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

Abstract

Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting-state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia.Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19-37 years) underwent a randomized, three-way, cross-over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long-distance (seed-based and dual-regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10 −3 ), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05).Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia-related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = −.17, p = .65). The subtraction of ketamine and Bhim M. Adhikari and Juergen Dukart contributed equally to this study.

Neuropsychopharmacological effects of midazolam on the human brain

“…For the SN, in our previous work, we only identified a slight reduction in functional connectivity strength by using a lower uncorrected threshold [66]. In line with this, in one recent study, midazolam also showed no significant changes in the functional connectivity strength for the SN [78]. As for the DAN and DMN, results of the drug effect are still inconsistent.…”

“…For example, in our previous work, no significant functional connectivity changes within the DMN were observed during midazolam-induced light sedation [66]. In contrast, significant reductions in resting-state functional connectivity for DMN were reported during propofol or ketamine-induced mild sedation [78,88,89]. Midazolam or propofol-induced decrease in consciousness correlates with decreased functional connectivity within the FPN, whereas ketamine administration leads to no significant reduction in the connectivity strength in the FPN [66,88,89].…”

“…In our previous work, no significant functional connectivity changes within the DMN and DAN were observed during midazolam-induced light sedation [66]. In contrast, another study showed that midazolam administration led to a significant reduction in the connectivity strength in the DMN and DAN [78]. Many factors may contribute to these inconsistent results.…”

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

“…ENIGMA's future developments will include the coordinated analyses of new data modalities (such as resting state and task-related functional MRI [160][161][162][163] , as well as geostatistical and mobile sensor data), and deeper or more refined analyses of current imaging modalities. Diffusion MRI, in particular, is moving towards multi-shell protocols that can better differentiate cellular and microstructural sources of variance that may explain patterns observed with DTI 17 .…”

The ENIGMA Stroke Recovery Working Group: Big data neuroimaging to study brain-behavior relationships after stroke

“…Resting state fMRI (rs-fMRI) offers an approach to understand patterns of synchronized brain activity in the resting state, which can further be decomposed into networks with known functions (e.g., default mode, salience, attention networks) (Biswal, Yetkin, Haughton, & Hyde, 1995;Biswal et al, 2010). Harmonized processing of rs-fMRI in ENIGMA has used one of two pipelines: (1) an echo-planar imaging-based pipeline, based on Analysis of Functional NeuroImages (AFNI) software, that does not require the use of a co-registered anatomical MRI dataset (Adhikari et al, 2019a;Adhikari et al, 2018;Adhikari et al, 2019b); and (2) a pipeline known as fMRIprep+, based on the fMRIprep approach (Esteban et al, 2019), which can also be used for analysis of multi-site task-based functional MRI (Veer, Waller, Lett, Erk, & Walter, 2019).…”