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Ambient seismic noise can often be seen as problematic but with the right analysis can act as a tool to image the Earth. Wind turbines are known to generate low frequency vibrations; however, the wave types that are generated are currently unknown. Characterizing these vibrations will allow wind turbines to be used as a seismic source and be of value to geotechnical applications and seismic interferometry. This paper uses polarization analysis of the seismic wavefield around a small wind turbine to identify the type of wave being generated by the turbine and to clarify the source. The seismic data recorded 190 m from the wind turbine are processed using a window length of 0.1 s and bandpass filtered on a selection of frequency ranges. Polarization analysis is performed for two different wind speed ranges, in order to show the variation of wave characteristics between operational and non-operational modes of the wind turbine. Polarized surface waves are identified as the predominant wave type at blade rotation harmonics, making this work particularly relevant to multichannel analysis of surface waves and seismic interferometry. Copyright © 2017 John Wiley & Sons, Ltd.

A hybrid intelligent system involves combining two intelligent technologies; e.g., a combination of a neural network with a fuzzy system to produce a hybrid neuro-fuzzy system. Generally combining probabilistic reasoning, fuzzy logic, evolutionary computation together with neural networks produces hybrid systems which form the core of soft computing.

Artificial neural networks are perhaps the most common method amongst intelligent methods in geophysics and are becoming increasingly popular. Because they are universal approximations, these tools can approximate any continuous function with any arbitrary precision.

As mentioned previously in the primary sections of chapter one, there are several, and varied applications of neural networks in geophysics; here we give a short list of some of these applications: Modeling of crustal velocity using Artificial Neural Networks (case study: Iran Geodynamic GPS Network (Ghaffari and Mohammadzadeh 2015) Crustal velocity field modeling with neural network and polynomials, SIDERIS, M.G. (Ed.), Moghtased-Azar and Zaletnyik (2009) Artificial neural network pruning approach for modular neural networks (Yilmaz 2013) Modular neural networks for seismic tomography (Barraez et al. 2002) Estimating one-dimensional models from frequency domain measurements Quantifying sand fraction from seismic attributes using modular artificial neural networks Borehole electrical resistivity modeling using neural networks Determination of facies from well logs using modular neural networks (Bhatt and Helle 2002) Inversion of self-potential anomalies caused by 2D-inclined sheets (Hesham 2009). 2D inverse modeling of residual gravity anomalies from Simple geometric shapes using Modular Feed-forward Neural Network (Eshaghzadeh and Hajian 2018)

We develop a new method of using feed-forward back-propagation (FFBP) neural networks to simultaneously estimate shape factor and depth of gravity anomalies. The advantages compared to neural network methods are the following: no pre-assumptions are made on source shape, the FFBP neural network estimates both depth and shape factor of source bodies and, once trained, works well for any new data in the training space, without repeating the initial calculations.

We review the distribution, timing and probable causes of ∼8000 onshore UK seismic events between the years 1970–2012. Of 1769 onshore seismic events with local magnitudes (M L ) ≥ 1.5, we estimate at least ∼21% of these have an anthropogenic origin, at least ∼40% were natural and ∼39% have an undetermined, anthropogenic or natural origin. The majority of the anthropogenic related earthquakes were caused by coal mining and the decline in their numbers from the 1980s to the 2000s was concurrent with a decline in UK coal production. To date, two earthquakes with M L ≥ 1.5 have been caused by hydraulic fracturing. We have a high level of confidence that the mean number of anthropogenic related earthquakes (M L ≥ 1.5) per year onshore in the UK since 1999 is at least three with an annual range of between zero and eight. If we assumed that 50% of the undetermined events had an anthropogenic origin the mean per year increases to twelve. Although there are inherent uncertainties in assigning an anthropogenic versus natural cause for historical earthquakes, these values provide a baseline for the UK, the first of its kind for any nation state, in advance of the presently planned shale gas and oil exploitation.

This paper presents a case study of the ground-borne vibrations generated by small wind turbines. This is of particular importance for assessing the possible impact on the detection capabilities of the International Monitoring System seismic array at Eskdalemuir in Scotland. Measurements were gathered from a selection of small wind turbines (≤50 kW), from three different manufacturers, varying in hub height, power and construction using a range of accelerometers and seismometers fixed to the tower and buried in the adjacent ground at increasing distances. Previous studies have shown that medium and large turbines generate harmonic vibrations. Planning guidelines exist but have inadvertently led to a ban on the deployment of individual small-turbines within 50 km of the array. This study investigates whether their inclusion in these guidelines is necessary. Vibration levels on the tower are in the region of 10 -3 m/sqrt(Hz), are transferred into the ground and decay rapidly away from the turbine (10 -5 m/sqrt(Hz) in the ground at 200 m). The spectral content of the vibrations shows variations between the turbines, but each have peaks in the band of interest for Eskdalemuir. Further, sources of the peaks in the spectra are identified as either originating from the blades’ rotation or the resonant modes of the turbines. Analysis of the relationship between wind speed and seismic amplitude on the tower shows an exponential trend, individual to each wind turbine and the frequency band of interest. Similarly, analysis of the seismic amplitude between the tower and foundation shows that this can be described by a power law, but this is individual to each turbine. It is our opinion that there is little requirement to include turbines of 50 kW or less in planning guidelines outside the statutory exclusion zone of 10 km, but each turbine should be considered on an individual basis.

Magnetic resonance imaging (MRI) is an established clinical tool for diagnosing multiple sclerosis (MS), the archetypal central nervous system neuroinflammatory disease. In this study, we have used a model of delayed-type hypersensitivity in the rat brain, which bears many of the hallmarks of an MS lesion, to investigate the development of MRI-detectable changes before the appearance of conventional indices of lesion development. In addition, we have correlated the MRI-detectable changes with the developing histopathology. Significant increases in regional cerebral blood volume (rCBV) preceded overt changes in blood–brain barrier (BBB) permeability, T2 relaxation and the diffusion properties of tissue water. Thus, changes in rCBV might be a more sensitive indicator of lesion onset than the conventional indices used clinically in MS patients, such as contrast enhancement. In addition, we show that BBB breakdown, and consequent edema formation, are more closely correlated with astrogliosis than any other histopathologic changes, while regions of T1 and T2 hypointensity appear to reflect hypercellularity.

Functional magnetic resonance imaging (fMRI) in animal models provides a platform for more extensive investigation of drug effects and underlying physiological mechanisms than is possible in humans. However, it is usually necessary for the animal to be anesthetized. In this study, we have used a rat model of direct cortical stimulation to investigate the effects of anesthesia in rodent fMRI. Specifically, we have sought to answer two questions (i) what is the relationship between baseline neuronal activity and the BOLD response to stimulation under halothane anesthesia? And (ii) how does the BOLD response change after transferring from halothane to the commonly used anesthetic alpha-chloralose? In the first set of experiments, we found no significant differences in the amplitude of the BOLD response at the different halothane doses studied, despite electroencephalography (EEG) recordings indicating a dose-dependent reduction in baseline neuronal activity with increasing halothane levels. In the second set of experiments, a reduction in the spatial extent of the BOLD response was apparent immediately after transfer from halothane to alpha-chloralose anesthesia, although no change in the peak signal change was evident. However, several hours after transfer to alpha-chloralose, a significant increase in both the spatial extent and peak height of the BOLD response was observed, as well as an increased sensitivity to secondary cortical and subcortical activation. These findings suggest that, although alpha-chloralose anesthesia is associated with a greater BOLD response for a fixed stimulus relative to halothane, there is substantial variation in the extent and magnitude of the response over time that could introduce considerable variability in studies using this anesthetic.

Magnetic resonance techniques were used to investigate haemodynamic abnormalities and their consequences in normal pressure hydrocephalus (NPH) and to assess changes in these parameters following surgery. Eleven patients with NPH were studied pre- and post-operatively using perfusion and diffusion weighted imaging and compared with ten age-matched controls. Pre-operative periventricular relative cerebral blood volume (rCBV) was reduced in patients (0.76+/-0.11) compared with control (1.16+/-0.16, P0.01). There was no difference between outcome groups and no change in haemodynamic parameters following surgery. The periventricular apparent diffusion coefficient (ADC) was elevated in the poor outcome group (1.67+/-0.3 x 10(-3) mm(2) s(-1)) compared with both controls (1.04+/-0.4 x 10(-3) mm(2) s(-1), P0.05) and the good outcome group (0.99+/-0.3 x 10(-3) mm(2) s(-1), P0.05) despite appearing normal on conventional imaging. In white matter hyperintensities (WMH), rCBV was reduced (0.70+/-0.12 vs. 1.00+/-0.10, P0.01), and the ADC was increased (1.98+/-0.6 vs. 1.04+/-0.4 x 10(-3) mm(2) s(-1), P0.05) compared with the same anatomical location in controls. As low rCBV and high ADC is characteristic of chronic infarction, the findings in WMH regions suggest they are irreversibly damaged. Normal appearing periventricular tissue rCBV was reduced, implying that significant haemodynamic consequences contribute to symptoms in NPH. The elevated pre-operative ADC of the same region, was correlated with poor outcome, and may, therefore, be useful in selecting patients for surgery.

This paper describes the results of a series of measurements using a variety of systems comprising vibration sensors and sound-level measuring devices. These were carried out at the homes of people experiencing the effects of low frequency noise and in other environments where low-frequency noise was likely to be generated. Suggestions are made as to the possible reasons for the perception of low-frequency noise by sufferers.

Major advances have been made in the ever-expanding field of magnetic resonance imaging and related technologies, such as magnetic resonance spectroscopy, haemodynamic and functional imaging. Although these magnetic resonance modalities are of great research interest, it is still questionable as to how useful these investigations are in the clinical setting. All of these modalities strive to define a few variables that might dominate the heterogeneous but common aetiopathology of traumatic brain injury. Recent studies have found that the use of various magnetic resonance imaging techniques at early and delayed time points can provide useful information with regard to the severity and clinical outcome of patients following traumatic brain injury. These new observations offer opportunities for improved clinical management in such patients.

Friedreich's ataxia (FA) is the most common form of autosomal recessive spinocerebellar ataxia and is often associated with a cardiomyopathy. The disease is caused by an expanded intronic GAA repeat, which results in deficiency of a mitochondrial protein called frataxin. In the yeast YFH1 knockout model of the disease there is evidence that frataxin deficiency leads to a severe defect of mitochondrial respiration, intramitochondrial iron accumulation, and associated production of oxygen free radicals. Recently, the analysis of FA cardiac and skeletal muscle samples and in vivo phosphorus magnetic resonance spectroscopy (31P-MRS) has confirmed the deficits of respiratory chain complexes in these tissues. The role of oxidative stress in FA is further supported by the accumulation of iron and decreased aconitase activities in cardiac muscle. We used 31P-MRS to evaluate the effect of 6 months of antioxidant treatment (Coenzyme Q10 400 mg/day, vitamin E 2,100 IU/day) on cardiac and calf muscle energy metabolism in 10 FA patients. After only 3 months of treatment, the cardiac phosphocreatine to ATP ratio showed a mean relative increase to 178% (p = 0.03) and the maximum rate of skeletal muscle mitochondrial ATP production increased to 139% (p = 0.01) of their respective baseline values in the FA patients. These improvements, greater in prehypertrophic hearts and in the muscle of patients with longer GAA repeats, were sustained after 6 months of therapy. The neurological and echocardiographic evaluations did not show any consistent benefits of the therapy after 6 months. This study demonstrates partial reversal of a surrogate biochemical marker in FA with antioxidant therapy and supports the evaluation of such therapy as a disease-modifying strategy in this neurodegenerative disorder.

The long-term clinical outcome following traumatic brain injury (TBI) can be difficult to predict. Proton magnetic resonance spectroscopy (MRS) has previously been used to demonstrate abnormalities in regions of white matter that appear normal on conventional imaging in patients following TBI. We report MRI and MRS studies of 26 patients performed at an early time point following injury (mean 12 days, n = 21) and at a later time point (mean 6.2 months, n = 15). The proton MRS was acquired from the posterior part of a normal-appearing frontal lobe containing predominantly white matter using stimulated echo acquisition mode to localize, with a relaxation time of 3000 ms and echo time of 30 ms. At both the early and late time points the N:-acetylaspartate/creatine ratio (NAA/Cr) was significantly reduced (P = 0.03, P = 0.005, respectively), the choline/creatine ratio (Cho/Cr) significantly increased (P = 0.001, P = 0.004, respectively) and the myo-inositol/creatine ratio (Ins/Cr) significantly increased (P = 0.03, P = 0.03, respectively) compared with controls. There was a small, but significant, further reduction (P = 0.02) in the NAA/Cr between the two studies in the 10 patients for whom data was available, at both time points. The NAA/Cr acquired at the early time point significantly correlated with the clinical outcome of the patients, assessed using either the Glasgow outcome scale (P = 0.005, n = 17) or the disability rating scale (P < 0.001, n = 17). We conclude that there is a sustained alteration in NAA and Cho. These findings provide possible evidence for cellular injury (NAA loss reflecting neuroaxonal cell damage and raised Cho and Ins reflecting glial proliferation) not visible by conventional imaging techniques. This may be relevant to understanding the extent of disability following TBI.

Neuropsychological studies in patients who have suffered traumatic brain injury show that the eventual clinical outcome is frequently worse than might be predicted from using conventional (CT or T(1)/T(2)-weighted MRI) imaging. Furthermore, patients who have sustained an initial mild or moderate injury may show long-term disability. This implies that there may be abnormalities in areas of the brain that actually appear normal on conventional imaging. Proton magnetic resonance spectroscopy studies have shown that N-acetylaspartate and choline-containing compounds can provide measures of cellular injury. We report MRI and proton magnetic resonance spectroscopy studies of 19 head-injured patients performed once the patients were clinically stable (mean 11 days after injury, range 3-38 days). Proton magnetic resonance spectra were acquired from frontal white matter that on conventional MRI appeared normal. The brain N-acetylaspartate/creatine ratio was reduced [patients (mean +/- standard deviation), 1.28 +/- 0.25; controls, 1.47 +/- 0. 24; P = 0.04] and the choline/creatine ratio was increased (patients, 0.85 +/- 0.18; controls, 0.63 +/- 0.10; P0.001) compared with controls. When the severity of the injury was assessed using either the Glasgow coma scale or the length of post-traumatic amnesia, the increase in the choline/creatine ratio was significant even in the mildly injured group (P = 0.008 and P = 0.04, respectively). Furthermore, there was a significant correlation (P = 0.008) between the severity of head injury and the N-acetylaspartate/choline ratio. We conclude that there is an early reduction in N-acetylaspartate and an increase in choline compounds in normal-appearing white matter which correlate with head injury severity, and that this may provide a pathological basis for the long-term neurological disability that is seen in these patients.

The primary pathological mechanisms in stroke and multiple sclerosis (MS) are very different but in both diseases, impairment may arise from a final common pathway of axonal damage. We aimed to examine the relationship between motor impairment, magnetisation transfer ratio (MTR) (an index of demyelination), and N-acetyl aspartate (NAA) loss (an index of axonal injury) localised to the descending motor pathways in stroke and MS. Twelve patients between 1 and 10 months after first ischaemic stroke causing a motor deficit and 12 patients with stable MS with asymmetric motor deficit were examined. T(2)-weighted imaging of the brain together with MTR and proton (voxel 1.5x2x2 cm(3)) MRS localised to the posterior limb of the internal capsule were performed and correlated to a composite motor deficit score. MTR and NAA in the internal capsule were reduced in both stroke and MS patients compared to controls. NAA loss correlated with motor deficit score in both stroke and MS (p

Purpose: MR imaging of post mortem brains has the potential to yield volumetric information and define the extent of structural changes prior to pathological examination. Although standard T2-weighted clinical imaging sequences have been used for the examination of formalin-fixed brains, these protocols may not yield optimum contrast. We examined the effect of varying durations of formalin fixation on the transverse relaxation time (T2) and the tissue spin density. Material and Methods: Three post mortem brains were examined weekly during formalin fixation from the unfixed state to 35 days fixation. Standard MR spin-echo imaging was used at 5 echo times (20–100 ms) to calculate transverse relaxation time (T2) and spin density. Results: T2 decreased significantly (ANOVA, p Conclusion: Our results suggest that spin density-weighted imaging sequences would provide improved grey to white matter contrast over T2-weighted sequences.

Summary Background Neurological and physiological deficits have been reported in the brain in developmental dyslexia. The temporoparietal cortex has been directly implicated in dyslexic dysfunction, and substantial indirect evidence suggests that the cerebellum is also implicated. We wanted to find out whether the neurological and physiological deficits manifested as biochemical changes in the brain. Methods We obtained localised proton magnetic resonance spectra bilaterally from the temporo-parietal cortex and cerebellum of 14 well-defined dyslexic men and 15 control men of similar age. Findings We found biochemical differences between dyslexic men and controls in the left temporo-parietal lobe (ratio of choline-containing compounds [Cho] to N-acetylaspartate [NA] p≤0·01) and right cerebellum (Cho/NA, p≤0·01; creatine [Cre] to NA p≤0·05; (not significant). We found lateral biochemical differences in dyslexic men in both these brain regions (Cho/NA in temporo-parietal lobe, left vs right, p≤0·01; Cre/NA in cerebellum, left vs right, p≤0·001). We found no such lateral differences in controls. There was no significant relation between the degree of contralateral chemical difference and handedness in dyslexic or control men. Interpretation We suggest that the observed differences reflect changes in cell density in the temporo-parietal lobe in developmental dyslexia and that the altered cerebral structural symmetry in dyslexia is associated with abnormal development of cells or intracellular connections or both. The cerebellum is biochemically asymmetric in dyslexic men, indicating altered development of this organ. These differences provide direct evidence of the involvement of the cerebellum in dyslexic dysfunction.

We combined magnetic resonance (MR) imaging and phosphorus magnetic resonance spectroscopy ( 31 P-MRS) to study skeletal muscle in seven patients with limb girdle muscular dystrophy (LGMD) with a variable deficiency of the α -, β -, and γ -sarcoglycan but normal dystrophin expression on muscle biopsy. T1- and T2-weighted spin-echo axial leg images showed the highest degree of fat replacement in soleus, tibialis anterior and peroneal muscles while gastrocnemius and tibialis posterior were less affected. In LGMD patients as a group, calf muscle phosphorylated compound content did not differ from controls, but the cytosolic pH was increased ( P =0.02). The degree of calf muscle fat replacement correlated inversely with cytosolic pH ( r =0.74) and directly with PCr/ATP ( r =0.74). Muscle oxidative metabolism was normal in LGMD patients. Our findings show that primary deficits of sarcoglycan complex lead to specific morphological and metabolic patterns of skeletal muscle involvement.

To determine whether 130 felt earth tremors around Edwinstowe, Nottinghamshire, UK, which also experienced severe surface fissuring, were caused by coal extraction, a surface seismometer array was established around Thoresby Colliery. Over the next year, 785 microseismic events were detected. The spatial and temporal variations in seismicity are clearly associated with the commencement, continuing extraction and closure of faces. Of particular note are events which locate at the surface and appear to be related to the active fissuring. Events occur within days of commencement of production and cease when production finishes, with good correlation between face advance and hypocentral position. Naturally occurring microseismic events have also been detected up to 1 km ahead of active longwall faces in the Midlands using triaxial geophone packages grouted into the seam together with a surface seismometer in the top of the borehole. The quality of these data was very high and guided waves can clearly be seen with the dispersive characteristics associated with seam waves. In one experiment, more than 2000 events were detected in only two days of monitoring even in a relatively noisy surface environment. This paper demonstrates how useful locations can be generated using three-component digital data from only one borehole. The event distributions give a dynamic, three-dimensional image of the developing patterns of fracturing above, below and ahead of the longwall face with important implications for roof control, subsidence prediction and gas migration.

We show how quantitative information about proton handling in human skeletal muscle in exercise and recovery can be obtained by 31P MRS and illustrate this with data from metabolic disorders. Proton production, proton efflux and passive buffering can be distinguished by comparing changes in [phosphocreatine] and pH at the end of exercise and by calculating ATP turnover during ischaemic exercise and in the 'natural experiment' of myophosphorylase deficiency (McArdle's disease). We calculate the effective buffer capacity to be 20-30 mmol/L/pH unit (slykes), somewhat lower than published measurements made in vitro but similar to other values obtained in vivo. This analysis is applied to data from normal muscle and a variety of disease states to estimate proton efflux during recovery and ATP production during exercise: (i) proton efflux during recovery is pH-dependent, reaching a 10 mmol/L/min at pH 6.2, and is increased in some cases of mitochondrial myopathy and in hypertension; (ii) glycogenolytic ATP production during exercise can reach 25 mmol/L/min in normal muscle and correlates approximately with [Pi] at the start of aerobic exercise and throughout ischaemic exercise; (iii) oxidative ATP production can reach 20-25 mmol/L/min and (as during recovery) correlates approximately with [Pi].

Background and Purpose— Previous 31 P–magnetic resonance spectroscopy ( 31 P-MRS) studies have shown that cerebral cortical energy metabolism is abnormal in migraine and that cortical energy reserves decrease with increasing severity and duration of aura. Migrainous infarction is a rare complication of migraine with aura, and its pathophysiology is poorly understood. We used 31 P-MRS to determine whether migrainous stroke shows similar interictal abnormalities in cortical energy metabolism as severe, prolonged aura. Methods— We used 31 P-MRS to study patients with a diagnosis of either migrainous infarction or migraine with persistent aura without infarction (aura duration >7 days) according to International Headache Society criteria. We compared clinical presentation and metabolite ratios between patient groups. We also studied healthy controls with no history of migraine. Results— Patients with persistent aura without infarction had lower phosphocreatine-phosphate (PCr/Pi) ratios (mean±SD, 1.61±0.10) compared with controls (1.94±0.35, P =0.011) and with patients with migrainous stroke (1.96±0.16, P Conclusions— The differences in cortical energy reserves between patients with migrainous stroke and in those with migraine with persistent aura suggest that the pathomechanisms of these conditions differ and that migrainous infarction does not simply represent a particularly severe form of migrainous aura. This finding supports the revised International Headache Society criteria, which now distinguish between migrainous infarction and migraine with persistent aura without infarction.

BACKGROUND: The Marfan syndrome is an inherited multisystem disorder caused by mutations in fibrillin 1, with cardiovascular involvement being the most important feature of the phenoptype. Affected individuals have impaired flow-mediated dilatation (FMD) of large arteries of a similar severity to patients with chronic heart failure (CHF). AIMS: Skeletal muscle bioenergetics were studied in patients with the Marfan syndrome in order to evaluate the impact of impaired flow-mediated dilatation on skeletal muscle metabolism. Skeletal muscle metabolism is abnormal in CHF and the aetiology is unclear. METHODS: Thirteen patients and 12 controls were studied by phosphorus Magnetic Resonance spectroscopy of the calf muscle using an incremental exercise protocol and by Magnetic Resonance imaging. RESULTS: Metabolic variables measured at rest were normal in Marfan patients. For a similar total work output measured at end of the standardized incremental exercise, the total rate of energy consumption (EC) was significantly increased in patients (21.2 +/- 2.3 mM ATP/min/W vs 13.6 +/- 1.4 mM ATP/min/W in controls). Similarly, both PCr and pH time-dependent changes were significantly different between groups. The absolute contributions of aerobic and glycolytic pathways to energy production were significantly higher in patients whereas they were similar when expressed relative to EC. CONCLUSIONS: The higher EC measured in patients with Marfan syndrome was supported by both oxidative and anaerobic metabolic pathways, thereby suggesting a decrease in muscle efficiency and/or muscle mass, as previously described in other diseases affecting skeletal muscle function such as heart failure and peripheral vascular disease.

Background: Chronic heart failure (CHF) is associated with abnormalities of skeletal muscle metabolism. This may be due to impaired oxygen delivery as a result of endothelial dysfunction. Aims: We postulated that ascorbic acid would improve oxygen delivery to exercising muscle and improve skeletal muscle metabolism. Methods: We studied skeletal muscle metabolism using 31P magnetic resonance spectroscopy in 39 CHF patients. Endothelial function was assessed by changes in pulse wave velocity. Subjects were randomised to receive 4g ascorbic acid daily for 4weeks in a placebo-controlled double-blind study. Results: Ascorbic acid significantly increased phosphocreatine utilization during exercise. In addition, glycolytic ATP synthesis increased in the ascorbic acid group (change in rate of ATP synthesis at 1min −0.21±0.76 with placebo, 2.06±0.60 following ascorbic acid; p

Background: Decreased mitochondrial respiratory chain function and increased oxidative stress have been implicated in the pathogenesis of Friedreich ataxia (FRDA), raising the possibility that energy enhancement and antioxidant therapies may be an effective treatment.Objective: To evaluate the long-term efficacy of a combined antioxidant and mitochondrial enhancement therapy on the bioenergetics and clinical course of FRDA.Design: Open-labeled pilot trial over 47 months.Patients: Seventy-seven patients with clinical and genetically defined FRDA.Intervention: A combined coenzyme Q(10) (400 mg/d) and vitamin E (2100 IU/d) therapy of 10 patients with FRDA over 47 months.Main Outcome Measures: Clinical assessment using echocardiography and the International Cooperative Ataxia Rating Scale and cardiac and skeletal muscle bioenergetics, as assessed using phosphorus P 31 magnetic resonance spectroscopy.Results: There was a significant improvement in cardiac and skeletal muscle bioenergetics that was maintained throughout the 47 months of therapy. Echocardiographic data revealed significantly increased fractional shortening at the 35- and 47-month time points. Comparison with cross-sectional data from 77 patients with FRDA indicated the changes in total International Cooperative Ataxia Rating Scale and kinetic scores over the trial period were better than predicted for 7 patients, but the posture and gait and hand dexterity scores progressed as predicted.Conclusion: This therapy resulted in sustained improvement in mitochondrial energy synthesis that was associated with a slowing of the progression of certain clinical features and a significant improvement in cardiac function.

Calcium-mediated excitotoxicity and defective energy metabolism have been implicated in the pathogenesis of Huntington disease (HD).1 In R6/2 HD transgenic mice, administration of 2% dietary creatine presymptomatically at 6 and 8 weeks improved survival, delayed motor progression, and reduced weight loss and brain atrophy.2,3 Creatine buffers intracellular energy reserves and has several neuroprotective effects demonstrated both in vivo and in vitro.4 A placebo-controlled pilot trial of 5 g/day of creatine for 1 year appeared ineffective in 26 patients with HD,5 although this dose was lower than the equivalent dose given to R6/2 HD mice. We previously reported clinical and MR spectroscopy (MRS) findings in a 1-year open-label pilot study of high-dose creatine (10 g/day) supplementation in 13 patients with HD.6 Serial 31P-MRS of muscle monitored changes in energy metabolism in vivo, and 1H-MRS was used to determine creatine levels in brain tissue. High-dose creatine was well tolerated, and total motor score (TMS), functional capacity, and neuropsychology testing remained stable at 12 months. We now report …

Following diffuse traumatic brain injury, there may be persistent functional or psychological deficits despite the presence of normal conventional MR images. Previous experimental animal and human studies have shown diffusion abnormalities following focal brain injury. Our aim was to quantify changes in apparent diffusion coefficient (ADC) and absolute relaxation times of normal appearing white matter (NAWM) in humans following traumatic brain injury. Twenty-three patients admitted with a diagnosis of head injury (nine mild, eight moderate, and six severe) were scanned an average of 7.6 days after injury using a quantitative echo planar imaging acquisition to obtain co-registered T1, T2, and ADC parametric maps. Mean NAWM values were compared with a control group (n = 13). The patient group showed a small but significant increase in ADC in NAWM, with no significant change in T1 or T2 relaxation times. There was a correlation between injury severity and increasing ADC (p = 0.03) but no correlation with either T1 or T2, suggesting that ADC is a sensitive and independent marker of diffuse white matter tissue damage following traumatic insult. None of the patients had a reduced ADC, making ischaemia unlikely in this cohort. Pathophysiological mechanisms that may explain diffusely raised ADC include vasogenic edema, chronic ischemic phenomena, or changes in tissue cytoarchitecture or neurofilament alignment.

Background— It is well known that patients with type 2 diabetes have increased risk of cardiovascular disease, but it is not known whether they have underlying abnormalities in cardiac or skeletal muscle high-energy phosphate metabolism. Methods and Results— We studied 21 patients with type 2 diabetes with no evidence of coronary artery disease or impaired cardiac function, as determined by echocardiography, and 15 age-, sex-, and body mass index-matched control subjects. Cardiac high-energy phosphate metabolites were measured at rest using 31 P nuclear magnetic resonance spectroscopy (MRS). Skeletal muscle high-energy phosphate metabolites, intracellular pH, and oxygenation were measured using 31 P MRS and near infrared spectrophotometry, respectively, before, during, and after exercise. Although their cardiac morphology, mass, and function appeared to be normal, the patients with diabetes had significantly lower phosphocreatine (PCr)/ATP ratios, at 1.50±0.11, than the healthy volunteers, at 2.30±0.12. The cardiac PCr/ATP ratios correlated negatively with the fasting plasma free fatty acid concentrations. Although skeletal muscle energetics and pH were normal at rest, PCr loss and pH decrease were significantly faster during exercise in the patients with diabetes, who had lower exercise tolerance. After exercise, PCr recovery was slower in the patients with diabetes and correlated with tissue reoxygenation times. The exercise times correlated negatively with the deoxygenation rates and the hemoglobin (Hb)A 1c levels and the reoxygenation times correlated positively with the HbA 1c levels. Conclusions— Type 2 diabetic patients with apparently normal cardiac function have impaired myocardial and skeletal muscle energy metabolism related to changes in circulating metabolic substrates.

A two-dimensional COSY-based localization sequence was designed to allow the in vivo monitoring of proton metabolites in rat brain [particularly gamma-aminobutyric acid (GABA), glutamine, taurine and myo-inositol]. The sequence incorporated OSIRIS signal localization, B1-insensitive water suppression and phase-sensitive COSY acquisition. The method was used to study the effects of the GABA-transaminase inhibitor vigabatrin on rat brain metabolite concentrations. Wistar rats were treated daily for 3 days with an oral dose of vigabatrin (200 mg/kg, n = 4). Localized COSY spectra were obtained during a 120 min acquisition from a 270 microl central brain voxel and compared with nine untreated control animals. Significant elevations were observed in GABA (267% of control, p < 0.005, Mann-Witney test), glutamine (130% of control, p < 0.005) and taurine (113% of control, p < 0.05). Changes in GABA and taurine were consistent with previous data on the action of Vigabatrin, and support a previously hypothesized link between these compounds. The increase in glutamine was more surprising and may reflect the balance between the level and/or site of GABA-transaminase inhibition and downregulation of GABA synthesis.

Progression of disability in multiple sclerosis (MS) appears related to axonal damage, which is at least in part associated with white matter lesions. Beta-interferon (BIFN) substantially reduces new inflammatory activity in MS and a recent report suggested that it may reverse a component of axonal injury. To test the generalisability of this conclusion, particularly in a population with relatively active disease, we used magnetic resonance spectroscopy measures to test whether BIFN can reverse or arrest progression of axonal injury in patients with MS. Eleven patients with a history of active (median, 1.5 relapses/year) relapsing-remitting MS were treated with BIFN and responses to treatment were monitored with serial MRI and single voxel magnetic resonance spectroscopic measurements of relative concentrations of brain N-acetylaspartate (NAA), a measure of axonal integrity from a central, predominantly white matter brain region. BIFN treatment was associated with a significant reduction in relapse rate (p = 0.007) and white matter water T2 relaxation time (p = 0.047) over 12 months. Also consistent with a treatment effect, white matter T2-hyperintense lesion loads did not increase. However, the central white matter NAA/creatine ratio (NAA/Cr, which was reduced over 16 % in patients relative to healthy controls at the start of treatment), continued to decrease in the patients over the period of observation (mean 6.2 % decrease, p = 0.02). For individual patients the magnitude of the NAA/Cr decrease was correlated with the frequency of relapses over the two years prior to treatment (r = -0.76, p = 0.006). These data suggest that reduction of new inflammatory activity with BIFN does not invariably halt progression of axonal injury. Nonetheless, there appears to be a relationship between the rate of progression of axonal injury and relapse rate over the previous two years. The consequences of reduced inflammation on pathological progression relevant to disability therefore may be present, but substantially delayed. Alternatively, distinct mechanisms may contribute to the two processes.

Quantitative MRI and phosphorus magnetic resonance spectroscopy ((31)P-MRS) were used to investigate skeletal muscle metabolism in vivo in patients with dermatomyositis (DM) and polymyositis (PM) in order to evaluate the role of mitochondrial abnormalities in the pathogenesis and clinical expression of these conditions. Nine patients with DM (mean age +/- SD, 57 +/- 14 years) and five with PM (42 +/- 12 years) and with age at disease onset 53 +/- 16 and 38 +/- 12 years, respectively, were included in the study together with 18 age-matched controls. Post-exercise (31)P-MRS indices of muscle oxidative metabolism were all impaired in DM and PM. In both groups of patients, the phosphocreatine and adenosine diphosphate recovery half-times were almost twice as long as in controls (P < 0.05 for each variable) and the maximum rate of mitochondrial ATP production was half that found in normal subjects (P < 0.001). The rate of proton efflux from muscle fibres was significantly reduced in DM (P < 0.001) and PM (P = 0.02). The impairment of (31)P-MRS recovery indices in DM and PM patients was similar to that found in a group of 10 patients with a primary mitochondrial disorder that showed a normal proton efflux rate. There was no correlation between the MRS-detectable abnormalities and the degree of inflammation or fatty infiltration of the muscle, as measured by MRI. The in vivo findings in DM and PM patients indicate impaired muscle aerobic function, which, considering the reduced proton efflux, is likely to be secondary to an impaired blood supply. Our results suggest that the abnormal mitochondria seen in some muscle biopsies are unlikely to be the primary cause of the oxidative insufficiency in these patients.

Echo-planar imaging (EPI) commonly suffers from ghosting artifacts caused by zero- or first-order phase differences between the odd and even echoes that constitute an EPI dataset. Small-bore imaging systems with shielded gradients may suffer significantly from cross-term eddy currents due to the high degree of manufacturing precision required in such systems compared to larger whole-body coils. A Nyquist ghost caused by cross-term eddy current contributions from the read-out to the phase-encode axis was identified in a small-bore system and characterized using a modified EPI experiment and a computer simulation. The artifact was corrected for using both a postprocessing approach and compensation blips along the phase-encode axis. Correction using compensation blips proved to be a more effective strategy to reduce this artifact than the postprocessing method used.

Aim To examine daytime liver glycogen accumulation in prepubertal children with Type 1 diabetes mellitus (Type 1 DM) compared with non-diabetic controls. Methods Liver glycogen content was ascertained in the fasting (morning) and fed (afternoon) state using 13C magnetic resonance (MR) spectroscopy. Data were analysed from six children with Type 1 DM (median (range) age 8.7 (6.3–12.2) years), who were all on conventional insulin regimens, and six healthy controls (age 8.9 (7–10.2) years). Results Children with diabetes tended to have lower fasting glycogen values than controls but this did not reach statistical significance (median (range) 154 (70–177) vs. 178 (120–203) mM glycosyl units, Type 1 DM vs. controls respectively; P = 0.06). Glycogen increased in all children with diabetes during the day and concentrations were similar to those in controls by the afternoon (175 (157–299) vs. 172 (136–238) mM glycosyl units; P = 0.7). Conclusions The ability of young children with Type 1 DM to replace liver glycogen depleted after an overnight fast was at least as good as that in control subjects, suggesting that impaired glycogen storage is not a contributory factor in nocturnal hypoglycaemia. Diabet. Med. 18, 659–662 (2001)

OBJECTIVES: Our aim was to measure the cardiac phosphocreatine to adenosine triphosphate ratio (PCr/ATP) noninvasively in patients and carriers of Xp21 muscular dystrophy and to correlate the results with left ventricular (LV) function as measured by echocardiography. BACKGROUND: Duchenne and Becker muscular dystrophy (the Xp21 dystrophies) are associated with the absence or altered expression of dystrophin in cardiac and skeletal muscles. They are frequently complicated by cardiac hypertrophy and dilated cardiomyopathy. The main role of dystrophin is believed to be structural, but it may also be involved in signaling processes. Defects in energy metabolism have been found in skeletal muscle in patients with Xp21 muscular dystrophy. We therefore hypothesized that a defect in energy metabolism may be part of the mechanism leading to the cardiomyopathy of Xp21 muscular dystrophy. METHODS: Thirteen men with Becker muscular dystrophy, 10 female carriers and 23 control subjects were studied using phosphorus-31 magnetic resonance spectroscopy and echocardiography. RESULTS: The PCr/ATP was significantly reduced in patients (1.55+/-0.37) and carriers (1.37+/-0.25) as compared with control subjects (2.44+/-0.33; p

Background —Sympathetic activation may limit exercise performance by restraining muscle blood flow or by negatively affecting skeletal muscle metabolic behavior. To test this hypothesis, we studied the effect of thoracoscopic sympathetic trunkotomy (TST) on forearm exercise duration, blood flow, and muscle bioenergetics in 13 patients with idiopathic palmar hyperhidrosis. Methods and Results —Heart rate and beat-by-beat mean arterial pressure were recorded at rest and during right and left rhythmic handgrip before and 4 to 7 weeks after right TST. Forearm blood flow was measured bilaterally at rest and on the right during exercise. Right forearm muscle phosphocreatine content and intracellular pH were assessed by 31 phosphorus magnetic resonance spectroscopy. After right TST, exercise duration increased from 8.9±1.4 to 13.4±1.8 minutes ( P P P P Conclusions —Sympathetic denervation of the upper limb significantly improves forearm skeletal muscle bioenergetics and exercise performance in patients with idiopathic palmar hyperhidrosis.

Background and Purpose —Infarct size on T2-weighted MRI correlates only modestly with outcome, particularly for small strokes. This may be largely because of differences in the locations of infarcts and consequently in the functional pathways that are damaged. To test this hypothesis quantitatively, we developed a “mask” of the corticospinal pathway to determine whether the extent of stroke intersection with the pathway would be more closely related to clinical motor deficit and axonal injury in the descending motor pathways than total stroke lesion volume. Methods —Eighteen patients were studied ≥1 month after first ischemic stroke that caused a motor deficit by use of brain T2-weighted imaging, MR spectroscopic (MRS) measurements of the neuronal marker compound N -acetyl aspartate in the posterior limb of the internal capsule, and motor impairment and disability measures. A corticospinal mask based on neuroanatomic landmarks was generated from a subset of the MRI data. The maximum proportion of the cross-sectional area of this mask occupied by stroke was determined for each patient after all brain images were transformed into a common stereotaxic brain space. Results —There was a significant linear relationship between the maximum proportional cross-sectional area of the corticospinal mask occupied by stroke and motor deficit ( r 2 =0.82, P r 2 =0.76, P N -acetyl aspartate reduction. Conclusions —Segmentation of functional motor pathways on MRI allows estimation of the extent of damage specifically to that pathway by the stroke lesion. The extent of stroke intersection with the motor pathways was more linearly related to the magnitude of motor deficit than total lesion volume and appeared to be a better discriminator between small strokes with regard to motor deficit. This emphasizes the importance of the anatomic relationship of the infarct to local structures in determining functional impairment. Prospective studies are necessary to assess whether this approach would allow improved early estimation of prognosis after stroke.

ANovartisPharmaAG, Basle, Switzerland Summary Background: MKT 077 is a rhodacyanine dye analogue which preferentially accumulates in tumour cell mitochondria. It is cytotoxic to a range of tumours. In this phase I study, MKT 077 was administered as a five-day infusion once every three weeks. Patients and methods: Ten patients, median age 59 (38-70) years, with advanced solid cancers were treated at three dose levels: 30, 40 and 50 mg/m 2 /day for a total of 18 cycles. 31 Phosphorus magnetic resonance spectroscopy (MRS) was used to evaluate the effect of MKT077 on skeletal muscle mitochondrial function. Results: The predominant toxicity was recurrent reversible functional renal impairment (grade 2, two patients). One patient with renal cancer attained stable disease and the remainder progressive disease. There were no MRS changes in the first or second treatment cycles but one patient received 11 treatment cycles and developed changes consistent with a mitochondrial myopathy. Mean values for all pharmacokinetic parameters were at sub micromolar levels and did not exceed IC50 values (>1 uM). Conclusions: Because of the renal toxicity, and animal studies showing MKT 077 causes eventual irreversible renal toxicity, further recruitment was halted. The study shows, however, that it is feasible to target mitochondria with rhodacyanine analogues, if drugs with higher therapeutic indices could be developed.

OBJECTIVE: To examine the effect of a relatively low dose of creatine on skeletal muscle metabolism and oxygen supply in a group of training athletes. METHODS: 31P magnetic resonance and near-infrared spectroscopy were used to study calf muscle metabolism in a group of 10 female members of a university swimming team. Studies were performed before and after a six week period of training during which they took either 2 g creatine daily or placebo. Calf muscle metabolism and creatine/choline ratios were studied in resting muscle, during plantar flexion exercise (10-15 min), and during recovery from exercise. RESULTS: There was no effect of creatine on metabolite ratios at rest or on metabolism during exercise and recovery from exercise. Muscle oxygen supply and exercise performance were not improved by creatine if compared to placebo treated subjects. CONCLUSIONS: Oral creatine supplementation at 2 g daily has no effect on muscle creatine concentration, muscle oxygen supply or muscle aerobic or anaerobic metabolism during endurance exercise.

Duchenne muscular dystrophy (DMD) is one of a range of muscular dystrophies caused by abnormalities of the short arm of the X chromosome (Xp21), which often cause mental retardation in addition to progressive muscular weakness. Normal dystrophin expression is lacking in both skeletal muscle and brain of affected subjects. Phosphorus-31 magnetic resonance spectroscopy has shown several abnormalities in skeletal muscle in DMD. We looked for similar abnormalities in brain in patients with DMD and related the findings to neuropsychological test results. We studied by magnetic resonance spectroscopy 19 boys (aged 76-167 months) diagnosed as having DMD and 19 control boys of similar age (87-135 months). Intelligence quotient (IQ) was assessed with the Wechsler Intelligence Scale for children. The DMD patients had significantly higher values than the controls in the brain ratios of inorganic phosphate to adenosine triphosphate (mean 0.53 [SD 0.21] vs 0.36 [0.09], p = 0.003), to phosphomonoesters (0.40 [0.07] vs 0.29 [0.07], p = 0.0001), and to phosphocreatine (0.44 [0.10] vs 0.37 [0.08], p = 0.02). There were significant differences between the DMD patients and the controls in full-scale IQ (76 [16] vs 101 [16], p = 0.0001), performance IQ (78 [17] vs 94 [14], p = 0.003), and verbal IQ (78 [17] vs 106 [17], p = 0.0001). These altered metabolite ratios parallel the findings in dystrophic muscle and suggest bioenergetic similarities in tissues that lack dystrophin.

Magnetic Resonance Imaging has become popular over the last few years as a technique for non-invasively imaging the internal structures of live subjects. In this paper we describe a technique to assist in the analysis of this type of data. We use quadratic B-splines and dynamic contours to track tagged regions of an infused rat heart, and analyse the motion of the tagged regions in terms of various predefined characteristic motions.

Ischaemic brain events necessitate prompt diagnosis and clinical intervention if the ischaemia is to be reversed. At present, MR is unable to distinguish between reversibly and irreversibly damaged tissue. Although apparent diffusion coefficient (ADC) MRI is established as a sensitive indicator of acute ischaemia, an unresolved challenge is to non-invasively distinguish between reversibly and irreversibly damaged tissue early in the ischaemic event. Endothelin-1 (ET-1) produces a potent and prolonged vasoconstrictive effect on the brain vasculature and has been used as a model of low flow ischaemia in the rat brain. We hypothesise that a focal striatal injection of ET-1 creates a graduated lesion consisting of both reversibly and irreversibly damaged tissue. A longitudinal study of MR-visible changes following intrastriatal ET-1 injection in the juvenile rat brain was conducted and correlated with the metabolic status of brain tissue using phosphorus (31P) MRS. Male Wistar rats (50-55 g) were anaesthetised by inhalation using 2% isoflurane in 70% N2O:30% O2. Using a minimally-invasive stereotaxic procedure, 160pmoles of ET-1 was injected in a volume of 1.0 l of sterile saline into the striatum (n=8). Animals were positioned in a purpose-built head restraint system and a 2 cm-diameter single-turn circular surface phosphorus coil was placed over the animal's head. Anaesthesia was maintained in the magnet using 1% isoflurane in 70% N2O:30% O2. T1 and T2-weighted images, DWI and 31P spectra were obtained using a 7 T horizontal bore magnet (Magnex Scientific) interfaced to a Varian/SISCO spectrometer (Varian, Palo Alto, CA, USA). We observed a significant decrease in the ADC around the site of injection at 2.5 h post-injection [Figure 1a & e]. MRI was repeated at 6, 24 and 72 hrs over which time ADC changes resolved in the periphery of the lesion, but remained low at the core. These findings suggest that the tissue at the core of the lesion may be irreversibly damaged whereas normalisation of ADC in the periphery may be indicative of reversibly damaged tissue. 31P spectra from the whole of the injected hemisphere did not detect any reductions in the PCr to ATP ratio. Significant changes in these metabolites may only occur in the speculated irreversibly damaged core of the lesion, which constitutes less than 25% of the 31P MRS voxel. The inclusion of a significant volume of healthy tissue in the 31P MRS voxel may explain the absence of a change in metabolite levels. Ongoing studies are investigating the perfusion changes in the core and peripheral regions of ET-1-induced focal lesions and their correlation with ADC changes.

Surface coils are widely used for spectroscopy in vivo because they are sensitive and effect a degree of spatial localization. However, they produce an inhomogeneous B1 field. In this paper, a concentric surface-coil probe is described which reduces this imperfection, and it is shown how the electrical interactions between magnetically coupled coils may be controlled.

A circuit is described for the electrical isolation of double coil probes where separate transmitter and receiver coils are both tuned to the same frequency and are coupled by mutual inductance. There are only passive components in the probe, and so no additional control signals are required for switching between transmit and receive conditions. An analysis of the operation of the circuit is included together with details of component selection and setting-up procedures, thus facilitating the implementation of the design for a variety of applications in both imaging and spectroscopy.

Phase-modulated rotating-frame imaging, a technique which has been used for localized 31P spectroscopy in vivo, has been modeled using rotation matrices to predict the response of an isolated spin- 1 2 system to the two-pulse experiment under conditions of off resonance and nonideal phase-encoding pulse. Two experiments are carried out in order to remove the phase twist inherent in the phase-modulated experiment; the incremental pulse (θ) is applied with phase φσ = 0 and φσ = π with respect to the phase-encoding pulse (λ) phase of φλ = π/2 The peak shape resulting from the 2D FT is described in terms of a combination of absorption- and dispersion-mode peaks in the chemical-shift and spatial dimensions. Using this model, it is possible to set out guidelines for the implementation of the phase-modulated rotating-frame imaging method. The effective sweep width in (B0) and (B1) over which the experiment can be usefully performed and the nature of the two-dimensional peak shape at a point can be readily derived from the model.

Rotating-frame depth selection, a reduction of the full rotating-frame imaging experiment, has recently been developed as a method for spatial localization of NMR spectra. Using selected pulses and tailoring the number of transients, a region of sensitivity may be specified and maximum signal received from the desired position of interest in the sample. The application of the technique to human spectroscopy is particularly demanding due to the shape of the sample and the need for optimum sensitivity. Here a two-coil system is used for transmit and receive which can interrogate flat, planar slices to a depth of up to 7 cm, retaining maximum slice excitation and negligible surface contamination. Possible artifacts include distortions due to partial saturation, harmonic excitation, and off resonance effects; these are analyzed and, where possible, eliminated. This technique, which is now in routine use in a clinical laboratory, can give good quality spectra from several human organs and is illustrated by results from brain, liver, heart, and muscle.