Acute conceptual disorganization in untreated first-episode psychosis: a combined magnetic resonance spectroscopy and diffusion imaging study of the cingulum

Abstract

Background: Disorganized thinking is a core feature of acute psychotic episodes that is linked to social and vocational functioning. Several lines of evidence implicate disrupted cognitive control, excitatory overdrive and oxidative stress relating to the anterior cingulate cortex as mechanisms of conceptual disorganization (CD). We examined 3 candidate mechanistic markers related to CD in firstepisode psychosis: glutamate excess, cortical antioxidant (glutathione) status and the integrity of the cingulum bundle that connects regions implicated in cognitive control. Methods: We used fractional anisotropy maps from 7 T diffusion-weighted imaging to investigate the bilateral cingulum based on a probabilistic white matter atlas. We compared high CD, low CD and healthy control groups and performed probabilistic fibre tracking from the identified clusters (regions of interest within the cingulum) to the rest of the brain. We quantified glutamate and glutathione using magnetic resonance spectroscopy (MRS) in the dorsal anterior cingulate cortex. Results: We found a significant fractional anisotropy reduction in a cluster in the left cingulum in the high CD group compared to the low CD group (Cohen’s d = 1.39; p < 0.001) and controls (Cohen’s d = 0.86; p = 0.009). Glutamate levels did not vary among groups, but glutathione levels were higher in the high CD group than in the low CD group. We also found higher glutathione related to lower fractional anisotropy in the cingulum cluster in the high CD group. Limitations: The MRS measures of glutamine were highly uncertain, and MRS was acquired from a single voxel only. Conclusion: Acute CD relates to indicators of oxidative stress, as well as reduced white matter integrity of the cingulum, but not to MRI-based glutamatergic excess. We propose that both oxidative imbalance and structural dysconnectivity underlie acute disorganization.

Glutathione as a Molecular Marker of Functional Impairment in Patients with At-Risk Mental State: 7-Tesla 1H-MRS Study

“…In line with our prior work demonstrating the potentially counteracting effect of GSH on glutamatergic excitotoxicity in early stages of psychosis [ 54 , 55 ], we only examined the dACC in this study. GSH levels in the dACC also relate to core symptoms of psychosis such as disorganization [ 56 ], which strongly predict poor outcomes when present in CHR [ 57 ]. Nevertheless, antioxidant aberrations related to psychosis are unlikely to be limited only to the dACC, as striatal and thalamic reductions of GSH were also demonstrated in prior MRS studies [ 24 , 58 ].…”

Salience network glutamate and brain connectivity in medication-naïve first episode patients – A multimodal magnetic resonance spectroscopy and resting state functional connectivity MRI study

“…An increasing number of magnetic resonance spectroscopy (MRS) studies in schizophrenia, including studies investigating the dACC, suggest altered glutamate metabolism in vivo. Because of the considerable heterogeneity of these studies definite conclusions are difficult to draw ( Egerton et al, 2017 , Merritt et al, 2016 ), but it seems clear that stage of illness ( Stone et al, 2009 ), functional status of the recruited sample ( Dempster et al, 2020 ), acuity of illness ( Pan et al, 2021 ), magnet strength (3 T vs. 7 T) ( Sydnor and Roalf, 2020 ), and medication status ( de la Fuente-Sandoval et al, 2013 , Kraguljac et al, 2019 , Kraguljac et al, 2012 ) are affecting MRS measurements.…”

Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?

“…This small but significant GSH reduction in schizophrenia has been reported by 2 other meta-analyses, one restricted to ultra-high field 7T MRS studies (effect size = 0.21) [66] and the other including all central measures of GSH MRS, CSF and post-mortem samples (effect size = 0.26) [67]. Since 2018, several MRS studies on ACC GSH in schizophrenia have been published [68][69][70][71][72][73][74] (Table 1). While the largest study to date supports Das and colleagues' report of GSH reduction in early stages of schizophrenia, smaller studies find no differences in patients when compared to healthy controls.…”

“…Intracortical myelin mostly insulates parvalbumin containing interneurons [116] that are highly susceptible to GSH deficit and associated glutamate-mediated excitotoxicity [117,118]. In a subsample of patients reported by Pan and colleagues [73], we obtained quantitative intracortical myelin measurement and noted several regions where patients had lower intracortical myelin in the presence of higher glutamate, only when GSH levels were lower than the median (bilateral dorsolateral prefrontal cortex, right superior temporal and left precentral gyrus and right subgenual ACC). Thus, higher ACC glutamate related to lower prefrontal intracortical myelin, only when ACC GSH levels were also lower, indicating a gatekeeping role for GSH in glutamate-related dysmyelination (Figure 1).…”

“…ACC GSH levels were not examined in their sample. We observed that in untreated first episode patients, an elevated ACC GSH at the time of presentation occurred in those with more florid disorganization [73] but most of these subjects responded briskly to the regular antipsychotic treatments over the next 6 months [69]. Help seeking subjects with subthreshold psychotic symptoms display better social and occupational functioning when ACC GSH levels are higher [77].…”