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 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 twenty-two subjects and to an additional, partially overlapping, sample of twelve subjects. Symptoms before and after the experimental session were rated with the Positive and Negative Symptom 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 minutes 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.

Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks

“…Full data are shown in Supplementary Table S2A-D. of information received by the PFC, by the promotion of an abnormally increased functional connectivity of this neural subsystem. This suggested mechanism is not only consistent with recent human brain imaging data showing that subanesthetic ketamine treatment increases global brain functional connectivity (Driesen et al, 2013), but is also consistent with emerging electophysiological data supporting a reduced signal-to-noise after ketamine treatment in the hippocampal CA3 subfield (Saunders et al, 2011) and of gamma oscillations in the somatosensory thalamocortical system (Kulikova et al, 2012) of rodents. Our data suggest that similar mechanisms may occur in the PFC, where ketamine is known to directly increase the amplitude of gamma oscillations through the blockade of local NMDA receptors (McNally et al, 2011) and where the NMDA receptor antagonist MK-801 has been shown to disrupt the firing pattern of PFC neurons (Jackson et al, 2004).…”

“…networks of mice treated with ketamine in our study parallels the increased functional connectivity found in the brain of healthy humans treated with subanesthetic ketamine (Driesen et al, 2013). These data suggest that, at a systems level, the mechanisms through which acute ketamine treatment induces schizophrenia-like symptoms may be profoundly divergent from those that contribute to these symptoms in the disorder.…”

Alterations in High-Frequency Neuronal Oscillations in a Cynomolgus Macaque Test of Sustained Attention Following NMDA Receptor Antagonism

“…Potentially, this dysregulation may lead to a decoupling of local gamma oscillators from the controlling influence of extended networks that are fundamental for processing information during cognition. This global, hyperconnectivity following acute NMDA receptor antagonist treatment has been reported previously in healthy humans (Driesen et al, 2013) and rodents (Kocsis et al, 2013), and supports the hypothesis that pathological increases in resting brain functional connectivity contribute to the emergence of symptoms associated with schizophrenia. Further investigation is warranted for our studies, perhaps including sub-chronic treatment of NMDA receptor antagonists to allow cortical changes and neurophysiological deficits correlated with CIAS to emerge and more closely mimic observations in schizophrenic patients.…”

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

“…NVHLs result in restructuring and electrophysiological changes within the PFC (Ryan et al 2013), and hyper-correlated expression of schizophrenia-linked genes in the PFC and NAC (Swerdlow et al 2013a, b). Others have reported aberrant limbic-cortical connectivity associated with both endogenous ) and drug-induced psychosis (Driesen et al 2013) in humans; similarly, excessive fronto-striatal metabolic correlation ["Brain Lock" (Schwartz 1997)] has been demonstrated in other disorders associated with the reduced PPI, such as OCD. Importantly, in OCD, therapeutic response to medication or psychotherapy is associated with a metabolic "uncoupling" of fronto-striatal regions (Schwartz et al 1996;Schwartz 1998).…”