Abstract This chapter describes the journey of signals once they enter the brain, and the roles played by the human hippocampus in their processing. This includes perception, short-term maintenance of information, replay, consolidation, and how representations are transformed or lost over time. The reconstruction of representations during retrieval is then considered, along with other flexible applications of hippocampal representations such as future planning, imagination, navigating through physical, conceptual and social space, and decision making. Coming full circle, we outline how prior experiences influence subsequent perception, attention and memory. The chapter ends by discussing hippocampal theories and whether they can account for extant data, identifying where knowledge gaps remain, and how they might be bridged in the future using new technologies.

The hippocampus reconstructs past experiences by integrating sensory, perceptual, and conceptual information across a cortico-hippocampal autobiographical memory network. Here, in 18 human participants with amnesia, we decode the effects of bilateral focal hippocampal damage on distinct autobiographical representations using representational dissimilarity matrices (RDMs). Hippocampal pathology results in impaired generalized episodic memory retrieval RDM model fit in the left angular gyrus and in reduced distinct episodic memory RDM model fit in the right inferior frontal gyrus (rIFG), while right angular gyrus (rANG) and right orbitofrontal cortex (rOFC) fall below multiple correction thresholds. Trial-by-trial voxel-representational stability is reduced in the rANG, rIFG, and rOFC. The RDM model fits and mnemonic stability are predicted by total CA2/3 volumes. Trial-by-trial retrieval stability within the rOFC and rIFG predicts episodic memory performance, providing a direct neural correlation between hippocampal dysfunction, altered mnemonic representations, and amnesia.

The hippocampus reconstructs past experiences by integrating sensory, perceptual, and conceptual information across a cortico-hippocampal autobiographical memory network (AMN). Here, in 18 human participants with amnesia, we decoded the effects of bilateral focal hippocampal damage on distinct autobiographical representations using representational dissimilarity matrices (RDMs). Hippocampal pathology resulted in: (1) impaired generalised episodic memory retrieval RDM model fit in the left angular gyrus; and, (2) reduced distinct episodic memory RDM model fit and trial-by-trial voxel-representational stability in the right angular gyrus, right orbitofrontal cortex, and right inferior frontal gyrus. RDM model fits and mnemonic stability were predicted by total CA23 volumes. Trial-by-trial retrieval stability within the right orbitofrontal cortex and right inferior frontal gyrus predicted autobiographical memory performance, providing the first direct neural correlate between hippocampal dysfunction, altered mnemonic representations, and amnesia. The results demonstrate that hippocampal-mediated amnesia results from impaired mnemonic representational distinctiveness and stability within the AMN. ### Competing Interest Statement The authors have declared no competing interest.

When working with sensor-level data recorded using on-scalp neuroimaging methods such as electroencephalography (EEG), it is common practice to use two-dimensional (2D) representations of sensor positions to aid interpretation. Positioning of sensors relative to anatomy, as in the classic 10-20 system of EEG electrode placement, enables the use of 2D topographies that are familiar to many researchers and clinicians. However, when using another increasingly popular on-scalp neuroimaging method, optically pumped magnetometer-based magnetoencephalography (OP-MEG), bespoke sensor arrays are much more common, and these are not prepared according to any standard principle. Consequently, polar projection is often used to produce individual sensor topographies that are not directly related to anatomy and cannot be averaged across people simply. Given the current proliferation of OP-MEG facilities globally, this issue will become an increasing hindrance when visualising OP-MEG data, particularly for group studies. To address this problem, we adapted and extended the 10-20 system to build a flexible, anatomical projection method applied to digitised head shape, fiducials and sensor positions. We demonstrate that the method maintains spatially veridical representations across individuals improving on standard polar projections at varying OPM sensor array densities. By applying our projection method, the benefits of anatomically veridical 2D topographies can now be enjoyed when visualising data, such as those from OP-MEG, regardless of variation in sensor placement as in sparse or focal arrays.

Researchers who study the human hippocampus are naturally interested in how its subfields function. However, many researchers are precluded from examining subfields because their manual delineation from magnetic resonance imaging (MRI) scans (still the gold standard approach) is time consuming and requires significant expertise. To help ameliorate this issue, we present here two protocols, one for 3T MRI and the other for 7T MRI, that permit automated hippocampus segmentation into six subregions, namely dentate gyrus/cornu ammonis (CA)4, CA2/3, CA1, subiculum, pre/parasubiculum, and uncus along the entire length of the hippocampus. These protocols are particularly notable relative to existing resources in that they were trained and tested using large numbers of healthy young adults (n = 140 at 3T, n = 40 at 7T) whose hippocampi were manually segmented by experts from MRI scans. Using inter-rater reliability analyses, we showed that the quality of automated segmentations produced by these protocols was high and comparable to expert manual segmenters. We provide full open access to the automated protocols, and anticipate they will save hippocampus researchers a significant amount of time. They could also help to catalyze subfield research, which is essential for gaining a full understanding of how the hippocampus functions.

We share data from N = 217 healthy adults (mean age 29 years, range 20–41; 109 females, 108 males) who underwent extensive cognitive assessment and neuroimaging to examine the neural basis of individual differences, with a particular focus on a brain structure called the hippocampus. Cognitive data were collected using a wide array of questionnaires, naturalistic tests that examined imagination, autobiographical memory recall and spatial navigation, traditional laboratory-based tests such as recalling word pairs, and comprehensive characterisation of the strategies used to perform the cognitive tests. 3 Tesla MRI data were also acquired and include multi-parameter mapping to examine tissue microstructure, diffusion-weighted MRI, T2-weighted high-resolution partial volume structural MRI scans (with the masks of hippocampal subfields manually segmented from these scans), whole brain resting state functional MRI scans and partial volume high resolution resting state functional MRI scans. This rich dataset will be of value to cognitive and clinical neuroscientists researching individual differences, real-world cognition, brain-behaviour associations, hippocampal subfields and more. All data are freely available on Dryad.

People vary substantially in their capacity to recall past experiences, known as autobiographical memories. Here we investigated whether the volumes of specific hippocampal subfields were associated with autobiographical memory retrieval ability. We manually segmented the full length of the two hippocampi in 201 healthy young adults into DG/CA4, CA2/3, CA1, subiculum, pre/parasubiculum and uncus, in the largest such manually segmented subfield sample yet reported. Across the group we found no evidence for an association between any subfield volume and autobiographical memory recall ability. However, when participants were assigned to lower and higher performing groups based on their memory recall scores, we found that bilateral CA2/3 volume was significantly and positively associated with autobiographical memory recall performance specifically in the lower performing group. We further observed that this effect was attributable to posterior CA2/3. By contrast, semantic details from autobiographical memories, and performance on a range of laboratory-based memory tests, did not correlate with CA2/3 volume. Overall, our findings highlight that posterior CA2/3 may be particularly pertinent for autobiographical memory recall. They also reveal that there may not be direct one-to-one mapping of posterior CA2/3 volume with autobiographical memory ability, with size mattering perhaps only in those with poorer memory recall.

Geometric distortion is a major concern for cortical depth-dependent fMRI using EPI readouts that suffer from low bandwidth in the phase-encoded direction. Distortions are exacerbated at higher field strengths due to increased B0 field inhomogeneity. In this study, we quantitatively compared two distortion correction methods (B0 field-mapping and reversed-PE) applied to submillimeter (0.8mm isotropic) 3DEPI data at 7T. Cortical alignment was evaluated through comparison with an anatomically-faithful MP2RAGE reference by computing the dice coefficient and normalised mutual information. Both distortion correction methods usefully improve alignment. The reversed-PE approach performed better.

Altered autobiographical memory (ABM) processing characterizes some individuals with experiences of childhood maltreatment. This fMRI study of ABM processing evaluated potential developmental plasticity in neural functioning following maltreatment. Adolescents with (N = 19; MT group) and without (N = 18; Non-MT group) documented childhood maltreatment recalled specific ABMs in response to emotionally valenced cue words during fMRI at baseline (age 12.71 ± 1.48) and follow-up (14.88 ± 1.53 years). Psychological assessments were collected at both timepoints. Longitudinal analyses were carried out with BOLD signal changes during ABM recall and psychopathology to investigate change over time. In both groups there was relative stability of the ABM brain network, with some developmental maturational changes observed in cortical midline structures (ventromedial PFC (vmPFC), posterior cingulate cortex (pCC), and retrosplenial cortex (rSC). Significantly increased activation of the right rSC was observed only in the MT group, which was associated with improved psychological functioning. Baseline group differences in relation to hippocampal functioning, were not detected at follow-up. This study provides preliminary empirical evidence of functional developmental plasticity in children with documented maltreatment experience using fMRI. This suggests that altered patterns of brain function, associated with maltreatment experience, are not fixed and may reflect the potential to track a neural basis of resilience.

There is renewed interest in electrical activity that extends beyond the typical electrophysiological 100 Hz bandwidth. This activity, often in the anterior temporal lobe, has been attributed to processes ranging from memory consolidation to epileptiform activity. Here, using an open-access resting state magnetoencephalography (MEG) dataset (n = 89), and a second task-based MEG dataset, we could reliably localise high-frequency power to the temporal lobes across multiple bands up to 300–400 Hz. A functional connectivity analysis of this activity revealed a robust resting state bilateral network between the temporal lobes. However, we also found robust coherence in the 100–200 and 200–300 Hz bands between source reconstructed MEG data and the electrooculography (EOG) localised to within the temporal poles. Additional denoising schemes applied to the data could reduce power localisation to the temporal poles but the topography of the functional network did not drastically alter. Whilst it is clear that this network is biological and robust to established denoising methods, we cannot definitively rule yet on whether this is of neural or myogenic origin.

Geometric distortion is a major limiting factor for spatial specificity in high-resolution fMRI using EPI readouts and is exacerbated at higher field strengths due to increased B0 field inhomogeneity. Prominent correction schemes are based on B0 field-mapping or acquiring reverse phase-encoded (reversed-PE) data. However, to date, comparisons of these techniques in the context of fMRI have only been performed on 2DEPI data, either at lower field or lower resolution. In this study, we investigate distortion compensation in the context of sub-millimetre 3DEPI data at 7T. B0 field-mapping and reversed-PE distortion correction techniques were applied to both partial coverage BOLD-weighted and whole brain MT-weighted 3DEPI data with matched distortion. Qualitative assessment showed overall improvement in cortical alignment for both correction techniques in both 3DEPI fMRI and whole-brain MT-3DEPI datasets. The distortion-corrected MT-3DEPI images were quantitatively evaluated by comparing cortical alignment with an anatomical reference using dice coefficient (DC) and correlation ratio (CR) measures. These showed that B0 field-mapping and reversed-PE methods both improved correspondence between the MT-3DEPI and anatomical data, with more substantial improvements consistently obtained using the reversed-PE approach. Regional analyses demonstrated that the largest benefit of distortion correction, and in particular of the reversed-PE approach, occurred in frontal and temporal regions where susceptibility-induced distortions are known to be greatest, but had not led to complete signal dropout. In conclusion, distortion correction based on reversed-PE data has shown the greater capacity for achieving faithful alignment with anatomical data in the context of high-resolution fMRI at 7T using 3DEPI.

Purpose: Universal Pulses (UPs) are excitation pulses that reduce the flip angle inhomogeneity in high field MRI systems without subject-specific optimization, originally developed for parallel transmit (PTX) systems at 7T. We investigated the potential benefits of UPs for single channel (SC) transmit systems at 3T, which are widely used for clinical and research imaging, and for which flip angle inhomogeneity can still be problematic. Methods: SC-UPs were designed using a spiral nonselective k-space trajectory for brain imaging at 3T using transmit field maps (B1+) and off-resonance maps (B0) acquired on two different scanner types: a 'standard' single channel transmit system and a system with a PTX body coil. The effect of training group size was investigated using data (200 subjects) from the standard system. The PTX system was used to compare SC-UPs to PTX-UPs (15 subjects). In two additional subjects, prospective imaging using SC-UP was studied. Results: Average flip angle error fell from 9.5+/-0.5% for 'default' excitation to 3.0+/-0.6% using SC-UPs trained over 50 subjects. Performance of the UPs was found to steadily improve as training group size increased, but stabilized after ~15 subjects. On the PTX-enabled system, SC-UPs again outperformed default excitation in simulations (4.8+/-0.6% error versus 10.6+/-0.8% respectively) though greater homogenization could be achieved with PTX-UPs (3.9+/-0.6%) and personalized pulses (SC-PP 3.6+/-1.0%, PTX-PP 2.9+/-0.6%). MP-RAGE imaging using SC-UP resulted in greater separation between grey and white matter signal intensities than default excitation. Conclusions: SC-UPs can improve excitation homogeneity in standard 3T systems without further calibration and could be used instead of a default excitation pulse for nonselective neuroimaging at 3T.

Neural oscillations often occur as transient bursts with variable amplitude and frequency dynamics. Quantifying these effects is important for understanding brain-behaviour relationships, especially in continuous datasets. To robustly measure bursts, rhythmical periods of oscillatory activity must be separated from arrhythmical background 1/f activity, which is ubiquitous in electrophysiological recordings. The Better OSCillation (BOSC) framework achieves this by defining a power threshold above the estimated background 1/f activity, combined with a duration threshold. Here we introduce a modification to this approach called fBOSC which uses a spectral parametrisation tool to accurately model background 1/f activity in neural data. fBOSC (which is openly available as a MATLAB toolbox) is robust to power spectra with oscillatory peaks and can also model non-linear spectra. Through a series of simulations, we show that fBOSC more accurately models the 1/f power spectrum compared with existing methods. fBOSC was especially beneficial where power spectra contained a “knee” below ∼0.5-10 Hz, which is typical in neural data. We also found that, unlike other methods, fBOSC was unaffected by oscillatory peaks in the neural power spectrum. Moreover, by robustly modelling background 1/f activity, the sensitivity for detecting oscillatory bursts was standardised across frequencies (e.g. theta- and alpha-bands). Finally, using openly available resting state magnetoencephalography and intracranial electrophysiology datasets, we demonstrate the application of fBOSC for oscillatory burst detection in the theta-band. These simulations and empirical analyses highlight the value of fBOSC in detecting oscillatory bursts, including in datasets that are long and continuous with no distinct experimental trials. GRAPHICAL ABSRACT To determine a power threshold for burst detection, the Better OSCillation framework (BOSC) estimates background 1/f activity by modelling neural power spectra. Here we introduce a modification, termed fBOSC, to more robustly estimate 1/f activity in situations with prominent oscillatory peaks and/or the presence of a non-linear “knee” in the power spectrum. This was shown to standardise burst detection across frequency bands in both simulated and empirical data.

How do we remember our past experiences? This question remains stubbornly resistant to resolution. The next 25 years may see significant traction on this and other outstanding issues if memory researchers capitalise on exciting technological developments that allow embodied cognition to be studied in ways that closely approximate real life.

The precise role played by the hippocampus in supporting cognitive functions such as episodic memory and future thinking is debated, but there is general agreement that it involves constructing representations comprised of numerous elements. Visual scenes have been deployed extensively in cognitive neuroscience because they are paradigmatic multi-element stimuli. However, questions remain about the specificity and nature of the hippocampal response to scenes. Here, we devised a paradigm in which we had participants search pairs of images for either colour or layout differences, thought to be associated with perceptual or spatial constructive processes respectively. Importantly, images depicted either naturalistic scenes or phase-scrambled versions of the same scenes, and were either simple or complex. Using this paradigm during functional MRI scanning, we addressed three questions: 1. Is the hippocampus recruited specifically during scene processing? 2. If the hippocampus is more active in response to scenes, does searching for colour or layout differences influence its activation? 3. Does the complexity of the scenes affect its response? We found that, compared to phase-scrambled versions of the scenes, the hippocampus was more responsive to scene stimuli. Moreover, a clear anatomical distinction was evident, with colour detection in scenes engaging the posterior hippocampus whereas layout detection in scenes recruited the anterior hippocampus. The complexity of the scenes did not influence hippocampal activity. These findings seem to align with perspectives that propose the hippocampus is especially attuned to scenes, and its involvement occurs irrespective of the cognitive process or the complexity of the scenes.

Individual differences in scene imagination, autobiographical memory recall, future thinking and spatial navigation have long been linked with hippocampal structure in healthy people, although evidence for such relationships is, in fact, mixed. Extant studies have predominantly concentrated on hippocampal volume. However, it is now possible to use quantitative neuroimaging techniques to model different properties of tissue microstructure in vivo such as myelination and iron. Previous work has linked such measures with cognitive task performance, particularly in older adults. Here we investigated whether performance on scene imagination, autobiographical memory, future thinking and spatial navigation tasks was associated with hippocampal grey matter myelination or iron content in young, healthy adult participants. Magnetic resonance imaging data were collected using a multi-parameter mapping protocol (0.8 mm isotropic voxels) from a large sample of 217 people with widely-varying cognitive task scores. We found little evidence that hippocampal grey matter myelination or iron content were related to task performance. This was the case using different analysis methods (voxel-based quantification, partial correlations), when whole brain, hippocampal regions of interest, and posterior:anterior hippocampal ratios were examined, and across different participant sub-groups (divided by gender and task performance). Variations in hippocampal grey matter myelin and iron levels may not, therefore, help to explain individual differences in performance on hippocampal-dependent tasks, at least in young, healthy individuals.

One of the primary technical challenges facing magnetoencephalography (MEG) is that the magnitude of neuromagnetic fields is several orders of magnitude lower than interfering signals. Recently, a new type of sensor has been developed - the optically pumped magnetometer (OPM). These sensors can be placed directly on the scalp and move with the head during participant movement, making them wearable. This opens up a range of exciting experimental and clinical opportunities for OPM-based MEG experiments, including paediatric studies, and the incorporation of naturalistic movements into neuroimaging paradigms. However, OPMs face some unique challenges in terms of interference suppression, especially in situations involving mobile participants, and when OPMs are integrated with electrical equipment required for naturalistic paradigms, such as motion capture systems. Here we briefly review various hardware solutions for OPM interference suppression. We then outline several signal processing strategies aimed at increasing the signal from neuromagnetic sources. These include regression-based strategies, temporal filtering and spatial filtering approaches. The focus is on the practical application of these signal processing algorithms to OPM data. In a similar vein, we include two worked-through experiments using OPM data collected from a whole-head sensor array. These tutorial-style examples illustrate how the steps for suppressing external interference can be implemented, including the associated data and code so that researchers can try the pipelines for themselves. With the popularity of OPM-based MEG rising, there will be an increasing need to deal with interference suppression. We hope this practical paper provides a resource for OPM-based MEG researchers to build upon.

Optically pumped magnetometer-based magnetoencephalography (OP-MEG) can be used to measure neuromagnetic fields while participants move in a magnetically shielded room. Head movements in previous OP-MEG studies have been up to 20 cm translation and ∼30° rotation in a sitting position. While this represents a step-change over stationary MEG systems, naturalistic head movement is likely to exceed these limits, particularly when participants are standing up. In this proof-of-concept study, we sought to push the movement limits of OP-MEG even further. Using a 90 channel (45-sensor) whole-head OP-MEG system and concurrent motion capture, we recorded auditory evoked fields while participants were: (i) sitting still, (ii) standing up and still, and (iii) standing up and making large natural head movements continuously throughout the recording – maximum translation 120 cm, maximum rotation 198°. Following pre-processing, movement artefacts were substantially reduced but not eliminated. However, upon utilisation of a beamformer, the M100 event-related field localised to primary auditory regions. Furthermore, the event-related fields from auditory cortex were remarkably consistent across the three conditions. These results suggest that a wide range of movement is possible with current OP-MEG systems. This in turn underscores the exciting potential of OP-MEG for recording neural activity during naturalistic paradigms that involve movement (e.g. navigation), and for scanning populations who are difficult to study with stationary MEG (e.g. young children).

Our lives unfold as sequences of events. We experience these events as seamless, although they are composed of individual images captured in between the interruptions imposed by eye blinks and saccades. Events typically involve visual imagery from the real world (scenes), and the hippocampus is frequently engaged in this context. It is unclear, however, whether the hippocampus would be similarly responsive to unfolding events that involve abstract imagery. Addressing this issue could provide insights into the nature of its contribution to event processing, with relevance for theories of hippocampal function. Consequently, during magnetoencephalography (MEG), we had female and male humans watch highly matched unfolding movie events composed of either scene image frames that reflected the real world, or frames depicting abstract patterns. We examined the evoked neuronal responses to each image frame along the time course of the movie events. Only one difference between the two conditions was evident, and that was during the viewing of the first image frame of events, detectable across frontotemporal sensors. Further probing of this difference using source reconstruction revealed greater engagement of a set of brain regions across parietal, frontal, premotor, and cerebellar cortices, with the largest change in broadband (1-30 Hz) power in the hippocampus during scene-based movie events. Hippocampal engagement during the first image frame of scene-based events could reflect its role in registering a recognizable context perhaps based on templates or schemas. The hippocampus, therefore, may help to set the scene for events very early on.

Beamforming is one of the most commonly used source reconstruction methods for magneto- and electroencephalography (M/EEG). One underlying assumption, however, is that distant sources are uncorrelated and here we tested whether this is an appropriate model for the human hippocampal data. We revised the Empirical Bayesian Beamfomer (EBB) to accommodate specific a-priori correlated source models. We showed in simulation that we could use model evidence (as approximated by Free Energy) to distinguish between different correlated and uncorrelated source scenarios. Using group MEG data in which the participants performed a hippocampal-dependent task, we explored the possibility that the hippocampus or the cortex or both were correlated in their activity across hemispheres. We found that incorporating a correlated hippocampal source model significantly improved model evidence. Our findings help to explain why, up until now, the majority of MEG-reported hippocampal activity (typically making use of beamformers) has been estimated as unilateral.