TIS for Improving Cognitive Impairment in Schizophrenia

Efficacy and Safety of Time Interference Stimulation on Cognitive Impairment in Patients With Schizophrenia

This study aims to evaluate the efficacy, safety, and underlying neural mechanisms of TIS targeting the hippocampus in ameliorating cognitive impairment associated with schizophrenia (CIAS). Researchers will compare active TIS to a sham control to see if TIS works to treat CIAS. Participants will receive TIS twice a day for 2 weeks. Their clinical data, including the baseline clinical symptom scale score, cognitive function, E/I imbalance index recorded by EEG, and MRI data, will be collected at baseline, at the end of the 2-week intervention, and 4 weeks after the intervention.

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.

Inclusion Criteria:

• Age 18-50 years old;
• meet the Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM-5) diagnostic criteria;
• the diagnosis of schizophrenia is confirmed by the Structured Clinical Interview for DSM-5 (SCID-5);
• the disease duration does not exceed 8 years;
• 1-2 antipsychotic drugs are taken, and the treatment dose of antipsychotic drugs was stable for at least 1 week before enrollment. Mood stabilizers, antidepressants, and excessive benzodiazepines (lorazepam when 2 doses exceeded 2 mg/d) are not allowed;
• The type of antipsychotic drugs remains unchanged during treatment, and the dose is adjusted by no more than 25%;
• Impaired functioning in daily activities;
• The Global Deficit Score (GDS) for the MATRICS Consensus Cognitive Battery (MCCB) reaches 0.5 or above;
• Agree to participate in this study and provide written informed consent

Exclusion Criteria:

• Presence of other psychiatric comorbidities, intellectual disability, obvious mood symptoms, or substance use disorders (other than caffeine and/or tobacco);
• with clear drug-induced extrapyramidal reaction;
• A history of seizures, meningitis, or encephalitis;
• with contraindications to transcranial electrical stimulation;
• History of intracranial tumors or surgery;
• history of severe head trauma;
• have received other regimens of electrical or magnetic therapy in 1 month before enrollment.