Quantification of the neurokinin 1 receptor ligand [¹¹C]R116301.

PURPOSE: Neurokinin 1 (NK1) receptors have been implicated in depression, anxiety, and pain perception. Recently, it was shown that, in the human brain, a specific NK1 receptor-related signal was obtained with the novel radioligand, [¹¹C]R116301, using positron emission tomography. The purpose of this study was to evaluate various methods for quantifying specific [¹¹C]R116301 binding. METHODS: Two dynamic 90-min [¹¹C]R116301 scans, separated by 5 h, were performed in 11 healthy volunteers. In three patients, the second scan was performed after an oral blocking dose of 125 mg of aprepitant, whereas in the other eight, no intervention was performed (test-retest). Whole striatum was used as the tissue of interest, as it has the highest density of NK1 receptors. Cerebellum was used as the reference tissue. RESULTS: Reference tissue models were stable with the simplified reference tissue model (SRTM) performing best. Average (± standard deviation) SRTM-derived mean nondisplaceable binding potential (BP(ND)) of all (first) baseline scans was 0.64±0.31 (n=11), which reduced to -0.01±0.03 (n=3) after aprepitant administration. Test-retest results showed low variability (14.0±10.7%) and excellent reliability, as indicated by the intraclass correlation coefficient (0.93). The ratio of standardized uptake values of striatum and cerebellum minus 1, an approximation of BP(ND), showed very low variability (6.2±3.1%) with excellent reliability (intraclass correlation coefficient=0.98), and correlated well with SRTM-derived BP(ND) (R²=0.96). CONCLUSION: SRTM is the model of choice for quantifying [¹¹C]R116301 binding. Semiquantitative tissue ratios hold promise for routine clinical applications.

First evaluation of [11C]R116301 as an in vivo tracer of NK1 receptors in man.

PURPOSE: NK1 receptors have been implicated in various neuropsychiatric and other disorders. R116301 is a selective NK1 receptor antagonist. In this pilot study, [(11)C]R116301 was evaluated as a potential positron emission tomography (PET) ligand for the NK1 receptor. PROCEDURES: Two dynamic PET studies were performed in three normal volunteers before and after a blocking dose of aprepitant. Data were analyzed using striatum to cerebellum standardized uptake value (SUV) ratios. RESULTS: Baseline SUV ratios at 60-90 min after injection ranged from 1.22 to 1.70. Following aprepitant administration, this specific signal was completely blocked. Aprepitant administration did not significantly affect uptake in cerebellum, confirming the absence of NK1 receptors in cerebellum. CONCLUSION: These preliminary results indicate that [(11)C]R116301 has potential as a radioligand for in vivo assessment of NK1 receptors in the human brain.

Comparison of 3D-OP-OSEM and 3D-FBP reconstruction algorithms for High-Resolution Research Tomograph studies: effects of randoms estimation methods.

The High-Resolution Research Tomograph (HRRT) is a dedicated human brain positron emission tomography (PET) scanner. Recently, a 3D filtered backprojection (3D-FBP) reconstruction method has been implemented to reduce bias in short duration frames, currently observed in 3D ordinary Poisson OSEM (3D-OP-OSEM) reconstructions. Further improvements might be expected using a new method of variance reduction on randoms (VRR) based on coincidence histograms instead of using the delayed window technique (DW) to estimate randoms. The goal of this study was to evaluate VRR in combination with 3D-OP-OSEM and 3D-FBP reconstruction techniques. To this end, several phantom studies and a human brain study were performed. For most phantom studies, 3D-OP-OSEM showed higher accuracy of observed activity concentrations with VRR than with DW. However, both positive and negative deviations in reconstructed activity concentrations and large biases of grey to white matter contrast ratio (up to 88%) were still observed as a function of scan statistics. Moreover 3D-OP-OSEM+VRR also showed bias up to 64% in clinical data, i.e. in some pharmacokinetic parameters as compared with those obtained with 3D-FBP+VRR. In the case of 3D-FBP, VRR showed similar results as DW for both phantom and clinical data, except that VRR showed a better standard deviation of 6-10%. Therefore, VRR should be used to correct for randoms in HRRT PET studies.

Amygdala responses to emotional faces in twins discordant or concordant for the risk for anxiety and depression.

BACKGROUND: Functional brain imaging studies have shown deviant amygdala responses to emotional stimuli in subjects suffering from anxiety and depressive disorder, but both hyperactivity and hypoactivity compared to healthy controls have been reported. To account for these discrepant findings, we hypothesize that genetic and environmental risk factors differently impact on amygdala functioning. METHODS: To test this hypothesis, we assessed amygdala responses to an emotional faces paradigm during functional magnetic resonance imaging in monozygotic twin pairs discordant for the risk of anxiety and depression (n=10 pairs) and in monozygotic twin pairs concordant for high (n=7 pairs) or low (n=15 pairs) risk for anxiety and depression. RESULTS: Main effects (all faces vs. baseline) revealed robust bilateral amygdala activity across groups. In discordant twins, increased amygdala responses were found for negatively valenced stimuli (angry/anxious faces) in high-risk twins compared to their low-risk co-twins. In contrast, concordant high-risk pairs revealed blunted amygdala reactivity to both positive and negative faces compared with concordant low-risk pairs. Post-hoc analyses showed that these findings were independent of 5-HTTLPR genotype. CONCLUSIONS: Our findings indicate amygdala hyperactivity in subjects who are at high risk for anxiety and depression through environmental factors and amygdala hypoactivity in those at risk mainly through genetic factors. We suggest that this result reflects a difference in baseline amygdala activation in these groups. Future imaging studies on anxiety and depression should aim to avoid admixture of subjects who are at genetic risk with those at risk due to environmental factors.

The neural correlates of verbal encoding and retrieval in monozygotic twins at low or high risk for depression and anxiety.

Emotional processing and brain activation were examined during an encoding and recognition paradigm using emotionally salient words in a sample of monozygotic twin pairs at low or high risk for anxiety and depression. Discordant twin pairs were used to chart the effects of environmental risk factors and concordant twin pairs were used to chart the effects of genetic risk factors on performance and brain activation. Performance data did not support the existence of a negative response bias in subjects at high risk. At the neural level, however, increased left inferior frontal gyrus (LIFG) activation by negative words was found in high-risk subjects, most prominently during recognition. Increased LIFG activity was found in subjects at high risk through either genetic or environmental risk factors. These results suggest that fMRI activation of the LIFG in a verbal emotional memory task may be a useful vulnerability marker for anxiety and depression.

Intrapair differences in hippocampal volume in monozygotic twins discordant for the risk for anxiety and depression.

BACKGROUND: Current biological psychiatric models assume that genetic and environmental risk factors for anxiety and depression act on the same brain structures. METHODS: To test this assumption, we assessed brain anatomy by using optimized voxel-based morphometry on magnetic resonance images obtained in monozygotic twin pairs who were discordant for the risk of anxiety and depression (n = 10 pairs) and in monozygotic twin pairs who were concordant for high (n = 7 pairs) or low (n = 15 pairs) risk for anxiety and depression. RESULTS: We observed volume reductions in the temporal lobe, most notably in the left posterior hippocampal region in subjects at high risk for anxiety and depression, but exclusively in the intrapair comparison of discordant monozygotic twins. Because monozygotic twins are genetically identical, any discordance in their risk for anxiety and depression and hippocampal volume must arise from differential exposure to environmental influences. A group comparison between pairs concordant for low or high risk, which is more likely to reflect differences in genetic vulnerability, did not show reduced temporal-lobe and posterior hippocampal volumes in the pairs at high risk for anxiety and depression. CONCLUSIONS: This pattern of results suggests that damage to temporal-lobe structures may be specific to an environmentally driven etiology of anxiety and depression.