Effects of Individualized Theta-tACS on a Working Memory Training at SCD

The aim of the study is to investigate the effects and mechanisms of action of an individualized transcranial alternating current stimulation in the theta-range (ITF-tACS) on a three day spatial working memory training in healthy older adults with subjective cognitive decline (SCD).

This study uses a randomized, double-blind, two-armed, sham-controlled between-subjects design. It is conducted at the University Hospital for Psychiatry and Psychotherapy Tübingen, Germany. Participants older than 60 years and with subjective cognitive decline (SCD) will be included. Other inclusion and exclusion criteria are displayed under "Eligibility". Participants are recruited via email-newsletters at the University of Tübingen, flyers and newspaper advertisement. Participants will receive financial compensation. A stratified block randomization is applied after the inclusion of the participants and before the baseline-session. The person generating the randomization list is not involved with data collection. Operators do not have access to the randomization list during the data collection.

Sample size is N = 36 with n = 18 participants in each group. As a phase 2 study, the aim of this study is the determination of effect sizes which can be used for further investigations. Thus due to a lack of comparable studies, no power analysis could be conducted. The group size is therefore based on the most frequently found group size (n = 18) observed in a systematic review regarding the effects of tACS targeting the memory in healthy adults.

The study includes seven time points: screening-session, baseline-session (in the end of the first week of data-collection), three training sessions (within the second week of data-collection, each session two days apart), post-session (10-12 days after the baseline-session; in the beginning of the third week of data-collection) and follow-up session (one month after the post-session). Online tACS is applied during the training sessions while the participants will conduct an adaptive spatial n-back task (online stimulation). Resting-state EEG as well as EEGs during the spatial 2-, 3-, 4-back at the baseline- and the post-session are conducted. Two groups are compared: one group with individualized theta-tACS (ITF-tACS) and one with sham-tACS.

Hypothesis H1 contains the effect on the trained task (spatial 2-, 3-, 4-back) at the post-session. The investigators expect a higher performance in the group with ITF-tACS compared to sham-tACS. To test this hypothesis, two ANCOVAs (dependent variable = performance at post-session (Reaction time and d prime, Covariate = performance at baseline-session) will be conducted.

Hypothesis H2.1 contains the effect on the trained task in the training sessions concurrent to the tACS. The investigators expect a higher performance in the group with ITF-tACS compared to sham-tACS in all sessions. To test the hypothesis, a linear mixed model will be conducted.

Hypothesis H2.2 contains the long-term effect on the trained task at the follow-up session. The investigators expect a higher performance in the group with ITF-tACS compared to sham-tACS. To test the hypothesis, two ANCOVAs will be conducted.

Hypothesis H2.3 contains the transfer effects on the verbal working memory (digit span task) at the post-session. The investigators expect a higher performance in the group with ITF-tACS compared to sham-tACS. To test the hypothesis, three ANCOVAs will be conducted.

Hypothesis H2.4 contains the effect of the training on the subjective cognitive decline (10-point Likert-scale) at the post-session. The investigators expect a lower scoring in the group with ITF-tACS compared to sham-tACS. To test the hypothesis, an ANCOVA will be conducted.

Hypothesis H2.5 contains the effect of neurophysiological measures of the spatial working memory (EEG). The investigators expect a higher theta-power and fronto-parietal connectivity in the group with ITF-tACS compared to sham-tACS.

Exploratively measures for the accuracy in the trained task, transfer effect at follow-up session for the transfer task, subjective cognitive decline (subjective cognitive decline questionnaire), quality of live (WHO-5), side effects and for sleep (Karolinska sleepiness scale, Insomnia Severity Index) are evaluated.

For all analyses the alpha level for significance is set to p \< 0.05. Because reaction times \< 150 ms are regarded as unintended and \> mean reaction time + 3 SD per participant are regarded as additionally including different processes than only working memory, reaction times \< 150 ms and \> mean reaction time + 3 SD per participant per session are excluded from the analyses. Participants who did not complete the post-session or will miss \> 1/3 of the training sessions are excluded from analyses. We test model assumptions in all analyses and control for multiple testing in the primary analyses. An interim analysis is conducted in 09/2024.

The study will provide important implications for the usage of multi-session ITF-tACS in the context of healthy aging.

Eligibility Criteria:
Inclusion Criteria:

* age \>/= 60 years
* subjective cognitive decline with a duration \> 6 month and without a concrete cause
* right-handedness (score \> 48 in the Edinburgh Handedness Inventory (EHI; Oldfield, 1971))
* corrected or sufficient eyesight
* sufficient knowledge in German
* ability to consent

Exclusion Criteria:

* neuropsychiatric diagnose
* score \> 13 in the DemTect (Kalbe et al., 2019)
* score \> 4 in the Geriatric Depression Scale Short Form (GDS-SF; Sheikh \& Yesavage, 1986)
* score \> 16 Geriatric Anxiety Scale German version(GAS-G; Gottschling et al., 2016)
* substance abuse or dependence
* epileptic seizure in medical history
* metall in skalp-area
* pacemaker
* gravidity
* psychiatric medication
* benzodiazepines in a dosage \> 1 mg Lorazepam
* participation in a tACS in history