Dopamine D3 receptor binding of (18)F-fallypride: Evaluation using in vitro and in vivo PET imaging studies.

Identification of dopamine D3 receptors (D3R) in vivo is important to understand several brain functions related to addiction. The goal of this work was to identify D3R binding of the dopamine D2 receptor (D2R)/D3R imaging agent, (18)F-fallypride. Brain slices from male Sprague-Dawley rats (n = 6) and New Zealand White rabbits (n = 6) were incubated with (18)F-fallypride and D3R selective agonist (R)-7-OH-DPAT (98-fold D3R selective). Rat slices were also treated with BP 897 (68-fold D3R selective partial agonist) and NGB 2904 (56-fold D3R selective antagonist). In vivo rat studies (n = 6) were done on Inveon PET using 18-37 MBq (18)F-fallypride and drug-induced displacement by (R)-7-OH-DPAT, BP 897 and NGB 2904. PET/CT imaging of wild type (WT, n = 2) and D2R knock-out (KO, n = 2) mice were carried out with (18)F-fallypride. (R)-7-OH-DPAT displaced binding of (18)F-fallypride, both in vitro and in vivo. In vitro, at 10 nM (R)-7-OH-DPAT, (18)F-fallypride binding in the rat ventral striatum (VST) and dorsal striatum (DST) and rabbit nucleus accumbens were reduced by ∼10-15%. At 10 µM (R)-7-OH-DPAT all regions in rat and rabbit were reduced by ≥85%. In vivo reductions for DST and VST before and after (R)-7-OH-DPAT were: low-dose (0.015 mg kg(-1)) DST -22%, VST -29%; high-dose (1.88 mg kg(-1)) DST -58%, VST -77%, suggesting D3R/D2R displacement. BP 897 and NGB 2904 competed with (18)F-fallypride in vitro, but unlike BP 897, NGB 2904 did not displace (18)F-fallypride in vivo. The D2R KO mice lacked (18)F-fallypride binding in the DST. In summary, our findings suggest that up to 20% of (18)F-fallypride may be bound to D3R sites in vivo.

Neural correlates of voluntary and involuntary risk taking in the human brain: an fMRI Study of the Balloon Analog Risk Task (BART).

Increasing effort has been devoted to understanding the neural mechanisms underlying decision making during risk, yet little is known about the effect of voluntary choice on risk taking. The Balloon Analog Risk Task (BART), in which subjects inflate a virtual balloon that can either grow larger or explode [Lejuez, C.W., Read, J.P., Kahler, C.W., Richards, J.B., Ramsey, S.E., Stuart, G.L., Strong, D.R., Brown, R.A., 2002. Evaluation of a behavioral measure of risk taking: the Balloon Analogue Risk Task BART. J. Exp. Psychol. Appl. 8, 75-84.], provides an ecologically valid model to assess human risk taking propensity and behaviour. In the present study, we modified this task for use during functional magnetic resonance imaging (fMRI) and administered it in both an active choice mode and a passive no-choice mode in order to examine the neural correlates of voluntary and involuntary risk taking in the human brain. Voluntary risk in the active choice task is associated with robust activation in mesolimbic-frontal regions, including the midbrain, ventral and dorsal striatum, anterior insula, dorsal lateral prefrontal cortex (DLPFC), and anterior cingulate/medial frontal cortex (ACC/MFC), in addition to activation in visual pathway regions. However, these mesolimbic-frontal activation patterns were not observed for involuntary risk in the passive no-choice task. Decision making was associated with neural activity in the right DLPFC. These findings demonstrate the utility of the modified BART paradigms for using during fMRI to assess risk taking in the human brain, and suggest that recruitment of the brain mesolimbic-frontal pathway during risk-taking is contingent upon the agency of the risk taker. The present paradigm may be extended to pathological populations to determine the specific neural components of their impaired risk behavior.

Minimizing acquisition time of arterial spin labeling at 3T.

An improved arterial spin labeling (ASL) perfusion technique that combines pseudo-continuous labeling and a T2*-insensitive sequence (GRASE) with background suppression was used to acquire perfusion maps in normal volunteers and stroke patients. It is shown that perfusion measurements obtained in less than 1 min of scan time are reproducible, with a coefficient of variation of 7%. The perfusion maps generated from these data can be used to characterize the stroke lesion.

Functional magnetic resonance imaging and working memory in adolescents with gestational cocaine exposure.

OBJECTIVE: To assess the effect of gestational cocaine exposure on the prefrontal cortex (PFC) with functional magnetic resonance imaging (fMRI). STUDY DESIGN: Using an n-back task, we obtained fMRI with a 3T Siemens scanner on 49 adolescents, 25 who were exposed to cocaine and 24 who were not exposed. The primary outcome was PFC activation during task performance. Five functionally derived regions of interest (ROI) were defined; in addition, 2 a priori anatomical ROIs were generated for Brodmann regions 10 and 46. RESULTS: Of the 49 adolescents who underwent imaging, data from 17 who were exposed to cocaine and 17 who were not exposed were in the final analysis. Groups had similar performance on the n-back task (P >/= .4), with both showing a fewer number of correct responses on the 2-back than the 1-back (P < .001), indicating increased demands on working memory with greater task difficulty. In functionally derived ROIs, imaging results showed increased activation for both groups in the 2-back versus the 1-back condition. In anatomical ROIs, both groups showed greater activation in the 2-back versus the 1-back condition, with activation in the non-exposed group proportionally greater for the left prefrontal region (P = .05). CONCLUSION: In this sample of adolescents, participants who were exposed to cocaine and participants who were not exposed were similar in performance on an executive function task and in fMRI activation patterns during task performance.

Hippocampus-specific fMRI group activation analysis using the continuous medial representation.

We present a new shape-based approach for regional group activation analysis in fMRI studies. The method restricts anatomical normalization, spatial smoothing and random effects statistical analysis to the space inside and around a structure of interest. Normalization involves finding intersubject correspondences between manually outlined masks, and it leverages the continuous medial representation, which makes it possible to extend surface-based shape correspondences to the space inside and outside of structures. Our approach is an alternative to whole-brain normalization in cases where the latter may fail due to anatomical variability or pathology. It also provides an opportunity to analyze the shape and thickness of structures concurrently with functional activation. We apply the technique to the hippocampus and evaluate it using data from a visual scene encoding fMRI study, where activation in the hippocampus is expected. We produce detailed statistical maps of hippocampal activation, as well as maps comparing activation inside and outside of the hippocampus. We find that random effects statistics computed by the new approach are more significant than those produced using the Statistical Parametric Mapping framework (Friston, K.J., Holmes, A.P., Worsley, K.J., Poline, J.-P., Firth, C.D., Frackowiak, R.S.J. 1994, Statistical parametric maps in functional imaging: a general linear approach. Human Brain Mapping, 2(4): 189-210) at low levels of smoothing, suggesting that greater specificity can be achieved by the new method without a severe tradeoff in sensitivity.

Hippocampus-specific fMRI group activation analysis with continuous M-Reps.

A new approach to group activation analysis in fMRI studies that test hypotheses focused on specific brain structures is presented and used to analyze hippocampal activation in a visual scene encoding study. The approach leverages the cm-rep method to normalize hippocampal anatomy and project intra-subject hippocampal activation maps into a common reference space, eliminating normalization errors inherent in whole-brain approaches and guaranteeing that peaks detected in the random effects activation map are indeed associated with the hippocampus. When applied to real fMRI data, the method detects more significant hippocampal activation than the established whole-brain method.