Michèle Desjardins

Hearts and minds: linking vascular rigidity and aerobic fitness with cognitive aging

Human aging is accompanied by both vascular and cognitive changes. Although arteries throughout the body are known to become stiffer with age, this vessel hardening is believed to start at the level of the aorta and progress to other organs, including the brain. Progression of this vascular impairment may contribute to cognitive changes that arise with a similar time course during aging. Conversely, it has been proposed that regular exercise plays a protective role, attenuating the impact of age on vascular and metabolic physiology. Here, the impact of vascular degradation in the absence of disease was investigated within 2 groups of healthy younger and older adults. Age-related changes in executive function, elasticity of the aortic arch, cardiorespiratory fitness, and cerebrovascular reactivity were quantified, as well as the association between these parameters within the older group. In the cohort studied, older adults exhibited a decline in executive functions, measured as a slower performance in a modified Stroop task (1247.90 ± 204.50 vs. 898.20 ± 211.10 ms on the inhibition and/or switching component, respectively) than younger adults. Older participants also showed higher aortic pulse wave velocity (8.98 ± 3.56 vs. 3.95 ± 0.82 m/s, respectively) and lower VO₂ max (29.04 ± 6.92 vs. 42.32 ± 7.31 mL O2/kg/min, respectively) than younger adults. Within the older group, faster performance of the modified Stroop task was associated with preserved aortic elasticity (lower aortic pulse wave velocity; p = 0.046) and higher cardiorespiratory fitness (VO₂ max; p = 0.036). Furthermore, VO₂ max was found to be negatively associated with blood oxygenation level dependent cerebrovascular reactivity to CO₂ in frontal regions involved in the task (p = 0.038) but positively associated with cerebrovascular reactivity in periventricular watershed regions and within the postcentral gyrus. Overall, the results of this study support the hypothesis that cognitive status in aging is linked to vascular health, and that preservation of vessel elasticity may be one of the key mechanisms by which physical exercise helps to alleviate cognitive aging.

Higher levels of cardiovascular fitness are associated with better executive function and prefrontal oxygenation in younger and older women

Aim: Many studies have suggested that physical exercise training improves cognition and more selectively executive functions. There is a growing interest to clarify the neurophysiological mechanisms that underlie this effect. The aim of the current study was to evaluate the neurophysiological changes in cerebral oxygenation associated with physical fitness level and executive functions. Method: In this study, 22 younger and 36 older women underwent a maximal graded continuous test (i.e., V˙O2max) in order to classify them into a fitness group (higher vs. lower fit). All participants completed neuropsychological paper and pencil testing and a computerized Stroop task (which contained executive and non-executive conditions) in which the change in prefrontal cortex oxygenation was evaluated with near infrared spectroscopy (NIRS). Results: Our findings revealed a Fitness × Condition interaction (p < 0.05) such that higher fit women scored better on measures of executive functions than lower fit women. In comparison to lower fit women, higher fit women had faster reaction times in the Executive condition of the computerized Stroop task. No significant effect was observed in the non-executive condition of the test and no interactions were found with age. In measures of cerebral oxygenation (ΔHbT and ΔHbO2), we found a main effect of fitness on cerebral oxygenation during the Stroop task such that only high fit women demonstrated a significant increase in the right inferior frontal gyrus. Discussion/Conclusion: Higher fit individuals who demonstrate better cardiorespiratory functions (as measured by V˙O2max) show faster reaction times and greater cerebral oxygenation in the right inferior frontal gyrus than women with lower fitness levels. The lack of interaction with age, suggests that good cardiorespiratory functions can have a positive impact on cognition, regardless of age.

Cell type specificity of neurovascular coupling in cerebral cortex

Identification of the cellular players and molecular messengers that communicate neuronal activity to the vasculature driving cerebral hemodynamics is important for (1) the basic understanding of cerebrovascular regulation and (2) interpretation of functional Magnetic Resonance Imaging (fMRI) signals. Using a combination of optogenetic stimulation and 2-photon imaging in mice, we demonstrate that selective activation of cortical excitation and inhibition elicits distinct vascular responses and identify the vasoconstrictive mechanism as Neuropeptide Y (NPY) acting on Y1 receptors. The latter implies that task-related negative Blood Oxygenation Level Dependent (BOLD) fMRI signals in the cerebral cortex under normal physiological conditions may be mainly driven by the NPY-positive inhibitory neurons. Further, the NPY-Y1 pathway may offer a potential therapeutic target in cerebrovascular disease. DOI: http://dx.doi.org/10.7554/eLife.14315.001

Wavelet-based estimation of the hemodynamic responses in diffuse optical imaging

Diffuse optical imaging uses light to provide a surrogate measure of neuronal activation through the hemodynamic responses. The relative low absorption of near-infrared light enables measurements of hemoglobin changes at depths reaching the first centimeter of the cortex. The rapid rate of acquisition and the access to both oxy and deoxy-hemoglobin leads to new challenges when trying to uncouple physiology from the signal of interest. In particular, recent work provided evidence of the presence of a 1/f noise structure in optical signals and showed that a general linear model based on wavelets can be used to decorrelate the structured noise and provide a superior estimator of response amplitude when compared with conventional techniques. In this work the wavelet techniques are extended to recover the full temporal shape of the hemodynamic responses. A comparison with other models is provided as well as a case study on finger-tapping data.

The roadmap for estimation of cell-type-specific neuronal activity from non-invasive measurements

The computational properties of the human brain arise from an intricate interplay between billions of neurons connected in complex networks. However, our ability to study these networks in healthy human brain is limited by the necessity to use non-invasive technologies. This is in contrast to animal models where a rich, detailed view of cellular-level brain function with cell-type-specific molecular identity has become available due to recent advances in microscopic optical imaging and genetics. Thus, a central challenge facing neuroscience today is leveraging these mechanistic insights from animal studies to accurately draw physiological inferences from non-invasive signals in humans. On the essential path towards this goal is the development of a detailed ‘bottom-up’ forward model bridging neuronal activity at the level of cell-type-specific populations to non-invasive imaging signals. The general idea is that specific neuronal cell types have identifiable signatures in the way they drive changes in cerebral blood flow, cerebral metabolic rate of O2 (measurable with quantitative functional Magnetic Resonance Imaging), and electrical currents/potentials (measurable with magneto/electroencephalography). This forward model would then provide the ‘ground truth’ for the development of new tools for tackling the inverse problem—estimation of neuronal activity from multimodal non-invasive imaging data. This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’.

Biophysical model estimation of neurovascular parameters in a rat model of healthy aging

Neuronal, vascular and metabolic factors result in a deterioration of the cerebral hemodynamic response with age. The interpretation of neuroimaging studies in the context of aging is rendered difficult due to the challenge in untangling the composite effect of these modifications. In this work we integrate multimodal optical imaging in biophysical models to investigate vascular and metabolic changes occurring in aging. Multispectral intrinsic optical imaging of an animal model of healthy aging, the LOU/c rat, is used in combination with somatosensory stimulation to study the modifications of the hemodynamic response with increasing age. Results are fitted with three macroscopic biophysical models to extract parameters, providing a phenomenological description of vascular and metabolic changes. Our results show that 1) biophysical parameters are estimable from multimodal data and 2) parameter estimates in this population change with aging.

Multimodal study of the hemodynamic response to hypercapnia in anesthetized aged rats

With aging, the brain undergoes changes in metabolism and perfusion, both of which influence the widely used blood-oxygenation-level-dependent (BOLD) MRI signal. To isolate the vascular effects associated with age, this study measured the response to a hypercapnic challenge using different imaging modalities in 19 young (3 months-old) and 13 old (24 months-old) Long-Evans rats. Intrinsic optical imaging was used to measure oxy (HbO), deoxy (HbR) and total (HbT) hemoglobin concentration changes, laser speckle for cerebral blood flow (CBF) changes, and MRI for the BOLD signal. Older rats had smaller HbO (41% smaller), HbT (50%) and CBF (34%) responses, but the temporal dynamics did not exhibit significant age differences. The ratio of CBV to CBF responses was also smaller in older adults, potentially indicating a change in the compliance of vessels.

An Exploration of the Effect of Hemodynamic Changes Due to Normal Aging on the fNIRS Response to Semantic Processing of Words

Like other neuroimaging techniques assessing cerebral blood oxygenation, near-infrared spectroscopy (NIRS) has been applied in many neurocognitive studies. With NIRS, neural activation can be explored indirectly via hemodynamic changes in the imaged region. In studies of aging, changes in baseline physiology and brain anatomy confound NIRS measures seeking to investigate age-related changes in neuronal activity. The field is thus hampered by the complexity of the aging process itself, and statistical inferences from functional data acquired by optical imaging techniques must be interpreted with care. Multimodal integration of NIRS with both structural and baseline physiological assessments is crucial to avoid misinterpreting neuroimaging signals. In this study, a combination of two different optical techniques, anatomical MRI and Arterial Spin Labeling (ASL), was used to investigate age-related changes in activation during a lexical-semantic processing task. Quantitative analysis revealed decreased baseline oxyhemoglobin and cerebral blood flow in the older adults. Using baseline physiology measures as regressors in the investigation of functional concentration changes when doing analyses of variance, we found significant changes in task-induced areas of activity. In the right hemisphere, more significant age-related activity was observed around the junction of the inferior frontal gyrus and inferior precentral sulcus, along with engagement of Wernicke’s area. In the left hemisphere, the degree and extent of frontal activation, including the dorsolateral prefrontal cortex and inferior frontal gyrus, differed between age groups. Measuring background physiological differences and using their values as regressors in statistical analyses allowed a more appropriate, age-corrected understanding of the functional differentiations between age groups. Age-corrected baselines are thus essential to investigate which components of the NIRS signal are altered by aging.

Shedding light on the effect of priority instructions during dual-task performance in younger and older adults: A fNIRS study

Age-related differences in the ability to perform two tasks simultaneously (or dual-task) have become a major concern in aging neurosciences and have often been assessed with two distinct paradigms; the Psychological Refractory Period (PRP) and the Dual-Task (DT) paradigms. PRP studies assess participants when they give Priority to one task over the other (complete A then B), whereas in DT studies participants give Equal priority to both tasks (complete A and B). The Equal condition could be viewed as adding an executive control component to the task since the participants must spontaneously monitor attention between tasks. In the current study, we assessed the effect of priority instructions (Priority vs. Equal) on the dual-task performance and brain activity of younger (n = 16) and older adults (n = 19) with functional near infra-red spectroscopy (fNIRS). In younger adults, the Priority condition showed right-sided activation in the prefrontal cortex during DT execution. Older adults showed bilateral frontal activation, yet restrained to specific areas. They showed increased activation in DT vs. single task condition in the left dorsolateral prefrontal cortex (DLPFC) and the bilateral ventrolateral prefrontal cortex (VLPFC). In the Equal condition, the DT condition showed isolated left DLPFC and VLPFC activation in younger adults and widespread bilateral DLPFC activation in older adults. These results suggest that for both older and younger adults, priority effects are associated with distinct patterns of prefrontal activation. Age-related differences also exist in these patterns such that prefrontal activation seems to be more spread out at different sites in older adults when they are instructed to give Equal priority to both tasks.

Magnetic resonance fingerprinting based on realistic vasculature in mice

ABSTRACT Magnetic resonance fingerprinting (MRF) was recently proposed as a novel strategy for MR data acquisition and analysis. A variant of MRF called vascular MRF (vMRF) followed, that extracted maps of three parameters of physiological importance: cerebral oxygen saturation (SatO2), mean vessel radius and cerebral blood volume (CBV). However, this estimation was based on idealized 2‐dimensional simulations of vascular networks using random cylinders and the empirical Bloch equations convolved with a diffusion kernel. Here we focus on studying the vascular MR fingerprint using real mouse angiograms and physiological values as the substrate for the MR simulations. The MR signal is calculated ab initio with a Monte Carlo approximation, by tracking the accumulated phase from a large number of protons diffusing within the angiogram. We first study the identifiability of parameters in simulations, showing that parameters are fully estimable at realistically high signal‐to‐noise ratios (SNR) when the same angiogram is used for dictionary generation and parameter estimation, but that large biases in the estimates persist when the angiograms are different. Despite these biases, simulations show that differences in parameters remain estimable. We then applied this methodology to data acquired using the GESFIDE sequence with SPIONs injected into 9 young wild type and 9 old atherosclerotic mice. Both the pre injection signal and the ratio of post‐to‐pre injection signals were modeled, using 5‐dimensional dictionaries. The vMRF methodology extracted significant differences in SatO2, mean vessel radius and CBV between the two groups, consistent across brain regions and dictionaries. Further validation work is essential before vMRF can gain wider application. HighlightsModeling GESFIDE fingerprinting from realistic angiograms of microvasculature.Validation with in vivo acquisition in wild‐type and atherosclerotic mice.Evidence of bias in the vMRF extracted parameters, using simulations.However, differences in vMRF extracted parameters are more robust to bias.Group differences observed in cerebral oxygen saturation, mean vessel radius and CBV.