Effects of Transcranial Electrical Stimulation Combined With Retrieval Practice on Semantic Memory in Patients With Schizophrenia
Phase: NA
Conditions: Schizophrenic Patients
Sponsor: Northeast Normal University

 
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Unique Protocol ID: No.2023025 
 
Official Title: Effects of transcranial electrical stimulation 
combined with retrieval practice on semantic memory in 
patients with schizophrenia 
 
Document Title: Study Protocol 
 
 
 
 
Date of the Document: 2024/08/03 
 
 
 
 
 
 
 

 
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Study Protocol  
Effects of transcranial electrical stimulation combined with retrieval 
practice on semantic memory in patients with schizophrenia 
1. Introduction 
Research on semantic memory in schizophrenia patients has revealed weaker activation 
in the prefrontal cortex, potentially linked to cognitive impairments [1,2]. Prior studies have 
suggested that continuous periodic tES intervention in the left dorsolateral prefrontal cortex 
(L-DLPFC) can enhance semantic recognition abilities [3]. Semantic memory organization in 
schizophrenia patients approaches that of healthy individuals after undergoing continuous tES 
stimulation of the left DLPFC for five days, ten times [4]. Thus, stimulating the excitability of 
the L-DLPFC through tES can effectively ameliorate semantic memory impairments in 
schizophrenia patients and is the preferred area for interventions in semantic memory treatment. 
As an effective learning strategy, retrieval practice can assist patients in enhancing 
semantic elaboration and boosting memory performance [5]. Research utilizing near-infrared 
brain imaging technology to observe brain regions during retrieval practice has revealed that 
during challenging word retrieval tasks, activation levels in the inferior frontal gyrus, Frontal 
polar region, and dorsolateral prefrontal cortex area are significantly higher compared to 
conditions without retrieval, aligning closely with the regions activated by tES [6]. This 
suggests that there is consistency in brain activation between tES and retrieval practice, and 
combining the two may result in mutually reinforcing effects. 

 
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A study involving 119 healthy subjects investigated the combination of tES intervention 
with retrieval practice and found that the strong retrieval practice effect left no room for tES to 
improve memory performance[7]. The combination of single-session online tES with retrieval 
practice in healthy individuals and found that the memory performance of anodal stimulation 
was inferior to cathodal stimulation and sham stimulation [8]. We have already explored the 
role of continuous periodic tES combined with interim testing on spatial route learning in 
patients with schizophrenia in a previous study [9], and found that both the learning strategy 
and tES independently facilitated the ability of patients with schizophrenia to learn new 
information in spatial route learning, suggesting that the tES of L-DLPFC has a significant 
improvement effect. In contrast, targeted tES treatment may be more effective for memory-
impaired populations such as schizophrenia [10]. Therefore, further investigation is needed to 
determine the effectiveness of combining tES and retrieval practice for semantic memory 
intervention in schizophrenia patients. From a theoretical perspective, this combination may 
have a dual activation effect because (1) tES stimulation can enhance activation levels of the 
L-DLPFC, improving its cognitive function impairment; (2) retrieval practice can not only help 
patients initiate semantic memory strategies and promote semantic elaboration but also actively 
activate the brain regions stimulated by tES, thereby producing a synergistic effect. 
Therefore, this study aims to investigate whether combining tDCS, tACS with retrieval 
practice facilitates the maintenance of semantic memory and improvement of semantic 
organization by comparing the use of retrieval practice strategies in patients receiving anodal 
L-DLPFC stimulation, sham stimulation. 

 
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2. Methods 
2.1 Participants 
60 schizophrenic patients plan to be recruited from the mental health center. All patients 
must sign an informed consent form. 
Patients with schizophrenia are diagnosed and assessed by two chief psychiatrists. 
Neuropsychological background tests included the Montreal Cognitive Assessment 
(MoCA)[11] for general cognitive function and the Positive and Negative Syndrome Scale 
(PANSS)[12]. A parallel-group, single-blind study design was used to assign subjects to the 
two stimulus types using a stratified randomization method based on baseline Montreal 
Cognitive Assessment performance. The characteristics of the participants are presented in 
Table 1, showing no significant differences in participant characteristics between the two 
stimulation types groups. 
Patients with schizophrenia were included based on the following criteria: (1) meeting the 
diagnostic criteria for schizophrenia according to the Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (DSM-5); (2) aged 18 years or older, regardless of gender, with 
an educational level of elementary school or above; (3) all patients received stable-level 
antipsychotic medication treatment, were in a stable phase of disease treatment, able to 
understand the testing requirements, and cooperated to complete all research tasks; (4) no 
history of neurological disorders or other serious physical illnesses, and no history of 
intellectual disability; (5) no color blindness, color weakness, or other color vision impairments, 
with normal vision or corrected vision. 

 
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Exclusion criteria were as follows: (1) clear cognitive impairment caused by somatic or 
cerebral organic lesions, such as cerebrovascular diseases, traumatic brain injury, etc; (2) 
individuals with mental disorders caused by substance dependence or abuse, or the use of 
psychoactive substances; (3) history of brain injury or other central nervous system-related 
organic diseases; (4) individuals at significant risk of suicide or harming others; (5) 
participation in similar experiments in the past 30 days prior to baseline. 
2.2 Design 
A mixed experimental design of 3 (Stimulation type: tES stimulation, tACS stimulation, 
sham stimulation) × 2 (Learning strategy: retrieval practice, restudy) × 2 (Retention interval: 
Immediate recall, Delayed recall) was employed. Stimulation type was a between-subjects 
variable, while learning strategy and testing time were within-subject variables. The dependent 
variables were the correct recall rate and Adjusted Ratio of Clustering (ARC) scores in the 
testing phase. 
2.3 Devices and Materials 
2.3.1 Devices 
The direct current stimulation device powered by batteries used in this study was the 
Starstim system from NE (Neuroelectrics) company in Spain. All groups utilized the same 
electrode montage, and the electrode placement followed the international 10-20 system for 
electroencephalography. The tES intervention employed 8 cm2 circular sponge electrodes. The 
anode was placed over F3 (i.e., L-DLPFC) and the cathode over FP2 (i.e., right supraorbital 
area).  

 
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2.3.2 Materials 
Thirty-four words from eight common semantic categories were selected as the learning 
materials. Among them, five words were chosen from each of the six categories (fruits, clothing, 
musical instruments, sports, stationery, media) as experimental items, while two words were 
selected from each of the remaining two categories (daily necessities, body organs) as filler 
items. These filler items were presented at the beginning and end of the learning list to control 
for primacy and recency effects, respectively. 
The selection of experimental categories followed the following rules:(1)To control for 
the mutual influence between categories, relatively unrelated categories were chosen (the main 
control was the degree of association between categories and their knowledge domains, such 
as choosing between fruits and vegetables); (2)Two-character words with clear semantics were 
selected as sample words. The selection of sample words followed these rules: 1) Each sample 
word was a two-character word with clear semantics; 2) Each sample word had a different 
pronunciation [13]. 
Prior to the formal experiment, 20 schizophrenia patients were randomly selected as 
participants to assess the semantic familiarity and relevance of 30 pairs of category sample 
word pairs. Evaluation was conducted on a Likert five-point scale (1 indicating complete 
unfamiliarity or no relation, and 5 indicating complete familiarity or very close relation). The 
results indicated that there were no significant differences between the familiarity（M = 4.42, 
SD = 0.76）and relevance（M = 4.75, SD = 0.47）of the retrieval practice list (fruits, clothing, 
instruments) and the familiarity（M = 4.61, SD = 0.59）and relevance（M = 4.65, SD = 0.45）

 
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of the restudy list (sports, stationery, media), t(19) = -1.765, p = .094, 95% CI [-0.41, 0.03], 
t(19) = 1.344, p = .195, 95% CI [-0.05, 0.25]. 
2.4 Procedure 
Treatment is administered by two examiners, each patient receives transcranial electrical 
stimulation with simultaneous learning of word lists. Each participant of each stimulation type 
was involved in both learning conditions, meaning that all participants completed both retrieval 
and restudy learning and testing (experimental procedure in Figure 1).  
(1) Stimulation phase 
In the tDCS group, the anode was placed over the left DLPFC (F3), and the cathode was 
placed over the contralateral supraorbital area (FP2). A direct current of 2mA was applied for 
20 minutes during each stimulation session. In the tACS group, the anode was placed in the F3 
region of the left dorsolateral prefrontal cortex (DLPFC), and the cathode was placed in the 
right supraorbital region (Fp2), and the current used was 2 mA AC at 40 Hz, with a stimulation 
time of 20 min. In the sham group, the stimulation parameters, including the stimulation site 
and duration, were identical to those of the anodal group. However, during the 10-second ramp-
up and ramp-down periods before and after stimulation, patients were unaware that the current 
was turned off.  
(2) Learning phase 
The experimental procedure followed the classic retrieval practice paradigm, which 
included a learning phase and a final test phase. 
During the experiment, participants were informed that they would learn two lists of 

 
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words. Subsequently, they might either learn the words again or complete a list recall test, and 
will be given a final test shortly thereafter. The learning of the retrieval practice list and the 
restudy list was conducted in a randomly balanced manner. Each word was presented for 5 
seconds, with a 500-millisecond interval between words. To avoid providing secondary 
retrieval cues between examples, all words were shuffled pseudo-randomly within categories. 
Each list contained 17 words, consisting of 5 examples from each of the 3 experimental 
categories (15 experimental examples, 2 filler examples). The first and last words presented in 
each list were filler words, thus controlling for the primacy and recency effects on memory. 
For the retrieval practice list, participants underwent two learning sessions and two 
retrieval sessions (S-T-S-T). During retrieval, participants were instructed to write down all the 
words they had just remembered within 5 minutes. For the restudy list, participants underwent 
four study sessions (S-S-S-S). Between each learning cycle, participants completed a 3-minute 
simple arithmetic task (dispersed attention task). 
(3) Testing phase 
Immediate Test: Participants were instructed to recall as many words as possible from the 
learned lists within 10 minutes after completing all learning tasks.  
Delayed Test: Participants were informed to recall as many words as possible from the 

 
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learned lists within 10 minutes 24 hours later.  
Figure 1. Experiment procedure. 
2.5 Date scoring & analysis 
The experimental results were processed using SPSS 26.0. The correct recall rate of word 
lists was calculated for each subject by the experimental assistant. Then, Free recall 
organization was measured by the Adjusted Ratio of Clustering (ARC) scores [14,15]. ARC 
scores range from 1 to 1. A 0 score indicates a level of clustering similar to what would be 
expected by chance, and a score of 1 implies perfect clustering. Negative values of ARC scores 
mean atypical and uninterpretable recall patterns[16]. For that reason, negative scores were 
excluded from analyses.  
A mixed-design analysis of variance (ANOVA) was conducted to compare the correct 
recall rates and ARC clustering scores between the two learning strategies under two 
stimulation conditions. All statistical tests were performed at a significance level of 0.05, and 
post-hoc comparisons were adjusted using Bonferroni correction. Effect sizes were reported 
using partial eta-squared (𝜂𝑝
2; ANOVAs). 

 
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Study Status 
Record Verification: August 2024   
Overall Status: Not yet recruiting 
Study Start: August 12, 2024 [Anticipated] 
Primary Completion: September 15, 2024 [Anticipated] 
Study Completion: September 20, 2024 [Anticipated] 
List of abbreviations 
tES transcranial electrical stimulation 
L-DLPFC left dorsolateral prefrontal cortex 
VLPFC ventrolateral prefrontal cortex 
ARC Adjusted Ratio of Clustering 
 
 
 
 
 
 
 
 

 
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