Hippocampal Dysconnectivity and Altered Glutamatergic Modulation of the Default Mode Network: A Combined Resting-State Connectivity and Magnetic Resonance Spectroscopy Study in Schizophrenia

Abstract

Background: Converging lines of evidence point to hippocampal dysfunction in schizophrenia. It is thought that hippocampal dysfunction spreads across hippocampal subfields and to cortical regions by way of long-range efferent projections. Importantly, abnormalities in the excitation/inhibition balance could impair the long-range modulation of neural networks. The goal of this project was twofold. First, we sought to identify replicable patterns of hippocampal dysconnectivity in patients with a psychosis spectrum disorder. Second, we aimed to investigate a putative link between glutamatergic metabolism and hippocampal connectivity alterations.

Methods: We evaluated resting-state hippocampal functional connectivity alterations in two cohorts of patients with a psychosis spectrum disorder. The first cohort consisted of 55 medication-naïve patients with first-episode psychosis and 41 matched healthy control subjects, and the second cohort consisted of 42 unmedicated patients with schizophrenia and 41 matched control subjects. We also acquired measurements of glutamate + glutamine in the left hippocampus using magnetic resonance spectroscopy for 42 patients with first-episode psychosis and 37 healthy control subjects from our first cohort.

Results: We observed a pattern of hippocampal functional hypoconnectivity to regions of the default mode network and hyperconnectivity to the lateral occipital cortex in both cohorts. We also show that in healthy control subjects, greater hippocampal glutamate + glutamine levels predicted greater hippocampal functional connectivity to the anterior default mode network. Furthermore, this relationship was reversed in medication-naïve subjects with first-episode psychosis.

Conclusions: These results suggest that an alteration in the relationship between glutamate and functional connectivity may disrupt the dynamic of major neural networks.

Keywords: Default mode network; First episode; Glutamate; Hippocampus; Magnetic resonance spectroscopy; Psychosis; Resting-state functional connectivity.

Figure 1.. Hippocampal Functional Connectivity:

In healthy controls (HC), hippocampal functional connectivity (FC) from datasets 1 and 2 showed consistent patterns of positive hippocampal functional connectivity to regions of the default mode network, including the posterior cingulate cortex (PCC)/precuneus, medial prefrontal cortex (mPFC), parahippocampus, superior temporal gyrus and temporal pole. Negative FC patterns were seen in the dorsolateral PFC and supramarginal gyrus. Group differences in FC between medication-naïve first episode psychosis patients and HC (dataset 1) were seen in the PCC/precuneus, mPFC, parahippocampus, visual cortex, lateral PFC, and middle temporal cortex. Group differences between the unmedicated patients with schizophrenia and HC (dataset 2) were seen in more restricted, but overlapping regions. All analyses were corrected using voxel (p < 0.05, uncorrected) and cluster level correction (p < 0.05, FDR corrected). Age, sex, and mean framewise displacement were included as covariates of no interest.

Figure 2:. Hippocampus Spectroscopy.

(A) Example of magnetic resonance spectroscopy (MRS) voxel placement in the left hippocampus (2.7×1.5×1cm). The image is displayed in radiological convention (right side of image is subject’s left side). (B) Example spectrum. The black line is a spectrum obtained from the left hippocampus voxel, the red line is an overlay of spectral fit. Arrows indicate peaks for glutamate + glutamine (Glx) and N-acetylaspartate (NAA). Spectra are measured in parts per million (ppm). (C) Scatterplot of individual glutamate+glutamine (Glx) measures for first episode psychosis patients (FEP) and healthy controls (HC). Dots represent individual measurements, the line represents the group mean.

Figure 3.. Hippocampal Functional Connectivity and Hippocampal Glx:

In healthy controls (HC), hippocampal functional connectivity (FC) was positively correlated with glutamate + glutamine (Glx) in precuneus/posterior cingulate cortex and ventromedial prefrontal cortex. The same pattern was seen in medication-naïve first episode psychosis patients. All analyses were corrected using voxel (p < 0.05, uncorrected) and cluster level correction (p < 0.05, FDR corrected). Age, sex, and mean framewise displacement were included as covariates of no interest.

Figure 4.. Interaction Between Groups of Functional Hippocampal Connectivity and Hippocampal Glx:

An interaction between groups, hippocampal functional connectivity (FC), and hippocampal glutamate + glutamine (Glx) was seen in the orbitofrontal and entorhinal cortex. Z-scored FC beta weight values from the interaction region of interest ROI were extracted and plotted against hippocampal Glx levels. Healthy controls showed a positive correlation between hippocampal FC and Glx. Medication naïve first episode psychosis patients showed an opposite, negative correlation between FC and Glx.