Assessment of White Matter Hyperintensity, Cerebral Blood Flow, and Cerebral Oxygenation in Older Subjects Stratified by Cerebrovascular Risk

Objective: Cerebrovascular disease (CVD) is the fifth most common cause of mortality in the United States. Diagnosis of CVD at an early stage is critical for optimal intervention designed to prevent ongoing and future brain injury. CVD is commonly associated with abnormalities of the cerebral microvasculature leading to tissue dysfunction, neuronal injury and death, and resultant clinical symptoms, which in turn, further impacts cerebral autoregulation (CA). This series of studies aims to test the hypothesis that white matter hyperintensities (WMH) and cerebral hemodynamics (quantified by magnetic resonance imaging (MRI) and an by innovative hybrid near-infrared diffuse optical instrument) can be used as biomarkers to distinguish cognitively healthy older subjects with high or low risk for developing CVD. Methods: Using functional MRI, WMH and cerebral blood flow (CBF) were quantified in 26 cognitively healthy older subjects (age: 77.8 ± 6.8 years). In a follow-up study, significant variability in WMH quantification methodology was addressed, with sources of variability identified in selecting image center of gravity, software compatibility, thresholding techniques, and manual editing procedures. Accordingly, post-acquisition processing methods were optimized to develop a standardized protocol with less than 0.5% inter-rater variance. Using a novel laboratory-made hybrid near-infrared spectroscopy/diffuse correlation spectroscopy (NIRS/DCS) and a finger plethysmograph, low-frequency oscillations (LFOs) of CBF, cerebral oxygenation, and main arterial pressure (MAP) were simultaneously measured before, during, and after 70° head-up-tilting (HUT). Gains (associated with CAs) to magnify LFOs were determined by transfer function analyses with MAP as the input and cerebral hemodynamic parameters as the outputs. In a follow-up study, a fast software correlator for DCS and a parallel detection technique for NIRS/DCS were adapted to improve the sampling rate of hybrid optical measurements. In addition, a new DCS probe was developed to measure CBF at the occipital lobe, which represents a novel application of the NIRS/DCS technique. Results: MRI measurements demonstrate that deep WMH (dWMH) and periventricular WMH (pWMH) volumetric measures are associated with reduced regional cortical CBF in patients at high-risk of CVD. Moreover, CBF in white matter (WM) was reduced in regions demonstrating both pWMH and dWMHs. NIRS/DCS optical measurements demonstrate that at resting baseline, LFO gains in the high-risk group were relatively lower compared to the low-risk group. The lower baseline gains in the high-risk group may be attributed to compensatory mechanisms that allow the maintenance of a stronger steady-state CA. However, HUT resulted in smaller gain reductions in the high-risk group compared to the low-risk group, suggesting weaker dynamic CA in association with increased CVD risks. A noteworthy finding in these experiments was that CVD risk more strongly influenced CBF than cerebral oxygenation. Conclusions: Regional WMH volumes, cortical and WM CBF values, and LFO gains of cerebral hemodynamics demonstrate specific associations with CA and may serve as important potential biomarkers for early diagnosis of CVD. The high spatial resolution, large penetration depth, and variety of imaging-sequences afforded by MRI make it an appealing imaging modality for evaluation of CVD, although MRI is costly, time-limited, and requires transfer of subjects from bed to imaging facility. In contrast, low-cost, portable, mobile diffuse optical technologies provide a complementary alternative for early screening of CVD, that can further allow continuous monitoring of disease attenuation or progression at the subject’s bedside. Thus, development of both methodologies is essential for progress in our future understanding of CVD as a major contributor to the morbidity and mortality associated with CVD today

Multimodal Diffuse Optical Imaging Evidence of Age-Related Changes in Neural Substrates of Semantic Words Processing

RÉSUMÉ Le vieillissement rapide de la population au Canada changera les aspects démographiques à l’avenir par le fait que les personnes âgées de 65 ans et plus vont dépasser en volume les jeunes de moins de 20 ans. En sachant les coûts associés au traitement et au soutien des personnes âgées atteintes par une ou plusieurs démences cognitives, on admet l’importance des études gériatriques pour mieux comprendre les mécanismes neurophysiologiques du vieillissement. L’intérêt principal est de trouver un lien entre les effets neurologiques du vieillissement et ceux du déclin cognitif afin d’établir des stratégies qui encourageront un vieillissement en santé. Notre compréhension du cerveau a beaucoup évolué au cours des dernières décennies grâce à de nouvelles techniques en imagerie cérébrale. Pourtant, l’interprétation de ces données reste un défi. Dans le cas de l’imagerie fonctionnelle par résonance magnétique (IRM) ou par optique diffuse (IOD), la réponse neuronale est indirectement dérivée de l’hémodynamique. Cette dernière est sujette à de complexes interactions entre l’oxygénation du cerveau, le volume et le débit sanguin, ainsi que la structure hétérogène du cortex. Ces interactions rendent difficile une interprétation quantitative des données. Dans le cas des études en vieillissement cognitif, ces paramètres sont de plus modifiés par l’âge, ce qui mène à une importante variabilité interindividuelle dans l’interprétation des données. La caractérisation des effets neurophysiologiques du vieillissement sur les signaux d’imagerie cérébrale est donc essentielle pour permettre des études rigoureuses du déclin cognitif avec l’âge. Vu les limites en rapport avec les signaux intrinsèques de chacune des modalités d’imagerie non-invasive, l’intérêt pour les études multimodales s’accroît car elles permettent de calibrer avec plus de précision les données fonctionnelles. L’intégration des données complémentaires acquises via différentes modalités de neuroimagerie, dans cette étude, nous a permis de quantifier les activations neuronales et de surveiller leurs modifications reliées au vieillissement. Un montage de spectroscopie en temps résolu, fait au laboratoire, nous a fourni des données au repos sur la concentration en oxy- et déoxyhémoglobine, ainsi que sur le volume sanguin. En imagerie par résonance magnétique, une séquence anatomique nous a servi à 1) évaluer une potentielle corrélation entre l’épaisseur corticale (matières grise et blanche) et le niveau de la réponse hémodynamique et 2) Recaller la carte d’activité cérébrale de chaque participant sur son image anatomique. On rajoute ces dernières mesures comme régresseur à un modèle linéaire généralisé de la réponse hémodynamique. En faisant l’hypothèse que ces changements de bases sont liés à la physiologie,----------ABSTRACT The demographic features of the population of Canada will experience an unprecedented historical change in the near future by the number of individuals above 65 years surpassing the number of youngsters under 20 years. Considering the costly consequences of age-related cognitive decline, both for individuals and the society, studying the neurophysiological mechanisms of these unfavorable changes has become an utmost priority in health research. The main goal of this field is to link the effects of cerebral aging to those of cognitive aging in order to stablish strategies promoting healthy aging. Normal cerebral aging is accompanied by some neurophysiological and neuroanatomical alterations depending on epigenetics of individuals. Amongst neurophysiological deteriorations causing cognitive decline, one should account for the neural loss, cortical density reduction, neurovascular, metabolic, and neurotransmission dysfunctions. Taken together these alterations with age, we were interested to determine whether older adults are affected in their cognitive abilities by more than one simple factor. In another word, we aimed at exploring the potential relationship between the abovementioned age-related alterations with cognitive performance. However, the main challenge of such study appears when interpreting functional data regarding baseline measures of each individual. Thus, the increased inter and intra-individual variability in cognitive studies is mainly due to their large variations in structural and neurophysiological characteristics in the course of their lifespan. In this project, we defined a multi-modal neuroimaging protocol with the aim of calibrating the functional measures of task-related activity by measured individual baseline neurophysiological characteristics. To assess individuals` cerebral blood flow at rest, one of the constituent of hemodynamic response, we used an arterial-spin labeling sequence of magnetic resonance imaging. This technique based on tagging water in blood, gives the blood quantity emerging to brain. Carotids, the main arterial vessels that supply blood to brain, neck and face, are well known to be affected by age inter-individually and play as a non-functional moderator in hemodynamic response formation. As an estimate of total blood volume and baseline concentration of oxy- and deoxyhaemoglobin, we used a home-made 4-chanel time resolution optical device to acquire data from each participant’s prefrontal lobe. To refine the spatial resolution of non-invasive optical imaging, we also acquired anatomical MR images of each participant to 1) calculate cortical thickness with the objective of evaluating the correlatio

Contributions and complexities from the use of in-vivo animal models to improve understanding of human neuroimaging signals.

Many of the major advances in our understanding of how functional brain imaging signals relate to neuronal activity over the previous two decades have arisen from physiological research studies involving experimental animal models. This approach has been successful partly because it provides opportunities to measure both the hemodynamic changes that underpin many human functional brain imaging techniques and the neuronal activity about which we wish to make inferences. Although research into the coupling of neuronal and hemodynamic responses using animal models has provided a general validation of the correspondence of neuroimaging signals to specific types of neuronal activity, it is also highlighting the key complexities and uncertainties in estimating neural signals from hemodynamic markers. This review will detail how research in animal models is contributing to our rapidly evolving understanding of what human neuroimaging techniques tell us about neuronal activity. It will highlight emerging issues in the interpretation of neuroimaging data that arise from in-vivo research studies, for example spatial and temporal constraints to neuroimaging signal interpretation, or the effects of disease and modulatory neurotransmitters upon neurovascular coupling. We will also give critical consideration to the limitations and possible complexities of translating data acquired in the typical animals models used in this area to the arena of human fMRI. These include the commonplace use of anaesthesia in animal research studies and the fact that many neuropsychological questions that are being actively explored in humans have limited homologues within current animal models for neuroimaging research. Finally we will highlighting approaches, both in experimental animals models (e.g. imaging in conscious, behaving animals) and human studies (e.g. combined fMRI-EEG), that mitigate against these challenges

The impact of cerebral vasomotor reactivity on cerebrovascular diseases and cognitive impairment

The regulation of cerebral blood flow (CBF) is a complex and tightly controlled function ensuring delivery of oxygen and nutrients and removal of metabolic wastes from brain tissue. Cerebral vasoreactivity (CVR) refers to the ability of the nervous system to regulate CBF according to metabolic demands or changes in the microenvironment. This can be assessed through a variety of nuclear medicine and imaging techniques and protocols. Several studies have investigated the association of CVR with physiological and pathological conditions, with particular reference to the relationship with cognitive impairment and cerebrovascular disorders (CVD). A better understanding of the interaction between CVR and cognitive dysfunction in chronic and particularly acute CVD could help improving treatment and rehabilitation strategies in these patients. In this paper, we reviewed current knowledge on CVR alterations in the context of acute and chronic CVD and cognitive dysfunction. Alterations in CVR and hemodynamics have been described in patients with both neurodegenerative and vascular cognitive impairment, and the severity of these alterations seems to correlate with CVR derailment. Furthermore, an increased risk of cognitive impairment progression has been associated with alterations in CVR parameters and hemodynamics. Few studies have investigated these associations in acute cerebrovascular disorders and the results are inconsistent; thus, further research on this topic is encouraged

Quantitative functional magnetic resonance imaging in cerebral small vessel disease

Introduction: Cerebral small vessel disease (cSVD) is an important, but relatively poorly understood cause of both lacunar strokes and vascular dementia. Structural magnetic resonance imaging (MRI) markers of cSVD, including lacunes, white matter lesions (WML) and microbleeds, have been shown not to correlate consistently with clinical severity, as gauged by cognitive decline, and might offer little more than endpoint markers of disease. However, alternative developing MR techniques, including functional MRI (fMRI) using the blood-oxygen-level-dependent (BOLD) signal, offer a promising approach to charting disease severity. Aims: The primary aim is to determine whether ‘n’, a measure of neurovascular coupling (NVC) which underpins interpretation of the BOLD signal, differs between patients with cSVD and healthy matched controls. If ‘n’ does differ, a secondary aim is to determine whether ‘n’ correlates with tests of cognitive function. Methods: Eleven patients with cSVD and sixteen age-, education- and gender-matched healthy controls were recruited. Participants underwent a battery of cognitive tests focused upon executive functions and a series of MRI scans. These included structural scans, arterial spin labelling (ASL) to measure cerebral blood flow and BOLD signal. Oxygen calibrated fMRI was used with a modified Stroop Interference Task. Results: The cSVD group performed worse on the digit symbol substitution test (DSST) (p = 0.00005) than the control group. There was a significantly different BOLD response in 11 regions between patient and control groups, which were aggregated into frontal, parietal, motor, insular and total regions. ‘n’ was reduced across total regions (p = 0.02) in the patient group. ‘M’ was increased in the patient group and correlated inversely with ‘n’. DSST did not correlate with ‘n’ in patients. Conclusion: The results suggest an uncoupling of the neurovascular response in patients with cSVD, possibly associated with an increase in the oxygen extraction fraction. A larger sample size would be needed to investigate whether altered neurovascular coupling might highlight at-risk subjects who have not yet had a stroke

Vector-Based Approach for the Detection of Initial Dips Using Functional Near-Infrared Spectroscopy

Functional near-infrared spectroscopy (fNIRS) is a non-invasive method for the detection of local brain activity using changes in the local levels of oxyhemoglobin (oxyHb) and deoxyhemoglobin (deoxyHb). Simultaneous measurement of the levels of oxyHb and deoxyHb is an advantage of fNIRS over other modalities. This review provides a historical description of the physiological problems involved in the accurate identification of local brain activity using fNIRS. The need for improved spatial and temporal identification of local brain activity is described in terms of the physiological challenges of task selection and placement of probes. In addition, this review discusses challenges with data analysis based on a single index, advantages of the simultaneous analysis of multiple indicators, and recently established composite indicators. The vector-based approach provides quantitative imaging of the phase and intensity contrast for oxygen exchange responses in a time series and may detect initial dips related to neuronal activity in the skull. The vector plane model consists of orthogonal vectors of oxyHb and deoxyHb. Initial dips are hemodynamic reactions of oxyHb and deoxyHb induced by increased oxygen consumption in the early tasks of approximately 2–3 seconds. The new analytical concept of fNIRS, able to effectively detect initial dips, may extend further the clinical and social applications of fNIRS

Distinction of directional coupling in sensorimotor networks between active and passive finger movements using fNIRS

The purpose of this study is to investigate cerebral cortex activation during active movement and passive movement by using a functional near-infrared spectroscopy (fNIRS). Tasks were the flexion/extension of the right hand finger by active movement and passive movement. Oxy-hemoglobin concentration changes calculated from fNIRS and analyzed the activation and connectivity so as to understand dynamical brain relationship. The results demonstrated that the brain activation in passive movements is similar to motor execution. During active movement, the estimated causality patterns showed significant causality value from the supplementary motor area (SMA) to the primary motor cortex (M1). During the passive movement, the causality from the primary somatosensory cortex (S1) to the primary motor cortex (M1) was stronger than active movement. These results demonstrated that active and passive movements had a direct effect on the cerebral cortex but the stimulus pathway of active and passive movement is different. This study may contribute to better understanding how active and passive movements can be expressed into cortical activation by means of fNIRS. © 2018 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.1