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

Abstract

Acute treatment with subanesthetic ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, is widely utilized as a translational model for schizophrenia. However, how acute NMDA receptor blockade impacts on brain functioning at a systems level, to elicit translationally relevant symptomatology and behavioral deficits, has not yet been determined. Here, for the first time, we apply established and recently validated topological measures from network science to brain imaging data gained from ketamine-treated mice to elucidate how acute NMDA receptor blockade impacts on the properties of functional brain networks. We show that the effects of acute ketamine treatment on the global properties of these networks are divergent from those widely reported in schizophrenia. Where acute NMDA receptor blockade promotes hyperconnectivity in functional brain networks, pronounced dysconnectivity is found in schizophrenia. We also show that acute ketamine treatment increases the connectivity and importance of prefrontal and thalamic brain regions in brain networks, a finding also divergent to alterations seen in schizophrenia. In addition, we characterize how ketamine impacts on bipartite functional interactions between neural subsystems. A key feature includes the enhancement of prefrontal cortex (PFC)-neuromodulatory subsystem connectivity in ketamine-treated animals, a finding consistent with the known effects of ketamine on PFC neurotransmitter levels. Overall, our data suggest that, at a systems level, acute ketamine-induced alterations in brain network connectivity do not parallel those seen in chronic schizophrenia. Hence, the mechanisms through which acute ketamine treatment induces translationally relevant symptomatology may differ from those in chronic schizophrenia. Future effort should therefore be dedicated to resolve the conflicting observations between this putative translational model and schizophrenia.

Losing Control Under Ketamine: Suppressed Cortico-Hippocampal Drive Following Acute Ketamine in Rats

“…Our analysis of these acute effects of ketamine may be a more appropriate analogy of the prodromal phase of schizophrenia (Honey et al, 2008) rather than later, at disease manifestation. This is consistent with recent imaging studies in rodents, which also suggest aspects of frontal hyperconnectivity following acute ketamine (Gass et al, 2014;Dawson et al, 2014).…”

Ketamine-Induced Changes in the Signal and Noise of Rule Representation in Working Memory by Lateral Prefrontal Neurons

“…The effect of ketamine on LPFC neurons may have its origins within the LPFC itself or may be a secondary effect of changes in the firing of neurons in afferent regions. In support of this latter possibility, acute ketamine administration has been reported to cause hyperconnectivity between the PFC and other cortical and thalamic regions (Dawson et al, 2013(Dawson et al, , 2014Anticevic et al, 2015b). Such hyperconnectivity was also observed in patients with early-stage schizophrenia (Anticevic et al, 2015a,b).…”

“…NMDA receptor function (D'Souza et al, 2012) may be necessary to restore both the strength and the consistency in working memory representation in the LPFC.…”

Acute ketamine challenge increases resting state prefrontal-hippocampal connectivity in both humans and rats

“…NMDA antagonists increase the levels of excitatory neurotransmitters, such as glutamate, acetylcholine, and histamine and disinhibit GABAergic interneurons (Olney and Farber 1995). In a recent study, mice treated with a high dose of ketamine (30 mg/kg) showed a global increase in graphtheory-based connectivity measures (degree and mean clustering coefficient), as well as an increase in thalamo-cortical and cortical-subcortical (PFC to dorsal raphe nuclei and locus coeruleus) connectivity (Dawson et al 2014). In this study, the authors did not provide specific data on PFC-HC coupling.…”