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Objective: Schizotypal personality traits are associated with schizophrenia spectrum disorders, and individuals with schizophrenia spectrum disorders demonstrate increased dopamine transmission in the striatum. The authors sought to determine whether individual differences in normal variation in schizotypal traits are correlated with dopamine transmission in the striatum and in extrastriatal brain regions.Method: Sixty-three healthy volunteers with no history of psychiatric illness completed the Schizotypal Personality Questionnaire and underwent positron emission tomography imaging with [(18)F]fallypride at baseline and after administration of oral d-amphetamine (0.43 mg/kg). Dopamine release, quantified by subtracting each participant's d-amphetamine scan from his or her baseline scan, was correlated with Schizotypal Personality Questionnaire total and factor scores using region-of-interest and voxel-wise analyses.Results: Dopamine release in the striatum was positively correlated with overall schizotypal traits. The association was especially robust in the associative subdivision of the striatum. Voxel-wise analyses identified additional correlations between dopamine release and schizotypal traits in the left middle frontal gyrus and left supramarginal gyrus. Exploratory analyses of Schizotypal Personality Questionnaire factor scores revealed correlations between dopamine release and disorganized schizotypal traits in the striatum, thalamus, medial prefrontal cortex, temporal lobe, insula, and inferior frontal cortex.Conclusions: The association between dopamine signaling and psychosis phenotypes extends to individual differences in normal variation in schizotypal traits and involves dopamine transmission in both striatal and extrastriatal brain regions. Amphetamine-induced dopamine release may be a useful endophenotype for investigating the genetic basis of schizophrenia spectrum disorders. [ABSTRACT FROM AUTHOR]

Background: The group-I metabotropic glutamate receptor subtype 5 (mGlu5) has been implicated in methamphetamine exposure in animals and in human cognition. Because people with methamphetamine use disorder (MUD) exhibit cognitive deficits, we evaluated mGlu5 in people with MUD and controls and tested its association with cognitive performance., Methods: Positron emission tomography was performed to measure the total VT of [18F]FPEB, a radiotracer for mGlu5, in brains of participants with MUD (abstinent from methamphetamine for at least 2 weeks, N = 14) and a control group (N = 14). Drug use history questionnaires and tests of verbal learning, spatial working memory, and executive function were administered. Associations of VT with methamphetamine use, tobacco use, and cognitive performance were tested., Results: MUD participants did not differ from controls in global or regional VT, and measures of methamphetamine use were not correlated with VT. VT was significantly higher globally in nonsmoking vs smoking participants (main effect, P = .0041). MUD participants showed nonsignificant weakness on the Rey Auditory Verbal Learning Task and the Stroop test vs controls (P = .08 and P = .13, respectively) with moderate to large effect sizes, and significantly underperformed controls on the Spatial Capacity Delayed Response Test (P = .015). Across groups, Rey Auditory Verbal Learning Task performance correlated with VT in the dorsolateral prefrontal cortex and superior frontal gyrus., Conclusion: Abstinent MUD patients show no evidence of mGlu5 downregulation in brain, but association of VT in dorsolateral prefrontal cortex with verbal learning suggests that medications that target mGlu5 may improve cognitive performance., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

The fire modeling community currently lacks full-scale experi- mental data from fires in residential-style structures with heat- ing, ventilation, and air conditioning (HVAC) systems. Further, there is an absence of data quantifying the generation of H 2 O due to combustion and the subsequent transport of those gases with a structure. Propane gas burner fire experiments were con- ducted in a purpose-built two-story structure instrumented to measure temperature, pressure, velocity, and gas concentrations. Experiments were conducted to assess heat and gas species trans- fer due to HVAC operating status (off vs. on), fire location and heat release rate, and bedroom door position (open vs. closed)., Competing Interests: The authors declare that they have no known competing financial interests or personal relation- ships which have, or could be perceived to have, influenced the work reported in this article., (© 2022 The Author(s).)

We aim to identify physiologic regulators of dopamine (DA) signaling in obesity but previously did not find a compelling relationship with insulin sensitivity measured by oral-minimal model (OMM) and DA subtype 2 and 3 receptor (D2/3R) binding potential (BPND). Reduced disposition index (DI), a β-cell function metric that can also be calculated by OMM, was shown to predict a negative reward behavior that occurs in states of lower endogenous DA. We hypothesized that reduced DI would occur with higher D2/3R BPND, reflecting lower endogenous DA. Participants completed PET scanning, with a displaceable radioligand to measure D2/3R BPND, and a 5-hour oral glucose tolerance test to measure DI by OMM. We studied 26 age-similar females without (n = 8) and with obesity (n = 18) (22 vs 39 kg/m2). Reduced DI predicted increased striatal D2/3R BPND independent of BMI. By accounting for β-cell function, we were able to determine that the state of insulin and glucose metabolism is pertinent to striatal D2/3R BPND in obesity. Clinical Trial Registration Number: NCT00802204., Competing Interests: The authors have declared that no competing interests exist.

Rationale: Sex differences in the dopaminergic response to psychostimulants could have implications for drug abuse risk and other psychopathology involving the dopamine system, but human data are limited and mixed., Objectives: Here, we sought to investigate sex differences in dopamine release after oral D-amphetamine administration., Methods: We used [ 18 F]fallypride positron emission tomography (PET) to measure the change in dopamine D2/3 receptor availability (%ΔBP ND , an index of dopamine release) between placebo and D-amphetamine sessions in two independent datasets containing a total of 39 females (on either hormonal birth control n = 18, postmenopausal n = 10, or studied in the first 10 days of their menstrual cycle n = 11) and 37 males., Results: Using both a priori anatomical regions of interest based on previous findings and voxelwise analyses, we failed to consistently detect broad sex differences in D-amphetamine-induced dopamine release. Nevertheless, there was limited evidence for greater right ventral striatal dopamine release in young adult males relative to similarly aged females, but this was not consistently observed across samples. Plasma estradiol did not correlate with dopamine release and this measure did not differ in females on and off hormonal birth control., Conclusions: While our finding in young adults from one dataset of greater %ΔBP ND in males is partially consistent with a previously published study on sex differences in D-amphetamine-induced dopamine release, our data do not support the presence of consistent widespread sex differences in this measure of dopamine release.

The nigrostriatal and mesocorticolimbic dopamine networks regulate reward-driven behavior. Regional alterations to mesolimbic dopamine D 2/3 receptor expression are described in drug-seeking and addiction disorders. Parkinson's disease (PD) patients are frequently prescribed D 2 -like dopamine agonist (DAgonist) therapy for motor symptoms, yet a proportion develop clinically significant behavioral addictions characterized by impulsive and compulsive behaviors (ICBs). Until now, changes in D 2/3 receptor binding in both striatal and extrastriatal regions have not been concurrently quantified in this population. We identified 35 human PD patients (both male and female) receiving DAgonist therapy, with ( n = 17) and without ( n = 18) ICBs, matched for age, disease duration, disease severity, and dose of dopamine therapy. In the off-dopamine state, all completed PET imaging with [ 18 F]fallypride, a high affinity D 2 -like receptor ligand that can measure striatal and extrastriatal D 2/3 nondisplaceable binding potential (BP ND ). Striatal differences between ICB+/ICB- patients localized to the ventral striatum and putamen, where ICB+ subjects had reduced BP ND In this group, self-reported severity of ICB symptoms positively correlated with midbrain D 2/3 receptor BP ND Group differences in regional D 2/3 BP ND relationships were also notable: ICB+ (but not ICB-) patients expressed positive correlations between midbrain and caudate, putamen, globus pallidus, and amygdala BP ND s. These findings support the hypothesis that compulsive behaviors in PD are associated with reduced ventral and dorsal striatal D 2/3 expression, similar to changes in comparable behavioral disorders. The data also suggest that relatively preserved ventral midbrain dopaminergic projections throughout nigrostriatal and mesolimbic networks are characteristic of ICB+ patients, and may account for differential DAgonist therapeutic response. SIGNIFICANCE STATEMENT The biologic determinants of compulsive reward-based behaviors have broad clinical relevance, from addiction to neurodegenerative disorders. Here, we address biomolecular distinctions in Parkinson's disease patients with impulsive compulsive behaviors (ICBs). This is the first study to image a large cohort of ICB+ patients using positron emission tomography with [18F]fallypride, allowing quantification of D 2/3 receptors throughout the mesocorticolimbic network. We demonstrate widespread differences in dopaminergic networks, including (1) D2-like receptor distinctions in the ventral striatum and putamen, and (2) a preservation of widespread dopaminergic projections emerging from the midbrain, which is associated with the severity of compulsive behaviors. This clearly illustrates the roles of D 2/3 receptors and medication effects in maladaptive behaviors, and localizes them specifically to nigrostriatal and extrastriatal regions., (Copyright © 2018 the authors 0270-6474/18/383231-10$15.00/0.)

Parkinson's disease (PD) is characterized by widespread degeneration of monoaminergic (especially dopaminergic) networks, manifesting with a number of both motor and non-motor symptoms. Regional alterations to dopamine D 2/3 receptors in PD patients are documented in striatal and some extrastriatal areas, and medications that target D 2/3 receptors can improve motor and non-motor symptoms. However, data regarding the combined pattern of D 2/3 receptor binding in both striatal and extrastriatal regions in PD are limited. We studied 35 PD patients off-medication and 31 age- and sex-matched healthy controls (HCs) using PET imaging with [ 18 F]fallypride, a high affinity D 2/3 receptor ligand, to measure striatal and extrastriatal D 2/3 nondisplaceable binding potential (BP ND ). PD patients completed PET imaging in the off medication state, and motor severity was concurrently assessed. Voxel-wise evaluation between groups revealed significant BP ND reductions in PD patients in striatal and several extrastriatal regions, including the locus coeruleus and mesotemporal cortex. A region-of-interest (ROI) based approach quantified differences in dopamine D 2/3 receptors, where reduced BP ND was noted in the globus pallidus, caudate, amygdala, hippocampus, ventral midbrain, and thalamus of PD patients relative to HC subjects. Motor severity positively correlated with D 2/3 receptor density in the putamen and globus pallidus. These findings support the hypothesis that abnormal D 2/3 expression occurs in regions related to both the motor and non-motor symptoms of PD, including areas richly invested with noradrenergic neurons.

Background: PD patients treated with dopamine therapy can develop maladaptive impulsive and compulsive behaviors, manifesting as repetitive participation in reward-driven activities. This behavioral phenotype implicates aberrant mesocorticolimbic network function, a concept supported by past literature. However, no study has investigated the acute hemodynamic response to dopamine agonists in this subpopulation., Objectives: We tested the hypothesis that dopamine agonists differentially alter mesocortical and mesolimbic network activity in patients with impulsive-compulsive behaviors., Methods: Dopamine agonist effects on neuronal metabolism were quantified using arterial-spin-labeling MRI measures of cerebral blood flow in the on-dopamine agonist and off-dopamine states. The within-subject design included 34 PD patients, 17 with active impulsive compulsive behavior symptoms, matched for age, sex, disease duration, and PD severity., Results: Patients with impulsive-compulsive behaviors have a significant increase in ventral striatal cerebral blood flow in response to dopamine agonists. Across all patients, ventral striatal cerebral blood flow on-dopamine agonist is significantly correlated with impulsive-compulsive behavior severity (Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease- Rating Scale). Voxel-wise analysis of dopamine agonist-induced cerebral blood flow revealed group differences in mesocortical (ventromedial prefrontal cortex; insular cortex), mesolimbic (ventral striatum), and midbrain (SN; periaqueductal gray) regions., Conclusions: These results indicate that dopamine agonist therapy can augment mesocorticolimbic and striato-nigro-striatal network activity in patients susceptible to impulsive-compulsive behaviors. Our findings reinforce a wider literature linking studies of maladaptive behaviors to mesocorticolimbic networks and extend our understanding of biological mechanisms of impulsive compulsive behaviors in PD. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Objective: It has been previously reported that early after Roux-en-Y-gastric bypass, dopamine (DA) type 2 and 3 receptor (D2/3R) binding potential (BP ND ) was decreased from preoperative levels. The current study aimed to determine whether calorie restriction without weight loss modifies D2/3R BP ND and whether such changes are explained by neuroendocrine regulation., Methods: Fifteen females with obesity (BMI = 39 ± 6 kg/m 2 ) were studied before and after ∼10 days of a very-low-calorie-diet (VLCD). Outcome measures included fasting insulin, leptin, acyl ghrelin, and glucose, and insulin sensitivity and disposition index were estimated using the oral-minimal model (OMM) method. Participants underwent positron emission tomography scanning with the displaceable radioligand [ 18 F]fallypride to estimate available regional D2/3R levels. Regions of interest included the caudate, putamen, ventral striatum, hypothalamus, and substantia nigra (SN)., Results: With the VLCD, weight decreased slightly (-3 kg). Insulin, glucose, and leptin decreased significantly, but there was no change in acyl ghrelin or measures from OMM. SN D2/3R BP ND decreased significantly, with trends toward decreased levels in the remaining regions. The decrease in leptin concentration strongly predicted the change in D2/3R BP ND in all regions (all P ≤ 0.004)., Conclusions: In obesity, reductions in regional D2/3R availability after VLCD are suggestive of increased endogenous DA competing with the radioligand. Changes in regional D2/3R availability were associated with decreases in leptin concentrations that occurred before clinically significant weight loss., (© 2017 The Obesity Society.)

Dopamine function is broadly implicated in multiple neuropsychiatric conditions believed to have a genetic basis. Although a few positron emission tomography (PET) studies have investigated the impact of single-nucleotide polymorphisms (SNPs) in the dopamine D2 receptor gene (DRD2) on D2/3 receptor availability (binding potential, BP ND ), these studies have often been limited by small sample size. Furthermore, the most commonly studied SNP in D2/3 BP ND (Taq1A) is not located in the DRD2 gene itself, suggesting that its linkage with other DRD2 SNPs may explain previous PET findings. Here, in the largest PET genetic study to date (n=84), we tested for effects of the C957T and -141C Ins/Del SNPs (located within DRD2) as well as Taq1A on BP ND of the high-affinity D2 receptor tracer 18 F-Fallypride. In a whole-brain voxelwise analysis, we found a positive linear effect of C957T T allele status on striatal BP ND bilaterally. The multilocus genetic scores containing C957T and one or both of the other SNPs produced qualitatively similar striatal results to C957T alone. The number of C957T T alleles predicted BP ND in anatomically defined putamen and ventral striatum (but not caudate) regions of interest, suggesting some regional specificity of effects in the striatum. By contrast, no significant effects arose in cortical regions. Taken together, our data support the critical role of C957T in striatal D2/3 receptor availability. This work has implications for a number of psychiatric conditions in which dopamine signaling and variation in C957T status have been implicated, including schizophrenia and substance use disorders.

Subjective responses to psychostimulants vary, the basis of which is poorly understood, especially in relation to possible cortical contributions. Here, we tested for relationships between participants' positive subjective responses to oral d-amphetamine (dAMPH) versus placebo and variability in striatal and extrastriatal dopamine (DA) receptor availability and release, measured via positron emission tomography (PET) with the radiotracer (18)F-fallypride. Analyses focused on 35 healthy adult participants showing positive subjective effects to dAMPH measured via the Drug Effects Questionnaire (DEQ) Feel, Like, High, and Want More subscales (Responders), and were repeated after inclusion of 11 subjects who lacked subjective responses. Associations between peak DEQ subscale ratings and both baseline (18)F-fallypride binding potential (BPnd; an index of D2/D3 receptor availability) and the percentage change in BPnd post dAMPH (%ΔBPnd; a measure of DA release) were assessed. Baseline BPnd in ventromedial prefrontal cortex (vmPFC) predicted the peak level of High reported following dAMPH. Furthermore, %ΔBPnd in vmPFC positively correlated with DEQ Want More ratings. DEQ Want More was also positively correlated with %ΔBPnd in right ventral striatum and left insula. This work indicates that characteristics of DA functioning in vmPFC, a cortical area implicated in subjective valuation, are associated with both subjective high and incentive (wanting) responses. The observation that insula %ΔBPnd was associated with drug wanting converges with evidence suggesting its role in drug craving. These findings highlight the importance of variability in DA signaling in specific paralimbic cortical regions in dAMPH's subjective response, which may confer risk for abusing psychostimulants., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Relatively little is known about the neuropathophysiology of binge-eating disorder (BED). Here, the evidence from neuroimaging, neurocognitive, genetics, and animal studies are reviewed to synthesize our current understanding of the pathophysiology of BED. Binge-eating disorder may be conceptualized as an impulsive/compulsive disorder, with altered reward sensitivity and food-related attentional biases. Neuroimaging studies suggest there are corticostriatal circuitry alterations in BED similar to those observed in substance abuse, including altered function of prefrontal, insular, and orbitofrontal cortices and the striatum. Human genetics and animal studies suggest that there are changes in neurotransmitter networks, including dopaminergic and opioidergic systems, associated with binge-eating behaviors. Overall, the current evidence suggests that BED may be related to maladaptation of the corticostriatal circuitry regulating motivation and impulse control similar to that found in other impulsive/compulsive disorders. Further studies are needed to understand the genetics of BED and how neurotransmitter activity and neurocircuitry function are altered in BED and how pharmacotherapies may influence these systems to reduce BED symptoms., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rate of delivery of psychostimulants has been associated with their positive euphoric effects and potential addiction liability. However, information on individual differences in onset of d-amphetamine's effects remains scarce. We examined individual differences in the time to peak subjective and physiological effects and the pharmacokinetics/pharmacodynamics of oral d-amphetamine. We considered two independent studies that used different dosing regimens where subjects completed the drug effects questionnaire at multiple time points post d-amphetamine. Based on the observation of distinct individual differences in time course of drug effects questionnaire "feel", "high", and "like" ratings (DEQH+L+F) in Study 1, subjects in both studies were categorized as early peak responders (peak within 60 minutes), late peak responders (peak > 60 minutes) or nonresponders; 20-25% of participants were categorized as early peak responders, 50-55% as late peak responders and 20-30% as nonresponders. Physiological (both studies) and plasma d-amphetamine (Study 1) were compared among these groups. Early peak responders exhibited an earlier rise in plasma d-amphetamine levels and more sustained elevation in heart rate compared to late peak responders. The present data illustrate the presence of significant individual differences in the temporal pattern of responses to oral d-amphetamine, which may contribute to heightened abuse potential., (© The Author(s) 2016.)

Case-control studies comparing ADHD with typically developing individuals suggest that anatomical asymmetry of the caudate nucleus is a marker of attention deficit hyperactivity disorder (ADHD). However, there is no consensus on whether the asymmetry favors the right or left caudate nucleus in ADHD, or whether the asymmetry is increased or decreased in ADHD. The current study aimed to clarify this relationship by applying a dimensional approach to assessing ADHD symptoms that, instead of relying on clinical classification, utilizes the natural behavioral continuum of traits related to ADHD. Structural T1-weighted MRI was collected from 71 adults between 18 and 35 years and analyzed for caudate asymmetry. ADHD-like attentional symptoms were assessed with an objective measure of attentional problems, the ADHD score from the Test of Variables of Attention (TOVA). Impulsivity, a core feature in ADHD, was measured using the Barratt Impulsiveness Scale, a self-report measure that assesses attentional, non-planning, and motor features of impulsivity. We found that larger right relative to left caudate volumes correlated with both higher attentional impulsiveness and worse ADHD scores on the TOVA. Higher attentional impulsiveness also correlated with worse ADHD scores, establishing coherence between the objective measure and the self-report measure of attentional problems. These results suggest that a differential passage of information through frontal-striatal networks may produce instability leading to attentional problems. The findings also demonstrate the utility of a dimensional approach to understanding structural correlates of ADHD symptoms.

Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu5) have exciting potential as therapeutic agents for multiple brain disorders. Translational studies with mGlu5 modulators have relied on mGlu5 allosteric site positron emission tomography (PET) radioligands to assess receptor occupancy in the brain. However, recent structural and modeling studies suggest that closely related mGlu5 allosteric modulators can bind to overlapping but not identical sites, which could complicate interpretation of in vivo occupancy data, even when PET ligands and drug leads are developed from the same chemical scaffold. We now report that systemic administration of the novel mGlu5 positive allosteric modulator VU0092273 displaced the structurally related mGlu5 PET ligand, [(18)F]FPEB, with measures of in vivo occupancy that closely aligned with its in vivo efficacy. In contrast, a close analog of VU0092273 and [(18)F]FPEB, VU0360172, provided robust efficacy in rodent models in the absence of detectable occupancy. Furthermore, a structurally unrelated mGlu5 negative allosteric modulator, VU0409106, displayed measures of in vivo occupancy that correlated well with behavioral effects, despite the fact that VU0409106 is structurally unrelated to [(18)F]FPEB. Interestingly, all three compounds inhibit radioligand binding to the prototypical MPEP/FPEB allosteric site in vitro. However, VU0092273 and VU0409106 bind to this site in a fully competitive manner, whereas the interaction of VU0360172 is noncompetitive. Thus, while close structural similarity between PET ligands and drug leads does not circumvent issues associated with differential binding to a given target, detailed molecular pharmacology analysis accurately predicts utility of ligand pairs for in vivo occupancy studies.

Unlabelled: (18)F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ((18)F-FPEB) is a potent and specific radioligand for the metabotropic glutamate receptor subtype 5 (mGluR5). Before undertaking clinical research studies with (18)F-FPEB, we performed studies of human radiation dosimetry., Methods: Serial whole-body scans were obtained in 9 healthy human subjects (5 men, 4 women) for 190-440 min after the intravenous administration of (18)F-FPEB. Radiation doses were estimated using the OLINDA/EXM software., Results: Peak organ doses were to the urinary bladder wall, 0.258 mGy/MBq (0.955 rad/mCi), and gallbladder wall, 0.193 mGy/MBq (0.716 rad/mCi). The effective dose was 0.025 mSv/MBq (0.0922 rem/mCi). The doses to the red marrow and spleen were 0.00797 mGy/MBq (0.0295 rad/mCi) and 0.00709 mGy/MBq (0.0262 rad/mCi), respectively. Reducing the urinary voiding interval to 60 or 90 min lowered the urinary bladder wall dose to 0.0885 mGy/MBq (0.327 rad/mCi) or 0.128 mGy/MBq (0.473 rad/mCi), respectively, and the effective dose to 0.0149 mSv/MBq (0.0551 rem/mCi) or 0.0171 mSv/MBq (0.0634 rem/mCi), respectively., Conclusion: Urinary voiding should be performed during (18)F-FPEB studies to minimize radiation exposure to research subjects., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Objective: To investigate the relationship of novelty seeking traits (NS) with midbrain dopamine (DA) receptors and acyl ghrelin levels (AG) in normal weight (NW) and obese females.NS predict addictive behaviors and are hypothesized to contribute to eating behaviors. In healthy, NS are negatively associated with DA receptors in the substantia nigra (SN). The influence of obesity on the regulation of NS by DA signaling and AG was hypothesized., Methods: PET scanning to measure DA type 2/type 3 receptor (D2/D3R) binding potential (BPND ) in the SN was used. Participants completed Tridimensional Personality Questionnaire-Novelty-Seeking Scale (TPQ-NS) and AG were measured., Results: In eight NW and 19 obese (BMI 22 vs 38 kg/m(2) ), TPQ-NS (16 vs 15) and SN D2/D3R BPND (2.48 vs 2.66) were similar, while AG higher (256 vs 60, P < 0.01), respectively. D2/D3R BPND and TPQ-NS had a negative relationship in NW (r = -0.7) but not in obese (P > 0.10). AG and TPQ-NS were positively correlated in NW (r = 0.9) but not in obese (P > 0.10). D2R BPND and AG were negatively correlated in NW (r = -0.8) but positively in obese (r = 0.6)., Conclusion: Obese do not maintain posited regulatory relationships for NS to either midbrain D2/D3R availability or AG present in NW. Also opposite relationships exist for NW and obese between SN D2/D3R availability and AG. The altered regulation of NS in obesity needs to be further explored., (Copyright © 2014 The Obesity Society.)

Background: Everyday life demands continuous flexibility in thought and behavior. We examined whether individual differences in dopamine function are related to variability in the effects of amphetamine on one aspect of flexibility: task switching., Methods: Forty healthy human participants performed a task-switching paradigm following placebo and oral amphetamine administration. [(18)F]fallypride was used to measure D2/D3 baseline receptor availability and amphetamine-stimulated dopamine release., Results: The majority of the participants showed amphetamine-induced benefits through reductions in switch costs. However, such benefits were variable. Individuals with higher baseline thalamic and cortical receptor availability and striatal dopamine release showed greater reductions in switch costs following amphetamine than individuals with lower levels. The relationship between dopamine receptors and stimulant-enhanced flexibility was partially mediated by striatal dopamine release., Conclusions: These data indicate that the impact of the psychostimulant on cognitive flexibility is influenced by the status of dopamine within a thalamocorticostriatal network. Beyond demonstrating a link between this dopaminergic network and the enhancement in task switching, these neural measures accounted for unique variance in predicting the psychostimulant-induced cognitive enhancement. These results suggest that there may be measurable aspects of variability in the dopamine system that predispose certain individuals to benefit from and hence use psychostimulants for cognitive enhancement., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Preferences for different combinations of costs and benefits are a key source of variability in economic decision-making. However, the neurochemical basis of individual differences in these preferences is poorly understood. Studies in both animals and humans have demonstrated that direct manipulation of the neurotransmitter dopamine (DA) significantly impacts cost/benefit decision-making, but less is known about how naturally occurring variation in DA systems may relate to individual differences in economic behavior. In the present study, 25 healthy volunteers completed a dual-scan PET imaging protocol with [(18)F]fallypride and d-amphetamine to measure DA responsivity and separately completed the effort expenditure for rewards task, a behavioral measure of cost/benefit decision-making in humans. We found that individual differences in DA function in the left striatum and ventromedial prefrontal cortex were correlated with a willingness to expend greater effort for larger rewards, particularly when probability of reward receipt was low. Additionally, variability in DA responses in the bilateral insula was negatively correlated with willingness to expend effort for rewards, consistent with evidence implicating this region in the processing of response costs. These findings highlight the role of DA signaling in striatal, prefrontal, and insular regions as key neurochemical mechanisms underlying individual differences in cost/benefit decision-making.

Objective: Midbrain dopamine (DA) neurons, which are involved with reward and motivation, are modulated by hormones that regulate food intake (insulin, leptin, and acyl ghrelin [AG]). We hypothesized that these hormones are associated with deficits in DA signaling in obesity., Research Design and Methods: We assessed the relationships between fasting levels of insulin and leptin, and AG, BMI, and insulin sensitivity index (S(I)) with the availability of central DA type 2 receptor (D2R). We measured D2R availability using positron emission tomography and [(18)F]fallypride (radioligand that competes with endogenous DA) in lean (n = 8) and obese (n = 14) females. Fasting hormones were collected prior to scanning and S(I) was determined by modified oral glucose tolerance test., Results: Parametric image analyses revealed associations between each metabolic measure and D2R. The most extensive findings were negative associations of AG with clusters involving the striatum and inferior temporal cortices. Regional regression analyses also found extensive negative relationships between AG and D2R in the caudate, putamen, ventral striatum (VS), amygdala, and temporal lobes. S(I) was negatively associated with D2R in the VS, while insulin was not. In the caudate, BMI and leptin were positively associated with D2R availability. The direction of associations of leptin and AG with D2R availability are consistent with their opposite effects on DA levels (decreasing and increasing, respectively). After adjusting for BMI, AG maintained a significant relationship in the VS. We hypothesize that the increased D2R availability in obese subjects reflects relatively reduced DA levels competing with the radioligand., Conclusions: Our findings provide evidence for an association between the neuroendocrine hormones and DA brain signaling in obese females.

Unlabelled: In the previous work, we reported a method that utilized imaging data collected from 60 to 120 min following [(18) F]fallypride administration to estimate the distribution volume ratio DVR' (DVR' ∝ DVR; DVR = 1 + BP(ND) , where BP(ND) is a measure of receptor density, DA D2 in this case). In this work, we use this method to assess the effects of isoflurane anesthesia on [(18) F]fallypride DVR'., Methods: Rats were injected with [(18) F]fallypride either unconsciously under ∼1.5% isoflurane via the tail vein (Group 1) or consciously via a catheter inserted either in the jugular vein (Group 2) or the tail vein (Group 3). After about 1 h of free access to food and water the rats were anesthetized with 1.5% isoflurane and imaged in a microPET for 60 min. The rats that were injected consciously (Groups 2 and 3) were placed in a rat restrainer during [(18) F]fallypride injection. They were habituated in that restrainer for 3 days prior to the experiment day to minimize restraint-related stress. For comparison, a control group of rats was imaged for 120 min simultaneously with the administration of [(18) F]fallypride i.v. while under 1.5% isoflurane. The DVR' estimates from the 60 min acquisitions were compared with the DVR' from the last 60 min of the 120 min acquisitions (after neglecting the first 60 min). In addition, the striatal time-activity curves were fit with a 2-tissue + plasma compartment model using an arbitrary simulated plasma input function to obtain k(3) /k(4) (≈ BP(ND) ) for the 60 and 120 min acquisitions., Results: Isoflurane anesthesia caused a significant reduction, up to 22%, in the DVR' estimates, which were 15.7 ± 0.3 (mean ± SE) for the controls, 17.7 ± 0.3 for Group 1, 19.2 ± 0.4 for Group 2, and 18.8 ± 0.7 for Group 3. The compartmental model fit produced similar results, ∼30% reduction in k(3) /k(4) for the 120-min acquisitions compared with the 60-min acquisitions (initial conscious uptake of the radiotracer)., Conclusion: The results of this study demonstrate that isoflurane anesthesia significantly decreases striatal [(18) F]fallypride BP(ND) in rats. Of similar importance, this work demonstrates the effectiveness of delayed scans following radiotracer injection and the implication that different types of studies can be conducted simultaneously with this method, including studies of behavioral and environmental impact on brain receptors., (Copyright © 2011 Wiley-Liss, Inc.)

Serotonin is synthesized from its precursor, tryptophan, by brainstem raphé neurons and their synaptic terminals in limbic regions. The omission of tryptophan from an Acute Tryptophan Depletion (ATD) diet transiently diminishes serotonin synthesis, alters raphé activity, and mimics symptoms of depression. Raphé functional magnetic resonance imaging (fMRI) poses challenges using signal-averaging analyses. Time-series properties of fMRI blood oxygenation level dependent (BOLD) signals may hold promise, so we analyzed raphé signals for changes with the ATD diet. Eleven remitted (previously depressed) patients were awake with eyes-closed during seven-minute resting scans with 0.5s(-1) sampling. BOLD signal time-series data were frequency-filtered using wavelet transforms, yielding three octave-width frequency bands from 0.25 to 0.03s(-1) and an unbounded band below 0.03s(-1). Spectral power, reflecting signal information, increased in pontine raphé at high frequencies (0.25 to 0.125s(-1)) during ATD (compared to control, balanced, diet, P<0.004) but was unchanged at other frequencies. Functional connectivity, the correlation between time-series data from pairs of regions, weakened between pontine raphé and anterior thalamus at low frequencies during ATD (P<0.05). This preliminarily supports using fMRI time-series features to assess pontine raphé function. Whether, and how, high frequency activity oscillations interfere with low frequency signaling requires further study., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Diminished dopaminergic neurotransmission contributes to decreased reward and negative eating behaviors in obesity. Bariatric surgery is the most effective therapy for obesity and rapidly reduces hunger and improves satiety through unknown mechanisms. We hypothesized that dopaminergic neurotransmission would be enhanced after Roux-en-Y-Gastric Bypass (RYGB) and Vertical Sleeve Gastrectomy (VSG) surgery and that these changes would influence eating behaviors and contribute to the positive outcomes from bariatric surgery., Methods: Five females with obesity were studied preoperatively and at approximately 7 weeks after RYGB or VSG surgery. Subjects underwent positron emission tomography (PET) imaging with a dopamine type 2 (DA D2) receptor radioligand whose binding is sensitive to competition with endogenous dopamine. Regions of interest (ROI) relevant to eating behaviors were delineated. Fasting enteroendocrine hormones were quantified at each time point., Results: Body weight decreased as expected after surgery. DA D2 receptor availability decreased after surgery. Regional decreases (mean+/-SEM) were caudate 10+/-3%, putamen 9+/-4%, ventral striatum 8+/-4%, hypothalamus 9+/-3%, substantia nigra 10+/-2%, medial thalamus 8+/-2%, and amygdala 9+/-3%. These were accompanied by significant decreases in plasma insulin (62%) and leptin (41%)., Conclusion: The decreases in DA D2 receptor availability after RYGB and VSG most likely reflect increases in extracellular dopamine levels. Enhanced dopaminergic neurotransmission may contribute to improved eating behavior (e.g. reduced hunger and improved satiety) following these bariatric procedures., (2010 Elsevier B.V. All rights reserved.)

Dopamine (DA) has long been implicated in impulsivity, but the precise mechanisms linking human variability in DA signaling to differences in impulsive traits remain largely unknown. By using a dual-scan positron emission tomography approach in healthy human volunteers with amphetamine and the D2/D3 ligand [18F]fallypride, we found that higher levels of trait impulsivity were predicted by diminished midbrain D2/D3 autoreceptor binding and greater amphetamine-induced DA release in the striatum, which was in turn associated with stimulant craving. Path analysis confirmed that the impact of decreased midbrain D2/D3 autoreceptor availability on trait impulsivity is mediated in part through its effect on stimulated striatal DA release.

Individual differences in dopamine D2-like receptor availability arise across all brain regions expressing D2-like receptors. However, the interrelationships in receptor availability across brain regions are poorly understood. To address this issue, we examined the relationship between D2-like binding potential (BPND) across striatal and extrastriatal regions in a sample of healthy participants. PET imaging was performed with the high affinity D2/D3 ligand [18F]fallypride in 45 participants. BPND images were submitted to voxel-wise principal component analysis to determine the pattern of associations across brain regions. Individual differences in D2-like BPND were explained by three distinguishable components. A single component explained almost all of the variance within the striatum, indicating that individual differences in receptor availability vary in a homogenous manner across the caudate, putamen, and ventral striatum. Cortical BPND was only modestly related to striatal BPND and mostly loaded on a distinct component. After controlling for the general level of cortical D2-like BPND, an inverse relationship emerged between receptor availability in the striatum and the ventral temporal and ventromedial frontal cortices, suggesting possible cross-regulation of D2-like receptors in these regions. The analysis additionally revealed evidence of: (1) a distinct component involving the midbrain and limbic areas; (2) a dissociation between BPND in the medial and lateral temporal regions; and (3) a dissociation between BPND in the medial/midline and lateral thalamus. In summary, individual differences in D2-like receptor availability reflect several distinct patterns. This conclusion has significant implications for neuropsychiatric models that posit global or regionally specific relationships between dopaminergic tone and behavior., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Psychopathy is a personality disorder that is strongly linked to criminal behavior. Using [(18)F]fallypride positron emission tomography and blood oxygen level-dependent functional magnetic resonance imaging, we found that impulsive-antisocial psychopathic traits selectively predicted nucleus accumbens dopamine release and reward anticipation-related neural activity in response to pharmacological and monetary reinforcers, respectively. These findings suggest that neurochemical and neurophysiological hyper-reactivity of the dopaminergic reward system may comprise a neural substrate for impulsive-antisocial behavior and substance abuse in psychopathy.

Unlabelled: [(18)F]Fallypride PET studies can be used to estimate the nondisplaceable binding potential (BP(ND)) in vivo of dopamine D2/D3 receptor-rich regions of the brain. These studies often take considerable time, up to >or=2 h, limiting the throughput. In this work, we investigated whether limited-duration scans performed subsequent to tracer administration yielded stable BP(ND) estimates. In particular, we applied a modified version of the Logan plot method on the last 60 min of 120-min data and compared the results to those from analysis of the full data set., Methods: Fourteen male Sprague-Dawley rats were injected with [(18)F]fallypride intravenously while under isoflurane anesthesia, and dynamic data were acquired on the microPET Focus 220 scanner for 120 min. The distribution volume ratio (DVR=BP(ND)+1) was calculated from a Logan plot using 120 min of data and from a modified version using only the last 60 min. Three of these rats were imaged again on a second day to test the reproducibility. A two-tissue compartment model also was used to fit the time-activity curves (TACs) of the 120-min scans to estimate the parameters K(1), k(2), k(on), k(4) and B(max). These parameters were then used to simulate similar TACs while changing k(on) to reflect changes in the dopaminergic system. The simulated TACs were used as a means for exploring the differences in DVR estimates between the last 60 min only and the full 120 min of simulated data., Results: The average DVR from the full 120-min scans was 13.8+/-0.9, whereas the average DVR estimated from only the last 60 min of data (DVR') was 16.3+/-1.0. The DVR estimates showed good reproducibility in the three rats (mean DVR=13.8+/-1.5 on Day 1 and DVR=13.8+/-0.9 on Day 2). The simulations showed that the relationship between DVR' and DVR estimates follows a semilinear form with varying k(on)., Conclusion: Although the BP(ND) estimates are slightly overestimated in a delayed scan mode (i.e., no initial radiotracer uptake measurements) compared to a full scan, this overestimation depends primarily on k(3) (approximately k(on) x B(max)) and has been evaluated in this work for a wide range of k(on) values using simulated TACs. In particular, the sensitivity of DVR' to changes in k(on) is similar to that of DVR. This method of delayed scans eliminates the necessity of imaging during the initial uptake of the radiotracer and, thus, can be used to increase the throughput of studies.

Background: Studies in schizophrenic patients have reported dopaminergic abnormalities in striatum, substantia nigra, thalamus, anterior cingulate, hippocampus, and cortex that have been related to positive symptoms and cognitive impairments., Methods: [(18)F]fallypride positron emission tomography studies were performed in off-medication or never-medicated schizophrenic subjects (n = 11, 6 men, 5 women; mean age of 30.5 +/- 8.0 [SD] years; 4 drug-naive) and age-matched healthy subjects (n = 11, 5 men, 6 women, mean age of 31.6 +/- 9.2 [SD]) to examine dopamine D(2) receptor (DA D(2)r) levels in the caudate, putamen, ventral striatum, medial thalamus, posterior thalamus, substantia nigra, amygdala, temporal cortex, anterior cingulate, and hippocampus., Results: In schizophrenic subjects, increased DA D(2)r levels were seen in the substantia nigra bilaterally; decreased levels were seen in the left medial thalamus. Correlations of symptoms with ROI data demonstrated a significant correlation of disorganized thinking/nonparanoid delusions with the right temporal cortex ROI (r = .94, p = .0001), which remained significant after correction for multiple comparisons (p < .03). Correlations of symptoms with parametric images of DA D(2)r levels revealed no significant clusters of correlations with negative symptoms but significant clusters of positive correlations of total positive symptoms, delusions and bizarre behavior with the lateral and anterior temporal cortex, and hallucinations with the left ventral striatum., Conclusions: The results of this study demonstrate abnormal DA D(2)r-mediated neurotransmission in the substantia nigra consistent with nigral dysfunction in schizophrenia and suggest that both temporal cortical and ventral striatal DA D(2)r mediate positive symptoms.

The relationship between cerebral morphology and the expression of dopamine receptors has not been extensively studied in humans. Elucidation of such relationships may have important methodological implications for clinical studies of dopamine receptor ligand binding differences between control and patient groups. The association between cerebral morphology and dopamine receptor distribution was examined in 45 healthy subjects who completed T1-weighted structural MRI and PET scanning with the D(2)/D(3) ligand [(18)F]fallypride. Optimized voxel-based morphometry was used to create grey matter volume and density images. Grey matter volume and density images were correlated with binding potential (BP(ND)) images on a voxel-by-voxel basis using the Biological Parametric Mapping toolbox. Associations between cerebral morphology and BP(ND) were also examined for selected regions-of-interest (ROIs) after spatial normalization. Voxel-wise analyses indicated that grey matter volume and density positively correlated with BP(ND) throughout the midbrain, including the substantia nigra. Positive correlations were observed in medial cortical areas, including anterior cingulate and medial prefrontal cortex, and circumscribed regions of the temporal, frontal, and parietal lobes. ROI analyses revealed significant positive correlations between BP(ND) and cerebral morphology in the caudate, thalamus, and amygdala. Few negative correlations between morphology and BP(ND) were observed. Overall, grey matter density appeared more strongly correlated with BP(ND) than grey matter volume. Cerebral morphology, particularly grey matter density, correlates with [(18)F]fallypride BP(ND) in a regionally specific manner. Clinical studies comparing dopamine receptor availability between clinical and control groups may benefit by accounting for potential differences in cerebral morphology that exist even after spatial normalization.

Novelty-seeking personality traits are a major risk factor for the development of drug abuse and other unsafe behaviors. Rodent models of temperament indicate that high novelty responding is associated with decreased inhibitory autoreceptor control of midbrain dopamine neurons. It has been speculated that individual differences in dopamine functioning also underlie the personality trait of novelty seeking in humans. However, differences in the dopamine system of rodents and humans, as well as the methods for assessing novelty responding/seeking across species leave unclear to what extent the animal models inform our understanding of human personality. In the present study we examined the correlation between novelty-seeking traits in humans and D(2)-like (D(2)/D(3)) receptor availability in the substantia nigra/ventral tegmental area. Based on the rodent literature we predicted that novelty seeking would be characterized by lowered levels of D(2)-like (auto)receptor availability in the midbrain. Thirty-four healthy adults (18 men, 16 women) completed the Tridimensional Personality Questionnaire-Novelty-Seeking Scale and PET scanning with the D(2)/D(3) ligand [(18)F]fallypride. Novelty-Seeking personality traits were inversely associated with D(2)-like receptor availability in the ventral midbrain, an effect that remained significant after controlling for age. We speculate that the lower midbrain (auto)receptor availability seen in high novelty seekers leads to accentuated dopaminergic responses to novelty and other conditions that induce dopamine release.

Recent studies suggest that subtype-selective activators of M(1)/M(4) muscarinic acetylcholine receptors (mAChRs) may offer a novel approach for the treatment of psychotic symptoms associated with schizophrenia and Alzheimer's disease. Previously developed muscarinic agonists have provided clinical data in support of this hypothesis, but failed in clinical development because of a lack of true subtype specificity and adverse effects associated with activation of other mAChR subtypes. We now report characterization of a novel highly selective agonist for the M(1) receptor with no agonist activity at any of the other mAChR subtypes, termed TBPB [1-(1'-2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one]. Mutagenesis and molecular pharmacology studies revealed that TBPB activates M(1) through an allosteric site rather than the orthosteric acetylcholine binding site, which is likely critical for its unprecedented selectivity. Whole-cell patch-clamp recordings demonstrated that activation of M(1) by TBPB potentiates NMDA receptor currents in hippocampal pyramidal cells but does not alter excitatory or inhibitory synaptic transmission, responses thought to be mediated by M(2) and M(4). TBPB was efficacious in models predictive of antipsychotic-like activity in rats at doses that did not produce catalepsy or peripheral adverse effects of other mAChR agonists. Finally, TBPB had effects on the processing of the amyloid precursor protein toward the non-amyloidogenic pathway and decreased Abeta production in vitro. Together, these data suggest that selective activation of M(1) may provide a novel approach for the treatment of symptoms associated with schizophrenia and Alzheimer's disease.

Clozapine and quetiapine have a low incidence of extrapyramidal side effects at clinically effective doses, which appears to be related to their significantly lower occupancy of striatal dopamine D2 receptors (DA D2r) compared to typical antipsychotic drugs (APDs). Animal studies have indicated that clozapine and quetiapine produce selective effects on cortical and limbic regions of the brain and in particular on dopaminergic neurotransmission in these regions. Previous PET and SPECT studies have reported conflicting results regarding whether clozapine produces preferential occupancy of cortical DA D2r. To examine whether clozapine and/or quetiapine produce preferential occupancy of DA D2r in cortex and limbic regions, we studied the occupancy of putamenal, ventral striatal, thalamic, amygdala, substantia nigra, and temporal cortical DA D2r using PET with [18F]fallypride in six schizophrenic subjects receiving clozapine monotherapy and in seven schizophrenic subjects receiving quetiapine monotherapy. Doses were chosen clinically to minimize psychopathology at tolerable levels of side effects such as drowsiness. All had minimal positive symptoms at the time of the study. Regional receptor occupancies were estimated using mean regional DA D2r levels calculated for 10 off-medication schizophrenic subjects. Both clozapine and quetiapine produced lower levels of putamenal DA D2r occupancy than those reported for typical APDs, 47.8 and 33.5%, respectively. Clozapine produced preferential occupancy of temporal cortical vs putamenal DA D2r, 59.8% (p=0.05, corrected for multiple comparisons), and significantly lower levels of occupancy in the substantia nigra, 18.4% (p=0.0015, corrected for multiple comparisons). Quetiapine also produced preferential occupancy of temporal cortical DA D2r, 46.9% (p=0.03, corrected for multiple comparisons), but did not spare occupancy of substantia nigra DA D2r. The therapeutic effects of clozapine and quetiapine appear to be achieved at less than the 65% threshold for occupancy seen with typical APDs, consistent with the involvement of non-DA D2r mechanisms in at least partially mediating the therapeutic effects of these drugs. Preferential occupancy of cortical DA D2r, sparing occupancy of substantia nigra receptors, and non-DA D2r-mediated actions may contribute to the antipsychotic actions of these and other atypical APDs.

There have been conflicting reports as to whether olanzapine produces lower occupancy of striatal dopamine D(2)/D(3) receptor than typical antipsychotic drugs and preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors. We performed [(18)F] fallypride PET studies in six schizophrenic subjects treated with olanzapine and six schizophrenic subjects treated with haloperidol to examine the occupancy of striatal and extrastriatal dopamine receptors by these antipsychotic drugs. [(18)F] setoperone PET studies were performed in seven olanzapine-treated subjects to determine 5-HT(2A) receptor occupancy. Occupancy of dopamine D(2)/D(3) receptors by olanzapine was not significantly different from that seen with haloperidol in the putamen, ventral striatum, medial thalamus, amygdala, or temporal cortex, that is, 67.5-78.2% occupancy; olanzapine produced no preferential occupancy of dopamine D(2)/D(3) receptors in the ventral striatum, medial thalamus, amygdala, or temporal cortex. There was, however, significantly lower occupancy of substantia nigra/VTA dopamine D(2)/D(3) receptors in olanzapine-treated compared to haloperidol-treated subjects, that is, 40.2 vs 59.3% (p=0.0014, corrected for multiple comparisons); in olanzapine-treated subjects, the substantia nigra/VTA was the only region with significantly lower dopamine D(2)/D(3) receptor occupancy than the putamen, that is, 40.2 vs 69.2% (p<0.001, corrected for multiple comparison). Occupancy of 5-HT(2A) receptors was 85-93% in the olanzapine- treated subjects. The results of this study demonstrated that olanzapine does not produce preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors but does spare substantia nigra/VTA receptors. Sparing of substantia nigra/VTA dopamine D(2)/D(3) receptor occupancy may contribute to the low incidence of extrapyramidal side effects in olanzapine-treated patients.

The distribution of dopamine (DA) D(2)-like receptors in the human thalamus was studied using in vitro autoradiographic techniques and in vivo positron emission tomography in normal control subjects. [(125)I]Epidepride, which binds with high affinity to DA D(2) and D(3) receptors, was used in autoradiographic studies to determine the distribution and density of D(2)-like receptors, and the epidepride analogue [(18)F]fallypride positron was used for positron emission tomography studies to delineate D(2)-like receptors in vivo. Both approaches revealed a heterogeneous distribution of thalamic D(2/3) receptors, with relatively high densities in the intralaminar and midline thalamic nuclei, including the paraventricular, parataenial, paracentral, centrolateral, and centromedian/parafascicular nuclei. Moderate densities of D(2/3) sites were seen in the mediodorsal and anterior nuclei, while other thalamic nuclei expressed lower levels of D(2)-like receptors. Most thalamic nuclei that express high densities of D(2)-like receptors project to forebrain DA terminal fields, suggesting that both the thalamic neurons expressing D(2)-like receptors and the projection targets of these neurons are regulated by DA. Because the midline/intralaminar nuclei receive prominent projections from both the ascending reticular activating core and the hypothalamus, these thalamic nuclei may integrate activity conveying both interoceptive and exteroceptive information to telencephalic DA systems involved in reward and cognition.

Imaging of brain function and neurotransmission is an important bridge between basic and clinical research. Regional cerebral energy metabolism and blood flow are normally coupled to regional cerebral function. Positron tomography (PET) studies of cerebral glucose metabolism and blood flow, single photon tomography (SPECT) and MRI studies of cerebral perfusion, have been used to image cerebral development and aging in man. The sensitivity, temporal resolution, spatial resolution and lack of radiation have led to the widespread utilization of blood oxygen level dependent (BOLD) and MRI perfusion techniques. PET and SPECT methods for studying cerebral neurotransmission include studies of dopaminergic, serotonergic, cholinergic, opiate and GABAergic neurotransmission in man. Studies of cerebral neurotransmission in man have helped to delineate the mechanisms of action of antipsychotic and antidepressant drugs, the diagnosis and progression of Parkinson's disease, and to evaluate neuroprotective drugs. The strengths, limitations, and application of these modalities are reviewed. The application of these methods to cerebral development and aging are briefly discussed.

Orthostatic intolerance, seen predominantly in young women, is characterized by symptoms of lightheadedness, fatigue and palpitations in the upright posture. With standing, plasma norepinephrine levels rise dramatically and heart rate often increases by more than 30 beats per minute, although blood pressure does not usually fall. A theory recently popularized in the media suggests that some cases of orthostatic intolerance are related to hindbrain compression, with or without a Chiari I malformation. As a preliminary investigation of this hypothesis, head or cervical spine MRI scans from 23 females with orthostatic intolerance were reviewed. The cerebellar tonsils averaged 0.3 +/- 1.9 mm below the foramen magnum. These results were compared to measurements from a control group averaging 0.4 +/- 2.6 mm above the foramen magnum (P > 0.05). Tonsillar depression of at least 3 mm occurred in 13 % of both the patient group and the control group. Tonsillar herniation was not found to influence supine or upright blood pressure, heart rate or plasma norepinephrine levels in the patients. We conclude that herniation of the cerebellar tonsils is not a common cause of orthostatic intolerance. However, the single measurement of tonsillar depression might underestimate the number of patients with hindbrain compression.

Mycobacterium avium complex (MAC) is a rare cause of isolated intrathoracic disease in the immunocompetent child; delays in diagnosis and treatment are common. The current case is an 11-month-old girl with symptoms, signs, and radiographic findings of bronchial obstruction. Comparison of this case to the literature revealed that there is a characteristic presentation of intrathoracic MAC infection in immunocompetent children (children aged 3 years or less, without exposure to Mycobacterium tuberculosis, presenting with clinical and radiographic evidence of bronchial obstruction) that should increase our index of suspicion for this diagnosis. This is particularly important since M. tuberculosis can present in a similar pattern.

Two cases of patients with paraneoplastic limbic encephalitis, difficult to control seizures, and unilateral hippocampal hypermetabolism on positron emission tomography (PET) are described. Two women aged 33 and 61 presented with uncontrolled complex partial seizures, profound memory loss and cognitive decline. One was later diagnosed with breast cancer and the other with lung cancer. Video-EEG on the first patient recorded multifocal sharp waves and bilateral independent seizure onsets. The second patient had no epileptiform discharges and bitemporal ictal onset, even though the clinical seizures suggested a right temporal onset. Magnetic resonance imaging (MRI) was normal in both patients. PET scans obtained in the interictal state showed right hippocampal hypermetabolism in both patients. In the second patient, the lung cancer was irradiated with resolution of seizures and improvement of memory function. A PET scan six months later was normal. Subsequent seizure recurrence and worsening of memory led to the discovery of widespread metastases. Limbic encephalitis should be considered in the differential diagnosis of intractable partial epilepsy, particularly if accompanied by severe memory loss and cognitive decline. Treatment of the underlying cancer may be lead to improved seizure control. Hippocampal hypermetabolism may be a common feature on PET, and may indicate subclinical seizure activity., (Copyright 1999 BEA Trading Ltd.)

The primary objective of this study is to perform a blinded evaluation of two groups of retrospective image registration techniques, using as a gold standard a prospective marker-based registration method, and to compare the performance of one group with the other. These techniques have already been evaluated individually [27]. In this paper, however, we find that by grouping the techniques as volume based or surface based, we can make some interesting conclusions which were not visible in the earlier study. In order to ensure blindness, all retrospective registrations were performed by participants who had no knowledge of the gold-standard results until after their results had been submitted. Image volumes of three modalities: X-ray computed tomography (CT), magnetic resonance (MR), and positron emission tomography (PET) were obtained from patients undergoing neurosurgery at Vanderbilt University Medical Center on whom bone-implanted fiducial markers were mounted. These volumes had all traces of the markers removed and were provided via the Internet to project collaborators outside Vanderbilt, who then performed retrospective registrations on the volumes, calculating transformations from CT to MR and/or from PET to MR. These investigators communicated their transformations, again via the Internet, to Vanderbilt, where the accuracy of each registration was evaluated. In this evaluation, the accuracy is measured at multiple volumes of interest (VOI's). Our results indicate that the volume-based techniques in this study tended to give substantially more accurate and reliable results than the surface-based ones for the CT-to-MR registration tasks, and slightly more accurate results for the PET-to-MR tasks. Analysis of these results revealed that the rotational component of error was more pronounced for the surface-based group. It was also apparent that all of the registration techniques we examined have the potential to produce satisfactory results much of the time, but that visual inspection is necessary to guard against large errors.