Faculty Bibliography

We address the development of triple-quantum-filtered sodium MRI as a non-invasive surrogate measure for cell proliferation in brain tumors. We demonstrate that through careful consideration of the theoretical description of the signal, triple-quantum-filtered sodium images of adequate signal-to-noise ratio (SNR) can be acquired in clinically acceptable imaging times.

Transplantation of cultured neuronal cells was performed in two human clinical trials after safety and efficacy was demonstrated in animal models of stroke. The studies tested the utility of human neuronal cellular transplantation into and around the small stroke volume. We developed a stereotactic surgical technique for cell delivery and evaluated that method in 26 patients with basal ganglia region motor stroke. Human neuronal cells (hNT cells; LBS neurons) were delivered frozen then thawed and formulated on the morning of surgery. Patients in a first trial received 2 or 6 million cells in three or nine implants, and in a second trial, 5 or 10 million in 25 implants. A novel cell delivery cannula was designed, manufactured, tested, and used in surgery. Immediate postoperative CT scans and later serial MR scans were used to evaluate the surgical site. Tests on the cell implantation cannula showed that the cells were not damaged and remained viable after injection. All patients underwent uncomplicated surgeries. Cells could be implanted within a 2-h period, maintaining viability of the preparation. Serial evaluations (maximum 5 years) showed no cell-related adverse serologic or imaging-defined effects. One patient had burr hole drainage of an asymptomatic chronic subdural hematoma. Human neuronal cells can be produced in culture and implanted stereotactically into the brains of patients with stroke. Surgical cell delivery did not lead to new neurological deficits, and imaging studies showed no adverse effects. The cannula used allowed precise injection of the clinical cell dose within a time period that maintained cell viability.

Essential tremor can be surgically treated by thalamotomy or deep brain stimulation. During the surgical procedure for both of these procedures, a transient microthalamotomy effect has been observed. This benefit is usually short-lived and appears to be predictive of patient outcome. This report describes a patient who underwent a temporary placement of a stimulating electrode within the ventral intermediate nucleus of the motor thalamus. The procedure was aborted intraoperatively and the patient demonstrated a microthalamotomy effect. This microthalamotomy effect has remained persistent for 24 months, and the patient remains tremor free. This case report lends evidence to the idea that the volume of motor thalamus responsible for tremor may be small and precise. By recognizing the benefit obtained from small lesions with minimal tissue manipulation, surgeons can continue to refine the target for movement disorder surgery.

Glial tumors occur as intraaxial masses in the brain and are uniformly fatal due to lack of effective therapy. Resection combined with radiation and chemotherapy fails to eradicate malignant cells infiltrating into normal brain, and recurrence at the original site is ultimately fatal. Gene transfer offers the potential to enhance tumor cell killing while sparing surrounding normal brain. Several approaches have been developed to deliver genes to tumor cells in order to kill these cells. The first strategy involves the use of viral vectors that are replication-competent, but depend on attributes unique to the tumor cell to support viral growth. Both replication-competent adenovirus and herpes simplex virus (HSV) vectors have been employed in pre-clinical studies and most recently in human clinical trials. For this purpose, HSV vectors have been engineered that replicate in dividing cells, such as tumor cells, but not in normal neurons. The use of conditional replication competent viruses could allow for their spread in tumor tissue while minimizing damage to normal brain, thus increasing the specificity and effectiveness. Such mutants include those lacking the viral thymidine kinase (tk) gene (4-7), ribonucleotide reductase gene (8,9), a protein kinase gene, or a gene (gamma34.5) required for growth specifically in neurons (11-13).

We demonstrate the use of triple quantum (TQ) filtered sodium MRI for the monitoring of primary brain tumors. The TQ images were acquired using a twisted-projection readout in tandem with a three-pulse triple quantum filter. Our results demonstrate that TQ sodium MRI provides a source of contrast that it is not biased by the large sodium content of the extracellular pool and is, therefore, better suited for monitoring the changes in intracellular sodium content associated with the development of neoplastic changes