Non-invasive Brain Stimulation and Strategic Memory Training (StMe-tDCS)

The Efficacy of Strategic Memory Training Coupled With Non-invasive Brain Stimulation Techniques in Healthy Aging Population and Subjective Cognitive Decline Patients: a Randomized-controlled Study

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Healthy Aging; Cognitive Decline
• Intervention / Treatment: Other: Non-invasive brain stimulation; Other: Sham non-invasive brain stimulation

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Estimated): 56
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sara Bottiroli, Dc.; Phone Number: +39 0382 380201; Email: sara.bottiroli@unipv.it
• Study Contact Backup: Name: Cinzia Fattore, MD; Phone Number: +39 0382 380385; Email: cinzia.fattore@mondino.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental group; The experimental group receives strategic memory training plus non-invasive brain stimulation (ACTIVE tDCS).	Other: Non-invasive brain stimulation; ACTIVE transcranial direct current stimulation( tDCS)
Sham Comparator: Control Group; The control group receives strategic memory training plus sham non-invasive brain stimulation (SHAM tDCS).	Other: Sham non-invasive brain stimulation; SHAM tDCS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Associative learning test scores	Participants are presented with 40 paired associates. Pairs consist of words chosen from Paivio, Yuille, and Madigan (1968) concreteness and imagery norms and from De Mauro, Mancini, Vedovelli, and Voghera (1993) word frequency norms. Each pair is printed in the middle of a 5 x 7 index card. The 40 cards are handed to participants, who are instructed to study the pairs for up to 20 minutes. After study, each stimulus is individually presented, and participants Are asked to write the corresponding response	Immediately after the intervention program (T1).
Associative learning test scores	Participants are presented with 40 paired associates. Pairs consist of words chosen from Paivio, Yuille, and Madigan (1968) concreteness and imagery norms and from De Mauro, Mancini, Vedovelli, and Voghera (1993) word frequency norms. Each pair is printed in the middle of a 5 x 7 index card. The 40 cards are handed to participants, who are instructed to study the pairs for up to 20 minutes. After study, each stimulus is individually presented, and participants Are asked to write the corresponding response	1 month (T2) after the end of the intervention program.
Associative learning test scores	Participants are presented with 40 paired associates. Pairs consist of words chosen from Paivio, Yuille, and Madigan (1968) concreteness and imagery norms and from De Mauro, Mancini, Vedovelli, and Voghera (1993) word frequency norms. Each pair is printed in the middle of a 5 x 7 index card. The 40 cards are handed to participants, who are instructed to study the pairs for up to 20 minutes. After study, each stimulus is individually presented, and participants Are asked to write the corresponding response	3 months (T3) after the end of the intervention program.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
List learning tests scores	Participants are presented with 40 words. Words are also taken from Paivio Yuille, and Madigan (1968) and De Mauro, Mancini, Vedovelli, and Voghera (1993) norms. Each word is printed in the middle of a 5 x 7 index card. The 40 cards are handed to participants, who are instructed to study the words for up to 20 minutes. After study, participants are asked to write down as many words as they could remember (in any order) on an answer sheet.	Immediately after the intervention program (T1).
List learning tests scores	Participants are presented with 40 words. Words are also taken from Paivio Yuille, and Madigan (1968) and De Mauro, Mancini, Vedovelli, and Voghera (1993) norms. Each word is printed in the middle of a 5 x 7 index card. The 40 cards are handed to participants, who are instructed to study the words for up to 20 minutes. After study, participants are asked to write down as many words as they could remember (in any order) on an answer sheet.	1 month (T2) after the end of the intervention program.
List learning tests scores	Participants are presented with 40 words. Words are also taken from Paivio Yuille, and Madigan (1968) and De Mauro, Mancini, Vedovelli, and Voghera (1993) norms. Each word is printed in the middle of a 5 x 7 index card. The 40 cards are handed to participants, who are instructed to study the words for up to 20 minutes. After study, participants are asked to write down as many words as they could remember (in any order) on an answer sheet.	3 months (T3) after the end of the intervention program.
Name-face learning test scores	Participants are presented with 20 black and white photographs of faces (2.75 x 4) paired with the last name printed below it. The 20 name-face cards are handed to participants, who are instructed to study the pairs for up to 20 minutes. After study, each face is individually presented, and participants are asked to write down the name that had been previously paired with it.	Immediately after the intervention program (T1).
Name-face learning test scores	Participants are presented with 20 black and white photographs of faces (2.75 x 4) paired with the last name printed below it. The 20 name-face cards are handed to participants, who are instructed to study the pairs for up to 20 minutes. After study, each face is individually presented, and participants are asked to write down the name that had been previously paired with it.	1 month (T2) after the end of the intervention program.
Name-face learning test scores	Participants are presented with 20 black and white photographs of faces (2.75 x 4) paired with the last name printed below it. The 20 name-face cards are handed to participants, who are instructed to study the pairs for up to 20 minutes. After study, each face is individually presented, and participants are asked to write down the name that had been previously paired with it.	3 months (T3) after the end of the intervention program.
Place learning test scores	Participants are presented a map of a city. The map includes the location and name of 20 target places (e.g., bank) across the streets of an imaginary city. They are given up to 15 minutes to study, and then they have to write the position and name of places on a blank map.	Immediately after the intervention program (T1).
Place learning test scores	Participants are presented a map of a city. The map includes the location and name of 20 target places (e.g., bank) across the streets of an imaginary city. They are given up to 15 minutes to study, and then they have to write the position and name of places on a blank map.	1 month (T2) after the end of the intervention program.
Place learning test scores	Participants are presented a map of a city. The map includes the location and name of 20 target places (e.g., bank) across the streets of an imaginary city. They are given up to 15 minutes to study, and then they have to write the position and name of places on a blank map.	3 months (T3) after the end of the intervention program.
Text learning test scores	Participants are presented with a short story with 22 major ideas (e.g., It was a quiet Sunday at Tirano railway station./ The locomotive, to which the carriages had already been coupled, was standing on the track./ The engine driver and his assistants got down to make sure everything was all right./ Some damage to the brakes...). They have up to 15 minutes to study the story, and then they are asked to recall and write down as much as possible from memory.	Immediately after the intervention program (T1).
Text learning test scores	Participants are presented with a short story with 22 major ideas (e.g., It was a quiet Sunday at Tirano railway station./ The locomotive, to which the carriages had already been coupled, was standing on the track./ The engine driver and his assistants got down to make sure everything was all right./ Some damage to the brakes...). They have up to 15 minutes to study the story, and then they are asked to recall and write down as much as possible from memory.	1 month (T2) after the end of the intervention program.
Text learning test scores	Participants are presented with a short story with 22 major ideas (e.g., It was a quiet Sunday at Tirano railway station./ The locomotive, to which the carriages had already been coupled, was standing on the track./ The engine driver and his assistants got down to make sure everything was all right./ Some damage to the brakes...). They have up to 15 minutes to study the story, and then they are asked to recall and write down as much as possible from memory.	3 months (T3) after the end of the intervention program.
Grocery learning test scores	Participants are presented with a list of 40 grocery items (e.g., butter). Each item is printed in the middle of a 5 x 7 index card. The 40 cards are handed to participants, who are instructed to study the pairs for up to 15 minutes. In the recall phase, participants are asked to write down as many grocery items (in any order) as they could remember.	Immediately after the intervention program (T1).
Grocery learning test scores	Participants are presented with a list of 40 grocery items (e.g., butter). Each item is printed in the middle of a 5 x 7 index card. The 40 cards are handed to participants, who are instructed to study the pairs for up to 15 minutes. In the recall phase, participants are asked to write down as many grocery items (in any order) as they could remember.	1 month (T2) after the end of the intervention program.
Grocery learning test scores	Participants are presented with a list of 40 grocery items (e.g., butter). Each item is printed in the middle of a 5 x 7 index card. The 40 cards are handed to participants, who are instructed to study the pairs for up to 15 minutes. In the recall phase, participants are asked to write down as many grocery items (in any order) as they could remember.	3 months (T3) after the end of the intervention program.

Collaborators and Investigators

• Sponsor: IRCCS National Neurological Institute "C. Mondino" Foundation
• Collaborators: University of Pavia
• Investigators: Principal Investigator: Stefano Cappa, MD, Dementia Research Center

Publications and helpful links

General Publications

• Kane MJ, Engle RW. Working-memory capacity and the control of attention: the contributions of goal neglect, response competition, and task set to Stroop interference. J Exp Psychol Gen. 2003 Mar;132(1):47-70. doi: 10.1037/0096-3445.132.1.47.
• Antonenko D, Thams F, Grittner U, Uhrich J, Glockner F, Li SC, Floel A. Randomized trial of cognitive training and brain stimulation in non-demented older adults. Alzheimers Dement (N Y). 2022 Feb 23;8(1):e12262. doi: 10.1002/trc2.12262. eCollection 2022.
• Assecondi S, Hu R, Kroeker J, Eskes G, Shapiro K. Older adults with lower working memory capacity benefit from transcranial direct current stimulation when combined with working memory training: A preliminary study. Front Aging Neurosci. 2022 Oct 10;14:1009262. doi: 10.3389/fnagi.2022.1009262. eCollection 2022.
• Bottiroli S, Cavallini E, Dunlosky J, Vecchi T, Hertzog C. The importance of training strategy adaptation: a learner-oriented approach for improving older adults' memory and transfer. J Exp Psychol Appl. 2013 Sep;19(3):205-18. doi: 10.1037/a0034078. Epub 2013 Aug 26.
• Grady C. The cognitive neuroscience of ageing. Nat Rev Neurosci. 2012 Jun 20;13(7):491-505. doi: 10.1038/nrn3256.
• Lu H, Cheng PL, Lim BK, Khoshnevisrad N, Poo MM. Elevated BDNF after cocaine withdrawal facilitates LTP in medial prefrontal cortex by suppressing GABA inhibition. Neuron. 2010 Sep 9;67(5):821-33. doi: 10.1016/j.neuron.2010.08.012.
• Park DC, Lautenschlager G, Hedden T, Davidson NS, Smith AD, Smith PK. Models of visuospatial and verbal memory across the adult life span. Psychol Aging. 2002 Jun;17(2):299-320.
• Pergher V, Au J, Alizadeh Shalchy M, Santarnecchi E, Seitz A, Jaeggi SM, Battelli L. The benefits of simultaneous tDCS and working memory training on transfer outcomes: A systematic review and meta-analysis. Brain Stimul. 2022 Nov-Dec;15(6):1541-1551. doi: 10.1016/j.brs.2022.11.008. Epub 2022 Nov 29.
• Reisberg B, Shulman MB. Commentary on "a roadmap for the prevention of dementia II: Leon Thal Symposium 2008." Subjective cognitive impairment as an antecedent of Alzheimer's dementia: policy import. Alzheimers Dement. 2009 Mar;5(2):154-6. doi: 10.1016/j.jalz.2009.01.011. No abstract available.
• Ripp I, Emch M, Wu Q, Lizarraga A, Udale R, von Bastian CC, Koch K, Yakushev I. Adaptive working memory training does not produce transfer effects in cognition and neuroimaging. Transl Psychiatry. 2022 Dec 13;12(1):512. doi: 10.1038/s41398-022-02272-7.
• Teixeira-Santos AC, Moreira CS, Pereira DR, Pinal D, Fregni F, Leite J, Carvalho S, Sampaio A. Working Memory Training Coupled With Transcranial Direct Current Stimulation in Older Adults: A Randomized Controlled Experiment. Front Aging Neurosci. 2022 Apr 12;14:827188. doi: 10.3389/fnagi.2022.827188. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (Estimated): July 30, 2023
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: June 16, 2023
• First Submitted That Met QC Criteria: June 29, 2023
• First Posted (Actual): July 3, 2023

Study Record Updates

• Last Update Posted (Actual): July 3, 2023
• Last Update Submitted That Met QC Criteria: June 29, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Transcranial direct current stimulation; Healthy aging; Subjective cognitive decline; Non-pharmacological treatments; Memory training
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction
• Other Study ID Numbers: StMe-tDCS2023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No