Dynamic multivoxel-localized 31 P MRS during plantar flexion exercise with variable knee angle.

Exercise studies investigating the metabolic response of calf muscles using 31 P MRS are usually performed with a single knee angle. However, during natural movement, the distribution of workload between the main contributors to force, gastrocnemius and soleus is influenced by the knee angle. Hence, it is of interest to measure the respective metabolic response of these muscles to exercise as a function of knee angle using localized spectroscopy. Time-resolved multivoxel 31 P MRS at 7 T was performed simultaneously in gastrocnemius medialis and soleus during rest, plantar flexion exercise and recovery in 12 healthy volunteers. This experiment was conducted with four different knee angles. PCr depletions correlated negatively with knee angle in gastrocnemius medialis, decreasing from 79±14 % (extended leg) to 35±23 %(∼40°), and positively in soleus, increasing from 20±21 % to 36±25 %; differences were significant. Linear correlations were found between knee angle and end-exercise PCr depletions in gastrocnemius medialis (R2 =0.8) and soleus (R2 =0.53). PCr recovery times and end-exercise pH changes that correlated with PCr depletion were consistent with the literature in gastrocnemius medialis and differences between knee angles were significant. These effects were less pronounced in soleus and not significant for comparable PCr depletions. Maximum oxidative capacity calculated for all knee angles was in excellent agreement with the literature and showed no significant changes between different knee angles. In conclusion, these findings confirm that plantar flexion exercise with a straight leg is a suitable paradigm, when data are acquired from gastrocnemius only (using either localized MRS or small surface coils), and that activation of soleus requires the knee to be flexed. The present study comprises a systematic investigation of the effects of the knee angle on metabolic parameters, measured with dynamic multivoxel 31 P MRS during muscle exercise and recovery, and the findings should be used in future study design.

Heme arginate improves reperfusion patterns after ischemia: a randomized, placebo-controlled trial in healthy male subjects.

BACKGROUND: Heme arginate can induce heme oxygenase-1 to protect tissue against ischemia-reperfusion injury. Blood oxygen level dependent (BOLD) functional magnetic resonance imaging measures changes in tissue oxygenation with a high spatial and temporal resolution. BOLD imaging was applied to test the effect of heme arginate on experimental ischemia reperfusion injury in the calf muscles. METHODS: A two period, controlled, observer blinded, crossover trial was performed in 12 healthy male subjects. Heme arginate (1 mg/kg body weight) or placebo were infused 24 h prior to a 20 min leg ischemia induced by a thigh cuff. 3 Tesla BOLD-imaging of the calf was performed and signal time courses from soleus, gastrocnemius and tibialis anterior muscle were available from 11 participants for technical reasons. RESULTS: Peak reactive hyperemia signal of the musculature was significantly increased and occurred earlier after heme arginate compared to placebo (106.2 ± 0.6% at 175 ± 16s vs. 104.5 ± 0.6% at 221 ± 19s; p = 0.025 for peak reperfusion and p = 0.012 for time to peak). CONCLUSIONS: A single high dose of heme arginate improves reperfusion patterns during ischemia reperfusion injury in humans. BOLD sensitive, functional MRI is applicable for the assessment of experimental ischemia reperfusion injury in skeletal muscle.

Comparing localized and nonlocalized dynamic 31P magnetic resonance spectroscopy in exercising muscle at 7 T.

By improving spatial and anatomical specificity, localized spectroscopy can enhance the power and accuracy of the quantitative analysis of cellular metabolism and bioenergetics. Localized and nonlocalized dynamic (31)P magnetic resonance spectroscopy using a surface coil was compared during aerobic exercise and recovery of human calf muscle. For localization, a short echo time single-voxel magnetic resonance spectroscopy sequence with adiabatic refocusing (semi-LASER) was applied, enabling the quantification of phosphocreatine, inorganic phosphate, and pH value in a single muscle (medial gastrocnemius) in single shots (T(R) = 6 s). All measurements were performed in a 7 T whole body scanner with a nonmagnetic ergometer. From a series of equal exercise bouts we conclude that: (a) with localization, measured phosphocreatine declines in exercise to a lower value (79 ± 7% cf. 53 ± 10%, P = 0.002), (b) phosphocreatine recovery shows shorter half time (t(1/2) = 34 ± 7 s cf. t(1/2) = 42 ± 7 s, nonsignificant) and initial postexercise phosphocreatine resynthesis rate is significantly higher (32 ± 5 mM/min cf. 17 ± 4 mM/min, P = 0.001) and (c) in contrast to nonlocalized (31)P magnetic resonance spectroscopy, no splitting of the inorganic phosphate peak is observed during exercise or recovery, just an increase in line width during exercise. This confirms the absence of contaminating signals originating from weaker-exercising muscle, while an observed inorganic phosphate line broadening most probably reflects variations across fibers in a single muscle.

A resting state network in the motor control circuit of the basal ganglia.

BACKGROUND: In the absence of overt stimuli, the brain shows correlated fluctuations in functionally related brain regions. Approximately ten largely independent resting state networks (RSNs) showing this behaviour have been documented to date. Recent studies have reported the existence of an RSN in the basal ganglia - albeit inconsistently and without the means to interpret its function. Using two large study groups with different resting state conditions and MR protocols, the reproducibility of the network across subjects, behavioural conditions and acquisition parameters is assessed. Independent Component Analysis (ICA), combined with novel analyses of temporal features, is applied to establish the basis of signal fluctuations in the network and its relation to other RSNs. Reference to prior probabilistic diffusion tractography work is used to identify the basal ganglia circuit to which these fluctuations correspond. RESULTS: An RSN is identified in the basal ganglia and thalamus, comprising the pallidum, putamen, subthalamic nucleus and substantia nigra, with a projection also to the supplementary motor area. Participating nuclei and thalamo-cortical connection probabilities allow this network to be identified as the motor control circuit of the basal ganglia. The network was reproducibly identified across subjects, behavioural conditions (fixation, eyes closed), field strength and echo-planar imaging parameters. It shows a frequency peak at 0.025 +/- 0.007 Hz and is most similar in spectral composition to the Default Mode (DM), a network of regions that is more active at rest than during task processing. Frequency features allow the network to be classified as an RSN rather than a physiological artefact. Fluctuations in this RSN are correlated with those in the task-positive fronto-parietal network and anticorrelated with those in the DM, whose hemodynamic response it anticipates. CONCLUSION: Although the basal ganglia RSN has not been reported in most ICA-based studies using a similar methodology, we demonstrate that it is reproducible across subjects, common resting state conditions and imaging parameters, and show that it corresponds with the motor control circuit. This characterisation of the basal ganglia network opens a potential means to investigate the motor-related neuropathologies in which the basal ganglia are involved.

Abnormal hepatic energy homeostasis in type 2 diabetes.

UNLABELLED: Increased hepatocellular lipids relate to insulin resistance and are typical for individuals with type 2 diabetes mellitus (T2DM). Steatosis and T2DM have been further associated with impaired muscular adenosine triphosphate (ATP) turnover indicating reduced mitochondrial fitness. Thus, we tested the hypothesis that hepatic energy metabolism could be impaired even in metabolically well-controlled T2DM. We measured hepatic lipid volume fraction (HLVF) and absolute concentrations of gammaATP, inorganic phosphate (Pi), phosphomonoesters and phosphodiesters using noninvasive (1)H/ (31)P magnetic resonance spectroscopy in individuals with T2DM (58 +/- 6 years, 27 +/- 3 kg/m (2)), and age-matched and body mass index-matched (mCON; 61 +/- 4 years, 26 +/- 4 kg/m (2)) and young lean humans (yCON; 25 +/- 3 years, 22 +/- 2 kg/m (2), P < 0.005, P < 0.05 versus T2DM and mCON). Insulin-mediated whole-body glucose disposal (M) and endogenous glucose production (iEGP) were assessed during euglycemic-hyperinsulinemic clamps. Individuals with T2DM had 26% and 23% lower gammaATP (1.68 +/- 0.11; 2.26 +/- 0.20; 2.20 +/- 0.09 mmol/L; P < 0.05) than mCON and yCON individuals, respectively. Further, they had 28% and 31% lower Pi than did individuals from the mCON and yCON groups (0.96 +/- 0.06; 1.33 +/- 0.13; 1.41 +/- 0.07 mmol/L; P < 0.05). Phosphomonoesters, phosphodiesters, and liver aminotransferases did not differ between groups. HLVF was not different between those from the T2DM and mCON groups, but higher (P = 0.002) than in those from the yCON group. T2DM had 13-fold higher iEGP than mCON (P < 0.05). Even after adjustment for HLVF, hepatic ATP and Pi related negatively to hepatic insulin sensitivity (iEGP) (r =-0.665, P = 0.010, r =-0.680, P = 0.007) but not to whole-body insulin sensitivity. CONCLUSION: These data suggest that impaired hepatic energy metabolism and insulin resistance could precede the development of steatosis in individuals with T2DM.

Functional electrical stimulation of long-term denervated, degenerated human skeletal muscle: estimating activation using T2-parameter magnetic resonance imaging methods.

Functional electrical stimulation (FES) of long-term denervated, degenerated human skeletal muscle has proven to be a suitable method for improving a number of physiological parameters. The underlying mechanisms of activation of a denervated muscle fiber can be described with suitably modified and extended Hodgin-Huxley type models, coupled with three-dimensional (3D) finite element models of the surrounding electrical field. Regions of activation within a muscle can be determined using a 3D computer model. However, simulation results have not yet been validated experimentally. During and immediately after exercise, muscle shows increased T2-relaxation times. It is thus possible to estimate muscle activation noninvasively and spatially resolved with the magnetic resonance imaging (MRI) method of T2 mapping, which was, therefore, chosen as a suitable validation approach. Six patients were scanned prior to FES training with a multislice multiecho MSME-sequence at 3 Tesla and then asked to perform one of their regular daily training-sessions (leg extensions). Subjects were then repositioned in the MR-scanner and two to five postexercise scans were recorded. Pre- and postexercise scans were coregistered and T2-parameter maps were calculated. Regions of interest (ROIs) were drawn manually around quadriceps femoris and its antagonists. Activation was detected in all patients. In well-trained patients, activation in the quadriceps was found to be considerably higher than in its antagonists. These experimental results will help further improve existing models of FES of denervated degenerated human skeletal muscle.

Effects of functional electrical stimulation in denervated thigh muscles of paraplegic patients mapped with T2 imaging.

OBJECT: Functional electrical stimulation (FES) for paraplegic patients, with the long-term goal of ultimately restoring muscle function, is associated with several positive effects: improvement of blood circulation, skin condition, peripheral trophism and metabolism, prophylaxis against decubitus ulcer and better physical fitness. Since fibres of denervated muscles (lacking a supplying nerve) need to be activated directly, the fraction of elicited muscle tissue follows the geometric distribution of the electrical field, which can be simulated using electrophysiological computer models. Experimental validation of these results, however, has not yet been established. MATERIALS AND METHODS: We acquired T (2) parameter images using a multislice multi-spin-echo MR sequence before and immediately after FES in nine denervated paraplegic patients and three healthy subjects in order to visualise the geometric distribution of activation by electrically induced muscle stimulation in denervated versus innervated (healthy) thigh muscle. RESULTS AND CONCLUSION: After realigning and normalisation, maps of relative T (2) increase were calculated. The results demonstrate that the spatial distribution of short-term effects of FES of denervated muscle tissue of paraplegic patients who regularly perform FES can be visualised by T (2) parameter images. This may be used to refine models of the electrical field of FES in muscle and fibre activation in the future.

Absolute quantification of phosphorus metabolite concentrations in human muscle in vivo by 31P MRS: a quantitative review.

31P MRS offers a unique view of muscle metabolism in vivo, but correct quantification is important. Inter-study correlation of estimates of [Pi] and [phosphocreatine (PCr)] in a number of published studies suggest that the main technical problem in calibrated 31P MRS studies is the measurement of PCr and Pi signal intensities, rather than absolute quantification of [ATP]. For comparison, we discuss the few published biopsy studies of calf muscle and a selection of the many studies of quadriceps muscle. The ATP concentration is close to the value that we obtained in calf muscle in our own study, presented here, on four healthy subjects, by localised 31P MRS using a surface coil incorporating an internal reference and calibrated using an external phantom. However, the freeze-clamp biopsy PCr concentration is approximately 20% lower than the value obtained by 31P MRS, consistent with PCr breakdown by creatine kinase during freezing. Finally, we illustrate some consequences of uncertainty in resting [PCr] for analysis of mitochondrial function from PCr kinetics using a published 31P MRS study of exercise and recovery: the lower the assumed resting [PCr], the lower the absolute rate of oxidative ATP synthesis estimated from the PCr resynthesis rate; in addition, the lower the assumed resting [PCr], or the higher the assumed [total creatine], the higher the apparent resting [ADP], and therefore the more sigmoid the relationship between the rate of oxidative ATP synthesis and [ADP]. Correct quantification of resting metabolite concentrations is crucially important for this sort of analysis. Our own results ([PCr] = 33 +/- 2 mM, [Pi] = 4.5 +/- 0.2 mM, and [ATP] = 8.2 +/- 0.4 mM; mean +/- SEM) are close to the overall mean values of the 10 published studies on calf muscle by 'calibrated' 31P MRS (as in the present work), and of [PCr] and [Pi] in a representative selection of 'uncalibrated' 31P MRS studies (i.e. from measured PCr/ATP and Pi/ATP ratios, assuming a literature value for [ATP]).

Amygdala activation at 3T in response to human and avatar facial expressions of emotions.

Facial expressions of emotions are important in nonverbal communication. Although numerous neural structures have been identified to be involved in emotional face processing, the amygdala is thought to be a core moderator. While previous studies have relied on facial images of humans, the present study is concerned with the effect of computer-generated (avatar) emotional faces on amygdala activation. Moreover, elicited activation patterns in response to viewing avatar faces are compared with the neuronal responses to human facial expressions of emotions. Twelve healthy subjects (five females) performed facial emotion recognition tasks with optimized 3T event-related fMRI. Robust amygdala activation was apparent in response to both human and avatar emotional faces, but the response was significantly stronger to human faces in face-sensitive structures, i.e. fusiform gyri. We suggest that avatars could be a useful tool in neuroimaging studies of facial expression processing because they elicit amygdala activation similarly to human faces, yet have the advantage of being highly manipulable and fully controllable. However, the finding of differences between human and avatar faces in face-sensitive regions indicates the presence of mechanisms by which human brains can differentiate between them. This mechanism merits further investigation.

Quantification of metabolic differences in the frontal brain of depressive patients and controls obtained by 1H-MRS at 3 Tesla.

RATIONALE AND OBJECTIVES: This study compared metabolic differences in the frontal brain of depressed patients versus age- and sex-matched controls using proton magnetic resonance spectroscopy and absolute quantification of metabolites (NAA, Cr, Cho, mI) at 3 Tesla. METHODS: Short-echo-time stimulated echo acquisition mode (TE/TM/TR=20/30/6000 milliseconds) was applied in the prefrontal region of 17 depressed patients and 17 age- and sex-matched controls. Metabolic ratios, ie, N-acetyl-aspartate/creatine (Cr), choline/Cr, and myo-inositol/Cr, and absolute concentrations (using internal water as a reference together with LCModel-based spectra fitting) were calculated and compared between groups and published reference data. RESULTS: Metabolic ratios showed significantly lower N-acetyl-aspartate/Cr (P = 0.016/0.006, left/right), choline/Cr (P = n.s./0.016), and myo-inositol/Cr (P = 0.022/0.026) for depressive patients versus controls. However, depressive patients showed significantly higher absolute concentrations of Cr (P = 0.017/0.0004) compared with controls with no differences in all other metabolites estimated. CONCLUSIONS: The authors demonstrate that absolute quantification of metabolite concentration is essential in properly identifying pathologic differences of brain metabolites in depression.

Oral beta-hydroxybutyrate supplementation in two patients with hyperinsulinemic hypoglycemia: monitoring of beta-hydroxybutyrate levels in blood and cerebrospinal fluid, and in the brain by in vivo magnetic resonance spectroscopy.

In persistent hyperinsulinemic hypoglycemia of infancy, ketone body concentrations are abnormally low at times of hypoglycemia, depriving the brain of its most important alternative fuel. The neuroprotective effect of endogenous ketone bodies is evidenced by animal and human studies, but knowledge about exogenous supply is limited. Assuming that exogenous ketone body compounds as a dietetic food might replace this alternative energy source for the brain, we have monitored the fate of orally supplemented DL sodium beta-hydroxybutyrate (beta-OHB) in two 6-mo-old infants with persistent hyperinsulinemic hypoglycemia for 5 and 7 mo, while on frequent tube-feedings and treatment with octreotide. Near total (95%) pancreatectomy had been ineffective in one patient and was refused in the other. In blood, concentrations of beta-OHB increased to levels comparable to a 16- to 24-h fast while on DL sodium beta-OHB 880 to 1000 mg/kg per day. In cerebrospinal fluid, concentrations of beta-OHB increased to levels comparable to a 24- to 40-h fast, after single dosages of 4 and 8 g, respectively. High ratios of beta-OHB to acetoacetate indicated exogenous origin of beta-OHB. An increase of intracerebral concentrations of beta-OHB could be demonstrated by repetitive single-voxel proton magnetic resonance spectroscopy by a clear doublet at 1.25 ppm. Oral DL sodium beta-OHB was tolerated without side effects. This first report on oral supplementation of DL sodium beta-OHB in two patients with persistent hyperinsulinemic hypoglycemia demonstrates effective uptake across the blood-brain barrier and could provide the basis for further evaluation of the neuroprotective effect of beta-OHB in conditions with hypoketotic hypoglycemia.