Real-time neurofeedback, its neurotransmitter underpinnings, and therapeutic effects: study protocol for a randomized controlled trial in individuals at clinical high risk

The clinical high risk (CHR) phase of psychosis, characterized by attenuated psychotic symptoms and cognitive impairments, represents a critical window for intervention. Neurobiological alterations observed in schizophrenia (e.g., default mode network (DMN) hyperconnectivity and weakened DMN anticorrelations with the central executive network (CEN)), have been shown to extend to CHR. While neurochemical alterations, specifically glutamate (Glu) and gamma-aminobutyric acid (GABA) activity, are implicated in schizophrenia, their involvement in CHR remains less clear, as does their influence on the large-scale network alterations (e.g., DMN). Previous studies suggest that real-time neurofeedback (rtNFB) using functional magnetic resonance imaging (fMRI) modulates DMN connectivity, offering a potential therapeutic intervention for CHR. However, the efficacy of this approach in modulating neurobiological mechanisms in CHR remains unexplored. This protocol describes a randomized controlled trial evaluating the efficacy of modulating atypical DMN connectivity in CHR individuals. Forty CHR participants (aged 18–30) will be randomized to either a real-rtNFB (N = 20) or sham-rtNFB (N = 20) condition. In the real-rtNFB group, neurofeedback will be derived from DMN-CEN activity, while the sham group will receive feedback from the somatomotor (SMOT) network. We will measure network connectivity pre- and post-intervention, testing two hypotheses: (1) real-rtNFB will reduce DMN hyperconnectivity and strengthen DMN-CEN anticorrelations in CHR, with no such changes occurring in the sham condition, and (2) post-intervention connectivity in the real-rtNFB group will more closely resemble that of neurotypical (NT; N = 20) individuals. A secondary aim will explore the relationship between network connectivity and neurotransmitter concentrations (GABA and Glu) across all participants, and whether they are altered pre- and post-rtNFB. This study will contribute to our understanding of the neurobiological mechanisms of CHR and assess whether rtNFB can alter atypical connectivity in CHR. Ultimately, we aim to inform intervention strategies that could improve both clinical and cognitive outcomes in CHR individuals. The study has been registered with ClinicalTrials.gov (ID: NCT06492343, https://clinicaltrials.gov/study/NCT06492343, Last Update Posted: July 9th, 2024).