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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

Comparison of resting state stability between anesthetized and awake imaging and test-retest reliability of awake baseline signal.(A) Resting state variation of BOLD signal (mean ± SD) obtained from each non-human primate (NHP) imaged under either awake (Awa, test and retest) or anesthetized (Ane) condition. (B) Bland-Altman plot for awake imaging data and the dash lines highlight the 95% limits of agreement (P1: represents the first test, P2 represents the retest).
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pone-0110432-g004: Comparison of resting state stability between anesthetized and awake imaging and test-retest reliability of awake baseline signal.(A) Resting state variation of BOLD signal (mean ± SD) obtained from each non-human primate (NHP) imaged under either awake (Awa, test and retest) or anesthetized (Ane) condition. (B) Bland-Altman plot for awake imaging data and the dash lines highlight the 95% limits of agreement (P1: represents the first test, P2 represents the retest).

Mentions: Figure 4A shows the percentage variation in resting state baseline signals within the whole brain volume (mean ± SD) from individual animals imaged under awake and anesthetized conditions. Our data indicate that compared to anesthetized imaging, the level of baseline variation was significantly higher (4∼5 fold) under the awake condition (paired t-test, p<0.01). This observation is not unexpected, since there was some animal movement during awake imaging. These findings suggest that a larger change in drug-induced phMRI signals may be needed in order to achieve comparable sensitivity offered by imaging anesthetized animals (i.e. to offset the increased baseline noise). Reasonable test-retest reliability was found from the awake baseline data, considering all the data points were within 95% limits of agreement of the Bland Altman plot (see Fig. 4b). Finally, two animals were deselected from the Phase 3 drug study, due to the increased body weight thus unable to fit into the animal restrainer or the need for repetitive head-post repairs.


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)

Comparison of resting state stability between anesthetized and awake imaging and test-retest reliability of awake baseline signal.(A) Resting state variation of BOLD signal (mean ± SD) obtained from each non-human primate (NHP) imaged under either awake (Awa, test and retest) or anesthetized (Ane) condition. (B) Bland-Altman plot for awake imaging data and the dash lines highlight the 95% limits of agreement (P1: represents the first test, P2 represents the retest).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0110432-g004: Comparison of resting state stability between anesthetized and awake imaging and test-retest reliability of awake baseline signal.(A) Resting state variation of BOLD signal (mean ± SD) obtained from each non-human primate (NHP) imaged under either awake (Awa, test and retest) or anesthetized (Ane) condition. (B) Bland-Altman plot for awake imaging data and the dash lines highlight the 95% limits of agreement (P1: represents the first test, P2 represents the retest).
Mentions: Figure 4A shows the percentage variation in resting state baseline signals within the whole brain volume (mean ± SD) from individual animals imaged under awake and anesthetized conditions. Our data indicate that compared to anesthetized imaging, the level of baseline variation was significantly higher (4∼5 fold) under the awake condition (paired t-test, p<0.01). This observation is not unexpected, since there was some animal movement during awake imaging. These findings suggest that a larger change in drug-induced phMRI signals may be needed in order to achieve comparable sensitivity offered by imaging anesthetized animals (i.e. to offset the increased baseline noise). Reasonable test-retest reliability was found from the awake baseline data, considering all the data points were within 95% limits of agreement of the Bland Altman plot (see Fig. 4b). Finally, two animals were deselected from the Phase 3 drug study, due to the increased body weight thus unable to fit into the animal restrainer or the need for repetitive head-post repairs.

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