Temporal dynamics of the pharmacological MRI response to subanaesthetic ketamine in healthy volunteers: A simultaneous EEG/fMRI study

Abstract

Background: Pharmacological magnetic resonance imaging has been used to investigate the neural effects of subanaesthetic ketamine in healthy volunteers. However, the effect of ketamine has been modelled with a single time course and without consideration of physiological noise. Aims: This study aimed to investigate ketamine-induced alterations in resting neural activity using conventional pharmacological magnetic resonance imaging analysis techniques with physiological noise correction, and a novel analysis utilising simultaneously recorded electroencephalography data. Methods: Simultaneous electroencephalography/functional magnetic resonance imaging and physiological data were collected from 30 healthy male participants before and during a subanaesthetic intravenous ketamine infusion. Results: Consistent with previous literature, we show widespread cortical blood-oxygen-level dependent signal increases and decreased blood-oxygenlevel dependent signals in the subgenual anterior cingulate cortex following ketamine. However, the latter effect was attenuated by the inclusion of motion regressors and physiological correction in the model. In a novel analysis, we modelled the pharmacological magnetic resonance imaging response with the power time series of seven electroencephalography frequency bands. This showed evidence for distinct temporal time courses of neural responses to ketamine. No electroencephalography power time series correlated with decreased blood-oxygen-level dependent signal in the subgenual anterior cingulate cortex. Conclusions: We suggest the decrease in blood-oxygen-level dependent signals in the subgenual anterior cingulate cortex typically seen in the literature is the result of physiological noise, in particular cardiac pulsatility. Furthermore, modelling the pharmacological magnetic resonance imaging response with a single temporal model does not completely capture the full spectrum of neuronal dynamics. The use of electroencephalography regressors to model the response can increase confidence that the pharmacological magnetic resonance imaging is directly related to underlying neural activity.

Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers

“…Our interpretation is consistent with a recent report [ 37 ] showing that ketamine produces a measurable pharmacoBOLD response after correcting for the physiologic response. Thus, we believe our results reflect mGluR2/3 agonist target engagement, as neither POMA nor TS-134 had any independent effects on heart rate or respiration.…”

“…We observed marked changes in heartrate and respiration, in response to ketamine in the course of the studies, so we continuously monitored these physiologic parameters on a subset of subjects across studies ( n = 61) using a pulse oximeter and respiration belt. Consistent with a prior report [ 37 ], the time course of heart rate changes mirrored that of the pharmacoBOLD response to ketamine (Supplemental Fig. 4 ).…”

“…A potential limitation of BOLD fMRI as a biomarker is the potential for confounding cardio-respiratory effects. Physiologic responses to ketamine can influence cerebrovascular volume and oxygenation [ 37 , 45 – 47 ], and thus pharmacoBOLD. However, preclinical studies show that the tachycardic effects of NMDAR antagonism are brain mediated [ 48 – 54 ], potentially via glutamate [ 49 , 51 – 54 ].…”

Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia

“…Written informed consent was obtained from all participants and the local Ethics Committee approved the study. The data analyzed here have been previously reported in (Forsyth et al, ; McMillan et al, ).…”

Clinical Efficacy and Target Engagement of Glutamatergic Drugs: Placebo-Controlled RCTs of Pomaglumetad and TS-134 for Reversal of Ketamine-Induced Psychotic Symptoms and PharmacoBOLD in Healthy Volunteers

“…This argues that cardiorespiratory effects are not driving the pharmacoBOLD signal, but may add "noise" to phBOLD comparisons, and confirms that the model can still be a sensitive measure of target engagement even without adjusting for nonspecific perfusion effects. These results notwithstanding, further optimization of the approach seems warranted, including parametric variation in ketamine dose, increased physiological monitoring and statistical modeling of whole brain BOLD effects [37].…”