TIS for Improving Cognitive Impairment in Schizophrenia

Schizophrenia is a chronic psychiatric disorder that imposes a substantial and increasing global disease burden. Cognitive impairment associated with schizophrenia (CIAS) is a core deficit that strongly predicts global function and quality of life. While effective for positive symptoms, antipsychotics cannot meet treatment requirements on CIAS and are limited by severe metabolic and extrapyramidal side effects. Consequently, there is an urgent need to explore effective treatments for CIAS.

Non-invasive brain stimulation (NIBS), including TMS and TES, has emerged as a promising adjunctive therapy for CIAS by modulating cortical excitability and neuroplasticity. However, conventional NIBS is constrained by limited focal depth, indirectly influencing subcortical circuits. Temporal Interference Stimulation (TIS) overcomes these limitations by utilizing intersecting high-frequency electric fields to generate a low-frequency envelope, enabling the selective modulation of deep neural targets while sparing the superficial cortex. TIS offers superior spatial precision and tolerability for treating neuropsychiatric disorders involving deep-circuit dysfunction.

Neurophysiological evidence implicates glutamatergic dysregulation and excitatory-inhibitory (E/I) imbalance as key mechanisms in schizophrenia. Hippocampal hyperactivity enhances excitatory drive to the prefrontal cortex, disrupting cortico-hippocampal communication, attenuating γ-band oscillations, and impairing network synchrony that supports working memory and executive processes.

Recent studies in healthy individuals demonstrate that 5 Hz TIS targeting the left anterior hippocampus enhances episodic memory and hippocampal-prefrontal connectivity. Intermittent theta-burst stimulation (iTBS) of the right hippocampus improves spatial memory. Only one pilot study in schizophrenia has examined high-frequency (130 Hz) TIS targeting the right nucleus accumbens, showing improvements in negative and cognitive symptoms.

This study aims to evaluate the efficacy and underlying neural mechanisms of TIS targeting the hippocampus in ameliorating CIAS.

The investigators will conduct a randomized controlled clinical trial. 50 participants with schizophrenia (25 in each group) will be recruited and randomly assigned to an active treatment group or a sham treatment group. The intervention will be given twice a day for 2 weeks. The changes in clinical symptoms, cognitive function, E/I imbalance, and brain structure and function will be collected at baseline, at the end of the 2-week intervention, and 4 weeks after the intervention to explore the short-term efficacy, safety, and neurobiological mechanism of TIS in improving cognitive function in schizophrenia.

• Changes in Positive and Negative Symptom Scale (PANSS) scores [Срок оценки: Baseline, after 2-week intervention, 4 weeks post-treatment]
• Change in Scale for Assessment of Negative Symptoms (SANS) score [Срок оценки: Baseline, after 2-week intervention, 4 weeks post-treatment]
• Changes in Calgary Depression Scale for Schizophrenia (CDSS) score [Срок оценки: Baseline, after 2-week intervention, 4 weeks post-treatment]
• Changes in brain function [Срок оценки: Baseline, after 2-week intervention]
• changes on neuroelectrophysiological signals [Срок оценки: Baseline, after 2-week intervention, 4 weeks post-treatment]
• changes on global function [Срок оценки: Baseline, after 2-week intervention, 4 weeks post-treatment]
• changes in social function. [Срок оценки: Baseline, 4 weeks post-treatment]
• changes on aperiodic 1/f-like signal exponent [Срок оценки: Baseline, after 2-week intervention, 4 weeks post-treatment]
• changes on long-range temporal correlations (LRTCs) [Срок оценки: Baseline, after 2-week intervention, 4 weeks post-treatment]
• changes on functional E/I ratio [Срок оценки: Baseline, after 2-week intervention, 4 weeks post-treatment]
• changes on oscillation power across all frequency bands [Срок оценки: Baseline, after 2-week intervention, 4 weeks post-treatment]
• changes on 40 Hz auditory steady-state responses (40Hz-ASSRs) [Срок оценки: Baseline, after 2-week intervention, 4 weeks post-treatment]