David Berron

Functional subregions of the human entorhinal cortex

The entorhinal cortex (EC) is the primary site of interactions between the neocortex and hippocampus. Studies in rodents and nonhuman primates suggest that EC can be divided into subregions that connect differentially with perirhinal cortex (PRC) vs parahippocampal cortex (PHC) and with hippocampal subfields along the proximo-distal axis. Here, we used high-resolution functional magnetic resonance imaging at 7 Tesla to identify functional subdivisions of the human EC. In two independent datasets, PRC showed preferential intrinsic functional connectivity with anterior-lateral EC and PHC with posterior-medial EC. These EC subregions, in turn, exhibited differential connectivity with proximal and distal subiculum. In contrast, connectivity of PRC and PHC with subiculum followed not only a proximal-distal but also an anterior-posterior gradient. Our data provide the first evidence that the human EC can be divided into functional subdivisions whose functional connectivity closely parallels the known anatomical connectivity patterns of the rodent and nonhuman primate EC. DOI: http://dx.doi.org/10.7554/eLife.06426.001

Strong Evidence for Pattern Separation in Human Dentate Gyrus.

The hippocampus is proposed to be critical in distinguishing between similar experiences by performing pattern separation computations that create orthogonalized representations for related episodes. Previous neuroimaging studies have provided indirect evidence that the dentate gyrus (DG) and CA3 hippocampal subregions support pattern separation by inferring the nature of underlying representations from the observation of novelty signals. Here, we use ultra-high-resolution fMRI at 7 T and multivariate pattern analysis to provide compelling evidence that the DG subregion specifically sustains representations of similar scenes that are less overlapping than in other hippocampal (e.g., CA3) and medial temporal lobe regions (e.g., entorhinal cortex). Further, we provide evidence that novelty signals within the DG are stimulus specific rather than generic in nature. Our study, in providing a mechanistic link between novelty signals and the underlying representations, constitutes the first demonstration that the human DG performs pattern separation. SIGNIFICANCE STATEMENT A fundamental property of an episodic memory system is the ability to minimize interference between similar episodes. The dentate gyrus (DG) subregion of the hippocampus is widely viewed to realize this function through a computation referred to as pattern separation, which creates distinct nonoverlapping neural codes for individual events. Here, we leveraged 7 T fMRI to test the hypothesis that this region supports pattern separation. Our results demonstrate that the DG supports representations of similar scenes that are less overlapping than those in neighboring subregions. The current study therefore is the first to offer compelling evidence that the human DG supports pattern separation by obtaining critical empirical data at the representational level: the level where this computation is defined.

Laminar activity in the hippocampus and entorhinal cortex related to novelty and episodic encoding

The ability to form long-term memories for novel events depends on information processing within the hippocampus (HC) and entorhinal cortex (EC). The HC–EC circuitry shows a quantitative segregation of anatomical directionality into different neuronal layers. Whereas superficial EC layers mainly project to dentate gyrus (DG), CA3 and apical CA1 layers, HC output is primarily sent from pyramidal CA1 layers and subiculum to deep EC layers. Here we utilize this directionality information by measuring encoding activity within HC/EC subregions with 7 T high resolution functional magnetic resonance imaging (fMRI). Multivariate Bayes decoding within HC/EC subregions shows that processing of novel information most strongly engages the input structures (superficial EC and DG/CA2–3), whereas subsequent memory is more dependent on activation of output regions (deep EC and pyramidal CA1). This suggests that while novelty processing is strongly related to HC–EC input pathways, the memory fate of a novel stimulus depends more on HC–EC output.

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.

Context-specific activation of hippocampus and SN/VTA by reward is related to enhanced long-term memory for embedded objects.

Highlights • We tested if a rewarding context improved memory for embedded objects.• Pattern-separation demands associated with context discrimination were manipulated.• Contextual reward improved object memory in the similar condition alone.• Improved memory was linked to context-related activation of the DG/CA3 and SN/VTA.• SN/VTA engagement may determine whether memories are improved by contextual reward.

A protocol for manual segmentation of medial temporal lobe subregions in 7 Tesla MRI

Recent advances in MRI and increasing knowledge on the characterization and anatomical variability of medial temporal lobe (MTL) anatomy have paved the way for more specific subdivisions of the MTL in humans. In addition, recent studies suggest that early changes in many neurodegenerative and neuropsychiatric diseases are better detected in smaller subregions of the MTL rather than with whole structure analyses. Here, we developed a new protocol using 7 Tesla (T) MRI incorporating novel anatomical findings for the manual segmentation of entorhinal cortex (ErC), perirhinal cortex (PrC; divided into area 35 and 36), parahippocampal cortex (PhC), and hippocampus; which includes the subfields subiculum (Sub), CA1, CA2, as well as CA3 and dentate gyrus (DG) which are separated by the endfolial pathway covering most of the long axis of the hippocampus. We provide detailed instructions alongside slice-by-slice segmentations to ease learning for the untrained but also more experienced raters. Twenty-two subjects were scanned (19–32 yrs, mean age = 26 years, 12 females) with a turbo spin echo (TSE) T2-weighted MRI sequence with high-resolution oblique coronal slices oriented orthogonal to the long axis of the hippocampus (in-plane resolution 0.44 × 0.44 mm2) and 1.0 mm slice thickness. The scans were manually delineated by two experienced raters, to assess intra- and inter-rater reliability. The Dice Similarity Index (DSI) was above 0.78 for all regions and the Intraclass Correlation Coefficients (ICC) were between 0.76 to 0.99 both for intra- and inter-rater reliability. In conclusion, this study presents a fine-grained and comprehensive segmentation protocol for MTL structures at 7 T MRI that closely follows recent knowledge from anatomical studies. More specific subdivisions (e.g. area 35 and 36 in PrC, and the separation of DG and CA3) may pave the way for more precise delineations thereby enabling the detection of early volumetric changes in dementia and neuropsychiatric diseases.

Parsing the role of the hippocampus in approach-avoidance conflict

Abstract The hippocampus plays a central role in the approach‐avoidance conflict that is central to the genesis of anxiety. However, its exact functional contribution has yet to be identified. We designed a novel gambling task that generated approach‐avoidance conflict while controlling for spatial processing. We fit subjects’ behavior using a model that quantified the subjective values of choice options, and recorded neural signals using functional magnetic resonance imaging (fMRI). Distinct functional signals were observed in anterior hippocampus, with inferior hippocampus selectively recruited when subjects rejected a gamble, to a degree that covaried with individual differences in anxiety. The superior anterior hippocampus, in contrast, uniquely demonstrated value signals that were potentiated in the context of approach‐avoidance conflict. These results implicate the anterior hippocampus in behavioral avoidance and choice monitoring, in a manner relevant to understanding its role in anxiety. Our findings highlight interactions between subregions of the hippocampus as an important focus for future study.

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.

EFFECTS OF AGE AND CSF MEASURES OF TAU ON MNEMONIC DISCRIMINATION OF OBJECTS AND SCENES IN MEDIAL TEMPORAL LOBE PATHWAYS

of PiB preprocessing methods are previously described (i.e, ADNI by Jagust et al. (2010) and the KBASE by Choi et al. (2017)). Major differences included spatial normalization, reference region-of-interest for intensity normalization, global means calculations, and the cutoff values for Ab positivity. For each participant, their global mean values and Ab positivity statuses were derived using both methods. Results:Within the KBASE cohort, the global PiB values obtained using two different methods differed significantly in all clinical diagnosis groups. Within the ADNI cohort, the global PiB values showed significant difference between KBASE and ADNI method in NC and showed difference at trend level in AD. The proportions of Ab positive individuals significantly differed between the ADNI and KBASE cohorts for NC and MCI groups regardless of the methods used. Although the proportions of Ab positive individuals within the ADNI cohort did not vary depending on the method used (ADNI vs. KBASE methods), the proportions of Ab positive individuals among NC in KBASE cohort differed at trend level depending on the method used (Z1⁄41.95, p1⁄4.051). Conclusions: The current study demonstrated that (1) two cohorts differed in their distribution of Ab deposition levels using the same methods, (2) the different methods of obtaining the global means resulted in different Ab deposition levels within the same cohort, (3) the proportions of Ab positive individuals differed between the cohorts using the same method, and (4) depending on the method used, proportion of Ab positive individuals differed in healthy Korean adults. Based on these findings, more caution is essential when comparing or combining amyloid PET data from different cohorts.

EFFECTS OF TAU AND AMYLOID DEPOSITION MEASURED BY PET ON DOMAIN-SPECIFIC MEMORY FUNCTION IN OLD AGE

IC-P-101 EFFECTS OF TAU AND AMYLOID DEPOSITION MEASURED BY PET ON DOMAIN-SPECIFIC MEMORY FUNCTION IN OLD AGE AnneMaass, David Berron, TheresaM. Harrison, Suzanne L. Baker, Taylor J. Mellinger, Kaitlin N. Swinnerton, Rachel K. Bell, Emrah D€uzel, William J. Jagust, Jenna N. Adams, German Center for Neurodegenerative Diseases, Magdeburg, Germany; University of California Berkeley, Berkeley, CA, USA; Institute of Cognitive Neurology and Dementia Research, Otto von Guericke University, Magdeburg, Germany; Lawrence Berkeley National Laboratory, Berkeley, CA, USA; University of California Berkeley, Berkeley, CA, USA. Contact e-mail: anne.maass@dzne.de