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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

Differences in plasma cortisol concentration and cumulative behavioral scores during Phase 1a used to select animals for Phase 1b.Cumulative behavioral scores over the Phase 1a training obtained from all animals (n = 12), in which animals with lower behavioral scores (n = 8, ‘O’) were selected to transition into the Phase 1b study and ones with higher scores were deselected (n = 4, ‘×’). In addition, to assess the stress level during the awake training, plasma cortisol concentrations were measured from these animals at two separate time points (∼ one month apart) during this phase, and results indicated that the reduction in cortical level is likely associated with better habituation (i.e. lower behavioral scores).
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pone-0110432-g002: Differences in plasma cortisol concentration and cumulative behavioral scores during Phase 1a used to select animals for Phase 1b.Cumulative behavioral scores over the Phase 1a training obtained from all animals (n = 12), in which animals with lower behavioral scores (n = 8, ‘O’) were selected to transition into the Phase 1b study and ones with higher scores were deselected (n = 4, ‘×’). In addition, to assess the stress level during the awake training, plasma cortisol concentrations were measured from these animals at two separate time points (∼ one month apart) during this phase, and results indicated that the reduction in cortical level is likely associated with better habituation (i.e. lower behavioral scores).

Mentions: Cumulative behavioral scores obtained from all the animals (n = 12) over the entire Phase 1a period are plotted in Figure 2, in which animals with lower overall behavioral scores (better habituated) were selected to transition from Phase 1a to 1b (n = 8). These results demonstrate that levels of acclimation can vary within the training cohort, and thereby the selection of desired animals is essential. Within this phase, differences in the cortisol levels measured at two time points (separated by a month) are shown in Figure 2, indicating that elevated cortisol levels are likely observed from animals with higher behavioral scores. To assess the effect of training on stress levels, Figure 3 illustrates the cortisol concentrations obtained from untrained/control animals (n = 6) as well as our imaging cohort (n = 8) at pre- and 90-minute-post training session (Phase 1b). As shown, cortisol levels were significantly elevated in untrained animals after they underwent the training session (paired t-test, p<0.01), while no significant difference was observed in habituated animals. Further, only one from the trained imaging cohort had cortisol concentrations substantially above the previously reported normal range (between 276 nmol/L and 1104 nmol/L) [52]. The lower cortisol level found in the trained cohort implies reduced stress levels in these animals and effective habituation to the restrainer and MRI scanner environment. Finally, two animals were deselected from the cohort due to medical conditions (unrelated to the training), while the remaining six animals were moved forward to Phase 1c.


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)

Differences in plasma cortisol concentration and cumulative behavioral scores during Phase 1a used to select animals for Phase 1b.Cumulative behavioral scores over the Phase 1a training obtained from all animals (n = 12), in which animals with lower behavioral scores (n = 8, ‘O’) were selected to transition into the Phase 1b study and ones with higher scores were deselected (n = 4, ‘×’). In addition, to assess the stress level during the awake training, plasma cortisol concentrations were measured from these animals at two separate time points (∼ one month apart) during this phase, and results indicated that the reduction in cortical level is likely associated with better habituation (i.e. lower behavioral scores).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0110432-g002: Differences in plasma cortisol concentration and cumulative behavioral scores during Phase 1a used to select animals for Phase 1b.Cumulative behavioral scores over the Phase 1a training obtained from all animals (n = 12), in which animals with lower behavioral scores (n = 8, ‘O’) were selected to transition into the Phase 1b study and ones with higher scores were deselected (n = 4, ‘×’). In addition, to assess the stress level during the awake training, plasma cortisol concentrations were measured from these animals at two separate time points (∼ one month apart) during this phase, and results indicated that the reduction in cortical level is likely associated with better habituation (i.e. lower behavioral scores).
Mentions: Cumulative behavioral scores obtained from all the animals (n = 12) over the entire Phase 1a period are plotted in Figure 2, in which animals with lower overall behavioral scores (better habituated) were selected to transition from Phase 1a to 1b (n = 8). These results demonstrate that levels of acclimation can vary within the training cohort, and thereby the selection of desired animals is essential. Within this phase, differences in the cortisol levels measured at two time points (separated by a month) are shown in Figure 2, indicating that elevated cortisol levels are likely observed from animals with higher behavioral scores. To assess the effect of training on stress levels, Figure 3 illustrates the cortisol concentrations obtained from untrained/control animals (n = 6) as well as our imaging cohort (n = 8) at pre- and 90-minute-post training session (Phase 1b). As shown, cortisol levels were significantly elevated in untrained animals after they underwent the training session (paired t-test, p<0.01), while no significant difference was observed in habituated animals. Further, only one from the trained imaging cohort had cortisol concentrations substantially above the previously reported normal range (between 276 nmol/L and 1104 nmol/L) [52]. The lower cortisol level found in the trained cohort implies reduced stress levels in these animals and effective habituation to the restrainer and MRI scanner environment. Finally, two animals were deselected from the cohort due to medical conditions (unrelated to the training), while the remaining six animals were moved forward to Phase 1c.

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