The perception of a voice in the absence of an external auditory source-an auditory verbal hallucination-is a characteristic symptom of schizophrenia. To better understand this phenomenon requires integration of findings across behavioural, functional, and neurochemical levels. We address this with a locally adapted MEGA-PRESS sequence incorporating interleaved unsuppressed water acquisitions, allowing concurrent assessment of behaviour, blood-oxygenation-level-dependent (BOLD) functional changes, Glutamate + Glutamine (Glx), and GABA, synchronised with a cognitive (flanker) task. We acquired data from the anterior cingulate cortex (ACC) of 51 patients with psychosis (predominantly schizophrenia spectrum disorder) and hallucinations, matched to healthy controls. Consistent with the notion of an excitatory/inhibitory imbalance, we hypothesized differential effects for Glx and GABA between groups, and aberrant dynamics in response to task. Results showed impaired task performance, lower baseline Glx and positive association between Glx and BOLD in patients, contrasting a negative correlation in healthy controls. Task-related increases in Glx were observed in both groups, with no significant difference between groups. No significant effects were observed for GABA. These findings suggest that a putative excitatory/inhibitory imbalance affecting inhibitory control in the ACC is primarily observed as tonic, baseline glutamate differences, rather than GABAergic effects or aberrant dynamics in relation to a task.

Department of Biological and Medical Psychology University of Bergen Jonas Lies vei 91 5009 Bergen Norway

Department of Clinical Engineering Haukeland University Hospital Bergen Norway

Department of Clinical Medicine University of Bergen Bergen Norway

Department of Physics and Technology University of Bergen Bergen Norway

Department of Radiology Haukeland University Hospital Bergen Norway

Division of Psychiatry Haukeland University Hospital Bergen Norway

GE HealthCare Berlin Germany

Institute of Computer Science Czech Academy of Sciences Prague Czechia

Zobrazit více v PubMed

Hugdahl, K. & Sommer, I. E. Auditory verbal hallucinations in schizophrenia from a levels of explanation perspective. Schizophr Bull.44, 234–241 (2018). PubMed PMC

Hugdahl, K. Auditory hallucinations: A review of the ERC VOICE project. World J. Psychiatry. 5, 193 (2015). PubMed PMC

Jardri, R. et al. Are hallucinations due to an imbalance between excitatory and inhibitory influences on the brain?? Schizophr Bull.42, 1124–1134 (2016). PubMed PMC

Ćurčić-Blake, B. et al. Interaction of Language, auditory and memory brain networks in auditory verbal hallucinations. Prog. Neurobiol.148, 1–20 (2017). PubMed PMC

Craven, A. R. et al. Linewidth-related bias in modelled concentration estimates from GABA-edited 1 H-MRS. http://biorxiv.org/lookup/doi/ (2024). 10.1101/2024.02.27.582249 doi:10.1101/2024.02.27.582249.

Hennig, J., Emst, T., Speck, O., Deuschl, G. & Feifel, E. Detection of brain activation using oxygenation sensitive functional spectroscopy. Magn. Reson. Med.31, 85–90 (1994). PubMed

Zhu, X. H. & Chen, W. Observed BOLD effects on cerebral metabolite resonances in human visual cortex during visual stimulation: A functional1H MRS study at 4 T. Magn. Reson. Med.46, 841–847 (2001). PubMed

Apšvalka, D., Gadie, A., Clemence, M. & Mullins, P. G. Event-related dynamics of glutamate and BOLD effects measured using functional magnetic resonance spectroscopy (fMRS) at 3 T in a repetition suppression paradigm. NeuroImage118, 292–300 (2015). PubMed

Mescher, M., Merkle, H., Kirsch, J., Garwood, M. & Gruetter, R. Simultaneous in vivo spectral editing and water suppression. NMR Biomed.11, 266–272 (1998). PubMed

Rothman, D. L., Petroff, O. A., Behar, K. L. & Mattson, R. H. Localized 1H NMR measurements of gamma-aminobutyric acid in human brain in vivo. Proc. Natl. Acad. Sci.90, 5662–5666 (1993). PubMed PMC

Craven, A. R. et al. GABA, glutamatergic dynamics and BOLD contrast assessed concurrently using functional MRS during a cognitive task. NMR Biomed.e506510.1002/nbm.5065 (2023). PubMed

Falkenberg, L. E. et al. Impact of glutamate levels on neuronal response and cognitive abilities in schizophrenia. NeuroImage Clin.4, 576–584 (2014). PubMed PMC

World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines (World Health Organization, 1992).

World Health Organization. ICD-10 Psykiske Lidelser Og Atferdsforstyrrelser: Kliniske Beskrivelser Og Diagnostiske Retningslinjer (Universitetsforlaget, 2016).

Kay, S. R., Fiszbein, A. & Opler, L. A. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull.13, 261–276 (1987). PubMed

Chadwick, P., Lees, S. & Birchwood, M. The revised beliefs about voices questionnaire (BAVQ–R). Br. J. Psychiatry. 177, 229–232 (2000). PubMed

Hugdahl, K. et al. The phenomenology of auditory verbal hallucinations in schizophrenia assessed with the MiniVoiceQuestionnaire (MVQ). (2023). 10.1101/2023.02.16.23285636

WHO Collaborating Centre for Drug Statistics Methodology. ATC Classification Index with DDDs, 2024 (WHO Collaborating Centre for Drug Statistics Methodology, 2024).

Lin, A. et al. Minimum reporting standards for in vivo magnetic resonance spectroscopy (MRSinMRS): Experts’ consensus recommendations. NMR Biomed.10.1002/nbm.4484 (2021). PubMed PMC

Eriksen, B. A. & Eriksen, C. W. Effects of noise letters upon the identification of a target letter in a nonsearch task. Percept. Psychophys. 16, 143–149 (1974).

Kopp, B., Mattler, U. & Rist, F. Selective attention and response competition in schizophrenic patients. Psychiatry Res.53, 129–139 (1994). PubMed

Lally, N. et al. Glutamatergic correlates of gamma-band oscillatory activity during cognition: A concurrent ER-MRS and EEG study. NeuroImage85, 823–833 (2014). PubMed

Edden, R. A. E. et al. A batch-processing tool for the quantitative analysis of gamma-aminobutyric acid-edited MR spectroscopy spectra: Gannet: GABA analysis toolkit. J. Magn. Reson. Imaging. 40, 1445–1452 (2014). PubMed PMC

Near, J. et al. Frequency and phase drift correction of magnetic resonance spectroscopy data by spectral registration in the time domain: MRS drift correction using spectral registration. Magn. Reson. Med.73, 44–50 (2015). PubMed PMC

Mikkelsen, M. et al. Correcting frequency and phase offsets in MRS data using robust spectral registration. NMR Biomed33, (2020). PubMed PMC

Craven, A. R., Ersland, L., Hugdahl, K. & Gruner, R. Modelling inter-shot variability for robust temporal sub-sampling of dynamic, GABA-edited MR spectroscopy data. http://biorxiv.org/lookup/doi/ (2024). 10.1101/2024.12.05.627018 doi:10.1101/2024.12.05.627018.

Bartha, R., Drost, D. J., Menon, R. S. & Williamson, P. C. Spectroscopic lineshape correction by QUECC: Combined QUALITY Deconvolution and eddy current correction. Magn. Reson. Med.44, 641–645 (2000). PubMed

Metz, K. R., Lam, M. M. & Webb, A. G. Reference Deconvolution: A simple and effective method for resolution enhancement in nuclear magnetic resonance spectroscopy. Concepts Magn. Reson.12, 21–42 (2000).

Maudsley, A. A. Spectral lineshape determination by self-deconvolution. J. Magn. Reson. B. 106, 47–57 (1995). PubMed

Jenkinson, M., Bannister, P., Brady, M. & Smith, S. Improved optimization for the robust and accurate linear registration and motion correction of brain images. NeuroImage17, 825–841 (2002). PubMed

Smith, S. M. Fast robust automated brain extraction. Hum. Brain Mapp.17, 143–155 (2002). PubMed PMC

Jenkinson, M. & Smith, S. A global optimisation method for robust affine registration of brain images. Med. Image Anal.5, 143–156 (2001). PubMed

Andersson, J. L., Jenkinson, M. & Smith, S. Non-linear optimisation FMRIB technical report TR07JA1. Practice (2007).

Andersson, J. L., Jenkinson, M. & Smith, S. & others. Non-linear registration, aka Spatial normalisation FMRIB technical report TR07JA2. FMRIB Anal. Group Univ. Oxf.2, e21 (2007).

Grabner, G. et al. Springer Berlin Heidelberg,. Symmetric Atlasing and Model Based Segmentation: An Application to the Hippocampus in Older Adults. In Medical Image Computing and Computer-Assisted Intervention – MICCAI 2006 (eds. Larsen, R., Nielsen, M. & Sporring, J.) vol. 4191 58–66 (2006). PubMed

Woolrich, M. W., Ripley, B. D., Brady, M. & Smith, S. M. Temporal autocorrelation in univariate linear modeling of FMRI data. NeuroImage14, 1370–1386 (2001). PubMed

Worsley, K. J. Statistical analysis of activation images. Ch 14. In Functional MRI: An introduction to methods (eds. Jezzard, P., Matthews, P. M. & Smith, S. M.) 251–270 (2001).

Pernet, C., Wilcox, R. & Rousselet, G. Robust correlation analyses: False positive and power validation using a new open source matlab toolbox. Front Psychol3, (2013). PubMed PMC

Rousselet, G. A. & Pernet, C. R. Improving standards in brain-behavior correlation analyses. Front Hum. Neurosci6, (2012). PubMed PMC

Belsley, D. A., Kuh, E. & Welsch, R. E. Regression Diagnostics: Identifying Influential Data and Sources of Collinearity (Wiley, 1980).

Jarque, C. M. & Bera, A. K. A test for normality of observations and regression residuals. Int. Stat. Rev. Rev. Int. Stat.55, 163 (1987).

White, H. A. & Heteroskedasticity-Consistent Covariance matrix estimator and a direct test for heteroskedasticity. Econometrica48, 817 (1980).

Seabold, S. & Perktold, J. statsmodels: Econometric and statistical modeling with python. in (2010).

Vallat, R. Pingouin: Statistics in Python. J. Open. Source Softw.3, 1026 (2018).

SciPy 1.0 et al. SciPy 1.0: Fundamental algorithms for scientific computing in Python. Nat. Methods 17, 261–272 (2020). PubMed PMC

McKinney, W. Data Structures for Statistical Computing in Python. In (eds. van der Walt, S. & Millman, J.) 56–61 (2010). 10.25080/Majora-92bf1922-00a

Harris, C. R. et al. Array programming with numpy. Nature585, 357–362 (2020). PubMed PMC

Hunter, J. D. & Matplotlib A 2D graphics environment. Comput. Sci. Eng.9, 90–95 (2007).

Waskom, M. Seaborn: Statistical data visualization. J. Open. Source Softw.6, 3021 (2021).

Charlier, F. et al. trevismd/statannotations: v0.5. (2022). 10.5281/ZENODO.7213391

Davelaar, E. J. & Stevens, J. Sequential dependencies in the Eriksen flanker task: A direct comparison of two competing accounts. Psychon Bull. Rev.16, 121–126 (2009). PubMed

Ridderinkhof, K. R., Wylie, S. A., van den Wildenberg, W. P. M., Bashore, T. R. & van der Molen, M. W. The arrow of time: Advancing insights into action control from the arrow version of the Eriksen flanker task. Atten. Percept. Psychophys. 83, 700–721 (2021). PubMed PMC

Stoffels, E. J. & van der Molen, M. W. Effects of visual and auditory noise on visual choice reaction time in a continuous-flow paradigm. Percept. Psychophys. 44, 7–14 (1988). PubMed

Ettinger, U. et al. Response Inhibition and interference control: Effects of schizophrenia, genetic risk, and schizotypy. J. Neuropsychol.12, 484–510 (2018). PubMed

Yücel, M. et al. Impairments of response conflict monitoring and resolution in schizophrenia. Psychol. Med.32, 1251–1260 (2002). PubMed

Gooding, D. C., Braun, J. G. & Studer, J. A. Attentional network task performance in patients with schizophrenia–spectrum disorders: Evidence of a specific deficit. Schizophr Res.88, 169–178 (2006). PubMed

Hjelmervik, H. et al. Intra-Regional Glu-GABA vs Inter-Regional Glu-Glu imbalance: A 1H-MRS study of the neurochemistry of auditory verbal hallucinations in schizophrenia. Schizophr Bull.46, 633–642 (2020). PubMed PMC

Hjelmervik, H. et al. Negative Valence of hallucinatory voices as predictor of cortical glutamatergic metabolite levels in schizophrenia patients. Brain Behav.12, (2022). PubMed PMC

Li, J. et al. Anterior cingulate cortex glutamate levels are related to response to initial antipsychotic treatment in Drug-Naive First-Episode schizophrenia patients. Front. Psychiatry. 11, 553269 (2020). PubMed PMC

Hugdahl, K. et al. Glutamate as a mediating transmitter for auditory hallucinations in schizophrenia: A 1H MRS study. Schizophr Res.161, 252–260 (2015). PubMed

Ćurčić-Blake, B. et al. Glutamate in dorsolateral prefrontal cortex and auditory verbal hallucinations in patients with schizophrenia: A 1 H MRS study. Prog Neuropsychopharmacol. Biol. Psychiatry. 78, 132–139 (2017). PubMed

Singh, S. et al. Evidence for regional hippocampal damage in patients with schizophrenia. Neuroradiology60, 199–205 (2018). PubMed PMC

Merritt, K. et al. Variability and magnitude of brain glutamate levels in schizophrenia: A meta and mega-analysis. Mol. Psychiatry. 28, 2039–2048 (2023). PubMed PMC

Merritt, K., Egerton, A., Kempton, M. J., Taylor, M. J. & McGuire, P. K. Nature of glutamate alterations in schizophrenia: A meta-analysis of proton magnetic resonance spectroscopy studies. JAMA Psychiatry. 73, 665 (2016). PubMed

Nakahara, T. et al. Glutamatergic and GABAergic metabolite levels in schizophrenia-spectrum disorders: A meta-analysis of 1H-magnetic resonance spectroscopy studies. Mol. Psychiatry. 27, 744–757 (2022). PubMed

Brandt, A. S. et al. Age-related changes in anterior cingulate cortex glutamate in schizophrenia: A 1H MRS study at 7Tesla. Schizophr Res.172, 101–105 (2016). PubMed PMC

Liemburg, E. et al. Prefrontal NAA and Glx levels in different stages of psychotic disorders: A 3T 1H-MRS study. Sci. Rep.6, 21873 (2016). PubMed PMC

Ohrmann, P. et al. Cognitive impairment and in vivo metabolites in first-episode neuroleptic-naive and chronic medicated schizophrenic patients: A proton magnetic resonance spectroscopy study. J. Psychiatr Res.41, 625–634 (2007). PubMed

Kubota, M., Moriguchi, S., Takahata, K., Nakajima, S. & Horita, N. Treatment effects on neurometabolite levels in schizophrenia: A systematic review and meta-analysis of proton magnetic resonance spectroscopy studies. Schizophr Res.222, 122–132 (2020). PubMed

Mouchlianitis, E. et al. Treatment-Resistant schizophrenia patients show elevated anterior cingulate cortex glutamate compared to Treatment-Responsive. Schizophr Bull.42, 744–752 (2016). PubMed PMC

Egerton, A. et al. Response to initial antipsychotic treatment in first episode psychosis is related to anterior cingulate glutamate levels: A multicentre 1H-MRS study (OPTiMiSE). Mol. Psychiatry. 23, 2145–2155 (2018). PubMed

Aoyama, N. et al. Grey matter and social functioning correlates of glutamatergic metabolite loss in schizophrenia. Br. J. Psychiatry. 198, 448–456 (2011). PubMed

Coyle, J. T. & Konopaske, G. Glutamatergic dysfunction in schizophrenia evaluated with magnetic resonance spectroscopy. JAMA Psychiatry. 73, 649 (2016). PubMed

Coyle, J. T. Glutamate and schizophrenia: Beyond the dopamine hypothesis. Cell. Mol. Neurobiol.26, 363–382 (2006). PubMed PMC

Dwyer, G. E., Hugdahl, K., Specht, K. & Grüner, R. Current practice and new developments in the use of in vivo magnetic resonance spectroscopy for the assessment of key metabolites implicated in the pathophysiology of schizophrenia. Curr. Top. Med. Chem.18, 1908–1924 (2019). PubMed

Duarte, J. M. N. & Xin, L. Magnetic resonance spectroscopy in schizophrenia: Evidence for glutamatergic dysfunction and impaired energy metabolism. Neurochem Res.44, 102–116 (2019). PubMed PMC

Benes, F. M., Sorensen, I., Vincent, S. L., Bird, E. D. & Sathi, M. Increased density of Glutamate-immunoreactive vertical processes in superficial laminae in cingulate cortex of schizophrenic brain. Cereb. Cortex. 2, 503–512 (1992). PubMed

Woo, T. U. W., Shrestha, K., Lamb, D., Minns, M. M. & Benes, F. M. N-Methyl-D-Aspartate receptor and Calbindin-Containing neurons in the anterior cingulate cortex in schizophrenia and bipolar disorder. Biol. Psychiatry. 64, 803–809 (2008). PubMed PMC

Mangia, S. et al. Sustained neuronal activation raises oxidative metabolism to a new Steady-State level: Evidence from 1 H NMR spectroscopy in the human visual cortex. J. Cereb. Blood Flow. Metab.27, 1055–1063 (2007). PubMed

Rothman, D. L., Behar, K. L., Hyder, F. & Shulman, R. G. In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: implications for brain function. Annu. Rev. Physiol.65, 401–427 (2003). PubMed

Northoff, G., Duncan, N. W. & Hayes, D. J. The brain and its resting state activity—Experimental and methodological implications. Prog. Neurobiol.92, 593–600 (2010). PubMed

Mennes, M. et al. Inter-individual differences in resting-state functional connectivity predict task-induced BOLD activity. NeuroImage50, 1690–1701 (2010). PubMed PMC

Mullins, P. G. Towards a theory of functional magnetic resonance spectroscopy (fMRS): A meta-analysis and discussion of using MRS to measure changes in neurotransmitters in real time. Scand. J. Psychol.59, 91–103 (2018). PubMed

Kühn, S. et al. Neurotransmitter changes during interference task in anterior cingulate cortex: Evidence from fMRI-guided functional MRS at 3 T. Brain Struct. Funct.221, 2541–2551 (2016). PubMed

Taylor, R. et al. Increased glutamate levels observed upon functional activation in the anterior cingulate cortex using the Stroop task and functional spectroscopy. NeuroReport26, 107–112 (2015). PubMed PMC

Taylor, R. et al. Functional magnetic resonance spectroscopy of glutamate in schizophrenia and major depressive disorder: Anterior cingulate activity during a color-word Stroop task. Npj Schizophr. 1, 15028 (2015). PubMed PMC

Lea-Carnall, C. A., El-Deredy, W., Stagg, C. J., Williams, S. R. & Trujillo-Barreto, N. J. A mean-field model of glutamate and GABA synaptic dynamics for functional MRS. NeuroImage266, 119813 (2023). PubMed PMC

Kauppinen, R. A., Pirttilä, T. R. M., Auriola, S. O. K. & Williams, S. R. Compartmentation of cerebral glutamate in situ as detected by 1H/13 C N.m.r. Biochem. J.298, 121–127 (1994). PubMed PMC

Rae, C. et al. Inhibition of glutamine transport depletes glutamate and GABA neurotransmitter pools: further evidence for metabolic compartmentation: Role of glutamine transport in CNS metabolism. J. Neurochem. 85, 503–514 (2003). PubMed

Hancu, I. & Port, J. The case of the missing glutamine. NMR Biomed.24, 529–535 (2011). PubMed

Cohen, S. M., Tsien, R. W., Goff, D. C. & Halassa, M. M. The impact of NMDA receptor hypofunction on GABAergic neurons in the pathophysiology of schizophrenia. Schizophr Res.167, 98–107 (2015). PubMed PMC