NIA R01 grant AG059878 ($3,459,850)
2018-2023
Inactivity and lack of cardiorespiratory fitness are among the most important risk factors for cerebral arteriosclerosis, a condition that has long been associated with steep cognitive decline in older individuals, ultimately leading to dementia. In this research, based on a mixed cross-sectional and longitudinal design on young-old individuals (50-70 years of age) not yet affected by MCI or dementia, we investigate the use of novel measures of cerebral arterial elasticity (an optical measure of the cerebral arterial pulse, pulse-DOT), for the measurement of early stages of cerebral arteriosclerosis. Specifically, we use these measures to investigate a pathogenetic pathway leading from aging and low physical fitness, through the development of cerebral arteriosclerosis, hypoperfusion, and reduced cerebrovascular reactivity, to structural brain alterations and cognitive decline.

NIA R01 grant AG062666 ($3,024,580)
2019-2024
Declines in cognitive control are among the most important problems that characterize cognitive aging and dementia, such as Alzheimer’s disease. In this research, we hypothesize that this decline is, at least in part, attributable to a decline in arterial elasticity (i.e., arteriosclerosis), through a chain-of-events in which structural changes in gray and white matter and changes in brain function (both in the functional organization of the brain, as well as in phasic and oscillatory brain activities) play important mediating roles. Specifically, we use a cross-sectional design with a large sample size (300 adults, 25-75 years of age, 50% females and with sizeable presence of minorities) to test a series of mediation models describing a chain linking arteriosclerosis to brain atrophy (both in gray and white matter), to changes in brain function (measured with both fMRI and EEG/ERPs), to behavioral changes (drop in performance in cognitive control tasks).

Our laboratory uses near-infrared light to study two distinct signals the brain produces during cognitive activity; the Event-Related Optical Signal (EROS) and Near-Infrared Spectroscopy (NIRS). Via the use of near-infrared light (NIR), which penetrates several centimeters into the head, changes in the optical properties of brain tissue can aid in detecting neuronal activity. And with the appropriate methods, it is possible to localize the measurements to relatively small areas (less than 1 cc) and to distinguish signals from different depths. This yields a good spatial resolution. Other advantages of these techniques are safety (because only a very small amount of non-ionizing radiation is used), relatively low costs, and versatility.

EROS is based on the measurement of the changes in optical parameters (scattering and absorption) of active neurons. Some of these changes co-occur with the rapid electrical activity of neurons. For this reason, EROS has a good temporal resolution. This means that EROS can be used to analyze the relative timing of activity in different brain regions, which in turn reveals information about functional connections between areas. This is difficult to study with other brain imaging methods.

NIRS is a widely used technique that measures changes in the absorption of two (or more) wavelengths of light and allows detection and quantification of changes in the concentration of oxy and deoxy-hemoglobin resulting from brain activity. These relatively slow changes (taking several seconds) are also the basis for the fMRI BOLD signal, but NIRS is able to separately estimate changes in blood volume and hemoglobin concentration, which fMRI is not able to do. Because NIRS and EROS measurements can be made simultaneously from the same tissue, they provide unique opportunities for studying the relation between neuronal activity and the hemodynamic response.

Current limitations of EROS include its shallow penetration (~3-4 cm), which makes it particularly suitable for studying cortical (rather than sub-cortical) activity and its signal-to-noise ratio, which typically requires averaging data across a number of subjects. The development of EROS is one of the major lines of research in our Lab and has been funded by the National Institute of Mental Health. Additional relevant research in this area is conducted at the Laboratory for Fluorescence Dynamics (LFD, University of California, Irvine), directed by Dr. Enrico Gratton.

Our lab investigates changes in brain volume, cortical thinning, grey and white matter density, and white matter integrity by using a variety of cutting edge techniques (FreeSurfer, VBM, FSL, etc). We also employ techniques of arterial spin labeling (ASL), optical imaging, and angiography to discover how vascular changes affect patterns of anatomical change. We seek to understand which life-style factors lead to various changes in brain anatomy. We also seek to understand the relationship between brain anatomy (sMRI), brain function (EEG, Optical Imaging, fMRI), and cognition (Gratton et al., 2009). Participants in our studies range from pre-mature infants to older adults.

Throughout the course of our life, our brain changes in many ways. When we are young, our brain undergoes a growth in volume, increases in dendritic and axonal connections, and changes in grey and white matter density. The middle-aged brain undergoes pruning and other forms of refinement. In older age, a significant loss is noticed in both pathological and “healthy” aging. Recent research in our lab has demonstrated that not all regions decline at the same rate during “healthy” aging. Furthermore, there are significant differences in atrophy patterns between various “healthy” individuals. Some “healthy” older adults experience high degrees of atrophy throughout the brain whereas others follow a less dramatic trajectory. Through the use of Structural Magnetic Resonance Imaging (sMRI), we seek to discover which factors lead to various patterns of change throughout the entire life-span. Such knowledge will allow us to design specific interventions in order to bolster successful aging.

Recent studies in our lab have provided evidence that cardiorespiratory fitness and/or education may help attenuate age-related losses normally experienced with advanced aging (Gordon et al., 2008). The data indicate that there are numerous areas of tissue loss throughout the brain in older adults. However, a positive association between fitness and gray matter volume was noticed in the inferior frontal, medial-temporal, and anterior parietal areas. Additionally, our research demonstrated an association between years of formal education and white matter preservation in the anterior and inferior frontal areas. These results remain significant even when accounting for differences in age and gender. Current studies in our lab seek to expand upon these results and determine what role nutrition may have on the aging brain.

Functional Magnetic Resonance Imaging (fMRI) is an imaging technique that allows us to study brain activity by measuring changes in blood oxygen levels in the brain. Although its temporal resolution (0.5-5s) is not as good as ERP or EROS, its excellent spatial resolution (<5mm) and non-invasive nature make it a popular brain imaging technique.

One line of research in our lab using fMRI includes a study on memory processing in younger and older adults (Schneider-Garces et al, 2010). While they were in the scanner, participants completed a modified Sternberg task where they first see a set of 2-6 letters followed by a single "probe" letter. They then indicated whether the probe was present in the set that preceded its appearance. The results indicated that older adults engaged more brain areas than younger adults during lower task demand levels (set sizes 2-4) while younger adults engaged more brain areas than older adults during higher task demand levels (set sizes 4-6). This suggested that age differences in brain activation can be attributed to individual differences in working memory span.

More recently, our lab used fMRI simultaneously with EROS, ERP, and NIRS to study the relationship between hemodynamic and neuronal changes during a visual stimulation task where both older and younger participants viewed a checkerboard reversing at different frequencies (Fabiani et al, in press). The results demonstrated that while there were reduced levels of increases in hemodynamic responses at higher levels of neuronal activity in both age groups, the coupling between oxy and de-oxy hemoglobin changes decreased with age and increased with fitness.

ERP methodology has been steadily advancing for the last 35 years. This technique has a great temporal resolution, which makes it extremely useful for studying the time-course of neural activity after stimulation or in preparation for a response. ERPs can also be recorded in a variety of populations, including children, older adults, and clinical populations.

A major advantage of ERPs is that they can be recorded in most experimental paradigms used in cognitive psychology. A limitation of ERPs is the difficulty of localizing the brain areas involved in their generation. Recently, advancements in this area have been accomplished by using realistic forward modeling of the surface-recorded activity. This can be obtained by combining ERPs and other imaging methodologies (e.g., magnetic resonance imaging, or MRI). Our Lab has computer software (the EMSE package by Source-Signal Imaging, San Diego) designed to perform this integration, as well as source analysis of ERPs

It is well-documented that cognitive abilities such as working memory and attentional control change across the lifespan, and that individual differences in fitness, education and cognitive reserve predict a higher level of functioning in old age. Given the complex dynamics that contribute to cognition in older age, our research is guided by the GOLDEN Aging (Growth of Lifelong Differences Explains Normal Aging) framework (Fabiani, 2012), which proposes that normal aging is characterized by quantitative shifts in pre-existing individual differences. We investigate the factors that influence the healthy functioning of brain networks and employ converging neuroimaging methods to better understand the dynamics of these processes.

We use structural MRI to investigate the relationship between age, lifestyle and brain anatomy, and how these contribute to brain function and cognitive performance. In line with previous findings, we have found that frontal and parietal brain regions are important in a variety of control-demanding situations, show significant atrophy with age, but greater preservation with higher levels of fitness and education (Gordon et al., 2008). Consistent with the GOLDEN Aging framework, we have found that age differences in frontal and parietal BOLD activity during a working memory task can be largely linked to working span differences across individuals and not age per se (Schneider-Garces et al, 2009). In another study using EROS and EEG, we found that the degree to which older participants overcame the cost of switching and activated task-relevant processes depended on the main connection between the left and right prefrontal cortices: greater volume in the anterior corpus callosum predicted better performance, with the same effect present, albeit more weakly, in younger adults (Gratton et al., 2009). We also capitalize on the excellent spatiotemporal properties of EROS and have employed cross-correlation analyses to better elucidate the functional and structural interactions that support cognitive performance across the lifespan (Baniqued et al., 2013).

A major focus of our aging research is the study of the link between cardiovascular health and brain function. In collaboration with Beckman and Bioengineering faculty member Brad Sutton, we are developing and integrating optical and magnetic resonance techniques to evaluate the health of the brain’s vasculature. Using arterial spin labeling (ASL), we find that cerebral blood flow is mediated by cardiorespiratory fitness, suggesting that preserving or improving brain oxygenation and perfusion is important for cognition in old age (Zimmerman et al., 2014). Using the fine spatiotemporal properties of EROS, we are also able to measure arterial brain elasticity, which is another important measure of neurovascular health and as such shows robust associations with fitness and predicts cognitive performance and cortical white matter and gray matter volumes, especially in lower-fit individuals (Fabiani et al., 2014).

Our lab has a long history of investigating the processes by which or sensory perception of the world is boosted by attention (e.g. Gratton, 1997). We are interested in how moment to moment changes in the state of our brain influence how we perceive the world. For instance, a current lab focus is on the influence of ongoing brain activity on the subsequent processing of information. We have found that the power and, importantly, the phase of ongoing alpha oscillations can predict subjects’ awareness of a subsequent flash of light (Mathewson et al., 2009). We have also localized the underlying sources of these alpha oscillations with simultaneous EROS and EEG recording during a similar task (Mathewson et al., 2014). We have further found that by entraining ongoing brain oscillations with rhythmic visual stimulation, one can control the ongoing phase of these oscillations, creating waves in the ongoing stream of consciousness (Mathewson et al., 2010, 2012).

We are also interested in the influence of these ongoing sensory modulations on ongoing learning during tasks. We record EEG during complex tasks such as during video gameplay in the Space Fortress game and measure the changes with training in the brain’s response to the important events in the game (Maclin et al., 2011). We have further found that the levels of baseline and evoked oscillations before training can predict the rate of subsequent improvements in the game, as well as the amount of transfer of the skills learning in the game to untrained tasks (Boot et al., 2008; Mathewson et al., 2012).

We are currently investigating the enhanced attention to peripheral visual stimuli exhibited by deaf individuals (Seymour et al., 2017), the extent to which the brain attentional networks play important roles in fluctuations in bistable visual illusions (Metzger et al., 2017). We are also trying to gain further experimental control over the timing and power of these oscillatory attentional modulations by using a combination of Transcranial Magnetic Stimulation (TMS) with simultaneous EROS (Parks et al., 2012) and EEG recording.