David Elmenhorst

Mesolimbic Functional Magnetic Resonance Imaging Activations during Reward Anticipation Correlate with Reward-Related Ventral Striatal Dopamine Release

The dopaminergic mechanisms that control reward-motivated behavior are the subject of intense study, but it is yet unclear how, in humans, neural activity in mesolimbic reward-circuitry and its functional neuroimaging correlates are related to dopamine release. To address this question, we obtained functional magnetic resonance imaging (fMRI) measures of reward-related neural activity and [11C]raclopride positron emission tomography measures of dopamine release in the same human participants, while they performed a delayed monetary incentive task. Across the cohort, a positive correlation emerged between neural activity of the substantia nigra/ventral tegmental area (SN/VTA), the main origin of dopaminergic neurotransmission, during reward anticipation and reward-related [11C]raclopride displacement as an index of dopamine release in the ventral striatum, major target of SN/VTA dopamine neurons. Neural activity in the ventral striatum/nucleus accumbens itself also correlated with ventral striatal dopamine release. Additionally, high-reward-related dopamine release was associated with increased activation of limbic structures, such as the amygdala and the hippocampus. The observed correlations of reward-related mesolimbic fMRI activation and dopamine release provide evidence that dopaminergic neurotransmission plays a quantitative role in human mesolimbic reward processing. Moreover, the combined neurochemical and hemodynamic imaging approach used here opens up new perspectives for the investigation of molecular mechanisms underlying human cognition.

Sleep Deprivation Increases A1 Adenosine Receptor Binding in the Human Brain: A Positron Emission Tomography Study

It is currently hypothesized that adenosine is involved in the induction of sleep after prolonged wakefulness. This effect is partially reversed by the application of caffeine, which is a nonselective blocker of adenosine receptors. Here, we report that the most abundant and highly concentrated A1 subtype of cerebral adenosine receptors is upregulated after 24 h of sleep deprivation. We used the highly selective A1 adenosine receptor (A1AR) radioligand [18F]CPFPX ([18F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine) and quantitative positron emission tomography to assess cerebral A1ARs before and after sleep deprivation in 12 healthy volunteers and a control group (n = 10) with regular sleep. In sleep deprived subjects, we found an increase of the apparent equilibrium total distribution volume in a region-specific pattern in all examined brain regions with a maximum increase in the orbitofrontal cortex (15.3%; p = 0.014). There were no changes in the control group with regular sleep. This is the first molecular imaging study that provides in vivo evidence for an A1AR upregulation in cortical and subcortical brain regions after prolonged wakefulness, indicating that A1AR expression is contributing to the homeostatic sleep regulation.

5-HT2A receptor density is decreased in the at-risk mental state

RationaleCurrent perspectives on the pathophysiology of schizophrenia direct attention to serotonergic (serotonin, 5-HT) dysregulation in the prodrome or at-risk mental state (ARMS).ObjectiveTo study the cerebral 5-HT2A receptor (5-HT2AR) in the ARMS with [18F]altanserin positron emission tomography (PET) and a bolus-infusion paradigm.Materials and methodsWe quantified the spatial distribution of 5-HT2AR binding potential (BP1′) in never-medicated subjects assigned to early (n = 6) and late (n = 8) prodromal states of schizophrenia relative to healthy controls (n = 21). Five single nucleotide polymorphisms (SNPs) in the 5-HT2AR-encoding gene (HTR2A; 13q14-21) were genotyped to control for a potential bias in BP1′ due to between-group differences in genotype distributions.ResultsGroup comparisons of partial-volume corrected PET data by statistical parametric mapping and confirmatory volume of interest analysis yielded a dissemination of BP1′ decreases consistent with increasing levels of risk. An additional decrease in caudate BP1′ was present in subjects who subsequently converted to first-episode psychosis (n = 5), but absent in non-converters (n = 9). Between-group differences were not confounded by a differential distribution of SNP genotypes.ConclusionThese results suggest a progressive reduction of cortical 5-HT2AR density as a surrogate biological measure of increased risk for schizophrenia, irrespective of conversion. Progressive reductions of subcortical 5-HT2AR density could provide an indicator of illness activity and help to predict imminent conversion to schizophrenia. Moreover, our findings substantiate the rationale for establishing a phase-specific psychopharmacological intervention in the ARMS that addresses the serotonergic component of vulnerability to schizophrenia.

Sleep deprivation upregulates A1 adenosine receptors in the rat basal forebrain.

Sleep deprivation increases the levels of extracellular adenosine and A1 receptor (A1R)mRNA in the cholinergic zone of the basal forebrain, a region involved in sleep homeostasis. To evaluate homeostatic control mechanisms, we examined the sleep deprivation-induced changes in the A1R density in rodent brain using [3H]CPFPX receptor autoradiography. We also examined the role of nuclear factor-κB (NF-κB) in transcriptional upregulation of A1R mRNA by use of the inhibitor peptide SN50 to inhibit nuclear translocation of NF-κB. We found a significant increase in cholinergic basal forebrain A1R density following 24 h of sleep deprivation and evidence that the upregulation of A1R is mediated by NF-κB. The A1R increase may be important in sleep homeostasis, since the increase in A1R density would increase the inhibitory effect of given level of adenosine, thus increasing the gain of the homeostat.

Sleep deprivation increases A1 adenosine receptor density in the rat brain

Adenosine, increasing after sleep deprivation and acting via the A(1) adenosine receptor (A(1)AR), is likely a key factor in the homeostatic control of sleep. This study examines the impact of sleep deprivation on A(1)AR density in different parts of the rat brain with [(3)H]CPFPX autoradiography. Binding of [(3)H]CPFPX was significantly increased in parietal cortex (PAR) (7%), thalamus (11%) and caudate-putamen (9%) after 24 h of sleep deprivation compared to a control group with an undisturbed circadian sleep-wake rhythm. Sleep deprivation of 12 h changed receptor density regionally between -5% and +9% (motor cortex (M1), statistically significant) compared to the circadian control group. These results suggest cerebral A(1)ARs are involved in effects of sleep deprivation and the regulation of sleep. The increase of A(1)AR density could serve the purpose of not only maintaining the responsiveness to increased adenosine levels but also amplifying the effect of sleep deprivation and is in line with a sleep-induced homoeostatic reorganization at the synaptic level.

Oxytocin enhances attractiveness of unfamiliar female faces independent of the dopamine reward system.

Evidence from animal studies suggests that the social attraction and bonding effects of the neuropeptide oxytocin (OXT) are mediated by its modulation of dopamine (DA) release in brain reward centers, but this has not yet been demonstrated in humans. DA release can be measured by positron emission tomography (PET) using the radioligand [11C]raclopride. Its binding to DA D2 receptors (D2R) is sensitive and reciprocally related to endogenous DA, especially in the striatum. In a randomized double-blind placebo-controlled within-subjects trial on 18 adult male volunteers we combined [11C]raclopride PET and a facial attractiveness rating task to establish whether intranasal OXT (24 IU) increased both the perceived attractiveness of unfamiliar female faces and striatal DA release compared with placebo administration. While our behavioral data confirmed that subjects rated unfamiliar female faces as more attractive following OXT treatment, and this correlated with an increased perfusion rate in the striatum, there was no evidence for altered [11C]raclopride binding in the striatum or pallidum. Instead under OXT we rather observed an increased [11C]raclopride binding and reduced perfusion rate in subregions of the right dorsomedial prefrontal gyrus and superior parietal gyrus. The absence of OXT effects on dopamine release and D2 receptors in brain reward centers, despite increased striatal activity, implies that the peptide may facilitate perceived attraction via non-dopaminergic actions.

Caffeine Occupancy of Human Cerebral A1 Adenosine Receptors: In Vivo Quantification with 18F-CPFPX and PET

Caffeine is the neuroactive agent in coffee and tea and is a broadly consumed stimulant. It is a nonselective antagonist of the neuromodulator adenosine and, if applied in commonly consumed doses, evokes its stimulating effects through the blockade of adenosine receptors. 18F-8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (18F-CPFPX) has been established as a highly selective and affine PET ligand for the A1 adenosine receptor (A1AR). The objective of the present study was to visualize and quantify the in vivo occupancy of the human cerebral A1AR by caffeine using 18F-CPFPX and PET. Methods: Fifteen subjects (age range, 24–68 y) underwent a 140-min bolus–plus–constant-infusion PET experiment after at least 36 h of caffeine abstinence. Metabolite-corrected blood data were used to calculate steady-state distribution volumes (VT) during the baseline condition of the scan between 70 and 90 min. Subsequently, subjects received a 10-min infusion of varying concentrations (0.5–4.3 mg/kg of body weight) of caffeine at 90 min. Occupancy VT of the A1AR was thereafter estimated using data acquired between 120 and 140 min. Occupancy levels were calculated using the Lassen plot, from which the inhibitory concentrations of 50% were derived. Plasma levels of caffeine were determined at regular intervals. One subject received an intravenous vehicle as a placebo. Results: Caffeine displaced 5%–44% of 18F-CPFPX binding in a concentration-dependent manner. There was no change of radioligand binding after the administration of placebo. Half-maximal displacement was achieved at a plasma caffeine concentration of 67 μM, which corresponds to 450 mg in a 70-kg subject or approximately 4.5 cups of coffee. Conclusion: Given a biologic half-life of about 5 h, caffeine might therefore occupy up to 50% of the cerebral A1AR when caffeinated beverages are repeatedly consumed during a day. Furthermore, the present study provides evidence that 18F-CPFPX PET is suitable for studying the cerebral actions of caffeine, the most popular neurostimulant worldwide.

Sleep Deprivation Increases Cerebral Serotonin 2A Receptor Binding in Humans

STUDY OBJECTIVES Serotonin and its cerebral receptors play an important role in sleep-wake regulation. The aim of the current study is to investigate the effect of 24-h total sleep deprivation on the apparent serotonin 2A receptor (5-HT(2A)R) binding capacity in the human brain to test the hypothesis that sleep deprivation induces global molecular alterations in the cortical serotonergic receptor system. DESIGN Volunteers were tested twice with the subtype-selective radiotracer [(18)F]altanserin and positron emission tomography (PET) for imaging of 5-HT(2A)Rs at baseline and after 24 h of sleep deprivation. [(18)F]Altanserin binding potentials were analyzed in 13 neocortical regions of interest. The efficacy of sleep deprivation was assessed by questionnaires, waking electroencephalography, and cognitive performance measurements. SETTING Sleep laboratory and neuroimaging center. PATIENTS OR PARTICIPANTS Eighteen healthy volunteers. INTERVENTIONS Sleep deprivation. MEASUREMENTS AND RESULTS A total of 24 hours of sleep deprivation led to a 9.6% increase of [(18)F]altanserin binding on neocortical 5-HT(2A) receptors. Significant region-specific increases were found in the medial inferior frontal gyrus, insula, and anterior cingulate, parietal, sensomotoric, and ventrolateral prefrontal cortices. CONCLUSIONS This study demonstrates that a single night of total sleep deprivation causes significant increases of 5-HT(2A)R binding potentials in a variety of cortical regions although the increase declines as sleep deprivation continued. It provides in vivo evidence that total sleep deprivation induces adaptive processes in the serotonergic system of the human brain.

Cerebral A1 adenosine receptors (A1AR) in liver cirrhosis

PurposeThe cerebral mechanisms underlying hepatic encephalopathy (HE) are poorly understood. Adenosine, a neuromodulator that pre- and postsynaptically modulates neuronal excitability and release of classical neurotransmitters via A1 adenosine receptors (A1AR), is likely to be involved. The present study investigates changes of cerebral A1AR binding in cirrhotic patients by means of positron emission tomography (PET) and [18F]CPFPX, a novel selective A1AR antagonist.MethodsPET was performed in cirrhotic patients (n = 10) and healthy volunteers (n = 10). Quantification of in vivo receptor density was done by Logan’s non-invasive graphical analysis (pons as reference region). The outcome parameter was the apparent binding potential (aBP, proportional to Bmax/KD).ResultsCortical and subcortical regions showed lower A1AR binding in cirrhotic patients than in controls. The aBP changes reached statistical significance vs healthy controls (p < 0.05, U test with Bonferroni-Holm adjustment for multiple comparisons) in cingulate cortex (−50.0%), precentral gyrus (−40.9%), postcentral gyrus (−38.6%), insular cortex (−38.6%), thalamus (−32.9%), parietal cortex (−31.7%), frontal cortex (−28.6), lateral temporal cortex (−28.2%), orbitofrontal cortex (−27.9%), occipital cortex (−24.6), putamen (−22.7%) and mesial temporal lobe (−22.4%).ConclusionRegional cerebral adenosinergic neuromodulation is heterogeneously altered in cirrhotic patients. The decrease of cerebral A1AR binding may further aggravate neurotransmitter imbalance at the synaptic cleft in cirrhosis and hepatic encephalopathy. Different pathomechanisms may account for these alterations including decrease of A1AR density or affinity, as well as blockade of the A1AR by endogenous adenosine or exogenous xanthines.

A1 adenosine receptor PET using [18F]CPFPX: Displacement studies in humans

BACKGROUND Imaging of cerebral A(1) adenosine receptors (A(1)AR) with positron emission tomography (PET) has recently become available for neurological research. To date, it has still not been unraveled if there is a valid reference region without specific radioligand binding that may be used to improve image quantification. We conducted in vivo displacement studies in humans to elucidate this important question using the A(1)AR ligand [(18)F]CPFPX. METHODS Five healthy male volunteers underwent [(18)F]CPFPX bolus/infusion PET with short infusion of unlabelled CPFPX as competitor (n = 4; 0.9 to 4.0 mg) or vehicle (n = 1; control condition) after equilibrium of [(18)F]CPFPX distribution was attained. RESULTS Infusion of CPFPX induced a rapid displacement of [(18)F]CPFPX binding in all regions, including the cerebellum (region with lowest binding). Even at the highest competitor dose, no full displacement was reached. Displacement was dose-dependent in all regions except the cerebellum where floor effects and/or noise might have obscured dose dependency. Specific binding was estimated to account for about one third and two thirds of total equilibrium uptake in cerebellum and cortex, respectively. CONCLUSIONS Although the cerebellum is the region with lowest in vivo [(18)F]CPFPX binding, it is not an ideal reference region devoid of specific binding. Nevertheless, as will be discussed, the use of a reference region analysis may be a useful, non-invasive alternative analysis method in carefully selected applications.