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      Postmortem examination of patient H.M.’s brain based on histological sectioning and digital 3D reconstruction

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          Abstract

          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.

          Abstract

          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.

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          Most cited references40

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          The cognitive neuroscience of human memory since H.M.

          Work with patient H.M., beginning in the 1950s, established key principles about the organization of memory that inspired decades of experimental work. Since H.M., the study of human memory and its disorders has continued to yield new insights and to improve understanding of the structure and organization of memory. Here we review this work with emphasis on the neuroanatomy of medial temporal lobe and diencephalic structures important for memory, multiple memory systems, visual perception, immediate memory, memory consolidation, the locus of long-term memory storage, the concepts of recollection and familiarity, and the question of how different medial temporal lobe structures may contribute differently to memory functions.
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            Preserved learning and retention of pattern-analyzing skill in amnesia: dissociation of knowing how and knowing that

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              Unbiased stereological estimation of the number of neurons in the human hippocampus.

              The total numbers of neurons in five subdivisions of human hippocampi were estimated using unbiased stereological principles and systematic sampling techniques. The method addresses the problems associated with the results and conclusions of previous quantitative studies, virtually all of which have been based on biased estimates of neuron densities. For each subdivision, the total number of neurons was calculated as the product of the estimate of the volume of the neuron-containing layers and the estimate of the numerical density of neurons in the layers. Each hippocampus was cut into 3-mm-thick slabs, transverse to the rostrocaudal axis. One 70-micron-thick section from each slab was used in the analysis. The volumes of the layers containing neurons in five major subdivisions of the hippocampus (granule cell layer, hilus, CA3-2, CA1, and subiculum) were estimated with point-counting techniques after delineation of the layers on each section. The numerical densities of neurons in each subdivision were estimated on the same sections with optical disectors. The sampling used in both estimates was performed systematically in all three dimensions. In an example of five hippocampi, the mean numbers of neurons (CV = SD/mean) in the different subdivisions were as follows: granule cells 15 X 10(6) (0.28), hilus 2.0 X 10(6) (0.16), CA3-2 2.7 X 10(6) (0.22), CA1 16 X 10(6) (0.32), subiculum 4.5 X 10(6) (0.19). The stereological measurements contributed approximately 25% of the observed variance. Among the five subjects there was a significant inverse relationship between age (which ranged from 47 to 85 years) and the total number of neurons in CA1 (which ranged from 24 to 11 X 10(6)). An optimized sampling scheme for studies of the number of neurons in the human hippocampus has been designed on the basis of an analysis of variance of the estimates at different levels of the sampling scheme. Counting neurons in the five subdivisions of the human hippocampus with the optimized sampling scheme takes less than 4 hours.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Pub. Group
                2041-1723
                28 January 2014
                : 5
                : 3122
                Affiliations
                [1 ]The Brain Observatory , San Diego, California 92101, USA
                [2 ]Department of Radiology, University of California San Diego , San Diego, California 92093, USA
                [3 ]C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital and Harvard Medical School , Massachusetts 02114, USA
                [4 ]Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology , Massachusetts 02139, USA
                [5 ]These authors contributed equally to this work
                Author notes
                Article
                ncomms4122
                10.1038/ncomms4122
                3916843
                24473151
                a3d13d2c-d944-48f2-86c5-e4bc11d21df7
                Copyright © 2014, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 13 October 2013
                : 16 December 2013
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