Functional Ultrasound Neuroimaging.

Hypercapnia induces cerebral vasodilation and increases cerebral blood volume (CBV), and hypocapnia induces cerebral vasoconstriction and decreases CBV. Cerebral blood volume measured by positron emission tomography (PET) is the sum of three components, that is, arterial, capillary, and venous blood volumes. Changes in arterial blood volume (V(a)) and CBV during hypercapnia and hypocapnia were investigated in humans using PET with H(2)(15)O and (11)CO. Arterial blood volume was determined from H(2)(15)O PET data by means of a two-compartment model that takes V(a) into account. Baseline CBV and values during hypercapnia and hypocapnia in the cerebral cortex were 0.034+/-0.003, 0.038+/-0.003, and 0.031+/-0.003 mL/mL (mean+/-s.d.), respectively. Baseline V(a) and values during hypercapnia and hypocapnia were 0.015+/-0.003, 0.025+/-0.011, and 0.007+/-0.003 mL/mL, respectively. Cerebral blood volume changed significantly owing to changes in PaCO(2), and V(a) changed significantly in the direction of CBV changes. However, no significant change was observed in venous plus capillary blood volume (=CBV-V(a)). This indicates that changes in CBV during hypercapnia and hypocapnia are caused by changes in arterial blood volume without changes in venous and capillary blood volume.

A method of simultaneously measuring the changes in cerebral blood volume (CBV) and T(*) (2) that occur on brain activation with high temporal resolution was developed. The method involves measuring the change in the longitudinal relaxation time (T(1)) that occurs following a bolus injection of Gd-DTPA and converting this measurement to a change in blood volume assuming fast exchange. The sequence was optimized for the measurement of changes in CBV with high temporal resolution. A change in CBV of 27 +/- 4% on activation of the primary visual cortex (V1) was measured across four subjects. The time course of changes in T(*) (2) showed a poststimulus undershoot (P = 0.008) corresponding approximately to a period over which CBV was still elevated above baseline, but falling (P = 0.01). The effects of perfusion, nonfulfillment of the assumption of fast exchange and of intrinsic T(1) changes on activation on the model used to calculate the change in CBV are discussed.

The measure theory of cerebral blood flow (CBF), and cerebral blood volume (CBV) with time-resolved Near-infrared spectroscopy (NIRs) has been introduced in this paper, and calculation equations of CBF and CBV are developed also. Then NIRs Oximeter is used to monitor real-time data of CBF and CBV, one research path for non-invasive measurement of CBF and CBV characteristics is obtained. CBF and CBV changes at foreheads of 15 volunteers are monitoring under three conditions (be awaked from sleeping state, visual stimulation, aural stimulation). All the experimental results show that brain activity has a close relationship with cerebral local oxygen metabolism and hemodynamic variables like CBF, CBV, oxygen saturation of hemoglobin (SO <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> ), de-oxygenated hemoglobin concentration ([Hb]) oxy-hemoglobin concentration ([HbO <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> ]) and total hemoglobin concentration ([Hb <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">T</sub> ]). This noninvasive technique may be a powerful tool for brain functional research.

Changes in posture affect cerebral blood volume (CBV), and moderate head-up tilt is used as a therapeutic maneuver to reduce CBV and intracranial pressure. However, CBV is rarely measured in the clinical setting. Near-infrared spectroscopy allows real-time bedside monitoring of cerebral hemodynamics, and we have used this technique to measure changes in CBV with changes in posture in 10 normal subjects and 10 propofol-anesthetized patients. In the awake subjects, changes in CBV were correlated with the degree of table tilt. CBV decreased with 18 degrees head-up tilt and increased with 18 degrees head-down tilt (P < 0.0001, r = -0.924). In anesthetized patients, there were differences between head-up and head-down tilt. In the head-down position, CBV was also correlated with the degree of table tilt (P < 0.001, r = -0.782), whereas there was a clinically insignificant reduction in CBV in the head-up position. Near-infrared spectroscopy allows continuous, real time measurement of changes in CBV at the bedside. Near-infrared spectroscopy, a bedside technique, has been used to measure changes in cerebral blood volume in normal subjects. We have used the same technique in anesthetized patients and have shown that, when a patient is placed in the head up position, the decrease in cerebral blood volume is attenuated, relative to normal subjects.

O131 Non-invasive, multimodal analysis of cortical activity, blood volume and neurovascular coupling in infantile spasms using EEG-FNIRS monitoring

To study the behavior of cerebral physiological parameters and to further the understanding of the functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent (BOLD) effect, multisource frequency-domain near-infrared and BOLD fMRI signals were recorded simultaneously during motor functional activation in humans. From the near-infrared data information was obtained on the changes in cerebral blood volume and oxygenation. To relate our observations to changes in cerebral blood flow the well-known “balloon” model was employed. Our data showed that the deoxyhemoglobin concentration is the major factor determining the time course of the BOLD signal. The increase in cerebral blood oxygenation during functional activation is due to an increase in the velocity of blood flow, and occurs without significant swelling of the blood vessels.

Although perfusion-weighted imaging techniques are increasingly used to study stroke, no particular hemodynamic variable has emerged as a standard marker for accumulated ischemic damage. To better characterize the hemodynamic signature of infarction. the authors have assessed the severity and temporal evolution of ischemic hemodynamics in a middle cerebral artery occlusion model in the rat. Cerebral blood flow (CBF) and total and microvascular cerebral blood volume (CBV) changes were measured with arterial spin labeling and steady-state susceptibility contrast magnetic resonance imaging (MRI), respectively, and analyzed in regions corresponding to infarcted and spared ipsilateral tissue, based on 2,3,5-triphenyltetrazolium chloride histology sections after 24 hours ischemia. Spin echo susceptibility contrast was used to measure microvascular-weighted CBV, which had a maximum sensitivity for vessels with radii between 4 and 30 microm. Serial measurements between 1 and 3 hours after occlusion showed no change in CBF (22 +/- 20% of contralateral, mean +/- SD) or in total CBV (78 +/- 13% of contralateral) in regions destined to infarct. However, microvascular CBV progressively declined from 72 +/- 5% to 64 +/- 11% (P < 0.01) during this same period. Microvascular CBV changes with time were entirely due to decreases in subcortical infarcted zones (from 73 +/- 9% to 57 +/- 14%. P < 0.001) without changes in the cortical infarcted territory. The hemodynamic variables showed differences in magnitude and temporal response, and these changes varied based on histologic outcome and brain architecture. Such factors should be considered when designing imaging studies for human stroke.

Quantitative measurement of cerebral physiology using respiratory-calibrated MRI

Feasibility of functional MRI at ultralow magnetic field via changes in cerebral blood volume

We have shown previously that blood sampling via umbilical artery catheters decreases cerebral oxygenation and cerebral blood volume in preterm infants. To evaluate alternative methods, we assessed the effects of blood sampling via umbilical vein catheters in a cohort of preterm infants. Twenty neonates (median birth weight 900 g [range 410-1900 g], median gestational age 27 weeks [24-31 weeks]) were studied during routine blood sampling via umbilical vein catheters by near-infrared spectroscopy. Tissue oxygenation index and changes in concentrations of cerebral oxygenated and deoxygenated haemoglobin were measured and changes in cerebral oxygenation and cerebral blood volume were calculated. Oxygen saturation and heart rate were recorded simultaneously. There was a significant drop of cerebral oxygenation (-2.135 +/- 0.532 micromol/L) and cerebral blood volume (-0.037 +/- 0.019 mL/100 g tissue) during umbilical vein blood sampling. Although peripheral arterial oxygen saturation remained unchanged, cerebral tissue oxygenation index decreased from 64.8 +/- 2.5% to 62.4 +/- 2.6% (p < 0.01), accompanied by a slight increase in heart rate (from 140 +/- 2.9 to 144 +/- 2.9 beats/min, p < 0.01). Umbilical vein blood sampling reduces cerebral oxygenation and cerebral blood volume. The magnitude of the effects is similar to those during umbilical artery blood sampling.

To investigate changes in cerebral blood volume during standing in healthy children with or without abnormal cardiovascular responses. We studied 53 children (age, 10-15 years). Cerebral oxygenated haemoglobin (oxy-Hb) and deoxygenated Hb (deoxy-Hb) were non-invasively and continuously measured using near-infrared spectroscopy (NIRS) (NIRO 300, Hamamatsu Photomedics, Shizuoka, Japan) during active standing. Beat-to-beat arterial pressure was monitored by Portapres. Of 49 children with complete data acquisition, 33 had a normal cardiovascular response to the test (Group I) and 16 showed an abnormal response (Group II); nine with instantaneous orthostatic hypotension, three with postural tachycardia syndrome, three with neutrally mediated syncope and one with delayed orthostatic hypotension. At the onset of standing, Group II showed a significantly larger fall of oxy-Hb than Group I did (-2.9 +/- 2.8 micromol/L vs. -6.4 +/- 7.2 micromol/L, respectively, p < 0.05). During min 1 to 7 of standing, with one exception, changes in oxy-Hb were normally distributed over the level of -4 micromol/L in Group I. Group II also showed a significantly marked decrease in oxy-Hb compared to Group I. Decreases in oxy-Hb were not correlated with blood pressure changes. This study shows that precise change in cerebral blood volume caused by orthostatic stress can be determined by NIRS in children in a quantitative manner of NIRS. Children with abnormal circulatory responses to standing showed a significant reduction of oxy-Hb compared with normal counterparts, suggesting impairment of cerebral autoregulation in these children.

Patients with traumatic brain injury (TBI) are characterized by premature fatigue that may be related to their low aerobic capacity and reduced cortical activation. Near infrared spectroscopy (NIRS) is a valid, noninvasive technique for determining cerebral oxygenation (Cox) and blood volume (Cbv) during exercise. An increase in Cox and Cbv measured by NIRS is reflective of increased cortical activation. PURPOSE: To examine the inter-relationships among the peak values of the power output, oxygen uptake (peak VO2), Cox and Cbv during incremental cycle exercise to voluntary fatigue in patients with TBI. METHODS: Twenty-one inpatients (17 males, 4 females) with TBI from a rehabilitation center consented to perform a symptom limited incremental exercise test to voluntary fatigue. Cardiorespiratory responses were continuously monitored using an automated metabolic measurement cart (Vmax, Sensormedics, CA) interfaced with an electro-cardiogram. NIRS was used to continuosuly record Cox and Cbv from both the frontal lobes using a dual wave-length instrument (MicroRunman, NIM Inc., PA). Data were averaged over 20 sec intervals for statistical analysis. RESULTS: Regression analysis indicated that oxygen uptake and heart rate increased linearly with work rate while Cox and Cbv increased in a curvilinear manner. Patients attained a peak heart rate that corresponded to 76% of their age predicted maximum heart rate (220 - age), indicating an inability to fully tax their cardiovascular system. The peak values of power (86.4 ± 59.4 Watts), VO2 (20.5 ± 8.1 ml/kg/min) and O2 pulse (11.0 ± 5.3 ml/beat) were considerably lower than those reported for healthy individuals matched for age and gender. A significant (P < .05) relationship was observed between peak power vs absolute peak VO2 (r = 0.76) and relative peak VO2 (r = 0.72). In general, stronger correlations were observed between the hemodynamic variables on the left side and the peak power and peak oxygen uptake as compared to the right side. However, only Cbv on the left side was significantly related to the peak power output (r = 0.51), absolute peak VO2 (r = 0.61) and relative peak VO2 (r = 0.54). CONCLUSIONS: These findings suggest that changes in cerebral blood volume in the left frontal lobe may play an important role in determining the peak exercise capacity in patients with TBI. Support: Alberta Heritage Foundation for Medical

Studying brain-wide hemodynamic responses to different stimuli at high spatiotemporal resolutions can help gain new insights into the mechanisms of neuro- diseases and -disorders. Nonetheless, this task is challenging, primarily due to the complexity of neurovascular coupling, which encompasses interdependent hemodynamic parameters including cerebral blood volume (CBV), cerebral blood flow (CBF), and cerebral oxygen saturation (SO2). The current brain imaging technologies exhibit inherent limitations in resolution, sensitivity, and imaging depth, restricting their capacity to comprehensively capture the intricacies of cerebral functions. To address this, a multimodal functional ultrasound and photoacoustic (fUSPA) imaging platform is reported, which integrates ultrafast ultrasound and multispectral photoacoustic imaging methods in a compact head-mountable device, to quantitatively map individual dynamics of CBV, CBF, and SO2 as well as contrast agent enhanced brain imaging at high spatiotemporal resolutions. Following systematic characterization, the fUSPA system is applied to study brain-wide cerebrovascular reactivity (CVR) at single-vessel resolution via relative changes in CBV, CBF, and SO2 in response to hypercapnia stimulation. These results show that cortical veins and arteries exhibit differences in CVR in the stimulated state and consistent anti-correlation in CBV oscillations during the resting state, demonstrating the multiparametric fUSPA system's unique capabilities in investigating complex mechanisms of brain functions.

We reviewed the literature on human cerebral circulation and oxygen metabolism, as measured by positron emission tomography (PET), with respect to normal values and of regulation of cerebral circulation. A multicenter study in Japan showed that between-center variations in cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) values were not considerably larger than the corresponding within-center variations. Overall mean +/- SD values in cerebral cortical regions of normal human subjects were as follows: CBF = 44.4 +/- 6.5 ml/100 ml/min; CBV = 3.8 +/- 0.7 ml/100 ml; OEF = 0.44 +/- 0.06; CMRO2 = 3.3 +/- 0.5 ml/100 ml/min (11 PET centers, 70 subjects). Intrinsic regulation of cerebral circulation involves several factors. Autoregulation maintains CBF in response to changes in cerebral perfusion pressure; chemical factors such as PaCO2 affect cerebral vascular tone and alter CBF; changes in neural activity cause changes in cerebral energy metabolism and CBF; neurogenic control of CBF occurs by sympathetic innervation. Regional differences in vascular response to changes in PaCO2 have been reported, indicating regional differences in cerebral vascular tone. Relations between CBF and CBV during changes in PaCO2 and during changes in neural activity were in good agreement with Poiseuille's law. The mechanisms of vascular response to neural activation and deactivation were independent on those of responses to PaCO2 changes. CBV in a brain region is the sum of three components: arterial, capillary and venous blood volumes. It has been reported that the arterial blood volume fraction is approximately 30% in humans and that changes in human CBV during changes in PaCO2 are caused by changes in arterial blood volume without changes in venous blood volume. These findings should be considered in future studies of the pathophysiology of cerebrovascular diseases.

Acute mountain sickness (AMS) and high-altitude cerebral edema share common clinical characteristics, suggesting cerebral swelling may be an important factor in the pathophysiology of AMS. Hypoxia and hypocapnia associated with high altitude are known to exert strong effects on the control of the cerebral circulation, yet how these effects interact during acute hypoxia, and whether AMS-susceptible subjects may have a unique response, is still unclear. To test if self-identified AMS-susceptible individuals show altered brain swelling in response to acute hypoxia, we used quantitative arterial spin-labeling and volumetric MRI to measure cerebral blood flow and cerebrospinal fluid (CSF) volume changes during 40 min of acute hypoxia. We estimated changes in cerebral blood volume (CBV) (from changes in cerebral blood flow) and brain parenchyma swelling (from changes in CBV and CSF). Subjects with extensive high-altitude experience in two groups participated: self-identified AMS-susceptible (n = 6), who invariably experienced AMS at altitude, and self-identified AMS-resistant (n = 6), who almost never experienced symptoms. During 40-min hypoxia, intracranial CSF volume decreased significantly [-10.5 ml (SD 6.9), P < 0.001]. There were significant increases in CBV [+2.3 ml (SD 2.5), P < 0.005] and brain parenchyma volume [+8.2 ml (SD 6.4), P < 0.001]. However, there was no significant difference between self-identified AMS-susceptible and AMS-resistant groups for these acute-phase changes. In acute hypoxia, brain swelling occurs earlier than previously described, with significant shifts in intracranial CSF occurring as early as 40 min after exposure. These acute-phase changes are present in all individuals, irrespective of susceptibility to AMS.