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Investigation of cross-species translatability of pharmacological MRI in awake nonhuman primate - a buprenorphine challenge study.

Seah S, Asad AB, Baumgartner R, Feng D, Williams DS, Manigbas E, Beaver JD, Reese T, Henry B, Evelhoch JL, Chin CL - PLoS ONE (2014)

Bottom Line: However, it has been demonstrated anesthesia could attenuate basal neuronal activity, which can confound interpretation of drug-induced brain activation patterns.Conversely, no significant change in activated brain regions was found in the same animals imaged under the anesthetized condition.Our data highlight the utility and importance of awake NHP imaging as a translational imaging biomarker for drug research.

View Article: PubMed Central - PubMed

Affiliation: Imaging, Merck & Co. Inc., West Point, Pennsylvania, United States of America; Translational Medicine Research Centre, MSD, Singapore, Singapore.

ABSTRACT

Background: Pharmacological MRI (phMRI) is a neuroimaging technique where drug-induced hemodynamic responses can represent a pharmacodynamic biomarker to delineate underlying biological consequences of drug actions. In most preclinical studies, animals are anesthetized during image acquisition to minimize movement. However, it has been demonstrated anesthesia could attenuate basal neuronal activity, which can confound interpretation of drug-induced brain activation patterns. Significant efforts have been made to establish awake imaging in rodents and nonhuman primates (NHP). Whilst various platforms have been developed for imaging awake NHP, comparison and validation of phMRI data as translational biomarkers across species remain to be explored.

Methodology: We have established an awake NHP imaging model that encompasses comprehensive acclimation procedures with a dedicated animal restrainer. Using a cerebral blood volume (CBV)-based phMRI approach, we have determined differential responses of brain activation elicited by the systemic administration of buprenorphine (0.03 mg/kg i.v.), a partial µ-opioid receptor agonist, in the same animal under awake and anesthetized conditions. Additionally, region-of-interest analyses were performed to determine regional drug-induced CBV time-course data and corresponding area-under-curve (AUC) values from brain areas with high density of µ-opioid receptors.

Principal findings: In awake NHPs, group-level analyses revealed buprenorphine significantly activated brain regions including, thalamus, striatum, frontal and cingulate cortices (paired t-test, versus saline vehicle, p<0.05, n = 4). This observation is strikingly consistent with µ-opioid receptor distribution depicted by [6-O-[(11)C]methyl]buprenorphine ([(11)C]BPN) positron emission tomography imaging study in baboons. Furthermore, our findings are consistent with previous buprenorphine phMRI studies in humans and conscious rats which collectively demonstrate the cross-species translatability of awake imaging. Conversely, no significant change in activated brain regions was found in the same animals imaged under the anesthetized condition.

Conclusions: Our data highlight the utility and importance of awake NHP imaging as a translational imaging biomarker for drug research.

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Related in: MedlinePlus

Area-under-curve of regional time-course rCBV change during post-drug infusion derived from the region-of-interest analysis.Results obtained from region-of-interest (ROI) analyses of rCBV time-course data showing the area-under-curve (mean ± SEM) of the entire post-drug infusion period (AUC) or only the steady-state time period (AUCss). Animals (n = 4) were imaged under awake (Awa) or anesthetized (Ane) conditions and treated with either buprenorphine (BUP at 0.03 mg/kg i.v.) or vehicle (VEH). Our data indicated that in awake animals AUC and AUCss calculated from thalamus, caudate nucleus, and putamen are significantly higher in buprenorphine-treated animals (paired t-test, *p<0.05, **p<0.01 vs vehicle).
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pone-0110432-g007: Area-under-curve of regional time-course rCBV change during post-drug infusion derived from the region-of-interest analysis.Results obtained from region-of-interest (ROI) analyses of rCBV time-course data showing the area-under-curve (mean ± SEM) of the entire post-drug infusion period (AUC) or only the steady-state time period (AUCss). Animals (n = 4) were imaged under awake (Awa) or anesthetized (Ane) conditions and treated with either buprenorphine (BUP at 0.03 mg/kg i.v.) or vehicle (VEH). Our data indicated that in awake animals AUC and AUCss calculated from thalamus, caudate nucleus, and putamen are significantly higher in buprenorphine-treated animals (paired t-test, *p<0.05, **p<0.01 vs vehicle).

Mentions: Plots of time-course rCBV changes derived from our ROI analyses are shown in Figure 6, in which activated brain regions identified in the group-level brain activation maps (see Fig. 5) showed significant increases in rCBV following buprenorphine infusion. Buprenorphine produced significant increases in rCBV change (mean ± SD) at frontal cortex (7.3%±0.2%), thalamus (6.5%±0.2%), caudate nucleus (6.2%±0.2%), putamen (5.8%±0.2%), and cingulate cortex (5.1%±0.2%). Of note, it appears that rCBV reached the maximum value around 10-minute-post onset of drug infusion and then maintained at steady state that prolonged over the rest of the imaging period. Area-under-curve of the rCBV time-course data over the entire drug infusion period (AUC), or the above-mentioned steady state period (AUCss), were calculated and shown in Figure 7. Results depicted that both AUC and AUCss calculated from thalamus, caudate nucleus, and putamen are significantly higher in buprenorphine-treated awake animals (paired t-test, p<0.05, vs vehicle), whilst no significant increases in AUC and AUCss were found in any brain region from the anesthetized study.


Investigation of cross-species translatability of pharmacological MRI in awake nonhuman primate - a buprenorphine challenge study.

Seah S, Asad AB, Baumgartner R, Feng D, Williams DS, Manigbas E, Beaver JD, Reese T, Henry B, Evelhoch JL, Chin CL - PLoS ONE (2014)

Area-under-curve of regional time-course rCBV change during post-drug infusion derived from the region-of-interest analysis.Results obtained from region-of-interest (ROI) analyses of rCBV time-course data showing the area-under-curve (mean ± SEM) of the entire post-drug infusion period (AUC) or only the steady-state time period (AUCss). Animals (n = 4) were imaged under awake (Awa) or anesthetized (Ane) conditions and treated with either buprenorphine (BUP at 0.03 mg/kg i.v.) or vehicle (VEH). Our data indicated that in awake animals AUC and AUCss calculated from thalamus, caudate nucleus, and putamen are significantly higher in buprenorphine-treated animals (paired t-test, *p<0.05, **p<0.01 vs vehicle).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4206294&req=5

pone-0110432-g007: Area-under-curve of regional time-course rCBV change during post-drug infusion derived from the region-of-interest analysis.Results obtained from region-of-interest (ROI) analyses of rCBV time-course data showing the area-under-curve (mean ± SEM) of the entire post-drug infusion period (AUC) or only the steady-state time period (AUCss). Animals (n = 4) were imaged under awake (Awa) or anesthetized (Ane) conditions and treated with either buprenorphine (BUP at 0.03 mg/kg i.v.) or vehicle (VEH). Our data indicated that in awake animals AUC and AUCss calculated from thalamus, caudate nucleus, and putamen are significantly higher in buprenorphine-treated animals (paired t-test, *p<0.05, **p<0.01 vs vehicle).
Mentions: Plots of time-course rCBV changes derived from our ROI analyses are shown in Figure 6, in which activated brain regions identified in the group-level brain activation maps (see Fig. 5) showed significant increases in rCBV following buprenorphine infusion. Buprenorphine produced significant increases in rCBV change (mean ± SD) at frontal cortex (7.3%±0.2%), thalamus (6.5%±0.2%), caudate nucleus (6.2%±0.2%), putamen (5.8%±0.2%), and cingulate cortex (5.1%±0.2%). Of note, it appears that rCBV reached the maximum value around 10-minute-post onset of drug infusion and then maintained at steady state that prolonged over the rest of the imaging period. Area-under-curve of the rCBV time-course data over the entire drug infusion period (AUC), or the above-mentioned steady state period (AUCss), were calculated and shown in Figure 7. Results depicted that both AUC and AUCss calculated from thalamus, caudate nucleus, and putamen are significantly higher in buprenorphine-treated awake animals (paired t-test, p<0.05, vs vehicle), whilst no significant increases in AUC and AUCss were found in any brain region from the anesthetized study.

Bottom Line: However, it has been demonstrated anesthesia could attenuate basal neuronal activity, which can confound interpretation of drug-induced brain activation patterns.Conversely, no significant change in activated brain regions was found in the same animals imaged under the anesthetized condition.Our data highlight the utility and importance of awake NHP imaging as a translational imaging biomarker for drug research.

View Article: PubMed Central - PubMed

Affiliation: Imaging, Merck & Co. Inc., West Point, Pennsylvania, United States of America; Translational Medicine Research Centre, MSD, Singapore, Singapore.

ABSTRACT

Background: Pharmacological MRI (phMRI) is a neuroimaging technique where drug-induced hemodynamic responses can represent a pharmacodynamic biomarker to delineate underlying biological consequences of drug actions. In most preclinical studies, animals are anesthetized during image acquisition to minimize movement. However, it has been demonstrated anesthesia could attenuate basal neuronal activity, which can confound interpretation of drug-induced brain activation patterns. Significant efforts have been made to establish awake imaging in rodents and nonhuman primates (NHP). Whilst various platforms have been developed for imaging awake NHP, comparison and validation of phMRI data as translational biomarkers across species remain to be explored.

Methodology: We have established an awake NHP imaging model that encompasses comprehensive acclimation procedures with a dedicated animal restrainer. Using a cerebral blood volume (CBV)-based phMRI approach, we have determined differential responses of brain activation elicited by the systemic administration of buprenorphine (0.03 mg/kg i.v.), a partial µ-opioid receptor agonist, in the same animal under awake and anesthetized conditions. Additionally, region-of-interest analyses were performed to determine regional drug-induced CBV time-course data and corresponding area-under-curve (AUC) values from brain areas with high density of µ-opioid receptors.

Principal findings: In awake NHPs, group-level analyses revealed buprenorphine significantly activated brain regions including, thalamus, striatum, frontal and cingulate cortices (paired t-test, versus saline vehicle, p<0.05, n = 4). This observation is strikingly consistent with µ-opioid receptor distribution depicted by [6-O-[(11)C]methyl]buprenorphine ([(11)C]BPN) positron emission tomography imaging study in baboons. Furthermore, our findings are consistent with previous buprenorphine phMRI studies in humans and conscious rats which collectively demonstrate the cross-species translatability of awake imaging. Conversely, no significant change in activated brain regions was found in the same animals imaged under the anesthetized condition.

Conclusions: Our data highlight the utility and importance of awake NHP imaging as a translational imaging biomarker for drug research.

Show MeSH
Related in: MedlinePlus