Age-Related Alterations in Gray Matter Microstructure in Older People With Remitted Major Depression at Risk for Dementia.

Background: Major depressive disorder (MDD) in late life is a risk factor for mild cognitive impairment (MCI) and Alzheimer's disease. However, studies of gray matter changes have produced varied estimates of which structures are implicated in MDD and dementia. Changes in gray matter volume and cortical thickness are macrostructural measures for the microstructural processes of free water accumulation and dendritic spine loss. Methods: We conducted multishell diffusion imaging to assess gray matter microstructure in 244 older adults with remitted MDD (n = 44), MCI (n = 115), remitted MDD+MCI (n = 61), or without psychiatric disorders or cognitive impairment (healthy control participants; n = 24). We estimated measures related to neurite density, orientation dispersion, and free water (isotropic volume fraction) using a biophysically plausible model (neurite orientation dispersion and density imaging). Results: Results showed that increasing age was correlated with an increase in isotropic volume fraction and a decrease in orientation dispersion index, which is consistent with neuropathology dendritic loss. In addition, this relationship between age and increased isotropic volume fraction was more disrupted in the MCI group than in the remitted MDD or healthy control groups. However, the association between age and orientation dispersion index was similar for all 3 groups. Conclusions: The findings suggest that the neurite orientation dispersion and density imaging measures could be used to identify biological risk factors for Alzheimer's disease, signifying both conventional neurodegeneration observed with MCI and dendritic loss seen in MDD.

Examining the consistency in bilingualism and white matter research: A meta-analysis.

This study aimed to systematically investigate the relationship between bilingualism, age, L2 onset age of acquisition (AoA), and white matter integrity (operationalized as fractional anisotropy, FA), addressing inconsistencies in the literature. We conducted a meta-analysis of 23 studies and used meta-regression models to assess the influence of age and L2AoA on effect sizes in studies comparing monolinguals and bilinguals. Even though the overall between-group effect size across the whole brain was unreliable, bilingualism was associated with increased white matter integrity in specific tracts and in groups with a limited range of age and L2AoA. Age had a small, negative effect on white matter integrity, with differences between monolinguals and bilinguals more pronounced in younger adults, consistent with a view of an initial increase in white matter integrity, followed by remodeling for efficiency over time. In contrast, later L2AoA was associated with greater white matter integrity in bilinguals than monolinguals, again consistent with the remodeling for efficiency model. Our findings highlight the importance of considering age and L2AoA when examining the neural basis of bilingualism on white matter in the brain and how bilingualism contributes to structural changes that stave off cognitive decline in older age.

Sexual orientation and cognition in aging populations: Results from the Canadian Longitudinal Study on Aging.

The current study utilized the Canadian Longitudinal Study on Aging (CLSA) data to investigate the relationship between sexual orientation and cognitive health of the aging population. Cognitive flexibility and verbal fluency were examined as outcome variables in the study. A total of 45,993 respondents were included in the analyses. Each model had social support or social participation as a mediator. A series of mediation analysis, stratified by gender, revealed that aging gay men performed better in cognitive tasks related to cognitive flexibility when compared to their heterosexual counterparts. The results also indicated that social support is a protective factor for cognitive health in aging lesbian women. This study provides an opportunity to consider how clinical and social services can strategize to build inclusive environments for the aging sexual minority population.

A neural mechanism of cognitive reserve: The case of bilingualism.

Cognitive Reserve (CR) refers to the preservation of cognitive function in the face of age- or disease-related neuroanatomical decline. While bilingualism has been shown to contribute to CR, the extent to which, and what particular aspect of, second language experience contributes to CR are debated, and the underlying neural mechanism(s) unknown. Intrinsic functional connectivity reflects experience-dependent neuroplasticity that occurs across timescales ranging from minutes to decades, and may be a neural mechanism underlying CR. To test this hypothesis, we used voxel-based morphometry and resting-state functional connectivity analyses of MRI data to compare structural and functional brain integrity between monolingual and bilingual older adults, matched on cognitive performance, and across levels of second language proficiency measured as a continuous variable. Bilingualism, and degree of second language proficiency specifically, were associated with lower gray matter integrity in a hub of the default mode network - a region that is particularly vulnerable to decline in aging and dementia - but preserved intrinsic functional network organization. Bilingualism moderated the association between neuroanatomical differences and cognitive decline, such that lower gray matter integrity was associated with lower executive function in monolinguals, but not bilinguals. Intrinsic functional network integrity predicted executive function when controlling for group differences in gray matter integrity and language status. Our findings confirm that lifelong bilingualism is a CR factor, as bilingual older adults performed just as well as their monolingual peers on tasks of executive function, despite showing signs of more advanced neuroanatomical aging, and that this is a consequence of preserved intrinsic functional network organization.

From Lung to Brain: Respiration Modulates Neural and Mental Activity.

Respiration protocols have been developed to manipulate mental states, including their use for therapeutic purposes. In this systematic review, we discuss evidence that respiration may play a fundamental role in coordinating neural activity, behavior, and emotion. The main findings are: (1) respiration affects the neural activity of a wide variety of regions in the brain; (2) respiration modulates different frequency ranges in the brain's dynamics; (3) different respiration protocols (spontaneous, hyperventilation, slow or resonance respiration) yield different neural and mental effects; and (4) the effects of respiration on the brain are related to concurrent modulation of biochemical (oxygen delivery, pH) and physiological (cerebral blood flow, heart rate variability) variables. We conclude that respiration may be an integral rhythm of the brain's neural activity. This provides an intimate connection of respiration with neuro-mental features like emotion. A respiratory-neuro-mental connection holds the promise for a brain-based therapeutic usage of respiration in mental disorders.

Impact of Neighborhood Deprivation on Aging Sexual Minority People's Depression: Results from the CANUE and CLSA data.

As the aging population grows across the world, exploring the impact of social environment on minority populations' aging and well-being would be an essential step towards building an inclusive society. Using the Canadian Longitudinal Study on Aging (CLSA) and Canadian Urban Environmental Health Research Consortium (CANUE) data, the study investigated the relationship between deprivation and depression level in aging sexual minority people to examine how neighborhood level social and material deprivation influence mental health. 48,792 survey respondents were included in our analyses and the average age was 62.9. The study had 47,792 heterosexual, 760 gay/lesbian, and 240 bisexual individuals (23,977 men and 24,815 women). Regression analyses were conducted while controlling for age in each model. Results revealed that neighborhood material deprivation has a significant impact on mental health outcomes of aging lesbian women and bisexual men. The study provides an opportunity for intervention considerations for materially deprived neighborhoods to serve the aging sexual minority people residing in such areas.

OViTAD: Optimized Vision Transformer to Predict Various Stages of Alzheimer's Disease Using Resting-State fMRI and Structural MRI Data.

Advances in applied machine learning techniques for neuroimaging have encouraged scientists to implement models to diagnose brain disorders such as Alzheimer's disease at early stages. Predicting the exact stage of Alzheimer's disease is challenging; however, complex deep learning techniques can precisely manage this. While successful, these complex architectures are difficult to interrogate and computationally expensive. Therefore, using novel, simpler architectures with more efficient pattern extraction capabilities, such as transformers, is of interest to neuroscientists. This study introduced an optimized vision transformer architecture to predict the group membership by separating healthy adults, mild cognitive impairment, and Alzheimer's brains within the same age group (>75 years) using resting-state functional (rs-fMRI) and structural magnetic resonance imaging (sMRI) data aggressively preprocessed by our pipeline. Our optimized architecture, known as OViTAD is currently the sole vision transformer-based end-to-end pipeline and outperformed the existing transformer models and most state-of-the-art solutions. Our model achieved F1-scores of 97%±0.0 and 99.55%±0.39 from the testing sets for the rs-fMRI and sMRI modalities in the triple-class prediction experiments. Furthermore, our model reached these performances using 30% fewer parameters than a vanilla transformer. Furthermore, the model was robust and repeatable, producing similar estimates across three runs with random data splits (we reported the averaged evaluation metrics). Finally, to challenge the model, we observed how it handled increasing noise levels by inserting varying numbers of healthy brains into the two dementia groups. Our findings suggest that optimized vision transformers are a promising and exciting new approach for neuroimaging applications, especially for Alzheimer's disease prediction.

Gray Matter Volume as Evidence for Cognitive Reserve in Bilinguals With Mild Cognitive Impairment.

BACKGROUND: Compared with monolinguals, bilinguals have a later onset of mild cognitive impairment (MCI) and Alzheimer disease symptoms and greater neuropathology at similar cognitive and clinical levels. The present study follows a previous report showing the faster conversion from MCI to Alzheimer disease for bilingual patients than comparable monolinguals, as predicted by a cognitive reserve (CR). PURPOSE: Identify whether the increased CR found for bilinguals in the previous study was accompanied by greater gray matter (GM) atrophy than was present for the monolinguals. METHODS: A novel deep-learning technique based on convolutional neural networks was used to enhance clinical scans into 1 mm MPRAGEs and analyze the GM volume at the time of MCI diagnosis in the earlier study. PATIENTS: Twenty-four bilingual and 24 monolingual patients were diagnosed with MCI at a hospital memory clinic. RESULTS: Bilingual patients had more GM loss than monolingual patients in areas related to language processing, attention, decision-making, motor function, and episodic memory retrieval. Bilingualism and age were the strongest predictors of atrophy after other variables such as immigration and education were included in a multivariate model. DISCUSSION: CR from bilingualism is evident in the initial stages of neurodegeneration after MCI has been diagnosed.

Coordinate-Based Network Mapping of Brain Structure in Major Depressive Disorder in Younger and Older Adults: A Systematic Review and Meta-Analysis.

OBJECTIVE: Structural neuroimaging findings in younger and older adults with major depressive disorder (MDD) are highly heterogeneous, possibly as a result of methodological limitations, lack of distinction between MDD and late-life depression (LLD), or clinical moderators. Using a novel meta-analytic network mapping approach, the authors sought to identify the circuits affected in different clinical subtypes of MDD. METHODS: The authors identified all voxel-based and surface-based morphometry studies published through October 2020 that compared younger adults with MDD or older adults with LLD to nonpsychiatric control participants. An activation likelihood estimation (ALE) analysis and a novel coordinate-based network mapping approach were used to identify brain circuits affected in MDD and LLD. Meta-regressions examined the impact of age at onset in older patients with LLD and treatment with antidepressants in younger patients with MDD. RESULTS: The authors analyzed 145 comparisons from 143 articles, including a total of 14,318 participants (MDD: N=6,362; LLD: N=535; control subjects: N=7,421). Significant ALE results confirmed previous findings implicating the left and right parahippocampus and anterior cingulate in MDD and the anterior cingulate in LLD. In contrast, coordinate-based network mapping showed differences in the frontoparietal, dorsal attention, and visual networks both in MDD and LLD. Meta-regressions showed that late onset was significantly associated with widespread structural abnormalities in LLD, and treatment with antidepressants showed a significant association with abnormalities in the anterior cingulate (Brodmann's area 32) and dorsolateral prefrontal cortex (Brodmann's area 9) in MDD. CONCLUSIONS: These findings help to clarify the shared circuitry of depression across the adult lifespan and highlight some unique circuitry relevant to late-onset depression, which may explain some of the risk for cognitive decline and dementia.

Bilingualism contributes to reserve and working memory efficiency: Evidence from structural and functional neuroimaging.

This study compared brain and behavioral outcomes for monolingual and bilingual older adults who reported no cognitive or memory problems on three types of memory that typically decline in older age, namely, working memory (measured by n-back), item, and associative recognition. The results showed that bilinguals were faster on the two-back working memory task than monolinguals but used a set of frontostriatal regions less than monolinguals. There was no group difference on an item/associative recognition task. In brain structure, gray matter volume and white matter integrity (fractional anisotropy) were generally lower in bilinguals than in monolinguals, but bilinguals had better white matter integrity than monolinguals in the bilateral superior corona radiata and better gray matter density in the left inferior temporal gyrus. These regions may help preserve bilinguals' executive functions despite generally more significant atrophy throughout the brain than monolinguals in that these structures contribute to efficient communication between executive frontal regions and subcortical motor regions, and perceptual pathways. Reliable negative correlations between brain structure and age were only observed in bilinguals, and to the extent that bilinguals (but not monolinguals) had better brain structure, their performance was enhanced. Collectively, the findings provide evidence for reserve in bilingual older adults.

Visuomotor Activation of Inhibition-Processing in Pediatric Obsessive Compulsive Disorder: A Magnetoencephalography Study.

Background: Response inhibition engages the cortico-striato-thalamo-cortical (CSTC) circuit, which has been implicated in children, and youth with obsessive compulsive disorder (OCD). This study explored whether CSTC engagement during response inhibition, measured using magnetoencephalography (MEG), differed in a sample of medication-naïve youth with OCD, compared to typically developing controls (TDC). Methods: Data was analyzed in 17 medication-naïve children and youth with OCD (11.7 ± 2.2 SD years) and 13 TDC (12.6 ± 2.2 SD years). MEG was used to localize and characterize neural activity during a Go/No-Go task. Task performance on Go/No-Go conditions and regional differences in amplitude of activity during Go and No-Go condition between OCD vs. TDC were examined using two-sample t-tests. Post-hoc analysis with Bayesian t-tests was used to estimate the certainty of outcomes. Results: No differences in Go/No-Go performance were found between OCD and TDC groups. In response to the visual cue presented during the Go condition, participants with OCD showed significantly increased amplitude of activity in the primary motor (MI) cortex compared to TDC. In addition, significantly reduced amplitude of PCu was found following successful stopping to No-Go cues in OCD vs. TDC during No-Go task performance. Bayesian t-tests indicated high probability and large effect sizes for the differences in MI and PCu amplitude found between groups. Conclusion: Our preliminary study in a small medication-naïve sample extends previous work indicating intact response inhibition in pediatric OCD. While altered neural response in the current study was found during response inhibition performance in OCD, differences localized to regions outside of the CSTC. Our findings suggest that additional imaging research in medication-naïve samples is needed to clarify regional differences associated with OCD vs. influenced by medication effects, and suggest that MEG may be sensitive to detecting such differences.

Poorer clinical outcomes for older adult monolinguals when matched to bilinguals on brain health.

Previous studies have reported bilingualism to be a proxy of cognitive reserve (CR) based on evidence that bilinguals express dementia symptoms ~ 4 years later than monolinguals yet present with greater neuropathology at time of diagnosis when clinical levels are similar. The current study provides new evidence supporting bilingualism's contribution to CR using a novel brain health matching paradigm. Forty cognitively normal bilinguals with diffusion-weighted magnetic resonance images recruited from the community were matched with monolinguals drawn from a pool of 165 individuals in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. White matter integrity was determined for all participants using fractional anisotropy, axial diffusivity, and radial diffusivity scores. Propensity scores were obtained using white matter measures, sex, age, and education as predictive covariates, and then used in one-to-one matching between language groups, creating a matched sample of 32 participants per group. Matched monolinguals had poorer clinical diagnoses than that predicted by chance from a theoretical null distribution, and poorer cognitive performances than matched bilinguals as measured by scores on the MMSE. The findings provide support for the interpretation that bilingualism acts as a proxy of CR such that monolinguals have poorer clinical and cognitive outcomes than bilinguals for similar levels of white matter integrity even before clinical symptoms appear.

Frontal-executive and corticolimbic structural brain circuitry in older people with remitted depression, mild cognitive impairment, Alzheimer's dementia, and normal cognition.

A history of depression is a risk factor for dementia. Despite strong epidemiologic evidence, the pathways linking depression and dementia remain unclear. We assessed structural brain alterations in white and gray matter of frontal-executive and corticolimbic circuitries in five groups of older adults putatively at-risk for developing dementia- remitted depression (MDD), non-amnestic MCI (naMCI), MDD+naMCI, amnestic MCI (aMCI), and MDD+aMCI. We also examined two other groups: non-psychiatric ("healthy") controls (HC) and individuals with Alzheimer's dementia (AD). Magnetic resonance imaging (MRI) data were acquired on the same 3T scanner. Following quality control in these seven groups, from diffusion-weighted imaging (n = 300), we compared white matter fractional anisotropy (FA), mean diffusivity (MD), and from T1-weighted imaging (n = 333), subcortical volumes and cortical thickness in frontal-executive and corticolimbic regions of interest (ROIs). We also used exploratory graph theory analysis to compare topological properties of structural covariance networks and hub regions. We found main effects for diagnostic group in FA, MD, subcortical volume, and cortical thickness. These differences were largely due to greater deficits in the AD group and to a lesser extent aMCI compared with other groups. Graph theory analysis revealed differences in several global measures among several groups. Older individuals with remitted MDD and naMCI did not have the same white or gray matter changes in the frontal-executive and corticolimbic circuitries as those with aMCI or AD, suggesting distinct neural mechanisms in these disorders. Structural covariance global metrics suggested a potential difference in brain reserve among groups.

In Vivo Imaging of Gray Matter Microstructure in Major Psychiatric Disorders: Opportunities for Clinical Translation.

Postmortem studies reveal that individuals with major neuropsychiatric disorders such as schizophrenia and autism spectrum disorder have gray matter microstructural abnormalities. These include abnormalities in neuropil organization, expression of proteins supporting neuritic and synaptic integrity, and myelination. Genetic and postmortem studies suggest that these changes may be causally linked to the pathogenesis of these disorders. Advances in diffusion-weighted magnetic resonance image (dMRI) acquisition techniques and biophysical modeling allow for the quantification of gray matter microstructure in vivo. While several biophysical models for imaging microstructural properties are available, one in particular, neurite orientation dispersion and density imaging (NODDI), holds great promise for clinical applications. NODDI can be applied to both gray and white matter and requires only a single extra shell beyond a standard dMRI acquisition. Since its development only a few years ago, the NODDI algorithm has been used to characterize gray matter microstructure in schizophrenia, Alzheimer's disease, healthy aging, and development. These investigations have shown that microstructural findings in vivo, using NODDI, align with postmortem findings. Not only do NODDI and other advanced dMRI-based modeling methods provide a window into the brain previously only available postmortem, but they may be more sensitive to certain brain changes than conventional magnetic resonance imaging approaches. This opens up exciting new possibilities for clinicians to more rapidly detect disease signatures and allows earlier intervention in the course of the disease. Given that neurites and gray matter microstructure have the capacity to rapidly remodel, these novel dMRI-based methods represent an opportunity to noninvasively monitor neuroplastic changes posttherapy within much shorter time scales.

Does bilingualism protect against dementia? A meta-analysis.

Evidence suggests that bilingualism may contribute to neuroplasticity and cognitive reserve, allowing individuals to resist cognitive decline associated with Alzheimer's disease progression, although the idea remains controversial. Here, we argue that the reason for the discrepancy stems from conflating incidence rates of dementia and the age at which the symptoms first appear, as well as statistical and methodological issues in the study designs. To clarify the issues, we conducted a comprehensive meta-analysis on the available literature regarding bilingualism and Alzheimer's disease, including both retrospective and prospective studies, as well as age of onset and incidence rates. Results revealed a moderate effect size for the protective effect of bilingualism on age of onset of symptoms of Alzheimer's disease (Cohen's d = 0.32), and weaker evidence that bilingualism prevents the occurrence of disease incidence itself (Cohen's d = 0.10). Moreover, our results cannot be explained by SES, education, or publication bias. We conclude with a discussion on how bilingualism contributes to cognitive reserve and protects against Alzheimer's disease and recommend that future studies report both age of onset as well as incidence rates when possible.

The relation between brain signal complexity and task difficulty on an executive function task.

On a daily basis, we constantly deal with changing environmental cues and perceptual conflicts and as such, our brains must flexibly adapt to current demands in order to act appropriately. Brains become more efficient and are able to switch states more readily by increasing the complexity of their neural networks. However, it is unclear how brain signal complexity relates to behavior in young adults performing cognitively demanding executive function tasks. Here we used multiscale entropy analysis and multivariate statistics on EEG data while participants performed a bivalency effect task-switching paradigm to show that brain signal complexity in young adults increases as task demands increase, that increases in brain signal complexity are associated with both speed gains and losses depending on scalp location, and that more difficult tasks are associated with more circumscribed complexity across the scalp. Overall, these findings highlight a critical role for brain signal complexity in predicting behavior on an executive function task among young adults.

Sex differences in the relationship between cardiorespiratory fitness and brain function in older adulthood.

We investigated sex differences in the association between a measure of physical health, cardiorespiratory fitness (CRF), and brain function using resting-state functional connectivity fMRI. We examined these sex differences in the default, frontoparietal control, and cingulo-opercular networks, assemblies of functionally connected brain regions known to be impacted by both age and fitness level. Healthy older adults ( n = 49; 29 women) were scanned to obtain measures of intrinsic connectivity within and across these 3 networks. We calculated global efficiency (a measure of network integration) and local efficiency (a measure of network specialization) using graph theoretical methods. Across all three networks combined, local efficiency was positively associated with CRF, and this was more robust in male versus female older adults. Furthermore, global efficiency was negatively associated with CRF, but only in males. Our findings suggest that in older adults, associations between brain network integrity and physical health are sex-dependent. These results underscore the importance of considering sex differences when examining associations between fitness and brain function in older adulthood. NEW & NOTEWORTHY We examined the association between cardiorespiratory fitness and resting state functional connectivity in several brain networks known to be impacted by age and fitness level. We found significant associations between fitness and measures of network integration and network specialization, but in a sex-dependent manner, highlighting the interplay between sex differences, fitness, and aging brain health. Our findings underscore the importance of considering sex differences when examining associations between fitness and brain function in older adulthood.

Intrinsic neurocognitive network connectivity differences between normal aging and mild cognitive impairment are associated with cognitive status and age.

Mild cognitive impairment (MCI) of the amnestic type is considered to be a transitionary stage between healthy aging and Alzheimer's disease (AD). Previous studies have demonstrated that intrinsic functional connectivity of the default network (DN) is altered in normal aging and AD and impacts both within- and between-network connectivity. Although changes within the DN have been reported in MCI, it remains uncertain how interactions with other large-scale brain networks are altered in this prodromal stage of AD. We investigated within- and between-network connectivity in healthy older adults (HOAs) and older adults with MCI across 3 canonical brain networks: DN, dorsal attention network, and frontoparietal control network. We also assessed how patterns of functional connectivity among the 3 networks predicted cognitive status and age using multivariate partial least squares. A total of 91 MCI and 71 HOA resting-state scans were analyzed from the Alzheimer's Disease Neuroimaging Initiative. There were 3 key findings. First, a circumscribed pattern of greater between-network and interhemispheric connectivity was associated with higher cognitive status in HOAs. Second, for individuals with MCI, cognitive status was positively associated with a more distributed, less-differentiated pattern of intrinsic functional connectivity across the 3 networks. Finally, greater within-network functional connectivity was positively associated with cognitive status for HOAs irrespective of age; however, this compensation-like effect diminished with increasing age for participants with MCI. Although reliable differences between healthy aging and MCI in the intrinsic network architecture of the brain are apparent, these differences emerge as shifting associations between network interactivity, cognitive functioning, and age.

Language and cognitive control networks in bilinguals and monolinguals.

Neuroimaging studies have reported overlapping neural circuits for cognitive control when engaging in tasks that involve verbal and nonverbal stimuli in young adult bilinguals. However, no study to date has examined the neural basis of verbal and nonverbal task switching in both monolinguals and bilinguals due to the inherent challenge of testing verbal task switching with monolinguals. Therefore, it is not clear whether the finding for overlapping networks is unique to bilingualism or indicative of general cognitive control. To address this question, the current study compared functional neural activation for young adults who were bilingual speakers of English and French or monolingual English speakers who had limited French learning experience ("functional monolinguals") on verbal and nonverbal task switching. Analyses showed common variance explaining general cognitive control in task switching across verbal and nonverbal domains for both groups, in line with the explanation that task switching involves general cognitive control, as well as unique brain regions recruited by monolinguals and bilinguals. Specifically, beyond the processing common to the tasks, monolinguals also recruited distinct networks for each of verbal and nonverbal switching but bilinguals used a common shared network. Thus, the domain-general aspect of switching is different for monolinguals and bilinguals.