# Effects of an 18-month meditation training on regional brain volume and perfusion in older adults: The Age-Well Randomized Clinical Trial

Gael Chételat, Antoine Lutz, Olga Klimecki, Eric Frison, Julien Asselineau, Marco Schlosser, M Arenaza-Urquijo, Florence Mézenge, Elizabeth Kuhn, Inès Moulinet, et al.

► To cite this version:

Gael Chételat, Antoine Lutz, Olga Klimecki, Eric Frison, Julien Asselineau, et al. Effects of an 18-month meditation training on regional brain volume and perfusion in older adults: The Age-Well Randomized Clinical Trial. JAMA neurology, 2022, 79 (11), pp.1165-1174. 10.1001/jamaneurol.2022.3185. inserm-04386132

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https://inserm.hal.science/inserm-04386132

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<figure><img src="image_1.png" /></figure>
# Effects of an 18-month meditation training on regional brain volume and perfusion in older adults: The Age-Well Randomized Clinical Trial

Gael Chételat, Antoine Lutz, Olga Klimecki, Eric Frison, Julien Asselineau, Marco Schlosser, M Arenaza-Urquijo, Florence Mézenge, Elizabeth Kuhn, Inès Moulinet, et al.

► To cite this version:

Gael Chételat, Antoine Lutz, Olga Klimecki, Eric Frison, Julien Asselineau, et al. Effects of an 18-month meditation training on regional brain volume and perfusion in older adults: The Age-Well Randomized Clinical Trial. JAMA neurology, 2022, 79 (11), pp.1165-1174. 10.1001/jamaneurol.2022.3185. inserm-04386132

HAL Id: inserm-04386132

https://inserm.hal.science/inserm-04386132v1

Submitted on 10 Jan 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>
JAMA Neurology | Original Investigation

# Effect of an 18-Month Meditation Training on Regional Brain Volume and Perfusion in Older Adults

## The Age-Well Randomized Clinical Trial

Gael Chételat, PhD; Antoine Lutz, PhD; Olga Klimecki, PhD; Eric Frison, MD, PhD; Julien Asselineau, MSc; Marco Schlosser, MSc; Eider M. Arenaza-Urquijo, PhD; Florence Mézenge, MSc; Elizabeth Kuhn, PhD; Inès Moulinet, PhD; Edelweiss Touron, MSc; Sophie Dautricourt, PhD; Claire André, PhD; Cassandre Palix, MSc; Valentin Ourry, PhD; Francesca Felisatti, MSc; Julie Gonneaud, PhD; Brigitte Landeau, MSc; Géraldine Rauchs, PhD; Anne Chocat, MD; Anne Quillard, MD; Eglantine Ferrand Devouge, MD; Patrik Vuilleumier, MD; Vincent de La Sayette, MD; Denis Vivien, PhD; Fabienne Collette, PhD; Géraldine Poisnel, PhD; Natalie L. Marchant, PhD; for the Medit-Ageing Research Group

**IMPORTANCE** No lifestyle-based randomized clinical trial directly targets psychoaffective risk factors of dementia. Meditation practices recently emerged as a promising mental training exercise to foster brain health and reduce dementia risk.

**OBJECTIVE** To investigate the effects of meditation training on brain integrity in older adults.

**DESIGN, SETTING, AND PARTICIPANTS** Age-Well was a randomized, controlled superiority trial with blinded end point assessment. Community-dwelling cognitively unimpaired adults 65 years and older were enrolled between November 24, 2016, and March 5, 2018, in France. Participants were randomly assigned (1:1:1) to (1) an 18-month meditation-based training, (2) a structurally matched non-native language (English) training, or (3) no intervention arm. Analysis took place between December 2020 and October 2021.

**INTERVENTIONS** Meditation and non-native language training included 2-hour weekly group sessions, practice of 20 minutes or longer daily at home, and 1-day intensive practices.

**MAIN OUTCOMES AND MEASURES** Primary outcomes included volume and perfusion of anterior cingulate cortex (ACC) and insula. Main secondary outcomes included a global composite score capturing metacognitive, prosocial, and self-regulatory capacities and constituent subscores.

**RESULTS** Among 137 participants (mean [SD] age, 69.4 [3.8] years; 83 [60.6%] female; 54 [39.4%] male) assigned to the meditation (n = 45), non-native language training (n = 46), or no intervention (n = 46) groups, all but 1 completed the trial. There were no differences in volume changes of ACC (0.01 [98.75% CI, -0.02 to 0.05]; P = .36) or insula (0.01 [98.75% CI, -0.02 to 0.03]; P = .58) between meditation and no intervention or non-native language training groups, respectively. Differences in perfusion changes did not reach statistical significance for meditation compared with no intervention in ACC (0.02 [98.75% CI, -0.01 to 0.05]; P = .06) or compared with non-native language training in insula (0.02 [98.75% CI, -0.01 to 0.05]; P = .09). Meditation was superior to non-native language training on 18-month changes in a global composite score capturing attention regulation, socioemotional, and self-knowledge capacities (Cohen d, 0.52 [95% CI, 0.19-0.85]; P = .002).

**CONCLUSIONS AND RELEVANCE** The study findings confirm the feasibility of meditation and non-native language training in elderly individuals, with high adherence and very low attrition. Findings also show positive behavioral effects of meditation that were not reflected on volume, and not significantly on perfusion, of target brain areas.

**TRIAL REGISTRATION** ClinicalTrials.gov Identifier: NCT02977819

JAMA Neurol. 2022;79(11):1165-1174. doi:10.1001/jamaneurol.2022.3185
Published online October 10, 2022.

<figure><img src="image_2.png" /></figure>

Visual Abstract

<figure><img src="image_3.png" /></figure>

Supplemental content

**Author Affiliations:** Author affiliations are listed at the end of this article.

**Group Information:** The Medit-Ageing Research Group is listed in Supplement 3.

**Corresponding Author:** Gael Chételat, PhD, INSERM Unité U1237, GIP CYCERON, Bd Henri Becquerel - BP 5229, 14074 Caen Cedex 5, France (chetelat@cyceron.fr).
JAMA Neurology | Original Investigation

# Effect of an 18-Month Meditation Training on Regional Brain Volume and Perfusion in Older Adults

## The Age-Well Randomized Clinical Trial

Gael Chételat, PhD; Antoine Lutz, PhD; Olga Klimecki, PhD; Eric Frison, MD, PhD; Julien Asselineau, MSc; Marco Schlosser, MSc; Eider M. Arenaza-Urquijo, PhD; Florence Mézenge, MSc; Elizabeth Kuhn, PhD; Inès Moulinet, PhD; Edelweiss Touron, MSc; Sophie Dautricourt, PhD; Claire André, PhD; Cassandre Palix, MSc; Valentin Ourry, PhD; Francesca Felisatti, MSc; Julie Gonneaud, PhD; Brigitte Landeau, MSc; Géraldine Rauchs, PhD; Anne Chocat, MD; Anne Quillard, MD; Eglantine Ferrand Devouge, MD; Patrik Vuilleumier, MD; Vincent de La Sayette, MD; Denis Vivien, PhD; Fabienne Collette, PhD; Géraldine Poisnel, PhD; Natalie L. Marchant, PhD; for the Medit-Ageing Research Group

**IMPORTANCE** No lifestyle-based randomized clinical trial directly targets psychoaffective risk factors of dementia. Meditation practices recently emerged as a promising mental training exercise to foster brain health and reduce dementia risk.

**OBJECTIVE** To investigate the effects of meditation training on brain integrity in older adults.

**DESIGN, SETTING, AND PARTICIPANTS** Age-Well was a randomized, controlled superiority trial with blinded end point assessment. Community-dwelling cognitively unimpaired adults 65 years and older were enrolled between November 24, 2016, and March 5, 2018, in France. Participants were randomly assigned (1:1:1) to (1) an 18-month meditation-based training, (2) a structurally matched non-native language (English) training, or (3) no intervention arm. Analysis took place between December 2020 and October 2021.

**INTERVENTIONS** Meditation and non-native language training included 2-hour weekly group sessions, practice of 20 minutes or longer daily at home, and 1-day intensive practices.

**MAIN OUTCOMES AND MEASURES** Primary outcomes included volume and perfusion of anterior cingulate cortex (ACC) and insula. Main secondary outcomes included a global composite score capturing metacognitive, prosocial, and self-regulatory capacities and constituent subscores.

**RESULTS** Among 137 participants (mean [SD] age, 69.4 [3.8] years; 83 [60.6%] female; 54 [39.4%] male) assigned to the meditation (n = 45), non-native language training (n = 46), or no intervention (n = 46) groups, all but 1 completed the trial. There were no differences in volume changes of ACC (0.01 [98.75% CI, -0.02 to 0.05]; P = .36) or insula (0.01 [98.75% CI, -0.02 to 0.03]; P = .58) between meditation and no intervention or non-native language training groups, respectively. Differences in perfusion changes did not reach statistical significance for meditation compared with no intervention in ACC (0.02 [98.75% CI, -0.01 to 0.05]; P = .06) or compared with non-native language training in insula (0.02 [98.75% CI, -0.01 to 0.05]; P = .09). Meditation was superior to non-native language training on 18-month changes in a global composite score capturing attention regulation, socioemotional, and self-knowledge capacities (Cohen d, 0.52 [95% CI, 0.19-0.85]; P = .002).

**CONCLUSIONS AND RELEVANCE** The study findings confirm the feasibility of meditation and non-native language training in elderly individuals, with high adherence and very low attrition. Findings also show positive behavioral effects of meditation that were not reflected on volume, and not significantly on perfusion, of target brain areas.

**TRIAL REGISTRATION** ClinicalTrials.gov Identifier: NCT02977819

JAMA Neurol. 2022;79(11):1165-1174. doi:10.1001/jamaneurol.2022.3185
Published online October 10, 2022.

<figure><img src="image_2.png" /></figure>

Visual Abstract

<figure><img src="image_3.png" /></figure>

Supplemental content

**Author Affiliations:** Author affiliations are listed at the end of this article.

**Group Information:** The Medit-Ageing Research Group is listed in Supplement 3.

**Corresponding Author:** Gael Chételat, PhD, INSERM Unité U1237, GIP CYCERON, Bd Henri Becquerel - BP 5229, 14074 Caen Cedex 5, France (chetelat@cyceron.fr).
Strategies to prevent dementia are urgently needed. In later life, the main risk factors for dementia include smoking, depression, social isolation, physical inactivity, air pollution, and diabetes.¹ There is also evidence for other potentially modifiable risk factors, including hearing loss, poor diet, anxiety, neuroticism, repetitive negative thinking, and sleep disorders.¹⁻³ Recent and ongoing lifestyle-based multi-domain interventions thus include cognitive stimulation, physical activity, diet, and cardiovascular recommendations.⁴⁻⁶ However, psychoaffective risk factors, including depression, stress, and anxiety have not been directly targeted, to our knowledge.

Mental training that targets stress and attention regulation has the potential to improve both cognitive and emotional aspects of aging.⁷,⁸ Previous studies have shown that mindfulness meditation improves cognition, specifically in older adults across multiple domains including attention, executive functions, and self-awareness or meta-cognition.⁹⁻¹² Mindfulness meditation can also reduce stress, anxiety, and depression,¹³⁻¹⁵ including in older adults.¹⁶ Moreover, meditation in young adults has been associated with brain structural and functional changes mainly in frontal and limbic networks,¹⁰,¹⁷ with the insula and anterior cingulate cortex (ACC) being the most sensitive regions to meditation training according to a recent meta-analysis.¹⁸ These interconnected brain regions form the salience network and are particularly involved in self-awareness,¹⁹,²⁰ attentional, emotional and empathic processing,¹⁵ and self-regulation of attention and emotion.²⁰,²¹ They are consistently reported in task-related functional magnetic resonance imaging (MRI) studies on meditation,¹⁰,¹⁷ showing increased activity during mindfulness and/or compassion meditation.⁷ Interestingly, these brain areas are also particularly sensitive to aging.²²⁻²⁴ Studies on meditation in elderly populations are sparse, with high risk of bias, and there are no randomized clinical trials (RCTs) with large samples. The 3 RCTs in older adults with neuroimaging end points used 8-week training and reported conflicting findings.²⁵⁻²⁷ Two cross-sectional studies assessing elderly expert meditators showed more age-preserved gray matter volume and/or glucose metabolism in various brain regions including the ACC and insula compared with nonmeditators.²²,²⁸

Thus, meditation appears to be a promising approach to preserve brain structure and function as well as cognition and thus to reduce dementia risk by directly targeting psychoaffective factors. Faced with methodological limitations in previous or ongoing studies, the Age-Well RCT of the Medit-Aging European project was designed to investigate the impact of an 18-month meditation intervention on the volume and perfusion of the ACC and insula (coprprimary outcomes) compared with active (non-native language training) and passive (no intervention) control groups, respectively, and on a self-report-based global composite score capturing attention regulation, socioemotional, and self-knowledge capacities and its constituent subscores (main secondary outcomes) compared with the active control group to test for meditation-specific effects.

## Key Points

**Question** Could meditation, a mental training approach toward attention and emotion regulation, preserve brain structure and function in cognitively unimpaired older adults?

**Findings** In this randomized clinical trial that included 137 cognitively unimpaired community-dwelling older individuals, the 18-month meditation-based intervention did not significantly modify the volume of the anterior cingulate cortex and insula compared with a passive or active control, respectively.

**Meaning** Future analyses on secondary outcomes will determine the measures most sensitive to meditation training and the factors associated with responsiveness to the intervention.

## Methods

### Study Design and Participants

The design and method of Age-Well have been described previously.²⁹ The trial protocol and statistical analysis plan are available in Supplement 1. Briefly, our study was an 18-month monocentric, randomized, observer-blind controlled superiority clinical trial with 3 parallel groups: 1 group with a meditation-based training (intervention group), 1 group with structurally matched non-native language training (English learning = active control group), and 1 group with no intervention (passive control group). Participants fulfilling eligibility criteria were invited to the baseline preintervention visit and then randomized. Participants were enrolled between November 24, 2016, and March 5, 2018. The 18-month intervention period started just after randomization, and participants had a midintervention visit at 9 months and a postintervention visit at the end of the intervention. Participants were 65 years or older, community-dwelling, native French speakers, retired for at least 1 year, had 7 years or more of education, and performed within the normal range for age and educational level on standardized cognitive tests (see Tables 1 and 2 in Poisnel et al²⁹ for details). They had no evidence of major neurological or psychiatric disorders, no history of cerebrovascular disease, chronic disease or acute unstable illness, and no current medication that could interfere with cognitive functioning. Full eligibility criteria are listed in eAppendix 1 in Supplement 2. All participants gave their written informed consent to participate in the study. The Age-Well RCT, sponsored by Institut National de la Santé et de la Recherche Médicale (INSERM), was approved by the ethics committee (CPP Nord-Ouest III, Caen).

Detailed biological, behavioral, neuroimaging, and sleep measures were collected in Caen, France, at the preintervention and postintervention visits (the full list is available from Poisnel et al²⁹ and eAppendix 2 in Supplement 2), including the structural T1-weighted MRI and early ¹⁸F-florbetapir (Amyvid; Lily Diagnostics) positron emission tomography (PET) scan, used for the primary outcomes, and the self-reported measures used to compute the global composite score and subscores used as the main secondary outcomes.³⁰
Strategies to prevent dementia are urgently needed. In later life, the main risk factors for dementia include smoking, depression, social isolation, physical inactivity, air pollution, and diabetes.¹ There is also evidence for other potentially modifiable risk factors, including hearing loss, poor diet, anxiety, neuroticism, repetitive negative thinking, and sleep disorders.¹⁻³ Recent and ongoing lifestyle-based multi-domain interventions thus include cognitive stimulation, physical activity, diet, and cardiovascular recommendations.⁴⁻⁶ However, psychoaffective risk factors, including depression, stress, and anxiety have not been directly targeted, to our knowledge.

Mental training that targets stress and attention regulation has the potential to improve both cognitive and emotional aspects of aging.⁷,⁸ Previous studies have shown that mindfulness meditation improves cognition, specifically in older adults across multiple domains including attention, executive functions, and self-awareness or meta-cognition.⁹⁻¹² Mindfulness meditation can also reduce stress, anxiety, and depression,¹³⁻¹⁵ including in older adults.¹⁶ Moreover, meditation in young adults has been associated with brain structural and functional changes mainly in frontal and limbic networks,¹⁰,¹⁷ with the insula and anterior cingulate cortex (ACC) being the most sensitive regions to meditation training according to a recent meta-analysis.¹⁸ These interconnected brain regions form the salience network and are particularly involved in self-awareness,¹⁹,²⁰ attentional, emotional and empathic processing,¹⁵ and self-regulation of attention and emotion.²⁰,²¹ They are consistently reported in task-related functional magnetic resonance imaging (MRI) studies on meditation,¹⁰,¹⁷ showing increased activity during mindfulness and/or compassion meditation.⁷ Interestingly, these brain areas are also particularly sensitive to aging.²²⁻²⁴ Studies on meditation in elderly populations are sparse, with high risk of bias, and there are no randomized clinical trials (RCTs) with large samples. The 3 RCTs in older adults with neuroimaging end points used 8-week training and reported conflicting findings.²⁵⁻²⁷ Two cross-sectional studies assessing elderly expert meditators showed more age-preserved gray matter volume and/or glucose metabolism in various brain regions including the ACC and insula compared with nonmeditators.²²,²⁸

Thus, meditation appears to be a promising approach to preserve brain structure and function as well as cognition and thus to reduce dementia risk by directly targeting psychoaffective factors. Faced with methodological limitations in previous or ongoing studies, the Age-Well RCT of the Medit-Aging European project was designed to investigate the impact of an 18-month meditation intervention on the volume and perfusion of the ACC and insula (coprprimary outcomes) compared with active (non-native language training) and passive (no intervention) control groups, respectively, and on a self-report-based global composite score capturing attention regulation, socioemotional, and self-knowledge capacities and its constituent subscores (main secondary outcomes) compared with the active control group to test for meditation-specific effects.

## Key Points

**Question** Could meditation, a mental training approach toward attention and emotion regulation, preserve brain structure and function in cognitively unimpaired older adults?

**Findings** In this randomized clinical trial that included 137 cognitively unimpaired community-dwelling older individuals, the 18-month meditation-based intervention did not significantly modify the volume of the anterior cingulate cortex and insula compared with a passive or active control, respectively.

**Meaning** Future analyses on secondary outcomes will determine the measures most sensitive to meditation training and the factors associated with responsiveness to the intervention.

## Methods

### Study Design and Participants

The design and method of Age-Well have been described previously.²⁹ The trial protocol and statistical analysis plan are available in Supplement 1. Briefly, our study was an 18-month monocentric, randomized, observer-blind controlled superiority clinical trial with 3 parallel groups: 1 group with a meditation-based training (intervention group), 1 group with structurally matched non-native language training (English learning = active control group), and 1 group with no intervention (passive control group). Participants fulfilling eligibility criteria were invited to the baseline preintervention visit and then randomized. Participants were enrolled between November 24, 2016, and March 5, 2018. The 18-month intervention period started just after randomization, and participants had a midintervention visit at 9 months and a postintervention visit at the end of the intervention. Participants were 65 years or older, community-dwelling, native French speakers, retired for at least 1 year, had 7 years or more of education, and performed within the normal range for age and educational level on standardized cognitive tests (see Tables 1 and 2 in Poisnel et al²⁹ for details). They had no evidence of major neurological or psychiatric disorders, no history of cerebrovascular disease, chronic disease or acute unstable illness, and no current medication that could interfere with cognitive functioning. Full eligibility criteria are listed in eAppendix 1 in Supplement 2. All participants gave their written informed consent to participate in the study. The Age-Well RCT, sponsored by Institut National de la Santé et de la Recherche Médicale (INSERM), was approved by the ethics committee (CPP Nord-Ouest III, Caen).

Detailed biological, behavioral, neuroimaging, and sleep measures were collected in Caen, France, at the preintervention and postintervention visits (the full list is available from Poisnel et al²⁹ and eAppendix 2 in Supplement 2), including the structural T1-weighted MRI and early ¹⁸F-florbetapir (Amyvid; Lily Diagnostics) positron emission tomography (PET) scan, used for the primary outcomes, and the self-reported measures used to compute the global composite score and subscores used as the main secondary outcomes.³⁰
Randomization and Masking

Eligible participants from each of the 3 waves were random-
ized after their baseline assessment. They were randomly as-
signed (1:1:1) to the meditation, non-native language training
(active control), or no intervention (passive control) arm
according to a randomization list with permuted blocks of
varying size (6 and 9), which was generated centrally by a
biostatistician at the EUCLID clinical trials platform. All
study personnel, including the investigators and outcome
assessors, were masked to treatment allocation. Only the
meditation and non-native language teachers and the trial-
independent statisticians and data monitoring infrastructure
staff were unmasked or partially unmasked. See further de-
tails in eAppendix 3 in Supplement 2.

Interventions

The meditation and non-native language training interven-
tions were structurally equivalent in overall course length, class
time, and home activities, as well as level of expertise and num-
ber of teachers per class. Thus, they had 2-hour weekly group
sessions, daily home practice (minimum 20 minutes), and 1-day
intensive practice (5 hours) during the intervention. During the
study, participants were strongly encouraged not to practice
the activity proposed in the other group(s).

For each intervention, a manual describing the detailed
procedure was written before the study started. Both inter-
ventions have been described in detail previously.²⁹ Briefly,
the meditation intervention consisted of a secular program of
meditation training labeled the Silver Santé Study Medita-
tion Programme especially designed for this study, based on
preexisting interventions, and composed of mindfulness and
loving kindness and compassion meditations. The non-
native language training program consisted of English lan-
guage exercises designed to reinforce each participant's abili-
ties in comprehension, writing, and speaking. Participants in
the passive control group were requested not to change their
habits, ie, continue living as they used to before entering
the study.

Outcomes Measures

The copriginary outcomes were (1) for the comparison be-
tween meditation and no intervention groups, the 18-month
changes in ACC volume and perfusion (from pre- to postinter-
vention) and (2) for the comparison between meditation and
non-native language training groups, the 18-month changes
in insula volume and perfusion. These brain regions were se-
lected as they are known to be particularly sensitive both to
aging and to meditation practice (see Introduction and Lutz
et al7). The ACC was expected to be modified by both inter-
ventions (compared with no intervention), as this structure is
considered a brain signature of cognitive reserve and brain
maintenance in general,31 and to be more resistant to aging with
bilingual experience in particular.32 In contrast, the insula was
expected to be modified specifically in the meditation com-
pared with the non-native language training group, given its
role in emotional and empathic processing.33

The ACC and insula volume and perfusion measures were
obtained from T1-weighted MRI and early ¹⁸F-florbetapir PET

scans, respectively. Note that while early-phase florbetapir
has been shown to be highly correlated with fludeoxyglu-
cose-, arterial spin-labeled-, and H₂O-PET, it remains a surro-
gate marker of perfusion and glucose metabolism. The proce-
dure is detailed in eAppendix 3 in Supplement 2 and described
elsewhere.³⁴ Briefly, T1-weighted images were segmented, nor-
malized, and corrected for nonlinear warping so that values
were corrected for brain size. Early ¹⁸F-florbetapir-PET im-
ages were normalized and scaled by the white matter to ob-
tain standardized uptake values ratio. Averaged gray matter
volume and perfusion values were extracted from the result-
ing images in our 2 regions of interest.

The main secondary outcomes have been defined after
trial commencement so as to select, among the huge amount
of secondary outcomes (eAppendix 2 in Supplement 2), the
most relevant according to the goal and hypotheses of the
Age-Well RCT. They consisted of the comparison between
meditation and non-native language training on changes from
baseline to 18 months in a self-report-based global composite
score and its constituent subscores capturing (1) attention
regulation (ie, attentional subscore), (2) socioemotional ca-
capacities (ie, constructive subscore), and (3) self-knowledge
capacities to understand one's own psychological processes
(ie, deconstructive subscore). This global score and its sub-
scores, recently operationalized,³⁰,³⁵ draw on self-report mea-
sures used in Age-Well (eAppendix 4 in Supplement 2).²⁹ Each
composite subscore was computed by averaging the z scores
of the scales that were assigned to the respective composite,
while the global composite score corresponded to the mean
of the 3 composite subscores.

Adverse events and serious adverse events were re-
corded throughout the study when reported by the partici-
pants and systematically at each study visit during a consul-
tation with a physician.

Sample Size

The trial was powered to detect a relevant effect size of 0.75
for the meditation intervention, as suggested by a meta-
analysis of meditation effects on morphometric neuroimag-
ing markers.¹⁷ To detect an effect size of 0.75 for each of the
4 comparisons, with 80% power and a 2-sided type I error of
1.25% (Bonferroni correction for test multiplicity), 42 partici-
pants per arm (126 in total) were required. To account for analy-
ses on secondary outcomes, a total sample size of 150 partici-
pants was fixed. A statistical analysis plan was developed and
validated by the trial steering committee before database lock
and analyses.

Statistical Analyses

The primary outcome analysis was performed according to an
intention-to-treat principle, including all randomized partici-
pants, as planned in the statistical analysis plan. Missing
data on neuroimaging markers were handled using a miss-
ing = failure strategy, where missing values were replaced by
the most detrimental value of change observed in all groups
combined for a given outcome. Outcomes were compared
between groups using a linear regression model adjusted for
baseline prognostic factors (sex, median-centered age, level
Randomization and Masking

Eligible participants from each of the 3 waves were random-
ized after their baseline assessment. They were randomly as-
signed (1:1:1) to the meditation, non-native language training
(active control), or no intervention (passive control) arm
according to a randomization list with permuted blocks of
varying size (6 and 9), which was generated centrally by a
biostatistician at the EUCLID clinical trials platform. All
study personnel, including the investigators and outcome
assessors, were masked to treatment allocation. Only the
meditation and non-native language teachers and the trial-
independent statisticians and data monitoring infrastructure
staff were unmasked or partially unmasked. See further de-
tails in eAppendix 3 in Supplement 2.

Interventions

The meditation and non-native language training interven-
tions were structurally equivalent in overall course length, class
time, and home activities, as well as level of expertise and num-
ber of teachers per class. Thus, they had 2-hour weekly group
sessions, daily home practice (minimum 20 minutes), and 1-day
intensive practice (5 hours) during the intervention. During the
study, participants were strongly encouraged not to practice
the activity proposed in the other group(s).

For each intervention, a manual describing the detailed
procedure was written before the study started. Both inter-
ventions have been described in detail previously.²⁹ Briefly,
the meditation intervention consisted of a secular program of
meditation training labeled the Silver Santé Study Medita-
tion Programme especially designed for this study, based on
preexisting interventions, and composed of mindfulness and
loving kindness and compassion meditations. The non-
native language training program consisted of English lan-
guage exercises designed to reinforce each participant's abili-
ties in comprehension, writing, and speaking. Participants in
the passive control group were requested not to change their
habits, ie, continue living as they used to before entering
the study.

Outcomes Measures

The copriginary outcomes were (1) for the comparison be-
tween meditation and no intervention groups, the 18-month
changes in ACC volume and perfusion (from pre- to postinter-
vention) and (2) for the comparison between meditation and
non-native language training groups, the 18-month changes
in insula volume and perfusion. These brain regions were se-
lected as they are known to be particularly sensitive both to
aging and to meditation practice (see Introduction and Lutz
et al7). The ACC was expected to be modified by both inter-
ventions (compared with no intervention), as this structure is
considered a brain signature of cognitive reserve and brain
maintenance in general,31 and to be more resistant to aging with
bilingual experience in particular.32 In contrast, the insula was
expected to be modified specifically in the meditation com-
pared with the non-native language training group, given its
role in emotional and empathic processing.33

The ACC and insula volume and perfusion measures were
obtained from T1-weighted MRI and early ¹⁸F-florbetapir PET

scans, respectively. Note that while early-phase florbetapir
has been shown to be highly correlated with fludeoxyglu-
cose-, arterial spin-labeled-, and H₂O-PET, it remains a surro-
gate marker of perfusion and glucose metabolism. The proce-
dure is detailed in eAppendix 3 in Supplement 2 and described
elsewhere.³⁴ Briefly, T1-weighted images were segmented, nor-
malized, and corrected for nonlinear warping so that values
were corrected for brain size. Early ¹⁸F-florbetapir-PET im-
ages were normalized and scaled by the white matter to ob-
tain standardized uptake values ratio. Averaged gray matter
volume and perfusion values were extracted from the result-
ing images in our 2 regions of interest.

The main secondary outcomes have been defined after
trial commencement so as to select, among the huge amount
of secondary outcomes (eAppendix 2 in Supplement 2), the
most relevant according to the goal and hypotheses of the
Age-Well RCT. They consisted of the comparison between
meditation and non-native language training on changes from
baseline to 18 months in a self-report-based global composite
score and its constituent subscores capturing (1) attention
regulation (ie, attentional subscore), (2) socioemotional ca-
capacities (ie, constructive subscore), and (3) self-knowledge
capacities to understand one's own psychological processes
(ie, deconstructive subscore). This global score and its sub-
scores, recently operationalized,³⁰,³⁵ draw on self-report mea-
sures used in Age-Well (eAppendix 4 in Supplement 2).²⁹ Each
composite subscore was computed by averaging the z scores
of the scales that were assigned to the respective composite,
while the global composite score corresponded to the mean
of the 3 composite subscores.

Adverse events and serious adverse events were re-
corded throughout the study when reported by the partici-
pants and systematically at each study visit during a consul-
tation with a physician.

Sample Size

The trial was powered to detect a relevant effect size of 0.75
for the meditation intervention, as suggested by a meta-
analysis of meditation effects on morphometric neuroimag-
ing markers.¹⁷ To detect an effect size of 0.75 for each of the
4 comparisons, with 80% power and a 2-sided type I error of
1.25% (Bonferroni correction for test multiplicity), 42 partici-
pants per arm (126 in total) were required. To account for analy-
ses on secondary outcomes, a total sample size of 150 partici-
pants was fixed. A statistical analysis plan was developed and
validated by the trial steering committee before database lock
and analyses.

Statistical Analyses

The primary outcome analysis was performed according to an
intention-to-treat principle, including all randomized partici-
pants, as planned in the statistical analysis plan. Missing
data on neuroimaging markers were handled using a miss-
ing = failure strategy, where missing values were replaced by
the most detrimental value of change observed in all groups
combined for a given outcome. Outcomes were compared
between groups using a linear regression model adjusted for
baseline prognostic factors (sex, median-centered age, level
Figure 1. Trial Profile

<figure><img src="image_4.png" /></figure>

Of 137 randomized participants, 1 was excluded from all analyses due to major eligibility criteria not met (not included in the analyses), 1 died during follow-up, and 1 revealed not to have followed his allocated arm (randomized to no intervention but attended non-native language training); those 2 later participants were retained in the analyses and treated by the intention-to-treat principle, as specified in the statistical analysis plan. MRI indicates magnetic resonance imaging.

of education, and Mini-Mental State Examination) and baseline outcome value. Comparisons were made with a 1.25 type I error rate. Additional analyses were performed, including a sensitivity analysis to missing data, a “minimum intervention” analysis, and post hoc analyses for additional adjustment, stratification, and subgroup analyses (eAppendix 3 in Supplement 2).

For the secondary outcomes, the statistical analysis plan focused on between-group differences in mean changes in the global composite score and subscores in meditation vs non-native language training so as to highlight the specific effects of meditation compared with its active control. For each composite score and subscore, we built 1 mixed-effect linear regression model incorporating data from pre- and postintervention with an interaction term between visit and group, controlling for baseline scores of the outcome. In all mixed-effects regression models, missing data were not replaced and assumed to be missing at random.

Analyses were performed using SAS statistical software version 9.4 (SAS Institute) for the coprinary outcomes and R version 4.0.2 (R Foundation) for the secondary outcomes. Two-sided *P* values were statistically significant at less than .0125 for each coprinary outcome (Bonferroni correction for test multiplicity) and less than .05 for secondary outcomes. Analysis took place between December 2020 and October 2021 (and April 2022 for the supplementary analyses during the revision process).

## Results

Of 157 participants assessed for eligibility, 137 were randomized (mean [SD] age, 69.4 [3.8] years; 83 [60.6%] female; 54

[39.4%] male), among whom 1 participant was excluded from all analyses because of major eligibility criteria not met (decision by the trial steering committee blinded to group allocation for head trauma with loss of consciousness >1 hour; **Figure 1**). Among 136 participants included in the analyses, 45 were randomized to meditation, 45 to non-native language training, and 46 to the no intervention groups. One participant died during follow-up, while another participant was revealed to have not followed his allocated arm; both were retained in the analyses and included using the intention-to-treat principle, as specified in the statistical analysis plan.

Baseline characteristics of the 136 participants included in the intention-to-treat analysis are detailed in **Table 1**. There were no major clinical differences in any demographic or clinical characteristics between groups. The median (IQR) follow-up time between pre- and postintervention visits was 21.1 (20.7-21.7) months. The mean (SD) class attendance for meditation and non-native language groups was 62.0 (8.9) and 57.9 (12.2) of 72 classes, respectively. Of 45 participants, 44 in the meditation/non-native language groups attended at least 20% of their intervention classes.

For the coprinary outcomes, data were missing on baseline early ¹⁸F-florbetapir-PET scans due to extravasation and technical problems for 2 participants (meditation, n = 1 and no intervention, n = 1), and data were missing on 18-month MRI and early ¹⁸F-florbetapir-PET scans for 1 participant in the no intervention group who died during follow-up.

Primary end points at baseline and 18 months and their mean changes are reported in the eTable in Supplement 2, and intervention effects on the coprinary outcome measures in the intention-to-treat analyses are presented in **Figure 2**. The differences in the mean volume changes over 18 months be-
Figure 1. Trial Profile

<figure><img src="image_4.png" /></figure>

Of 137 randomized participants, 1 was excluded from all analyses due to major eligibility criteria not met (not included in the analyses), 1 died during follow-up, and 1 revealed not to have followed his allocated arm (randomized to no intervention but attended non-native language training); those 2 later participants were retained in the analyses and treated by the intention-to-treat principle, as specified in the statistical analysis plan. MRI indicates magnetic resonance imaging.

of education, and Mini-Mental State Examination) and baseline outcome value. Comparisons were made with a 1.25 type I error rate. Additional analyses were performed, including a sensitivity analysis to missing data, a “minimum intervention” analysis, and post hoc analyses for additional adjustment, stratification, and subgroup analyses (eAppendix 3 in Supplement 2).

For the secondary outcomes, the statistical analysis plan focused on between-group differences in mean changes in the global composite score and subscores in meditation vs non-native language training so as to highlight the specific effects of meditation compared with its active control. For each composite score and subscore, we built 1 mixed-effect linear regression model incorporating data from pre- and postintervention with an interaction term between visit and group, controlling for baseline scores of the outcome. In all mixed-effects regression models, missing data were not replaced and assumed to be missing at random.

Analyses were performed using SAS statistical software version 9.4 (SAS Institute) for the coprprimary outcomes and R version 4.0.2 (R Foundation) for the secondary outcomes. Two-sided *P* values were statistically significant at less than .0125 for each coprprimary outcome (Bonferroni correction for test multiplicity) and less than .05 for secondary outcomes. Analysis took place between December 2020 and October 2021 (and April 2022 for the supplementary analyses during the revision process).

## Results

Of 157 participants assessed for eligibility, 137 were randomized (mean [SD] age, 69.4 [3.8] years; 83 [60.6%] female; 54

[39.4%] male), among whom 1 participant was excluded from all analyses because of major eligibility criteria not met (decision by the trial steering committee blinded to group allocation for head trauma with loss of consciousness >1 hour; **Figure 1**). Among 136 participants included in the analyses, 45 were randomized to meditation, 45 to non-native language training, and 46 to the no intervention groups. One participant died during follow-up, while another participant was revealed to have not followed his allocated arm; both were retained in the analyses and included using the intention-to-treat principle, as specified in the statistical analysis plan.

Baseline characteristics of the 136 participants included in the intention-to-treat analysis are detailed in **Table 1**. There were no major clinical differences in any demographic or clinical characteristics between groups. The median (IQR) follow-up time between pre- and postintervention visits was 21.1 (20.7-21.7) months. The mean (SD) class attendance for meditation and non-native language groups was 62.0 (8.9) and 57.9 (12.2) of 72 classes, respectively. Of 45 participants, 44 in the meditation/non-native language groups attended at least 20% of their intervention classes.

For the coprprimary outcomes, data were missing on baseline early ¹⁸F-florbetapir-PET scans due to extravasation and technical problems for 2 participants (meditation, n = 1 and no intervention, n = 1), and data were missing on 18-month MRI and early ¹⁸F-florbetapir-PET scans for 1 participant in the no intervention group who died during follow-up.

Primary end points at baseline and 18 months and their mean changes are reported in the eTable in Supplement 2, and intervention effects on the coprprimary outcome measures in the intention-to-treat analyses are presented in **Figure 2**. The differences in the mean volume changes over 18 months be-
<table><caption>Table 1. Baseline Characteristics</caption><thead><tr><th rowspan="2">Characteristic</th><th colspan="3">Mean (SD)</th></tr><tr><th>Meditation (n = 45)</th><th>Non-native language training (n = 45)</th><th>No intervention (n = 46)</th></tr></thead><tbody><tr><td>Age, median (IQR), y</td><td>68 (67-72)</td><td>69 (67-73)</td><td>68 (66-70)</td></tr><tr><td>Female, No. (%)</td><td>31 (69)</td><td>24 (53)</td><td>28 (61)</td></tr><tr><td>Male, No. (%)</td><td>14 (31)</td><td>21 (47)</td><td>18 (39)</td></tr><tr><td>Years of education</td><td>13 (3)</td><td>12 (3)</td><td>14 (2)</td></tr><tr><td>Years in retirement</td><td>7 (5-13)</td><td>9 (5-13)</td><td>6 (4-10)</td></tr><tr><td>Handedness laterality</td><td>92 (83-100)</td><td>91 (83-100)</td><td>92 (83-100)</td></tr><tr><td>BP level, mm Hg</td><td></td><td></td><td></td></tr><tr><td>Systolic</td><td>143.6 (20.1)</td><td>145.3 (16.4)</td><td>136.7 (20.5)</td></tr><tr><td>Diastolic</td><td>86.1 (10.5)</td><td>86.6 (10.0)</td><td>84.8 (11.7)</td></tr><tr><td>BMI</td><td>26.1 (4.6)</td><td>26.5 (4.3)</td><td>25.9 (4.0)</td></tr><tr><td>Mini-Mental State Examination score</td><td>28.9 (1.2)</td><td>29.0 (1.0)</td><td>29.2 (0.9)</td></tr><tr><td>Montgomery-Åsberg Depression Rating Scale score</td><td>1.2 (1.2)</td><td>1.2 (1.5)</td><td>0.7 (1.0)</td></tr><tr><td>APOE ε4 carriers (≥1 allele), No. (%)</td><td>13 (29)</td><td>13 (29)</td><td>11 (24)</td></tr><tr><td>Positive for brain amyloid,<sup>a</sup> No. (%)</td><td>11 (24)</td><td>11 (24)</td><td>6 (13)</td></tr><tr><td>Amyloid SUVR</td><td>1.26 (0.16)</td><td>1.27 (0.19)</td><td>1.21 (0.10)</td></tr><tr><td>Familial history of dementia, No. (%)</td><td>14 (31)</td><td>11 (24)</td><td>14 (30)</td></tr><tr><td>Presence of ≥1 Alzheimer disease risk factors,<sup>b</sup> No. (%)</td><td>28 (62)</td><td>23 (51)</td><td>23 (51)</td></tr></tbody></table>

Abbreviations: APOE, apolipoprotein E; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); BP, blood pressure; SUVR, standardized uptake values ratio.

<sup>a</sup> Methods detailed in eAppendix 3 in Supplement 2.

<sup>b</sup> Alzheimer disease risk factors include APOE ε4 (≥1 allele), brain amyloid positivity, and familial history of dementia.

<figure><img src="image_5.png" /><figcaption>Figure 2. Forest Plots for Anterior Cingulate Cortex (ACC) and Insula Volume and Perfusion</figcaption></figure>

<figure><img src="image_6.png" /></figure>

Results of the intention-to-treat analyses with missing = failure strategy are shown.

tween meditation and no intervention in the ACC (0.01 [98.75% CI, -0.02 to 0.05]) or the non-native language group in the insula (0.01 [98.75% CI, -0.02 to 0.03]) were not statistically significant (P = .36 and P = .58, respectively). As for perfusion, differences in the mean changes over 18 months, in favor of meditation compared with no intervention in the ACC (0.02 [98.75% CI, -0.01 to 0.05]) and compared with non-native language training in the insula (0.02 [98.75% CI, -0.01 to 0.05]) did not reach statistical significance (P = .06 and P = .09, respectively).

Results of the sensitivity and post hoc analyses are presented in Figure 3 and in eAppendix 5 in Supplement 2. Briefly, results were very similar to those of the main analyses, showing no between-group differences in the volume changes of the ACC or insula. Changes in the perfusion of the ACC or insula always favored meditation (compared with no intervention or

non-native language training, respectively), but the between-group differences never reached statistical significance. Finally, the subgroup analyses showed that neither the recruitment wave nor the presence of risk factor(s) for Alzheimer disease (apolipoprotein E ε4 genotype, brain amyloid positivity, familial history of dementia, or presence of at least 1 of these risk factors) affected the results.

Regarding secondary outcomes, the global composite score and attention regulation subscore were not computed for 1 participant because of missing data at baseline on a subscale assigned to the attention regulation subscore. Secondary end points at baseline and 18 months and their standardized mean changes are reported in Table 2 and in eAppendix 6 and 7 in Supplement 2. The differences in the mean changes over 18 months between meditation and non-native language training in the global composite score (0.52
<table><caption>Table 1. Baseline Characteristics</caption><thead><tr><th rowspan="2">Characteristic</th><th colspan="3">Mean (SD)</th></tr><tr><th>Meditation (n = 45)</th><th>Non-native language training (n = 45)</th><th>No intervention (n = 46)</th></tr></thead><tbody><tr><td>Age, median (IQR), y</td><td>68 (67-72)</td><td>69 (67-73)</td><td>68 (66-70)</td></tr><tr><td>Female, No. (%)</td><td>31 (69)</td><td>24 (53)</td><td>28 (61)</td></tr><tr><td>Male, No. (%)</td><td>14 (31)</td><td>21 (47)</td><td>18 (39)</td></tr><tr><td>Years of education</td><td>13 (3)</td><td>12 (3)</td><td>14 (2)</td></tr><tr><td>Years in retirement</td><td>7 (5-13)</td><td>9 (5-13)</td><td>6 (4-10)</td></tr><tr><td>Handedness laterality</td><td>92 (83-100)</td><td>91 (83-100)</td><td>92 (83-100)</td></tr><tr><td>BP level, mm Hg</td><td></td><td></td><td></td></tr><tr><td>Systolic</td><td>143.6 (20.1)</td><td>145.3 (16.4)</td><td>136.7 (20.5)</td></tr><tr><td>Diastolic</td><td>86.1 (10.5)</td><td>86.6 (10.0)</td><td>84.8 (11.7)</td></tr><tr><td>BMI</td><td>26.1 (4.6)</td><td>26.5 (4.3)</td><td>25.9 (4.0)</td></tr><tr><td>Mini-Mental State Examination score</td><td>28.9 (1.2)</td><td>29.0 (1.0)</td><td>29.2 (0.9)</td></tr><tr><td>Montgomery-Åsberg Depression Rating Scale score</td><td>1.2 (1.2)</td><td>1.2 (1.5)</td><td>0.7 (1.0)</td></tr><tr><td>APOE ε4 carriers (≥1 allele), No. (%)</td><td>13 (29)</td><td>13 (29)</td><td>11 (24)</td></tr><tr><td>Positive for brain amyloid,<sup>a</sup> No. (%)</td><td>11 (24)</td><td>11 (24)</td><td>6 (13)</td></tr><tr><td>Amyloid SUVR</td><td>1.26 (0.16)</td><td>1.27 (0.19)</td><td>1.21 (0.10)</td></tr><tr><td>Familial history of dementia, No. (%)</td><td>14 (31)</td><td>11 (24)</td><td>14 (30)</td></tr><tr><td>Presence of ≥1 Alzheimer disease risk factors,<sup>b</sup> No. (%)</td><td>28 (62)</td><td>23 (51)</td><td>23 (51)</td></tr></tbody></table>

Abbreviations: APOE, apolipoprotein E; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); BP, blood pressure; SUVR, standardized uptake values ratio.

<sup>a</sup> Methods detailed in eAppendix 3 in Supplement 2.

<sup>b</sup> Alzheimer disease risk factors include APOE ε4 (≥1 allele), brain amyloid positivity, and familial history of dementia.

<figure><img src="image_5.png" /><figcaption>Figure 2. Forest Plots for Anterior Cingulate Cortex (ACC) and Insula Volume and Perfusion</figcaption></figure>

<figure><img src="image_6.png" /></figure>

Results of the intention-to-treat analyses with missing = failure strategy are shown.

tween meditation and no intervention in the ACC (0.01 [98.75% CI, -0.02 to 0.05]) or the non-native language group in the insula (0.01 [98.75% CI, -0.02 to 0.03]) were not statistically significant (P = .36 and P = .58, respectively). As for perfusion, differences in the mean changes over 18 months, in favor of meditation compared with no intervention in the ACC (0.02 [98.75% CI, -0.01 to 0.05]) and compared with non-native language training in the insula (0.02 [98.75% CI, -0.01 to 0.05]) did not reach statistical significance (P = .06 and P = .09, respectively).

Results of the sensitivity and post hoc analyses are presented in **Figure 3** and in eAppendix 5 in Supplement 2. Briefly, results were very similar to those of the main analyses, showing no between-group differences in the volume changes of the ACC or insula. Changes in the perfusion of the ACC or insula always favored meditation (compared with no intervention or

non-native language training, respectively), but the between-group differences never reached statistical significance. Finally, the subgroup analyses showed that neither the recruitment wave nor the presence of risk factor(s) for Alzheimer disease (apolipoprotein E ε4 genotype, brain amyloid positivity, familial history of dementia, or presence of at least 1 of these risk factors) affected the results.

Regarding secondary outcomes, the global composite score and attention regulation subscore were not computed for 1 participant because of missing data at baseline on a subscale assigned to the attention regulation subscore. Secondary end points at baseline and 18 months and their standardized mean changes are reported in **Table 2** and in eAppendix 6 and 7 in Supplement 2. The differences in the mean changes over 18 months between meditation and non-native language training in the global composite score (0.52
<figure><img src="image_7.png" /><figcaption>Figure 3. Sensitivity Analyses for Anterior Cingulate Cortex (ACC) and Insula Volume and Perfusion</figcaption></figure>

a No missing outcome values for participants included in the comparison.

[95% CI, 0.19-0.85]; P = .002], attention regulation (0.38 [95% CI, 0.10-0.67]; P = .009], and socioemotional (0.31 [95% CI, 0.06-0.57]; P = .01) subscores were all statistically significant, while it was not statistically significant for the self-knowledge subscore (0.28 [95% CI, -0.01 to 0.58]; P = .06).

## Adverse Events

One death was reported during study follow-up for a participant in the no intervention group (myocardial infarction, not related to the study). A total of 170 adverse events were recorded, 41 of which were considered serious (meditation, 13; non-native language training, 15; no intervention, 13). Among
<figure><img src="image_7.png" /><figcaption>Figure 3. Sensitivity Analyses for Anterior Cingulate Cortex (ACC) and Insula Volume and Perfusion</figcaption></figure>

a No missing outcome values for participants included in the comparison.

[95% CI, 0.19-0.85]; P = .002], attention regulation (0.38 [95% CI, 0.10-0.67]; P = .009], and socioemotional (0.31 [95% CI, 0.06-0.57]; P = .01) subscores were all statistically significant, while it was not statistically significant for the self-knowledge subscore (0.28 [95% CI, -0.01 to 0.58]; P = .06).

## Adverse Events

One death was reported during study follow-up for a participant in the no intervention group (myocardial infarction, not related to the study). A total of 170 adverse events were recorded, 41 of which were considered serious (meditation, 13; non-native language training, 15; no intervention, 13). Among
<table><caption>Table 2. Results From Mixed-Effects Models Assessing Change From Baseline to 18 Months in Meditation and Non-Native Language Training in Composite Scoresª</caption><thead><tr><th rowspan="2">Outcome</th><th colspan="2">Standardized estimated change (95% CI)</th><th colspan="2">Between-group difference in change meditation vs non-native language training</th></tr><tr><th>Meditation</th><th>Non-native language training</th><th>Mean (95% CI)</th><th>P value</th></tr></thead><tbody><tr><td>Global</td><td>0.43 (0.20 to 0.67)</td><td>-0.09 (-0.12 to 0.30)</td><td>0.52 (0.19 to 0.85)</td><td>.002</td></tr><tr><td>Attention regulation capacities</td><td>0.48 (0.28 to 0.69)</td><td>0.10 (-0.10 to 0.30)</td><td>0.38 (0.10 to 0.67)</td><td>.009</td></tr><tr><td>Socioemotional capacities</td><td>0.04 (-0.15 to 0.23)</td><td>-0.27 (-0.46 to -0.08)</td><td>0.31 (0.06 to 0.57)</td><td>.02</td></tr><tr><td>Self-knowledge capacities</td><td>0.27 (0.07 to 0.48)</td><td>-0.01 (-0.22 to 0.20)</td><td>0.28 (-0.01 to 0.58)</td><td>.06</td></tr></tbody></table>

ª All analyses were adjusted for baseline scores of the outcome. Positive (negative) estimated mean between-group differences reflect increases (decreases) in composite scores in the meditation intervention.

these, 7 adverse events (meditation, 3; non-native language training, 3; no intervention, 1) were judged to be related to study procedures (procedural complication, 4 [scans had to be redone]; extravasation, 2; asthenia, 1). No serious adverse event was related to the intervention.

## Discussion

Results indicate that the 18-month meditation-based intervention did not significantly modify the volume of the ACC and insula in older adults compared with a passive or active control, respectively; the between-group differences did not reach statistical significance for perfusion either. Regarding the main secondary outcomes, there were significant effects of meditation compared with non-native language training on the global composite score reflecting attention regulation, socio-emotional, and self-knowledge capacities and two-thirds of its constituent subscores.

The fact that no effects were found on anterior cingulate and insula volumes in our study, despite being identified as structures most sensitive to meditation,³⁶ might indicate that 18 months of meditation training is not sufficient to alter the effects of age on their volume. Meditation might alter volume in younger and more plastic brains but not halt the age- and disease-related brain volume decreases at older ages. While larger brain volumes were observed in cross-sectional studies in older expert meditators vs nonmeditators, especially in the ACC and insula,²² these differences might reflect meditation effects in younger ages, intense meditation practice accumulated throughout the adult lifespan, and/or between-group differences on other variables, such as lifestyle. Note that the lack of meditation effect on brain structure is consistent with the very recent publication from a large and rigorously controlled study.³⁷

Regarding perfusion, both the differences in the anterior cingulate between the meditation and no intervention groups, and in the insula between the meditation and non-native language training, were not statistically significant but close to the threshold. Mean differences between groups, in favor of meditation, were rather low (0.023 and 0.022, respectively) but could represent a substantial gain compared with the mean 18-month change observed in the no intervention group (0.031 for both the ACC and insula). Assuming

a linear loss over 18 months, the 74% and 71% reduction in rate of loss could translate into about 13 months less loss over the course of the intervention, in favor of the meditation group. One could hypothesize that a larger sample size or longer follow-up time would have yielded a significant effect of the intervention on perfusion.

The lack of significant effects on the coprinary outcomes could also be related to the design of the study, eg, the use of an RCT when the intervention, by its nature and duration, strongly relies on the motivation, preferences, and adherence of the participants. Alternative trial designs taking into account patient preference might be particularly relevant in the context of such nonpharmacological interventions.³⁸ Moreover, as in most preventive trials, our population resulted in being, through self-selection, enriched with healthy participants with high education and reserve, and low probability of cognitive decline, which left limited room for lifestyle changes and intervention-related improvements.³⁹ Finally, the selected coprinary outcomes were very specific neuroimaging measures that show variability and significant but protracted age-related changes from which it might be difficult to show a deviation in a short period of time in terms of aging effects.

Regarding secondary outcomes, meditation was superior to non-native language training on changing a global composite score and 2 of its subscores reflecting attention regulation and socioemotional capacities. As this composite score and its subscores are thought to measure core dimensions of well-being,⁴⁰ these findings suggest meditation training-related effects on mental health and human flourishing. The attention regulation subscore increased after meditation only; in the context of meditation practices, this capacity allows a heightened awareness and monitoring of the contents of experience without becoming absorbed by them. Socioemotional capacities decreased substantially after non-native language training but not meditation training, suggesting that the difference observed may be due to maintenance of skills by meditation training.

## Limitations and Strengths

Our study has several limitations. The sample size was defined based on an expected effect size of 0.75 on neuroimaging measures, which was likely overestimated as it was defined from a meta-analysis including both preintervention-
<table><caption>Table 2. Results From Mixed-Effects Models Assessing Change From Baseline to 18 Months in Meditation and Non-Native Language Training in Composite Scoresª</caption><thead><tr><th rowspan="2">Outcome</th><th colspan="2">Standardized estimated change (95% CI)</th><th colspan="2">Between-group difference in change meditation vs non-native language training</th></tr><tr><th>Meditation</th><th>Non-native language training</th><th>Mean (95% CI)</th><th>P value</th></tr></thead><tbody><tr><td>Global</td><td>0.43 (0.20 to 0.67)</td><td>-0.09 (-0.12 to 0.30)</td><td>0.52 (0.19 to 0.85)</td><td>.002</td></tr><tr><td>Attention regulation capacities</td><td>0.48 (0.28 to 0.69)</td><td>0.10 (-0.10 to 0.30)</td><td>0.38 (0.10 to 0.67)</td><td>.009</td></tr><tr><td>Socioemotional capacities</td><td>0.04 (-0.15 to 0.23)</td><td>-0.27 (-0.46 to -0.08)</td><td>0.31 (0.06 to 0.57)</td><td>.02</td></tr><tr><td>Self-knowledge capacities</td><td>0.27 (0.07 to 0.48)</td><td>-0.01 (-0.22 to 0.20)</td><td>0.28 (-0.01 to 0.58)</td><td>.06</td></tr></tbody></table>

ª All analyses were adjusted for baseline scores of the outcome. Positive (negative) estimated mean between-group differences reflect increases (decreases) in composite scores in the meditation intervention.

these, 7 adverse events (meditation, 3; non-native language training, 3; no intervention, 1) were judged to be related to study procedures (procedural complication, 4 [scans had to be redone]; extravasation, 2; asthenia, 1). No serious adverse event was related to the intervention.

## Discussion

Results indicate that the 18-month meditation-based intervention did not significantly modify the volume of the ACC and insula in older adults compared with a passive or active control, respectively; the between-group differences did not reach statistical significance for perfusion either. Regarding the main secondary outcomes, there were significant effects of meditation compared with non-native language training on the global composite score reflecting attention regulation, socioemotional, and self-knowledge capacities and two-thirds of its constituent subscores.

The fact that no effects were found on anterior cingulate and insula volumes in our study, despite being identified as structures most sensitive to meditation,³⁶ might indicate that 18 months of meditation training is not sufficient to alter the effects of age on their volume. Meditation might alter volume in younger and more plastic brains but not halt the age- and disease-related brain volume decreases at older ages. While larger brain volumes were observed in cross-sectional studies in older expert meditators vs nonmeditators, especially in the ACC and insula,²² these differences might reflect meditation effects in younger ages, intense meditation practice accumulated throughout the adult lifespan, and/or between-group differences on other variables, such as lifestyle. Note that the lack of meditation effect on brain structure is consistent with the very recent publication from a large and rigorously controlled study.³⁷

Regarding perfusion, both the differences in the anterior cingulate between the meditation and no intervention groups, and in the insula between the meditation and non-native language training, were not statistically significant but close to the threshold. Mean differences between groups, in favor of meditation, were rather low (0.023 and 0.022, respectively) but could represent a substantial gain compared with the mean 18-month change observed in the no intervention group (0.031 for both the ACC and insula). Assuming

a linear loss over 18 months, the 74% and 71% reduction in rate of loss could translate into about 13 months less loss over the course of the intervention, in favor of the meditation group. One could hypothesize that a larger sample size or longer follow-up time would have yielded a significant effect of the intervention on perfusion.

The lack of significant effects on the coprinary outcomes could also be related to the design of the study, eg, the use of an RCT when the intervention, by its nature and duration, strongly relies on the motivation, preferences, and adherence of the participants. Alternative trial designs taking into account patient preference might be particularly relevant in the context of such nonpharmacological interventions.³⁸ Moreover, as in most preventive trials, our population resulted in being, through self-selection, enriched with healthy participants with high education and reserve, and low probability of cognitive decline, which left limited room for lifestyle changes and intervention-related improvements.³⁹ Finally, the selected coprinary outcomes were very specific neuroimaging measures that show variability and significant but protracted age-related changes from which it might be difficult to show a deviation in a short period of time in terms of aging effects.

Regarding secondary outcomes, meditation was superior to non-native language training on changing a global composite score and 2 of its subscores reflecting attention regulation and socioemotional capacities. As this composite score and its subscores are thought to measure core dimensions of well-being,⁴⁰ these findings suggest meditation training-related effects on mental health and human flourishing. The attention regulation subscore increased after meditation only; in the context of meditation practices, this capacity allows a heightened awareness and monitoring of the contents of experience without becoming absorbed by them. Socioemotional capacities decreased substantially after non-native language training but not meditation training, suggesting that the difference observed may be due to maintenance of skills by meditation training.

## Limitations and Strengths

Our study has several limitations. The sample size was defined based on an expected effect size of 0.75 on neuroimaging measures, which was likely overestimated as it was defined from a meta-analysis including both preintervention-
postintervention studies and cross-sectional studies in long-
term meditation experts but also due to publication bias,
considerable methodological caveats in the existing literature
at that time, and general biases in estimating effect sizes in
neuroimaging studies.¹⁷,⁴¹ We were not able to observe this
effect size in the present study and may have been under-
powered to observe a smaller but still clinically significant
effect. Moreover, our sample was not representative of the
global aging population as it included very healthy individu-
als (see above). Finally, early-phase florbetapir is an indirect,
surrogate marker, of perfusion or fludeoxyglucose-PET, and
the optimal processing method (scaling and timeframe) is
still unclear.

Several strengths must also be noted. The primary end
points were measured blinded to allocated intervention, the
intervention was particularly long, we used both a passive
and a carefully matched active control condition, and the
exceptionally high adherence and low attrition (1 of 137 par-
ticipants only) demonstrates the appropriateness of the inter-

ventions and feasibility of this approach in healthy and moti-
vated elderly. The Age-Well clinical trial includes many
complementary biological and behavioral measures of men-
tal health and well-being. Future analyses on secondary out-
comes, including whole-brain voxelwise analyses of gray
matter volume and perfusion, but also other brain and
behavior modalities, will allow us to determine the measures
most sensitive to meditation practice, and investigate the
mechanisms of these effects.

Conclusions

Future secondary analyses from this trial will allow assess-
ment of the impact of meditation on volume and perfusion
throughout the whole brain and on other measures, and will
examine factors (participants' characteristics, additional out-
comes, intervention doses) associated with responsiveness
to the intervention.

ARTICLE INFORMATION

Accepted for Publication: June 1, 2022.

**Published Online:** October 10, 2022.
doi:10.1001/jamaneurol.2022.3185

**Open Access:** This is an open access article
distributed under the terms of the CC-BY License.
© 2022 Chételat G et al. JAMA Neurology.

**Author Affiliations:** Normandie Univ, UNICAEN, INSERM, U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Institut Blood and Brain @ Caen-Normandie, Cyceron, France (Chételat, Arenaza-Urquijo, Mézenge, Kuhn, Moulinet, Touro, Dautricourt, André, Palix, Ourry, Felisatti, Gonneaud, Landeau, Rauchs, Chocat, Quillard, Devouge, Vivien, Poisnel); Lyon Neuroscience Research Center INSERM U1028, CNRS UMR5292, Lyon 1 University, Lyon, France (Lutz); Swiss Center for Affective Sciences, Department of Neuroscience, University of Geneva Medical School, Geneva, Switzerland (Klimecki, Vuilleumier); EUCLID/F-CRIN Clinical Trials Platform, INSERM, CHU Bordeaux, University of Bordeaux, CIC1401-EC, Bordeaux, France (Frison, Asselineau); Division of Psychiatry, University College London, London, United Kingdom (Schlosser, Marchant); Department of Psychology, Faculty of Psychology and Educational Sciences, University of Geneva, Geneva, Switzerland (Schlosser); Barcelonabeta Brain Research Center, Fundación Pasqual Maragall, Barcelona, Spain (Arenaza-Urquijo); Normandie Univ, UNIROUEN, Department of General Practice, Rouen, France (Devouge); Rouen University Hospital, CIC-CRB 1404, F 76000, Rouen, France (Devouge); CHU Caen-Normandie, Department of Neurology, Caen, France (de La Sayette); CHU Caen-Normandie, Department of Clinical Research, Caen, France (Vivien); GIGA-CRC, In Vivo Imaging, Université de Liège and Belgian National Fund for Scientific Research, Liège, Belgium (Collette).

**Author Contributions:** Dr Chételat had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Chételat and Lutz served as co-first authors. Drs Klimecki and Frison

served as co-second authors. Drs Collette, Poisnel,
and Marchant served as co-last authors.

**Concept and design:** Chételat, Lutz, Klimecki, Frison, Arenaza-Urquijo, Gonneaud, Quillard, Vuilleumier, de la Sayette, Vivien, Collette, Poisnel, Marchant.

**Acquisition, analysis, or interpretation of data:**
Chételat, Lutz, Klimecki, Frison, Asselineau, Schlosser, Arenaza-Urquijo, Mézenge, Kuhn, Moulinet, Touro, Dautricourt, André, Palix, Ourry, Felisatti, Gonneaud, Landeau, Rauchs, Chocat, Ferrand Devouge, Vuilleumier, Collette, Poisnel, Marchant.

**Drafting of the manuscript:** Chételat, Lutz, Frison, Asselineau, Schlosser, Mézenge, Landeau, Vuilleumier, de la Sayette.

**Critical revision of the manuscript for important intellectual content:** Klimecki, Frison, Asselineau, Schlosser, Arenaza-Urquijo, Mézenge, Kuhn, Moulinet, Touro, Dautricourt, André, Palix, Ourry, Felisatti, Gonneaud, Landeau, Rauchs, Chocat, Quillard, Ferrand Devouge, Vuilleumier, Vivien, Collette, Poisnel, Marchant.

**Statistical analysis:** Frison, Asselineau, Schlosser.

**Obtained funding:** Chételat, Lutz, Klimecki, Arenaza-Urquijo, Vuilleumier, Vivien, Collette, Poisnel, Marchant.

**Administrative, technical, or material support:** Lutz, Klimecki, Moulinet, Rauchs, Ferrand Devouge, Vuilleumier, Vivien, Poisnel.

**Supervision:** Chételat, Lutz, Frison, Vuilleumier, de la Sayette, Poisnel, Marchant.

**Conflict of Interest Disclosures:** Drs Chételat, Lutz, Klimecki, Gonneaud, Poisnel, Collette, and Marchant have received research support from the European Union's Horizon 2020 research and innovation programme under grant 667696. Drs Chételat, Lutz, Kuhn, Moulinet, and André have received support from their institution Institut National de la Santé et de la Recherche Médicale (Inserm). Dr Chételat has received research support from Fondation Alzheimer, Fondation Recherche Alzheimer, Région Normandie, Association France Alzheimer et maladies apparentées, and Fondation Vaincre Alzheimer and personal fees from Caen, Paris, Lyon and Nice Universities (salary for lectures), and Fondation Alzheimer (as member

of the operational committee) outside the
submitted work. Drs Chételat and Lutz have
received research support from Fondation
d'Entreprise MMA des Entrepreneurs du Futur
and MMA (payments made to the institution).
Dr Klimecki reported consulting companies and
teaching meditation in addition to her scientific
work. Dr Kuhn reported grants from French
Ministry of Higher Education and Research
(3 years of PhD, 2017-2020) during the conduct
of the study and grants from Fondation Philippe
Chatrier (2022 postdoctoral grant) outside the
submitted work. Dr Touro reported grants from
Ministry of Higher Education and Research
(thesis grant, France) outside the submitted work.
Dr André has received research support from
Fonds Européen de Développement Régional
 payment made to the institution). Dr Gonneaud
reported grants from Fondation Alzheimer and
Fondation de France, which covered her salary
during the conduct of the study. Dr Vuilleumier
reported grants from Swiss National Science
Foundation and European Commission H2020
during the conduct of the study. Dr Poisnel
reported grants and nonfinancial support from
INSERM during the conduct of the study; grants
from INSERM outside the submitted work; and
has participated in the data safety monitoring
board of the Age-Well trial and to the executive
committee of Medit-Ageing. Dr Marchant received
grants from Alzheimer's Society and Medical
Research Council (payment made to the institution)
outside the submitted work. No other disclosures
were reported.

**Funding/Support:** This study was funded by European Union's Horizon 2020 research and innovation programme and Fondation d'Entreprise MMA des Entrepreneurs du Futur.

**Role of the Funder/Sponsor:** The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

**Group Information:** The Medit-Ageing Research Group is listed in Supplement 3.
postintervention studies and cross-sectional studies in long-
term meditation experts but also due to publication bias,
considerable methodological caveats in the existing literature
at that time, and general biases in estimating effect sizes in
neuroimaging studies.¹⁷,⁴¹ We were not able to observe this
effect size in the present study and may have been under-
powered to observe a smaller but still clinically significant
effect. Moreover, our sample was not representative of the
global aging population as it included very healthy individu-
als (see above). Finally, early-phase florbetapir is an indirect,
surrogate marker, of perfusion or fludeoxyglucose-PET, and
the optimal processing method (scaling and timeframe) is
still unclear.

Several strengths must also be noted. The primary end
points were measured blinded to allocated intervention, the
intervention was particularly long, we used both a passive
and a carefully matched active control condition, and the
exceptionally high adherence and low attrition (1 of 137 par-
ticipants only) demonstrates the appropriateness of the inter-

ventions and feasibility of this approach in healthy and moti-
vated elderly. The Age-Well clinical trial includes many
complementary biological and behavioral measures of men-
tal health and well-being. Future analyses on secondary out-
comes, including whole-brain voxelwise analyses of gray
matter volume and perfusion, but also other brain and
behavior modalities, will allow us to determine the measures
most sensitive to meditation practice, and investigate the
mechanisms of these effects.

Conclusions

Future secondary analyses from this trial will allow assess-
ment of the impact of meditation on volume and perfusion
throughout the whole brain and on other measures, and will
examine factors (participants' characteristics, additional out-
comes, intervention doses) associated with responsiveness
to the intervention.

ARTICLE INFORMATION

Accepted for Publication: June 1, 2022.

**Published Online:** October 10, 2022.
doi:10.1001/jamaneurol.2022.3185

**Open Access:** This is an open access article
distributed under the terms of the CC-BY License.
© 2022 Chételat G et al. JAMA Neurology.

**Author Affiliations:** Normandie Univ, UNICAEN, INSERM, U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Institut Blood and Brain @ Caen-Normandie, Cyceron, France (Chételat, Arenaza-Urquijo, Mézenge, Kuhn, Moulinet, Touro, Dautricourt, André, Palix, Ourry, Felisatti, Gonneaud, Landeau, Rauchs, Chocat, Quillard, Devouge, Vivien, Poisnel); Lyon Neuroscience Research Center INSERM U1028, CNRS UMR5292, Lyon 1 University, Lyon, France (Lutz); Swiss Center for Affective Sciences, Department of Neuroscience, University of Geneva Medical School, Geneva, Switzerland (Klimecki, Vuilleumier); EUCLID/F-CRIN Clinical Trials Platform, INSERM, CHU Bordeaux, University of Bordeaux, CIC1401-EC, Bordeaux, France (Frison, Asselineau); Division of Psychiatry, University College London, London, United Kingdom (Schlosser, Marchant); Department of Psychology, Faculty of Psychology and Educational Sciences, University of Geneva, Geneva, Switzerland (Schlosser); Barcelonabeta Brain Research Center, Fundación Pasqual Maragall, Barcelona, Spain (Arenaza-Urquijo); Normandie Univ, UNIROUEN, Department of General Practice, Rouen, France (Devouge); Rouen University Hospital, CIC-CRB 1404, F 76000, Rouen, France (Devouge); CHU Caen-Normandie, Department of Neurology, Caen, France (de La Sayette); CHU Caen-Normandie, Department of Clinical Research, Caen, France (Vivien); GIGA-CRC, In Vivo Imaging, Université de Liège and Belgian National Fund for Scientific Research, Liège, Belgium (Collette).

**Author Contributions:** Dr Chételat had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Chételat and Lutz served as co-first authors. Drs Klimecki and Frison

served as co-second authors. Drs Collette, Poisnel,
and Marchant served as co-last authors.

**Concept and design:** Chételat, Lutz, Klimecki, Frison, Arenaza-Urquijo, Gonneaud, Quillard, Vuilleumier, de la Sayette, Vivien, Collette, Poisnel, Marchant.

**Acquisition, analysis, or interpretation of data:**
Chételat, Lutz, Klimecki, Frison, Asselineau, Schlosser, Arenaza-Urquijo, Mézenge, Kuhn, Moulinet, Touro, Dautricourt, André, Palix, Ourry, Felisatti, Gonneaud, Landeau, Rauchs, Chocat, Ferrand Devouge, Vuilleumier, Collette, Poisnel, Marchant.

**Drafting of the manuscript:** Chételat, Lutz, Frison, Asselineau, Schlosser, Mézenge, Landeau, Vuilleumier, de la Sayette.

**Critical revision of the manuscript for important intellectual content:** Klimecki, Frison, Asselineau, Schlosser, Arenaza-Urquijo, Mézenge, Kuhn, Moulinet, Touro, Dautricourt, André, Palix, Ourry, Felisatti, Gonneaud, Landeau, Rauchs, Chocat, Quillard, Ferrand Devouge, Vuilleumier, Vivien, Collette, Poisnel, Marchant.

**Statistical analysis:** Frison, Asselineau, Schlosser.

**Obtained funding:** Chételat, Lutz, Klimecki, Arenaza-Urquijo, Vuilleumier, Vivien, Collette, Poisnel, Marchant.

**Administrative, technical, or material support:** Lutz, Klimecki, Moulinet, Rauchs, Ferrand Devouge, Vuilleumier, Vivien, Poisnel.

**Supervision:** Chételat, Lutz, Frison, Vuilleumier, de la Sayette, Poisnel, Marchant.

**Conflict of Interest Disclosures:** Drs Chételat, Lutz, Klimecki, Gonneaud, Poisnel, Collette, and Marchant have received research support from the European Union's Horizon 2020 research and innovation programme under grant 667696. Drs Chételat, Lutz, Kuhn, Moulinet, and André have received support from their institution Institut National de la Santé et de la Recherche Médicale (Inserm). Dr Chételat has received research support from Fondation Alzheimer, Fondation Recherche Alzheimer, Région Normandie, Association France Alzheimer et maladies apparentées, and Fondation Vaincre Alzheimer and personal fees from Caen, Paris, Lyon and Nice Universities (salary for lectures), and Fondation Alzheimer (as member

of the operational committee) outside the
submitted work. Drs Chételat and Lutz have
received research support from Fondation
d'Entreprise MMA des Entrepreneurs du Futur
and MMA (payments made to the institution).
Dr Klimecki reported consulting companies and
teaching meditation in addition to her scientific
work. Dr Kuhn reported grants from French
Ministry of Higher Education and Research
(3 years of PhD, 2017-2020) during the conduct
of the study and grants from Fondation Philippe
Chatrier (2022 postdoctoral grant) outside the
submitted work. Dr Touro reported grants from
Ministry of Higher Education and Research
(thesis grant, France) outside the submitted work.
Dr André has received research support from
Fonds Européen de Développement Régional
 payment made to the institution). Dr Gonneaud
reported grants from Fondation Alzheimer and
Fondation de France, which covered her salary
during the conduct of the study. Dr Vuilleumier
reported grants from Swiss National Science
Foundation and European Commission H2020
during the conduct of the study. Dr Poisnel
reported grants and nonfinancial support from
INSERM during the conduct of the study; grants
from INSERM outside the submitted work; and
has participated in the data safety monitoring
board of the Age-Well trial and to the executive
committee of Medit-Ageing. Dr Marchant received
grants from Alzheimer's Society and Medical
Research Council (payment made to the institution)
outside the submitted work. No other disclosures
were reported.

**Funding/Support:** This study was funded by European Union's Horizon 2020 research and innovation programme and Fondation d'Entreprise MMA des Entrepreneurs du Futur.

**Role of the Funder/Sponsor:** The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

**Group Information:** The Medit-Ageing Research Group is listed in Supplement 3.
**Additional Contributions:** We thank D. Roquet, PhD (Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), and Oriane Hébert, MSc (Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), for their help with the reviewing process; A. Cognet, MSc (Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), M. Botton, MSc (Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), S. Egret, MSc (Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), P. Lacheray, MSc (Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), J. Lebahar, PhD (Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), C. Tomadesso, PhD (Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), F. Allais (EUCLID data manager; Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), and Jeanne Lepetit MSc (Mediapilote); M. Ricard, PhD (Mind and Life Europe, Winterthur, Switzerland & Shechen Monastery, Kathmandu, Nepal), J. F. Lemoine, MD (EUROPEI), Jon Kabat-Zinn, PhD (UMass Medical School, Worcester, MA), Rhonda Smith, MSc (Minerva), Charlotte Reid (Minerva), and Amanda Beard (Minerva); the sponsor, Hélène Espérou, MD (Pôle de recherche clinique Inserm), and the Cyteron staff members for their help with recruitment and data acquisition or administrative support. Compensation was not received. We also acknowledge all the participants of the study for their contribution.

**Data Sharing Statement:** See Supplement 4.

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**Additional Contributions:** We thank D. Roquet, PhD (Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), and Oriane Hébert, MSc (Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), for their help with the reviewing process; A. Cognet, MSc (Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), M. Botton, MSc (Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), S. Egret, MSc (Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), J. Lebahar, PhD (Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), C. Tomadesso, PhD (Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), F. Allais (EUCLID data manager; Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyteron, 14000 Caen, France), and Jeanne Lepetit MSc (Mediapilote); M. Ricard, PhD (Mind and Life Europe, Winterthur, Switzerland & Shechen Monastery, Kathmandu, Nepal), J. F. Lemoine, MD (EUROPEI), Jon Kabat-Zinn, PhD (UMass Medical School, Worcester, MA), Rhonda Smith, MSc (Minerva), Charlotte Reid (Minerva), and Amanda Beard (Minerva); the sponsor, Hélène Espérou, MD (Pôle de recherche clinique Inserm), and the Cyteron staff members for their help with recruitment and data acquisition or administrative support. Compensation was not received. We also acknowledge all the participants of the study for their contribution.

**Data Sharing Statement:** See Supplement 4.

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26. Cotier FA, Zhang R, Lee TMC. A longitudinal study of the effect of short-term meditation training on functional network organization of the aging brain. *Sci Rep.* 2017;7(1):598. doi:10.1038/ s41598-017-00678-8

27. Shao R, Keuper K, Geng X, Lee TMC. Pons to posterior cingulate functional projections predict affective processing changes in the elderly following eight weeks of meditation training. *EBioMedicine*. 2016;10:236-248. doi:10.1016/j.ebiom. 2016.06.018

28. Luders E, Cherbuin N, Kurth F. Forever young(er): potential age-defying effects of long-term meditation on gray matter atrophy. *Front Psychol*. 2015;5:1551. doi:10.3389/fpsyg.2014. 01551

29. Poisnel G, Arenaza-Urquijo E, Collette F, et al; Medit-Ageing Research Group. The Age-Well randomized controlled trial of the Medit-Ageing European project: effect of meditation or foreign language training on brain and mental health in older adults. *Alzheimers Dement (N Y)*. 2018;4:714- 723. doi:10.1016/j.trci.2018.10.011

30. Schlosser M, Barnhofer T, Requier F, et al. Measuring psychological mechanisms in meditation practice: Using a phenomenologically grounded classification system to develop theory-based

composite scores. *Mindfulness*. 2022;13(3):600-614. doi:10.1007/s12671-021-01816-0

31. de Godoy LL, Alves CAPF, Saavedra JSM, et al. Understanding brain resilience in superagers: a systematic review. *Neuroradiology*. 2021;63(5): 663-683. doi:10.1007/s00234-020-02562-1

32. Ware C, Dautricourt S, Gonneaud J, Chételat G. Does second language learning promote neuroplasticity in aging? a systematic review of cognitive and neuroimaging studies. *Front Aging Neurosci*. 2021;13:706672. doi:10.3389/fnagi.2021.706672

33. Menon V, Uddin LQ. Saliency, switching, attention and control: a network model of insula function. *Brain Struct Funct*. 2010;214(5-6):655-667. doi:10.1007/s00429-010-0262-0

34. André C, Rehel S, Kuhn E, et al; Medit-Ageing Research Group. Association of sleep-disordered breathing with Alzheimer disease biomarkers in community-dwelling older adults: a secondary analysis of a randomized clinical trial. *JAMA Neurol*. 2020;77(6):716-724. doi:10.1001/ jamaneurol.2020.0311

35. Dahl CJ, Lutz A, Davidson RJ. Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice. *Trends Cogn Sci*. 2015;19 (9):515-523. doi:10.1016/j.tics.2015.07.001

36. Pernet CR, Belov N, Delorme A, Zammit A. Mindfulness related changes in grey matter:

a systematic review and meta-analysis. *Brain Imaging Behav*. 2021;15(5):2720-2730. doi:10.1007/ s11682-021-00453-4

37. Kral TRA, Davis K, Korponay C, et al. Absence of structural brain changes from mindfulness-based stress reduction: two combined randomized controlled trials. *Sci Adv*. 2022;8(20):eabk3316. doi:10.1126/sciadv.abk3316

38. Corbett MS, Watson J, Eastwood A. Randomised trials comparing different healthcare settings: an exploratory review of the impact of pre-trial preferences on participation, and discussion of other methodological challenges. *BMC Health Serv Res*. 2016;16(1):589.

39. Scarmeas N. Dementia: multimodal dementia prevention: does trial design mask efficacy? *Nat Rev Neurol*. 2017;13(6):322-323. doi:10.1038/nrneurol. 2017.73

40. Dahl CJ, Wilson-Mendenhall CD, Davidson RJ. The plasticity of well-being: a training-based framework for the cultivation of human flourishing. *Proc Natl Acad Sci U S A*. 2020;117(51):32197-32206. doi:10.1073/pnas.2014859117

41. Poldrack RA, Fletcher PC, Henson RN, Worsley KJ, Brett M, Nichols TE. Guidelines for reporting an fMRI study. *Neuroimage*. 2008;40(2): 409-414. doi:10.1016/j.neuroimage.2007.11.048