Faculty Bibliography

Purpose: To develop and evaluate highly-accelerated real-time cine MRI using compressed sensing and parallel imaging. Introduction Breath-hold cine MRI with balanced steady-steady free precession (b-SSFP) may yield non diagnostic image quality in patients with impaired breath-hold capacity and/or arrhythmias. In such patients, it may be necessary to perform real-time cine MRI. Currently, dynamic parallel imaging methods, such as TSENSE [1] and TGRAPPA [2], can be used to achieve only moderate acceleration rates (R) of 2-3 using standard body and spine coil arrays. We propose the application of a recently developed joint acceleration technique (CS-PI) [3] that combines compressed sensing [4] and parallel imaging for highly-accelerated, real-time cine MRI with clinically acceptable spatiotemporal resolution. Methods: Real-time cine MRI pulse sequences with b-SSFP readouts and TGRAPPA and CS-PI accelerations with R=4 and R=8 were implemented on 3T whole-body MRI scanners (Siemens; Tim-Trio & Verio) equipped with standard body and spine coil arrays (12 elements total). The relevant imaging parameters include: FOV=320mm x 320mm, acquisition matrix size=128x128, TE/ TR=1.37/2.7ms, receiver bandwidth=1184 Hz/pixel, and flip angle=40degree. The temporal resolutions were 86.4, and 43.2 ms for R = 4 and 8, respectively. Seven patients (mean age=41.5+/-20.7 years) undergoing clinical CMR were imaged in mid-ventricular short-axis and long-axis planes, following completion of the clinical examination (Figure Presented) using free breathing and electrocardiogram gating. The cine data sets were randomized and blinded for qualitative evaluation (image quality, artifact, noise; 1-5; lowest- highest) by a cardiologist and a radiologist. Statistical analysis was performed to compare the mean scores between the 4 groups (TGRAPPA-R4, TGRAPPA-R8, CS-PI-R4, CS-PI-R8) and between each pair of groups. Results: Figure 1 shows images of end-systolic frames in midventricular short-axis and 2-chamber views. According to the Kruskal-Wallis test, the 4 groups were significantly different (p0.05): image quality, CS-PI-R4 vs. CS-PI-R8; artifact, CS-PI-R4 vs. CS-PI-R8; noise, TGRAPPA-R4 vs. CS-PI-R8, TGRAPPA-R4 vs. CS-PIR4, CS-PI-R4 vs. CS-PI-R8. These preliminary results suggest that TGRAPPA can yield robust results at R=4, whereas CS-PI can yield robust results up to R=8. Discussion This study demonstrates the feasibility of performing highly-accelerated real-time cine MRI using a joint CSPI technique. An 8-fold accelerated real-time cine MRI protocol can achieve spatial resolution of 2.5mm x 2.5mm and temporal resolution of 43.2 ms, with adequate image quality. This accelerated protocol may be useful for debilitated patients with reduced breathhold capacity and/or arrhythmias for rapid left ventricular functional evaluation

Background: Visceral sensations are relayed to the brain through a network of afferent nerves. Awareness of these sensations differs among individuals, likely due to different thresholds and CNS processing characteristics. Differences in the conscious awareness of bodily sensations may explain specific cardiovascular phenotypes. Thus, our goal was to evaluate the role, if any, of conscious awareness of body sensations and their relationship with hemodynamic responses to tilt in patients with orthostatic intolerance. Methods: Thirty-two otherwise healthy patients who complained of orthostatic intolerance participated in the study. We assessed perception of body sensations on a self-reported body vigilance scale. We measured blood pressure, heart rate and plasma catecholamine responses to passive upright tilt. Thirteen patients experienced typical vasovagal syncope (i.e., a fall in blood pressure and heart rate) 4; patients had an increase in heart rate >30 beat/min without a fall in blood pressure and were diagnosed as postural tachycardia syndrome; and 15 patients had normal cardiovascular responses to tilt and were classified as having unexplained orthostatic intolerance. Results: Self-reported feelings of shortness of breath (p<0.05), tingling (p<0.01), numbness (p<0.003) and chest discomfort (p<0.01) were correlated positively with supine plasma epinephrine levels and the increase in plasma epinephrine levels with tilt (p<0.02). Higher body vigilance was significantly related with the increase in heart rate during tilt, both at 3 min (p<0.02) and the maximum heart rate recorded (p<0.002). Patients with unexplained orthostatic intolerance scored higher for the time spent 'scanning their body for sensations' compared with patients who had vasovagal syncope during tilt (52 +/- 9 vs. 23 +/- 6%, p<0.02). Conclusion: Increased somatic vigilance is associated with a greater release of epinephrine on standing and faster heart rates. Increased somatic vigilance is associated with the postural tachycardia syndrome and may be the cause of hitherto unexplained orthostatic intolerance

BACKGROUND: Mutations in eukaryotic translation initiation factor 2B (eIF2B) cause Childhood Ataxia with CNS Hypomyelination (CACH), also known as Vanishing White Matter disease (VWM), which is associated with a clinical pathology of brain myelin loss upon physiological stress. eIF2B is the guanine nucleotide exchange factor (GEF) of eIF2, which delivers the initiator tRNA(Met) to the ribosome. We recently reported that a R132H mutation in the catalytic subunit of this GEF, causing a 20% reduction in its activity, leads under normal conditions to delayed brain development in a mouse model for CACH/VWM. To further explore the effect of the mutation on global gene expression in the brain, we conducted a wide-scale transcriptome analysis of the first three critical postnatal weeks. METHODOLOGY/PRINCIPAL FINDINGS: Genome-wide mRNA expression of wild-type and mutant mice was profiled at postnatal (P) days 1, 18 and 21 to reflect the early proliferative stage prior to white matter establishment (P1) and the peak of oligodendrocye differentiation and myelin synthesis (P18 and P21). At each developmental stage, between 441 and 818 genes were differentially expressed in the mutant brain with minimal overlap, generating unique time point-specific gene expression signatures. CONCLUSIONS: The current study demonstrates that a point mutation in eIF2B, a key translation initiation factor, has a massive effect on global gene expression in the brain. The overall changes in expression patterns reflect multiple layers of indirect effects that accumulate as the brain develops and matures. The differentially expressed genes seem to reflect delayed waves of gene expression as well as an adaptation process to cope with hypersensitivity to cellular stress.

Background: Hereditary sensory and autonomic neuropathy type IV (HSAN-IV) is a recessive disease caused by mutations affecting the tyrosine kinase receptor. The disorder affects the development of sensory and sudomotor sympathetic nerve fibers resulting in complete insensitivity to pain and anhidrosis. However, little is known about the cardiovascular autonomic phenotype of the disorder. Methods: We measured blood pressure, heart rate and catecholamines, vasopressin, endothelin and renin activity in plasma while supine and after 10 min of passive upright tilt in 10 patients with typical clinical features of HSAN-IV and diagnostic confirmation with genetic testing (mean age 9 +/- 2 years old, 4 females). Results: In the supine position, blood pressures (104 +/- 5/ 58 +/- 4 mmHg) and heart rates (87 +/- 9 beats/min) were normal. During upright tilt, mean arterial blood pressure changed little (-5 +/- 5 mmHg, p = 0.17) and heart rate increased appropriately (+23 +/- 5 beat/min, p<0.001). In all patients, plasma norepinephrine levels were low or undetectable while in the supine position (31 +/- 3 pg/ml) and failed to increase with upright tilt (4 +/- 5 pg/ml). Plasma renin activity levels increased slightly from 2.0 +/- 0.6 to 3.6 +/- 1.1 pg/ml with head-up tilt (+68 +/- 33 D%, p<0.03). Plasma vasopressin increased little and endothelin levels were essentially unchanged during upright tilt. Conclusions: Patients with HSAN-IV have very low levels of norepinephrine while supine and upright, but do not have orthostatic hypotension. Other vasoactive peptides involved in orthostatic blood pressure maintenance are not increased. These results challenge our current concepts of the role of norepinephrine in the regulation of blood pressure. The mechanism by which patients with HSAN-IV maintain their blood pressure is unknown

Consider the decomposition of a signal into features that undergo transformations drawn from a continuous family. Current methods discretely sample the transformations and apply sparse recovery methods to the resulting finite dictionary. These methods do not exploit the underlying continuous structure, thereby limiting the ability to produce sparse solutions. Instead, we employ interpolation functions which linearly approximate the manifold of scaled and transformed features. Coefficients are interpreted as interpolation weights, and we formulate a convex optimization problem for obtaining them, enforcing both reconstruction accuracy and sparsity. We compare our method, which we call continuous basis pursuit (CBP) with the standard basis pursuit approach on a sparse deconvolution task. CBP yields substantially sparser solutions without sacrificing accuracy, and does so with a smaller dictionary. We conclude that for signals generated by transformation-invariant processes, a representation that explicitly accommodates the transformation(s) can yield sparser and more interpretable decompositions.

The glutamate neurotransmitter system has the potential to transform our knowledge of the pathophysiology of schizophrenia and help us identify potential treatment targets. In this section of the supplement, the dopamine system is first reviewed as it relates to schizophrenia and its treatment with the currently available antipsychotics, followed by a discussion of glutamate receptors and how they, too, can impact on positive, negative, and cognitive symptoms. Symptoms of schizophrenia can be theoretically explained by a hyper-dopaminergic state existing in the mesolimbic pathway and a hypodopaminergic state in the mesocortical pathways; the former results in positive symptoms and the latter leads to negative, cognitive, and affective symptoms. Current FDA-approved pharmacologic options for the treatment of schizophrenia involve dopamine blockade at the dopamine D2 receptor. Although commercially available antipsychotic agents have at least some degree of antagonism at the dopamine D2 receptor, there are some investigational agents that produce an antipsychotic effect in the absence of direct dopamine D2 receptor antagonism. The glutamate-dopamine model of schizophrenia offers new therapeutic targets, including NMDA agonists, glycine transport inhibitors, and metabotropic glutamate receptor agonists.

Background: Patients with familial dysautonomia (FD) fail to increase respiratory drive in response to low oxygen and high CO₂ levels. Many hypoventilate and have frequent apneic events during sleep, a time associated with an increased incidence of sudden death. To assess the need for non-invasive ventilation, patients with FD routinely undergo sleep studies with end-tidal CO₂ monitoring. Because most have severe lung disease, it is not known, however, whether end-tidal CO₂ levels accurately reflect arterial blood CO₂ levels. Methods: We studied 88 patients with FD (mean age 25 +/- 1, 45; females:43 males). We measured the partial pressure of CO₂ in blood obtained from the radial artery at the wrist (ABL80 FLEX, Radiometer, Denmark). End-tidal CO₂ was continuously sampled from a nasal canula (infrared analysis 5200 Ohmeda, USA). The average CO₂ value obtained over 10 full tidal breaths was used. All measurements were obtained during relaxed spontaneous breathing in the supine position. The relationship between end-tidal and arterial CO₂ measurements was examined using Pearson correlations. Results: All patients had a history of at least one aspiration pneumonia. The average partial pressure of oxygen in arterial blood was 87 +/- 2 mmHg. Thirty-one patients (36%) had arterial oxygen levels B80 mmHg. The average partial pressure of CO₂ was 43 +/- 0.4 mmHg (range 34-57 mmHg). Thirty-four patients (39%) had hypercapnia with CO₂ in arterial blood >=45 mmHg. Measurements of end-tidal CO₂ correlated tightly with CO₂ measured in arterial blood (y = 0.88x + 2.23, R² = 0.50, p<0.001). Conclusions: Our results show that in patients with FD, despite severe lung disease, the partial pressure of CO₂ measured in expired air (i.e. end tidal CO₂) accurately reflects the partial pressure ofCO₂ in arterial blood. Monitoring end tidal CO₂ is critically important to determine the potential role of apnea/hypoventilation in sudden death during sleep

A portable real-time speech processor that implements an acoustic simulation model of a cochlear implant (CI) has been developed on the Apple iPhone / iPod Touch to permit testing and experimentation under extended exposure in real-world environments. This simulator allows for both a variable number of noise band channels and electrode insertion depth. Utilizing this portable CI simulator, we tested perceptual learning in normal hearing listeners by measuring word and sentence comprehension behaviorally before and after 2 weeks of exposure. To evaluate changes in neural activation related to adaptation to transformed speech, fMRI was also conducted. Differences in brain activation after training occurred in the inferior frontal gyrus and areas related to language processing. A 15-20% improvement in word and sentence comprehension of cochlear implant simulated speech was also observed. These results demonstrate the effectiveness of a portable CI simulator as a research tool and provide new information about the physiological changes that accompany perceptual learning of degraded auditory input.