Modulation of simultaneously collected hemodynamic and electrophysiological functional connectivity by ketamine and midazolam

Abstract

The pharmacological modulation of functional connectivity in the brain may underlie therapeutic efficacy for several neurological and psychiatric disorders. Functional magnetic resonance imaging (fMRI) provides a noninvasive method of assessing this modulation, however, the indirect nature of the blood‐oxygen level dependent signal restricts the discrimination of neural from physiological contributions. Here we followed two approaches to assess the validity of fMRI functional connectivity in developing drug biomarkers, using simultaneous electroencephalography (EEG)/fMRI in a placebo‐controlled, three‐way crossover design with ketamine and midazolam. First, we compared seven different preprocessing pipelines to determine their impact on the connectivity of common resting‐state networks. Independent components analysis (ICA)‐denoising resulted in stronger reductions in connectivity after ketamine, and weaker increases after midazolam, than pipelines employing physiological noise modelling or averaged signals from cerebrospinal fluid or white matter. This suggests that pipeline decisions should reflect a drug's unique noise structure, and if this is unknown then accepting possible signal loss when choosing extensive ICA denoising pipelines could engender more confidence in the remaining results. We then compared the temporal correlation structure of fMRI to that derived from two connectivity metrics of EEG, which provides a direct measure of neural activity. While electrophysiological estimates based on the power envelope were more closely aligned to BOLD signal connectivity than those based on phase consistency, no significant relationship between the change in electrophysiological and hemodynamic correlation structures was found, implying caution should be used when making cross‐modal comparisons of pharmacologically‐modulated functional connectivity.

The Effect of Ketamine on Electrophysiological Connectivity in Major Depressive Disorder

“…A dynamic causal modeling (DCM) study, which modeled observed resting-state neuromagnetic connectivity using a biophysical model of neuronal responses incorporating AMPA and NMDA connectivity parameters, found an acute decrease in AMPA and NMDA-mediated frontal to parietal connectivity in HVs (27); the same study observed reductions in alpha-and beta-band amplitude envelope connectivity in visual parietal and motor networks. In addition, another electroencephalography (EEG) study demonstrated significant and widespread decreases in amplitude envelope connectivity in the alpha-band, particularly for nodes within the occipital lobe, as well as between the occipital lobe and frontal, parietal, and temporal nodes (3). Decreases in low beta-band connectivity have also been observed in healthy male participants, primarily in motor areas (3).…”

“…Thus, ketamine's inherent neural effects cannot be completely disambiguated from its cardiovascular effects using a hemodynamic-based imaging technique. As a result, fMRI analyses are extremely sensitive to the type of pre-processing used to remove physiological effects, and differences in preprocessing pipelines may yield different results with regard to connectivity changes (up versus down) post-ketamine (3). The significant heterogeneity in the literature is therefore not surprising.…”

Neuropsychopharmacological effects of midazolam on the human brain

“…One recent study assessed the validity of fMRI functional connectivity using simultaneous electroencephalography (EEG)/ fMRI in a placebo-controlled design with midazolam. The results suggested that different preprocessing strategies demonstrated the effects on the results of functional connectivity of RSNs [68] (Table 1).…”

“…It is also widely indicated that low-frequency fuctuations of BOLD fMRI signal in the resting state, an indirect measure of regional brain activity, is correlated with spontaneous neuronal activity [64,65]. Based on accumulating experimental evidence, midazolam-induced sedation affects within and between network connectivity of the RSNs [66][67][68][69]. Some of RSNs are thought of as lower-level networks including the sensorimotor network (SMN), auditory network (AN), and visual network (VN), which relate to sensory processing.…”

“…The results suggested that different preprocessing strategies demonstrated the effects on the results of functional connectivity of RSNs [ 68 ] (Table 1 ).…”