Effects of arterial cannulation stress on regional cerebral blood flow in major depressive disorder

Individuals with major depressive disorder (MDD) display abnormal neurophysiological responses to psychological stress but little is known about their neurophysiological responses to physiological stressors. Using [15O-H2O] positron emission tomography we assessed whether the regional cerebral blood flow (rCBF) response to arterial cannulation differed between patients with MDD and healthy controls (HCs). Fifty-one MDD patients and 62 HCs were scanned following arterial cannulation and 15 MDD patients and 17 HCs were scanned without arterial cannulation. A region-of-interest analysis showed that a significantly increased rCBF of the anterior cingulate cortex and right amygdala was associated with arterial cannulation in MDD. A whole brain analysis showed increased rCBF of the right post-central gyrus, left temporopolar cortex, and right amygdala during arterial cannulation in MDD patients. The rCBF in the right amygdala was significantly correlated with depression severity. Conceivably, the limbic response to invasive physical stress is greater in MDD subjects than in HCs

Population-based input function modeling for [(18)F]FMPEP-d 2, an inverse agonist radioligand for cannabinoid CB1 receptors: validation in clinical studies.

BACKGROUND: Population-based input function (PBIF) may be a valid alternative to full blood sampling for quantitative PET imaging. PBIF is typically validated by comparing its quantification results with those obtained via arterial sampling. However, for PBIF to be employed in actual clinical research studies, its ability to faithfully capture the whole spectrum of results must be assessed. The present study validated a PBIF for [(18)F]FMPEP-d 2, a cannabinoid CB1 receptor radioligand, in healthy volunteers, and also attempted to utilize PBIF to replicate three previously published clinical studies in which the input function was acquired with arterial sampling. METHODS: The PBIF was first created and validated with data from 42 healthy volunteers. This PBIF was used to assess the retest variability of [(18)F]FMPEP-d 2, and then to quantify CB1 receptors in alcoholic patients (n = 18) and chronic daily cannabis smokers (n = 29). Both groups were scanned at baseline and after 2-4 weeks of monitored drug abstinence. RESULTS: PBIF yielded accurate results in the 42 healthy subjects (average Logan-distribution volume (V T) was 13.3±3.8 mL/cm(3) for full sampling and 13.2±3.8 mL/cm(3) for PBIF; R(2) = 0.8765, p<0.0001) and test-retest results were comparable to those obtained with full sampling (variability: 16%; intraclass correlation coefficient: 0.89). PBIF accurately replicated the alcoholism study, showing a widespread ∼20% reduction of CB1 receptors in alcoholic subjects, without significant change after abstinence. However, a small PBIF-V T bias of -9% was unexpectedly observed in cannabis smokers. This bias led to substantial errors, including a V T decrease in regions that had shown no downregulation in the full input function. Simulated data showed that the original findings could only have been replicated with a PBIF bias between -6% and +4%. CONCLUSIONS: Despite being initially well validated in healthy subjects, PBIF may misrepresent clinical protocol results and be a source of variability between different studies and institutions

Effects of arterial cannulation stress on regional cerebral blood flow in major depressive disorder

Individuals with major depressive disorder (MDD) display abnormal neurophysiological responses to psychological stress but little is known about their neurophysiological responses to physiological stressors. Using [O-15]-H2O positron emission tomography we assessed whether the regional cerebral blood flow (rCBF) response to arterial cannulation differed between patients with MDD and healthy controls (HCs). Fifty-one MDDpatients and 62 HCs were scanned following arterial cannulation and 15MDDpatients and 17 HCs were scanned without arterial cannulation. A region-of-interest analysis showed that a significantly increased rCBF of the anterior cingulate cortex and right amygdala was associated with arterial cannulation in MDD. A whole brain analysis showed increased rCBF of the right post-central gyrus, left temporopolar cortex, and right amygdala during arterial cannulation in MDD patients. The rCBF in the right amygdala was significantly correlated with depression severity. Conceivably, the limbic response to invasive physical stress is greater in MDD subjects than in HCs

The positron emission tomographic radioligand 18F-FIMX images and quantifies metabotropic glutamate receptor 1 in proportion to the regional density of its gene transcript in human brain

A recent study from our laboratory found that (18)F-FIMX is an excellent positron emission tomography (PET) radioligand for quantifying metabotropic glutamate receptor 1 (mGluR1) in monkey brain. This study evaluated the ability of (18)F-FIMX to quantify mGluR1 in humans. A second goal was to use the relative density of mGluR1 gene transcripts in brain regions to estimate specific uptake (VS) and nondisplaceable uptake (VND) in each brain region.METHODS: After injection of 189 ± 3 MBq of (18)F-FIMX, 12 healthy volunteers underwent a dynamic PET scan over 120 minutes. In six of them, images were acquired until 210 minutes. A metabolite-corrected arterial input function was measured from the radial artery. Four other subjects had whole-body scans to estimate radiation exposure.RESULTS: (18)F-FIMX uptake into human brain was high (SUV = 4-6 in cerebellum), peaked at about 10 minutes, and washed out rapidly. An unconstrained two-tissue compartment model fitted the data well, and distribution volume (VT) (mL • cm-3) values ranged from 1.5 in caudate to 11 in cerebellum. A 120-minute scan provided stable VT values in all regions except the cerebellum, for which an acquisition time of at least 170 minutes was necessary. VT values in brain regions correlated well with mGluR1 transcript density, and the correlation suggested that VND of (18)F-FIMX was quite low (0.5 mL • cm-3). This measure of VND in humans was very similar to that from a receptor blocking study in monkeys, after correcting for differences in plasma protein binding. Similar to other (18)F-labeled ligands, the effective dose was about 23 µSv/MBq.CONCLUSION: (18)F-FIMX can quantify mGluR1 in human brain with a 120 - 170 minute scan. Correlation of brain uptake with the relative density of mGluR1 transcript allows specific receptor binding of a radioligand to be quantified without injecting pharmacological doses of a blocking agent

The PET Radioligand 18

A recent study from our laboratory found that (18)F-FIMX is an excellent positron emission tomography (PET) radioligand for quantifying metabotropic glutamate receptor 1 (mGluR1) in monkey brain. This study evaluated the ability of (18)F-FIMX to quantify mGluR1 in humans. A second goal was to use the relative density of mGluR1 gene transcripts in brain regions to estimate specific uptake (VS) and nondisplaceable uptake (VND) in each brain region.METHODS: After injection of 189 ± 3 MBq of (18)F-FIMX, 12 healthy volunteers underwent a dynamic PET scan over 120 minutes. In six of them, images were acquired until 210 minutes. A metabolite-corrected arterial input function was measured from the radial artery. Four other subjects had whole-body scans to estimate radiation exposure.RESULTS: (18)F-FIMX uptake into human brain was high (SUV = 4-6 in cerebellum), peaked at about 10 minutes, and washed out rapidly. An unconstrained two-tissue compartment model fitted the data well, and distribution volume (VT) (mL • cm-3) values ranged from 1.5 in caudate to 11 in cerebellum. A 120-minute scan provided stable VT values in all regions except the cerebellum, for which an acquisition time of at least 170 minutes was necessary. VT values in brain regions correlated well with mGluR1 transcript density, and the correlation suggested that VND of (18)F-FIMX was quite low (0.5 mL • cm-3). This measure of VND in humans was very similar to that from a receptor blocking study in monkeys, after correcting for differences in plasma protein binding. Similar to other (18)F-labeled ligands, the effective dose was about 23 μSv/MBq.CONCLUSION: (18)F-FIMX can quantify mGluR1 in human brain with a 120 - 170 minute scan. Correlation of brain uptake with the relative density of mGluR1 transcript allows specific receptor binding of a radioligand to be quantified without injecting pharmacological doses of a blocking agent

Retest variability for 2TCM, Logan with full input, and Logan with PBIF, respectively.

<p>In the present study, results with Logan and the PBIF (variability: 16%; ICC = 0.89) were nearly identical to those obtained with Logan and the full input function. <i>V</i>_T values obtained with 2TCM, Logan with full input and Logan with PBIF were strongly correlated (scatter plots are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060231#pone.0060231.s001" target="_blank">Figure S1</a>).</p

Areas under the curve, expressed in SUV, of the peak area (first 5 minutes) and the rest of the arterial input function in the three populations of subjects.

<p>Areas under the curve, expressed in SUV, of the peak area (first 5 minutes) and the rest of the arterial input function in the three populations of subjects.</p

Results from the alcohol and cannabis studies using PBIF.

<p>Bold text underscores differences between PBIF and full sampling modeling.</p

Comparison of Logan-<i>V</i>_T results in cortical and subcortical regions for healthy volunteers, alcoholic subjects and cannabis smokers, obtained with full input and the PBIF.

<p>Results at baseline in alcoholic subjects (A) and cannabis smokers (B), compared to healthy controls for both full input and PBIF. PBIF provided accurate Logan-<i>V</i>_T values in healthy subjects and alcoholic patients and closely replicated previous findings of widespread downregulation. In cannabis smokers, PBIF underestimated Logan-<i>V</i>_T (arrows); the results suggest the erroneous conclusion that downregulation also occurred in subcortical regions.</p