A preclinical study of diffusion-weighted MRI contrast as an early indicator of thermal ablation.

PURPOSE: Intraoperative T2 -weighted (T2-w) imaging unreliably captures image contrast specific to thermal ablation after transcranial MR-guided focused ultrasound surgery, impeding dynamic imaging feedback. Using a porcine thalamotomy model, we test the unproven hypothesis that intraoperative DWI can improve dynamic feedback by detecting lesioning within 30 minutes of transcranial MR-guided focused ultrasound surgery. METHODS: Twenty-five thermal lesions were formed in six porcine models using a clinical transcranial MR-guided focused ultrasound surgery system. A novel diffusion-weighted pulse sequence monitored the formation of T2-w and diffusion-weighted lesion contrast after ablation. Using postoperative T2-w contrast to indicate lesioning, apparent intraoperative image contrasts and diffusion coefficients at each lesion site were computed as a function of time after ablation, observed peak temperature, and observed thermal dose. Lesion sizes segmented from imaging and thermometry were compared. Image reviewers estimated the time to emergence of lesion contrast. Intraoperative image contrasts were analyzed using receiver operator curves. RESULTS: On average, the apparent diffusion coefficient at lesioned sites decreased within 5 minutes after ablation relative to control sites. In-plane lesion areas on intraoperative DWI varied from postoperative T2-w MRI and MR thermometry by 9.6±9.7 mm2 and -4.0±7.1 mm2 , respectively. The 0.25, 0.5, and 0.75 quantiles of the earliest times of observed T2-w and diffusion-weighted lesion contrast were 10.7, 21.0, and 27.8 minutes and 3.7, 8.6, and 11.8 minutes, respectively. The T2-w and diffusion-weighted contrasts and apparent diffusion coefficient values produced areas under the receiver operator curve of 0.66, 0.80, and 0.74, respectively. CONCLUSION: Intraoperative DWI can detect MR-guided focused ultrasound surgery lesion formation in the brain within several minutes after treatment.

Histologic safety of transcranial focused ultrasound neuromodulation and magnetic resonance acoustic radiation force imaging in rhesus macaques and sheep.

BACKGROUND: Neuromodulation by transcranial focused ultrasound (FUS) offers the potential to non-invasively treat specific brain regions, with treatment location verified by magnetic resonance acoustic radiation force imaging (MR-ARFI). OBJECTIVE: To investigate the safety of these methods prior to widespread clinical use, we report histologic findings in two large animal models following FUS neuromodulation and MR-ARFI. METHODS: Two rhesus macaques and thirteen Dorset sheep were studied. FUS neuromodulation was targeted to the primary visual cortex in rhesus macaques and to subcortical locations, verified by MR-ARFI, in eleven sheep. Both rhesus macaques and five sheep received a single FUS session, whereas six sheep received repeated sessions three to six days apart. The remaining two control sheep did not receive ultrasound but otherwise underwent the same anesthetic and MRI procedures as the eleven experimental sheep. Hematoxylin and eosin-stained sections of brain tissue (harvested zero to eleven days following FUS) were evaluated for tissue damage at FUS and control locations as well as tissue within the path of the FUS beam. TUNEL staining was used to evaluate for the presence of apoptosis in sheep receiving high dose FUS. RESULTS: No FUS-related pre-mortem histologic findings were observed in the rhesus macaques or in any of the examined sheep. Extravascular red blood cells (RBCs) were present within the meninges of all sheep, regardless of treatment group. Similarly, small aggregates of perivascular RBCs were rarely noted in non-target regions of neural parenchyma of FUS-treated (8/11) and untreated (2/2) sheep. However, no concurrent histologic abnormalities were observed, consistent with RBC extravasation occurring as post-mortem artifact following brain extraction. Sheep within the high dose FUS group were TUNEL-negative at the targeted site of FUS. CONCLUSIONS: The absence of FUS-related histologic findings suggests that the neuromodulation and MR-ARFI protocols evaluated do not cause tissue damage.

Elimination of peripheral auditory pathway activation does not affect motor responses from ultrasound neuromodulation.

BACKGROUND: Recent studies in a variety of animal models including rodents, monkeys, and humans suggest that transcranial focused ultrasound (tFUS) has considerable promise for non-invasively modulating neural activity with the ability to target deep brain structures. However, concerns have been raised that motor responses evoked by tFUS may be due to indirect activation of the auditory pathway rather than direct activation of motor circuits. OBJECTIVE: In this study, we sought to examine the involvement of peripheral auditory system activation from tFUS stimulation applied to elicit motor responses. The purpose was to determine to what extent ultrasound induced auditory artifact could be a factor in ultrasound motor neuromodulation. METHODS: In this study, tFUS-induced electromyography (EMG) signals were recorded and analyzed in wild-type (WT) normal hearing mice and two strains of genetically deaf mice to examine the involvement of the peripheral auditory system in tFUS-stimulated motor responses. In addition, auditory brainstem responses (ABRs) were measured to elucidate the effect of the tFUS stimulus envelope on auditory and motor responses. We also varied the tFUS stimulation duration to measure its effect on motor response duration. RESULTS: We show, first, that the sharp edges in a tFUS rectangular envelope stimulus activate the peripheral afferent auditory pathway and, second, that smoothing these edges eliminates the auditory responses without affecting the motor responses in normal hearing WT mice. We further show that by eliminating peripheral auditory activity using two different strains of deaf knockout mice, motor responses are the same as in normal hearing WT mice. Finally, we demonstrate a high correlation between tFUS pulse duration and EMG response duration. CONCLUSION: These results support the concept that tFUS-evoked motor responses are not a result of stimulation of the peripheral auditory system.

Testing Different Combinations of Acoustic Pressure and Doses of Quinolinic Acid for Induction of Focal Neuron Loss in Mice Using Transcranial Low-Intensity Focused Ultrasound.

The goal of this study was to test different combinations of acoustic pressure and doses of quinolinic acid (QA) for producing a focal neuronal lesion in the murine hippocampus without causing unwanted damage to adjacent brain structures. Sixty male CD-1 mice were divided into 12 groups that underwent magnetic resonance-guided focused ultrasound at high (0.67 MPa), medium (0.5 MPa) and low (0.33 MPa) acoustic peak negative pressures and received QA at high (0.012 mmol), medium (0.006 mmol) and low (0.003 mmol) dosages. Neuronal loss occurred only when magnetic resonance-guided focused ultrasound with adequate acoustic power (0.67 or 0.5 MPa) was combined with QA. The animals subjected to the highest acoustic power had larger lesions than those treated with medium acoustic power, but two mice had evidence of bleeding. When the intermediate acoustic power was used, medium and high dosages of QA produced lesions larger than those produced by the low dosage.

Diffusion MRI tractography for improved transcranial MRI-guided focused ultrasound thalamotomy targeting for essential tremor.

Purpose: To evaluate the use of diffusion magnetic resonance imaging (MRI) tractography for neurosurgical guidance of transcranial MRI-guided focused ultrasound (tcMRgFUS) thalamotomy for essential tremor (ET). Materials and methods: Eight patients with medication-refractory ET were treated with tcMRgFUS targeting the ventral intermediate nucleus (Vim) of the thalamus contralateral to their dominant hand. Diffusion and structural MRI data and clinical evaluations were acquired pre-treatment and post-treatment. To identify the optimal target location, tractography was performed on pre-treatment diffusion MRI data between the treated thalamus and the hand-knob region of the ipsilateral motor cortex, the entire ipsilateral motor cortex and the contralateral dentate nucleus. The tractography-identified locations were compared to the lesion location delineated on 1 year post-treatment T2-weighted MR image. Their overlap was correlated with the clinical outcomes measured by the percentage change of the Clinical Rating Scale for Tremor scores acquired pre-treatment, as well as 1 month, 3 months, 6 months and 1 year post-treatment. Results: The probabilistic tractography was consistent from subject-to-subject and followed the expected anatomy of the thalamocortical radiation and the dentatothalamic tract. Higher overlap between the tractography-identified location and the tcMRgFUS treatment-induced lesion highly correlated with better treatment outcome (r = -0.929, -0.75, -0.643, p = 0.00675, 0.0663, 0.139 for the tractography between the treated thalamus and the hand-knob region of the ipsilateral motor cortex, the entire ipsilateral motor cortex and the contralateral dentate nucleus, respectively, at 1 year post-treatment). The correlation for the tractography between the treated thalamus and the hand-knob region of the ipsilateral motor cortex is the highest for all time points (r = -0.719, -0.976, -0.707, -0.929, p = 0.0519, 0.000397, 0.0595, 0.00675 at 1 month, 3 months, 6 months and 1 year post-treatment, respectively). Conclusion: Our data support the use of diffusion tractography as a complementary approach to current targeting methods for tcMRgFUS thalamotomy.

A feasibility study on monitoring the evolution of apparent diffusion coefficient decrease during thermal ablation.

PURPOSE: Evaluate whether a decrease in apparent diffusion coefficient (ADC), associated with loss of tissue viability (LOTV), can be observed during the course of thermal ablation of the prostate. METHODS: Thermal ablation was performed in a healthy in vivo canine prostate model (N = 2, ages: 5 yr healthy, mixed breed, weights: 13-14 kg) using a transurethral high-intensity ultrasound catheter and was monitored using a strategy that interleaves diffusion weighted images and gradient-echo images. The two sequences were used to measure ADC and changes in temperature during the treatment. Changes in temperature were used to compute expected changes in ADC. The difference between expected and measured ADC, ADCDIFF, was analyzed in regions ranging from moderate hyperthermia to heat fixation. A receiver operator characteristic (ROC) curve analysis was used to select a threshold of detection of LOTV. Time of threshold activation, tLOTV, was compared with time to reach CEM43 = 240, tDOSE. RESULTS: The observed relationship between temperature and ADC in vivo (2.2%/ °C, 1.94%-2.47%/ °C 95% confidence interval) was not significantly different than the previously reported value of 2.4%/ °C in phantom. ADCDIFF changes after correction for temperature showed a mean decrease of 25% in ADC 60 min post-treatment in regions where sufficient thermal dose (CEM43 > 240) was achieved. Following our ROC analysis, a threshold of 2.25% decrease in ADCDIFF for three consecutive time points was chosen as an indicator of LOTV. The ADCDIFF was found to decrease quickly (1-2 min) after reaching CEM43 = 240 in regions associated with heat fixation and more slowly (10-20 min) in regions that received slower heating. CONCLUSIONS: Simultaneous monitoring of ADC and temperature during treatment might allow for a more complete tissue viability assessment of ablative thermal treatments in the prostate. ADCDIFF decreases during the course of treatment may be interpreted as loss of tissue viability.

Hybrid referenceless and multibaseline subtraction MR thermometry for monitoring thermal therapies in moving organs.

PURPOSE: Magnetic resonance thermometry using the proton resonance frequency (PRF) shift is a promising technique for guiding thermal ablation. For temperature monitoring in moving organs, such as the liver and the heart, problems with motion must be addressed. Multi-baseline subtraction techniques have been proposed, which use a library of baseline images covering the respiratory and cardiac cycle. However, main field shifts due to lung and diaphragm motion can cause large inaccuracies in multi-baseline subtraction. Referenceless thermometry methods based on polynomial phase regression are immune to motion and susceptibility shifts. While referenceless methods can accurately estimate temperature within the organ, in general, the background phase at organ/tissue interfaces requires large polynomial orders to fit, leading to increased danger that the heated region itself will be fitted by the polynomial and thermal dose will be underestimated. In this paper, a hybrid method for PRF thermometry in moving organs is presented that combines the strengths of referenceless and multi-baseline thermometry. METHODS: The hybrid image model assumes that three sources contribute to image phase during thermal treatment: Background anatomical phase, spatially smooth phase deviations, and focal, heat-induced phase shifts. The new model and temperature estimation algorithm were tested in the heart and liver of normal volunteers, in a moving phantom HIFU heating experiment, and in numerical simulations of thermal ablation. The results were compared to multi-baseline and referenceless methods alone. RESULTS: The hybrid method allows for in vivo temperature estimation in the liver and the heart with lower temperature uncertainty compared to multi-baseline and referenceless methods. The moving phantom HIFU experiment showed that the method accurately estimates temperature during motion in the presence of smooth main field shifts. Numerical simulations illustrated the method's sensitivity to algorithm parameters and hot spot features. CONCLUSIONS: This new hybrid method for MR thermometry in moving organs combines the strengths of both multi-baseline subtraction and referenceless thermometry and overcomes their fundamental weaknesses.

Transurethral ultrasound applicators with dynamic multi-sector control for prostate thermal therapy: in vivo evaluation under MR guidance.

The purpose of this study was to explore the feasibility and performance of a multi-sectored tubular array transurethral ultrasound applicator for prostate thermal therapy, with potential to provide dynamic angular and length control of heating under MR guidance without mechanical movement of the applicator. Test configurations were fabricated, incorporating a linear array of two multi-sectored tubular transducers (7.8-8.4 MHz, 3 mm OD, 6 mm length), with three 120 degrees independent active sectors per tube. A flexible delivery catheter facilitated water cooling (100 ml min(-1)) within an expandable urethral balloon (35 mm long x 10 mm diameter). An integrated positioning hub allows for rotating and translating the transducer assembly within the urethral balloon for final targeting prior to therapy delivery. Rotational beam plots indicate approximately 90 degrees-100 degrees acoustic output patterns from each 120 degrees transducer sector, negligible coupling between sectors, and acoustic efficiencies between 41% and 53%. Experiments were performed within in vivo canine prostate (n = 3), with real-time MR temperature monitoring in either the axial or coronal planes to facilitate control of the heating profiles and provide thermal dosimetry for performance assessment. Gross inspection of serial sections of treated prostate, exposed to TTC (triphenyl tetrazolium chloride) tissue viability stain, allowed for direct assessment of the extent of thermal coagulation. These devices created large contiguous thermal lesions (defined by 52 degrees C maximum temperature, t43 = 240 min thermal dose contours, and TTC tissue sections) that extended radially from the applicator toward the border of the prostate (approximately15 mm) during a short power application (approximately 8-16 W per active sector, 8-15 min), with approximately 200 degrees or 360 degrees sector coagulation demonstrated depending upon the activation scheme. Analysis of transient temperature profiles indicated progression of lethal temperature and thermal dose contours initially centered on each sector that coalesced within approximately 5 min to produce uniform and contiguous zones of thermal destruction between sectors, with smooth outer boundaries and continued radial propagation in time. The dimension of the coagulation zone along the applicator was well-defined by positioning and active array length. Although not as precise as rotating planar and curvilinear devices currently under development for MR-guided procedures, advantages of these multi-sectored transurethral applicators include a flexible delivery catheter and that mechanical manipulation of the device using rotational motors is not required during therapy. This multi-sectored tubular array transurethral ultrasound technology has demonstrated potential for relatively fast and reasonably conformal targeting of prostate volumes suitable for the minimally invasive treatment of BPH and cancer under MR guidance, with further development warranted.

Referenceless MR thermometry for monitoring thermal ablation in the prostate.

Referenceless proton resonance frequency (PRF) shift thermometry provides a means to measure temperature changes during minimally invasive thermotherapy that is inherently robust to motion and tissue displacement. However, if the referenceless method is used to determine temperature changes during prostate ablation, phase gaps between water and fat in image regions used to determine the background phase can confound the phase estimation. We demonstrate an extension to referenceless thermometry which eliminates this problem by allowing background phase estimation in the presence of phase discontinuities between aqueous and fatty tissue. In this method, images are acquired with a multiecho sequence and binary water and fat maps are generated from a Dixon reconstruction. For the background phase estimation, water and fat regions are treated separately and the phase offset between the two tissue types is determined. The method is demonstrated feasibile in phantoms and during in vivo thermal ablation of canine prostate.

Multisectored interstitial ultrasound applicators for dynamic angular control of thermal therapy.

Dynamic angular control of thermal ablation and hyperthermia therapy with current interstitial heating technology is limited in capability, and often relies upon nonadjustable angular power deposition patterns and/or mechanical manipulation of the heating device. The objective of this study was to investigate the potential of multisectored tubular interstitial ultrasound devices to provide control of the angular heating distribution without device manipulation. Multisectored tubular transducers with independent sector power control were incorporated into modified versions of internally cooled (1.9 mm OD) and catheter-cooled (2.4 mm OD) interstitial ultrasound applicators in this work. The heating capabilities of these multisectored devices were evaluated by measurements of acoustic output properties, measurements of thermal lesions produced in ex vivo tissue samples, biothermal simulations of thermal ablation and hyperthermia treatments, and MR temperature imaging of ex vivo and in vivo experiments. Acoustic beam measurements of each applicator type displayed a 35 degrees -40 degrees acoustic dead zone between each independent sector, with negligible mechanical or electrical coupling. Thermal lesions produced in ex vivo liver tissue with one, two, or three sectors activated ranged from 13-18 mm in radius with contiguous zones of coagulation between active sectors. The simulations demonstrated the degree of angular control possible by using variable power levels applied to each sector, variable duration of applied constant power to individual sectors, respectively, or a multipoint temperature controller to vary the power applied to each sector. Despite the acoustic dead zone between sectors, the simulations also showed that the variance from the maximum lesion radius with three elements activated is within 4%-13% for tissue perfusions from 1-10 kg m(-3) s(-1). Simulations of hyperthermia with maximum tissue temperatures of 45 degrees C and 48 degrees C displayed radial penetration up to 2 cm of the 40 degrees C steady-state contour. Thermal characterizations of trisectored applicators in ex vivo and in vivo muscle, using real-time MR thermal imaging, reinforced angular controllability and negligible radial variance of the heating pattern from the applicators, demonstrated effective heating penetration, and displayed MR compatibility. The multisectored interstitial ultrasound applicators developed in this study demonstrated a significant degree of dynamic angular control of a heating pattern without device manipulation, while maintaining heat penetration consistent with previously reported results from other interstitial ultrasound applicators.