Paul M. Grasby

Evidence for striatal dopamine release during a video game

Dopaminergic neurotransmission may be involved in learning, reinforcement of behaviour, attention, and sensorimotor integration,. Binding of the radioligand 11C-labelled raclopride to dopamine D2 receptors is sensitive to levels of endogenous dopamine, which can be released by pharmacological challenge. Here we use 11C-labelled raclopride and positron emission tomography scans to provide evidence that endogenous dopamine is released in the human striatum during a goal-directed motor task, namely a video game. Binding of raclopride to dopamine receptors in the striatum was significantly reduced during the video game compared with baseline levels of binding, consistent with increased release and binding of dopamine to its receptors. The reduction in binding of raclopride in the striatum positively correlated with the performance level during the task and was greatest in the ventral striatum. These results show, to our knowledge for the first time, behavioural conditions under which dopamine is released in humans, and illustrate the ability of positron emission tomography to detect neurotransmitter fluxes in vivo during manipulations of behaviour.

Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient

Synaptic dopamine release from embryonic nigral transplants has been monitored in the striatum of a patient with Parkinsons disease using [11C]-raclopride positron emission tomography to measure dopamine D2 receptor occupancy by the endogenous transmitter. In this patient, who had received a transplant in the right putamen 10 years earlier, grafts had restored both basal and drug-induced dopamine release to normal levels. This was associated with sustained, marked clinical benefit and normalized levels of dopamine storage in the grafted putamen. Despite an ongoing disease process, grafted neurons can thus continue for a decade to store and release dopamine and give rise to substantial symptomatic relief.

Elevated striatal dopamine function linked to prodromal signs of schizophrenia.

CONTEXT A major limitation on the development of biomarkers and novel interventions for schizophrenia is that its pathogenesis is unknown. Although elevated striatal dopamine activity is thought to be fundamental to schizophrenia, it is unclear when this neurochemical abnormality develops in relation to the onset of illness and how this relates to the symptoms and neurocognitive impairment seen in individuals with prodromal symptoms of schizophrenia. OBJECTIVES To determine whether striatal dopamine function is elevated in individuals with prodromal symptoms of schizophrenia before the onset of psychosis and to assess how this relates to the symptoms and neurocognitive impairment. DESIGN Case-control study of in vivo striatal dopaminergic function. SETTING Academic research. Patients Patients were recruited from a community mental health service. Twenty-four patients having prodromal symptoms of schizophrenia were compared with 7 patients having schizophrenia and with 12 matched healthy control subjects from the same community. Main Outcome Measure Striatal 6-fluoro-l-dopa F 18-dopa uptake measured using positron emission tomographic (18)F-dopa imaging. RESULTS Striatal (18)F-dopa uptake was elevated in patients with prodromal symptoms of schizophrenia (effect size, 0.75) to an intermediate degree compared with that in patients with schizophrenia (effect size, 1.25). The elevation was localized in the associative striatum in both groups. Moreover, striatal (18)F-dopa uptake in patients with prodromal symptoms of schizophrenia was correlated with the severity of prodromal psychopathologic and neuropsychological impairment but not with the severity of anxiety or depressive symptoms. CONCLUSIONS These findings indicate that dopamine overactivity predates the onset of schizophrenia in individuals with prodromal psychotic symptoms, is predominantly localized in the associative striatum, and is correlated with the severity of symptoms and neurocognitive dysfunction.

Generic brain activation mapping in functional magnetic resonance imaging : A nonparametric approach

We report a novel method to identify brain regions generically activated by periodic experimental design in functional magnetic resonance imaging data. This involves: 1) registering each of N individual functional magnetic resonance imaging datasets in a standard space; 2) computing the median standardised power of response to the experimental design; 3) testing median standardised power at each voxel against its nonparametrically ascertained distribution under the null hypothesis of no experimental effect; and 4) constructing a generic brain activation map. The method is validated by analysis of 6 null images, acquired under conditions when the null hypothesis was known to be true; 8 images acquired during periodic auditory-verbal stimulation; and 6 images acquired during periodic performance of a covert verbal fluency task.

Meta-analysis, Database, and Meta-regression of 98 Structural Imaging Studies in Bipolar Disorder

CONTEXT Despite 25 years of structural imaging in bipolar disorder, brain regions affected in the disorder are ill defined. OBJECTIVES To use meta-analytical techniques to investigate structural brain changes in bipolar disorder and to assess the effect of medication use and demographic and clinical variables. DATA SOURCES The MEDLINE, EMBASE, and PsycINFO databases were searched from 1980-2007 for studies using magnetic resonance imaging or x-ray computed tomography to compare brain structure in patients with bipolar disorder and controls. STUDY SELECTION We identified 1471 unique publications from which 141 studies were included in a database and 98 were selected for meta-analysis. DATA EXTRACTION Twenty-six demographic and clinical variables were extracted from each study where available. For the meta-analysis, mean structure size and standard deviation were extracted for continuous variables, and numbers of patients and controls with an abnormality were extracted for binary variables. DATA SYNTHESIS Bipolar disorder was associated with lateral ventricle enlargement (effect size = 0.39; 95% confidence interval, 0.24-0.55; P = 8 x 10(-7)) and increased rates of deep white matter hyperintensities (odds ratio = 2.49; 95% confidence interval, 1.64-3.79; P = 2 x 10(-5)) but not periventricular hyperintensities. Gray matter volume increased among patients when the proportion of patients using lithium increased (P = .004). Calculations from this meta-analysis show current imaging studies (which typically examine 8 regions) have a 34% chance of making a type I error. Type II errors are also appreciable (for example, 70% when measuring the lateral ventricular volume in a typical study involving 25 patients and 33 controls). CONCLUSIONS The meta-analyses revealed robust but regionally nonspecific changes of brain structure in bipolar disorder. Individual studies will remain underpowered unless sample size is increased or improvements in phenotypic selection and imaging methods are made to reduce within-study heterogeneity. The provision of online databases, as illustrated herein, may facilitate a more refined design and analysis of structural imaging data sets in bipolar disorder.

Tracer Kinetic Modeling of the 5-HT1AReceptor Ligand [carbonyl-11C]WAY-100635 for PET

[Carbonyl-11C]WAY-100635 is a promising PET radioligand for the 5-HT1A receptor, having demonstrated more favorable characteristics for in vivo imaging than the previously available [O-methyl-11C]WAY-100635. The current study evaluates different tracer kinetic modelling strategies for the quantification of 5-HT1A receptor binding in human brain. Mathematical modelling of the carbonyl-labeled radiotracer is investigated using compartmental structures, including both plasma input and reference tissue approaches. Furthermore, the application of basis function methods allows for the investigation of parametric imaging, providing functional maps of both delivery and binding of the radioligand. Parameter estimates of binding from normal volunteers indicate a low intra- versus a high intersubject variability. It is concluded that a simplified reference tissue approach may be used to quantify 5-HT1A binding either in terms of ROI data or as parametric images.

A Functional Genetic Variation of the Serotonin (5-HT) Transporter Affects 5-HT1A Receptor Binding in Humans

In humans, 5-HT1A receptors are implicated in anxiety and depressive disorders and their treatment. However, the physiological and genetic factors controlling 5-HT1A receptor expression are undetermined in health and disease. In this study, the influence of two genetic factors on 5-HT1A receptor expression in the living human brain was assessed using the 5-HT1A-selective positron emission tomography (PET) ligand [11C]WAY 100635. After the genotyping of 140 healthy volunteers to study population frequencies of known single nucleotide polymorphisms (SNPs) in the 5-HT1A receptor gene, the influence of the common SNP [(-1018) C>G] on 5-HT1A receptor expression was examined in a group of 35 healthy individuals scanned with [11C]WAY 100635. In the PET group, we also studied the influence of a common variable number tandem repeat polymorphism [short (S) and long (L) alleles] of the 5-HT transporter (5-HTT) gene on 5-HT1A receptor density. Whereas, the 5-HT1A receptor genotype did not show any significant effects on [11C]WAY 100635 binding, 5-HT1A receptor binding potential values were lower in all brain regions in subjects with 5-HTTLPR short (SS or SL) genotypes than those with long (LL) genotypes. Although the PET groups are necessarily a small sample size for a genetic association study, our results demonstrate for the first time that a functional polymorphism in the 5-HTT gene, but not the 5-HT1A receptor gene, affects 5-HT1A receptor availability in man. The results may offer a plausible physiological mechanism underlying the association between 5-HTTLPR genotype, behavioral traits, and mood states.

Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635.

Positron emission tomography (PET) studies with the selective 5-HT1A receptor ligand, [11C]WAY-100635, have indicated that the binding potential (BP) of brain 5-HT1A receptors is lowered in unmedicated subjects with acute major depression. However, it is unclear if these changes persist after recovery from depression. To resolve this issue, we used [11C]WAY-100635 in conjunction with PET imaging to compare 5-HT1A BP in 18 healthy controls and 14 male subjects with recurrent major depression who were clinically recovered and free of antidepressant medication. BP values, derived from a reference tissue model, were analysed by region of interest and statistical parametric mapping. Both analyses showed a widespread and substantial (17%) decrease in 5-HT1A receptor BP in cortical areas in the recovered depressed subjects. In contrast, 5-HT1A BP in the raphe nuclei did not distinguish depressed subjects from controls. Our results suggest a persistent dysfunction in cortical 5-HT1A BP as measured by [11C]WAY-100635 in recovered depressed men. Lowered 5-HT1A receptor binding availability could represent a trait abnormality that confers vulnerability to recurrent major depression.

Discrete neurophysiological correlates in prefrontal cortex during hysterical and feigned disorder of movement

The clinical distinction between hysterical symptoms and those that are feigned awaits objective validation. We used functional neuroimaging to examine the neural correlates of these two disorders.

Exquisite delineation of 5-HT1A receptors in human brain with PET and [carbonyl-11C]WAY-100635

The 5-HT1A receptor antagonist, WAY-100635 [N-(2-(4-(2-methoxyphenyl)- 1-piperazinyl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide], was labelled in its carbonyl group with carbon-11 (t1/2 = 20.4 min), injected intravenously into healthy male volunteers and studied with positron emission tomography (PET). The acquired data provide exquisite delineation of 5-HT1A receptors in brain, with the ratio of radioactivity uptake in receptor-rich regions, such as medial temporal cortex, to that in receptor-devoid cerebellum reaching 25 by 60 min after radioligand injection. Application of biomathematical modelling to the data revealed high values (7.8) for binding potential, a measure of Bmax/Kp, in receptor-rich regions. Only very polar radioactive metabolites were present in plasma, a finding consistent with the low level of nonspecific binding seen in cerebellum. [carbonyl-11C]WAY-100635 is concluded to be far superior to the previously reported [0-methyl-11C]WAY-100635 as a radioligand for PET studies of 5-HT1A receptors in human brain.