Pharmacological and electrical modulation of disturbed networks in schizophrenia and the clinical high-risk state for psychosis – Pharmacological modulation of an attentional network in the ketamine model of schizophrenia combined with multimodal EEG/fMRI-DTI imaging

• Applicant: Moritz Nils Haaf, Ph.D.
• Subject Area: Biological Psychiatry
• Term: Funded in 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 522570761

N-methyl-D-aspartate receptor (NMDAR) function appears to contribute significantly to the pathophysiology of schizophrenia. Hypofunction of this glutamatergic receptor is associated with an excitatory/inhibitory (E/I) imbalance that is manifested inter alia in changes in oscillatory neuronal activity in the gamma frequency range (30-100 Hz). Synchronized evoked gamma activity plays a central role in cognitive functions such as attention and perception and exhibits reduced activity in an auditory information processing network in people with schizophrenia. Ketamine induces NMDAR hypofunction in healthy subjects, which is accompanied by transient schizophrenia-like symptoms. In addition, the healthy subjects also show changes in gamma activity comparable to patients with schizophrenia. This provides a unique opportunity to modulate E/I imbalance with NMDAR co-agonists (e.g., glycine) in the ketamine model of schizophrenia. To date, the effects of NMDAR modulation on the functional connectivity of the auditory information processing network and the microstructural integrity of the underlying pathways have not been investigated. Accordingly, the main goal of the proposed research project is to investigate the effects of NMDA receptor modulation on: (I) functional (gamma band) connectivity (EEG and fMRI) during auditory information processing in a fronto-temporal network and (II) white matter microstructural integrity (measured as fractional anisotropy) between components of the network and (III) a possible interplay between these changes. For this purpose, simultaneous EEG/fMRI acquired during performance of an auditory choice reaction task and subsequent DTI recordings from 28 healthy male subjects will be analyzed. In a baseline session, participants will each receive placebo infusions as pretreatment and during task performance. At a follow-up visit, EEG/fMRI data collection is combined with pharmacological modulation of NMDAR neurotransmission, which is immediately followed by a second DTI recording. During the pharmacological modulation, half of the participants will receive glycine pretreatment (n = 14) and the other half will receive matching placebo (n = 14), with both pretreatments followed by a continuous subanesthetic ketamine infusion during the processing of the choice response task. The results of this project may expand knowledge regarding the role of NMDAR hypofunction in information processing and its potential therapeutic modulation by receptor co-agonists.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Martha Shenton, Ph.D.