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Antonio V. Lorenzo, Ferenc A. Jolesz, James K. Wallman and Paul W. Ruenzel

✓ To better understand the role of myelin-associated water in the differentiation of white and gray matter in magnetic resonance (MR) imaging, changes in MR relaxation processes were studied in rabbits during myelination and after induction of cytotoxic edema with triethyltin (TET). Normal rabbits were killed at various age intervals ranging from premature (28 days' gestation) to adult, and changes in MR relaxation times (T1 and T2) and in water and electrolyte content were determined for various areas of brain and muscle. Similar measurements were made in rabbits of comparable age exposed to TET. Light and electron microscopy and MR imaging were used to follow myelin development and morphological changes induced by TET. During the first 30 postnatal days, both T1 and T2 declined by 50% in normal rabbits, a fall that paralleled the loss in brain water and sodium that occurred during the same period. Exposure to TET prolonged T1 and T2 in white but not gray matter, reflecting the accumulation of sodium and water (edema fluid) in white matter areas. Multiexponential analysis revealed a second, longer component in T2 magnetization decay of TET-exposed white matter, presumably attributable to accumulation of non-ordered water within intramyelinic vacuoles, a supposition consistent with electron microscopic and MR imaging findings. In contrast to reports by others, changes in T1 (but not T2) closely correlated with alterations in brain water (r = 0.93, df = 39). The absence of tissue disruption in the animals in the present study may account for these differences, but further studies will be required both to resolve this question and to fully understand MR images of white matter edema in mature and immature brain.

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Costas D. Arvanitis, Natalia Vykhodtseva, Ferenc Jolesz, Margaret Livingstone and Nathan McDannold

OBJECT

Transcranial MRI-guided focused ultrasound (TcMRgFUS) is an emerging noninvasive alternative to surgery and radiosurgery that is undergoing testing for tumor ablation and functional neurosurgery. The method is currently limited to central brain targets due to skull heating and other factors. An alternative ablative approach combines very low intensity ultrasound bursts and an intravenously administered microbubble agent to locally destroy the vasculature. The objective of this work was to investigate whether it is feasible to use this approach at deep brain targets near the skull base in nonhuman primates.

METHODS

In 4 rhesus macaques, targets near the skull base were ablated using a clinical TcMRgFUS system operating at 220 kHz. Low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes in conjunction with the ultrasound contrast agent Definity, which was administered as a bolus injection or continuous infusion. The acoustic power level was set to be near the inertial cavitation threshold, which was measured using passive monitoring of the acoustic emissions. The resulting tissue effects were investigated with MRI and with histological analysis performed 3 hours to 1 week after sonication.

RESULTS

Thirteen targets were sonicated in regions next to the optic tract in the 4 animals. Inertial cavitation, indicated by broadband acoustic emissions, occurred at acoustic pressure amplitudes ranging from 340 to 540 kPa. MRI analysis suggested that the lesions had a central region containing red blood cell extravasations that was surrounded by edema. Blood-brain barrier disruption was observed on contrast-enhanced MRI in the lesions and in a surrounding region corresponding to the prefocal area of the FUS system. In histology, lesions consisting of tissue undergoing ischemic necrosis were found in all regions that were sonicated above the inertial cavitation threshold. Tissue damage in prefocal areas was found in several cases, suggesting that in those cases the sonication exceeded the inertial cavitation threshold in the beam path.

CONCLUSIONS

It is feasible to use a clinical TcMRgFUS system to ablate skull base targets in nonhuman primates at time-averaged acoustic power levels at least 2 orders of magnitude below what is needed for thermal ablation with this device. The results point to the risks associated with the method if the exposure levels are not carefully controlled to avoid inertial cavitation in the acoustic beam path. If methods can be developed to provide this control, this nonthermal approach could greatly expand the use of TcMRgFUS for precisely targeted ablation to locations across the entire brain.

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Kanaris P. Panagopoulos, Ferenc A. Jolesz, Mustapha El-Azouzi and Peter McL. Black

✓ This report describes two cases of a mucinous cyst (Rathke's cleft cyst) in the pituitary stalk: the first was found in a 29-year-old woman 5 years following pregnancy and the second in a 30-year-old woman 6 years after pregnancy. The presenting symptoms are analyzed and the diagnosis is discussed, with emphasis on the role of magnetic resonance imaging.

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Nathan McDannold, Yong-Zhi Zhang, Chanikarn Power, Ferenc Jolesz and Natalia Vykhodtseva

Object

Tumors at the skull base are challenging for both resection and radiosurgery given the presence of critical adjacent structures, such as cranial nerves, blood vessels, and brainstem. Magnetic resonance imaging–guided thermal ablation via laser or other methods has been evaluated as a minimally invasive alternative to these techniques in the brain. Focused ultrasound (FUS) offers a noninvasive method of thermal ablation; however, skull heating limits currently available technology to ablation at regions distant from the skull bone. Here, the authors evaluated a method that circumvents this problem by combining the FUS exposures with injected microbubble-based ultrasound contrast agent. These microbubbles concentrate the ultrasound-induced effects on the vasculature, enabling an ablation method that does not cause significant heating of the brain or skull.

Methods

In 29 rats, a 525-kHz FUS transducer was used to ablate tissue structures at the skull base that were centered on or adjacent to the optic tract or chiasm. Low-intensity, low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes after intravenous injection of an ultrasound contrast agent (Definity, Lantheus Medical Imaging Inc.). Using histological analysis and visual evoked potential (VEP) measurements, the authors determined whether structural or functional damage was induced in the optic tract or chiasm.

Results

Overall, while the sonications produced a well-defined lesion in the gray matter targets, the adjacent tract and chiasm had comparatively little or no damage. No significant changes (p > 0.05) were found in the magnitude or latency of the VEP recordings, either immediately after sonication or at later times up to 4 weeks after sonication, and no delayed effects were evident in the histological features of the optic nerve and retina.

Conclusions

This technique, which selectively targets the intravascular microbubbles, appears to be a promising method of noninvasively producing sharply demarcated lesions in deep brain structures while preserving function in adjacent nerves. Because of low vascularity—and thus a low microbubble concentration—some large white matter tracts appear to have some natural resistance to this type of ablation compared with gray matter. While future work is needed to develop methods of monitoring the procedure and establishing its safety at deep brain targets, the technique does appear to be a potential solution that allows FUS ablation of deep brain targets while sparing adjacent nerve structures.

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Claudia Martin, Eben Alexander III, Terry Wong, Richard Schwartz, Ferenc Jolesz and Peter McL. Black

Radical resection of low-grade gliomas can decrease the incidence of recurrence, the time to tumor progression, and the incidence of malignant transformation. The authors present a series of 25 patients who underwent craniotomy and resection of low-grade tumor in an intraoperative magnetic resonance (MR) imager. This is an open configuration 0.5-tesla imager developed by The Brigham and Women's Hospital and General Electric, in which a patient can be placed to undergo surgery. Gross-total removal was accomplished under real-time image guidance. These intraoperative images allow definitive localization and targeting of the lesions and accommodate anatomical changes that may occur during surgery. The authors consistently found that the extent of abnormality seen on the intraoperatively obtained films of resection was larger than that apparent in the surgical field of view alone. Intraoperative imaging made accurate surgical identification of these abnormal areas and subsequent resection possible. Patients with tumors adjacent to or within motor or language cortex underwent resection while awake, with monitoring of neurological function. In these cases, an aggressive resection without increased neurological morbidity was accomplished using the image guidance in conjunction with serial testing. A 1-month postoperative MR image was obtained in all patients. These correlated with the final intraoperative images obtained after the resection was completed. Only one patient had a mild postoperative deficit that remained at the 1-month follow-up examination. As the long-term outcome in patients with low-grade gliomas has been shown to correspond to the degree of resection, surgical resection in which intraoperative MR imaging guidance is used can be an invaluable modality in the treatment of these tumors.

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Kullervo Hynynen, Nathan McDannold, Natalia Vykhodtseva, Scott Raymond, Ralph Weissleder, Ferenc A. Jolesz and Nickolai Sheikov

Object

The goal of this study was to explore the feasibility of using low-frequency magnetic resonance (MR) image–guided focused ultrasound as a noninvasive method for the temporary disruption of the blood–brain barrier (BBB) at targeted locations.

Methods

Rabbits were placed inside a clinical 1.5-tesla MR imaging unit, and sites in their brains were targeted for 20-second burst sonications (frequency 260 kHz). The peak pressure amplitude during the burst varied between 0.1 and 0.9 MPa. Each sonication was performed after an intravenous injection of an ultrasound contrast agent (Optison). The disruption of the BBB was evaluated with the aid of an injection of an MR imaging contrast agent (MAG-NEVIST). Additional tests involving the use of MION-47, a 20-nm magnetic nanoparticle contrast agent, were also performed. The animals were killed at different time points between 3 minutes and 5 weeks postsonication, after which light or electron microscopic evaluation was performed.

The threshold for BBB disruption was approximately 0.2 MPa. More than 80% of the brain sites sonicated showed BBB disruption when the pressure amplitude was 0.3 MPa; at 0.4 MPa, this percentage was greater than 90%. Tissue necrosis, ischemia, and apoptosis were not found in tissue in which the pressure amplitude was less than 0.4 MPa; however, in a few areas of brain tissue erythrocytes were identified outside blood vessels following exposures of 0.4 MPa or higher. Survival experiments did not show any long-term adverse events.

Conclusions

These results demonstrate that low-frequency ultrasound bursts can induce local, reversible disruption of the BBB without undesired long-term effects. This technique offers a potential noninvasive method for targeted drug delivery in the brain aided by a relatively simple low-frequency device.

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Alexandra Chabrerie, Fatma Ozlen, Shin Nakajima, Michael E. Leventon, Hideki Atsumi, Eric Grimson, Ferenc Jolesz, Ron Kikinis and Peter McL. Black

Three-dimensional image reconstruction for preoperative surgical planning and intraoperative navigation for the resection of low-grade gliomas was performed in 20 patients. Thirteen of these surgeries were performed while the patient received a local anesthetic to allow for cortical mapping. Ninety percent of the patients were functionally intact postoperatively. The authors propose that the combination of the three-dimensional image reconstruction and surgical navigation, in conjunction with intraoperative cortical mapping, provides an additional means for surgeons to improve the safety and precision of the procedures.

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Mustapha El-Azouzi, Dora W. Hsu, Peter McL. Black, Ferenc Jolesz, E. Tessa Hedley-Whyte, Anne Klibanski and Nicholas T. Zervas

✓ The factors responsible for the production of prolactin-secreting tumors are obscure. One hypothesis, that chronic loss of dopamine control from the hypothalamus may be associated with prolactinoma formation, was tested. Female adult Fischer 344 rats were subjected to ovariectomy and were then given subcutaneous implants of diethylstilbestrol (DES) Silastic capsules to produce lactotrophic hyperplasia. Sequential studies assessed the neuronal activity of the tuberoinfundibular dopaminergic neurons of the arcuate nucleus of the hypothalamus (A12) during and after this estrogen-induced pituitary growth. Immunocytochemical staining for tyrosine hydroxylase was used as a marker for dopamine synthesis, plasma radioimmunoassay provided plasma prolactin levels, and magnetic resonance imaging and histological studies were performed to examine the structural changes occurring in the pituitary gland. Animals were sacrificed from 3 to 67 days after DES implantation. To determine the reversibility of the estrogen-induced changes, rats were also sacrificed at different time intervals after the removal of 30-, 40-, or 60-day DES implants.

After 30 days of DES treatment, plasma prolactin levels increased 40-fold and pituitary weight increased more than threefold. Tyrosine hydroxylase immunoreactivity diminished gradually and was almost completely depleted at 30 days. Pituitary histology revealed marked prolactin cell hyperplasia. These changes were completely reversible; removal of the capsule after 30 days resulted in eventual normalization of plasma prolactin levels and pituitary size and in restoration of tyrosine hydroxylase immunoreactivity in the A12 region.

Sixty days of DES treatment produced large hemorrhagic tumors with sustained high plasma prolactin levels and an irreversibly distorted A12 area. These observations suggest that in these animals loss of dopamine regulation secondary to estrogen stimulation initially produces prolactin hyperplasia but that prolonged loss leads to adenoma formation.

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Mitsunori Matsumae, Ron Kikinis, István Mórocz, Antonio V. Lorenzo, Marilyn S. Albert, Peter McL. Black and Ferenc A. Jolesz

✓ Magnetic resonance image—based computerized segmentation was used to measure the volumes of the brain, gray and white matter components, and to identify regions with prolonged enhancement on T2-weighted imaging, such as periventricular or deep white matter hyperintensities. The authors also determined the volumes of the ventricles and subarachnoid space in control subjects and in patients with: 1) aqueductal stenosis (AS); 2) other causes of obstructive hydrocephalus (OH); 3) Alzheimer's disease (AD); and 4) normal-pressure hydrocephalus (NPH). In AS the volume of the brain was smaller, whereas that of ventricles and subarachnoid cerebrospinal fluid space was larger than that of controls. The decrease in brain volume was due primarily to white matter loss. Although in OH the ventricles were larger, the subarachnoid space was smaller than in controls, presumably due to encroachment by the brain, in which the volume remained unchanged. In AD, loss of both gray and white matter resulted in a smaller brain volume, whereas that of ventricles and subarachnoid space was larger than in controls. In NPH patients, only ventricular volume was greater, whereas all other compartments were similar to controls. The brain normally occupies 87% to 92% of the intracranial volume and consequently, as observed in our patients, relatively small decrements in brain size lead to large increments in ventricular and/or extraventricular volumes. The magnitude of such changes differed markedly among our patient groups, and whether such changes prove useful in clinical assessment and differentiation needs to be determined.

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Mitsunori Matsumae, Ron Kikinis, István A. Mórocz, Antonio V. Lorenzo, Tamás Sándor, Marilyn S. Albert, Peter McL. Black and Ferenc A. Jolesz

✓ Magnetic resonance (MR) image—based computerized segmentation was used to measure various intracranial compartments in 49 normal volunteers ranging in age from 24 to 80 years to determine age-related changes in brain, ventricular, and extraventricular cerebrospinal fluid (CSF) volumes. The total intracranial volume (sum of brain, ventricular, and extraventricular CSF) averaged 1469 ± 102 cm3 in men and 1289 ± 111 cm3 in women. The difference was attributable primarily to brain volume, which accounted for 88.6% of the respective intracranial volumes in both sexes, but was significantly larger in men (1302 ± 112 cm3) than in women (1143 ± 105 cm3). In both, the cranial CSF volume averaged 11.4%. Total intracranial volume did not change with age, although the normalized brain volume of both men and women began to decrease after the age of 40 years. This decrease was best reflected by expansion of the extraventricular CSF volume which, after the age of 50 years, was more marked in men than in women.

The volume of the cranial CSF, as determined by MR image-based computerized segmentation, is considerably larger than traditionally accepted and resides mostly extraventricularly. Expansion of CSF volume with age provides a good index of brain shrinkage although evolving changes and growth of the head with age tend to confound the results.