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.

Catheter-based ultrasound devices and MR thermal monitoring for conformal prostate thermal therapy.

Catheter-based ultrasound applicators have been developed for delivering hyperthermia or high-temperature thermal ablation of cancer and benign disease of the prostate. These devices allow for control of heating along the length and angular expanse during therapy delivery. Four types of transurethral applicators were devised for thermal treatment of prostate combined with MR thermal monitoring: sectored tubular transducer devices with directional heating patterns and rotation; planar and curvilinear devices with narrow heating patterns and rotation; and multi-sectored tubular devices capable of dynamic angular control without applicator movement. Interstitial devices (2.4 mm OD) have been developed for percutaneous implantation with directional or dynamic angular control. In vivo experiments in canine prostate under MR temperature imaging were used to evaluate these devices and develop treatment delivery strategies. MR thermal imaging was used to monitor temperature and thermal dose in multiple slices through the target volume. Multi-sectored transurethral applicators can dynamically control the angular heating profile and target large regions of the gland in short treatment times without applicator manipulation. The sectored tubular, planar, and curvilinear transurethral devices produce directional coagulation zones, extending 15-20 mm radial distance to the outer prostate capsule. Sequential rotation under motor control and modulated dwell time can be used to tightly conform thermal ablation to selected regions. Interstitial implants with directional devices can be used to effectively ablate targeted regions of the gland while protecting the rectum. The MR derived 52 degrees C and lethal thermal dose contours (t43=240 min) effectively defined the extent of thermal damage and provided a means for real-time control of the applicators. Catheter-based ultrasound devices, combined with MR thermal monitoring, can produce relatively fast (5-40 min) and precise thermal ablation of prostate.

Curvilinear transurethral ultrasound applicator for selective prostate thermal therapy.

Thermal therapy offers a minimally invasive option for treating benign prostatic hyperplasia (BPH) and localized prostate cancer. In this study we investigated a transurethral ultrasound applicator design utilizing curvilinear, or slightly focused, transducers to heat prostatic tissue rapidly and controllably. The applicator was constructed with two independently powered transducer segments operating at 6.5 MHz and measuring 3.5 mm x 10 mm with a 15 mm radius of curvature across the short axis. The curvilinear applicator was characterized by acoustic efficiency measurements, acoustic beam plots, biothermal simulations of human prostate, ex vivo heating trials in bovine liver, and in vivo heating trials in canine prostate (n=3). Each transducer segment was found to emit a narrow acoustic beam (max width <3 mm), which extended the length of the transducer, with deeper penetration than previously developed planar or sectored tubular transurethral ultrasound applicators. Acoustic and biothermal simulations of human prostate demonstrated three treatment schemes for the curvilinear applicator: single shot (10 W, 60 s) schemes to generate narrow ablation zones (13 x 4 mm, 52 degrees C at the lesion boundary), incremental rotation (10 W, 10 degrees/45 s) to generate larger sector-shaped ablation zones (16 mm x 180 degrees sector), and rotation with variable sonication times (10 W, 10 degrees/15-90 s) to conform the ablation zone to a predefined boundary (9-17 mm x 180 degrees sector, 13 min total treatment time). During in vivo canine prostate experiments, guided by MR temperature imaging, single shot sonications (6 W/transducer, 2-3 min) with the curvilinear applicator ablated 20 degree sections of tissue to the prostate boundary (9-15 mm). Multiple adjacent sonications ("sweeping") ablated large sections of the prostate (180 degrees) by using the MR temperature imaging to adjust the power (4-6.4 W/transducer) and sonication time (30-180 s) at each 10 degrees rotation such that the periphery of the prostate reached 52 degrees C before the next rotation. The conclusion of this study was that the curvilinear applicator produces a narrow and penetrating ultrasound beam that, when combined with image guidance, can provide a precise technique for ablating target regions with a contoured outer boundary, such as the prostate capsule, by rotating in small steps while dynamically adjusting the net applied electrical power and sonication time at each position.

The antinociceptive effect of transcranial electrostimulation with combined direct and alternating current in freely moving rats.

UNLABELLED: Transcranial electrostimulation (TES) has been reported to elicit significant analgesia, allowing a substantial reduction of intraoperative opioids. Acceptance of TES into clinical practice is hampered by lack of controlled clinical trials and inconclusive animal data regarding the TES antinociceptive action. This inconclusive data may be explained, in part, by failure in rat experiments to simulate the variables used in humans when TES electrodes are positioned on the skin. In this study we validated the TES antinociceptive effect in a novel animal model of cutaneously administered TES, when the stimulating conditions mimic the ones used in clinical practice. The antinociceptive effect was assessed by measuring nociceptive thresholds in the tail-flick and hot-plate latency tests in awake, unrestrained male rats. Data were analyzed by analysis of variance and mixed-effects population modeling. The administration of TES at 2.25 mA produced an almost immediate, sustained, frequency-dependent (40-60 Hz) antinociceptive effect, reaching approximately 50% of the maximal possible value. We conclude that an antinociceptive effect of cutaneously administered TES can be demonstrated in the rat. Some characteristics of the effect suggest an important role of the sensory nerves of the rat's scalp in mediating the TES antinociceptive response. IMPLICATIONS: Transcranial electrostimulation produces a significant, frequency-dependent antinociceptive effect that may be mediated by cutaneous nerves of the scalp.

Inhibition of delta-protein kinase C protects against reperfusion injury of the ischemic heart in vivo.

BACKGROUND: Current treatment for acute myocardial infarction (AMI) focuses on reestablishing blood flow (reperfusion). Paradoxically, reperfusion itself may cause additional injury to the heart. We previously found that delta-protein kinase C (deltaPKC) inhibition during simulated ischemia/reperfusion in isolated rat hearts is cardioprotective. We focus here on the role for deltaPKC during reperfusion only, using an in vivo porcine model of AMI. METHODS AND RESULTS: An intracoronary application of a selective deltaPKC inhibitor to the heart at the time of reperfusion reduced infarct size, improved cardiac function, inhibited troponin T release, and reduced apoptosis. Using 31P NMR in isolated perfused mouse hearts, we found a faster recovery of ATP levels in hearts treated with the deltaPKC inhibitor during reperfusion only. CONCLUSIONS: Reperfusion injury after cardiac ischemia is mediated, at least in part, by deltaPKC activation. This study suggests that including a deltaPKC inhibitor at reperfusion may improve the outcome for patients with AMI.