Ketamine modulates hippocampal neurochemistry and functional connectivity: a combined magnetic resonance spectroscopy and resting-state fMRI study in healthy volunteers

Abstract

A growing body of evidence suggests glutamate excess in schizophrenia and that N-methyl-d-aspartate receptor (NMDAR) hypofunction on γ-aminobutyric acid (GABA) interneurons disinhibiting pyramidal cells may be relevant to this hyperglutamatergic state. To better understand how NMDAR hypofunction affects the brain, we used Magnetic Resonance Spectroscopy and resting state functional MRI to study the effects of ketamine on hippocampal neurometabolite levels and functional connectivity in 15 healthy human subjects. We observed a ketamine induced increase of hippocampal Glx (glutamate+glutamine; F= 3.76; p= 0.04), a decrease in fronto-temporal (t=4.92, pFDR< .05, kE= 2198, x= -30, y= 52, z= 14) and temporo-parietal functional connectivity (t=5.07, pFDR< .05, kE= 6094, x= -28, y= -36, z= -2), and a possible link between connectivity changes and elevated Glx. Our data empirically support that hippocampal glutamatergic elevation and resting state network alterations may arise from NMDAR hypofunction and establish a proof of principle whereby experimental modelling of a disorder can help mechanistically integrate distinct neuroimaging abnormalities in schizophrenia.

Decreased Directed Functional Connectivity in the Psychedelic State

“…A number of fMRI studies have examined modifications of connectivity at sub-anesthetic doses of ketamine. However, a confusing pattern emerges in these papers, with some showing increases in connectivity (Driesen et al, 2013;Anticevic et al, 2015;Dandash et al, 2015), whereas others show decreases (Kraguljac et al, 2017;Wong et al, 2016). This pattern may be related to the many different analytical techniques to both preprocess and quantify FC in the BOLD data.…”

Glutamatergic regulation of cognition and functional brain connectivity: insights from pharmacological, genetic and translational schizophrenia research

“…Subchronic PCP treatment also results in decreased thalamic, hippocampal and PFC connectivity and induces a decrease in the functional integration between the hippocampus and PFC (Dawson et al, ), which could contribute to the cognitive deficits seen as a result of prolonged NMDA receptor hypofunction. Decreased hippocampal‐PFC resting‐state FC is also seen in patients with SZ (Kraguljac et al, ) and genetic rodent models relevant to the disorder (Dawson et al, ; Sigurdsson et al, ). Again, a central role for altered neuromodulatory system connectivity is indicated as a result of prolonged NMDA receptor hypofunction, with decreased PFC – LC connectivity supported (Dawson et al, ).…”

Neural and neuronal discoordination in schizophrenia: From ensembles through networks to symptoms

“…Notably, Grimm observed increased FC of the dlPFC bilaterally to only the left HPC, a finding consistent with hypermetabolism of the left CA1 hippocampal region present in clinical high risk individuals that precedes hippocampal atrophy . However, Kraguljac and colleagues reported a decrease in HPC FC with the frontal cluster. Thus, HPC‐prefrontal FC seems to be altered by acute ketamine infusion in humans, but the direction of change is unclear and more studies using comparable experimental settings and methods of analysis are needed to elucidate under which conditions ketamine increases or decreases hippocampal FC.…”