The beneficial effects of cognitive training with simple calculation and reading aloud in an elderly postsurgical population: study protocol for a randomized controlled trial

This study is an open-label, randomized, controlled trial conducted in Sendai City, Miyagi Prefecture, Japan. Each participant in this study will provide written informed consent prior to participating. The protocol of the study and the consent form have been approved by the Ethics Committee of the Tohoku University Graduate School of Medicine. This study was registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN000019832).

To assess the effects of SCRA on elderly patients who have undergone surgery, all the participants will be randomly assigned to one of two groups: the SCRA intervention group and the waitlisted control group, which does not undergo the SCRA intervention. The study design is shown in Figs. 1 and 2.

Respiratory patients undergoing lung surgery will be recruited from Tohoku University Hospital. Patients admitted to the hospital prior to surgery will be informed about the study. If interested in participating, the patient will receive both a written and a verbal explanation of the study and be asked to sign the approved informed consent form.

Approximately 50 volunteers will be recruited from respiratory patients undergoing lung surgery with general anesthesia lasting 2–8 hours. As previously mentioned, this is a pilot study, so 25 volunteers in each group should be enough to provide information on the changes in cognitive function. Participants must be native Japanese speakers who are 60 years and older and self-report to be right-handed. Participants should be unconcerned with their memory functions. A thoracic surgery physician from the Tohoku University Hospital will refer potential participants. Other data that will be recorded includes the type of general anesthesia, the amount of anesthesia administered, duration of anesthetic administration, duration of surgery, age, and sex. These additional data will be collected by the collaborating surgeons.

Participants will be randomly placed into one of two groups: 1) the group undergoing SCRA cognitive intervention and 2) the no-SCRA waitlisted control group. Random assignment using an online computer program (http://​www.​graphpad.​com/​quickcalcs/​index.​cfm) will take place after informed consent and baseline testing. Participants are stratified by gender and randomized to SCRA or waitlisted control groups. In order to obtain a similar size for both groups, blocked randomization (block size 4) is applied with an allocation ratio of 1:1. Since the participants of the study are patients undergoing cognitive intervention or are being waitlisted, designing a blinded study is difficult. As a result, the trial design is open-label.

First, the Mini-Mental State Examination-Japanese (MMSE-J) will be administered to the participant after receiving consent. The MMSE-J is a 30-point questionnaire used extensively in both clinical and research settings to measure cognitive impairment [52]. To assess dementia, clinicians will consider a person’s MMSE-J score along with their history, a physical health exam, symptoms, and results from other tests. A higher MMSE-J score indicates better cognitive performance. The MMSE is the most common mental status test used to determine POCD [53, 54]. For test-retest intervals of 2 months or less, the MMSE has been shown to have good test-retest reliability [53, 55, 56].

Following the MMSE-J, the participant will be given the Frontal Assessment Battery (FAB). The FAB is an 18-point questionnaire that is commonly performed at bedside or in a clinical setting to help measure cognitive impairment in executive functions [47‐49]. Again, higher scores indicate better performance. The Japanese translation of the FAB has previously been shown to be comparable to the original English versions and has a good test-retest reliability at 3 weeks [48, 49]. Both the MMSE and FAB are commonly administered in studies determining cognitive decline [57‐59].

After the FAB, the participant will be given a laptop running the Cogstate software to measure the speed of processing, visual attention, and visual learning and memory via Cogstate’s “Brief Battery” (https://​cogstate.​com/​). This computerized battery has been shown to effectively determine cognitive decline [25, 60]. Previous studies on the test-retest reliability of the CBB have indicated that there are no retest-related increases in scores after 1 month. However, the retest scores have been shown to increase at 1 week or less [60‐62]. Additionally, the Japanese version of the CBB has previously been shown to yield reliable results for Japanese subjects [63]. This computerized test will be administered via a laptop. Trained project investigators will give detailed instructions and will be nearby to provide reassurance to the elderly participants and to help with any confusion regarding computer use. In order to measure these indicators, the software will run four tasks in sequence, which lasts approximately 15 min in total. First, the software will run a detection task to measure the speed of processing. The participant will be asked to hit the “Yes” button when the trump card turns face up. The unit of measurement will be Log10 milliseconds of the reaction times for correct responses. Incidentally, a lower score indicates better performance. The next task will be an identification task to measure visual attention. The participant will be asked to press “Yes” if the card is red and “No” if the card is black. Again, the unit of measurement is Log10 milliseconds of the reaction times for correct responses. The third task is a one-card memory task in which the participant is asked to press “Yes” if they have already been shown the card. The accuracy of performance will be measured with the arcsine transformation of the square root of correct responses. Therefore, a higher score indicates better performance. The final task is a working memory task called “One Back,” in which the participant is asked to press “Yes” if the card is the same as the previous card, and “No” if it is different. The accuracy of performance is measured using the arcsine transformation of the square root of the proportion of correct answers. Again, a higher score reflects better performance.

These tests will be administered and scored by trained project investigators, and they will be administered to the participant three times: 1) prior to surgery as a baseline, 2) after the surgery to determine a decline in cognition (about 1 week after surgery), and 3) 12 weeks after surgery to determine the effects of SCRA. The type of general anesthesia administered, the amount of anesthesia administered, the anesthesia duration, the surgery duration, age, and sex will be noted. Additionally, several health questionnaires will be administered to determine emotional and mental wellbeing.

The group receiving the SCRA cognitive intervention will be randomly selected from the entire pool of participants, without regard to whether there was a decline in cognitive functions after surgery. SCRA intervention will be conducted at home 3–5 times a week for 30 minutes. The cognitive intervention method consists of two simple tasks: 1) solving simple arithmetic, and 2) reading aloud in Japanese. Various materials will be prepared from Dr. Ryuta Kawashima’s published book series “Training the Brain: The Adult’s Arithmetic Drills” 「脳を鍛える大人の計算ドリル」and “Training the Brain: The Adult’s Verbal Reading Drills” 「脳を鍛える大人の音読ドリル」. These training materials have previously been shown to be effective [35, 45]. The difficulty of arithmetic materials used will range from solving single-digit addition to double-digit division. Materials for reading Japanese aloud consist of 1–2 page stories and essays. Example training worksheets are shown in Fig. 3. The training materials will be given to the participant during their scheduled hospital visits (at discharge, 2 weeks postsurgery, 1 month post-surgery, and 2 months postsurgery). The percentage of correct answers and the time it takes to complete each task will be recorded.

Additionally, during the scheduled hospital visits, we will also ask about daily habits. Knowledge of the individual differences in emotional state is important because it could possibly affect the study results.

This cognitive intervention will continue for 12 weeks. Participants will be given all the tests mentioned above (MMSE-J, FAB, CBB, and health questionnaires) one final time at the end of the 12 weeks.

The waitlisted control group will also be randomly selected from the pool of participants after surgery. During the duration of the study, the waitlisted control group will continue life as usual and will not receive SCRA cognitive intervention. After completing the study, they will be given the opportunity to experience the cognitive intervention. No placebo will be used for this group. Results from previous intervention studies [32, 64] report that a placebo group is unnecessary for this type of study because no differences were observed in cognitive function improvement between the placebo group and the control groups. These participants will also travel to the hospital to meet with their doctors. As with the experimental group, during these visits, control group participants will also be queried about their daily habits. Twelve weeks after surgery the control group will be administered the final round of tests (MMSE-J, FAB, CBB, and health questionnaires).

The outcome measures for all participants are the test scores from the MMSE-J, FAB, computerized tests, and health questionnaires. Additionally, the type of general anesthetic administered, the amount of anesthetic administered, the anesthesia duration, the surgery duration, age, and sex will be recorded.

This is a pilot study. Because a similar study has not been conducted, calculation of a sample size is not possible. However, we will aim to include 50 participants.

Personal information and data for all experiments are handled by the personal information manager director of Tohoku University. Access to information requires a key that is securely kept and has limited access. These internal checks and balances ensure the security of all data and personal information. After the end of the experimental period, the data will be consolidated, and any information linking data back to the participant will be discarded to ensure that the data is truly anonymous. Data destruction will not be conducted.

This study is designed to 1) determine whether there is a decline in cognition after lung surgery in elderly patients and 2) evaluate the beneficial effect of SCRA cognitive intervention in this patient population. The analysis will be based on the intention-to-treat principle.

For comparison of cognitive function before and after surgery, a Wilcoxon Signed-Rank test will be used to compare all participants in both groups. This will determine whether cognitive functions declined postsurgery. Participants will have been randomly placed into a group receiving SCRA intervention, or a waitlisted control group. To evaluate the effects of the cognitive intervention, we will calculate the change in score (post-training score minus pre-training score) for each measure and conduct a between-group variance ANCOVA test. The change in scores is the dependent variable, while the treatment group (cognitive intervention group, waitlisted control group) is the independent variable. Pretraining scores in the dependent variable, sex, and age categories are the covariates to exclude the possibility that any pre-existing difference of measure between groups will affect the result of each measure and to adjust for background characteristics. This is a pilot study that will likely be conducted with a small number of participants, and the effects are unlikely to be significant.

The level of significance is set at p < 0.05. However, since this study includes six different cognitive tests (MMSE-J, FAB, and four computerized tests), we will use Benjamini and Hochverg’s false discovery rate (FDR) correction methods to adjust the p values [65]. As a result, the statistical threshold of the behavioral data was set at p < 0.05, FDR-corrected. Moreover, we will report eta squared (h2) as an index of the effect size. This index is the standardized difference in the change score between the intervention groups (cognitive intervention group, waitlisted control group). In actuality, h2 ≥ 0.01 is regarded as a small effect, h2 ≥ .006 as a medium effect, and h2 ≥ 0.14 as a large effect [66]. The level of significance is set at p < 0.05. Missing data are imputed using the multiple imputation method, as implemented in the Statistical Package for the Social Sciences (SPSS). SPSS uses a fully conditional specification, or chained equations, imputation algorithm. Essentially, incomplete variables are individually imputed and uses the filled-in variable as a predictor in all subsequent steps. Linear regression is used for continuous variables, and logistic regression is used for categorical variables [67]. All randomized participants are included in the analyses in line with their allocation, irrespective of how many sessions they complete (intention-to-treat principle). All statistical analysis will be conducted using SPSS software (Statistical Package for Social Science).

We will follow the recommended guidelines for clinical research in Japan (http://​www.​mhlw.​go.​jp/​topics/​bukyoku/​seisaku/​kojin/​dl/​161228rinsyou.​pdf). According to the guidelines, data monitoring by a third party is unnecessary for this study since we are not providing participants with any medications, nor are we conducting surgery.

Participants are unlikely to encounter any serious risks or burdens. Nevertheless, the three cognitive tests together are expected to take 1 hour. Therefore, participants will possibly experience fatigue and discomfort during testing. The participant will be informed in advance that, should they feel any discomfort, the test can be interrupted at any time. In addition, this study requires participants to undergo cognitive training for 12 weeks. The training tasks (reading aloud and solving simple arithmetic) are not particularly difficult and should not cause the participants any pain. However, if for some reason the participant experiences pain, they will have been previously informed that they may immediately interrupt the training.

In accordance with the provisions of the university, the participants will be given a monetary reward. The reward amount is based on the number of hours invested. Therefore, should the participant decide to leave partway through the study, the reward amount received will coincide with the number of hours they partook.

The protocol of the study and the consent form were approved by the Ethics Committee of Tohoku University Graduate School of Medicine. Participants will be given both an oral explanation and a written file that documents the details of the study. Upon understanding, the participant will be asked to give written consent by signing the consent form approved by the ethics committee. Participants may choose to withdraw from the study at any point in time.

Should they choose to do so, their data will be destroyed.

All participants will be given subject identification numbers to which all the data will be tied. The file records that connect each participant to their identification number will be securely kept on lab servers during the duration of the study. After the study is concluded, the file will be destroyed.

This study is carried out using the operating grants of the group of Tohoku University of implementation officer. For the practice of the present research program, no relationship exists between the particular companies. In other words, no conflict of interest exists in this research project.

As previously mentioned, all personal information and data for the experiment are handled by the personal information manager director of Tohoku University. Access to information requires a securely kept key with limited access. These internal checks and balances ensure the security of all data and personal information.

Results of the study will be formally published in a journal. Participants, healthcare professionals, the public, and other relevant groups will not be individually notified of the results. There are no publication restrictions to note. Authorship of the study belongs to those specifically listed; no professional writers were involved. Currently, no plans exist to grant public access to the full protocol, participant-level dataset, and statistical code.