Karen F. LaRocque

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.

What do differences between multi-voxel and univariate analysis mean? How subject-, voxel-, and trial-level variance impact fMRI analysis

Multi-voxel pattern analysis (MVPA) has led to major changes in how fMRI data are analyzed and interpreted. Many studies now report both MVPA results and results from standard univariate voxel-wise analysis, often with the goal of drawing different conclusions from each. Because MVPA results can be sensitive to latent multidimensional representations and processes whereas univariate voxel-wise analysis cannot, one conclusion that is often drawn when MVPA and univariate results differ is that the activation patterns underlying MVPA results contain a multidimensional code. In the current study, we conducted simulations to formally test this assumption. Our findings reveal that MVPA tests are sensitive to the magnitude of voxel-level variability in the effect of a condition within subjects, even when the same linear relationship is coded in all voxels. We also find that MVPA is insensitive to subject-level variability in mean activation across an ROI, which is the primary variance component of interest in many standard univariate tests. Together, these results illustrate that differences between MVPA and univariate tests do not afford conclusions about the nature or dimensionality of the neural code. Instead, targeted tests of the informational content and/or dimensionality of activation patterns are critical for drawing strong conclusions about the representational codes that are indicated by significant MVPA results.

Global similarity and pattern separation in the human medial temporal lobe predict subsequent memory.

Intense debate surrounds the role of medial temporal lobe (MTL) structures in recognition memory. Using high-resolution fMRI and analyses of pattern similarity in humans, we examined the encoding computations subserved by MTL subregions. Specifically, we tested the theory that MTL cortex supports memory by encoding overlapping representations, whereas hippocampus supports memory by encoding pattern-separated representations. Consistent with this view, the relationship between encoding pattern similarity and subsequent memory dissociated MTL cortex and hippocampus: later memory was predicted by greater across-item pattern similarity in perirhinal cortex and in parahippocampal cortex, but greater pattern distinctiveness in hippocampus. Additionally, by comparing neural patterns elicited by individual stimuli regardless of subsequent memory, we found that perirhinal cortex and parahippocampal cortex exhibited differential content sensitivity for multiple stimulus categories, whereas hippocampus failed to demonstrate content sensitivity. These data provide novel evidence that complementary MTL encoding computations subserve declarative memory.

Prospective representation of navigational goals in the human hippocampus

Brain activity to represent the future How do humans navigate from A to B? Brown et al. developed a virtual reality task to investigate the neural representations that support human navigational planning. Highly specific activity of the hippocampus and related brain areas represented the future locations to which participants eventually moved. Network-level interactions of the hippocampus with the prefrontal cortex thus enable flexible representation of planned destinations. Science, this issue p. 1323 The human hippocampus and hippocampal-cortical interactions simulate navigational events during goal-directed planning. Mental representation of the future is a fundamental component of goal-directed behavior. Computational and animal models highlight prospective spatial coding in the hippocampus, mediated by interactions with the prefrontal cortex, as a putative mechanism for simulating future events. Using whole-brain high-resolution functional magnetic resonance imaging and multi-voxel pattern classification, we tested whether the human hippocampus and interrelated cortical structures support prospective representation of navigational goals. Results demonstrated that hippocampal activity patterns code for future goals to which participants subsequently navigate, as well as for intervening locations along the route, consistent with trajectory-specific simulation. The strength of hippocampal goal representations covaried with goal-related coding in the prefrontal, medial temporal, and medial parietal cortex. Collectively, these data indicate that a hippocampal-cortical network supports prospective simulation of navigational events during goal-directed planning.

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.

Where Is Human V4? Predicting the Location of hV4 and VO1 from Cortical Folding

A strong relationship between cortical folding and the location of primary sensory areas in the human brain is well established. However, it is unknown if coupling between functional responses and gross anatomy is found at higher stages of sensory processing. We examined the relationship between cortical folding and the location of the retinotopic maps hV4 and VO1, which are intermediate stages in the human ventral visual processing stream. Our data show a consistent arrangement of the eccentricity maps within hV4 and VO1 with respect to anatomy, with the consequence that the hV4/VO1 boundary is found consistently in the posterior transverse collateral sulcus (ptCoS) despite individual variability in map size and cortical folding. Understanding this relationship allowed us to predict the location of visual areas hV4 and VO1 in a separate set of individuals, using only their anatomies, with >85% accuracy. These findings have important implications for understanding the relation between cortical folding and functional maps as well as for defining visual areas from anatomical landmarks alone.

Human hippocampal increases in low-frequency power during associative prediction violations

Environmental cues often trigger memories of past events (associative retrieval), and these memories are a form of prediction about imminent experience. Learning is driven by the detection of prediction violations, when the past and present diverge. Using intracranial electroencephalography (iEEG), we show that associative prediction violations elicit increased low-frequency power (in the slow-theta range) in human hippocampus, that this low-frequency power increase is modulated by whether conditions allow predictions to be generated, that the increase rapidly onsets after the moment of violation, and that changes in low-frequency power are not present in adjacent perirhinal cortex. These data suggest that associative mismatch is computed within hippocampus when cues trigger predictions that are violated by imminent experience.

Electrocorticography reveals the temporal dynamics of posterior parietal cortical activity during recognition memory decisions

Significance Over the past decade, human posterior parietal cortex (PPC) has been unexpectedly implicated in remembering and memory-related decision making. Functional neuroimaging indicates that memory-related responses differ across PPC, and patients with PPC lesions show subtle to significant changes in memory behavior. These surprising observations have motivated novel theorizing, yet current understanding of PPC contributions to memory is limited by the absence of temporal information about activity in PPC subregions as retrieval decisions unfold. In this study, recordings from the human brain show for the first time that distinct temporal and functional profiles of activity are present in PPC subregions as participants make recognition memory decisions. These new findings inform theories of parietal functional contributions to memory, decision making, and attention. Theories of the neurobiology of episodic memory predominantly focus on the contributions of medial temporal lobe structures, based on extensive lesion, electrophysiological, and imaging evidence. Against this backdrop, functional neuroimaging data have unexpectedly implicated left posterior parietal cortex (PPC) in episodic retrieval, revealing distinct activation patterns in PPC subregions as humans make memory-related decisions. To date, theorizing about the functional contributions of PPC has been hampered by the absence of information about the temporal dynamics of PPC activity as retrieval unfolds. Here, we leveraged electrocorticography to examine the temporal profile of high gamma power (HGP) in dorsal PPC subregions as participants made old/new recognition memory decisions. A double dissociation in memory-related HGP was observed, with activity in left intraparietal sulcus (IPS) and left superior parietal lobule (SPL) differing in time and sign for recognized old items (Hits) and correctly rejected novel items (CRs). Specifically, HGP in left IPS increased for Hits 300–700 ms poststimulus onset, and decayed to baseline ∼200 ms preresponse. By contrast, HGP in left SPL increased for CRs early after stimulus onset (200−300 ms) and late in the memory decision (from 700 ms to response). These memory-related effects were unique to left PPC, as they were not observed in right PPC. Finally, memory-related HGP in left IPS and SPL was sufficiently reliable to enable brain-based decoding of the participant’s memory state at the single-trial level, using multivariate pattern classification. Collectively, these data provide insights into left PPC temporal dynamics as humans make recognition memory decisions.

The Medial Temporal Lobe and Episodic Memory

Memories for the events of ones personal past take multiple forms that are differentially enabled by distinct computations performed by the medial temporal lobe (MTL). MTL cortex is posited to establish similar representations of similar events, enabling later recognition of single event attributes; the hippocampus is posited to establish distinct representations of similar events, enabling later memory for ensembles of co-occurring event attributes. These MTL contributions to episodic memory are situated within broader large-scale network interactions, including interactions with regions in the lateral prefrontal and lateral parietal cortices.