Hemispheric asymmetry in cerebrovascular reactivity of the human primary motor cortex: an in vivo study at 7 T

Current functional MRI (fMRI) approaches assess underlying neuronal activity through monitoring the related local variations in cerebral blood oxygenation, blood volume and blood flow. This vascular response is likely to vary across brain regions and across individuals, depending on the composition of the local vascular bed and on the vascular capacity to dilate. The most widely used technique uses the blood oxygen level dependent (BOLD) fMRI signal, which arises from a complex combination of all of these factors. The model of handedness provides a case where one brain region (dominant motor cortex) is known to have a stronger BOLD response over another (non‐dominant motor cortex) during hand motor task performance. We predict that this is accompanied by a higher vascular reactivity in the dominant motor cortex, when compared with the non‐dominant motor cortex. Precise measurement of end‐tidal CO₂ and a novel sinusoidal CO₂ respiratory challenge were combined with the high sensitivity and finer spatial resolution available for fMRI at 7 T to measure BOLD cerebrovascular reactivity (CVR) in eight healthy male participants. BOLD CVR was compared between the left (dominant) and right (non‐dominant) primary motor cortices of right‐handed adults. Hemispheric asymmetry in vascular reactivity was predicted and observed in the primary motor cortex (left CVR = 0.60 ± 0.15%/mm Hg; right CVR = 0.47 ± 0.08%/mm Hg; left CVR > right CVR, P = 0.04), the first reported evidence of such a vascular difference. These findings demonstrate a cerebral vascular asymmetry between the left and right primary motor cortex. The origin of this asymmetry largely arises from the contribution of large draining veins. This work has implications for future motor laterality studies that use BOLD, and it is also suggestive of a vascular plasticity in the human primary motor cortex. Copyright © 2015 John Wiley & Sons, Ltd.     

Time‐efficient measurement of multi‐phase arterial spin labeling MR signal in white matter

White matter (WM) perfusion has great potential as a physiological biomarker in many neurological diseases. Although it has been demonstrated previously that arterial spin labeling magnetic resonance imaging (ASL‐MRI) enables the detection of the perfusion‐weighted signal in most voxels in WM, studies of cerebral blood flow (CBF) in WM by ASL‐MRI are relatively scarce because of its particular challenges, such as significantly lower perfusion and longer arterial transit times relative to gray matter (GM). Recently, ASL with a spectroscopic readout has been proposed to enhance the sensitivity for the measurement of WM perfusion. However, this approach suffers from long acquisition times, especially when acquiring multi‐phase ASL datasets to improve CBF quantification. Furthermore, the potential increase in the signal‐to‐noise ratio (SNR) by spectroscopic readout compared with echo planar imaging (EPI) readout has not been proven experimentally. In this study, we propose the use of time‐encoded pseudo‐continuous ASL (te‐pCASL) with single‐voxel point‐resolved spectroscopy (PRESS) readout to quantify WM cerebral perfusion in a more time‐efficient manner. Results are compared with te‐pCASL with a conventional EPI readout for both WM and GM perfusion measurements. Perfusion measurements by te‐pCASL PRESS and conventional EPI showed no significant difference for quantitative WM CBF values (Student's t‐test, p = 0.19) or temporal SNR (p = 0.33 and p = 0.81 for GM and WM, respectively), whereas GM CBF values (p = 0.016) were higher using PRESS than EPI readout. WM CBF values were found to be 18.2 ± 7.6 mL/100 g/min (PRESS) and 12.5 ± 5.5 mL/100 g/min (EPI), whereas GM CBF values were found to be 77.1 ± 11.2 mL/100 g/min (PRESS) and 53.6 ± 9.6 mL/100 g/min (EPI). This study demonstrates the feasibility of te‐pCASL PRESS for the quantification of WM perfusion changes in a highly time‐efficient manner, but it does not result in improved temporal SNR, as does traditional te‐pCASL EPI, which remains the preferred option because of its flexibility in use.     

On the assessment of cerebrovascular reactivity using hypercapnia BOLD MRI

Cerebrovascular reactivity (CVR) reflects the capacity of blood vessels to dilate and is an important marker for brain vascular reserve. It may provide a useful addition to the traditional baseline blood flow measurement when assessing vascular factors in brain disorders. Blood‐oxygenation‐level‐dependent MRI under CO₂ inhalation offers a non‐invasive and quantitative means to estimate CVR in humans. In this study, we investigated several important methodological aspects of this technique with the goal of optimizing the experimental and data processing strategies for clinical use. Comparing 4 min of 5% CO₂ inhalation (less comfortable) to a 1 min inhalation (more comfortable) duration, it was found that the CVR values were 0.31 ± 0.05%/mmHg (N = 11) and 0.31 ± 0.08%/mmHg (N = 9), respectively, showing no significant differences between the two breathing paradigms. Therefore, the 1 min paradigm is recommended for future application studies for patient comfort and tolerability. Furthermore, we have found that end‐tidal CO₂ recording was useful for accurate quantification of CVR because it provided both timing and amplitude information regarding the input function to the brain vascular system, which can be subject‐dependent. Finally, we show that inter‐subject variations in CVR are of physiologic origin and affect the whole brain in a similar fashion. Based on this, it is proposed that relative CVR (normalized against the CVR of the whole brain or a reference tissue) may be a more sensitive biomarker than absolute CVR in clinical applications as it minimizes inter‐subject variations. With these technological optimizations, CVR mapping may become a useful method for studies of neurological and psychiatric diseases. Copyright © 2009 John Wiley & Sons, Ltd.     

Simultaneous multi‐slice (SMS) acquisition enhances the sensitivity of hemodynamic mapping using gas challenges

Hemodynamic mapping using gas inhalation has received increasing interest in recent years. Cerebrovascular reactivity (CVR), which reflects the ability of the brain vasculature to dilate in response to a vasoactive stimulus, can be measured by CO₂ inhalation with continuous acquisition of blood oxygen level‐dependent (BOLD) magnetic resonance images. Cerebral blood volume (CBV) can be measured by O₂ inhalation. These hemodynamic mapping methods are appealing because of their absence of gadolinium contrast agent, their ability to assess both baseline perfusion and vascular reserve, and their utility in calibrating the functional magnetic resonance imaging (fMRI) signal. However, like other functional and physiological indices, a major drawback of these measurements is their poor sensitivity and reliability. Simultaneous multi‐slice echo planar imaging (SMS EPI) is a fast imaging technology that allows the excitation and acquisition of multiple two‐dimensional slices simultaneously, and has been shown to enhance the sensitivity of several MRI applications. To our knowledge, the benefit of SMS in gas inhalation imaging has not been investigated. In this work, we compared the sensitivity of CO₂ and O₂ inhalation data collected using SMS factor 2 (SMS2) and SMS factor 3 (SMS3) with those collected using conventional EPI (SMS1). We showed that the sensitivity of SMS scans was significantly (p = 0.01) higher than that of conventional EPI, although no difference was found between SMS2 and SMS3 (p = 0.3). On a voxel‐wise level, approximately 20–30% of voxels in the brain showed a significant enhancement in sensitivity when using SMS compared with conventional EPI, with other voxels showing an increase, but not reaching statistical significance. When using SMS, the scan duration can be reduced by half, whilst maintaining the sensitivity of conventional EPI. The availability of a sensitive acquisition technique can further enhance the potential of gas inhalation MRI in clinical applications.     

Errors in 1H‐MRS estimates of brain metabolite concentrations caused by failing to take into account tissue‐specific signal relaxation

Accurate measurement of brain metabolite concentrations with proton magnetic resonance spectroscopy (¹H‐MRS) can be problematic because of large voxels with mixed tissue composition, requiring adjustment for differing relaxation rates in each tissue if absolute concentration estimates are desired. Adjusting for tissue‐specific metabolite signal relaxation, however, also requires a knowledge of the relative concentrations of the metabolite in gray (GM) and white (WM) matter, which are not known a priori. Expressions for the estimation of the molality and molarity of brain metabolites with ¹H‐MRS are extended to account for tissue‐specific relaxation of the metabolite signals and examined under different assumptions with simulated and real data. Although the modified equations have two unknowns, and hence are unsolvable explicitly, they are nonetheless useful for the estimation of the effect of tissue‐specific metabolite relaxation rates on concentration estimates under a range of assumptions and experimental parameters using simulated and real data. In simulated data using reported GM and WM T₁ and T₂ times for N‐acetylaspartate (NAA) at 3 T and a hypothetical GM/WM NAA ratio, errors of 6.5–7.8% in concentrations resulted when TR = 1.5 s and TE = 0.144 s, but were reduced to less than 0.5% when TR = 6 s and TE = 0.006 s. In real data obtained at TR/TE = 1.5 s/0.04 s, the difference in the results (4%) was similar to that obtained with simulated data when assuming tissue‐specific relaxation times rather than GM–WM‐averaged times. Using the expressions introduced in this article, these results can be extrapolated to any metabolite or set of assumptions regarding tissue‐specific relaxation. Furthermore, although serving to bound the problem, this work underscores the challenge of correcting for relaxation effects, given that relaxation times are generally not known and impractical to measure in most studies. To minimize such effects, the data should be acquired with pulse sequence parameters that minimize the effect of signal relaxation.     

Bi‐exponential 23Na T2* component analysis in the human brain

The purpose of this study was to measure the sodium transverse relaxation time T₂* in the healthy human brain. Five healthy subjects were scanned with 18 echo times (TEs) as short as 0.17 ms. T₂* values were fitted on a voxel‐by‐voxel basis using a bi‐exponential model. Data were also analysed using a continuous distribution fit with a region of interest‐based inverse Laplace transform. Average T₂* values were 3.4 ± 0.2 ms and 23.5 ± 1.8 ms in white matter (WM) for the short and long components, respectively, and 3.9 ± 0.5 ms and 26.3 ± 2.6 ms in grey matter (GM) for the short and long components, respectively, using the bi‐exponential model. Continuous distribution fits yielded results of 3.1 ± 0.3 ms and 18.8 ± 3.2 ms in WM for the short and long components, respectively, and 2.9 ± 0.4 ms and 17.2 ± 2 ms in GM for the short and long components, respectively. ²³Na T₂* values of the brain for the short and long components for various anatomical locations using ultra‐short TEs are presented for the first time.     

Medial frontal and dorsal cortical morphometric abnormalities are related to obsessive-compulsive disorder

Whole-brain voxel-based morphometry (VBM) studies provide support for orbitofrontal, medial frontal as well as for dorsal cortical volumetric alteration in obsessive-compulsive disorder (OCD). However, there is still a need to replicate a priori unpredicted findings and to elucidate white matter volumetric abnormalities and relationships between grey (GM) and white (WM) matter volume and clinical characteristics of OCD. We compared GM and WM volume in a group of 14 patients with OCD and 15 healthy controls using a 3 T MRI scanner and an optimized VBM protocol. Regression analysis was used to examine relationships between GM and WM volume and clinical variables. In OCD we have found total WM volume reduction and marked mediofrontal, right temporo-parieto-occipital, right precentral, left middle temporal, left cerebellar and bilateral pons and mesencephalon GM volume reduction in the voxel-based analysis (p ≤ 0.05, FDR corrected, extent threshold 100 voxels). Regression analysis indicated a positive relationship between left orbitofrontal GM volume and severity of obsessive-compulsive symptoms and a negative relationship between symptom severity and GM volume in supramarginal gyri. Earlier age of OCD onset and longer illness duration were associated with smaller left occipital GM and right parietal WM and with greater left medial frontal GM and left frontal WM (p ≤ 0.001, uncorrected, extent threshold 50 voxels). Our results confirm volumetric abnormalities in the medial frontal and dorsal cortical areas in OCD. The relationships between OCD and clinical variables provide further evidence that frontal, parietal and occipital structures play a role in the disorder.     

Global gray and white matter metabolic changes after simian immunodeficiency virus infection in CD8‐depleted rhesus macaques: proton MRS imaging at 3 T

To test the hypotheses that global decreased neuro‐axonal integrity reflected by decreased N‐acetylaspartate (NAA) and increased glial activation reflected by an elevation in its marker, the myo‐inositol (mI), present in a CD8‐depleted rhesus macaque model of HIV‐associated neurocognitive disorders. To this end, we performed quantitative MRI and 16 × 16 × 4 multivoxel proton MRS imaging (TE/TR = 33/1400 ms) in five macaques pre‐ and 4–6 weeks post‐simian immunodeficiency virus infection. Absolute NAA, creatine, choline (Cho), and mI concentrations, gray and white matter (GM and WM) and cerebrospinal fluid fractions were obtained. Global GM and WM concentrations were estimated from 224 voxels (at 0.125 cm³ spatial resolution over ~35% of the brain) using linear regression. Pre‐ to post‐infection global WM NAA declined 8%: 6.6 ± 0.4 to 6.0 ± 0.5 mM (p = 0.05); GM Cho declined 20%: 1.3 ± 0.2 to 1.0 ± 0.1 mM (p < 0.003); global mI increased 11%: 5.7 ± 0.4 to 6.5 ± 0.5 mM (p < 0.03). Global GM and WM brain volume fraction changes were statistically insignificant. These metabolic changes are consistent with global WM (axonal) injury and glial activation, and suggest a possible GM host immune response. Copyright © 2013 John Wiley & Sons, Ltd.     

Optimization of inhomogeneous magnetization transfer (ihMT) MRI contrast for preclinical studies using dipolar relaxation time (T1D) filtering

A pulsed inhomogeneous magnetization transfer (ihMT)‐prepared fast imaging sequence was implemented at 11.75 T for preclinical studies on mouse central nervous system. A strategy based on filtering the ihMT signal originating from short dipolar relaxation time (T_1D) components is proposed. It involves increasing the repetition time of consecutive radiofrequency (RF) pulses of the dual saturation and allows improved signal specificity for long T_1D myelinated structures. Furthermore, frequency offset, power and timing saturation parameters were adjusted to optimize the ihMT sensitivity. The optimization of the ihMT sensitivity, whilst preserving the strong specificity for the long T_1D component of myelinated tissues, allowed measurements of ihMT ratios on the order of 4–5% in white matter (WM), 2.5% in gray matter (GM) and 1–1.3% in muscle. This led to high relative ihMT contrasts between myelinated tissues and others (~3–4 between WM and muscle, and ≥2 between GM and muscle). Conversely, higher ihMT ratios (~6–7% in WM) could be obtained using minimal T_1D filtering achieved with short saturation pulse repetition time or cosine‐modulated pulses for the dual‐frequency saturation. This study represents a first stage in the process of validating ihMT as a myelin biomarker by providing optimized ihMT preclinical sequences, directly transposable and applicable to other preclinical magnetic fields and scanners. Finally, ihMT ratios measured in various central nervous system areas are provided for future reference.     

Cardiac vagal withdrawal and reactivation during repeated rest–exercise transitions

It is not known whether subjects that have higher cardiac vagal reactivation (CVR) during repeated exercise transitions also have higher cardiac vagal withdrawal (CVW) at the onset of exercise, which would lead to better heart rate (HR) regulation during exercise transitions. Therefore, our aims were to investigate: (a) the influence of CVR on CVW during repeated rest–exercise transitions; and (b) the influence of the sympathetic activity on CVR and CVW. Fifty-eight healthy men (22 ± 4 years) performed 20 rest–exercise transitions interspaced by 30 s. In addition, nine healthy men (24 ± 3 years) ingested either 25 mg of atenolol or placebo, on a crossover, double-blind, randomized design, then performed 20 rest–exercise transitions interspaced by 30 s. Cardiac vagal reactivation was assessed by a HR variability index (RMSSD) and CVW by the HR increase at the onset of a valid and reliable cycling protocol. The CVR and CVW responses were associated (partial r ranged from 0.60 to 0.66; p < 0.05). Participants with higher CVR over transitions maintained their CVW over repeated transitions [first transition (mean ± SEM) = 1.59 ± 0.04 vs. 20th = 1.50 ± 0.03 (a.u.), p = 0.24], while participants with lower CVR had a CVW decrease over repeated transitions [first transition (mean ± SEM) = 1.38 ± 0.04 vs. 20th = 1.19 ± 0.03 (a.u.), p < 0.01). In addition, the CVR and CVW over the rest–exercise transitions were similar during atenolol and placebo (ANCOVA interaction p = 0.12 and p = 0.48, respectively). In conclusion, the CVR among repeated rest–exercise transitions influenced the CVW at the onset of exercise, which was not affected by a partial β₁ cardioselective adrenoceptor blockade.     

Forebrain-dominant deficit in cerebrovascular reactivity in Alzheimer's disease

Epidemiologic evidence and postmortem studies of cerebral amyloid angiopathy suggest that vascular dysfunction may play an important role in the pathogenesis of Alzheimer's disease (AD). However, alterations in vascular function under in vivo conditions are poorly understood. In this study, we assessed cerebrovascular-reactivity (CVR) in AD patients and age-matched controls using CO₂-inhalation while simultaneously acquiring Blood-Oxygenation-Level-Dependent (BOLD) MR images. Compared with controls, AD patients had widespread reduction in CVR in the rostral brain including prefrontal, anterior cingulate, and insular cortex (p < 0.01). The deficits could not be explained by cardiovascular risk factors. The spatial distribution of the CVR deficits differed drastically from the regions of cerebral blood flow (CBF) deficits, which were found in temporal and parietal cortices. Individuals with greater CVR deficit tended to have a greater volume of leukoaraiosis as seen on FLAIR MRI (p = 0.004). Our data suggest that early AD subjects have evidence of significant forebrain vascular contractility deficits. The localization, while differing from CBF findings, appears to be spatially similar to PIB amyloid imaging findings.     

Post‐contractile BOLD contrast in skeletal muscle at 7 T reveals inter‐individual heterogeneity in the physiological responses to muscle contraction

Muscle blood oxygenation‐level dependent (BOLD) contrast is greater in magnitude and potentially more influenced by extravascular BOLD mechanisms at 7 T than it is at lower field strengths. Muscle BOLD imaging of muscle contractions at 7 T could, therefore, provide greater or different contrast than at 3 T. The purpose of this study was to evaluate the feasibility of using BOLD imaging at 7 T to assess the physiological responses to in vivo muscle contractions. Thirteen subjects (four females) performed a series of isometric contractions of the calf muscles while being scanned in a Philips Achieva 7 T human imager. Following 2 s maximal isometric plantarflexion contractions, BOLD signal transients ranging from 0.3 to 7.0% of the pre‐contraction signal intensity were observed in the soleus muscle. We observed considerable inter‐subject variability in both the magnitude and time course of the muscle BOLD signal. A subset of subjects (n = 7) repeated the contraction protocol at two different repetition times (T_R: 1000 and 2500 ms) to determine the potential of T₁‐related inflow effects on the magnitude of the post‐contractile BOLD response. Consistent with previous reports, there was no difference in the magnitude of the responses for the two T_R values (3.8 ± 0.9 versus 4.0 ± 0.6% for T_R = 1000 and 2500 ms, respectively; mean ± standard error). These results demonstrate that studies of the muscle BOLD responses to contractions are feasible at 7 T. Compared with studies at lower field strengths, post‐contractile 7 T muscle BOLD contrast may afford greater insight into microvascular function and dysfunction.     

Measurement of regional variation of GABA in the human brain by optimized point‐resolved spectroscopy at 7 T in vivo

The ¹H resonances of γ‐aminobutyric acid (GABA) in the human brain in vivo are extensively overlapped with the neighboring abundant resonances of other metabolites and remain indiscernible in short‐TE MRS at 7 T. Here we report that the GABA resonance at 2.28 ppm can be fully resolved by means of echo time optimization of a point‐resolved spectroscopy (PRESS) scheme. Following numerical simulations and phantom validation, the subecho times of PRESS were optimized at (TE, TE₂) = (31, 61) ms for detection of GABA, glutamate (Glu), glutamine (Gln), and glutathione (GSH). The in vivo feasibility of the method was tested in several brain regions in nine healthy subjects. Spectra were acquired from the medial prefrontal, left frontal, medial occipital, and left occipital brain and analyzed with LCModel. Following the gray and white matter (GM and WM) segmentation of T₁‐weighted images, linear regression of metabolite estimates was performed against the fractional GM contents. The GABA concentration was estimated to be about seven times higher in GM than in WM. GABA was overall higher in frontal than in occipital brain. Glu was about twice as high in GM as in WM in both frontal and occipital brain. Gln was significantly different between frontal GM and WM while being similar between occipital GM and WM. GSH did not show significant dependence on tissue content. The signals from N‐acetylaspartylglutamate were clearly resolved, giving the concentration more than 10 times higher in WM than in GM. Our data indicate that the PRESS TE = 92 ms method provides an effective means for measuring GABA and several challenging J‐coupled spin metabolites in human brain at 7 T. Copyright © 2014 John Wiley & Sons, Ltd.     

The role of gray and white matter segmentation in quantitative proton MR spectroscopic imaging

Since the brain's gray matter (GM) and white matter (WM) metabolite concentrations differ, their partial volumes can vary the voxel's ¹H MR spectroscopy (¹H‐MRS) signal, reducing sensitivity to changes. While single‐voxel ¹H‐MRS cannot differentiate between WM and GM signals, partial volume correction is feasible by MR spectroscopic imaging (MRSI) using segmentation of the MRI acquired for VOI placement. To determine the magnitude of this effect on metabolic quantification, we segmented a 1‐mm³ resolution MRI into GM, WM and CSF masks that were co‐registered with the MRSI grid to yield their partial volumes in approximately every 1 cm³ spectroscopic voxel. Each voxel then provided one equation with two unknowns: its i‐ metabolite's GM and WM concentrations C_i^GM, C_i^WM. With the voxels' GM and WM volumes as independent coefficients, the over‐determined system of equations was solved for the global averaged C_i^GM and C_i^WM. Trading off local concentration differences offers three advantages: (i) higher sensitivity due to combined data from many voxels; (ii) improved specificity to WM versus GM changes; and (iii) reduced susceptibility to partial volume effects. These improvements made no additional demands on the protocol, measurement time or hardware. Applying this approach to 18 volunteered 3D MRSI sets of 480 voxels each yielded N‐acetylaspartate, creatine, choline and myo‐inositol C_i^GM concentrations of 8.5 ± 0.7, 6.9 ± 0.6, 1.2 ± 0.2, 5.3 ± 0.6mM, respectively, and C_i^WM concentrations of 7.7 ± 0.6, 4.9 ± 0.5, 1.4 ± 0.1 and 4.4 ± 0.6mM, respectively. We showed that unaccounted voxel WM or GM partial volume can vary absolute quantification by 5–10% (more for ratios), which can often double the sample size required to establish statistical significance. Copyright © 2012 John Wiley & Sons, Ltd.     

Effect of hyperventilation and prior heavy exercise on O2 uptake and muscle deoxygenation kinetics during transitions to moderate exercise

The effect of hyperventilation-induced hypocapnic alkalosis (HYPO) and prior heavy-intensity exercise (HVY) on pulmonary O₂ uptake ([(V)\dot]\textO _{2 \textp}) (\dot{V}{\text{O}}_{{ 2 {\text{p}}}}) kinetics were examined in young adults (n = 7) during moderate-intensity exercise (MOD). Subjects completed leg cycling exercise during (1) normal breathing (CON, P_ETCO₂ ~ 40 mmHg) and (2) controlled hyperventilation (HYPO, P_ETCO₂ ~ 20 mmHg) throughout the protocol, with each condition repeated on four occasions. The protocol consisted of two MOD transitions (MOD1, MOD2) to 80% estimated lactate threshold with MOD2 preceded by HVY (Δ50%); each transition lasted 6 min and was preceded by 20 W cycling. [(V)\dot]\textO _{2 \textp} \dot{V}{\text{O}}_{{ 2 {\text{p}}}} was measured breath-by-breath and concentration changes in oxy- and deoxy-hemoglobin/myoglobin (Δ[HHb]) of the vastus lateralis muscle were measured by near-infrared spectroscopy. Adjustment of [(V)\dot]\textO _{2 \textp} \dot{V}{\text{O}}_{{ 2 {\text{p}}}} and Δ[HHb] were modeled using a mono-exponential equation by non-linear regression. During MOD1, the phase 2 time constant (τ) for [(V)\dot]\textO _{2 \textp}  (t[(V)\dot]\textO _{2 \textp} ) \dot{V}{\text{O}}_{{ 2 {\text{p}}}} \,(\tau \dot{V}{\text{O}}_{{ 2 {\text{p}}}} ) was greater (P < 0.05) in HYPO (45 ± 24 s) than CON (28 ± 17 s). During MOD2, t[(V)\dot]\textO _{2 \textp} \tau \dot{V}{\text{O}}_{{ 2 {\text{p}}}} was reduced (P < 0.05) in both conditions (HYPO: 24 ± 7 s, CON: 20 ± 8 s). The Δ[Hb_TOT] and Δ[O₂Hb] were greater (P < 0.05) prior to and throughout MOD2. The Δ[HHb] mean response time was similar in MOD1 and MOD2, and between conditions, however, the MOD1 Δ[HHb] amplitude was greater (P < 0.05) in HYPO compared to CON, with no differences between conditions in MOD2. These findings suggest that the speeding of [(V)\dot]\textO _{2 \textp} \dot{V}{\text{O}}_{{ 2 {\text{p}}}} kinetics after prior HVY in HYPO was related, in part, to an increase in microvascular perfusion.     

Simultaneous spin‐echo and gradient‐echo BOLD measurements by dynamic MRS

This study aimed to dissociate the intravascular and extravascular contributions to spin‐echo (SE) and gradient‐echo (GE) blood oxygenation level‐dependent (BOLD) signals at 7 T, using dynamic diffusion‐weighted MRS. We simultaneously acquired SE and GE data using a point‐resolved spectroscopy sequence with diffusion weightings of 0, 600, and 1200 s/mm². The BOLD signals were quantified by fitting the free induction decays starting from the SE center to a mono‐exponential decay function. Without diffusion weighting, BOLD signals measured with SE and GE increased by 1.6 ± 0.5% (TE_SE = 40 ms) and 5.2 ± 1.4% (nominal TE_GE = 40 ms) during stimulation, respectively. With diffusion weighting, the BOLD increase during stimulation measured with SE decreased from 1.6 ± 0.5% to 1.3 ± 0.4% (P < 0.001), whereas that measured by GE was unaffected (P > 0.05); the post‐stimulation undershoots in the BOLD signal time courses were largely preserved in both SE and GE measurements. These results demonstrated the feasiblity of simultaneous SE and GE measurements of BOLD signals with and without interleaved diffusion weighting. The results also indicated a predominant extravascular contribution to the BOLD signal time courses, including post‐stimulation undershoots in both SE and GE measurements at 7 T.     

Analysis of end-tidal and arterial PCO2 gradients using a breathing model

The aim of this paper was to analyse the difference between end-tidal carbon dioxide tension (P _ETCO₂) and arterial carbon dioxide tension (P _aCO₂) at rest and during exercise using a homogeneous lung model that simulates the cyclic feature of breathing. The model was a catenary two-compartment model that generated five non-linear first-order differential equations and two equations for gas exchange. The implemented mathematical modelling described variations in CO₂ and O₂ compartmental fractions and alveolar volume. The model also included pulmonary capillary gas exchange. Ventilatory experimental data were obtained from measurements performed on a subject at rest and during four 5-min bouts of exercise on a cycle ergometer at 50, 100, 150 and 200 W, respectively. Analysis of the P _ETCO₂-P _aCO₂ difference between experimental and sinusoidally adjusted ventilatory flow profiles at rest and during exercise showed that the model produced similar values in P _ETCO₂-P _aCO₂ for different respiratory flow dynamics (P ≅ 0.75). The model simulations allowed us to study the effects of metabolic, circulatory and respiratory parameters on P _ETCO₂-P _aCO₂ at rest and during exercise. During exercise, metabolic CO₂ production, O₂ uptake and cardiac output affected significantly the P _ETCO₂-P _aCO₂ difference from the 150-W workload (P < 0.001). The pattern of breathing had a significant effect on the P _ETCO₂-P _aCO₂ difference. The mean (SD) P _ETCO₂-P _aCO₂ differences simulated using experimental profiles were 0.80 (0.95), 1.65 (0.40), 2.40 (0.20), 3.30 (0.30) and 4.90 (0.20) mmHg, at rest and during exercise at 50, 100, 150 and 200 W, respectively. The relationship between P _ETCO₂-P _aCO₂ and tidal volume was similar to data published by Jones et al. (J Appl Physiol 47: 954–960, 1979). Accepted: 30 May 2000     

Precision and accuracy of diffusion kurtosis estimation and the influence of b‐value selection

Diffusion kurtosis imaging (DKI) is an extension of diffusion tensor imaging that accounts for leading non‐Gaussian diffusion effects. In DKI studies, a wide range of different gradient strengths (b‐values) is used, which is known to affect the estimated diffusivity and kurtosis parameters. Hence there is a need to assess the accuracy and precision of the estimated parameters as a function of b‐value. This work examines the error in the estimation of mean of the kurtosis tensor (MKT) with respect to the ground truth, using simulations based on a biophysical model for both gray (GM) and white (WM) matter. Model parameters are derived from densely sampled experimental data acquired in ex vivo rat brain and in vivo human brain. Additionally, the variability of MKT is studied using the experimental data. Prevalent fitting protocols are implemented and investigated. The results show strong dependence on the maximum b‐value of both net relative error and standard deviation of error for all of the employed fitting protocols. The choice of b‐values with minimum MKT estimation error and standard deviation of error was found to depend on the protocol type and the tissue. Protocols that utilize two terms of the cumulant expansion (DKI) were found to achieve minimum error in GM at b‐values less than 1 ms/μm², whereas maximal b‐values of about 2.5 ms/μm² were found to be optimal in WM. Protocols including additional higher order terms of the cumulant expansion were found to provide higher accuracy for the more commonly used b‐value regime in GM, but were associated with higher error in WM. Averaged over multiple voxels, a net average error of around 15% for both WM and GM was observed for the optimal b‐value choice. These results suggest caution when using DKI generated metrics for microstructural modeling and when comparing results obtained using different fitting techniques and b‐values.     

No effect of skin temperature on human ventilation response to hypercapnia during light exercise with a normothermic core temperature

Hyperthermia potentiates the influence of CO₂ on pulmonary ventilation ( [(V)\dot]_\textE \dot{V}_{\text{E}} ). It remains to be resolved how skin and core temperatures contribute to the elevated exercise ventilation response to CO₂. This study was conducted to assess the influences of mean skin temperature ( [`(T)]<sub>\textSK</sub> \overline{T}_{\text{SK}} ) and end-tidal PCO<sub>2</sub> (P<sub>ET</sub>CO<sub>2</sub>) on [(V)\dot]<sub>\textE</sub> \dot{V}_{\text{E}} during submaximal exercise with a normothermic esophageal temperature (T <sub>ES</sub>). Five males and three females who were 1.76 ± 0.11 m tall (mean ± SD), 75.8 ± 15.6 kg in weight and 22.0 ± 2.2 years of age performed three 1 h exercise trials in a climatic chamber with the relative humidity (RH) held at 31.5 ± 9.5% and the ambient temperature (T <sub>AMB</sub>) maintained at one of 25, 30, or 35°C. In each trial, the volunteer breathed eucapnic air for 5 min during a rest period and subsequently cycle ergometer exercised at 50 W until T <sub>ES</sub> stabilized at ~37.1 ± 0.4°C. Once T <sub>ES</sub> stabilized in each trial, the volunteer breathed hypercapnic air twice for ~5 min with P<sub>ET</sub>CO<sub>2</sub> elevated by approximately +4 or +7.5 mmHg. The significantly (P < 0.05) different increases of P<sub>ET</sub>CO<sub>2</sub> of +4.20 ± 0.49 and +7.40 ± 0.51 mmHg gave proportionately larger increases in [(V)\dot]<sub>\textE</sub> \dot{V}_{\text{E}} of 10.9 ± 3.6 and 15.2 ± 3.6 L min<sup>−1</sup> (P = 0.001). This hypercapnia-induced hyperventilation was uninfluenced by varying the [`(T)]_\textSK \overline{T}_{\text{SK}} to three significantly different levels (P < 0.001) of 33.2 ± 1.2°C, to 34.5 ± 0.8°C to 36.4 ± 0.5°C. In conclusion, the results support that skin temperature between ~33 and ~36°C has neither effect on pulmonary ventilation nor on hypercapnia-induced hyperventilation during a light exercise with a normothermic core temperature.     

Quantification of γ‐aminobutyric acid (GABA) in 1H MRS volumes composed heterogeneously of grey and white matter

The quantification of γ‐aminobutyric acid (GABA) concentration using localised MRS suffers from partial volume effects related to differences in the intrinsic concentration of GABA in grey (GM) and white (WM) matter. These differences can be represented as a ratio between intrinsic GABA in GM and WM: r_M. Individual differences in GM tissue volume can therefore potentially drive apparent concentration differences. Here, a quantification method that corrects for these effects is formulated and empirically validated. Quantification using tissue water as an internal concentration reference has been described previously. Partial volume effects attributed to r_M can be accounted for by incorporating into this established method an additional multiplicative correction factor based on measured or literature values of r_M weighted by the proportion of GM and WM within tissue‐segmented MRS volumes. Simulations were performed to test the sensitivity of this correction using different assumptions of r_M taken from previous studies. The tissue correction method was then validated by applying it to an independent dataset of in vivo GABA measurements using an empirically measured value of r_M. It was shown that incorrect assumptions of r_M can lead to overcorrection and inflation of GABA concentration measurements quantified in volumes composed predominantly of WM. For the independent dataset, GABA concentration was linearly related to GM tissue volume when only the water signal was corrected for partial volume effects. Performing a full correction that additionally accounts for partial volume effects ascribed to r_M successfully removed this dependence. With an appropriate assumption of the ratio of intrinsic GABA concentration in GM and WM, GABA measurements can be corrected for partial volume effects, potentially leading to a reduction in between‐participant variance, increased power in statistical tests and better discriminability of true effects.