The mouse cortico-basal ganglia-thalamic network.

The cortico-basal ganglia-thalamo-cortical loop is one of the fundamental network motifs in the brain. Revealing its structural and functional organization is critical to understanding cognition, sensorimotor behaviour, and the natural history of many neurological and neuropsychiatric disorders. Classically, this network is conceptualized to contain three information channels: motor, limbic and associative1-4. Yet this three-channel view cannot explain the myriad functions of the basal ganglia. We previously subdivided the dorsal striatum into 29 functional domains on the basis of the topography of inputs from the entire cortex5. Here we map the multi-synaptic output pathways of these striatal domains through the globus pallidus external part (GPe), substantia nigra reticular part (SNr), thalamic nuclei and cortex. Accordingly, we identify 14 SNr and 36 GPe domains and a direct cortico-SNr projection. The striatonigral direct pathway displays a greater convergence of striatal inputs than the more parallel striatopallidal indirect pathway, although direct and indirect pathways originating from the same striatal domain ultimately converge onto the same postsynaptic SNr neurons. Following the SNr outputs, we delineate six domains in the parafascicular and ventromedial thalamic nuclei. Subsequently, we identify six parallel cortico-basal ganglia-thalamic subnetworks that sequentially transduce specific subsets of cortical information through every elemental node of the cortico-basal ganglia-thalamic loop. Thalamic domains relay this output back to the originating corticostriatal neurons of each subnetwork in a bona fide closed loop.

Cellular anatomy of the mouse primary motor cortex.

An essential step toward understanding brain function is to establish a structural framework with cellular resolution on which multi-scale datasets spanning molecules, cells, circuits and systems can be integrated and interpreted1. Here, as part of the collaborative Brain Initiative Cell Census Network (BICCN), we derive a comprehensive cell type-based anatomical description of one exemplar brain structure, the mouse primary motor cortex, upper limb area (MOp-ul). Using genetic and viral labelling, barcoded anatomy resolved by sequencing, single-neuron reconstruction, whole-brain imaging and cloud-based neuroinformatics tools, we delineated the MOp-ul in 3D and refined its sublaminar organization. We defined around two dozen projection neuron types in the MOp-ul and derived an input-output wiring diagram, which will facilitate future analyses of motor control circuitry across molecular, cellular and system levels. This work provides a roadmap towards a comprehensive cellular-resolution description of mammalian brain architecture.

Organization of the inputs and outputs of the mouse superior colliculus.

The superior colliculus (SC) receives diverse and robust cortical inputs to drive a range of cognitive and sensorimotor behaviors. However, it remains unclear how descending cortical input arising from higher-order associative areas coordinate with SC sensorimotor networks to influence its outputs. Here, we construct a comprehensive map of all cortico-tectal projections and identify four collicular zones with differential cortical inputs: medial (SC.m), centromedial (SC.cm), centrolateral (SC.cl) and lateral (SC.l). Further, we delineate the distinctive brain-wide input/output organization of each collicular zone, assemble multiple parallel cortico-tecto-thalamic subnetworks, and identify the somatotopic map in the SC that displays distinguishable spatial properties from the somatotopic maps in the neocortex and basal ganglia. Finally, we characterize interactions between those cortico-tecto-thalamic and cortico-basal ganglia-thalamic subnetworks. This study provides a structural basis for understanding how SC is involved in integrating different sensory modalities, translating sensory information to motor command, and coordinating different actions in goal-directed behaviors.

Connectivity characterization of the mouse basolateral amygdalar complex.

The basolateral amygdalar complex (BLA) is implicated in behaviors ranging from fear acquisition to addiction. Optogenetic methods have enabled the association of circuit-specific functions to uniquely connected BLA cell types. Thus, a systematic and detailed connectivity profile of BLA projection neurons to inform granular, cell type-specific interrogations is warranted. Here, we apply machine-learning based computational and informatics analysis techniques to the results of circuit-tracing experiments to create a foundational, comprehensive BLA connectivity map. The analyses identify three distinct domains within the anterior BLA (BLAa) that house target-specific projection neurons with distinguishable morphological features. We identify brain-wide targets of projection neurons in the three BLAa domains, as well as in the posterior BLA, ventral BLA, posterior basomedial, and lateral amygdalar nuclei. Inputs to each nucleus also are identified via retrograde tracing. The data suggests that connectionally unique, domain-specific BLAa neurons are associated with distinct behavior networks.

Mechanical performance of cementless total knee replacements: It is not all about the maximum loads.

Finite element (FE) models are frequently used to assess mechanical interactions between orthopedic implants and surrounding bone. However, FE studies are often limited by the small number of bones that are modeled; the use of normal bones that do not reflect the altered bone density distributions that result from osteoarthritis (OA); and the application of simplified load cases usually based on peak forces and without consideration of tibiofemoral kinematics. To overcome these limitations, we undertook an integrated approach to determine the most critical scenario for the interaction between an uncemented tibial component and surrounding proximal tibial bone. A cementless component, based on a modern design, was virtually implanted using computed-tomography scans from 13 patients with knee OA. FE simulations were performed across a demanding activity, stair ascent, by combining in vivo experimental forces from the literature with tibiofemoral kinematics measured from patients who had received the same design of knee component. The worst conditions for the bone-implant interaction, in terms of micromotion and percentage of interfacial bone mass at risk of failure, did not arise from the maximum applied loads. We also found large variability among bones and tibiofemoral kinematics sets. Our results suggest that future FE studies should not focus solely on peak loads as this approach does not consistently correlate to worst-case scenarios. Moreover, multiple load cases and multiple bones should be considered to best reflect variations in tibiofemoral kinematics, anatomy, and tissue properties. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:350-357, 2019.

Integration of gene expression and brain-wide connectivity reveals the multiscale organization of mouse hippocampal networks.

Understanding the organization of the hippocampus is fundamental to understanding brain function related to learning, memory, emotions, and diseases such as Alzheimer's disease. Physiological studies in humans and rodents have suggested that there is both structural and functional heterogeneity along the longitudinal axis of the hippocampus. However, the recent discovery of discrete gene expression domains in the mouse hippocampus has provided the opportunity to re-evaluate hippocampal connectivity. To integrate mouse hippocampal gene expression and connectivity, we mapped the distribution of distinct gene expression patterns in mouse hippocampus and subiculum to create the Hippocampus Gene Expression Atlas (HGEA). Notably, previously unknown subiculum gene expression patterns revealed a hidden laminar organization. Guided by the HGEA, we constructed the most detailed hippocampal connectome available using Mouse Connectome Project ( http://www.mouseconnectome.org ) tract tracing data. Our results define the hippocampus' multiscale network organization and elucidate each subnetwork's unique brain-wide connectivity patterns.

The effects of cerebral amyloid angiopathy on integrity of the blood-brain barrier.

Cerebral amyloid angiopathy (CAA), in which amyloid accumulates predominantly in the walls of arterioles and capillaries, is seen in most patients with Alzheimer disease (AD) and may contribute to compromise of blood-brain barrier (BBB) function seen in AD. We investigated the effects of CAA on BBB integrity by examining the expression of the endothelial marker CD31, basement membrane protein collagen IV (COL4), tight junction protein claudin-5, and fibrinogen, a marker of BBB leakage, by immunohistochemistry in the occipital cortex of autopsy brains with AD and capillary CAA (CAA type 1; n = 8), AD with noncapillary CAA (CAA type 2; n = 10), and AD without CAA (n = 7) compared with elderly controls (n = 10). Given the difference in pathogenesis of capillary and noncapillary CAA, we hypothesize that features of BBB breakdown are observed only in capillary CAA. We found decreased expression of CD31 in AD subjects with CAA types 1 and 2 compared with AD without CAA and an increase in COL4 in AD without CAA compared with controls. Furthermore, there was increased immunoreactivity for fibrinogen in AD with CAA type 1 compared with controls. These findings suggest that capillary CAA is associated with morphologic and possibly physiologic alterations of the neurovascular unit and increased BBB permeability in AD.

Associations between hippocampal morphometry and neuropathologic markers of Alzheimer's disease using 7 T MRI.

Hippocampal atrophy, amyloid plaques, and neurofibrillary tangles are established pathologic markers of Alzheimer's disease. We analyzed the temporal lobes of 9 Alzheimer's dementia (AD) and 7 cognitively normal (NC) subjects. Brains were scanned post-mortem at 7 Tesla. We extracted hippocampal volumes and radial distances using automated segmentation techniques. Hippocampal slices were stained for amyloid beta (Aß), tau, and cresyl violet to evaluate neuronal counts. The hippocampal subfields, CA1, CA2, CA3, CA4, and subiculum were manually traced so that the neuronal counts, Aß, and tau burden could be obtained for each region. We used linear regression to detect associations between hippocampal atrophy in 3D, clinical diagnosis and total as well as subfield pathology burden measures. As expected, we found significant correlations between hippocampal radial distance and mean neuronal count, as well as diagnosis. There were subfield specific associations between hippocampal radial distance and tau in CA2, and cresyl violet neuronal counts in CA1 and subiculum. These results provide further validation for the European Alzheimer's Disease Consortium Alzheimer's Disease Neuroimaging Initiative Center Harmonized Hippocampal Segmentation Protocol (HarP).

Relationship between hippocampal atrophy and neuropathology markers: a 7T MRI validation study of the EADC-ADNI Harmonized Hippocampal Segmentation Protocol.

OBJECTIVE: The pathologic validation of European Alzheimer's Disease Consortium Alzheimer's Disease Neuroimaging Initiative Center Harmonized Hippocampal Segmentation Protocol (HarP). METHODS: Temporal lobes of nine Alzheimer's disease (AD) and seven cognitively normal subjects were scanned post-mortem at 7 Tesla. Hippocampal volumes were obtained with HarP. Six-micrometer-thick hippocampal slices were stained for amyloid beta (Aß), tau, and cresyl violet. Hippocampal subfields were manually traced. Neuronal counts, Aß, and tau burden for each hippocampal subfield were obtained. RESULTS: We found significant correlations between hippocampal volume and Braak and Braak staging (ρ = -0.75, P = .001), tau (ρ = -0.53, P = .034), Aß burden (ρ = -0.61, P = .012), and neuronal count (ρ = 0.77, P < .001). Exploratory subfield-wise significant associations were found for Aß in Cornu Ammonis (CA)1 (ρ = -0.58, P = .019) and subiculum (ρ = -0.75, P = .001), tau in CA2 (ρ = -0.59, P = .016), and CA3 (ρ = -0.5, P = .047), and neuronal count in CA1 (ρ = 0.55, P = .028), CA3 (ρ = 0.65, P = .006), and CA4 (ρ = 0.76, P = .001). CONCLUSIONS: The observed associations provide pathological confirmation of hippocampal morphometry as a valid biomarker for AD and pathologic validation of HarP.

Use of a custom alignment guide to improve glenoid component position in total shoulder arthroplasty.

PURPOSE: Total and reverse total shoulder arthroplasty (TSA) are used to treat patients with glenohumeral joint osteoarthritis. The revision rate remains high compared with hip and knee arthroplasty. Glenoid component loosening is an important complication and may be caused by poor positioning of the component. We aimed to evaluate the safety and accuracy of a custom glenoid jig created using preoperative computed tomography (CT) imaging with 3D modelling for glenoid component implantation. METHODS: Preoperative CT scans of each shoulder (N = 7) were obtained. Implants were virtually aligned and custom templates were created for intraoperative use. A two-part custom jig was manufactured for alignment of the central peg and the peripheral screws. Three-dimensional orientation of the component and screws was evaluated in postoperative CT scans. The difference between the preoperative plan and the result was then calculated. RESULTS: No technical difficulties or complications occurred. The mean absolute difference between the planned alignment and the postoperative placement of the glenoid component in the three-dimensional space was 3.4 mm (SD = 1 mm). The total average difference for all screws (N = 10) was 6.3° (SD = 3.2°). CONCLUSION: A CT-based custom glenoid component alignment can reliably guide the placement of the glenoid component during conventional and reverse TSA. This custom jig may be useful for optimizing glenoid component position in the setting of reverse and TSA.

Reliability of navigated lower limb alignment in high tibial osteotomies.

BACKGROUND: Navigation allows for determination of the mechanical axis of the lower extremity during high tibial osteotomy (HTO) procedures. The objectives of this study were to (1) evaluate the reliability of noninvasive registration with an image-free navigation system for HTO and (2) determine the accuracy of the navigation system to monitor changes in lower limb alignment as compared with alignment measured with a novel 3-dimensional computed tomography method. HYPOTHESIS: Navigated limb alignment demonstrates good reliability and accuracy in all 3 planes. STUDY DESIGN: Descriptive laboratory study. METHODS: Thirteen cadaver legs were used to examine the intra- and interobserver registration reliability of 3 observers. Initial coronal, sagittal, and axial alignment was measured on 6 legs, 3 times each, at intervals >36 hours. Navigated HTOs were then performed on all 13 legs, pre- and postoperative alignment was recorded, and data were compared with equivalent measures obtained by 3-dimensional computed tomography. Reliability and accuracy data were both analyzed using intraclass correlation coefficients with the following established thresholds: good, >0.75; fair, 0.4 to 0.75; and poor, <0.4. RESULTS: Intraclass correlation coefficients for intraobserver reliability were categorized as follows: varus-valgus, good; flexion-extension, fair; and femoral-tibial rotation, poor. For interobserver reliability, results were varus-valgus, fair; flexion-extension, fair; and femoral-tibial rotation, poor. Intraclass correlation coefficients for navigation accuracy were varus-valgus, good; tibial slope, good; and tibial torsion, poor. Maximum differences in navigation-computed tomography measurements were Delta varus-valgus angle, 4.5 degrees; Delta tibial slope, 8.8 degrees; and Delta tibial torsion, 16.5 degrees. CONCLUSION AND CLINICAL RELEVANCE: Navigation may be reliable and clinically useful for dynamic monitoring of coronal leg alignment but has limits in determination of sagittal and axial plane alignment.