Effects of Meditation Training and Non-Native Language Training on Cognition in Older Adults: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Nonpharmacological interventions are a potential strategy to maintain or promote cognitive functioning in older adults. Objective: To investigate the effects of 18 months' meditation training and 18 months' non-native language training on cognition in older adults. Design, Setting, and Participants: This study was a secondary analysis of the Age-Well trial, an 18-month, observer-masked, randomized clinical trial with 3 parallel arms. Eligible participants were community-dwelling adults aged 65 years and older residing in Caen, France. Participants were enrolled from November 24, 2016, to March 5, 2018, and randomly assigned (1:1:1) to meditation training, non-native language (English) training, or no intervention arms. Final follow-up was completed on February 6, 2020. Data were analyzed between December 2021 and November 2022. Interventions: The 18-month meditation and non-native language training interventions were structurally equivalent and included 2-hour weekly group sessions, daily home practice of 20 minutes or longer, and 1 day of more intensive home practice. The no intervention group was instructed not to change their habits and to continue living as usual. Main Outcomes and Measures: Cognition (a prespecified secondary outcome of the Age-Well trial) was assessed preintervention and postintervention via the Preclinical Alzheimer Cognitive Composite 5 (PACC5), and composites assessing episodic memory, executive function, and attention. Results: Among 137 randomized participants, 2 were excluded for not meeting eligibility criteria, leaving 135 (mean [SD] age, 69.3 [3.8] years; 83 female [61%]) eligible for analysis. One participant among the remaining 135 did not complete the trial. In adjusted mixed effects models, no interaction effects were observed between visit and group for PACC5 (F2,131.39 = 2.58; P = .08), episodic memory (F2,131.60 = 2.34; P = .10), executive function (F2,131.26 = 0.89; P = .41), or attention (F2,131.20 = 0.34; P = .79). Results remained substantively unchanged across sensitivity and exploratory analyses. Conclusions and Relevance: In this secondary analysis of an 18-month randomized trial, meditation and non-native language training did not confer salutary cognitive effects. Although further analyses are needed to explore the effects of these interventions on other relevant outcomes related to aging and well-being, these findings did not support the use of these interventions for enhancing cognition in cognitively healthy older adults. Trial Registration: ClinicalTrials.gov Identifier: NCT02977819.

Effects of a mindfulness-based versus a health self-management intervention on objective cognitive performance in older adults with subjective cognitive decline (SCD): a secondary analysis of the SCD-Well randomized controlled trial.

BACKGROUND: Older individuals with subjective cognitive decline (SCD) perceive that their cognition has declined but do not show objective impairment on neuropsychological tests. Individuals with SCD are at elevated risk of objective cognitive decline and incident dementia. Non-pharmacological interventions (including mindfulness-based and health self-management approaches) are a potential strategy to maintain or improve cognition in SCD, which may ultimately reduce dementia risk. METHODS: This study utilized data from the SCD-Well randomized controlled trial. One hundred forty-seven older adults with SCD (MAge = 72.7 years; 64% female) were recruited from memory clinics in four European countries and randomized to one of two group-based, 8-week interventions: a Caring Mindfulness-based Approach for Seniors (CMBAS) or a health self-management program (HSMP). Participants were assessed at baseline, post-intervention (week 8), and at 6-month follow-up (week 24) using a range of cognitive tests. From these tests, three composites were derived-an "abridged" Preclinical Alzheimer's Cognitive Composite 5 (PACC5Abridged), an attention composite, and an executive function composite. Both per-protocol and intention-to-treat analyses were performed. Linear mixed models evaluated the change in outcomes between and within arms and adjusted for covariates and cognitive retest effects. Sensitivity models repeated the per-protocol analyses for participants who attended ≥ 4 intervention sessions. RESULTS: Across all cognitive composites, there were no significant time-by-trial arm interactions and no measurable cognitive retest effects; sensitivity analyses supported these results. Improvements, however, were observed within both trial arms on the PACC5Abridged from baseline to follow-up (Δ [95% confidence interval]: CMBAS = 0.34 [0.19, 0.48]; HSMP = 0.30 [0.15, 0.44]). There was weaker evidence of an improvement in attention but no effects on executive function. CONCLUSIONS: Two non-pharmacological interventions conferred small, non-differing improvements to a global cognitive composite sensitive to amyloid-beta-related decline. There was weaker evidence of an effect on attention, and no evidence of an effect on executive function. Importantly, observed improvements were maintained beyond the end of the interventions. Improving cognition is an important step toward dementia prevention, and future research is needed to delineate the mechanisms of action of these interventions and to utilize clinical endpoints (i.e., progression to mild cognitive impairment or dementia). TRIAL REGISTRATION: ClinicalTrials.gov, NCT03005652.

The Rise of Synaptic Density PET Imaging.

Many neurological disorders are related to synaptic loss or pathologies. Before the boom of positrons emission tomography (PET) imaging of synapses, synaptic quantification could only be achieved in vitro on brain samples after autopsy or surgical resections. Until the mid-2010s, electron microscopy and immunohistochemical labelling of synaptic proteins were the gold-standard methods for such analyses. Over the last decade, several PET radiotracers for the synaptic vesicle 2A protein have been developed to achieve in vivo synapses visualization and quantification. Different strategies were used, namely radiolabelling with either 11C or 18F, preclinical development in rodent and non-human primates, and binding quantification with different kinetic modelling methods. This review provides an overview of these PET tracers and underlines their perspectives and limitations by focusing on radiochemical aspects, as well as preclinical proof-of-concept and the main clinical outcomes described so far.

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.

INTRODUCTION: The Age-Well clinical trial is an ongoing monocentric, randomized, controlled trial aiming to assess an 18-month preventive meditation-based intervention directly targeting the attentional and emotional dimensions of aging to promote mental health and well-being in elderly people. METHODS: One hundred thirty-seven cognitively unimpaired older adults are randomized to either an 18-month meditation-based intervention, a structurally matched foreign language training, or a passive control arm. The impact of the intervention and underlying mechanisms are assessed with detailed cognitive, behavioral, biological, neuroimaging and sleep examinations. RESULTS: Recruitment began in late 2016 and ended in May 2018. The interventions are ongoing and will be completed by early 2020. DISCUSSION: This is the first trial addressing the emotional and cognitive dimension of aging with a long-term nonpharmacological approach and using comprehensive assessments to investigate the mechanisms. Results are expected to foster the development of preventive strategies reducing the negative impact of mental conditions and disorders.

The Age-Well observational study on expert meditators in the Medit-Ageing European project.

INTRODUCTION: The Age-Well observational, cross-sectional study investigates the affective and cognitive mechanisms of meditation expertise with behavioral, neuroimaging, sleep, and biological measures sensitive to aging and Alzheimer's disease (AD). METHODS: Thirty cognitively unimpaired individuals aged 65 years or older with at least 10,000 hours of practice in mindfulness meditation (MM) and loving-kindness and compassion meditation (LKCM) are selected. The outcomes are the neuroimaging brain correlates of MM and LKCM and the assessments of long-term meditation practices on behavioral, neural, and biological measures as compared to nonmeditator older controls from the Age-Well randomized controlled trial. RESULTS: Recruitment and data collection began in late 2016 and will be completed by late 2019. DISCUSSION: Results are expected to foster the understanding of the effects of meditation expertise on aging and of the mechanisms of action underlying the meditation intervention in the Age-Well randomized controlled trial. These finding will contribute to the design of meditation-based prevention randomized controlled trials for the aged population and to the exploration of the possible long-time developmental trajectory of meditation training.

Cognitive brain responses during circadian wake-promotion: evidence for sleep-pressure-dependent hypothalamic activations.

The two-process model of sleep-wake regulation posits that sleep-wake-dependent homeostatic processes interact with the circadian timing system to affect human behavior. The circadian timing system is fundamental to maintaining stable cognitive performance, as it counteracts growing homeostatic sleep pressure during daytime. Using magnetic resonance imaging, we explored brain responses underlying working memory performance during the time of maximal circadian wake-promotion under varying sleep pressure conditions. Circadian wake-promoting strength was derived from the ability to sleep during an evening nap. Hypothalamic BOLD activity was positively linked to circadian wake-promoting strength under normal, but not under disproportionally high or low sleep pressure levels. Furthermore, higher hypothalamic activity under normal sleep pressure levels predicted better performance under sleep loss. Our results reappraise the two-process model by revealing a homeostatic-dose-dependent association between circadian wake-promotion and cognition-related hypothalamic activity.

Episodic autobiographical memory in amnestic mild cognitive impairment: what are the neural correlates?

Autobiographical memory in amnestic Mild Cognitive Impairment (aMCI) is characterized by impaired retrieval of episodic memories, but relatively preserved personal semantic knowledge. This study aimed to identify (via FDG-PET) the neural substrates of impaired episodic specificity of autobiographical memories in 35 aMCI patients compared with 24 healthy elderly controls. Significant correlations between regional cerebral activity and the proportion of episodic details in autobiographical memories from two life periods were found in specific regions of an autobiographical brain network. In aMCI patients, more than in controls, specifically episodic memories from early adulthood were associated with metabolic activity in the cuneus and in parietal regions. We hypothesized that variable retrieval of episodic autobiographical memories in our aMCI patients would be related to their variable capacity to reactivate specific sensory-perceptual and contextual details of early adulthood events linked to reduced (occipito-parietal) visual imagery and less efficient (parietal) attentional processes. For recent memories (last year), a correlation emerged between the proportion of episodic details and activity in lateral temporal regions and the temporo-parietal junction. Accordingly, variable episodic memory for recent events may be related to the efficiency of controlled search through general events likely to provide cues for the retrieval of episodic details and to the ability to establish a self perspective favouring recollection.

The commonality of neural networks for verbal and visual short-term memory.

Although many neuroimaging studies have considered verbal and visual short-term memory (STM) as relying on neurally segregated short-term buffer systems, the present study explored the existence of shared neural correlates supporting verbal and visual STM. We hypothesized that networks involved in attentional and executive processes, as well as networks involved in serial order processing, underlie STM for both verbal and visual list information, with neural specificity restricted to sensory areas involved in processing the specific items to be retained. Participants were presented sequences of nonwords or unfamiliar faces, and were instructed to maintain and recognize order or item information. For encoding and retrieval phases, null conjunction analysis revealed an identical fronto-parieto-cerebellar network comprising the left intraparietal sulcus, bilateral dorsolateral prefrontal cortex, and the bilateral cerebellum, irrespective of information type and modality. A network centered around the right intraparietal sulcus supported STM for order information, in both verbal and visual modalities. Modality-specific effects were observed in left superior temporal and mid-fusiform areas associated with phonological and orthographic processing during the verbal STM tasks, and in right hippocampal and fusiform face processing areas during the visual STM tasks, wherein these modality effects were most pronounced when storing item information. The present results suggest that STM emerges from the deployment of modality-independent attentional and serial ordering processes toward sensory networks underlying the processing and storage of modality-specific item information.

Homeostatic sleep pressure and responses to sustained attention in the suprachiasmatic area.

Throughout the day, cognitive performance is under the combined influence of circadian processes and homeostatic sleep pressure. Some people perform best in the morning, whereas others are more alert in the evening. These chronotypes provide a unique way to study the effects of sleep-wake regulation on the cerebral mechanisms supporting cognition. Using functional magnetic resonance imaging in extreme chronotypes, we found that maintaining attention in the evening was associated with higher activity in evening than morning chronotypes in a region of the locus coeruleus and in a suprachiasmatic area (SCA) including the circadian master clock. Activity in the SCA decreased with increasing homeostatic sleep pressure. This result shows the direct influence of the homeostatic and circadian interaction on the neural activity underpinning human behavior.

Perspective taking to assess self-personality: what's modified in Alzheimer's disease?

Personality changes are frequently described by caregivers of patients with Alzheimer's disease, while they are less often reported by the patients. This relative anosognosia of Alzheimer disease (AD) patients for personality changes might be related to impaired self-judgment and to decreased ability to understand their caregiver's perspective. To investigate this issue, we explored the cerebral correlates of self-assessment and perspective taking in patients with mild AD, elderly and young volunteers. All subjects assessed relevance of personality traits adjectives for self and a relative, taking either their own or their relative's perspective, during a functional imaging experiment. The comparison of subject's and relative's answers provided congruency scores used to assess self-judgment and perspective taking performance. The self-judgment "accuracy" score was diminished in AD, and when patients assessed adjectives for self-relevance, they predominantly activated bilateral intraparietal sulci (IPS). Previous studies associated IPS activation with familiarity judgment, which AD patients would use more than recollection when retrieving information to assess self-personality. When taking a third-person perspective, patients activated prefrontal regions (similarly to young volunteers), while elderly controls recruited visual associative areas (also activated by young volunteers). This suggests that mild AD patients relied more on reasoning processes than on visual imagery of autobiographical memories to take their relative's perspective. This strategy may help AD patients to cope with episodic memory impairment even if it does not prevent them from making some mind-reading errors.

Involvement of both prefrontal and inferior parietal cortex in dual-task performance.

This PET study explored the neural substrate of both dual-task management and integration task using single tasks that are known not to evoke any prefrontal activation. The paradigm included two simple (visual and auditory) discrimination tasks, a dual task and an integration task (requiring simultaneous visual and auditory discrimination), and baseline tasks (passive viewing and hearing). Data were analyzed using SPM99. As predicted, the comparison of each single task to the baseline task showed no activity in prefrontal areas. The comparison of the dual task to the single tasks demonstrated left-sided foci of activity in the frontal gyrus (BA 9/46, BA 10/47 and BA 6), inferior parietal gyrus (BA 40), and cerebellum. By reference to previous neuroimaging studies, BA 9/46 was associated with the coordinated manipulation of simultaneously presented information, BA 10/47 with selection processes, BA 6 with articulatory rehearsal, and BA 40 with attentional shifting. Globally similar regions were found for the integration task, except that the inferior parietal gyrus was not recruited. These results confirm the hypothesis that the left prefrontal cortex is implicated in dual-task performance. Moreover, the involvement of a parietal area in the dual task is in keeping with the hypothesis that a parieto-frontal network sustains executive functioning.

Modulation of brain activity during phonological familiarization.

We measured brain activity in 12 adults for the repetition of auditorily presented words and nonwords, before and after repeated exposure to their phonological form. The nonword phoneme combinations were either of high (HF) or low (LF) phonotactic frequency. After familiarization, we observed, for both word and nonword conditions, decreased activation in the left posterior superior temporal gyrus, in the bilateral temporal pole and middle temporal gyri. At the same time, interaction analysis showed that the magnitude of decrease of activity in bilateral posterior temporal lobe was significantly smaller for LF nonwords, relative to words and HF nonwords. Decrease of activity in this area also correlated with the size of behavioral familiarization effects for LF nonwords. The results show that the posterior superior temporal gyrus plays a fundamental role during phonological learning. Its relationship to sublexical and lexical phonological processing as well as to phonological short-term memory is discussed.

Neural correlates of "hot" and "cold" emotional processing: a multilevel approach to the functional anatomy of emotion.

The neural correlates of two hypothesized emotional processing modes, i.e., schematic and propositional modes, were investigated with positron emission tomography. Nineteen subjects performed an emotional mental imagery task while mentally repeating sentences linked to the meaning of the imagery script. In the schematic conditions, participants repeated metaphoric sentences, whereas in the propositional conditions, the sentences were explicit questions about specific emotional appraisals of the imagery scenario. Five types of emotional scripts were proposed to the subjects (happiness, anger, affection, sadness, and a neutral scenario). The results supported the hypothesized distinction between schematic and propositional emotional processing modes. Specifically, schematic mode was associated with increased activity in the ventromedial prefrontal cortex whereas propositional mode was associated with activation of the anterolateral prefrontal cortex. In addition, interaction analyses showed that schematic versus propositional processing of happiness (compared with the neutral scenario) was associated with increased activity in the ventral striatum whereas "schematic anger" was tentatively associated with activation of the ventral pallidum.