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1.  Neuronal Populations in the Basolateral Nuclei of the Amygdala Are Differentially Increased in Humans Compared With Apes: A Stereological Study 
The Journal of comparative neurology  2012;520(13):3035-3054.
In human and nonhuman primates, the amygdala is known to play critical roles in emotional and social behavior. Anatomically, individual amygdaloid nuclei are connected with many neural systems that are either differentially expanded or conserved over the course of primate evolution. To address amygdala evolution in humans and our closest living relatives, the apes, we used design-based stereological methods to obtain neuron counts for the amygdala and each of four major amygdaloid nuclei (the lateral, basal, accessory basal, and central nuclei) in humans, all great ape species, lesser apes, and one monkey species. Our goal was to determine whether there were significant differences in the number or percent of neurons distributed to individual nuclei among species. Additionally, regression analyses were performed on independent contrast data to determine whether any individual species deviated from allometric trends. There were two major findings. In humans, the lateral nucleus contained the highest number of neurons in the amygdala, whereas in apes the basal nucleus contained the highest number of neurons. Additionally, the human lateral nucleus contained 59% more neurons than predicted by allometric regressions on nonhuman primate data. Based on the largest sample ever analyzed in a comparative study of the hominoid amygdala, our findings suggest that an emphasis on the lateral nucleus is the main characteristic of amygdala specialization over the course of human evolution.
PMCID: PMC4904735  PMID: 22473387
amygdala; comparative neuroanatomy; human evolution; lateral nucleus; ape; stereology
2.  Shallow Encoding and Forgetting Are Associated with Dependence in Instrumental Activities of Daily Living Among Older Adults Living with HIV Infection 
Aging and HIV are both risk factors for memory deficits and declines in real-world functioning. However, we know little about the profile of memory deficits driving instrumental activities of daily living (IADL) declines across the lifespan in HIV. This study examined 145 younger (<50 years) and 119 older (≥50 years) adults with HIV who completed the California Verbal Learning Test-Second Edition (CVLT-II), the Wechsler Memory Scale-Third Edition Logical Memory subtest (WMS-III LM), and a modified Lawton and Brody ADL questionnaire. No memory predictors of IADL dependence emerged in the younger cohort. In the older group, IADL dependence was uniquely associated with worse performance on all primary CVLT-II variables, as well as elevated recency effects. Poorer immediate and delayed recall of the WMS-III LM was also associated with IADL dependence, although recognition was intact. Findings suggest older HIV-infected adults with shallow encoding and forgetting are at risk for IADL dependence.
PMCID: PMC4000232  PMID: 24695591
Aging; Disability; Everyday functioning; Learning and memory
3.  Cortical Mapping by Magnetic Resonance Imaging (MRI) and Quantitative Cytological Analysis in the Human Brain: A Feasibility Study in the Fusiform Gyrus 
The cerebral cortex is a layered cellular structure that is tangentially organized into a mosaic of anatomically and functionally distinct fields. In spite of centuries of investigation, the precise localization and classification of many areas in the cerebral cortex remain problematic because the relationship between functional specificity and intra-cortical structure has not been firmly established. Furthermore, it is not yet clear how surface landmarks, visible through gross examination and, more recently, using non-invasive magnetic resonance imaging (MRI), relate to underlying microstructural borders and to the topography of functional activation.
We have designed a multi-modal neuroimaging protocol that combines MRI and quantitative microscopic analysis in the same individual to clarify the topography of cytoarchitecture underlying gross anatomical landmarks in the cerebral cortex. We tested our approach in the region of the fusiform gyrus (FG), because in spite of its seemingly smooth appearance on the ventral aspect of both hemispheres, this structure houses many functionally defined areas whose histological borders remain unclear. In practice, we used MRI-based automated segmentation to define the region of interest from which we could then collect quantitative histological data (specifically, neuronal size and density). A modified stereological approach was used to sample the cortex within the FG without a priori assumptions on the location of architectonic boundaries. The results of these analyses illustrate architectonic variations along the FG and demonstrate that it is possible to correlate quantitative histological data to measures that are obtained in the context of large-scale, non-invasive MRI-based population studies.
PMCID: PMC3708974  PMID: 23628159
histology; temporal lobe; visual cortex; cerebral cortex; brain mapping
4.  Automated Determination of Axonal Orientation in the Deep White Matter of the Human Brain 
Brain Connectivity  2012;2(5):284-290.
The wide-spread utilization of diffusion-weighted imaging in the clinical neurosciences to assess white-matter (WM) integrity and architecture calls for robust validation strategies applied to the data that are acquired with noninvasive imaging. However, the pathology and detailed fiber architecture of WM tissue can only be observed postmortem. With these considerations in mind, we designed an automated method for the determination of axonal orientation in high-resolution microscope images. The algorithm was tested on tissue that was stained using a silver impregnation technique that was optimized to resolve axonal fibers against very low levels of background. The orientation of individual nerve fibers was detected using spatial filtering and a template-matching algorithm, and the results are displayed as color-coded overlays. Quantitative models of WM fiber architecture at the microscopic level can lead to improved interpretation of low-resolution neuroimaging data and to more accurate mapping of fiber pathways in the human brain.
PMCID: PMC3621296  PMID: 23030312
anatomical connectivity; axonal fiber; Fourier transform; human brain connectivity; white matter
5.  Quantification of anisotropy and fiber orientation in human brain histological sections 
Diffusion weighted imaging (DWI) has provided unparalleled insight into the microscopic structure and organization of the central nervous system. Diffusion tensor imaging (DTI) and other models of the diffusion MRI signal extract microstructural properties of tissues with relevance to the normal and injured brain. Despite the prevalence of such techniques and applications, accurate and large-scale validation has proven difficult, particularly in the human brain. In this report, human brain sections obtained from a digital public brain bank were employed to quantify anisotropy and fiber orientation using structure tensor analysis. The derived maps depict the intricate complexity of white matter fibers at a resolution not attainable with current DWI experiments. Moreover, the effects of multiple fiber bundles (i.e., crossing fibers) and intravoxel fiber dispersion were demonstrated. Examination of the cortex and hippocampal regions validated-specific features of previous in vivo and ex vivo DTI studies of the human brain. Despite the limitation to two dimensions, the resulting images provide a unique depiction of white matter organization at resolutions currently unattainable with DWI. The method of analysis may be used to validate tissue properties derived from DTI and alternative models of the diffusion signal.
PMCID: PMC3561729  PMID: 23378830
anisotropy; diffusion tensor imaging; structure tensor; crossing fibers; histology; fiber orientation
6.  Are Time- and Event-based Prospective Memory Comparably Affected in HIV Infection?† 
According to the multi-process theory of prospective memory (ProM), time-based tasks rely more heavily on strategic processes dependent on prefrontal systems than do event-based tasks. Given the prominent frontostriatal pathophysiology of HIV infection, one would expect HIV-infected individuals to demonstrate greater deficits in time-based versus event-based ProM. However, the two prior studies examining this question have produced variable results. We evaluated this hypothesis in 143 individuals with HIV infection and 43 demographically similar seronegative adults (HIV−) who completed the research version of the Memory for Intentions Screening Test, which yields parallel subscales of time- and event-based ProM. Results showed main effects of HIV serostatus and cue type, but no interaction between serostatus and cue. Planned pair-wise comparisons showed a significant effect of HIV on time-based ProM and a trend-level effect on event-based ProM that was driven primarily by the subset of participants with HIV-associated neurocognitive disorders. Nevertheless, time-based ProM was more strongly correlated with measures of executive functions, attention/working memory, and verbal fluency in HIV-infected persons. Although HIV-associated deficits in time- and event-based ProM appear to be of comparable severity, the cognitive architecture of time-based ProM may be more strongly influenced by strategic monitoring and retrieval processes.
PMCID: PMC3081684  PMID: 21459901
AIDS dementia complex; Episodic memory; Executive functions; Neuropsychological assessment
7.  The importance of combining MRI and large-scale digital histology in neuroimaging studies of brain connectivity and disease 
One of the major issues hindering a comprehensive connectivity model for the human brain is the difficulty in linking Magnetic Resonance Imaging (MRI) measurements to anatomical evidence produced by histological methods. In vivo and postmortem neuroimaging methodologies are still largely incompatible in terms of sample size, scale, and resolution. To help bridge the hiatus between different approaches we have established a program that characterizes the brain of individual subjects, combining MRI with postmortem neuroanatomy. The direct correlation of MRI and histological features is possible, because registered images from different modalities represent the same regions in the same brain. Comparisons are also facilitated by large-scale, digital microscopy techniques that afford images of the whole-brain sections at cellular resolution. The goal is to create a neuroimaging catalog representative of discrete age groups and specific neurological conditions. Individually, the datasets allow for investigating the relationship between different modalities; combined, they provide sufficient predictive power to inform analyses and interpretations made in the context of non-invasive studies of brain connectivity and disease.
PMCID: PMC3334523  PMID: 22536182
histology; MRI; DTI; fibers; pathology; connectivity; human; brain
8.  Postmortem examination of patient H.M.’s brain based on histological sectioning and digital 3D reconstruction 
Nature Communications  2014;5:3122.
Modern scientific knowledge of how memory functions are organized in the human brain originated from the case of Henry G. Molaison (H.M.), an epileptic patient whose amnesia ensued unexpectedly following a bilateral surgical ablation of medial temporal lobe structures, including the hippocampus. The neuroanatomical extent of the 1953 operation could not be assessed definitively during H.M.’s life. Here we describe the results of a procedure designed to reconstruct a microscopic anatomical model of the whole brain and conduct detailed 3D measurements in the medial temporal lobe region. This approach, combined with cellular-level imaging of stained histological slices, demonstrates a significant amount of residual hippocampal tissue with distinctive cytoarchitecture. Our study also reveals diffuse pathology in the deep white matter and a small, circumscribed lesion in the left orbitofrontal cortex. The findings constitute new evidence that may help elucidate the consequences of H.M.’s operation in the context of the brain’s overall pathology.
Studies on Patient H.M. showed that bilateral resection of the hippocampus results in impaired consolidation of long-term memory. Annese et al. create a digital map of Henry Molaison’s brain and find that a significant portion of the posterior hippocampus is actually histologically intact.
PMCID: PMC3916843  PMID: 24473151

Results 1-8 (8)