Olfactory conditioning facilitates diet transition in human infants.

We evaluated whether Pavlovian conditioning methods could be used to increase the ingestion of non-preferred solutions by formula-fed human infants. In baseline measures, 5-7 month old infants sucked less frequently and consumed less water than regular formula. During a 3-day olfactory conditioning period, parents placed a small scented disk, the conditioned stimulus, on the rim of their infants' formula bottle at every feeding. Following this training, infants' responses to water were tested when their water bottles had a disk scented with the training odor, a novel odor, or no odor. Infants tested with the training odor sucked more frequently and consumed significantly more water than they had at baseline. Infants tested with no odor or a novel odor consumed water at or below baseline levels. These data demonstrate that olfactory conditioning can be used to enhance ingestion in infants and suggest that such methods may be useful for infants experiencing difficulty when making transitions from one diet to another.

Frontal-striatal circuits in cognitive aging: Evidence for caudate involvement

Changes in cognition with aging have been claimed to be due in large part to a decline in frontal lobe function. However, at our present state of knowledge, the emphasis on the frontal lobes to the exclusion of the rest of the frontal-striatal circuits of which they are a part is unwarranted. To argue this point, I consider another anatomical candidate within these circuits, the caudate. Evidence is presented that the caudate decreases in size with age as much as the frontal lobes and that damage to either the frontal lobes or the caudate is accompanied by declines in inhibitory processes, executive control, and cognitive speed similar to those seen in normal aging. Separating the unique contributions of the frontal lobes and the caudate to these circuits is difficult but should be the focus of future studies of the biological basis of cognitive aging.

Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits.

Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a poly-glutamine (poly-Q) stretch in the huntingtin (Htt) protein. Gain-of-function effects of mutant Htt have been extensively investigated as the major driver of neurodegeneration in HD. However, loss-of-function effects of poly-Q mutations recently emerged as potential drivers of disease pathophysiology. Early synaptic problems in the excitatory cortical and striatal connections have been reported in HD, but the role of Htt protein in synaptic connectivity was unknown. Therefore, we investigated the role of Htt in synaptic connectivity in vivo by conditionally silencing Htt in the developing mouse cortex. When cortical Htt function was silenced, cortical and striatal excitatory synapses formed and matured at an accelerated pace through postnatal day 21 (P21). This exuberant synaptic connectivity was lost over time in the cortex, resulting in the deterioration of synapses by 5 weeks. Synaptic decline in the cortex was accompanied with layer- and region-specific reactive gliosis without cell loss. To determine whether the disease-causing poly-Q mutation in Htt affects synapse development, we next investigated the synaptic connectivity in a full-length knock-in mouse model of HD, the zQ175 mouse. Similar to the cortical conditional knock-outs, we found excessive excitatory synapse formation and maturation in the cortices of P21 zQ175, which was lost by 5 weeks. Together, our findings reveal that cortical Htt is required for the correct establishment of cortical and striatal excitatory circuits, and this function of Htt is lost when the mutant Htt is present.

Metacognition in monkeys during an oculomotor task.

This study investigated whether rhesus monkeys show evidence of metacognition in a reduced, visual oculomotor task that is particularly suitable for use in fMRI and electrophysiology. The 2-stage task involved punctate visual stimulation and saccadic eye movement responses. In each trial, monkeys made a decision and then made a bet. To earn maximum reward, they had to monitor their decision and use that information to bet advantageously. Two monkeys learned to base their bets on their decisions within a few weeks. We implemented an operational definition of metacognitive behavior that relied on trial-by-trial analyses and signal detection theory. Both monkeys exhibited metacognition according to these quantitative criteria. Neither external visual cues nor potential reaction time cues explained the betting behavior; the animals seemed to rely exclusively on internal traces of their decisions. We documented the learning process of one monkey. During a 10-session transition phase, betting switched from random to a decision-based strategy. The results reinforce previous findings of metacognitive ability in monkeys and may facilitate the neurophysiological investigation of metacognitive functions.

Signal Improvement and Contrast Enhancement in Magnetic Resonance Imaging

This thesis reports advances in magnetic resonance imaging (MRI), with the ultimate goal of improving signal and contrast in biomedical applications. More specifically, novel MRI pulse sequences have been designed to characterize microstructure, enhance signal and contrast in tissue, and image functional processes. In this thesis, rat brain and red bone marrow images are acquired using iMQCs (intermolecular multiple quantum coherences) between spins that are 10 μm to 500 μm apart. As an important application, iMQCs images in different directions can be used for anisotropy mapping. We investigate tissue microstructure by analyzing anisotropy mapping. At the same time, we simulated images expected from rat brain without microstructure. We compare those with experimental results to prove that the dipolar field from the overall shape only has small contributions to the experimental iMQC signal. Besides magnitude of iMQCs, phase of iMQCs should be studied as well. The phase anisotropy maps built by our method can clearly show susceptibility information in kidneys. It may provide meaningful diagnostic information. To deeply study susceptibility, the modified-crazed sequence is developed. Combining phase data of modified-crazed images and phase data of iMQCs images is very promising to construct microstructure maps. Obviously, the phase image in all above techniques needs to be highly-contrasted and clear. To achieve the goal, algorithm tools from Susceptibility-Weighted Imaging (SWI) and Susceptibility Tensor Imaging (STI) stands out superb useful and creative in our system.

The role of stimulus salience and attentional capture across the neural hierarchy in a stop-signal task.

Inhibitory motor control is a core function of cognitive control. Evidence from diverse experimental approaches has linked this function to a mostly right-lateralized network of cortical and subcortical areas, wherein a signal from the frontal cortex to the basal ganglia is believed to trigger motor-response cancellation. Recently, however, it has been recognized that in the context of typical motor-control paradigms those processes related to actual response inhibition and those related to the attentional processing of the relevant stimuli are highly interrelated and thus difficult to distinguish. Here, we used fMRI and a modified Stop-signal task to specifically examine the role of perceptual and attentional processes triggered by the different stimuli in such tasks, thus seeking to further distinguish other cognitive processes that may precede or otherwise accompany the implementation of response inhibition. In order to establish which brain areas respond to sensory stimulation differences by rare Stop-stimuli, as well as to the associated attentional capture that these may trigger irrespective of their task-relevance, we compared brain activity evoked by Stop-trials to that evoked by Go-trials in task blocks where Stop-stimuli were to be ignored. In addition, region-of-interest analyses comparing the responses to these task-irrelevant Stop-trials, with those to typical relevant Stop-trials, identified separable activity profiles as a function of the task-relevance of the Stop-signal. While occipital areas were mostly blind to the task-relevance of Stop-stimuli, activity in temporo-parietal areas dissociated between task-irrelevant and task-relevant ones. Activity profiles in frontal areas, in turn, were activated mainly by task-relevant Stop-trials, presumably reflecting a combination of triggered top-down attentional influences and inhibitory motor-control processes.

Transsynaptic Tracing from Peripheral Targets with Pseudorabies Virus Followed by Cholera Toxin and Biotinylated Dextran Amines Double Labeling.

Transsynaptic tracing has become a powerful tool used to analyze central efferents that regulate peripheral targets through multi-synaptic circuits. This approach has been most extensively used in the brain by utilizing the swine pathogen pseudorabies virus (PRV)(1). PRV does not infect great apes, including humans, so it is most commonly used in studies on small mammals, especially rodents. The pseudorabies strain PRV152 expresses the enhanced green fluorescent protein (eGFP) reporter gene and only crosses functional synapses retrogradely through the hierarchical sequence of synaptic connections away from the infection site(2,3). Other PRV strains have distinct microbiological properties and may be transported in both directions (PRV-Becker and PRV-Kaplan)(4,5). This protocol will deal exclusively with PRV152. By delivering the virus at a peripheral site, such as muscle, it is possible to limit the entry of the virus into the brain through a specific set of neurons. The resulting pattern of eGFP signal throughout the brain then resolves the neurons that are connected to the initially infected cells. As the distributed nature of transsynaptic tracing with pseudorabies virus makes interpreting specific connections within an identified network difficult, we present a sensitive and reliable method employing biotinylated dextran amines (BDA) and cholera toxin subunit b (CTb) for confirming the connections between cells identified using PRV152. Immunochemical detection of BDA and CTb with peroxidase and DAB (3, 3'-diaminobenzidine) was chosen because they are effective at revealing cellular processes including distal dendrites(6-11).

Efficacy of Pharmacokinetics-Directed Busulfan, Cyclophosphamide, and Etoposide Conditioning and Autologous Stem Cell Transplantation for Lymphoma: Comparison of a Multicenter Phase II Study and CIBMTR Outcomes.

Busulfan, cyclophosphamide, and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem cell transplantation (ASCT). This multicenter, phase II study examined the safety and efficacy of BuCyE with individually adjusted busulfan based on preconditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients ages 18 to 80 years but was amended due to high early treatment-related mortality (TRM) in patients > 65 years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine, and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (n = 66) or NHL (n = 141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (n = 203), patients > 65 years (n = 17), and patients ≤ 65 years (n = 186) were 4.5%, 23.5%, and 2.7%, respectively. The estimated rates of 2-year progression-free survival (PFS) were 33% for HL and 58%, 77%, and 43% for diffuse large B cell lymphoma (DLBCL; n = 63), mantle cell lymphoma (MCL; n = 29), and follicular lymphoma (FL; n = 23), respectively. The estimated rates of 2-year overall survival (OS) were 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL, respectively. In the matched analysis rates of 2-year TRM were 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower rates of 2-year PFS with BuCyE, 33% (95% CI, 21% to 46%), than with BEAM, 59% (95% CI, 52% to 66%), with no differences in TRM or OS. BuCyE provided adequate disease control and safety in B cell NHL patients ≤ 65 years but produced worse PFS in HL patients when compared with BEAM.

A new inversion procedure for confocal scanning microscopy and other bandlimited signal processing problems

We find a simple analytic expression for the inverse of an infinite matrix related to the problem of data reduction in confocal scanning microscopy and other band-limited signal processing problems. Potential applications of this result to practical problems are outlined. The matrix arises from a sampling expansion approach to the integral equation.

Signal restoration from band-pass filtered data

The restoration problem for a band-pass linear system is examined in the case the input signal is weighted by a profile function. The singular system is evaluated analytically for three different forms of the profile function. An example of restoration process is presented.

Solid phase velocity measurements utilising electrostatic sensors and cross correlation signal processing

Gas-solids two phase systems are widely employed within process plant in the form of pneumatic conveyors, dust extraction systems and solid fuel injection systems. The measurement of solids phase velocity therefore has wide potential application in flow monitoring and, in conjunction with density measurement instrumentation, solids mass flow rate measurement. Historically, a number of authors have detailed possible measurement techniques, and some have published limited test results. It is, however, apparent that none of these technologies have found wide application in industry. Solids phase velocity measurements were undertaken using real time cross correlation of signals from two electrostatic sensors spaced axially along a pipeline conveying pulverised coal (PF). Details of the measurement equipment, the pilot scale test rig and the test results are presented.