Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS.

Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.

The distinct and overlapping brain networks supporting semantic and spatial constructive scene processing.

Scene imagery features prominently when we recall autobiographical memories, imagine the future and navigate around in the world. Consequently, in this study we sought to better understand how scene representations are supported by the brain. Processing scenes involves a variety of cognitive processes that in the real world are highly interactive. Here, however, our goal was to separate semantic and spatial constructive scene processes in order to identify the brain areas that were distinct to each process, those they had in common, and the connectivity between regions. To this end, participants searched for either semantic or spatial constructive impossibilities in scenes during functional MRI. We focussed our analyses on only those scenes that were possible, thus removing any error detection that would evoke reactions such as surprise or novelty. Importantly, we also counterbalanced possible scenes across participants, enabling us to examine brain activity and connectivity for the same possible scene images under two different conditions. We found that participants adopted different cognitive strategies, which were reflected in distinct oculomotor behaviour, for each condition. These were in turn associated with increased engagement of lateral temporal and parietal cortices for semantic scene processing, the hippocampus for spatial constructive scene processing, and increased activation of the ventromedial prefrontal cortex (vmPFC) that was common to both. Connectivity analyses showed that the vmPFC switched between semantic and spatial constructive brain networks depending on the task at hand. These findings further highlight the well-known semantic functions of lateral temporal areas, while providing additional support for the previously-asserted contribution of the hippocampus to scene construction, and recent suggestions that the vmPFC may play a key role in orchestrating scene processing.

Characterising the hippocampal response to perception, construction and complexity.

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.

Dreaming with hippocampal damage.

The hippocampus is linked with both sleep and memory, but there is debate about whether a salient aspect of sleep - dreaming - requires its input. To address this question, we investigated if human patients with focal bilateral hippocampal damage and amnesia engaged in dreaming. We employed a provoked awakening protocol where participants were woken up at various points throughout the night, including during non-rapid eye movement and rapid eye movement sleep, to report their thoughts in that moment. Despite being roused a similar number of times, dream frequency was reduced in the patients compared to control participants, and the few dreams they reported were less episodic-like in nature and lacked content. These results suggest that hippocampal integrity may be necessary for typical dreaming to occur, and aligns dreaming with other hippocampal-dependent processes such as episodic memory that are central to supporting our mental life.

Dreaming has intrigued humans for thousands of years, but why we dream still remains somewhat of a mystery. Although dreams are not a precise replay of our memories, one idea is that dreaming helps people process past experiences as they sleep. If this is true, then part of the brain called the hippocampus that is important for memory should also be necessary for dreaming. Damage to the hippocampus can cause a condition called amnesia that prevents people from forming new memories and remembering past experiences. However, studies examining dreaming in people with amnesia have produced mixed results: some found that damage to the hippocampus had no effect on dreams, while others found it caused people to have repetitive dreams that lacked detail. One reason for these inconsistencies is that some studies asked participants about their dreams the next morning by which time most people, particularly those with amnesia, have forgotten if they dreamed. To overcome this limitation, Spanò et al. asked participants about their dreams immediately after being woken up at various points during the night. The experiment was carried out with four people who had damage to both the left and right hippocampus and ten healthy volunteers. Spanò et al. found that the people with hippocampal damage reported fewer dreams and the dreams they had were much less detailed. These findings suggest that a healthy hippocampus is necessary for both memory and dreaming, reinforcing the link between the two. Hippocampal damage is associated with a number of diseases, including dementia. If these diseases cause patients to dream less, this may worsen the memory difficulties associated with these conditions.

vmPFC Drives Hippocampal Processing during Autobiographical Memory Recall Regardless of Remoteness.

Our ability to recall past experiences, autobiographical memories (AMs), is crucial to cognition, endowing us with a sense of self and underwriting our capacity for autonomy. Traditional views assume that the hippocampus orchestrates event recall, whereas recent accounts propose that the ventromedial prefrontal cortex (vmPFC) instigates and coordinates hippocampal-dependent processes. Here we sought to characterize the dynamic interplay between the hippocampus and vmPFC during AM recall to adjudicate between these perspectives. Leveraging the high temporal resolution of magnetoencephalography, we found that the left hippocampus and the vmPFC showed the greatest power changes during AM retrieval. Moreover, responses in the vmPFC preceded activity in the hippocampus during initiation of AM recall, except during retrieval of the most recent AMs. The vmPFC drove hippocampal activity during recall initiation and also as AMs unfolded over subsequent seconds, and this effect was evident regardless of AM age. These results recast the positions of the hippocampus and the vmPFC in the AM retrieval hierarchy, with implications for theoretical accounts of memory processing and systems-level consolidation.

Sleeping with Hippocampal Damage.

The hippocampus plays a critical role in sleep-related memory processes [1-3], but it is unclear which specific sleep features are dependent upon this brain structure. The examination of sleep physiology in patients with focal bilateral hippocampal damage and amnesia could supply important evidence regarding these links. However, there is a dearth of such studies, despite these patients providing compelling insights into awake cognition [4, 5]. Here, we sought to identify the contribution of the hippocampus to the sleep phenotype by characterizing sleep via comprehensive qualitative and quantitative analyses in memory-impaired patients with selective bilateral hippocampal damage and matched control participants using in-home polysomnography on 4 nights. We found that, compared to control participants, patients had significantly reduced slow-wave sleep-likely due to decreased density of slow waves-as well as slow-wave activity. In contrast, slow and fast spindles were indistinguishable from those of control participants. Moreover, patients expressed slow oscillations (SOs), and SO-fast spindle coupling was observed. However, on closer scrutiny, we noted that the timing of spindles within the SO cycle was delayed in the patients. The shift of patients' spindles into the later phase of the up-state within the SO cycle may indicate a mismatch in timing across the SO-spindle-ripple events that are associated with memory consolidation [6, 7]. The substantial effect of selective bilateral hippocampal damage on large-scale oscillatory activity in the cortex suggests that, as with awake cognition, the hippocampus plays a significant role in sleep physiology, which may, in turn, be necessary for efficacious episodic memory.

[Anti-tau therapies-what can be expected?] / Anti-Tau-Therapien ­ was können wir erwarten?

Alzheimer's disease is histopathologically characterized by aggregation of two proteins, namely amyloid-beta peptide and tau protein. Whereas former intervention trials focused particularly on the amyloid pathology, recent therapeutic approaches are directed against the tau pathology. This article summarizes recent progress in anti-tau therapies, especially therapies based on anti-tau immunization and antisense oligonucleotides (ASO).

Scene processing following damage to the ventromedial prefrontal cortex.

It has been suggested that the mental construction of scene imagery is a core process underpinning functions such as autobiographical memory, future thinking and spatial navigation. Damage to the ventromedial prefrontal cortex in humans can cause deficits in all of these cognitive domains. Moreover, it has also been reported that patients with ventromedial prefrontal cortex lesions are impaired at imagining fictitious scenes, although they seem able to describe specific scenes from autobiographical events. In general, not much is known about how ventromedial prefrontal cortex patients process scenes. Here, we deployed a recently-developed task to provide insights into this issue, which involved detecting either semantic (e.g. an elephant with butterflies for ears) or constructive (e.g. an endless staircase) violations in scene images. Identifying constructive violations typically provokes the formation of internal scene models in healthy control participants. We tested patients with bilateral ventromedial prefrontal cortex damage, brain-damaged control patients and healthy control participants. We found no evidence for statistically significant differences between the groups in detecting either type of violation. These results suggest that an intact ventromedial prefrontal cortex is not necessary for some aspects of scene processing, with implications for understanding its role in functions such as autobiographical memory and future thinking.

Functional connectivity along the anterior-posterior axis of hippocampal subfields in the ageing human brain.

While age-related volumetric changes in human hippocampal subfields have been reported, little is known about patterns of subfield functional connectivity (FC) in the context of healthy ageing. Here we investigated age-related changes in patterns of FC down the anterior-posterior axis of each subfield. Using high resolution structural MRI we delineated the dentate gyrus (DG), CA fields (including separating DG from CA3), the subiculum, pre/parasubiculum, and the uncus in healthy young and older adults. We then used high resolution resting state functional MRI to measure FC in each group and to directly compare them. We first examined the FC of each subfield in its entirety, in terms of FC with other subfields and with neighboring cortical regions, namely, entorhinal, perirhinal, posterior parahippocampal, and retrosplenial cortices. Next, we analyzed subfield to subfield FC within different portions along the hippocampal anterior-posterior axis, and FC of each subfield portion with the neighboring cortical regions of interest. In general, the FC of the older adults was similar to that observed in the younger adults. We found that, as in the young group, the older group displayed intrinsic FC between the subfields that aligned with the tri-synaptic circuit but also extended beyond it, and that FC between the subfields and neighboring cortical areas differed markedly along the anterior-posterior axis of each subfield. We observed only one significant difference between the young and older groups. Compared to the young group, the older participants had significantly reduced FC between the anterior CA1-subiculum transition region and the transentorhinal cortex, two brain regions known to be disproportionately affected during the early stages of age-related tau accumulation. Overall, these results contribute to ongoing efforts to characterize human hippocampal subfield connectivity, with implications for understanding hippocampal function and its modulation in the ageing brain.

Differences in functional connectivity along the anterior-posterior axis of human hippocampal subfields.

There is a paucity of information about how human hippocampal subfields are functionally connected to each other and to neighbouring extra-hippocampal cortices. In particular, little is known about whether patterns of functional connectivity (FC) differ down the anterior-posterior axis of each subfield. Here, using high resolution structural MRI we delineated the hippocampal subfields in healthy young adults. This included the CA fields, separating DG/CA4 from CA3, separating the pre/parasubiculum from the subiculum, and also segmenting the uncus. We then used high resolution resting state functional MRI to interrogate FC. We first analysed the FC of each hippocampal subfield in its entirety, in terms of FC with other subfields and with the neighbouring regions, namely entorhinal, perirhinal, posterior parahippocampal and retrosplenial cortices. Next, we analysed FC for different portions of each hippocampal subfield along its anterior-posterior axis, in terms of FC between different parts of a subfield, FC with other subfield portions, and FC of each subfield portion with the neighbouring cortical regions of interest. We found that intrinsic functional connectivity between the subfields aligned generally with the tri-synaptic circuit but also extended beyond it. Our findings also revealed that patterns of functional connectivity between the subfields and neighbouring cortical areas differed markedly along the anterior-posterior axis of each hippocampal subfield. Overall, these results contribute to ongoing efforts to characterise human hippocampal subfield connectivity, with implications for understanding hippocampal function.

Differentiable Processing of Objects, Associations, and Scenes within the Hippocampus.

The hippocampus is known to be important for a range of cognitive functions, including episodic memory, spatial navigation, and thinking about the future. However, researchers have found it difficult to agree on the exact nature of this brain structure's contribution to cognition. Some theories emphasize the role of the hippocampus in associative processes. Another theory proposes that scene construction is its primary role. To directly compare these accounts of hippocampal function in human males and females, we devised a novel mental imagery paradigm where different tasks were closely matched for associative processing and mental construction, but either did or did not evoke scene representations, and we combined this with high-resolution functional MRI. The results were striking in showing that different parts of the hippocampus, along with distinct cortical regions, were recruited for scene construction or nonscene-evoking associative processing. The contrasting patterns of neural engagement could not be accounted for by differences in eye movements, mnemonic processing, or the phenomenology of mental imagery. These results inform conceptual debates in the field by showing that the hippocampus does not seem to favor one type of process over another; it is not a story of exclusivity. Rather, there may be different circuits within the hippocampus, each associated with different cortical inputs, which become engaged depending on the nature of the stimuli and the task at hand. Overall, our findings emphasize the importance of considering the hippocampus as a heterogeneous structure, and that a focus on characterizing how specific portions of the hippocampus interact with other brain regions may promote a better understanding of its role in cognition.SIGNIFICANCE STATEMENT The hippocampus is known to be important for a range of cognitive functions, including episodic memory, spatial navigation, and thinking about the future. However, researchers have found it difficult to agree on the exact nature of this brain structure's contribution to cognition. Here we used a novel mental imagery paradigm and high-resolution functional MRI to compare accounts of hippocampal function that emphasize associative processes with a theory that proposes scene construction as a primary role. The results were striking in showing that different parts of the hippocampus, along with distinct cortical regions, were recruited for scene construction or nonscene-evoking associative processing. We conclude that a greater emphasis on characterizing how specific portions of the hippocampus interact with other brain regions may promote a better understanding of its role in cognition.

Boundary extension is attenuated in patients with ventromedial prefrontal cortex damage.

The ventromedial prefrontal cortex (vmPFC) and hippocampus have been implicated in the mental construction of scenes and events. However, little is known about their specific contributions to these cognitive functions. Boundary extension (BE) is a robust indicator of fast, automatic, and implicit scene construction. BE occurs when individuals who are viewing scenes automatically imagine what might be beyond the view, and consequently later misremember having seen a greater expanse of the scene. Patients with hippocampal damage show attenuated BE because of their scene construction impairment. In the current study, we administered BE tasks to patients with vmPFC damage, brain-damaged control patients, and healthy control participants. We also contrasted the performance of these patients to the previously-published data from patients with hippocampal lesions (Mullally, Intraub, & Maguire, 2012). We found that vmPFC-damaged patients showed reduced BE compared to brain-damaged and healthy controls. Indeed, BE attenuation was similar following vmPFC or hippocampal damage. Notably, however, whereas hippocampal damage seems to particularly impair the spatial coherence of scenes, vmPFC damage leads to a difficulty constructing scenes in a broader sense, with the prediction of what should be in a scene, and the monitoring or integration of the scene elements being particularly compromised. We conclude that vmPFC and hippocampus play important and complementary roles in scene construction.

Mind-Wandering in People with Hippocampal Damage.

Subjective inner experiences, such as mind-wandering, represent the fundaments of human cognition. Although the precise function of mind-wandering is still debated, it is increasingly acknowledged to have influence across cognition on processes such as future planning, creative thinking, and problem-solving and even on depressive rumination and other mental health disorders. Recently, there has been important progress in characterizing mind-wandering and identifying the associated neural networks. Two prominent features of mind-wandering are mental time travel and visuospatial imagery, which are often linked with the hippocampus. People with selective bilateral hippocampal damage cannot vividly recall events from their past, envision their future, or imagine fictitious scenes. This raises the question of whether the hippocampus plays a causal role in mind-wandering and, if so, in what way. Leveraging a unique opportunity to shadow people (all males) with bilateral hippocampal damage for several days, we examined, for the first time, what they thought about spontaneously, without direct task demands. We found that they engaged in as much mind-wandering as control participants. However, whereas controls thought about the past, present, and future, imagining vivid visual scenes, hippocampal damage resulted in thoughts primarily about the present comprising verbally mediated semantic knowledge. These findings expose the hippocampus as a key pillar in the neural architecture of mind-wandering and also reveal its impact beyond episodic memory, placing it at the heart of our mental life.SIGNIFICANCE STATEMENT Humans tend to mind-wander ∼30-50% of their waking time. Two prominent features of this pervasive form of thought are mental time travel and visuospatial imagery, which are often associated with the hippocampus. To examine whether the hippocampus plays a causal role in mind-wandering, we examined the frequency and phenomenology of mind-wandering in patients with selective bilateral hippocampal damage. We found that they engaged in as much mind-wandering as controls. However, hippocampal damage changed the form and content of mind-wandering from flexible, episodic, and scene based to abstract, semanticized, and verbal. These findings expose the hippocampus as a key pillar in the neural architecture of mind-wandering and reveal its impact beyond episodic memory, placing it at the heart of our mental life.

Comparing and Contrasting the Cognitive Effects of Hippocampal and Ventromedial Prefrontal Cortex Damage: A Review of Human Lesion Studies.

The hippocampus and ventromedial prefrontal cortex (vmPFC) are closely connected brain regions whose functions are still debated. In order to offer a fresh perspective on understanding the contributions of these two brain regions to cognition, in this review we considered cognitive tasks that usually elicit deficits in hippocampal-damaged patients (e.g., autobiographical memory retrieval), and examined the performance of vmPFC-lesioned patients on these tasks. We then took cognitive tasks where performance is typically compromised following vmPFC damage (e.g., decision making), and looked at how these are affected by hippocampal lesions. Three salient motifs emerged. First, there are surprising gaps in our knowledge about how hippocampal and vmPFC patients perform on tasks typically associated with the other group. Second, while hippocampal or vmPFC damage seems to adversely affect performance on so-called hippocampal tasks, the performance of hippocampal and vmPFC patients clearly diverges on classic vmPFC tasks. Third, although performance appears analogous on hippocampal tasks, on closer inspection, there are significant disparities between hippocampal and vmPFC patients. Based on these findings, we suggest a tentative hierarchical model to explain the functions of the hippocampus and vmPFC. We propose that the vmPFC initiates the construction of mental scenes by coordinating the curation of relevant elements from neocortical areas, which are then funneled into the hippocampus to build a scene. The vmPFC then engages in iterative re-initiation via feedback loops with neocortex and hippocampus to facilitate the flow and integration of the multiple scenes that comprise the coherent unfolding of an extended mental event.

Different neural routes to autobiographical memory recall in healthy people and individuals with left medial temporal lobe epilepsy.

Individuals with medial temporal lobe epilepsy (mTLE) are poor at recalling vivid details from autobiographical memories (AM), instead retrieving gist-like schematic memories. Recent research has suggested that this impoverished recall in comparison to controls may reflect (1) differential engagement of anterior vs posterior regions of the hippocampus (HC) and/or (2) differences between the engagement of the HC vs the ventromedial prefrontal cortex (vmPFC). Here we examined these hypotheses by comparing connectivity amongst hippocampal regions and between vmPFC and other brain regions during construction (retrieval of a particular event) vs elaboration (retrieval of perceptual detail) phases of AM recall in 12 individuals with left mTLE and 12 matched controls. Whereas functional connectivity amongst hippocampal regions changed from AM construction to elaboration in controls, the pattern of intra-hippocampal connectivity was unvarying in patients. Furthermore, patterns of connectivity from the vmPFC differed between phases in distinct ways in the two groups of participants. In patients, vmPFC activation was correlated with other prefrontal and lateral temporal cortices during construction and with visual-perceptual cortices during elaboration. While controls did not show a difference in whole-brain connectivity, they did uniquely show a dynamic shift from vmPFC connectivity to anterior HC during construction and to posterior HC during elaboration. Together, these findings suggest that impoverished AM recall in mTLE is a consequence of reduced activation and flexibility of bilateral hippocampal networks and greater reliance on neocortical contributions to memory retrieval.

Deciding what is possible and impossible following hippocampal damage in humans.

There is currently much debate about whether the precise role of the hippocampus in scene processing is predominantly constructive, perceptual, or mnemonic. Here, we developed a novel experimental paradigm designed to control for general perceptual and mnemonic demands, thus enabling us to specifically vary the requirement for constructive processing. We tested the ability of patients with selective bilateral hippocampal damage and matched control participants to detect either semantic (e.g., an elephant with butterflies for ears) or constructive (e.g., an endless staircase) violations in realistic images of scenes. Thus, scenes could be semantically or constructively 'possible' or 'impossible'. Importantly, general perceptual and memory requirements were similar for both types of scene. We found that the patients performed comparably to control participants when deciding whether scenes were semantically possible or impossible, but were selectively impaired at judging if scenes were constructively possible or impossible. Post-task debriefing indicated that control participants constructed flexible mental representations of the scenes in order to make constructive judgements, whereas the patients were more constrained and typically focused on specific fragments of the scenes, with little indication of having constructed internal scene models. These results suggest that one contribution the hippocampus makes to scene processing is to construct internal representations of spatially coherent scenes, which may be vital for modelling the world during both perception and memory recall. © 2016 The Authors. Hippocampus Published by Wiley Periodicals, Inc.

Hippocampal Damage Increases Deontological Responses during Moral Decision Making.

Complex moral decision making is associated with the ventromedial prefrontal cortex (vmPFC) in humans, and damage to this region significantly increases the frequency of utilitarian judgments. Since the vmPFC has strong anatomical and functional links with the hippocampus, here we asked how patients with selective bilateral hippocampal damage would derive moral decisions on a classic moral dilemmas paradigm. We found that the patients approved of the utilitarian options significantly less often than control participants, favoring instead deontological responses-rejecting actions that harm even one person. Thus, patients with hippocampal damage have a strikingly opposite approach to moral decision making than vmPFC-lesioned patients. Skin-conductance data collected during the task showed increased emotional arousal in the hippocampal-damaged patients and they stated that their moral decisions were based on emotional instinct. By contrast, control participants made moral decisions based on the integration of an adverse emotional response to harming others, visualization of the consequences of one's action, and the rational re-evaluation of future benefits. This integration may be disturbed in patients with either hippocampal or vmPFC damage. Hippocampal lesions decreased the ability to visualize a scenario and its future consequences, which seemed to render the adverse emotional response overwhelmingly dominant. In patients with vmPFC damage, visualization might also be reduced alongside an inability to detect the adverse emotional response, leaving only the utilitarian option open. Overall, these results provide insights into the processes involved in moral decision making and highlight the complementary roles played by two closely connected brain regions. SIGNIFICANCE STATEMENT: The ventromedial prefrontal cortex (vmPFC) is closely associated with the ability to make complex moral judgements. When this area is damaged, patients become more utilitarian (the ends justify the means) and have decreased emotional arousal during moral decision making. The vmPFC is closely connected with another brain region-the hippocampus. In this study we found that patients with selective bilateral hippocampal damage show a strikingly opposite response pattern to those with vmPFC damage when making moral judgements. They rejected harmful actions of any kind (thus their responses were deontological) and showed increased emotional arousal. These results provide new insights into the processes involved in moral decision making and highlight the complementary roles played by two closely connected brain regions.

Semantic congruence affects hippocampal response to repetition of visual associations.

Recent research has shown complementary engagement of the hippocampus and medial prefrontal cortex (mPFC) in encoding and retrieving associations based on pre-existing or experimentally-induced schemas, such that the latter supports schema-congruent information whereas the former is more engaged for incongruent or novel associations. Here, we attempted to explore some of the boundary conditions in the relative involvement of those structures in short-term memory for visual associations. The current literature is based primarily on intentional evaluation of schema-target congruence and on study-test paradigms with relatively long delays between learning and retrieval. We used a continuous recognition paradigm to investigate hippocampal and mPFC activation to first and second presentations of scene-object pairs as a function of semantic congruence between the elements (e.g., beach-seashell versus schoolyard-lamp). All items were identical at first and second presentation and the context scene, which was presented 500ms prior to the appearance of the target object, was incidental to the task which required a recognition response to the central target only. Very short lags 2-8 intervening stimuli occurred between presentations. Encoding the targets with congruent contexts was associated with increased activation in visual cortical regions at initial presentation and faster response time at repetition, but we did not find enhanced activation in mPFC relative to incongruent stimuli at either presentation. We did observe enhanced activation in the right anterior hippocampus, as well as regions in visual and lateral temporal and frontal cortical regions, for the repetition of incongruent scene-object pairs. This pattern demonstrates rapid and incidental effects of schema processing in hippocampal, but not mPFC, engagement during continuous recognition.

Distinct hippocampal functional networks revealed by tractography-based parcellation.

Recent research suggests the anterior and posterior hippocampus form part of two distinct functional neural networks. Here we investigate the structural underpinnings of this functional connectivity difference using diffusion-weighted imaging-based parcellation. Using this technique, we substantiated that the hippocampus can be parcellated into distinct anterior and posterior segments. These structurally defined segments did indeed show different patterns of resting state functional connectivity, in that the anterior segment showed greater connectivity with temporal and orbitofrontal cortex, whereas the posterior segment was more highly connected to medial and lateral parietal cortex. Furthermore, we showed that the posterior hippocampal connectivity to memory processing regions, including the dorsolateral prefrontal cortex, parahippocampal, inferior temporal and fusiform gyri and the precuneus, predicted interindividual relational memory performance. These findings provide important support for the integration of structural and functional connectivity in understanding the brain networks underlying episodic memory.