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Ketamine Reveals Schizophrenia-Like Shift in Brain Network

4 October 2012. Disrupting glutamate signaling blurs the contrast between the brain’s background “default” activity and its task-related engagement, according to a study published online 25 September in Proceedings of the National Academy of Sciences. Led by Phillip Corlett and John Krystal of Yale University in New Haven, Connecticut, the functional magnetic resonance imaging (fMRI) study investigated the effects of ketamine, an N-methyl-D-aspartate (NMDA) receptor blocker that transiently induces features similar to schizophrenia in healthy people. Ketamine induced changes in brain activation that were associated with resulting working memory deficits and negative symptom-like behavior.

The study suggests that the network properties of the brain, which reflect information flow between different regions, can shape cognition and, when disrupted, result in schizophrenia-like thought abnormalities and behavior. Though neuromodulators like dopamine and serotonin are typically associated with network-wide changes, the study argues that glutamate, a fast-acting, workaday neurotransmitter, can achieve something similar.

A picture of the brain’s network of connections has been emerging from the background hum of activity while a person is awake but at rest. This resting state activity highlights a “default-mode network” consisting of a set of interconnected brain regions that powers down once a person begins a task. This task-related deactivation seems critical for cognition (Daselaar et al., 2004), and appears impaired in schizophrenia, with default activity persisting during tasks (see SRF related news story). The new study focused on both the default-mode network and its complement, the task-positive network, which takes over when a person begins to do something. The push-pull between these two networks offers a more comprehensive view of the brain’s connectivity. Because ketamine transiently induces schizophrenia-like symptoms (Krystal et al., 1994)—a finding that originally suggested that underactive glutamate signaling underlies the disorder (see SRF Hypothesis)—it allowed the researchers a chance to investigate a discrete pharmacological perturbation to these networks that might approximate their state in schizophrenia.

Global seesaw
First author Alan Anticevic and colleagues scanned the brain activity of 19 healthy participants while they rested and while they performed a working memory task that required them to indicate the location of circles on a screen that had disappeared. Each person was scanned during a saline infusion and during a ketamine infusion. As expected, ketamine impaired working memory, resulting in a significant decrease in correct trials (-8 percent).

Brain activity-wise, the researchers found an “anti-correlated” relationship between the task-positive network and the default-mode network during saline infusion. During rest, the default-mode network predominated, but during the working memory task, it turned off as task-positive network activity emerged. Ketamine, however, attenuated this seesaw action: during the task, default activity dribbled on, and task-positive activity did not reach its usual heights. Consistent with this, measures of functional connectivity between these networks showed decreased connectivity during the task under saline, but not ketamine.

The researchers then turned to computational modeling to understand how ketamine might exert these effects. With a model consisting of a task-activated module and a task-deactivated module, they found that attenuating glutamate signals from excitatory neurons onto inhibitory ones led to disinhibition in the circuit that could recapitulate their fMRI findings. Further simulations suggested that this disinhibition rendered a module hyperactive, and so less able to heed the instructions to turn off from its complementary network. This suggests that the state of local circuitry can alter global networks.

Simulating schizophrenia?
To see whether the ketamine-induced shifts in network activity had consequences for behavior, the researchers related trial-by-trial performance with brain activity. This revealed a significant association with the default-mode network: during saline infusion, correct trials were associated with more suppression of default-mode network regions than incorrect ones, but under ketamine, less suppression occurred during correct trials. This is consistent with the hyperactivity found previously in the default-mode network in schizophrenia (see SRF related news story), and supports the idea that deactivation of this network is critical for working memory and other realms of cognition.

This degree of default-mode network deactivation also correlated with schizophrenia-like symptoms assessed immediately after scanning. Under ketamine, those with the more hyperactive default-mode network during a task also scored higher on negative symptoms severity (r = 0.61, P <0.006). The authors suggest that the default-mode hyperactivity under ketamine may indicate a brain tilted toward a passive, self-reflective state—so much so that it interferes with goal-directed behavior. Other measures of positive and dissociative symptoms did not reach statistical significance.

The study’s pharmacological before-and-after design allows it to sidestep the usual chicken versus egg conundrum that comes with any brain abnormality detected in schizophrenia. Whether ketamine offers a useful approximation of schizophrenia remains to be seen, but the findings support the idea that reduced glutamate signals on interneurons represent a core pathology in schizophrenia (Marín, 2012), and highlight the involvement of the default-mode network.—Michele Solis.

Anticevic A, Gancsos M, Murray JD, Repovs G, Driesen NR, Ennis DJ, Niciu MJ, Morgan PT, Surti TS, Bloch MH, Ramani R, Smith MA, Wang XJ, Krystal JH, Corlett PR. NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia. Proc Natl Acad Sci U S A. 2012 Sep 25. Abstract

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