Abstract:

The present study explores the innovative application of Temporal Interference Stimulation (TIS) for addressing working memory deficits (WMD) in schizophrenia (SCZ), emphasising its potential efficacy, brain region specificity, and underlying cross-frequency coupling mechanisms. This research represents a pioneering contribution to the field of non-invasive brain stimulation techniques, offering a novel approach to the treatment of schizophrenia by targeting theta oscillations in specific brain regions, namely the inferior parietal lobule (IPL) and the dorsolateral prefrontal cortex (DLPFC).

This study introduces TIs as a novel and promising neuromodulation tool. Compared to traditional transcranial alternating current stimulation (tACS), TIs demonstrate superior focality and the ability to induce specific neural responses. This project is based on preliminary evidence indicating that theta oscillation TIs can markedly improve WMD in SCZ patients and animal models. This evidence justifies further investigation into the clinical effectiveness and neural underpinnings of this technique.

In a randomised controlled trial, 100 patients presenting with a first episode of schizophrenia will be allocated to four groups. The study will employ two forms of non-invasive brain stimulation: TIs and tACS, with both targeting the IPL. The objective is to validate the therapeutic impact of TIs on WMD and to compare its efficacy with tACS by collecting behavioural and electroencephalogram (EEG) data pre- and post-intervention. A comparative analysis is essential for establishing TIs as a potential alternative to tACS in the treatment of SCZ.

In a subsequent cohort, the focus shifts to the DLPFC, allowing us to explore the brain region specificity of TIs. By contrasting the effects of TIs targeting the DLPFC versus the IPL, we aim to determine if TIs exhibit region-specific improvements in WMD, thereby enhancing our understanding of how different brain regions contribute to WMD and respond to TIs intervention.

Moreover, this project aims to elucidate the electroencephalogram (EEG) mechanisms associated with the therapeutic intervention (TI), with a particular focus on cross-frequency coupling. It is hypothesised that TIs may modulate WMD by affecting the energy of theta oscillations, inter-regional phase synchronisation, and theta-gamma cross-frequency coupling. By analysing these EEG parameters before and after the intervention and comparing them across groups, the aim is to identify the neural mechanisms that support or underpin the behavioural improvements observed.

The innovation of this study lies in its multifaceted approach to understanding and treating WMD in SCZ. By integrating behavioural assessments, electroencephalogram (EEG) recordings and clinical interventions, we are not only validating TIs as an efficacious treatment but also elucidating its mechanisms of action. This comprehensive investigation has the potential to pave the way for more targeted and effective treatments for patients with schizophrenia, and it may also facilitate the application of TIs to other neuropsychiatric disorders.

In conclusion, this project represents a substantial advancement in the field of neuromodulation for SCZ, offering a novel therapeutic strategy with potential implications for clinical practice and theoretical understanding of WMD. The findings may not only validate TIs as an effective intervention for SCZ but also provide insights into the brain's functional specificity and cross-frequency coupling, thus contributing to a broader understanding of cognitive deficits and their remediation.

Key words: schizophrenia, working memory, temporal interference stimulation, brain region specificity, cross- frequency coupling