Postcontraction [acetylcarnitine] reflects interindividual variation in skeletal muscle ATP production patterns in vivo.

In addition to its role in substrate selection (carbohydrate vs. fat) for oxidative metabolism in muscle, acetylcarnitine production may be an important modulator of the energetic pathway by which ATP is produced. A combination of noninvasive magnetic resonance spectroscopy measures of cytosolic acetylcarnitine and ATP production pathways was used to investigate the link between [acetylcarnitine] and energy production in vivo. Intracellular metabolites were measured in the vastus lateralis muscle of eight males (mean: 28.4 yr, range: 25-35) during 8 min of incremental, dynamic contractions (0.5 Hz, 2-min stages at 6%, 9%, 12%, and 15% maximal torque) that increased [acetylcarnitine] approximately fivefold from resting levels. ATP production via oxidative phosphorylation, glycolysis, and the creatine kinase reaction was calculated based on phosphorus metabolites and pH. Spearman rank correlations indicated that postcontraction [acetylcarnitine] was positively associated with both absolute (mM) and relative (% total ATP) glycolytic ATP production (rs = 0.95, P = 0.001; rs = 0.93, P = 0.002), and negatively associated with relative (rs = -0.81, P = 0.02) but not absolute (rs = -0.14, P = 0.75) oxidative ATP production. Thus, acetylcarnitine accumulated more when there was a greater reliance on "nonoxidative" glycolysis and a relatively lower contribution from oxidative phosphorylation, reflecting the fate of pyruvate in working skeletal muscle. Furthermore, these data indicate striking interindividual variation in responses to the energy demand of submaximal contractions. Overall, the results of this preliminary study provide novel evidence of the coupling in vivo between ATP production pathways and the carnitine system.NEW & NOTEWORTHY Production of acetylcarnitine from acetyl-CoA and free carnitine may be important for energy pathway regulation in contracting skeletal muscle. Noninvasive magnetic resonance spectroscopy was used to investigate the link between acetylcarnitine and energy production in the vastus lateralis muscle during dynamic contractions (n = 8 individuals). A positive correlation between acetylcarnitine accumulation and "nonoxidative" glycolysis and an inverse relationship with oxidative phosphorylation, provides novel evidence of the coupling between ATP production and the carnitine system in vivo.

Frontal cortex neurometabolites and mobility in older adults: a preliminary study.

BACKGROUND: The frontal cortex, relevant to global cognition and motor function, is recruited to compensate for mobility dysfunction in older adults. However, the in vivo neurophysiological (e.g., neurometabolites) underpinnings of the frontal cortex compensation for mobility dysfunction remain poorly understood. The purpose of this study was to investigate the relationships among frontal cortex neurophysiology, mobility, and cognition in healthy older adults. METHODS: Magnetic Resonance Spectroscopy (MRS) quantified N-acetylasparate (tNAA) and total choline (tCho) concentrations and ratios in the frontal cortex in 21 older adults. Four inertial sensors recorded the Timed Up & Go (TUG) test. Cognition was assessed using the Flanker Inhibitory Control and Attention Test which requires conflict resolution because of response interference from flanking distractors during incongruent trials. Congruent trials require no conflict resolution. RESULTS: tNAA concentration significantly related to the standing (p = 0.04) and sitting (p = 0.03) lean angles. tCho concentration (p = 0.04) and tCho ratio (p = 0.02) significantly related to TUG duration. tCho concentration significantly related to incongruent response time (p = 0.01). tCho ratio significantly related to both congruent (p = 0.009) and incongruent (p < 0.001) response times. Congruent (p = 0.02) and incongruent (p = 0.02) Flanker response times significantly related to TUG duration. CONCLUSIONS: Altered levels of frontal cortex neurometabolites are associated with both mobility and cognitive abilities in healthy older adults. Identifying neurometabolites associated with frontal cortex compensation of mobility dysfunction could improve targeted therapies aimed at improving mobility in older adults.

Dictionary learning compressed sensing reconstruction: pilot validation of accelerated echo planar J-resolved spectroscopic imaging in prostate cancer.

OBJECTIVES: This study aimed at developing dictionary learning (DL) based compressed sensing (CS) reconstruction for randomly undersampled five-dimensional (5D) MR Spectroscopic Imaging (3D spatial + 2D spectral) data acquired in prostate cancer patients and healthy controls, and test its feasibility at 8x and 12x undersampling factors. MATERIALS AND METHODS: Prospectively undersampled 5D echo-planar J-resolved spectroscopic imaging (EP-JRESI) data were acquired in nine prostate cancer (PCa) patients and three healthy males. The 5D EP-JRESI data were reconstructed using DL and compared with gradient sparsity-based Total Variation (TV) and Perona-Malik (PM) methods. A hybrid reconstruction technique, Dictionary Learning-Total Variation (DLTV), was also designed to further improve the quality of reconstructed spectra. RESULTS: The CS reconstruction of prospectively undersampled (8x and 12x) 5D EP-JRESI data acquired in prostate cancer and healthy subjects were performed using DL, DLTV, TV and PM. It is evident that the hybrid DLTV method can unambiguously resolve 2D J-resolved peaks including myo-inositol, citrate, creatine, spermine and choline. CONCLUSION: Improved reconstruction of the accelerated 5D EP-JRESI data was observed using the hybrid DLTV. Accelerated acquisition of in vivo 5D data with as low as 8.33% samples (12x) corresponds to a total scan time of 14 min as opposed to a fully sampled scan that needs a total duration of 2.4 h (TR = 1.2 s, 32 [Formula: see text]×16 [Formula: see text]×8 [Formula: see text], 512 [Formula: see text] and 64 [Formula: see text]).

Effects of old age and contraction mode on knee extensor muscle ATP flux and metabolic economy in vivo.

KEY POINTS: We used 31-phosphorus magnetic resonance spectroscopy to quantify in vivo skeletal muscle metabolic economy (ME; mass-normalized torque or power produced per ATP consumed) during three 24 s maximal-effort contraction protocols: (1) sustained isometric (MVIC), (2) intermittent isokinetic (MVDCIsoK ), and (3) intermittent isotonic (MVDCIsoT ) in the knee extensor muscles of young and older adults. ME was not different between groups during the MVIC but was lower in older than young adults during both dynamic contraction protocols. These results are consistent with an increased energy cost of locomotion, but not postural support, with age. The effects of old age on ME were not due to age-related changes in muscle oxidative capacity or ATP flux. Specific power was lower in older than young adults, despite similar total ATP synthesis between groups. Together, this suggests a dissociation between cross-bridge activity and ATP utilization with age. ABSTRACT: Muscle metabolic economy (ME; mass-normalized torque or power produced per ATP consumed) is similar in young and older adults during some isometric contractions, but less is known about potential age-related differences in ME during dynamic contractions. We hypothesized that age-related differences in ME would exist only during dynamic contractions, due to the increased energetic demand of dynamic versus isometric contractions. Ten young (Y; 27.5 ± 3.9 years, 6 men) and 10 older (O; 71 ± 5 years, 5 men) healthy adults performed three 24 s bouts of maximal contractions: (1) sustained isometric (MVIC), (2) isokinetic (120°·s-1 , MVDCIsoK ; 0.5 Hz), and (3) isotonic (load = 20% MVIC, MVDCIsoT ; 0.5 Hz). Phosphorus magnetic resonance spectroscopy of the vastus lateralis muscle was used to calculate ATP flux (mM ATP·s-1 ) through the creatine kinase reaction, glycolysis and oxidative phosphorylation. Quadriceps contractile volume (cm3 ) was measured by MRI. ME was calculated using the torque-time integral (MVIC) or power-time integral (MVDCIsoK and MVDCIsoT ), total ATP synthesis and contractile volume. As hypothesized, ME was not different between Y and O during the MVIC (0.12 ± 0.03 vs. 0.12 ± 0.02 Nm. s. cm-3. mM ATP-1 , mean ± SD, respectively; P = 0.847). However, during both MVDCIsoK and MVDCIsoT , ME was lower in O than Y adults (MVDCIsoK : 0.011 ± 0.003 vs. 0.007 ± 0.002 J. cm-3. mM ATP-1 ; P < 0.001; MVDCIsoT : 0.011 ± 0.002 vs. 0.008 ± 0.002; P = 0.037, respectively), despite similar muscle oxidative capacity, oxidative and total ATP flux in both groups. The lower specific power in older than young adults, despite similar total ATP synthesis between groups, suggests there is a dissociation between cross-bridge activity and ATP utilization with age.

Oxidative ATP synthesis in human quadriceps declines during 4 minutes of maximal contractions.

KEY POINTS: During maximal exercise, skeletal muscle metabolism and oxygen consumption remain elevated despite precipitous declines in power. Presently, it is unclear whether these responses are caused by an increased ATP cost of force generation (ATPCOST ) or mitochondrial uncoupling; a process that reduces the efficiency of oxidative ATP synthesis (ATPOX ). To address this gap, we used 31-phosphorus magnetic resonance spectroscopy to measure changes in ATPCOST and ATPOX in human quadriceps during repeated trials of maximal intensity knee extensions lasting up to 4 min. ATPCOST remained unchanged. In contrast, ATPOX plateaued by ∼2 min and then declined (∼15%) over the final 2 min. The maximal capacity for ATPOX (Vmax ), as well as ADP-specific rates of ATPOX , were also significantly diminished. Collectively, these results suggest that mitochondrial uncoupling, and not increased ATPCOST , is responsible for altering the regulation of skeletal muscle metabolism and oxygen consumption during maximal exercise. ABSTRACT: The relationship between skeletal muscle oxygen consumption and power output is augmented during exercise at workloads above the lactate threshold. Potential mechanisms for this response have been hypothesized, including increased ATP cost of force generation (ATPCOST ) and mitochondrial uncoupling, a process that reduces the efficiency of oxidative ATP synthesis (ATPOX ). To test these hypotheses, we used phosphorus magnetic resonance spectroscopy to non-invasively measure changes in phosphate concentrations and pH in the vastus lateralis muscle of nine young adults during repeated trials of maximal, all-out dynamic knee extensions (120°s-1 , 1 every 2 s) lasting 24, 60, 120, and 240 s. ATPOX was measured at each time point from the initial velocity of PCr resynthesis, and ATPCOST was calculated as the sum of ATP synthesized by the creatine and adenylate kinase reactions, non-oxidative glycolysis, ATPOX and net changes in [ATP]. Power output declined in a reproducible manner for all four trials. ATPCOST did not change over time (main effect P = 0.45). ATPOX plateaued from 60 to 120 s and then decreased over the final 120 s (main effect P = 0.001). The maximal capacity for oxidative ATP synthesis (Vmax ), as well as ADP-specific rates of ATPOX , also decreased over time (main effect P = 0.001, both). Collectively, these results demonstrate that prolonged maximal contraction protocols impair oxidative energetics and implicate mitochondrial uncoupling as the mechanism for this response. The causes of mitochondrial uncoupling are presently unknown but may offer a potential explanation for the dissociation between skeletal muscle power output and oxygen consumption during maximal, all-out exercise protocols.

Validity and accuracy of calculating oxidative ATP synthesis in vivo during high-intensity skeletal muscle contractions.

Several methods have been developed for using 31 P-MRS to calculate rates of oxidative ATP synthesis (ATPOX ) during muscular contractions based on assumptions that (1) the ATP cost of force generation (ATPCOST ) remains constant or (2) Michaelis-Menten coupling between cytosolic ADP and ATPOX does not change. However, growing evidence suggests that one, or both, of these assumptions are invalid during high-intensity fatigue protocols. Consequently, there is a need to examine the validity and accuracy of traditional ATPOX calculation methods under these conditions. To address this gap, we measured phosphate concentrations and pH in the vastus lateralis muscle of nine young adults during four rest-contraction-recovery trials lasting 24, 60, 120, and 240 s. The initial velocity of phosphocreatine resynthesis (ViPCr ) following each trial served as the criterion measure of ATPOX because this method makes no assumptions of constant ATPCOST or Michaelis-Menten coupling between changes in cytosolic ADP and ATPOX . Subsequently, we calculated ATPOX throughout the 240 s trial using several traditional calculation methods and compared estimations of ATPOX from each method with time-matched measurements of ViPCr . Method 1, which assumes that ATPCOST does not change, was able to model changes in ViPCr over time, but showed poor accuracy for predicting ViPCr across a wide range of ATPOX values. In contrast, Michaelis-Menten methods, which assume that the relationship between changes in cytosolic ADP and ATPOX remains constant, were invalid because they could not model the decline in ViPCr . However, adjusting these Michaelis-Menten methods for observed changes in maximal ATPOX capacity (i.e., Vmax ) permitted modeling of the decline in ViPCr and markedly improved accuracy. The results of these comprehensive analyses demonstrate that valid, accurate measurements of ATPOX can be obtained during high-intensity contractions by adjusting Michaelis-Menten ATPOX calculations for changes in Vmax observed from baseline to post-fatigue.

Non-invasive detection of 2-hydroxyglutarate in IDH-mutated gliomas using two-dimensional localized correlation spectroscopy (2D L-COSY) at 7 Tesla.

BACKGROUND: Mutations in the isocitrate dehydrogenase enzyme are present in a majority of lower-grade gliomas and secondary glioblastomas. This mis-sense mutation results in the neomorphic reduction of isocitrate dehydrogenase resulting in an accumulation of the "oncometabolite" 2-hydroxyglutarate (2HG). Detection of 2HG can thus serve as a surrogate biomarker for these mutations, with significant translational implications including improved prognostication. Two dimensional localized correlated spectroscopy (2D L-COSY) at 7T is a highly-sensitive non-invasive technique for assessing brain metabolism. This study aims to assess tumor metabolism using 2D L-COSY at 7T for the detection of 2HG in IDH-mutant gliomas. METHODS: Nine treatment-naïve patients with suspected intracranial neoplasms were scanned at 7T MRI/MRS scanner using the 2D L-COSY technique. 2D-spectral processing and analyses were performed using a MATLAB-based reconstruction algorithm. Cross and diagonal peak volumes were quantified in the 2D L-COSY spectra and normalized with respect to the creatine peak at 3.0 ppm and quantified data were compared with previously-published data from six normal subjects. Detection of 2HG was validated using findings from immunohistochemical (IHC) staining in patients who subsequently underwent surgical resection. RESULTS: 2HG was detected in both of the IDH-mutated gliomas (grade III Anaplastic Astrocytoma and grade II Diffuse Astrocytoma) and was absent in IDH wild-type gliomas and in a patient with breast cancer metastases. 2D L-COSY was also able to resolve complex and overlapping resonances including phosphocholine (PC) from glycerophosphocholine (GPC), lactate (Lac) from lipids and glutamate (Glu) from glutamine (Gln). CONCLUSIONS: This study demonstrates the ability of 2D L-COSY to unambiguously detect 2HG in addition to other neuro metabolites. These findings may aid in establishing 2HG as a biomarker of malignant progression as well as for disease monitoring in IDH-mutated gliomas.

Obstructive sleep apnea is associated with low GABA and high glutamate in the insular cortex.

The insular cortex is injured in obstructive sleep apnea (OSA) and responds inappropriately to autonomic challenges, suggesting neural reorganization. The objective of this study was to assess whether the neural changes might result from γ-aminobutyric acid (GABA) and glutamate alterations. We studied 14 OSA patients [mean age ± standard deviation (SD): 47.5 ± 10.5 years; nine male; apnea-hypopnea index (AHI): 29.5 ± 15.6 events h(-1) ] and 22 healthy participants (47.5 ± 10.1 years; 11 male), using magnetic resonance spectroscopy to detect GABA and glutamate levels in insular cortices. We localized the cortices with anatomical scans, and measured neurochemical levels from anterior to mid-regions. Left and right anterior insular cortices showed lower GABA and higher glutamate in OSA versus healthy subjects [GABA left: OSA n = 6: 0.36 ± 0.10 (mean ± SD), healthy n = 5: 0.62 ± 0.18; P < 0.05), right: OSA n = 11: 0.27 ± 0.09, healthy n = 14: 0.45 ± 0.16; P < 0.05; glutamate left: OSA n = 6: 1.61 ± 0.32, healthy n = 8: 0.94 ± 0.34; P < 0.05, right: OSA n = 14: 1.26 ± 0.28, healthy n = 19: 1.02 ± 0.28; P < 0.05]. GABA and glutamate levels were correlated only within the healthy group in the left insula (r: -0.9, P < 0.05). The altered anterior insular levels of GABA and glutamate may modify integration and projections to autonomic areas, contributing to the impaired cardiovascular regulation in OSA.

Accelerated echo planar J-resolved spectroscopic imaging in prostate cancer: a pilot validation of non-linear reconstruction using total variation and maximum entropy.

The overlap of metabolites is a major limitation in one-dimensional (1D) spectral-based single-voxel MRS and multivoxel-based MRSI. By combining echo planar spectroscopic imaging (EPSI) with a two-dimensional (2D) J-resolved spectroscopic (JPRESS) sequence, 2D spectra can be recorded in multiple locations in a single slice of prostate using four-dimensional (4D) echo planar J-resolved spectroscopic imaging (EP-JRESI). The goal of the present work was to validate two different non-linear reconstruction methods independently using compressed sensing-based 4D EP-JRESI in prostate cancer (PCa): maximum entropy (MaxEnt) and total variation (TV). Twenty-two patients with PCa with a mean age of 63.8 years (range, 46-79 years) were investigated in this study. A 4D non-uniformly undersampled (NUS) EP-JRESI sequence was implemented on a Siemens 3-T MRI scanner. The NUS data were reconstructed using two non-linear reconstruction methods, namely MaxEnt and TV. Using both TV and MaxEnt reconstruction methods, the following observations were made in cancerous compared with non-cancerous locations: (i) higher mean (choline + creatine)/citrate metabolite ratios; (ii) increased levels of (choline + creatine)/spermine and (choline + creatine)/myo-inositol; and (iii) decreased levels of (choline + creatine)/(glutamine + glutamate). We have shown that it is possible to accelerate the 4D EP-JRESI sequence by four times and that the data can be reliably reconstructed using the TV and MaxEnt methods. The total acquisition duration was less than 13 min and we were able to detect and quantify several metabolites.

A pilot validation of multi-echo based echo-planar correlated spectroscopic imaging in human calf muscles.

A current limitation of MR spectroscopic imaging of multiple skeletal muscles is prolonged scan duration. A significant reduction in the total scan duration using the echo-planar correlated spectroscopic imaging (EP-COSI) sequence was accomplished using two bipolar readout trains with different phase-encoded echoes for one of two spatial dimensions within a single repetition time (TR). The second bipolar readout was used for spatially encoding the outer k-space, whereas the first readout was used for the central k-space only. The performance of this novel sequence, called multi-echo based echo-planar correlated spectroscopic imaging (ME-EPCOSI), was demonstrated by localizing specific key features in calf muscles and bone marrow of 11 healthy volunteers and five subjects with type 2 diabetes (T2D). A 3 T MRI-MRS scanner equipped with a transmit-receive extremity coil was used. Localization of the ME-EPCOSI sequence was in good agreement with the earlier single-readout based EP-COSI sequence and the required scan time was reduced by a factor of two. In agreement with an earlier report using single-voxel based 2D MRS, significantly increased unsaturated pools of intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) and decreased IMCL and EMCL unsaturation indices (UIs) were observed in the soleus and tibialis anterior muscle regions of subjects with T2D compared with healthy controls. In addition, significantly decreased choline content was observed in the soleus of T2D subjects compared with healthy controls. Multi-voxel characterization of IMCL and EMCL ratios and UI in the calf muscle may be useful for the non-invasive assessment of altered lipid metabolism in the pathophysiology of T2D.

Multidimensional MR spectroscopic imaging of prostate cancer in vivo.

Prostate cancer (PCa) is the second most common type of cancer among men in the United States. A major limitation in the management of PCa is an inability to distinguish, early on, cancers that will progress and become life threatening. One-dimensional (1D) proton ((1)H) MRS of the prostate provides metabolic information such as levels of choline (Ch), creatine (Cr), citrate (Cit), and spermine (Spm) that can be used to detect and diagnose PCa. Ex vivo high-resolution magic angle spinning (HR-MAS) of PCa specimens has revealed detection of more metabolites such as myo-inositol (mI), glutamate (Glu), and glutamine (Gln). Due to the J-modulation and signal overlap, it is difficult to quantitate Spm and other resonances in the prostate clearly by single- and multivoxel-based 1D MR spectroscopy. This limitation can be minimized by adding at least one more spectral dimension by which resonances can be spread apart, thereby increasing the spectral dispersion. However, recording of multivoxel-based two-dimensional (2D) MRS such as J-resolved spectroscopy (JPRESS) and correlated spectroscopy (L-COSY) combined with 2D or three-dimensional (3D) magnetic resonance spectroscopic imaging (MRSI) using conventional phase-encoding can be prohibitively long to be included in a clinical protocol. To reduce the long acquisition time required for spatial encoding, the echo-planar spectroscopic imaging (EPSI) technique has been combined with correlated spectroscopy to give four-dimensional (4D) echo-planar correlated spectroscopic imaging (EP-COSI) as well as J-resolved spectroscopic imaging (EP-JRESI) and the multi-echo (ME) variants. Further acceleration can be achieved using non-uniform undersampling (NUS) and reconstruction using compressed sensing (CS). Earlier versions of 2D MRS, theory of 2D MRS, spectral apodization filters, newer developments and the potential role of multidimensional MRS in PCa detection and management will be reviewed here.

Implementation of two-dimensional L-COSY at 7 Tesla: an investigation of reproducibility in human brain.

PURPOSE: To evaluate the utility of two-dimensional (2D) Localized Correlated Spectroscopy (L-COSY) in metabolic profiling of the human brain at 7 Tesla (T). MATERIALS AND METHODS: The 2D L-COSY sequence was implemented at 7 T and its reliability was assessed by test-retest studies of a metabolite phantom and a healthy volunteer. L-COSY data were acquired from the occipital lobe of healthy subjects (n = 6; all male; age, 30-72 years) to assess intersubject variability. Additionally, two subjects underwent scans from the parieto-occipital region, basal ganglia, frontal lobe or dorsolateral prefrontal cortex to test the versatility of L-COSY in studying differing anatomy. Integral/volume measurements of L-COSY spectra were used to estimate normalized metabolite-to-creatine concentrations. RESULTS: Phantom test-retest studies revealed coefficients of variation (CVs) of 3-20% for most metabolites. Human 2D L-COSY spectra permitted detection of several metabolite resonances from multiple locations and inter-subject variation studies demonstrated CVs of 4-26%. Cross-peaks from gamma-aminobutyric acid (GABA), isoleucine (Ile), lysine (Lys) and Ethanolamine (Eth) were quantified, which are not readily resolvable with conventional one-dimensional (1D) MR spectroscopy. CONCLUSION: 2D L-COSY at 7 T demonstrated improved sensitivity in detecting additional metabolites with reliability comparable to established techniques at lower fields, which may aid in the metabolic assessment of diseased states.

Measurements of in vivo skeletal muscle oxidative capacity are lower following sustained isometric compared with dynamic contractions.

Human skeletal muscle oxidative capacity can be quantified non-invasively using 31-phosphorus magnetic resonance spectroscopy (31P-MRS) to measure the rate constant of phosphocreatine (PCr) recovery (kPCr) following contractions. In the quadricep muscles, several studies have quantified kPCr following 24-30 s of sustained maximal voluntary isometric contraction (MVIC). This approach has the advantage of simplicity but is potentially problematic because sustained MVICs inhibit perfusion, which may limit muscle oxygen availability or increase the intracellular metabolic perturbation, and thus affect kPCr. Alternatively, dynamic contractions allow reperfusion between contractions, which may avoid limitations in oxygen delivery. To determine whether dynamic contraction protocols elicit greater kPCr than sustained MVIC protocols, we used a cross-sectional design to compare quadriceps kPCr in 22 young and 11 older healthy adults following 24 s of maximal voluntary: (1) sustained MVIC and (2) dynamic (MVDC; 120°·s-1, 1 every 2 s) contractions. Muscle kPCr was ∼20% lower following the MVIC protocol compared with the MVDC protocol (p ≤ 0.001), though this was less evident in older adults (p = 0.073). Changes in skeletal muscle pH (p ≤ 0.001) and PME accumulation (p ≤ 0.001) were greater following the sustained MVIC protocol, and pH (p ≤ 0.001) and PME (p ≤ 0.001) recovery were slower. These results demonstrate that (i) a brief, sustained MVIC yields a lower value for skeletal muscle oxidative capacity than an MVDC protocol of similar duration and (ii) this difference may not be consistent across populations (e.g., young vs. old). Thus, the potential effect of contraction protocol on comparisons of kPCr in different study groups requires careful consideration in the future.

Assessing the Dose-Dependent Effects of tDCS on Neurometabolites using Magnetic Resonance Spectroscopy.

Concurrent transcranial direct current stimulation (tDCS) and proton Magnetic Resonance Spectroscopy ( 1 H MRS) experiments have shown up- or downregulation of neurotransmitter concentration. However, effects have been modest applying mostly lower current doses and not all studies found significant effects. Dose of stimulation might be an important variable in eliciting a consistent response. To investigate dose effects of tDCS on neurometabolites, we placed an electrode over the left supraorbital region (with a return electrode over the right mastoid bone) and utilized an MRS voxel (3x3x3cm) that was centered over the anterior cingulate/inferior mesial prefrontal region which is in the path of the current distribution. We conducted 5 epochs of acquisition, each one with a 9:18min acquisition time, and applied tDCS in the third epoch. We observed significant dose and polarity dependent modulation of GABA and to a lesser degree of Glutamine/Glutamate (GLX) with the highest and reliable changes seen with the highest current dose, 5mA (current density 0.39 mA/cm 2 ), during and after the stimulation epoch compared with pre-stimulation baselines. The strong effect on GABA concentration (achieving a mean change of 63% from baseline, more than twice as much as reported with lower doses of stimulation) establishes tDCS-dose as an important parameter in eliciting a regional brain engagement and response. Furthermore, our experimental design in examining tDCS parameters and effects using shorter epochs of acquisitions might constitute a framework to explore the tDCS parameter space further and establish measures of regional engagement by non-invasive brain-stimulation.

Alterations of gray and white matter volumes and cortical thickness in treated HIV-positive patients.

Brain structural changes in HIV identified by voxel-based morphometry (VBM) alone could arise from a variety of causes that are difficult to distinguish without further information, such as cortical thickness (CT), gyrification index (GI) or sulcal depth (SD). Hence, our goal was to assess these additional metrics in HIV using high-resolution 3D T1-weighted images and investigate if surface-based morphometric (SBM) analysis would reveal significant changes in the gray matter (GM) and white matter (WM) volumes combined with alterations in cortical thickness (CT), gyrification index (GI), sulcal depth (SD). T1-w magnetization-prepared-rapid-acquisition gradient-echo (MP-RAGE) scans were acquired in 27 HIV-infected individuals on antiretroviral therapy (ART) and 15 HIV-uninfected healthy controls using a 3T MRI scanner equipped with a 16-channel head "receive" and a quadrature body "transmit" coil. Voxel-based and surface-based morphometric analyses were performed using the MATLAB based SPM Computational Anatomy Toolbox (CAT12.7(1700)). HIV-infected patients showed significantly altered GM and WM volumes, CT, GI, and SD, in multiple brain regions. This study showed the association of altered GM and WM volumes in local brain regions with the changes in region-wise CT, GI and SD measures of HIV-infected patients, especially in the parahippocampal and middle frontal regions as compared to uninfected healthy controls. The outcome of this study suggests that the findings of VBM may not necessarily indicate the volumetric shrinkage or increase alone, but might also be due to altered CT, GI, or SD. Correlation analysis showed a significantly accelerated gray matter loss with age in HIV-infected individuals compared to uninfected healthy controls.

Use of MR imaging to determine preservation of the neurovascular bundles at robotic-assisted laparoscopic prostatectomy.

PURPOSE: To determine whether findings at preoperative endorectal coil magnetic resonance (MR) imaging influence the decision to preserve neurovascular bundles and the extent of surgical margins in robotic-assisted laparoscopic prostatectomy (RALP). MATERIALS AND METHODS: This study was approved by the investigational review board and was compliant with the HIPAA; the requirement to obtain informed consent was waived. The authors prospectively evaluated 104 consecutive men with biopsy-proved prostate cancer who underwent preoperative endorectal coil MR imaging of the prostate and subsequent RALP. MR imaging was performed at 1.5 T between January 2004 and April 2008 and included T2-weighted imaging (n = 104), diffusion-weighted imaging (n = 88), dynamic contrast-enhanced imaging (n = 51), and MR spectroscopy (n = 91). One surgeon determined the planned preoperative extent of resection bilaterally on the basis of clinical information and then again after review of the final MR imaging report. The differences in the surgical plan before and after review of the MR imaging report were determined and compared with the actual surgical and pathologic results by using logistic regression analysis. Continuous and ranked variables underwent Pearson and Spearman analysis. RESULTS: After review of MR imaging results, the initial surgical plan was changed in 28 of the 104 patients (27%); the surgical plan was changed to a nerve-sparing technique in 17 of the 28 patients (61%) and to a non-nerve-sparing technique in 11 (39%). Seven of the 104 patients (6.7%) had positive surgical margins. In patients whose surgical plan was changed to a nerve-sparing technique, there were no positive margins on the side of the prostate with a change in treatment plan. CONCLUSION: Preoperative prostate MR imaging data changed the decision to use a nerve-sparing technique during RALP in 27% of patients in this series.

Application of compressed sensing to multidimensional spectroscopic imaging in human prostate.

The application of compressed sensing is demonstrated in a recently implemented four-dimensional echo-planar based J-resolved spectroscopic imaging sequence combining two spatial and two spectral dimensions. The echo-planar readout simultaneously acquires one spectral and one spatial dimension. Therefore, the compressed sensing undersampling is performed along the indirectly acquired spatial and spectral dimensions, and the reconstruction is performed using the split Bregman algorithm, an efficient TV-minimization solver. The four-dimensional echo-planar-based J-resolved spectroscopic imaging data acquired in a prostate phantom containing metabolites at physiological concentrations are accurately reconstructed with as little as 20% of the original data. Experimental data acquired in six healthy prostates using the external body matrix "receive" coil on a 3T magnetic resonance imaging scanner are reconstructed with acquisitions using only 25% of the Nyquist-Shannon required amount of data, indicating the potential for a 4-fold acceleration factor in vivo, bringing the required scan time for multidimensional magnetic resonance spectroscopic imaging within clinical feasibility.

MR spectroscopic imaging and diffusion-weighted imaging of prostate cancer with Gleason scores.

PURPOSE: To investigate functional changes in prostate cancer patients with three pathologically proven different Gleason scores (GS) (3+3, 3+4, and 4+3) using magnetic resonance spectroscopic imaging (MRSI) and diffusion-weighted imaging (DWI). MATERIALS AND METHODS: In this study MRSI and DWI data were acquired in 41 prostate cancer patients using a 1.5T MRI scanner with a body matrix combined with an endorectal coil. The metabolite ratios of (Cho+Cr)/Cit were calculated from the peak integrals of total choline (Cho), creatine (Cr), and citrate (Cit) in MRSI. Apparent diffusion coefficient (ADC) values were derived from DWI for three groups of Gleason scores. The sensitivity and specificity of MRSI and DWI in patients were calculated using receiver operating characteristic curve (ROC) analysis. RESULTS: The mean and standard deviation of (Cho+Cr)/Cit ratios of GS 3+3, GS 3+4, and GS 4+3 were: 0.44 ± 0.02, 0.56 ± 0.06, and 0.88 ± 0.11, respectively. For the DWI, the mean and standard deviation of ADC values in GS 3+3, GS 3+4, and GS 4+3 were: 1.13 ± 0.11, 0.97 ± 0.10, and 0.83 ± 0.08 mm(2) /sec, respectively. Statistical significances were observed between the GS and metabolite ratio as well as ADC values and GS. CONCLUSION: Combined MRSI and DWI helps identify the presence and the proportion of aggressive cancer (ie, Gleason grade 4) that might not be apparent on biopsy sampling. This information can guide subsequent rebiopsy management, especially for active surveillance programs.

Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy.

Mutations of the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are commonly found in primary brain cancers. We previously reported that a novel enzymatic activity of these mutations results in the production of the putative oncometabolite, R(-)-2-hydroxyglutarate (2-HG). Here we investigated the ability of magnetic resonance spectroscopy (MRS) to detect 2-HG production in order to non-invasively identify patients with IDH1 mutant brain tumors. Patients with intrinsic glial brain tumors (n = 27) underwent structural and spectroscopic magnetic resonance imaging prior to surgery. 2-HG levels from MRS data were quantified using LC-Model software, based upon a simulated spectrum obtained from a GAMMA library added to the existing prior knowledge database. The resected tumors were then analyzed for IDH1 mutational status by genomic DNA sequencing, Ki-67 proliferation index by immunohistochemistry, and concentrations of 2-HG and other metabolites by liquid chromatography-mass spectrometry (LC-MS). MRS detected elevated 2-HG levels in gliomas with IDH1 mutations compared to those with wild-type IDH1 (P = 0.003). The 2-HG levels measured in vivo with MRS were significantly correlated with those measured ex vivo from the corresponding tumor samples using LC-MS (r (2) = 0.56; P = 0.0001). Compared with wild-type tumors, those with IDH1 mutations had elevated choline (P = 0.01) and decreased glutathione (P = 0.03) on MRS. Among the IDH1 mutated gliomas, quantitative 2-HG values were correlated with the Ki-67 proliferation index of the tumors (r ( 2 ) = 0.59; P = 0.026). In conclusion, water-suppressed proton ((1)H) MRS provides a non-invasive measure of 2-HG in gliomas, and may serve as a potential biomarker for patients with IDH1 mutant brain tumors. In addition to 2-HG, alterations in several other metabolites measured by MRS correlate with IDH1 mutation status.