Per Mindus

Imaging of [11C]-labelled RO 15-1788 binding to benzodiazepine receptors in the human brain by positron emission tomography

The benzodiazepine antagonist Ro 15-1788 was labelled with [11C] and examined for possible use as ligand for PET scan studies on benzodiazepine receptors in the brain of cynomolgus monkeys and human subjects. [11C] Ro 15-1788 allowed the in vivo visualization of benzodiazepine receptor binding in cerebral and cerebellar cortical areas as well as in basal brain nuclei in PET scan images. [11C] Ro 15-1788 exhibited a high ratio of specific benzodiazepine receptor binding (cerebral cortex) to non-specific binding (pons) and the kinetics of binding should be satisfactory for quantitative clinical PET scan studies using [11C]. The in vivo binding of [11C] Ro 15-1788 in the cerebral cortex of cynomolgus monkeys and healthy human subjects was reduced by approximately 90% within 10 min after the intravenous injection of a high dose of unlabelled Ro 15-1788 (0.5 mg/kg i.v.). Different areas of the healthy human brain showed an approximately 10-fold variation in maximal [11C] Ro 15-1788 binding that corresponded to the previously known distribution of benzodiazepine receptors in these regions. The highest degree of binding was obtained in the medial occipital cerebral cortex followed by frontal cortex, cerebellum, thalamus, striatum and pons. Two psychiatric patients with anxiety syndromes who had been treated for a long time with high doses of benzodiazepines had roughly the same degree of maximal [11C] Ro 15-1788 binding in brain regions as the healthy subjects but the rate of decline of [11C] Ro 15-1788 in the brain was higher. This indicates that there is measurable competition between [11C] Ro 15-1788 binding and clinical benzodiazepine concentrations in the body fluids of psychiatric patients. The results demonstrate that [11C] Ro 15-1788 should be a valuable tool for quantitative analyses of benzodiazepine receptor characteristics and receptor occupancy in the brain of patients with neuropsychiatric disorders.

Lesion topography and outcome after thermocapsulotomy or gamma knife capsulotomy for obsessive-compulsive disorder: relevance of the right hemisphere.

OBJECTIVES Obsessive-compulsive disorder is a common mental disorder, notorious for its chronicity and intractability. Stereotactic lesions within the anterior limb of the internal capsule have been shown to provide symptomatic relief in such refractory cases, but only few systematic evaluations have correlated anatomic lesion location with individual postoperative outcome. PATIENTS AND METHODS Between 1976 and 1989, extremely disabled and otherwise intractable patients with a chronic deteriorating clinical course of obsessive-compulsive disorder underwent bilateral thermocapsulotomy (n = 22) or radiosurgical gamma knife capsulotomy (n = 13) at the Karolinska Hospital, Stockholm. Clinical morbidity was monitored prospectively pre- and postoperatively by using standardized psychiatric rating scales. In 29 patients (thermocapsulotomy, n = 19; gamma knife capsulotomy, n = 10), both psychiatric and magnetic resonance imaging follow-up data (median, 8.4 yr) were available. RESULTS A right-sided anatomically defined lesion volume was identified in all successfully treated patients. This common topographic denominator was defined in the approximate middle of the anterior limb of the internal capsule on the plane parallel to the anterior commissure-posterior commissure line at the level of the foramen of Monro and 4 mm above on the plane defined by the internal cerebral vein. This region was unaffected in patients with poor outcomes. On the left side, no particular lesion topography was associated with clinical outcome. Topographic differences of lesion overlap between good and poor outcome groups were significant for the right side (Fishers exact test, P < 0.005). CONCLUSION The current anatomic long-term analysis after thermocapsulotomy or gamma knife capsulotomy for obsessive-compulsive disorder reveals common topographic features within the right-sided anterior limb of the internal capsule independent of treatment modality.

Radiobiology of Radiosurgery for Refractory Anxiety Disorders

The neuroradiological manifestations of bilateral single-session gamma (gamma)-irradiation to normal tissue contained in the internal capsule after gamma knife capsulotomy for otherwise intractable anxiety disorders were studied. In nine consecutive patients, a target maximum dose of 200 Gy was administered in a target volume of 276 +/- 42 mm3 (mean +/- SD) within the 50% isodose level. Serial computed tomographic and magnetic resonance imaging scans were undertaken from 3 to 44 months after irradiation. After surgery, a necrotic lesion appeared on computed tomographic scans, reaching its maximum volume (900 +/- 800 mm3) at 6 to 9 months, then decreasing (to 457 +/- 400 mm3) over the first postoperative year. This volume correlated with the mean isodose level of 91 (range, 41-143) Gy. On T2-weighted magnetic resonance imaging scans, the reaction tissue volumes were considerably larger and took longer to disappear than expected. In 15 targets, maximum reaction volumes were recorded at 1 to (approximately) 2 years after irradiation. In the remaining seven targets, smaller reaction volumes were observed, with no clear maxima appearing during 3 years of observation. In a pilot case, a lower target maximum dose of 160 Gy and a radiation volume of 275 mm3 within the 50% isodose gave only minimal surrounding tissue reactions. This report serves to alert clinicians that the tissue reaction volumes and the time course of their development after high irradiation doses may be less predictable than expected from previous observations in smaller radiation volumes. For this reason, lower irradiation doses and smaller volumes should be used in the future, and the time factor should be taken into account when interpreting computed tomographic and magnetic resonance images of gamma-knife-induced lesions.

Radiosurgical lesions in the normal human brain 17 years after gamma knife capsulotomy.

OBJECTIVE To our knowledge, this is the first long-term follow-up study of high-dose single-session irradiation to the human brain and provides new data concerning late tissue reactions after irradiation to small target volumes. The long-term lesional brain changes in 14 patients subjected to bilateral gamma knife capsulotomy for otherwise intractable anxiety disorders were retrospectively analyzed by magnetic resonance imaging. METHODS The prototype gamma unit was used for the radiosurgical procedure, and the collimators provided rectangular cross-sectional fields with an anteroposterior diameter of 3 mm and a transverse diameter of 5 or 11 mm. Maximum target doses were 120 to 180 Gy. Magnetic resonance imaging was performed 15 to 18 years (mean, 17 yr) after treatment, and dose-volume histograms were calculated for the dose distributions. RESULTS One patient had been irradiated twice on one side. In all but one of the remaining 27 targets, lesions with a volume of less than 100 mm3 were revealed by magnetic resonance imaging. The volumes of the lesions were confined within the volume corresponding to a minimum dose of approximately 110 Gy, with one exception. In one of three targets receiving a maximum dose of 120 Gy, no lesion was detected. There were no late radiation effects such as cyst formations, telangiectasias, hemorrhagic infarctions, or neoplasms. CONCLUSION This investigation indicates that a minimum dose of 110 Gy, with the currently used 4-mm collimator, to the edge of the target volume is required to create a lesion. The results prove that gamma knife surgery can be used in functional neurosurgery for producing small permanent lesions in the normal human brain.

The Role of Anterior Internal Capsulotomy in Psychiatric Surgery

In 1947, Spiegel and Wycis first reported the application of stereotactic techniques to psychiatric surgery [29]. A few years later, such treatment was used systematically by Leksell [16] in Sweden and Talairach [31] in France. It was more than another decade before stereotactic technique was recognized widely as the preferred way to perform psychiatric surgery.

Frontal lobe and basal ganglia metabolism studied with PET in patients with incapacitating obsessive-compulsive disorder undergoing capsulotomy

Regional cerebral metabolic rates of glucose (rCMRgl) were determined with positron emission tomography (PET) in five patients with chronic, treatment-resistant, incapacitating obsessive-compulsive disorder (OCD) undergoing psychosurgery. Preoperative values were compared with rates observed in healthy volunteers examined with the same PET system. Here we report primary data pertaining to the orbital gyri and the caudate nuclei, regions in which disordered metabolism has been observed in OCD. In contrast to previous reports, our patients did not display increased rCMRgl relative to controls, a possible reflection of the particularly malignant forms of OCD which they had. Our findings neither address the issue of the causes of OCD nor preclude that other brain regions may be dysfunctional in that illness