Energy Expenditure of Dynamic Submaximal Human Plantarflexion Movements: Model Prediction and Validation by in-vivo Magnetic Resonance Spectroscopy.

To understand the organization and efficiency of biological movement, it is important to evaluate the energy requirements on the level of individual muscles. To this end, predicting energy expenditure with musculoskeletal models in forward-dynamic computer simulations is currently the most promising approach. However, it is challenging to validate muscle models in-vivo in humans, because access to the energy expenditure of single muscles is difficult. Previous approaches focused on whole body energy expenditure, e.g., oxygen consumption (VO2), or on thermal measurements of individual muscles by tracking blood flow and heat release (through measurements of the skin temperature). This study proposes to validate models of muscular energy expenditure by using functional phosphorus magnetic resonance spectroscopy (31P-MRS). 31P-MRS allows to measure phosphocreatine (PCr) concentration which changes in relation to energy expenditure. In the first 25 s of an exercise, PCr breakdown rate reflects ATP hydrolysis, and is therefore a direct measure of muscular enthalpy rate. This method was applied to the gastrocnemius medialis muscle of one healthy subject during repetitive dynamic plantarflexion movements at submaximal contraction, i.e., 20% of the maximum plantarflexion force using a MR compatible ergometer. Furthermore, muscle activity was measured by surface electromyography (EMG). A model (provided as open source) that combines previous models for muscle contraction dynamics and energy expenditure was used to reproduce the experiment in simulation. All parameters (e.g., muscle length and volume, pennation angle) in the model were determined from magnetic resonance imaging or literature (e.g., fiber composition), leaving no free parameters to fit the experimental data. Model prediction and experimental data on the energy supply rates are in good agreement with the validation phase (<25 s) of the dynamic movements. After 25 s, the experimental data differs from the model prediction as the change in PCr does not reflect all metabolic contributions to the energy expenditure anymore and therefore underestimates the energy consumption. This shows that this new approach allows to validate models of muscular energy expenditure in dynamic movements in vivo.

The pH heterogeneity in human calf muscle during neuromuscular electrical stimulation.

PURPOSE: The aim of the study was to examine pH heterogeneity during fatigue induced by neuromuscular electrical stimulation (NMES) using phosphorus magnetic resonance spectroscopy (31 P-MRS). It is hypothesized that three pH components would occur in the 31 P-MRS during fatigue, representing three fiber types. METHODS: The medial gastrocnemius of eight subjects was stimulated within a 3-Tesla whole body MRI scanner. The maximal force during stimulation (Fstim ) was examined by a pressure sensor. Phosphocreatine (PCr), adenosintriphosphate, inorganic phosphate (Pi), and the corresponding pH were estimated by a nonvolume-selective 31 P-MRS using a small loop coil at rest and during fatigue. RESULTS: During fatigue, Fstim and PCr decreased to 27% and 33% of their initial levels, respectively. In all cases, the Pi peak increased when NMES was started and split into three different peaks. Based on the single Pi peaks during fatigue, an alkaline (6.76 ± 0.08), a medium (6.40 ± 0.06), and an acidic (6.09 ± 0.05) pH component were observed compared to the pH (7.02 ± 0.02) at rest. CONCLUSION: It is suggested that NMES is able to induce pH heterogeneity in the medial gastrocnemius, and that the single Pi peaks represent the different muscle fiber types of the skeletal muscle. Magn Reson Med 77:2097-2106, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

The reproducibility of different metabolic markers for muscle fiber type distributions investigated by functional 31P-MRS during dynamic exercise.

PURPOSE: The objective of the study was to investigate the reproducibility of exercise induced pH-heterogeneity by splitting of the inorganic phosphate (Pi) signal in the corresponding 31P-MRS spectra and to compare results of this approach with other fiber-type related markers, like phosphocreatine/adenosine triphosphate (PCr/ATP) ratio, and PCr-recovery parameters. MATERIAL AND METHODS: Subjects (N=3) with different sportive background were tested in 10 test sessions separated by at least 3 days. A MR-compatible pedal ergometer was used to perform the exercise and to induce a pH-based splitting of the Pi-signal in 31P-MR spectra of the medial gastrocnemius muscle. The PCr recovery was analyzed using a non-negative least square algorithm (NNLS) and multi-exponential regression analysis to estimate the number of non-exponential components as well as their amplitude and time constant. The reproducibility of the estimated metabolic marker and the resulting fiber-type distributions between the 10 test sessions were compared. RESULTS: The reproducibility (standard deviation between measurements) based on (1) Pi components varied from 2% to 4%, (2) PCr recovery time components varied from 10% to 12% and (3) phosphate concentrations at rest varied from 8% to 11% between test sessions. Due to the sportive activity differences between the 3 subjects were expected in view of fiber type distribution. All estimated markers indicate the highest type I percentage for volunteer 3 medium for volunteer 2 and the lowest for volunteer 1. CONCLUSIONS: The relative high reproducibility of pH dependent Pi components during exercise indicates a high potential of this method to estimate muscle fiber-type distributions in vivo. To make this method usable not only to detect differences in muscle fiber distributions but also to determine individual fiber-type volume contents it is therefore recommended to validate this marker by histological methods and to reveal the effects of muscle fiber recruitments and fiber-type specific Pi concentrations on the intensity ratios between the splitted Pi-components.

Glutamatergic dysfunction linked to energy and membrane lipid metabolism in frontal and anterior cingulate cortices of never treated first-episode schizophrenia patients.

BACKGROUND: Glutamatergic dysfunction and altered membrane lipid and energy metabolism have been repeatedly demonstrated in the frontal/prefrontal and anterior cingulate cortex (ACC) in schizophrenia. Though having been already studied in animals, the presumed link between glutamatergic function and structural plasticity has not been investigated directly in the human brain yet. We measured glutamate (Glu), focal energy metabolism, and membrane phospholipid turnover to investigate main pathologies in those key brain regions of schizophrenia. METHODS: (1)H- and (31)P-Chemical Shift Imaging (CSI) was combined in a single session to assess Glu and markers of energy (PCr, ATP) and membrane lipid (PME, PDE) metabolism in 31 neuroleptic-naïve first acute onset psychosis patients and 31 matched healthy controls. Multivariate analyses of covariance were used to assess disease effects on Glu and to investigate the impact of Glu alterations on phospholipid and energy metabolites. RESULTS: Glu levels of patients were increased in the frontal and prefrontal cortex bilaterally and in the ACC. Higher Glu was associated with increased left frontal/prefrontal PME and right frontal/prefrontal PDE in patients, which was not observed in healthy controls. In contrast, higher Glu levels were associated with lower PCr or ATP values in the frontal/prefrontal cortex bilaterally and in the right ACC of controls. This was not observed in the right ACC and left frontal/prefrontal cortex of patients. CONCLUSION: Frontal glutamatergic hyperactivity is disconnected from physiologically regulated energy metabolism and is associated with increased membrane breakdown in right and increased membrane restoration in left frontal and prefrontal cortical regions. As indicated by previous findings, this pathology is likely dynamic during the course of first acute illness and possibly associated with negative symptoms and cognitive impairment. Our findings underline the importance of further research on neuroprotective treatment options during the early acute or even better for the ultra-high risk state of psychotic illness.

Age-related structural and functional changes of low back muscles.

During aging declining maximum force capacity with more or less unchanged fatigability is observed with the underlying mechanisms still not fully understood. Therefore, we compared morphology and function of skeletal muscles between different age groups. Changes in high-energy phosphate turnover (PCr, Pi and pH) and muscle functional MRI (mfMRI) parameters, including proton transverse relaxation time (T2), diffusion (D) and vascular volume fraction (f), were investigated in moderately exercised low back muscles of young and late-middle-aged healthy subjects with (31)P-MR spectroscopy, T2- and diffusion-weighted MRI at 3T. In addition, T1-weighted MRI data were acquired to determine muscle cross-sectional areas (CSA) and to assess fat infiltration into muscle tissue. Except for pH, both age groups showed similar load-induced MR changes and rates of perceived exertion (RPE), which indicates comparable behavior of muscle activation at moderate loads. Changes of mfMRI parameters were significantly associated with RPE in both cohorts. Age-related differences were observed, with lower pH and higher Pi/ATP ratios as well as lower D and f values in the late-middle-aged subjects. These findings are ascribed to age-related changes of fiber type composition, fiber size and vascularity. Interestingly, post exercise f was negatively associated with fat infiltration with the latter being significantly higher in late-middle-aged subjects. CSA of low back muscles remained unchanged, while CSA of inner back muscle as well as mean T2 at rest were associated with maximum force capacity. Overall, applying the proposed MR approach provides evidence of age-related changes in several muscle tissue characteristics and gives new insights into the physiological processes that take place during aging.

Interrelations of muscle functional MRI, diffusion-weighted MRI and (31) P-MRS in exercised lower back muscles.

Exercise-induced changes of transverse proton relaxation time (T2 ), tissue perfusion and metabolic turnover were investigated in the lower back muscles of volunteers by applying muscle functional MRI (mfMRI) and diffusion-weighted imaging (DWI) before and after as well as dynamic (31) P-MRS during the exercise. Inner (M. multifidus, MF) and outer lower back muscles (M. erector spinae, ES) were examined in 14 healthy young men performing a sustained isometric trunk-extension. Significant phosphocreatine (PCr) depletions ranging from 30% (ES) to 34% (MF) and Pi accumulations between 95% (left ES) and 120%-140% (MF muscles and right ES) were observed during the exercise, which were accompanied by significantly decreased pH values in all muscles (∆pH ≈ -0.05). Baseline T2 values were similar across all investigated muscles (approximately 27 ms at 3 T), but revealed right-left asymmetric increases (T2 ,inc ) after the exercise (right ES/MF: T2 ,inc = 11.8/9.7%; left ES/MF: T2 ,inc = 4.6/8.9%). Analyzed muscles also showed load-induced increases in molecular diffusion D (p = .007) and perfusion fraction f (p = .002). The latter parameter was significantly higher in the MF than in the ES muscles both at rest and post exercise. Changes in PCr (p = .03), diffusion (p < .01) and perfusion (p = .03) were strongly associated with T2,inc , and linear mixed model analysis revealed that changes in PCr and perfusion both affect T2,inc (p < .001). These findings support previous assumptions that T2 changes are not only an intra-cellular phenomenon resulting from metabolic stress but are also affected by increased perfusion in loaded muscles.

MR-compatible pedal ergometer for reproducible exercising of the human calf muscle.

A pneumatic MR-compatible pedal ergometer was designed to perform dynamic contraction exercises of the human calf muscle in a whole-body 3T MR scanner. The set-up includes sensors for monitoring mechanical parameters, such as pedal angle, cadence as well as applied force and power. Actual parameter values during the exercise were presented to the volunteer as a visual feedback to enable real-time self-adjustment of pedal deflection and cadence to the target reference value. Time-resolved dynamic (31)P-MR spectroscopic measurements of phosphocreatine (PCr), inorganic phosphate (Pi) and pH were performed in a pilot experiment before, during, and after the exercise by a single volunteer. Two different load strengths were applied in these experiments (15% and 25% of the maximum voluntary contraction, MVC). As expected, mechanical and metabolic parameters differed for the two load levels. Small variations of the cadence, power and metabolic changes (time constants of PCr depletion and Pi accumulation) during the experiments demonstrate a highly reproducible mechanical output by the volunteer mediated by the ergometer.

Superior temporal metabolic changes related to auditory hallucinations: a (31)P-MR spectroscopy study in antipsychotic-free schizophrenia patients.

Structural deficits in the superior temporal cortex and transverse temporal gyri appear to be related to auditory hallucinations in schizophrenia, which are a key symptom of this disorder. However, the cellular and neurochemical underpinnings are poorly understood and hardly studied in vivo. We used (31)P-MRS (magnetic resonance spectroscopy) with chemical shift imaging to assess the association between left superior temporal cortex metabolism and severity of auditory hallucinations in 29 schizophrenia patients off antipsychotics. Hallucinations scores derived from the Scale for the Assessment of Positive Symptoms showed significant positive correlations with both measures of phospholipids (phosphomonoesters and phosphodiesters), and energy (inorganic phosphate and phosphocreatine, but not adenosine tri-phosphate) metabolism in left superior temporal gyrus/Heschl gyrus voxels. There was no correlation of metabolites in these regions with formal thought disorder, a symptom also linked to superior temporal pathology, thus suggesting symptom specificity. Our findings provide a link between established structural deficits and neurochemical pathology related to membrane pathology and markers of general metabolic turnover.

Effects of olanzapine on 31P MRS metabolic markers in schizophrenia.

Antipsychotic drug action might include mechanisms related to normalising phospholipid and high-energy metabolism. We applied brain metabolic imaging with (31)P magnetic resonance spectroscopy ((31)P MRS) and two-dimensional chemical shift imaging to assess changes of metabolism of phospholipids and high-energy phosphates in schizophrenia patients at baseline (four antipsychotic-naïve and three off antipsychotics) and at follow-up, after 6 weeks of treatment with olanzapine. Results indicate a significant increase of adenosine-triphosphate (ATP) in the right inferior temporal cortex and a trend towards ATP decrease in the left cerebellum. This suggests a shift in high-energy phosphates (rather than phospholipids), possibly related to normalisation of functioning in these areas.

Absolute quantitation of brain metabolites with respect to heterogeneous tissue compositions in (1)H-MR spectroscopic volumes.

OBJECT: Referencing metabolite intensities to the tissue water intensity is commonly applied to determine metabolite concentrations from in vivo (1)H-MRS brain data. However, since the water concentration and relaxation properties differ between grey matter, white matter and cerebrospinal fluid (CSF), the volume fractions of these compartments have to be considered in MRS voxels. MATERIALS AND METHODS: The impact of partial volume correction was validated by phantom measurements in voxels containing mixtures of solutions with different NAA and water concentrations as well as by analyzing in vivo (1)H-MRS brain data acquired with various voxel compositions. RESULTS: Phantom measurements indicated substantial underestimation of NAA concentrations when assuming homogeneously composed voxels, especially for voxels containing solution, which simulated CSF (error: ≤ 92%). This bias was substantially reduced by taking into account voxel composition (error: ≤ 10%). In the in vivo study, tissue correction reduced the overall variation of quantified metabolites by up to 35% and revealed the expected metabolic differences between various brain tissues. CONCLUSIONS: Tissue composition affects extraction of metabolite concentrations and may cause misinterpretations when comparing measurements performed with different voxel sizes. This variation can be reduced by considering the different tissue types by means of combined analysis of spectroscopic and imaging data.

Compatibility of temporary pacemaker myocardial pacing leads with magnetic resonance imaging: an ex vivo tissue study.

The presence of temporary myocardial pacing leads is considered a safety contraindication for magnetic resonance imaging (MRI). The aim of this ex vivo tissue study was to measure the heating effects at the tip of the leads using proton magnetic resonance spectroscopy ((1)HMRS) thermometry. The tissue effects were verified by histological analyses. Pig hearts with implanted temporary pacemaker myocardial pacing leads were examined by whole-body MRI at 1.5 Tesla. The tests were performed either by a sequence with high specific absorption rate (SAR) or by standard clinical sequences with lower SAR. Temperature changes were detected via (1)HMRS thermometry, by monitoring the frequency difference between water protons and the reference signals of N-methyl protons of creatine/phosphocreatine (Cr/PCr) and trimethylamine (TMA). Histology was performed using several staining techniques. Standard low-SAR and high-SAR sequences did not cause significant temperature increases in the myocardial tissue surrounding the implanted leads. There were no histopathological signs of thermal damage around the tips of the leads in any of the hearts or in a control implanted heart not subjected to MRI. The present data suggest that temporary pacemaker myocardial pacing leads may be compatible with MR scanning at 1.5 Tesla. However, further in vivo studies and carefully monitored patient studies are needed before final safety recommendations can be made.

Effect of contrast agent on the results of in vivo ¹H MRS of breast tumors - is it clinically significant?

Choline (Cho) signal identification and quantification in (1)H MRS are used in breast cancer diagnosis. However, an influence of the gadolinium-based contrast agent on the Cho amplitude has been reported experimentally. This study aims to identify the impact of gadolinium-based contrast agents on Cho detection and quantification in postcontrast breast MRS. Consecutive patients were recruited prospectively and randomly allocated to two groups. Group A received a neutral (gadolinium diethylenetriaminepentaacetic acid bis-methylamide) and group B an ionic (gadolinium diethylenetriaminepentaacetic acid) contrast agent, each at a dosage of 0.1 mmol/kg. First, the presence of Cho was identified visually. Then, the normalized Cho intensity in malignant lesions was quantified. Multivariate analysis was applied to identify independent influencing factors on Cho. Sixty-three lesions were investigated [A, n = 34; B, n = 29; 43 malignant (one bilaterally malignant), 20 benign]. Cho was identified visually in 14 of 20 malignant tumors in group A and 12 of 22 malignant tumors in group B (p = 0.477). Normalized Cho differed significantly (p = 0.001) between groups A (mean, 26.8 ± 6.0 AU) and B (mean, 18.2 ± 12.5 AU). No linewidth differences were identified (p > 0.05). Multivariate analysis revealed only group membership (A versus B) as an independent predictor of Cho (p = 0.017). The results suggest stronger negative effects of an ionic relative to a neutral gadolinium-based contrast agent on breast tumor MRS in vivo. These results should be considered when conducting and comparing quantitative Cho measurements in the breast.

1H-MR spectroscopic detection of metabolic changes in pain processing brain regions in the presence of non-specific chronic low back pain.

Reliable detection of metabolic changes in the brain in vivo induced by chronic low back pain may provide improved understanding of neurophysiological mechanisms underlying the manifestation of chronic pain. In the present study, absolute concentrations of N-acetyl-aspartate (NAA), creatine (Cr), total choline (tCho), myo-inositol (mI), glutamate (Glu) and glutamine (Gln) were measured in three different pain processing cortical regions (anterior insula, anterior cingulate cortex, and thalamus) of ten patients with non-specific chronic low back pain by means of proton MR spectroscopy ((1)H-MRS) and compared to matched healthy controls. Significant decrease of Glu was observed in the anterior cingulate cortex of patients. Patients also revealed a trend of decreasing Gln concentrations in all investigated brain areas. Reductions of NAA were observed in the patient group in anterior insula and in anterior cingulated cortex, whereas mI was reduced in anterior cingulated cortex and in thalamus of patients. Reduced concentrations of Glu and Gln may indicate disordered glutamatergic neurotransmission due to prolonged pain perception, whereas decrease of NAA and mI may be ascribed to neuron and glial cell loss. No significant changes were found for Cr. The morphological evaluation of anatomic brain data revealed a significantly decreased WM volume of 17% (p<0.05) as well as a non significant trend for GM volume increase in the anterior insula of patients.

Time-resolved functional 1H MR spectroscopic detection of glutamate concentration changes in the brain during acute heat pain stimulation.

Non-invasive in vivo detection of cortical neurotransmitter concentrations and their changes in the presence of pain may help to better understand the biochemical principles of pain processing in the brain. In the present study acute heat pain related changes of the excitatory neurotransmitter glutamate were investigated in the anterior insular cortex of healthy volunteers by means of time-resolved functional proton magnetic resonance spectroscopy ((1)H-MRS). Dynamic metabolite changes were estimated with a temporal resolution of five seconds by triggering data acquisition to the time course of the cyclic stimulus application. An overall increase of glutamate concentration up to 18% relative to the reference non-stimulus condition was observed during the application of short pain stimuli.

WITHDRAWN: Erratum to "1H-MR spectroscopic detection of metabolic changes in pain processing brain regions in the presence of non-specific chronic low back pain" [NeuroImage 54/2 (2011) 1315-1323].

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.neuroimage.2010.11.069. The duplicate article has therefore been withdrawn.

First-pass myocardial perfusion abnormalities in Churg-Strauss syndrome with cardiac involvement.

This study sought to evaluate whether representative abnormalities can be identified by first-pass perfusion (FPP) studies in patients with Churg-Strauss Syndrome (CSS), a rare disease characterized by small-vessel vasculitis. Seven patients with CSS (3 men, 4 women; mean age 55 +/- 7 years) were investigated. Echocardiography was performed in all patients and coronary angiography in 5 patients. Magnetic resonance imaging (MRI) was performed with a 1.5 T whole body scanner in all patients. Functional cardiac imaging, T2-weighted turbo inversion recovery magnitude images, and T2-weighted turbo spin echo sequences with fat saturation were also performed. Cardiac viability was assessed by myocardial FPP imaging at rest and by delayed contrast enhancement (DCE) images. The FPP was abnormal in 5 of the 7 CSS patients. The abnormality was localized in the subendocardium of the left ventricle, particularly in areas of myocardial inflammatory edema. All patients showed subendocardial DCE abnormalities in the left ventricle, and 2 patients also in the right ventricle. The localization was typically subendocardial. This study describes a myocardial FPP deficit at rest in patients with CSS. The deficit is localized in areas of inflammatory myocardial edema. This diagnostic technique and image evaluation is simple, quick, and harmless. Due to the rarity of CSS, further studies are necessary to evaluate the impact of these findings.

Investigations of back muscle fatigue by simultaneous 31P MRS and surface EMG measurements.

Investigations of back muscle fatigue are important for understanding the role of muscle strain in the development of low back pain. The aim of this contribution is to review the two main techniques used for in vivo investigations of metabolic and electrophysiological changes, namely magnetic resonance phosphorous spectroscopy ((31)P MRS) and surface electromyography (SEMG), and to report some of our recent results on simultaneous measurements using these techniques during isometric back-muscle contraction in volunteers. Since it appears that electrophysiological and metabolic factors are simultaneously involved in the processes of fatigue and muscle recovery during load application, simultaneous acquisition of complete information is quite promising for obtaining new insights into the metabolic origin of electrophysiological changes or vice versa. Performing these measurements simultaneously, however, is more intricate owing to the occurrence of signal artifacts caused by mutual signal interferences of both techniques. Besides these mutual disturbances, further experimental difficulties are related to spatial limitations within the bore of clinical whole-body high-field magnetic resonance (MR) systems (1.5 T) and the sensitivity of MR measurements to motion-induced artifacts. Our own experimental results are presented, and problems that occur using both techniques simultaneously, as well as possibilities to resolve them, are discussed. The results shed light on the interrelation of electrophysiological and metabolic changes during fatigue of the back muscle while performing an exercise.

Reduction of excitability ("inhibition") in the ipsilateral primary motor cortex is mirrored by fMRI signal decreases.

Functional magnetic resonance imaging (fMRI) was used to investigate how focal cortical inhibition affects the blood oxygen level-dependent (BOLD) signal. Phasic low force pinch grip reduces excitability of the ipsilateral primary motor cortex. This task was used to study BOLD signal changes during inhibition. Six right-handed normal volunteers participated in the study. They were asked to perform a right-handed pinch grip repetitively at 1 Hz and 5% of their individual maximal voluntary contraction (MVC). Data were acquired with a 1.5 Tesla Magnetom and continuous multislice T2*-weighted images. The contralateral primary motor cortex (M1) revealed an activation in the knob-shaped hand representation of the central sulcus area. More importantly, a decreased (often referred to as "negative") BOLD signal in the ipsilateral M1 was observed. We suggest phasic low force pinch grip as a reproducible, easy model of focal inhibition. Decreased cortical excitability presents as decreased BOLD signal using fMRI.