Validation of ketamine as a pharmacological model of thalamic dysconnectivity across the illness course of schizophrenia

Abstract

N-methyl-D-aspartate receptor (NMDAR) hypofunction is a leading pathophysiological model of schizophrenia. Resting-state functional magnetic resonance imaging (rsfMRI) studies demonstrate a thalamic dysconnectivity pattern in schizophrenia involving excessive connectivity with sensory regions and deficient connectivity with frontal, cerebellar, and thalamic regions. The NMDAR antagonist ketamine, when administered at sub-anesthetic doses to healthy volunteers, induces transient schizophrenia-like symptoms and alters rsfMRI thalamic connectivity. However, the extent to which ketamine-induced thalamic dysconnectivity resembles schizophrenia thalamic dysconnectivity has not been directly tested. The current double-blind, placebo-controlled study derived an NMDAR hypofunction model of thalamic dysconnectivity from healthy volunteers undergoing ketamine infusions during rsfMRI. To assess whether ketamine-induced thalamic dysconnectivity was mediated by excess glutamate release, we tested whether pre-treatment with lamotrigine, a glutamate release inhibitor, attenuated ketamine's effects. Ketamine produced robust thalamo-cortical hyper-connectivity with sensory and motor regions that was not reduced by lamotrigine pre-treatment. To test whether the ketamine thalamic dysconnectivity pattern resembled the schizophrenia pattern, a whole-brain template representing ketamine's thalamic dysconnectivity effect was correlated with individual participant rsfMRI thalamic dysconnectivity maps, generating "ketamine similarity coefficients" for people with chronic (SZ) and early illness (ESZ) schizophrenia, individuals at clinical high-risk for psychosis (CHR-P), and healthy controls (HC). Similarity coefficients were higher in SZ and ESZ than in HC, with CHR-P showing an intermediate trend. Higher ketamine similarity coefficients correlated with greater hallucination severity in SZ. Thus, NMDAR hypofunction, modeled with ketamine, reproduces the thalamic hyper-connectivity observed in schizophrenia across its illness course, including the CHR-P period preceding psychosis onset, and may contribute to hallucination severity.

Fig. 1. Connectivity increases following active ketamine infusion.

Increased connectivity between bilateral thalamus (purple) and sensory regions for [active ketamine – saline] > [placebo ketamine – saline]. There were no significant clusters for [placebo ketamine – saline] < [ketamine ketamine – saline]. A anterior, L left. The color bar shows voxel-wise z-values. Coordinates (x, y, z) are reported in MNI space. Map is thresholded using a voxel-wise cluster defining threshold of z > 3.29 (p < 0.001) and FWE-corrected cluster significance threshold of p < 0.05.

Fig. 2. Distributions of placebo ketamine, active ketamine, and active lamotrigine + active ketamine connectivity from significant clusters.

Boxplots showing distributions of participant-level connectivity means for each drug condition, for each significant cluster obtained from the [active ketamine – saline] > [placebo ketamine – saline] contrast (voxel-z > 3.29, corrected cluster-p < 0.05); anatomical location details for clusters 1 through 7 are found in Supplementary Table S4. PL placebo ketamine, Ket active ketamine, Lam active lamotrigine. Asterisks reflect significance levels from follow-up two-sided pairwise tests (based on the corresponding repeated measures ANOVA for that cluster). Uncorrected ***p < 0.001.

Fig. 3. Visualization of the method used to correlate the ketamine-induced thalamic dysconnectivity pattern with thalamic connectivity in an independent data set of healthy control and schizophrenia participants.

a The 3D group-level [active ketamine – saline] > [placebo ketamine – saline] thalamic dysconnectivity z-statistic map (orange) was converted into a 1D vector. Each healthy control and schizophrenia participant’s site- or age-corrected 3D thalamic dysconnectivity map (purple), in which voxel values were expressed as deviations from the normative values expected from the respective healthy control group, was converted into a 1D vector, with the same orientation as the ketamine-dysconnectivity map (to allow the two to be correlated). The color bars show voxel-wise z-values. b The [active ketamine – saline] > [placebo ketamine – saline] thalamic dysconnectivity z-statistic map was correlated with individual thalamic dysconnectivity maps to obtain a ketamine similarity coefficient for each healthy control and schizophrenia participant. c Ketamine similarity coefficients were significantly higher for individuals with schizophrenia relative to healthy controls; significance level (asterisks above the horizontal line) and Cohen’s d are based on an ANOVA comparing ketamine similarity coefficients across groups, controlling for sex and study site. Black horizontal lines represent within-group means, and vertical asterisks reflect significance levels for within-group tests comparing the mean similarity coefficient value against 0 (two-sided). d Ketamine similarity coefficients were significantly higher for early illness schizophrenia participants relative to healthy controls and those at clinical high-risk for psychosis; significance level (asterisks above the horizontal line) and Cohen’s d are based on an ANOVA model comparing ketamine similarity coefficients across groups, controlling for sex. Black horizontal lines represent within-group means, and vertical asterisks reflect significance levels for within-group tests comparing the mean similarity coefficient value against 0 (two-sided). Clinical high-risk for psychosis participants who converted to a psychotic disorder within 24 months of study entry (n = 10) are highlighted in maroon. HC healthy control participant, SZ schizophrenia participant, ESZ early illness schizophrenia participant, CHR-P clinical high-risk for psychosis participant.

Fig. 4. Relationships between ketamine similarity coefficients with clinical symptom ratings among schizophrenia participants.

Relationship between SAPS Hallucination scores with ketamine similarity coefficients, controlling for the effects of sex and study site. SAPS Scale for the Assessment of Positive Symptoms, sqrt square-root, resid residualized.