Midlife Cardiovascular Fitness Is Reflected in the Brain's White Matter.

Disappointing results from clinical trials designed to delay structural brain decline and the accompanying increase in risk for dementia in older adults have precipitated a shift in testing promising interventions from late in life toward midlife before irreversible damage has accumulated. This shift, however, requires targeting midlife biomarkers that are associated with clinical changes manifesting only in late life. Here we explored possible links between one putative biomarker, distributed integrity of brain white matter, and two intervention targets, cardiovascular fitness and healthy lifestyle behaviors, in midlife. At age 45, fractional anisotropy (FA) derived from diffusion weighted MRI was used to estimate the microstructural integrity of distributed white matter tracts in a population-representative birth cohort. Age-45 cardiovascular fitness (VO2Max; N = 801) was estimated from heart rates obtained during submaximal exercise tests; age-45 healthy lifestyle behaviors were estimated using the Nyberg Health Index (N = 854). Ten-fold cross-validated elastic net predictive modeling revealed that estimated VO2Max was modestly associated with distributed FA. In contrast, there was no significant association between Nyberg Health Index scores and FA. Our findings suggest that cardiovascular fitness levels, but not healthy lifestyle behaviors, are associated with the distributed integrity of white matter in the brain in midlife. These patterns could help inform future clinical intervention research targeting ADRDs.

Childhood self-control forecasts the pace of midlife aging and preparedness for old age.

The ability to control one's own emotions, thoughts, and behaviors in early life predicts a range of positive outcomes in later life, including longevity. Does it also predict how well people age? We studied the association between self-control and midlife aging in a population-representative cohort of children followed from birth to age 45 y, the Dunedin Study. We measured children's self-control across their first decade of life using a multi-occasion/multi-informant strategy. We measured their pace of aging and aging preparedness in midlife using measures derived from biological and physiological assessments, structural brain-imaging scans, observer ratings, self-reports, informant reports, and administrative records. As adults, children with better self-control aged more slowly in their bodies and showed fewer signs of aging in their brains. By midlife, these children were also better equipped to manage a range of later-life health, financial, and social demands. Associations with children's self-control could be separated from their social class origins and intelligence, indicating that self-control might be an active ingredient in healthy aging. Children also shifted naturally in their level of self-control across adult life, suggesting the possibility that self-control may be a malleable target for intervention. Furthermore, individuals' self-control in adulthood was associated with their aging outcomes after accounting for their self-control in childhood, indicating that midlife might offer another window of opportunity to promote healthy aging.

Is cardiovascular fitness associated with structural brain integrity in midlife? Evidence from a population-representative birth cohort study.

Improving cardiovascular fitness may buffer against age-related cognitive decline and mitigate dementia risk by staving off brain atrophy. However, it is unclear if such effects reflect factors operating in childhood (neuroselection) or adulthood (neuroprotection). Using data from 807 members of the Dunedin Study, a population-representative birth cohort, we investigated associations between cardiovascular fitness and structural brain integrity at age 45, and the extent to which associations reflected possible neuroselection or neuroprotection by controlling for childhood IQ. Higher fitness, as indexed by VO2Max, was not associated with average cortical thickness, total surface area, or subcortical gray matter volume including the hippocampus. However, higher fitness was associated with thicker cortex in prefrontal and temporal regions as well as greater cerebellar gray matter volume. Higher fitness was also associated with decreased hippocampal fissure volume. These associations were unaffected by the inclusion of childhood IQ in analyses. In contrast, a higher rate of decline in cardiovascular fitness from 26 to 45 years was not robustly associated with structural brain integrity. Our findings are consistent with a neuroprotective account of adult cardiovascular fitness but suggest that effects are not uniformly observed across the brain and reflect contemporaneous fitness more so than decline over time.

Cardiovascular fitness and structural brain integrity: an update on current evidence.

An aging global population and accompanying increases in the prevalence of age-related disorders are leading to greater financial, social, and health burdens. Aging-related dementias are one such category of age-related disorders that are associated with progressive loss of physical and cognitive integrity. One proposed preventative measure against risk of aging-related dementia is improving cardiovascular fitness, which may help reverse or buffer age-related brain atrophy associated with worse aging-related outcomes and cognitive decline. However, research into the beneficial potential of cardiovascular fitness has suffered from extreme heterogeneity in study design methodology leading to a lack of cohesion in the field and undermining any potential causal evidence that may exist. In addition, cardiovascular fitness and exercise are often conflated, leading to a lack of clarity in results. Here, I review recent literature on cardiovascular fitness, brain structure, and aging with the following goals: (a) to disentangle and lay out recent findings specific to aging, cardiovascular fitness, and brain structure, and (b) to ascertain the extent to which causal evidence actually exists. I suggest that, while there is some preliminary evidence for a link between cardiovascular fitness and brain structure in older adults, more research is still needed before definitive causal conclusions can be drawn. I conclude with a discussion of existing gaps in the field and suggestions for how they may be addressed by future research.

Application of long-interval paired-pulse transcranial magnetic stimulation to motion-sensitive visual cortex does not lead to changes in motion discrimination.

The perception of visual motion is dependent on a set of occipitotemporal regions that are readily accessible to neuromodulation. The current study tested if paired-pulse Transcranial Magnetic Stimulation (ppTMS) could modulate motion perception by stimulating the occipital cortex as participants viewed near-threshold motion dot stimuli. In this sham-controlled study, fifteen subjects completed two sessions. On the first visit, resting motor threshold (RMT) was assessed, and participants performed an adaptive direction discrimination task to determine individual motion sensitivity. During the second visit, subjects performed the task with three difficulty levels as TMS pulses were delivered 150 and 50 ms prior to motion stimulus onset at 120% RMT, under the logic that the cumulative inhibitory effect of these pulses would alter motion sensitivity. ppTMS was delivered at one of two locations: 3 cm dorsal and 5 cm lateral to inion (scalp-based coordinate), or at the site of peak activation for "motion" according to the NeuroSynth fMRI database (meta-analytic coordinate). Sham stimulation was delivered on one-third of trials by tilting the coil 90°. Analyses showed no significant active-versus-sham effects of ppTMS when stimulation was delivered to the meta-analytic (p = 0.15) or scalp-based coordinates (p = 0.17), which were separated by 29 mm on average. Active-versus-sham stimulation differences did not interact with either stimulation location (p = 0.12) or difficulty (p = 0.33). These findings fail to support the hypothesis that long-interval ppTMS recruits inhibitory processes in motion-sensitive cortex but must be considered within the limited parameters used in this design.

Functional connectivity predicts the dispositional use of expressive suppression but not cognitive reappraisal.

INTRODUCTION: Previous research has identified specific brain regions associated with regulating emotion using common strategies such as expressive suppression and cognitive reappraisal. However, most research focuses on a priori regions and directs participants how to regulate, which may not reflect how people naturally regulate outside the laboratory. METHOD: Here, we used a data-driven approach to investigate how individual differences in distributed intrinsic functional brain connectivity predict emotion regulation tendency outside the laboratory. Specifically, we used connectome-based predictive modeling to extract functional connections in the brain significantly related to the dispositional use of suppression and reappraisal. These edges were then used in a predictive model and cross-validated in novel participants to identify a neural signature that reflects individual differences in the tendency to suppress and reappraise emotion. RESULTS: We found a significant neural signature for the dispositional use of suppression, but not reappraisal. Within this whole-brain signature, the intrinsic connectivity of the default mode network was most informative of suppression tendency. In addition, the predictive performance of this model was significant in males, but not females. CONCLUSION: These findings help inform how whole-brain networks of functional connectivity characterize how people tend to regulate emotion outside the laboratory.

Association of Neurocognitive and Physical Function With Gait Speed in Midlife.

Importance: Gait speed is a well-known indicator of risk of functional decline and mortality in older adults, but little is known about the factors associated with gait speed earlier in life. Objectives: To test the hypothesis that slow gait speed reflects accelerated biological aging at midlife, as well as poor neurocognitive functioning in childhood and cognitive decline from childhood to midlife. Design, Setting, and Participants: This cohort study uses data from the Dunedin Multidisciplinary Health and Development Study, a population-based study of a representative 1972 to 1973 birth cohort in New Zealand that observed participants to age 45 years (until April 2019). Data analysis was performed from April to June 2019. Exposures: Childhood neurocognitive functions and accelerated aging, brain structure, and concurrent physical and cognitive functions in adulthood. Main Outcomes and Measures: Gait speed at age 45 years, measured under 3 walking conditions: usual, dual task, and maximum gait speeds. Results: Of the 1037 original participants (91% of eligible births; 535 [51.6%] male), 997 were alive at age 45 years, of whom 904 (90.7%) had gait speed measured (455 [50.3%] male; 93% white). The mean (SD) gait speeds were 1.30 (0.17) m/s for usual gait, 1.16 (0.23) m/s for dual task gait, and 1.99 (0.29) m/s for maximum gait. Adults with more physical limitations (standardized regression coefficient [ß], -0.27; 95% CI, -0.34 to -0.21; P < .001), poorer physical functions (ie, weak grip strength [ß, 0.36; 95% CI, 0.25 to 0.46], poor balance [ß, 0.28; 95% CI, 0.21 to 0.34], poor visual-motor coordination [ß, 0.24; 95% CI, 0.17 to 0.30], and poor performance on the chair-stand [ß, 0.34; 95% CI, 0.27 to 0.40] or 2-minute step tests [ß, 0.33; 95% CI, 0.27 to 0.39]; all P < .001), accelerated biological aging across multiple organ systems (ß, -0.33; 95% CI, -0.40 to -0.27; P < .001), older facial appearance (ß, -0.25; 95% CI, -0.31 to -0.18; P < .001), smaller brain volume (ß, 0.15; 95% CI, 0.06 to 0.23; P < .001), more cortical thinning (ß, 0.09; 95% CI, 0.02 to 0.16; P = .01), smaller cortical surface area (ß, 0.13; 95% CI, 0.04 to 0.21; P = .003), and more white matter hyperintensities (ß, -0.09; 95% CI, -0.15 to -0.02; P = .01) had slower gait speed. Participants with lower IQ in midlife (ß, 0.38; 95% CI, 0.32 to 0.44; P < .001) and participants who exhibited cognitive decline from childhood to adulthood (ß, 0.10; 95% CI, 0.04 to 0.17; P < .001) had slower gait at age 45 years. Those with poor neurocognitive functioning as early as age 3 years had slower gait in midlife (ß, 0.26; 95% CI, 0.20 to 0.32; P < .001). Conclusions and Relevance: Adults' gait speed is associated with more than geriatric functional status; it is also associated with midlife aging and lifelong brain health.

Microstructural integrity of white matter moderates an association between childhood adversity and adult trait anger.

Amongst a number of negative life sequelae associated with childhood adversity is the later expression of a higher dispositional tendency to experience anger and frustration to a wide range of situations (i.e., trait anger). We recently reported that an association between childhood adversity and trait anger is moderated by individual differences in both threat-related amygdala activity and executive control-related dorsolateral prefrontal cortex (dlPFC) activity, wherein individuals with relatively low amygdala and high dlPFC activity do not express higher trait anger even when having experienced childhood adversity. Here, we examine possible structural correlates of this functional dynamic using diffusion magnetic resonance imaging data from 647 young adult men and women volunteers. Specifically, we tested whether the degree of white matter microstructural integrity as indexed by fractional anisotropy modulated the association between childhood adversity and trait anger. Our analyses revealed that higher microstructural integrity of multiple pathways was associated with an attenuated link between childhood adversity and adult trait anger. Amongst these pathways was the uncinate fasciculus (UF; ΔR 2 = 0.01), which not only provides a major anatomical link between the amygdala and prefrontal cortex but also is associated with individual differences in regulating negative emotion through top-down cognitive reappraisal. These findings suggest that higher microstructural integrity of distributed white matter pathways including but not limited to the UF may represent an anatomical foundation serving to buffer against the expression of childhood adversity as later trait anger, which is itself associated with multiple negative health outcomes.

White matter hyperintensities are common in midlife and already associated with cognitive decline.

White matter hyperintensities proliferate as the brain ages and are associated with increased risk for cognitive decline as well as Alzheimer's disease and related dementias. As such, white matter hyperintensities have been targeted as a surrogate biomarker in intervention trials with older adults. However, it is unclear at what stage of aging white matter hyperintensities begin to relate to cognition and if they may be a viable target for early prevention. In the Dunedin Study, a population-representative cohort followed since birth, we measured white matter hyperintensities in 843 45-year-old participants using T2-weighted magnetic resonance imaging and we assessed cognitive decline from childhood to midlife. We found that white matter hyperintensities were common at age 45 and that white matter hyperintensity volume was modestly associated with both lower childhood (ß = -0.08, P = 0.013) and adult IQ (ß=-0.15, P < 0.001). Moreover, white matter hyperintensity volume was associated with greater cognitive decline from childhood to midlife (ß=-0.09, P < 0.001). Our results demonstrate that a link between white matter hyperintensities and early signs of cognitive decline is detectable decades before clinical symptoms of dementia emerge. Thus, white matter hyperintensities may be a useful surrogate biomarker for identifying individuals in midlife at risk for future accelerated cognitive decline and selecting participants for dementia prevention trials.

Emotion Regulation and the Experience of Future Negative Mood: The Importance of Assessing Social Support.

Emotion regulation refers to the use of various strategies, such as cognitive reappraisal and expressive suppression, to help manage our negative experiences, emotions, and thoughts. Although such emotion regulation often occurs within broader social dynamics and interactions, little is known about how social contexts interact with specific regulation strategies to shape the experience of negative emotions. Using data from 544 young adult university students, we provide initial evidence that habitual use of cognitive reappraisal is associated with lower future experience of depression and anxiety primarily through higher perceived social support (PSS). In contrast, expressive suppression is associated with higher future depression and anxiety primarily through lower PSS. These patterns are consistent with the importance of interpersonal influences on emotion regulation and suggest that assessment of social support can help elucidate the mechanisms of successfully regulating negative mood.

Microstructural integrity of a pathway connecting the prefrontal cortex and amygdala moderates the association between cognitive reappraisal and negative emotions.

Cognitive reappraisal is a commonly used form of emotion regulation that utilizes frontal-executive control to reframe an approaching emotional event to moderate its potential psychological impact. Use of cognitive reappraisal has been associated with diminished experience of anxiety and depressive symptoms, as well as greater overall well-being. Using data from a study of 647 healthy young adults, we provide initial evidence that an association between typical use of cognitive reappraisal in daily life and the experience of anxiety and depressive symptoms is moderated by the microstructural integrity of the uncinate fasciculus, which provides a major anatomical link between the amygdala and prefrontal cortex. Our findings are consistent with the nature of top-down regulation of bottom-up negative emotions and suggest the uncinate fasciculus may be a useful target in the search for biomarkers predicting not only disorder risk but also response to psychotherapy utilizing cognitive reappraisal. (PsycINFO Database Record

A Link Between Childhood Adversity and Trait Anger Reflects Relative Activity of the Amygdala and Dorsolateral Prefrontal Cortex.

BACKGROUND: Trait anger, or the dispositional tendency to experience a wide range of situations as annoying or frustrating, is associated with negative mental and physical health outcomes. The experience of adversity during childhood is one risk factor for the later emergence of high trait anger. This association has been hypothesized to reflect alterations in neural circuits supporting bottom-up threat processing and top-down executive control. METHODS: Here, using functional magnetic resonance imaging and self-report questionnaire data from 220 volunteers, we examined how individual differences in top-down prefrontal executive control and bottom-up amygdala threat activity modulate the association between childhood adversity and trait anger during young adulthood. RESULTS: We report that the association between childhood adversity and trait anger is attenuated specifically in young adults who have both relatively low threat-related amygdala activity and high executive control-related dorsolateral prefrontal cortex activity. CONCLUSIONS: These brain activity patterns suggest that simultaneous consideration of their underlying cognitive processes-namely, threat processing and executive control-may be useful in strategies designed to mitigate the negative mental health consequences of childhood adversity.