Individualized transcranial temporal interference stimulation (tTIS) for cognitive impairments and negative symptoms in patients with schizophrenia: a study protocol for a randomized controlled trial

Cognitive deficits and negative symptoms are core features of schizophrenia (SCZ) and remain major therapeutic challenges due to their limited responsiveness to antipsychotic medications. Transcranial temporal interference stimulation (tTIS) is a novel, non-invasive brain stimulation technique that enables targeted modulation of deep brain structures with high spatial specificity. While tTIS has shown promise in preliminary studies of other neuropsychiatric conditions, its clinical utility in SCZ has not been established. This study aims to evaluate the safety and efficacy of tTIS targeting the right nucleus accumbens (NAc) in ameliorating cognitive deficits and negative symptoms in SCZ individuals. In this randomized, double-blind, controlled trial, 76 SCZ patients with prominent cognitive deficits and negative symptoms will be recruited and randomly assigned to receive either active or sham tTIS. All participants will maintain stable antipsychotic regimens for at least 30 days prior to and throughout the intervention. The tTIS protocol comprises ten 30-min weekday stimulation sessions. Outcome assessments will be conducted at four time points: baseline (T0), post-intervention (T1), two weeks (T2), and four weeks (T3) after the final sesseion. The primary outcome is the change in cognitive performance, measured by the MATRICS Consensus Cognitive Battery (MCCB). Secondary outcomes include changes in positive and negative symptoms, depressive and anxiety symptoms, sleep quality, quality of life, and resting-state functional magnetic resonance imaging (rs-fMRI) parameters. This trial will provide the first randomized controlled evidence on the clinical efficacy and neural effects of tTIS in SCZ patients. We hypothesize that participants receiving active tTIS will demonstrate significantly greater improvements in cognitive function and negative symptoms compared to those receiving sham stimulation. Chinese Clinical Trial Registry (ChiCTR2500102724). Recruitment is scheduled to begin on May 27, 2025.