Publications by authors named "Partha P Mitra"

51 Publications

Rapid Emergence of SARS-CoV-2 in the Greater New York Metropolitan Area: Geolocation, Demographics, Positivity Rates, and Hospitalization for 46 793 Persons Tested by Northwell Health.

Clin Infect Dis 2020 12;71(12):3204-3213

Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Hempstead, New York, USA.

Background: In March 2020, the greater New York metropolitan area became an epicenter for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The initial evolution of case incidence has not been well characterized.

Methods: Northwell Health Laboratories tested 46 793 persons for SARS-CoV-2 from 4 March through 10 April. The primary outcome measure was a positive reverse transcription-polymerase chain reaction test for SARS-CoV-2. The secondary outcomes included patient age, sex, and race, if stated; dates the specimen was obtained and the test result; clinical practice site sources; geolocation of patient residence; and hospitalization.

Results: From 8 March through 10 April, a total of 26 735 of 46 793 persons (57.1%) tested positive for SARS-CoV-2. Males of each race were disproportionally more affected than females above age 25, with a progressive male predominance as age increased. Of the positive persons, 7292 were hospitalized directly upon presentation; an additional 882 persons tested positive in an ambulatory setting before subsequent hospitalization, a median of 4.8 days later. Total hospitalization rate was thus 8174 persons (30.6% of positive persons). There was a broad range (>10-fold) in the cumulative number of positive cases across individual zip codes following documented first caseincidence. Test positivity was greater for persons living in zip codes with lower annual household income.

Conclusions: Our data reveal that SARS-CoV-2 incidence emerged rapidly and almost simultaneously across a broad demographic population in the region. These findings support the premise that SARS-CoV-2 infection was widely distributed prior to virus testing availability.
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http://dx.doi.org/10.1093/cid/ciaa922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454448PMC
December 2020

Multimodal cross-registration and quantification of metric distortions in marmoset whole brain histology using diffeomorphic mappings.

J Comp Neurol 2021 Feb 1;529(2):281-295. Epub 2020 Jun 1.

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.

Whole brain neuroanatomy using tera-voxel light-microscopic data sets is of much current interest. A fundamental problem in this field is the mapping of individual brain data sets to a reference space. Previous work has not rigorously quantified in-vivo to ex-vivo distortions in brain geometry from tissue processing. Further, existing approaches focus on registering unimodal volumetric data; however, given the increasing interest in the marmoset model for neuroscience research and the importance of addressing individual brain architecture variations, new algorithms are necessary to cross-register multimodal data sets including MRIs and multiple histological series. Here we present a computational approach for same-subject multimodal MRI-guided reconstruction of a series of consecutive histological sections, jointly with diffeomorphic mapping to a reference atlas. We quantify the scale change during different stages of brain histological processing using the Jacobian determinant of the diffeomorphic transformations involved. By mapping the final image stacks to the ex-vivo post-fixation MRI, we show that (a) tape-transfer assisted histological sections can be reassembled accurately into 3D volumes with a local scale change of 2.0 ± 0.4% per axis dimension; in contrast, (b) tissue perfusion/fixation as assessed by mapping the in-vivo MRIs to the ex-vivo post fixation MRIs shows a larger median absolute scale change of 6.9 ± 2.1% per axis dimension. This is the first systematic quantification of local metric distortions associated with whole-brain histological processing, and we expect that the results will generalize to other species. These local scale changes will be important for computing local properties to create reference brain maps.
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http://dx.doi.org/10.1002/cne.24946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666050PMC
February 2021

Open access resource for cellular-resolution analyses of corticocortical connectivity in the marmoset monkey.

Nat Commun 2020 02 28;11(1):1133. Epub 2020 Feb 28.

Australian Research Council, Centre of Excellence for Integrative Brain Function, Monash University Node, Clayton, VIC, 3800, Australia.

Understanding the principles of neuronal connectivity requires tools for efficient quantification and visualization of large datasets. The primate cortex is particularly challenging due to its complex mosaic of areas, which in many cases lack clear boundaries. Here, we introduce a resource that allows exploration of results of 143 retrograde tracer injections in the marmoset neocortex. Data obtained in different animals are registered to a common stereotaxic space using an algorithm guided by expert delineation of histological borders, allowing accurate assignment of connections to areas despite interindividual variability. The resource incorporates tools for analyses relative to cytoarchitectural areas, including statistical properties such as the fraction of labeled neurons and the percentage of supragranular neurons. It also provides purely spatial (parcellation-free) data, based on the stereotaxic coordinates of 2 million labeled neurons. This resource helps bridge the gap between high-density cellular connectivity studies in rodents and imaging-based analyses of human brains.
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http://dx.doi.org/10.1038/s41467-020-14858-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048793PMC
February 2020

ZEBrA: Zebra finch Expression Brain Atlas-A resource for comparative molecular neuroanatomy and brain evolution studies.

J Comp Neurol 2020 08 19;528(12):2099-2131. Epub 2020 Feb 19.

Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon.

An in-depth understanding of the genetics and evolution of brain function and behavior requires a detailed mapping of gene expression in functional brain circuits across major vertebrate clades. Here we present the Zebra finch Expression Brain Atlas (ZEBrA; www.zebrafinchatlas.org, RRID: SCR_012988), a web-based resource that maps the expression of genes linked to a broad range of functions onto the brain of zebra finches. ZEBrA is a first of its kind gene expression brain atlas for a bird species and a first for any sauropsid. ZEBrA's >3,200 high-resolution digital images of in situ hybridized sections for ~650 genes (as of June 2019) are presented in alignment with an annotated histological atlas and can be browsed down to cellular resolution. An extensive relational database connects expression patterns to information about gene function, mouse expression patterns and phenotypes, and gene involvement in human diseases and communication disorders. By enabling brain-wide gene expression assessments in a bird, ZEBrA provides important substrates for comparative neuroanatomy and molecular brain evolution studies. ZEBrA also provides unique opportunities for linking genetic pathways to vocal learning and motor control circuits, as well as for novel insights into the molecular basis of sex steroids actions, brain dimorphisms, reproductive and social behaviors, sleep function, and adult neurogenesis, among many fundamental themes.
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http://dx.doi.org/10.1002/cne.24879DOI Listing
August 2020

ESTIMATING DIFFEOMORPHIC MAPPINGS BETWEEN TEMPLATES AND NOISY DATA: VARIANCE BOUNDS ON THE ESTIMATED CANONICAL VOLUME FORM.

Q Appl Math 2019 20;77:467-488. Epub 2018 Nov 20.

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21218.

Anatomy is undergoing a renaissance driven by the availability of large digital data sets generated by light microscopy. A central computational task is to map individual data volumes to standardized templates. This is accomplished by regularized estimation of a diffeomorphic transformation between the coordinate systems of the individual data and the template, building the transformation incrementally by integrating a smooth flow field. The canonical volume form of this transformation is used to quantify local growth, atrophy, or cell density. While multiple implementations exist for this estimation, less attention has been paid to the variance of the estimated diffeomorphism for noisy data. Notably, there is an infinite dimensional unobservable space defined by those diffeomorphisms which leave the template invariant. These form the stabilizer subgroup of the diffeomorphic group acting on the template. The corresponding flat directions in the energy landscape are expected to lead to increased estimation variance. Here we show that a least-action principle used to generate geodesics in the space of diffeomor-phisms connecting the subject brain to the template removes the stabilizer. This provides reduced-variance estimates of the volume form. Using simulations we demonstrate that the asymmetric large deformation diffeomorphic mapping methods (LDDMM), which explicitly incorporate the asymmetry between idealized template images and noisy empirical images, provide lower variance estimators than their symmetrized counterparts (cf. ANTs). We derive Cramer-Rao bounds for the variances in the limit of small deformations. Analytical results are shown for the Jacobian in terms of perturbations of the vector fields and divergence of the vector field.
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http://dx.doi.org/10.1090/qam/1527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924927PMC
November 2018

Traumatic microbleeds suggest vascular injury and predict disability in traumatic brain injury.

Brain 2019 11;142(11):3550-3564

Center for Neuroscience and Regenerative Medicine, Bethesda, Maryland, USA.

Traumatic microbleeds are small foci of hypointensity seen on T2*-weighted MRI in patients following head trauma that have previously been considered a marker of axonal injury. The linear appearance and location of some traumatic microbleeds suggests a vascular origin. The aims of this study were to: (i) identify and characterize traumatic microbleeds in patients with acute traumatic brain injury; (ii) determine whether appearance of traumatic microbleeds predict clinical outcome; and (iii) describe the pathology underlying traumatic microbleeds in an index patient. Patients presenting to the emergency department following acute head trauma who received a head CT were enrolled within 48 h of injury and received a research MRI. Disability was defined using Glasgow Outcome Scale-Extended ≤6 at follow-up. All magnetic resonance images were interpreted prospectively and were used for subsequent analysis of traumatic microbleeds. Lesions on T2* MRI were stratified based on 'linear' streak-like or 'punctate' petechial-appearing traumatic microbleeds. The brain of an enrolled subject imaged acutely was procured following death for evaluation of traumatic microbleeds using MRI targeted pathology methods. Of the 439 patients enrolled over 78 months, 31% (134/439) had evidence of punctate and/or linear traumatic microbleeds on MRI. Severity of injury, mechanism of injury, and CT findings were associated with traumatic microbleeds on MRI. The presence of traumatic microbleeds was an independent predictor of disability (P < 0.05; odds ratio = 2.5). No differences were found between patients with punctate versus linear appearing microbleeds. Post-mortem imaging and histology revealed traumatic microbleed co-localization with iron-laden macrophages, predominately seen in perivascular space. Evidence of axonal injury was not observed in co-localized histopathological sections. Traumatic microbleeds were prevalent in the population studied and predictive of worse outcome. The source of traumatic microbleed signal on MRI appeared to be iron-laden macrophages in the perivascular space tracking a network of injured vessels. While axonal injury in association with traumatic microbleeds cannot be excluded, recognizing traumatic microbleeds as a form of traumatic vascular injury may aid in identifying patients who could benefit from new therapies targeting the injured vasculature and secondary injury to parenchyma.
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http://dx.doi.org/10.1093/brain/awz290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821371PMC
November 2019

Can One Concurrently Record Electrical Spikes from Every Neuron in a Mammalian Brain?

Neuron 2019 09 5;103(6):1005-1015. Epub 2019 Sep 5.

Howard Hughes Medical Institutes, Janelia Research Campus, Ashburn, VA, USA; Department of Bioengineering, Johns Hopkins University, Baltimore, MD, USA. Electronic address:

The classic approach to measure the spiking response of neurons involves the use of metal electrodes to record extracellular potentials. Starting over 60 years ago with a single recording site, this technology now extends to ever larger numbers and densities of sites. We argue, based on the mechanical and electrical properties of existing materials, estimates of signal-to-noise ratios, assumptions regarding extracellular space in the brain, and estimates of heat generation by the electronic interface, that it should be possible to fabricate rigid electrodes to concurrently record from essentially every neuron in the cortical mantle. This will involve fabrication with existing yet nontraditional materials and procedures. We further emphasize the need to advance materials for improved flexible electrodes as an essential advance to record from neurons in brainstem and spinal cord in moving animals.
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http://dx.doi.org/10.1016/j.neuron.2019.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763354PMC
September 2019

Relation of koniocellular layers of dorsal lateral geniculate to inferior pulvinar nuclei in common marmosets.

Eur J Neurosci 2019 12 16;50(12):4004-4017. Epub 2019 Aug 16.

Laboratory for Marmoset Neural Architecture, RIKEN Center for Brain Science, Wako, Japan.

Traditionally, the dorsal lateral geniculate nucleus (LGN) and the inferior pulvinar (IPul) nucleus are considered as anatomically and functionally distinct thalamic nuclei. However, in several primate species it has also been established that the koniocellular (K) layers of LGN and parts of the IPul have a shared pattern of immunoreactivity for the calcium-binding protein calbindin. These calbindin-rich cells constitute a thalamic matrix system which is implicated in thalamocortical synchronisation. Further, the K layers and IPul are both involved in visual processing and have similar connections with retina and superior colliculus. Here, we confirmed the continuity between calbindin-rich cells in LGN K layers and the central lateral division of IPul (IPulCL) in marmoset monkeys. By employing a high-throughput neuronal tracing method, we found that both the K layers and IPulCL form comparable patterns of connections with striate and extrastriate cortices; these connections are largely different to those of the parvocellular and magnocellular laminae of LGN. Retrograde tracer-labelled cells and anterograde tracer-labelled axon terminals merged seamlessly from IPulCL into LGN K layers. These results support continuity between LGN K layers and IPulCL, providing an anatomical basis for functional congruity of this region of the dorsal thalamic matrix and calling into question the traditional segregation between LGN and the inferior pulvinar nucleus.
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http://dx.doi.org/10.1111/ejn.14529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928438PMC
December 2019

An active texture-based digital atlas enables automated mapping of structures and markers across brains.

Nat Methods 2019 04 11;16(4):341-350. Epub 2019 Mar 11.

Department of Physics, University of California, San Diego, CA, USA.

Brain atlases enable the mapping of labeled cells and projections from different brains onto a standard coordinate system. We address two issues in the construction and use of atlases. First, expert neuroanatomists ascertain the fine-scale pattern of brain tissue, the 'texture' formed by cellular organization, to define cytoarchitectural borders. We automate the processes of localizing landmark structures and alignment of brains to a reference atlas using machine learning and training data derived from expert annotations. Second, we construct an atlas that is active; that is, augmented with each use. We show that the alignment of new brains to a reference atlas can continuously refine the coordinate system and associated variance. We apply this approach to the adult murine brainstem and achieve a precise alignment of projections in cytoarchitecturally ill-defined regions across brains from different animals.
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http://dx.doi.org/10.1038/s41592-019-0328-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736610PMC
April 2019

On variational solutions for whole brain serial-section histology using a Sobolev prior in the computational anatomy random orbit model.

PLoS Comput Biol 2018 12 26;14(12):e1006610. Epub 2018 Dec 26.

Center for Imaging Science, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.

This paper presents a variational framework for dense diffeomorphic atlas-mapping onto high-throughput histology stacks at the 20 μm meso-scale. The observed sections are modelled as Gaussian random fields conditioned on a sequence of unknown section by section rigid motions and unknown diffeomorphic transformation of a three-dimensional atlas. To regularize over the high-dimensionality of our parameter space (which is a product space of the rigid motion dimensions and the diffeomorphism dimensions), the histology stacks are modelled as arising from a first order Sobolev space smoothness prior. We show that the joint maximum a-posteriori, penalized-likelihood estimator of our high dimensional parameter space emerges as a joint optimization interleaving rigid motion estimation for histology restacking and large deformation diffeomorphic metric mapping to atlas coordinates. We show that joint optimization in this parameter space solves the classical curvature non-identifiability of the histology stacking problem. The algorithms are demonstrated on a collection of whole-brain histological image stacks from the Mouse Brain Architecture Project.
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http://dx.doi.org/10.1371/journal.pcbi.1006610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324828PMC
December 2018

Unidirectional monosynaptic connections from auditory areas to the primary visual cortex in the marmoset monkey.

Brain Struct Funct 2019 Jan 4;224(1):111-131. Epub 2018 Oct 4.

Monash University Node, Australian Research Council, Centre of Excellence for Integrative Brain Function, Clayton, VIC, 3800, Australia.

Until the late twentieth century, it was believed that different sensory modalities were processed by largely independent pathways in the primate cortex, with cross-modal integration only occurring in specialized polysensory areas. This model was challenged by the finding that the peripheral representation of the primary visual cortex (V1) receives monosynaptic connections from areas of the auditory cortex in the macaque. However, auditory projections to V1 have not been reported in other primates. We investigated the existence of direct interconnections between V1 and auditory areas in the marmoset, a New World monkey. Labelled neurons in auditory cortex were observed following 4 out of 10 retrograde tracer injections involving V1. These projections to V1 originated in the caudal subdivisions of auditory cortex (primary auditory cortex, caudal belt and parabelt areas), and targeted parts of V1 that represent parafoveal and peripheral vision. Injections near the representation of the vertical meridian of the visual field labelled few or no cells in auditory cortex. We also placed 8 retrograde tracer injections involving core, belt and parabelt auditory areas, none of which revealed direct projections from V1. These results confirm the existence of a direct, nonreciprocal projection from auditory areas to V1 in a different primate species, which has evolved separately from the macaque for over 30 million years. The essential similarity of these observations between marmoset and macaque indicate that early-stage audiovisual integration is a shared characteristic of primate sensory processing.
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http://dx.doi.org/10.1007/s00429-018-1764-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373361PMC
January 2019

Towards a comprehensive atlas of cortical connections in a primate brain: Mapping tracer injection studies of the common marmoset into a reference digital template.

J Comp Neurol 2016 08;524(11):2161-81

Neuroscience Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.

The marmoset is an emerging animal model for large-scale attempts to understand primate brain connectivity, but achieving this aim requires the development and validation of procedures for normalization and integration of results from many neuroanatomical experiments. Here we describe a computational pipeline for coregistration of retrograde tracing data on connections of cortical areas into a 3D marmoset brain template, generated from Nissl-stained sections. The procedure results in a series of spatial transformations that are applied to the coordinates of labeled neurons in the different cases, bringing them into common stereotaxic space. We applied this procedure to 17 injections, placed in the frontal lobe of nine marmosets as part of earlier studies. Visualizations of cortical patterns of connections revealed by these injections are supplied as Supplementary Materials. Comparison between the results of the automated and human-based processing of these cases reveals that the centers of injection sites can be reconstructed, on average, to within 0.6 mm of coordinates estimated by an experienced neuroanatomist. Moreover, cell counts obtained in different areas by the automated approach are highly correlated (r = 0.83) with those obtained by an expert, who examined in detail histological sections for each individual. The present procedure enables comparison and visualization of large datasets, which in turn opens the way for integration and analysis of results from many animals. Its versatility, including applicability to archival materials, may reduce the number of additional experiments required to produce the first detailed cortical connectome of a primate brain. J. Comp. Neurol. 524:2161-2181, 2016. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/cne.24023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892968PMC
August 2016

Comparative three-dimensional connectome map of motor cortical projections in the mouse brain.

Sci Rep 2016 Feb 2;6:20072. Epub 2016 Feb 2.

Department of Biological Sciences, Korea Advanced Institute of Science &Technology, Daejeon, Korea, 305-338.

The motor cortex orchestrates simple to complex motor behaviors through its output projections to target areas. The primary (MOp) and secondary (MOs) motor cortices are known to produce specific output projections that are targeted to both similar and different target areas. These projections are further divided into layer 5 and 6 neuronal outputs, thereby producing four cortical outputs that may target other areas in a combinatorial manner. However, the precise network structure that integrates these four projections remains poorly understood. Here, we constructed a whole-brain, three-dimensional (3D) map showing the tract pathways and targeting locations of these four motor cortical outputs in mice. Remarkably, these motor cortical projections showed unique and separate tract pathways despite targeting similar areas. Within target areas, various combinations of these four projections were defined based on specific 3D spatial patterns, reflecting anterior-posterior, dorsal-ventral, and core-capsular relationships. This 3D topographic map ultimately provides evidence for the relevance of comparative connectomics: motor cortical projections known to be convergent are actually segregated in many target areas with unique targeting patterns, a finding that has anatomical value for revealing functional subdomains that have not been classified by conventional methods.
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http://dx.doi.org/10.1038/srep20072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735720PMC
February 2016

Conventions and nomenclature for double diffusion encoding NMR and MRI.

Magn Reson Med 2016 Jan 29;75(1):82-7. Epub 2015 Sep 29.

Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Stejskal and Tanner's ingenious pulsed field gradient design from 1965 has made diffusion NMR and MRI the mainstay of most studies seeking to resolve microstructural information in porous systems in general and biological systems in particular. Methods extending beyond Stejskal and Tanner's design, such as double diffusion encoding (DDE) NMR and MRI, may provide novel quantifiable metrics that are less easily inferred from conventional diffusion acquisitions. Despite the growing interest on the topic, the terminology for the pulse sequences, their parameters, and the metrics that can be derived from them remains inconsistent and disparate among groups active in DDE. Here, we present a consensus of those groups on terminology for DDE sequences and associated concepts. Furthermore, the regimes in which DDE metrics appear to provide microstructural information that cannot be achieved using more conventional counterparts (in a model-free fashion) are elucidated. We highlight in particular DDE's potential for determining microscopic diffusion anisotropy and microscopic fractional anisotropy, which offer metrics of microscopic features independent of orientation dispersion and thus provide information complementary to the standard, macroscopic, fractional anisotropy conventionally obtained by diffusion MR. Finally, we discuss future vistas and perspectives for DDE.
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http://dx.doi.org/10.1002/mrm.25901DOI Listing
January 2016

High-Throughput Method of Whole-Brain Sectioning, Using the Tape-Transfer Technique.

PLoS One 2015 16;10(7):e0102363. Epub 2015 Jul 16.

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.

Cryostat sectioning is a popular but labor-intensive method for preparing histological brain sections. We have developed a modification of the commercially available CryoJane tape collection method that significantly improves the ease of collection and the final quality of the tissue sections. The key modification involves an array of UVLEDs to achieve uniform polymerization of the glass slide and robust adhesion between the section and slide. This report presents system components and detailed procedural steps, and provides examples of end results; that is, 20 μm mouse brain sections that have been successfully processed for routine Nissl, myelin staining, DAB histochemistry, and fluorescence. The method is also suitable for larger brains, such as rat and monkey.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102363PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504703PMC
April 2016

The circuit architecture of whole brains at the mesoscopic scale.

Authors:
Partha P Mitra

Neuron 2014 Sep;83(6):1273-83

Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA. Electronic address:

Vertebrate brains of even moderate size are composed of astronomically large numbers of neurons and show a great degree of individual variability at the microscopic scale. This variation is presumably the result of phenotypic plasticity and individual experience. At a larger scale, however, relatively stable species-typical spatial patterns are observed in neuronal architecture, e.g., the spatial distributions of somata and axonal projection patterns, probably the result of a genetically encoded developmental program. The mesoscopic scale of analysis of brain architecture is the transitional point between a microscopic scale where individual variation is prominent and the macroscopic level where a stable, species-typical neural architecture is observed. The empirical existence of this scale, implicit in neuroanatomical atlases, combined with advances in computational resources, makes studying the circuit architecture of entire brains a practical task. A methodology has previously been proposed that employs a shotgun-like grid-based approach to systematically cover entire brain volumes with injections of neuronal tracers. This methodology is being employed to obtain mesoscale circuit maps in mouse and should be applicable to other vertebrate taxa. The resulting large data sets raise issues of data representation, analysis, and interpretation, which must be resolved. Even for data representation the challenges are nontrivial: the conventional approach using regional connectivity matrices fails to capture the collateral branching patterns of projection neurons. Future success of this promising research enterprise depends on the integration of previous neuroanatomical knowledge, partly through the development of suitable computational tools that encapsulate such expertise.
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http://dx.doi.org/10.1016/j.neuron.2014.08.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256953PMC
September 2014

Cell-type-based model explaining coexpression patterns of genes in the brain.

Proc Natl Acad Sci U S A 2014 Apr 25;111(14):5397-402. Epub 2014 Mar 25.

Department of Mathematical Sciences, Xi'an Jiaotong-Liverpool University, Suzhou 215123, China.

Spatial patterns of gene expression in the vertebrate brain are not independent, as pairs of genes can exhibit complex patterns of coexpression. Two genes may be similarly expressed in one region, but differentially expressed in other regions. These correlations have been studied quantitatively, particularly for the Allen Atlas of the adult mouse brain, but their biological meaning remains obscure. We propose a simple model of the coexpression patterns in terms of spatial distributions of underlying cell types and establish its plausibility using independently measured cell-type-specific transcriptomes. The model allows us to predict the spatial distribution of cell types in the mouse brain.
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http://dx.doi.org/10.1073/pnas.1312098111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986204PMC
April 2014

NSF workshop report: discovering general principles of nervous system organization by comparing brain maps across species.

Brain Behav Evol 2014 28;83(1):1-8. Epub 2014 Feb 28.

Department of Neurobiology and Behavior, University of California Irvine, Irvine, Calif., USA.

Efforts to understand nervous system structure and function have received new impetus from the federal Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Comparative analyses can contribute to this effort by leading to the discovery of general principles of neural circuit design, information processing, and gene-structure-function relationships that are not apparent from studies on single species. We here propose to extend the comparative approach to nervous system 'maps' comprising molecular, anatomical, and physiological data. This research will identify which neural features are likely to generalize across species, and which are unlikely to be broadly conserved. It will also suggest causal relationships between genes, development, adult anatomy, physiology, and, ultimately, behavior. These causal hypotheses can then be tested experimentally. Finally, insights from comparative research can inspire and guide technological development. To promote this research agenda, we recommend that teams of investigators coalesce around specific research questions and select a set of 'reference species' to anchor their comparative analyses. These reference species should be chosen not just for practical advantages, but also with regard for their phylogenetic position, behavioral repertoire, well-annotated genome, or other strategic reasons. We envision that the nervous systems of these reference species will be mapped in more detail than those of other species. The collected data may range from the molecular to the behavioral, depending on the research question. To integrate across levels of analysis and across species, standards for data collection, annotation, archiving, and distribution must be developed and respected. To that end, it will help to form networks or consortia of researchers and centers for science, technology, and education that focus on organized data collection, distribution, and training. These activities could be supported, at least in part, through existing mechanisms at NSF, NIH, and other agencies. It will also be important to develop new integrated software and database systems for cross-species data analyses. Multidisciplinary efforts to develop such analytical tools should be supported financially. Finally, training opportunities should be created to stimulate multidisciplinary, integrative research into brain structure, function, and evolution.
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http://dx.doi.org/10.1159/000360152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028317PMC
November 2014

NSF workshop report: discovering general principles of nervous system organization by comparing brain maps across species.

J Comp Neurol 2014 May;522(7):1445-53

Department of Neurobiology and Behavior, University of California Irvine, Irvine, California.

Efforts to understand nervous system structure and function have received new impetus from the federal Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Comparative analyses can contribute to this effort by leading to the discovery of general principles of neural circuit design, information processing, and gene-structure-function relationships that are not apparent from studies on single species. We here propose to extend the comparative approach to nervous system 'maps' comprising molecular, anatomical, and physiological data. This research will identify which neural features are likely to generalize across species, and which are unlikely to be broadly conserved. It will also suggest causal relationships between genes, development, adult anatomy, physiology, and, ultimately, behavior. These causal hypotheses can then be tested experimentally. Finally, insights from comparative research can inspire and guide technological development. To promote this research agenda, we recommend that teams of investigators coalesce around specific research questions and select a set of 'reference species' to anchor their comparative analyses. These reference species should be chosen not just for practical advantages, but also with regard for their phylogenetic position, behavioral repertoire, well-annotated genome, or other strategic reasons. We envision that the nervous systems of these reference species will be mapped in more detail than those of other species. The collected data may range from the molecular to the behavioral, depending on the research question. To integrate across levels of analysis and across species, standards for data collection, annotation, archiving, and distribution must be developed and respected. To that end, it will help to form networks or consortia of researchers and centers for science, technology, and education that focus on organized data collection, distribution, and training. These activities could be supported, at least in part, through existing mechanisms at NSF, NIH, and other agencies. It will also be important to develop new integrated software and database systems for cross-species data analyses. Multidisciplinary efforts to develop such analytical tools should be supported financially. Finally, training opportunities should be created to stimulate multidisciplinary, integrative research into brain structure, function, and evolution.
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http://dx.doi.org/10.1002/cne.23568DOI Listing
May 2014

Spectral methods for functional brain imaging.

Cold Spring Harb Protoc 2014 Mar 1;2014(3):248-62. Epub 2014 Mar 1.

Dynamic functional imaging experiments typically generate large, multivariate data sets that contain considerable spatial and temporal complexity. The goal of this introduction is to present signal-processing techniques that allow the underlying spatiotemporal structure to be readily distilled and that also enable signal versus noise contributions to be separated.
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http://dx.doi.org/10.1101/pdb.top081075DOI Listing
March 2014

The angular interval between the direction of progression and body orientation in normal, alcohol- and cocaine treated fruit flies.

PLoS One 2013 16;8(10):e76257. Epub 2013 Oct 16.

Department of Zoology, Tel Aviv University, Tel Aviv, Israel ; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.

In this study we characterize the coordination between the direction a fruit-fly walks and the direction it faces, as well as offer a methodology for isolating and validating key variables with which we phenotype fly locomotor behavior. Our fundamental finding is that the angular interval between the direction a fly walks and the direction it faces is actively managed in intact animals and modulated in a patterned way with drugs. This interval is small in intact flies, larger with alcohol and much larger with cocaine. The dynamics of this interval generates six coordinative modes that flow smoothly into each other. Under alcohol and much more so under cocaine, straight path modes dwindle and modes involving rotation proliferate. To obtain these results we perform high content analysis of video-tracked open field locomotor behavior. Presently there is a gap between the quality of descriptions of insect behaviors that unfold in circumscribed situations, and descriptions that unfold in extended time and space. While the first describe the coordination between low-level kinematic variables, the second quantify cumulative measures and subjectively defined behavior patterns. Here we reduce this gap by phenotyping extended locomotor behavior in terms of the coordination between low-level kinematic variables, which we quantify, combining into a single field two disparate fields, that of high content phenotyping and that of locomotor coordination. This will allow the study of the genes/brain/locomotor coordination interface in genetically engineered and pharmacologically manipulated animal models of human diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076257PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797839PMC
August 2014

The challenge of connecting the dots in the B.R.A.I.N.

Neuron 2013 Oct;80(2):270-4

Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA; Department of Radiology, University of California San Diego, La Jolla, CA 92093, USA; Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address:

The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has focused scientific attention on the necessary tools to understand the human brain and mind. Here, we outline our collective vision for what we can achieve within a decade with properly targeted efforts and discuss likely technological deliverables and neuroscience progress.
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http://dx.doi.org/10.1016/j.neuron.2013.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864648PMC
October 2013

Co-expression profiling of autism genes in the mouse brain.

PLoS Comput Biol 2013 25;9(7):e1003128. Epub 2013 Jul 25.

MindSpec, McLean, Virginia, United States of America.

Autism spectrum disorder (ASD) is one of the most prevalent and highly heritable neurodevelopmental disorders in humans. There is significant evidence that the onset and severity of ASD is governed in part by complex genetic mechanisms affecting the normal development of the brain. To date, a number of genes have been associated with ASD. However, the temporal and spatial co-expression of these genes in the brain remain unclear. To address this issue, we examined the co-expression network of 26 autism genes from AutDB (http://mindspec.org/autdb.html), in the framework of 3,041 genes whose expression energies have the highest correlation between the coronal and sagittal images from the Allen Mouse Brain Atlas database (http://mouse.brain-map.org). These data were derived from in situ hybridization experiments conducted on male, 56-day old C57BL/6J mice co-registered to the Allen Reference Atlas, and were used to generate a normalized co-expression matrix indicating the cosine similarity between expression vectors of genes in this database. The network formed by the autism-associated genes showed a higher degree of co-expression connectivity than seen for the other genes in this dataset (Kolmogorov-Smirnov P = 5×10⁻²⁸). Using Monte Carlo simulations, we identified two cliques of co-expressed genes that were significantly enriched with autism genes (A Bonferroni corrected P<0.05). Genes in both these cliques were significantly over-expressed in the cerebellar cortex (P = 1×10⁻⁵) suggesting possible implication of this brain region in autism. In conclusion, our study provides a detailed profiling of co-expression patterns of autism genes in the mouse brain, and suggests specific brain regions and new candidate genes that could be involved in autism etiology.
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http://dx.doi.org/10.1371/journal.pcbi.1003128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723491PMC
February 2014

Digital atlas of the zebra finch (Taeniopygia guttata) brain: a high-resolution photo atlas.

J Comp Neurol 2013 Nov;521(16):3702-15

Department of Neuroscience, University of California at San Diego, La Jolla, California, 92093.

We describe a set of new comprehensive, high-quality, high-resolution digital images of histological sections from the brain of male zebra finches (Taeniopygia guttata) and make them publicly available through an interactive website (http://zebrafinch.brainarchitecture.org/). These images provide a basis for the production of a dimensionally accurate and detailed digital nonstereotaxic atlas. Nissl- and myelin-stained brain sections are provided in the transverse, sagittal, and horizontal planes, with the transverse plane approximating the more traditional Frankfurt plane. In addition, a separate set of brain sections in this same plane is stained for tyrosine hydroxylase, revealing the distribution of catecholaminergic neurons (dopaminergic, noradrenergic, and adrenergic) in the songbird brain. For a subset of sagittal sections we also prepared a corresponding set of drawings, defining and annotating various nuclei, fields, and fiber tracts that are visible under Nissl and myelin staining. This atlas of the zebra finch brain is expected to become an important tool for birdsong research and comparative studies of brain organization and evolution.
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http://dx.doi.org/10.1002/cne.23443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931548PMC
November 2013

Panoptic neuroanatomy: digital microscopy of whole brains and brain-wide circuit mapping.

Brain Behav Evol 2013 14;81(4):203-5. Epub 2013 Jun 14.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

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http://dx.doi.org/10.1159/000350241DOI Listing
March 2014

A low-cost technique to cryo-protect and freeze rodent brains, precisely aligned to stereotaxic coordinates for whole-brain cryosectioning.

J Neurosci Methods 2013 Sep 29;218(2):206-13. Epub 2013 Mar 29.

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.

A major challenge in the histological sectioning of brain tissue is achieving accurate alignment in the standard coronal, horizontal, or sagittal planes. Correct alignment is desirable for ease of subsequent analysis and is a prerequisite for computational registration and algorithm-based quantification of experimental data. We have developed a simple and low-cost technique for whole-brain cryosectioning of rodent brains that reliably results in a precise alignment of stereotactic coordinates. The system utilises a 3-D printed model of a mouse brain to create a tailored cavity that is used to align and support the brain during freezing. The alignment of the frozen block is achieved in relation to the fixed edge of the mold. The system also allows for two brains to be frozen and sectioned simultaneously. System components, procedural steps, and examples of the end results are presented.
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http://dx.doi.org/10.1016/j.jneumeth.2013.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4265468PMC
September 2013

Drug discovery in tuberculosis: a molecular approach.

Authors:
Partha P Mitra

Indian J Tuberc 2012 Oct;59(4):194-206

Research Wing, Diamantina Institute, Princess Alexandra Hospital, University of Queensland, Level 4, 20 Cornwall Street, Woolloongabba, Queensland - 4102, Australia.

Despite unquestionable success of the combination drug therapy, tuberculosis (TB) very recently has drawn major attention because of the global upsurge of MDR-TB, XDR -TB and HIV-TB co-infection cases. In the last four decades, only one compound is added to the treatment regimen leaving ample opportunities to find out a new generation of TB drugs. The modern concept of drug discovery utilizes the integrated knowledge of genomics, proteomics, molecular biology and systems biology to identify more specific targets. The purpose of this review is to revisit the field of tuberculosis drug discovery based on those new concepts to identify novel targets.
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October 2012

Computational methods and challenges for large-scale circuit mapping.

Curr Opin Neurobiol 2012 Feb 3;22(1):162-9. Epub 2012 Jan 3.

Structure of Neocortical Circuits Group, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany.

The connectivity architecture of neuronal circuits is essential to understand how brains work, yet our knowledge about the neuronal wiring diagrams remains limited and partial. Technical breakthroughs in labeling and imaging methods starting more than a century ago have advanced knowledge in the field. However, the volume of data associated with imaging a whole brain or a significant fraction thereof, with electron or light microscopy, has only recently become amenable to digital storage and analysis. A mouse brain imaged at light-microscopic resolution is about a terabyte of data, and 1mm(3) of the brain at EM resolution is about half a petabyte. This has given rise to a new field of research, computational analysis of large-scale neuroanatomical data sets, with goals that include reconstructions of the morphology of individual neurons as well as entire circuits. The problems encountered include large data management, segmentation and 3D reconstruction, computational geometry and workflow management allowing for hybrid approaches combining manual and algorithmic processing. Here we review this growing field of neuronal data analysis with emphasis on reconstructing neurons from EM data cubes.
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http://dx.doi.org/10.1016/j.conb.2011.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406305PMC
February 2012

Chronux: a platform for analyzing neural signals.

J Neurosci Methods 2010 Sep 15;192(1):146-51. Epub 2010 Jul 15.

Medametrics LLC, 42 West 24th Street, New York, NY 10010, United States.

Chronux is an open-source software package developed for the analysis of neural data. The current version of Chronux includes software for signal processing of neural time-series data including several specialized mini-packages for spike-sorting, local regression, audio segmentation, and other data-analysis tasks typically encountered by a neuroscientist. Chronux is freely available along with user tutorials, sample data, and extensive documentation from http://chronux.org/.
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http://dx.doi.org/10.1016/j.jneumeth.2010.06.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2934871PMC
September 2010

An assay for social interaction in Drosophila fragile X mutants.

Fly (Austin) 2010 Jul-Sep;4(3):216-25. Epub 2010 Jul 1.

Watson School of Biological Sciences, Cold Spring Harbor, NY, USA.

We developed a novel assay to examine social interactions in Drosophila and, as a first attempt, apply it here at examining the behavior of Drosophila Fragile X Mental Retardation gene (dfmr1) mutants. Fragile X syndrome is the most common cause of single gene intellectual disability (ID) and is frequently associated with autism. Our results suggest that dfmr1 mutants are less active than wild-type flies and interact with each other less often. In addition, mutants for one allele of dfmr1, dfmr1(B55), are more likely to come in close contact with a wild-type fly than another dfmr1(B55) mutant. Our results raise the possibility of defective social expression with preserved receptive abilities. We further suggest that the assay may be applied in a general strategy of examining endophenoypes of complex human neurological disorders in Drosophila, and specifically in order to understand the genetic basis of social interaction defects linked with ID.
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http://dx.doi.org/10.4161/fly.4.3.12280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322501PMC
February 2014