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

Abstract

Rationale There is significant interest in the NMDA-receptor antagonist ketamine due to its efficacy in treating depressive disorders and its induction of psychotic-like symptoms that make it a useful tool for modeling psychosis. Objective The present study extends the successful development of an apparatus and methodology to conduct pharmacological MRI studies in awake rhesus monkeys in order to evaluate the CNS effects of ketamine. Methods Functional MRI scans were conducted in four awake adult female rhesus monkeys during sub-anesthetic i.v. infusions of ketamine (0.345 mg/kg bolus followed by 0.256 mg/kg/hr constant infusion) with and without risperidone pretreatment (0.06mg/kg). Statistical parametric maps of ketamine-induced BOLD activation were obtained with appropriate GLM models incorporating motion and hemodynamics of ketamine infusion. Results Ketamine infusion induced and sustained robust BOLD activation in a number of cortical and subcortical regions, including the thalamus, cingulate gyrus, and supplementary motor area. Pretreatment with the antipsychotic drug risperidone markedly blunted ketamine-induced activation in many brain areas. Conclusions The results are remarkably similar to human imaging studies showing ketamine-induced BOLD activation in many of the same brain areas, and pretreatment with risperidone or another antipsychotic blunting the ketamine response to a similar extent. The strong concordance of the functional imaging data in humans with these results from nonhuman primates highlights the translational value of the model and provides an excellent avenue for future research examining the CNS effects of ketamine. This model may also be a useful tool for evaluating the efficacy of novel antipsychotic drugs.

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

“…They performed the phMRI scans during ketamine treatment and correlated the acute effects of ketamine with the alleviation of depression symptoms (BDI) 24hours post infusion. They found a similar pattern of acute ketamine-evoked BOLD activation in subjects with MDD to what has been shown previously in healthy control subjects (De Simoni et al, 2013; Deakin et al, 2008; Doyle et al, 2013) as well as in nonhuman primates (Maltbie et al, 2016). Further, they found that ketamine-induced BOLD activation in the rostral anterior cingulate cortex (rACC) correlated strongly (r=0.61) with alleviation of depression symptoms (measured by BDI).…”

“…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). Moreover, pretreatment with risperidone attenuated the ketamine-induced changes in BOLD (Maltbie et al, 2016) to a similar extent as reported in humans (Doyle et al, 2013).…”

“…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). Moreover, pretreatment with risperidone attenuated the ketamine-induced changes in BOLD (Maltbie et al, 2016) to a similar extent as reported in humans (Doyle et al, 2013). These data suggest that the pharmacological effects of ketamine are well conserved across species and attest to the validity of using ketamine in animal models of schizophrenia.…”

“…Data acquisition begins prior to the administration of ketamine to establish a baseline signal and continues for at least several minutes beyond the start of ketamine infusion. Various ketamine infusion protocols have been used (Table 2) in human (Deakin et al, 2008), nonhuman primate (Maltbie et al, 2016), and rat (Chin et al, 2011) studies, with each showing a significant ketamine-induced BOLD-response that appears to be proportional to the ketamine dose (De Simoni et al, 2013) and highly robust across species (Maltbie et al, 2016). Sub-anesthetic ketamine induces a reliable pattern of regional increases in BOLD signal indicative of neuronal excitation, which is consistent with the ketamine-induced increases observed in regional glucose metabolism (Duncan et al, 1998; Langsjo et al, 2004).…”

“…On the other hand, a region that becomes disinhibited may increase its functional coupling to downstream areas and hence may show increased functional connectivity even when it does not show a strong enhancement in BOLD signal (Gusnard et al, 2001). This may explain why the dlPFC shows the most extensive increases in functional connectivity (Gopinath et al, 2016) but only moderate increases in BOLD signal during ketamine infusion (De Simoni et al, 2013; Maltbie et al, 2016). …”