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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
50
TIS will use 2 pairs of electrodes placed according to a 10-10 EEG system and fixed with conductive paste to produce a theta burst stimulation pattern. Electric field modeling will be performed utilizing MRI T1 images to optimize the individualized electrode configuration to generate electric field intensities above 0.6 V/m in the hippocampus of each patient. Each session of stimulation lasts 30 minutes.
The sham stimulation only includes a 15-second ramp-up at the start and ramp-down at the beginning of each stimulus, which could simulate the scalp pulsing sensation caused by the change of current at the beginning and end of the stimulus.
Second Xiangya Hospital, Central South University
Changsha, Hunan, China
RECRUITINGchanges on the MATRICS Consensus Cognitive Battery (MCCB) scores
The MATRICS Consensus Cognitive Battery (MCCB) can be used for cognitive assessment of schizophrenia, bipolar disorder, and other neuropsychiatric diseases. The MCCB covers nine cognitive domains, including attention, information processing speed, verbal learning and memory, visual learning and memory, spatial working memory, reasoning, problem solving, social cognition, executive function, and fine motor skills. The working memory domain does not include verbal working memory because the Chinese language would not make feasible the inclusion of the LNS test.
Time frame: Baseline, after 2-week intervention, 4 weeks post-treatment
Changes in Positive and Negative Symptom Scale (PANSS) scores
Range from 30 to 210, higher score indicates more severe positive and negative symptoms.
Time frame: Baseline, after 2-week intervention, 4 weeks post-treatment
Change in Scale for Assessment of Negative Symptoms (SANS) score
The score range is 0-120; the higher the score, the more severe the negative symptoms are.
Time frame: Baseline, after 2-week intervention, 4 weeks post-treatment
Changes in Calgary Depression Scale for Schizophrenia (CDSS) score
Ranges from 0 to 27; a higher score indicates more severe affective symptoms.
Time frame: Baseline, after 2-week intervention, 4 weeks post-treatment
Changes in brain function
Functional MRI (fMRI) is based on the blood oxygen level dependent (BOLD) contrast that can detect changes in blood oxygenation to analyze the change of brain function after intervention.
Time frame: Baseline, after 2-week intervention
changes on neuroelectrophysiological signals
The changes of neuroelectrophysiological signals were collected under the task-based electroencephalogram.
Time frame: Baseline, after 2-week intervention, 4 weeks post-treatment
changes on global function
Global function will be measured by the Global Assessment of Functioning (GAF). GAF is a 0-100 numerical scale used by clinicians to subjectively rate a person's overall psychological, social, and occupational functioning. Higher scores (91-100) indicate superior functioning, while lower scores (1-10) indicate severe danger or impairment.
Time frame: Baseline, after 2-week intervention, 4 weeks post-treatment
changes in social function.
Social function will be assessed by the Global Functioning: Social (GF:Social) and Role (GF:Role) scales (GFS) and the Social Functioning Scale (SFS). The GFS is a clinician-rated, 1-10 point tool designed to measure social and occupational functioning. They focus on development, allowing for the assessment of change over time, and avoid confounding functioning with psychiatric symptoms. The SFS is a 79-item self-report measure designed to assess social functioning in schizophrenia. Items assess ability and performance related to social engagement, interpersonal contact, recreation, independence and competence in activities, activities of daily living, and employment.
Time frame: Baseline, 4 weeks post-treatment
changes on aperiodic 1/f-like signal exponent
The aperiodic component of the neural power spectrum, quantified as the slope of the 1/f-like signal recorded by electroencephalogram, will be used as an index of excitation/inhibition balance. The unit of measure is the exponent (unitless).
Time frame: Baseline, after 2-week intervention, 4 weeks post-treatment
changes on long-range temporal correlations (LRTCs)
Long-range temporal correlations of neural oscillations recorded by electroencephalogram will be measured as an index of the temporal stability of excitation/inhibition balance. The unit of measure is the Hurst exponent (unitless).
Time frame: Baseline, after 2-week intervention, 4 weeks post-treatment
changes on functional E/I ratio
The ratio of excitatory to inhibitory neural activity derived from electroencephalogram signals will be calculated as a functional excitation/inhibition balance index. The unit of measure is a ratio (unitless).
Time frame: Baseline, after 2-week intervention, 4 weeks post-treatment
changes on oscillation power across all frequency bands
The power of neural oscillations across all frequency bands (e.g., delta, theta, alpha, beta, gamma) recorded by electroencephalogram will be measured. The power values from all bands will be averaged to produce a single composite oscillation power index. The unit of measure is microvolts squared (μV²).
Time frame: Baseline, after 2-week intervention, 4 weeks post-treatment
changes on 40 Hz auditory steady-state responses (40Hz-ASSRs)
The 40 Hz auditory steady-state responses recorded by electroencephalogram will be measured, including both evoked power and inter-trial phase coherence. The unit of measure for evoked power is μV², and the unit of measure for phase coherence is unitless.
Time frame: Baseline, after 2-week intervention, 4 weeks post-treatment
changes on mismatch negativity (MMN)
The mismatch negativity amplitude recorded by electroencephalogram using an oddball paradigm will be measured. The unit of measure is microvolts (μV).
Time frame: Baseline, after 2-week intervention, 4 weeks post-treatment
changes on P300 event-related potential
The P300 amplitude recorded by electroencephalogram using an oddball paradigm will be measured. The unit of measure is microvolts (μV).
Time frame: Baseline, after 2-week intervention, 4 weeks post-treatment
changes on behavioral performance - Sternberg Item-Recognition Paradigm
Behavioral performance will be evaluated using the Sternberg Item-Recognition Paradigm, a memory task that measures reaction time and accuracy. The unit of measure for reaction time is milliseconds (ms), and the unit of measure for accuracy is percentage correct (%).
Time frame: Baseline, after 2-week intervention, 4 weeks post-treatment
changes on behavioral performance - Mnemonic Similarity Task
Behavioral performance will be evaluated using the Mnemonic Similarity Task, a memory task that measures pattern separation and recognition memory. Three indices will be derived and reported separately: the Lure Discrimination Index (LDI), the similarity object recognition index, and the old object recognition index. All three indices are measured in d-prime (unitless).
Time frame: Baseline, after 2-week intervention, 4 weeks post-treatment
changes on peripheral blood allostatic load index
Approximately 10 mL of blood will be collected intravenously to measure peripheral blood biomarkers: brain-derived neurotrophic factor (BDNF) in ng/mL, C-reactive protein (CRP) in mg/L, interleukin-6 (IL-6) in pg/mL, Kynurenic acid in nM, high-density lipoprotein (HDL) in mg/dL, low-density lipoprotein (LDL) in mg/dL, and triglycerides (TG) in mg/dL. These biomarkers will be combined into a single allostatic load index using a standardized high-risk count algorithm. For each biomarker, a cutoff score based on population norms or clinical thresholds (e.g., highest-risk quartile) will be applied to determine high-risk status (1 = high-risk, 0 = not high-risk). The allostatic load score is the sum of high-risk indicators across all biomarkers. The unit of measure is the allostatic load score (unitless, integer count).
Time frame: Baseline, 4 weeks post-treatment
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