Temporal interference stimulation for working memory deficits in schizophrenia: a pilot trial

Working memory impairment represents a core domain of cognitive dysfunction in schizophrenia. Temporal interference stimulation (TIs) is a novel neuromodulation approach that enables focal and noninvasive stimulation across cortical and subcortical regions. This study was performed to assess the feasibility, safety, and working memory changes associated with TIs in schizophrenia. This single-arm trial enrolled 20 patients with schizophrenia and working memory impairment from March to April 2025. TIs targeting the posterior parietal cortex was administered twice daily for five consecutive days. Clinical and cognitive assessments were conducted at baseline, week 1, and week 2. The primary outcome was the change in spatial span test score from baseline to week 1. Secondary outcomes included week-2 change in the spatial span test score, changes in the delay-estimation task and continuous performance test (CPT), and changes in clinical symptoms. Twenty patients completed the trial. Spatial span test scores were significantly higher at week 1 than at baseline, and statistically significant increases from baseline were also observed at week 2 in the spatial span test and CPT. No significant correlations were found between cognitive changes and clinical changes. Exploratory subgroup analyses indicated significant increases in spatial span test performance at weeks 1 and 2 among patients in the clinically impaired subgroup, but not among those in the mildly impaired subgroup. No serious adverse events were reported. This trial offers preliminary evidence that TIs is safe and well-tolerated in schizophrenia and is associated with dissociable cognitive increases, particularly among those with clinically significant cognitive impairment at baseline. The trial was registered in the Chinese Clinical Trial Registry (ChiCTR2500098361) on March 6, 2025.