Michael Zeineh

A Dissociation of Encoding and Retrieval Processes in the Human Hippocampus

The hippocampal formation performs two related but distinct memory functions: encoding of novel information and retrieval of episodes. Little evidence, however, resolves how these two processes are implemented within the same anatomical structure. Here we use high-resolution functional magnetic resonance imaging to show that distinct subregions of the hippocampus are differentially involved in encoding and retrieval. We found that regions early in the hippocampal circuit (dentate gyrus and CA fields 2 and 3) were selectively active during episodic memory formation, whereas a region later in the circuit (the subiculum) was active during the recollection of the learning episode. Different components of the hippocampal circuit likely contribute to different degrees to the two basic memory functions.

Rapid and effective correction of rf inhomogeneity for high field magnetic resonance imaging

The well‐known variability in the distribution of high frequency electromagnetic fields in the human body causes problems in the analysis of structural information in high field magnetic resonance images. We describe a method of compensating for the purely intensity‐based effects. In our simple and rapid correction algorithm, we first use statistical means to determine the background image noise level and the edges of the image features. We next populate all “noise” pixels with the mean signal intensity of the image features. These data are then smoothed by convolution with a gaussian filter using Fourier methods. Finally, the original data that are above the noise level are normalized to the smoothed images, thereby eliminating the lowest spatial frequencies in the final, corrected data. Processing of a 124 slice, 256 × 256 volume dataset requires under 70 sec on a laptop personal computer. Overall, the method is less prone to artifacts from edges or from sensitivity to absolute head position than are other correction techniques. Following intensity correction, the images demonstrated obvious qualitative improvement and, when subjected to automated segmentation tools, the accuracy of segmentation improved, in one example, from 35.3% to 84.7% correct, as compared to a manually‐constructed gold standard. Hum. Brain Mapping 10:204–211, 2000.

Reduced cortical thickness in hippocampal subregions among cognitively normal apolipoprotein E e4 carriers.

Our objective was to investigate whether asymptomatic carriers of apolipoprotein E epsilon4 [APOE-4] demonstrate pathological differences and atrophy in medial temporal lobe (MTL) subregions. We measured cortical thickness and volume in MTL subregions (hippocampal CA fields 1, 2 and 3; dentate gyrus; entorhinal cortex; subiculum; perirhinal cortex; parahippocampal cortex; and fusiform gyrus) using a high-resolution in-plane (0.4x0.4 mm) MRI sequence in 30 cognitively normal volunteers (14 APOE-4 carriers, 16 non-carriers, mean age 57 years). A cortical unfolding procedure maximized the visibility of this convoluted cortex, providing cortical ribbon thickness measures throughout individual subregions of the hippocampus and surrounding cortex. APOE-4 carriers had reduced cortical thickness compared with non-carriers in entorhinal cortex (ERC) and the subiculum (Sub), but not in the main hippocampal body or perirhinal cortex. Average cortical thickness was 14.8% lower (p=1.0e(- 6)) for ERC and 12.6% lower (p=6.8e(- 5)) for Sub in APOE-4 carriers. Standard volumetric measures of the same regions showed similar, but non-significant trends. Cognitively intact carriers of APOE-4 show regionally specific thinning of the cortical ribbon compared to APOE-3 carriers; cortical thickness may be a more sensitive measure of pathological differences in genetic risk subjects than standard volumetry.

Quantitative comparison of 21 protocols for labeling hippocampal subfields and parahippocampal subregions in in vivo MRI: Towards a harmonized segmentation protocol

OBJECTIVE An increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1-3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol. METHOD MRI scans of a single healthy adult human subject were acquired both at 3 T and 7 T. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement. RESULTS The differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail. CONCLUSIONS The combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies.

Hippocampal CA1 apical neuropil atrophy and memory performance in Alzheimer's disease

Memory loss is often the first and most prominent symptom of Alzheimers disease (AD), coinciding with the spread of neurofibrillary pathology from the entorhinal cortex (ERC) to the hippocampus. The apical dendrites of hippocampal CA1 pyramidal neurons, in the stratum radiatum/stratum lacunosum-moleculare (SRLM), are among the earliest targets of this pathology, and atrophy of the CA1-SRLM is apparent in postmortem tissue from patients with mild AD. We previously demonstrated that CA1-SRLM thinning is also apparent in vivo, using ultra-high field 7-Tesla (7T) MRI to obtain high-resolution hippocampal microstructural imaging. Here, we hypothesized that CA1-SRLM thickness would correlate with episodic memory performance among patients with mild AD. We scanned nine patients, using an oblique coronal T2-weighted sequence through the hippocampal body with an in-plane resolution of 220 μm, allowing direct visual identification of subfields - dentate gyrus (DG)/CA3, CA2, CA1, and ERC - and hippocampal strata - SRLM and stratum pyramidale (SP). We present a novel semi-automated method of measuring stratal width that correlated well with manual measurements. We performed multi-domain neuropsychological evaluations that included three tests of episodic memory, yielding composite scores for immediate recall, delayed recall, and delayed recognition memory. Strong correlations occurred between delayed recall performance and the widths of CA1-SRLM (r(2)=0.69; p=0.005), CA1-SP (r(2)=0.5; p=0.034), and ERC (r(2)=0.62; p=0.012). The correlation between CA1-SRLM width and delayed recall lateralized to the left hemisphere. DG/CA3 size did not correlate significantly with any aspect of memory performance. These findings highlight a role for 7T hippocampal microstructural imaging in revealing focal structural pathology that correlates with the central cognitive feature of AD.

Unfolding the human hippocampus with high resolution structural and functional MRI

The hippocampus is a region of the brain that is crucial to memory function. Functional neuroimaging allows for the noninvasive investigation of the neurophysiology of human memory by observing changes in blood flow in the brain. We have developed a technique that employs high‐resolution functional magnetic resonance imaging (fMRI) in combination with cortical unfolding to provide activation maps of the hippocampal region that surpass in anatomic and functional detail other methods of in vivo human brain mapping of the medial temporal lobe. We explain the principles behind this method and illustrate its application to a novelty‐encoding paradigm. Anat Rec (New Anat) 265:111–120, 2001.

Deficient MWF mapping in multiple sclerosis using 3D whole-brain multi-component relaxation MRI.

Recent multiple sclerosis (MS) MRI research has highlighted the need to move beyond the lesion-centric view and to develop and validate new MR imaging strategies that quantify the invisible burden of disease in the brain and establish much more sensitive and specific surrogate markers of clinical disability. One of the most promising of such measures is myelin-selective MRI that allows the acquisition of myelin water fraction (MWF) maps, a parameter that is correlated to brain white matter (WM) myelination. The aim of our study was to apply the newest myelin-selective MRI method, multi-component Driven Equilibrium Single Pulse Observation of T1 and T2 (mcDESPOT) in a controlled clinical MS pilot trial. This study was designed to assess the capabilities of this new method to explain differences in disease course and degree of disability in subjects spanning a broad spectrum of MS disease severity. The whole-brain isotropically-resolved 3D acquisition capability of mcDESPOT allowed for the first time the registration of 3D MWF maps to standard space, and consequently a formalized voxel-based analysis of the data. This approach combined with image segmentation further allowed the derivation of new measures of MWF deficiency: total deficient MWF volume (DV) in WM, in WM lesions, in diffusely abnormal white matter and in normal appearing white matter (NAWM). Deficient MWF volume fraction (DVF) was derived from each of these by dividing by the corresponding region volume. Our results confirm that lesion burden does not correlate well with clinical disease activity measured with the extended disability status scale (EDSS) in MS patients. In contrast, our measurements of DVF in NAWM correlated significantly with the EDSS score (R2=0.37; p<0.001). The same quantity discriminated clinically isolated syndrome patients from a normal control population (p<0.001) and discriminated relapsing-remitting from secondary-progressive patients (p<0.05); hence this new technique may sense early disease-related myelin loss and transitions to progressive disease. Multivariate analysis revealed that global atrophy, mean whole-brain myelin water fraction and white matter atrophy were the three most important image-derived parameters for predicting clinical disability (EDSS). Overall, our results demonstrate that mcDESPOT-defined measurements in NAWM show great promise as imaging markers of global clinical disease activity in MS. Further investigation will determine if this measure can serve as a risk factor for the conversion into definite MS and for the secondary transition into irreversible disease progression.

Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease.

Although amyloid plaques and neurofibrillary pathology play important roles in Alzheimer disease (AD), our understanding of AD is incomplete, and the contribution of microglia and iron to neurodegeneration is unknown. High-field magnetic resonance imaging (MRI) is exquisitely sensitive to microscopic iron. To explore iron-associated neuroinflammatory AD pathology, we studied AD and control human brain specimens by (1) performing ultra-high resolution ex vivo 7 Tesla MRI, (2) coregistering the MRI with successive histologic staining for iron, microglia, amyloid beta, and tau, and (3) quantifying the relationship between magnetic resonance signal intensity and histological staining. In AD, we identified numerous small MR hypointensities primarily within the subiculum that were best explained by the combination of microscopic iron and activated microglia (p = 0.025), in contradistinction to the relatively lesser contribution of tau or amyloid. Neuropathologically, this suggests that microglial-mediated neurodegeneration may occur in the hippocampal formation in AD and is detectable by ultra-high resolution MRI.

Ultra-high resolution diffusion tensor imaging of the microscopic pathways of the medial temporal lobe ☆

Diseases involving the medial temporal lobes (MTL) such as Alzheimers disease and mesial temporal sclerosis pose an ongoing diagnostic challenge because of the difficulty in identifying conclusive imaging features, particularly in pre-clinical states. Abnormal neuronal connectivity may be present in the circuitry of the MTL, but current techniques cannot reliably detect those abnormalities. Diffusion tensor imaging (DTI) has shown promise in defining putative abnormalities in connectivity, but DTI studies of the MTL performed to date have shown neither dramatic nor consistent differences across patient populations. Conventional DTI methodology provides an inadequate depiction of the complex microanatomy present in the medial temporal lobe because of a typically employed low isotropic resolution of 2.0-2.5 mm, a low signal-to-noise ratio (SNR), and echo-planar imaging (EPI) geometric distortions that are exacerbated by the inhomogeneous magnetic environment at the skull base. In this study, we pushed the resolving power of DTI to near-mm isotropic voxel size to achieve a detailed depiction of mesial temporal microstructure at 3 T. High image fidelity and SNR at this resolution are achieved through several mechanisms: (1) acquiring multiple repetitions of the minimum field of view required for hippocampal coverage to boost SNR; (2) utilizing a single-refocused diffusion preparation to enhance SNR further; (3) performing a phase correction to reduce Rician noise; (4) minimizing distortion and maintaining left-right distortion symmetry with axial-plane parallel imaging; and (5) retaining anatomical and quantitative accuracy through the use of motion correction coupled with a higher-order eddy-current correction scheme. We combined this high-resolution methodology with a detailed segmentation of the MTL to identify tracks in all subjects that may represent the major pathways of the MTL, including the perforant pathway. Tractography performed on a subset of the data identified similar tracks, although they were lesser in number. This detailed analysis of MTL substructure may have applications to clinical populations.

Shared Vulnerability of Two Synaptically-Connected Medial Temporal Lobe Areas to Age and Cognitive Decline: A Seven Tesla Magnetic Resonance Imaging Study

The medial temporal lobe (MTL) is the first brain area to succumb to neurofibrillary tau pathology in Alzheimers disease (AD). Postmortem human tissue evaluation suggests that this pathology propagates in an ordered manner, with the entorhinal cortex (ERC) and then CA1 stratum radiatum and stratum lacunosum-moleculare (CA1–SRLM)—two monosynaptically connected structures—exhibiting selective damage. Here, we hypothesized that, if ERC and CA1–SRLM share an early vulnerability to AD pathology, then atrophy should occur in a proportional manner between the two structures. We tested this hypothesis in living humans, using ultra-high field 7.0 T MRI to make fine measurements of MTL microstructure. Among a pool of age-matched healthy controls and patients with amnestic mild cognitive impairment and mild AD, we found a significant correlation between ERC and CA1–SRLM size that could not be explained by global atrophy affecting the MTL. Of the various structures that contribute axons or dendrites into the CA1–SRLM neuropil, only ERC emerged as a significant predictor of CA1–SRLM size in a linear regression analysis. In contrast, other synaptically connected elements of the MTL did not exhibit size correlations. CA1–SRLM and ERC structural covariance was significant for older controls and not patients, whereas the opposite pattern emerged for a correlation between CA1–SRLM and episodic memory performance. Interestingly, CA1–SRLM and ERC were the only MTL structures to atrophy in older controls relative to a younger comparison group. Together, these findings suggest that ERC and CA1–SRLM share vulnerability to both age and AD-associated atrophy.