A Basal Forebrain-Cingulate Circuit in Macaques Decides It Is Time to Act.

The medial frontal cortex has been linked to voluntary action, but an explanation of why decisions to act emerge at particular points in time has been lacking. We show that, in macaques, decisions about whether and when to act are predicted by a set of features defining the animal's current and past context; for example, respectively, cues indicating the current average rate of reward and recent previous voluntary action decisions. We show that activity in two brain areas-the anterior cingulate cortex and basal forebrain-tracks these contextual factors and mediates their effects on behavior in distinct ways. We use focused transcranial ultrasound to selectively and effectively stimulate deep in the brain, even as deep as the basal forebrain, and demonstrate that alteration of activity in the two areas changes decisions about when to act.

Potential impact of thermal effects during ultrasonic neurostimulation: retrospective numerical estimation of temperature elevation in seven rodent setups.

In the past decade, a handful but growing number of groups have reported worldwide successful low intensity focused ultrasound induced neurostimulation trials on rodents. Its effects range from movement elicitations to reduction of anesthesia time or reduction of the duration of drug induced seizures. The mechanisms underlying ultrasonic neuromodulation are still not fully understood. Given the low intensities used in most of the studies, a mechanical effect is more likely to be responsible for the neuromodulation effect, but a clear description of the thermal and mechanical effects is necessary to optimize clinical applications. Based on five studies settings, we calculated the temperature rise and thermal doses in order to evaluate its implication in the neuromodulation phenomenon. Our retrospective analysis shows thermal rise ranging from 0.002 °C to 0.8 °C in the brain for all setups, except for one setup for which the temperature increase is estimated to be as high as 7 °C. We estimate that in the latter case, temperature rise cannot be neglected as a possible cause of neuromodulation. Simulations results were supported by temperature measurements on a mouse with two different sets of parameters. Although the calculated temperature is compatible with the absence of visible thermal lesions on the skin, it is high enough to impact brain circuits. Our study highlights the usefulness of performing thermal simulations prior to experiment in order to fully take into account not only the impact of the peak intensity but also pulse duration and pulse repetition.

MR-Guided Transcranial Focused Ultrasound.

Previous chapters introduced the ability of using focused ultrasound to ablate tissues. It has led to various clinical applications in the treatment of uterine fibroid, prostate or liver cancers. Nevertheless, treating the brain non-invasively with focused ultrasound has been considered beyond reach for almost a century: The skull bone protects the brain from mechanical injuries, but it also reflects and refracts ultrasound, making it difficult to target the brain with focused ultrasound. Fortunately, aberration correction techniques have been developed recently and thermal lesioning in the thalamus has been achieved clinically. This chapter introduces the aberration effect of the skull bone and how it can be corrected non-invasively. It also presents the latest clinical results obtained with thermal ablation and introduces novel non-thermal approaches that could revolutionize brain therapy in the future.

Intracranial inertial cavitation threshold and thermal ablation lesion creation using MRI-guided 220-kHz focused ultrasound surgery: preclinical investigation.

OBJECT: In biological tissues, it is known that the creation of gas bubbles (cavitation) during ultrasound exposure is more likely to occur at lower rather than higher frequencies. Upon collapsing, such bubbles can induce hemorrhage. Thus, acoustic inertial cavitation secondary to a 220-kHz MRI-guided focused ultrasound (MRgFUS) surgery is a serious safety issue, and animal studies are mandatory for laying the groundwork for the use of low-frequency systems in future clinical trials. The authors investigate here the in vivo potential thresholds of MRgFUS-induced inertial cavitation and MRgFUS-induced thermal coagulation using MRI, acoustic spectroscopy, and histology. METHODS: Ten female piglets that had undergone a craniectomy were sonicated using a 220-kHz transcranial MRgFUS system over an acoustic energy range of 5600-14,000 J. For each piglet, a long-duration sonication (40-second duration) was performed on the right thalamus, and a short sonication (20-second duration) was performed on the left thalamus. An acoustic power range of 140-300 W was used for long-duration sonications and 300-700 W for short-duration sonications. Signals collected by 2 passive cavitation detectors were stored in memory during each sonication, and any subsequent cavitation activity was integrated within the bandwidth of the detectors. Real-time 2D MR thermometry was performed during the sonications. T1-weighted, T2-weighted, gradient-recalled echo, and diffusion-weighted imaging MRI was performed after treatment to assess the lesions. The piglets were killed immediately after the last series of posttreatment MR images were obtained. Their brains were harvested, and histological examinations were then performed to further evaluate the lesions. RESULTS: Two types of lesions were induced: thermal ablation lesions, as evidenced by an acute ischemic infarction on MRI and histology, and hemorrhagic lesions, associated with inertial cavitation. Passive cavitation signals exhibited 3 main patterns identified as follows: no cavitation, stable cavitation, and inertial cavitation. Low-power and longer sonications induced only thermal lesions, with a peak temperature threshold for lesioning of 53°C. Hemorrhagic lesions occurred only with high-power and shorter sonications. The sizes of the hemorrhages measured on macroscopic histological examinations correlated with the intensity of the cavitation activity (R2 = 0.74). The acoustic cavitation activity detected by the passive cavitation detectors exhibited a threshold of 0.09 V·Hz for the occurrence of hemorrhages. CONCLUSIONS: This work demonstrates that 220-kHz ultrasound is capable of inducing a thermal lesion in the brain of living swines without hemorrhage. Although the same acoustic energy can induce either a hemorrhage or a thermal lesion, it seems that low-power, long-duration sonication is less likely to cause hemorrhage and may be safer. Although further study is needed to decrease the likelihood of ischemic infarction associated with the 220-kHz ultrasound, the threshold established in this work may allow for the detection and prevention of deleterious cavitations.

A magnetic resonance imaging, histological, and dose modeling comparison of focused ultrasound, radiofrequency, and Gamma Knife radiosurgery lesions in swine thalamus.

OBJECT: The purpose of this study was to use MRI and histology to compare stereotactic lesioning modalities in a large brain model of thalamotomy. METHODS: A unilateral thalamotomy was performed in piglets utilizing one of 3 stereotactic lesioning modalities: focused ultrasound (FUS), radiofrequency, and radiosurgery. Standard clinical lesioning parameters were used for each treatment; and clinical, MRI, and histological assessments were made at early (< 72 hours), subacute (1 week), and later (1-3 months) time intervals. RESULTS: Histological and MRI assessment showed similar development for FUS and radiofrequency lesions. T2-weighted MRI revealed 3 concentric lesional zones at 48 hours with resolution of perilesional edema by 1 week. Acute ischemic infarction with macrophage infiltration was most prominent at 72 hours, with subsequent resolution of the inflammatory reaction and coalescence of the necrotic zone. There was no apparent difference in ischemic penumbra or "sharpness" between FUS or radiofrequency lesions. The radiosurgery lesions presented differently, with latent effects, less circumscribed lesions at 3 months, and apparent histological changes seen in white matter beyond the thalamic target. Additionally, thermal and radiation lesioning gradients were compared with modeling by dose to examine the theoretical penumbra. CONCLUSIONS: In swine thalamus, FUS and radiosurgery lesions evolve similarly as determined by MRI, histological examination, and theoretical modeling. Radiosurgery produces lesions with more delayed effects and seemed to result in changes in the white matter beyond the thalamic target.

Direct phase projection and transcranial focusing of ultrasound for brain therapy.

Ultrasound can be used to noninvasively treat the human brain with hyperthermia by focusing through the skull. To obtain an accurate focus, especially at high frequencies (>500 kHz), the phase of the transmitted wave must be modified to correct the aberrations introduced by the patient's individual skull morphology. Currently, three-dimensional finite-difference time-domain simulations are used to model a point source at the target. The outward-propagating wave crosses the measured representation of the human skull and is recorded at the therapy array transducer locations. The signal is then time reversed and experimentally transmitted back to its origin. These simulations are resource intensive and add a significant delay to treatment planning. Ray propagation is computationally efficient because it neglects diffraction and only describes two propagation parameters: the wave's direction and the phase. We propose a minimal method that is based only on the phase. The phase information is projected from the external skull surface to the array locations. This replaces computationally expensive finite-difference computations with an almost instantaneous direct phase projection calculation. For the five human skull samples considered, the phase distribution outside of the skull is shown to vary by less than λ/20 as it propagates over a 5 cm distance and the validity of phase projection is established over these propagation distances. The phase aberration introduced by the skull is characterized and is shown to have a good correspondence with skull morphology. The shape of this aberration is shown to have little variation with propagation distance. The focusing quality with the proposed phase-projection algorithm is shown to be indistinguishable from the gold-standard full finite-difference simulation. In conclusion, a spherical wave that is aberrated by the skull has a phase propagation that can be accurately described as radial, even after it has been distorted. By combining finite-difference simulations with a phase-projection algorithm, the time required for treatment planning is significantly reduced. The correlation length of the phase is used to validate the algorithm and it can also be used to provide guiding parameters for clinical array transducer design in terms of transducer spacing and phase error.

Physical performance and image optimization of megavoltage cone-beam CT.

Megavoltage cone-beam CT (MVCBCT) is the most recent addition to the in-room CT systems developed for image-guided radiation therapy. The first generation MVCBCT system consists of a 6 MV treatment x-ray beam produced by a conventional linear accelerator equipped with a flat panel amorphous silicon detector. The objective of this study was to evaluate the physical performance of MVCBCT in order to optimize the system acquisition and reconstruction parameters for image quality. MVCBCT acquisitions were performed with the clinical system but images were reconstructed and analyzed with a separate research workstation. The geometrical stability and the positioning accuracy of the system were evaluated by comparing geometrical calibrations routinely performed over a period of 12 months. The beam output and detector intensity stability during MVCBCT acquisition were also evaluated by analyzing in-air acquisitions acquired at different exposure levels. Several system parameters were varied to quantify their impact on image quality including the exposure (2.7, 4.5, 9.0, 18.0, and 54.0 MU), the craniocaudal imaging length (2, 5, 15, and 27.4 cm), the voxel size (0.5, 1, and 2 mm), the slice thickness (1, 3, and 5 mm), and the phantom size. For the reconstruction algorithm, the study investigated the effect of binning, averaging and diffusion filtering of raw projections as well as three different projection filters. A head-sized water cylinder was used to measure and improve the uniformity of MVCBCT images. Inserts of different electron densities were placed in a water cylinder to measure the contrast-to-noise ratio (CNR). The spatial resolution was obtained by measuring the point-spread function of the system using an iterative edge blurring technique. Our results showed that the geometric stability and accuracy of MVCBCT were better than 1 mm over a period of 12 months. Beam intensity variations per projection of up to 35.4% were observed for a 2.7 MU MVCBCT acquisition. These variations did not cause noticeable reduction in the image quality. The results on uniformity suggest that the cupping artifact occurring with MVCBCT is mostly due to off-axis response of the detector and not scattered radiation. Simple uniformity correction methods were developed to nearly eliminate this cupping artifact. The spatial resolution of the baseline MVCBCT reconstruction protocol was approximately 2 mm. An optimized reconstruction protocol was developed and showed an improvement of 75% in CNR with a penalty of only 8% in spatial resolution. Using this new reconstruction protocol, large adipose and muscular structures were differentiated at an exposure of 9 MU. A reduction of 36% in CNR was observed on a larger (pelvic-sized) phantom. This study demonstrates that soft-tissue visualization with MVCBCT can be substantially improved with proper system settings. Further improvement is expected from the next generation MVCBCT system with an optimized megavoltage imaging beamline.

Dose recalculation and the Dose-Guided Radiation Therapy (DGRT) process using megavoltage cone-beam CT.

PURPOSE: At the University of California San Francisco, daily or weekly three-dimensional images of patients in treatment position are acquired for image-guided radiation therapy. These images can be used for calculating the actual dose delivered to the patient during treatment. In this article, we present the process of performing dose recalculation on megavoltage cone-beam computed tomography images and discuss possible strategies for dose-guided radiation therapy (DGRT). MATERIALS AND METHODS: A dedicated workstation has been developed to incorporate the necessary elements of DGRT. Patient image correction (cupping, missing data artifacts), calibration, completion, recontouring, and dose recalculation are all implemented in the workstation. Tools for dose comparison are also included. Examples of image correction and dose analysis using 6 head-and-neck and 2 prostate patient datasets are presented to show possible tracking of interfraction dosimetric endpoint variation over the course of treatment. RESULTS: Analysis of the head-and-neck datasets shows that interfraction treatment doses vary compared with the planning dose for the organs at risk, with the mean parotid dose and spinal cord D(1) increasing by as much as 52% and 10%, respectively. Variation of the coverage to the target volumes was small, with an average D(5) dose difference of 1%. The prostate patient datasets revealed accurate dose coverage to the targeted prostate and varying interfraction dose distributions to the organs at risk. CONCLUSIONS: An effective workflow for the clinical implementation of DGRT has been established. With these techniques in place, future clinical developments in adaptive radiation therapy through daily or weekly dosimetric measurements of treatment day images are possible.

Correction of megavoltage cone-beam CT images of the pelvic region based on phantom measurements for dose calculation purposes.

Megavoltage cone-beam CT (MVCBCT) is an imaging technology that provides a 3D representation of the patient in treatment position. Because it is a form of x-ray tomography, MVCBCT images give information about the attenuation coefficients of the imaged tissues, and thus could be used for dose calculation. However, the cupping and missing data artifacts seen on MVCBCT images can cause inaccuracies in dose calculations. To eliminate these inaccuracies, a correction method specific to pelvis imaging and based on phantom measurements has been devised. Pelvis-shaped water phantoms of three different sizes were designed and imaged with MVCBCT. Three sets of correction factors were created from the artifacts observed in these MVCBCT images by dividing the measured CT number by the predefined CT number for water. Linear interpolation is performed between the sets of correction factors to take into account the varying size of different patients. To compensate for the missing anatomy due to the limited field of view of the MVCBCT system, the MVCBCT image is complemented with the kilovoltage CT (kVCT) image acquired for treatment planning.When the correction method is applied to an anthropomorphic pelvis phantom, the standard deviation between dose calculations performed with kVCT and MVCBCT images is 0.6%, with 98% of the dose points agreeing within +/- 3%.With uncorrected MVCBCT images this percentage falls to 75%. An example of dose calculation performed with a corrected clinicalMVCBCT image of a prostate cancer patient shows that changes in anatomy of normal tissues result in variation of the dose distribution received by these tissues.This correction method enablesMVCBCT images to be used for the verification of the daily dose distribution for patients treated in the pelvis region.

Correction of megavoltage cone-beam CT images for dose calculation in the head and neck region.

Megavoltage cone-beam computed tomography (MVCBCT) imaging systems are now available for image-guided radiation therapy delivery and verification. In order to use the three-dimensional anatomical information for dose calculation, the MVCBCT image must provide accurate electron density. This work proposes a new method that has been developed to correct for the cupping and missing data artifacts seen on MVCBCT images of the head and neck region. It uses a conventional kilovoltage CT (kVCT) image as a reference for electron density and rigid registration with a MVCBCT image to obtain correction factors. Dose calculations performed on MVCBCT images corrected with the proposed method agree with calculations done on kVCT images within +/- 1% on phantoms. With patients images the agreement is within +/- 13% above the shoulders and +/- 5% below the shoulder line. This level of dose calculation accuracy allows the use of MVCBCT images for dose verification purposes.

Dose calculation using megavoltage cone-beam CT.

PURPOSE: To demonstrate the feasibility of performing dose calculation on megavoltage cone-beam CT (MVCBCT) of head-and-neck patients in order to track the dosimetric errors produced by anatomic changes. METHODS AND MATERIALS: A simple geometric model was developed using a head-size water cylinder to correct an observed cupping artifact occurring with MVCBCT. The uniformity-corrected MVCBCT was calibrated for physical density. Beam arrangements and weights from the initial treatment plans defined using the conventional CT were applied to the MVCBCT image, and the dose distribution was recalculated. The dosimetric inaccuracies caused by the cupping artifact were evaluated on the water phantom images. An ideal test patient with no observable anatomic changes and a patient imaged with both CT and MVCBCT before and after considerable weight loss were used to clinically validate MVCBCT for dose calculation and to determine the dosimetric impact of large anatomic changes. RESULTS: The nonuniformity of a head-size water phantom ( approximately 30%) causes a dosimetric error of less than 5%. The uniformity correction method developed greatly reduces the cupping artifact, resulting in dosimetric inaccuracies of less than 1%. For the clinical cases, the agreement between the dose distributions calculated using MVCBCT and CT was better than 3% and 3 mm where all tissue was encompassed within the MVCBCT. Dose-volume histograms from the dose calculations on CT and MVCBCT were in excellent agreement. CONCLUSION: MVCBCT can be used to estimate the dosimetric impact of changing anatomy on several structures in the head-and-neck region.