yielded the lowest standard deviation. With frame rates around 3 s, the scan was tolerant to a small number of receive coils, and temperature standard deviation was 48% higher than a standard two-dimensional Fourier transform temperature mapping scan, but provided whole-brain coverage. Phantom temperature maps with no visible aliasing were produced for dynamic scan times as short as 0.38 s. k-Space hybrid reconstructions were more tolerant to acceleration. CONCLUSION: Three-dimensional stack-of-stars echo-planar imaging temperature mapping provides volumetric brain coverage and fine spatiotemporal resolution. Magn Reson Med 79:2003-2013, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Snapshot MR technique to measure OEF using rapid frequency mapping.

Magnetic resonance (MR)-based oxygen extraction fraction (OEF) measurement techniques that use blood oxygen level-dependent (BOLD)-based approaches require the measurement of the R2' decay rate and deoxygenated blood volume to derive the local oxygen saturation in vivo. We describe here a novel approach to measure OEF using rapid local frequency mapping. By modeling the MR decay process in the static dephasing regime as two separate dissipative and oscillatory effects, we calculate the OEF from local frequencies measured across the brain by assuming that the biophysical mechanisms causing OEF-related frequency changes can be determined from the oscillatory effects. The Parameter Assessment by Retrieval from Signal Encoding (PARSE) technique was used to acquire the local frequency change maps. The PARSE images were taken on 11 normal volunteers, and 1 patient exhibiting hemodynamic stress. The mean MR-OEF in 11 normal subjects was 36.66±7.82%, in agreement with positron emission tomography (PET) literature. In regions of hemodynamic stress induced by vascular steal, OEF exhibits the predicted focal increases. These preliminary results show that it is possible to measure OEF using a rapid frequency mapping technique. Such a technique has numerous advantages including speed of acquisition, is noninvasive, and has sufficient spatial and temporal resolution.

RAZER: a pulse sequence for whole-brain bolus tracking at high frame rates.

PURPOSE: To introduce a pulse sequence that obtains whole-brain perfusion measurements at 1.7 mm isotropic voxel resolution by dynamic susceptibility contrast MRI bolus tracking despite using a temporal resolution of 10.3 s: RAdial kZ-blipped 3D GRE-echo-planar imaging (GRE-EPI) for whole-brain pERfusion (RAZER). METHODS: In RAZER, in-plane radial and through-plane 3D GRE-EPI Cartesian sampling was used to produce a 3D stack-of-stars k-space. In vivo scans on one healthy volunteer and one patient with Moyamoya disease were performed using RAZER and a typical 2D GRE-EPI pulse sequence as a reference standard. Agreement in perfusion metrics was reported using linear regression analysis and Bland-Altman plots. RESULTS: Sliding window reconstruction recovered dynamic information lost in the large temporal acquisition window of RAZER. Inline phase correction scans corrected N/2 ghosting artifacts and view-dependent phase variations. Whole-brain images of cerebral blood volume, cerebral blood flow, and mean transit time were calculated with RAZER at 1.7 mm isotropic voxel resolution and good reference standard agreement in both subjects when sliding window reconstruction was used (r(2) > 0.7, mean bias in mean transit time measurements < 0.5 s). CONCLUSIONS: Despite using a temporal resolution of 10.3 s, in vivo data indicates that RAZER is able to obtain whole-brain perfusion measurements at 1.7 mm isotropic voxel resolution and good reference standard agreement.