Subanaesthetic Ketamine Treatment Alters Prefrontal Cortex Connectivity With Thalamus and Ascending Subcortical Systems

Dawson, Neil; Morris, Brian J.; Pratt, Judith A.

doi:10.1093/schbul/sbr144

Cited by 81 publications

(100 citation statements)

References 41 publications

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“…This findings are in line with rodent data showing that ketamine (NMDA receptor antagonist) alters functional connectivity between several mPFC regions and thalamic nuclei and hippocampus (Dawson et al, 2015; Dawson, Morris, & Pratt, 2013). …”

Section: Discussionsupporting

confidence: 89%

The increase in medial prefrontal glutamate/glutamine concentration during memory encoding is associated with better memory performance and stronger functional connectivity in the human medial prefrontal–thalamus–hippocampus network

Thielen

Hong

Rankouhi

et al. 2018

Human Brain Mapping

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The classical model of the declarative memory system describes the hippocampus and its interactions with representational brain areas in posterior neocortex as being essential for the formation of long‐term episodic memories. However, new evidence suggests an extension of this classical model by assigning the medial prefrontal cortex (mPFC) a specific, yet not fully defined role in episodic memory. In this study, we utilized 1H magnetic resonance spectroscopy (MRS) and psychophysiological interaction (PPI) analysis to lend further support for the idea of a mnemonic role of the mPFC in humans. By using MRS, we measured mPFC γ‐aminobutyric acid (GABA) and glutamate/glutamine (GLx) concentrations before and after volunteers memorized face–name association. We demonstrate that mPFC GLx but not GABA levels increased during the memory task, which appeared to be related to memory performance. Regarding functional connectivity, we used the subsequent memory paradigm and found that the GLx increase was associated with stronger mPFC connectivity to thalamus and hippocampus for associations subsequently recognized with high confidence as opposed to subsequently recognized with low confidence/forgotten. Taken together, we provide new evidence for an mPFC involvement in episodic memory by showing a memory‐related increase in mPFC excitatory neurotransmitter levels that was associated with better memory and stronger memory‐related functional connectivity in a medial prefrontal–thalamus–hippocampus network.

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Section: Discussionsupporting

confidence: 89%

The increase in medial prefrontal glutamate/glutamine concentration during memory encoding is associated with better memory performance and stronger functional connectivity in the human medial prefrontal–thalamus–hippocampus network

Thielen

Hong

Rankouhi

et al. 2018

Human Brain Mapping

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“…Acute ketamine treatment produced both significant increases and decreases in cerebral metabolism on a region-dependent basis, consistent with previous reports (Dawson et al, 2013;Duncan et al, 1999). Significant overt alterations in cerebral metabolism were identified in 32 of the 66 regions analyzed (Supplementary Table S1A-D); select regions shown in Figure 1).…”

Section: Ketamine-induced Alterations In Overt Cerebral Metabolismsupporting

confidence: 89%

“…For example, in rodents the subanesthetic dose of ketamine used in this study (30 mg/kg) has been shown to induce deficits in the startle response (as measured by pre-pulse inhibition), hyperlocomotion and deficits in working memory that have translational relevance to schizophrenia (Galci et al, 2008;Irifune et al, 1991;Kos et al, 2006;Miyamoto et al, 2000;Verma and Moghaddam, 1996;Yang et al, 2010). In addition many studies, in both humans (Langsjo et al, 2004;Vollenweider et al, 1997aVollenweider et al, , 1997b and animals (Chih-Liang et al, 2011;Dawson et al, 2013), have been dedicated to elucidate the impact of acute, subanesthetic ketamine treatment on regional brain functioning, with PFC hypermetabolism (hyperfrontality) most consistently reported. The paradox of this ketamine-induced hyperfrontality given the hypofrontality characteristic of long-term schizophrenia (Hill et al, 2004) has not been resolved.…”

Section: Introductionmentioning

confidence: 79%

“…), n ¼ 9) or physiological saline (1.25 ml/kg, i.p., n ¼ 9) in accordance with previously published protocols (Dawson et al, , 2013. Mice were injected with 4.625 MBq/kg of [ 14 C]-2-DG (Perkin-Elmer, UK) at a steady rate over a 10-s period before being returned to their home cage.…”

Section: Semiquantitative 14 C-2-dg Autoradiographic Imagingmentioning

confidence: 99%

“…Surprisingly, despite the widespread use of ketamine treatment as a translational model there is a relative paucity of data on how acute ketamine treatment impacts on the functional interactions between brain regions and the neural subsystems known to be dysfunctional in schizophrenia. Indeed, only recently have efforts begun to elucidate how acute, subanesthetic doses of ketamine impact on functional connectivity between select brain regions (Niesters et al, 2012;Dawson et al, 2013). Furthermore, to our knowledge, no study has considered the impact of subanesthetic ketamine treatment on functional brain network structure or on functional interactions between neural subsytems within the context of complex brain networks.…”

Section: Introductionmentioning

confidence: 99%

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

Dawson

McDonald

Higham

et al. 2014

Neuropsychopharmacol

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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.

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Aquaporin‐4 knockout mice exhibit increased hypnotic susceptibility to ketamine

Dai

et al. 2018

Brain and Behavior

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PurposeThis study examines anesthetic/hypnotic effects of ketamine in AQP4 knockout (KO) and wild‐type (WT) mice with the particular focus on neurotransmission.Materials and MethodsKetamine (100 mg/kg) was intraperitoneally injected in 16 WT and 16 KO mice. The hypnotic potencies were evaluated by the loss of the righting reflex (LORR). The amino acids neurotransmitter levels in prefrontal cortex were measured by microdialysis.ResultsThis study demonstrated that AQP4 knockout significantly shortened the latency compared with WT mice (98.0 ± 4.2 vs. 138.1 ± 15.0 s, p < .05) and prolonged duration of LORR (884.7 ± 58.6 vs. 562.0 ± 51.7 s, p < .05) compared with WT mice in LORR induced by ketamine. Microdialysis showed that lack of AQP4 markedly decreased glutamate level within 20 min (p < .05) and increased γ‐aminobutyric acid (GABA) level within 30–40 min (p < .05) after use of ketamine. Moreover, the levels of taurine were remarkably higher in KO mice than in WT mice, but no obvious differences in aspartate were observed between two genotypes.Conclusion AQP4 deficiency led to more susceptibility of mice to ketamine, which is probably due to the modulation of specific neurotransmitters, hinting an essential maintenance of synaptic activity mediated by AQP4 in the action of ketamine.

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Subanaesthetic Ketamine Treatment Alters Prefrontal Cortex Connectivity With Thalamus and Ascending Subcortical Systems

Cited by 81 publications

References 41 publications

The increase in medial prefrontal glutamate/glutamine concentration during memory encoding is associated with better memory performance and stronger functional connectivity in the human medial prefrontal–thalamus–hippocampus network

The increase in medial prefrontal glutamate/glutamine concentration during memory encoding is associated with better memory performance and stronger functional connectivity in the human medial prefrontal–thalamus–hippocampus network

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

Aquaporin‐4 knockout mice exhibit increased hypnotic susceptibility to ketamine

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