Dataset Information

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 midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug.

SUBMITTER: Adhikari BM

PROVIDER: S-EPMC7267897 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Adhikari Bhim M BM Dukart Juergen J Hipp Joerg F JF Forsyth Anna A McMillan Rebecca R Muthukumaraswamy Suresh D SD Ryan Meghann C MC Hong L Elliot LE Eickhoff Simon B SB Jahandshad Neda N Thompson Paul M PM Rowland Laura M LM Kochunov Peter P

Human brain mapping 20191021 3

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) underw ...[more]

PMID: 31633254

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Project description:Disturbed functional connectivity is assumed to cause neurocognitive deficits in patients suffering from schizophrenia. A Glutamate N-methyl-D-aspartate receptor (NMDAR) dysfunction has been suggested as a possible mechanism underlying altered connectivity in schizophrenia, especially in the gamma- and theta-frequency range. The present study aimed to investigate the effects of the NMDAR-antagonist ketamine on resting-state power, functional connectivity, and schizophrenia-like psychopathological changes in healthy volunteers. In a placebo-controlled crossover design, 25 healthy subjects were recorded using resting-state 64-channel-electroencephalography (EEG) (eyes closed). The imaginary coherence-based Multivariate Interaction Measure (MIM) was used to measure gamma and theta connectivity across 80 cortical regions. The network-based statistic was applied to identify involved networks under ketamine. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). Ketamine caused an increase in all PANSS (p < 0.001) as well as 5D-ASC scores (p < 0.01). Significant increases in resting-state gamma and theta power were observed under ketamine compared to placebo (p < 0.05). The source-space analysis revealed two distinct networks with an increased mean functional gamma- or theta-band connectivity during the ketamine session. The gamma-network consisted of midline regions, the cuneus, the precuneus, and the bilateral posterior cingulate cortices, while the theta-band network involved the Heschl gyrus, midline regions, the insula, and the middle cingulate cortex. The current source density (CSD) within the gamma-band correlated negatively with the PANSS negative symptom score, and the activity within the gamma-band network correlated negatively with the subjective changed meaning of percepts subscale of the 5D-ASC. These results are in line with resting-state patterns seen in people who have schizophrenia and argue for a crucial role of the glutamate system in mediating dysfunctional gamma- and theta-band-connectivity in schizophrenia. Resting-state networks could serve as biomarkers for the response to glutamatergic drugs or drug development efforts within the glutamate system.

Project description:The reliability of magnetoencephalography (MEG) resting-state functional connectivity in schizophrenia (SZ) is unknown as previous research has focused on healthy controls (HC). Here, we examined reliability in 26 participants (13-SZ, 13-HC). Eyes opened and eyes closed resting-state data were collected on 4 separate occasions during 2 visits, 1 week apart. For source modeling, we used minimum norm software to apply dynamic statistical parametric mapping. Source analyses compared the following functional connectivity metrics from each data run: coherence (coh), imaginary coherence (imcoh), pairwise phase consistency (ppc), phase-locking value (plv), phase lag index (pli), weighted phase lag index (wpli), and weighted phase lag index debiased (wpli2). Intraclass correlation coefficients (ICCs) were calculated for whole brain, network, and network pair averages. For reliability, ICCs above 0.75 = excellent, above 0.60 = good, above 0.40 = fair, and below 0.40 = poor reliability. We found the reliability of these metrics varied greatly depending on frequency band, network, network pair, and participant group examined. Broadband (1-58 Hz) whole brain averages in both HC and SZ showed excellent reliability for wpli2, and good to fair reliability for ppc, plv, and coh. Broadband network averages showed excellent to good reliability across 1 hour and 1 week for coh, imcoh, ppc, plv, wpli within default mode, cognitive control, and visual networks in HC, while the same metrics had excellent to fair reliability in SZ. Regional network pair averages showed good to fair reliability for coh, ppc, plv within default mode, cognitive control and visual network pairs in HC and SZ. In general, HC had higher reliability compared to SZ, and the default mode, cognitive control, and visual networks had higher reliability compared to somatosensory and auditory networks. Similar reliability levels occurred for both eyes opened and eyes closed resting-states for most metrics. The functional connectivity metrics of coh, ppc, and plv performed best across 1 hour and 1 week in HC and SZ. We also found that SZ had reduced coh, plv, and ppc in the dmn average and pair values indicating dysconnectivity in SZ. These findings encourage collecting both eyes opened and eyes closed resting-state MEG, while demonstrating that clinical populations may differ in reliability.

Dataset Information

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

Publications

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

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