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Breathing, Relaxation, Attention Training, & Health in Older Adults (BREATHE)


Trial ID: NCT04522791


A recently completed study suggested that processing speed and attention (PS/A) oriented cognitive training (VSOP) produced robust effect on PS/A and working memory, but not in cognitive control or episodic memory, and long-term effects were overall modest. The proposed R01 renewal proposes to identify additional attributes to further enhance transferred and long-term effects of PS/A training in older adults with amnestic mild cognitive impairment (MCI) by addressing adaptation capacity that underpins adaptive learning and neuroplasticity. The goal of the stage II double-blinded randomized trial is to test whether adding resonance frequency breathing (RFB) training to VSOP will strengthen multiple contributors to adaptation capacity, particularly the central and peripheral pathways of autonomic nervous system (ANS) flexibility, which will strengthen VSOP training effect on cognitive and brain function and slow the progress of dementia in MCI. The central hypothesis is that strengthening adaptation capacity, via improving autonomic nervous system (ANS) flexibility, will enhance neuroplasticity and slow progress of dementia in MCI, since adaptation capacity is critical for neuroplasticity of VSOP, but compromised in neurodegenerative process. Older adults with MCI (n = 114) will be randomly assigned to an 8-week combined intervention (RFB+VSOP), VSOP with guided imagery relaxation (IR) control, and a waitlist IR control, with periodical booster training sessions at follow-ups. Mechanistic and distal outcomes include ANS flexibility and multiple markers of dementia progress. Data will be collected across a 14-month period. The two primary aims are to examine long-term effects of the combined intervention on ANS flexibility (Aim 1), as well as the cognitive, behavioral, and functional capacity (Aim 2). The exploratory aim will be to determine the preliminary long-term effect of the combined intervention on neurodegeneration. This can be a reasonable renewal plan from the completed study, aiming to identify additional attributes to further enhance transferred and long-term effects of cognitive training in MCI. This will be among the first randomized controlled trials to examine a novel, combined intervention targeting adaptation capacity in MCI, with an ultimate goal for slowing neurodegeneration. In addition, research on how to monitor adherence - the extent to which VSOP training is delivered and followed as intended - has been conceptually and methodologically limited. Robust monitoring of adherence to cognitive training requires valid assessment of effective engagement. Here, we apply our well-supported, novel framework of mental fatigability for measuring effective engagement in cognitive training. Mental fatigability, the failure to remain engaged in tasks requiring sustained mental effort, can be captured via measures of self-reported disengagement, increase in reaction time during tasks, and facial expression of negative valence/low arousal. These markers of disengagement relate to ventromedial prefrontal cortex dysfunction. We will apply this framework to advance understanding of the underpinnings of adherence to VSOP training by monitoring the extent of effective engagement while using the training platform.

Official Title

Breathing, Relaxation, Attention Training, & Health in Older Adults

Stanford Investigator(s)


Inclusion Criteria:

   1. All participants will require a diagnosis of "mild cognitive impairment due to
   Alzheimer's disease"using the most recent NIA and Alzheimer's Association workshop

      1. Presence of memory complaint,

      2. Rey Auditory Verbal Learning Test delayed recall (for memory) < 6,

      3. Montreal Cognitive Assessment (for global cognition) ranged 18 and 25,

      4. Activities of Daily Living Questionnaire ≤ 30,

   2. Intact score for San Diego Brief Assessment of Capacity to Consent (UBACC).

   3. If a participant is on Alzheimer's disease medication (i.e., memantine or
   cholinesterase inhibitors), antidepressants, anxiolytics, or vascular risk or diseases
   related medications (e.g., beta- blocker), the dose should be stable for 3 months
   prior to recruitment.

   4. Age 60-89,

   5. English-speaking,

   6. Adequate visual and hearing acuity for using mobile-based apps and testing by
   self-report, and

   7. Community-dwelling.

Exclusion Criteria:

   1. Current enrollment in another cognitive improvement study;

   2. Uncontrollable symptoms of major depression;

   3. Major cerebrovascular and cardiovascular diseases (e.g., congestive heart failure,
   pacemaker, prior myocardial infarction);

   4. Neurological diseases (e.g., Parkinson's disease, Multiple Sclerosis);

   5. Having an active legal guardian (indicating impaired capacity for decision making);

   6. MRI contraindication (e.g., pacemaker, claustrophobia).

   7. Color blindedness

   8. Alcohol dependency in the past 5 years that are the main contributor to MCI


behavioral: RFB

behavioral: VSOP

behavioral: IR


Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305