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1.  Stepped Impedance Resonators for High Field Magnetic Resonance Imaging 
Multi-element volume radio-frequency (RF) coils are an integral aspect of the growing field of high field magnetic resonance imaging (MRI). In these systems, a popular volume coil of choice has become the transverse electromagnetic (TEM) multi-element transceiver coil consisting of microstrip resonators. In this paper, to further advance this design approach, a new microstrip resonator strategy in which the transmission line is segmented into alternating impedance sections referred to as stepped impedance resonators (SIRs) is investigated. Single element simulation results in free space and in a phantom at 7 tesla (298 MHz) demonstrate the rationale and feasibility of the SIR design strategy. Simulation and image results at 7 tesla in a phantom and human head illustrate the improvements in transmit magnetic field, as well as, RF efficiency (transmit magnetic field versus SAR) when two different SIR designs are incorporated in 8-element volume coil configurations and compared to a volume coil consisting of microstrip elements.
doi:10.1109/TBME.2013.2250973
PMCID: PMC4142687  PMID: 23508243
MRI; RF coils; TEM; microstrip; stepped impedance resonators (SIR)
2.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci 
Ripke, Stephan | Neale, Benjamin M | Corvin, Aiden | Walters, James TR | Farh, Kai-How | Holmans, Peter A | Lee, Phil | Bulik-Sullivan, Brendan | Collier, David A | Huang, Hailiang | Pers, Tune H | Agartz, Ingrid | Agerbo, Esben | Albus, Margot | Alexander, Madeline | Amin, Farooq | Bacanu, Silviu A | Begemann, Martin | Belliveau, Richard A | Bene, Judit | Bergen, Sarah E | Bevilacqua, Elizabeth | Bigdeli, Tim B | Black, Donald W | Bruggeman, Richard | Buccola, Nancy G | Buckner, Randy L | Byerley, William | Cahn, Wiepke | Cai, Guiqing | Campion, Dominique | Cantor, Rita M | Carr, Vaughan J | Carrera, Noa | Catts, Stanley V | Chambert, Kimberley D | Chan, Raymond CK | Chan, Ronald YL | Chen, Eric YH | Cheng, Wei | Cheung, Eric FC | Chong, Siow Ann | Cloninger, C Robert | Cohen, David | Cohen, Nadine | Cormican, Paul | Craddock, Nick | Crowley, James J | Curtis, David | Davidson, Michael | Davis, Kenneth L | Degenhardt, Franziska | Del Favero, Jurgen | Demontis, Ditte | Dikeos, Dimitris | Dinan, Timothy | Djurovic, Srdjan | Donohoe, Gary | Drapeau, Elodie | Duan, Jubao | Dudbridge, Frank | Durmishi, Naser | Eichhammer, Peter | Eriksson, Johan | Escott-Price, Valentina | Essioux, Laurent | Fanous, Ayman H | Farrell, Martilias S | Frank, Josef | Franke, Lude | Freedman, Robert | Freimer, Nelson B | Friedl, Marion | Friedman, Joseph I | Fromer, Menachem | Genovese, Giulio | Georgieva, Lyudmila | Giegling, Ina | Giusti-Rodríguez, Paola | Godard, Stephanie | Goldstein, Jacqueline I | Golimbet, Vera | Gopal, Srihari | Gratten, Jacob | de Haan, Lieuwe | Hammer, Christian | Hamshere, Marian L | Hansen, Mark | Hansen, Thomas | Haroutunian, Vahram | Hartmann, Annette M | Henskens, Frans A | Herms, Stefan | Hirschhorn, Joel N | Hoffmann, Per | Hofman, Andrea | Hollegaard, Mads V | Hougaard, David M | Ikeda, Masashi | Joa, Inge | Julià, Antonio | Kahn, René S | Kalaydjieva, Luba | Karachanak-Yankova, Sena | Karjalainen, Juha | Kavanagh, David | Keller, Matthew C | Kennedy, James L | Khrunin, Andrey | Kim, Yunjung | Klovins, Janis | Knowles, James A | Konte, Bettina | Kucinskas, Vaidutis | Kucinskiene, Zita Ausrele | Kuzelova-Ptackova, Hana | Kähler, Anna K | Laurent, Claudine | Lee, Jimmy | Lee, S Hong | Legge, Sophie E | Lerer, Bernard | Li, Miaoxin | Li, Tao | Liang, Kung-Yee | Lieberman, Jeffrey | Limborska, Svetlana | Loughland, Carmel M | Lubinski, Jan | Lönnqvist, Jouko | Macek, Milan | Magnusson, Patrik KE | Maher, Brion S | Maier, Wolfgang | Mallet, Jacques | Marsal, Sara | Mattheisen, Manuel | Mattingsdal, Morten | McCarley, Robert W | McDonald, Colm | McIntosh, Andrew M | Meier, Sandra | Meijer, Carin J | Melegh, Bela | Melle, Ingrid | Mesholam-Gately, Raquelle I | Metspalu, Andres | Michie, Patricia T | Milani, Lili | Milanova, Vihra | Mokrab, Younes | Morris, Derek W | Mors, Ole | Murphy, Kieran C | Murray, Robin M | Myin-Germeys, Inez | Müller-Myhsok, Bertram | Nelis, Mari | Nenadic, Igor | Nertney, Deborah A | Nestadt, Gerald | Nicodemus, Kristin K | Nikitina-Zake, Liene | Nisenbaum, Laura | Nordin, Annelie | O’Callaghan, Eadbhard | O’Dushlaine, Colm | O’Neill, F Anthony | Oh, Sang-Yun | Olincy, Ann | Olsen, Line | Van Os, Jim | Pantelis, Christos | Papadimitriou, George N | Papiol, Sergi | Parkhomenko, Elena | Pato, Michele T | Paunio, Tiina | Pejovic-Milovancevic, Milica | Perkins, Diana O | Pietiläinen, Olli | Pimm, Jonathan | Pocklington, Andrew J | Powell, John | Price, Alkes | Pulver, Ann E | Purcell, Shaun M | Quested, Digby | Rasmussen, Henrik B | Reichenberg, Abraham | Reimers, Mark A | Richards, Alexander L | Roffman, Joshua L | Roussos, Panos | Ruderfer, Douglas M | Salomaa, Veikko | Sanders, Alan R | Schall, Ulrich | Schubert, Christian R | Schulze, Thomas G | Schwab, Sibylle G | Scolnick, Edward M | Scott, Rodney J | Seidman, Larry J | Shi, Jianxin | Sigurdsson, Engilbert | Silagadze, Teimuraz | Silverman, Jeremy M | Sim, Kang | Slominsky, Petr | Smoller, Jordan W | So, Hon-Cheong | Spencer, Chris C A | Stahl, Eli A | Stefansson, Hreinn | Steinberg, Stacy | Stogmann, Elisabeth | Straub, Richard E | Strengman, Eric | Strohmaier, Jana | Stroup, T Scott | Subramaniam, Mythily | Suvisaari, Jaana | Svrakic, Dragan M | Szatkiewicz, Jin P | Söderman, Erik | Thirumalai, Srinivas | Toncheva, Draga | Tosato, Sarah | Veijola, Juha | Waddington, John | Walsh, Dermot | Wang, Dai | Wang, Qiang | Webb, Bradley T | Weiser, Mark | Wildenauer, Dieter B | Williams, Nigel M | Williams, Stephanie | Witt, Stephanie H | Wolen, Aaron R | Wong, Emily HM | Wormley, Brandon K | Xi, Hualin Simon | Zai, Clement C | Zheng, Xuebin | Zimprich, Fritz | Wray, Naomi R | Stefansson, Kari | Visscher, Peter M | Adolfsson, Rolf | Andreassen, Ole A | Blackwood, Douglas HR | Bramon, Elvira | Buxbaum, Joseph D | Børglum, Anders D | Cichon, Sven | Darvasi, Ariel | Domenici, Enrico | Ehrenreich, Hannelore | Esko, Tõnu | Gejman, Pablo V | Gill, Michael | Gurling, Hugh | Hultman, Christina M | Iwata, Nakao | Jablensky, Assen V | Jönsson, Erik G | Kendler, Kenneth S | Kirov, George | Knight, Jo | Lencz, Todd | Levinson, Douglas F | Li, Qingqin S | Liu, Jianjun | Malhotra, Anil K | McCarroll, Steven A | McQuillin, Andrew | Moran, Jennifer L | Mortensen, Preben B | Mowry, Bryan J | Nöthen, Markus M | Ophoff, Roel A | Owen, Michael J | Palotie, Aarno | Pato, Carlos N | Petryshen, Tracey L | Posthuma, Danielle | Rietschel, Marcella | Riley, Brien P | Rujescu, Dan | Sham, Pak C | Sklar, Pamela | St Clair, David | Weinberger, Daniel R | Wendland, Jens R | Werge, Thomas | Daly, Mark J | Sullivan, Patrick F | O’Donovan, Michael C
Nature  2014;511(7510):421-427.
Summary
Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
doi:10.1038/nature13595
PMCID: PMC4112379  PMID: 25056061
3.  Shared intermediate phenotypes for schizophrenia and bipolar disorder: neuroanatomical features of subtypes distinguished by executive dysfunction 
Background
Shared genetic vulnerability for schizophrenia and bipolar disorder may be associated with common neuroanatomical features. In view of the evidence for working memory dysfunction as a candidate intermediate phenotype for both disorders, we explored neuroanatomical distinctions between subtypes defined according to working memory (n-back task) performance.
Methods
We analyzed T1-weighted MRI scans for patients with schizophrenia-spectrum disorder, bipolar-I disorder (BD-I) and healthy controls. The VBM8 toolbox was used to assess differences in grey and white matter volume across traditional diagnostic groups (schizophrenia v. BD-I). Subsequently, groups were defined as “executively spared” (ES) based on the achievement of greater than 50% accuracy in the 2-back task performance (comparable to performance in the control group) or “executively deficit” (ED) based on the achievement of less than 50% accuracy.
Results
Our study included 40 patients with schizophrenia-spectrum disorders, 30 patients with BD-I and 34 controls. Both the schizophrenia and BD-I groups showed grey matter volume reductions relative to the control group, but not relative to each other. The ED subtype (n = 32 [10 BD-I, 22 schizophrenia]) showed grey matter volume reductions in the bilateral superior and medial frontal gyri, right inferior opercular gyri and hippocampus relative to controls. The ES subtype (n = 38 [20 BD-I, 18 schizophrenia]) showed grey matter volume reductions in the right precuneus and left superior and medial orbital frontal gyri relative to controls. The ED subtype showed grey matter volume reduction in the right inferior frontal and precentral gyri relative to the ES subtype. There were no significant differences in white matter volume in any group comparisons.
Limitations
This analysis was limited by small sample sizes. Further, insufficient numbers were available to assess a control-deficit comparison group. We were unable to assess the effects of mood stabilizer dose on brain structure.
Conclusion
Neuroanatomical commonalities are evident among patients with schizophrenia-spectrum disorders and BD-I with working memory deficits. Reduced inferior frontal lobe volume may mediate cognitive deficits shared across the psychosis–mood spectrum.
doi:10.1503/jpn.130283
PMCID: PMC4275333  PMID: 25268788
4.  Ten-year audit of clients presenting to a specialised service for young people experiencing or at increased risk for psychosis 
BMC Psychiatry  2014;14(1):318.
Background
Despite strong research interest in psychosis risk identification and the potential for early intervention, few papers have sought to document the implementation and evaluation of specialised psychosis related services. Assessment of Ultra High Risk (UHR) has been given priority, but it is equally as important to identify appropriate comparison groups and other baseline differences. This largely descriptive service evaluation paper focuses on the ‘baseline characteristics’ of referred clients (i.e., previously assessed characteristics or those identified within the first two months following service presentation).
Methods
Data are reported from a 10-year layered service audit of all presentations to a ‘Psychological Assistance Service’ for young people (PAS, Newcastle, Australia). Baseline socio-demographic and clinical characteristics (N =1,997) are described (including clients’ psychosis and UHR status, previous service contacts, hospitalisation rates, and diagnostic and comorbidity profiles). Key groups are identified and comparisons made between clients who received ongoing treatment and those who were primarily assessed and referred elsewhere.
Results
Clients averaged 19.2 (SD =4.5) years of age and 59% were male. One-tenth of clients (9.6%) were categorised as UHR, among whom there were relatively high rates of attenuated psychotic symptoms (69.1%), comorbid depression (62.3%), anxiety (42.9%), and attentional and related problems (67.5%). Overall, one-fifth (19.8%) experienced a recent psychotic episode, while a further 14.5% were categorised as having an existing psychosis (46.7% with a schizophrenia diagnosis), amongst whom there were relatively high rates of comorbid substance misuse (52.9%), psychosocial (70.2%) and physical health (37.7%) problems. The largest group presenting to PAS were those with non-psychotic disorders (43.7%), who provide a valuable comparison group against which to contrast the health trajectories of those with UHR and recent psychosis. Ongoing treatment by PAS was preferentially given to those experiencing or at risk for psychosis and those reporting greater current distress or dysfunction.
Conclusions
Whether or not UHR clients transition to psychosis, they displayed high rates of comorbid depression and anxiety at service presentation, with half receiving ongoing treatment from PAS. Although international comparisons with similar services are difficult, the socio-demographic and comorbidity patterns observed here were viewed as largely consistent with those reported elsewhere.
doi:10.1186/s12888-014-0318-4
PMCID: PMC4239381  PMID: 25403891
Psychosis; Risk status; Service evaluation; Comorbidity; Youth; Early intervention
5.  Cardiac Imaging at 7T: Single- and Two-Spoke RF Pulse Design with 16-channel Parallel Excitation 
Purpose
Higher SNR and improved contrast have been demonstrated at Ultra-high magnetic fields (≥7T) in multiple targets, often with multi-channel transmit B1+ methods to address the deleterious impact on tissue contrast due to spatial variations in B1+ profiles.
When imaging the heart at 7T, however, respiratory and cardiac motion, as well as B0 inhomogeneity, greatly increase the methodological challenge. In this study we compare 2-spoke parallel transmit (pTX) RF pulses with static B1+ shimming in cardiac imaging at 7T.
Methods
Using a 16-channel pTX system, slice-selective 2-spoke pTX pulses and static B1+ shimming were applied in cardiac CINE imaging. B1+ and B0 mapping required modified cardiac triggered sequences. Excitation homogeneity and RF energy were compared in different imaging orientations.
Results
2-spoke pulses provide higher excitation homogeneity than B1+ shimming, especially in the more challenging posterior region of the heart. The peak value of channel-wise RF energy was reduced, allowing for higher flip angle, hence increased tissue contrast. Image quality with 2-spoke excitation proved to be stable throughout the entire cardiac cycle.
Conclusion
2-spoke pTX excitation has been successfully demonstrated in the human heart at 7T, with improved image quality and reduced RF pulse energy when compared to B1+ shimming.
doi:10.1002/mrm.24935
PMCID: PMC3960017  PMID: 24038314
6.  Inversion Recovery at 7 Tesla in the human myocardium: measurement of T1, inversion efficiency and B1+ 
At clinical MRI field strengths (1.5 and 3T), quantitative maps of the longitudinal relaxation time T1 of the myocardium reveal diseased tissue without requiring contrast agents. Cardiac T1 maps can be measured by Look-Locker inversion recovery sequences such as ShMOLLI at 1.5 and 3T. Cardiovascular MRI at a field strength of 7T has recently become feasible, but doubts have remained as to whether magnetization inversion is possible in the heart because of subject heating and technical limitations. This work extends the repertoire of 7T cardiovascular MRI by implementing an adiabatic inversion pulse optimized for use in the heart at 7T. A “ShMOLLI+IE” adaptation of the ShMOLLI pulse sequence has been introduced together with new post-processing that accounts for the possibility of incomplete magnetization inversion. These methods were validated in phantoms and then used in a study of 6 healthy volunteers to determine the degree of magnetization inversion and the T1 of normal myocardium at 7T within a a 22 heartbeat breathhold. Using a scanner with 16 1kW radiofrequency outputs, inversion efficiencies ranging from −0.79 to −0.83 (intra-segment means; perfect 180° would give −1) were attainable across the myocardium. The myocardial T1 was 1925 ± 48ms (mean ± SD).
doi:10.1002/mrm.24548
PMCID: PMC4134266  PMID: 23197329
7 Tesla; Cardiac longitudinal relaxation time T1; ShMOLLI; Adiabatic pulses; Inversion recovery; Saturation correction
7.  Multivariate neuroanatomical classification of cognitive subtypes in schizophrenia: A support vector machine learning approach 
NeuroImage : Clinical  2014;6:229-236.
Heterogeneity in the structural brain abnormalities associated with schizophrenia has made identification of reliable neuroanatomical markers of the disease difficult. The use of more homogenous clinical phenotypes may improve the accuracy of predicting psychotic disorder/s on the basis of observable brain disturbances. Here we investigate the utility of cognitive subtypes of schizophrenia – ‘cognitive deficit’ and ‘cognitively spared’ – in determining whether multivariate patterns of volumetric brain differences can accurately discriminate these clinical subtypes from healthy controls, and from each other. We applied support vector machine classification to grey- and white-matter volume data from 126 schizophrenia patients previously allocated to the cognitive spared subtype, 74 cognitive deficit schizophrenia patients, and 134 healthy controls. Using this method, cognitive subtypes were distinguished from healthy controls with up to 72% accuracy. Cross-validation analyses between subtypes achieved an accuracy of 71%, suggesting that some common neuroanatomical patterns distinguish both subtypes from healthy controls. Notably, cognitive subtypes were best distinguished from one another when the sample was stratified by sex prior to classification analysis: cognitive subtype classification accuracy was relatively low (<60%) without stratification, and increased to 83% for females with sex stratification. Distinct neuroanatomical patterns predicted cognitive subtype status in each sex: sex-specific multivariate patterns did not predict cognitive subtype status in the other sex above chance, and weight map analyses demonstrated negative correlations between the spatial patterns of weights underlying classification for each sex. These results suggest that in typical mixed-sex samples of schizophrenia patients, the volumetric brain differences between cognitive subtypes are relatively minor in contrast to the large common disease-associated changes. Volumetric differences that distinguish between cognitive subtypes on a case-by-case basis appear to occur in a sex-specific manner that is consistent with previous evidence of disrupted relationships between brain structure and cognition in male, but not female, schizophrenia patients. Consideration of sex-specific differences in brain organization is thus likely to assist future attempts to distinguish subgroups of schizophrenia patients on the basis of neuroanatomical features.
Highlights
•We classified cognitive subtypes of schizophrenia using volumetric brain data.•Cognitive deficit and cognitive spared subtypes were distinguished from controls.•Common neuroanatomical patterns distinguished both subtypes from controls.•Cognitive subtypes were distinguished from each other in a sex-specific manner.
doi:10.1016/j.nicl.2014.09.009
PMCID: PMC4215428  PMID: 25379435
Cognition; Cognitive deficit; Subtypes; Voxel based morphometry; Magnetic resonance imaging; Sex differences
8.  Human cardiac 31P magnetic resonance spectroscopy at 7 Tesla 
Purpose
Phosphorus magnetic resonance spectroscopy (31P-MRS) affords unique insight into cardiac energetics but has a low intrinsic signal-to-noise ratio (SNR) in humans.
Theory predicts an increased 31P-MRS SNR at 7T, offering exciting possibilities to better investigate cardiac metabolism. We therefore compare the performance of human cardiac 31P-MRS at 7T to 3T, and measure T1s for 31P metabolites at 7T.
Methods
Matched 31P-MRS data were acquired at 3T and 7T, on 9 normal volunteers. A novel Look-Locker CSI acquisition and fitting approach was used to measure T1s on 6 normal volunteers.
Results
T1s in the heart at 7T were: PCr 3.05 ± 0.41s, γ-ATP 1.82 ± 0.09s, α-ATP 1.39 ± 0.09s, β-ATP 1.02 ± 0.17s and 2,3-DPG 3.05 ± 0.41s (N=6).
In the field comparison (N=9), PCr SNR increased 2.8× at 7T relative to 3T, the Cramer-Ráo uncertainty (CRLB) in PCr concentration decreased 2.4×, the mean CRLB in PCr/ATP decreased 2.7× and the PCr/ATP SD decreased 2×.
Conclusion
Cardiac 31P-MRS at 7T has higher SNR and the spectra can be quantified more precisely than at 3T. Cardiac 31P T1s are shorter at 7T than at 3T. We predict that 7T will become the field strength of choice for cardiac 31P-MRS.
doi:10.1002/mrm.24922
PMCID: PMC4106879  PMID: 24006267
31P magnetic resonance spectroscopy; phosphorus; cardiac; 7 tesla; field strength; T1
9.  A Method to Localize RF B1 Field in High-Field Magnetic Resonance Imaging Systems 
In high-field magnetic resonance imaging (MRI) systems, B0 fields of 7 and 9.4 T, the RF field shows greater inhomogeneity compared to clinical MRI systems with B0 fields of 1.5 and 3.0 T. In multichannel RF coils, the magnitude and phase of the input to each coil element can be controlled independently to reduce the nonuniformity of the RF field. The convex optimization technique has been used to obtain the optimum excitation parameters with iterative solutions for homogeneity in a selected region of interest. The pseudoinverse method has also been used to find a solution. The simulation results for 9.4- and 7-T MRI systems are discussed in detail for the head model. Variation of the simulation results in a 9.4-T system with the number of RF coil elements for different positions of the regions of interest in a spherical phantom are also discussed. Experimental results were obtained in a phantom in the 9.4-T system and are compared to the simulation results and the specific absorption rate has been evaluated.
doi:10.1109/TBME.2012.2208965
PMCID: PMC4041104  PMID: 22929360
Convex optimization; high-field MRI; magnetic resonance imaging (MRI); pseudoinverse; parallel excitation; RF B1 field; transmission line head coil
10.  Functional Consequences of Human Induced Pluripotent Stem Cell Therapy 
Circulation  2013;127(9):997-1008.
Background
The use of cells derived from human induced pluripotent stem cells as cellular therapy for myocardial injury has yet to be examined in a large-animal model.
Methods and Results
Immunosuppressed Yorkshire pigs were assigned to 1 of 3 groups: A myocardial infarction group (MI group; distal left anterior descending coronary artery ligation and reperfusion; n=13); a cell-treatment group (MI with 4×106 vascular cells derived from human induced pluripotent stem cells administered via a fibrin patch; n=14); and a normal group (n=15). At 4 weeks, left ventricular structural and functional abnormalities were less pronounced in hearts in the cell-treated group than in MI hearts (P<0.05), and these improvements were accompanied by declines in scar size (10.4±1.6% versus 8.3±1.1%, MI versus cell-treatment group, P<0.05). The cell-treated group displayed a significant increase in vascular density and blood flow (0.83±0.11 and 1.05±0.13 mL·min−1·g−1, MI versus cell-treatment group, P<0.05) in the periscar border zone (BZ), which was accompanied by improvements in systolic thickening fractions (infarct zone, −10±7% versus 5±5%; BZ, 7±4% versus 23±6%; P<0.05). Transplantation of vascular cells derived from human induced pluripotent stem cells stimulated c-kit+ cell recruitment to BZ and the rate of bromodeoxyuridine incorporation in both c-kit+ cells and cardiomyocytes (P<0.05). Using a magnetic resonance spectroscopic saturation transfer technique, we found that the rate of ATP hydrolysis in BZ of MI hearts was severely reduced, and the severity of this reduction was linearly related to the severity of the elevations of wall stresses (r=0.82, P<0.05). This decline in BZ ATP utilization was markedly attenuated in the cell-treatment group.
Conclusions
Transplantation of vascular cells derived from human induced pluripotent stem cells mobilized endogenous progenitor cells into the BZ, attenuated regional wall stress, stimulated neovascularization, and improved BZ perfusion, which in turn resulted in marked increases in BZ contractile function and ATP turnover rate.
doi:10.1161/CIRCULATIONAHA.112.000641
PMCID: PMC3980462  PMID: 23371930
heart; adenosine triphosphate; stem cells; myocardium; hypertrophy
11.  A fluid–structure interaction model to characterize bone cell stimulation in parallel-plate flow chamber systems 
Bone continuously adapts its internal structure to accommodate the functional demands of its mechanical environment and strain-induced flow of interstitial fluid is believed to be the primary mediator of mechanical stimuli to bone cells in vivo. In vitro investigations have shown that bone cells produce important biochemical signals in response to fluid flow applied using parallel-plate flow chamber (PPFC) systems. However, the exact mechanical stimulus experienced by the cells within these systems remains unclear. To fully understand this behaviour represents a most challenging multi-physics problem involving the interaction between deformable cellular structures and adjacent fluid flows. In this study, we use a fluid–structure interaction computational approach to investigate the nature of the mechanical stimulus being applied to a single osteoblast cell under fluid flow within a PPFC system. The analysis decouples the contribution of pressure and shear stress on cellular deformation and for the first time highlights that cell strain under flow is dominated by the pressure in the PPFC system rather than the applied shear stress. Furthermore, it was found that strains imparted on the cell membrane were relatively low whereas significant strain amplification occurred at the cell–substrate interface. These results suggest that strain transfer through focal attachments at the base of the cell are the primary mediators of mechanical signals to the cell under flow in a PPFC system. Such information is vital in order to correctly interpret biological responses of bone cells under in vitro stimulation and elucidate the mechanisms associated with mechanotransduction in vivo.
doi:10.1098/rsif.2012.0900
PMCID: PMC3627095  PMID: 23365189
parallel-plate flow chamber; fluid–structure interaction; bone cell mechanotransduction; fluid shear stress stimulation
12.  Heating Induced near Deep Brain Stimulation Lead Electrodes during Magnetic Resonance Imaging with a 3T Transceive Volume Head Coil 
Physics in medicine and biology  2012;57(17):5651-5665.
Heating induced near deep brain stimulation (DBS) lead electrodes during MRI with a 3T transceive head coil was measured, modeled, and imaged in three cadaveric porcine heads (mean body weight = 85.47±3.19 kg, mean head weight = 5.78±0.32 kg). The effect of the placement of the extra-cranial portion of the DBS lead on the heating was investigated by looping the extra-cranial lead on the top, side, and back of the head; and placing it parallel to the coil’s longitudinal axial direction. The heating was induced using a 641 s long turbo spin echo sequence with the mean whole head average SAR of 3.16 W/kg. Temperatures were measured using fluoroptic probes at the scalp, first and second electrodes from the distal lead tip, and 6 mm distal from electrode 1 (T6mm). The heating was modeled using the maximum T6mm and imaged using a proton resonance frequency shift based MR thermometry method. Results showed that the heating was significantly reduced when the extra-cranial lead was placed in the longitudinal direction compared to the other placements (peak temperature change = 1.5–3.2 °C vs 5.1–24.7 °C). Thermal modeling and MR thermometry may be used together to determine the heating and improve patient safety online.
doi:10.1088/0031-9155/57/17/5651
PMCID: PMC3469254  PMID: 22892760
MRI; Safety; DBS; Heating; 3T
13.  Activation of NF-κB in Placentas of Women with Preeclampsia 
Objective
Placentas are oxidatively stressed during preeclampsia and produce more TNFα and more thromboxane (TX) than normal. Oxidative stress may cause these abnormalities by activating NF-κB. We measured levels of activated NF-κB in normal and preeclamptic placentas and determined whether oxidative stress activates NF-κB in a trophoblast-like cell line.
Methods
We used immunohistochemistry to determine the percentage of the total tissue area that stained for the p65 subunit of NF-κB in placentas obtained from normal and preeclamptic pregnancies. In a second set of experiments, we used a reporter plasmid bearing the NF-κB binding site and transfected it into trophoblast-like cells. The cells were incubated with medium control, linoleic acid (LA), an oxidizing solution (Ox), or Ox enriched with linoleic acid (OxLA), TNFα, or OxLA plus TNFα for 20 hours. Cell lysates were analyzed using a dual luciferase assay kit.
Results
Placentas obtained from women with preeclampsia showed nearly a 10-fold increase in the extent of area stained for activated NF-κB as compared to normal placentas. In cell culture experiments, Ox and OxLA induced a 3-fold increase in NF-κB activation as compared to medium control or LA. TNFα induced a 3-fold increase in NF-κB activation. The combination of TNFα with OxLA caused a 10-fold increase in NF-κB activation.
Conclusions
Placental NF-κB is activated nearly 10-fold in preeclampsia. Oxidative stress causes NF-κB activation in a trophoblast-like cell line, which is enhanced by TNFα. These data suggest that oxidative stress is likely an important in vivo activator of placental NF-κB in preeclampsia.
doi:10.3109/10641955.2011.642436
PMCID: PMC3542769  PMID: 22380486
Nuclear factor-κB (NF-κB); trophoblast; placenta; oxidative stress; tumor necrosis factor α (TNFα)
15.  Reduced neural activity of the prefrontal cognitive control circuitry during response inhibition to negative words in people with schizophrenia 
Background
Schizophrenia is characterized by deficits in executive control and impairments in emotion processing. This study assessed the nature and extent of potential alterations in the neural substrates supporting the interaction between cognitive control mechanisms and emotion attribution processes in people with schizophrenia.
Methods
Functional magnetic resonance imaging was performed during a verbal emotional go/no-go task. People with schizophrenia and healthy controls responded to word stimuli of a prespecified emotional valence (positive, negative or neutral) while inhibiting responses to stimuli of a different valence.
Results
We enrolled 20 people with schizophrenia and 23 controls in the study. Healthy controls activated an extensive dorsal prefrontal–parietal network while inhibiting responses to negative words compared to neutral words, but showed deactivation of the midcingulate cortex while inhibiting responses to positive words compared to neutral words. People with schizophrenia failed to activate this network during response inhibition to negative words, whereas during response inhibition to positive words they did not deactivate the cingulate, but showed increased responsivity in the frontal cortex.
Limitations
Sample heterogeneity is characteristic of studies of schizophrenia and may have contributed to more variable neural responses in the patient sample despite the care taken to control for potentially confounding variables.
Conclusion
Our results showed that schizophrenia is associated with aberrant modulation of neural responses during the interaction between cognitive control and emotion processing. Failure of the frontal circuitry to regulate goal-directed behaviour based on emotion attributions may contribute to deficits in psychosocial functioning in daily life.
doi:10.1503/jpn.110088
PMCID: PMC3493093  PMID: 22617625
16.  Radiofrequency Heating in Porcine Models with a “Large” 32 cm Internal Diameter, 7 T (296 MHz) Head Coil 
Magnetic Resonance in Medicine  2011;66(1):255-263.
Temperatures were measured in vivo in four pigs (mean animal weight = 110.75 kg and standard deviation = 6.13 kg) due to a continuous wave radiofrequency (RF) power irradiation with a 31.75 cm internal diameter and a 15.24 cm long, 7 T (296 MHz), eight channel, transverse electromagnetic head coil. The temperatures were measured in the subcutaneous layer of the scalp, 5, 10, 15, and 20 mm deep in the brain, and rectum using fluoroptic temperature probes. The RF power was delivered to the pig’s head for ~3 h (mean deposition time = 3.14 h and standard deviation = 0.06 h) at the whole head average specific absorption rate of = 3 W kg−1 (mean average specific absorption rate = 3.08 W kg−1 and standard deviation = 0.09 W kg−1). Next, simple bioheat transfer models were used to simulate the RF power induced temperature changes. Results show that the RF power produced uniform temperature changes in the pigs’ heads (mean temperature change = 1.68°C and standard deviation = 0.13°C) with no plateau achieved during the heating. No thermoregulatory alterations were detected due to the heating because the temperature responses of the pre-RF and post- RF epochs were not statistically significantly different. Simple, validated bioheat models may provide accurate temperature changes.
doi:10.1002/mrm.22790
PMCID: PMC3339408  PMID: 21337423
safety; radiofrequency; MRI; 7 T; bioheat
17.  Transcriptome Sequencing Revealed Significant Alteration of Cortical Promoter Usage and Splicing in Schizophrenia 
PLoS ONE  2012;7(4):e36351.
Background
While hybridization based analysis of the cortical transcriptome has provided important insight into the neuropathology of schizophrenia, it represents a restricted view of disease-associated gene activity based on predetermined probes. By contrast, sequencing technology can provide un-biased analysis of transcription at nucleotide resolution. Here we use this approach to investigate schizophrenia-associated cortical gene expression.
Methodology/Principal Findings
The data was generated from 76 bp reads of RNA-Seq, aligned to the reference genome and assembled into transcripts for quantification of exons, splice variants and alternative promoters in postmortem superior temporal gyrus (STG/BA22) from 9 male subjects with schizophrenia and 9 matched non-psychiatric controls. Differentially expressed genes were then subjected to further sequence and functional group analysis. The output, amounting to more than 38 Gb of sequence, revealed significant alteration of gene expression including many previously shown to be associated with schizophrenia. Gene ontology enrichment analysis followed by functional map construction identified three functional clusters highly relevant to schizophrenia including neurotransmission related functions, synaptic vesicle trafficking, and neural development. Significantly, more than 2000 genes displayed schizophrenia-associated alternative promoter usage and more than 1000 genes showed differential splicing (FDR<0.05). Both types of transcriptional isoforms were exemplified by reads aligned to the neurodevelopmentally significant doublecortin-like kinase 1 (DCLK1) gene.
Conclusions
This study provided the first deep and un-biased analysis of schizophrenia-associated transcriptional diversity within the STG, and revealed variants with important implications for the complex pathophysiology of schizophrenia.
doi:10.1371/journal.pone.0036351
PMCID: PMC3338678  PMID: 22558445
18.  Methylphenidate for gait impairment in Parkinson disease 
Neurology  2011;76(14):1256-1262.
Background:
There is a paucity of therapies for gait impairment in Parkinson disease (PD). Open-label studies have suggested improved gait after treatment with methylphenidate (MPD).
Objective:
To evaluate the efficacy of MPD for the treatment of gait impairment in PD.
Methods:
Twenty-seven subjects with PD and moderate gait impairment were screened for this 6-month placebo-controlled, double-blind study. Subjects were randomly assigned to MPD (maximum, up to 80 mg/day) or placebo for 12 weeks and crossed over after a 3-week washout. The primary outcome measure was change in a gait composite score (stride length + velocity) between groups at 4 and 12 weeks. Secondary outcome measures included changes in motor function, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS), Freezing of Gait Questionnaire (FOGQ), number of gait-diary freezing episodes, and measures of depression, sleepiness, and quality of life. Three-factor repeated-measures analysis of variance was used to measure changes between groups.
Results:
Twenty-three eligible subjects with PD were randomized and 17 completed the trial. There was no change in the gait composite score or treatment or time effect for any of the variables. Treatment effect was not modified by state or study visit. Although there was a trend for reduced frequency of freezing and shuffling per diary, the FOGQ and UPDRS scores worsened in the MPD group compared to placebo. There was a marginal improvement in some measures of depression.
Conclusions:
MPD did not improve gait and tended to worsen measures of motor function, sleepiness, and quality of life.
Classification of evidence:
This study provides Class III evidence for the lack of benefit of MPD on PD-associated gait impairment. Clinical trial registration: NCT00526630.
doi:10.1212/WNL.0b013e3182143537
PMCID: PMC3068005  PMID: 21464430
19.  Effect of the Extra-cranial DBS Lead on Radiofrequency Heating at 9.4T (400.2 MHz) 
Purpose
To study the effect of the extra-cranial portion of a deep brain stimulation (DBS) lead on radiofrequency (RF) heating with a transmit and receive 9.4 tesla head coil.
Material and Methods
The RF heating was studied in four excised porcine heads (mean animal head weight = 5.46 ± 0.14 kg) for each of the following two extra-cranial DBS lead orientations: one, parallel to the coil axial direction; two, perpendicular to the coil axial direction (i.e., azimuthal). Temperatures were measured using fluoroptic probes at four locations: one, scalp; two, near the second DBS lead electrode-brain contact; three, near the distal tip of the DBS lead; and four, air surrounding the head. A continuous wave RF power was delivered to each head for 15 minutes using the coil. Net, delivered RF power was measured at the coil (mean whole head average specific absorption rate = 2.94 ± 0.08 W/kg).
Result
RF heating was significantly reduced when the extra-cranial DBS lead was placed in the axial direction (temperature change = 0-5 °C) compared to the azimuthal direction (temperature change = 1-27 °C).
Conclusion
Development of protocols seems feasible to keep RF heating near DBS electrodes clinically safe during ultra-high field head imaging.
doi:10.1002/jmri.22292
PMCID: PMC2933930  PMID: 20815057
Safety; MRI; RF heating; DBS; high field
20.  In Vivo 1H NMR Spectroscopy of the Human Brain at 9.4 Tesla: Initial Results 
In vivo proton NMR spectroscopy allows non-invasive detection and quantification of a wide range of biochemical compounds in the brain. Higher field strength is generally considered advantageous for spectroscopy due to increased signal-to-noise and increased spectral dispersion. So far 1H NMR spectra have been reported in the human brain up to 7 Tesla. In this study we show that excellent quality short echo time STEAM and LASER 1H NMR spectra can be measured in the human brain at 9.4 Tesla. The information content of the human brain spectra appears very similar to that measured in the past decade in rodent brains at the same field strength, in spite of broader linewidth in human brain. Compared to lower fields, the T1 relaxation times of metabolites were slightly longer while T2 relaxation values of metabolites were shorter (< 100 ms) at 9.4 Tesla. The linewidth of the total creatine (tCr) resonance at 3.03 ppm increased linearly with magnetic field (1.35 Hz/Tesla from 1.5 T to 9.4 T), with a minimum achievable tCr linewidth of around 12.5 Hz at 9.4 Tesla. At very high-field, B0 microsusceptibility effects are the main contributor to the minimum achievable linewidth.
doi:10.1016/j.jmr.2010.06.006
PMCID: PMC2940249  PMID: 20598925
Proton NMR spectroscopy; brain; human; relaxation times; ultra-high field
21.  Adapted RF Pulse Design for SAR Reduction in Parallel Excitation with Experimental Verification at 9.4 Tesla 
Parallel excitation holds strong promises to mitigate the impact of large transmit B1 (B1+) distortion at very high magnetic field. Accelerated RF pulses, however, inherently tend to require larger values in RF peak power which may result in substantial increase in Specific Absorption Rate in tissues, which is a constant concern for patient safety at very high field. In this study, we demonstrate adapted rate RF pulse design allowing for SAR reduction while preserving excitation target accuracy. Compared with other proposed implementations of adapted rate RF pulses, our approach is compatible with any k-space trajectories, does not require an analytical expression of the gradient waveform and can be used for large flip angle excitation. We demonstrate our method with numerical simulations based on electromagnetic modeling and we include an experimental verification of transmit pattern accuracy on an 8 transmit channel 9.4 T system.
PMCID: PMC2919242  PMID: 20556882
22.  Urocortin 3 transgenic mice exhibit a metabolically favourable phenotype resisting obesity and hyperglycaemia on a high-fat diet 
Diabetologia  2011;54(9):2392-2403.
Aims/hypothesis
Urocortins are the endogenous ligands for the corticotropin-releasing factor receptor type 2 (CRFR2), which is implicated in regulating energy balance and/or glucose metabolism. We determined the effects of chronic CRFR2 activation on metabolism in vivo, by generating and phenotyping transgenic mice overproducing the specific CRFR2 ligand urocortin 3.
Methods
Body composition, glucose metabolism, insulin sensitivity, energy efficiency and expression of key metabolic genes were assessed in adult male urocortin 3 transgenic mice (Ucn3+) under control conditions and following an obesogenic high-fat diet (HFD) challenge.
Results
Ucn3+ mice had increased skeletal muscle mass with myocyte hypertrophy. Accelerated peripheral glucose disposal, increased respiratory exchange ratio and hypoglycaemia on fasting demonstrated increased carbohydrate metabolism. Insulin tolerance and indices of insulin-stimulated signalling were unchanged, indicating these effects were not mediated by increased insulin sensitivity. Expression of the transgene in Crfr2 (also known as Crhr2)-null mice negated key aspects of the Ucn3+ phenotype. Ucn3+ mice were protected from the HFD-induced hyperglycaemia and increased adiposity seen in control mice despite consuming more energy. Expression of uncoupling proteins 2 and 3 was higher in Ucn3+ muscle, suggesting increased catabolic processes. IGF-1 abundance was upregulated in Ucn3+ muscle, providing a potential paracrine mechanism in which urocortin 3 acts upon CRFR2 to link the altered metabolism and muscular hypertrophy observed.
Conclusions/interpretation
Urocortin 3 acting on CRFR2 in skeletal muscle of Ucn3+ mice results in a novel metabolically favourable phenotype, with lean body composition and protection against diet-induced obesity and hyperglycaemia. Urocortins and CRFR2 may be of interest as potential therapeutic targets for obesity.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2205-6) contains supplementary material, which is available to authorised users.
doi:10.1007/s00125-011-2205-6
PMCID: PMC3149678  PMID: 21667214
CRFR2; Energy balance; Glucose uptake; IGF-1; Obesity; Skeletal muscle; Transgenic mice; Urocortin 3
23.  Parallel Excitation in the Human Brain at 9.4 T counteracting K-Space Errors with RF Pulse Design 
Multidimensional spatially selective RF pulses have been proposed as a method to mitigate transmit B1 inhomogeneity in MR experiments. These RF pulses, however, have been considered impractical for many years because they typically require very long RF pulse durations. The recent development of parallel excitation techniques makes it possible to design multidimensional RF pulses that are short enough for use in actual experiments. However, hardware and experimental imperfections can still severely alter the excitation patterns obtained with these accelerated pulses. In this note, we report at 9.4 T on a human eight-channel transmit system, substantial improvements in 2D excitation pattern accuracy obtained when measuring k-space trajectories prior to parallel transmit RF pulse design (acceleration ×4). Excitation patterns based on numerical simulations closely reproducing the experimental conditions were in good agreement with the experimental results.
doi:10.1002/mrm.22247
PMCID: PMC3066148  PMID: 20017161
24.  Radio-Frequency Heating at 9.4 T (400.2 MHz) – In Vivo Thermoregulatory Temperature Response in Swine 
In vivo thermoregulatory temperature response to RF heating at 9.4 T was studied by measuring temperatures in nine anesthetized swine. Temperatures were measured in the scalp, brain, and rectum. The RF energy was deposited using a four loop head coil tuned to 400.2 MHz. Sham RF was delivered to three swine to understand thermal effects of anesthesia (animal weight = 54.16 kg, SD = 3.08 kg). Continuous wave RF energy was delivered to the other six animals for 2.5–3.4 hours (animal weight = 74.01 ± 26.0 kg, heating duration = 3.05 ± 0.29 hours). The whole head specific absorption rate (SAR) varied between 2.71 W/kg and 3.20 W/kg (SAR = 2.93 ± 0.18 W/kg). Anesthesia caused the brain and rectal temperatures to drop linearly. Altered thermoregulatory response was detected by comparing the difference in the temperature slopes before and after the RF delivery from zero. RF heating statistically significantly altered the rate of cooling down of the animal. The temperature slope changes correlated well with the RF energy per unit head weight and heating duration, and the maximum rectal temperature change during heating in heated animals. The temperature slope changes did not correlate well to the whole head average SARs.
doi:10.1002/mrm.22072
PMCID: PMC2782895  PMID: 19572392
RF safety; RF heating; MR safety; ultra high field MRI; MR heating; 9.4 T
25.  7 T Whole Body Imaging: Preliminary Results 
The objective of this study was to investigate the feasibility of whole body imaging at 7 T. To achieve this objective, new technology and methods were developed. Radio frequency field distribution and specific absorption rate were first explored through numerical modeling. A body coil was then designed and built. Multi-channel transmit and receive coils were also developed and implemented. With this new technology in hand, an imaging survey of the “landscape” of the human body at 7 T was conducted. Cardiac imaging at 7 T appeared to be possible. The potential for breast imaging and spectroscopy was demonstrated. Preliminary results of the first human body imaging at 7 T suggest both promise and directions for further development.
doi:10.1002/mrm.21751
PMCID: PMC2875945  PMID: 19097214
7 T Body MRI; 7 T Cardiac MRI; 7 T Breast MRI; 7 T Breast MRS

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