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).

The M1/M4 agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain

“…NMDA antagonist evoked increases in HFO activity in nucleus accumbens have previously be shown to be reduced by clozapine (Hunt et al, 2015). The ketamine-induced power changes in β -power and γ-power observed here and in other preclinical studies (Phillips et al, 2012) have been recapitulated in humans (Muthukumaraswamy et al, 2015) and correlated with fMRI connectivity changes (Zacharias et al, 2020). However, HFO activity has not yet been reported in humans.…”

“…Complementary to this approach, a deeper understanding of the central effects of xanomeline could be obtained by profiling its effect on inter-regional fMRI synchronization, or "functional connectivity", in distributed brain circuits via resting-state fMRI (rsfMRI) (Errico et al, 2015;Gozzi and Schwarz, 2016). In addition, oxygen (O 2 ) amperometry provides a complementary probe-based method to measure the local hemodynamic response in conscious mobile animals (Lowry et al, 1997;Li et al, 2016), and quantitative electro-encephalography (qEEG) provides a means of monitoring the power-frequency profile of the brain's electrical rhythms more directly, unfiltered by the hemodynamic response underlying the fMRI signals (Ye et al, 2018;Zacharias et al, 2020). Given the established role of cholinergic systems in arousal and neocortical excitation, cholinergic modulation could conceivably also affect large-scale cortical coupling and electrical activity of the brain, resulting in rsfMRI-and qEEG-detectable effects.…”

Transient effects of multi‐infusion ketamine augmentation on treatment‐resistant depressive symptoms in patients with treatment‐resistant bipolar depression – An open‐label three‐week pilot study

“…Compared to the substantial number of studies focused on ketamine‐induced brain alterations in patients with unipolar depression (Chen et al., 2019; McMillan et al., 2019; Morris et al., 2020; Nugent et al., 2019; Zacharias et al., 2020), only a few studies have investigated the functional brain alterations associated with ketamine augmentation in patients with TRBPD. Recently, Diazgranados et al conducted a 2‐week study to investigate the antidepressant effects of ketamine infusions in patients with TRBPD and found that 71% of patients with TRBPD responded to ketamine augmentation (Diazgranados et al, 2010).…”

“…Compared to the substantial number of studies focused on ketamine-induced brain alterations in patients with unipolar depression (Chen et al, 2019;McMillan et al, 2019;Morris et al, 2020;Nugent et al, 2019;Zacharias et al, 2020), only a few studies have investigated the functional brain alterations associated with ketamine augmentation in patients with TRBPD.…”

The Effect of Ketamine on Electrophysiological Connectivity in Major Depressive Disorder

“…The significant heterogeneity in the literature is therefore not surprising. With regard to healthy volunteers (HVs), some studies that used resting-state fMRI to examine ketamine's acute effects found primarily increased connectivity (4-7), others reported mainly reductions (8)(9)(10), and some reported patterns of increases and decreases in connectivity depending on the brain region examined (11)(12)(13)(14). Studies of functional connectivity between one hour and 24 h post-infusion have produced similarly heterogeneous results (15)(16)(17)(18)(19)(20).…”