Participants of the active control condition started within one week after condition assignment with an introduction into the home-based n-back working memory training program. We used a very demanding version of the dual n-back task, in which participants had to monitor and update series of both visually presented spatial locations and auditorily presented letters (). The value of n varied between blocks of trials, with adjustments made continuously based on performance. The task demand thus changed adaptively according to the individual performance of the participant. Participants trained 30 min each day for 40 days. Logfiles of the training sessions were checked each day to control for compliance. In case of a missed or too short training session, participants were contacted on the following morning and instructed to expand the following training session to make up for the missed training time. Once a week, subjects came to the laboratory, were interviewed regarding problems with the training regime, and trained under direct supervision.

Immediately after the 24 hr free recall of session 1, all participants of the training arm were pseudo-randomly assigned to one of three training conditions. Participants of the mnemonic training condition started within one week after condition assignment with a 2 hr introduction course in mnemonic strategies at the Max Planck Institute of Psychiatry. They were introduced into the method of loci, were taught their first loci route within and outside of the institute, applied this route in a first memorization task under supervision, were familiarized with the home-based training platform ( https://memocamp.com ), instructed how to build new routes, and provided with a training plan for the upcoming week. Training plans gave instructions on which set of locations to use to ensure equal training of all routes and reduce interference of word list memorized on preceding days. The training consisted of 30 min of training per day for 40 days at home via a web-based training platform. During the first two weeks of the training, participants built and memorized three further loci routes, with which they trained to memorize lists of random words. During the next four weeks, training was restricted to memorizing lists of random words or images with the four loci routes. The task demand (number of words to be memorized) changed dynamically according to the individual performance of the participant: 5 to be memorized words were presented on the first trial; the number of presented words increased in subsequent training runs by 5 as soon as a subject managed to perfectly remember all words in a given run. Speed of training success was defined as the average number of training runs a participant needed per level increase until he successfully reached level 8 (i.e., 40 words presented), as this level was reached by most mnemonic training participants (16 out of 17), but can hardly be achieved by mnemonics-naive individuals. Logfiles of the training sessions were checked each day to monitor compliance. In case of a missed or too short training session, participants were contacted on the following morning and instructed to expand the following training session to make up for the missed training time. Once a week, subjects came to the laboratory, were interviewed regarding problems with the training regime, trained under direct supervision, and were provided with a training plan for the next week.

Behavioral data acquisition

All participants of the training arm of the study and performed a word-encoding task in the scanner during pre- and post-training sessions. In the post-training session, participants of the mnemonic training condition were asked to apply the method of loci to the task. We used two lists of 72 concrete nouns, with one list being presented per session. Words in both lists were counterbalanced for word length and frequency, and were presented in a random order within each list. To prevent order effects across sessions, word lists were presented in a crossover-designed manner. Words were presented individually for 2 s each, with a jittered inter-stimulus interval of 2-5 s. After six words, a fixation cross was presented for 30 s, which was followed by the next 6 words etc. Participants were instructed not to rehearse during the fixation cross periods, and to think of nothing in particular, comparable to the resting state scan before, however with eyes open.

After the encoding task, a word order recognition task of all 72 words followed. Triplets of words from the word lists encoded before were presented for 10 s, after which participants had to indicate within 3 s if the order of words was exactly as presented before or in a changed order. Presentation and response to each triplet of target words was followed by a control condition, in which participants had to indicate if triplets of new words were shown in ascending order according to their number of syllables. Recognition data have not been analyzed yet and will be presented elsewhere.

Immediately after leaving the scanner, participants had to indicate on a 4-point scale if they had been continuously alert, partly tired, partly drowsy, or partly asleep during the rs-fMRI scan, and if they had their eyes closed during the resting state and open during the encoding session. Analysis of this data indicated that all participants adhered to the eyes closed instructions and no participant reported having been drowsy or asleep during rs-fMRI. Participants were then brought to the behavioral laboratory, where had to freely recall all 72 words presented during the encoding session. Subjects wrote down all remembered words; after 5 min they were asked if they would need more time; after another 5 min recall was terminated. After 24 hr, another free recall of 5+5 min was performed via telephone. Recall score was defined as number of words correctly recalled ignoring order and spelling mistakes. On average, participants forgot 10.3 ± 7.0 words in the 24 hr recall compared to 20 min recall in the pre-training assessment, and 10.7 ± 8.5 words in the 24 hr recall compared to 20 min recall in the post-training assessment (paired t test: t > 8.9, p < 0.01 each).

During the final retest after four months, participants performed the encoding task once more, this time outside the scanner. The word list of their first session was used for re-test, and long-term effects were calculated as difference between first session and re-test session performance. Participants of the mnemonic training condition were asked to use the method of loci for encoding, and all confirmed use of the strategy after the task. Encoding was followed by a delay period of 15 min, filled with a reasoning task, after which participants had to freely recall all memorized words. Of the 51 study participants, 2 participants each of the mnemonic training and passive control conditions and 1 participant of the passive control group were not available for the follow-up test session.