Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans

Abstract

N-methyl-D-aspartate glutamate receptor (NMDA-R) antagonists produce schizophrenia-like positive and negative symptoms in healthy human subjects. Preclinical research suggests that NMDA-R antagonists interfere with the function of gamma-aminobutyric acid (GABA) neurons and alter the brain oscillations. These changes have been hypothesized to contribute to psychosis. In this investigation, we evaluated the hypothesis that the NMDA-R antagonist ketamine produces alterations in cortical functional connectivity during rest that are related to symptoms. We administered ketamine to a primary sample of 22 subjects and to an additional, partially overlapping, sample of 12 subjects. Symptoms before and after the experimental session were rated with the Positive and Negative Syndrome Scale (PANSS). In the primary sample, functional connectivity was measured via functional magnetic resonance imaging almost immediately after infusion began. In the additional sample, this assessment was repeated after 45 min of continuous ketamine infusion. Global, enhanced functional connectivity was observed at both timepoints, and this hyperconnectivity was related to symptoms in a region-specific manner. This study supports the hypothesis that pathological increases in resting brain functional connectivity contribute to the emergence of positive and negative symptoms associated with schizophrenia.

Fig. 1

Ketamine increases GBC in the brain. A) Distribution of GBC change scores for all voxels in the group connectivity map (ketamine-saline) immediately after the bolus (primary sample). Green line indicates 0, the predicted mean under the null hypothesis. B) Mean group connectivity map under saline immediately after bolus. C) Mean group connectivity map under ketamine immediately after bolus D) Distribution of GBC change scores for all voxels in the group connectivity map (ketamine-saline) after 45 minutes of continuous ketamine infusion (additional sample). Green line indicates 0, the predicted mean under the null hypothesis.

Fig 2

PANSS factor scores during saline (blue) and ketamine (red). * = <0.05, * * = <0.001.

Fig. 3

Areas in which increased global connectivity during ketamine was associated with greater increases in positive symptoms. A) Cluster map, axial slice. Each cluster is shown in a different color. Relationship between change in positive symptoms and GBC change in B) paracentral lobule and C) left precentral gyrus.

Fig. 4

Areas in which increased global connectivity during ketamine was associated with greater increases in negative symptoms, all voxels are in a single cluster with volume of 440 voxels, 3520 mm3, center-of-mass −18, 4, 1. A) saggital view, B) coronal view at the level of the anterior commissure, anterior-posterior (A-P) = 8. Nucleus accumbens shown in green [Harvard-Oxford Subcortical Atlas supplied in FSL], C) coronal view caudal to the anterior commissure, A-P = −12. Ventral lateral nucleus shown in cross-hairs [Talairach Daemon Labels supplied in FSL].