Ketamine effects on default mode network activity and vigilance: A randomized, placebo-controlled crossover simultaneous fMRI/EEG study

Abstract

In resting-state functional connectivity experiments, a steady state (of consciousness) is commonly supposed. However, recent research has shown that the resting state is a rather dynamic than a steady state. In particular, changes of vigilance appear to play a prominent role. Accordingly, it is critical to assess the state of vigilance when conducting pharmacodynamic studies with resting-state functional magnetic resonance imaging (fMRI) using drugs that are known to affect vigilance such as (subanesthetic) ketamine. In this study, we sought to clarify whether the previously described ketamine-induced prefrontal decrease of functional connectivity is related to diminished vigilance as assessed by electroencephalography (EEG). We conducted a randomized, double-blind, placebo-controlled crossover study with subanesthetic S-Ketamine in N = 24 healthy, young subjects by simultaneous acquisition of resting-state fMRI and EEG data. We conducted seed-based default mode network functional connectivity and EEG power spectrum analyses. After ketamine administration, decreased functional connectivity was found in medial prefrontal cortex whereas increased connectivities were observed in intraparietal cortices. In EEG, a shift of energy to slow (delta, theta) and fast (gamma) wave frequencies was seen in the ketamine condition. Frontal connectivity is negatively related to EEG gamma and theta activity while a positive relationship is found for parietal connectivity and EEG delta power. Our results suggest a direct relationship between ketamine-induced functional connectivity changes and the concomitant decrease of vigilance in EEG. The observed functional changes after ketamine administration may serve as surrogate end points and provide a neurophysiological framework, for example, for the antidepressant action of ketamine (trial name: 29JN1556, EudraCT Number: 2009-012399-28).

Keywords: EEG-fMRI; antidepressant action; depression; ketamine; vigilance control.

Figure 1

The experimental design including scanning sequences and information about drug application. During the neuroimaging investigation, subjects received in random order either a subanesthetic dose of S‐Ketamine HCl (Esketaminehydrochlorid) [Ketanest® S, Pfizer] or placebo (crossover design, 1 week apart), both administered intravenously in 0.9% NaCl. This administration was carried out as a bolus of S‐Ketamine (0.1 mg/kg during 5 min) immediately before measurements in the MRI scanner and a continuous infusion of S‐Ketamine (0.015625 mg kg⁻¹ min⁻¹ for the duration of the investigation, i.e., 1 hr maximum) during the measurement. To avoid a slow increase of ketamine plasma levels, a reduction by 10% every 10 min (Umbricht et al., 2000) was determined. The resting‐state fMRI measurement started 34 min after the beginning of the ketamine infusion

Figure 2

The ketamine effect on seed‐based functional connectivity. (a) Significant T‐values (two‐sided) of seed to voxel functional connectivity for ketamine > placebo comparison (FWE cluster‐corrected: p _FWE = .002). Seed (marked as green dot) is centered at 1, −61, 38 (MNI) and covers PCC/precuneus area. Significant clusters cover mPFC (decreased connectivity) and left and right IPL areas (increased connectivity). (b) Boxplot of individual mean Fisher Z‐transformed functional connectivities for placebo (black) and ketamine (red) condition for the different significant clusters. Of further interest, for ketamine condition, mPFC connectivities were close to zero. Same could be observed for left and right IPL connectivities for placebo condition

Figure 3

Row 1 and 2 show heatmaps of geometric mean FFT_P for all 30 electrodes of placebo and ketamine condition for five frequency bands (delta: 0.53–4 Hz; theta: 4–8 Hz; alpha: 8–12 Hz; beta: 12–25 Hz; gamma: 30–50 Hz). Row 3 shows heatmaps of factors of how the GM FFT_P of the two conditions scale to each other (red = higher GM FFT_P for ketamine condition, blue = higher GM FFT_P for placebo condition, green = equal GM FFT_P). Please note logarithmic scaling for row 1 to 3. Row 4 shows heatmaps of uncorrected p values <.1 (one‐way repeated measure ANOVA, blue p < .1, green p < .05, red p < .001). Despite of some electrodes, in alpha and beta, no clustering of electrodes shows neither high scaling factors, nor significant differences between conditions. In delta and theta, cluster of electrodes with high scaling factors and significantly different (p < .05) FFT_P over conditions were observable for parietal‐temporal regions and fronto‐central regions, respectively. Highest scaling factors could be seen in fronto‐central electrodes for gamma but without significant difference (p < .05) between conditions

Figure 4

Left side shows b‐spline smoothed mean logarithmic FFT_P of placebo (black) and ketamine (red) condition of electrode Fz (a) and Pz (b) against frequency bins from 0 to 45 Hz (bin‐size = 0.48) with regarding 95% confidence interval (light black and light red, respectively). For both electrodes, overlapping graphs could be seen for frequency ranges from 8 to 25 Hz indicating no ketamine related differences. For Fz electrode, the graphs start to spread open at frequencies higher 25 Hz with higher ln(FFT_P) for ketamine condition. Same could be seen for both electrodes for frequencies between 1 and 7 Hz. Please be aware that for both electrodes, the energy content of small frequencies is at least one magnitude higher than those from high frequencies. For illustrative reasons and to account for the higher energy content of small frequencies, we plotted on the right side of (a) and (b) for the corresponding electrodes the mean FFT_P of both conditions against a logarithmically scaled frequency axis. This leads to an emphasis on the difference between ketamine and placebo conditions at lower frequencies

Figure 5

Plots with gray background show the individual difference (ketamine − placebo) of the logarithmic EEG Power (Δln[FFT_P]) against the matching individual difference of default mode network functional connectivity (Δconnectivity). Plots with white background show the individual ln(FFT_P) against corresponding functional connectivity for placebo (black) and ketamine condition (red) with associated linear regressions (lines). (a) For delta, an increase in Δln(FFT_P) of electrode CP5 is significantly accompanied with an increased Δ in left IPL‐PCC/precuneus functional connectivity with a Pearson's R of 0.52 (p = .032). This is related to the right shifted parallel offset of the linear regression of ketamine condition shown in (b) with higher FFT_P and functional connectivity values for ketamine condition. (c, d) A comparable analysis of theta for C4 electrode and DMN functional connectivity between mPFC and PCC/precuneus shows a trend‐wise negative correlation for Δ analysis with a significant decreased correlation for placebo condition (R = −0.635, p = .006). For ketamine condition, a floor effect with connectivity values close to zero could be observed which leads to low Pearson's R of −0.296 (p = .249). (e, f) Analyzing ln(FFT_P) of gamma for electrode Fz against DMN functional connectivity of mPFC, comparable results with a significant negative correlation for Δ analysis and a trend‐wise negative correlation between ln(FFT_P) and functional connectivity for placebo condition could be seen. Because of the aforementioned floor effect of ketamine related DMN functional connectivity of mPFC, a correlation between ln(FFT_P) and DMN functional connectivity for ketamine condition could not be observed