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Introduction: Based on previous research on electroconvulsive therapy (ECT) we have proposed a model where disruption, potentiation, and rewiring of brain networks occur in sequence and serve as the underlying therapeutic mechanism of ECT. This model implies that a temporary disturbance of neuronal networks (disruption) is followed by a trophic effect (potentiation), which enables the rewiring of neuronal circuits to a more euthymic functioning brain. We hypothesized that disruption of neuronal networks could trigger biochemical alterations leading to a temporary decrease in N-acetylaspartate (tNAA, considered a marker of neuronal integrity), while choline (a membrane component), myo-Inositol (mI, astroglia marker), and glutamate/glutamine (Glx, excitatory neurotransmitter) were postulated to increase. Previous magnetic resonance spectroscopy studies, reporting diverse findings, have used two different referencing methods - creatine ratios and tissue corrected values referenced to water - for the quantification of brain metabolites. Changes in creatine during ECT have also been reported, which may confound estimates adopting this as an internal reference., Methods: Using MR spectroscopy, we investigated 31 moderately to severely depressed patients and 19 healthy controls before, during, and after ECT or at similar time points (for controls). We tested whether biochemical alterations in tNAA, choline, mI, and Glx lend support to the disrupt, potentiate, and rewire hypothesis. We used both creatine ratios and water-scaled values for the quantification of brain metabolites to validate the results across referencing methods., Results: Levels of tNAA in the anterior cingulate cortex decreased after an ECT treatment series (average 10.6 sessions) by 6% ( p  = 0.007, creatine ratio) and 3% ( p  = 0.02, water referenced) but returned to baseline 6 months after ECT. Compared to after treatment series tNAA levels at 6-month follow-up had increased in both creatine ratio (+6%, p  < 0.001) and water referenced data (+7%, p  < 0.001). Findings for other brain metabolites varied and could not be validated across referencing methods., Discussion: Our findings suggest that prior research must be interpreted with care, as several referencing and processing methods have been used in the past. Yet, the results for tNAA were robust across quantification methods and concur with relevant parts of the disrupt, potentiate, and rewire model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Erchinger, Craven, Ersland, Oedegaard, Bartz-Johannessen, Hammar, Haavik, Riemer, Kessler and Oltedal.)

Background: Auditory verbal hallucinations (AVH) have been linked to aberrant interhemispheric connectivity between the left and the right superior temporal gyrus (STG), labeled the interhemispheric miscommunication theory. The present study investigated if interhemispheric miscommunication is modulated at the neurochemical level by glutamate (Glu) and gamma-aminobutyric acid (GABA) concentrations in temporal and prefrontal lobe areas, as proposed by the theory. Methods: We combined resting-state fMRI connectivity with MR spectroscopy (MRS) in a sample of 81 psychosis patients, comparing patients with high hallucination severity (high-AVH) and low hallucination severity (low-AVH) groups. Glu and GABA concentrations were acquired from the left STG and the anterior cingulate cortex (ACC), an area of cognitive control that has been proposed to modulate STG functioning in AVH. Results: Functional connectivity showed significant interaction effects between AVH Group and ACC-recorded Glu and GABA metabolites. Follow-up tests showed that there was a significant positive association for Glu concentration and interhemispheric STG connectivity in the high-AVH group, while there was a significant negative association for GABA concentration and interhemispheric STG connectivity in the low-AVH group. Conclusion: The results show neurochemical modulation of STG interhemispheric connectivity, as predicted by the interhemispheric miscommunication hypothesis. Furthermore, the findings are in line with an excitatory/inhibitory imbalance model for AVH. By combining different neuroimaging modalities, the current results provide a more comprehensive insight into the neural correlates of AVH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Weber, Hjelmervik, Craven, Johnsen, Kroken, Løberg, Ersland, Kompus and Hugdahl.)