Faculty Bibliography

Background: Evaluation of myocardial function with MRI is challenging on patients with impaired breath-hold (BH) capabilities or arrhythmias due to the difficulty of respiratory motion suspension and synchronization of cardiac cycles. Compressed sensing (CS) enables free breathing (FB) real-time cine imaging with improved spatiotemporal resolution, but conventional temporal sparsifying transforms do not account for respiratory motion, which limits its performance. In this work, we propose to acquire data continuously in FB using a golden-angle radial sampling scheme and reconstruct images with separated but synchronized cardiac and respiratory motion dimensions using self-detected motion signals. For patients with arrhythmias, both "normal" and "ectopic" cycles are reconstructed by sorting out cardiac cycles with different lengths. The performance of the proposed method was compared to Cartesian BH approach using retrospective ECG-gating in 9 patients. Methods: Both BH and FB cine sequences (b-SSFP) were implemented on a 1.5T MRI scanner (Avanto, Siemens). Imaging parameters for BH cine were: spatial resolution = 1.8 x 1.8 mm², slice thickness = 8 mm, TR/TE = 2.5/1.25 ms, FA = 55degree. Imaging parameters for FB cine were: spatial resolution = 2 x 2 mm², slice thickness = 8 mm, TR/TE2.8/1.4 ms, FA = 70degree. Both sequences achieved temporal resolution ~30-40 ms. Cardiac imaging was performed on 9 patients (mean age = 56; 4 had normal sinus rhythm, 4 had arrhythmias including bigeminy PVCs, atrial fibrillation and Mobitz I, 1 was incapable of prolonged BH). One short axis and one 4 chamber cine image set were acquired on each patient at ~12-15s per slice. In FB cine imaging, central k-space positions (green dots, Figure 1a) were used to extract cardiac and respiratory signals from coils near the heart and diaphragm respectively (Figure 1b). Data were sorted and synchronized to separately reconstruct cardiac cycles of different lengths at different respiratory states. A mul!

Post-mortem and imaging studies have observed that white matter (WM) degenerates in a pattern inverse to myelin development, suggesting preferential regional vulnerabilities influencing cognitive decline in AD. This study applied novel WM tract integrity (WMTI) metrics derived from diffusional kurtosis imaging (DKI) to examine WM tissue properties in AD within this framework. Using data from amnestic mild cognitive impairment (aMCI, n = 12), AD (n = 14), and normal control (NC; n = 15) subjects, mixed models revealed interaction effects: specific WMTI metrics of axonal density and myelin integrity (i.e. axonal water fraction, radial extra-axonal diffusivity) in late-myelinating tracts (i.e. superior and inferior longitudinal fasciculi) changed in the course of disease, but were stable in the initial stages for early-myelinating tracts (i.e. posterior limb of the internal capsule, cerebral peduncles). WMTI metrics in late-myelinating tracts correlated with semantic verbal fluency, a cognitive function known to decline in AD. These findings corroborate the preferential vulnerability of late-myelinating tracts, and illustrate an application of WMTI metrics to characterizing the regional course of WM changes in AD.

Background: For patients with impaired breath-hold capacity or arrhythmias, free breathing real-time cine MRI is preferred at the expense of compromised spatiotemporal resolution. Compressed sensing (CS) has been used to achieve higher spatiotemporal resolutions in real-time cine MRI, but the superposition of respiratory and cardiac motion limits temporal sparsity. In this work, we propose a novel approach that sorts out cardiac and respiratory motion into separated but synchronized dimensions and performs a joint multicoil CS reconstruction with different sparsity constraints on cardiac and respiratory dimensions. Golden-angle radial sampling was employed for flexible data sorting. In arrhythmias cases, data are also sorted according to cardiac cycles with different length to reconstruct both "normal" and "ectopic" cycles. Methods: Cardiac imaging was performed on one volunteer (male age = 27) and one patient (female age = 49) with Mobitz I arrhythmia during free breathing without external gating on a 1.5T MRI scanner (Avanto, Siemens). Data were continuously acquired for 15 s in a short axis plane using a 2D golden-angle radial b-SSFP sequence. Imaging parameters were: spatial resolution = 2 x 2 mm², TR/TE = 2.8/1.4 ms, FA = 70degree and slice thickness = 8 mm. Temporal evolution of the central k-space positions (green dots, Figure 1a) was used to estimate cardiac contraction and respiration from coil-elements close to the heart and diaphragm respectively (Figure 1b). Raw data were then sorted into an expanded dataset of images containing two dynamic dimensions, one for cardiac and the other for respiratory motion. As shown in Figure 1b, each colored rectangular block represents an individual cardiac phase from a short "snapshot" period (e.g. 13 adjacent spokes). Data were sorted first into a higher dimensional matrix using the cardiac motion signal (Figure 1c left) followed by a second sorting along the respiratory dimension from expiration to inspiration using the respiratory mot!

Background: Observation of the kinetics of tissue enhancement after the injection of a bolus of tracer has been used for the analysis of perfusion and related variables. In general, a gradient of concentration in the exchanging vascular compartment between the arterial and venous ends is represented in models via focus on maintaining the detailed balance between the advective and diffusive exchange processes. Conventionally, this is by considering the exchange in an Eulerian framework, based on considering the exchange within each compartment as a separate unit (e.g., tissue homogeneity (TH) model [1]). Herein, we present a Lagrangian approach to the exchange modeling, such that the blood flowing between compartments is considered as the primary unit, and, thereby, allowing for coarser discretization and more efficient calculations (Figure 1a). Methods: Eight patients (age 63 + 12 years) underwent first-pass perfusion (FPP) rest and regadenoson stress cardiac MRI (CMR) (3T scanner, Tim Trio, Siemens), followed by invasive coronary angiography. Images were obtained at 4 slice locations (the aortic root for the arterial input function (AIF) and 3 short-axis slices of the left ventricle for the wall) using a TurboFLASH readout with centric k-space reordering [2]. A proton density-weighted image was acquired for normalization [3]. Myocardial blood flow (MBF) (mL/g/min) and perfusion reserve index (MPRI) were calculated in endocardial and epicardial areas (total 32 segments) using our method by an expert in the field of MRI blinded to coronary angiography results. Results: The results of a representative patient (66 year old man) with history of hypertension, hyperlipidemia, Diabetes Mellitus and known coronary artery disease with prior stents on maximal medical therapy are shown in Figure 1b-f. Coronary angiography was performed via the right femoral artery and demonstrated severe triple-vessel disease with left to right collaterals (Figure 1b). First-pass CMR perfusion imaging demonstrates a delay!

The present hardware circuit was designed as a fast and energy efficient motor control system based on cerebellar oscillatory neuron activity and network dynamics. Specifically, a hardware model of the olivo-cerebellar dynamics controlling vertebrate motor coordination is used to control movement in an underwater robotic vehicle. Single shot oscillatory phase resetting is used for instantaneous motor plant reorganization based on incoming sensory information. Such a rapid feedback mode, which is rapid enough to prevent animals from falling when they stumble, has been previously described in biological and mathematical papers (Pellionisz and Llinas, 1979, Velarde et al., 2002, 2004). In the present control system, the direction of the vehicle displacement is captured by a camera, and transformed into a phase shift modulation of sets of oscillatory elements that embody internal dynamics. This design provides a novel real time control platform for robotic control in three dimensions. (C) 2013 Elsevier B.V. All rights reserved. C1 [Porras, A.; Llinas, R.] NYU, Sch Med, Dept Neurosci & Physiol, New York, NY 10016 USA

Presenilin 1 (PSEN1) encodes the catalytic subunit of gamma-secretase, and PSEN1 mutations are the most common cause of early onset familial Alzheimer's disease (FAD). In order to elucidate pathways downstream of PSEN1, we characterized neural progenitor cells (NPCs) derived from FAD mutant PSEN1 subjects. Thus, we generated induced pluripotent stem cells (iPSCs) from affected and unaffected individuals from two families carrying PSEN1 mutations. PSEN1 mutant fibroblasts, and NPCs produced greater ratios of Abeta42 to Abeta40 relative to their control counterparts, with the elevated ratio even more apparent in PSEN1 NPCs than in fibroblasts. Molecular profiling identified 14 genes differentially-regulated in PSEN1 NPCs relative to control NPCs. Five of these targets showed differential expression in late onset AD/Intermediate AD pathology brains. Therefore, in our PSEN1 iPSC model, we have reconstituted an essential feature in the molecular pathogenesis of FAD, increased generation of Abeta42/40, and have characterized novel expression changes.

Spike-wave discharges (SWDs) are thalamocortical oscillations that are often considered to be the EEG correlate of absence seizures. Genetic absence epilepsy rats of Strasbourg (GAERS) and Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) exhibit SWDs and are considered to be genetic animal models of absence epilepsy. However, it has been reported that other rat strains have SWDs, suggesting that SWDs may vary in their prevalence, but all rats have a predisposition for them. This is important because many of these rat strains are used to study temporal lobe epilepsy (TLE), where it is assumed that there is no seizure-like activity in controls. In the course of other studies using the Sprague-Dawley rat, a common rat strain for animal models of TLE, we found that approximately 19% of 2- to 3-month-old naive female Sprague-Dawley rats exhibited SWDs spontaneously during periods of behavioral arrest, which continued for months. Males exhibited SWDs only after 3months of age, consistent with previous reports (Buzsaki et al., 1990). Housing in atypical lighting during early life appeared to facilitate the incidence of SWDs. Spike-wave discharges were often accompanied by behaviors similar to stage 1-2 limbic seizures. Therefore, additional analyses were made to address the similarity. We observed that the frequency of SWDs was similar to that of hippocampal theta rhythm during exploration for a given animal, typically 7-8Hz. Therefore, activity in the frequency of theta rhythm that occurs during frozen behavior may not reflect seizures necessarily. Hippocampal recordings exhibited high frequency oscillations (>250Hz) during SWDs, suggesting that neuronal activity in the hippocampus occurs during SWDs, i.e., it is not a passive structure. The data also suggest that high frequency oscillations, if rhythmic, may reflect SWDs. We also confirmed that SWDs were present in a common animal model of TLE, the pilocarpine model, using female Sprague-Dawley rats. Therefore, damage and associated changes to thalamic, hippocampal, and cortical neurons do not prevent SWDs, at least in this animal model. The results suggest that it is possible that SWDs occur in rodent models of TLE and that investigators mistakenly assume that they are stage 1-2 limbic seizures. We discuss the implications of the results and ways to avoid the potential problems associated with SWDs in animal models of TLE.

The ascendancy of functional neuroimaging has facilitated the addition of network-based approaches to the neuropsychologist's toolbox for evaluating the sequelae of brain insult. In particular, intrinsic functional connectivity (iFC) mapping of resting state fMRI (R-fMRI) data constitutes an ideal approach to measuring macro-scale networks in the human brain. Beyond the value of iFC mapping for charting how the functional topography of the brain is altered by insult and injury, iFC analyses can provide insights into experience-dependent plasticity at the macro level of large-scale functional networks. Such insights are foundational to the design of training and remediation interventions that will best facilitate recovery of function. In this review, we consider what is currently known about the origin and function of iFC in the brain, and how this knowledge is informative in neuropsychological settings. We then summarize studies that have examined experience-driven plasticity of iFC in healthy control participants, and frame these findings in terms of a schema that may aid in the interpretation of results and the generation of hypotheses for rehabilitative studies. Finally, we outline some caveats to the R-fMRI approach, as well as some current developments that are likely to bolster the utility of the iFC paradigm for neuropsychology.

Clinical neuropathologic studies suggest that the selective vulnerability of hippocampal CA1 pyramidal projection neurons plays a key role in the onset of cognitive impairment during the early phases of Alzheimer's disease (AD). Disruption of this neuronal population likely affects hippocampal pre- and postsynaptic efficacy underlying episodic memory circuits. Therefore, identifying perturbations in the expression of synaptic gene products within CA1 neurons prior to frank AD is crucial for the development of disease modifying therapies. Here we used custom-designed microarrays to examine progressive alterations in synaptic gene expression within CA1 neurons in cases harvested from the Rush Religious Orders Study who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI, a putative prodromal AD stage), or mild/moderate AD. Quantitative analysis revealed that 21 out of 28 different transcripts encoding regulators of synaptic function were significantly downregulated (1.4-1.8 fold) in CA1 neurons in MCI and AD compared to NCI, whereas synaptic transcript levels were not significantly different between MCI and AD. The downregulated transcripts encoded regulators of presynaptic vesicle trafficking, including synaptophysin and synaptogyrin, regulators of vesicle docking and fusion/release, such as synaptotagmin and syntaxin 1, and regulators of glutamatergic postsynaptic function, including PSD-95 and synaptopodin. Clinical pathologic correlation analysis revealed that downregulation of these synaptic markers was strongly associated with poorer antemortem cognitive status and postmortem AD pathological criteria such as Braak stage, NIA-Reagan, and CERAD diagnosis. In contrast to the widespread loss of synaptic gene expression observed in CA1 neurons in MCI, transcripts encoding beta-amyloid precursor protein (APP), APP family members, and regulators of APP metabolism were not differentially regulated in CA1 neurons across the clinical diagnostic groups. Taken together, these data suggest that CA1 synaptic gene dysregulation occurs early in the cascade of pathogenic molecular events prior to the onset of AD, which may form the basis for novel pharmacological treatment approaches for this dementing disorder. This article is part of a Special Issue entitled 'Neurodegenerative Disorders'.

In addition to the well-known signals of retinal image slip, floccular complex spikes (CSs) also convey nonvisual signals. We recorded eye movement and CS activity from Purkinje cells in awake rabbits sinusoidally oscillated in the dark on a vestibular turntable. The stimulus frequency ranged from 0.2 to 1.2 Hz, and the velocity amplitude ranged from 6.3 to 50 degrees /s. The average CS modulation was evaluated at each combination of stimulus frequency and amplitude. More than 75% of the Purkinje cells carried nonvisual CS signals. The amplitude of this modulation remained relatively constant over the entire stimulus range. The phase response of the CS modulation in the dark was opposite to that during the vestibulo-ocular reflex (VOR) in the light. With increased frequency, the phase response systematically shifted from being aligned with contraversive head velocity toward peak contralateral head position. At fixed frequency, the phase response was dependent on peak head velocity, indicating a system nonlinearity. The nonvisual CS modulation apparently reflects a competition between eye movement and vestibular signals, resulting in an eye movement error signal inferred from nonvisual sources. The combination of this error signal with the retinal slip signal in the inferior olive results in a net error signal reporting the discrepancy between the actual visually measured eye movement error and the inferred eye movement error derived from measures of the internal state. The presence of two error signals requires that the role of CSs in models of the floccular control of VOR adaption be expanded beyond retinal slip.