Application of calibrated fMRI in Alzheimer's disease.

Calibrated fMRI based on arterial spin-labeling (ASL) and blood oxygen-dependent contrast (BOLD), combined with periods of hypercapnia and hyperoxia, can provide information on cerebrovascular reactivity (CVR), resting blood flow (CBF), oxygen extraction fraction (OEF), and resting oxidative metabolism (CMRO2). Vascular and metabolic integrity are believed to be affected in Alzheimer's disease (AD), thus, the use of calibrated fMRI in AD may help understand the disease and monitor therapeutic responses in future clinical trials. In the present work, we applied a calibrated fMRI approach referred to as Quantitative O2 (QUO2) in a cohort of probable AD dementia and age-matched control participants. The resulting CBF, OEF and CMRO2 values fell within the range from previous studies using positron emission tomography (PET) with 15O labeling. Moreover, the typical parietotemporal pattern of hypoperfusion and hypometabolism in AD was observed, especially in the precuneus, a particularly vulnerable region. We detected no deficit in frontal CBF, nor in whole grey matter CVR, which supports the hypothesis that the effects observed were associated specifically with AD rather than generalized vascular disease. Some key pitfalls affecting both ASL and BOLD methods were encountered, such as prolonged arterial transit times (particularly in the occipital lobe), the presence of susceptibility artifacts obscuring medial temporal regions, and the challenges associated with the hypercapnic manipulation in AD patients and elderly participants. The present results are encouraging and demonstrate the promise of calibrated fMRI measurements as potential biomarkers in AD. Although CMRO2 can be imaged with 15O PET, the QUO2 method uses more widely available imaging infrastructure, avoids exposure to ionizing radiation, and integrates with other MRI-based measures of brain structure and function.

Differential modulation of descending signals from the reticulospinal system during reaching and locomotion.

We tested the hypothesis that the same spinal interneuronal pathways are activated by the reticulospinal system during locomotion and reaching. If such were the case, we expected that microstimulation within the pontomedullary reticular formation (PMRF) would evoke qualitatively similar responses in muscles active during both behaviors. To test this, we stimulated in 47 sites within the PMRF during both tasks. Stimulation during locomotion always produced a strongly phase-dependent, bilateral pattern of activity in which activity in muscles was generally facilitated or suppressed during one phase of activity (swing or stance) and was unaffected in the other. During reaching, stimulation generally activated the same muscles as during locomotion, although the modulation of the magnitude of the evoked responses was less limb dependent than during locomotion. An exception was found for some forelimb flexor muscles that were strongly facilitated by stimulation during the swing phase of locomotion but were not influenced by stimulation during the transport phase of the reach. We suggest that during locomotion the activity in interneuronal pathways mediating signals from the reticulospinal system is subject to strong modulation by the central pattern generator for locomotion. During reach, we suggest that, for most muscles, the same spinal interneuronal pathways are used to modify muscle activity but are not as strongly gated according to limb use as during locomotion. Finally, we propose that the command for movement during discrete voluntary movements suppresses the influence of the reticulospinal system on selected forelimb flexor muscles, possibly to enhance fractionated control of movement.

Sustained hyperaemia stimulus is necessary to induce flow-mediated dilation of the human brachial artery.

We studied the relative importance of the magnitude and duration of the shear stimulus to induce flow-mediated dilation (FMD) in the brachial artery of 10 healthy men by ultrasound imaging. The shear stress stimulus was induced by different durations of reactive hyperaemia following 15-min forearm occlusion. The control condition of continuous postocclusion hyperaemia was compared to 20, 40 and 60 s of reactive hyperaemia followed by reapplication of circulatory arrest for 2 min and a second cuff release. In response to the first cuff release, peak shear rate was not different between conditions; total shear during the first minute was reduced in the 40 s and further reduced in the 20 s conditions. FMD in control (10·0 ± 3·0%), 60 s (10·5 ± 3·2%) and 40 s (7·8 ± 3·6%) were greater than the 20-s condition (2·9 ± 2·8%). At second cuff release, peak shear of the 20-s condition was slightly reduced from the first release, but 40 and 60-s conditions were progressively reduced. Total shear to peak dilation was reduced after the second cuff release for the 20 and 40-s conditions and further after the 60-s condition. FMD was maintained in the 20-s condition (8·3 ± 3·7%) but reduced in the 40-s (3·7 ± 1·7%) and 60-s conditions (1·5 ± 2·6%). FMD was not related to peak shear rate after the first occlusion (r = 0·003) but was after the second cuff release (r = 0·32, P = 0·004). The FMD response was correlated with the total shear to time of peak diameter after the first (r = 0·35, P<0·001) and the second (r = 0·25, P = 0·009) cuff release.

Prolonged ischaemia impairs muscle blood flow and oxygen uptake dynamics during subsequent heavy exercise.

Muscle oxygen uptake ( ˙VO2,mus) dynamics at the onset of exercise can be affected by prior heavy exercise.We tested the hypothesis that elevated forearm blood flow (FBF) following prior circulatory occlusion would also be associated with accelerated ˙VO2,mus dynamics during subsequent heavy hand-grip exercise. Ten trained young men performed 5 min of heavy hand-grip exercise at 30% MVC as a control (CON), and four additional heavy bouts after brief recovery from: (1) prior heavy exercise (Heavy A), (2) heavy exercise followed by 2 min occlusion (Heavy B), (3) 15 min occlusion (Heavy C), and (4) 5 min occlusion with 1 min of moderate exercise during occlusion (Heavy D). FBF was measured by ultrasound and arterial venous oxygen content difference was calculated from venous blood samples to estimate ˙VO2,mus. FBF and ˙VO2,mus dynamics were quantified from the rise time. All priming conditions elevated FBF immediately before the start of subsequent heavy bout (Heavy A: 207.4 ±92.8, B: 207.8±75.8, C: 135.8±59.2, D: 199.5±59.0 vs. CON: 57.4±16.6mlmin−1, P <0.01). Unexpectedly, prior occlusion reduced FBF and O2 extraction at the onset of subsequent heavy exercise and consequently slowed ˙VO2,mus dynamics (Heavy C: rise time=95.9±28.9 vs. CON: 58.6±14.3 s, P <0.01). FBF and ˙VO2,mus dynamics were faster in Heavy A, B and D compared to CON (P <0.05). Overall, there was a positive correlation between the rise times for ˙VO2,mus and FBF (r² =0.75) indicating that ˙VO2,mus dynamics during heavy forearm exercise are linked to O2 delivery in trained young men. To investigate a possible mechanism for slower adaptation of ˙VO2,mus following ischaemia, the prior occlusion condition was repeated after ingesting a high dose of ibuprofen. This resulted in restoration of the FBF and ˙VO2,mus to control levels suggesting that a prostaglandin-mediated mechanism after occlusion retarded the adaptation of blood flow and oxygen consumption at the onset of subsequent heavy exercise.

Modelflow estimates of cardiac output compared with Doppler ultrasound during acute changes in vascular resistance in women.

We compared Modelflow (MF) estimates of cardiac stroke volume (SV) from the finger pressure-pulse waveform (Finometer) with pulsed Doppler ultrasound (DU) of the ascending aorta during acute changes in total peripheral resistance (TPR) in the supine and head-up-tilt (HUT) postures. Twenty-four women were tested during intravenous infusion of 0.005 or 0.01 microg kg(-1) min(-1) isoprenaline, 10 or 50 ng kg(-1) min(-1) noradrenaline and 0.3 mg sublingual nitroglycerine. Responses to static hand-grip exercise (SHG), graded lower body negative pressure (LBNP, from 20 to 45 mmHg) and 45 deg HUT were evaluated on separate days. Bland-Altman analysis indicated that SV(MF) yielded lower estimates than SV(DU) during infusion of 0.01 microg kg(-1) min(-1) isoprenaline (SV(MF) 92.7 +/- 15.5 versus SV(DU) 104.3 +/- 22.9 ml, P = 0.03) and SHG (SV(MF) 78.8 +/- 12.0 versus SV(DU) 106.1 +/- 28.5 ml, P < 0.01), while larger estimates were recorded with SV(MF) during 45 mmHg LBNP (SV(MF) 52.6 +/- 10.7 versus SV(DU) 46.2 +/- 14.5 ml, P = 0.04) and HUT (SV(MF) 59.3 +/- 13.6 versus SV(DU) 45.2 +/- 11.3 ml, P < 0.01). Linear regression analysis revealed a relationship (r(2) = 0.41, P < 0.01) between the change in TPR from baseline and the between-methods discrepancy in SV measurements. This relationship held up under all of the experimental protocols (regression for fixed effects, P = 0.46). These results revealed a discrepancy in MF estimates of SV, in comparison with those measured by DU, during acute changes in TPR.

Effect of acute sympathetic nervous system activation on flow-mediated dilation of brachial artery.

We tested the hypothesis that flow-mediated dilation (FMD) of the brachial artery would be impaired by acute increases in sympathetic nervous system activity (SNA) in models where similar peak shear stress stimulus was achieved by varying the duration of forearm muscle ischemia. Eleven healthy young men were studied under four different conditions, each with its own control: lower body suction (LBS), cold pressor test (CPT), mental arithmetic task (MAT), and activation of muscle chemoreflex (MCR). The duration of ischemia before observation of FMD by ultrasound imaging was 5 min each for control, LBS, and CPT; 3 min for MAT; and 2-min for MCR. Peak shear rate was not different between control and any of the SNA conditions, although total shear in the first minute was reduced in MAT. MCR was the only condition in which brachial artery vasoconstriction was observed before forearm occlusion [4.38 (SD 0.53) vs. control 4.60 (SD 0.53) mm, P < 0.05]; however, diameter increased to the same absolute value as that of the control, so the percent FMD was greater for MCR [9.85 (SD 2.33) vs. control 5.29 (SD 1.50)%]. Blunting of the FMD response occurred only in the CPT model [1.51 (SD 1.20)%]. During SNA, the increase in plasma cortisol from baseline was significant only for MCR; the increase in plasma norepinephrine was significant for MCR, LBS, and CPT; and the increase in epinephrine was significant only for MCR. These results showed that the four models employed to achieve increases in SNA had different effects on baseline brachial artery diameter and that blunted FMD is not a general response to increased SNA.