Faculty Bibliography

Diffusional kurtosis imaging (DKI) is extended to double-pulsed-field-gradient (d-PFG) diffusion MRI sequences. This gives a practical approach for acquiring and analyzing d-PFG data. In particular, the leading d-PFG effects, beyond what conventional single-pulsed field gradient (s-PFG) provides, are interpreted in terms of the kurtosis for a diffusion displacement probability density function (dPDF) in a six-dimensional (6D) space. The 6D diffusional kurtosis encodes the unique information provided by d-PFG sequences up to second order in the b-value. This observation leads to a compact expression for the signalmagnitude, and it suggests novel data acquisition and analysis methods. Double-pulsed DKI (DP-DKI) is demonstrated for in vivo mouse brain with d-PFG data obtained at 7 T.

PURPOSE: To quantify the two principal forms of hepatic storage iron, diffuse, soluble iron (primarily ferritin), and aggregated, insoluble iron (primarily hemosiderin) using a new MRI method in patients with transfusional iron overload. MATERIALS AND METHODS: Six healthy volunteers and 20 patients with transfusion-dependent thalassemia syndromes and iron overload were examined. Ferritin- and hemosiderin-like iron were determined based on the measurement of two distinct relaxation parameters: the "reduced" transverse relaxation rate, RR2 , and the "aggregation index," A, using three sets of Carr-Purcell-Meiboom-Gill (CPMG) datasets with different interecho spacings. Agarose phantoms, simulating the relaxation and susceptibility properties of tissue with different concentrations of dispersed (ferritin-like) and aggregated (hemosiderin-like) iron, were used for validation. RESULTS: Both phantom and in vivo human data confirmed that transverse relaxation components associated with the dispersed and aggregated iron could be separated using the two-parameter (RR2 , A) method. The MRI-determined total hepatic storage iron was highly correlated (r = 0.95) with measurements derived from biopsy or biosusceptometry. As total hepatic storage iron increased, the proportion stored as aggregated iron became greater. CONCLUSION: This method provides a new means for noninvasive MRI determination of the partition of hepatic storage iron between ferritin and hemosiderin in iron overload disorders.

Hyaluronan (HA), a large anionic polysaccharide (glycosaminoglycan), is a major constituent of the extracellular matrix of the adult brain. To address its function, we examined the neurophysiology of knock-out mice deficient in hyaluronan synthase (Has) genes. Here we report that these Has mutant mice are prone to epileptic seizures, and that in Has3(-/-) mice, this phenotype is likely derived from a reduction in the size of the brain extracellular space (ECS). Among the three Has knock-out models, namely Has3(-/-), Has1(-/-), and Has2(CKO), the seizures were most prevalent in Has3(-/-) mice, which also showed the greatest HA reduction in the hippocampus. Electrophysiology in Has3(-/-) brain slices demonstrated spontaneous epileptiform activity in CA1 pyramidal neurons, while histological analysis revealed an increase in cell packing in the CA1 stratum pyramidale. Imaging of the diffusion of a fluorescent marker revealed that the transit of molecules through the ECS of this layer was reduced. Quantitative analysis of ECS by the real-time iontophoretic method demonstrated that ECS volume was selectively reduced in the stratum pyramidale by approximately 40% in Has3(-/-) mice. Finally, osmotic manipulation experiments in brain slices from Has3(-/-) and wild-type mice provided evidence for a causal link between ECS volume and epileptiform activity. Our results provide the first direct evidence for the physiological role of HA in the regulation of ECS volume, and suggest that HA-based preservation of ECS volume may offer a novel avenue for development of antiepileptogenic treatments.

Transcriptional silencing of the Fmr1 gene encoding fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS), the most common form of inherited intellectual disability and the leading genetic cause of autism. FMRP has been suggested to play important roles in regulating neurotransmission and short-term synaptic plasticity at excitatory hippocampal and cortical synapses. However, the origins and mechanisms of these FMRP actions remain incompletely understood, and the role of FMRP in regulating synaptic release probability and presynaptic function remains debated. Here we used variance-mean analysis and peak-scaled nonstationary variance analysis to examine changes in both presynaptic and postsynaptic parameters during repetitive activity at excitatory CA3-CA1 hippocampal synapses in a mouse model of FXS. Our analyses revealed that loss of FMRP did not affect the basal release probability or basal synaptic transmission, but caused an abnormally elevated release probability specifically during repetitive activity. These abnormalities were not accompanied by changes in excitatory postsynaptic current kinetics, quantal size or postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor conductance. Our results thus indicate that FMRP regulates neurotransmission at excitatory hippocampal synapses specifically during repetitive activity via modulation of release probability in a presynaptic manner. Our study suggests that FMRP function in regulating neurotransmitter release is an activity-dependent phenomenon that may contribute to the pathophysiology of FXS.

Background: Epidemiological data indicate that rates of pediatric bipolar disorder (BD) and attention deficit/hyperactivity disorder (ADHD) have increased dramatically over the past two decades. Overlapping diagnostic criteria contribute to concerns about over- or mis-diagnosis of both disorders. Movement towards a nosology informed by neurobiology and symptoms, rather than symptoms alone, has the potential to improve the speed and clarity of diagnoses and treatments. To this end, the present study evaluated resting-state functional connectivity (RSFC) in children with primary BD (n=25), primary ADHD (n=24), and typically developing controls (TDCs; n=30) with no history of psychiatric illness. Methods: We enrolled children ages 7-17. Group status was determined via the Child Schedule for Affective Disorders (KSADs-PL). Participants completed an 8-minute RSFC EPI BOLD sequence and a T1 MPRAGE scan. We evaluated RSFC between seeds from the left dorsolateral prefrontal cortex (DLPFC), amygdala, and accumbens areas based on prior research implicating these areas in pediatric BD. Images were analyzed using the CPAC pipeline. Results: Analyses revealed significantly greater RSFC between the (1) left DLPFC and left occipital gyrus proximal to fusiform gyrus and (2) left accumbens area and right superior parietal lobule in TDC vs. BD participants (pairwise comparison ps = .026 and .013, respectively). Conclusions: Data indicate that altered task-independent functional connectivity in the DLPFC and accumbens areas may be specific to pediatric BD. Further study is warranted to determine if this specificity extends to other psychiatric disorders involving irritability, such as anxiety, as a potential biological diagnostic or treatment marker

Central venous stenosis is a well-described sequel to the placement of hemodialysis catheters in the central venous system. The presence of an ipsilateral arteriovenous fistula or graft often leads to severe venous dilatation, arm edema and recurrent infections. Vascular access thrombosis, compromised blood flow and inadequate dialysis delivery are dreaded complications that eventually render the access unusable. We report the case of a 58-year-old male hemodialysis patient who developed symptomatic central venous stenosis to illustrate the problem and review the pertinent literature. This patient developed severe enlargement of upper extremity veins due to central venous stenosis. The symptoms were refractory to multiple endovascular interventions and eventually necessitated ligation of his arteriovenous fistula. Central venous stenosis remains a pervasive problem despite advances in our understanding of its etiology and recognition of the enormity of its consequences. Due to the lack of effective therapeutic options, prevention is better than cure.

A method based on a set of new theorems for the analysis of multichannel time series is described, based on precise Fourier transform and coherence analysis of the restored signals from a detailed set of frequency components. Magnetic field recordings of spontaneous and evoked activity by means of magnetic encephalography demonstrated that multichannel precise Fourier spectrum contains a very large set of harmonics with high coherence. The inverse problem can be solved with great precision based on coherent harmonics, so the technique is a promising platform of general analysis in brain imaging. The analysis method makes it possible to reconstruct sites and timing of electrical activity generated by both spontaneous and evoked brain function at different depths in the brain in the millisecond time range.

Although neuronal spikes can be readily detected from extracellular recordings, synaptic and subthreshold activity remains undifferentiated within the local field potential (LFP). In the hippocampus, neurons discharge selectively when the rat is at certain locations, while LFPs at single anatomical sites exhibit no such place-tuning. Nonetheless, because the representation of position is sparse and distributed, we hypothesized that spatial information can be recovered from multiple-site LFP recordings. Using high-density sampling of LFP and computational methods, we show that the spatiotemporal structure of the theta rhythm can encode position as robustly as neuronal spiking populations. Because our approach exploits the rhythmicity and sparse structure of neural activity, features found in many brain regions, it is useful as a general tool for discovering distributed LFP codes.

Deformable models integrate bottom-up information derived from image appearance cues and top-down priori knowledge of the shape. They have been widely used with success in medical image analysis. One limitation of traditional deformable models is that the information extracted from the image data may contain gross errors, which adversely affect the deformation accuracy. To alleviate this issue, we introduce a new family of deformable models that are inspired from the compressed sensing, a technique for accurate signal reconstruction by harnessing some sparseness priors. In this paper, we employ sparsity constraints to handle the outliers or gross errors, and integrate them seamlessly with deformable models. The proposed new formulation is applied to the analysis of cardiac motion using tagged magnetic resonance imaging (tMRI), where the automated tagging line tracking results are very noisy due to the poor image quality. Our new deformable models track the heart motion robustly, and the resulting strains are consistent with those calculated from manual labels.

The emergence of limb-driven locomotor behaviors was a key event in the evolution of vertebrates and fostered the transition from aquatic to terrestrial life. We show that the generation of limb-projecting lateral motor column (LMC) neurons in mice relies on a transcriptional autoregulatory module initiated via transient activity of multiple genes within the HoxA and HoxC clusters. Repression of this module at thoracic levels restricts expression of LMC determinants, thus dictating LMC position relative to the limbs. This suppression is mediated by a key regulatory domain that is specifically found in the Hoxc9 proteins of appendage-bearing vertebrates. The profile of Hoxc9 expression inversely correlates with LMC position in land vertebrates and likely accounts for the absence of LMC neurons in limbless species such as snakes. Thus, modulation of both Hoxc9 protein function and Hoxc9 gene expression likely contributed to evolutionary transitions between undulatory and ambulatory motor circuit connectivity programs.