[Show abstract][Hide abstract] ABSTRACT: Methylphenidate (MPH) inhibits the reuptake of dopamine and noradrenaline. PET studies with MPH challenge show increased competition at postsynaptic D2/3-receptors, thus indirectly revealing presynaptic dopamine release. We used [(18)F]fluorodopamine ([(18)F]FDOPA)-PET in conjunction with the inlet-outlet model (IOM) of Kumakura et al. (2007) to investigate acute and long-term changes in dopamine synthesis capacity and turnover in nigrostriatal fibers of healthy subjects with MPH challenge. Twenty healthy human females underwent two dynamic [(18)F]FDOPA PET scans (124 min; slow bolus-injection; arterial blood sampling), with one scan in untreated baseline condition and the other after MPH administration (0.5 mg/kg, p.o.), in randomized order. Subjects underwent cognitive testing at each PET session. Time activity curves were obtained for ventral putamen and caudate and were analyzed according to the IOM to obtain the regional net-uptake of [(18)F]FDOPA (K; dopamine synthesis capacity) as well as the [(18)F]fluorodopamine washout rate (kloss, index of dopamine turnover). MPH substantially decreased kloss in putamen (-22%; p = 0.003). In the reversed treatment order group (MPH/no drug), K was increased by 18% at no drug follow-up. The magnitude of K at the no drug baseline correlated with cognitive parameters. Furthermore, individual kloss changes correlated with altered cognitive performance under MPH. [(18)F]FDOPA PET in combination with the IOM detects an MPH-evoked decrease in striatal dopamine turnover, in accordance with the known acute pharmacodynamics of MPH. Furthermore, the scan-ordering effect on K suggested that a single MPH challenge persistently increased striatal dopamine synthesis capacity. Attenuation of dopamine turnover by MPH is linked to enhanced cognitive performance in healthy females.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 10/2014; 34(44):14769-76. DOI:10.1523/JNEUROSCI.1560-14.2014 · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cerebral dopamine (DA) transmission is thought to be an important modulator for the development and occurrence of aggressive behavior. However, the link between aggression and DA transmission in humans has not been investigated using molecular imaging and standardized behavioral tasks. We investigated aggression as a function of DA transmission in a group of (N = 21) healthy male volunteers undergoing 6-[(18)F]-fluoro-l-DOPA (FDOPA)-positron emission tomography (PET) and a modified version of the Point Subtraction Aggression Paradigm (PSAP). This task measures aggressive behavior during a monetary reward-related paradigm, where a putative adversary habitually tries to cheat. The participant can react in three ways (i.e., money substraction of the putative opponent [aggressive punishment], pressing a defense button, or continuing his money-making behavior). FDOPA-PET was analyzed using a steady-state model yielding estimates of the DA-synthesis capacity (K), the turnover of tracer DA formed in living brain (kloss), and the tracer distribution volume (Vd), which is an index of DA storage capacity. Significant negative correlations between PSAP aggressive responses and the DA-synthesis capacity were present in several regions, most prominently in the midbrain (r = -0.640; p = 0.002). Lower degrees of aggressive responses were associated with higher DA storage capacity in the striatum and midbrain. Additionally, there was a significant positive correlation between the investment into monetary incentive responses on the PSAP and DA-synthesis capacity, notably in the midbrain (r = +0.618, p = 0.003). The results suggest that individuals with low DA transmission capacity are more vulnerable to reactive/impulsive aggression in response to provocation.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 10/2013; 33(43):16889-96. DOI:10.1523/JNEUROSCI.1398-13.2013 · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A previous study of the DOPA decarboxylase substrate 6-[(18)F]fluoro-L-DOPA (FDOPA) with positron emission tomography (PET) detected no difference of the net blood-brain transfer rate (Kin (app) ) between detoxified alcoholic patients and healthy controls. Instead, the study revealed an inverse correlation between Kin (app) in left ventral striatum and alcohol craving scores. To resolve the influx and efflux phases of radiolabeled molecules, we independently estimated the unidirectional blood-brain FDOPA clearance rate (K) and the washout rate of [(18)F]fluorodopamine and its deaminated metabolites (k loss), and we also calculated the total distribution volume of decarboxylated metabolites and unmetabolized FDOPA as a steady-state index of the dopamine storage capacity (Vd ) in brain. The craving scores in the 12 alcoholics correlated positively with the rate of loss (kloss ) in the left ventral striatum. We conclude that craving is most pronounced in the individuals with relatively rapid dopamine turnover in the left ventral striatum. The blood-brain clearance rate (K), corrected for subsequent loss of radiolabeled molecules from brain, was completely normal throughout the brain of the alcoholics, in whom the volume of distribution (Vd ) was found to be significantly lower in the left caudate nucleus. The magnitude of Vd in the left caudate head was reduced by 43% relative to the 16 controls, consistent with a 58% increase of kloss . We interpret the findings as indicating that a trait for rapid dopamine turnover in the ventral striatum subserves craving and reward-dependence, leading to an acquired state of increased dopamine turnover in the dorsal striatum of detoxified alcoholic patients.
PLoS ONE 09/2013; 8(9):e73903. DOI:10.1371/journal.pone.0073903 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Negative mood states after alcohol detoxification may enhance the relapse risk. As recently shown in healthy volunteers, dopamine storage capacity (V d) in the left amygdala was positively correlated with functional activation in the left amygdala and anterior cingulate cortex (ACC) during an emotional task; high functional connectivity between the amygdala and the ACC, a region important for emotion regulation, was associated with low trait anxiety. Based on these findings, we now tested whether detoxified alcohol-dependent patients have a disrupted modulation of the anterior cingulate cortex activation in response to aversive stimuli by amygdala dopamine. Furthermore, we asked whether disrupted functional coupling between amygdala and ACC during aversive processing is related to trait anxiety.We used combined 6-[18F]-fluoro-l-DOPA positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and Spielberger's state-trait anxiety questionnaire (STAI) in 11 male detoxified alcohol-dependent patients compared to 13 matched healthy controls.Unlike healthy controls, patients showed no significant correlation between our PET metric for dopamine storage capacity (FDOPA V d), in left amygdala and activation in left ACC. Moreover, the functional connectivity between amygdala and ACC during processing of aversive emotional stimuli was reduced in patients. Voxel-based morphometry did not reveal any discernible group differences in amygdala volume.These results suggest that dopamine-modulated corticolimbic circuit function is important for responding to emotional information such that apparent functional deficits in this neuromodulatory circuitry may contribute to trait anxiety in alcohol-dependent patients.
[Show abstract][Hide abstract] ABSTRACT: Age-related decline in cognitive speed has been associated with prefrontal dopamine D1 receptor availability, but the contribution of presynaptic dopamine and noradrenaline innervation to age-related changes in cognition is unknown.
In a group of 16 healthy participants aged 22-61 years, we used PET and the radioligand FDOPA to measure catecholamine synthesis capacity (K (in) (app); millilitres per gram per minute) and the digit symbol substitution test to measure cognitive speed, a component of fluid IQ.
Cognitive speed was associated with the magnitude of K (in) (app) in the prefrontal cortex (p < 0.0005). Both cognitive speed (p = 0.003) and FDOPA K (in) (app) (p < 0.0005) declined with age, both in a standard voxel-wise analysis and in a volume-of-interest analysis with partial volume correction, and the correlation between cognitive speed and K (in) (app) remained significant beyond the effects of age (p = 0.047). MR-based segmentation revealed that these age-related declines were not attributable to age-related alterations in grey matter density.
Our findings indicate that age-related changes in the capacity of the prefrontal cortex to synthesize catecholamines, irrespective of cortical atrophy, may underlie age-related decline in cognitive speed.
European Journal of Nuclear Medicine 06/2012; 39(9):1462-6. DOI:10.1007/s00259-012-2162-4 · 5.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Quantitative interpretation of brain [¹⁸F]FDOPA PET data has been made possible by several kinetic modeling approaches, which are based on different assumptions about complex [¹⁸F]FDOPA metabolic pathways in brain tissue. Simple kinetic macro parameters are often utilized to quantitatively evaluate metabolic and physiological processes of interest, which may include DDC activity, vesicular storage, and catabolism from (18) F-labeled dopamine to DOPAC and HVA. A macro parameter most sensitive to the changes of these processes would be potentially beneficial to identify impaired processes in a neurodegenerative disorder such as Parkinson's disease. The purpose of this study is a systematic comparison of several [¹⁸F]FDOPA macro parameters in terms of sensitivities to process-specific changes in simulated time-activity curve (TAC) data of [¹⁸F]FDOPA PET. We introduced a multiple-compartment kinetic model to simulate PET TACs with physiological changes in the dopamine pathway. TACs in the alteration of dopamine synthesis, storage, and metabolism were simulated with a plasma input function obtained by a non-human primate [¹⁸F]FDOPA PET study. Kinetic macro parameters were calculated using three conventional linear approaches (Gjedde-Patlak, Logan, and Kumakura methods). For simulated changes in dopamine storage and metabolism, the slow clearance rate (k(loss) ) as calculated by the Kumakura method showed the highest sensitivity to these changes. Although k(loss) performed well at typical ROI noise levels, there was large bias at high noise level. In contrast, for simulated changes in DDC activity it was found that K(i) and V(T), estimated by Gjedde-Patlak and Logan method respectively, have better performance than k(loss).
[Show abstract][Hide abstract] ABSTRACT: Sensation seeking is a core personality trait that declines with age in both men and women, as do also both density and availability of the dopamine D(2/3) receptors in striatum and cortical regions. In contrast, novelty seeking at a given age relates inversely to dopamine receptor availability. The simplest explanation of these findings is an inverted-U-shaped correlation between ratings of sensation seeking on the Zuckerman scale and dopamine D(2/3) receptor availability. To test the claim of an inverted-U-shaped relation between ratings of the sensation-seeking personality and measures of dopamine receptor availability, we used PET to record [(11)C]raclopride binding in striatum of 18 healthy men. Here we report that an inverted-U shape significantly matched the receptor availability as a function of the Zuckerman score, with maximum binding potentials observed in the midrange of the scale. The inverted-U shape is consistent with a negative correlation between sensation seeking and the reactivity ("gain") of dopaminergic neurotransmission to dopamine. The correlation reflects Zuckerman scores that are linearly linked to dopamine receptor densities in the striatum but nonlinearly linked to dopamine concentrations. Higher dopamine occupancy and dopamine concentrations explain the motivation that drives afflicted individuals to seek sensations, in agreement with reduced protection against addictive behavior that is characteristic of individuals with low binding potentials.
Proceedings of the National Academy of Sciences 02/2010; 107(8):3870-5. DOI:10.1073/pnas.0912319107 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PET studies with the DOPA decarboxylase substrate 6-[(18)F]fluoro-l-DOPA (FDOPA) reveal the storage of [(18)F]-fluorodopamine within synaptic vesicles, mainly of dopamine fibres. As such, FDOPA PET is a sensitive indicator of the integrity of the nigrostriatal dopamine innervation. Nonetheless, there have been several reports of focal elevations of FDOPA utilization in brain of patients with Parkinson's disease (PD), all based on reference tissue methods. To investigate this phenomenon further, we used voxel-wise steady-state kinetic analysis to search for regions of elevated FDOPA utilization (K; ml g(-1) min(-1)) and steady-state trapping (V(d); ml g(-1)) in a group of well-characterized patients with early, asymmetric PD, who were contrasted with an age-matched control group. Subtraction of the population mean parametric maps revealed foci of increased FDOPA utilization K (+25%) in the bilateral medial nucleus accumbens, whereas the expected declines in the trapping of FDOPA were seen in the caudate and putamen. This observation suggests hyperfunction of catecholamine fibres innervating specifically the limbic striatum, which could guide the design of future prospective FDOPA-PET studies of the impulse control disorders occurring in some PD patients under treatment with dopamine agonists. A focus of increased FDOPA influx and also V(d) was detected in the periaqueductal grey, consistent with some earlier reports based on reference tissue analysis. Increased FDOPA trapping in the periaqueductal grey of PD patients seems consistent with recent reports of increased activity of serotonin neurons in a rat model of parkinsonism.
[Show abstract][Hide abstract] ABSTRACT: [(18)F]Fluoro-3,4-dihydroxyphenyl-L-alanine (FDOPA) was one of the first successful tracers for molecular imaging by positron emission tomography (PET), and has proven immensely valuable for studies of Parkinson's disease. Following intravenous FDOPA injection, the decarboxylated metabolite [(18)F] fluorodopamine is formed and trapped within terminals of the nigrostriatal dopamine neurons; reduction in the simple ratio between striatum and cerebellum is indicative of nigrostriatal degeneration. However, the kinetic analysis of dynamic FDOPA-PET recordings is formidably complex due to the entry into brain of the plasma metabolite O-methyl-FDOPA and due to the eventual washout of decarboxylated metabolites. Linear graphical analysis relative to a reference tissue input function is popular and convenient for routine clinical studies in which serial arterial blood samples are unavailable. This simplified approach has facilitated longitudinal studies in large patient cohorts. Linear graphical analysis relative to the metabolite-corrected arterial FDOPA input yields a more physiological index of FDOPA utilization, the net blood-brain clearance. Using a constrained compartmental model, FDOPA-PET recordings can be used to calculate the relative activity of the enzyme DOPA decarboxylase in living brain. We have extended this approach so as to obtain an index of steady-state trapping of [( 18)F]fluorodopamine in synaptic vesicles. Although simple methods of image analysis are sufficient for the purposes of routine clinical studies, the more complex approaches have revealed hidden aspects of brain dopamine in personality, healthy aging, and in the pathophysiologies of Parkinson's disease and schizophrenia.
The Neuroscientist 09/2009; 15(6):635-50. DOI:10.1177/1073858409338217 · 6.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dopamine is released under stress and modulates processing of aversive stimuli. We found that dopamine storage capacity in human amygdala, measured with 6-[(18)F]fluoro-L-DOPA positron emission tomography, was positively correlated with functional magnetic resonance imaging blood oxygen level-dependent signal changes in amygdala and dorsal anterior cingulate cortex that were evoked by aversive stimuli. Furthermore, functional connectivity between these two regions was inversely related to trait anxiety. Our results suggest that individual dopamine storage capacity in amygdala subserves modulation of emotional processing in amygdala and dorsal cingulate, thereby contributing to individual differences in anxious temperament.
[Show abstract][Hide abstract] ABSTRACT: Conventional indices of the utilization of FDOPA in living human brain have not consistently revealed important declines in dopamine function with normal aging. However, most methods of kinetic analysis have assumed irreversible trapping of decarboxylated FDOPA metabolites in brain, an assumption that is violated even in PET recordings of short duration. Therefore, we have developed methods for the calculation of steady-state storage of FDOPA together with its decarboxylated metabolites (V(d), mlg(-1)), based upon improved kinetic analysis of 120-min emission recordings. In a group of 28 normal male subjects, of age ranging from 23 to 73 years, the magnitude of V(d) in the striatum and in extrastriatal regions declined by approximately 10% with each decade. The utilization of FDOPA was also calculated by several conventional methods assuming irreversible trapping, i.e. the net blood brain clearance (K(in)(app), mlg(-1)min(-1)), the DOPA decarboxylase activity relative to a reference tissue input (k(3)(S), min(-1)), and relative to the arterial input (k(3)(D), min(-1)). None of these methods revealed an age-related decline in FDOPA utilization in the extended striatum, although the magnitude of K(in)(app) did decline in cerebral cortex. Thus, the capacity to synthesize [(18)F]fluorodopamine remained largely intact in striatum of the elderly subjects, but in the presence of a substantially increased rate of washout (k(loss)), which was evident in all brain regions examined. Consequently, the magnitude of V(d) declined with healthy aging, possibly reflecting impaired vesicular storage capacity, resulting in enhanced exposure of cytosolic [(18)F]fluorodopamine to monoamine oxidase.
Neurobiology of aging 07/2008; 31(3):447-63. DOI:10.1016/j.neurobiolaging.2008.05.005 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alpha-[11C]methyl-L-tryptophan (alpha-MTrp) positron emission tomography (PET) is a promising tool in the localization of the epileptogenic area in selected group of focal epilepsy patients. Electrophysiological evidence suggests the involvement of the neocortex in periventricular nodular heterotopia (PVNH).
To determine whether alpha-MTrp PET can detect neocortical changes in patients with PVNH.
Four patients (2 male, mean age 28, range 23-35 years) with PVNH and intractable seizures were studied. The functional image in each patient was compared with those from 21 healthy controls (mean age 34.6 +/- 14.2 years) by using statistical parametric mapping (SPM). The location of increased alpha-MTrp uptake was compared with the location of the EEG focus. A significant cluster was defined as a cluster with a height p = 0.005 and an extent threshold 100.
Alpha-MTrp PET revealed increased cortical uptake in two of four patients. The area of increased alpha-MTrp uptake in one patient was widespread. In the other patient, the area of increased uptake did not include the region where most seizures were generated on EEG. alpha-MTrp PET did not show increased uptake in the heterotopic nodules in any of the patients.
Alpha-MTrp PET suggests abnormal metabolism of tryptophan in the neocortex. The increased uptake may be diffuse and may not co-localize with the EEG focus. This preliminary study suggests that alpha-MTrp PET may be useful, in conjunction with other evaluations, in localizing epileptic focus in patients with PVNH and refractory seizures.
[Show abstract][Hide abstract] ABSTRACT: The telencephalic dopamine innervations contribute to the modulation of cognitive processing. However, the relationship between cognitive effects of D(2/3)-receptor antagonism and dopamine transmission is not described in healthy subjects. We therefore tested effects of acute haloperidol (5 mg/d over 3 days) on continuous performance task (CPT) performance and 6-[(18)F]-fluoro-l-DOPA (FDOPA) PET parameters. Nine physically and mentally healthy male men performed two FDOPA-PET scans including arterial plasma withdrawal. Over 3 days before the second scan, all subjects were treated with 5 mg/d haloperidol orally. Using our novel steady-state analysis, we calculated the intrinsic rate of the cerebral FDOPA utilization (K), the turnover of [(18)F]fluorodopamine formed in brain (k(loss)) and the storage for FDOPA and its brain metabolites (V(d)). Furthermore, a ds-CPT and EPS-screening was performed before every PET scan. We found that FDOPA kinetics in those normal subjects with relatively high baseline K showed a more pronounced sensitivity to haloperidol treatment, manifesting in reduced storage capacity and elevated turnover of [(18)F]fluorodopamine, whereas subjects with lower K showed the opposite pattern of responses. Furthermore, low baseline K predicted improvements in the CPT task after haloperidol, whereas participants with higher baseline K showed a decline in cognitive performance. We conclude that the initial increase of [(18)F]fluorodopamine turnover after acute haloperidol challenge is associated with an over-stimulation in individuals with initially more pharmacologically responsive dopamine systems, but optimizes cognitive performance in those with lower normal FDOPA utilization at baseline. We hypothesize that these effects may be driven by D(1)-receptor mediated transmission during D(2) blockade.
[Show abstract][Hide abstract] ABSTRACT: Dopamine neurotransmission influences those cognitive processes, which are generally regarded as prefrontal cortical functions. In previous positron-emission-tomography (PET) studies, net blood-brain clearance of [18F]-fluoro-l-DOPA (FDOPA) correlated with impaired cognitive performance in patients with Parkinson's disease or schizophrenia. We hypothesized that FDOPA influx also correlates with performance of cognitive tasks associated with prefrontal functioning in healthy volunteers. The net blood-brain clearance of FDOPA (K(in)(app)) was mapped in a group of 11 healthy volunteers and calculated in striatal volumes-of-interest. The Wisconsin-Card-Sorting-Test (WCST), Stroop-Test, Trail-Making-Test (TMT-A/B), and Continuous-Performance-Test (CPT-M) had been administered previously to the same subjects. No correlation of K(in) (app) with perseverative errors in WCST or age could be found. However, there were significant positive correlations between the magnitude of K(in)(app) in caudate nucleus, putamen, and midbrain with performance of the TMT-B, CPT-M, and the Stroop test. Highest correlations were found between the time needed to perform the Stroop interference task and the K(in)(app) of striatal areas (Caudate nucleus: -0.780, P = 0.005; putamen: -0.870, P < 0. 001). Thus, the present findings reveal a strong correlation between dopamine synthesis capacity in striatum of healthy volunteers and performance of cognitive tasks linked to the prefrontal cortex.
Human Brain Mapping 10/2007; 28(10):931-9. DOI:10.1002/hbm.20325 · 5.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous positron emission tomography (PET) studies with levodopa analogs have revealed a modestly increased capacity for dopamine synthesis in the striatum of patients with schizophrenia compared with healthy age-matched control subjects. We hypothesized that not just the synthesis but also the turnover of radiolabeled dopamine is elevated in patients. To test the hypothesis, we reanalyzed 2-h-long [18F]fluorodopa (FDOPA)/PET recordings from eight unmedicated patients with schizophrenia and 15 healthy age-matched control subjects, using new methods for the quantification of [18F]fluorodopamine steady-state kinetics. The fractional rate constant for the catabolism and elimination of [18F]fluorodopamine was elevated nearly twofold in striatum, the largest biochemical difference in brain of schizophrenics yet reported. The magnitude of the intrinsic blood-brain FDOPA clearance with correction for this loss of [18F]fluorodopamine metabolites was increased by 20% in caudate and putamen and by 50% in amygdala and midbrain of the patients. However, the magnitude of the steady-state storage of FDOPA and its decarboxylated metabolites (V(d)) was reduced by one-third in the caudate nucleus and amygdala of the schizophrenic group. Thus, reduced steady-state storage of [18F]fluorodopamine occurs in the midst of accelerated synthesis in brain of untreated patients. Positive scores of the positive and negative syndrome scale correlated inversely with the magnitude of V(d) in amygdala, suggesting an association between positive symptoms and impaired steady-state storage of FDOPA metabolites in that structure.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2007; 27(30):8080-7. DOI:10.1523/JNEUROSCI.0805-07.2007 · 6.34 Impact Factor