Quantification of Cerebral Blood Flow as Biomarker of Drug Effect: Arterial Spin Labeling phMRI After a Single Dose of Oral Citalopram

Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 02/2011; 89(2):251-8. DOI: 10.1038/clpt.2010.296
Source: PubMed


Arterial spin labeling (ASL) allows noninvasive quantification of cerebral blood flow (CBF), which can be used as a biomarker of drug effects in pharmacological magnetic resonance imaging (phMRI). In a double-blind, placebo-controlled crossover study, we investigated the effects of a single oral dose of citalopram (20 mg) on resting CBF in 12 healthy subjects, using ASL phMRI. Support-vector machine (SVM) analysis detected significant drug-induced reduction in CBF in brain regions including the amygdala, fusiform gyrus, insula, and orbitofrontal cortex. These regions have been shown to have abnormally elevated CBF in patients with major depression, as well as in subjects genetically prone to depression. Mixed-effects analysis on data extracted from selected regions of interest (ROIs) revealed significant drug effect only in serotonergic areas of the brain (z = -4.45, P < 0.005). These results demonstrate the utility of ASL phMRI as a biomarker of pharmacological activity of orally administered drugs in the brain.

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Available from: Danny JJ Wang, Feb 07, 2016
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    • "ASL perfusion MRI has received considerable attention in clinical neuroscience due to its quantitative and non-invasive nature. Absolute CBF values obtained using ASL in the whole brain and specific brain regions have been shown to be reproducible across time scales of minutes, hours to days (Chen et al., 2011; Jain et al., 2012; Jann et al., 2013; Wu et al., 2011). There is a good correlation between ASL CBF and the gold standard of 15 O-PET in both resting state and activation studies (Feng et al., 2004; Kilroy et al., 2013; Ye et al., 2000). "
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    ABSTRACT: Resting-state functional connectivity (FC) fMRI (rs-fcMRI) offers an appealing approach to mapping the brain's intrinsic functional organization. Blood oxygen level dependent (BOLD) and arterial spin labeling (ASL) are the two main rs-fcMRI approaches to assess alterations in brain networks associated with individual differences, behavior and psychopathology. While the BOLD signal is stronger with a higher temporal resolution, ASL provides quantitative, direct measures of the physiology and metabolism of specific networks. This study systematically investigated the similarity and reliability of resting brain networks (RBNs) in BOLD and ASL. A 2×2×2 factorial design was employed where each subject underwent repeated BOLD and ASL rs-fcMRI scans on two occasions on two MRI scanners respectively. Both independent and joint FC analyses revealed common RBNs in ASL and BOLD rs-fcMRI with a moderate to high level of spatial overlap, verified by Dice Similarity Coefficients. Test-retest analyses indicated more reliable spatial network patterns in BOLD (average modal Intraclass Correlation Coefficients: 0.905±0.033 between-sessions; 0.885±0.052 between-scanners) than ASL (0.545±0.048; 0.575±0.059). Nevertheless, ASL provided highly reproducible (0.955±0.021; 0.970±0.011) network-specific CBF measurements. Moreover, we observed positive correlations between regional CBF and FC in core areas of all RBNs indicating a relationship between network connectivity and its baseline metabolism. Taken together, the combination of ASL and BOLD rs-fcMRI provides a powerful tool for characterizing the spatiotemporal and quantitative properties of RBNs. These findings pave the way for future BOLD and ASL rs-fcMRI studies in clinical populations that are carried out across time and scanners. Copyright © 2014 Elsevier Inc. All rights reserved.
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    • "Despite the novelty of the approach, the reliability of the study using perfusion SPECT to explore functional connectivity in depression was reinforced by the large number of investigated subjects and the high statistical reliability of the study since the sampling error decreases with increase of sample size. In the present study, 32% of patients were medicated with various drugs, mainly selective serotonin reuptake inhibitors and anxiolytics, whose use has been reported to decrease CBF (Chen et al., 2011). "
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    ABSTRACT: Several studies have demonstrated altered brain functional connectivity in the resting state in depression. However, no study has investigated interregional networking in patients with persistent depressive disorder (PDD). The aim of this study was to assess differences in brain perfusion distribution and connectivity between large groups of patients and healthy controls. Participants comprised 91 patients with PDD and 65 age- and sex-matched healthy controls. Resting state perfusion was investigated by single photon emission computed tomography, and group differences were assessed by Statistical Parametric Mapping. Brain connectivity was explored through a voxel-wise interregional correlation analysis using as covariate of interest the normalized values of clusters of voxels in which perfusion differences were found in group analysis. Significantly increased regional brain perfusion distribution covering a large part of the cerebellum was observed in patients as compared with controls. Patients showed a significant negative functional connectivity between the cerebellar cluster and caudate, bilaterally. This study demonstrated inverse relative perfusion between the cerebellum and the caudate in PDD. Functional uncoupling may be associated with a dysregulation between the role of the cerebellum in action control and of the caudate in action selection, initiation and decision making in the patients. The potential impact of the resting state condition and the possibility of mitochondrial impairment are discussed.
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    • "In the simplest form of phMRI, the central hemodynamic response to the compound administration is measured in the absence of any overt physical stimulus or specific cognitive task (Chen et al., 2011). In other words, the signal changes measured are those occurring in direct response to the compound itself (chemical stimulus), in contrast to a modulation design in which the effect of a compound in altering the response evoked by an applied task or stimulus. "
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    ABSTRACT: Pharmacological magnetic resonance imaging (phMRI) is one method by which a drug's pharmacodynamic effects in the brain can be assessed. Although, phMRI has been frequently utilized in preclinical and clinical settings, the extent to which a phMRI signature for a compound translates between rodents and humans has not been systematically examined. In the current investigation, we aimed to build on recent clinical work where the functional response to 0.1 and 0.2 mg/70kg intravenous (IV) buprenorphine (partial μ-opioid receptor agonist) was measured in healthy humans. Here, we measured the phMRI response to 0.04 and 0.1 mg/kg IV buprenorphine in conscious, naive rats with the aim of establishing the parallelism of the phMRI signature of buprenorphine across species. PhMRI of 0.04 and 0.1 mg/kg IV buprenorphine yielded dose-dependent activation in a brain network comprising of the somatosensory cortex, cingulate, insula, striatum, thalamus, periaqueductal gray and cerebellum. Similar dose-dependent phMRI activation was observed in the human phMRI studies. These observations indicate an overall preservation of pharmacodynamic responses to buprenorphine between conscious, naive rodents and healthy human subjects, particularly in brain regions implicated in pain and analgesia. This investigation further demonstrates the utility of phMRI as a translational tool in neuroscience research that can provide mechanistic insight and guide dose selection in drug development.
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