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Background: Person-specific computational models can estimate transcranial direct current stimulation (tDCS) current dose delivered to the brain and predict treatment response. Artificially created electrode models derived from virtual 10-20 EEG measurements are typically included in these models as current injection and removal sites. The present study directly compares current flow models generated via artificially placed electrodes ("artificial" electrode models) against those generated using real electrodes acquired from structural MRI scans ("real" electrode models) of older adults., Methods: A total of 16 individualized head models were derived from cognitively healthy older adults (mean age = 71.8 years) who participated in an in-scanner tDCS study with an F3-F4 montage. Visible tDCS electrodes captured within the MRI scans were segmented to create the "real" electrode model. In contrast, the "artificial" electrodes were generated in ROAST. Percentage differences in current density were computed in selected regions of interest (ROIs) as examples of stimulation targets within an F3-F4 montage., Main Results: We found significant inverse correlations ( p < 0.001) between median current density values and brain atrophy in both electrode pipelines with slightly larger correlations found in the artificial pipeline. The percent difference (PD) of the electrode distances between the two models predicted the median current density values computed in the ROIs, gray, and white matter, with significant correlation between electrode distance PDs and current density. The correlation between PD of the contact areas and the computed median current densities in the brain was found to be non-significant., Conclusions: This study demonstrates potential discrepancies in generated current density models using real versus artificial electrode placement when applying tDCS to an older adult cohort. Our findings strongly suggest that future tDCS clinical work should consider closely monitoring and rigorously documenting electrode location during stimulation to model tDCS montages as closely as possible to actual placement. Detailed physical electrode location data may provide more precise information and thus produce more robust tDCS modeling results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Indahlastari, Dunn, Pedersen, Kraft, Someya, Albizu and Woods.)

Aging is associated with declines in mitochondrial efficiency and energy production which directly impacts the availability of adenosine triphosphate (ATP), which contains high energy phosphates critical for a variety of cellular functions. Previous phosphorous magnetic resonance spectroscopy ( 31 P MRS) studies demonstrate cerebral ATP declines with age. The purpose of this study was to explore the functional relationships of frontal and posterior ATP levels with cognition in healthy aging. Here, we measured frontal and posterior ATP levels using 31 P MRS at 3 Tesla (3 T) and assessed cognition using the Montreal Cognitive Assessment (MoCA) in 30 healthy older adults. We found that greater frontal, but not posterior, ATP levels were significantly associated with better MoCA performance. This relationship remained significant after controlling for age, sex, years of education, and brain atrophy. In conclusion, our findings indicate that cognition is related to ATP in the frontal cortex. These preliminary findings may have important implications in the search for non-invasive markers of in vivo mitochondrial function and the impact of ATP availability on cognition. Future studies are needed to confirm the functional significance of regional ATP and cognition across the lifespan., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lopez, O’Shea, Rosenberg, Leeuwenburgh, Anton, Bowers and Woods.)

Background: Older adults are at a greater risk for contracting and experiencing severe illness from COVID-19 and may be further affected by pandemic-related precautions (e.g., social distancing and isolation in quarantine). However, the longitudinal impact of the COVID-19 pandemic on older adults is unclear. The current study examines changes in health behaviors, psychosocial factors, and cognitive functioning in a large sample of older adults using a pre-pandemic baseline and longitudinal follow-up throughout 9 months of the COVID-19 pandemic. Methods: One hundred and eighty-nine older adults (ages 65-89) were recruited from a multisite clinical trial to complete additional virtual assessments during the COVID-19 pandemic. Mixed effects models evaluated changes in health behaviors, psychosocial factors, and cognitive functioning during the pandemic compared to a pre-pandemic baseline and over the course of the pandemic (i.e., comparing the first and last COVID-19 timepoints). Results: Compared to their pre-pandemic baseline, during the pandemic, older adults reported worsened sleep quality, perceived physical health and functioning, mental health, slight increases in depression and apathy symptoms, reduced social engagement/perceived social support, but demonstrated better performance on objective cognitive tasks of attention and working memory. Throughout the course of the pandemic, these older adults reported continued worsening of perceived physical health and function, fewer depression symptoms, and they demonstrated improved cognitive performance. It is important to note that changes on self-report mood measures and cognitive performance were relatively small regarding clinical significance. Education largely served as a protective factor, such that greater years of education was generally associated with better outcomes across domains. Conclusions: The present study provides insights into the longitudinal impact of the COVID-19 pandemic on health behaviors, psychosocial factors, and cognitive functioning in a population disproportionately affected by the virus. Replicating this study design in a demographically representative older adult sample is warranted to further inform intervention strategies targeting older adults negatively impacted by the COVID-19 pandemic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hausman, Dai, O’Shea, Dominguez, Fillingim, Calfee, Carballo, Hernandez, Perryman, Kraft, Evangelista, Van Etten, Smith, Bharadwaj, Song, Porges, DeKosky, Hishaw, Marsiske, Cohen, Alexander, Wu and Woods.)

The neural systems underlying semantic processing have been characterized with functional neuroimaging in young adults. Whether the integrity of these systems degrade with advanced age remains unresolved. The current study examined functional connectivity during abstract and concrete word processing. Thirty-eight adults, aged 55-91, engaged in semantic association decision tasks during a mixed event-related block functional magnetic resonance imaging (fMRI) paradigm. During the semantic trials, the task required participants to make a judgment as to whether pairs were semantically associated. During the rhyme trials, the task required participants to determine if non-word pairs rhymed. Seeds were placed in putative semantic hubs of the left anterior middle temporal gyrus (aMTG) and the angular gyrus (AG), and also in the left inferior frontal gyrus (IFG), an area considered important for semantic control. Greater connectivity between aMTG, AG, and IFG and multiple cortical areas occurred during semantic processing. Connectivity from the three seeds differed during semantic processing: the left AG and aMTG were strongly connected with frontal, parietal, and occipital areas bilaterally, whereas the IFG was most strongly connected with other frontal cortical areas and the AG in the ipsilateral left hemisphere. Notably, the strength and extent of connectivity differed for abstract and concrete semantic processing; connectivity from the left aMTG and AG to bilateral cortical areas was greater during abstract processing, whereas IFG connectivity with left cortical areas was greater during concrete processing. With advanced age, greater connectivity occurred only between the left AG and supramarginal gyrus during the processing of concrete word-pairs, but not abstract word-pairs. Among older adults, robust functional connectivity of the aMTG, AG, and IFG to widely distributed bilateral cortical areas occurs during abstract and concrete semantic processing in a manner consistent with reports from past studies of young adults. There was not a significant degradation of functional connectivity during semantic processing between the ages of 55 and 85 years. As the study focused on semantic functioning in older adults, a comparison group of young adults was not included, limiting generalizability. Future longitudinal neuroimaging studies that compare functional connectivity of young and older adults under different semantic demands will be valuable., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Garcia, Cohen, Porges, Williamson and Woods.)

The amygdala has been shown to be responsive to face trustworthiness. While older adults typically give higher face trustworthiness ratings than young adults, a direct link between amygdala response and age-related differences in face trustworthiness evaluation has not yet been confirmed. Additionally, there is a possible modulatory role of the neuropeptide oxytocin in face trustworthiness evaluation, but the results are mixed and effects unexplored in aging. To address these research gaps, young, and older adults were randomly assigned to oxytocin or placebo self-administration via a nasal spray before rating faces on trustworthiness while undergoing functional magnetic resonance imaging. There was no overall age-group difference in face trustworthiness ratings, but older compared to young participants gave higher trustworthiness ratings to ambivalently untrustworthy-looking faces. In both age groups, lower face trustworthiness ratings were associated with higher left amygdala activity. A comparable negative linear association was observed in right amygdala but only among young participants. Also, in the right amygdala, lower and higher, compared to moderate, face trustworthiness ratings were associated with greater right amygdala activity (i.e., positive quadratic (U-shaped) association) for both age groups. Neither the behavioral nor the brain effects were modulated by a single dose of intranasal oxytocin administration, however. These results suggest dampened response to faces with lower trustworthiness among older compared to young adults, supporting the notion of reduced sensitivity to cues of untrustworthiness in aging. The findings also extend evidence of an age-related positivity effect to the evaluation of face trustworthiness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lin, Pehlivanoglu, Ziaei, Liu, Woods, Feifel, Fischer and Ebner.)

Background and Objectives: Prediction of decline to dementia using objective biomarkers in high-risk patients with amnestic mild cognitive impairment (aMCI) has immense utility. Our objective was to use multimodal MRI to (1) determine whether accurate and precise prediction of dementia conversion could be achieved using baseline data alone, and (2) generate a map of the brain regions implicated in longitudinal decline to dementia. Methods: Participants meeting criteria for aMCI at baseline ( N = 55) were classified at follow-up as remaining stable/improved in their diagnosis ( N = 41) or declined to dementia ( N = 14). Baseline T1 structural MRI and resting-state fMRI (rsfMRI) were combined and a semi-supervised support vector machine (SVM) which separated stable participants from those who decline at follow-up with maximal margin. Cross-validated model performance metrics and MRI feature weights were calculated to include the strength of each brain voxel in its ability to distinguish the two groups. Results: Total model accuracy for predicting diagnostic change at follow-up was 92.7% using baseline T1 imaging alone, 83.5% using rsfMRI alone, and 94.5% when combining T1 and rsfMRI modalities. Feature weights that survived the p < 0.01 threshold for separation of the two groups revealed the strongest margin in the combined structural and functional regions underlying the medial temporal lobes in the limbic system. Discussion: An MRI-driven SVM model demonstrates accurate and precise prediction of later dementia conversion in aMCI patients. The multi-modal regions driving this prediction were the strongest in the medial temporal regions of the limbic system, consistent with literature on the progression of Alzheimer's disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gullett, Albizu, Fang, Loewenstein, Duara, Rosselli, Armstrong, Rundek, Hausman, Dekosky, Woods and Cohen.)

Objective: This study examines the impact of transcranial direct current stimulation (tDCS) combined with cognitive training on neurotransmitter concentrations in the prefrontal cortex. Materials and Methods: Twenty-three older adults were randomized to either active-tDCS or sham-tDCS in combination with cognitive training for 2 weeks. Active-tDCS was delivered over F3 (cathode) and F4 (anode) electrode placements for 20 min at 2 mA intensity. For each training session, 40-min of computerized cognitive training were applied with active or sham stimulation delivered during the first 20-min. Glutamine/glutamate (Glx) and gamma-aminobutyric acid (GABA) concentrations via proton magnetic resonance spectroscopy were evaluated at baseline and at the end of 2-week intervention. Results: Glx concentrations increased from pre- to post-intervention ( p = 0.010) in the active versus sham group after controlling for age, number of intervention days, MoCA scores, and baseline Glx concentration. No difference in GABA concentration was detected between active and sham groups ( p = 0.650) after 2-week intervention. Conclusion: Results provide preliminary evidence suggesting that combining cognitive training and tDCS over the prefrontal cortex elicits sustained increase in excitatory neurotransmitter concentrations. Findings support the combination of tDCS and cognitive training as a potential method for altering neurotransmitter concentrations in the frontal cortices, which may have implications for neuroplasticity in the aging brain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Alvarez-Alvarado, Boutzoukas, Kraft, O’Shea, Indahlastari, Albizu, Nissim, Evangelista, Cohen, Porges and Woods.)

Background : Changes in both circulating cytokines and neurochemical concentrations have been observed in aging. Patterns of change across these factors are associated with age-related pathologies, including neurodegenerative disease. More evidence to define patterns of change that are characteristic of healthy aging is needed, as is an investigation into how age-related changes in blood cytokines and brain neurochemicals may relate to one another in a healthy older adult population. Methods : Single voxel 1 H-proton magnetic resonance spectroscopy was collected in medial frontal and medial parietal regions. Phosphocholine and glycerophosphocholine (Cho), myo- inositol (MI), N-acetylaspertate and N-acetylasperglutamate (NAA), creatine and phosphocreatine (Cr), and glutamate and glutamine (Glx) were measured in a sample of 83 healthy, cognitively normal adults aged 52-89. Blood data were collected to quantify 12 cytokines: interleukins (IL-) 2, 5, 6, 7, 8, 10, 12, 13, IL-1 β, tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), and IL-17 α. Correlation analyses were performed to assess age relationships between each of these factors. Backward linear regressions were performed. Cytokine data and age were used as predictors of each cerebrospinal fluid (CSF)-corrected metabolite concentration in both voxels. Results : Associations were identified between a variety of cytokines and concentrations of frontal NAA, Cr, and Glx, and of parietal MI, Cho, NAA, and Cr. In the frontal voxel, NAA was predicted by more IL-1B and less TNF-α, Cr by less TNF-α and more IL-5, and Glx by less TNF-α. In the parietal voxel, MI was predicted by more IL-10 and IL-8 and less IL-2, Cho by more TNF-α and less IL-2, NAA by more IL-1B and TNF-α and less IL-13, IL-2, and IL-7, and Cr by more IL-10 and less IL-2. Conclusions : Associations were identified between circulating cytokines and neurometabolite concentrations in this sample of older adults. The present results serve as the initial evidence of relationships between circulating cytokines and neurophysiology. Findings invite further investigation to understand the physiological consequences of aging, and how peripheral inflammatory markers may relate to neurochemical concentrations in healthy aging., (Copyright © 2021 Langer, Cohen, Porges, Williamson and Woods.)

Neural dedifferentiation refers to an age-related phenomenon whereby brain functions that are localized to specific, distinct, and differentiated brain areas in young adults become less so as people reach more advanced age. Older adults tend to exhibit greater spread of cortical activation on fMRI during cognitive processing compared to younger adults, with evidence that this occurs during visuoperceptual processing. Some age-related functional changes are considered compensatory, but whether dedifferentiation is compensatory is not clearly understood. The current study assessed dedifferentiation and visual discrimination performance during simultaneous match-to-sample tasks from the Visual Assessment Battery (VAB) among 40 healthy middle-aged and older adults using fMRI. Task-relevant regions of interest (ROIs) were created in the dorsal stream for discrimination of spatial location, the ventral stream for shape, and an area encompassing V5 for velocity. Dedifferentiation, or less specificity in functional activation, was associated with greater discrimination accuracy and more years of education. Secondary analyses showed that reduced functional activation in task-relevant ROIs was associated with faster discrimination speed. Age was unassociated with functional activation. Results suggest that dedifferentiation is compensatory. Lack of age effects suggest that other factors beyond age, such as cognitive or brain reserve, may better predict performance when considering cognitive skills that are relatively stable as adults age, such as visual discrimination., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Seider, Porges, Woods and Cohen.)

Frontal lobe structures decline faster than most other brain regions in older adults. Age-related change in the frontal lobe is associated with poorer executive function (e.g., working memory, switching/set-shifting, and inhibitory control). The effects and presence of frontal lobe white matter hyperintensities (WMH) on executive function in normal aging is relatively unknown. The current study assessed relationships between region-specific frontal WMH load and cognitive performance in healthy older adults using three executive function tasks from the NIH Toolbox (NIHTB) Cognition Battery. A cohort of 279 healthy older adults ages 65-88 completed NIHTB and 3T T1-weighted and FLAIR MRI. Lesion Segmentation Toolbox quantified WMH volume and generated lesion probability maps. Individual lesion maps were registered to the Desikan-Killiany atlas in FreeSurfer 6.0 to define regions of interest (ROI). Independent linear regressions assessed relationships between executive function performance and region-specific WMH in frontal lobe ROIs. All models included age, sex, education, estimated total intracranial volume, multi-site scanner differences, and cardiovascular disease risk using Framingham criteria as covariates. Poorer set-shifting performance was associated with greater WMH load in three frontal ROIs including bilateral superior frontal (left β = -0.18, FDR- p = 0.02; right β = -0.20, FDR- p = 0.01) and right medial orbitofrontal (β = -0.17, FDR- p = 0.02). Poorer inhibitory performance associated with higher WMH load in one frontal ROI, the right superior frontal (right β = -0.21, FDR- p = 0.01). There were no significant associations between working memory and WMH in frontal ROIs. Our study demonstrates that location and pattern of frontal WMH may be important to assess when examining age-related differences in cognitive functions involving switching/set-shifting and inhibition. On the other hand, working memory performance was not related to presence of frontal WMH in this sample. These data suggest that WMH may contribute selectively to age-related declines in executive function. Findings emerged beyond predictors known to be associated with WMH presence, including age and cardiovascular disease risk. The spread of WMH within the frontal lobes may play a key role in the neuropsychological profile of cognitive aging. Further research should explore whether early intervention on modifiable vascular factors or cognitive interventions targeted for executive abilities may help mitigate the effect of frontal WMH on executive function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Boutzoukas, O'Shea, Albizu, Evangelista, Hausman, Kraft, Van Etten, Bharadwaj, Smith, Song, Porges, Hishaw, DeKosky, Wu, Marsiske, Alexander, Cohen and Woods.)

Background: Cerebral metabolites are associated with different physiological processes in brain aging. Cortical and limbic structures play important roles in cognitive aging; however, the relationship between these structures and age remains unclear with respect to physiological underpinnings. Regional differences in metabolite levels may be related to different structural and cognitive changes in aging., Methods: Magnetic resonance imaging and spectroscopy were obtained from 117 cognitively healthy older adults. Limbic and other key structural volumes were measured. Concentrations of N-acetylaspartate (NAA) and choline-containing compounds (Cho) were measured in frontal and parietal regions. Neuropsychological testing was performed including measures of crystallized and fluid intelligence and memory., Results: NAA in the frontal voxel was associated with limbic and cortical volumes, whereas Cho in parietal cortex was negatively associated with hippocampal and other regional volumes. Hippocampal volume was associated with forgetting, independent of age. Further, parietal Cho and hippocampal volume contributed independent variance to age corrected discrepancy between fluid and crystallized abilities., Conclusion: These findings suggest that physiological changes with age in the frontal and parietal cortices may be linked to structural changes in other connected brain regions. These changes are differentially associated with cognitive performance, suggesting potentially divergent mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Williamson, Lamb, Porges, Bottari, Woods, Datta, Langer and Cohen.)

Objective : The association between hippocampal volume and memory is continuing to be characterized in healthy older adults. Prior research suggests smaller hippocampal volume in healthy older adults is associated with poorer episodic memory and processing speed, as well as working memory, verbal learning, and executive functioning as measured by the NIH Toolbox Fluid (Fluid Cognition Composite, FCC) and Crystalized Cognition Composites (CCC). This study aimed to replicate these findings and to evaluate the association between: (1) hippocampal asymmetry index and cognition; and (2) independent contributions of the left and right hippocampal volume and cognition in a large sample of healthy older adults. Participants and Methods : One-hundred and eighty-three healthy older adults (M age = 71.72, SD = 5.3) received a T1-weighted sequence on a 3T scanner. Hippocampal subfields were extracted using FreeSurfer 6.0 and combined to provide left, right, and total hippocampal volumes. FCC subtests include Dimensional Change Card Sort, Flanker Inhibitory Control and Attention, List Sorting, Picture Sequence Memory, and Pattern Comparison. CCC subtests include Picture Vocabulary and Oral Reading Recognition. Multiple linear regressions were performed predicting cognition composites from the total, left and right, and asymmetry of hippocampal volume, controlling for sex, education, scanner, and total intracranial volume. Multiple comparisons in primary analyses were corrected using a false discovery rate (FDR) of p < 0.05. Results : FCC scores were positively associated with total ( β = 0.226, FDR q = 0.044) and left ( β = 0.257, FDR q = 0.024) hippocampal volume. Within FCC, Picture Sequence Memory scores positively associated with total ( β = 0.284, p = 0.001) and left ( β = 0.98, p = 0.001) hippocampal volume. List Sorting scores were also positively associated with left hippocampal volume ( β = 0.189, p = 0.029). Conclusions : These results confirm previous research suggesting that bilateral hippocampal volume is associated with FCC, namely episodic memory. The present study also suggests the left hippocampal volume may be more broadly associated with both episodic and working memory. Studies should continue to investigate lateralized hippocampal contributions to aging processes to better identify predictors of cognitive decline., (Copyright © 2020 Hardcastle, O’Shea, Kraft, Albizu, Evangelista, Hausman, Boutzoukas, Van Etten, Bharadwaj, Song, Smith, Porges, Dekosky, Hishaw, Wu, Marsiske, Cohen, Alexander and Woods.)

Speed of processing is a cognitive domain that encompasses the speed at which an individual can perceive a given stimulus, interpret the information, and produce a correct response. Speed of processing has been shown to decline more rapidly than other cognitive domains in an aging population, suggesting that this domain is particularly vulnerable to cognitive aging (Chee et al., 2009). However, given the heterogeneity of neuropsychological measures used to assess the domains underpinning speed of processing, a diffuse pattern of brain regions has been implicated. The current study aims to investigate the structural neural correlates of speed of processing by assessing cortical volume and speed of processing scores on the POSIT Double Decision task within a healthy older adult population ( N = 186; mean age = 71.70 ± 5.32 years). T1-weighted structural images were collected via a 3T Siemens scanner. The current study shows that less cortical thickness in right temporal, posterior frontal, parietal and occipital lobe structures were significantly associated with poorer Double Decision scores. Notably, these include the lateral orbitofrontal gyrus, precentral gyrus, superior, transverse, and inferior temporal gyrus, temporal pole, insula, parahippocampal gyrus, fusiform gyrus, lingual gyrus, superior and inferior parietal gyrus and lateral occipital gyrus. Such findings suggest that speed of processing performance is associated with a wide array of cortical regions that provide unique contributions to performance on the Double Decision task., (Copyright © 2020 Kraft, O’Shea, Albizu, Evangelista, Hausman, Boutzoukas, Nissim, Van Etten, Bharadwaj, Song, Smith, Porges, DeKosky, Hishaw, Wu, Marsiske, Cohen, Alexander and Woods.)

Aging is associated with disruptions in the resting-state functional architecture of the brain. Previous studies have primarily focused on age-related declines in the default mode network (DMN) and its implications in Alzheimer's disease. However, due to mixed findings, it is unclear if changes in resting-state network functional connectivity are linked to cognitive decline in healthy older adults. In the present study, we evaluated the influence of intra-network coherence for four higher-order cognitive resting-state networks on a sensitive measure of cognitive aging (i.e., NIH Toolbox Fluid Cognition Battery) in 154 healthy older adults with a mean age of 71 and education ranging between 12 years and 21 years (mean = 16). Only coherence within the cingulo-opercular network (CON) was significantly related to Fluid Cognition Composite scores, explaining more variance in scores than age and education. Furthermore, we mapped CON connectivity onto fluid cognitive subdomains that typically decline in advanced age. Greater CON connectivity was associated with better performance on episodic memory, attention, and executive function tasks. Overall, the present study provides evidence to propose CON coherence as a potential novel neural marker for nonpathological cognitive aging., (Copyright © 2020 Hausman, O’Shea, Kraft, Boutzoukas, Evangelista, Van Etten, Bharadwaj, Smith, Porges, Hishaw, Wu, DeKosky, Alexander, Marsiske, Cohen and Woods.)

Background: Working memory, a fundamental short-term cognitive process, is known to decline with advanced age even in healthy older adults. Normal age-related declines in working memory can cause loss of independence and decreased quality of life. Cognitive training has shown some potential at enhancing certain cognitive processes, although, enhancements are variable. Transcranial direct current stimulation (tDCS), a form of non-invasive brain stimulation, has shown promise at enhancing working memory abilities, and may further the benefits from cognitive training interventions. However, the neural mechanisms underlying tDCS brain-based enhancements remain unknown., Objective/hypothesis: Assess the effects of a 2-week intervention of active-tDCS vs. sham paired with cognitive training on functional connectivity of the working memory network during an N-Back working memory task., Methods: Healthy older adults ( N = 28; mean age = 74 ± 7.3) completed 10-sessions of cognitive training paired with active or sham-tDCS. Functional connectivity was evaluated at baseline and post-intervention during an N-Back task (2-Back vs. 0-Back)., Results: Active-tDCS vs. sham demonstrated a significant increase in connectivity between the left dorsolateral prefrontal cortex and right inferior parietal lobule at post-intervention during 2-Back. Target accuracy on 2-Back was significantly improved for active vs. sham at post-intervention., Conclusion: These results suggest pairing tDCS with cognitive training enhances functional connectivity and working memory performance in older adults, and thus may hold promise as a method for remediating age-related cognitive decline. Future studies evaluating optimal dose and long-term effects of tDCS on brain function will help to maximize potential clinical impacts of tDCS paired with cognitive training in older adults., Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02137122., (Copyright © 2019 Nissim, O’Shea, Indahlastari, Kraft, von Mering, Aksu, Porges, Cohen and Woods.)

Working memory is an executive memory process essential for everyday decision-making and problem solving that declines with advanced age. Transcranial direct current stimulation (tDCS) is a non-invasive form of brain stimulation that has demonstrated potential for improving working memory performance in older adults. However, the neural mechanisms underlying effects of tDCS on working memory are not well understood. This mechanistic study investigated the acute and after-effects of bilateral frontal (F3/F4) tDCS at 2 mA for 12-min on functional connectivity of the working memory network in older adults. We hypothesized active tDCS over sham would increase frontal connectivity during working memory performance. The study used a double-blind within-subject 2 session crossover design. Participants performed an functional magnetic resonance imaging (fMRI) N-Back working memory task before, during, and after active or sham stimulation. Functional connectivity of the working memory network was assessed within and between stimulation conditions (FDR < 0.05). Active tDCS produced a significant increase in functional connectivity between left ventrolateral prefrontal cortex (VLPFC) and left dorsolateral PFC (DLPFC) during stimulation, but not after stimulation. Connectivity did not significantly increase with sham stimulation. In addition, our data demonstrated both state-dependent and time-dependent effects of tDCS working memory network connectivity in older adults. tDCS during working memory performance produces a selective change in functional connectivity of the working memory network in older adults. These data provide important mechanistic insight into the effects of tDCS on brain connectivity in older adults, as well as key methodological considerations for tDCS-working memory studies.

Time is talked about in terms of space more frequently than the other way around. Some have suggested that this asymmetry runs deeper than language. The idea that we think about abstract domains (like time) in terms of relatively more concrete domains (like space) but not vice versa can be traced to Conceptual Metaphor Theory. This theoretical account has some empirical support. Previous experiments suggest an embodied basis for space-time asymmetries that runs deeper than language. However, these studies frequently involve verbal and/or visual stimuli. Because vision makes a privileged contribution to spatial processing it is unclear whether these results speak to a general asymmetry between time and space based on each domain's general level of relative abstractness, or reflect modality-specific effects. The present study was motivated by this uncertainty and what appears to be audition's privileged contribution to temporal processing. In Experiment 1, using an auditory perceptual task, temporal duration and spatial displacement were shown to be mutually contagious. Irrelevant temporal information influenced spatial judgments and vice versa with a larger effect of time on space. Experiment 2 examined the mutual effects of space, time, and pitch . Pitch was investigated because it is a fundamental characteristic of sound perception. It was reasoned that if space is indeed less relevant to audition than time, then spatial distance judgments should be more easily contaminated by variations in auditory frequency, while variations in distance should be less effective in contaminating pitch perception. While time and pitch were shown to be mutually contagious in Experiment 2, irrelevant variation in auditory frequency affected estimates of spatial distance while variations in spatial distance did not affect pitch judgments. Results overall suggest that the perceptual asymmetry between spatial and temporal domains does not necessarily generalize across modalities, and that time is not generally more abstract than space.

Objective: To examine whether educational attainment, as a proxy of cognitive reserve, moderated the association between hippocampal volumes and episodic verbal memory performances in healthy older adults. Methods: Data from 76 community dwelling older adults were included in the present study. Measures of hippocampal volumes (total, left, and right) were obtained using FreeSurfer software. Immediate and delayed verbal recall scores were derived from performances on the California Verbal Learning Test-Second Edition and the Wechsler Memory Scale- Third Edition. Educational attainment was defined by years of education. Linear regression analyses were performed using immediate and delayed recall as dependent variables and hippocampal volumes, years of education, and their interaction terms as independent variables. All analyses were controlled for age, sex, depression, and health status. Results: Total and left Hippocampal volumes had a positive main effect on delayed recall only. Additionally, the interaction between total, left, and right hippocampal volumes and education was a significant predictor for delayed recall performance but not for immediate recall performance. The positive association between hippocampal volumes and delayed recall was greatest in those with more years of education. Conclusion: Larger hippocampal volumes were associated with better delayed verbal recall and the effect on delayed recall was greatest in those with more years of education. Having higher levels of education, or cognitive reserve, may enable individuals to capitalize on greater structural integrity in the hippocampus to support delayed recall in old age. However, longitudinal research is needed to investigate the directionality of these associations.

The impact of cognitive aging on brain function and structure is complex, and the relationship between aging-related structural changes and cognitive function are not fully understood. Physiological and pathological changes to the aging brain are highly variable, making it difficult to estimate a cognitive trajectory with which to monitor the conversion to cognitive decline. Beyond the information on the structural and functional consequences of cognitive aging gained from brain imaging and neuropsychological studies, non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) can enable stimulation of the human brain in vivo , offering useful insights into the functional integrity of intracortical circuits using electrophysiology and neuromodulation. TMS measurements can be used to identify and monitor changes in cortical reactivity, the integrity of inhibitory and excitatory intracortical circuits, the mechanisms of long-term potentiation (LTP)/depression-like plasticity and central cholinergic function. Repetitive TMS and tDCS can be used to modulate neuronal excitability and enhance cortical function, and thus offer a potential means to slow or reverse cognitive decline. This review will summarize and critically appraise relevant literature regarding the use of TMS and tDCS to probe cortical areas affected by the aging brain, and as potential therapeutic tools to improve cognitive function in the aging population. Challenges arising from intra-individual differences, limited reproducibility, and methodological differences will be discussed.

Objective: Research has shown that depression is a risk factor for Alzheimer's disease (AD) and subsequent cognitive decline. This is compounded by evidence showing an association between depression and reduced hippocampal volumes; a primary structure implicated in the pathogenesis of the disease. Less is known about the relationship between depression and other AD vulnerable regions such as the entorhinal cortex. Given the heterogeneity of depressive symptom presentation, we examined whether symptom dimensions were associated with hippocampal and entorhinal cortex volumes in community dwelling older adults. Methods: Eighty-one community dwelling adults completed the Beck Depression Inventory - second edition and underwent structural neuroimaging. Measures of hippocampal and entorhinal cortex volumes were obtained using FreeSurfer software. Linear regression models included regions of interest as dependent variables, with depressive symptom dimensions, as independent variables, controlling for total intracranial volumes, age, education, and gender. Results: Somatic symptoms were negatively associated with total, right, and left hippocampal volumes. Affective symptoms were negatively associated with total entorhinal cortex volumes, with a marginal main effect on left entorhinal cortex volumes. Conclusion: Our findings provide support for examining depressive symptoms and their association with AD vulnerable regions along subdimensions of affective, cognitive, and somatic symptoms to better understand profiles of symptoms most associated with these regions. Conceptualizing depressive symptoms in this way may also better inform treatment approaches in terms of targeting types of symptoms that may be more closely linked to poorer brain and cognitive health outcomes.

Community dwelling older individuals from the North Florida region were examined for health status and a comprehensive neuropsychological battery, including the Montreal Cognitive Assessment (MoCA), was performed on each participant. A subpopulation (58 females and 39 males) met the criteria for age (60-89) and no evidence of mild cognitive impairment, with a MoCA score ≥23. Despite the stringent criteria for participation, MoCA scores were negatively correlated within the limited age range. Extracellular microvesicles were isolated from the plasma and samples were found to be positive for the exosome marker CD63, with an enrichment of particles within the size range for exosomes. miRNA was extracted and examined using next generation sequencing with a stringent criterion (average of ≥10 counts per million reads) resulting in 117 miRNA for subsequent analysis. Characterization of expression confirmed pervious work concerning the relative abundance and overall pattern of expression of miRNA in plasma. Correlation analysis indicated that most of the miRNAs (74 miRNAs) were positively correlated with age ( p <0.01). Multiple regression was employed to identify the relationship of miRNA expression and MoCA score, accounting for age. MoCA scores were negatively correlated with 13 miRNAs. The pattern of expression for cognition-related miRNA did not match that previously described for Alzheimer's disease. Enrichment analysis was employed to identify miRNA-gene interactions to reveal possible links to brain function.

Working memory is an executive memory process that allows transitional information to be held and manipulated temporarily in memory stores before being forgotten or encoded into long-term memory. Working memory is necessary for everyday decision-making and problem solving, making it a fundamental process in the daily lives of older adults. Working memory relies heavily on frontal lobe structures and is known to decline with age. The current study aimed to determine the neural correlates of decreased working memory performance in the frontal lobes by comparing cortical thickness and cortical surface area from two demographically matched groups of healthy older adults, free from cognitive impairment, with high versus low N-Back working memory performance ( N = 56; average age = 70.29 ± 10.64). High-resolution structural T1-weighted images (1 mm isotropic voxels) were obtained on a 3T Philips MRI scanner. When compared to high performers, low performers exhibited significantly decreased cortical surface area in three frontal lobe regions lateralized to the right hemisphere: medial orbital frontal gyrus, inferior frontal gyrus, and superior frontal gyrus (FDR p < 0.05). There were no significant differences in cortical thickness between groups, a proxy for neurodegenerative tissue loss. Our results suggest that decreases in cortical surface area (a proxy for brain structural integrity) in right frontal regions may underlie age-related decline of working memory function.

The hippocampus is one of the most well studied structures in the human brain. While age-related decline in hippocampal volume is well documented, most of our knowledge about hippocampal structure-function relationships was discovered in the context of neurological and neurodegenerative diseases. The relationship between cognitive aging and hippocampal structure in the absence of disease remains relatively understudied. Furthermore, the few studies that have investigated the role of the hippocampus in cognitive aging have produced contradictory results. To address these issues, we assessed 93 older adults from the general community (mean age = 71.9 ± 9.3 years) on the Montreal Cognitive Assessment (MoCA), a brief cognitive screening measure for dementia, and the NIH Toolbox-Cognitive Battery (NIHTB-CB), a computerized neurocognitive battery. High-resolution structural magnetic resonance imaging (MRI) was used to estimate hippocampal volume. Lower MoCA Total ( p = 0.01) and NIHTB-CB Fluid Cognition ( p < 0.001) scores were associated with decreased hippocampal volume, even while controlling for sex and years of education. Decreased hippocampal volume was significantly associated with decline in multiple NIHTB-CB subdomains, including episodic memory, working memory, processing speed and executive function. This study provides important insight into the multifaceted role of the hippocampus in cognitive aging.

Neuroimaging studies of cognitive and brain aging often yield massive datasets that create many analytic and statistical challenges. In this paper, we discuss and address several limitations in the existing work. (1) Linear models are often used to model the age effects on neuroimaging markers, which may be inadequate in capturing the potential nonlinear age effects. (2) Marginal correlations are often used in brain network analysis, which are not efficient in characterizing a complex brain network. (3) Due to the challenge of high-dimensionality, only a small subset of the regional neuroimaging markers is considered in a prediction model, which could miss important regional markers. To overcome those obstacles, we introduce several advanced statistical methods for analyzing data from cognitive and brain aging studies. Specifically, we introduce semiparametric models for modeling age effects, graphical models for brain network analysis, and penalized regression methods for selecting the most important markers in predicting cognitive outcomes. We illustrate these methods using the healthy aging data from the Active Brain Study.

As the population ages and dementia becomes a growing healthcare concern, it is increasingly important to identify targets for intervention to delay or attenuate cognitive decline. Research has shown that the most successful interventions aim at altering lifestyle factors. Thus, this study examined how involvement in physical, cognitive, and social activity is related to brain structure in older adults. Sixty-five adults (mean age = 71.4 years, standard deviation = 8.9) received the Community Healthy Activities Model Program for Seniors (CHAMPS), a questionnaire that polls everyday activities in which older adults may be involved, and also underwent structural magnetic resonance imaging. Stepwise regression with backward selection was used to predict weekly time spent in either social, cognitive, light physical, or heavy physical activity from the volume of one of the cortical or subcortical regions of interest (corrected by intracranial volume) as well as age, education, and gender as control variables. Regressions revealed that more time spent in cognitive activity was associated with greater volumes of all brain regions studied: total cortex (β = 0.289, p = 0.014), frontal (β = 0.276, p = 0.019), parietal (β = 0.305, p = 0.009), temporal (β = 0.275, p = 0.020), and occipital (β = 0.256, p = 0.030) lobes, and thalamus (β = 0.310, p = 0.010), caudate (β = 0.233, p = 0.049), hippocampus (β = 0.286, p = 0.017), and amygdala (β = 0.336, p = 0.004). These effects remained even after accounting for the positive association between cognitive activity and education. No other activity variable was associated with brain volumes. Results indicate that time spent in cognitively engaging activity is associated with greater cortical and subcortical brain volume. Findings suggest that interventions aimed at increasing levels of cognitive activity may delay cognitive consequences of aging and decrease the risk of developing dementia.

Age is associated with reductions in surface area and cortical thickness, particularly in prefrontal regions. There is also evidence of greater thickness in some regions at older ages. Non-linear age effects in some studies suggest that age may continue to impact brain structure in later decades of life, but relatively few studies have examined the impact of age on brain structure within middle-aged to older adults. We investigated age differences in prefrontal surface area and cortical thickness in healthy adults between the ages of 51 and 81 years. Participants received a structural 3-Tesla magnetic resonance imaging scan. Based on a priori hypotheses, primary analyses focused on surface area and cortical thickness in the dorsolateral prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex. We also performed exploratory vertex-wise analyses of surface area and cortical thickness across the entire cortex. We found that older age was associated with smaller surface area in the dorsolateral prefrontal and orbitofrontal cortices but greater cortical thickness in the dorsolateral prefrontal and anterior cingulate cortices. Vertex-wise analyses revealed smaller surface area in primarily frontal regions at older ages, but no age effects were found for cortical thickness. Results suggest age is associated with reduced surface area but greater cortical thickness in prefrontal regions during later decades of life, and highlight the differential effects age has on regional surface area and cortical thickness.

In American football, pass interference calls can be difficult to make, especially when the timing of contact between players is ambiguous. American football history contains many examples of controversial pass interference decisions, often with fans, players, and officials interpreting the same event differently. The current study sought to evaluate the influence of experience with concepts important for officiating decisions in American football on the probability (i.e., response criteria) of pass interference calls. We further investigated the extent to which such experience modulates perceptual biases that might influence the interpretation of such events. We hypothesized that observers with less experience with the American football concepts important for pass interference would make progressively more pass interference calls than more experienced observers, even when given an explicit description of the necessary criteria for a pass interference call. In a go/no-go experiment using photographs from American football games, three groups of participants with different levels of experience with American football (Football Naïve, Football Player, and Football Official) made pass interference calls for pictures depicting left-moving and right-moving events. More experience was associated with progressively and significantly fewer pass interference calls [F (2,48) = 10.4, p < 0.001], with Football Naïve participants making the most pass interference calls, and Football Officials the least. In addition, our data replicated a prior finding of spatial biases for interpreting left-moving images more harshly than identical right-moving images, but only in Football Players. These data suggest that experience with the concepts important for making a decision may influence the rate of decision-making, and may also play a role in susceptibility to spatial biases.

Motion perception is a fundamental feature of the human visual system. As part of our daily life we often have to determine the direction of motion, even in ambiguous (AMB) situations. These situations force us to rely on exogenous cues, such as other environmental motion, and endogenous cues, such as our own actions, or previously learned experiences. In three experiments, we asked participants to report the direction of an AMB motion display, while manipulating exogenous and endogenous sources of information. Specifically, in all three experiments the exogenous information was represented by another motion cue while the endogenous cue was represented, respectively, by movement execution, movement planning, or a learned association about the motion display. Participants were consistently biased by less AMB motion cues in the environment when reporting the AMB target direction. In the absence of less AMB exogenous motion information, participants were biased by their motor movements and even the planning of such movements. However, when participants learned a specific association about the target motion, this acquired endogenous knowledge countered exogenous motion cues in biasing participants' perception. Taken together, our findings demonstrate that we disambiguate AMB motion using different sources of exogenous and endogenous cues, and that learned associations may be particularly salient in countering the effects of environmental cues.

Humans use kinematic temporal and spatial information from the environment to infer the causal dynamics (e.g., force) of an event. We hypothesize that the basis for these inferences are malleable and modulated by contextual temporal and spatial information. Specifically, the present research investigates whether the extent of a person's ongoing experience with direct causal events (e.g., temporally contiguous and spatially continuous) alters their use of time and space in judgments of causality. Participants made inferences of causality on animated launching events depicting a blue ball colliding with and then "launching" a red ball. We parametrically manipulated temporal contiguity and spatial continuity by varying the duration of contact between the balls and the angle of the second ball's movement. We manipulated participants' level of exposure to direct causal events (i.e., events with no delay or angle change) between experiments (Experiment 1: 2%, Experiment 2: 25%, Experiment 3: 75%). We found that participants adjust the temporal and spatial parameters they use to judge causality to accommodate the context in which they apprehended launching events. Participants became more conservative in their use of temporal and spatial parameters to judge causality as their exposure to direct causal events increased. People use time and space flexibly to infer causality based on their ongoing experiences. Such flexibility in making causal inferences may have adaptive significance.