Apolipoprotein E (APOE) ε4 moderates the relationship between c-reactive protein, cognitive functioning, and white matter integrity.

Elevated serum C-reactive protein (CRP) and possessing an APOE ε4 allele are two of the most prominent risk factors for cognitive and neurological dysfunction in older adults, but little is known about the unique or cumulative effects of these risk factors in young-to-middle-aged adults. To further characterize these potential relationships, measures of cognition and microstructural white matter integrity were examined using data from a sample of 329 post-9/11 war veterans that was collected as part of a comprehensive evaluation that included assessment of neuropsychological functioning, MRI scanning, psychiatric diagnoses, health screening, markers of inflammation, and APOE genotypes. Hierarchical linear regression analyses revealed the CRP and APOE ε4 interaction was associated with global cognition (ß = -0.633), executive functioning (ß = -0.566), and global fractional anisotropy (ß = -0.470), such that elevated CRP was associated with worse cognition and white matter integrity in APOE ε4 carriers. Diffusion tensor imaging (DTI) was used to determine if CRP × APOE ε4 presence was associated with regionally specific fractional anisotropy in white matter tracts. Tract-based spatial statistics revealed CRP × APOE ε4 presence was associated with fractional anisotropy in the corpus callosum, right superior longitudinal fasciculus, right posterior corona radiata, as well as the bilateral anterior and superior corona radiatas. This suggests that APOE ε4 carriers may be uniquely vulnerable to the potentially negative impact of elevated systematic inflammation to cognition and microstructural white matter integrity.

Apolipoprotein E (APOE) ε4 Status Moderates the Relationship Between Close-Range Blast Exposure and Cognitive Functioning.

OBJECTIVES: Recent studies suggest that close-range blast exposure (CBE), regardless of acute concussive symptoms, may have negative long-term effects on brain health and cognition; however, these effects are highly variable across individuals. One potential genetic risk factor that may impact recovery and explain the heterogeneity of blast injury's long-term cognitive outcomes is the inheritance of an apolipoprotein (APOE) ε4 allele, a well-known genetic risk factor for Alzheimer's disease. We hypothesized that APOE ε4 carrier status would moderate the impact of CBE on long-term cognitive outcomes. METHODS: To test this hypothesis, we examined 488 post-9/11 veterans who completed assessments of neuropsychological functioning, psychiatric diagnoses, history of blast exposure, military and non-military mild traumatic brain injuries (mTBIs), and available APOE genotypes. We separately examined the effects of CBE on attention, memory, and executive functioning in individuals with and without the APOE ε4 allele. RESULTS: As predicted, we observed a differential impact of CBE status on cognition as a function of APOE ε4 status, in which CBE ε4 carriers displayed significantly worse neuropsychological performance, specifically in the domain of memory. These results persisted after adjusting for clinical, demographic, and genetic factors and were not observed when examining other neurotrauma variables (i.e., lifetime or military mTBI, distant blast exposure), though these variables displayed similar trends. CONCLUSIONS: These results suggest APOE ε4 carriers are more vulnerable to the impact of CBE on cognition and highlight the importance of considering genetic risk when studying cognitive effects of neurotrauma.

The relationship between sustained attention and parasympathetic functioning.

Sustained attention (SA) is an important cognitive ability that plays a crucial role in successful cognitive control. Resting vagally-mediated heart rate variability (vmHRV) has emerged as an informative index of parasympathetic nervous system activity and a sensitive correlate of individual differences in cognitive control. However, it is unclear how resting vmHRV is associated with individual differences in sustained attention. The primary aim of the current study was to assess if resting vmHRV was associated with individual differences in performance on a neuropsychological assessment of sustained attention. We further aimed to characterize the relationship between resting vmHRV and dispositional factors related to sustained attention, specifically attentional errors in daily life, self-regulation, mindfulness and media-multitasking. Based on previous work, we hypothesized higher resting vmHRV would be associated with better sustained attention across task-based and self-report measures. We did not find resting vmHRV to be significantly associated with performance measures on a task-based assessment of sustained attention. Further, resting vmHRV was not significantly associated with attention errors, self-regulation, mindfulness, or media-multitasking. This work stands to expand the current understanding between parasympathetic functioning, cognition, and behavior, investigating the unexplored domain of sustained attention and related dispositional factors.

Evaluating the efficacy of cranial electrotherapy stimulation in mitigating anxiety-induced cognitive deficits.

Cranial electrotherapy stimulation (CES) is a form of non-invasive brain stimulation (NIBS) that has demonstrated potential to modulate neural activity in a manner that may be conducive to improved cognitive performance. While other forms of NIBS, such as transcranial direct current stimulation (tDCS), have received attention in the field as potential acute cognitive enhancers, CES remains relatively unexplored. The current study aimed to assess the efficacy of CES in improving acute cognitive performance under normal experimental conditions, as well as during sessions of induced situational anxiety (threat of shock or ToS). To study this question, participants completed a cognitive battery assessing processing speed and distinct aspects of executive functioning (working memory, inhibition, and task switching) in two separate sessions in which they received active and sham CES. Participants were randomly assigned to between subject groups of either situational anxiety (ToS) or control condition (no ToS). We predicted that active CES would improve performance on assessments of executive functioning (working memory, inhibition, and task switching) relative to sham CES under ToS. We did not find any significant effects of ToS, CES, or an interaction between ToS and CES for any measures of executive functioning or processing speed. These findings suggest that a single dose of CES does not enhance executive functioning or processing speed under normal conditions or during ToS.

Modulating Cognitive-Motor Multitasking with Commercial-off-the-Shelf Non-Invasive Brain Stimulation.

One growing area of multitasking research involves a focus on performing cognitive and motor tasks in tandem. In these situations, increasing either cognitive or motor demands has implications for performance in both tasks, an effect which is thought to be due to competing neural resources. Separate research suggests that non-invasive brain stimulation may offer a means to mitigate performance decrements experienced during multitasking. In the present study, we investigated the degree to which a commercially available non-invasive brain stimulation device (Halo Sport) alters balance performance in the presence of different types of cognitive demands. Specifically, we tested if performing a secondary cognitive task impacts postural sway in healthy young adults and if we could mitigate this impact using transcranial direct current stimulation (tDCS) applied over the primary motor cortex. Furthermore, we included conditions of unstable and stable surfaces and found that lower surface stability increased postural sway. In addition, we found that cognitive load impacted postural sway but in the opposite pattern we had anticipated, with higher sway found in the single-task control condition compared to executive function conditions. Finally, we found a small but significant effect of tDCS on balance with decreased sway for active (compared to sham) tDCS.

A Critical Review of Cranial Electrotherapy Stimulation for Neuromodulation in Clinical and Non-clinical Samples.

Cranial electrotherapy stimulation (CES) is a neuromodulation tool used for treating several clinical disorders, including insomnia, anxiety, and depression. More recently, a limited number of studies have examined CES for altering affect, physiology, and behavior in healthy, non-clinical samples. The physiological, neurochemical, and metabolic mechanisms underlying CES effects are currently unknown. Computational modeling suggests that electrical current administered with CES at the earlobes can reach cortical and subcortical regions at very low intensities associated with subthreshold neuromodulatory effects, and studies using electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) show some effects on alpha band EEG activity, and modulation of the default mode network during CES administration. One theory suggests that CES modulates brain stem (e.g., medulla), limbic (e.g., thalamus, amygdala), and cortical (e.g., prefrontal cortex) regions and increases relative parasympathetic to sympathetic drive in the autonomic nervous system. There is no direct evidence supporting this theory, but one of its assumptions is that CES may induce its effects by stimulating afferent projections of the vagus nerve, which provides parasympathetic signals to the cardiorespiratory and digestive systems. In our critical review of studies using CES in clinical and non-clinical populations, we found severe methodological concerns, including potential conflicts of interest, risk of methodological and analytic biases, issues with sham credibility, lack of blinding, and a severe heterogeneity of CES parameters selected and employed across scientists, laboratories, institutions, and studies. These limitations make it difficult to derive consistent or compelling insights from the extant literature, tempering enthusiasm for CES and its potential to alter nervous system activity or behavior in meaningful or reliable ways. The lack of compelling evidence also motivates well-designed and relatively high-powered experiments to assess how CES might modulate the physiological, affective, and cognitive responses to stress. Establishing reliable empirical links between CES administration and human performance is critical for supporting its prospective use during occupational training, operations, or recovery, ensuring reliability and robustness of effects, characterizing if, when, and in whom such effects might arise, and ensuring that any benefits of CES outweigh the risks of adverse events.

The Specificity of Cognitive-Motor Dual-Task Interference on Balance in Young and Older Adults.

Standing upright on stable and unstable surfaces requires postural control. Postural control declines as humans age, presenting greater risk of fall-related injury and other negative health outcomes. Secondary cognitive tasks can further impact balance, which highlights the importance of coordination between cognitive and motor processes. Past research indicates that this coordination relies on executive function (EF; the ability to control, maintain, and flexibly direct attention to achieve goals), which coincidentally declines as humans age. This suggests that secondary cognitive tasks requiring EF may exert a greater influence on balance compared to non-EF secondary tasks, and this interaction could be exaggerated among older adults. In the current study, we had younger and older adults complete two Surface Stability conditions (standing upright on stable vs. unstable surfaces) under varying Cognitive Load; participants completed EF (Shifting, Inhibiting, Updating) and non-EF (Processing Speed) secondary cognitive tasks on tablets, as well as a single task control scenario with no secondary cognitive task. Our primary balance measure of interest was sway area, which was measured with an array of wearable inertial measurement unit sensors. Replicating prior work, we found a main effect of Surface Stability with less sway on stable surfaces compared to unstable surfaces, and we found an interaction between Age and Surface Stability with older adults exhibiting significantly greater sway selectively on unstable surfaces compared to younger adults. New findings revealed a main effect of Cognitive Load on sway, with the single task condition having significantly less sway than two of the EF conditions (Updating and Shifting) and the non-EF condition (Processing Speed). We also found an interaction of Cognitive Load and Surface Stability on postural control, where Surface Stability impacted sway the most for the single task and two of the executive function conditions (Inhibition and Shifting). Interestingly, Age did not interact with Cognitive Load, suggesting that both age groups were equally impacted by secondary cognitive tasks, regardless the presence or type of secondary cognitive task. Taken together, these patterns suggest that cognitive demands vary in their impact on posture control across stable vs. unstable surfaces, and that EF involvement may not be the driving mechanism explaining cognitive-motor dual-task interference on balance.

Multiscale Dynamics of Spontaneous Brain Activity Is Associated With Walking Speed in Older Adults.

BACKGROUND: In older adults, compromised white matter tract integrity within the brain has been linked to impairments in mobility. We contend that poorer integrity disrupts mobility by altering the processing of sensorimotor and cognitive and attentional resources in neural networks. The richness of information processing in a given network can be quantified by calculating the complexity of resting-state functional MRI time series. We hypothesized that (i) older adults with lower brain complexity, specifically within sensorimotor, executive, and attention networks, would exhibit slower walking speed and greater dual-task costs (ie, dual-task cost) and (ii) such complexity would mediate the effect of white matter integrity on these metrics of mobility. METHODS: Fifty-three older adults completed a walking assessment and a neuroimaging protocol. Brain complexity was quantified by calculating the multiscale entropy of the resting-state functional MRI signal within seven previously defined functional networks. The white matter integrity across structures of the corpus callosum was quantified using fractional anisotropy. RESULTS: Participants with lower resting-state complexity within the sensorimotor, executive, and attention networks walked more slowly under single- and dual-task (ie, walking while performing a serial-subtraction task) conditions (ß > 0.28, p ≤ .01) and had a greater dual-task cost (ß < -0.28, p < .04). Complexity in these networks mediated the influence of the corpus callosum genu on both single- (indirect effects > 0.15, 95% confidence intervals = 0.02-0.32) and dual-task walking speeds (indirect effects > 0.13, 95% confidence intervals = 0.02-0.33). CONCLUSION: These results suggest that the multiscale dynamics of resting-state brain activity correlate with mobility and mediate the effect of the microstructural integrity in the corpus callosum genu on walking speed in older adults.

Motor-Cognitive Neural Network Communication Underlies Walking Speed in Community-Dwelling Older Adults.

While walking was once thought to be a highly automated process, it requires higher-level cognition with older age. Like other cognitive tasks, it also becomes further challenged with increased cognitive load (e.g., the addition of an unrelated dual task) and often results in poorer performance (e.g., slower speed). It is not well known, however, how intrinsic neural network communication relates to walking speed, nor to this "cost" to gait performance; i.e., "dual-task cost (DTC)." The current study investigates the relationship between network connectivity, using resting-state functional MRI (rs-fMRI), and individual differences in older adult walking speed. Fifty participants (35 females; 84 ± 4.5 years) from the MOBILIZE Boston Study cohort underwent an MRI protocol and completed a gait assessment during two conditions: walking quietly at a preferred pace and while concurrently performing a serial subtraction task. Within and between neural network connectivity measures were calculated from rs-fMRI and were correlated with walking speeds and the DTC (i.e., the percent change in speed between conditions). Among the rs-fMRI correlates, faster walking was associated with increased connectivity between motor and cognitive networks and decreased connectivity between limbic and cognitive networks. Smaller DTC was associated with increased connectivity within the motor network and increased connectivity between the ventral attention and executive networks. These findings support the importance of both motor network integrity as well as inter-network connectivity amongst higher-level cognitive networks in older adults' ability to maintain mobility, particularly under dual-task (DT) conditions.

Metabolic risk in older adults is associated with impaired sustained attention.

OBJECTIVE: Metabolic syndrome (MetS), the presence of three or more cardiovascular risk factors, has been associated with subtle and diffuse neural compromise but has not been consistently associated with cognitive dysfunction. Sustained attention is a fundamental cognitive operation that relies on multiple brain networks and is impaired in a broad array of neurologic conditions. We examined whether a well-validated measure of sustained attention would be sensitive to vascular risk, as compared with more standard neuropsychological measures of attention and executive functioning. METHOD: We assessed vascular risk factors (VRFs; blood pressure, waist circumference, cholesterol, glucose, and triglycerides) in 93 middle-to-older aged adults (45-75 years). MetS was defined based on current guidelines from the National Cholesterol Education Program Adult Training Program (NCEP ATP III). Participants were grouped according to number of VRFs: high risk (MetS; 3+ VRFs; N = 32), medium risk (1 or 2 VRFs; N = 35), and low risk (0 VRFs; N = 26). All participants underwent a neuropsychological battery of tests measuring executive functioning. Participants also performed the gradual-onset continuous performance task (gradCPT), a measure of sustained attention. RESULTS: There was a significant main effect of VRF group on sustained attention performance; participants with lower vascular risk were better able to sustain attention. No significant effects were detected on standard neuropsychological tests of executive function. CONCLUSION: Our results suggest that the gradCPT is sensitive to the potentially negative effects of MetS on subtle aspects of neurocognitive functioning. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Compromised prefrontal structure and function are associated with slower walking in older adults.

Our previous work demonstrates that reduced activation of the executive network is associated with slow walking speed in a cohort of older adults from the MOBILIZE Boston Study. However, the influence of underlying white matter integrity on the activation of this network and walking speed is unknown. Thus, we used diffusion-weighted imaging and fMRI during an n-back task to assess associations between executive network structure, function, and walking speed. Whole-brain tract-based spatial statistics (TBSS) were used to identify regions of white matter microstructural integrity that were associated with walking speed. The integrity of these regions was then entered into multiple regression models to predict task performance and executive network activation during the n-back task. Among the significant associations of FA with walking speed, we observed the anterior thalamic radiation and superior longitudinal fasciculus were further associated with both n-back response speed and executive network activation. These findings suggest that subtle damage to frontal white matter may contribute to altered executive network activation and slower walking in older adults.