Faculty Bibliography

BACKGROUND: Familial dysautonomia (FD) is a rare hereditary disease characterized by loss of afferent autonomic neural fiber signaling and consequent profound impairment of arterial baroreflex function and blood pressure regulation. Whether vascular endothelial dysfunction contributes to defective vasomotor control in this form of afferent autonomic failure is not known. METHODS: We assessed blood pressure response to orthostatic stress and vascular endothelial function with brachial artery reactivity testing in 34 FD subjects with afferent autonomic failure and 34 healthy control subjects. RESULTS: Forty-four percent of the afferent autonomic failure subjects had uncontrolled hypertension at supine rest (median systolic blood pressure = 148mm Hg, interquartile range (IQR) = 144-155mm Hg; median diastolic blood pressure = 83mm Hg, IQR = 78-105mm Hg), and 88% had abnormal response to orthostatic stress (median decrease in systolic blood pressure after upright tilt = 48mm Hg, IQR = 29-61mm Hg). Flow-mediated brachial artery reactivity did not differ in subjects with afferent autonomic failure vs. healthy control subjects (median = 6.00%, IQR = 1.86-11.77%; vs. median = 6.27%, IQR = 4.65-9.34%; P = 0.75). In afferent autonomic failure subjects, brachial artery reactivity was not associated with resting blood pressure or the magnitude of orthostatic hypotension but was decreased in association with reduced glomerular filtration rate (r = 0.62; P < 0.001). CONCLUSIONS: Brachial artery reactivity was preserved in subjects with afferent autonomic failure despite the presence of marked blood pressure dysregulation. Comorbid renal dysfunction was associated with reduced brachial artery reactivity.

Abnormalities in cortical structure are commonly observed in children with dyslexia in key regions of the "reading network." Whether alteration in cortical features reflects pathology inherent to dyslexia or environmental influence (e.g., impoverished reading experience) remains unclear. To address this question, we compared MRI-derived metrics of cortical thickness (CT), surface area (SA), gray matter volume (GMV), and their lateralization across three different groups of children with a historical diagnosis of dyslexia, who varied in current reading level. We compared three dyslexia subgroups with: (1) persistent reading and spelling impairment; (2) remediated reading impairment (normal reading scores), and (3) remediated reading and spelling impairments (normal reading and spelling scores); and a control group of (4) typically developing children. All groups were matched for age, gender, handedness, and IQ. We hypothesized that the dyslexia group would show cortical abnormalities in regions of the reading network relative to controls, irrespective of remediation status. Such a finding would support that cortical abnormalities are inherent to dyslexia and are not a consequence of abnormal reading experience. Results revealed increased CT of the left fusiform gyrus in the dyslexia group relative to controls. Similarly, the dyslexia group showed CT increase of the right superior temporal gyrus, extending into the planum temporale, which resulted in a rightward CT asymmetry on lateralization indices. There were no group differences in SA, GMV, or their lateralization. These findings held true regardless of remediation status. Each reading level group showed the same "double hit" of atypically increased left fusiform CT and rightward superior temporal CT asymmetry. Thus, findings provide evidence that a developmental history of dyslexia is associated with CT abnormalities, independent of remediation status.

While the dopamine hypothesis has dominated schizophrenia research for several decades, more recent studies have highlighted the role of fast synaptic transmitters and their receptors in schizophrenia etiology. Here we review evidence that schizophrenia is associated with a reduction in N-methyl-d-aspartate receptor (NMDAR) function. By highlighting postmortem, neuroimaging and electrophysiological studies, we provide evidence for preferential disruption of GABAergic circuits in the context of NMDAR hypo-activity states. The functional relationship between NMDARs and GABAergic neurons is realized at the molecular, cellular, microcircuit and systems levels. A synthesis of findings across these levels explains how NMDA-mediated inhibitory dysfunction may lead to aberrant interactions among brain regions, accounting for key clinical features of schizophrenia. This synthesis of schizophrenia unifies observations from diverse fields and may help chart pathways for developing novel diagnostics and therapeutics.

Radial spin-echo diffusion imaging allows motion-robust imaging of tissues with very low T2 values like articular cartilage with high spatial resolution and signal-to-noise ratio (SNR). However, in vivo measurements are challenging, due to the significantly slower data acquisition speed of spin-echo sequences and the less efficient k-space coverage of radial sampling, which raises the demand for accelerated protocols by means of undersampling. This work introduces a new reconstruction approach for undersampled diffusion-tensor imaging (DTI). A model-based reconstruction implicitly exploits redundancies in the diffusion-weighted images by reducing the number of unknowns in the optimization problem and compressed sensing is performed directly in the target quantitative domain by imposing a total variation (TV) constraint on the elements of the diffusion tensor. Experiments were performed for an anisotropic phantom and the knee and brain of healthy volunteers (three and two volunteers, respectively). Evaluation of the new approach was conducted by comparing the results with reconstructions performed with gridding, combined parallel imaging and compressed sensing and a recently proposed model-based approach. The experiments demonstrated improvements in terms of reduction of noise and streaking artifacts in the quantitative parameter maps, as well as a reduction of angular dispersion of the primary eigenvector when using the proposed method, without introducing systematic errors into the maps. This may enable an essential reduction of the acquisition time in radial spin-echo diffusion-tensor imaging without degrading parameter quantification and/or SNR

Therapeutic attempts to cure Alzheimer's disease (AD) have failed, and new strategies are desperately needed. Motivated by this reality, many laboratories (including our own) have focused on synaptic dysfunction in AD because synaptic changes are highly correlated with the severity of clinical dementia. In particular, memory formation is accompanied by altered synaptic strength, and this phenomenon (and its dysfunction in AD) has been a recent focus for many laboratories. The molecule cyclic adenosine monophosphate response element-binding protein (CREB) is at a central converging point of pathways and mechanisms activated during the processes of synaptic strengthening and memory formation, as CREB phosphorylation leads to transcription of memory-associated genes. Disruption of these mechanisms in AD results in a reduction of CREB activation with accompanying memory impairment. Thus, it is likely that strategies aimed at these mechanisms will lead to future therapies for AD. In this review, we will summarize literature that investigates 5 possible therapeutic pathways for rescuing synaptic dysfunction in AD: 4 enzymatic pathways that lead to CREB phosphorylation (the cyclic adenosine monophosphate cascade, the serine/threonine kinases extracellular regulated kinases 1 and 2, the nitric oxide cascade, and the calpains), as well as histone acetyltransferases and histone deacetylases (2 enzymes that regulate the histone acetylation necessary for gene transcription).

BACKGROUND AND PURPOSE: Diffusion MRI is a promising, clinically feasible imaging technique commonly used to describe white matter changes after stroke. We investigated the sensitivity of diffusion MRI to detect microstructural alterations in gray matter after sensorimotor cortex stroke in adult male rats. METHODS: The mean diffusivity (MD) and mean kurtosis of perilesional motor cortex were compared with measures in the contralesional forelimb area of sensorimotor cortex at 2 hours, 24 hours, 72 hours, or 25 days after surgery. MD and mean kurtosis were correlated to the surface densities of glia, dendrites, and axons. RESULTS: Perilesional mean kurtosis was increased at 72 hours and 25 days after stroke, whereas MD was no longer different from contralesional sensorimotor cortex at 24 hours after stroke. There was a significant increase in the density of glial processes at 72 hours after stroke in perilesional motor cortex, which correlated with perilesional MD. CONCLUSION: These data support that mean kurtosis and MD provide different but complimentary information on acute and chronic changes in perilesional cortex. Glia infiltration is associated with pseudonormalization of MD in the perilesional motor cortex at 72 hours after lesion; however, this association is absent 25 days after lesion. These data suggest that there are likely several different, time-specific microstructural changes underlying these 2 complimentary diffusion measures.

Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre- and postsynaptic defects, yet whether the pre- and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interaction with the large-conductance calcium-activated potassium (BK) channels that modulate AP width. These results reveal a presynaptic- and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.

This protocol details a free-operant avoidance paradigm that has been developed to evaluate the relative contribution of different sources of reinforcement of avoidance behavior that may play an important role in the development and maintenance of human anxiety disorders. The task enables the assessment of the effects of safety cues that signal a period free from danger on lever-press avoidance behavior. Avoidance behavior trained using this protocol has been shown to be sensitive to both behavioral and pharmacological manipulations and has been optimized so that it takes approximately 1 month for rats to perform at high levels of stable avoidance responding. (c) 2015 by John Wiley & Sons, Inc.

Research indicates that female risk of developing Alzheimer's disease (AD) is greater than that of males. Moderate reduction of calorie intake, known as calorie restriction (CR), reduces pathology in AD mouse models and is a potentially translatable prevention measure for individuals at-risk for AD, as well as an important tool for understanding how the brain endogenously attenuates age-related pathology. Whether sex influences the response to CR remains unknown. In this study, we assessed the effect of CR on beta-amyloid peptide (Abeta) pathology and hippocampal CA1 neuron specific gene expression in the Tg2576 mouse model of cerebral amyloidosis. Relative to ad libitum (AL) feeding, CR feeding significantly reduced hippocampal Abeta burden in 15-month-old female, but not age-matched male, Tg2576 mice. Sustained CR also significantly reduced expression of presenilin enhancer 2 (Psenen) and presenilin 1, components of the gamma-secretase complex, in Tg2576 females. These results indicate that long-term CR significantly reduces age-dependent female Tg2576 Abeta pathology, which is likely to involve CR-mediated reductions in gamma-secretase-dependent amyloid precursor protein (APP) metabolism.