Julie A. Koeppel

Effects of Smoking Marijuana on Brain Perfusion and Cognition

The effects of smoking marijuana on regional cerebral blood flow (rCBF) and cognitive performance were assessed in 12 recreational users in a double-blinded, placebo-controlled study. PET with [15Oxygen]-labeled water ([15O]H2O) was used to measure rCBF before and after smoking of marijuana and placebo cigarettes, as subjects repeatedly performed an auditory attention task. Smoking marijuana resulted in intoxication, as assessed by a behavioral rating scale, but did not significantly alter mean behavioral performance on the attention task. Heart rate and blood pressure increased dramatically following smoking of marijuana but not placebo cigarettes. However, mean global CBF did not change significantly. Increased rCBF was observed in orbital and mesial frontal lobes, insula, temporal poles, anterior cingulate, as well as in the cerebellum. The increases in rCBF in anterior brain regions were predominantly in “paralimbic” regions and may be related to marijuanas mood-related effects. Reduced rCBF was observed in temporal lobe auditory regions, in visual cortex, and in brain regions that may be part of an attentional network (parietal lobe, frontal lobe and thalamus). These rCBF decreases may be the neural basis of perceptual and cognitive alterations that occur with acute marijuana intoxication. There was no significant rCBF change in the nucleus accumbens or other reward-related brain regions, nor in basal ganglia or hippocampus, which have a high density of cannabinoid receptors.

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.

Effect of Acute Marijuana on Cardiovascular Function and Central Nervous System Pharmacokinetics of [15O]Water: Effect in Occasional and Chronic Users

The objective of this study was to evaluate the effect of the acute administration of marijuana (MJ) on cardiovascular (CV) function and CNS pharmacokinetics (PK) of [15O]water in occasional (O) versus chronic (C) MJ users. Each subject received four injections of [15O]water (one prior and three postsmoking) on two occasions in which they received active or placebo MJ. For each injection, measures of CV function and CNS PK [15O]water were made. Postsmoking, MJ influenced all measured CV and [15O]water PK parameters. C users reported significantly lower “highness” and smaller heart rate (HR) changes, which resulted in reduced rate pressure product (RPP) changes compared to O users, even though Δ9‐tetrahydrocannabinol levels were higher, whereas changes in blood pressure (BP), arrival time, and [15O]water concentration were not significantly different between the groups. Significant CV changes resulted in changes in the whole‐body distribution of cardiac output rather than changes in cerebral blood flow. Chronic MJ use produces tolerance to the HR increases induced by acute MJ smoking compared to changes observed in occasional users, without changing the effects on BP and [15O]water PK.

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.

Preliminary Investigation of Cerebral Blood Flow and Amyloid Burden in Veterans With and Without Combat-Related Traumatic Brain Injury

This study aimed to examine global and regional cerebral blood flow and amyloid burden in combat veterans with and without traumatic brain injury (TBI). Cerebral blood flow (in milliliters per minute per 100 mL) was measured by quantitative [(15)O]water, and amyloid burden was measured by [(11)C]PIB imaging. Mean global cerebral blood flow was significantly lower in veterans with TBI compared with non-TBI veterans. There were essentially no differences between groups for globally normalized regional cerebral blood flow. Amyloid burden did not differ between TBI and non-TBI veterans. Veterans who have suffered a TBI have significantly lower cerebral blood flow than non-TBI controls but did not manifest increased levels of amyloid, globally or regionally.

Cerebral white matter correlates of delay discounting in adolescents.

The adolescent brain undergoes extensive structural white matter (WM) changes. Adolescence is also a critical time period during which cognitive, emotional and social maturation occurs in transition into adulthood. Compared to adults, adolescents are generally more impulsive with increased risk-taking behaviors. The goal of this study is to examine whether adolescent impulsivity may be related to cerebral WM maturation. In 89 healthy adolescents, we assessed impulsivity using the delay discounting task, and MRI WM volumes in brain regions previously implicated in delay discounting behaviors. We found that smaller delay discounting AUC (area under the curve) was associated with larger WM volumes in orbitofrontal, dorsolateral and medial prefrontal cortices (PFC) and motor cortex. There were no significant effects of AUC on WM volumes within somatosensory brain regions. In our sample, younger age was significantly associated with greater WM volumes in orbitofrontal and dorsolateral PFC subregions. Even after accounting for age-related effects, preference for immediate rewards (or greater impulsivity) still correlated with larger WM volumes in prefrontal regions known to mediate cognitive control. Our findings lend further support to the notion that reduced brain WM maturity may limit the ability in adolescents to forgo immediate rewards leading to greater impulsivity.

Impulsivity in unaffected adolescent biological relatives of schizophrenia patients

OBJECTIVE Although schizophrenia is not a prototypic impulse-control disorder, patients report more impulsive behaviors, have higher rates of substance use, and show dysfunction in brain circuits that underlie impulsivity. We investigate impulsivity in unaffected biological relatives of schizophrenia patients to further understand the relationships between schizophrenia risk and impulse control during adolescence. METHOD Group differences in impulsivity (UPPS-P Impulsive Behavior Scale and delay discounting) were tested in 210 adolescents contrasting 39 first- and 53 second-degree biological relatives of schizophrenia patients, and 118 subjects with no schizophrenia family history (NSFH). RESULTS Compared to NSFH adolescents and to second-degree relatives, first-degree relatives of schizophrenia patients had increased impulsivity-related behaviors (higher UPPS-P Perseverance, Positive Urgency and Premeditation subscale scores) and greater preference for immediate rewards (smaller AUC and larger discounting constant). Second-degree relatives did not differ significantly from NSFH adolescents on self-report impulsive behaviors or on measures of impulsive decision-making. These group differences remained even after careful consideration of potential confounding factors. CONCLUSION Impulsivity is associated with schizophrenia risk, and its severity increases with greater familial relatedness to the schizophrenia proband. Additional studies are needed to understand the role impulsivity may play in mediating schizophrenia susceptibility during adolescence.

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-