Non-invasive Brain Stimulation and Strategic Memory Training

Physiological aging is often associated with memory function decline. Recently, the use of transcranial direct current stimulation (tDCS), a type of non-invasive brain stimulation, has been combined with adaptive working memory training interventions in healthy older adults, providing evidence for a significant improvement in memory functions. To the best of our knowledge, no study addressed the use of strategic memory training coupled with the use of tDCS in normal aging. Strategic memory trainings allow to improve participants' performance in the practiced task and to generalize the use of memory strategies to new materials. This Randomized Controlled Trial (RCT) aims to evaluate the effectiveness of a combined intervention associating strategic memory training with the use of tDCS. Healthy older adults and participants with subjective cognitive decline will be recruited and randomly assigned to the experimental group (strategic memory training + ACTIVE tDCS) or the control group (strategic memory training + SHAM tDCS). All participants will be evaluated on transfer and practiced tasks before (T0) and after (T1) the treatment and during follow-up visits, scheduled at 1 month (T2) and 3 months (T3) after the intervention.

The use of cognitive functions such as memory is essential for the execution of daily activities and represents a crucial element for autonomy maintenance during aging. It is known that the physiological cognitive decline associated with aging also involves memory and can significantly impact the older person's independence. For these reasons, great interest has been generated by two tools that have proved to be decisive in supporting memory functions: non-invasive neurostimulation and memory training. Transcranial direct current stimulation (tDCS) is a form of noninvasive brain stimulation that modulates brain activity by employing a direct current delivered through electrodes applied to the scalp. Recently, the use of tDCS has been combined with training interventions focused on working memory in healthy older adults, providing evidence of a significant improvement in memory function when memory training is associated with the use of tDCS compared to when it is performed without it. In particular, adaptive memory trainings coupled with stimulation of the dorsolateral prefrontal cortex provide benefits that last also at follow-up visits after 1 or 3 months, especially in participants who exhibit a lower baseline performance.

While it was observed that adaptive working memory training alone is unable to modulate brain plasticity mechanisms, it was hypothesized that tDCS can modulate brain plasticity by acting through long-term potentiation (LTP) mechanisms and that it can modulate brain neurotrophic factor (BDNF), a protein that plays a relevant role in LTP.

Several adaptive memory trainings focused on working memory, which is essential for decision-making processes and daily activities.

Even if promising results have been shown so far, it appears that no study addressed the implementation of strategic memory training coupled with the use of tDCS. Adaptive trainings allow improving the performance in each task by gradually increasing its difficulty, without however resorting to teaching a strategy. Strategic memory trainings permit not only to improve participants' performance in the practiced task but also to generalize the use of memory strategies to new tasks.

Intending to prevent cognitive impairment, using these intervention methods in healthy aging and the prodromal phases can be useful. To this end, subjective cognitive decline (SCD) indeed represents an intermediate state between normal cognition and mild cognitive impairment (nMCD) and may predict the development of objective cognitive decline.

In this frame, the primary goal of this double-blind randomized controlled trial is to assess whether the application of transcranial direct current stimulation during strategic memory training (on-line neurostimulation) enhances the effect of strategic memory training. The follow-up visits allow for investigating whether eventual improvements are preserved over time and if this combined intervention affects the evolution of cognitive decline.

The treatment protocol consists of 5 sessions (2/3 session/week, 1 hour/day) of strategic memory training combined with on-line tDCS (anodic tDCS, 2mA for 20 minutes, versus sham tDCS, applied to the dorsolateral prefrontal cortex - DLPFC).

Healthy old participants will be recruited from the general population. Participants with subjective cognitive decline (SCD) are recruited from Neuropsychology/Alzheimer's Disease Assessment Unit and Neurorehabilitation Unit of IRCCS Mondino Foundation. The diagnosis of SCD is formulated based on a comprehensive neuropsychological evaluation (baseline cognitive assessment - T0) according to the guidelines presented in the literature.

At T0, the following standardized tests are used:

* Global cognitive function is assessed using Mini-Mental State Examination (MMSE);
* Cognitive reserve is assessed using Cognitive Reserve Index Questionnaire (CRIq);
* Mood is assessed using Geriatric Depression Scale (GDS).

At T0, practiced and not practiced memory tasks (Bottiroli et al., 2013) will be administered to the participants as pre-tests:

1. Associative learning;
2. List learning;
3. Name-face learning;
4. Place learning;
5. Text learning;
6. Grocery learning;

Participants who met the inclusion and exclusion criteria are enrolled and randomly assigned to the experimental group (strategic memory training + ACTIVE tDCS) or control group (strategic memory training + SHAM tDCS).

Eligibility Criteria:
Inclusion Criteria:

* MMSE ≥ 24.
* GDS \< e uguale 11.
* Age between 65 and 85 years.
* Educational level ≥ 5 years.

Exclusion Criteria:

* Pre-existing cognitive impairment (e.g. aphasia, neglect).
* Dementia.
* Severe disturbances in consciousness.
* Concomitant severe psychiatric disease or other neurological conditions (e.g. depression and behavioral disorders).
* Motor or sensory diseases that may interfere with test execution or strategic memory training.