Development of an apparatus and methodology for conducting functional magnetic resonance imaging (fMRI) with pharmacological stimuli in conscious rhesus monkeys

Abstract

Functional magnetic resonance imaging (fMRI) is a technique with significant potential to advance our understanding of multiple brain systems. However, when human subjects undergo fMRI studies they are typically conscious whereas pre-clinical fMRI studies typically utilize anesthesia, which complicates comparisons across studies. Therefore, we have developed an apparatus suitable for imaging conscious rhesus monkeys. In order to minimize subject stress and spatial motion, each subject was acclimated to the necessary procedures over several months. The effectiveness of this process was then evaluated, in fully trained subjects, by quantifying objective physiological measures. These physiological metrics were stable both within and across sessions and did not differ from when these same subjects were immobilized using standard primate handling procedures. Subject motion and blood oxygenation level dependent (BOLD) fMRI measurements were then evaluated by scanning subjects under three different conditions: the absence of stimulation, presentation of a visual stimulus, or administration of intravenous (i.v.) cocaine (0.3 mg/kg). Spatial motion differed neither by condition nor along the three principal axes. In addition, maximum translational and rotational motion never exceeded one half of the voxel size (0.75 mm) or 1.5 degrees, respectively. Furthermore, the localization of changes in blood oxygenation closely matched those reported in previous studies using similar stimuli. These findings document the feasibility of fMRI data collection in conscious rhesus monkeys using these procedures and allow for the further study of the neural effects of psychoactive drugs.

Ketamine-induced brain activation in awake female nonhuman primates: a translational functional imaging model

“…The apparatus and animal habituation protocol have been described in detail previously (Murnane and Howell 2010). Scans were conducted in a Siemens (Siemens Healthcare, Erlangen, Germany) Trio 3 Tesla magnet.…”

“…Scans were conducted in a Siemens (Siemens Healthcare, Erlangen, Germany) Trio 3 Tesla magnet. The monkeys lay prone in a custom-built restraint cradle optimized for acquiring phMRI data from fully-conscious rhesus monkeys (Murnane and Howell 2010) and attached to a NHP head coil (RAPID MR International, LLC). Heart rate, oxygen saturation and expired gases were continuously monitored to ensure the safety of the animals inside the scanner.…”

“…Both schizophrenia (Lewis and Lieberman 2000) and depression (Mayberg 2003) are characterized in part by altered processing in prefrontal cortex (PFC) and limbic circuits and NHPs represent an excellent animal model because their behavioral repertoires are sophisticated and their PFC is closely aligned with humans (Preuss 1995). The present study extends the successful development of an apparatus and methodology to conduct phMRI studies in conscious rhesus monkeys (Murnane et al 2015; Murnane and Howell 2010) in order to evaluate the CNS effects of antipsychotics. The first aim of this study was to validate NHPs as a model for studying the CNS effects of ketamine by using phMRI in awake rhesus monkeys to examine BOLD activation/deactivation profile of ketamine against time.…”

Functional connectivity in frontal-striatal brain networks and cocaine self-administration in female rhesus monkeys

“…Over a period of at least 6 years starting in early adulthood, all three subjects engaged in daily cocaine self-administration with no planned periods of extended abstinence. Drug histories were complex and varied across subjects as reported in published studies for RMv-3 (Kimmel et al 2008; Lindsey et al 2004; Murnane and Howell 2010; Wilcox et al 2002), RRg-4 (Howell et al 2001; Howell et al 2002; Kimmel et al 2008) and RBp-3 (Banks et al 2009; Howell et al 2006; Murnane and Howell 2010). Based on self-administration protocols used in these studies and the duration of study assignments, each subject consumed > 10 g of cocaine.…”

Ketamine and pharmacological imaging: use of functional magnetic resonance imaging to evaluate mechanisms of action

“…This result aligns well with observations reported in human subjects. Methods have also been developed that enable rhesus monkeys to undergo MRI scanning without the use of anesthesia and with minimal restraint stress (Murnane and Howell, 2010). A recent study has shown that awake rhesus monkeys display ketamine-induced BOLD activation (Maltbie et al, 2016) that corresponds closely in both magnitude and extent to what has been reported in humans (De Simoni et al, 2013; Deakin et al, 2008; Doyle et al, 2013).…”