Respiratory challenge MRI: practical aspects

Respiratory challenge MRI is the modification of arterial oxygen (PaO2) and/or carbon dioxide (PaCO2) concentration to induce a change in cerebral function or metabolism which is then measured by MRI. Alterations in arterial gas concentrations can lead to profound changes in cerebral haemodynamics which can be studied using a variety of MRI sequences. Whilst such experiments may provide a wealth of information, conducting them can be complex and challenging. In this paper we review the rationale for respiratory challenge MRI including the effects of oxygen and carbon dioxide on the cerebral circulation. We also discuss the planning, equipment, monitoring and techniques that have been used to undertake these experiments. We finally propose some recommendations in this evolving area for conducting these experiments to enhance data quality and comparison between techniques

A novel method of combining blood oxygenation and blood flow sensitive magnetic resonance imaging techniques to measure the cerebral blood flow and oxygen metabolism responses to an unknown neural stimulus.

Simultaneous implementation of magnetic resonance imaging methods for Arterial Spin Labeling (ASL) and Blood Oxygenation Level Dependent (BOLD) imaging makes it possible to quantitatively measure the changes in cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO(2)) that occur in response to neural stimuli. To date, however, the range of neural stimuli amenable to quantitative analysis is limited to those that may be presented in a simple block or event related design such that measurements may be repeated and averaged to improve precision. Here we examined the feasibility of using the relationship between cerebral blood flow and the BOLD signal to improve dynamic estimates of blood flow fluctuations as well as to estimate metabolic-hemodynamic coupling under conditions where a stimulus pattern is unknown. We found that by combining the information contained in simultaneously acquired BOLD and ASL signals through a method we term BOLD Constrained Perfusion (BCP) estimation, we could significantly improve the precision of our estimates of the hemodynamic response to a visual stimulus and, under the conditions of a calibrated BOLD experiment, accurately determine the ratio of the oxygen metabolic response to the hemodynamic response. Importantly we were able to accomplish this without utilizing a priori knowledge of the temporal nature of the neural stimulus, suggesting that BOLD Constrained Perfusion estimation may make it feasible to quantitatively study the cerebral metabolic and hemodynamic responses to more natural stimuli that cannot be easily repeated or averaged

Greater V˙O2peak is correlated with greater skeletal muscle deoxygenation amplitude and hemoglobin concentration within individual muscles during ramp-incremental cycle exercise.

It is axiomatic that greater aerobic fitness (V˙O2peak) derives from enhanced perfusive and diffusive O2 conductances across active muscles. However, it remains unknown how these conductances might be reflected by regional differences in fractional O2 extraction (i.e., deoxy [Hb+Mb] and tissue O2 saturation [StO2]) and diffusive O2 potential (i.e., total[Hb+Mb]) among muscles spatially heterogeneous in blood flow, fiber type, and recruitment (vastus lateralis, VL; rectus femoris, RF). Using quantitative time-resolved near-infrared spectroscopy during ramp cycling in 24 young participants (V˙O2peak range: ~37.4-66.4 mL kg-1 min-1), we tested the hypotheses that (1) deoxy[Hb+Mb] and total[Hb+Mb] at V˙O2peak would be positively correlated with V˙O2peak in both VL and RF muscles; (2) the pattern of deoxygenation (the deoxy[Hb+Mb] slopes) during submaximal exercise would not differ among subjects differing in V˙O2peak Peak deoxy [Hb+Mb] and StO2 correlated with V˙O2peak for both VL (r = 0.44 and -0.51) and RF (r = 0.49 and -0.49), whereas for total[Hb+Mb] this was true only for RF (r = 0.45). Baseline deoxy[Hb+Mb] and StO2 correlated with V˙O2peak only for RF (r = -0.50 and 0.54). In addition, the deoxy[Hb+Mb] slopes were not affected by aerobic fitness. In conclusion, while the pattern of deoxygenation (the deoxy[Hb+Mb] slopes) did not differ between fitness groups the capacity to deoxygenate [Hb+Mb] (index of maximal fractional O2 extraction) correlated significantly with V˙O2peak in both RF and VL muscles. However, only in the RF did total[Hb+Mb] (index of diffusive O2 potential) relate to fitness

Dynamic Assessment of Cerebral Metabolic Rate of Oxygen (cmro2) With Magnetic Resonance Imaging

The brain is almost entirely dependent on oxidative metabolism to meet its energy requirements. As such, the cerebral metabolic rate of oxygen (CMRO2) is a direct measure of brain energy use. CMRO2 provides insight into brain functional architecture and has demonstrated potential as a clinical tool for assessing many common neurological disorders. Recent developments in magnetic resonance imaging (MRI)-based CMRO2 quantification have shown promise in spatially resolving CMRO2 in clinically feasible scan times. However, brain energy requirements are both spatially heterogeneous and temporally dynamic, responding to rapid changes in oxygen supply and demand in response to physiologic stimuli and neuronal activation. Methods for dynamic quantification of CMRO2 are lacking, and this dissertation aims to address this gap. Given the fundamental tradeoff between spatial and temporal resolution in MRI, we focus initially on the latter. Central to each proposed method is a model-based approach for deriving venous oxygen saturation (Yv) – the critical parameter for CMRO2 quantification – from MRI signal phase using susceptometry-based oximetry (SBO). First, a three-second-temporal-resolution technique for whole-brain quantification of Yv and CMRO2 is presented. This OxFlow method is applied to measure a small but highly significant increase in CMRO2 in response to volitional apnea. Next, OxFlow is combined with a competing approach for Yv quantification based on blood T2 relaxometry (TRUST). The resulting interleaved-TRUST (iTRUST) pulse sequence greatly improves T2-based CMRO2 quantification, while allowing direct, simultaneous comparison of SBO- and T2-based Yv. iTRUST is applied to assess the CMRO2 response to hypercapnia – a topic of great interest in functional neuroimaging – demonstrating significant biases between SBO- and T2-derived Yv and CMRO2. To address the need for dynamic and spatially resolved CMRO2 quantification, we explore blood-oxygen-level-dependent (BOLD) calibration, introducing a new calibration model and hybrid pulse sequence combining OxFlow with standard BOLD/CBF measurement. Preliminary results suggest Ox-BOLD provides improved calibration “M-maps” for converting BOLD signal to CMRO2. Finally, OxFlow is applied clinically to patients with obstructive sleep apnea (OSA). A small clinical pilot study demonstrates OSA-associated reductions in CMRO2 at baseline and in response to apnea, highlighting the potential utility of dynamic CMRO2 quantification in assessing neuropathology

Development of a novel diffuse correlation spectroscopy platform for monitoring cerebral blood flow and oxygen metabolism: from novel concepts and devices to preclinical live animal studies

New optical technologies were developed to continuously measure cerebral blood flow (CBF) and oxygen metabolism (CMRO2) non-invasively through the skull. Methods and devices were created to improve the performance of near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) for use in experimental animals and humans. These were employed to investigate cerebral metabolism and cerebrovascular reactivity under different states of anesthesia and during models of pathological states. Burst suppression is a brain state arising naturally in pathological conditions or under deep general anesthesia, but its mechanism and consequences are not well understood. Electroencephalography (EEG) and cortical hemodynamics were simultaneously measured in rats to evaluate the coupling between cerebral oxygen metabolism and neuronal activity in the burst suppressed state. EEG bursts were used to deconvolve NIRS and DCS signals into the hemodynamic and metabolic response function for an individual burst. This response was found to be similar to the stereotypical functional hyperemia evoked by normal brain activation. Thus, spontaneous burst activity does not cause metabolic or hemodynamic dysfunction in the cortex. Furthermore, cortical metabolic activity was not associated with the initiation or termination of a burst. A novel technique, time-domain DCS (TD-DCS), was introduced to significantly increase the sensitivity of transcranial CBF measurements to the brain. A new time-correlated single photon counting (TCSPC) instrument with a custom high coherence pulsed laser source was engineered for the first-ever simultaneous measurement of photon time of flight and DCS autocorrelation decays. In this new approach, photon time tags are exploited to determine path-length-dependent autocorrelation functions. By correlating photons according to time of flight, CBF is distinguished from superficial blood flow. Experiments in phantoms and animals demonstrate TD-DCS has significantly greater sensitivity to the brain than existing transcranial techniques. Intracranial pressure (ICP) modulates both steady-state and pulsatile CBF, making CBF a potential marker for ICP. In particular, the critical closing pressure (CrCP) has been proposed as a surrogate measure of ICP. A new DCS device was developed to measure pulsatile CBF non-invasively. A novel method for estimating CrCP and ICP from DCS measurement of pulsatile microvascular blood flow in the cerebral cortex was demonstrated in rats.2018-03-08T00:00:00

Nasopharyngeal method for selective brain cooling and development of a time-resolved near-infrared technique to monitor brain temperature and oxidation status during hypothermia

Mild hypothermia at 32-35oC (HT) has been shown to be neuroprotective for neurological emergencies following severe head trauma, cardiac arrest and neonatal asphyxia. However, HT has not been widely deployed in clinical settings because: firstly, cooling the whole body below 33-34°C can induce severe complications; therefore, applying HT selectively to the brain could minimize adverse effects by maintaining core body temperature at normal level. Secondly, development of an effective and easy to implement selective brain cooling (SBC) technique, which can quickly induce brain hypothermia while avoiding complications from whole body cooling, remains a challenge. In this thesis, we studied the feasibility and efficiency of selective brain cooling (SBC) through nasopharyngeal cooling. To control the cooling and rewarming rate and because core body temperature is different from brain temperature, we also developed a non-invasive technique based on time-resolved near infrared spectroscopy (TR-NIRS) to measure local brain temperature. In normal brain, cerebral blood flow (CBF) and energy metabolism as reflected by the cerebral metabolic rate of oxygen (CMRO2) is tightly coupled leading to an oxygen extraction efficiency (OEF) of around ~33%. A decoupling of the two as in ischemia signifies oxidative stress and would lead to an increase in OEF beyond the normal value of ~33%. The final goal of this thesis is to evaluate TR-NIRS methods for measurements of CBF and CMRO2 to monitor for oxidative metabolism in the brain with and without HT treatment. Chapter 2 presents investigations on the feasibility and efficiency of the nasopharyngeal SBC by blowing room temperature or humidified cooled air into the nostrils. Effective brain cooling at a median cooling rate of 5.6 ± 1.1°C/hour compared to whole body cooling rate of 3.2 ± 0.7 was demonstrated with the nasopharyngeal cooling method. Chapter 3 describes TR-NIRS experiments performed to measure brain temperature non-invasively based on the temperature-dependence of the water absorption peaks at ~740 and 840nm. The TR-NIRS method was able to measure brain temperature with a mean difference of 0.5 ± 1.6°C (R2 = 0.66) between the TR-NIRS and thermometer measurements. Chapter 4 describes the TR-NIR technique developed to measure CBF and CMRO2 in a normoxia animal model under different anesthetics at different brain temperatures achieved by whole-body cooling. Both CBF and CMRO2 decreased with decreasing brain temperature but the ratio CMRO2:CBF (OEF) remained unchanged around the normal value of ~33%. These results demonstrate that TR-NIR can be used to monitor the oxidative status of the brain in neurological emergencies and its response to HT treatment. In summary, this thesis has established a convenient method for selective brain cooling without decreasing whole body temperature to levels when adverse effects could be triggered. TR-NIRS methods are also developed for monitoring local brain temperature to guide SBC treatment and for monitoring the oxidation status of the brain as treatment progresses

A Model of Brain Circulation and Metabolism: NIRS Signal Changes during Physiological Challenges

We construct a model of brain circulation and energy metabolism. The model is designed to explain experimental data and predict the response of the circulation and metabolism to a variety of stimuli, in particular, changes in arterial blood pressure, CO2 levels, O2 levels, and functional activation. Significant model outputs are predictions about blood flow, metabolic rate, and quantities measurable noninvasively using near-infrared spectroscopy (NIRS), including cerebral blood volume and oxygenation and the redox state of the CuA centre in cytochrome c oxidase. These quantities are now frequently measured in clinical settings; however the relationship between the measurements and the underlying physiological events is in general complex. We anticipate that the model will play an important role in helping to understand the NIRS signals, in particular, the cytochrome signal, which has been hard to interpret. A range of model simulations are presented, and model outputs are compared to published data obtained from both in vivo and in vitro settings. The comparisons are encouraging, showing that the model is able to reproduce observed behaviour in response to various stimuli

Functional Imaging of Autonomic Regulation: Methods and Key Findings.

Central nervous system processing of autonomic function involves a network of regions throughout the brain which can be visualized and measured with neuroimaging techniques, notably functional magnetic resonance imaging (fMRI). The development of fMRI procedures has both confirmed and extended earlier findings from animal models, and human stroke and lesion studies. Assessments with fMRI can elucidate interactions between different central sites in regulating normal autonomic patterning, and demonstrate how disturbed systems can interact to produce aberrant regulation during autonomic challenges. Understanding autonomic dysfunction in various illnesses reveals mechanisms that potentially lead to interventions in the impairments. The objectives here are to: (1) describe the fMRI neuroimaging methodology for assessment of autonomic neural control, (2) outline the widespread, lateralized distribution of function in autonomic sites in the normal brain which includes structures from the neocortex through the medulla and cerebellum, (3) illustrate the importance of the time course of neural changes when coordinating responses, and how those patterns are impacted in conditions of sleep-disordered breathing, and (4) highlight opportunities for future research studies with emerging methodologies. Methodological considerations specific to autonomic testing include timing of challenges relative to the underlying fMRI signal, spatial resolution sufficient to identify autonomic brainstem nuclei, blood pressure, and blood oxygenation influences on the fMRI signal, and the sustained timing, often measured in minutes of challenge periods and recovery. Key findings include the lateralized nature of autonomic organization, which is reminiscent of asymmetric motor, sensory, and language pathways. Testing brain function during autonomic challenges demonstrate closely-integrated timing of responses in connected brain areas during autonomic challenges, and the involvement with brain regions mediating postural and motoric actions, including respiration, and cardiac output. The study of pathological processes associated with autonomic disruption shows susceptibilities of different brain structures to altered timing of neural function, notably in sleep disordered breathing, such as obstructive sleep apnea and congenital central hypoventilation syndrome. The cerebellum, in particular, serves coordination roles for vestibular stimuli and blood pressure changes, and shows both injury and substantially altered timing of responses to pressor challenges in sleep-disordered breathing conditions. The insights into central autonomic processing provided by neuroimaging have assisted understanding of such regulation, and may lead to new treatment options for conditions with disrupted autonomic function

Developing novel fluorescent probe for peroxynitrite: implication for understanding the roles of peroxynitrite and drug discovery in cerebral ischemia reperfusion injury

Session 7 - Oral PresentationsSTUDY GOAL: Peroxynitrite (ONOO‐) is a cytotoxic factor. As its short lifetime, ONOO‐ is hard to be detected in biological systems. This study aims to develop novel probe for detecting ONOO‐ and understand the roles of ONOO‐ in ischemic brains and drug discovery ABSTRACT: MitoPN‐1 was found to be a ONOO‐ specific probe with no toxicity. With MitoPN‐1, we studied the roles of ONOO‐ in hypoxic neuronal cells in vitro and MCAO …postprin