Pathophysiology of multiple sclerosis damage and repair: Linking cerebral hypoperfusion to the development of irreversible tissue loss in multiple sclerosis using magnetic resonance imaging.

BACKGROUND AND PURPOSE: Reduced cerebral perfusion has been observed in multiple sclerosis (MS) and may contribute to tissue loss both acutely and chronically. Here, we test the hypothesis that hypoperfusion occurs in MS and relates to the presence of irreversible tissue damage. METHODS: In 91 patients with relapsing MS and 26 healthy controls (HC), gray matter (GM) cerebral blood flow (CBF) was assessed using pulsed arterial spin labeling. GM volume, T1 hypointense and T2 hyperintense lesion volumes (T1LV and T2LV, respectively), and the proportion of T2-hyperintense lesion volume that appears hypointense on T1-weighted magnetic resonance imaging (T1LV/T2LV) were quantified. GM CBF and GM volume were evaluated globally, as well as regionally, using an atlas-based approach. RESULTS: Global GM CBF was lower in patients (56.9 ± 12.3 mL/100 g/min) than in HC (67.7 ± 10.0 mL/100 g/min; p < 0.001), a difference that was widespread across brain regions. Although total GM volume was comparable between groups, significant reductions were observed in a subset of subcortical structures. GM CBF negatively correlated with T1LV (r = -0.43, p = 0.0002) and T1LV/T2LV (r = -0.37, p = 0.0004), but not with T2LV. CONCLUSIONS: GM hypoperfusion occurs in MS and is associated with irreversible white matter damage, thus suggesting that cerebral hypoperfusion may actively contribute and possibly precede neurodegeneration by hampering tissue repair abilities in MS.

Cerebral blood flow patterns in preterm and term neonates assessed with pseudo-continuous arterial spin labeling perfusion MRI.

In preterm (PT) infants, regional cerebral blood flow (CBF) disturbances may predispose to abnormal brain maturation even without overt brain injury. Therefore, it would be informative to determine the spatial distribution of grey matter (GM) CBF in PT and full-term (FT) newborns at term-equivalent age (TEA) and to assess the relationship between the features of the CBF pattern and both prematurity and prematurity-related brain lesions. In this prospective study, we obtained measures of CBF in 66 PT (51 without and 15 with prematurity-related brain lesions) and 38 FT newborns through pseudo-continuous arterial spin labeling (pCASL) MRI acquired at TEA. The pattern of GM CBF was characterized by combining an atlas-based automated segmentation of structural MRI with spatial normalization and hierarchical clustering. The effects of gestational age (GA) at birth and brain injury on the CBF pattern were investigated. We identified 4 physiologically-derived clusters of brain regions that were labeled Fronto-Temporal, Parieto-Occipital, Insular-Deep GM (DGM) and Sensorimotor, from the least to the most perfused. We demonstrated that GM perfusion was associated with GA at birth in the Fronto-Temporal and Sensorimotor clusters, positively and negatively, respectively. Moreover, the presence of periventricular leukomalacia was associated with significantly increased Fronto-Temporal GM perfusion and decreased Insular-DGM perfusion, while the presence of germinal matrix hemorrhage appeared to mildly decrease the Insular-DGM perfusion. Prematurity and prematurity-related brain injury heterogeneously affect brain perfusion. ASL MRI may, therefore, have strong potential as a noninvasive tool for the accurate stratification of individuals at risk of domain-specific impairment.

Reduced brain oxygen metabolism in patients with multiple sclerosis: Evidence from dual-calibrated functional MRI.

Cerebral energy deficiency is increasingly recognised as an important feature of multiple sclerosis (MS). Until now, we have lacked non-invasive imaging methods to quantify energy utilisation and mitochondrial function in the human brain. Here, we used novel dual-calibrated functional magnetic resonance imaging (dc-fMRI) to map grey-matter (GM) deoxy-haemoglobin sensitive cerebral blood volume (CBVdHb), cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen consumption (CMRO2) in patients with MS (PwMS) and age/sex matched controls. By integrating a flow-diffusion model of oxygen transport, we evaluated the effective oxygen diffusivity of the capillary network (DC) and the partial pressure of oxygen at the mitochondria (PmO2). Significant between-group differences were observed as decreased CBF (p = 0.010), CMRO2 (p < 0.001) and DC (p = 0.002), and increased PmO2 (p = 0.043) in patients compared to controls. No significant differences were observed for CBVdHb (p = 0.389), OEF (p = 0.358), or GM volume (p = 0.302). Regional analysis showed widespread reductions in CMRO2 and DC for PwMS. Our findings may be indicative of reduced oxygen demand or utilisation in the MS brain and mitochondrial dysfunction. Our results suggest changes in brain physiology may precede MRI-detectable GM loss and may contribute to disease progression and neurodegeneration.

A flow-diffusion model of oxygen transport for quantitative mapping of cerebral metabolic rate of oxygen (CMRO2) with single gas calibrated fMRI.

One promising approach for mapping CMRO2 is dual-calibrated functional MRI (dc-fMRI). This method exploits the Fick Principle to combine estimates of CBF from ASL, and OEF derived from BOLD-ASL measurements during arterial O2 and CO2 modulations. Multiple gas modulations are required to decouple OEF and deoxyhemoglobin-sensitive blood volume. We propose an alternative single gas calibrated fMRI framework, integrating a model of oxygen transport, that links blood volume and CBF to OEF and creates a mapping between the maximum BOLD signal, CBF and OEF (and CMRO2). Simulations demonstrated the method's viability within physiological ranges of mitochondrial oxygen pressure, PmO2, and mean capillary transit time. A dc-fMRI experiment, performed on 20 healthy subjects using O2 and CO2 challenges, was used to validate the approach. The validation conveyed expected estimates of model parameters (e.g., low PmO2), with spatially uniform OEF maps (grey matter, GM, OEF spatial standard deviation ≈ 0.13). GM OEF estimates obtained with hypercapnia calibrated fMRI correlated with dc-fMRI (r = 0.65, p = 2·10-3). For 12 subjects, OEF measured with dc-fMRI and the single gas calibration method were correlated with whole-brain OEF derived from phase measures in the superior sagittal sinus (r = 0.58, p = 0.048; r = 0.64, p = 0.025 respectively). Simplified calibrated fMRI using hypercapnia holds promise for clinical application.

Distinct effects of prematurity on MRI metrics of brain functional connectivity, activity, and structure: Univariate and multivariate analyses.

Premature birth affects the developmental trajectory of the brain during a period of intense maturation with possible lifelong consequences. To better understand the effect of prematurity on brain structure and function, we performed blood-oxygen-level dependent (BOLD) and anatomical magnetic resonance imaging (MRI) at 40 weeks of postmenstrual age on 88 newborns with variable gestational age (GA) at birth and no evident radiological alterations. We extracted measures of resting-state functional connectivity and activity in a set of 90 cortical and subcortical brain regions through the evaluation of BOLD correlations between regions and of fractional amplitude of low-frequency fluctuation (fALFF) within regions, respectively. Anatomical information was acquired through the assessment of regional volumes. We performed univariate analyses on each metric to examine the association with GA at birth, the spatial distribution of the effects, and the consistency across metrics. Moreover, a data-driven multivariate analysis (i.e., Machine Learning) framework exploited the high dimensionality of the data to assess the sensitivity of each metric to the effect of premature birth. Prematurity was associated with bidirectional alterations of functional connectivity and regional volume and, to a lesser extent, of fALFF. Notably, the effects of prematurity on functional connectivity were spatially diffuse, mainly within cortical regions, whereas effects on regional volume and fALFF were more focal, involving subcortical structures. While the two analytical approaches delivered consistent results, the multivariate analysis was more sensitive in capturing the complex pattern of prematurity effects. Future studies might apply multivariate frameworks to identify premature infants at risk of a negative neurodevelopmental outcome.

Evidence of Neurovascular Un-Coupling in Mild Alzheimer's Disease through Multimodal EEG-fNIRS and Multivariate Analysis of Resting-State Data.

Alzheimer's disease (AD) is associated with modifications in cerebral blood perfusion and autoregulation. Hence, neurovascular coupling (NC) alteration could become a biomarker of the disease. NC might be assessed in clinical settings through multimodal electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS). Multimodal EEG-fNIRS was recorded at rest in an ambulatory setting to assess NC and to evaluate the sensitivity and specificity of the methodology to AD. Global NC was evaluated with a general linear model (GLM) framework by regressing whole-head EEG power envelopes in three frequency bands (theta, alpha and beta) with average fNIRS oxy- and deoxy-hemoglobin concentration changes in the frontal and prefrontal cortices. NC was lower in AD compared to healthy controls (HC) with significant differences in the linkage of theta and alpha bands with oxy- and deoxy-hemoglobin, respectively (p = 0.028 and p = 0.020). Importantly, standalone EEG and fNIRS metrics did not highlight differences between AD and HC. Furthermore, a multivariate data-driven analysis of NC between the three frequency bands and the two hemoglobin species delivered a cross-validated classification performance of AD and HC with an Area Under the Curve, AUC = 0.905 (p = 2.17 × 10-5). The findings demonstrate that EEG-fNIRS may indeed represent a powerful ecological tool for clinical evaluation of NC and early identification of AD.

Wireless, implantable catheter-type oximeter designed for cardiac oxygen saturation.

Accurate, real-time monitoring of intravascular oxygen levels is important in tracking the cardiopulmonary health of patients after cardiothoracic surgery. Existing technologies use intravascular placement of glass fiber-optic catheters that pose risks of blood vessel damage, thrombosis, and infection. In addition, physical tethers to power supply systems and data acquisition hardware limit freedom of movement and add clutter to the intensive care unit. This report introduces a wireless, miniaturized, implantable optoelectronic catheter system incorporating optical components on the probe, encapsulated by soft biocompatible materials, as alternative technology that avoids these disadvantages. The absence of physical tethers and the flexible, biocompatible construction of the probe represent key defining features, resulting in a high-performance, patient-friendly implantable oximeter that can monitor localized tissue oxygenation, heart rate, and respiratory activity with wireless, real-time, continuous operation. In vitro and in vivo testing shows that this platform offers measurement accuracy and precision equivalent to those of existing clinical standards.

Spatiotemporal dynamics of attentional orienting and reorienting revealed by fast optical imaging in occipital and parietal cortices.

The mechanisms of visuospatial attention are mediated by two distinct fronto-parietal networks: a bilateral dorsal network (DAN), involved in the voluntary orientation of visuospatial attention, and a ventral network (VAN), lateralized to the right hemisphere, involved in the reorienting of attention to unexpected, but relevant, stimuli. The present study consisted of two aims: 1) to characterize the spatio-temporal dynamics of attention and 2) to examine the predictive interactions between and within the two attention systems along with visual areas, by using fast optical imaging combined with Granger causality. Data were collected from young healthy participants performing a discrimination task in a Posner-like paradigm. Functional analyses revealed bilateral dorsal parietal (i.e. dorsal regions included in the DAN) and visual recruitment during orienting, highlighting a recursive predictive interplay between specific dorsal parietal regions and visual cortex. Moreover, we found that both attention networks are active during reorienting, together with visual cortex, highlighting a mutual interaction among dorsal and visual areas, which, in turn, predicts subsequent ventral activity. For attentional reorienting our findings indicate that dorsal and visual areas encode disengagement of attention from the attended location and trigger reorientation to the unexpected location. Ventral network activity could instead reflect post-perceptual maintenance of the internal model to generate and keep updated task-related expectations.

Cerebral perfusion and blood-brain barrier assessment in brain trauma using contrast-enhanced near-infrared spectroscopy with indocyanine green: A review.

Contrast-enhanced near-infrared spectroscopy (NIRS) with indocyanine green (ICG) can be a valid non-invasive, continuous, bedside neuromonitoring tool. However, its usage in moderate and severe traumatic brain injury (TBI) patients can be unprecise due to their clinical status. This review is targeted at researchers and clinicians involved in the development and application of contrast-enhanced NIRS for the care of TBI patients and can be used to design future studies. This review describes the methods developed to monitor the brain perfusion and the blood-brain barrier integrity using the changes of diffuse reflectance during the ICG passage and the results on studies in animals and humans. The limitations in accuracy of these methods when applied on TBI patients and the proposed solutions to overcome them are discussed. Finally, the analysis of relative parameters is proposed as a valid alternative over absolute values to address some current clinical needs in brain trauma care. In conclusion, care should be taken in the translation of the optical signal into absolute physiological parameters of TBI patients, as their clinical status must be taken into consideration. Discussion on where and how future studies should be directed to effectively incorporate contrast-enhanced NIRS into brain trauma care is given.

Age-related differences in functional brain network segregation are consistent with a cascade of cerebrovascular, structural, and cognitive effects.

Age-related declines in cognition are associated with widespread structural and functional brain changes, including changes in resting-state functional connectivity and gray and white matter status. Recently we have shown that the elasticity of cerebral arteries also explains some of the variance in cognitive and brain health in aging. Here, we investigated how network segregation, cerebral arterial elasticity (measured with pulse-DOT-the arterial pulse based on diffuse optical tomography) and gray and white matter status jointly account for age-related differences in cognitive performance. We hypothesized that at least some of the variance in brain and cognitive aging is linked to reduced cerebrovascular elasticity, leading to increased cortical atrophy and white matter abnormalities, which, in turn, are linked to reduced network segregation and decreases in cognitive performance. Pairwise comparisons between these variables are consistent with an exploratory hierarchical model linking them, especially when focusing on association network segregation (compared with segregation in sensorimotor networks). These findings suggest that preventing or slowing age-related changes in one or more of these factors may induce a neurophysiological cascade beneficial for preserving cognition in aging.

Optical measures of cerebral arterial stiffness are associated with white matter signal abnormalities and cognitive performance in normal aging.

Decline in fluid abilities in normal aging is associated with increased white matter lesions, measured on T1-weighted images as white matter signal abnormalities (WMSAs). WMSAs are particularly evident in hypertensive older adults, suggesting vascular involvement. However, because hypertension is assessed systemically, the specific role of cerebral arterial stiffening in WMSAs has yet to be demonstrated. In 93 cognitively normal adults (aged 18-87 years), we used a novel method to measure cerebral arterial elasticity (pulse relaxation function [PReFx]) with diffuse optical tomography (pulse-DOT) and investigated its association with WMSAs, age, and cognition. PReFx was associated with WMSAs, with older adults with low PReFx showing the greatest WMSA burden. PReFx in brain regions perfused by the middle cerebral artery showed the largest associations with WMSAs and partially mediated the relationship between age and WMSAs. Finally, WMSAs partially mediated the relationship between PReFx and fluid but not crystallized abilities scores. Taken together, these findings suggest that loss of cerebral arterial elasticity is associated with cerebral white matter lesions and age-related cognitive decline.

Data-driven assessment of cardiovascular ageing through multisite photoplethysmography and electrocardiography.

The cardiovascular system is designed to distribute a steady flow through its elastic properties. With ageing, fatigue and fracture of elastin lamellae cause a loss of elasticity defined arterial stiffness. Arterial stiffness causes changes of the pulse wave propagation through the arterial tree, which volumetric counterpart can be assessed non-invasively through photoplethysmography (PPG). PPG may be employed in combination with electrocardiography (ECG). It is here reported an implementation of analysis of multisite PPG and single lead ECG relying on Deep Convolutional Neural Networks (DCNNs). DCNNs generate peculiar filters allowing for data-driven automated selection of the features of interest. The ability of a DCNN to predict subject's age from PPG (left and right brachial, radial and tibial arteries plus fingers) and ECG (Lead I) in a healthy male population (age range: 20-70 years) was investigated. A performance in age prediction of 7 years of root mean square error was obtained, which was superior to other feature-based procedures. The accuracy in age prediction of the machinery in the healthy population may serve for the generation of age-matched normal ranges for the identification of outliers suggesting cardiovascular diseases manifesting as fastened cardiovascular ageing which is recognized as a risk factor for ischemic diseases.

Wireless, battery-free optoelectronic systems as subdermal implants for local tissue oximetry.

Monitoring regional tissue oxygenation in animal models and potentially in human subjects can yield insights into the underlying mechanisms of local O2-mediated physiological processes and provide diagnostic and therapeutic guidance for relevant disease states. Existing technologies for tissue oxygenation assessments involve some combination of disadvantages in requirements for physical tethers, anesthetics, and special apparatus, often with confounding effects on the natural behaviors of test subjects. This work introduces an entirely wireless and fully implantable platform incorporating (i) microscale optoelectronics for continuous sensing of local hemoglobin dynamics and (ii) advanced designs in continuous, wireless power delivery and data output for tether-free operation. These features support in vivo, highly localized tissue oximetry at sites of interest, including deep brain regions of mice, on untethered, awake animal models. The results create many opportunities for studying various O2-mediated processes in naturally behaving subjects, with implications in biomedical research and clinical practice.

The Optical Effective Attenuation Coefficient as an Informative Measure of Brain Health in Aging.

Aging is accompanied by widespread changes in brain tissue. Here, we hypothesized that head tissue opacity to near-infrared light provides information about the health status of the brain's cortical mantle. In diffusive media such as the head, opacity is quantified through the Effective Attenuation Coefficient (EAC), which is proportional to the geometric mean of the absorption and reduced scattering coefficients. EAC is estimated by the slope of the relationship between source-detector distance and the logarithm of the amount of light reaching the detector (optical density). We obtained EAC maps across the head in 47 adults (age range 18-75 years), using a high-density dual-wavelength optical system. We correlated regional and global EAC measures with demographic, neuropsychological, structural and functional brain data. Results indicated that EAC values averaged across wavelengths were strongly associated with age-related changes in cortical thickness, as well as functional and neuropsychological measures. This is likely because the EAC largely depends on the thickness of the sub-arachnoid cerebrospinal fluid layer, which increases with cortical atrophy. In addition, differences in EAC values between wavelengths were correlated with tissue oxygenation and cardiorespiratory fitness, indicating that information about cortical health can be derived non-invasively by quantifying the EAC.

Complexity of Frontal Cortex fNIRS Can Support Alzheimer Disease Diagnosis in Memory and Visuo-Spatial Tests.

Decline in visuo-spatial skills and memory failures are considered symptoms of Alzheimer's Disease (AD) and they can be assessed at early stages employing clinical tests. However, performance in a single test is generally not indicative of AD. Functional neuroimaging, such as functional Near Infrared Spectroscopy (fNIRS), may be employed during these tests in an ecological setting to support diagnosis. Indeed, neuroimaging should not alter clinical practice allowing free doctor-patient interaction. However, block-designed paradigms, necessary for standard functional neuroimaging analysis, require tests adaptation. Novel signal analysis procedures (e.g., signal complexity evaluation) may be useful to establish brain signals differences without altering experimental conditions. In this study, we estimated fNIRS complexity (through Sample Entropy metric) in frontal cortex of early AD and controls during three tests that assess visuo-spatial and short-term-memory abilities (Clock Drawing Test, Digit Span Test, Corsi Block Tapping Test). A channel-based analysis of fNIRS complexity during the tests revealed AD-induced changes. Importantly, a multivariate analysis of fNIRS complexity provided good specificity and sensitivity to AD. This outcome was compared to cognitive tests performances that were predictive of AD in only one test. Our results demonstrated the capabilities of fNIRS and complexity metric to support early AD diagnosis.

Assessment of cerebrovascular development and intraventricular hemorrhages in preterm infants with optical measures of the brain arterial pulse wave.

Preterm infants (born at 24-34 weeks of gestational age) suffer from a high incidence of neurological complications. Cerebrovascular lesions (intraventricular hemorrhages, IVH, and ischemic injury) due to the immaturity of the vascular system and its inability to adapt to the extra-uterine environment are the major causes of adverse neurological outcomes. We investigated the feasibility of assessing cerebrovascular status in preterm infants using a novel non-invasive optical procedure, pulse-DOT, usable within the incubator. Pulse-DOT, validated in adults, provides estimates of cerebral arterial status based on optical measurements of the pulse wave. These measurements are taken with a high-density optode montage and provide accurate spatial and temporal information. We found that two pulse parameters (pulse relaxation function, PReFx, and pulse rise time, PRT) in the investigated frontotemporal region, correlated with infant's age at recording, indexing cerebrovascular development. Moreover, PRT differentiated infants with and without concurrent IVH (sensitivity = 100%, specificity = 70%). These values are at least as high as those of the resistivity index obtained with transcranial Doppler of the middle cerebral artery, the current clinical method of choice for investigating arterial elasticity in preterm infants. This makes pulse-DOT a promising tool for investigating cerebrovascular risk factors and related pathologies in preterm infants.

Characterization of a fiber-less, multichannel optical probe for continuous wave functional near-infrared spectroscopy based on silicon photomultipliers detectors: in-vivo assessment of primary sensorimotor response.

We report development, testing, and in vivo characterization of a multichannel optical probe for continuous wave (CW) functional near-infrared spectroscopy (fNIRS) that relies on silicon photomultipliers (SiPMs) detectors. SiPMs are cheap, low voltage, and robust semiconductor light detectors with performances analogous to photomultiplier tubes (PMTs). In contrast with PMTs, SiPMs allow direct contact with the head and transfer of the analog signals through thin cables greatly increasing the system flexibility avoiding optical fibers. The coupling of SiPMs and light-emitting diodes (LEDs) made the optical probe lightweight and robust against motion artifacts. After characterization of SiPM performances, which was proven to provide a noise equivalent power below 3 fW, the apparatus was compared through an in vivo experiment to a commercial system relying on laser diodes, PMTs, and optical fibers for light probing and detection. The optical probes were located over the primary sensorimotor cortex and the similarities between the hemodynamic responses to the contralateral motor task were assessed. When compared to other state-of-the-art wearable fNIRS systems, where photodiode detectors are employed, the single photon sensitivity and dynamic range of SiPMs can fully exploit the long and variable interoptode distances needed for correct estimation of brain hemodynamics using CW-fNIRS.

Individual differences in regional cortical volumes across the life span are associated with regional optical measures of arterial elasticity.

Aging is often accompanied by changes in brain anatomy and cerebrovascular health. However, the specific relationship between declines in regional cortical volumes and loss of cerebral arterial elasticity is less clear, as only global or very localized estimates of cerebrovascular health have been available. Here we employed a novel tomographic optical method (pulse-DOT) to derive local estimates of cerebral arterial elasticity and compared regional volumetric estimates (obtained with FreeSurfer) with optical arterial elasticity estimates from the same regions in 47 healthy adults (aged 18-75). Between-subject analyses revealed a global correlation between cortical volume and cortical arterial elasticity, which was a significant mediator of the association between age and cortical volume. Crucially, a novel within-subject analysis highlighted the spatial association between regional variability in cortical volumes and arterial elasticity in the same regions. This association strengthened with age. Gains in the predictability of cortical volumes from arterial elasticity data were obtained by sharpening the resolution up to individual cortical regions. These results indicate that some of the variance of sub-clinical age-related brain atrophy is associated with differences in the status of cerebral arteries, and can help explain the unique patterns of brain atrophy found within each individual.

Miniaturized Battery-Free Wireless Systems for Wearable Pulse Oximetry.

Development of unconventional technologies for wireless collection, storage and analysis of quantitative, clinically relevant information on physiological status is of growing interest. Soft, biocompatible systems are widely regarded as important because they facilitate mounting on external (e.g. skin) and internal (e.g. heart, brain) surfaces of the body. Ultra-miniaturized, lightweight and battery-free devices have the potential to establish complementary options in bio-integration, where chronic interfaces (i.e. months) are possible on hard surfaces such as the fingernails and the teeth, with negligible risk for irritation or discomfort. Here we report materials and device concepts for flexible platforms that incorporate advanced optoelectronic functionality for applications in wireless capture and transmission of photoplethysmograms, including quantitative information on blood oxygenation, heart rate and heart rate variability. Specifically, reflectance pulse oximetry in conjunction with near-field communication (NFC) capabilities enables operation in thin, miniaturized flexible devices. Studies of the material aspects associated with the body interface, together with investigations of the radio frequency characteristics, the optoelectronic data acquisition approaches and the analysis methods capture all of the relevant engineering considerations. Demonstrations of operation on various locations of the body and quantitative comparisons to clinical gold standards establish the versatility and the measurement accuracy of these systems, respectively.