Modulatory Effects of mPFC-Derived Metabolites on P300 Responses in Schizophrenia

2378 

Abstract Submission 

Berkhan Karsli¹, Genc Hasanaj², Marcel Kallweit³, Verena Meisinger¹, Gizem Vural⁴, Lukas Röll³, Julian Melcher⁵, Boris Papazov⁶, Joanna Moussiopoulou⁷, Vladislav Yakimov³, Elias Wagner³, Florian Raabe⁸, Daniel Keeser⁹

¹Ludwig Maximilian University, Munich, Germany, ²Ludwig Maximillian University, Munich, Germany, ³LMU University Hospital, Munich, Germany, ⁴LMU Klinikum, Munich, Other, ⁵LMU Klinikum, Munich, Bavaria, ⁶LMU Munich, München, Bayern, ⁷LMU Klinikum, München, Germany, ⁸Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University, Munich, Germany, ⁹Department of Psychiatry and Psychotherapy, University Hospital LMU, Munich, Germany

Berkhan Karsli  
Ludwig Maximilian University
Munich, Germany

Genc Hasanaj  
Ludwig Maximillian University
Munich, Germany

Marcel Kallweit  
LMU University Hospital
Munich, Germany

Verena Meisinger  
Ludwig Maximilian University
Munich, Germany

Gizem Vural  
LMU Klinikum
Munich, Other

Lukas Röll  
LMU University Hospital
Munich, Germany

Julian Melcher  
LMU Klinikum
Munich, Bavaria

Boris Papazov  
LMU Munich
München, Bayern

Joanna Moussiopoulou  
LMU Klinikum
München, Germany

Vladislav Yakimov  
LMU University Hospital
Munich, Germany

Elias Wagner  
LMU University Hospital
Munich, Germany

Florian Raabe  
Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University
Munich, Germany

Daniel Keeser  
Department of Psychiatry and Psychotherapy, University Hospital LMU
Munich, Germany

Frontal brain regions including the Anterior Cingulate Cortex play a crucial role in auditory deviance and cognitive control processing and metabolite levels in frontal regions vary and significantly modulate brain responses in schizophrenia spectrum disorder (SSD) (Duncan et al., 2014). Specifically, higher levels of glutamate and gamma-aminobutyric acid (GABA) are associated with an increased amplitude of the Mismatch Negativity (Rowland et al., 2016; Bartolomeo et al., 2012). Less known are the modulatory effects of these metabolites on the more complex P300 component, an event-related potential peaking around 300 ms post-stimulus in response to infrequently presented stimuli among frequently presented stimuli, a psychosis biomarker characterized by decreased amplitude and increased latency (Wang et al., 2022). In this study, we investigated the potential modulatory role of mPFC-derived Glutamate+Glutamine (Glx) and GABA on brain responses during the P300 task.

A total of 58 patients with SSD and 61 healthy controls (HC) participated in this study at the University Hospital LMU. They underwent multimodal MRI with a 3T MRI scanner, focusing on Single Voxel Spectroscopy at the mPFC (voxel size 20x20x20 mm³) and task-based EEG measurement during the P300 task, in which they have to respond to the infrequent tone. The MRS data were processed using Osprey and LC-Model, and after excluding data based on Cramer-Rao lower bounds (>50% SD) and outliers (2.5 SD beyond the median), the analysis proceeded with data from 41 SSDs and 51 HCs. EEG data were preprocessed using an ICA preprocessing pipeline by Adams et al. (2022). Amplitude and latency of P300 were extracted for both frequent and infrequent tones within the 250-400 ms time window using MNE Python. Using multiple linear regression including patient group as a covariate, and Pearson correlation, metabolites were associated with P300 amplitude and latency at midline electrodes (Fz, Pz, Cz).

Pz Amplitude was reduced for SSD for both infrequent (t = -2.74, p = 0.008) and frequent (t = -2.32, p = 0.023) tones. However, we did not find any other differences between two groups. The regression analysis revealed significant effects of the Group and Group x GABA on the amplitudes at midline electrodes. For the Fz amplitude, the Group x GABA was significant (β = 2.74, t = 2.73, p = 0.008). In the case of Pz amplitude, both the effect of Group (β = -4.96, t = -2.82, p = 0.006) and the Group x GABA (β = 1.87, t = 1.99, p = 0.049) were significant. Similarly, for the Cz amplitude, significant effects were observed for the effect of Group (β = -4.91, t = -2.28, p = 0.025) and the Group x GABA (β = 2.77, t = 2.42, p = 0.018). Reflecting these results, for SSD, GABA correlated with amplitudes of Fz (r = 0.38, p = 0.014), Cz (r = 0.34, p = 0.031), and Pz (r = 0.37, p = 0.018) for the frequent tone only, while for the HC group, there were no significant correlations.

The group comparison results showed reduced P300 amplitude over the Pz electrode in SSD patients for both infrequent and frequent tones, aligning with previous research that identified differences across temporoparietal regions (Wang et al., 2022). Significant interaction effects were observed between GABA levels and SSD on the amplitudes at midline electrodes (Fz, Cz, and Pz) for frequent tones. GABA concentration also showed a positive correlation with all three midline electrodes, suggesting a specific link between GABA concentration and reduced Pz amplitudes for SSD during auditory processing (Bartolomeo et al., 2012). These findings offer valuable insights into the neural mechanisms of auditory processing deficits in SSD and highlight the potential role of GABA in modulating P300 responses to frequent auditory stimuli in this group. Further research is needed to clarify how GABA influences neural responses to auditory stimuli in SSD and to investigate possible ways for developing targeted interventions for individuals with SSD.

Psychiatric (eg. Depression, Anxiety, Schizophrenia)

Executive Function, Cognitive Control and Decision Making

EEG/MEG Modeling and Analysis

EEG ¹

MR Spectroscopy ²

Cognition

Electroencephaolography (EEG)

GABA

Glutamate

Magnetic Resonance Spectroscopy (MRS)

Schizophrenia

Other - P300