Transcranial Alternating Current Stimulation (tACS) as an Augmentation Treatment for Negative Symptoms and Cognitive Deficits in Long-term Hospitalized Schizophrenia Patients
Phase: NA
Conditions: Negative Symptoms in Schizophrenia, Cognition Function
Sponsor: Tongji University

 
Synergistic Treatment of Negative 
Symptoms and Cognitive Function Deficits 
in Long-Term Hospitalized Schizophrenia 
Patients Using tACS 
 
 
 
 
 
 
 
Principal Investigator:  
Protocol Number: PDJW-Y17 
Version/Date of Plan: V2.0/20250604 
Approved No. of ethic committee: PDJW-KY-2025-012 
 
 
 
 
 
 

1. Research Background 
Schizophrenia is a complex mental disorder, typically characterized by cognitive 
dysfunction, emotional flatness, hallucinations, and delusions. Although antipsychotic 
medications are the primary treatment method for schizophrenia, they have limited 
effectiveness in improving cognitive deficits and negative symptoms. Moreover, 
pharmacological treatment may be accompanied by various side effects. Therefore, 
finding more effective treatment strategies is crucial. 
 
Transcranial alternating current stimulation (tACS), as an emerging non-invasive 
brain stimulation technique, influences neural network function by modulating brain 
electrical activity, thus showing promising prospects in the treatment of mental 
disorders. Research indicates that tACS can enhance neuroplasticity in specific brain 
regions, thereby improving cognitive function and emotional states. For example, 
studies on depression patients have found that tACS can effectively improve mood 
and significantly reduce the severity of depressive symptoms[1]. Furthermore, tACS 
is believed to have potential benefits for treating anxiety and schizophrenia, with 
related research continuously increasing[2]. 
 
The working principle of tACS primarily involves applying low-intensity alternating 
current to regulate neuronal firing patterns, thereby achieving precise control of brain 
activity. Compared to traditional transcranial magnetic stimulation, tACS has greater 
advantages in stimulation depth and targeting, allowing more effective influence on 
deep brain region activities, which is particularly important for treating some 
treatment-resistant mental disorders[3]. For instance, recent research suggests that 
tACS can effectively improve cognitive function and negative symptoms in 
schizophrenia patients, providing new insights into the application of this technology 
in mental disorder treatment[4]. 
 
Although tACS shows promising prospects in clinical applications, more randomized 

controlled trials are needed to verify its safety and effectiveness. The existing studies 
have relatively small sample sizes and mostly focus on short-term effect assessments, 
lacking systematic research on long-term effects [5]. Moreover, individual differences 
may play an important role in the therapeutic effects of tACS, so future research 
needs to pay more attention to developing personalized treatment plans to achieve 
better therapeutic outcomes [6]. 
 
Eye-tracking technology has become a key tool for exploring human cognitive 
processes in psychological research, based on the "eye-mind hypothesis"—that visual 
attention allocation directly reflects underlying cognitive processing. Currently, this 
technology provides researchers with objective indicators of cognitive activities by 
precisely recording parameters such as fixation point distribution, dwell time, and 
saccadic paths. In cognitive psychology, eye movement data reveals information 
processing strategies in tasks like reading, visual search, and problem-solving; in 
developmental psychology, eye tracking helps researchers understand cognitive 
developmental trajectories of infants and young children; social psychology uses this 
technology to explore facial expression recognition and attention allocation patterns in 
social interactions; clinical psychology considers characteristic eye movement 
abnormalities as potential biomarkers for various psychological disorders. This 
multidisciplinary application not only enriches theoretical construction but also 
provides scientific basis for practical applications, such as developing auxiliary 
diagnostic tools, assessing treatment effects, and designing human-machine 
interactions. The non-invasive nature and increasingly improved portability of eye 
tracking make it an ideal bridge connecting subjective experiences with objective 
measurements. Therefore, it is also expected to serve as an important biomarker for 
measuring negative symptoms and cognitive deficits in schizophrenia. 
 
Research indicates that cognitive function impairment in schizophrenia patients may 
be closely related to elevated levels of peripheral inflammatory cytokines. 
Significantly increased levels of IL-6, IL-1β, TNF-α, and C-reactive protein (CRP) 

are closely associated with decreased performance in cognitive domains such as 
attention, executive function, working memory, verbal, and visual learning [7]. 
Additionally, studies on first-episode psychosis patients found that levels of TNF-α, 
IFN-γ, IL-1β, and IL-12 were negatively correlated with cognitive impairments in 
sustained attention, verbal learning, and executive functions [8]. In summary, 
inflammatory responses may play a crucial role in cognitive impairment in 
schizophrenia. Therefore, regularly monitoring serum levels of inflammatory 
cytokines such as IL-1β, IFN-γ, IL-6, and IL-10 has important clinical significance for 
early assessment and intervention of patient cognitive function. 
References 
[1] Tan G, Chen H, Leuthardt EC. Ultrasound Applications in the Treatment of Major Depressive 
Disorder (MDD): A Systematic Review of Techniques and Efficacy. medRxiv. . Published 2025 
Jan 24. doi:10.1101/2025.01.23.25320960 https://pubmed.ncbi.nlm.nih.gov/39974033/ 
[2] Zhang R, Ren J, Zhang C. Efficacy of transcranial alternating current stimulation for 
schizophrenia 
treatment: 
A 
systematic 
review. 
J 
Psychiatr 
Res. 
168:52-63. 
doi:10.1016/j.jpsychires.2023.10.021 https://pubmed.ncbi.nlm.nih.gov/37897837/ 
[3] Thiele C, Rufener KS, Repplinger S, Zaehle T, Ruhnau P. Transcranial temporal interference 
stimulation 
(tTIS) 
influences 
event-related 
alpha 
activity 
during 
mental 
rotation. 
Psychophysiology. 
2024;61(11):e14651. 
doi:10.1111/psyp.14651 
https://pubmed.ncbi.nlm.nih.gov/38997805/ 
[4] Pathak H, Sreeraj VS, Venkatasubramanian G. Transcranial Alternating Current Stimulation 
(tACS) and Its Role in Schizophrenia: A Scoping Review. Clin Psychopharmacol Neurosci. 
2023;21(4):634-649. doi:10.9758/cpn.22.1042 https://pubmed.ncbi.nlm.nih.gov/37859437/ 
[5] Agboada D, Zhao Z, Wischnewski M. Neuroplastic effects of transcranial alternating current 
stimulation (tACS): from mechanisms to clinical trials. Front Hum Neurosci. 19:1548478. 
Published 2025. doi:10.3389/fnhum.2025.1548478 https://pubmed.ncbi.nlm.nih.gov/40144589/ 
[6] Machado YC, Oliveira M, Mundoca MP, Viana B, Marques de Miranda D, Romano-Silva MA. 
Effects of non-invasive brain stimulation on impulsivity in patients with mental disorders: a 
systematic review and meta-analysis of randomised clinical trials. Gen Psychiatr. 
2024;37(6):e101220. 
Published 
2024. 
doi:10.1136/gpsych-2023-101220 
https://pubmed.ncbi.nlm.nih.gov/39737338/ 

[7] Derek J. Dean, Neil Woodward, Sebastian Walther, Maureen McHugo, Kristan Armstrong, 
Stephan Heckers, Cognitive motor impairments and brain structure in schizophrenia spectrum 
disorder patients with a history of catatonia, Schizophrenia Research, Volume 222,2020,Pages 
335-341,ISSN 0920-9964, https://doi.org/10.1016/j.schres.2020.05.012. 
[8] Baek, S.-H., Kim, H., Kim, J.-W., Ryu, S., Lee, J.-Y., Kim, J.-M., Shin, I.-S., & Kim, S.-W. 
(2022). Association between Peripheral Inflammatory Cytokines and Cognitive Function in 
Patients with First-Episode Schizophrenia. Journal of Personalized Medicine, 12(7), 1137. 
https://doi.org/10.3390/jpm12071137 
2. Research Objectives and Expected Results 
2.1. Research Objectives 
This study aims to investigate the augmented therapeutic effect of tACS on negative 
symptoms and cognitive function in long-term hospitalized patients with 
schizophrenia; Using event-related brain electrical activity induced by emotional 
stimuli in virtual reality scenarios as a biomarker, analyze its correlation with the 
clinical efficacy of tACS. 
2.2. Expected Outcomes 
Confirm that tACS can improve negative symptoms and cognitive function in 
long-term hospitalized schizophrenia patients; Predict the therapeutic effect of tACS 
on improving negative symptoms and cognitive function in long-term hospitalized 
schizophrenia patients through biomarkers, guiding precise clinical application. 
3. Research Content and Methods 
3.1. Research Content 
This study aims to investigate the augmentative therapeutic effect of transcranial 
alternating current stimulation (tACS) on negative symptoms and cognitive function 
in long-term hospitalized patients with schizophrenia; and to use emotion-induced 
event-related brain electrical activities under virtual reality scenarios as objective 
biomarkers for schizophrenia, analyzing their predictive value for the clinical efficacy 
of tACS. 
A case-control experiment comparing the differences in emotion-induced 
event-related brain electrical activities, eye movements, and serum inflammatory 
factors between 60 long-term hospitalized schizophrenia patients and 30 healthy 
controls under virtual reality scenarios. 

A randomized controlled experiment comparing the therapeutic effects on negative 
symptoms and cognitive function between the 30 tACS group and the 30 sham 
stimulation group of long-term hospitalized schizophrenia patients. Additionally, 
analyzing the relationship between treatment efficacy and baseline and post-treatment 
brain electrical biomarkers, susceptibility genes, and serum inflammatory factors. 
3.2. Research Methods 
Subject Recruitment: This study plans to recruit 60 long-term hospitalized 
schizophrenia patients from the hospital's outpatient and inpatient departments, and 30 
normal controls from the community. All participants will sign an informed consent 
form before the study begins and obtain ethical approval for participation, ensuring  
Intervention Protocol: The intervention will last 20 days, with two tACS stimulations 
per day, each lasting 40 minutes, using a current of 15mA. The tACS intervention 
group will receive real electrical stimulation, while the sham stimulation group will 
receive placebo stimulation (without current). 
Clinical Assessment: Using standardized clinical assessment tools, evaluate the 
negative symptoms (SANS, CAINS, BNSS) and cognitive functions (MCCB, 
including attention, executive function, visual memory, declarative memory, working 
memory, alertness, information processing speed, and social cognition) of 
schizophrenia patients. 
Tolerability and Safety Assessment: Using a custom questionnaire to monitor patient 
discomfort and any side effects during tACS stimulation intervention to evaluate the 
safety and tolerability of the method. 
Biomarker Detection: Monitor subjects' emotion-induced brain electrical activity as 
an objective biomarker for schizophrenia (high-frequency oscillation power in the 
prefrontal cortex, functional connectivity between PFC and somatosensory cortex, 
visual cortex) through EEG under virtual reality conditions. Track subjects' saccadic 
amplitude and direction through eye movement analysis, measuring subjects' gaze 
time when viewing specific stimuli (such as emotional faces or social scenes), and 
assess the scanning trajectory length in visual exploration tasks. Explore the effects of 
tACS stimulation on brain electrical activity. After cognitive assessment, 2ml of 
venous blood will be extracted and stored at -80°C for testing. Periodically detect 
serum inflammatory cytokines (IL1β, IFN-γ, IL6, IL10, etc.) and schizophrenia 
susceptibility genes (GAD1, GABAA, GRM3, etc.). 
Data Analysis: Using ANOVA to compare differences in baseline indicators between 
patient and normal control groups; using repeated measures ANOVA to compare 
differences in changes of negative symptom scales, cognitive measurement indicators, 
EEG indicators, serum factors, etc. between tACS intervention and sham stimulation 
groups. Using Pearson correlation analysis to explore the correlation between clinical 

indicator improvements and biomarker changes. 
4. Risks and Side Effects 
This study will collect blood samples from patients and normal controls. Patients will 
receive intervention with commercially available medical device alternating current 
stimulation. The potential risks of these measures are small, known to include fainting 
caused by blood drawing, dizziness caused by alternating current stimulation, but 
these are generally mild and controllable. A very small number of individuals may 
also potentially have other unknown risks. 
5. Withdrawal Conditions 
Patient death 
Patient actively withdraws from the study;  
The research physician determines that the patient is not suitable to continue 
participating in the study, 
Other reasons. 
6. Product Introduction 
The tACS device and electrodes were provided by Nexalin Technology, Inc. (CA, 
USA). The device is FDA and NMPA approved for clinical use in psychiatric patients 
(501K=K024377, stimulator, transcranial electrical treatment, CFR 882.5800, US 
Patent #6904322B2). The treatment was administered through 3 dedicated Nexalin 
electrodes, placed on the frontal lobe (corresponding to the Fp1, Fpz, Fp2 regions in 
the international 10-20 system EEG electrode placement, with electrode sizes of 4.45 
cm×9.53 cm), one electrode on the forehead and two electrodes on the bilateral 
mastoids (electrode sizes 3.18 cm×3.81 cm), with one electrode on each mastoid. 
Currently, the device has been used for treatment in multiple hospitals including 
Beijing Anding Hospital and Xuanwu Hospital, with published articles (Preliminary 
exploration of transcranial alternating current stimulation effectiveness in 
treatment-naive depression patients, and the efficacy and safety of transcranial 
alternating current stimulation combined with antidepressant drugs in depressive 
episodes) 
 

7. Conflict of Interest 
This study has no relevant conflicts of interest. 
8. Privacy and Confidentiality 
This study will implement a strict privacy protection policy. All information related to 
this project and its collaboration will be carefully managed, and no personally 
identifiable information about the participants will be disclosed to anyone outside this 
institution under any circumstances. Even if the research results are published, the 
participants' personal information will not be revealed. 
Participants have the right to know the final research results. Their personal 
information will be protected during the entire process of data collection, storage, and 
use (including analysis and comparison). 
Principal Investigator's Signature: 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
Long-term Hospitalized Schizophrenia Patient Inclusion and Exclusion Criteria 
Inclusion Criteria: 
1. Diagnosed with schizophrenia according to DSM-5 and hospitalized continuously 
for more than six months 
2. Age between 18 and 65 years old 
3.Willing to participate in the study and sign the informed consent form 
4.Stable condition, with minimal change (less than 15%) in total PANSS score in the 
two months prior to the study 
5.Education level of primary school or above 
6.Normal vision or correctable to normal 
Exclusion Criteria: 
1. Comorbid diagnoses of other mental disorders according to DSM-5 
2. History of severe neurological diseases, epilepsy, or craniocerebral trauma 
3. Presence of severe organic diseases with unstable vital organ functions (such as 
heart, liver, or kidney) 
4. Infectious skin disease 
5. Concomitant use of other drugs that may affect the results during the study, such as 
benzodiazepines, non-benzodiazepine sedatives, and psychostimulants 
6. Pregnant or lactating women 
7. Patients with claustrophobia 
8. Those with a history of alcohol or drug abuse 
9. Those who have previously received ineffective or intolerable TACS treatment 

 
 
 
Normal Control Group Inclusion and Exclusion Criteria 
Inclusion Criteria: 
1. No previously diagnosed mental illness 
2. Age between 18 and 65 years old 
3. Willing to participate in the research and sign the informed consent form 
4. Education level of elementary school or above 
5. Normal vision or corrected to normal vision 
6. Residents living in the Pudong community 
Exclusion Criteria: 
1. History of severe neurological diseases, such as epilepsy, history of craniocerebral 
trauma, etc. 
2. Those with severe organic diseases of vital organs such as heart, liver, and kidney 
that are unstable 
3. Those with infectious skin diseases 
4. Concurrent use of drugs during the study that may affect the results, such as 
benzodiazepines, non-benzodiazepine sedatives, and psychostimulants 
5. Pregnant or lactating women 
6. Patients with claustrophobia 
7. Individuals with a history of alcohol or substance abuse