Robert S.C. Amaral

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.

A harmonized segmentation protocol for hippocampal and parahippocampal subregions : why do we need one and what are the key goals?

The advent of high‐resolution magnetic resonance imaging (MRI) has enabled in vivo research in a variety of populations and diseases on the structure and function of hippocampal subfields and subdivisions of the parahippocampal gyrus. Because of the many extant and highly discrepant segmentation protocols, comparing results across studies is difficult. To overcome this barrier, the Hippocampal Subfields Group was formed as an international collaboration with the aim of developing a harmonized protocol for manual segmentation of hippocampal and parahippocampal subregions on high‐resolution MRI. In this commentary we discuss the goals for this protocol and the associated key challenges involved in its development. These include differences among existing anatomical reference materials, striking the right balance between reliability of measurements and anatomical validity, and the development of a versatile protocol that can be adopted for the study of populations varying in age and health. The commentary outlines these key challenges, as well as the proposed solution of each, with concrete examples from our working plan. Finally, with two examples, we illustrate how the harmonized protocol, once completed, is expected to impact the field by producing measurements that are quantitatively comparable across labs and by facilitating the synthesis of findings across different studies.

KIBRA Polymorphism Is Associated with Individual Differences in Hippocampal Subregions: Evidence from Anatomical Segmentation using High-Resolution MRI

The KIBRA gene has been associated with episodic memory in several recent reports; carriers of the T-allele show enhanced episodic memory performance relative to noncarriers. Gene expression studies in human and rodent species show high levels of KIBRA in the hippocampus, particularly in the subfields. The goal of the present study was to determine whether the KIBRA C→T polymorphism is also associated with volume differences in the human hippocampus and whether specific subfields are differentially affected by KIBRA genotype. High-resolution magnetic resonance imaging (T2-weighted, voxel size = 0.4 × 0.4 mm, in-plane) was used to manually segment hippocampal cornu ammonis (CA) subfields, dentate gyrus (DG), and the subiculum as well as adjacent medial temporal lobe cortices in healthy carriers and noncarriers of the KIBRA T-allele (rs17070145). Overall, we found that T-carriers had a larger hippocampal volume relative to noncarriers. The structural differences observed were specific to the CA fields and DG regions of the hippocampus, suggesting a potential neural mechanism for the effects of KIBRA on episodic memory performance reported previously.

Manual segmentation of the fornix, fimbria, and alveus on high-resolution 3T MRI: Application via fully-automated mapping of the human memory circuit white and grey matter in healthy and pathological aging.

ABSTRACT Recently, much attention has been focused on the definition and structure of the hippocampus and its subfields, while the projections from the hippocampus have been relatively understudied. Here, we derive a reliable protocol for manual segmentation of hippocampal white matter regions (alveus, fimbria, and fornix) using high‐resolution magnetic resonance images that are complementary to our previous definitions of the hippocampal subfields, both of which are freely available at https://github.com/cobralab/atlases. Our segmentation methods demonstrated high inter‐ and intra‐rater reliability, were validated as inputs in automated segmentation, and were used to analyze the trajectory of these regions in both healthy aging (OASIS), and Alzheimers disease (AD) and mild cognitive impairment (MCI; using ADNI). We observed significant bilateral decreases in the fornix in healthy aging while the alveus and cornu ammonis (CA) 1 were well preserved (all ps<0.006). MCI and AD demonstrated significant decreases in fimbriae and fornices. Many hippocampal subfields exhibited decreased volume in both MCI and AD, yet no significant differences were found between MCI and AD cohorts themselves. Our results suggest a neuroprotective or compensatory role for the alveus and CA1 in healthy aging and suggest that an improved understanding of the volumetric trajectories of these structures is required. HIGHLIGHTSNovel high‐resolution manual segmentation of human alveus, fimbria, and fornix.Validation (precision and accuracy) of manual atlases for use in automatic segmentation.Application of automatic segmentation on AD/MCI and healthy aging datasets.Results suggest neuroprotective role for alveus and hippocampal CA1 region.

Individual differences in visual imagery determine how event information is remembered

ABSTRACT Individuals differ in how they mentally imagine past events. When reminiscing about a past experience, some individuals remember the event accompanied by rich visual images, while others will remember it with few of these images. In spite of the implications that these differences in the use of imagery have to the understanding of human memory, few studies have taken them into consideration. We examined how imagery interference affecting event memory retrieval was differently modulated by spatial and object imagery ability. We presented participants with a series of video-clips depicting complex events. Participants subsequently answered true/false questions related to event, spatial, or feature details contained in the videos, while simultaneously viewing stimuli that interfered with visual imagery processes (dynamic visual noise; DVN) or a control grey screen. The impact of DVN on memory accuracy was related to individual differences in spatial imagery ability. Individuals high in spatial imagery were less accurate at recalling details from the videos when simultaneously viewing the DVN stimuli compared to those low in spatial imagery ability. This finding held for questions related to the event and spatial details but not feature details. This study advocates for the inclusion of individual differences when studying memory processes.

Regionally specific changes in the hippocampal circuitry accompany progression of cerebrospinal fluid biomarkers in preclinical Alzheimer's disease

Neuropathological and in vivo brain imaging studies agree that the cornu ammonis 1 and subiculum subfields of the hippocampus are most vulnerable to atrophy in the prodromal phases of Alzheimers disease (AD). However, there has been limited investigation of the structural integrity of the components of the hippocampal circuit, including subfields and extra‐hippocampal white matter structure, in relation to the progression of well‐accepted cerebrospinal fluid (CSF) biomarkers of AD, amyloid‐β 1‐42 (Aβ) and total‐tau (tau). We investigated these relationships in 88 aging asymptomatic individuals with a parental or multiple‐sibling familial history of AD. Apolipoprotein (APOE) ɛ4 risk allele carriers were identified, and all participants underwent cognitive testing, structural magnetic resonance imaging, and lumbar puncture for CSF assays of tau, phosphorylated‐tau (p‐tau) and Aβ. Individuals with a reduction in CSF Aβ levels (an indicator of amyloid accretion into neuritic plaques) as well as evident tau pathology (believed to be linked to neurodegeneration) exhibited lower subiculum volume, lower fornix microstructural integrity, and a trend towards lower cognitive score than individuals who showed only reduction in CSF Aβ. In contrast, persons with normal levels of tau showed an increase in structural MR markers in relation to declining levels of CSF Aβ. These results suggest that hippocampal subfield volume and extra‐hippocampal white matter microstructure demonstrate a complex pattern where an initial volume increase is followed by decline among asymptomatic individuals who, in some instances, may be a decade or more away from onset of cognitive or functional impairment.

Episodic autobiographical memory is associated with variation in the size of hippocampal subregions

Striking individual differences exist in the human capacity to recollect past events, yet, little is known about the neural correlates of such individual differences. Studies investigating hippocampal volume in relation to individual differences in laboratory measures of episodic memory in young adults suggest that whole hippocampal volume is unrelated (or even negatively associated) with episodic memory. However, anatomical and functional specialization across hippocampal subregions suggests that individual differences in episodic memory may be linked to particular hippocampal subregions, as opposed to whole hippocampal volume. Given that the DG/CA2/3 circuitry is thought to be especially critical for supporting episodic memory in humans, we predicted that the volume of this region would be associated with individual variability in episodic memory. This prediction was supported using high‐resolution MRI of the hippocampal subfields and measures of real‐world (autobiographical) episodic memory. In addition to the association with DG/CA2/3, we further observed a relationship between episodic autobiographical memory and subiculum volume, whereas no association was observed with CA1 or with whole hippocampal volume. These findings provide insight into the possible neural substrates that mediate individual differences in real‐world episodic remembering in humans.

A HARMONIZED PROTOCOL FOR MEDIAL TEMPORAL LOBE SUBFIELD SEGMENTATION: INITIAL RESULTS OF THE 3-TESLA PROTOCOL FOR THE HIPPOCAMPAL BODY

from humans, compared human amylin-expressing (HIP) rats (n1⁄415) with ageand glucose-matched diabetic rats expressing only endogenous non-amyloidogenic rat amylin (n1⁄415), studied mice injected with aggregated human amylin versus controls (n1⁄410 per group) and developed in vitro cell models. Results:LCMS/MS data convincingly demonstrated that amylin is contained in brain lysates from AD patients. In addition to amylin plaques and mixed amylin-ß amyloid deposits, brains of diabetic patients with AD show amylin immunoreactive deposits inside the neurons. Neuronal amylin formed adducts with 4-hydroxynonenal (4-HNE), a marker of peroxidative membrane injury, and increased (by 45% vs. control; P<0.001) synthesis of the proinflammatory cytokine interleukin (IL)-1ß. These pathological changes were mirrored in rats expressing human amylin in pancreatic islets (HIP rats) and mice intravenously injected with aggregated human amylin, but not in hyperglycemic rats secreting wild-type non-amyloidogenic rat amylin. In cultured primary hippocampal rat neurons, aggregated amylin increased IL-1ß synthesis via membrane destabilization and subsequent generation of 4-HNE. These effects were blocked by membrane stabilizers and lipid peroxidation inhibitors. Conclusions: Elevated blood levels of aggregated amylin can promote brain accumulation of amylin leading to peroxidative membrane injury and aberrant inflammatory responses independent of other confounding factors of diabetes. Present results are consistent with the pathological role of aggregated amylin in the pancreas, demonstrate a novel contributing mechanism to neurodegeneration and suggest a direct, potentially treatable link of type-2 diabetes with AD.

T172. MULTIMODAL QUANTIFICATION OF MEMORY CIRCUIT MICROSTRUCTURE IN FIRST EPISODE PSYCHOSIS

Abstract Background Integrity of hippocampal subfield structure and associated limbic circuitry subserves various memory processes, a domain that is impaired in psychosis and an important predictor of functional outcome. We use a novel atlas that encapsulates both hippocampal subfields and surrounding white matter (WM), forming the ‘memory circuit’, to assess volumes with high-resolution MRI, and microstructure with quantitative T1 (qT1). Our aims were to examine 1) group by time interactions on memory measures and the memory circuit, and 2) explore the relationships between the chosen memory measures and limbic structures, informed by results from 1), in a longitudinal sample of first episode of psychosis (FEP) patients. Methods Nineteen FEP and 20 controls with baseline and 3-month follow-up data were included. Logical Memory and Visual Reproduction Subscales of the Weschler Memory Scale, and MRI scans on a 3T scanner were collected. High-resolution T2-weighted images (0.64 mm3) were input to the MAGeT Brain algorithm to obtain volumes of hippocampal subfields and surrounding WM, defined by fimbria, alveus, fornix, and mammillary bodies. Mean qT1 values for each hippocampal subfield and WM structure were sampled from MP2RAGE (1 mm3) qT1 maps. Linear mixed models were used to assess group by time interactions on memory measures, volumes and qT1. To begin, total hippocampal volumes and WM structure for each hemisphere were examined using a Bonferroni correction for multiple comparisons, followed by post-hoc tests of individual subfields and WM structures. Linear models were then used to assess relationships between baseline memory and change in anatomical measures of interest in FEP. Models controlled for sex, education, age, and brain volume. Results Significant group by time interactions emerged on bilateral mean WM qT1 (left: F1,65=9.3, p=.003; right: F1,65=10.6, p=.002), where it was found that within the FEP group, qT1 (relaxation time in ms) increased over the 3-month follow-up period. Looking at WM structures separately, the interaction was driven by qT1 changes in fimbria, fornix, and mammillary bodies bilaterally (p’s<.05). No significant group by time interactions were found with respect to volumes or memory, although a trend-like group by time interaction on right fornix volume was found (F1,64=5.6, p-uncorrected=.02). Finally, brain-behaviour relationships were explored, restricting our anatomical measure of interest to mean qT1 values within bilateral WM. Although no tests passed correction for multiple comparisons, there was a trend association between better delayed recall of Visual Reproduction and decreases in qT1 of combined WM on the right hemisphere (F1,11=3.72, p=.08), driven by changes in qT1 of the right fornix (F1,11=4.4, p=.06). Discussion This study reveals significant microstructural changes in WM output circuitry of the hippocampus shortly after a FEP. Specifically, increases in qT1 were found within fimbria, fornix, and mammillary bodies bilaterally. Given that T1 relaxation times are typically shorter in WM, an increase in qT1 may reflect a combination of decreased myelin content and increased inflammation. Furthermore, preliminary data suggest better visual memory at baseline is associated with lower qT1 within WM microstructure over a 3-month period, suggesting that preserved non-verbal memory ability shortly after a FEP may manifest in a protective anatomical phenotype, particularly within the fornix. Given the importance of the hippocampal-fornix circuit in FEP, both with respect to memory and as a theorized hub of pathophysiology in psychosis, a better understanding of WM microstructure in relation to cognitive profiles in patients may offer a new perspective for treatment targets.