Faculty Bibliography

PURPOSE/OBJECTIVE:Introduce a novel coil design using an electrically long transversely oriented slot in a conductive sheet. THEORY AND METHODS/UNASSIGNED:Theoretical considerations, numerical simulations, and experimental measurements are presented for transverse slot antennas as compared with electric dipole antennas. RESULTS:Simulations show improved central and average transmit and receive efficiency, as well as larger coverage in the transverse plane, for a single slot as compared to a single dipole element. Experiments on a body phantom confirm the simulation results for a slot antenna relative to a dipole, demonstrating a large region of relatively high sensitivity and homogeneity. Images in a human subject also show a large imaging volume for a single slot and six slot antenna array. High central transmit efficiency was observed for slot arrays relative to dipole arrays. CONCLUSION/CONCLUSIONS:Transverse slots can exhibit improved sensitivity and larger field of view compared with traditional conductive dipoles. Simulations and experiments indicate high potential for slot antennas in high field MRI. Magn Reson Med, 2018. © 2018 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

BACKGROUND:Oligomeric forms of amyloid-β (Aβ) and tau are increasing being recognized as key toxins in the pathogenesis of Alzheimer's disease (AD). METHODS:We developed a novel monoclonal antibody (mAb), GW-23B7, that recognizes β-sheet secondary structure on pathological oligomers of neurodegenerative diseases. RESULTS:The pentameric immunoglobulin M kappa chain (IgMκp) we developed specifically distinguishes intra- and extracellular pathology in human AD brains. Purified GW-23B7 showed a dissociation constant in the nanomolar range for oligomeric Aβ and did not bind monomeric Aβ. In enzyme-linked immunosorbent assays, it recognized oligomeric forms of both Aβ and hyperphosphorylated tau. Aged triple-transgenic AD mice with both Aβ and tau pathology infused intraperitoneally for 2 months showed IgMκp in the soluble brain homogenate, peaking at 24 h postinoculation. Treated mice exhibited significant cognitive rescue on radial arm maze testing compared with vehicle control-infused mice. Immunohistochemically, treatment resulted in a significant decrease of extracellular pathology. Biochemically, treatment resulted in significant reductions of oligomeric forms of Aβ and tau. CONCLUSIONS:These results suggest that GW-23B7, an anti-β-sheet conformational mAb humanized for clinical trials, may be an effective therapeutic agent for human AD.

Topographic maps are a basic organizational feature of nervous systems, and their construction involves both spatial and temporal cues. A recent study reports a novel mechanism of topographic map formation which relies on the timing of axon initiation.

Expression of Tamm-Horsfall protein (THP or uromodulin) is highly restricted to the kidneys' thick ascending limb (TAL) of loop of Henle. Despite the unique location and recent association of THP gene mutations with hereditary uromodulin-associated kidney disease and THP single nucleotide polymorphisms with chronic kidney disease and hypertension, the physiological function(s) of THP and its pathological involvement remain incompletely understood. By studying age-dependent changes of THP knockout (KO) mice, we show here that young KO mice had significant salt and water wasting but were partially responsive to furosemide, due to decreased luminal translocation of Na-K-Cl cotransporter 2 (NKCC2) in the TAL. Aged THP KO mice were, however, markedly oliguric and unresponsive to furosemide, and their NKCC2 was localized primarily in the cytoplasm as evidenced by lipid raft floatation assay, cell fractionation, confocal and immunoelectron microscopy. These aged KO mice responded to metolazone and acetazolamide, known to target distal and proximal tubules, respectively. They also had marked upregulation of renin in juxtaglomerular apparatus and serum, and they were hypertensive. Finally, the aged THP KO mice had significant upregulation of Na-coupled urate transporters Slc5a8 and Slc22a12 as well as sodium-hydrogen exchanger 3 (NHE3) in the proximal tubule and elevated serum uric acid and allantoin. Collectively, our results suggest that THP deficiency can cause progressive disturbances in renal functions via initially NKCC2 dysfunction and later compensatory responses resulting in prolonged activation of the renin-angiotensin-aldosterone axis and hyperuricema.

Sequential change-point detection from time series data is a common problem in many neuroscience applications, such as seizure detection, anomaly detection, and pain detection. In our previous work (Chen et al., 2017, J. Neural Eng.), we have developed a latent state space model, known as Poisson linear dynamical system (PLDS), for detecting abrupt changes in neuronal ensemble spike activity. In online brain-machine interface (BMI) applications, a recursive filtering algorithm is used to track the changes in the latent variable. However, previous methods have restricted to Gaussian dynamical noise and have used Gaussian approximation for the Poisson likelihood. To improve the detection speed, we introduce non-Gaussian dynamical noise for modeling a stochastic jump process in the latent state space. To efficiently estimate the state posterior that accommodates non-Gaussian noise and non-Gaussian likelihood, we propose particle filtering and smoothing algorithms for the change-point detection problem. To speed up the computation, we implement the proposed particle filtering algorithms using advanced GPU (graphic processing unit) computing technology. We validate our algorithms using both computer simulations and experimental data for acute pain detection. Finally, we discuss several important practical issues in the context of real-time closed-loop BMI applications.

OBJECTIVE:CD16+ /CD163+ macrophages (MΦ)s and microglia accumulate in the brains of patients with HIV encephalitis (HIVE), a neuropathological correlate of the most severe form of HIV-associated neurocognitive disorders (HAND), HIV-associated dementia (HIV-D). Recently, we found that some parenchymal microglia in brain of HIV+ subjects without encephalitis (HIV/noE) but with varying degrees of neurocognitive impairment express CD16 and CD163, even in the absence of detectable virus production. To further our understanding of microglial activation in HIV, we investigated expression of specific genes by profiling parenchymal microglia from archival brain tissue of patients with HIVE, HIV/noE, and HIV- controls. METHODS:Single-population microarray analyses were performed on ∼2,500 laser capture microdissected CD163+ , CD16+ or CD68+ MΦs/microglia per case, using terminal continuation (TC) RNA amplification and a custom-designed array platform. RESULTS:Several classes of microglial transcripts in HIVE and HIV/noE, were altered, relative to HIV- subjects, including factors related to cell stress, immune activation, and apoptosis. Additionally, several neurotrophic factors are reduced in HIV infection, suggesting an additional mechanism of neuropathogenesis. The majority of transcripts altered in HIVE displayed intermediate changes in HIV/noE. INTERPRETATION/CONCLUSIONS:Our results support the notion that microglia contribute to the maintenance of brain homeostasis and their potential loss of function in the context of chronic inflammation contributes to neuropathogenesis. Furthermore, they indicate the utility of profiling MΦs/microglia to increase our understanding of microglia function, as well as ascertain alterations in specific pathways, genes, and, ostensibly, encoded proteins that may be amenable to targeted treatment modalities in diseases affecting the brain.

BACKGROUND:There is growing interest in detecting cerebro-cerebellar circuits, which requires adequate blood oxygenation level dependent contrast and signal-to-noise ratio (SNR) throughout the brain. Although 7T scanners offer increased SNR, coverage of commercial head coils is currently limited to the cerebrum. PURPOSE/OBJECTIVE:To improve cerebellar functional MRI (fMRI) at 7T with high permittivity material (HPM) pads extending the sensitivity of a commercial coil. STUDY TYPE/METHODS:Simulations were used to determine HPM pad configuration and assess radiofrequency (RF) safety. In vivo experiments were performed to evaluate RF field distributions and SNR and assess improvements of cerebellar fMRI. SUBJECTS/METHODS:Eight healthy volunteers enrolled in a prospective motor fMRI study with and without HPM. FIELD STRENGTH/SEQUENCE/UNASSIGNED:Gradient echo (GRE) echo planar imaging for fMRI, turbo FLASH for flip angle mapping, GRE sequence for SNR maps, and T1 -weighted MPRAGE were acquired with and without HPM pads at 7T. ASSESSMENT/RESULTS:Field maps, SNR maps, and anatomical images were evaluated for coverage. Simulation results were used to assess SAR levels of the experiment. Activation data from fMRI experiments were compared with and without HPM pads. STATISTICAL TESTS: fMRI data were analyzed using FEAT FSL for each subject followed by group level analysis using paired t-test of acquisitions with and without HPM. RESULTS:Simulations showed 52% improvement in transmit efficiency in cerebellum with HPM and SAR levels well below recommended limits. Experiments showed 27% improvement in SNR in cerebellum and improvement in coverage on T1 -weighted images. fMRI showed greater cerebellar activation in individual subjects with the HPM pad present (Z > = 4), especially in inferior slices of cerebellum, with 59% average increase in number of activated voxels in the cerebellum. Group-level analysis showed improved functional activation (Z > = 2.3) in cerebellar regions with HPM pads without loss of measured activation elsewhere. DATA CONCLUSION/UNASSIGNED:HPM pads can improve cerebellar fMRI at 7T with a commonly-used head coil without compromising RF safety. LEVEL OF EVIDENCE/METHODS:2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017.

Military personnel and athletes exposed to traumatic brain injury may develop chronic traumatic encephalopathy (CTE). Brain pathology in CTE includes intracellular accumulation of abnormally phosphorylated tau proteins (p-tau), the main constituent of neurofibrillary tangles (NFTs). Recently, we found that cholinergic basal forebrain (CBF) neurons within the nucleus basalis of Meynert (nbM), which provide the major cholinergic innervation to the cortex, display an increasing number of NFTs across the pathological stages of CTE.1 However, molecular mechanisms underlying nbM neurodegeneration post CTE remain unknown. Here, we assessed the genetic signature of nbM neurons containing the p-tau pretangle maker pS422 obtained from CTE subjects who came to autopsy and received a neuropathological CTE staging assessment (Stages II, III, and IV) using laser capture microdissection and custom-designed microarray analysis. Quantitative analysis revealed dysregulation of key genes in several gene ontology groups between CTE stages. Specifically, downregulation of the nicotinic cholinergic receptor subunit beta-2 gene (Chrnb2), monoaminergic enzymes catechol-O-methyltransferase (Comt) and dopa decarboxylase (Ddc), chloride channels Clcn4 and Clcn5, scaffolding protein caveolin 1 (Cav1), cortical development/cytoskeleton element lissencephaly 1 (Lis1) and intracellular signaling cascade member adenylate cyclase 3 (Adcy3) was observed in pS422-immunreactive nbM neurons in CTE patients. By contrast, upregulation of calpain 2 (Capn2) and microtubule-associated protein 2 (Map2) transcript levels was found in stage IV CTE patients. These single-population data in vulnerable neurons indicates alterations in gene expression associated with neurotransmission, signal transduction, the cytoskeleton, cell survival/death signaling, and microtubule dynamics suggesting novel molecular pathways to target for drug discovery in CTE.

Inhibitory interneurons represent 10-15% of the neurons in the somatosensory cortex, and their activity powerfully shapes sensory processing. Three major groups of GABAergic interneurons have been defined according to developmental, molecular, morphological, electrophysiological, and synaptic features. Dendritic-targeting somatostatin-expressing interneurons (SST-INs) have been shown to display diverse morphological, electrophysiological and molecular properties and activity patterns in vivo. However, the correlation between these properties and SST-IN subtype is unclear. In this study we aimed to correlate the morphological diversity of layer 5 (L5) SST-INs with their electrophysiological and molecular diversity in mice of either sex. Our morphological analysis demonstrated the existence of three subtypes of L5 SST-INs with distinct electrophysiological properties: T-shaped Martinotti cells innervate L1, and are low-threshold spiking; fanning-out Martinotti cells innervate L2/3 and the lower half of L1, and show adapting firing patterns; non-Martinotti cells innervate L4, and show a quasi-fast spiking firing pattern. We estimated the proportion of each subtype in L5 and found that T-shaped Martinotti, fanning-out Martinotti and Non-Martinotti cells represent ∼10, ∼50 and ∼40% of L5 SST-INs, respectively. Lastly we examined the connectivity between the three SST-IN subtypes and L5 pyramidal cells (PCs). We found that L5 T-shapped Martinotti cells inhibit the L1 apical tuft of nearby PCs; L5 fanning-out Martinotti cells also inhibit nearby PCs but they target the dendrite mainly in L2/3. On the other hand non-Martinotti cells inhibit the dendrites of L4 neurons while avoiding L5 PCs. Our data suggest that morphologically distinct SST-INs gate different excitatory inputs in the barrel cortex.SIGNIFICANCE STATEMENTMorphologically diverse layer 5 SST-INs show different patterns of activity in behaving animals. However, little is known about the abundance and connectivity of each morphological type and the correlation between morphological subtype and spiking properties. We demonstrate a correlation between the morphological and electrophysiological diversity of layer 5 SST-INs. Based on these findings we built a classifier to infer the abundance of each morphological subtype. Lastly, using paired recordings combined with morphological analysis, we investigated the connectivity of each morphological subtype. Our data suggest that, by targeting different cell types and cellular compartments, morphologically diverse SST-INs might gate different excitatory inputs in the mouse barrel cortex.

Motor output varies along the rostro-caudal axis of the tetrapod spinal cord. At limb levels, ∼60 motor pools control the alternation of flexor and extensor muscles about each joint, whereas at thoracic levels as few as 10 motor pools supply muscle groups that support posture, inspiration, and expiration. Whether such differences in motor neuron identity and muscle number are associated with segmental distinctions in interneuron diversity has not been resolved. We show that select combinations of nineteen transcription factors that specify lumbar V1 inhibitory interneurons generate subpopulations enriched at limb and thoracic levels. Specification of limb and thoracic V1 interneurons involves the Hox gene Hoxc9 independently of motor neurons. Thus, early Hox patterning of the spinal cord determines the identity of V1 interneurons and motor neurons. These studies reveal a developmental program of V1 interneuron diversity, providing insight into the organization of inhibitory interneurons associated with differential motor output.