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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

Group comparisons of brain activation patterns between buprenorphine and vehicle under awake and anesthetized imaging.Group comparisons of brain activation patterns showing significant effect of buprenorphine versus vehicle (paired t-test, p<0.05, n = 4) under awake and anesthetized imaging. In the awake study, buprenorphine activates brain regions with a high density of µ-opioid receptor, including frontal cortex (FC), thalamus (Tha), anterior cingulate cortices (ACC), caudate nucleus (CN), putamen (Put), and superior parietal lobule (sPar), and limited deactivation was found in occipital cortex (Occ). In contrast, no significant difference in brain activation between buprenorphine and vehicle infusion was observed in anesthetized animals.
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pone-0110432-g005: Group comparisons of brain activation patterns between buprenorphine and vehicle under awake and anesthetized imaging.Group comparisons of brain activation patterns showing significant effect of buprenorphine versus vehicle (paired t-test, p<0.05, n = 4) under awake and anesthetized imaging. In the awake study, buprenorphine activates brain regions with a high density of µ-opioid receptor, including frontal cortex (FC), thalamus (Tha), anterior cingulate cortices (ACC), caudate nucleus (CN), putamen (Put), and superior parietal lobule (sPar), and limited deactivation was found in occipital cortex (Occ). In contrast, no significant difference in brain activation between buprenorphine and vehicle infusion was observed in anesthetized animals.

Mentions: Figure 5 illustrates group comparisons of brain activation patterns showing significant effect of buprenorphine versus vehicle on rCBV changes (paired t-test, p<0.05, n = 4), while Table 1 lists the results of ROI analyses, including activated brain regions/coordinates, z-statistics, and total percentage activated volumes calculated from the awake study. As shown, under the awake imaging condition, buprenorphine activated brain regions with a high density of µ-opioid receptor including, frontal cortex, thalamus, cingulate cortex, caudate nucleus, putamen, occipital cortex, and superior parietal lobule. Notably, these findings are strikingly consistent with µ-opioid receptor distribution depicted by [6-O-[11C]methyl]buprenorphine ([11C]BPN) positron emission tomography (PET) study in baboons, where the highest [11C]BPN uptakes was observed in striatum (caudate nucleus and putamen) followed by thalamus, cingulate, frontal, parietal, occipital cortices, and then cerebellum [44]. In accordance with the results obtained from the previous study in conscious rodent and human studies [21], similar region-specificity of activated brain structures are also observed in our awake NHP data. Conversely, no significant activation was observed from anesthetized animals (paired t-test, vs. vehicle treatment; see Fig. 5B), despite animal physiological parameters (mean ± SEM, n = 4) being maintained within normal ranges during these experiments (mean heart rate  =  (119.9±5.1) beats/min, mean SpO2  = 98.8%±0.6%, mean EtCO2  = 22.0%±0.4%, and body temperature  = 36.5 °C±0.1 °C). These results exemplify the undesired anesthetic-drug interactions embedded in the anesthetized animal experiments, while highlighting the need for awake imaging for phMRI studies.


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)

Group comparisons of brain activation patterns between buprenorphine and vehicle under awake and anesthetized imaging.Group comparisons of brain activation patterns showing significant effect of buprenorphine versus vehicle (paired t-test, p<0.05, n = 4) under awake and anesthetized imaging. In the awake study, buprenorphine activates brain regions with a high density of µ-opioid receptor, including frontal cortex (FC), thalamus (Tha), anterior cingulate cortices (ACC), caudate nucleus (CN), putamen (Put), and superior parietal lobule (sPar), and limited deactivation was found in occipital cortex (Occ). In contrast, no significant difference in brain activation between buprenorphine and vehicle infusion was observed in anesthetized animals.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4206294&req=5

pone-0110432-g005: Group comparisons of brain activation patterns between buprenorphine and vehicle under awake and anesthetized imaging.Group comparisons of brain activation patterns showing significant effect of buprenorphine versus vehicle (paired t-test, p<0.05, n = 4) under awake and anesthetized imaging. In the awake study, buprenorphine activates brain regions with a high density of µ-opioid receptor, including frontal cortex (FC), thalamus (Tha), anterior cingulate cortices (ACC), caudate nucleus (CN), putamen (Put), and superior parietal lobule (sPar), and limited deactivation was found in occipital cortex (Occ). In contrast, no significant difference in brain activation between buprenorphine and vehicle infusion was observed in anesthetized animals.
Mentions: Figure 5 illustrates group comparisons of brain activation patterns showing significant effect of buprenorphine versus vehicle on rCBV changes (paired t-test, p<0.05, n = 4), while Table 1 lists the results of ROI analyses, including activated brain regions/coordinates, z-statistics, and total percentage activated volumes calculated from the awake study. As shown, under the awake imaging condition, buprenorphine activated brain regions with a high density of µ-opioid receptor including, frontal cortex, thalamus, cingulate cortex, caudate nucleus, putamen, occipital cortex, and superior parietal lobule. Notably, these findings are strikingly consistent with µ-opioid receptor distribution depicted by [6-O-[11C]methyl]buprenorphine ([11C]BPN) positron emission tomography (PET) study in baboons, where the highest [11C]BPN uptakes was observed in striatum (caudate nucleus and putamen) followed by thalamus, cingulate, frontal, parietal, occipital cortices, and then cerebellum [44]. In accordance with the results obtained from the previous study in conscious rodent and human studies [21], similar region-specificity of activated brain structures are also observed in our awake NHP data. Conversely, no significant activation was observed from anesthetized animals (paired t-test, vs. vehicle treatment; see Fig. 5B), despite animal physiological parameters (mean ± SEM, n = 4) being maintained within normal ranges during these experiments (mean heart rate  =  (119.9±5.1) beats/min, mean SpO2  = 98.8%±0.6%, mean EtCO2  = 22.0%±0.4%, and body temperature  = 36.5 °C±0.1 °C). These results exemplify the undesired anesthetic-drug interactions embedded in the anesthetized animal experiments, while highlighting the need for awake imaging for phMRI studies.

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