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1.  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
2.  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
3.  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
4.  Physiological identification of the human pedunculopontine nucleus 
Background
The pedunculopontine nucleus (PPN) is a brainstem structure with widespread connections to the basal ganglia. Despite the recent introduction of PPN deep brain stimulation (DBS) for the treatment of gait disorders, little is known about its physiology in humans.
Methods
We analyzed the discharge characteristics of single neurons in the PPN region in four patients and PPN local field potentials (LFP) in one patient, recorded during the course of DBS implantation. Two patients had Parkinson’s disease and two had non-sinemet responsive parkinsonism. Cell locations were plotted in the coordinate system of a human brainstem atlas.
Results
Fifty-six units in the PPN region were studied, of which 32 mapped to within PPN boundaries. The mean (+/− SD) discharge rate of neurons in the PPN was 23.2 (+/− 15.6) Hz. Spontaneous neuronal firing rate and burst discharge rate were significantly different between neurons in the region dorsal to PPN and those in the PPN. Responses to passive movement of contralateral and ipsilateral limbs were found. Theta and beta band oscillations were present in the PPN LFP.
Conclusion
PPN discharge characteristics may prove useful in the electrophysiologic identification of PPN during DBS implantation surgery.
doi:10.1136/jnnp.2009.179069
PMCID: PMC3806635  PMID: 19828478
Parkinson’s disease; neurophysiology; gait; neurosurgery
5.  Spontaneous Neuronal Activity in the Posterior Hypothalamic Region in Humans 
Neurosurgery  2009;64(3 0):ons161-ons169.
Introduction
Deep brain stimulation (DBS) of the posterior hypothalamic region (PHR) is an emerging technique for the treatment of medically intractable cluster headache (CH). Few reports have analyzed single unit neuronal recordings in the human PHR. We report properties of spontaneous neuronal discharge in PHR for six patients who underwent DBS for CH
Materials and Methods
Initial target coordinates, determined by magnetic resonance imaging (MRI) stereotactic localization, were 2 mm lateral, 3 mm posterior, and 5 mm inferior to the midpoint of the anterior commissure-posterior commissure (AC-PC) line. A single microelectrode penetration was performed beginning 10 mm above the anatomic target, without systemic sedation. Single units were discriminated off line by cluster cutting in principal components space. Discharge rates, interspike intervals, bursting activity, and oscillatory activity were analyzed and compared between ventromedial thalamic and hypothalamic units.
Results
Six patients and 24 units were evaluated. Units in the PHR had a slow, regular spontaneous discharge with wide, low amplitude action potentials. The mean discharge rate of hypothalamic neurons was significantly lower (13.2 ± 12.2; mean ± SD) than that of medial thalamic units (28.0 ±8.2). Oscillatory activity was not detected. Measures of bursting did not clearly distinguish medial thalamus from hypothalamus.
Conclusion
Single unit discharge rate of neurons in the posterior hypothalamic region of awake humans was 13.2 Hz and was significantly lower than medial thalamic neurons recorded dorsal to the target. The findings will be of utility for microelectrode localization of the CH target and for comparison with animal studies.
doi:10.1227/01.NEU.0000334051.91501.E3
PMCID: PMC3777657  PMID: 19240565
hypothalamus; periventricular gray (PVG); electrophysiology; single unit; microelectrode; cluster headache
6.  Cerebral blood volume changes during brain activation 
Cerebral blood volume (CBV) changes significantly with brain activation, whether measured using positron emission tomography, functional magnetic resonance imaging (fMRI), or optical microscopy. If cerebral vessels are considered to be impermeable, the contents of the skull incompressible, and the skull itself inextensible, task- and hypercapnia-related changes of CBV could produce intolerable changes of intracranial pressure. Because it is becoming clear that CBV may be useful as a well-localized marker of neural activity changes, a resolution of this apparent paradox is needed. We have explored the idea that much of the change in CBV is facilitated by exchange of water between capillaries and surrounding tissue. To this end, we developed a novel hemodynamic boundary-value model and found approximate solutions using a numerical algorithm. We also constructed a macroscopic experimental model of a single capillary to provide biophysical insight. Both experiment and theory model capillary membranes as elastic and permeable. For a realistic change of input pressure, a relative pipe volume change of 21±5% was observed when using the experimental setup, compared with the value of approximately 17±1% when this quantity was calculated from the mathematical model. Volume, axial flow, and pressure changes are in the expected range.
doi:10.1038/jcbfm.2012.63
PMCID: PMC3421101  PMID: 22569192
blood–brain barrier; capillaries; cerebral blood flow; cerebral hemodynamics; mathematical modeling; physiology
7.  Development and Evaluation of an Algorithm for the Computer-Assisted Segmentation of the Human Hypothalamus on 7-Tesla Magnetic Resonance Images 
PLoS ONE  2013;8(7):e66394.
Post mortem studies have shown volume changes of the hypothalamus in psychiatric patients. With 7T magnetic resonance imaging this effect can now be investigated in vivo in detail. To benefit from the sub-millimeter resolution requires an improved segmentation procedure. The traditional anatomical landmarks of the hypothalamus were refined using 7T T1-weighted magnetic resonance images. A detailed segmentation algorithm (unilateral hypothalamus) was developed for colour-coded, histogram-matched images, and evaluated in a sample of 10 subjects. Test-retest and inter-rater reliabilities were estimated in terms of intraclass-correlation coefficients (ICC) and Dice's coefficient (DC). The computer-assisted segmentation algorithm ensured test-retest reliabilities of ICC≥.97 (DC≥96.8) and inter-rater reliabilities of ICC≥.94 (DC = 95.2). There were no significant volume differences between the segmentation runs, raters, and hemispheres. The estimated volumes of the hypothalamus lie within the range of previous histological and neuroimaging results. We present a computer-assisted algorithm for the manual segmentation of the human hypothalamus using T1-weighted 7T magnetic resonance imaging. Providing very high test-retest and inter-rater reliabilities, it outperforms former procedures established at 1.5T and 3T magnetic resonance images and thus can serve as a gold standard for future automated procedures.
doi:10.1371/journal.pone.0066394
PMCID: PMC3720799  PMID: 23935821
8.  TESTING THE CONTRIBUTIONS OF STRIATAL DOPAMINE LOSS TO THE GENESIS OF PARKINSONIAN SIGNS 
Neurobiology of Disease  2012;47(1):114-125.
The diverse and independently-varying signs of Parkinson’s disease (PD) are often attributed to one simple mechanism: degeneration of the dopaminergic innervation of the posterolateral striatum. However, growing recognition of the dopamine (DA) loss and other pathology in extra-striatal brain regions has led to uncertainty whether loss of DA in the striatum is sufficient to cause parkinsonian signs. We tested this hypothesis by infusing cis-flupenthixol (cis-flu; a broad-spectrum D1/D2 receptor antagonist) into different regions of the macaque putamen (3 hemispheres of 2 monkeys) while the animal performed a visually-cued choice reaction time task in which visual cues indicated the arm to reach with and the peripheral target to contact to obtain food reward. Following reward delivery, the animal was required to self-initiate release of the peripheral target and return of the chosen hand to its home position (i.e., without the benefit of external sensory cues or immediate rewards). Infusions of cis-flu at 15 of 26 sites induced prolongations of reaction time (9 of 15 cases), movement duration (6 cases), and/or dwell time of the hand at the peripheral target (8 cases). Dwell times were affected more severely (+95%) than visually-triggered reaction times or movement durations (+25% and +15%, respectively). Specifically, the animal’s hand often ‘froze’ at the peripheral target for up to 25-s, similar to the akinetic freezing episodes observed in PD patients. Across injections, slowing of self-initiation did not correlate in severity with prolongations of visually-triggered reaction time or movement duration, although the latter two were correlated with each other. Episodes of slowed self-initiation appeared primarily in the arm contralateral to the injected hemisphere and were not associated with increased muscle co-contraction or global alterations in behavioral state (i.e., inattention or reduced motivation), consistent with idea that these episodes reflected a fundamental impairment of movement initiation. We found no evidence for an anatomic topography within the putamen for the effects elicited. We conclude that acute focal blockade of DA transmission in the putamen is sufficient to induce marked akinesia-like impairments. Furthermore, different classes of impairments can be induced independently, suggesting that specific parkinsonian signs have unique pathophysiologic substrates.
doi:10.1016/j.nbd.2012.03.028
PMCID: PMC3358361  PMID: 22498034
macaque; bradykinesia; akinesia; microinjection; cis-flupenthixol
9.  Basal ganglia activity patterns in parkinsonism and computational modeling of their downstream effects 
The European Journal of Neuroscience  2012;36(2):2213-2228.
The availability of suitable animal models and of the opportunity to record electrophysiologic data in movement disorder patients undergoing neurosurgical procedures has allowed researchers to investigate parkinsonism-related changes in neuronal firing patterns in the basal ganglia and associated areas of thalamus and cortex. These studies have shown that parkinsonism is associated with increased activity in the basal ganglia output nuclei, along with an increase in burst discharges, oscillatory firing, and synchronous firing patterns throughout the basal ganglia. Computational approaches have the potential to play an important role in the interpretation of these data. Such efforts can provide a formalized view of neuronal interactions in the network of connections between basal ganglia, thalamus and cortex, allow for the exploration of possible contributions of particular network components to parkinsonism, and potentially result in new conceptual frameworks and hypotheses that can be subjected to biological testing. It has proven very difficult, however, to integrate the wealth of the experimental findings into coherent models of the disease. In this review, we provide an overview of the abnormalities in neuronal activity that have been associated with parkinsonism. Subsequently, we discuss some particular efforts to model the pathophysiologic mechanisms that may link abnormal basal ganglia activity to the cardinal parkinsonian motor signs and may help explain the mechanisms underlying the therapeutic efficacy of deep brain stimulation for Parkinson’s disease. We emphasize the logical structure of these computational studies, making clear the assumptions from which they proceed and the consequences and predictions that follow from these assumptions.
doi:10.1111/j.1460-9568.2012.08108.x
PMCID: PMC3400124  PMID: 22805066
Parkinson’s disease; dopamine; striatum; globus pallidus; subthalamic nucleus; deep brain stimulation; burst; oscillation; synchrony
10.  Vaccine Effectiveness Against Laboratory-Confirmed Influenza Hospitalizations Among Elderly Adults During the 2010–2011 Season 
Although the benefits of influenza vaccines for preventing serious influenza outcomes in elderly adults are uncertain, the results of this study suggest that the 2010–2011 influenza vaccine was 42% effective in reducing laboratory-confirmed influenza hospitalizations in this high-risk population.
Background. Although annual influenza immunization is recommended for adults aged ≥65 years due to the substantial burden of illness, the evidence base for this recommendation is weak. Prior observational studies that examined influenza vaccine effectiveness against nonspecific serious outcomes suffered from selection bias and the lack of laboratory confirmation for influenza infection. The objective of this study was to determine the effectiveness of the 2010–2011 seasonal influenza vaccine against laboratory-confirmed influenza hospitalizations among community-dwelling elderly adults, a serious and highly specific outcome.
Methods. We conducted a test-negative study of community-dwelling adults aged >65 years in Ontario, Canada. Respiratory specimens collected between 1 December 2010 and 30 April 2011 from patients admitted to acute care hospitals were tested for influenza using nucleic acid amplification techniques. Influenza vaccination was ascertained from physician billing claims through linkage to health administrative datasets.
Results. Receipt of the 2010–2011 seasonal influenza vaccine was associated with a 42% (95% confidence interval, 29%–53%) reduction in laboratory-confirmed influenza hospitalizations. Vaccine effectiveness estimates were consistent across age groups, by sex, and regardless of outcome severity, timing of testing, and when considering individuals vaccinated <7 or <14 days prior to admission as unvaccinated.
Conclusions. Results of this study will better inform decision making regarding influenza vaccination of elderly adults. Similar analyses are needed annually due to antigenic drift and frequent changes in influenza vaccine composition. The linkage of routinely collected laboratory testing and health administrative data represents an efficient method for estimating influenza vaccine effectiveness that complements prospective studies.
doi:10.1093/cid/cit404
PMCID: PMC3749748  PMID: 23788243
influenza vaccine; hospitalization; vaccine effectiveness; elderly adults
11.  Pallidal neuronal discharge in Huntington’s disease: support for selective loss of striatal cells originating the indirect pathway 
Experimental neurology  2008;211(1):227-233.
Chorea is the predominant motor manifestation in the early symptomatic phase of adult onset Huntington’s disease (HD). Pathologically, this stage is marked by differential loss of striatal neurons contributing to the indirect pathway. This pattern of neuronal loss predicts decreased neuronal firing rates in GPi and increased firing rates in GPe, the opposite of the changes in firing rate known to occur in Parkinson’s disease (PD). We present single unit discharge characteristics (33 neurons) observed in an awake patient with HD (41 CAG repeats) undergoing microelectrode guided surgery for pallidal deep brain stimulation. Pallidal single unit activity at “rest” and during voluntary movement was discriminated off line by principal component analysis and evaluated with respect to discharge rate, bursting, and oscillatory activity in the 0–200 Hz range. 24 GPi and 9 GPe units were studied, and compared with 132 GPi and 50 GPe units from 14 patients with PD. The mean (+/− SEM) spontaneous discharge rate for HD was 58 +/− 4 for GPi and 73 +/− 5 for GPe. This contrasted with discharge rates in PD of 95 +/− 2 for GPi and 57 +/− 3 for GPe. HD GPi units showed more bursting than PD GPi units but much less oscillatory activity in the 2–35 Hz frequency range at rest. These findings are consistent with selective early loss of striatal cells originating the indirect pathway.
doi:10.1016/j.expneurol.2008.01.023
PMCID: PMC3673313  PMID: 18342309
Huntington’s disease; Parkinson’s disease; globus pallidus; microelectrode recording; electrophysiology; basal ganglia; indirect pathway
12.  Inhibition of anthrax lethal factor, lability of hydroxamate as a chelating group 
The metalloprotease activity of lethal factor (LF) from Bacillus anthracis (B. anthracis) is a main source of toxicity in the lethality of anthrax infection. Thus, the understanding of the enzymic activity and inhibition of B. anthracis LF is of scientific and clinical interests. We have designed, synthesized and studied a peptide inhibitor of LF, R9LF-1, with the structure NH2-(D-Arg)9-Val-Leu-Arg-CO-NHOH in which the C-terminal hydroxamic acid is commonly used in the inhibitors of metalloproteases to chelate the active-site Zinc. This inhibitor was shown to be very stable in solution and effectively inhibited LF in kinetic assays. However, its protection on murine macrophages against lethal toxin (LT) lysis activity was relatively week in longer assays. We further observed that the hydroxamic acid group in R9LF-1 was hydrolyzed by LF and the hydrolytic product of this inhibitor is considerably weaker in inhibition of potency. To resist this unique hydrolytic activity of LF, we further designed a new inhibitor R9LF-2 which contained the same structure as R9LF-1 except replacing the hydroxamic acid group with N, O-dimethyl hydroxamic acid, -N(CH3)-O-CH3, (DMHA). R9LF-2 was not hydrolyzed by LF in long term incubation. It has a high inhibitory potency vs. LF with a Ki of 6.4 nM and had a better protection of macrophages against LF toxicity than R9LF-1. These results suggest that in the development of new LF inhibitors, the stability of the chelating group should be carefully examined and that DMHA is a potentially useful moiety to be used in new LF inhibitors.
doi:10.1007/s00253-012-3893-7
PMCID: PMC3364607  PMID: 22270239
anthrax; lethal toxin; inhibitor; hydroxamate; metalloprotease
13.  Ultra-High Field Systems and Applications at 7T and Beyond: Progress, Pitfalls, and Potential 
Magnetic Resonance in Medicine  2011;67(2):317-321.
About 150 researchers around the world convened at the Chateau Lake Louise on Feb 20-23, 2011 to present and discuss the latest research in human and animal imaging and spectroscopy at field strengths of 7 Tesla or above (termed Ultra High Field or UHF) at the third ISMRM-sponsored high field workshop. The clear overall message from the workshop presentations and discussion is that UHF imaging is gaining momentum with regard to new clinically relevant findings, anatomic and fMRI results, susceptibility contrast advancements, solutions to high field related image quality challenges, and to generally pushing the limits of resolution and speed of high field imaging. This meeting report is organized in a manner reflecting the meeting organization itself, covering the seven sessions that were approximately titled: 1. High field overview from head to body to spectroscopy. 2. Susceptibility imaging. 3. Proffered session on susceptibility, ultra fast imaging, unique contrast at 7T and angiography. 4. Neuroscience applications. 5. Proffered session on coils, shimming, parallel imaging, diffusion tensor imaging, and MRI-PET fusion, 6. High field animal imaging and spectroscopy, as well as a vendor overview, and 7. Cutting edge technology at 7T.
doi:10.1002/mrm.23151
PMCID: PMC3265677  PMID: 22083719
14.  The functional architecture of S1 during touch observation described with 7 T fMRI 
Brain Structure & Function  2013;219:119-140.
Recent studies indicate that the primary somatosensory cortex (S1) is active not only when touch is physically perceived but also when it is merely observed to be experienced by another person. This social responsivity of S1 has important implications for our understanding of S1 functioning. However, S1 activity during touch observation has not been characterized in great detail to date. We focused on two features of the S1 functional architecture during touch observation, namely the topographical arrangement of index and middle finger receptive fields (RFs), and their dynamic shrinkage during concurrent activation. Both features have important implications for human behavior. We conducted two fMRI studies at 7 T, one where touch was physically perceived, and one where touch was observed. In the two experiments, participants either had their index finger and/or middle finger stimulated using paintbrushes, or just observed similar touch events on video. Our data show that observing and physically experiencing touch elicits overlapping activity changes in S1. In addition, observing touch to the index finger or the middle finger alone evoked topographically arranged activation foci in S1. Importantly, when co-activated, the index and middle finger RFs not only shrank during physical touch perception, but also during touch observation. Our data, therefore, indicate a similarity between the functional architecture of S1 during touch observation and physical touch perception with respect to single-digit topography and RF shrinkage. These results may allow the tentative conclusion that even primary somatosensory experiences, such as physical touch perception, can be shared amongst individuals.
Electronic supplementary material
The online version of this article (doi:10.1007/s00429-012-0489-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s00429-012-0489-z
PMCID: PMC3889700  PMID: 23283478
Empathy; Primary somatosensory cortex; Mirror neuron system; Shared representations; Suppressive interactions; Receptive field
15.  How to engage the right brain hemisphere in aphasics without even singing: evidence for two paths of speech recovery 
There is an ongoing debate as to whether singing helps left-hemispheric stroke patients recover from non-fluent aphasia through stimulation of the right hemisphere. According to recent work, it may not be singing itself that aids speech production in non-fluent aphasic patients, but rhythm and lyric type. However, the long-term effects of melody and rhythm on speech recovery are largely unknown. In the current experiment, we tested 15 patients with chronic non-fluent aphasia who underwent either singing therapy, rhythmic therapy, or standard speech therapy. The experiment controlled for phonatory quality, vocal frequency variability, pitch accuracy, syllable duration, phonetic complexity and other influences, such as the acoustic setting and learning effects induced by the testing itself. The results provide the first evidence that singing and rhythmic speech may be similarly effective in the treatment of non-fluent aphasia. This finding may challenge the view that singing causes a transfer of language function from the left to the right hemisphere. Instead, both singing and rhythmic therapy patients made good progress in the production of common, formulaic phrases—known to be supported by right corticostriatal brain areas. This progress occurred at an early stage of both therapies and was stable over time. Conversely, patients receiving standard therapy made less progress in the production of formulaic phrases. They did, however, improve their production of non-formulaic speech, in contrast to singing and rhythmic therapy patients, who did not. In light of these results, it may be worth considering the combined use of standard therapy and the training of formulaic phrases, whether sung or rhythmically spoken. Standard therapy may engage, in particular, left perilesional brain regions, while training of formulaic phrases may open new ways of tapping into right-hemisphere language resources—even without singing.
doi:10.3389/fnhum.2013.00035
PMCID: PMC3583105  PMID: 23450277
left-hemispheric stroke; non-fluent aphasia; melodic intonation therapy; singing; rhythmic speech; formulaic language; left perilesional brain regions; right corticostriatal brain areas
16.  High-Resolution MR Imaging of the Human Brainstem In vivo at 7 Tesla 
The human brainstem, which comprises a multitude of axonal nerve fibers and nuclei, plays an important functional role in the human brain. Depicting its anatomy non-invasively with high spatial resolution may thus in turn help to better relate normal and pathological anatomical variations to medical conditions as well as neurological and peripheral functions. We explored the potential of high-resolution magnetic resonance imaging (MRI) at 7 T for depicting the intricate anatomy of the human brainstem in vivo by acquiring and generating images with multiple contrasts: T2-weighted images, quantitative maps of longitudinal relaxation rate (R1 maps) and effective transverse relaxation rate (R2* maps), magnetic susceptibility maps, and direction-encoded track-density images. Images and quantitative maps were compared with histological stains and anatomical atlases to identify nerve nuclei and nerve fibers. Among the investigated contrasts, susceptibility maps displayed the largest number of brainstem structures. Contrary to R1 maps and T2-weighted images, which showed rather homogeneous contrast, R2* maps, magnetic susceptibility maps, and track-density images clearly displayed a multitude of smaller and larger fiber bundles. Several brainstem nuclei were identifiable in sections covering the pons and medulla oblongata, including the spinal trigeminal nucleus and the reticulotegmental nucleus on magnetic susceptibility maps as well as the inferior olive on R1, R2*, and susceptibility maps. The substantia nigra and red nuclei were visible in all contrasts. In conclusion, high-resolution, multi-contrast MR imaging at 7 T is a versatile tool to non-invasively assess the individual anatomy and tissue composition of the human brainstem.
doi:10.3389/fnhum.2013.00710
PMCID: PMC3810670  PMID: 24194710
brainstem; quantitative susceptibility mapping; effective transverse relaxation; longitudinal relaxation; diffusion tensor imaging; track-density imaging; brain; anatomy
17.  Primary motor cortex of the parkinsonian monkey: altered neuronal responses to muscle stretch 
Exaggeration of the long-latency stretch reflex (LLSR) is a characteristic neurophysiologic feature of Parkinson's disease (PD) that contributes to parkinsonian rigidity. To explore one frequently-hypothesized mechanism, we studied the effects of fast muscle stretches on neuronal activity in the macaque primary motor cortex (M1) before and after the induction of parkinsonism by unilateral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We compared results from the general population of M1 neurons and two antidromically-identified subpopulations: distant-projecting pyramidal-tract type neurons (PTNs) and intra-telecenphalic-type corticostriatal neurons (CSNs). Rapid rotations of elbow or wrist joints evoked short-latency responses in 62% of arm-related M1 neurons. As in PD, the late electromyographic responses that constitute the LLSR were enhanced following MPTP. This was accompanied by a shortening of M1 neuronal response latencies and a degradation of directional selectivity, but surprisingly, no increase in single unit response magnitudes. The results suggest that parkinsonism alters the timing and specificity of M1 responses to muscle stretch. Observation of an exaggerated LLSR with no change in the magnitude of proprioceptive responses in M1 is consistent with the idea that the increase in LLSR gain that contributes to parkinsonian rigidity is localized to the spinal cord.
doi:10.3389/fnsys.2013.00098
PMCID: PMC3840326  PMID: 24324412
stretch reflex; primary motor cortex; MPTP; Parkinson's disease; rigidity
18.  Mapping of the internal structure of human habenula with ex vivo MRI at 7T 
The habenula is a small but important nucleus located next to the third ventricle in front of the pineal body. It helps to control the human reward system and is considered to play a key role in emotion, showing increased activation in major depressive disorders. Its dysfunction may underlie several neurological and psychiatric disorders. It is now possible to visualize the habenula and its anatomical subdivisions—medial habenula (MHB) and lateral habenula (LHB)—using MR techniques. The aim of this study was to further differentiate substructures within human lateral habenula (LHB) using ex vivo ultra-high field MR structural imaging, distinguishing between a medial part (m-LHB) and a lateral part (l-LHB). High resolution T1w images with 0.3-mm isotropic resolution and T2*w images with 60-micrometer isotropic resolution were acquired on a 7T MR scanner and quantitative maps of T1 and T2* were calculated. Cluster analysis of image intensity was performed using the Fuzzy and Noise Tolerant Adaptive Segmentation Method (FANTASM) tool. Ultra-high resolution structural MRI of ex vivo brain tissue at 7T provided sufficient SNR and contrast to discriminate the medial and lateral habenular nuclei. Heterogeneity was observed in the lateral habenula (LHB) nuclei, with clear distinctions between lateral and medial parts (m-LHB, l-LHB) and with the neighboring medial habenula (MHB). Clustering analysis based on the T1 and T2* maps strongly showed 4–6 clusters as subcomponents of lateral and medial habenula.
doi:10.3389/fnhum.2013.00878
PMCID: PMC3870283  PMID: 24391571
human habenula; habenular nuclei; lateral habenula; medial habenula; ex vivo; MRI; 7T
19.  3D MDEFT imaging of the human brain at 4.7 T with reduced sensitivity to radiofrequency inhomogeneity 
A modification to the 3D modified driven equilibrium Fourier transform (MDEFT) imaging technique is proposed that reduces its sensitivity to RF inhomogeneity. This is especially important at high field strengths where RF focusing effects exacerbate B1 inhomogeneity, causing significant signal nonuniformity in the images. The adiabatic inversion pulse used during the preparation period of the MDEFT sequence is replaced by a hard (nonadiabatic) pulse with a nominal flip angle of 130°. The spatial inhomogeneity of the hard pulse preparation compensates for the inhomogeneity of the excitation pulses. Uniform signal intensity is obtained for a wide range of B1 amplitudes and the high CNR characteristic of MDEFT is retained. The new approach was validated by numerical simulations and successfully applied to human brain imaging at 4.7 T, resulting in highquality T1-weighted images of the whole human brain at high field strength with uniform signal intensity and contrast, despite the presence of significant RF inhomogeneity.
doi:10.1002/mrm.20482
PMCID: PMC1633717  PMID: 15906308
high field MRI; T1-weighted imaging; RF inhomogeneity; human brain imaging; structural brain imaging
21.  Layer-Specific Intracortical Connectivity Revealed with Diffusion MRI 
Cerebral Cortex (New York, NY)  2012;24(2):328-339.
In this work, we show for the first time that the tangential diffusion component is orientationally coherent at the human cortical surface. Using diffusion magnetic resonance imaging (dMRI), we have succeeded in tracking intracortical fiber pathways running tangentially within the cortex. In contrast with histological methods, which reveal little regarding 3-dimensional organization in the human brain, dMRI delivers additional understanding of the layer dependence of the fiber orientation. A postmortem brain block was measured at very high angular and spatial resolution. The dMRI data had adequate resolution to allow analysis of the fiber orientation within 4 notional cortical laminae. We distinguished a lamina at the cortical surface where diffusion was tangential along the surface, a lamina below the surface where diffusion was mainly radial, an internal lamina covering the Stria of Gennari, where both strong radial and tangential diffusion could be observed, and a deep lamina near the white matter, which also showed mainly radial diffusion with a few tangential compartments. The measurement of the organization of the tangential diffusion component revealed a strong orientational coherence at the cortical surface.
doi:10.1093/cercor/bhs311
PMCID: PMC3888365  PMID: 23099298
crossing-fiber tractography; diffusion tensor imaging; layer 1; Stria of Gennari; visual cortex
22.  Reduction of Seizure Occurrence from Exposure to Auditory Stimulation in Individuals with Neurological Handicaps: A Randomized Controlled Trial 
PLoS ONE  2012;7(10):e45303.
Background
The purpose of this work was to determine in a clinical trial the efficacy of reducing or preventing seizures in patients with neurological handicaps through sustained cortical activation evoked by passive exposure to a specific auditory stimulus (particular music). The specific type of stimulation had been determined in previous studies to evoke anti-epileptiform/anti-seizure brain activity.
Methods
The study was conducted at the Thad E. Saleeby Center in Harstville, South Carolina, which is a permanent residence for individuals with heterogeneous neurological impairments, many with epilepsy. We investigated the ability to reduce or prevent seizures in subjects through cortical stimulation from sustained passive nightly exposure to a specific auditory stimulus (music) in a three-year randomized controlled study. In year 1, baseline seizure rates were established. In year 2, subjects were randomly assigned to treatment and control groups. Treatment group subjects were exposed during sleeping hours to specific music at regular intervals. Control subjects received no music exposure and were maintained on regular anti-seizure medication. In year 3, music treatment was terminated and seizure rates followed. We found a significant treatment effect (p = 0.024) during the treatment phase persisting through the follow-up phase (p = 0.002). Subjects exposed to treatment exhibited a significant 24% decrease in seizures during the treatment phase, and a 33% decrease persisting through the follow-up phase. Twenty-four percent of treatment subjects exhibited a complete absence of seizures during treatment.
Conclusion/Significance
Exposure to specific auditory stimuli (i.e. music) can significantly reduce seizures in subjects with a range of epilepsy and seizure types, in some cases achieving a complete cessation of seizures. These results are consistent with previous work showing reductions in epileptiform activity from particular music exposure and offers potential for achieving a non-invasive, non-pharmacologic treatment of epilepsy.
Trial Registration
Clinicaltrials.gov NCT01459692
doi:10.1371/journal.pone.0045303
PMCID: PMC3469625  PMID: 23071510
23.  Emerging therapeutic options for myelofibrosis: a Canadian perspective 
Myelofibrosis (MF) is a clonal stem cell disorder characterized by cytopenias, splenomegaly, marrow fibrosis, and systemic symptoms due to elevated inflammatory cytokines. MF is associated with decreased survival. The quality of life of patients with MF is similar to other advanced malignancies. Allogeneic hematopoietic cell transplantation is a curative treatment, but is applicable to a minority of patients with MF. None of the conventional therapies are known to alter the natural history of the disease. Significant progress has been made in the last few years in the understanding of disease biology of MF. Discovery of the JAK2V617F mutation paved the way for drug discovery in MF, and the first JAK1/2 inhibitor, ruxolitinib, has been approved by FDA and Health Canada. Several other JAK1/2 inhibitors are at various stages of clinical development. As a consequence, the therapeutic landscape of MF is changing from a disease where no effective therapies existed to one with several novel treatment options on the horizon. In this report, we assess the changing therapeutic options for MF, and critically analyze the position of novel treatments in the current armamentarium.
PMCID: PMC3484412  PMID: 23119228
Myelofibrosis; JAK1/2; ruxolitinib; splenomegaly; treatment options
24.  The Ins and Outs of Hematopoietic Stem Cells: Studies to Improve Transplantation Outcomes 
Stem cell reviews  2011;7(3):590-607.
Deciphering the mechanisms of hematopoietic stem/progenitor cell (HSPC) mobilization and homing is important for the development of strategies to enhance the efficacy of HSPC transplantation and achieve the full potential of HSPC-based cellular therapy. Investigation of these mechanisms has revealed interdependence among the various molecules, pathways and cellular components involved, and underscored the complex nature of these two processes. This review summarizes recent progress in identifying the specific factors implicated in HSPC mobilization and homing, with emphasis on our own work. Particularly, we will discuss our studies on stromal cell-derived factor-1 and its interaction with its receptor CXCR4, proteases (matrix metalloproteinases and carboxypeptidase M), complement proteins (C1q, C3a, C5a, membrane attack complex), sphingosine-1-phosphate, and pharmacologic agents such as the histone deacetylase inhibitor valproic acid and hyaluronic acid.
doi:10.1007/s12015-010-9212-8
PMCID: PMC3113638  PMID: 21140298
Hematopoietic stem cells; Mobilization; Homing; Transplantation
25.  Membrane Type-1 Matrix Metalloproteinase Expression in Acute Myeloid Leukemia and Its Upregulation by Tumor Necrosis Factor-α 
Cancers  2012;4(3):743-762.
Membrane type-1 matrix metalloproteinase (MT1-MMP) has been implicated in tumor invasion, as well as trafficking of normal hematopoietic cells, and acts as a physiologic activator of proMMP-2. In this study we examined MT1-MMP expression in primary acute myeloid leukemia (AML) cells. Because tumor necrosis factor (TNF)-α is known to be elevated in AML, we also investigated the effect of TNF-α on MT1-MMP expression. We found (i) MT1-MMP mRNA expression in 41 out of 43 primary AML samples tested; (ii) activation of proMMP-2 in co-cultures of AML cells with normal bone marrow stromal cells; and (iii) inhibition of proMMP-2 activation and trans-Matrigel migration of AML cells by gene silencing using MT1-MMP siRNA. Moreover, recombinant human TNF-α upregulated MT1-MMP expression in AML cells resulting in enhanced proMMP-2 activation and trans-Matrigel migration. Thus, AML cells express MT1-MMP and TNF-α enhances it leading to increased MMP-2 activation and most likely contributing to the invasive phenotype. We suggest that MT1-MMP, together with TNF-α, should be investigated as potential therapeutic targets in AML.
doi:10.3390/cancers4030743
PMCID: PMC3712719  PMID: 24213464
acute myeloid leukemia; membrane type 1-matrix metalloproteinase; matrix metalloproteinase-2; tumor necrosis factor-α

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