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1.  Real Diffusion-Weighted MRI Enabling True Signal Averaging and Increased Diffusion Contrast 
NeuroImage  2015;122:373-384.
This project aims to characterize the impact of underlying noise distributions on diffusion-weighted imaging. The noise floor is a well-known problem for traditional magnitude-based diffusion-weighted MRI (dMRI) data, leading to biased diffusion model fits and inaccurate signal averaging. Here, we introduce a total-variation-based algorithm to eliminate shot-to-shot phase variations of complex-valued diffusion data with the intention to extract real-valued dMRI datasets. The obtained real-valued diffusion data are no longer superimposed by a noise floor but instead by a zero-mean Gaussian noise distribution, yielding dMRI data without signal bias. We acquired high-resolution dMRI data with strong diffusion weighting and, thus, low signal-to-noise ratio. Both the extracted real-valued and traditional magnitude data were compared regarding signal averaging, diffusion model fitting and accuracy in resolving crossing fibers. Our results clearly indicate that real-valued diffusion data enables idealized conditions for signal averaging. Furthermore, the proposed method enables unbiased use of widely employed linear least squares estimators for model fitting and demonstrates an increased sensitivity to detect secondary fiber directions with reduced angular error. The use of phase-corrected, real-valued data for dMRI will therefore help to clear the way for more detailed and accurate studies of white matter microstructure and structural connectivity on a fine scale.
doi:10.1016/j.neuroimage.2015.07.074
PMCID: PMC4651971  PMID: 26241680
2.  Urology Payments from Industry in the Sunshine Act 
Urology practice  2016;3(5):332-337.
Introduction
Payments to practitioners from drug and device manufacturers or group purchasing organizations are reported in the Centers for Medicare and Medicaid Services (CMS) databases as a part of the Sunshine Act. Characterizing these payments is a necessary step to identifying conflicts of interest and the influence of payments on practice patterns, if any. Payments have never been analyzed in detail amongst Urologists.
Materials and Methods
We reviewed the most recent CMS Open Payments database for the full year 2014, released on June 30, 2015. Urology practitioners were extracted and the database was analyzed for number of total payments, total dollar value of payments, mean, median, number of physicians, number of manufacturers, and number of drugs/biologicals. Data were further categorized according to provider specialty, form of payment, nature of payment, practitioner ownership, and dispute status.
Results
Payments totaled $32,450,382. Practitioner payments were unevenly distributed, with a median payment of $15. The majority of payments were in the form of food and beverage. Female pelvic medicine practitioners received the highest payments out of the provider specialties. The largest categorical difference from the median was in the form of stock, options, and other ownership interests ($24,050). Ownership status and disputed payments were associated with payment values above median values ($400 and $61, respectively).
Conclusions
There are major disparities in industry payments to urology practitioners. Whether or not this influences practice patterns remains to be seen, though identifying categorical differences in payments is an important first step in the process.
doi:10.1016/j.urpr.2015.12.002
PMCID: PMC5054748  PMID: 27722187
physician payments; urologist payments; sunshine act; compensation
3.  Uses, misuses, new uses and fundamental limitations of magnetic resonance imaging in cognitive science 
When blood oxygenation level-dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) was discovered in the early 1990s, it provoked an explosion of interest in exploring human cognition, using brain mapping techniques based on MRI. Standards for data acquisition and analysis were rapidly put in place, in order to assist comparison of results across laboratories. Recently, MRI data acquisition capabilities have improved dramatically, inviting a rethink of strategies for relating functional brain activity at the systems level with its neuronal substrates and functional connections. This paper reviews the established capabilities of BOLD contrast fMRI, the perceived weaknesses of major methods of analysis, and current results that may provide insights into improved brain modelling. These results have inspired the use of in vivo myeloarchitecture for localizing brain activity, individual subject analysis without spatial smoothing and mapping of changes in cerebral blood volume instead of BOLD activation changes. The apparent fundamental limitations of all methods based on nuclear magnetic resonance are also discussed.
This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’.
doi:10.1098/rstb.2015.0349
PMCID: PMC5003851  PMID: 27574303
magnetic resonance imaging; brain function; cerebral blood volume; neuroanatomy; cortical layers; myeloarchitecture
4.  Chunking as the result of an efficiency computation trade-off 
Nature Communications  2016;7:12176.
How to move efficiently is an optimal control problem, whose computational complexity grows exponentially with the horizon of the planned trajectory. Breaking a compound movement into a series of chunks, each planned over a shorter horizon can thus reduce the overall computational complexity and associated costs while limiting the achievable efficiency. This trade-off suggests a cost-effective learning strategy: to learn new movements we should start with many short chunks (to limit the cost of computation). As practice reduces the impediments to more complex computation, the chunking structure should evolve to allow progressively more efficient movements (to maximize efficiency). Here we show that monkeys learning a reaching sequence over an extended period of time adopt this strategy by performing movements that can be described as locally optimal trajectories. Chunking can thus be understood as a cost-effective strategy for producing and learning efficient movements.
Complex motions can be achieved by chunking together simple movements at the cost of producing smooth, efficient trajectories. Here the authors apply a new algorithm to monkeys learning complex motor sequences and show that optimization initially occurs within small chunks that are later combined.
doi:10.1038/ncomms12176
PMCID: PMC4942581  PMID: 27397420
5.  The Subthalamic Nucleus During Decision-Making With Multiple Alternatives 
Human brain mapping  2015;36(10):4041-4052.
Several prominent neurocomputational models predict that an increase of choice alternatives is modulated by increased activity in the subthalamic nucleus (STN). In turn, increased STN activity allows prolonged accumulation of information. At the same time, areas in the medial frontal cortex such as the anterior cingulate cortex (ACC) and the pre-SMA are hypothesized to influence the information processing in the STN. This study set out to test concrete predictions of STN activity in multiple-alternative decision-making using a multimodal combination of 7 Tesla structural and functional Magnetic Resonance Imaging, and ancestral graph (AG) modeling. The results are in line with the predictions in that increased STN activity was found with an increasing amount of choice alternatives. In addition, our study shows that activity in the ACC is correlated with activity in the STN without directly modulating it. This result sheds new light on the information processing streams between medial frontal cortex and the basal ganglia.
doi:10.1002/hbm.22896
PMCID: PMC4896390  PMID: 26178078
decision-making; basal ganglia; computational modeling; ultrahigh field magnetic resonance imaging; functional magnetic resonance imaging; diffusion weighted imaging
6.  Panniculectomy and Cystectomy: An Approach to the Morbidly Obese Patient 
Case Reports in Urology  2016;2016:6980843.
The obese patient undergoing radical cystectomy faces a unique set of challenges. We present the case of a 68-year-old gentleman who presented to our institution with Bacillus Calmette-Guerin refractory disease, a body mass index of 38.5, and a large pannus. The present paper describes our technique for performing radical cystectomy with ileal conduit urinary diversion and concomitant panniculectomy. We discuss the impact of obesity on patients undergoing radical cystectomy and how this may be mitigated by panniculectomy.
doi:10.1155/2016/6980843
PMCID: PMC4852348  PMID: 27195168
8.  Movement-Related Discharge in the Macaque Globus Pallidus during High-Frequency Stimulation of the Subthalamic Nucleus 
The Journal of Neuroscience  2015;35(9):3978-3989.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) has largely replaced ablative therapies for Parkinson's disease. Because of the similar efficacies of the two treatments, it has been proposed that DBS acts by creating an “informational lesion,” whereby pathologic neuronal firing patterns are replaced by low-entropy, stimulus-entrained firing patterns. The informational lesion hypothesis, in its current form, states that DBS blocks the transmission of all information from the basal ganglia, including both pathologic firing patterns and normal, task-related modulations in activity. We tested this prediction in two healthy rhesus macaques by recording single-unit spiking activity from the globus pallidus (232 neurons) while the animals completed choice reaction time reaching movements with and without STN-DBS. Despite strong effects of DBS on the activity of most pallidal cells, reach-related modulations in firing rate were equally prevalent in the DBS-on and DBS-off states. This remained true even when the analysis was restricted to cells affected significantly by DBS. In addition, the overall form and timing of perimovement modulations in firing rate were preserved between DBS-on and DBS-off states in the majority of neurons (66%). Active movement and DBS had largely additive effects on the firing rate of most neurons, indicating an orthogonal relationship in which both inputs contribute independently to the overall firing rate of pallidal neurons. These findings suggest that STN-DBS does not act as an indiscriminate informational lesion but rather as a filter that permits task-related modulations in activity while, presumably, eliminating the pathological firing associated with parkinsonism.
doi:10.1523/JNEUROSCI.4899-14.2015
PMCID: PMC4348192  PMID: 25740526
basal ganglia; nonhuman primate; reaching
9.  Slice Accelerated Gradient-Echo Spin-Echo Dynamic Susceptibility Contrast Imaging with Blipped CAIPI for Increased Slice Coverage 
Purpose
To improve slice coverage of gradient echo spin echo (GESE) sequences for dynamic susceptibility contrast (DSC) MRI using a simultaneous-multiple-slice (SMS) method.
Methods
Data were acquired on 3 Tesla (T) MR scanners with a 32-channel head coil. To evaluate use of SMS for DSC, an SMS GESE sequence with two-fold slice coverage and same temporal sampling was compared with a standard GESE sequence, both with 2× in-plane acceleration. A signal to noise ratio (SNR) comparison was performed on one healthy subject. Additionally, data with Gadolinium injection were collected on three patients with glioblastoma using both sequences, and perfusion analysis was performed on healthy tissues as well as on tumor.
Results
Retained SNR of SMS DSC is 90% for a gradient echo (GE) and 99% for a spin echo (SE) acquisition, compared with a standard acquisition without slice acceleration. Comparing cerebral blood volume maps, it was observed that the results of standard and SMS acquisitions are comparable for both GE and SE images.
Conclusion
Two-fold slice accelerated DSC MRI achieves similar SNR and perfusion metrics as a standard acquisition, while allowing a significant increase in slice coverage of the brain. The results also point to a possibility to improve temporal sampling rate, while retaining the same slice coverage.
doi:10.1002/mrm.24960
PMCID: PMC4002660  PMID: 24285593
DSC; GESE; CAIPIRINHA; blipped CAIPI; SMS; brain tumor
10.  Impact of the β-Lactam Resistance Modifier (−)-Epicatechin Gallate on the Non-Random Distribution of Phospholipids across the Cytoplasmic Membrane of Staphylococcus aureus 
The polyphenol (−)-epicatechin gallate (ECg) inserts into the cytoplasmic membrane (CM) of methicillin-resistant Staphylococcus aureus (MRSA) and reversibly abrogates resistance to β-lactam antibiotics. ECg elicits an increase in MRSA cell size and induces thickened cell walls. As ECg partially delocalizes penicillin-binding protein PBP2 from the septal division site, reduces PBP2 and PBP2a complexation and induces CM remodelling, we examined the impact of ECg membrane intercalation on phospholipid distribution across the CM and determined if ECg affects the equatorial, orthogonal mode of division. The major phospholipids of the staphylococcal CM, lysylphosphatidylglycerol (LPG), phosphatidylglycerol (PG), and cardiolipin (CL), were distributed in highly asymmetric fashion; 95%–97% of LPG was associated with the inner leaflet whereas PG (~90%) and CL (~80%) were found predominantly in the outer leaflet. ECg elicited small, significant changes in LPG distribution. Atomic force microscopy established that ECg-exposed cells divided in similar fashion to control bacteria, with a thickened band of encircling peptidoglycan representing the most recent plane of cell division, less distinct ribs indicative of previous sites of orthogonal division and concentric rings and “knobbles” representing stages of peptidoglycan remodelling during the cell cycle. Preservation of staphylococcal membrane lipid asymmetry and mode of division in sequential orthogonal planes appear key features of ECg-induced stress.
doi:10.3390/ijms160816710
PMCID: PMC4581164  PMID: 26213914
epicatechin gallate; Staphylococcus aureus; membrane phospholipids; membrane asymmetry; beta-lactam susceptibility; bacterial cell division
11.  Bacterial Cell Enlargement Requires Control of Cell Wall Stiffness Mediated by Peptidoglycan Hydrolases 
mBio  2015;6(4):e00660-15.
ABSTRACT
Most bacterial cells are enclosed in a single macromolecule of the cell wall polymer, peptidoglycan, which is required for shape determination and maintenance of viability, while peptidoglycan biosynthesis is an important antibiotic target. It is hypothesized that cellular enlargement requires regional expansion of the cell wall through coordinated insertion and hydrolysis of peptidoglycan. Here, a group of (apparent glucosaminidase) peptidoglycan hydrolases are identified that are together required for cell enlargement and correct cellular morphology of Staphylococcus aureus, demonstrating the overall importance of this enzyme activity. These are Atl, SagA, ScaH, and SagB. The major advance here is the explanation of the observed morphological defects in terms of the mechanical and biochemical properties of peptidoglycan. It was shown that cells lacking groups of these hydrolases have increased surface stiffness and, in the absence of SagB, substantially increased glycan chain length. This indicates that, beyond their established roles (for example in cell separation), some hydrolases enable cellular enlargement by making peptidoglycan easier to stretch, providing the first direct evidence demonstrating that cellular enlargement occurs via modulation of the mechanical properties of peptidoglycan.
IMPORTANCE
Understanding bacterial growth and division is a fundamental problem, and knowledge in this area underlies the treatment of many infectious diseases. Almost all bacteria are surrounded by a macromolecule of peptidoglycan that encloses the cell and maintains shape, and bacterial cells must increase the size of this molecule in order to enlarge themselves. This requires not only the insertion of new peptidoglycan monomers, a process targeted by antibiotics, including penicillin, but also breakage of existing bonds, a potentially hazardous activity for the cell. Using Staphylococcus aureus, we have identified a set of enzymes that are critical for cellular enlargement. We show that these enzymes are required for normal growth and define the mechanism through which cellular enlargement is accomplished, i.e., by breaking bonds in the peptidoglycan, which reduces the stiffness of the cell wall, enabling it to stretch and expand, a process that is likely to be fundamental to many bacteria.
doi:10.1128/mBio.00660-15
PMCID: PMC4551982  PMID: 26220963
12.  NADPH oxidase NOX4 supports renal tumorigenesis by promoting the expression and nuclear accumulation of HIF2α 
Cancer research  2014;74(13):3501-3511.
Most sporadically occurring renal tumors include a functional loss of the tumor suppressor VHL. Development of VHL-deficient renal cell carcinoma (RCC) relies upon activation of the hypoxia-inducible factor HIF-2α, a master transcriptional regulator of genes that drive diverse processes including angiogenesis, proliferation and anaerobic metabolism. In determining the critical functions for HIF-2α expression in RCC cells, the NADPH oxidase NOX4 has been identified, but the pathogenic contributions of NOX4 to RCC have not been evaluated directly. Here we report that NOX4 silencing in VHL-deficient RCC cells abrogates cell branching, invasion, colony formation and growth in a murine xenograft model RCC. These alterations were phenocopied by treatment of the superoxide scavenger, TEMPOL, or by overexpression of manganese superoxide dismutase or catalase. Notably, NOX4 silencing or superoxide scavenging was sufficient to block nuclear accumulation of HIF-2α in RCC cells. Our results offer direct evidence that NOX4 is critical for renal tumorigenesis and they show how NOX4 suppression and VHL re-expression in VHL-deficient RCC cells are genetically synonymous, supporting development of therapeutic regimens aimed at NOX4 blockade.
doi:10.1158/0008-5472.CAN-13-2979
PMCID: PMC4079760  PMID: 24755467
Nox4; HIF-2α; superoxide scavenger; renal cell carcinoma
13.  High-resolution 7T fMRI of Human Hippocampal Subfields during Associative Learning 
Journal of cognitive neuroscience  2014;27(6):1194-1206.
Examining the function of individual human hippocampal subfields remains challenging due to their small sizes and convoluted structures. Previous human functional magnetic resonance (fMRI) studies at 3 Tesla (T) have successfully detected differences in activation between hippocampal cornu ammonis (CA) field CA1, combined CA2, 3 and dentate gyrus (DG) region (CA23DG), and the subiculum during associative memory tasks. In this study we investigated hippocampal subfield activity in healthy participants using an associative memory paradigm during high-resolution functional magnetic resonance imaging (fMRI) scanning at 7T. We were able to localize fMRI activity to anterior CA2 and CA3 during learning, and to the posterior CA2 field, the CA1, and the posterior subiculum during retrieval of novel associations. These results provide insight into more specific human hippocampal subfield functions underlying learning and memory and a unique opportunity for future investigations of hippocampal subfield function in healthy individuals as well as those suffering from neurodegenerative diseases.
doi:10.1162/jocn_a_00772
PMCID: PMC4417053  PMID: 25514656
Hippocampus; memory; fMRI; MRI; high-resolution imaging
14.  Skeletal Muscle Radio-Density Is an Independent Predictor of Response and Outcomes in Follicular Lymphoma Treated with Chemoimmunotherapy 
PLoS ONE  2015;10(6):e0127589.
Skeletal muscle radio-density (SMD) measures muscle radiation attenuation (in Hounsfield Units, HU) on computed tomography (CT) scans. Low SMD is prognostic of poor survival in melanoma, however its significance is unknown for hematologic malignancies. We performed a single institution, retrospective review of all follicular lymphoma (FL) patients who received chemoimmunotherapy from 2004–2009. Patient demographics, FL International Prognostic Index 1 (FLIPI-1), progression free (PFS) and overall survival (OS) were collected as primary endpoints. Objective response rates (ORR) were secondary. SMD was calculated using pre-treatment CT scans. In 145 patients reviewed, median values were age 59, FLIPI-1 of 2, stage III, and 8 chemoimmunotherapy cycles received. Median PFS for those with low SMD (<36.6 and <33.1 HU for patients with BMI ≤ 25 and > 25 kg/m2, respectively) compared to those with high SMD was profoundly worse, 69.6 vs. 106.7 months (hazard ratio [HR] 1.85; p = 0.01), respectively. Median OS was not reached in patients with high SMD vs. 92.7 months in low SMD patients (HR 4.02; p = 0.0002). Multivariate analysis supported lower SMD’s OS detriment (HR = 3.40; p = 0.002) independent of FLIPI-1 (HR 1.46–2.76, p = 0.05) or gender. Low SMD predicted lower ORR, 83 vs. 96% (p = 0.01). SMD predicts survival independent of FLIPI-1 and potentially chemoimmunotherapy response. SMD is an inexpensive and powerful tool that can complement FLIPI-1.
doi:10.1371/journal.pone.0127589
PMCID: PMC4452316  PMID: 26030144
15.  Irreducible lateral dislocation of patella 
BMJ Case Reports  2013;2013:bcr2013009832.
doi:10.1136/bcr-2013-009832
PMCID: PMC3669832  PMID: 23645661
16.  Motor Cortex Stimulation: Mild Transient Benefit in a Primate Model of Parkinson’s Disease 
Journal of neurosurgery  2007;106(4):695-700.
Objective
We sought to examine the therapeutic efficacy of motor cortex stimulation (MCS) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques, and to characterize therapeutic differences with varying modes, frequencies, and durations of stimulation.
Methods
MCS was delivered at currents below motor threshold and at frequencies between 5Hz and 150Hz through epidural electrodes over primary motor cortex. The animals were studied on and off MCS using video analysis, activity logging, and food retrieval tasks. Animals were examined using two different stimulation protocols. The first protocol consisted of one hour of MCS therapy daily. The second protocol exposed the animal to continuous MCS for over 24 hours with at least 2 weeks between MCS therapy.
Conclusions
Daily MCS revealed no consistent change in symptoms, but MCS at two-week intervals resulted in significant increases in activity. Effects of biweekly MCS disappeared, however, within 24 hours of the onset of continuous MCS. In this study, MCS only temporarily reduced the severity of MPTP-induced parkinsonism.
doi:10.3171/jns.2007.106.4.695
PMCID: PMC4416648  PMID: 17432724
Parkinson’s Disease; MPTP; Cortical Stimulation; Non-human primate; Basal Ganglia; Primary Motor Cortex
17.  Reported Sports Participation, Race, Sex, Ethnicity, and Obesity in US Adolescents From NHANES Physical Activity (PAQ_D) 
Global Pediatric Health  2015;2:2333794X15577944.
Objective. To understand the relationships between participation in different types of leisure time sport activity and adolescent obesity, and how those relationships might differ based on race, gender, and household income. Methods. Data consisted of 6667 students that took part in the 1999 to 2006 National Health and Nutrition Examination Survey. The authors used adjusted Wald tests to examine differences in the prevalence of obesity (body mass index >95th percentile for age and sex) by sport for boys and girls separately. Results. Among adolescent youth age 12 to 19 years, 16.6% of male leisure time sport participants and 15.3% of female sport participants were obese, compared with 23.6% for male nonathlete participant-in-other-activities and 17.0% obesity rate for female nonathlete/participant-in-other-activities. For both males and females, reported participation in leisure time sports decreased between middle school and high school, and this reduction was associated with higher body mass index.
doi:10.1177/2333794X15577944
PMCID: PMC4784630  PMID: 27335953
sports; athletes; obesity; adolescents
18.  Emotion, rationality, and decision-making: how to link affective and social neuroscience with social theory 
In this paper, we argue for a stronger engagement between concepts in affective and social neuroscience on the one hand, and theories from the fields of anthropology, economics, political science, and sociology on the other. Affective and social neuroscience could provide an additional assessment of social theories. We argue that some of the most influential social theories of the last four decades—rational choice theory, behavioral economics, and post-structuralism—contain assumptions that are inconsistent with key findings in affective and social neuroscience. We also show that another approach from the social sciences—plural rationality theory—shows greater compatibility with these findings. We further claim that, in their turn, social theories can strengthen affective and social neuroscience. The former can provide more precise formulations of the social phenomena that neuroscientific models have targeted, can help neuroscientists who build these models become more aware of their social and cultural biases, and can even improve the models themselves. To illustrate, we show how plural rationality theory can be used to further specify and test the somatic marker hypothesis. Thus, we aim to accelerate the much-needed merger of social theories with affective and social neuroscience.
doi:10.3389/fnins.2015.00332
PMCID: PMC4585257  PMID: 26441506
affective and social neuroscience; social and political theory; somatic marker hypothesis; plural rationality
19.  Multi-modal ultra-high resolution structural 7-Tesla MRI data repository 
Scientific Data  2014;1:140050.
Structural brain data is key for the understanding of brain function and networks, i.e., connectomics. Here we present data sets available from the ‘atlasing of the basal ganglia (ATAG)’ project, which provides ultra-high resolution 7 Tesla (T) magnetic resonance imaging (MRI) scans from young, middle-aged, and elderly participants. The ATAG data set includes whole-brain and reduced field-of-view MP2RAGE and T2*-weighted scans of the subcortex and brainstem with ultra-high resolution at a sub-millimeter scale. The data can be used to develop new algorithms that help building high-resolution atlases both relevant for the basic and clinical neurosciences. Importantly, the present data repository may also be used to inform the exact positioning of electrodes used for deep-brain-stimulation in patients with Parkinson’s disease and neuropsychiatric diseases.
doi:10.1038/sdata.2014.50
PMCID: PMC4421933  PMID: 25977801
20.  Comparing Like with Like: The Power of Knowing Where You Are 
Brain Connectivity  2014;4(7):547-557.
Abstract
Magnetic resonance imaging can now provide human brain images of structure, function, and connectivity with isotropic voxels smaller than one millimeter, and thus much smaller than the cortical thickness. This resolution, achievable in a scan time of less than 1 h, enables visualization of myeloarchitectural layer structure, intracortical variations in functional activity—recorded in changes in blood oxygenation level dependent signal or cerebral blood volume CBV—and intracortical axonal orientational structure via diffusion-weighted magnetic resonance imaging. While recent improvements in radiofrequency receiver coils now enable excellent image data to be obtained at 3T, scanning at the ultra-high field of 7T offers further gains in signal-to-noise ratio and speed of image acquisition, with a structural image resolution of about 300 μm. These improvements throw into sharp question the strategies that have become conventional for the analysis of functional imaging data, especially the practice of spatial smoothing of raw functional data before further analysis. Creation of a native cortical map for each human subject that provides a reliable individual parcellation into cortical areas related to Brodmann Areas enables a strikingly different approach to functional image analysis. This proposed approach involves surface registration of the cortices of groups of subjects using maps of the longitudinal relaxation time T1 as an index of myelination, and methods for inferring statistical significance that do not entail spatial smoothing. The outcome should be a far more precise comparison of like-with-like cortical areas across subjects, with the potential to greatly increase experimental power, to discriminate activity in neighboring cortical areas, and to enable correlation of function and connectivity with specific cytoarchitecture. Such analyses should enable a far more convincing modeling of brain mechanisms than current graph-based methods that require gross over-simplification of brain activity patterns in order to be computationally tractable.
doi:10.1089/brain.2014.0261
PMCID: PMC4146387  PMID: 24999746
functional magnetic resonance imaging (fMRI); neuroanatomy; image analysis
21.  Bactericidal Activity of the Human Skin Fatty Acid cis-6-Hexadecanoic Acid on Staphylococcus aureus 
Human skin fatty acids are a potent aspect of our innate defenses, giving surface protection against potentially invasive organisms. They provide an important parameter in determining the ecology of the skin microflora, and alterations can lead to increased colonization by pathogens such as Staphylococcus aureus. Harnessing skin fatty acids may also give a new avenue of exploration in the generation of control measures against drug-resistant organisms. Despite their importance, the mechanism(s) whereby skin fatty acids kill bacteria has remained largely elusive. Here, we describe an analysis of the bactericidal effects of the major human skin fatty acid cis-6-hexadecenoic acid (C6H) on the human commensal and pathogen S. aureus. Several C6H concentration-dependent mechanisms were found. At high concentrations, C6H swiftly kills cells associated with a general loss of membrane integrity. However, C6H still kills at lower concentrations, acting through disruption of the proton motive force, an increase in membrane fluidity, and its effects on electron transfer. The design of analogues with altered bactericidal effects has begun to determine the structural constraints on activity and paves the way for the rational design of new antistaphylococcal agents.
doi:10.1128/AAC.01043-13
PMCID: PMC4068517  PMID: 24709265
22.  Spatial normalization of ultrahigh resolution 7 T magnetic resonance imaging data of the postmortem human subthalamic nucleus: a multistage approach 
Brain Structure & Function  2014;220(3):1695-1703.
In this paper, we describe a novel processing strategy for the spatial normalization of ultrahigh resolution magnetic resonance imaging (MRI) data of small ex vivo samples into MNI standard space. We present a multistage scanning and registration method for data of the subthalamic nucleus (STN) obtained using ultrahigh 7 T MRI on four human postmortem brain samples. Four whole brains were obtained and subjected to multistage MRI scanning, corresponding to four different brain dissection stages. Data sets were acquired with an isotropic resolution of 100 μm enabling accurate manual segmentation of the STN. Spatial normalization to MNI reference space was performed, probability maps were calculated, and results were cross-checked with an independent in vivo dataset showing significant overlay. Normalization of results obtained from small tissue samples into MNI standard space will facilitate comparison between individual subjects, as well as between studies. When combining ultrahigh resolution MRI of ex vivo samples with histological studies via blockface imaging, our method enables further insight and inference as multimodal data can be compared within the same reference space. This novel technique may be of value for research purposes using functional MRI techniques, and in the future may be of assistance for anatomical orientation in clinical practice.
doi:10.1007/s00429-014-0754-4
PMCID: PMC4409638  PMID: 24663802
Ultrahigh resolution MRI; Basal ganglia; Parkinson’s disease; Subthalamic nucleus; MR microscopy; Probability maps
23.  Deficient approaches to human neuroimaging 
Functional magnetic resonance imaging (fMRI) is the workhorse of imaging-based human cognitive neuroscience. The use of fMRI is ever-increasing; within the last 4 years more fMRI studies have been published than in the previous 17 years. This large body of research has mainly focused on the functional localization of condition- or stimulus-dependent changes in the blood-oxygenation-level dependent signal. In recent years, however, many aspects of the commonly practiced analysis frameworks and methodologies have been critically reassessed. Here we summarize these critiques, providing an overview of the major conceptual and practical deficiencies in widely used brain-mapping approaches, and exemplify some of these issues by the use of imaging data and simulations. In particular, we discuss the inherent pitfalls and shortcomings of methodologies for statistical parametric mapping. Our critique emphasizes recent reports of excessively high numbers of both false positive and false negative findings in fMRI brain mapping. We outline our view regarding the broader scientific implications of these methodological considerations and briefly discuss possible solutions.
doi:10.3389/fnhum.2014.00462
PMCID: PMC4076796  PMID: 25071503
fMRI; cognitive neuroscience; brain mapping; functional localization; critical neuroscience
24.  Prioritizing spatial accuracy in high-resolution fMRI data using multivariate feature weight mapping 
Although ultra-high-field fMRI at field strengths of 7T or above provides substantial gains in BOLD contrast-to-noise ratio, when very high-resolution fMRI is required such gains are inevitably reduced. The improvement in sensitivity provided by multivariate analysis techniques, as compared with univariate methods, then becomes especially welcome. Information mapping approaches are commonly used, such as the searchlight technique, which take into account the spatially distributed patterns of activation in order to predict stimulus conditions. However, the popular searchlight decoding technique, in particular, has been found to be prone to spatial inaccuracies. For instance, the spatial extent of informative areas is generally exaggerated, and their spatial configuration is distorted. We propose the combination of a non-parametric and permutation-based statistical framework with linear classifiers. We term this new combined method Feature Weight Mapping (FWM). The main goal of the proposed method is to map the specific contribution of each voxel to the classification decision while including a correction for the multiple comparisons problem. Next, we compare this new method to the searchlight approach using a simulation and ultra-high-field 7T experimental data. We found that the searchlight method led to spatial inaccuracies that are especially noticeable in high-resolution fMRI data. In contrast, FWM was more spatially precise, revealing both informative anatomical structures as well as the direction by which voxels contribute to the classification. By maximizing the spatial accuracy of ultra-high-field fMRI results, global multivariate methods provide a substantial improvement for characterizing structure-function relationships.
doi:10.3389/fnins.2014.00066
PMCID: PMC3997040  PMID: 24795548
fMRI; MVPA; searchlight; nonparametric statistics; decoding
25.  Limited encoding of effort by dopamine neurons in a cost-benefit trade-off task 
Animals are thought to evaluate the desirability of action options using a unified scale that combines predicted benefits (“rewards”), costs, and the animal’s internal motivational state. Midbrain dopamine neurons have long been associated with the reward part of this equation, but it is unclear whether these neurons also estimate the costs of taking an action. We studied the spiking activity of dopamine neurons in the substantia nigra pars compacta of monkeys (Macaca mulatta) during a reaching task in which the energetic costs incurred (friction loads) and the benefits gained (drops of food) were manipulated independently. Although the majority of dopamine neurons encoded the upcoming reward alone, a subset predicted net utility of a course of action by signaling the expected reward magnitude, discounted by the invested cost in terms of physical effort. In addition, the tonic activity of some dopamine neurons was slowly reduced in conjunction with the accumulated trials, which is consistent with the hypothesized role for tonic dopamine in the invigoration or motivation of instrumental responding. The present results shed light on an oft-hypothesized role for dopamine in the regulation of the balance in natural behaviors between the energy expended and the benefits gained, which could explain why dopamine disorders, such as Parkinson’s disease, lead to a breakdown of that balance.
doi:10.1523/JNEUROSCI.4619-12.2013
PMCID: PMC3698042  PMID: 23658169
reward; effort; dopamine; utility; vigor

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