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.

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.

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.

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

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.

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.

In this paper we address Ramsey et al.’s critical assessment of our method for learning partially directed graphs from meta-analysis imaging data (Neumann et al., 2010). We argue that our method provides valid and interpretable results when applied to data representing a single experimental paradigm. Simulations further suggest that, despite theoretical limitations, the application of our method to mixed probability distributions yields reliable results with error rates at acceptable levels. Finally, we discuss the nature of meta-analysis data and the notion of causality in the context of functional neuroimaging.

Dysfunction of primary motor cortex (M1) is thought to contribute to the pathophysiology of parkinsonism. What specific aspects of M1 function are abnormal remains uncertain, however. Moreover, few models consider the possibility that distinct cortical neuron subtypes may be affected differently. Those questions were addressed by studying the resting activity of intratelencephalic-type corticostriatal neurons (CSNs) and distant-projecting lamina 5b pyramidal-tract type neurons (PTNs) in the macaque M1 before and after the induction of parkinsonism by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Contrary to previous reports, the general population of M1 neurons (i.e., PTNs, CSNs, and unidentified neurons) showed reduced baseline firing rates following MPTP, attributable largely to a marked decrease in PTN firing rates. CSN firing rates were unmodified. Although burstiness and firing patterns remained constant in M1 neurons as a whole and CSNs in particular, PTNs became more bursty post-MPTP and less likely to fire in a regular-spiking pattern. Rhythmic spiking (found in PTNs predominantly) occurred at beta frequencies (14–32 Hz) more frequently following MPTP. These results indicate that MPTP intoxication induced distinct modifications in the activity of different M1 neuronal subtypes. The particular susceptibility of PTNs suggests that PTN dysfunction may be an important contributor to the pathophysiology of parkinsonian motor signs.

This functional magnetic resonance imaging study examines shared and distinct cortical areas involved in the auditory perception of song and speech at the level of their underlying constituents: words and pitch patterns. Univariate and multivariate analyses were performed to isolate the neural correlates of the word- and pitch-based discrimination between song and speech, corrected for rhythmic differences in both. Therefore, six conditions, arranged in a subtractive hierarchy were created: sung sentences including words, pitch and rhythm; hummed speech prosody and song melody containing only pitch patterns and rhythm; and as a control the pure musical or speech rhythm. Systematic contrasts between these balanced conditions following their hierarchical organization showed a great overlap between song and speech at all levels in the bilateral temporal lobe, but suggested a differential role of the inferior frontal gyrus (IFG) and intraparietal sulcus (IPS) in processing song and speech. While the left IFG coded for spoken words and showed predominance over the right IFG in prosodic pitch processing, an opposite lateralization was found for pitch in song. The IPS showed sensitivity to discrete pitch relations in song as opposed to the gliding pitch in speech. Finally, the superior temporal gyrus and premotor cortex coded for general differences between words and pitch patterns, irrespective of whether they were sung or spoken. Thus, song and speech share many features which are reflected in a fundamental similarity of brain areas involved in their perception. However, fine-grained acoustic differences on word and pitch level are reflected in the IPS and the lateralized activity of the IFG.

Dancers frequently present with hip pain. The etiology of this pathology has not been clearly identified from an anatomical perspective. Structural variations including hip dysplasia and dynamic variables from the foot to the pelvis will be discussed. Understanding the etiology as a structural entity, neuromuscular entity or a combination of the two, allows for a successful rehabilitative process and a successful return to dance. This article describes the possible correlation between hip dysplasia and hip pain in the dancer, the relationship of dance postures to the kinematic chain and outlines possible treatment strategies for management.

Bursts and oscillatory modulations in firing rate are hallmark features of abnormal neuronal activity in the parkinsonian Globus Pallidus internus (GPi). Although often implicated together in the pathophysiology of parkinsonian signs, little is known about how burst discharges and oscillatory firing (OF) relate to each other. To investigate this question, extracellular single-unit neuronal activity was recorded from 132 GPi cells in 14 Parkinson’s disease patients. We found that burst firing was equally prevalent in OF and non-oscillatory firing (NOF) cells (p>0.5). More than half of the cells were characterized by either aperiodic bursty activity or OF, but not both. OF and NOF cells had statistically-indistinguishable levels of mean burstiness (p=0.8). Even when bursting and OF co-existed in individual cells, levels of burstiness and oscillatory power were seldom correlated across time. Interestingly, however, the few OF cells with spectral peaks between 8–13-Hz (α-range) were substantially burstier than other cells (p<0.01) and showed an unique burst morphology and stronger temporal correlations between oscillatory power and burstiness. We conclude that independent mechanisms may underlie the burst discharges and OF typical of most neurons in the parkinsonian GPi.

Functional magnetic resonance data acquired in a task-absent condition (“resting state”) require new data analysis techniques that do not depend on an activation model. Here, we propose a new analysis method called Connectivity Concordance Mapping (CCM). The main idea is to assign a label to each voxel based on the reproducibility of its whole-brain pattern of connectivity. Specifically, we compute the correlations of time courses of each voxel with every other voxel for each measurement. Voxels whose correlation pattern is consistent across measurements receive high values. The result of a CCM analysis is thus a voxel-wise map of concordance values. Regions of high inter-subject concordance can be assumed to be functionally consistent, and may thus be of specific interest for further analysis. Here we present two fMRI studies to demonstrate the possible applications of the algorithm. The first is a eyes-open/eyes-closed paradigm designed to highlight the potential of the method in a relatively simple domain. The second study is a longitudinal repeated measurement of a patient following stroke. Longitudinal clinical studies such as this may represent the most interesting domain of applications for this algorithm.

The prevailing academic opinion holds that the subthalamic nucleus (STN) consists of three parts, each anatomically distinct and selectively associated with cognitive, emotional, or motor functioning. We independently tested this assumption by summarizing the results from 33 studies on STN subdivisions in human and nonhuman primates. The studies were conducted from 1925 to 2010 and feature three different techniques: electrical lesions, anterograde and retrograde tracers, and classical cytoarchitectonics. Our results reveal scant evidence in support of a tripartite STN. Instead, our results show that the variability across studies is surprisingly large, both in the number of subdivisions and in their anatomical localization. We conclude that the number of subdivisions in the STN remains uncertain, and that academic consensus in support of a tripartite STN is presently unwarranted.

SUMMARY OF RECENT ADVANCES

The roles of the basal ganglia (BG) in motor control are much debated. Many influential hypotheses have grown from studies in which output signals of the BG were not blocked, but pathologically-disturbed. A weakness of that approach is that the resulting behavioral impairments reflect degraded function of the BG per se mixed together with secondary dysfunctions of BG-recipient brain areas. To overcome that limitation, several studies have focused on the main skeletomotor output region of the BG, the globus pallidus internus (GPi). Using single-cell recording and inactivation protocols these studies provide consistent support for two hypotheses: the BG modulates movement performance (“vigor”) according to motivational factors (i.e., context-specific cost/reward functions) and the BG contributes to motor learning. Results from these studies also add to the problems that confront theories positing that the BG selects movement, inhibits unwanted motor responses, corrects errors online, or stores and produces well-learned motor skills.

The question of whether singing may be helpful for stroke patients with non-fluent aphasia has been debated for many years. However, the role of rhythm in speech recovery appears to have been neglected. In the current lesion study, we aimed to assess the relative importance of melody and rhythm for speech production in 17 non-fluent aphasics. Furthermore, we systematically alternated the lyrics to test for the influence of long-term memory and preserved motor automaticity in formulaic expressions. We controlled for vocal frequency variability, pitch accuracy, rhythmicity, syllable duration, phonetic complexity and other relevant factors, such as learning effects or the acoustic setting. Contrary to some opinion, our data suggest that singing may not be decisive for speech production in non-fluent aphasics. Instead, our results indicate that rhythm may be crucial, particularly for patients with lesions including the basal ganglia. Among the patients we studied, basal ganglia lesions accounted for more than 50% of the variance related to rhythmicity. Our findings therefore suggest that benefits typically attributed to melodic intoning in the past could actually have their roots in rhythm. Moreover, our data indicate that lyric production in non-fluent aphasics may be strongly mediated by long-term memory and motor automaticity, irrespective of whether lyrics are sung or spoken.

Magnetoencephalography (MEG) is an increasingly popular non-invasive tool used to record, on a millisecond timescale, the magnetic field changes generated by cortical neural activity. MEG has the advantage, over fMRI for example, that it is a direct measure of neural activity. In the current investigation we used MEG to measure cortical responses to tactile and auditory stimuli in the macaque monkey. We had two aims. First, we sought to determine whether MEG, a technique that may have low spatial accuracy, could be used to distinguish the location and organization of sensory cortical fields in macaque monkeys, a species with a relatively small brain compared to that of the human. Second, we wanted to examine the temporal dynamics of cortical responses in the macaque monkey relative to the human. We recorded MEG data from anesthetized monkeys and, for comparison, from awake humans that were presented with simple tactile and auditory stimuli. Neural source reconstruction of MEG data showed that primary somatosensory and auditory cortex could be differentiated and, further, that separate representations of the digit and lip within somatosensory cortex could be identified in macaque monkeys as well as humans. We compared the latencies of activity from monkey and human data for the three stimulation types and proposed a correspondence between the neural responses of the two species. We thus demonstrate the feasibility of using MEG in the macaque monkey and provide a non-human primate model for examining the relationship between external evoked magnetic fields and their underlying neural sources.

Recently, we demonstrated using functional magnetic resonance imaging (fMRI) that the outcome of free decisions can be decoded from brain activity several seconds before reaching conscious awareness. Activity patterns in anterior frontopolar cortex (BA 10) were temporally the first to carry intention-related information and thus a candidate region for the unconscious generation of free decisions. In the present study, the original paradigm was replicated and multivariate pattern classification was applied to functional images of frontopolar cortex, acquired using ultra-high field fMRI at 7 Tesla. Here, we show that predictive activity patterns recorded before a decision was made became increasingly stable with increasing temporal proximity to the time point of the conscious decision. Furthermore, detailed questionnaires exploring subjects' thoughts before and during the decision confirmed that decisions were made spontaneously and subjects were unaware of the evolution of their decision outcomes. These results give further evidence that FPC stands at the top of the prefrontal executive hierarchy in the unconscious generation of free decisions.

In this article, we argue that a combined anthropology/neuroscience field of enquiry can make a significant and distinctive contribution to the study of the relationship between culture and the brain. This field, which can appropriately be termed as neuroanthropology, is conceived of as being complementary to and mutually informative with social and cultural neuroscience. We start by providing an introduction to the culture concept in anthropology. We then present a detailed characterization of neuroanthropology and its methods and how they relate to the anthropological understanding of culture. The field is described as a humanistic science, that is, a field of enquiry founded on the perceived epistemological and methodological interdependence of science and the humanities. We also provide examples that illustrate the proposed methodological model for neuroanthropology. We conclude with a discussion about specific contributions the field can make to the study of the culture–brain nexus.

Objective

Having previously demonstrated that the complement system modulates mobilization of hematopoietic stem/progenitor cells (HSPC) in mice, we investigated the involvement of C5 cleavage fragments (C5a/desArgC5a) in human HSPC mobilization.

Methods

C5 cleavage fragments in the plasma were evaluated by ELISA using human anti-desArgC5a antibody, and the expression of the C5a/desArgC5a receptor (CD88) in hematopoietic cells by flow cytometry. We also examined the chemotactic responses of hematopoietic cells to C5 cleavage fragments and the expression of SDF-1-degrading proteases that perturb retention of HSPC in bone marrow (BM), namely matrix metalloproteinase (MMP)-9, membrane type (MT)1-MMP and carboxypeptidase M (CPM).

Results

We found that plasma levels of desArgC5a are significantly higher in patients who are good mobilizers and correlate with CD34+ cell and WBC counts in mobilized peripheral blood (mPB). C5 cleavage fragments did not chemoattract myeloid progenitors (CFU-GM) but desArgC5a did strongly chemoattract mature nucleated cells. Consistently, CD88 was not detected on CD34+ cells, but appeared on more mature myeloid precursors, monocytes and granulocytes. Moreover, G-CSF-mobilized PB MNC and PMN had a significantly higher percentage of cells expressing CD88 than non-mobilized PB. Furthermore, C5a stimulation of granulocytes and monocytes (i) decreased CXCR4 expression and chemotaxis towards an SDF-1 gradient, and ii) increased secretion of MMP-9 and expression of MT1-MMP and CPM.

Conclusion

C5 cleavage fragments not only induce a highly proteolytic microenvironment in the human BM which perturbs retention through the CXCR4/SDF-1 axis but also strongly chemoattract granulocytes, promoting their egress into mPB, which is crucial for subsequent mobilization of HSPC.

We propose a new exploratory method for the discovery of partially directed functional networks from fMRI meta-analysis data. The method performs structure learning of Bayesian networks in search of directed probabilistic dependencies between brain regions. Learning is based on the co-activation of brain regions observed across several independent imaging experiments. In a series of simulations, we first demonstrate the reliability of the method. We then present the application of our approach in an extensive meta-analysis including several thousand activation coordinates from more than 500 imaging studies. Results show that our method is able to automatically infer Bayesian networks that capture both directed and undirected probabilistic dependencies between a number of brain regions, including regions that are frequently observed in motor-related and cognitive control tasks.

The year 2009 marked the 100th anniversary of the publication of the famous brain map of Korbinian Brodmann. Although a “classic” guide to microanatomical parcellation of the cerebral cortex, it is – from today's state-of-the-art neuroimaging perspective – problematic to use Brodmann's map as a structural guide to functional units in the cortex. In this article we discuss some of the reasons, especially the problematic compatibility of the “post-mortem world” of microstructural brain maps with the “in vivo world” of neuroimaging. We conclude with some prospects for the future of in vivo structural brain mapping: a new approach which has the enormous potential to make direct correlations between microstructure and function in living human brains: “in vivo Brodmann mapping” with high-field magnetic resonance imaging.

Despite a lack of definitive evidence, it is frequently proposed that the Basal Ganglia (BG) motor circuit plays a critical role in the storage and execution of movement sequences (or motor habits). To test this hypothesis directly, we inactivated the sensorimotor territory of the globus pallidus internus (sGPi, the main BG motor output) in two monkeys trained to perform overlearned and random sequences of four out-and-back reaching movements directed to visual targets. Infusion of muscimol (a GABAA agonist) into sGPi caused dysmetria and slowing of individual movements, but these impairments were virtually identical for overlearned and random sequences. The fluid predictive execution of learned sequences and the animals’ tendency to reproduce the sequence pattern in random trials was preserved following pallidal blockade. These results suggest the BG motor circuit contributes to motor execution, but not to motor sequencing or the storage of overlearned serial skills.

Background

Cytoglobin (Cygb) and neuroglobin (Ngb) are recently identified globin molecules that are expressed in vertebrate tissues. Upregulation of Cygb and Ngb under hypoxic and/or ischemic conditions in vitro and in vivo increases cell survival, suggesting possible protective roles through prevention of oxidative damage. We have previously shown that Ngb is expressed in human glioblastoma multiforme (GBM) cell lines, and that expression of its transcript and protein can be significantly increased after exposure to physiologically relevant levels of hypoxia. In this study, we extended this work to determine whether Cygb is also expressed in GBM cells, and whether its expression is enhanced under hypoxic conditions. We also compared Cygb and Ngb expression in human primary tumor specimens, including brain tumors, as well as in human normal tissues. Immunoreactivity of carbonic anhydrase IX (CA IX), a hypoxia-inducible metalloenzyme that catalyzes the hydration of CO2 to bicarbonate, was used as an endogenous marker of hypoxia.

Results

Cygb transcript and protein were expressed in human GBM cells, and this expression was significantly increased in most cells following 48 h incubation under hypoxia. We also showed that Cygb and Ngb are expressed in both normal tissues and human primary cancers, including GBM. Among normal tissues, Cygb and Ngb expression was restricted to distinct cell types and was especially prominent in ductal cells. Additionally, certain normal organs (e.g. stomach fundus, small bowel) showed distinct regional co-localization of Ngb, Cygb and CA IX. In most tumors, Ngb immunoreactivity was significantly greater than that of Cygb. In keeping with previous in vitro results, tumor regions that were positively stained for CA IX were also positive for Ngb and Cygb, suggesting that hypoxic upregulation of Ngb and Cygb also occurs in vivo.

Conclusions

Our finding of hypoxic up-regulation of Cygb/Ngb in GBM cell lines and human tumor tissues suggests that these globin molecules may be part of the repertoire of defense mechanisms that allow cancer cells to survive in hypoxic microenvironments.