Jenna M. Sullivan

Sex Differences in the Brain's Dopamine Signature of Cigarette Smoking

Cigarette smoking is a major public health danger. Women and men smoke for different reasons and cessation treatments, such as the nicotine patch, are preferentially beneficial to men. The biological substrates of these sex differences are unknown. Earlier PET studies reported conflicting findings but were each hampered by experimental and/or analytical limitations. Our new image analysis technique, lp-ntPET (Normandin et al., 2012; Morris et al., 2013; Kim et al., 2014), has been optimized for capturing brief (lasting only minutes) and highly localized dopaminergic events in dynamic PET data. We coupled our analysis technique with high-resolution brain scanning and high-frequency motion correction to create the optimal experiment for capturing and characterizing the effects of smoking on the mesolimbic dopamine system in humans. Our main finding is that male smokers smoking in the PET scanner activate dopamine in the right ventral striatum during smoking but female smokers do not. This finding—men activating more ventrally than women—is consistent with the established notion that men smoke for the reinforcing drug effect of cigarettes whereas women smoke for other reasons, such as mood regulation and cue reactivity. lp-ntPET analysis produces a novel multidimensional endpoint: voxel-level temporal patterns of neurotransmitter release (“DA movies”) in individual subjects. By examining these endpoints quantitatively, we demonstrate that the timing of dopaminergic responses to cigarette smoking differs between men and women. Men respond consistently and rapidly in the ventral striatum whereas women respond faster in a discrete subregion of the dorsal putamen.

Kinetic Analysis of the Metabotropic Glutamate Subtype 5 Tracer [18F]FPEB in Bolus and Bolus-Plus-Constant-Infusion Studies in Humans

[18F]FPEB is a positron emission tomography tracer which, in preclinical studies, has shown high specificity and selectivity toward the metabotropic glutamate receptor 5 (mGluR5). It possesses the potential to be used in human studies to evaluate mGluR5 function in a range of neuropsychiatric disorders, such as anxiety and Fragile X syndrome. To define optimal scan methodology, healthy human subjects were scanned for 6 hours following either a bolus injection (n = 5) or bolus-plus-constant-infusion (n = 5) of [18F]FPEB. Arterial blood samples were collected and parent fraction measured by high-performance liquid chromatography (HPLC) to determine the metabolite-corrected plasma input function. Time activity curves were extracted from 13 regions and fitted by various models to estimate VT and BPND. [18F]FPEB was well fitted by the two-tissue compartment model, MA1 (t∗ = 30), and MRTM (using cerebellum white matter as a reference). Highest VT values were observed in the anterior cingulate and caudate, and lowest VT values were observed in the cerebellum and pallidum. For kinetic modeling studies, VT and BPND were estimated from bolus or bolus-plus-constant-infusion scans as short as 90 minutes. Bolus-plus-constant-infusion of [18F]FPEB reduced intersubject variability in VT and allowed equilibrium analysis to be completed with a 30-minute scan, acquired 90–120 minutes after the start of injection.

List-Mode PET Motion Correction Using Markerless Head Tracking: Proof-of-Concept With Scans of Human Subject

A custom designed markerless tracking system was demonstrated to be applicable for positron emission tomography (PET) brain imaging. Precise head motion registration is crucial for accurate motion correction (MC) in PET imaging. State-of-the-art tracking systems applied with PET brain imaging rely on markers attached to the patients head. The marker attachment is the main weakness of these systems. A healthy volunteer participating in a cigarette smoking study to image dopamine release was scanned twice for 2 h with 11C-racolopride on the high resolution research tomograph (HRRT) PET scanner. Head motion was independently measured, with a commercial marker-based device and the proposed vision-based system. A list-mode event-by-event reconstruction algorithm using the detected motion was applied. A phantom study with hand-controlled continuous random motion was obtained. Motion was time-varying with long drift motions of up to 18 mm and regular step-wise motion of 1-6 mm. The evaluated measures were significantly better for motion-corrected images compared to no MC. The demonstrated system agreed with a commercial integrated system. Motion-corrected images were improved in contrast recovery of small structures.

Voxelwise lp-ntPET for Detecting Localized, Transient Dopamine Release of Unknown Timing: Sensitivity Analysis and Application to Cigarette Smoking in the PET Scanner

The “linear parametric neurotransmitter PET” (lp‐ntPET) model estimates time variation in endogenous neurotransmitter levels from dynamic PET data. The pattern of dopamine (DA) change over time may be an important element of the brains response to addictive substances such as cigarettes or alcohol. We have extended the lp‐ntPET model from the original region of interest (ROI) ‐ based implementation to be able to apply the model at the voxel level. The resulting endpoint is a dynamic image, or movie, of transient neurotransmitter changes. Simulations were performed to select threshold values to reduce the false positive rate when applied to real 11C‐raclopride PET data. We tested the new voxelwise method on simulated data, and finally, we applied it to 11C‐raclopride PET data of subjects smoking cigarettes in the PET scanner. In simulation, the temporal precision of neurotransmitter response was shown to be similar to that of ROI‐based lp‐ntPET (standard deviation ∼ 3 min). False positive rates for the voxelwise method were well controlled by combining a statistical threshold (the F‐test) with a new spatial (cluster‐size) thresholding operation. Sensitivity of detection for the new algorithm was greater than 80% for the case of short‐lived DA changes that occur in subregions of the striatum as might be the case with cigarette smoking. Finally, in 11C‐raclopride PET data, DA movies reveal for the first time that different temporal patterns of the DA response to smoking may exist in different subregions of the striatum. These spatiotemporal patterns of neurotransmitter change created by voxelwise lp‐ntPET may serve as novel biomarkers for addiction and/or treatment efficacy. Hum Brain Mapp 35:4876–4891, 2014.

Imaging of alcohol-induced dopamine release in rats: Preliminary findings with [11C]raclopride PET

Microdialysis studies report that systemic alcohol increases extracellular dopamine (DA) in the rat striatum. The present study examined whether changes in striatal DA could be detected in rats using small animal positron emission tomography (PET). PET images were acquired in 44 alcohol‐naïve male Wistar and alcohol‐preferring (P) rats. Subjects received up to three [11C]raclopride scans (rest, alcohol, and saline). Animals were anesthetized with isoflurane and secured on a stereotactic‐like holder during all scans. Blood samples were collected from the tail or lateral saphenous vein of 12 animals 10 min after tracer injection for determination of blood alcohol concentration (BAC). Time activity curves were extracted from the striatum and the cerebellum and binding potential (BPND) was calculated as a measure of D2 receptor availability. Wistars given 1.0 g kg−1 alcohol (20%v/v) i.v. or 3.0 g kg−1 alcohol (20%v/v) i.p. showed significant alcohol‐induced decreases in BPND. In P rats (given 1.5, 2.25, or 3.0 g kg−1 alcohol), no individual group showed a statistical effect of alcohol on BPND, but taken together, all P rats receiving i.p. alcohol had significantly lower BPND than rest or saline scans. Large decreases in BPND were primarily observed in rats with BAC above 200 mg%. Also, a significant difference was found between baseline BPND of Wistars who had undergone jugular catheterization surgery for i.v. alcohol administration and those who had not. Preliminary results suggest that alcohol‐induced DA release in the rat striatum is detectable using small animal PET given sufficiently large cohorts and adequate blood alcohol levels. Synapse, 2011.

Kinetic modeling of the mGluR5 tracer [18F]F-FPEB in humans

Introduction: It has been shown that [F]F-FPEB displays high specificity and selectivity toward metabotropic glutamate receptor 5 (mGluR5), and it possesses the potential to be used in human studies to evaluate mGluR5 functions in a range of neuropsychiatric disorders, such as anxiety and Fragile X syndrome (Porter, 2005; Montana, 2009; Berry-Kravis, 2009). [F]F-FPEB has been previously evaluated in rats and non-human primates. The goal of the present study is to fully characterize the tracer kinetic methodology to use [F]F-FPEB in human subjects.