Temporal Interference Stimulation Targeting Thalamus for Schizophrenia-Related Cognitive Dysfunction

Group A receives active stimulation in the first session and sham stimulation in the second session.One day prior to each TIS session, participants complete two training runs of the Sternberg Item-Recognition Paradigm (SIRP) to eliminate confounding learning effects.Electrodes are placed according to the 10-10 EEG system and secured with conductive paste.Stimulation is individualized based on each participant's Individual Alpha Frequency (IAF). Resting-state EEG is recorded before stimulation to determine the IAF. A continuous high-frequency sinusoidal current pair with a base frequency of 2000 Hz and a beat frequency tuned to the IAF is delivered through each electrode to generate pulsed stimulation for individualized iTBS.Electric field modeling based on T1-weighted MRI images is used to optimize personalized electrode montages, ensuring an electric field strength ≥ 0.2 V/m within the left thalamus for each participant.

Thalamus-targeted temporal interference stimulation delivered via Dome Medical TES NEURO-800, individualized based on individual alpha frequency with electric field optimization from T1 MRI.

Sham temporal interference stimulation with identical setup; current only delivered during brief ramp-up/ramp-down periods to mimic scalp sensation without effective thalamic stimulation.

Group B receives sham stimulation in the first session and active stimulation in the second session.One day prior to each TIS session, participants complete two training runs of the Sternberg Item-Recognition Paradigm (SIRP) to eliminate confounding learning effects. Electrodes are placed according to the 10-10 EEG system and secured with conductive paste.Stimulation is individualized based on each participant's Individual Alpha Frequency (IAF). Resting-state EEG is recorded before stimulation to determine the IAF. A continuous high-frequency sinusoidal current pair with a base frequency of 2000 Hz and a beat frequency tuned to the IAF is delivered through each electrode to generate pulsed stimulation for individualized iTBS.Electric field modeling based on T1-weighted MRI images is used to optimize personalized electrode montages, ensuring an electric field strength ≥ 0.2 V/m within the left thalamus for each participant.

Thalamus-targeted temporal interference stimulation delivered via Dome Medical TES NEURO-800, individualized based on individual alpha frequency with electric field optimization from T1 MRI.

Sham temporal interference stimulation with identical setup; current only delivered during brief ramp-up/ramp-down periods to mimic scalp sensation without effective thalamic stimulation.

Participants in the sham group receive sham TIS following the identical schedule: two sessions daily for 10 days, 20 sessions in total. The sham paradigm uses the same 2000 Hz current pair. Current is only delivered during the 10-second ramp-up and ramp-down phases at the start and end of each session, while no current is applied during the middle period. This setup mimics the scalp tingling sensation induced by current changes at the beginning and end of active stimulation. All other hardware, electrode placement and study procedures are identical to the active TIS group.

Sham temporal interference stimulation with identical setup; current only delivered during brief ramp-up/ramp-down periods to mimic scalp sensation without effective thalamic stimulation.

Participants in the TIS group receive active TIS stimulation, with two intervention sessions per day for 10 consecutive days, totaling 20 sessions. Each session lasts 30 minutes. Electrodes are placed according to the 10-10 EEG system and secured with conductive paste. Stimulation is individualized based on each participant's Individual Alpha Frequency (IAF). Resting-state EEG is recorded before stimulation to determine the IAF. A continuous high-frequency sinusoidal current pair with a base frequency of 2000 Hz and a beat frequency tuned to the IAF is delivered through each electrode to generate pulsed stimulation for individualized iTBS. Electric field modeling based on T1-weighted MRI images is used to optimize personalized electrode montages, ensuring an electric field strength ≥ 0.2 V/m within the left thalamus for each participant. Each stimulation session lasts 30 minutes, with a 10-second ramp-up period at the onset and a 10-second ramp-down period at the end.

Thalamus-targeted temporal interference stimulation delivered via Dome Medical TES NEURO-800, individualized based on individual alpha frequency with electric field optimization from T1 MRI.

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.This outcome is for sub-trial 1 (single-session crossover TIS).

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.This outcome is for sub-trial 2 (2-week repeated TIS).

The PANSS-6 is a shortened version of the Positive and Negative Syndrome Scale for assessment of psychotic symptoms in schizophrenia. Scores range from 6 to 42, higher score indicates more severe psychotic symptoms. This outcome is for sub-trial 1 (single-session crossover TIS).

The Sternberg Item-Recognition Paradigm (SIRP) is a task fMRI paradigm for evaluating working memory processing. T1-weighted structural MRI at baseline is acquired for individual brain modeling. Task fMRI scans are obtained pre-stimulation, during stimulation, and post-stimulation for each session. This outcome is for sub-trial 1 (single-session crossover TIS).

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.This outcome is for sub-trial 2 (2-week repeated TIS).

The Positive and Negative Syndrome Scale (PANSS) is widely used to assess positive, negative and general psychopathology symptoms of schizophrenia. Scores range from 30 to 210, higher score indicates more severe positive and negative symptoms. This outcome is for sub-trial 2 (2-week repeated TIS).

The Psychotic Symptoms Rating Scale (PSYRATS) quantifies the severity and dimensional features of hallucinations and delusions in patients with psychosis. This outcome is for sub-trial 2 (2-week repeated TIS).

The Scale for the Assessment of Negative Symptoms (SANS) evaluates the severity of negative symptoms in schizophrenia, including affective flattening, alogia, avolition-apathy, anhedonia-asociality and attentional impairment. This outcome is for sub-trial 2 (2-week repeated TIS).

The Global Assessment of Functioning (GAF) scale rates overall psychological, social and occupational functioning. Scores range from 0 to 100, higher score represents better functional status. This outcome is for sub-trial 2 (2-week repeated TIS).

The Global Functioning Scale (GFS) assesses real-world social and role functioning among individuals with severe mental disorders. This outcome is for sub-trial 2 (2-week repeated TIS).

The Social Functioning Scale (SFS) measures multiple domains of social functioning for patients with schizophrenia spectrum disorders. This outcome is for sub-trial 2 (2-week repeated TIS).

Task fMRI based on the 2-back working memory paradigm used to assess working memory-related thalamocortical brain activity. High-resolution T1-weighted structural MRI at baseline is acquired for individual brain modeling. This outcome is for sub-trial 2 (2-week repeated TIS).

The 1/f aperiodic signal of resting-state electroencephalography is measured as an index of excitation-inhibition (E/I) balance. This outcome is for sub-trial 2 (2-week repeated TIS).This outcome is for sub-trial 2 (2-week repeated TIS).

Long-range temporal correlation (LRTC) of resting-state electroencephalography is measured as an index of excitation-inhibition (E/I) balance.This outcome is for sub-trial 2 (2-week repeated TIS).

Functional E/I ratio (fE/I) from resting-state electroencephalography is measured as an index of excitation-inhibition (E/I) balance.This outcome is for sub-trial 2 (2-week repeated TIS).

Gamma-band oscillatory power of resting-state electroencephalography is measured as an index of excitation-inhibition (E/I) balance.This outcome is for sub-trial 2 (2-week repeated TIS).

Beta-band oscillatory power of resting-state electroencephalography is measured as an index of excitation-inhibition (E/I) balance.This outcome is for sub-trial 2 (2-week repeated TIS).

40 Hz auditory steady-state response (40 Hz-ASSR) is recorded by electroencephalography for excitation-inhibition balance assessment.This outcome is for sub-trial 2 (2-week repeated TIS).

Mismatch negativity (MMN) is recorded by electroencephalography for excitation-inhibition balance assessment.This outcome is for sub-trial 2 (2-week repeated TIS).

P50 sensory gating ratio is recorded by electroencephalography for sensory gating assessment.This outcome is for sub-trial 2 (2-week repeated TIS).

Sleep spindle density is derived from sleep electroencephalography.This outcome is for sub-trial 2 (2-week repeated TIS).

Sleep spindle frequency is derived from sleep electroencephalography.This outcome is for sub-trial 2 (2-week repeated TIS).

Sleep spindle amplitude is derived from sleep electroencephalography.This outcome is for sub-trial 2 (2-week repeated TIS).

Sleep spindle duration is derived from sleep electroencephalography.This outcome is for sub-trial 2 (2-week repeated TIS).

Slow oscillation power is derived from sleep electroencephalography.This outcome is for sub-trial 2 (2-week repeated TIS).

Slow oscillation amplitude is derived from sleep electroencephalography.This outcome is for sub-trial 2 (2-week repeated TIS).

Slow oscillation slope is derived from sleep electroencephalography.This outcome is for sub-trial 2 (2-week repeated TIS).

Approximately 10 mL of intravenous blood is collected (2 mL whole blood, 4 mL serum, 4 mL plasma) at baseline and 4-week follow-up. Samples are sent to the clinical laboratory of the Second Xiangya Hospital, Central South University for routine blood examination. Samples are destroyed immediately after testing, and test data are limited for use by the Second Xiangya Hospital, Central South University. This outcome is for sub-trial 2 (2-week repeated TIS).

Approximately 10 mL of intravenous blood is collected (2 mL whole blood, 4 mL serum, 4 mL plasma) at baseline and 4-week follow-up. Samples are sent to the clinical laboratory of the Second Xiangya Hospital, Central South University for liver function testing. Samples are destroyed immediately after testing, and test data are limited for use by the Second Xiangya Hospital, Central South University. This outcome is for sub-trial 2 (2-week repeated TIS).

Approximately 10 mL of intravenous blood is collected (2 mL whole blood, 4 mL serum, 4 mL plasma) at baseline and 4-week follow-up. Samples are sent to the clinical laboratory of the Second Xiangya Hospital, Central South University for renal function testing. Samples are destroyed immediately after testing, and test data are limited for use by the Second Xiangya Hospital, Central South University. This outcome is for sub-trial 2 (2-week repeated TIS).

Approximately 10 mL of intravenous blood is collected (2 mL whole blood, 4 mL serum, 4 mL plasma) at baseline and 4-week follow-up. Samples are sent to the clinical laboratory of the Second Xiangya Hospital, Central South University for blood lipid testing. Samples are destroyed immediately after testing, and test data are limited for use by the Second Xiangya Hospital, Central South University. This outcome is for sub-trial 2 (2-week repeated TIS).

Approximately 10 mL of intravenous blood is collected (2 mL whole blood, 4 mL serum, 4 mL plasma) at baseline and 4-week follow-up. Samples are sent to the clinical laboratory of the Second Xiangya Hospital, Central South University for fasting glucose testing. Samples are destroyed immediately after testing, and test data are limited for use by the Second Xiangya Hospital, Central South University. This outcome is for sub-trial 2 (2-week repeated TIS).

Approximately 10 mL of intravenous blood is collected (2 mL whole blood, 4 mL serum, 4 mL plasma) at baseline and 4-week follow-up. Samples are sent to the clinical laboratory of the Second Xiangya Hospital, Central South University for inflammatory factor testing. Samples are destroyed immediately after testing, and test data are limited for use by the Second Xiangya Hospital, Central South University. This outcome is for sub-trial 2 (2-week repeated TIS).