Faculty Bibliography

Adaptive minimum variance beamformers are widely used analysis tools in MEG and EEG. When the target brain activity presents in the form of spatially localized responses, the procedure usually involves two steps. First, positions and orientations of the sources of interest are determined. Second, the filter weights are calculated and source time courses reconstructed. This last step is the object of the current study. Despite different approaches utilized at the source localization stage, basic expressions for the weights have the same form, dictated by the minimum variance condition. These classic expressions involve covariance matrix of the measured field, which includes contributions from both the sources of interest and the noise background. We show analytically that the same weights can alternatively be obtained, if the full field covariance is replaced with that of the noise, provided the beamformer points to the true sources precisely. In practice, however, a certain mismatch is always inevitable. We show that such mismatch results in partial suppression of the true sources if the traditional weights are used. To avoid this effect, the "alternative" weights based on properly estimated noise covariance should be applied at the second, source time course reconstruction step. We demonstrate mathematically and using simulated and real data that in many situations the alternative weights provide significantly better time course reconstruction quality than the traditional ones. In particular, they a) improve source-level SNR and yield more accurately reconstructed waveforms; b) provide more accurate estimates of inter-source correlations; c) reduce the adverse influence of the source correlations on the performance of single-source beamformers, which are used most often. Importantly, the alternative weights come at no additional computational cost, as the structure of the expressions remains the same.

OBJECTIVE: This study aimed to demonstrate feasibility of free-breathing radial acquisition with respiratory motion-resolved compressed sensing reconstruction [extra-dimensional golden-angle radial sparse parallel imaging (XD-GRASP)] for multiphase dynamic gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced liver imaging, and to compare image quality to compressed sensing reconstruction with respiratory motion-averaging (GRASP) and prior conventional breath-held Cartesian-sampled data sets [BH volume interpolated breath-hold examination (VIBE)] in same patients. SUBJECTS AND METHODS: In this Health Insurance Portability and Accountability Act-compliant prospective study, 16 subjects underwent free-breathing continuous radial acquisition during Gd-EOB-DTPA injection and had prior BH-VIBE available. Acquired data were reconstructed using motion-averaging GRASP approach in which consecutive 84 spokes were grouped in each contrast-enhanced phase for a temporal resolution of approximately 14 seconds. Additionally, respiratory motion-resolved reconstruction was performed from the same k-space data by sorting each contrast-enhanced phase into multiple respiratory motion states using compressed sensing algorithm named XD-GRASP, which exploits sparsity along both the contrast-enhancement and respiratory-state dimensions.Contrast-enhanced dynamic multiphase XD-GRASP, GRASP, and BH-VIBE images were anonymized, pooled together in a random order, and presented to 2 board-certified radiologists for independent evaluation of image quality, with higher score indicating more optimal examination. RESULTS: The XD-GRASP reconstructions had significantly (all P < 0.05) higher overall image quality scores compared to GRASP for early arterial (reader 1: 4.3 +/- 0.6 vs 3.31 +/- 0.6; reader 2: 3.81 +/- 0.8 vs 3.38 +/- 0.9) and late arterial (reader 1: 4.5 +/- 0.6 vs 3.63 +/- 0.6; reader 2: 3.56 +/- 0.5 vs 2.88 +/- 0.7) phases of enhancement for both readers. The XD-GRASP also had higher overall image quality score in portal venous phase, which was significant for reader 1 (4.44 +/- 0.5 vs 3.75 +/- 0.8; P = 0.002). In addition, the XD-GRASP had higher overall image quality score compared to BH-VIBE for early (reader 1: 4.3 +/- 0.6 vs 3.88 +/- 0.6; reader 2: 3.81 +/- 0.8 vs 3.50 +/- 1.0) and late (reader 1: 4.5 +/- 0.6 vs 3.44 +/- 0.6; reader 2: 3.56 +/- 0.5 vs 2.94 +/- 0.9) arterial phases. CONCLUSION: Free-breathing motion-resolved XD-GRASP reconstructions provide diagnostic high-quality multiphase images in patients undergoing Gd-EOB-DTPA-enhanced liver examination.

Synapses are highly plastic and are modified by changes in patterns of neural activity or sensory experience. Plasticity of cortical excitatory synapses is thought to be important for learning and memory, leading to alterations in sensory representations and cognitive maps. However, these changes must be coordinated across other synapses within local circuits to preserve neural coding schemes and the organization of excitatory and inhibitory inputs, i.e., excitatory-inhibitory balance. Recent studies indicate that inhibitory synapses are also plastic and are controlled directly by a large number of neuromodulators, particularly during episodes of learning. Many modulators transiently alter excitatory-inhibitory balance by decreasing inhibition, and thus disinhibition has emerged as a major mechanism by which neuromodulation might enable long-term synaptic modifications naturally. This review examines the relationships between neuromodulation and synaptic plasticity, focusing on the induction of long-term changes that collectively enhance cortical excitatory-inhibitory balance for improving perception and behavior.

Retinitis pigmentosa, caused predominantly by mutations in photoreceptor genes, currently lacks comprehensive treatment. We discover that retinal microglia contribute non-cell autonomously to rod photoreceptor degeneration by primary phagocytosis of living rods. Using rd10 mice, we found that the initiation of rod degeneration is accompanied by early infiltration of microglia, upregulation of phagocytic molecules in microglia, and presentation of "eat-me" signals on mutated rods. On live-cell imaging, infiltrating microglia interact dynamically with photoreceptors via motile processes and engage in rapid phagocytic engulfment of non-apoptotic rods. Microglial contribution to rod demise is evidenced by morphological and functional amelioration of photoreceptor degeneration following genetic ablation of retinal microglia. Molecular inhibition of microglial phagocytosis using the vitronectin receptor antagonist cRGD also improved morphological and functional parameters of degeneration. Our findings highlight primary microglial phagocytosis as a contributing mechanism underlying cell death in retinitis pigmentosa and implicate microglia as a potential cellular target for therapy.

Accumulation of amyloid-beta (Abeta) in synaptic mitochondria is associated with mitochondrial and synaptic injury. The underlying mechanisms and strategies to eliminate Abeta and rescue mitochondrial and synaptic defects remain elusive. Presequence protease (PreP), a mitochondrial peptidasome, is a novel mitochondrial Abeta degrading enzyme. Here, we demonstrate for the first time that increased expression of active human PreP in cortical neurons attenuates Alzheimer disease's (AD)-like mitochondrial amyloid pathology and synaptic mitochondrial dysfunction, and suppresses mitochondrial oxidative stress. Notably, PreP-overexpressed AD mice show significant reduction in the production of proinflammatory mediators. Accordingly, increased neuronal PreP expression improves learning and memory and synaptic function in vivo AD mice, and alleviates Abeta-mediated reduction of long-term potentiation. Our results provide in vivo evidence that PreP may play an important role in maintaining mitochondrial integrity and function by clearance and degradation of mitochondrial Abeta along with the improvement in synaptic and behavioral function in AD mouse model. Thus, enhancing PreP activity/expression may be a new therapeutic avenue for treatment of AD.

Mammalian species have co-evolved with intestinal microbial communities that can shape development and adapt to environmental changes, including antibiotic perturbation or nutrient flux. In humans, especially children, microbiota disruption is common, yet the dynamic microbiome recovery from early-life antibiotics is still uncharacterized. Here we use a mouse model mimicking paediatric antibiotic use and find that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide alters both host and microbiota development. Early-life PAT accelerates total mass and bone growth, and causes progressive changes in gut microbiome diversity, population structure and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic. Whereas control microbiota rapidly adapts to a change in diet, PAT slows the ecological progression, with delays lasting several months with previous macrolide exposure. This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment.

Dopamine (DA) is a key transmitter in motor, reward and cogitative pathways, with DA dysfunction implicated in disorders including Parkinson's disease and addiction. Located in midbrain, DA neurons of the substantia nigra pars compacta project via the medial forebrain bundle to the dorsal striatum (caudate putamen), and DA neurons in the adjacent ventral tegmental area project to the ventral striatum (nucleus accumbens) and prefrontal cortex. In addition to classical vesicular release from axons, midbrain DA neurons exhibit DA release from their cell bodies and dendrites. Somatodendritic DA release leads to activation of D2 DA autoreceptors on DA neurons that inhibit their firing via G-protein-coupled inwardly rectifying K+ channels. This helps determine patterns of DA signalling at distant axonal release sites. Somatodendritically released DA also acts via volume transmission to extrasynaptic receptors that modulate local transmitter release and neuronal activity in the midbrain. Thus, somatodendritic release is a pivotal intrinsic feature of DA neurons that must be well defined in order to fully understand the physiology and pathophysiology of DA pathways. Here, we review recent mechanistic aspects of somatodendritic DA release, with particular emphasis on the Ca2+ dependence of release and the potential role of exocytotic proteins.

Targeting pathological tau protein in Alzheimer's disease (AD) and related tauopathies has shown great potential in animal models. Given that tau lesions correlate better with the degree of dementia than do amyloid-beta (Abeta) plaques, their clearance may be clinically more efficacious than removing Abeta when cognitive deficits become evident in AD. Several complementary mechanisms of antibody-mediated removal of tau aggregates are likely to act in concert and the importance of each one may depend on antibody properties, the disease, and its stage. Clinical trials of tau immunotherapy are already underway and several more are likely to be initiated in the near future.