Spontaneous brain activity in healthy aging: an overview through fluctuations and regional homogeneity

Introduction: This study aims to explore whole-brain resting-state spontaneous brain activity using fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo) strategies to find differences among age groups within a population ranging from middle age to older adults. Methods: The sample comprised 112 healthy persons (M = 68.80, SD = 7.99) aged 48-89 who were split into six age groups (< 60, 60-64, 65-69, 70-74, 75-79, and ≥ 80). Fractional amplitude of low-frequency fluctuation and ReHo analyses were performed and were compared among the six age groups, and the significant results commonly found across groups were correlated with the gray matter volume of the areas and the age variable. Results: Increased activity was found using fALFF in the superior temporal gyrus and inferior frontal gyrus when comparing the first group and the fifth. Regarding ReHo analysis, Group 6 showed increased ReHo in the temporal lobe (hippocampus), right and left precuneus, right caudate, and right and left thalamus depending on the age group. Moreover, significant correlations between age and fALFF and ReHo clusters, as well as with their gray matter volume were found, meaning that the higher the age, the higher the regional synchronization, the lower the fALFF activation, and the lower gray matter of the right thalamus. Conclusion: Both techniques have been shown to be valuable and usable tools for disentangling brain changes in activation in a very low interval of years in healthy aging

Differential tDCS and tACS Effects on Working Memory-Related Neural Activity and Resting-State Connectivity

Transcranial direct and alternating current stimulation (tDCS and tACS, respectively) entail capability to modulate human brain dynamics and cognition. However, the comparability of these approaches at the level of large-scale functional networks has not been thoroughly investigated. In this study, 44 subjects were randomly assigned to receive sham (N = 15), tDCS (N = 15), or tACS (N = 14). The first electrode (anode in tDCS) was positioned over the left dorsolateral prefrontal cortex, the target area, and the second electrode (cathode in tDCS) was placed over the right supraorbital region. tDCS was delivered with a constant current of 2 mA. tACS was fixed to 2 mA peak-to-peak with 6 Hz frequency. Stimulation was applied concurrently with functional magnetic resonance imaging (fMRI) acquisitions, both at rest and during the performance of a verbal working memory (WM) task. After stimulation, subjects repeated the fMRI WM task. Our results indicated that at rest, tDCS increased functional connectivity particularly within the default-mode network (DMN), while tACS decreased it. When comparing both fMRI WM tasks, it was observed that tDCS displayed decreased brain activity post-stimulation as compared to online. Conversely, tACS effects were driven by neural increases online as compared to post-stimulation. Interestingly, both effects primarily occurred within DMN-related areas. Regarding the differences in each fMRI WM task, during the online fMRI WM task, tACS engaged distributed neural resources which did not overlap with the WM-dependent activity pattern, but with some posterior DMN regions. In contrast, during the post-stimulation fMRI WM task, tDCS strengthened prefrontal DMN deactivations, being these activity reductions associated with faster responses. Furthermore, it was observed that tDCS neural responses presented certain consistency across distinct fMRI modalities, while tACS did not. In sum, tDCS and tACS modulate fMRI-derived network dynamics differently. However, both effects seem to focus on DMN regions and the WM network-DMN shift, which are highly affected in aging and disease. Thus, albeit exploratory and needing further replication with larger samples, our results might provide a refined understanding of how the DMN functioning can be externally modulated through commonly used non-invasive brain stimulation techniques, which may be of eventual clinical relevance

Functional brain connectivity prior to the COVID-19 outbreak moderates the effects of coping and perceived stress on mental health changes. A first year of COVID-19 pandemic follow-up study.

Background: The COVID-19 pandemic provides a unique opportunity to investigate the psychological impact of a global major adverse situation. Our aim was to examine, in a longitudinal prospective study, the demographic, psychological, and neurobiological factors associated with interindividual differences in resilience to the mental health impact of the pandemic. Methods: We included 2023 healthy participants (age: 54.32 ± 7.18 years, 65.69% female) from the Barcelona Brain Health Initiative cohort. A linear mixed model was used to characterize the change in anxiety and depression symptoms based on data collected both pre-pandemic and during the pandemic. During the pandemic, psychological variables assessing individual differences in perceived stress and coping strategies were obtained. In addition, in a subsample (n = 433, age 53.02 ± 7.04 years, 46.88% female) with pre-pandemic resting-state functional magnetic resonance imaging available, the system segregation of networks was calculated. Multivariate linear models were fitted to test associations between COVID-19-related changes in mental health and demographics, psychological features, and brain network status. Results: The whole sample showed a general increase in anxiety and depressive symptoms after the pandemic onset, and both age and sex were independent predictors. Coping strategies attenuated the impact of perceived stress on mental health. The system segregation of the frontoparietal control and default mode networks were found to modulate the impact of perceived stress on mental health. Conclusions: Preventive strategies targeting the promotion of mental health at the individual level during similar adverse events in the future should consider intervening on sociodemographic and psychological factors as well as their interplay with neurobiological substrates

Functional brain connectivity prior to the COVID-19 outbreak moderates the effects of coping and perceived stress on mental health changes. A first year of COVID-19 pandemic follow-up study

The COVID-19 pandemic provides a unique opportunity to investigate the psychological impact of a global major adverse situation. Our aim was to study, in a longitudinal prospective, the demographic, psychological and neurobiological factors associated with inter-individual differences in resilience to mental health pandemic impact. We included 2,023 healthy participants (age: 54.32±7.18 years, 65.69% females) from the Barcelona Brain Health Initiative cohort. A linear mixed model was used to characterize the change in anxiety and depression symptoms based on the collected pre- and during-COVID-19 data. During pandemic, psychological variables assessing individual differences in perceived stress and coping strategies were obtained. Additionally, in a subsample (N=433, age:53.02 ± 7.04 years, 46.88% females) with pre-pandemic resting-state functional magnetic resonance imaging available, networks' system segregation (SyS) was calculated. Multivariate linear models were fitted to test associations between COVID-19-related changes in mental health and demographics, psychological features and brain networks status. The whole sample showed a general increase in anxiety and depressive symptoms after the pandemic onset, and both age and sex were independent predictors. Coping strategies attenuated the impact of perceived stress on mental health. SyS of fronto-parietal control and default mode networks were found to modulate the impact of perceived stress on mental health. Preventive strategies destined for the promotion of mental health at an individual's level during future similar adverse events should consider intervening on sociodemographic and psychological factors, as well as their interplay with neurobiological substrates

Educational attainment does not influence brain aging.

Education has been related to various advantageous lifetime outcomes. Here, using longitudinal structural MRI data (4,422 observations), we tested the influential hypothesis that higher education translates into slower rates of brain aging. Cross-sectionally, education was modestly associated with regional cortical volume. However, despite marked mean atrophy in the cortex and hippocampus, education did not influence rates of change. The results were replicated across two independent samples. Our findings challenge the view that higher education slows brain aging

Basal forebrain atrophy along the Alzheimer's disease continuum in adults with Down syndrome

[Background] Basal forebrain (BF) degeneration occurs in Down syndrome (DS)-associated Alzheimer's disease (AD). However, the dynamics of BF atrophy with age and disease progression, its impact on cognition, and its relationship with AD biomarkers have not been studied in DS.[Methods] We included 234 adults with DS (150 asymptomatic, 38 prodromal AD, and 46 AD dementia) and 147 euploid controls. BF volumes were extracted from T-weighted magnetic resonance images using a stereotactic atlas in SPM12. We assessed BF volume changes with age and along the clinical AD continuum and their relationship to cognitive performance, cerebrospinal fluid (CSF) and plasma amyloid/tau/neurodegeneration biomarkers, and hippocampal volume.[Results] In DS, BF volumes decreased with age and along the clinical AD continuum and significantly correlated with amyloid, tau, and neurofilament light chain changes in CSF and plasma, hippocampal volume, and cognitive performance.[Discussion] BF atrophy is a potentially valuable neuroimaging biomarker of AD-related cholinergic neurodegeneration in DS.This study was supported by the Fondo de Investigaciones Sanitario, Carlos III Health Institute (PI20/01473 to JF, PI13/01532, PI16/01825 to RB, PI18/00335 to MCI, PI18/00435 to DA, PI14/1561, PI20/01330 to AL, PI20/00613 to MJG) and the CIBERNED Program 1. This work was also supported by the National Institutes of Health (NIH) grants (1R01AG056850-01A1; 3RF1AG056850-01S1; AG056850, R21AG056974, and R01AG061566 to JF; P30AG066512 and P01AG060882 to TW), Departament de Salut de la Generalitat de Catalunya, Fundación Tatiana Pérez de Guzmán el Bueno (IIBSP-DOW-2020-151 to JF), and the European Union's Horizon 2020, ‘MES-CoBraD’ (H2020-SC1-BHC-2018-2020 / GA 965422 to JF). MRA acknowledges support from the Alzheimer's Association Research Fellowship to Promote Diversity (AARF-D) Program (AARFD-21-852492). MFI acknowledges support from the Jérôme Lejeune postdoctoral award and pilot grant (#1941). AB acknowledges support from a Miguel Servet grant (CP20/00038) from the Carlos III Health Institute. MJG acknowledges support from a Miguel Servet grant (CP19/00031) from the Carlos III Health Institute. MCI acknowledges support from the Alzheimer's Association and Global Brain Health Institute (GBHI_ALZ-18-543740), the Jérôme Lejeune Foundation (#1913 Cycle 2019B), and the Societat Catalana de Neurologia (Premi Beca Fundació SCN 2020). LVA was supported by Margarita Salas junior postdoctoral fellowship (UNI/551/2021, NextGenerationUE). VM and NVT acknowledge support from predoctoral grants from the Carlos III Health Institute (FI18/00275 to VM and FI22/00077 to NVT). MA and JA were supported by the Río Hortega Fellowship from Carlos III Health Institute (CM19/00066 to MA and CM21/00243 to JA). CP acknowledges support from a Sara Borrell Fellowship (CP20/00133) from the Carlos III Health Institute. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712 and #101053962), Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003). KB is supported by the Swedish Research Council (#2017-00915), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721 and #AF-968270), Hjärnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986 and #ALFGBG-965240), and the Alzheimer's Association 2021 Zenith Award (ZEN-21-848495).Peer reviewe

Characterizing cognitive aging through multimodal MRI and NIBS: influence of education and gene expression

[eng] The thesis entitled "Characterizing cognitive aging through multimodal MRI and NIBS: influence of education and gene expression" is based on the knowledge that the aging population is increasing throughout the world. This leads to an increase in cases of dementia, such as Alzheimer's disease and other pathologies that generate disability. However, there is strong evidence that healthy aging is also possible from a cognitive point of view. For this reason, the research challenge for the coming decades focuses on the development of new prevention strategies and, as this work has done, on the characterization of this cognitively preserved elderly population. Neuroimaging studies based on magnetic resonance imaging (MRI) show that physiological aging is characterized by generalized brain atrophy, but that it occurs unequally between regions and between subjects. Functional MRI (fMRI) findings also are in line with this heterogeneity, showing both reductions and increases in brain activity. In addition, there is high variability in the cognitive profile of older people and two non-mutually exclusive pathways have been proposed to explain why some aged people are able to achieve high cognitive performance: cognitive reserve (CR) and brain maintenance (BM). Currently, these two theoretical concepts are described as macroscopic constructs and are not linked to identifiable biological mechanisms through which their beneficial effect would be explained in terms of adaptability to cope with (i.e., CR) or the ability to not experience age-related brain changes (i.e., BM). In light of all this, the use of new technologies that allow us to understand the mechanisms related to optimal brain function in advanced ages becomes vital. Thus, the objective of this Doctoral Thesis was to characterize the brain substrates underlying healthy cognitive aging and reveal how CR estimates can modulate the relationship between the measures studied. The present work consists of four studies that were carried out in order to answer the above-mentioned objective. The Doctoral Thesis included data from more than 100 healthy elderly, using cross-sectional and longitudinal measures of cognition and variables derived from multimodal MRI analysis. Furthermore, we incorporate a novel methodology based on transcriptional architecture analysis using regional whole-brain gene expression data from the Allen Brain Human Atlas. Finally, an intervention was performed that combined transcranial direct current stimulation (tDCS) with fMRI. From different MRI modalities, our results revealed neuroprotective and compensatory effects of CR that support preserved cognition, and that appears to be related to differential associations between age and measures of gray and white matter integrity. Specifically, CR was associated with increased thickness of the prefrontal cortex, and this structural benefit was linked to a gene expression profile characterized by a relative up-regulation of a set of genes involved in cell communication, neurotransmission, and immune response, thus proposing some biological mechanisms related to plastic phenomena through which CR could act. From fMRI analyses, we identified that cognitive decline was associated with increases in brain activity in areas unrelated to assessed function in the presence of higher structural atrophy. Finally, combining fMRI and tDCS, we show how non-invasive brain stimulation was able to reverse this over-activation detected longitudinally in those subjects with cognitive decline. Thus, from a multimodal approach in elderly subjects, we were able to describe those anatomical-functional and molecular characteristics that underlay a successful cognitive performance. In addition, this work has helped to clarify part of the mechanisms of neuroprotection, compensation, and stability in aging.[cat] Envellir de manera saludable és possible, també des del punt de vista cognitiu. Estudis previs basats en dades de Ressonància Magnètica (RM) han evidenciat que algunes persones grans poden mantenir preservada la seva funció cognitiva perquè no experimenten canvis cerebrals. Tot i això, tenir un alt rendiment cognitiu durant la vellesa és possible mitjançant mecanismes compensatoris que permeten contrarestar el dany cerebral sofert per l'edat (teoria de la Reserva Cognitiva; RC). En aquest context, el principal objectiu de la present Tesi Doctoral va ser caracteritzar els substrats cerebrals estructurals i funcionals subjacents a un envelliment cognitiu saludable, així com revelar com la RC pot modular la relació entre les mesures estudiades. Per això, es van realitzar un total de 4 estudis en una població d'edat avançada cognitivament sana, usant enfocaments transversals i longitudinals de RM, i altres eines innovadores com la caracterització de l'expressió gènica de regions corticals utilitzant o l'estimulació cerebral no invasiva combinada amb RM. Els nostres resultats van demostrar que nivells més elevats de RC (mesurats com anys d'educació) s'associen amb un rendiment cognitiu alt, però no amb un manteniment d'aquest. Vam poder detectar que els efectes compensatoris i neuroprotectors de la RC coexisteixen a l'envelliment. Altes estimacions de RC es van relacionar amb un gruix cortical més gran (neuroprotecció) en àrees prefrontals que, al seu torn, es van associar amb una expressió a l'alça de gens involucrats en mecanismes biològics que podrien explicar l'efecte protector de la RC. A més, l'ús de RM funcional ens va permetre establir que els subjectes que mantenen un alt rendiment mostren patrons estables d'activació, mentre que els que declinen mostren major atròfia estructural i intents fracassats de compensació funcional. No obstant això, aquests subjectes declinadors són els que van mostrar un efecte més gran de l'estimulació cerebral no invasiva, evidenciant una normalització del patró funcional. Així, a partir de l'estudi multimodal de l'envelliment, hem descrit aquelles característiques anatomofuncionals i moleculars subjacents al rendiment cognitiu exitós, un coneixement útil per a la prevenció i el disseny de futures intervencions per promoure la salut cerebral en edats avançades

Reduced default mode network effective connectivity in healthy aging is modulated by years of education

Aging is a major risk factor for neurodegenerative diseases like dementia and Alzheimer's disease. Even in non-pathological aging, decline in cognitive functioning is observed in the majority of the elderly population, necessitating the importance of studying the processes involved in healthy aging in order to identify brain biomarkers that promote the conservation of functioning. The default mode network (DMN) has been of special interest to aging research due to its vulnerability to atrophy and functional decline over the course of aging. Prior work has focused almost exclusively on functional (i.e. undirected) connectivity, yet converging findings are scarce. Therefore, we set out to use spectral dynamic causal modeling to investigate changes in the effective (i.e. directed) connectivity within the DMN and to discover changes in information flow in a sample of cognitively normal adults spanning from 48 to 89 years (n = 63). Age was associated to reduced verbal memory performance. Modeling of effective connectivity revealed a pattern of age-related downregulation of posterior DMN regions driven by inhibitory connections from the hippocampus and middle temporal gyrus. Additionally, there was an observed decline in the hippocampus’ susceptibility to network inputs with age, effectively disconnecting itself from other regions. The estimated effective connectivity parameters were robust and able to predict the age in out of sample estimates in a leave-one-out cross-validation. Attained education moderated the effects of aging, largely reversing the observed pattern of inhibitory connectivity. Thus, medial prefrontal cortex, hippocampus and posterior DMN regions formed an excitatory cycle of extrinsic connections related to the interaction of age and education. This suggests a compensatory role of years of education in effective connectivity, stressing a possible target for interventions. Our findings suggest a connection to the concept of cognitive reserve, which attributes a protective effect of educational level on cognitive decline in aging (Stern, 2009)

Purpose in life promotes resilience to age‑related brain burden in middle‑aged adults

Disease‑modifying agents to counteract cognitive impairment in older age remain elusive. Hence, identifying modifiable factors promoting resilience, as the capacity of the brain to maintain cognition and function with aging and disease, is paramount. In Alzheimer’s disease (AD), education and occupation are typical cognitive reserve proxies. However, the importance of psychological factors is being increasingly recognized, as their operating biological mechanisms are elucidated. Purpose in life (PiL), one of the pillars of psychological well‑being, has previously been found to reduce the deleterious effects of AD‑related pathological changes on cognition. However, whether PiL operates as a resilience factor in middle‑aged individuals and what are the underlying neural mechanisms remain unknown.Medicin

Age-related changes in resting-state functional connectivity in older adults

Age-related changes in the brain connectivity of healthy older adults have been widely studied in recent years, with some differences in the obtained results. Most of these studies showed decreases in general functional connectivity, but they also found increases in some particular regions and areas. Frequently, these studies compared young individuals with older subjects, but few studies compared different age groups only in older populations. The purpose of this study is to analyze whole-brain functional connectivity in healthy older adult groups and its network characteristics through functional segregation. A total of 114 individuals, 48 to 89 years old, were scanned using resting-state functional magnetic resonance imaging in a resting state paradigm and were divided into six different age groups (< 60, 60–64, 65–69, 70–74, 75–79, ≥ 80 years old). A partial correlation analysis, a pooled correlation analysis and a study of 3-cycle regions with prominent connectivity were conducted. Our results showed progressive diminution in the functional connectivity among different age groups and this was particularly pronounced between 75 and 79 years old. The oldest group (≥ 80 years old) showed a slight increase in functional connectivity compared to the other groups. This occurred possibly because of compensatory mechanism in brain functioning. This study provides information on the brain functional characteristics of every age group, with more specific information on the functional progressive decline, and supplies methodological tools to study functional connectivity characteristics. Approval for the study was obtained from the ethics committee of the Comisión de Bioética de la Universidad de Barcelona (approval No. PSI2012-38257) on June 5, 2012, and from the ethics committee of the Barcelona’s Hospital Clínic (approval No. 2009-5306 and 2011-6604) on October 22, 2009 and April 7, 2011 respectively