Abstract
Several lines of evidence implicate the fornix–hippocampus circuit in schizophrenia. In early-phase psychosis, this circuit has not been extensively investigated and the underlying mechanisms affecting the circuit are unknown. The hippocampus and fornix are vulnerable to oxidative stress at peripuberty in a glutathione (GSH)-deficient animal model. The purposes of the current study were to assess the integrity of the fornix–hippocampus circuit in early-psychosis patients (EP), and to study its relationship with peripheral redox markers. Diffusion spectrum imaging and T1-weighted magnetic resonance imaging (MRI) were used to assess the fornix and hippocampus in 42 EP patients compared with 42 gender- and age-matched healthy controls. Generalized fractional anisotropy (gFA) and volumetric properties were used to measure fornix and hippocampal integrity, respectively. Correlation analysis was used to quantify the relationship of gFA in the fornix and hippocampal volume, with blood GSH levels and glutathione peroxidase (GPx) activity. Patients compared with controls exhibited lower gFA in the fornix as well as smaller volume in the hippocampus. In EP, but not in controls, smaller hippocampal volume was associated with high GPx activity. Disruption of the fornix–hippocampus circuit is already present in the early stages of psychosis. Higher blood GPx activity is associated with smaller hippocampal volume, which may support a role of oxidative stress in disease mechanisms.
Highlights
There were no statistical differences in age, gender, handedness or parental education between the early-psychosis patients (EP) and healthy control groups (Table 1), indicating that patients and controls were well matched for these criteria
There was no significant difference in body mass index (BMI) between patients and controls
There were no significant correlations between CPZ equivalents, number of daily cigarettes, cannabis use and fornix Generalized fractional anisotropy (gFA) or absolute hippocampal volume
Summary
Studies investigating the hippocampus in schizophrenia highlighted volume loss,[6,7,8,9] altered diffusion properties[10,11,12] and hypermetabolism[13,14] at the neuroimaging level and decrease in parvalbumin-immunoreactive γ-aminobutyric acid interneurons at the microscopic level.[14,15,16]. Given its direct anatomical link with the hippocampus, diffusion magnetic resonance imaging (MRI) studies focused on the fornix, a fine compact, arch-shaped white matter bundle connecting the hippocampus to the hypothalamus, and various other cortical and subcortical structures including mammillary bodies.[17] These studies consistently showed a decreased fractional anisotropy (FA) in the fornix in chronic schizophrenia.[4,18,19,20,21,22] Hippocampal volume (HV) correlates with the mean diffusivity in the fornix in patients only, indicating important structural relationship between these structures in disease.[22]. Neuropathological characterization of the fornix in schizophrenia showed no differences in fiber number but higher fiber density in the fornix in male schizophrenia patients compared with controls.[28]
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