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

 
1 
 
Unique Protocol ID: No.2023023 
 
Official Title: Effects of transcranial direct current 
stimulation combined with retrieval practice on semantic 
memory in patients with schizophrenia 
 
Document Title: Study Protocol 
 
 
 
 
Date of the Document: 2024/7/31 
 
 
 
 
 
 
 

 
2 
 
Study Protocol  
Effects of transcranial direct current 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 tDCS 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 
tDCS stimulation of the left DLPFC for five days, ten times [4]. Thus, stimulating the 
excitability of the L-DLPFC through tDCS 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 tDCS [6]. This 

 
3 
 
suggests that there is consistency in brain activation between tDCS and retrieval practice, and 
combining the two may result in mutually reinforcing effects. 
A study involving 119 healthy subjects investigated the combination of tDCS intervention 
with retrieval practice and found that the strong retrieval practice effect left no room for tDCS 
to improve memory performance[7]. The combination of single-session online tDCS 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 tDCS 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 tDCS independently facilitated the ability of patients with schizophrenia to learn 
new information in spatial route learning, suggesting that the tDCS of L-DLPFC has a 
significant improvement effect. In contrast, targeted tDCS treatment may be more effective for 
memory-impaired populations such as schizophrenia [10]. Therefore, further investigation is 
needed to determine the effectiveness of combining tDCS and retrieval practice for semantic 
memory intervention in schizophrenia patients. From a theoretical perspective, this 
combination may have a dual activation effect because (1) tDCS 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 tDCS, thereby producing 
a synergistic effect. 

 
4 
 
Therefore, this study aims to investigate whether combining tDCS 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. 
2. Methods 
2.1 Participants 
55 schizophrenic patients expected to be recruited from the mental health center. All 
patients must sign an informed consent form. 
Patients with schizophrenia were 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 

 
5 
 
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. 
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 2 (Stimulation type: anodal 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 

 
6 
 
electrode montage, and the electrode placement followed the international 10-20 system for 
electroencephalography. The tDCS 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).  
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 

 
7 
 
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）
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 was administered by two examiners, and after a total of 10 sessions over 5 
consecutive days, a final group of 52 patients participated in the learning and testing phase. 
Among them, 27 received anodal stimulation, while 25 received sham stimulation. 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 anodal 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. Stimulation was conducted twice a day, at 9 a.m. 
and 2 p.m., for 5 consecutive days, totaling 10 sessions. 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.  

 
8 
 
(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 
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 

 
9 
 
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). 

 
10 
 
 
3.Study Status 
Record Verification: July 2024   
Overall Status: Completed 
Study Start: July 24, 2023 [Actual] 
Primary Completion: January 30, 2024 [Actual] 
Study Completion: April 15, 2024 [Actual] 
 
List of abbreviations 
tDCS transcranial direct current stimulation 
L-DLPFC left dorsolateral prefrontal cortex 
VLPFC ventrolateral prefrontal cortex 
ARC Adjusted Ratio of Clustering 
 
 
 
 
 
 
 

 
11 
 
References 
[1] Koike S, Takizawa R, Nishimura Y, Kinou M, Kawasaki S, Kasai K. Reduced b
ut broader prefrontal activity in patients with schizophrenia during n-back workin
g memory tasks: A multi-channel near-infrared spectroscopy study. J Psychiatr Re
s 2013;47:1240–6. https://doi.org/10.1016/j.jpsychires.2013.05.009. 
[2] Marumo K, Takizawa R, Kinou M, Kawasaki S, Kawakubo Y, Fukuda M, et al. 
Functional abnormalities in the left ventrolateral prefrontal cortex during a semant
ic fluency task, and their association with thought disorder in patients with schiz
ophrenia. NeuroImage 2014;85:518–26. https://doi.org/10.1016/j.neuroimage.2013.04.
050. 
[3] Imperio CM, Chua EF. Differential effects of remotely supervised transcranial dire
ct current stimulation on recognition memory depending on task order. Front Hu
m Neurosci 2023;17:1239126. https://doi.org/10.3389/fnhum.2023.1239126. 
[4] Sumiyoshi C, Narita Z, Inagawa T, Yamada Y, Sueyoshi K, Hasegawa Y, et al. 
Facilitative Effects of Transcranial Direct Current Stimulation on Semantic Memor
y Examined by Text-Mining Analysis in Patients With Schizophrenia. Front Neur
ol 2021;12:583027. https://doi.org/10.3389/fneur.2021.583027. 
[5] Jantzi C, Mengin AC, Serfaty D, Bacon E, Elowe J, Severac F, et al. Retrieval 
practice improves memory in patients with schizophrenia: new perspectives for co
gnitive remediation. BMC Psychiatry 2019;19:355. https://doi.org/10.1186/s12888-0
19-2341-y. 

 
12 
 
[6] Zhang L, Jiang Y, Zhang J. The Facilitating Effect of Retrieval Difficulty on the 
Retrieval Practice Effect for Difficult Materials: Evidence from Behavior and fNI
RS. 25th Natl. Acad. Conf. Psychol., Chinese Psychological Society; 2023, p. 3. 
https://doi.org/10.26914/c.cnkihy.2023.057280. 
[7] Cavendish BA, de Lima MFR, Perícoli L, Buratto LG. Effects of combining retri
eval practice and tDCS over long-term memory: A randomized controlled trial. B
rain Cogn 2022;156:105807. https://doi.org/10.1016/j.bandc.2021.105807. 
[8] Brunyé TT, Smith AM, Horner CB, Thomas AK. Verbal long-term memory is en
hanced by retrieval practice but impaired by prefrontal direct current stimulation. 
Brain Cogn 2018;128:80–8. https://doi.org/10.1016/j.bandc.2018.09.008. 
[9] Li T, Ma X, Pan W, Huo X. The impact of transcranial direct current stimulatio
n combined with interim testing on spatial route learning in patients with schizop
hrenia. J Psychiatr Res 2024;177:169–76. https://doi.org/10.1016/j.jpsychires.2024.0
7.016. 
[10] Dedoncker J, Brunoni AR, Baeken C, Vanderhasselt M-A. A Systematic Review 
and Meta-Analysis of the Effects of Transcranial Direct Current Stimulation (tDC
S) Over the Dorsolateral Prefrontal Cortex in Healthy and Neuropsychiatric Sampl
es: Influence of Stimulation Parameters. Brain Stimulat 2016;9:501–17. https://doi.
org/10.1016/j.brs.2016.04.006. 
[11] Mahendran R, Chua J, Feng L, Kua EH, Preedy VR. Chapter 109 - The Mini-M
ental State Examination and Other Neuropsychological Assessment Tools for Dete

 
13 
 
cting Cognitive Decline. In: Martin CR, Preedy VR, editors. Diet Nutr. Dement. 
Cogn. Decline, San Diego: Academic Press; 2015, p. 1159–74. https://doi.org/10.1
016/B978-0-12-407824-6.00109-9. 
[12] Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PAN
SS) for schizophrenia. Schizophr Bull 1987;13:261–76. https://doi.org/10.1093/schb
ul/13.2.261. 
[13] Bordignon S, Zibetti MR, Trentini CM, Resende AC, Minervino CASM, Silva-Fil
ho JHD, et al. Normas de associação semântica para 20 categorias em adultos e 
idosos. Psico-USF 2015;20:97–108. https://doi.org/10.1590/1413-82712015200109. 
[14] Ma X, Li T, Li Z, Zhou A. Episodic context reinstatement promotes memory ret
ention in older but not younger elementary schoolchildren. Br J Dev Psychol 202
0;38:304–18. https://doi.org/10.1111/bjdp.12321. 
[15] Roenker DL, Thompson CP, Brown SC. Comparison of measures for the estimati
on of clustering in free recall. Psychol Bull 1971;76:45–8. https://doi.org/10.1037/
h0031355. 
[16] Kahana MJ, Howard MW, Polyn SM. Associative Retrieval Processes in Episodic 
Memory. Learn. Mem. Compr. Ref., Elsevier; 2008, p. 1–24. https://doi.org/10.101
6/B978-012370509-9.00185-6.