Gordon Watkins

Cerebellar hypoactivity in frequent marijuana users

It is uncertain whether frequent marijuana use adversely affects human brain function. Using PET, regional cerebral blood flow was compared in frequent marijuana users and comparable, non-using controls after at least 26 h of monitored abstention by all subjects. Marijuana users showed substantially lower brain blood flow than controls in a large region of posterior cerebellum, indicating altered brain function in frequent marijuana users. A cerebellar locus of some chronic and acute effects of marijuana is plausible, e.g. the cerebellum has been linked to an internal timing system, and alterations of time sense are common following marijuana smoking.

Age-related changes in regional cerebral blood flow among young to mid-life adults.

Using PET with [(15)O]H2O, we examined age in relation to regional cerebral blood flow (rCBF) among young to mid-life adults. Previous work has largely contrasted rCBF between young and elderly age groups dichotomously. This study maps the continuum of normal age-related changes in rCBF from early to mid-adulthood. We obtained images from 37 healthy volunteers between 19 and 50 years of age during an eyes-closed resting baseline condition. There was a negative correlation between age and rCBF in mesial frontal cortex, involving the anterior cingulate region (r = 0.63, p<0.001). These findings reflect differences in the distribution of rCBF evident in early to mid-adulthood that may be associated with subsequent changes in memory and executive functioning in later life.

Reliability of PET activation across statistical methods, subject groups, and sample sizes.

Four pixel‐based methods for estimating regional activation in positron emission tomography (PET) images were implemented so as to allow the comparison of their performances in the same dataset. Change distribution analysis, Worsleys method, a pixelwise general linear model, a nonparametric method, and several methods derived from them were investigated. Important technical factors, including the degree of smoothing, stereotactic transform, coregistration algorithm, search volume, and the volumetric alpha level, were held constant. The dataset, which was obtained with a verb generation paradigm, was large enough to permit assessment of concordance between independent samples of conventional size, as well assessment of within‐cohort replicability. (Eighteen normal subjects performed four GENERATE‐READ pairs each.) Same‐task (noise) images were also analyzed.

Acute marijuana effects on rCBF and cognition: a PET study.

The effects of smoking marijuana on cognition and brain function were assessed with PET using H215O. Regional cerebral blood flow (rCBF) was measured in five recreational users before and after smoking a marijuana cigarette, as they repeatedly performed an auditory attention task. Blood flow increased following smoking in a number of paralimbic brain regions (e.g. orbital frontal lobes, insula, temporal poles) and in anterior cingulate and cerebellum. Large reductions in rCBF were observed in temporal lobe regions that are sensitive to auditory attention effects. Brain regions showing increased rCBF may mediate the intoxicating and mood-related effects of smoking marijuana, whereas reduction of task-related rCBF in temporal lobe cortices may account for the impaired cognitive functions associated with acute intoxication.

Marijuana alters the human cerebellar clock.

The effects of marijuana on brain perfusion and internal timing were assessed using [15O] water PET in occasional and chronic users. Twelve volunteers who smoked marijuana recreationally about once weekly, and 12 volunteers who smoked daily for a number of years performed a self-paced counting task during PET imaging, before and after smoking marijuana and placebo cigarettes. Smoking marijuana increased rCBF in the ventral forebrain and cerebellar cortex in both groups, but resulted in significantly less frontal lobe activation in chronic users. Counting rate increased after smoking marijuana in both groups, as did a behavioral measure of self-paced tapping, and both increases correlated with rCBF in the cerebellum. Smoking marijuana appears to accelerate a cerebellar clock altering self-paced behaviors.

Vanadium-48: A renewable source for transmission scanning with PET

Abstract A 68Ge ( t 1 2 =271 d ) source is normally used to produce transmission images for PET studies. New PET scanners utilize two or three 10–15 mCi 68Ge sources for this purpose. 48V ( t 1 2 =15.98 d ) has been investigated as an alternative to 68Ge for routine transmission scanning in PET. A target system has been developed to produce nearly homogeneous (+/− 10%) sources of 1 mCi/cm (10 mCi over 10 cm) using the 48Ti(p,n)48V reaction (Ep=17 MeV). The target consists of a small diameter (3.17 mm) Ti tube (>99.99% Ti, 73.7% 48Ti) oriented at 6° to the incident proton beam and held rigidly within a water cooled aluminum target body. The Ti tube wall presents an effective target thickness of 8.5 mm to the grazing proton beam. The Ti tube is water cooled. Typical irradiations of 20 μA for 120 min on the tube yield 10 mCi sources. Short-lived 47V ( t 1 2 =32.6 min ) and 46V ( t 1 2 =422 ms ) impurities are allowed to decay prior to utilizing the source for routine PET transmission scanning. Ti tubes are reused to produce new sources each week.

Intelligent [F-18] fluoride target system

An automated target filling system has been developed for [F-18]F- production from [O-18]water. The system consists of a pair of standard syringe dispensing pumps, valve manifolds, pressure and flow sensors, RS-232 serial I/O modules, high pressure silver targets and X-windows software. Operations are controlled through a graphical interface and can be manipulated individually, in groups for specific functions, or as complex processes either manually or automatically. Major functional operations include: 1) system test, 2) target fill, 3) target empty, and 4) target clean up. Fault conditions if present are identified and flagged. Alternate (duplicate) pathways are automatically used if a nonfatal failure mode is detected. Results from the testing procedures are logged to a file for documented adherence to SOPs and trend assessment of performance.

Follow-up of treatment of a cerebral arteriovenous malformation with acetazolamide and positron emission tomography

Cerebral arteriovenous malformations (AVM) may cause decreased perfusion (steal) to the surrounding brain tissue. Abrupt occlusion of the shunt has led to fulminant hyperemic catastrophes in some patients. The perfusion reserve of these areas has been previously evaluated with acetazolamide, a vasodilatory agent, using SPECT. Abnormal response to acetazolamide has been shown to correlate with intraoperative and postoperative complications. A 34-year-old man with seizures had a 3 cm x 4 cm AVM at the left occipitoparietal region. Quantitative brain blood flow studies were performed using O-15 water and positron emission tomography (PET), before and immediately after the embolization, and 4 days later. These studies demonstrated no cerebral steal or abnormal response of the perilesional tissue to acetazolamide. Four weeks after the embolization the patient underwent surgical resection of the AVM with no complications and complete recovery. Cerebral blood flow measurements by either SPECT or PET are useful in the preoperative evaluation of patients with AVM..

Head to head comparison of N-13 ammonia and Rubidium-82 PET myocardial perfusion scans in subjects with no history of coronary artery disease (CAD)

REPLY: We always welcome a professional dialogue from esteemed colleagues in regard to studies that we have published, and we believe that such a dialogue helps us all move forward to a more accurate understanding of the world about us. Continuing in that spirit, I would like to address the various comments in the letter to the editor from Verburg et al. regarding our report comparing the number of metastatic lesions of differentiated thyroid cancer (DTC) detected after preparation with thyroid hormone withdrawal (THW) versus injections of recombinant thyroid-stimulating hormone (rhTSH) (1). Our understanding of the main point of their letter is that they believe that our recommendation regarding selective use of rhTSH is too strong and that they would like to see a more “nuanced” view on the data presented. Our recommendation was that, until more data become available, physicians should be cautious in using rhTSH for patient preparation before diagnostic scanning for the detection of DTC or treatment of distant metastases secondary to DTC with 131I. Insofar as the data support this recommendation, it would not appear appropriate to characterize the recommendation as being too strong. When data are clear-cut, there is less accommodation for “nuance.” With regard to the observation of Verburg et al. that our entire study appeared methodologically geared toward comparing 131I with 124I—indeed, the data were obtained from our previously published original study (2) comparing 131I planar imaging with 124I PET, with 16 additional patients studied and included. However, whether the data were derived from a study comparing lesion detection of 131I planar imaging with 124I PET is not in and of itself a limitation. Although there were limitations to our study that we recognized and discussed in the publication, we do not believe this is one of them. With regard to the interest of Verburg et al. in seeing further statistical analyses comparing the 2 radioisotopes, especially if we additionally had acquired and evaluated 131I SPECT/CT, we noted in our original publication (2) that a comparison of 131I SPECT/CT with 124I PET would have been valuable for that study. However, such a comparison was not critical to the present study (1) because we were comparing planar imaging with planar imaging and PET with PET. To address Verburg et al.’s further opinion that we analyzed differences between rhTSH and THW instead of comparing lesion detection on 131I planar imaging versus 124I PET, we did not perform evaluations after rhTSH and THW instead of lesion detection but in addition to lesion detection. Verburg et al. subsequently state that they were surprised we did not use 124I-PET to perform dosimetry for our patients. They believe this would have been clinically relevant, especially in patients with metastatic lesions, because visualization of metastases does not automatically indicate the possibility of an effective 131I treatment. Several important facts will help clarify this issue. First, the calculated radiation absorbed dose to a focal lesion or organ as determined by the various methods of 124I dosimetry does not necessarily correlate with clinical outcomes or side effects (3,4). However, we do agree that lesional dosimetry should be performed—not necessarily to indicate clinical relevance based on a calculated radiation absorbed dose but rather to indicate clinical relevance based on a comparison of relative lesional radiopharmacokinetics. We have such a study already under way, as well as another study comparing 124I dosimetry after preparation with THW and rhTSH injections in patients serving as their own controls. Nevertheless, because clinical outcomes are more important as an endpoint than the calculated radiation absorbed dose by 124I dosimetry, our paper (1) referred to work from our institution by Klubo-Gwiezdzinska et al., who demonstrated no difference in outcomes when patients with metastatic DTC were prepared for 131I treatment with either rhTSH or THW (5). Although THW scans may allow better detection of metastatic lesions than do rhTSH scans, preparation with THW may not necessarily result in significantly more radiation absorbed dose to the metastases than does preparation with rhTSH, thereby not improving outcomes. Thus, the caveat implied by Verburg et al. in regard to the lack of lesional dosimetry using 124I does not mitigate the fact that more lesions were detected after preparation with THW versus rhTSH injections and that—as concluded in our paper—until more data become available, physicians should be cautious in using rhTSH for patient preparation before diagnostic scanning for the detection of DTC or treatment of distant metastases secondary to DTC with 131I. In drawing attention to methodology-based drawbacks in our interpretation of the presented data, Verburg et al. are simply repeating limitations of our study that we already noted in our discussion. Next, Verburg et al. note that our statement that our result was most consistent with the data of Freudenberg et al. did not reflect the fact that the conclusion of Freudenberg et al. was more cautious. Our actual statement was, “In comparing our data with other reports that evaluated preparation with THW and rhTSH, our data are most consistent with those of Freudenberg et al. (6). . . .In the study of Freudenberg et al. (6), their endpoint was the estimation of the radiation absorbed dose to the metastatic foci after THW and rhTSH preparation. They reported that the mean radiation absorbed dose for the lesions identified in a group of patients (n 5 27) prepared with rhTSH was only 60% of the radiation absorbed dose to lesions in another group of patients (n5 36) prepared with THW. However, this difference was not statistically different.” I will leave the judgment to the reader regarding whether our statement reflected the data and conclusion of Freudenberg et al. and whether our data are most consistent with their data. Interestingly, Verburg et al. reference an article by Haugen et al. (7) as evidence that patient preparation with rhTSH injections has already been shown to be equivalent to patient preparation with THW. However, Verburg et al. do not point out the limitations of the study by Haugen et al. Notably, Haugen et al. reported that THW scans were superior to rhTSH scans in 16% (8/49) of patients, albeit not to a statistically significant extent (P 5 0.109). Second, although Verburg et al. state that this information was crucial for the approval of rhTSH (Thyrogen; Genzyme Corp.) by the Food and Drug Administration, it has not approved Thyrogen for use in metastatic DTC in the United States, which is stated in the drug insert. Third, the order of THW and rhTSH scans was not randomized; all rhTSH scans were performed first. Although Haugen et al. recog-

Investigation of signal averaging on image quality in positron emission tomography

Conventional [/sup 15/O]water PET rCBF methodology is composed of 1-10 injections of 10-50 mCi associated with multiple brain activation conditions (between 1-10). Injections occur at 10-15 min intervals. The current research compares the regional CBF signal using conventional PET studies with a method that involves summing data from 50-100 low dose injections (1-5 mCi) that have been administered in rapid but uniform succession (occurs at 1-2 min intervals) over a total study duration of 1-2 hours. This design allows for single subject studies. PET data from multiple occurrences are simulated for each specific activation condition and are summed to create a high statistics image for each activation condition. The results from the simulation are to be used to develop a computer controlled injection and data acquisition system.