A case of severe anterograde amnesia in the era of smartphone technology.

A.V. is a young herpes simplex encephalitis (HSE) survivor who suffered extensive bilateral damage to the medial temporal lobe (MTL) leading to a severe and pervasive form of anterograde amnesia. Structural Magnetic Resonance Imaging (MRI) revealed lesions that encompass the hippocampus and amygdala in both hemispheres and that extend more laterally in the right temporal lobe. At the same time, detailed neuropsychological testing showed that the disparity between A.V.'s preserved intellectual functioning (Full Scale IQ: 115) and severe memory deficit (Delayed Memory Index: 42) is one of the largest on record. Despite this deficit, A.V. has regained a higher level of functioning and autonomy compared to previously documented amnesic cases with major bilateral MTL lesions. As a millennial, one advantage which A.V. has over prior amnesic cases is fluency with digital technology - particularly the smartphone. The analysis of his phone and specific app usage showed a pattern that is consistent with the strategy to offload cognitive tasks that would normally be supported by the MTL. A.V.'s behavior is significant in terms of rehabilitation and may have broader implications at the societal level and for public health given the ubiquity of smartphone technology and its potential to become integrated with neural mnemonic functions.

Neuropsychological and neuropathological observations of a long-studied case of memory impairment.

We report neuropsychological and neuropathological findings for a patient (A.B.), who developed memory impairment after a cardiac arrest at age 39. A.B. was a clinical psychologist who, although unable to return to work, was an active participant in our neuropsychological studies for 24 y. He exhibited a moderately severe and circumscribed impairment in the formation of long-term, declarative memory (anterograde amnesia), together with temporally graded retrograde amnesia covering ∼5 y prior to the cardiac arrest. More remote memory for both facts and autobiographical events was intact. His neuropathology was extensive and involved the medial temporal lobe, the diencephalon, cerebral cortex, basal ganglia, and cerebellum. In the hippocampal formation, there was substantial cell loss in the CA1 and CA3 fields, the hilus of the dentate gyrus (with sparing of granule cells), and the entorhinal cortex. There was also cell loss in the CA2 field, but some remnants remained. The amygdala demonstrated substantial neuronal loss, particularly in its deep nuclei. In the thalamus, there was damage and atrophy of the anterior nuclear complex, the mediodorsal nucleus, and the pulvinar. There was also loss of cells in the medial and lateral mammillary nuclei in the hypothalamus. We suggest that the neuropathology resulted from two separate factors: the initial cardiac arrest (and respiratory distress) and the recurrent seizures that followed, which led to additional damage characteristic of temporal lobe epilepsy.

Inversion recovery ultrashort echo time magnetic resonance imaging: A method for simultaneous direct detection of myelin and high signal demonstration of iron deposition in the brain - A feasibility study.

Multiple sclerosis (MS) causes demyelinating lesions in the white matter and increased iron deposition in the subcortical gray matter. Myelin protons have an extremely short T2* (<1ms) and are not directly detected with conventional clinical magnetic resonance (MR) imaging sequences. Iron deposition also reduces T2*, leading to reduced signal on clinical sequences. In this study we tested the hypothesis that the inversion recovery ultrashort echo time (IR-UTE) pulse sequence can directly and simultaneously image myelin and iron deposition using a clinical 3T scanner. The technique was first validated on a synthetic myelin phantom (myelin powder in D2O) and a Feridex iron phantom. This was followed by studies of cadaveric MS specimens, healthy volunteers and MS patients. UTE imaging of the synthetic myelin phantom showed an excellent bi-component signal decay with two populations of protons, one with a T2* of 1.2ms (residual water protons) and the other with a T2* of 290µs (myelin protons). IR-UTE imaging shows sensitivity to a wide range of iron concentrations from 0.5 to ~30mM. The IR-UTE signal from white matter of the brain of healthy volunteers shows a rapid signal decay with a short T2* of ~300µs, consistent with the T2* values of myelin protons in the synthetic myelin phantom. IR-UTE imaging in MS brain specimens and patients showed multiple white matter lesions as well as areas of high signal in subcortical gray matter. This in specimens corresponded in position to Perl's diaminobenzide staining results, consistent with increased iron deposition. IR-UTE imaging simultaneously detects lesions with myelin loss in the white matter and iron deposition in the gray matter.

Episodic memory function is affected by lifestyle factors: a 14-year follow-up study in an elderly population.

Understanding the relationship between memory function and lifestyle offers great opportunities for promoting beneficial lifestyle choices to foster healthy cognitive aging and for the development of intervention programs for older adults. We studied a cohort of older adults (age 65 and older) enrolled in the Longitudinal Aging Study Amsterdam, an ongoing prospective population-based research project. A total of 1,966 men and women participated in an episodic memory test every 3 years over a period of 14 years. Lifestyle habits were repeatedly assessed using self-report measures. Physical activity, light-to-moderate alcohol consumption, difficulties staying asleep, and social engagement were associated with better memory function over the course of 14 years. In contrast, smoking and long sleep duration were associated with worse memory function. These findings suggest that certain lifestyle factors can have long-term protective or harmful effects on memory function in aging individuals.

H.M.'s contributions to neuroscience: a review and autopsy studies.

H.M., Henry Molaison, was one of the world's most famous amnesic patients. His amnesia was caused by an experimental brain operation, bilateral medial temporal lobe resection, carried out in 1953 to relieve intractable epilepsy. He died on December 2, 2008, and that night we conducted a wide variety of in situ MRI scans in a 3 T scanner at the Massachusetts General Hospital (Mass General) Athinoula A. Martinos Center for Biomedical Imaging. For the in situ experiments, we acquired a full set of standard clinical scans, 1 mm isotropic anatomical scans, and multiple averages of 440 µm isotropic anatomical scans. The next morning, H.M.'s body was transported to the Mass General Morgue for autopsy. The photographs taken at that time provided the first documentation of H.M.'s lesions in his physical brain. After tissue fixation, we obtained ex vivo structural data at ultra-high resolution using 3 T and 7 T magnets. For the ex vivo acquisitions, the highest resolution images were 210 µm isotropic. Based on the MRI data, the anatomical areas removed during H.M.'s experimental operation were the medial temporopolar cortex, piriform cortex, virtually all of the entorhinal cortex, most of the perirhinal cortex and subiculum, the amygdala (except parts of the dorsal-most nuclei-central and medial), anterior half of the hippocampus, and the dentate gyrus (posterior head and body). The posterior parahippocampal gyrus and medial temporal stem were partially damaged. Spared medial temporal lobe tissue included the dorsal-most amygdala, the hippocampal-amygdalo-transition-area, ∼2 cm of the tail of the hippocampus, a small part of perirhinal cortex, a small portion of medial hippocampal tissue, and ∼2 cm of posterior parahippocampal gyrus. H.M.'s impact on the field of memory has been remarkable, and his contributions to neuroscience continue with a unique dataset that includes in vivo, in situ, and ex vivo high-resolution MRI.

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

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.

Microstructural organization of axons in the human corpus callosum quantified by diffusion-weighted magnetic resonance spectroscopy of N-acetylaspartate and post-mortem histology.

Diffusion-weighted magnetic resonance spectroscopy of brain metabolites offers unique access to compartment-specific microstructural information on neural tissue. Here, we investigated in detail the diffusion characteristics of the neuronal/axonal markers N-acetylaspartate + N-acetyl aspartyl glutamate (tNAA) in a small region of the human corpus callosum at 7 T. The diffusion-weighted spectroscopy data were analyzed by fitting to a model in which information about cross-callosal tract orientation within the spectroscopy volume, obtained from diffusion tensor imaging data, was incorporated. We estimated the microscopic misalignment of axons (σ φ  = 18.6° ± 3.0°) in excellent agreement with independent histological results (σ φ  = 18.1° ± 4.6°) obtained from microscopic analysis of axonal orientations in the body of the corpus callosum from post-mortem human brain slices. We also robustly quantified the diffusion coefficient of tNAA (0.51 ± 0.06 × 10(-3) mm(2)/s) in axonal cytoplasm, unbiased by the tract curvature. This work supports the notion that microscopic axonal misalignment is a dominant microstructural property in white matter tracts and has a strong impact on the evaluation of tissue microstructure using diffusion information, and should therefore be taken into consideration in the evaluation of white matter microstructure. Additionally, this study enabled robust and unbiased assessment of the cytosolic diffusion coefficient of tNAA, a potential biomarker for axonopathy and neuronal degeneration.

Quantitative examination of the bottlenose dolphin cerebellum.

Neuroanatomical research into the brain of the bottlenose dolphin (Tursiops truncatus) has revealed striking similarities with the human brain in terms of size and complexity. However, the dolphin brain also contains unique allometric relationships. When compared to the human brain, the dolphin cerebellum is noticeably larger. Upon closer examination, the lobule composition of the cerebellum is distinct between the two species. In this study, we used magnetic resonance imaging to analyze cerebellar anatomy in the bottlenose dolphin and measure the volume of the separate cerebellar lobules in the bottlenose dolphin and human. Lobule identification was assisted by three-dimensional modeling. We find that lobules VI, VIIb, VIII, and IX are the largest lobules of the bottlenose dolphin cerebellum, while the anterior lobe (I-V), crus I, crus II, and the flocculonodular lobe are smaller. Different lobule sizes may have functional implications. Auditory-associated lobules VIIb, VIII, IX are likely large in the bottlenose dolphin due to echolocation abilities. Our study provides quantitative information on cerebellar anatomy that substantiates previous reports based on gross observation and subjective analysis. This study is part of a continuing effort toward providing explicit descriptions of cetacean neuroanatomy to support the interpretation of behavioral studies on cetacean cognition.

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.

Human amnesia and the medial temporal lobe illuminated by neuropsychological and neurohistological findings for patient E.P.

We present neurohistological information for a case of bilateral, symmetrical damage to the medial temporal lobe and well-documented memory impairment. E.P. developed profound memory impairment at age 70 y and then was studied for 14 y He had no capacity for learning facts and events and had retrograde amnesia covering several decades. He also had a modest impairment of semantic knowledge. Neurohistological analysis revealed bilaterally symmetrical lesions of the medial temporal lobe that eliminated the temporal pole, the amygdala, the entorhinal cortex, the hippocampus, the perirhinal cortex, and rostral parahippocampal cortex. The lesion also extended laterally to involve the fusiform gyrus substantially. Last, the superior, inferior, and middle temporal gyri were atrophic, and subjacent white matter was gliotic. Several considerations indicate that E.P.'s severe memory impairment was caused by his medial temporal lesions, whereas his impaired semantic knowledge was caused by lateral temporal damage. His lateral temporal damage also may have contributed to his extensive retrograde amnesia. The findings illuminate the anatomical relationship between memory, perception, and semantic knowledge.

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.

Automated determination of axonal orientation in the deep white matter of the human brain.

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.

Neuronal populations in the basolateral nuclei of the amygdala are differentially increased in humans compared with apes: a stereological study.

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.

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 analyzes and interpretations made in the context of non-invasive studies of brain connectivity and disease.

A scalable visualization environment for the correlation of radiological and histopathological data at multiple levels of resolution.

Until the introduction of non-invasive imaging techniques, the representation of anatomy and pathology relied solely on gross dissection and histological staining. Computerized Tomography (CT) and Magnetic Resonance Imaging (MRI) protocols allow for the clinical evaluation of anatomical images derived from complementary modalities, thereby increasing reliability of the diagnosis and the prognosis of disease. Despite the significant improvements in image contrast and resolution of MRI, autopsy and classical histopathological analysis are still indispensable for the correct diagnosis of specific disease. It is therefore important to be able to correlate multiple images from different modalities, in vivo and postmortem, in order to validate non-invasive imaging markers of disease. To that effect, we have developed a methodological pipeline and a visualization environment that allow for the concurrent observation of both macroscopic and microscopic image data relative to the same patient. We describe these applications and sample data relative to the study of the anatomy and disease of the Central Nervous System (CNS). The brain is approached as an organ with a complex 3-dimensional (3-D) architecture that can only be effectively studied combining observation and analysis at the system level as well as at the cellular level. Our computational and visualization environment allows seamless navigation through multiple layers of neurological data that are accessible quickly and simultaneously.

Anatomical methods for voxelation of the mammalian brain.

Voxelation allows high-throughput acquisition of three-dimensional gene expression patterns in the brain through analysis of spatially registered voxels (cubes). The method results in multiple volumetric maps of gene expression analogous to the images reconstructed in biomedical imaging techniques. An important issue for voxelation is the development of approaches to anchor correctly harvested voxels to the underlying anatomy. Here, we describe experiments to identify fixation and cryopreservation protocols for improved registration of harvested voxels with neuroanatomical structures. Paraformaldehyde fixation greatly reduced RNA recovery as judged by ribosomal RNA abundance. However, gene expression signals from paraformaldehyde-fixed samples were not appreciably diminished as judged by average signal-noise ratios from microarrays, highlighting the difficulties of accurate quantitation of cross-linked RNA. Additional use of cryoprotection helped to improve further RNA recovery and signal from fixed tissue. It appears that the best protocol to provide the necessary resolution of neuroanatomical information in voxelation entails a controlled dose of fixation and thorough cryoprotection, complemented by histological staining.