Integrating Nutrient Biomarkers, Cognitive Function, and Structural MRI Data to Build Multivariate Phenotypes of Healthy Aging.

BACKGROUND: Research in the emerging field of nutritional cognitive neuroscience demonstrates that many aspects of nutrition-from entire diets to specific nutrients-affect cognitive performance and brain health. OBJECTIVES: Although previous research has primarily examined the bivariate relationship between nutrition and cognition or nutrition and brain health, this study sought to investigate the joint relationship between these essential and interactive elements of human health. METHODS: We applied a state-of-the-art data fusion method, coupled matrix tensor factorization, to characterize the joint association between measures of nutrition (52 nutrient biomarkers), cognition (Wechsler Abbreviated Test of Intelligence and Wechsler Memory Scale), and brain health (high-resolution MRI measures of structural brain volume) within a cross-sectional sample of 111 healthy older adults, with an average age of 69.1 y, 62% being female, and an average body mass index of 26.0 kg/m2. RESULTS: Data fusion uncovered latent factors that capture the joint association between specific nutrient profiles, cognitive measures, and cortical volumes, demonstrating the respects in which these health domains are coupled. A hierarchical cluster analysis further revealed systematic differences between a subset of variables contributing to the underlying latent factors, providing evidence for multivariate phenotypes that represent high and low levels of performance across multiple health domains. The primary features that distinguish between each phenotype were as follows: 1) nutrient biomarkers for monounsaturated and polyunsaturated fatty acids; 2) cognitive measures of immediate, auditory, and delayed memory; and 3) brain volumes within frontal, temporal, and parietal cortexes. CONCLUSIONS: By incorporating innovations in nutritional epidemiology (nutrient biomarker analysis), cognitive neuroscience (high-resolution structural brain imaging), and statistics (data fusion), this study provides an interdisciplinary synthesis of methods that elucidate how nutrition, cognition, and brain health are integrated through lifestyle choices that affect healthy aging.

Nutrient biomarker patterns, cognitive function, and fMRI measures of network efficiency in the aging brain.

A central aim of research in the psychological and brain sciences is to establish therapeutic interventions to promote healthy brain aging. Accumulating evidence indicates that diet and the many bioactive substances present in food are reasonable interventions to examine for dementia prevention. However, interdisciplinary research that applies methods from nutritional epidemiology and network neuroscience to investigate the role of nutrition in shaping functional brain network efficiency remains to be conducted. The present study therefore sought to combine methods across disciplines, applying nutrient biomarker pattern (NBP) analysis to capture the effects of plasma nutrients in combination and to examine their collective influence on measures of functional brain network efficiency (small-world propensity). We examined the contribution of NBPs to multiple indices of cognition and brain health in non-demented elders (n = 116), investigating performance on measures of general intelligence, executive function, and memory, and resting-state fMRI measures of brain network efficiency within seven intrinsic connectivity networks. Statistical moderation investigated whether NBPs influenced network efficiency and cognitive outcomes. The results revealed five NBPs that were associated with enhanced cognitive performance, including biomarker patterns high in plasma: (1) ω-3 and ω-6 polyunsaturated fatty acids (PUFAs), (2) lycopene, (3) ω-3 PUFAs, (4) carotenoids, and (5) vitamins B (riboflavin, folate, B12) and D. Furthermore, three NBPs were associated with enhanced functional brain network efficiency, including biomarker patterns high in plasma: (1) ω-6 PUFAs, (2) ω-3 PUFAs, and (3) carotene. Finally, ω-3 PUFAs moderated the fronto-parietal network and general intelligence, while ω-6 PUFAs and lycopene moderated the dorsal attention network and executive function. In sum, NBPs account for a significant proportion of variance in measures of cognitive performance and functional brain network efficiency. The results motivate a multidisciplinary approach that applies methods from nutritional epidemiology (NBP analysis) and cognitive neuroscience (functional brain network efficiency) to characterize the impact of nutrition on human health, aging, and disease.

Nutrient biomarkers shape individual differences in functional brain connectivity: Evidence from omega-3 PUFAs.

A wealth of neuroscience evidence demonstrates that diet and nutrition play an important role in structural brain plasticity, promoting the development of gray matter volume and maintenance of white matter integrity across the lifespan. However, the role of nutrition in shaping individual differences in the functional brain connectome remains to be well established. We therefore investigated whether nutrient biomarkers known to have beneficial effects on brain structure (i.e., the omega-3 polyunsaturated fatty acids; ω-3 PUFAs), explain individual differences in functional brain connectivity within healthy older adults (N = 96). Our findings demonstrate that ω-3 PUFAs are associated with individual differences in functional connectivity within regions that support executive function (prefrontal cortex), memory (hippocampus), and emotion (amygdala), and provide key evidence that the influence of these regions on global network connectivity reliably predict general, fluid, and crystallized intelligence. The observed findings not only elucidate the role of ω-3 PUFAs in functional brain plasticity and intelligence, but also motivate future studies to examine their impact on psychological health, aging, and disease.

Aerobic Fitness Explains Individual Differences in the Functional Brain Connectome of Healthy Young Adults.

A wealth of neuroscience evidence demonstrates that aerobic fitness enhances structural brain plasticity, promoting the development of gray matter volume and maintenance of white matter integrity within networks for executive function, attention, learning, and memory. However, the role of aerobic fitness in shaping the functional brain connectome remains to be established. The present work therefore investigated the effects of aerobic fitness (as measured by VO2max) on individual differences in whole-brain functional connectivity assessed from resting state fMRI data. Using a connectome-wide association study, we identified significant brain-fitness relationships within a large sample of healthy young adults (N = 242). The results revealed several regions within frontal, temporal, parietal, and cerebellar cortex, having significant association with aerobic fitness. We further characterized the influence of these regions on 7 intrinsic connectivity networks, demonstrating the greatest association with networks that are known to mediate the beneficial effects of aerobic fitness on executive function (frontoparietal network), attention and learning (dorsal and ventral attention network), and memory (default mode network). In addition, we provide evidence that connectivity strength between these regions and the frontoparietal network is predictive of individuals' fluid intelligence.

Individual differences in decision making competence revealed by multivariate fMRI.

While an extensive literature in decision neuroscience has elucidated the neurobiological foundations of decision making, prior research has focused primarily on group-level effects in a sample population. Due to the presence of inherent differences between individuals' cognitive abilities, it is also important to examine the neural correlates of decision making that explain interindividual variability in cognitive performance. This study therefore investigated how individual differences in decision making competence, as measured by the Adult Decision Making Competence (A-DMC) battery, are related to functional brain connectivity patterns derived from resting-state fMRI data in a sample of 304 healthy participants. We examined connectome-wide associations, identifying regions within frontal, parietal, temporal, and occipital cortex that demonstrated significant associations with decision making competence. We then assessed whether the functional interactions between brain regions sensitive to decision making competence and seven intrinsic connectivity networks (ICNs) were predictive of specific facets of decision making assessed by subtests of the A-DMC battery. Our findings suggest that individual differences in specific facets of decision making competence are mediated by ICNs that support executive, social, and perceptual processes, and motivate an integrative framework for understanding the neural basis of individual differences in decision making competence.

Assessing blood oxygen level-dependent signal variability as a biomarker of brain injury in sport-related concussion.

Mild traumatic brain injury is a complex neurological disorder of significant concern among athletes who play contact sports. Athletes who sustain sport-related concussion typically undergo physical examination and neurocognitive evaluation to determine injury severity and return-to-play status. However, traumatic disruption to neurometabolic processes can occur with minimal detectable anatomic pathology or neurocognitive alteration, increasing the risk that athletes may be cleared for return-to-play during a vulnerable period and receive a repetitive injury. This underscores the need for sensitive functional neuroimaging methods to detect altered cerebral physiology in concussed athletes. The present study compared the efficacy of Immediate Post-concussion Assessment and Cognitive Testing composite scores and whole-brain measures of blood oxygen level-dependent signal variability for classifying concussion status and predicting concussion symptomatology in healthy, concussed and repetitively concussed athletes, assessing blood oxygen level-dependent signal variability as a potential diagnostic tool for characterizing functional alterations to cerebral physiology and assisting in the detection of sport-related concussion. We observed significant differences in regional blood oxygen level-dependent signal variability measures for concussed athletes but did not observe significant differences in Immediate Post-concussion Assessment and Cognitive Testing scores of concussed athletes. We further demonstrate that incorporating measures of functional brain alteration alongside Immediate Post-concussion Assessment and Cognitive Testing scores enhances the sensitivity and specificity of supervised random forest machine learning methods when classifying and predicting concussion status and post-concussion symptoms, suggesting that alterations to cerebrovascular status characterize unique variance that may aid in the detection of sport-related concussion and repetitive mild traumatic brain injury. These results indicate that altered blood oxygen level-dependent variability holds promise as a novel neurobiological marker for detecting alterations in cerebral perfusion and neuronal functioning in sport-related concussion, motivating future research to establish and validate clinical assessment protocols that can incorporate advanced neuroimaging methods to characterize altered cerebral physiology following mild traumatic brain injury.

Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden.

Disruption of functional connectivity between brain regions may represent an early functional consequence of ß-amyloid pathology prior to clinical Alzheimer's disease. We aimed to investigate if non-demented older individuals with increased amyloid burden demonstrate disruptions of functional whole-brain connectivity in cortical hubs (brain regions typically highly connected to multiple other brain areas) and if these disruptions are associated with neuronal dysfunction as measured with fluorodeoxyglucose-positron emission tomography. In healthy subjects without cognitive symptoms and patients with mild cognitive impairment, we used positron emission tomography to assess amyloid burden and cerebral glucose metabolism, structural magnetic resonance imaging to quantify atrophy and novel resting state functional magnetic resonance imaging processing methods to calculate whole-brain connectivity. Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism. Subtle connectivity disruptions and hypometabolism were already present in amyloid-positive asymptomatic subjects. Voxel-based morphometry measures indicate that these findings were not solely a consequence of regional atrophy. Whole-brain connectivity values and metabolism showed a positive correlation with each other and a negative correlation with amyloid burden. These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer's disease pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer's-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.

The organization of local and distant functional connectivity in the human brain.

Information processing in the human brain arises from both interactions between adjacent areas and from distant projections that form distributed brain systems. Here we map interactions across different spatial scales by estimating the degree of intrinsic functional connectivity for the local (14 mm) interactions. The balance between local and distant functional interactions measured at rest forms a map that separates sensorimotor cortices from heteromodal association areas and further identifies regions that possess both high local and distant cortical-cortical interactions. Map estimates of network measures demonstrate that high local connectivity is most often associated with a high clustering coefficient, long path length, and low physical cost. Task performance changed the balance between local and distant functional coupling in a subset of regions, particularly, increasing local functional coupling in regions engaged by the task. The observed properties suggest that the brain has evolved a balance that optimizes information-processing efficiency across different classes of specialized areas as well as mechanisms to modulate coupling in support of dynamically changing processing demands. We discuss the implications of these observations and applications of the present method for exploring normal and atypical brain function.

Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer's disease.

Recent evidence suggests that some brain areas act as hubs interconnecting distinct, functionally specialized systems. These nexuses are intriguing because of their potential role in integration and also because they may augment metabolic cascades relevant to brain disease. To identify regions of high connectivity in the human cerebral cortex, we applied a computationally efficient approach to map the degree of intrinsic functional connectivity across the brain. Analysis of two separate functional magnetic resonance imaging datasets (each n = 24) demonstrated hubs throughout heteromodal areas of association cortex. Prominent hubs were located within posterior cingulate, lateral temporal, lateral parietal, and medial/lateral prefrontal cortices. Network analysis revealed that many, but not all, hubs were located within regions previously implicated as components of the default network. A third dataset (n = 12) demonstrated that the locations of hubs were present across passive and active task states, suggesting that they reflect a stable property of cortical network architecture. To obtain an accurate reference map, data were combined across 127 participants to yield a consensus estimate of cortical hubs. Using this consensus estimate, we explored whether the topography of hubs could explain the pattern of vulnerability in Alzheimer's disease (AD) because some models suggest that regions of high activity and metabolism accelerate pathology. Positron emission tomography amyloid imaging in AD (n = 10) compared with older controls (n = 29) showed high amyloid-beta deposition in the locations of cortical hubs consistent with the possibility that hubs, while acting as critical way stations for information processing, may also augment the underlying pathological cascade in AD.

Heightened degree connectivity of the striatum in obsessive-compulsive disorder induced by symptom provocation.

BACKGROUND: Neurosurgical intervention studies have provided direct evidence that the ventral striatum/nucleus accumbens (NAc) mediates symptoms of obsessive-compulsive disorder (OCD), yet meta-analysis of functional neuroimaging studies using symptom provocation revealed no striatal activation differences, and the existing studies reporting hyperactivity found abnormalities in dorsal but not ventral striatal subdivisions. Resting-state neuroimaging evidence holds that corticostriatal areas are more connected both locally and to distant regions, but the functional inferences to be drawn from these altered network characteristics regarding the present experience of OCD symptoms remain limited. METHODS: The present study tested whether symptom provocation induces abnormally high striatal network connectivity using two independent datasets of unmedicated patients with OCD. One study (14 patients, 14 matched controls) required passive viewing of OC-related, emotionally aversive and neutral pictures, the other (21 patients, 21 controls) involved self-referential evaluation of the same picture types, as well as distraction from these stimuli (engagement in a simple task). RESULTS: Heightened local connectivity of the dorsal striatum occurred during passive viewing of briefly presented OC-related pictures in patients, however group differences were also observed in a neutral control condition. In contrast, distracted symptom provocation selectively yielded local connectivity differences of the ventral striatum, as heightened NAc connectivity to its immediate neighborhood was exclusively observed when OC-related pictures were accompanied by concurrent task demands. LIMITATIONS: Small samples sizes. CONCLUSIONS: In moderately affected patients with OCD, symptom provocation induces a discrete, condition-specific network abnormality anchored in NAc, the location targeted by deep brain stimulation for refractory patients with OCD.

Opposing associations between sedentary time and decision-making competence in young adults revealed by functional connectivity in the dorsal attention network.

How daily physical activity and sedentary time relate to human judgement and functional connectivity (FC) patterns that support them remains underexplored. We investigated the relationships between accelerometer-measured moderate-to-vigorous physical activity (MVPA) and sedentary time to decision-making competence (DMC) in young adults using a comprehensive Adult-Decision Making Competence battery. We applied graph theory measures of global and local efficiency to test the mediating effects of FC in cognitively salient brain networks (fronto-parietal; dorsal attention, DAN; ventral attention; and default mode), assessed from the resting-state fMRI. Sedentary time was related to lower susceptibility to a framing bias. However, once global and local efficiency of the DAN were considered we observed (1) higher susceptibility to framing with more sedentary time, mediated through lower local and global efficiency in the DAN, and (2) lower susceptibility to framing with more sedentary time. MVPA was not related to DMC or graph theory measures. These results suggest that remaining sedentary may reduce neurofunctional readiness for top-down control and decrease engagement of deliberate thought, required to ignore irrelevant aspects of a problem. The positive effect suggests that the relationship between sedentary time and DMC may be moderated by unmeasured factors such as the type of sedentary behavior.

Essential Amino Acids, Vitamins, and Minerals Moderate the Relationship between the Right Frontal Pole and Measures of Memory.

SCOPE: Nutrition has increasingly been recognized for its ability to help prevent and protect against disease, inspiring new programs of research that translate findings from nutritional science into innovative assessment tools, technologies, and therapies to advance the practice of modern medicine. A central aim in this effort is to discover specific dietary patterns that promote healthy brain aging and moderate the engagement of neural systems known to facilitate cognitive performance in later life. METHODS AND RESULTS: The present study therefore investigates estimates of nutrient intake derived from food frequency questionnaires, structural measures of brain volume via high-resolution magnetic resonance imaging, and standardized neuropsychological measures of memory performance in nondemented elders (n = 111) using a moderation analysis. The results reveal that the essential amino acids, vitamins, and minerals nutrient pattern moderates the positive relationship between the volume of the right frontal pole and measures of both delayed and auditory memory. CONCLUSIONS: Our findings demonstrate that a nutrient pattern including macro- and micronutrients moderate the effect of brain structure on cognitive function in old age and support the efficacy of interdisciplinary methods in nutritional cognitive neuroscience for the study of healthy brain aging.

Continuous correction of differential path length factor in near-infrared spectroscopy.

In continuous-wave near-infrared spectroscopy (CW-NIRS), changes in the concentration of oxyhemoglobin and deoxyhemoglobin can be calculated by solving a set of linear equations from the modified Beer-Lambert Law. Cross-talk error in the calculated hemodynamics can arise from inaccurate knowledge of the wavelength-dependent differential path length factor (DPF). We apply the extended Kalman filter (EKF) with a dynamical systems model to calculate relative concentration changes in oxy- and deoxyhemoglobin while simultaneously estimating relative changes in DPF. Results from simulated and experimental CW-NIRS data are compared with results from a weighted least squares (WLSQ) method. The EKF method was found to effectively correct for artificially introduced errors in DPF and to reduce the cross-talk error in simulation. With experimental CW-NIRS data, the hemodynamic estimates from EKF differ significantly from the WLSQ (p < 0.001). The cross-correlations among residuals at different wavelengths were found to be significantly reduced by the EKF method compared to WLSQ in three physiologically relevant spectral bands 0.04 to 0.15 Hz, 0.15 to 0.4 Hz and 0.4 to 2.0 Hz (p < 0.001). This observed reduction in residual cross-correlation is consistent with reduced cross-talk error in the hemodynamic estimates from the proposed EKF method.

Abnormally high degree connectivity of the orbitofrontal cortex in obsessive-compulsive disorder.

IMPORTANCE: Neurobiological models of obsessive-compulsive disorder (OCD) predict hyperactivity in brain circuits involving the orbitofrontal cortex and the basal ganglia, but it is unclear whether these areas are also characterized by altered brain network properties. OBJECTIVES: To determine regions of abnormal degree connectivity in patients with OCD and to investigate whether connectivity measures are affected by antidepressant medication in OCD. DESIGN: Case-control cross-sectional study using resting-state functional magnetic resonance imaging and a data-driven, model-free method to test for alterations in the degree of whole-brain, distant, and local connectivity in unmedicated patients with OCD compared with healthy controls. SETTING: Outpatient clinic for OCD. PARTICIPANTS: Twenty-three patients with OCD (12 women, 11 men) receiving no medication, 23 patients with OCD (14 women, 9 men) treated with antidepressant medication, and 2 equally sized control samples matched for age, sex, handedness, educational level, and IQ. MAIN OUTCOME MEASURES: Statistical parametric maps testing the degree of distant and local functional connectivity of each voxel (hub analysis at voxel level) and OCD symptom severity. RESULTS: Unmedicated patients with OCD showed greater distant connectivity in the orbitofrontal cortex and subthalamic nucleus and greater local connectivity in the orbitofrontal cortex and the putamen. Furthermore, distant connectivity of the orbitofrontal cortex and the putamen positively correlated with global OCD symptom severity. Medicated patients with OCD showed reduced local connectivity of the ventral striatum compared with the unmedicated patients. CONCLUSIONS AND RELEVANCE: Consistent with neurobiological models of OCD, the orbitofrontal cortex and the basal ganglia are hyperconnected in unmedicated patients. The finding of distant connectivity alterations of the orbitofrontal cortex and the basal ganglia represents initial evidence of greater connections with distant cortical areas outside of corticostriatal circuitry. Furthermore, these data suggest that antidepressant medication may reduce connectivity within corticobasal ganglia-thalamo-cortical circuits in OCD.

Task-free presurgical mapping using functional magnetic resonance imaging intrinsic activity.

OBJECT: Low-frequency components of the spontaneous functional MR imaging signal provide information about the intrinsic functional and anatomical organization of the brain. The ability to use such methods in individual patients may provide a powerful tool for presurgical planning. The authors explore the feasibility of presurgical motor function mapping in which a task-free paradigm is used. METHODS: Six surgical candidates with tumors or epileptic foci near the motor cortex participated in this study. The investigators directly compared task-elicited activation of the motor system to activation obtained from intrinsic activity correlations. The motor network within the unhealthy hemisphere was identified based on intrinsic activity correlations, allowing distortions of functional anatomy caused by the tumor and epilepsy to be directly visualized. The precision of the motor function mapping was further explored in 1 participant by using direct cortical stimulation. RESULTS: The motor regions localized based on the spontaneous activity correlations were quite similar to the regions defined by actual movement tasks and cortical stimulation. Using intrinsic activity correlations, it was possible to map the motor cortex in presurgical patients. CONCLUSIONS: This task-free paradigm may provide a powerful approach to map functional anatomy in patients without task compliance and allow multiple brain systems to be determined in a single scanning session.